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athletes, and 19 inactive patients, the risk of VT or SCD was significantly higher among competitive athletes compared with either recreational athletes (hazard ratio [HR] 2.0, 95% CI 1.2-3.3) or inactive patients (HR 2.1, 95% CI 1.1-3.9) [51]. In addition, there are increasing data that repetitive extreme conditioning/exertion enhances disease progression [51,52]. Any activity, competitive or not, that causes symptoms of palpitations, presyncope, or syncope should be avoided. Marfan syndrome Athletes with Marfan syndrome can selectively participate in low and moderate static/low dynamic competitive sports (classes IA and IIA) ( figure 1) if they do not have one or more of the following: aortic root dilatation, moderate-to-severe mitral regurgitation, or family history of dissection or sudden death in a Marfan relative [53]. These athletes should have an echocardiographic measurement of aortic root dimension repeated every 6 to 12 months (depending upon the size of the aorta, rate of growth, etc) for close surveillance of aortic enlargement. (See "Management of Marfan syndrome and related disorders", section on 'Monitoring MFS'.) Athletes with Marfan syndrome, familial aortic aneurysm or dissection, or congenital bicuspid aortic valve with any degree of ascending aortic enlargement should not participate in sports that involve the potential for bodily collision. On the other hand, some moderate-intensity and many low-intensity recreational activities are generally considered to be safe, including stationary biking, hiking, doubles tennis, swimming laps, golf, and skating. However, intense static (isometric) exertion is associated with increased wall stress; therefore, activities such as weight training with either free weights or weight machines should be avoided. Marfan syndrome is an autosomal dominant condition that is one of the most common inherited disorders of connective tissue. The full phenotype is characterized by arachnodactyly, tall stature, pectus excavatum, kyphoscoliosis, and lenticular dislocation. Malignant arrhythmias are not common in Marfan syndrome, but the cardiovascular manifestations include aortic https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 12/28 7/5/23, 11:14 AM Athletes: Overview of sudden cardiac death risk and sport participation - UpToDate dissection, which can lead to sudden death. The genetics, epidemiology, diagnosis, and management of Marfan syndrome are discussed in detail separately. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders" and "Management of Marfan syndrome and related disorders".) Myocarditis Persons with probable or definite evidence of myocarditis should be withdrawn from all competitive and recreational sports and undergo a prudent convalescent period of between three and six months following the onset of clinical manifestations [29,31]. Athletes may return to training and competition after this period of time if LV systolic function has returned to normal (based on echocardiography and/or CMR), clinically relevant arrhythmias such as frequent and/or complex repetitive forms of ventricular or supraventricular ectopic activity are absent on ambulatory Holter monitoring and graded exercise testing, and serum markers of inflammation and heart failure have normalized. The impact that persistent LGE on CMR represents following the apparent clinical resolution of myocarditis is still uncertain [29]. As patients with previous myocarditis are at increased risk of recurrence and/or silent progressive myocardial dysfunction, periodic clinical reevaluation (at least annually) is recommended, including clinical assessment and imaging testing [31]. Patients should be advised to seek medical attention for dyspnea on exertion, syncope, or arrhythmic events. Myocarditis has been reported in 6 to 7 percent of cases of SCD in competitive athletes and 20 percent of military recruits [16,25,42]. (See 'Etiology of sudden death' above.) The clinical presentation of myocarditis is quite broad, from subclinical cases with only mild reduction of physical performance or palpitation to more severe presentations with clinical findings of heart failure in an otherwise healthy young person. The ECG usually shows diffuse repolarization abnormalities, and global or regional wall motion abnormalities are present on cardiac imaging. Active myocarditis is associated with atrial and ventricular tachyarrhythmias, bradyarrhythmias, and SCD. Healed myocarditis leading to a dilated cardiomyopathy or persistent segmental abnormalities increases the risk of SCD, and this risk may be proportional to the degree of cardiac dysfunction and severity of clinical presentation. (See "Clinical manifestations and diagnosis of myocarditis in adults".) Myocarditis and other causes of myocardial injury in individuals with coronavirus disease 2019 (COVID-19), the risk of SARS-CoV-2 vaccine-associated myocarditis, and return to play after COVID-19 are discussed separately. (See "COVID-19: Cardiac manifestations in adults" and "COVID-19: Evaluation and management of cardiac disease in adults" and "COVID-19: Arrhythmias and conduction system disease" and "COVID-19: Vaccines", section on 'Myocarditis' and "COVID-19: Return to sport or strenuous activity following infection".) https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 13/28 7/5/23, 11:14 AM Athletes: Overview of sudden cardiac death risk and sport participation - UpToDate Congenital heart diseases The estimated prevalence of congenital abnormalities in the athlete is 0.2 percent. Recommendations for athletic activity in patients with congenital heart disease, which are based primarily on expert opinion, depend upon the nature of the abnormality [40]. The approach for exercise prescription in adolescents and adults with congenital heart disease should be individualized [54]. However, there is generally a prohibition of competitive sports in those who have: Significant pulmonary hypertension Cyanosis with an arterial saturation <80 percent Symptomatic arrhythmias Symptomatic ventricular dysfunction INHERITED ARRHYTHMIA SYNDROMES There is a partial divergence of opinions on competitive athletics for individuals with inherited arrhythmias, and specifically for long QT syndrome (LQTS) [55-58]. The 2015 American Heart Association/American College of Cardiology (AHA/ACC) Scientific Statement on Eligibility and Disqualification Recommendations for Competitive Athletes discusses participation in competitive events and training sessions in patients with channelopathies (namely, LQTS) as allowable if the patient is asymptomatic and an emergency action plan with an automated external defibrillator (AED) is immediately available on site. However, a different approach is dictated by the European guidelines, which advise precautionary restriction from competitive sports in these instances. Congenital long QT syndrome Guidelines for physical activity and sports participation in congenital LQTS are presented separately. (See "Congenital long QT syndrome: Treatment", section on 'Physical activity and LQTS'.) Brugada syndrome Professional society guidelines allow sports participation in patients with Brugada syndrome who are defined as low risk based on absence of symptoms and events after the clinician and patient participate in a fully informed discussion and shared decision-making process and take all appropriate precautionary measures [55]. In contrast to other inherited arrhythmia syndromes, most moderate- and low-intensity recreational, noncompetitive sports are considered safe for patients with Brugada syndrome or Brugada pattern ECG, except for those that would incur significant risk of trauma with impaired consciousness should syncope or presyncope result (eg, weightlifting with free weights, horseback riding, motor races, downhill skiing, scuba diving, or snorkeling). Moreover, patients https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 14/28 7/5/23, 11:14 AM Athletes: Overview of sudden cardiac death risk and sport participation - UpToDate should avoid triggering drugs [59], electrolyte imbalance, and increases in core temperature >39 C (eg, by avoiding saunas, steam rooms, and sports in warm/humid conditions, including prolonged endurance events such as marathons in unfavorable atmospheric conditions). Patients with Brugada syndrome have historically been advised to avoid most high-intensity competitive sports, including cycling, rowing, basketball, ice hockey, sprinting, and singles tennis. However, there is no evidence that exercise in patients with Brugada syndrome increases the risk of cardiac arrest. Brugada syndrome is characterized by the ECG findings of right bundle branch block (RBBB) pattern and ST-segment elevation in leads V1 to V3 ( waveform 1), and an increased risk of sudden death. Arrhythmic events generally occur between the ages of 22 and 65 and are more common at night than in the day and during sleep than while awake [60,61]. SCD in Brugada patients is usually not related to exercise [62]. (See "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) Catecholaminergic polymorphic ventricular tachycardia We agree with professional society recommendations that patients with catecholaminergic polymorphic VT (CPVT) who were previously symptomatic, and asymptomatic patients with exercise-induced ventricular premature beats in a pattern of bigeminy, couplets, or nonsustained VT, should be restricted from competitive sports with the exception of minimal contact, class IA activities ( figure 1) [55]. Among individuals with a genetic diagnosis of CPVT, but who remain asymptomatic with none of the clinical features of inducible VT (so-called genotype positive, phenotype negative patients), the natural history is not well defined. As such, no agreement exists in the guidelines, and specifically, a prudent precautionary restriction from competitive sports is advised by European recommendations with more uncertainty in the AHA/ACC Guidelines. CPVT occurs in the absence of structural heart disease or known associated syndromes. The disorder typically begins in childhood or adolescence, and affected patients may have a family history of juvenile sudden death or stress-induced syncope [63]. The disorder has been linked to mutations in the cardiac ryanodine receptor and calsequestrin 2 genes. (See "Catecholaminergic polymorphic ventricular tachycardia".) Affected patients present with life-threatening VT or ventricular fibrillation (VF) occurring during emotional or physical stress, with syncope often being the first manifestation of the disease [63]. Arrhythmic events during swimming, previously considered to be specific for LQTS type 1, have also been described with CPVT [64]. The VT may have a polymorphic appearance or may be a bidirectional VT that resembles the arrhythmia associated with digitalis toxicity. https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 15/28 7/5/23, 11:14 AM Athletes: Overview of sudden cardiac death risk and sport participation - UpToDate Short QT syndrome Short QT syndrome is an extremely rare inherited channelopathy associated with marked shortened QT intervals and SCD in individuals with a structurally normal heart. Based on expert opinion, short QT syndrome is managed similarly to other inherited arrhythmia syndromes (ie, LQTS), although there is a paucity of data regarding the risks of exercise in this condition. (See 'Inherited arrhythmia syndromes' above.) When an abnormally short QTc interval is identified in an athlete (QTc <320 milliseconds), causes of transient QT shortening (such as hypercalcemia, hyperkalemia, hyperthermia, acidosis, and some drugs [eg, digitalis, anabolic steroids]) must be ruled out. In the absence of acquired causes of short QT interval, the athlete may be referred for familial ECG clinical screening and molecular genetic evaluation. However, the limited specificity of a short QTc must be acknowledged; the vast majority of patients with a short QTc will not have the syndrome. The clinical features and management of short QT syndrome are discussed in detail separately. (See "Short QT syndrome".) Early repolarization syndrome The early repolarization syndrome is the combination of early repolarization pattern and arrhythmic symptoms and/or SCD, not just early repolarization pattern. At present, no data are available regarding the impact of regular exercise programs and sports participation on the natural outcome of the early repolarization syndrome, and a prudent precautionary attitude is advised. The term early repolarization has long been used to characterize a QRS-T variant with J-point elevation on the ECG. Two terms, distinguished by the presence or absence of symptomatic arrhythmias, have been used to describe patients with this ECG finding: the early repolarization pattern describes the patient with appropriate ECG findings in the absence of symptomatic arrhythmias, while the early repolarization syndrome applies to the patient with both appropriate ECG findings and symptomatic ventricular arrhythmias, typically VF. Recommendations regarding participation in athletics apply only to patients with the early repolarization syndrome. (See "Early repolarization".) Early repolarization pattern, meaning the presence of ST-segment elevation in precordial leads, usually preceded by J-point elevation, is a common finding in athletes and is associated with other typical features of the athlete's ECG, such as bradycardia, increased R/S wave voltages, and incomplete RBBB. Typically, early repolarization in athletes disappears during exercise. This ECG pattern is not associated with symptoms or family history of SCD and does not require additional testing for diagnosis. There are no sports restrictions for these individuals. CORONARY ARTERY DISEASE https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 16/28 7/5/23, 11:14 AM Athletes: Overview of sudden cardiac death risk and sport participation - UpToDate Our approach to participation Patients with clinically proven coronary artery disease (CAD) who are considered to be at low-risk for cardiac events after individual evaluation may be allowed to participate in competitive sports. As a measure of caution, in consideration of the high hemodynamic load and possible electrolyte imbalance, some restrictions may apply on an individual basis for sports with the highest cardiovascular demand, such as extreme power and endurance disciplines. Patients with clinically proven CAD who are considered to be at high risk should be temporarily restricted from competitive sports and receive appropriate management. In situations where full medical therapy has been implemented and persistent ischemia remains, revascularization may be considered on a case-by-case basis. After revascularization, the individual patient should be encouraged to start exercise programs without delay, as per the cardiac rehabilitation guidelines. In the early phase, exercise should be prescribed in a graduated fashion, starting with low-intensity exercise of limited duration and progressively increased. When the clinical situation is stable and the patient is asymptomatic, a more intense training and participation in competition should be considered after a graduated and progressive increase in rehabilitation training load. We recommend a minimum of three months after percutaneous coronary intervention before participation in competitive sports can be resumed. Participation in competitive sports may be selectively advised as per patients with CAD and well-treated risk factors if exercise is not associated with elements of high risk, such as critical coronary artery stenosis (>70 percent), LV dysfunction, inducible ischemia by exercise, or frequent, repetitive ventricular arrhythmias induced by exercise. Contact sports should be avoided while the patient is under dual antiplatelet therapy because of the risk of bleeding, but may be considered afterwards. (See "Cardiac rehabilitation: Indications, efficacy, and safety in patients with coronary heart disease".) In patients 35 years of age, the most frequent cause of exercise-related SCD is CAD. Ventricular arrhythmias can originate from myocardial scar (from prior MIs), or from acute ischemia. In addition, ischemia during exertion can result either from fixed, chronic coronary stenosis that precludes increased myocardial oxygen delivery during exercise (ie, demand ischemia), or from an acute coronary syndrome. Autopsy examination of adults with exercise-related SCD usually reveals advanced CAD and/or an acute coronary lesion [26]. (See "Pathophysiology and etiology of sudden cardiac arrest" and "Mechanisms of acute coronary syndromes related to atherosclerosis".) Risk assessment Prior to initiating systematic training or competition, athletes with previously documented CAD should have an assessment of LV function. Universal exercise testing is somewhat controversial, although many clinicians state it should be performed, both https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 17/28 7/5/23, 11:14 AM Athletes: Overview of sudden cardiac death risk and sport participation - UpToDate to assess exercise capacity to determine the possible induction of signs of ischemia and to ensure the absence of exercise-induced arrhythmias. Whenever possible, such testing should be performed while the patient is taking prescribed medications and should approximate the cardiovascular and metabolic demands of the planned athletic activity. The approach to screening is discussed in detail separately. (See "Screening to prevent sudden cardiac death in competitive athletes".) There are no data that directly relate the presence and severity of CAD to the risk of participating in competitive athletics. However, it is likely that the risk of a cardiac event during exercise increases with the presence of increasingly severe CAD, type of lesion (soft plaques are at higher risk of rupture), LV dysfunction, and ventricular arrhythmias, as well as with the intensity of the competitive sport and the individual's effort. As a result, risk assessment should involve a full evaluation of cardiac status in individual patients. Athletes with CAD are considered to be at low risk if all of the following are true [65]: LV ejection fraction 50 percent. Normal exercise tolerance for age. (See "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease", section on 'Relation to fitness'.) No inducible ischemia with exercise testing. (See "Prognostic features of stress testing in patients with known or suspected coronary disease".) No sustained or nonsustained VT during exercise testing. No hemodynamically significant coronary artery stenosis (ie, no stenosis 70 percent in a major coronary artery and no stenosis 50 percent in the left main coronary artery) if angiography is performed. Patients who have had successful revascularization of prior stenosis are also considered to be at low risk. SUMMARY AND RECOMMENDATIONS Sudden cardiac death (SCD) associated with athletic activity is a rare but devastating event. Victims can be young and apparently healthy, and while many of these deaths are unexplained, a substantial number harbor underlying undiagnosed cardiovascular disease. The majority of SCD events in athletes are due to malignant arrhythmias, usually ventricular tachycardia degenerating into ventricular fibrillation (VF) or primary VF itself. (See 'Introduction' above.) https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 18/28 7/5/23, 11:14 AM Athletes: Overview of sudden cardiac death risk and sport participation - UpToDate The balance between the risks and benefits of athletic activity depends upon several factors, including baseline fitness level, the nature and intensity of athletic activity, the presence and extent of cardiac disease, and the psychologic and physical benefit from sport. Although there are exceptions, for most individuals, the overall benefits of regular exercise far outweigh the risks. (See 'Competitive versus recreational athletics' above.) The incidence of SCD among young athletes is actually quite low, estimated to be between 1:50,000 and 1:100,000 young athletes per year. This rate is notably higher in older adults, closer to 1:7000 healthy adult athletes per year. (See 'Incidence of sudden cardiac death' above.) The potential etiologies of SCD include certain structural heart diseases, inherited arrhythmia syndromes, and coronary heart disease; the exact distribution of etiologies varies according to age and geography. (See 'Etiology of sudden death' above and "Pathophysiology and etiology of sudden cardiac arrest".) Some level of activity restriction ( figure 1) is recommended for nearly all individuals with underlying heart disease. The precise restrictions vary depending on the underlying disease process and other comorbidities. (See 'Structural abnormalities associated with SCD' above and 'Inherited arrhythmia syndromes' above and 'Coronary artery disease' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Maron BJ, Chaitman BR, Ackerman MJ, et al. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation 2004; 109:2807. 2. Franklin BA, Thompson PD, Al-Zaiti SS, et al. 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Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 9: Arrhythmias and Conduction Defects: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2412. 57. Pelliccia A, Fagard R, Bj rnstad HH, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005; 26:1422. 58. Turkowski KL, Bos JM, Ackerman NC, et al. Return-to-Play for Athletes With Genetic Heart Diseases. Circulation 2018; 137:1086. 59. www.brugadadrugs.org (Accessed on December 11, 2019). 60. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005; 111:659. 61. Matsuo K, Kurita T, Inagaki M, et al. The circadian pattern of the development of ventricular fibrillation in patients with Brugada syndrome. Eur Heart J 1999; 20:465. 62. Corrado D, Basso C, Buja G, et al. Right bundle branch block, right precordial st-segment elevation, and sudden death in young people. Circulation 2001; 103:710. 63. Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002; 106:69. 64. Choi G, Kopplin LJ, Tester DJ, et al. Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. Circulation 2004; 110:2119. 65. Borjesson M, Dellborg M, Niebauer J, et al. Recommendations for participation in leisure time or competitive sports in athletes-patients with coronary artery disease: a position statement from the Sports Cardiology Section of the European Association of Preventive Cardiology (EAPC). Eur Heart J 2019; 40:13. Topic 986 Version 36.0 https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 24/28 7/5/23, 11:14 AM Athletes: Overview of sudden cardiac death risk and sport participation - UpToDate GRAPHICS Classification of sports based on peak static and dynamic components during competition This classification is based on peak static and dynamic components achieved during competition; however, higher values may be reached during training. The increasing dynamic component is defined in terms of the estimated percentage of maximal oxygen uptake (VO max) achieved and results in an increasing cardiac output. The 2 increasing static component is related to the estimated percentage of maximal voluntary contraction reached and results in an increasing blood pressure load. The lowest total cardiovascular demands (cardiac output and blood pressure) are shown in the palest color, with increasing dynamic load depicted by increasing blue intensity and increasing static load by increasing red intensity. Note the graded transition between categories, which should be individualized on the basis of player position and style of play. https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 25/28 7/5/23, 11:14 AM Athletes: Overview of sudden cardiac death risk and sport participation - UpToDate Danger of bodily collision (refer to UpToDate content regarding sports according to risk of impact and educational background). Increased risk if syncope occurs. Reproduced from: Levine BD, Baggish AL, Kovacs RJ. Eligibility and disquali cation recommendations for competitive athletes with cardiovascular abnormalities: Task force 1: Classi cation of sports: Dynamic, static, and impact: A scienti c statement from the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2350. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 105651 Version 9.0 https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 26/28 7/5/23, 11:14 AM Athletes: Overview of sudden cardiac death risk and sport participation - UpToDate 12-lead electrocardiogram (ECG) from a patient with the Brugada syndrome shows downsloping ST elevation ST segment elevation and T wave inversion in the right precordial leads V1 and V2 (arrows); the QRS is normal. The widened S wave in the left lateral leads (V5 and V6) that is characteristic of right bundle branch block is absent. Courtesy of Rory Childers, MD, University of Chicago. Graphic 64510 Version 10.0 https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 27/28 7/5/23, 11:14 AM Athletes: Overview of sudden cardiac death risk and sport participation - UpToDate Contributor Disclosures

Med 1996; 334:1039. 45. Liberthson RR, Dinsmore RE, Fallon JT. Aberrant coronary artery origin from the aorta. Report of 18 patients, review of literature and delineation of natural history and management. Circulation 1979; 59:748. 46. Taylor AJ, Byers JP, Cheitlin MD, Virmani R. Anomalous right or left coronary artery from the contralateral coronary sinus: "high-risk" abnormalities in the initial coronary artery course and heterogeneous clinical outcomes. Am Heart J 1997; 133:428. 47. Basso C, Maron BJ, Corrado D, Thiene G. Clinical profile of congenital coronary artery anomalies with origin from the wrong aortic sinus leading to sudden death in young competitive athletes. J Am Coll Cardiol 2000; 35:1493. 48. Thiene G, Nava A, Corrado D, et al. Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med 1988; 318:129. 49. Blomstr m-Lundqvist C, Sabel KG, Olsson SB. A long term follow up of 15 patients with arrhythmogenic right ventricular dysplasia. Br Heart J 1987; 58:477. 50. Douglas PS, O'Toole ML, Hiller WD, Reichek N. Different effects of prolonged exercise on the right and left ventricles. J Am Coll Cardiol 1990; 15:64. 51. Ruwald AC, Marcus F, Estes NA 3rd, et al. Association of competitive and recreational sport participation with cardiac events in patients with arrhythmogenic right ventricular cardiomyopathy: results from the North American multidisciplinary study of arrhythmogenic right ventricular cardiomyopathy. Eur Heart J 2015; 36:1735. 52. James CA, Bhonsale A, Tichnell C, et al. Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. J Am Coll Cardiol 2013; 62:1290. 53. Braverman AC, Harris KM, Kovacs RJ, Maron BJ. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 7: Aortic Diseases, Including Marfan Syndrome: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2398. 54. Budts W, B rjesson M, Chessa M, et al. Physical activity in adolescents and adults with congenital heart defects: individualized exercise prescription. Eur Heart J 2013; 34:3669. https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 23/28 7/5/23, 11:14 AM Athletes: Overview of sudden cardiac death risk and sport participation - UpToDate 55. Ackerman MJ, Zipes DP, Kovacs RJ, Maron BJ. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 10: The Cardiac Channelopathies: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2424. 56. Zipes DP, Link MS, Ackerman MJ, et al. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 9: Arrhythmias and Conduction Defects: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2412. 57. Pelliccia A, Fagard R, Bj rnstad HH, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005; 26:1422. 58. Turkowski KL, Bos JM, Ackerman NC, et al. Return-to-Play for Athletes With Genetic Heart Diseases. Circulation 2018; 137:1086. 59. www.brugadadrugs.org (Accessed on December 11, 2019). 60. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005; 111:659. 61. Matsuo K, Kurita T, Inagaki M, et al. The circadian pattern of the development of ventricular fibrillation in patients with Brugada syndrome. Eur Heart J 1999; 20:465. 62. Corrado D, Basso C, Buja G, et al. Right bundle branch block, right precordial st-segment elevation, and sudden death in young people. Circulation 2001; 103:710. 63. Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002; 106:69. 64. Choi G, Kopplin LJ, Tester DJ, et al. Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. Circulation 2004; 110:2119. 65. Borjesson M, Dellborg M, Niebauer J, et al. Recommendations for participation in leisure time or competitive sports in athletes-patients with coronary artery disease: a position statement from the Sports Cardiology Section of the European Association of Preventive Cardiology (EAPC). Eur Heart J 2019; 40:13. Topic 986 Version 36.0 https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 24/28 7/5/23, 11:14 AM Athletes: Overview of sudden cardiac death risk and sport participation - UpToDate GRAPHICS Classification of sports based on peak static and dynamic components during competition This classification is based on peak static and dynamic components achieved during competition; however, higher values may be reached during training. The increasing dynamic component is defined in terms of the estimated percentage of maximal oxygen uptake (VO max) achieved and results in an increasing cardiac output. The 2 increasing static component is related to the estimated percentage of maximal voluntary contraction reached and results in an increasing blood pressure load. The lowest total cardiovascular demands (cardiac output and blood pressure) are shown in the palest color, with increasing dynamic load depicted by increasing blue intensity and increasing static load by increasing red intensity. Note the graded transition between categories, which should be individualized on the basis of player position and style of play. https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 25/28 7/5/23, 11:14 AM Athletes: Overview of sudden cardiac death risk and sport participation - UpToDate Danger of bodily collision (refer to UpToDate content regarding sports according to risk of impact and educational background). Increased risk if syncope occurs. Reproduced from: Levine BD, Baggish AL, Kovacs RJ. Eligibility and disquali cation recommendations for competitive athletes with cardiovascular abnormalities: Task force 1: Classi cation of sports: Dynamic, static, and impact: A scienti c statement from the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2350. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 105651 Version 9.0 https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 26/28 7/5/23, 11:14 AM Athletes: Overview of sudden cardiac death risk and sport participation - UpToDate 12-lead electrocardiogram (ECG) from a patient with the Brugada syndrome shows downsloping ST elevation ST segment elevation and T wave inversion in the right precordial leads V1 and V2 (arrows); the QRS is normal. The widened S wave in the left lateral leads (V5 and V6) that is characteristic of right bundle branch block is absent. Courtesy of Rory Childers, MD, University of Chicago. Graphic 64510 Version 10.0 https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 27/28 7/5/23, 11:14 AM Athletes: Overview of sudden cardiac death risk and sport participation - UpToDate Contributor Disclosures Antonio Pelliccia, MD No relevant financial relationship(s) with ineligible companies to disclose. Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Scott Manaker, MD, PhD Other Financial Interest: Expert witness in workers' compensation and in medical negligence matters [General pulmonary and critical care medicine]; National Board for Respiratory Care [Director]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/athletes-overview-of-sudden-cardiac-death-risk-and-sport-participation/print 28/28

7/5/23, 11:13 AM Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation : Mark S Link, MD, Antonio Pelliccia, MD : Scott Manaker, MD, PhD, Peter J Zimetbaum, MD : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 19, 2021. INTRODUCTION As in the general population, athletes can have atrial and ventricular arrhythmias. These arrhythmias are rarely fatal; however, sudden cardiac death resulting from a malignant ventricular tachyarrhythmia is a devastating event in young and apparently healthy persons. This topic will discuss the clinical manifestations and diagnostic evaluation of athletes with specific arrhythmias or arrhythmia-related syndromes. The treatment of arrhythmias in athletes, along with the discussion of returning to competition/participation, is discussed in detail separately. Additionally, the risk of sudden death in athletes and the approach to screening to prevent sudden death in athletes are discussed elsewhere. (See "Athletes with arrhythmias: Treatment and returning to athletic participation" and "Athletes: Overview of sudden cardiac death risk and sport participation" and "Athletes with arrhythmias: Electrocardiographic abnormalities and conduction disturbances" and "Screening to prevent sudden cardiac death in competitive athletes".) EPIDEMIOLOGY Supraventricular arrhythmias, such as supraventricular tachycardia, atrial fibrillation (AF), and atrial flutter, are rarely seen on a resting electrocardiogram (ECG) in athletes and are always abnormal; as such, when present, these conditions require investigation. In one study of 32,561 young athletes who underwent ECG screening, only six patients had an atrial tachyarrhythmia, https://www.uptodate.com/contents/athletes-with-arrhythmias-clinical-manifestations-and-diagnostic-evaluation/print 1/11 7/5/23, 11:13 AM Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation - UpToDate four with ectopic atrial tachycardia and two with AF [1]. Supraventricular arrhythmias are not thought to be more common in the athlete or caused by sports activity, with the possible exception of AF in master athletes. Some epidemiologic data demonstrate a higher than expected prevalence of AF in athletes at the extreme of training/exercise [2-4]. However, premature atrial complex (also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat) can be seen in athletes and these may fall under a variant of normal. Ventricular arrhythmia (ie, >1 premature ventricular complex [PVC]; in the standard 12-lead ECG) is uncommon in athletes, and not different from the general population, being present in <1 percent of athletes screened with ECGs [5]. If more frequent PVCs are recorded on a standard (10-second) ECG, it is likely that the athlete has a high 24-hour PVC burden. While PVCs are most likely benign in a highly trained athlete, their presence may nevertheless be the hallmark of an underlying heart disease and require careful evaluation [6-8]. CLINICAL PRESENTATION When present, symptoms should be evaluated to determine whether any action needs to be taken. Arrhythmic symptoms may be related to the arrhythmia itself (eg, palpitations) or due to the hemodynamic consequences of the arrhythmias (eg, dyspnea, dizziness). Patients with an arrhythmia can present with a variety of symptoms, including: Palpitations Syncope or presyncope Lightheadedness or dizziness Unexplained, transient impairment in physical performance Chest pain Shortness of breath Sudden cardiac arrest (SCA) Patients with a tachyarrhythmia most commonly present with palpitations, the sensation of a rapid or irregular heart beat felt in the anterior chest or neck. Usually, the symptoms are abrupt in onset, although this may vary depending on the specific arrhythmia. Palpitations may be associated with diaphoresis, lightheadedness, or dizziness. Patients with a tachyarrhythmia may also report shortness of breath or chest discomfort, with syncope and SCA being less common presentations. Patients with a bradyarrhythmia most commonly present with fatigue and/or exertional dyspnea, although patients may present with lightheadedness, dizziness, or syncope if the heart https://www.uptodate.com/contents/athletes-with-arrhythmias-clinical-manifestations-and-diagnostic-evaluation/print 2/11 7/5/23, 11:13 AM Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation - UpToDate rate is significantly slower or if there is a prolonged pause or period of asystole. Patients with a bradyarrhythmia may also report palpitations (ie, the feeling of irregular heart beating), though less commonly than in patients with a tachyarrhythmia. Chest pain is rare in patients with a bradyarrhythmia. Asymptomatic Athletes frequently have asymptomatic benign sinus bradycardia, due to high vagal tone. In some, the high vagal tone at rest or while asleep may even cause Mobitz type 1 (Wenckebach) second-degree atrioventricular (AV) block. When the vagal tone is removed, as is seen with exercise, AV conduction normalizes, and peak heart rate attained is normal. Although unusual, athletes may remain asymptomatic with a tachyarrhythmia typically when the resulting ventricular rate is in the normal range and is adequate to maintain the required cardiac output. In such cases, the arrhythmia is identified incidentally when the athlete is seeking medical attention for another reason or when the athlete undergoes preparticipation screening. (See "Screening to prevent sudden cardiac death in competitive athletes".) Palpitations Palpitations are a sensory symptom defined as an unpleasant awareness of the forceful, rapid, or irregular beating of the heart. Patients may at times describe the sensation as a rapid fluttering in the chest, flip-flopping in the chest, or a pounding sensation in the chest or neck, and these descriptions may help elucidate the cause of the palpitations. (See "Evaluation of palpitations in adults".) Syncope and presyncope Syncope (and presyncope, with lightheadedness or dizziness) in an athlete is an important symptom that requires a thorough evaluation. Syncope that occurs during exertion suggests a potentially life-threatening arrhythmic etiology (eg, aortic stenosis, hypertrophic cardiomyopathy [HCM], ventricular arrhythmia, etc) and should be evaluated very seriously and urgently. On the other hand, syncope in the recovery phase after exertion (eg, during cooling off period) is generally not arrhythmic and is more likely due to a vagal reflex. A common cause of syncope and presyncope in young athletes is neurally mediated (vasovagal) syncope, which is generally unassociated with cardiac disease and conveys a benign clinical outcome [9-13]. This type of syncope is due to neurally mediated mechanisms; however, hypovolemia from unreplaced fluid losses may contribute in athletes. Athletes (especially those engaged in endurance disciplines) may be more susceptible to neurally mediated syncope by nature of their increased vagal tone [14]. (See "Syncope in adults: Epidemiology, pathogenesis, and etiologies".) Athletes with classic reflex (neurally mediated) syncope do not require further workup. However, if there are concerning features for structural heart disease or cardiac cause of syncope, further evaluation is necessary. https://www.uptodate.com/contents/athletes-with-arrhythmias-clinical-manifestations-and-diagnostic-evaluation/print 3/11 7/5/23, 11:13 AM Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation - UpToDate Among the pathologic cardiac causes of exertional syncope are ventricular tachycardia associated with arrhythmogenic cardiomyopathies or obstruction resulting from HCM or aortic stenosis, and hypotension due to vagally-mediated vasodepression in patients with HCM. Exercise-associated syncope may also be related to hyponatremia or hyperthermia as a result of intense or prolonged exercise. (See "Syncope in adults: Clinical manifestations and initial diagnostic evaluation" and "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Syncope'.) The prevalence and nature of syncope in athletes was evaluated in a report on 7568 young athletes (mean age 16 years), 474 of whom (6.2 percent) reported a syncopal spell in the preceding five years [11]. Syncope was unrelated to exercise in 411 patients (87 percent), postexertional in 57 (12 percent), and exertional in six (1 percent). All episodes of nonexertional or postexertional syncope were diagnosed as vasovagal (neurally mediated syncope), situational, or postexertional postural hypotension based upon the clinical history. In the six patients with exertional syncope, further testing identified one case of HCM, one case of right ventricular outflow tract tachycardia, and four cases of neurocardiogenic syncope. At six years of follow-up, the rate of syncope recurrence was 2 per 100 patient-years. There were no other adverse cardiovascular events in follow-up. Chest discomfort and/or shortness of breath Chest discomfort and/or shortness of breath are not infrequent symptoms in patients with either a tachyarrhythmia or a bradyarrhythmia. Chest discomfort (not all patients will describe "pain" but instead a sensation that is different than normal) is more commonly seen in patients with a tachyarrhythmia, often in association with palpitations. Shortness of breath is typically exertional and may result from either a tachyarrhythmia, likely resulting in increased pulmonary vascular pressures and/or congestion, or from a bradyarrhythmia, usually due to inadequate cardiac output to meet the body s oxygen demands during exercise. (See "Outpatient evaluation of the adult with chest pain" and "Approach to the patient with dyspnea".) Sudden cardiac arrest SCA as the initial presentation of arrhythmia in an athlete is a rare and devastating event. Malignant arrhythmias, usually ventricular tachycardia (VT) or ventricular fibrillation (VF), are responsible for SCA in athletes. Usually, such arrhythmias occur in the setting of underlying structural cardiac disease (eg, HCM, arrhythmogenic cardiomyopathy, etc), although previously undiagnosed primary electrical disease (eg, Brugada syndrome, long QT syndrome, etc) may also be the cause of VT/VF. Preparticipation screening of athletes is largely directed at identifying underlying cardiac conditions, which would increase the risk of SCA for athletes. (See "Screening to prevent sudden cardiac death in competitive athletes" and "Approach to sudden cardiac arrest in the absence of apparent structural heart disease".) https://www.uptodate.com/contents/athletes-with-arrhythmias-clinical-manifestations-and-diagnostic-evaluation/print 4/11 7/5/23, 11:13 AM Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation - UpToDate DIAGNOSIS AND DIAGNOSTIC EVALUATION The initial evaluation of the athlete with an arrhythmia consists of a complete history (aimed at defining the type of symptoms, the timing of the arrhythmia, and potential underlying diseases), physical examination (with an emphasis on assessing hemodynamic stability if the patient is actively experiencing an arrhythmia), and 12-lead ECG. If possible, the ECG is obtained both during sinus rhythm and with symptoms. For patients in whom the initial ECG is normal or unrevealing, additional ambulatory ECG, particularly prolonged (two to four weeks) monitoring, is useful in the evaluation of athletes. The diagnosis cannot usually be made until there is an ECG obtained during the arrhythmia, as the correlation can be made between the ECG and a particular symptom(s) [15]. Following the initial evaluation (and stabilization of the patient, if necessary), additional cardiac testing is warranted to assess for underlying structural heart disease, which may influence subsequent diagnostic and therapeutic decision making. (See 'Additional testing' below.) Assessing the patient for hemodynamic stability The most important clinical determination when an arrhythmia is noted is whether the patient is experiencing signs and symptoms related to the arrhythmia. The appropriate evaluation and treatment will depend upon whether the patient is actively experiencing a tachyarrhythmia or bradyarrhythmia. The approach to assessing hemodynamic stability of both tachyarrhythmias and bradyarrhythmias is discussed in detail separately. (See "Narrow QRS complex tachycardias: Clinical manifestations, diagnosis, and evaluation", section on 'Assessing the patient for hemodynamic stability' and "Wide QRS complex tachycardias: Approach to the diagnosis", section on 'Assessment of hemodynamic stability' and "Third-degree (complete) atrioventricular block", section on 'Unstable patients'.) Evaluation of the ECG For most patients, a probable diagnosis may be made by reviewing an ECG obtained during the time of symptoms or arrhythmia. Without a simultaneous ECG at the time of symptoms, definitive diagnosis is not generally possible. Whenever possible, a previous ECG when the patient was in normal sinus rhythm may be helpful for comparison and for identifying potential underlying pathology (eg, preexisting conduction delays, accessory pathways with a delta wave, Q waves suggesting a prior myocardial infarction, etc). (See "Athletes with arrhythmias: Electrocardiographic abnormalities and conduction disturbances".) Key features to review on the ECG of a patient with a tachyarrhythmia include: Regular versus irregular QRS complexes Narrow versus wide QRS complexes https://www.uptodate.com/contents/athletes-with-arrhythmias-clinical-manifestations-and-diagnostic-evaluation/print 5/11 7/5/23, 11:13 AM Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation - UpToDate Rate of the tachycardia Initiation and termination of the tachycardia The presence and pattern of atrial activity and its relationship to the QRS complexes P wave and QRS complex morphologies Key features to review on the ECG of a patient with a bradyarrhythmia include: The relationship between P waves and QRS complexes QRS complex morphology and the likely origin of any escape rhythms The approach to evaluation of the ECG in patients with suspected tachyarrhythmias and bradyarrhythmias is discussed in detail separately. (See "Narrow QRS complex tachycardias: Clinical manifestations, diagnosis, and evaluation", section on 'Evaluation' and "Wide QRS complex tachycardias: Approach to the diagnosis", section on 'Evaluation of the electrocardiogram' and "Third-degree (complete) atrioventricular block", section on 'Electrocardiographic findings'.) Additional testing For athletes with a confirmed arrhythmia diagnosis (based on ECG results), as well as for those in whom an arrhythmia is highly suspected based upon the presenting signs and symptoms but without ECG documentation, additional cardiac testing is typically performed, including cardiac imaging in all patients, stress testing and ambulatory ECG monitoring in symptomatic patients, and selected additional testing on a case-by-case basis. The primary focus of any additional testing is to document the presence (or absence) of underlying structural heart disease. In some cases, additional testing may be performed with the intent of identifying the arrhythmia with prolonged ambulatory monitoring or with testing to provoke the arrhythmia. Cardiac imaging All athletes with a known arrhythmia, or those with a high suspicion for an arrhythmia, should have a transthoracic echocardiogram performed. Echocardiography is readily available and, in most patients, provides adequate visualization of the heart. However, if echocardiographic imaging is deemed to be nondiagnostic, additional imaging with cardiovascular magnetic resonance (CMR) should be performed. CMR is mandatory when the clinical suspicion for underlying cardiomyopathies (HCM, arrhythmogenic right ventricular cardiomyopathy [ARVC]) is high. Stress testing For athletes with symptoms suggestive of an arrhythmia during exertion, exercise stress testing is warranted. Exercise testing in patients with symptoms of arrhythmic origin is intended to assess the athlete's hemodynamic behavior during exercise (ie, the heart rate and blood pressure response to exercise) and the reproducibility of symptoms, as well as the potential recording of the arrhythmia. Cardiac monitoring during the test will allow the https://www.uptodate.com/contents/athletes-with-arrhythmias-clinical-manifestations-and-diagnostic-evaluation/print 6/11 7/5/23, 11:13 AM Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation - UpToDate determination of whether the symptoms, if reproduced, are due to an arrhythmia. Moreover, the exercise test may be part of the diagnostic evaluation for underlying cardiac disease (ie, coronary heart disease, hypertrophic or dilated cardiomyopathy, channelopathies, etc). Ideally, the stress test optimally should mimic the exertion, which brings on the symptoms. While a standard Bruce protocol may be acceptable for some athletes, this protocol (and other standard protocols used in the diagnosis of obstructive coronary heart disease) is often not optimal for competitive athletes with symptoms. For example, if the athlete has symptoms only with sprints, then sprints should be performed during the treadmill test. Alternatively, both symptomatic endurance athletes and lab personnel should be forewarned that a long duration test might be necessary to reproduce the type of endurance exercise in which symptoms have occurred. Arrhythmias may not always be reproducible in the exercise lab, and thus ambulatory ECG monitoring is relevant to the identification of the nature of arrhythmic event. Ambulatory ECG monitoring For athletes in whom an arrhythmia is highly suspected based upon the presenting signs and symptoms, but whose initial ECG is unrevealing, we perform ambulatory ECG monitoring. Ambulatory ECG, especially the long-term (two to four weeks) recording, significantly increases the likelihood of capturing abnormal heart rhythms and confirming the diagnosis. Ambulatory ECG monitoring is generally performed during normal routine activity as well as during exercise. The choice of a particular monitoring device and duration of monitoring depends primarily on the frequency and duration of symptoms. The approach to choosing an ambulatory ECG monitor is discussed in detail separately. For athletes with daily symptoms, a 24-hour monitor may be sufficient. However, most will need longer-term monitors. Continuous monitoring is possible with devices that attach to the skin with electrodes. Some of these devices store the entire ECG while others only store abnormally slow or fast arrhythmias or when the patient triggers a recording. Some will instantly alert the health care provider with abnormal results while others do not have this wireless capability. The ability to obtain a single-lead, real-time ECG by portable devices is rapidly expanding. These devices typically collect a lead I (right arm to left arm) ECG, which can be of very high quality. Some of these devices are linked to a cell phone while others stand alone. They are very valuable for individuals whose symptoms persist long enough to activate the device (typically around 30 seconds), while they are not valuable for those with very short episodes or to evaluate syncope and presyncope. (See "Ambulatory ECG monitoring", section on 'Our approach to choosing an ambulatory ECG monitoring strategy'.) Electrophysiology studies Invasive electrophysiologic studies (EPS) are not generally indicated in the work-up of the athlete s arrhythmias, which is mostly based on either ECG or ambulatory monitoring. If a tachyarrhythmia has been diagnosed by an ECG, then an EPS and ablation may be indicated, with an aim to cure the arrhythmia. EPS is rarely indicated in the https://www.uptodate.com/contents/athletes-with-arrhythmias-clinical-manifestations-and-diagnostic-evaluation/print 7/11 7/5/23, 11:13 AM Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation - UpToDate absence of an ECG diagnosis of tachyarrhythmia with the exception being those individuals with concerning syncope/presyncope or palpitations and a surface ECG documenting preexcitation (Wolff-Parkinson-White [WPW] syndrome). In these individuals, an EPS with electrophysiologic mapping can be used to identify and/or treat causes of sudden cardiac death. (See "Wolff- Parkinson-White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis", section on 'Electrophysiology studies (EPS)'.) Other studies In select patients, when a particular diagnosis is being investigated, additional testing may provide helpful information to confirm or exclude the diagnosis of the disease-causing arrhythmias. As examples: Brugada syndrome The presence of Brugada syndrome is suggested by the presence of sudden death in the family or by the presence of ECG abnormalities at rest or with provocative drug challenge (eg, repolarization abnormalities in the anterior leads ) [16]. (See "Brugada syndrome: Clinical presentation, diagnosis, and evaluation", section on 'Drug challenge for type 2 or equivocal ECG'.) Long QT syndrome The presence of long QT syndrome (LQTS) is suggested by family history of LQTS, syncope associated with various stimuli (eg, swimming, loud noises), or QTc prolongation at rest or with provocation [16]. (See "Congenital long QT syndrome: Diagnosis", section on 'Exercise testing'.) Hypertrophic cardiomyopathy The presence of HCM is suggested by an abnormal ECG, cardiac murmur, or family history of HCM and confirmed with additional diagnostic testing (eg, echocardiography, CMR testing) [17]. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Diagnostic evaluation'.) Arrhythmogenic right ventricular cardiomyopathy The presence of ARVC is suggested by family history (eg, sudden death, syncope), incomplete or complete right bundle branch block, and/or repolarization abnormalities in V1 to V3. (See "Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis", section on 'Cardiovascular magnetic resonance'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Supraventricular arrhythmias" and "Society guideline links: Ventricular arrhythmias".) https://www.uptodate.com/contents/athletes-with-arrhythmias-clinical-manifestations-and-diagnostic-evaluation/print 8/11 7/5/23, 11:13 AM Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation - UpToDate SUMMARY AND RECOMMENDATIONS Arrhythmias are not infrequently documented in athletes and can result in significant cardiac symptoms and occasional impaired athletic performance. Rarely are arrhythmias fatal; however, sudden cardiac death resulting from a malignant ventricular tachyarrhythmia is a devastating event in young and apparently healthy persons. (See 'Introduction' above.) Patients with an arrhythmia can present with a variety of symptoms, including palpitations, syncope/presyncope, lightheadedness/dizziness, chest pain, shortness of breath, and rarely sudden cardiac arrest. Arrhythmic symptoms may be related to the arrhythmia itself (eg, palpitations) or due to the hemodynamic consequences of the arrhythmias (eg, dyspnea, dizziness). Patients with a tachyarrhythmia most commonly present with palpitations. Patients with a bradyarrhythmia most commonly present with fatigue and/or exertional dyspnea, although patients may present with lightheadedness, dizziness, or syncope. (See 'Clinical presentation' above.) The initial evaluation of the athlete with an arrhythmia consists of a complete history, physical examination, and 12-lead electrocardiogram (ECG). If possible, the ECG is obtained both during sinus rhythm and the symptoms, and a previous ECG when the patient was in normal sinus rhythm may be helpful for comparison and for identifying potential underlying pathology. (See 'Evaluation of the ECG' above.) For athletes with a confirmed arrhythmia diagnosis (based on ECG results), as well as for those in whom an arrhythmia is highly suspected based upon the presenting signs and symptoms but without ECG documentation, additional cardiac testing is typically performed, including cardiac imaging and ambulatory ECG monitoring, and stress testing and selected additional testing on a case-by-case basis. (See 'Additional testing' above.) The arrhythmic diagnosis is often confirmed using the ECG obtained during the arrhythmia, as the correlation can be made between the type of arrhythmia and particular symptom(s), but may require additional ECG monitoring if the initial ECG is unrevealing. (See 'Diagnosis and diagnostic evaluation' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/athletes-with-arrhythmias-clinical-manifestations-and-diagnostic-evaluation/print 9/11 7/5/23, 11:13 AM Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation - UpToDate 1. Marek J, Bufalino V, Davis J, et al. Feasibility and findings of large-scale electrocardiographic screening in young adults: data from 32,561 subjects. Heart Rhythm 2011; 8:1555. 2. Flannery MD, Kalman JM, Sanders P, La Gerche A. State of the Art Review: Atrial Fibrillation in Athletes. Heart Lung Circ 2017; 26:983. 3. Calvo N, Brugada J, Sitges M, Mont L. Atrial fibrillation and atrial flutter in athletes. Br J Sports Med 2012; 46 Suppl 1:i37. 4. Mont L, Elosua R, Brugada J. Endurance sport practice as a risk factor for atrial fibrillation and atrial flutter. Europace 2009; 11:11. 5. D'Ascenzi F, Zorzi A, Alvino F, et al. The prevalence and clinical significance of premature ventricular beats in the athlete. Scand J Med Sci Sports 2017; 27:140. 6. Pelliccia A, Culasso F, Di Paolo FM, et al. Prevalence of abnormal electrocardiograms in a large, unselected population undergoing pre-participation cardiovascular screening. Eur Heart J 2007; 28:2006. 7. Biffi A, Maron BJ, Verdile L, et al. Impact of physical deconditioning on ventricular tachyarrhythmias in trained athletes. J Am Coll Cardiol 2004; 44:1053. 8. Biffi A, Pelliccia A, Verdile L, et al. Long-term clinical significance of frequent and complex ventricular tachyarrhythmias in trained athletes. J Am Coll Cardiol 2002; 40:446. 9. Sakaguchi S, Shultz JJ, Remole SC, et al. Syncope associated with exercise, a manifestation of neurally mediated syncope. Am J Cardiol 1995; 75:476. 10. Colivicchi F, Ammirati F, Biffi A, et al. Exercise-related syncope in young competitive athletes without evidence of structural heart disease. Clinical presentation and long-term outcome. Eur Heart J 2002; 23:1125. 11. Colivicchi F, Ammirati F, Santini M. Epidemiology and prognostic implications of syncope in young competing athletes. Eur Heart J 2004; 25:1749. 12. Calkins H, Seifert M, Morady F. Clinical presentation and long-term follow-up of athletes with exercise-induced vasodepressor syncope. Am Heart J 1995; 129:1159. 13. Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. J Am Coll Cardiol 2017. 14. Hastings JL, Levine BD. Syncope in the athletic patient. Prog Cardiovasc Dis 2012; 54:438. 15. Baggish AL, Battle RW, Beckerman JG, et al. Sports Cardiology: Core Curriculum for Providing Cardiovascular Care to Competitive Athletes and Highly Active People. J Am Coll Cardiol 2017; 70:1902. https://www.uptodate.com/contents/athletes-with-arrhythmias-clinical-manifestations-and-diagnostic-evaluation/print 10/11 7/5/23, 11:13 AM Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation - UpToDate 16. Ackerman MJ, Zipes DP, Kovacs RJ, Maron BJ. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 10: The Cardiac Channelopathies: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2424. 17. Maron BJ, Udelson JE, Bonow RO, et al. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 3: Hypertrophic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy and Other Cardiomyopathies, and Myocarditis: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2362. Topic 990 Version 25.0 Contributor Disclosures Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Antonio Pelliccia, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott Manaker, MD, PhD Other Financial Interest: Expert witness in workers' compensation and in medical negligence matters [General pulmonary and critical care medicine]; National Board for Respiratory Care [Director]. All of the relevant financial relationships listed have been mitigated. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/athletes-with-arrhythmias-clinical-manifestations-and-diagnostic-evaluation/print 11/11

7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Athletes with arrhythmias: Treatment and returning to athletic participation : Mark S Link, MD, Antonio Pelliccia, MD : Scott Manaker, MD, PhD, Peter J Zimetbaum, MD : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 09, 2020. INTRODUCTION As with the population in general, arrhythmias are not infrequently documented in athletes. Arrhythmias in athletes may present clinically with a variety of symptoms most commonly including palpitations or syncope. Occasionally reduced performance or general malaise may also be reported. Of critical relevance is the syncope induced by exercise. Rarely are arrhythmias fatal; however, sudden cardiac death (SCD) resulting from a malignant ventricular tachyarrhythmia is a devastating event in young and apparently healthy persons. This topic will discuss the treatment of arrhythmias in athletes, along with the discussion of returning to competition/participation. The clinical manifestations and diagnostic evaluation of athletes with specific arrhythmias or arrhythmia-related syndromes are discussed in detail separately. Additionally, the risk of sudden death in athletes and the approach to screening to prevent sudden death in athletes are discussed elsewhere. (See "Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation" and "Athletes: Overview of sudden cardiac death risk and sport participation" and "Athletes with arrhythmias: Electrocardiographic abnormalities and conduction disturbances" and "Screening to prevent sudden cardiac death in competitive athletes".) SYNCOPE https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 1/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Syncope that occurs during exertion suggests a potentially life-threatening arrhythmic etiology (eg, aortic stenosis, hypertrophic cardiomyopathy, ventricular arrhythmia, etc) and should be evaluated urgently. On the other hand, syncope occurring after exertion (eg, during cooling off period) is more likely reflex in origin, similar to the vasovagal faint. (See "Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation", section on 'Syncope and presyncope'.) Therapies to prevent recurrent syncope in athletes are highly variable depending upon the suspected etiology of the syncope. The diagnostic approach and management of syncope in athletes is similar to that in non-athletes and is discussed in detail separately. (See "Syncope in adults: Management and prognosis".) Athletes with concerning syncope should have a full evaluation to ascertain the presence of underlying cardiac disease responsible for the syncope. Return to sport is permitted after the cause has been determined and, if necessary, treated. When any underlying cardiac disease has been reasonably excluded, the athlete can safely return to sport without restriction [1]. However, athletes with syncope or presyncope with a high risk of recurrence should not participate in sports where the likelihood of even a momentary loss of consciousness may be hazardous and/or potentially responsible for adverse events (such as scuba diving, rock climbing, automobile racing, etc). AV CONDUCTION ABNORMALITIES Altered atrioventricular (AV) nodal conduction (eg, first degree AV block and Mobitz type I second degree AV block) can result from increased vagal tone, which is normally seen as an adaptive response to certain types of athletic conditioning, particularly endurance training ( table 1). No specific limitations are necessary in this setting as long as the athlete is asymptomatic and the conduction abnormalities improve (ie, disappear) with exertion. However, higher degrees of AV conduction abnormality will require attention prior to participation in athletics. First degree AV block First-degree AV block, characterized by prolongation of the PR interval ( waveform 1), is commonly seen in athletes and has no important implications. Often it is accompanied by resting sinus bradycardia. Athletes with isolated first degree AV block who are asymptomatic and have no evidence for structural heart disease can participate in all sports [1,2]. The nature and severity of underlying heart disease, if present, can independently dictate other restrictions. (See "First-degree atrioventricular block", section on 'Management'.) https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 2/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Second degree AV block: Mobitz type I (Wenckebach) Mobitz type I (Wenckebach) second degree AV block, especially at rest or sleep, is often present in normal, well-conditioned athletes due to enhanced vagal tone ( waveform 2). In general, Mobitz type I (Wenckebach) second degree AV block has no important clinical implications. Asymptomatic athletes with Mobitz type I (Wenckebach) second degree AV block and improvement of AV block with exercise can participate in all competitive sports ( figure 1) [1,2]. Asymptomatic athletes in whom Mobitz type I (Wenckebach) second degree AV block initially appears or worsens with exercise may need further evaluation, as worsening of Mobitz type I (Wenckebach) second degree AV block with exercise is highly suspicious for a structural pathologic condition affecting the AV node/His-Purkinje system ( figure 1). Though Mobitz type I (Wenckebach) second degree AV block rarely causes symptoms, symptomatic athletes may need ventricular pacing and should undergo treatment of any associated potentially reversible causes (eg, myocardial ischemia). The development of Mobitz type I (Wenckebach) second degree AV block during exercise should prompt referral to an electrophysiologist. (See "Second- degree atrioventricular block: Mobitz type I (Wenckebach block)", section on 'Management'.) Second degree AV block: Mobitz type II Mobitz type II second degree AV block ( waveform 3) is uncommon in athletes and, when present, usually is due to disease in the His- Purkinje system. Mobitz type II second degree AV block is by nature unstable and frequently progresses to third degree (complete) AV block. In the absence of a potentially reversible condition (ie, Lyme disease), Mobitz II AV block generally requires a pacemaker before permitting resumption of regular physical activity or sport activity [1]. The development of Mobitz II heart block should prompt referral to an electrophysiologist. (See "Second-degree atrioventricular block: Mobitz type II" and "Lyme carditis".) Third degree (complete) AV block Third degree (complete) AV block ( waveform 4 and waveform 5) is uncommon in athletes and, when present, usually is due to disease in the His- Purkinje system. Nearly all athletes with third degree (complete) AV block will present with some degree of symptoms (eg, lightheadedness, presyncope, syncope, fatigue, dyspnea, chest pain, sudden cardiac arrest), though the severity of the symptoms can be quite variable. In the absence of a potentially reversible condition (ie, Lyme carditis), acquired third degree (complete) AV block should be treated with a pacemaker before permitting resumption of regular physical or sport activity [1]. The development of complete heart block should prompt referral to an electrophysiologist. (See "Third-degree (complete) atrioventricular block" and "Lyme carditis".) A subset of patients with third degree (complete) AV block is the group with congenital third degree (complete) AV block, which usually is present at birth, but may develop later in childhood. https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 3/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Congenital third degree (complete) AV block may go unnoticed because of the higher junctional escape rate and lack of symptoms. Asymptomatic athletes with congenital heart block, a structurally normal heart and normal cardiac function, a narrow QRS complex, ventricular rates at rest greater than 40 to 50 beats per minute increasing appropriately with exertion (>120 beats per minute), no history of syncope or near syncope, and no ventricular tachycardia during exertion can selectively participate in competitive sports [1,2]. Evaluation of these cases should preferentially be performed by expert electrophysiologists. By contrast, athletes with ventricular arrhythmia, or those with symptoms of fatigue, near-syncope, or syncope, should have a pacemaker implanted before they participate in competitive sports. (See "Congenital third-degree (complete) atrioventricular block", section on 'Treatment'.) Bundle branch block While complete right bundle branch block (RBBB) ( waveform 6) is not uncommon among athletes and may be seen with or without underlying structural heart disease, complete left bundle branch block (LBBB) ( waveform 7) is rarely seen and often reflects an underlying pathologic condition [3]. (See "Right bundle branch block" and "Left bundle branch block".) Athletes with asymptomatic RBBB and no evidence of underlying cardiac disease have no restriction for sport participation [1]. Athletes with LBBB and no ventricular arrhythmias who do not develop AV block with exercise can participate in all competitive sports, consistent with the limitations due to the underlying cardiac condition and the existing recommendations [1,2]. Periodic follow-up is suggested for all individuals with complete LBBB to ascertain a possible incidence of symptoms or evidence for cardiac disease. There is no expert consensus or guideline recommendations regarding the frequency of follow-up, but we feel that in the absence of symptoms, one annual follow-up with repeat ECG and echocardiography is appropriate, with additional follow-up after one year to generally be determined by the development of symptoms. Screening of family members in the presence of fascicular block(s) The presence of bifascicular block (LBBB, RBBB and left anterior fascicular block, RBBB and left posterior fascicular block) in a young, otherwise healthy athlete also raises the possibility of an inherited conduction system disease such as Len gre disease, an autosomal dominant disorder that results in progressive conduction system dysfunction. First degree relatives of an athlete with bifascicular block on his/her ECG should be screened with an ECG to search for any evidence of conduction system disease [4]. (See "Etiology of atrioventricular block", section on 'Familial disease'.) https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 4/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate SINUS NODE DYSFUNCTION Most well-trained endurance athletes have resting sinus bradycardia (heart rate <60 beats per minute) ( table 1) [5,6]. This has traditionally been attributed to increased vagal tone induced by exercise conditioning. However, there is some evidence that this may be due in part to alteration of the intrinsic properties of the sinoatrial and atrioventricular (AV) nodes [7]. Athletes with a normal heart and sinus bradycardia in whom the heart rate increases appropriately during physical activity have no restriction for sport participation [1]. Athletes with symptoms including impaired consciousness or fatigue resulting from bradycardia should be restricted from competitive sports until appropriately evaluated and treated. If the subject remains asymptomatic for two to three months during treatment, participation in all competitive sports is permitted, consistent with the recommendation inherent to the cardiac condition responsible for symptoms. Sinus bradycardia and sinus tachycardia that are appropriate for the clinical situation are not considered abnormal, and further testing is not necessary. (See "Sinus bradycardia" and "Sinus tachycardia: Evaluation and management".) Sinus arrhythmia and a wandering atrial pacemaker are frequent in well-trained individuals due to increased vagal tone. No testing is necessary unless the arrhythmia results in inappropriately slow heart rates associated with symptoms. Asymptomatic sinus pauses or sinus arrest of less than three seconds duration are not uncommonly seen in Holter electrocardiogram (ECG) monitoring in normal athletes and are of no clinical significance [8]. They often occur in association with sinus bradycardia. However, longer pauses, sinoatrial exit block, and sinus node dysfunction are abnormal [9]. Athletes with a symptomatic tachycardia/bradycardia (sick sinus) syndrome should be restricted from participating in competitive sports. These patients should be treated and if they have no structural heart disease, the cause of inappropriate bradycardia (sick sinus) syndrome has been resolved, and they have remained asymptomatic for three months, they can participate in all competitive sports [1]. (See "Sinus node dysfunction: Treatment".) SUPRAVENTRICULAR ARRHYTHMIAS Atrial or junctional premature beats Premature atrial complexes (also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat) are common (junctional premature beats being less common) in the general population and in https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 5/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate athletes, and are not generally associated with underlying structural heart disease or symptoms. (See "Supraventricular premature beats".) Athletes with a structurally normal heart who have atrial or junctional premature beats, regardless of frequency, can participate in all competitive sports [1,10]. Athletes with underlying structural heart disease who have atrial or junctional premature beats can participate in competitive sports consistent with the limitations of the structural heart disease. (See "Athletes: Overview of sudden cardiac death risk and sport participation".) Atrial fibrillation Atrial fibrillation (AF) is an arrhythmia that may be present intermittently or persistently. In young athletes, AF may occur in the absence of any patent structural heart disease or other provoking condition and is often termed "lone AF," although many patients will have some underlying risk factors for AF. In older athletes, hypertension and coronary artery disease are common underlying conditions ( table 1). As with any patient with AF, athletes with AF should be evaluated for potential underlying causes and risk (eg, thyroid disease, binge alcohol use, etc). Athletes with self-terminating AF and no associated structural heart disease can participate in all competitive sports. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Classification and terminology'.) Generally, because of symptoms, a rhythm control strategy is the preferred method of treatment in athletes with AF, although there may be athletes with minimal symptoms or such infrequent episodes that a rhythm control strategy is not necessary. Rhythm control can be achieved with antiarrhythmic agents or ablation procedures. Increasingly, ablation provides a sustained benefit, particularly in those with paroxysmal AF in the presence of a normal or nearly normal heart, which is the most common scenario in athletes. Athletes without structural heart disease who have had successful AF ablation, including surgical ablation, may participate in all competitive sports ( figure 1) after four to six weeks. Athletes with recurrent/persistent AF (not undergoing ablation) can selectively participate in competitive sports if the ventricular rate increases and slows appropriately and is comparable with that of a normal sinus response in relation to the level of activity. In this case, evaluation should be individualized and regular follow-up is advised. (See "Management of atrial fibrillation: Rhythm control versus rate control".) The other component of management is anticoagulation. Most athletes will have a low risk of systemic thromboembolism as manifested by a low CHA2DS2-VASC score (calculator 1). Therefore, the decision to anticoagulate should be individually considered. However, athletes https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 6/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate who require anticoagulation should not participate in sports with danger of severe bodily collision (for example, football, basketball, or hockey) ( figure 1). Atrial flutter Sustained atrial flutter is uncommon in athletes. Typical atrial flutter is relatively easily cured with radiofrequency catheter ablation procedures. Athletes with typical atrial flutter either in the presence or in the absence of structural heart disease should be offered therapeutic resolution by radiofrequency catheter ablation, given the high likelihood of successfully curing atrial flutter [1]. In addition, if atrial flutter is cured, anticoagulation can be discontinued after four weeks. Athletes who have had atrial flutter resolved by ablation can participate in sports according to the limitation of any concurrent underlying cardiac disease (if present) after four weeks have elapsed without recurrences of atrial flutter. (See "Overview of atrial flutter", section on 'Maintenance of normal sinus rhythm'.) Only when curative ablation is not possible, drug therapy is advised. Antiarrhythmic agents may be effective in maintaining sinus rhythm, but patients should be treated with a rate-controlling agent in addition to an antiarrhythmic agent. Individuals who maintain a ventricular rate that increases and slows appropriately comparable with that of a normal sinus response in relation to the level of activity, while receiving therapy with AV nodal blocking drugs, can participate in class IA competitive sports ( figure 1) with the warning that rapid 1:1 conduction still may occur [1]. However, full participation in all competitive sports generally should not be allowed. Athletes in whom anticoagulation is deemed necessary cannot participate in competitive sports where the danger of bodily collision is present. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'Anticoagulation'.) Atrioventricular nodal reentrant tachycardia AVNRT is a common arrhythmia in young athletes and is usually associated with symptoms resulting from a rapid heart rate. Patients with infrequent episodes of AVNRT, or those with minimal or well-tolerated symptoms, may opt for a conservative management approach with either no specific therapy or pharmacologic suppression. If pharmacologic therapy fails or if the side effects result from chronic medical therapy, catheter ablation remains the preferred option. (See "Atrioventricular nodal reentrant tachycardia".) Athletes who have syncope, presyncope, or other manifestations of hemodynamic impairment secondary to the AVNRT, and do not have structural heart disease in addition to the arrhythmia, should not participate in any competitive sports until they have been adequately treated. Following catheter ablation, athletes without structural heart disease who are asymptomatic and have no recurrence of arrhythmia for four weeks after the procedure can participate in all competitive sports [1,10]. When ablation is not performed, athletes who do not have exercise- https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 7/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate induced AVNRT but who experience only sporadic, brief, and self-limited episodes without hemodynamic impairment during the episode can participate in all sports. In this case, regular follow-up is advised. Atrial tachycardia Atrial tachycardia (AT) may be due to an automatic focus or reentry; these arrhythmias are less common than atrioventricular nodal reentrant tachycardia (AVNRT) or atrioventricular reentrant tachycardia (AVRT) ( table 1). (See "Focal atrial tachycardia" and "Sinoatrial nodal reentrant tachycardia (SANRT)" and "Intraatrial reentrant tachycardia".) Patients with recurrent or refractory symptomatic AT are candidates for medical therapy or catheter ablation. Athletes with atrial tachycardia in the absence of structural heart disease who have elimination of the atrial tachyarrhythmia by an ablation technique, may participate in all competitive sports ( figure 1) after four weeks without a recurrence [1,10]. When ablation is not performed, athletes can participate in competitive sports if the ventricular rate increases and slows appropriately and is comparable with that of a normal sinus response in relation to the level of activity, with appropriate therapy. In this case, evaluation should be individualized and regular follow-up is advised. Wolff-Parkinson-White syndrome Patients with Wolff-Parkinson-White (WPW) pattern manifest ventricular pre-excitation on the surface electrocardiogram (ECG) ( table 1). When this pattern is associated with documented tachycardia or symptoms referable to tachycardia, the patient is said to have the WPW syndrome. The most common arrhythmia occurring in patients with WPW is an AVRT. (See "Wolff-Parkinson-White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis" and "Atrioventricular reentrant tachycardia (AVRT) associated with an accessory pathway".) The optimal approach to asymptomatic athletes with a WPW ECG pattern who have no history of palpitations or tachycardia and no evidence of structural heart disease is debated. The minimum diagnostic approach includes exercise ECG and/or Holter ECG monitoring to assess the abrupt reversibility of the abnormal conduction pathway with increasing heart rate (considered expression of low conduction capability and benign outcome). Abrupt loss of pre-excitation during an increasing sinus rate argues for a benign bypass tract, while gradual loss or no loss of pre-excitation does not prove that a bypass tract is benign (although this is not diagnostic of a malignant bypass tract) ( algorithm 1). Athletes with ventricular pre-excitation on the ECG and symptoms of palpitations, presyncope, or syncope, or with documented arrhythmia (ie, WPW syndrome) should be offered radiofrequency catheter ablation of the tract ( table 2) [1,10,11]. (See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'Catheter ablation'.) https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 8/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Asymptomatic athletes without structural heart disease, without a history of palpitations, or without tachycardia, and who have a stress test documenting benign bypass tract behavior (abrupt reversibility to normal conduction), particularly those >20 to 25 years old, can participate in all competitive sports. Asymptomatic athletes undergoing EP studies with induced AV reciprocating tachycardia or atrial fibrillation in whom the shortest cycle length is less than 250 ms should undergo ablation of the accessory pathway [10]. Athletes with episodes of atrial fibrillation and syncope or near syncope whose maximal ventricular rate at rest (without therapy) as a result of conduction over the accessory pathway >240 beats per minute should be considered for catheter ablation therapy of the accessory pathway prior to continuing competition. Athletes with no structural heart disease who have had successful ablation of the accessory pathway, who remain asymptomatic, and who have normal AV conduction and no evidence of pre-excitation on a 12-lead ECG can participate in all competitive sports after four weeks ( figure 1). VENTRICULAR ARRHYTHMIAS Ventricular premature beats Premature ventricular complexes/contractions (PVCs; also referred to as premature ventricular beats or premature ventricular depolarizations) are common in athletes of all age groups and occur in those with or without structural heart disease. The evaluation of athletes with PVCs should initially assess the presence of underlying pathologic substrate (ie, arrhythmogenic cardiomyopathies, coronary heart disease, inflammatory cardiac diseases, etc). Athletes without structural heart disease who have PVCs at rest and during exercise (ie, during exercise testing at a level comparable with the sport in which they compete), and who are asymptomatic or minimally symptomatic, can participate in all competitive sports [1]. If the PVCs increase in frequency during exercise or exercise testing to the extent that the athlete develops symptoms of impaired consciousness, significant fatigue, or dyspnea, the athlete should be further evaluated. In the presence of an underlying cardiac abnormality, the athlete should be treated accordingly. If no cardiac abnormality is found, the athlete should be treated for relief of symptoms and have close follow-up. In both of these cases, the athlete can participate in class IA competitive sports only ( figure 1) [1]. https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 9/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Catheter ablation should be offered to athletes with particularly frequent PVCs (>15 percent) that persist over time and are not reduced by medical treatment. (See "Athletes with arrhythmias: Clinical manifestations and diagnostic evaluation", section on 'Additional testing'.) Athletes with structural heart disease who are in high-risk groups and have PVCs should be properly treated and can participate in class IA competitive sports only ( figure 1) [1]. Nonsustained ventricular tachycardia In asymptomatic athletes with brief (generally <8 to 10 consecutive ventricular beats) episodes of nonsustained monomorphic ventricular tachycardia (VT), rates generally <150 beats per minute, and no structural heart disease established by noninvasive and invasive tests, there is no apparent increased risk for sudden cardiac death. If exercise testing (preferably by ambulatory electrocardiogram [ECG] recording during the specific competitive activity) demonstrates suppression of the VT or no significant worsening compared with baseline, participation in all competitive sports is permissible with regular follow-up ( figure 1) [1]. Sustained ventricular tachycardia In the athlete with sustained VT, a search for underlying heart disease is paramount. In the presence of underlying heart disease, these arrhythmias are potentially life-threatening. Athletes should be advised to immediately cease participation until further evaluation can be completed. Athletes with a structurally normal heart and monomorphic nonsustained or sustained VT that can be localized to a specific site(s) in the heart are candidates for a catheter ablation procedure that may potentially offer a cure. Following a successful ablation procedure, the athlete can resume full competitive activity within four weeks if there is no recurrence [1]. A more conservative approach is recommended for the athlete with a structurally normal heart, not undergoing ablation, who chooses drug suppression, because catecholamines released during athletic activity can counter the suppressive effects of the drug, and the VT can re-emerge. In this setting, the athlete should generally not compete in any sports for at least two to three months after the last VT episode [1]. If there have been no clinical recurrences and the VT is not inducible by exercise or exercise testing, and the athlete has no structural heart disease, all competitive sports may be permitted under periodical follow-up [1]. Because deconditioning can result in the loss or lessening of ventricular arrhythmias, a short period of deconditioning and retesting can be selectively advised. (See "Nonsustained VT in the absence of apparent structural heart disease" and "Ventricular tachycardia in the absence of apparent structural heart disease".) https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 10/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate For the athlete with structural heart disease, molecular or inflammatory disease, and VT, moderate- and high-intensity competition is contraindicated regardless of whether the VT is suppressed or ablated. Only class IA competitive sports are permitted ( figure 1). Ventricular flutter and fibrillation Athletes with conditions that result in cardiac arrest in the presence or absence of structural heart disease generally are treated with an ICD and have traditionally been counselled to not participate in any moderate- or high-intensity competitive sports ( figure 1) [1]. However, in today's shared decision making approach, athletes with ICDs and who have had no episodes of ventricular flutter or ventricular fibrillation requiring device therapy for three months may engage in competitive sports, with an understanding of the potential risks involved. (See 'Athletes with ICDs' below.) Recommendations in the section on VT also apply. (See "Pathophysiology and etiology of sudden cardiac arrest".) ATHLETES WITH A CARDIAC IMPLANTABLE ELECTRONIC DEVICE (CIED) Athletes with permanent pacemakers Athletes with permanent pacemakers should not participate in competitive sports when the danger of bodily collision exists because such trauma may damage the pacemaker system [1]. This restriction should generally exclude activities where direct blows to the chest are a part of the sport, such as football, rugby, boxing, martial arts, hockey, motorcycling, downhill skiing and lacrosse. Protective padding for the device is advisable for other sports such as soccer, basketball, baseball, and softball where trauma is possible but less likely. Before allowing athletes to engage in the other sport activities, an exercise test should be conducted at the level of activity demanded by the particular sport so as to be certain that the paced heart rate increases appropriately. Athletes with ICDs Although athletes with implantable cardioverter-defibrillators (ICDs) have been restricted to low-impact, low-static and dynamic sports (type IA) by previous ESC and ACC/AHA guidelines ( figure 1), the 2015 ACC/AHA Scientific Statement and 2018 ESC recommendation loosened that restriction [1,12,13]. In contemporary practice, participation in sports with higher static and dynamic components may be selectively considered if the patient has been free of arrhythmias for three months and, after appropriate information of the risks, he/she accepts the higher risk of sports-related arrhythmias and ICD appropriate and inappropriate discharge [1]. The decision regarding athletic participation should also be made with consideration of the underlying arrhythmogenic condition. Any sport in which there is a risk of traumatic injury to the device or lead system should be discouraged ( figure 1). https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 11/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate The best available data about outcomes among athletes with ICDs come from the ICD Sports Safety Registry. Among a cohort of 440 persons with ICDs (201 of whom had ventricular fibrillation [VF]/ventricular tachycardia [VT] prior to ICD implantation) who participated in organized sports and were followed for a median of 44 months, there were no deaths or VF/VT requiring external defibrillation [14]. However, there was an increased risk of shocks with exercise; 46 patients (10 percent) received an appropriate shock during participation in sports. Of those experiencing shock during sports, 14 percent quit all sports and 25 percent reduced sporting activity. In addition, another 44 patients (10 percent) experienced definite or possible lead malfunctions. In a post-hoc analysis from the ICD Sports Safety Registry which reviewed the data from 129 young athletes ( 21 years of age; mean age 16 years) followed for a median of 42 months, 35 athletes (27 percent) received a total of 49 shocks (29 appropriate, 20 inappropriate) [15]. No deaths or injuries occurred during sport participation, although lead malfunction occurred in 20 percent of patients over 10 years. The optimal approach to ICD programming in athletes is uncertain, but likely similar to the approach to programming in non-athletes. Among the same 440 patient cohort from the ICD Sports Safety Registry, 62 percent of participants were programmed with a high-rate cutoff ( 200 beats per minute) and 30 percent with a long-detection interval (defined as ">nominal" or standard programming intervals) [16]. Patients programmed with a high-rate cutoff received significantly fewer total and inappropriate shocks, and those with long-detection interval had fewer total shocks. A full discussion of the approach to optimal ICD programming is presented separately. (See "Implantable cardioverter-defibrillators: Optimal programming".) Furthermore, it is advised for athletes with an ICD to undergo exercise testing if there is a history of atrial fibrillation with a potentially rapid ventricular rate, a need for low tachyarrhythmia detection rates, or the potential to raise the sinus rate to near the ICD VT detection level. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions".) SUMMARY AND RECOMMENDATIONS Arrhythmias are not infrequently documented in athletes and can result in significant symptoms and impaired athletic performance. Rarely are supraventricular arrhythmias fatal; however, sudden cardiac death resulting from a malignant ventricular tachyarrhythmia is a devastating event in young and apparently healthy persons. (See 'Introduction' above.) https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 12/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Syncope that occurs during exertion suggests a potentially life-threatening arrhythmic etiology (eg, aortic stenosis, hypertrophic cardiomyopathy, ventricular arrhythmia, etc) and should be evaluated urgently. On the other hand, syncope occurring after exertion (eg, during cooling off period) is more likely reflex in origin, similar to the vasovagal faint. (See 'Syncope' above.) Altered atrioventricular (AV) nodal conduction (eg, first degree AV block and Mobitz type I second degree AV block) can result from increased vagal tone, which is normally seen as an adaptive response to certain types of athletic conditioning and is generally not a cause for concern. However, higher degrees of AV conduction abnormality (eg, Mobitz type II second degree AV block and third degree AV block) will require attention prior to participation in athletics. (See 'AV conduction abnormalities' above.) Sinus bradycardia and sinus tachycardia that are appropriate for the clinical situation are not considered abnormal, and further testing is not necessary. Asymptomatic sinus pauses or sinus arrest of less than three seconds duration are not uncommonly seen in normal athletes and are of no clinical significance. However, longer pauses, sinoatrial exit block, and sinus node dysfunction are abnormal. (See 'Sinus node dysfunction' above.) Atrial premature beats are common in the general population and in athletes, and are not generally associated with underlying structural heart disease or symptoms. Premature ventricular complexes (PVCs) are also common in athletes of all age groups and occur in those with or without structural heart disease; the identification of PVCs should prompt an evaluation for the presence of underlying pathologic substrate. (See 'Atrial or junctional premature beats' above and 'Ventricular premature beats' above.) Sustained atrial fibrillation and/or atrial flutter are uncommon in athletes. A full cardiac evaluation, should be performed and referral to an arrhythmia specialist for any patient with one of these arrhythmias. (See 'Atrial fibrillation' above and 'Atrial flutter' above.) Atrioventricular nodal reentrant tachycardia (AVNRT) is a common arrhythmia in young athletes and is often associated with symptoms resulting from a rapid heart rate. Patients with infrequent episodes of AVNRT, or those with minimal or well-tolerated symptoms, may opt for a conservative management approach with either no specific therapy or pharmacologic suppression. If pharmacologic therapy fails or if the side effects result from chronic medical therapy, catheter ablation remains the preferred option. (See 'Atrioventricular nodal reentrant tachycardia' above.) Patients with Wolff-Parkinson-White (WPW) pattern manifest ventricular pre-excitation on the surface electrocardiogram (ECG). When this pattern is associated with documented https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 13/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate tachycardia or symptoms referable to tachycardia, the patient is said to have the WPW syndrome. The most common arrhythmia occurring in patients with WPW is an atrioventricular reentrant tachycardia (AVRT), although atrial fibrillation and other arrhythmias may arise. Athletes with ventricular pre-excitation on the ECG and symptoms of palpitations, presyncope, or syncope, or with documented arrhythmia (ie, WPW syndrome) should undergo invasive electrophysiologic testing for both diagnostic and potential therapeutic (ie, catheter ablation of the accessory pathway) purposes. (See 'Wolff- Parkinson-White syndrome' above.) Most individuals with sustained or nonsustained symptomatic monomorphic or polymorphic ventricular tachycardia have underlying structural heart disease. Since these arrhythmias are potentially life-threatening, further evaluation is essential prior to the resumption of athletic activity. (See 'Nonsustained ventricular tachycardia' above and 'Sustained ventricular tachycardia' above.) Recommendations regarding the ability to participate in competitive athletics or intense athletic training are discussed in the relevant sections of the text.

has been free of arrhythmias for three months and, after appropriate information of the risks, he/she accepts the higher risk of sports-related arrhythmias and ICD appropriate and inappropriate discharge [1]. The decision regarding athletic participation should also be made with consideration of the underlying arrhythmogenic condition. Any sport in which there is a risk of traumatic injury to the device or lead system should be discouraged ( figure 1). https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 11/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate The best available data about outcomes among athletes with ICDs come from the ICD Sports Safety Registry. Among a cohort of 440 persons with ICDs (201 of whom had ventricular fibrillation [VF]/ventricular tachycardia [VT] prior to ICD implantation) who participated in organized sports and were followed for a median of 44 months, there were no deaths or VF/VT requiring external defibrillation [14]. However, there was an increased risk of shocks with exercise; 46 patients (10 percent) received an appropriate shock during participation in sports. Of those experiencing shock during sports, 14 percent quit all sports and 25 percent reduced sporting activity. In addition, another 44 patients (10 percent) experienced definite or possible lead malfunctions. In a post-hoc analysis from the ICD Sports Safety Registry which reviewed the data from 129 young athletes ( 21 years of age; mean age 16 years) followed for a median of 42 months, 35 athletes (27 percent) received a total of 49 shocks (29 appropriate, 20 inappropriate) [15]. No deaths or injuries occurred during sport participation, although lead malfunction occurred in 20 percent of patients over 10 years. The optimal approach to ICD programming in athletes is uncertain, but likely similar to the approach to programming in non-athletes. Among the same 440 patient cohort from the ICD Sports Safety Registry, 62 percent of participants were programmed with a high-rate cutoff ( 200 beats per minute) and 30 percent with a long-detection interval (defined as ">nominal" or standard programming intervals) [16]. Patients programmed with a high-rate cutoff received significantly fewer total and inappropriate shocks, and those with long-detection interval had fewer total shocks. A full discussion of the approach to optimal ICD programming is presented separately. (See "Implantable cardioverter-defibrillators: Optimal programming".) Furthermore, it is advised for athletes with an ICD to undergo exercise testing if there is a history of atrial fibrillation with a potentially rapid ventricular rate, a need for low tachyarrhythmia detection rates, or the potential to raise the sinus rate to near the ICD VT detection level. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions".) SUMMARY AND RECOMMENDATIONS Arrhythmias are not infrequently documented in athletes and can result in significant symptoms and impaired athletic performance. Rarely are supraventricular arrhythmias fatal; however, sudden cardiac death resulting from a malignant ventricular tachyarrhythmia is a devastating event in young and apparently healthy persons. (See 'Introduction' above.) https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 12/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Syncope that occurs during exertion suggests a potentially life-threatening arrhythmic etiology (eg, aortic stenosis, hypertrophic cardiomyopathy, ventricular arrhythmia, etc) and should be evaluated urgently. On the other hand, syncope occurring after exertion (eg, during cooling off period) is more likely reflex in origin, similar to the vasovagal faint. (See 'Syncope' above.) Altered atrioventricular (AV) nodal conduction (eg, first degree AV block and Mobitz type I second degree AV block) can result from increased vagal tone, which is normally seen as an adaptive response to certain types of athletic conditioning and is generally not a cause for concern. However, higher degrees of AV conduction abnormality (eg, Mobitz type II second degree AV block and third degree AV block) will require attention prior to participation in athletics. (See 'AV conduction abnormalities' above.) Sinus bradycardia and sinus tachycardia that are appropriate for the clinical situation are not considered abnormal, and further testing is not necessary. Asymptomatic sinus pauses or sinus arrest of less than three seconds duration are not uncommonly seen in normal athletes and are of no clinical significance. However, longer pauses, sinoatrial exit block, and sinus node dysfunction are abnormal. (See 'Sinus node dysfunction' above.) Atrial premature beats are common in the general population and in athletes, and are not generally associated with underlying structural heart disease or symptoms. Premature ventricular complexes (PVCs) are also common in athletes of all age groups and occur in those with or without structural heart disease; the identification of PVCs should prompt an evaluation for the presence of underlying pathologic substrate. (See 'Atrial or junctional premature beats' above and 'Ventricular premature beats' above.) Sustained atrial fibrillation and/or atrial flutter are uncommon in athletes. A full cardiac evaluation, should be performed and referral to an arrhythmia specialist for any patient with one of these arrhythmias. (See 'Atrial fibrillation' above and 'Atrial flutter' above.) Atrioventricular nodal reentrant tachycardia (AVNRT) is a common arrhythmia in young athletes and is often associated with symptoms resulting from a rapid heart rate. Patients with infrequent episodes of AVNRT, or those with minimal or well-tolerated symptoms, may opt for a conservative management approach with either no specific therapy or pharmacologic suppression. If pharmacologic therapy fails or if the side effects result from chronic medical therapy, catheter ablation remains the preferred option. (See 'Atrioventricular nodal reentrant tachycardia' above.) Patients with Wolff-Parkinson-White (WPW) pattern manifest ventricular pre-excitation on the surface electrocardiogram (ECG). When this pattern is associated with documented https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 13/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate tachycardia or symptoms referable to tachycardia, the patient is said to have the WPW syndrome. The most common arrhythmia occurring in patients with WPW is an atrioventricular reentrant tachycardia (AVRT), although atrial fibrillation and other arrhythmias may arise. Athletes with ventricular pre-excitation on the ECG and symptoms of palpitations, presyncope, or syncope, or with documented arrhythmia (ie, WPW syndrome) should undergo invasive electrophysiologic testing for both diagnostic and potential therapeutic (ie, catheter ablation of the accessory pathway) purposes. (See 'Wolff- Parkinson-White syndrome' above.) Most individuals with sustained or nonsustained symptomatic monomorphic or polymorphic ventricular tachycardia have underlying structural heart disease. Since these arrhythmias are potentially life-threatening, further evaluation is essential prior to the resumption of athletic activity. (See 'Nonsustained ventricular tachycardia' above and 'Sustained ventricular tachycardia' above.) Recommendations regarding the ability to participate in competitive athletics or intense athletic training are discussed in the relevant sections of the text. In general, athletes with symptomatic supraventricular arrhythmias, WPW, ventricular arrhythmias, and symptomatic bradyarrhythmias should be referred to a cardiac electrophysiologist. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Zipes DP, Link MS, Ackerman MJ, et al. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 9: Arrhythmias and Conduction Defects: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2412. 2. Pelliccia A, Fagard R, Bj rnstad HH, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005; 26:1422. 3. Kim JH, Noseworthy PA, McCarty D, et al. Significance of electrocardiographic right bundle branch block in trained athletes. Am J Cardiol 2011; 107:1083. https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 14/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate 4. Corrado D, Pelliccia A, Heidbuchel H, et al. Recommendations for interpretation of 12-lead electrocardiogram in the athlete. Eur Heart J 2010; 31:243. 5. Talan DA, Bauernfeind RA, Ashley WW, et al. Twenty-four hour continuous ECG recordings in long-distance runners. Chest 1982; 82:19. 6. Abdon NJ, Landin K, Johansson BW. Athlete's bradycardia as an embolising disorder? Symptomatic arrhythmias in patients aged less than 50 years. Br Heart J 1984; 52:660. 7. Stein R, Medeiros CM, Rosito GA, et al. Intrinsic sinus and atrioventricular node electrophysiologic adaptations in endurance athletes. J Am Coll Cardiol 2002; 39:1033. 8. Bj rnstad H, Storstein L, Meen HD, Hals O. Ambulatory electrocardiographic findings in top athletes, athletic students and control subjects. Cardiology 1994; 84:42. 9. Wang, YG, Mariman, et al. Various electrocardiographic and electrophysiologic presentations of normal and abnormal sinus node. J Cardiovasc Electrophysiol 1992; 3:187. 10. Brugada J, Katritsis DG, Arbelo E, et al. 2019 ESC Guidelines for the management of patients with supraventricular tachycardiaThe Task Force for the management of patients with supraventricular tachycardia of the European Society of Cardiology (ESC). Eur Heart J 2020; 41:655. 11. Pediatric and Congenital Electrophysiology Society (PACES), Heart Rhythm Society (HRS), American College of Cardiology Foundation (ACCF), et al. PACES/HRS expert consensus statement on the management of the asymptomatic young patient with a Wolff-Parkinson- White (WPW, ventricular preexcitation) electrocardiographic pattern: developed in partnership between the Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS). Endorsed by the governing bodies of PACES, HRS, the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), the American Academy of Pediatrics (AAP), and the Canadian Heart Rhythm Society (CHRS). Heart Rhythm 2012; 9:1006. 12. Heidbuchel H, Carr F. Exercise and competitive sports in patients with an implantable cardioverter-defibrillator. Eur Heart J 2014; 35:3097. 13. Pelliccia A, Solberg EE, Papadakis M, et al. Recommendations for participation in competitive and leisure time sport in athletes with cardiomyopathies, myocarditis, and pericarditis: position statement of the Sport Cardiology Section of the European Association of Preventive Cardiology (EAPC). Eur Heart J 2019; 40:19. 14. Lampert R, Olshansky B, Heidbuchel H, et al. Safety of Sports for Athletes With Implantable Cardioverter-Defibrillators: Long-Term Results of a Prospective Multinational Registry. Circulation 2017; 135:2310. https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 15/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate 15. Saarel EV, Law I, Berul CI, et al. Safety of Sports for Young Patients With Implantable Cardioverter-Defibrillators: Long-Term Results of the Multinational ICD Sports Registry. Circ Arrhythm Electrophysiol 2018; 11:e006305. 16. Olshansky B, Atteya G, Cannom D, et al. Competitive athletes with implantable cardioverter- defibrillators-How to program? Data from the Implantable Cardioverter-Defibrillator Sports Registry. Heart Rhythm 2019; 16:581. Topic 113533 Version 17.0 https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 16/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate GRAPHICS Seattle criteria classifying the normal and abnormal electrocardiogram findings in athletes Normal ECG findings in athletes 1. Sinus bradycardia ( 30 bpm) 2. Sinus arrhythmia 3. Ectopic atrial rhythm 4. Junctional escape rhythm 5. 1 AV block (PR interval >200 ms) 6. Mobitz Type I (Wenckebach) 2 AV block 7. Incomplete RBBB 8. Isolated QRS voltage criteria for LVH Except: QRS voltage criteria for LVH occurring with any non-voltage criteria for LVH such as left atrial enlargement, left axis deviation, ST segment depression, T-wave inversion, or pathological Q waves 9. Early repolarization (ST elevation, J-point elevation, J-waves, or terminal QRS slurring) 10. Convex ("domed") ST segment elevation combined with T-wave inversion in leads V1 V4 in black/African athletes These common training-related ECG alterations are physiological adaptations to regular exercise, considered normal variants in athletes and do not require further evaluation in asymptomatic athletes Abnormal ECG findings in athletes Abnormal ECG Definition finding T-wave inversion >1 mm in depth in two or more leads V2 V6, II and aVF, or I and aVL (excludes III, aVR and V1) 0.5 mm in depth in two or more leads ST segment depression Pathologic Q waves >3 mm in depth or >40 ms in duration in two or more leads (except for III and aVR) QRS 120 ms, predominantly negative QRS complex in lead V1 (QS or rS), and upright monophasic R wave in leads I and V6 Complete left bundle branch block https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 17/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Any QRS duration 140 ms Intraventricular conduction delay Left axis deviation 30 to 90 Left atrial enlargement Prolonged P wave duration of >120 ms in leads I or II with negative portion of the P wave 1 mm in depth and 40 ms in duration in lead V1 Right ventricular hypertrophy pattern R V1+S V5 >10.5 mm AND right axis deviation >120 Ventricular pre- excitation PR interval <120 ms with a delta wave (slurred upstroke in the QRS complex) and wide QRS (>120 ms) QTc 470 ms (male) Long QT interval* QTc 480 ms (female) QTc 500 ms (marked QT prolongation) Short QT interval* QTc 320 ms Brugada-like ECG pattern High take-off and downsloping ST segment elevation followed by a negative T wave in 2 leads in V1 V3 <30 bpm or sinus pauses 3 s Profound sinus bradycardia Atrial tachyarrhythmias Supraventricular tachycardia, atrial fibrillation, atrial flutter 2 PVCs per 10 s tracing Premature ventricular contractions Ventricular Couplets, triplets, and non-sustained ventricular tachycardia arrhythmias ECG: electrocardiogram; bpm: beats per minute; AV: atrioventricular; RBBB: right bundle branch block; LVH: left ventricular hypertrophy; PVC: premature ventricular contraction; ms: milliseconds. The QT interval corrected for heart rate is ideally measured with heart rates of 60 to 90 bpm. Consider repeating the ECG after mild aerobic activity for borderline or abnormal QTc values with a heart rate <50 bpm. From: Drezner JA, Ackerman MJ, Anderson J, et al. Electrocardiographic interpretation in athletes: The "Seattle Criteria". Br J Sports Med 2013; 47:123. Reproduced with permission from BMJ Publishing Group Ltd. Copyright 2013. Graphic 102509 Version 3.0 https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 18/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Single-lead electrocardiogram (ECG) showing first degree atrioventricular (AV) block I Electrocardiogram of lead II showing normal sinus rhythm, first degree atrioventricular block with a prolonged PR interval of 0.30 seconds, and a QRS complex of normal duration. The tall P waves and P wave duration of approximately 0.12 seconds suggest concurrent right atrial enlargement. Courtesy of Morton Arnsdorf, MD. Graphic 67882 Version 5.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 19/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Electrocardiogram showing Mobitz type I (Wenckebach) atrioventricular block Single-lead electrocardiogram showing Mobitz type I (Wenckebach) second-degree atrioventricular block with 5:4 conduction. The characteristics of this arrhythmia include: a progressively increasing PR interval until a P wave is not conducted (arrow), a progressive decrease in the increment in the PR interval, a progressive decrease in the RR interval, and the RR interval that includes the dropped beat (0.96 sec) is less than twice the RR interval between conducted beats (0.53 to 0.57 sec). Courtesy of Morton Arnsdorf, MD. Graphic 73051 Version 6.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 20/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Classification of sports based on peak static and dynamic components during competition This classification is based on peak static and dynamic components achieved during competition; however, higher values may be reached during training. The increasing dynamic component is defined in terms of the estimated percentage of maximal oxygen uptake (VO max) achieved and results in an increasing cardiac output. The increasing static component is related to the estimated percentage of maximal 2 voluntary contraction reached and results in an increasing blood pressure load. The lowest total cardiovascular demands (cardiac output and blood pressure) are shown in the palest color, with increasing dynamic load depicted by increasing blue intensity and increasing static load by increasing red intensity. Note the graded transition between categories, which should be individualized on the basis of player position and style of play. Danger of bodily collision (refer to UpToDate content regarding sports according to risk of impact and educational background). https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 21/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Increased risk if syncope occurs. Reproduced from: Levine BD, Baggish AL, Kovacs RJ. Eligibility and disquali cation recommendations for competitive athletes with cardiovascular abnormalities: Task force 1: Classi cation of sports: Dynamic, static, and impact: A scienti c statement from the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2350. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 105651 Version 9.0 https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 22/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Electrocardiographic and electrophysiologic features of Mobitz type II second-degree atrioventricular block The PR and RR intervals are constant, but the third atrial beat (A) is not conducted (arrow). His bundle electrocardiography (HBE) shows constant AH (85 msec) and HV (95 msec) intervals and normal AH but no HV conduction in the nonconducted beat. The last finding indicates that the block is distal to the His bundle, in contrast with the more proximal location of Mobitz type I atrioventricular block. Adapted from: Josephson ME, Clinical Cardiac Electrophysiology: Techniques and nd Interpretations, 2 ed, Lea & Febiger, Philadelphia 1993. Graphic 79539 Version 7.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 23/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Single-lead electrocardiogram (ECG) showing sinus rhythm with third degree (complete) AV block Sinus rhythm with third degree (complete) heart block. There is independent atrial (as shown by the P waves) and ventricular activity, with respective rates of 83 and 43 beats per minute. The wide QRS complexes may represent a junctional escape rhythm with underlying bundle branch block or an idioventricular pacemaker. Courtesy of Ary Goldberger, MD. Graphic 72863 Version 6.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 24/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Third degree (complete) atrioventricular block with wide QRS escape rhythm The P waves are completely dissociated from the QRS complexes and the PR intervals are variable. The atrial or PP rate (75 beats per minute) is faster than the ventricular or RR rate (30 beats per minute), establishing complete atrioventricular blockade as the etiology. The QRS complexes are wide indicating that the escape rhythm is ventricular. Graphic 51446 Version 5.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 25/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Electrocardiogram (ECG) showing common right bundle branch block (RBBB) Electrocardiogram showing characteristic changes in the precordial leads in complete RBBB. The asynchronous activation of the two ventricles increases the QRS duration (0.13 seconds). The terminal forces are rightward and anterior due to the delayed activation of the right ventricle, resulting in an rsR' pattern in the anterior-posterior lead V1 and a wide negative S wave in the left-right lead V6 (and, not shown, in lead I). Courtesy of Ary Goldberger, MD. Graphic 64393 Version 7.0 Normal ECG https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 26/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Normal electrocardiogram showing normal sinus rhythm at a rate of 75 beats/minute, a PR interval of 0.14 seconds, a QRS interval of 0.10 seconds, and a QRS axis of approximately 75 . Courtesy of Ary Goldberger, MD. Graphic 76183 Version 4.0 https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 27/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate 12-lead electrocardiogram (ECG) showing typical left bundle branch block Electrocardiogram in typical complete left bundle branch block. The asynchronous activation of the 2 ventricles increases the QRS duration (0.16 seconds in this example). The abnormal initial vector results in loss of "normal" septal forces as manifested by absence of q waves in leads I, aVL, and V6. The late activation of the left ventricle prolongs the dominant leftward progression of the middle and terminal forces, leading to a positive and widened R wave in the lateral leads. Both the ST segment and T wave vectors are opposite in direction from the QRS, a "secondary" repolarization abnormality. Courtesy of Ary Goldberger, MD. Graphic 61594 Version 9.0 Normal ECG https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 28/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Normal electrocardiogram showing normal sinus rhythm at a rate of 75 beats/minute, a PR interval of 0.14 seconds, a QRS interval of 0.10 seconds, and a QRS axis of approximately 75 . Courtesy of Ary Goldberger, MD. Graphic 76183 Version 4.0 https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 29/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Algorithmic approach to risk stratification of asymptomatic patients with Wolff-Parkinson-White ECG pattern ECG: electrocardiogram; EPS: electrophysiology studies; AVRT: atrioventricular reciprocating tachycardia; AF: atrial fibrillation; WPW: Wolff-Parkinson-White. Preexcitation on the surface ECG is identified by a short PR interval (less than 120 milliseconds) leading into QRS, which is widened with a slurred upstroke (delta wave). Preexcitation is defined as intermittent when an ECG at any point in time shows the loss of preexcitation. In patients who are unable to perform exercise testing (eg, very young patients), ambulatory ECG monitoring or, rarely, sodium channel blocker challenge with procainamide is an alternative to assess for persistent or intermittent preexcitation. All approaches to risk stratification in patients with ventricular preexcitation are imperfect and can be associated with false positives as well as false negatives. https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 30/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Options for invasive EPS include the standard transvenous intracardiac EPS or a transesophageal atrial EPS. Refer to the UpToDate topic on treatment of symptomatic arrhythmias in patients with WPW. For most asymptomatic patients with preexcitation and no high- risk features identified on EPS, particularly those over age 35 to 40 years, we suggest observation. However, in some asymptomatic patients, particularly children, some electrophysiologists discuss and/or proceed with catheter ablation as a therapeutic option even in the absence of high risk features. Refer to UpToDate content on treatment of WPW for additional information. Graphic 119379 Version 3.0 https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 31/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Recommendations for risk stratification for sudden cardiac death proposed by the European Society of Cardiology (ESC): Wolff-Parkinson-White syndrome Finding Recommendations Short (<250 ms) RR interval during atrial fibrillation Class IIa Short (<270 ms) anterograde refractory period of the accessory pathway Class IIa Multiple accessory pathways Class IIa Loss of pre-excitation ajmaline or procainamide test (lower risk) Class IIb Syncope Class III Classification Class I: Conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective. Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment. Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy. Class IIb: Usefulness/efficacy less well established by evidence/opinion. Class III: Conditions for which there is evidence and/or general agreement that the procedure/treatment is not useful and in some cases may be harmful. Recommendations from the European Society of Cardiology for additional risk stratification for sudden cardiac death in patients with specific clinical findings in the setting of Wolff-Parkinson-White syndrome. Priori SG, Aliot E, Blomstrom-Lundqvist C, et al. Eur Heart J 2001; 22:1374. Graphic 51644 Version 3.0 https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 32/33 7/5/23, 11:14 AM Athletes with arrhythmias: Treatment and returning to athletic participation - UpToDate Contributor Disclosures Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Antonio Pelliccia, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott Manaker, MD, PhD Other Financial Interest: Expert witness in workers' compensation and in medical negligence matters [General pulmonary and critical care medicine]; National Board for Respiratory Care [Director]. All of the relevant financial relationships listed have been mitigated. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/athletes-with-arrhythmias-treatment-and-returning-to-athletic-participation/print 33/33

7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cardiac arrhythmias due to digoxin toxicity : Ary L Goldberger, MD : Evan Schwarz, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Oct 20, 2022. INTRODUCTION Cardiac glycosides (digitalis preparations including digoxin and digitoxin) are used clinically in two situations: heart failure due to systolic dysfunction, and in certain supraventricular tachyarrhythmias [1]: The ability to enhance cardiac contractility and modulate neurohumoral activation can lead to symptomatic improvement in systolic heart failure, although it is unclear if survival is prolonged even in carefully selected patients with low therapeutic serum levels. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.) Digoxin also slows conduction through the atrioventricular (AV) junction (node) by increasing cardiac vagal tone modulation. It may also have a sympathoinhibitory effect in therapeutic doses. As a result, it is sometimes used (usually adjunctively with beta blockers or calcium channel blockers) for controlling the ventricular response in atrial fibrillation and atrial flutter when there is excessively rapid transmission of stimuli from the atria to the ventricles through the AV junction. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy" and "Control of ventricular rate in atrial flutter".) Digoxin may also be effective in the treatment of certain types of reentrant paroxysmal supraventricular tachycardia involving the AV node. https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 1/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Digoxin toxicity continues to be an important clinical problem which may be life-threatening [2]. The incidence of digoxin excess and toxicity, along with the potential associated arrhythmias, are presented here. The management of digoxin intoxication, including the treatment of cardiac arrhythmias associated with digoxin toxicity, is discussed separately. (See "Digitalis (cardiac glycoside) poisoning" and "Cardioversion for specific arrhythmias", section on 'Cardioversion in patients with digitalis toxicity'.) INCIDENCE OF DIGOXIN TOXICITY Technical advances and changes in practice patterns have lowered the incidence of digoxin overdose in patients receiving chronic therapy [3]. However, digoxin toxicity remains an important clinical syndrome in which potentially fatal cardiac arrhythmias can occur [4]. (See "Digitalis (cardiac glycoside) poisoning".) In a large study of patients with congestive heart failure who were treated with digoxin, definite digoxin toxicity occurred in 0.8 percent and possible toxicity in another 4 percent [5]. Digoxin toxicity was also reported in 4 percent of patients in a 1998 study [6]. In spite of efforts to educate prescribers to use lower digoxin doses (in heart failure patients) with a goal of lower plasma digoxin levels, the frequency of emergency department visits related to digoxin toxicity has remained relatively unchanged [7]. PLASMA DIGOXIN LEVELS ASSOCIATED WITH TOXICITY Life-threatening digoxin-induced arrhythmias and other toxic manifestations occur at substantially increasing frequency as the plasma digoxin concentration rises above 2.0 ng/mL (2.6 nmol/L). However, clinicians should be aware that signs of toxicity may occur at levels below 1.3 to 1.5 ng/mL (1.7 to 1.9 nmol/L), and such toxicity is more likely in the presence of one or more comorbid conditions (eg, hypokalemia, hypomagnesemia, hypercalcemia, myocardial ischemia). Hypokalemia is a particularly important risk factor that can promote digoxin-induced arrhythmias. Patients with heart failure who are older than 65 years are also at increased risk [8]. (See "Digitalis (cardiac glycoside) poisoning".) Retrospective analysis of data from the large digitalis investigation group (the DIG trial) revealed that serum digoxin levels ranging from 1.2 to 2.0 ng/mL (1.5 to 2.6 nmol/L) were associated with an excess mortality versus placebo in women with heart failure [9]. Therefore, we recommend maintaining trough digoxin levels at the lower range (eg, between 0.5 and 0.8 ng/mL [0.6 to 1.0 nmol/L]) in both male and female patients to help minimize toxicity [10,11]. https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 2/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate The safety and effectiveness of digoxin in patients with atrial fibrillation with and without chronic heart failure also continue to generate controversy and conflicting findings [12,13]. Until more definitive prospective clinical trial data are available [13], serum digoxin concentrations should be maintained within the low therapeutic range (0.5 to 0.8 ng/mL [0.6 to 1.0 nmol/L]), with careful monitoring of renal function and serum potassium concentrations. Plasma digoxin levels should be measured at least 6 hours and preferably 12 or more hours after the last dose since this is the time required for attainment of the steady state due to gradual distribution through the extravascular space. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification" and "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.) MECHANISMS OF CARDIAC TOXICITY The mechanism(s) by which digoxin toxicity promotes the development of arrhythmias remain incompletely understood. Two general categories have been described: enhanced ectopy with tachyarrhythmias, and bradyarrhythmias [14]. Digoxin can affect cardiac tissue in a number of ways which may result in toxicity: Digoxin directly inhibits the ATPase dependent sodium-potassium pump, increasing intracellular sodium. This, in turn, reduces the activity of a sodium-calcium exchanger that normally extrudes calcium from the cell [15]. The resulting increase in intracellular calcium is responsible for the positive inotropic action of digoxin. The fluxes in calcium can also have electrophysiologic effects. Cardiac glycosides activate ryanodine receptors, which could contribute to increased calcium release from the sarcoplasmic reticulum and could play a role in the inotropic action of glycosides in vivo [16]. Digoxin increases vagal tone through central and peripheral effects; however, at excess levels, digoxin may augment cardiac sympathetic tone [17]. As a result of the effect on intracellular calcium concentrations and vagal tone, high levels of digoxin can have a variety of effects that facilitate the development of arrhythmias. They can enhance and depress automaticity, induce triggered membrane activity (especially delayed afterdepolarizations), increase or decrease excitability, slow conduction, and alter refractoriness, also producing conditions conducive to the development of reentrant arrhythmias. https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 3/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate DIGOXIN-INDUCED ARRHYTHMIAS A wide range of arrhythmias occurring at almost any intracardiac location can be seen with digoxin toxicity, depending in part upon the age of the patient and the state of the myocardium. Accentuation of vagal effects and resulting bradyarrhythmias are more commonly seen in younger, healthier individuals. Conversely, patients with severe cardiac disease and concurrent digoxin toxicity are more susceptible to ventricular ectopy and tachyarrhythmias. (See "ECG tutorial: Miscellaneous diagnoses", section on 'Digitalis toxicity'.) There are, however, some arrhythmias that are generally not directly induced by digoxin. Atrial flutter, atrial fibrillation, and Mobitz type II second degree AV block are the least likely of all the arrhythmias to be caused by digoxin toxicity. However, superimposed digoxin toxicity may occur in these settings, for example leading to an excessively slow or regularized ventricular response in atrial fibrillation, or increased ventricular ectopy. The arrhythmias associated with digoxin toxicity will be discussed according to their myocardial site of origin, including the sinoatrial nodal tissue, atrial myocardium, atrioventricular nodal tissue, and ventricular myocardium. Sinus bradycardia, tachycardia, block, and arrest The effect of digoxin and digoxin toxicity on the sinoatrial (SA) node is often difficult to determine because of both indirect and direct actions. As an example, improved hemodynamics in heart failure usually results in a fall in heart rate due to alterations in autonomic balance. Alternatively, sinus bradycardia may also be one of the earliest signs of digoxin excess. Cardiac glycosides have no direct effect on slowing automaticity in the isolated SA node or in the transplanted human heart [18,19]. However, the diseased SA node may be quite sensitive to cardiac glycosides, resulting in sinus bradycardia and SA nodal block [5,20-22]. Animal and human studies suggest that the slowing of the heart rate in this setting is due both to increased vagal tone (mediated by hypersensitization of carotid sinus baroreceptors, central stimulation, increased vagal traffic, and possible potentiation of the effect of acetylcholine on the SA node) and to sympatholytic activity. While most commonly sinus bradycardia is seen, the sinus pacemaker may accelerate in the presence of excess digoxin. Both adrenergic stimulation [18,23-25] and direct stimulation of the SA node may contribute to this response [26-28]. Toxic levels of digoxin can also result in SA nodal block ( waveform 1A-B) or even nodal arrest. (See "Sinoatrial nodal pause, arrest, and exit block".) https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 4/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Ectopic atrial tachycardia with block Therapeutic concentrations of digoxin have little effect on atrial tissue, but toxic levels may result in an ectopic atrial tachycardia, often with 2:1 AV block. Animal studies suggest that the atrial tachycardia is probably mediated by increased automaticity in the atrium and/or delayed afterpotentials, often occurring near and perhaps sometimes within the SA node [27,29,30]. The AV block probably results from the rapid atrial rate, as well as the vagotonic activity and a direct effect of digoxin on AV nodal conduction (see below). Also referred to as "paroxysmal" (ectopic) atrial tachycardia (PAT) with AV block, this arrhythmia is strongly suggestive of digoxin toxicity in patients taking this medication or in cases of suspected overdose. However, the arrhythmia is typically not paroxysmal when induced by digoxin; rather, it is a persistent arrhythmia until specific therapy is instituted or digoxin levels fall below the toxic range (see "Focal atrial tachycardia", section on 'Treatment'). It should be noted that most cases of ectopic atrial tachycardia with block are not due to digoxin excess in contemporary practice. Clinically, up to one-half of patients with nonparoxysmal atrial tachycardia with AV nodal block have a P wave morphology similar to the sinus P wave ( waveform 2). This observation supports the suggestion in animal studies that the ectopic site is often near, or is perhaps in, the SA node. The remaining cases arise at other sites and typically have an abnormal P wave axis as seen in the ectopic atrial tachycardias. Atrial tachycardia with block may superficially resemble atrial flutter. There are two major distinguishing features between these arrhythmias: The atrial rate is faster (usually 250 to 350 beats/min) with atrial flutter. The baseline between P waves is isoelectric in atrial tachycardia with block, while there is a constantly undulating baseline between the flutter waves in atrial flutter. It is important to distinguish between atrial flutter and atrial tachycardia due to digoxin excess since the administration of additional digoxin, which may be an appropriate therapy for atrial flutter, can accelerate the atrial rate in an atrial tachycardia, increasing the degree of AV block and potentially precipitating a more serious digoxin-toxic arrhythmia. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) Atrial fibrillation and flutter Digoxin toxicity can occur in patients with atrial fibrillation or flutter, even though these arrhythmias are rarely caused by digoxin. A more important clinical problem is the effect of digoxin toxicity on transmission of atrial stimuli through the AV node in patients with preexisting atrial fibrillation. The electrocardiographic findings vary with increasing https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 5/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate degrees of digoxin toxicity and with the possible presence of block above or below the pacemaker ( waveform 3A-D) [31]. Casual evaluation of such a patient who might have severe digoxin toxicity may lead to the mistaken conclusion that the irregular rhythm is due to persistent AF and the digoxin may be inappropriately continued or the dose even increased. Atrial flutter is rarely, if ever, the result of digoxin intoxication. However, the diagnosis of atrial flutter may be difficult to establish when, as commonly occurs during digoxin therapy, the atrial flutter has a slow ventricular response, with a rate that overlaps that seen in other supraventricular tachycardias, such as nonparoxysmal atrial tachycardia with a 2:1 AV response due to digoxin intoxication. (See 'Ectopic atrial tachycardia with block' above.) Atrioventricular nodal block Therapeutic concentrations of digoxin decrease the conduction velocity through the AV node and increase the refractoriness of the AV node; this affects the conduction of the normal as well as a premature impulse. These effects are mediated primarily by an increase in vagal tone and, to a lesser degree, a reduction in sympathetic activity [5,20,21,26,32-35]. As a result of this dependence on autonomic balance, digoxin is of little value in controlling the ventricular response in patients who have undergone cardiac transplantation due to the denervated nature of the transplanted heart [34,35]. AV conduction may be blocked partially or completely by digoxin excess. First degree block (AV conduction delay) Some degree of PR lengthening may be expected with digoxin therapy ( waveform 4). More marked widening of the PR interval to above 0.2 sec suggests early digoxin toxicity. Second degree AV block With higher levels of digoxin, first degree AV block may progress to second degree block of the Mobitz type I (Wenckebach) variety ( waveform 5). By contrast, Mobitz type II second degree AV block is rarely, if ever, induced by digoxin alone. (See "Second-degree atrioventricular block: Mobitz type I (Wenckebach block)".) Third degree AV block Third-degree (complete) heart block and other types of AV dissociation may also occur with digoxin toxicity ( waveform 6). (See "Third-degree (complete) atrioventricular block".) AV block with digoxin is more likely to occur in the presence of atrial fibrillation, an ectopic atrial rhythm, or atrial flutter than during normal sinus rhythm. The reason is that more atrial impulses are present to reach the AV node during these atrial tachyarrhythmias than during slower rates. In atrial fibrillation, a high degree of AV block may occur, resulting in the ventricles being controlled intermittently by a lower junctional or ventricular pacemaker. https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 6/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate The ECG findings vary with atrial fibrillation, due to a number of factors, including the possible presence of exit block below the pacemaker. The following additional arrhythmias can be seen with increasing degrees of digoxin toxicity in the presence of atrial fibrillation ( waveform 3A-D) [31,36]: A high but not complete degree of AV block in atrial fibrillation will initially lead to single junctional, subjunctional, or ventricular escape beats with a cycle length characteristic of that of the underlying pacemaker. These escape beats recur episodically during a rhythm strip; they can be diagnosed by the demonstration that the recurring longest R-R intervals have a constant cycle length. A higher degree of AV or third degree block results in so few atrial impulses being conducted that a lower pacemaker takes over, leading to an escape junctional, subjunctional, or ventricular rhythm with a slow regular R-R interval for two or more cycles. The presence of an accelerated lower pacemaker (due, eg, to triggered activity causing an accelerated junctional rhythm) with regularization of the R-R intervals, in contrast to the irregularly irregular intervals in atrial fibrillation, strongly suggests digoxin toxicity. Simply palpating the peripheral pulse in this setting may lead to the erroneous assumption that the patient has converted to sinus rhythm; however, the ECG will continue to show fibrillatory waves [31]. More rarely, the lower pacemaker may be regular but there is a Wenckebach type of exit block, resulting in decreasing R-R intervals with group beating characteristic of the Wenckebach phenomenon. Casual evaluation of such a patient who might have severe digoxin toxicity may lead to the mistaken conclusion that the irregular rhythm is due to persistent atrial fibrillation and the digoxin may be continued or the dose increased. (See "Second-degree atrioventricular block: Mobitz type I (Wenckebach block)".) Even less commonly, impulses from the lower pacemaker travel alternately down the right and left bundle branches, resulting in a bidirectional ventricular tachycardia ( waveform 7). (See 'Bidirectional ventricular tachycardia' below.) Junctional rhythm, tachycardia, and bradycardia AV junctional rhythms are sometimes a sign of digoxin toxicity. Digoxin toxicity can result in varying degrees of AV block that may allow the appearance of junctional escape beats and escape junctional (or atrioventricular nodal) rhythms. The junctional rate may be normal (40 to 60 beats/min), accelerated (60 to 120 beats/min, due to direct effects or adrenergic influences), or depressed (less than 40 beats/min, due to enhanced vagal tone, dysfunctional pacemakers in organic heart disease, or to hyperkalemia caused by the digoxin toxicity) [5,20,21,37]. https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 7/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate The QRS complex is usually narrow with junctional rhythms, since the pacemaker is typically above the bifurcation of the bundle branches. However, the QRS may be wide if there is a conduction disturbance distal to the pacemaker, a dominant subjunctional pacemaker, or a dominant ventricular pacemaker. Ventricular arrhythmias A variety of ventricular arrhythmias may result from digoxin toxicity, including premature ventricular complexes (PVCs), ventricular tachycardia, and ventricular fibrillation. Premature ventricular complexes PVCs, often the first sign of digoxin toxicity, are also the most common arrhythmia due to digoxin toxicity. While isolated PVCs may be seen, the PVCs often appear in a bigeminal pattern ( waveform 8). Although ventricular bigeminy can result from organic heart disease, it should raise the suspicion of digoxin intoxication in relevant contexts. Ventricular tachycardia Due to reentry or possibly to triggered membrane activity (delayed afterdepolarizations), ventricular tachycardia (VT) can be induced by digoxin excess [30]. With triggered membrane activity, VT may be resistant to interruption by ventricular pacing since the faster rate of pacing may in itself increase the transient inward current and worsen the arrhythmia. The axis and width of the QRS complex on the ECG are determined by the site of origin of the VT, which may be in the specialized fascicles. Ventricular fibrillation Ventricular fibrillation (VF) can occur with digoxin toxicity, but is usually a late rhythm. VF can, however, be induced by the use of electric cardioversion in patients with an atrial tachyarrhythmia associated with excess digoxin [38]. Bidirectional ventricular tachycardia An unusual arrhythmia is the so-called "bidirectional" ventricular tachycardia in which the rhythm is regular but every other beat has a different axis as it travels alternately down different conduction pathways ( waveform 7). In most cases, the rhythm has a right bundle branch block morphology with an alternating left and right axis [39]. However, alternating right and left bundle branch patterns may be seen. Bidirectional ventricular tachycardia may be confused with ventricular bigeminy. In true bigeminy, the ventricular beat in the bigeminal pattern is premature. By comparison, the R-R interval is regular with a bidirectional tachycardia, since all of the beats arise from a single focus. Bidirectional ventricular tachycardia is not specific for digoxin intoxication. It is a frequent finding in familial catecholaminergic polymorphic VT, a much less common disorder [40]. SUMMARY AND RECOMMENDATIONS https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 8/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Background Arrhythmias resulting from digoxin toxicity are potentially life threatening; they are seen in up to 5 percent of patients receiving digoxin (or digitoxin). The incidence of digoxin toxicity has declined over time due to appropriate dose reductions in patients with renal dysfunction, more accurate methods for measuring plasma digoxin levels, and the availability of other medications for the treatment of chronic heart failure and tachyarrhythmias leading to a reduced reliance on digoxin. (See 'Introduction' above and 'Incidence of digoxin toxicity' above.) Digoxin levels Trough levels Maintaining trough serum digoxin concentration levels at a lower therapeutic range (eg, between 0.5 and 0.8 ng/mL [0.6 to 1.0 nmol/L]) is recommended to help minimize toxicity. Life-threatening digoxin-induced arrhythmias occur at substantially increased frequency as the plasma digoxin concentration rises above 2.0 ng/mL (2.6 nmol/L). However, signs of toxicity may occur at much lower plasma levels, especially in the presence of comorbid conditions (eg, electrolyte abnormalities, myocardial ischemia, older age with heart failure). Hypokalemia is a particularly important risk factor that can promote digoxin-induced arrhythmias even if the digoxin concentration is thought to be within the "therapeutic" range. (See 'Incidence of digoxin toxicity' above and 'Plasma digoxin levels associated with toxicity' above.) Digoxin-induced arrhythmias A wide range of arrhythmias occurring at almost any intracardiac location can be seen with digoxin toxicity, depending in part upon the age of the patient and the state of the myocardium. Accentuation of vagal effects and resulting bradyarrhythmias is more commonly seen in younger, healthier individuals. Conversely, patients with severe cardiac disease and concurrent digoxin toxicity are more susceptible to ventricular ectopy and tachyarrhythmias. (See 'Digoxin-induced arrhythmias' above.) Paroxysmal atrial tachycardia This arrhythmia results from toxic levels of digoxin that cause ectopic atrial tachycardia, often with 2:1 atrioventricular (AV) block ( waveform 2). This electrocardiographic (ECG) pattern is strongly suggestive of digoxin toxicity in patients on the drug. Contrary to its name, the arrhythmia is not typically paroxysmal when induced by digoxin; rather, it is a persistent arrhythmia until specific therapy is instituted or digoxin levels fall below the toxic range. (See 'Ectopic atrial tachycardia with block' above.) https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 9/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Atrial fibrillation or atrial flutter Digoxin toxicity can occur in patients with atrial fibrillation or flutter, even though these arrhythmias are rarely caused by digoxin. The ECG findings vary with increasing degrees of digoxin toxicity and with the possible presence of block above or below the pacemaker ( waveform 3A-D). (See 'Atrial fibrillation and flutter' above.) AV block and junctional rhythms These are frequently a sign of digoxin toxicity. Digoxin toxicity can result in varying degrees of AV block ( waveform 4 and waveform 5 and waveform 6). (See 'Atrioventricular nodal block' above.) This AV block may allow the appearance of junctional escape beats and escape junctional (or AV nodal) rhythms. Depending on other factors such as adrenergic or vagal tone, the junctional rate may be normal (40 to 60 beats/min), accelerated (60 to 120 beats/min), or depressed (less than 40 beats/min). (See 'Junctional rhythm, tachycardia, and bradycardia' above.) Ventricular arrhythmias A variety of ventricular arrhythmias may result from digoxin toxicity, including premature ventricular complexes (PVCs), ventricular tachycardia, and ventricular fibrillation. (See 'Ventricular arrhythmias' above.) PVCs are often the first sign of digoxin toxicity and are the most common arrhythmia due to digoxin toxicity. PVCs can be isolated or occur in a bigeminal pattern ( waveform 8). Although ventricular bigeminy can result from organic heart disease, it should raise the suspicion of digoxin intoxication. (See 'Premature ventricular complexes' above.). Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Gheorghiade M, Adams KF Jr, Colucci WS. Digoxin in the management of cardiovascular disorders. Circulation 2004; 109:2959. 2. Hauptman PJ, Kelly RA. Digitalis. Circulation 1999; 99:1265. 3. Angraal S, Nuti SV, Masoudi FA, et al. Digoxin Use and Associated Adverse Events Among Older Adults. Am J Med 2019; 132:1191. 4. Hussain Z, Swindle J, Hauptman PJ. Digoxin use and digoxin toxicity in the post-DIG trial era. J Card Fail 2006; 12:343. https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 10/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate 5. Mahdyoon H, Battilana G, Rosman H, et al. The evolving pattern of digoxin intoxication: observations at a large urban hospital from 1980 to 1988. Am Heart J 1990; 120:1189. 6. Williamson KM, Thrasher KA, Fulton KB, et al. Digoxin toxicity: an evaluation in current clinical practice. Arch Intern Med 1998; 158:2444. 7. See I, Shehab N, Kegler SR, et al. Emergency department visits and hospitalizations for digoxin toxicity: United States, 2005 to 2010. Circ Heart Fail 2014; 7:28. 8. Ambrosy AP, Pang PS, Gheorghiade M. Digoxin for Worsening Chronic Heart Failure: Underutilized and Underrated. JACC Heart Fail 2016; 4:365. 9. Adams KF Jr, Patterson JH, Gattis WA, et al. Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: a retrospective analysis. J Am Coll Cardiol 2005; 46:497. 10. Ahmed A, Pitt B, Rahimtoola SH, et al. Effects of digoxin at low serum concentrations on mortality and hospitalization in heart failure: a propensity-matched study of the DIG trial. Int J Cardiol 2008; 123:138. 11. Goldberger ZD, Goldberger AL. Therapeutic ranges of serum digoxin concentrations in patients with heart failure. Am J Cardiol 2012; 109:1818. 12. Washam JB, Stevens SR, Lokhnygina Y, et al. Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Lancet 2015; 385:2363. 13. Allen LA, Fonarow GC, Simon DN, et al. Digoxin Use and Subsequent Outcomes Among Patients in a Contemporary Atrial Fibrillation Cohort. J Am Coll Cardiol 2015; 65:2691. 14. Kelly RA, Smith TW. Recognition and management of digitalis toxicity. Am J Cardiol 1992; 69:108G. 15. Eisner DA, Smith TW. The Na-K pump and its effectors in cardiac muscle. In: The Heart and C ardiovascular System, Fozzard HA, Haber E, Katz AM, Morgan HE (Eds), Raven Press, New Yo rk 1991. p.863. 16. Sagawa T, Sagawa K, Kelly JE, et al. Activation of cardiac ryanodine receptors by cardiac glycosides. Am J Physiol Heart Circ Physiol 2002; 282:H1118. 17. Watanabe AM. Digitalis and the autonomic nervous system. J Am Coll Cardiol 1985; 5:35A. 18. Toda N, West TC. The influence of ouabain on cholinergic responses in the sinoatrial node. J Pharmacol Exp Ther 1966; 153:104. 19. Goodman DJ, Rossen RM, Ingham R, et al. Sinus node function in the denervated human heart. Effect of digitalis. Br Heart J 1975; 37:612. https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 11/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate 20. Smith TW, Antman EM, Friedman PL, et al. Digitalis glycosides: mechanisms and manifestations of toxicity. Part I. Prog Cardiovasc Dis 1984; 26:413. 21. Smith TW, Antman EM, Friedman PL, et al. Digitalis glycosides: mechanisms and manifestations of toxicity. Part II. Prog Cardiovasc Dis 1984; 26:495. 22. Reiffel JA, Bigger JT Jr, Cramer M. Effects of digoxin on sinus nodal function before and after vagal blockade in patients with sinus nodal dysfunction: a clue to the mechanisms of the action of digitalis on the sinus node. Am J Cardiol 1979; 43:983. 23. Vassalle M, Greenspan K, Hoffman BF. An Analysis of Arrhythmias Induced by Ouabain in Intact Dogs. Circ Res 1963; 13:132. 24. James TN, Nadeau RA. The chronotropic effect of digitalis studied by direct perfusion of the sinus node. J Pharmacol Exp Ther 1963; 139:42. 25. Scherlag BJ, Abelleira JL, Narula OS, Samet P. The differential effects of ouabain on sinus, A-V nodal, His bundle, and idioventricular rhythms. Am Heart J 1971; 81:227. 26. Mendez C, Aceves J, Mendez R. Inhibition of adrenergic cardiac acceleration by cardiac glycosides. J Pharmacol Exp Ther 1961; 131:191. 27. Steinbeck G, Bonke FI, Allessie MA, Lammers WJ. The effect of ouabain on the isolated sinus node preparation of the rabbit studied with microelectrodes. Circ Res 1980; 46:406. 28. Takayanagi K, Jalife J. Effects of digitalis intoxication on pacemaker rhythm and synchronization in rabbit sinus node. Am J Physiol 1986; 250:H567. 29. Geer MR, Wagner GS, Waxman M, Wallace AG. Chronotropic effect of acetylstrophanthidin infusion into the canine sinus nodal artery. Am J Cardiol 1977; 39:684. 30. Gorgels APM, Vos MA, Smeets JLRM, et al. Delayed afterdepolarizations and atrial and ventri cular arrhythmias. In: Cardiac Electrophysiology: A Textbook, Rosen MR, Janse MJ, Wit AL (Ed s), Futura Publishing, Mount Kisco 1990. p.341. 31. Kastor JA, Yurchak PM. Recognition of digitalis intoxication in the presence of atrial fibrillation. Ann Intern Med 1967; 67:1045. 32. Carleton RA, Miller PH, Graettinger JS. Effects of ouabain, atropine, and ouabain and atropine on A-V nodal conduction in man. Circ Res 1967; 20:283. 33. Toda N, West TC. The action of ouabain on the function of the atrioventricular node in rabbits. J Pharmacol Exp Ther 1969; 169:287. 34. Goodman DJ, Rossen RM, Cannom DS, et al. Effect of digoxin on atioventricular conduction. Studies in patients with and without cardiac autonomic innervation. Circulation 1975; 51:251. https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 12/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate 35. Ricci DR, Orlick AE, Reitz BA, et al. Depressant effect of digoxin on atrioventricular conduction in man. Circulation 1978; 57:898. 36. Childers R. Classification of cardiac dysrhythmias. Med Clin North Am 1976; 60:3. 37. Fisch C, Knoebel SB. Digitalis cardiotoxicity. J Am Coll Cardiol 1985; 5:91A. 38. Kleiger R, Lown B. Cardioversion and digitalis. II. Clinical studies. Circulation 1966; 33:878. 39. Morris SN, Zipes DP. His bundle electrocardiography during bidirectional tachycardia. Circulation 1973; 48:32. 40. Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002; 106:69. Topic 944 Version 29.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 13/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate GRAPHICS Single-lead electrocardiogram (ECG) showing lead V1 in type I (Wenckebach type) sinoatrial block There is a 3:2 SA block, resulting in group beating of pairs of sinus beats. The P-P interval during the pause has a duration (1040 msec) that is less than two P-P cycles (1360 msec); this finding distinguishes this arrhythmia from type II SA block in which the pause duration is the same as that of two P-P cycles. Courtesy of Morton Arnsdorf, MD. Graphic 68081 Version 3.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 14/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Single-lead electrocardiogram (ECG) showing lead V5 in type II sinoatrial block There is a 3:2 SA block, resulting in group beating of pairs of sinus beats. The P-P interval during the pause has a duration (1840 msec) that is approximately equal to two P-P cycles (920 msec); this finding distinguishes this arrhythmia from type I SA block in which the pause duration is less than that of two P-P cycles. There may be some sinus variability, as in this case, due to sinus arrhythmia and possibly to baroreceptor responses to varying diastolic filling intervals. Courtesy of Morton Arnsdorf, MD. Graphic 54936 Version 3.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 15/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Single-lead electrocardiogram (ECG) showing atrial tachycardia with 2:1 atrioventricular (AV) block Atrial tachycardia with 2:1 atrioventricular (AV) block. The atrial rate is about 160 beats/min while the ventricular rate is about 80 beats/min. The nonconducted P waves (arrows) are superimposed on the ST-T segments. The P waves have a similar morphology to normal P waves suggesting that the ectopic site is near or even in the sinoatrial node. This arrhythmia may be an important sign of digoxin toxicity, but can also occur in other settings. Courtesy of Ary Goldberger, MD. Graphic 56994 Version 4.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 16/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Single-lead electrocardiogram (ECG) showing atrial fibrillation (AF) with junctional escape beats suggesting digoxin toxicity The 4 electrocardiograms in this sequence demonstrate increasing severity of digoxin toxicity in a patient with atrial fibrillation. This ECG shows atrial fibrillation with an irregularly irregular ventricular response. However, the longest recurring R-R intervals are constant, suggesting junctional escape beats due to AV nodal block. The escape interval of 680 msec indicates an accelerated automatic pacemaker with a rate of 88 beats/min. The four electrocardiograms are adapted from: Childers R, Med Clin North Am 1976; 60:3. Graphic 64396 Version 5.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 17/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Single-lead electrocardiogram (ECG) showing atrial fibrillation with an accelerated junctional pacemaker The 4 electrocardiograms in this sequence demonstrate increasing severity of digoxin toxicity in a patient with atrial fibrillation. In this strip, the R-R intervals are constant, as the ventricles are controlled by an accelerated junctional pacemaker, resulting in a regular tachycardia at 115 beats per minute. Physical examination at this time might lead to the erroneous diagnosis of a regular sinus mechanism. The four electrocardiograms are adapted from: Childers R, Med Clin North Am 1976; 60:3. Graphic 76154 Version 6.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 18/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Single-lead electrocardiogram (ECG) showing atrial fibrillation with further accelerated junctional pacemaker The 4 electrocardiograms in this sequence demonstrate increasing severity of digoxin toxicity in a patient with atrial fibrillation. In this strip, the R-R intervals remain constant with further acceleration of the junctional pacemaker to a rate of 142 beats per minute. The four electrocardiograms are adapted from: Childers R, Med Clin North Am 1976; 60:3. Graphic 55119 Version 7.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 19/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Single-lead electrocardiogram (ECG) showing atrial fibrillation and a junctional pacemaker with a 4:3 Wenckebach exit block The 4 electrocardiograms in this sequence demonstrate increasing severity of digoxin toxicity in a patient with atrial fibrillation. In this strip, the result is group beating characterized by three beats with decreasing R-R intervals. On physical examination, this seemingly irregular

s), Futura Publishing, Mount Kisco 1990. p.341. 31. Kastor JA, Yurchak PM. Recognition of digitalis intoxication in the presence of atrial fibrillation. Ann Intern Med 1967; 67:1045. 32. Carleton RA, Miller PH, Graettinger JS. Effects of ouabain, atropine, and ouabain and atropine on A-V nodal conduction in man. Circ Res 1967; 20:283. 33. Toda N, West TC. The action of ouabain on the function of the atrioventricular node in rabbits. J Pharmacol Exp Ther 1969; 169:287. 34. Goodman DJ, Rossen RM, Cannom DS, et al. Effect of digoxin on atioventricular conduction. Studies in patients with and without cardiac autonomic innervation. Circulation 1975; 51:251. https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 12/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate 35. Ricci DR, Orlick AE, Reitz BA, et al. Depressant effect of digoxin on atrioventricular conduction in man. Circulation 1978; 57:898. 36. Childers R. Classification of cardiac dysrhythmias. Med Clin North Am 1976; 60:3. 37. Fisch C, Knoebel SB. Digitalis cardiotoxicity. J Am Coll Cardiol 1985; 5:91A. 38. Kleiger R, Lown B. Cardioversion and digitalis. II. Clinical studies. Circulation 1966; 33:878. 39. Morris SN, Zipes DP. His bundle electrocardiography during bidirectional tachycardia. Circulation 1973; 48:32. 40. Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002; 106:69. Topic 944 Version 29.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 13/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate GRAPHICS Single-lead electrocardiogram (ECG) showing lead V1 in type I (Wenckebach type) sinoatrial block There is a 3:2 SA block, resulting in group beating of pairs of sinus beats. The P-P interval during the pause has a duration (1040 msec) that is less than two P-P cycles (1360 msec); this finding distinguishes this arrhythmia from type II SA block in which the pause duration is the same as that of two P-P cycles. Courtesy of Morton Arnsdorf, MD. Graphic 68081 Version 3.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 14/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Single-lead electrocardiogram (ECG) showing lead V5 in type II sinoatrial block There is a 3:2 SA block, resulting in group beating of pairs of sinus beats. The P-P interval during the pause has a duration (1840 msec) that is approximately equal to two P-P cycles (920 msec); this finding distinguishes this arrhythmia from type I SA block in which the pause duration is less than that of two P-P cycles. There may be some sinus variability, as in this case, due to sinus arrhythmia and possibly to baroreceptor responses to varying diastolic filling intervals. Courtesy of Morton Arnsdorf, MD. Graphic 54936 Version 3.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 15/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Single-lead electrocardiogram (ECG) showing atrial tachycardia with 2:1 atrioventricular (AV) block Atrial tachycardia with 2:1 atrioventricular (AV) block. The atrial rate is about 160 beats/min while the ventricular rate is about 80 beats/min. The nonconducted P waves (arrows) are superimposed on the ST-T segments. The P waves have a similar morphology to normal P waves suggesting that the ectopic site is near or even in the sinoatrial node. This arrhythmia may be an important sign of digoxin toxicity, but can also occur in other settings. Courtesy of Ary Goldberger, MD. Graphic 56994 Version 4.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 16/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Single-lead electrocardiogram (ECG) showing atrial fibrillation (AF) with junctional escape beats suggesting digoxin toxicity The 4 electrocardiograms in this sequence demonstrate increasing severity of digoxin toxicity in a patient with atrial fibrillation. This ECG shows atrial fibrillation with an irregularly irregular ventricular response. However, the longest recurring R-R intervals are constant, suggesting junctional escape beats due to AV nodal block. The escape interval of 680 msec indicates an accelerated automatic pacemaker with a rate of 88 beats/min. The four electrocardiograms are adapted from: Childers R, Med Clin North Am 1976; 60:3. Graphic 64396 Version 5.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 17/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Single-lead electrocardiogram (ECG) showing atrial fibrillation with an accelerated junctional pacemaker The 4 electrocardiograms in this sequence demonstrate increasing severity of digoxin toxicity in a patient with atrial fibrillation. In this strip, the R-R intervals are constant, as the ventricles are controlled by an accelerated junctional pacemaker, resulting in a regular tachycardia at 115 beats per minute. Physical examination at this time might lead to the erroneous diagnosis of a regular sinus mechanism. The four electrocardiograms are adapted from: Childers R, Med Clin North Am 1976; 60:3. Graphic 76154 Version 6.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 18/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Single-lead electrocardiogram (ECG) showing atrial fibrillation with further accelerated junctional pacemaker The 4 electrocardiograms in this sequence demonstrate increasing severity of digoxin toxicity in a patient with atrial fibrillation. In this strip, the R-R intervals remain constant with further acceleration of the junctional pacemaker to a rate of 142 beats per minute. The four electrocardiograms are adapted from: Childers R, Med Clin North Am 1976; 60:3. Graphic 55119 Version 7.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 19/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Single-lead electrocardiogram (ECG) showing atrial fibrillation and a junctional pacemaker with a 4:3 Wenckebach exit block The 4 electrocardiograms in this sequence demonstrate increasing severity of digoxin toxicity in a patient with atrial fibrillation. In this strip, the result is group beating characterized by three beats with decreasing R-R intervals. On physical examination, this seemingly irregular rhythm might lead to the mistaken diagnosis of an irregularly irregular response to atrial fibrillation, rather than arrhythmia associated with severe digoxin toxicity. This patient presented with this ECG; the preceding electrocardiograms reflected (in reverse order) the sequence of recovery as the effect of digoxin wore off. The four electrocardiograms are adapted from: Childers R, Med Clin North Am 1976; 60:3. Graphic 66940 Version 7.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 20/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Single-lead electrocardiogram (ECG) showing first degree atrioventricular (AV) block I Electrocardiogram of lead II showing normal sinus rhythm, first degree atrioventricular block with a prolonged PR interval of 0.30 seconds, and a QRS complex of normal duration. The tall P waves and P wave duration of approximately 0.12 seconds suggest concurrent right atrial enlargement. Courtesy of Morton Arnsdorf, MD. Graphic 67882 Version 5.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 21/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Electrocardiogram showing Mobitz type I (Wenckebach) atrioventricular block Single-lead electrocardiogram showing Mobitz type I (Wenckebach) second-degree atrioventricular block with 5:4 conduction. The characteristics of this arrhythmia include: a progressively increasing PR interval until a P wave is not conducted (arrow), a progressive decrease in the increment in the PR interval, a progressive decrease in the RR interval, and the RR interval that includes the dropped beat (0.96 sec) is less than twice the RR interval between conducted beats (0.53 to 0.57 sec). Courtesy of Morton Arnsdorf, MD. Graphic 73051 Version 6.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 22/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Single-lead electrocardiogram (ECG) showing sinus rhythm with third degree (complete) AV block Sinus rhythm with third degree (complete) heart block. There is independent atrial (as shown by the P waves) and ventricular activity, with respective rates of 83 and 43 beats per minute. The wide QRS complexes may represent a junctional escape rhythm with underlying bundle branch block or an idioventricular pacemaker. Courtesy of Ary Goldberger, MD. Graphic 72863 Version 6.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 23/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Single-lead electrocardiogram (ECG) showing bidirectional ventricular tachycardia (VT) Rhythm strip showing bidirectional ventricular tachycardia (VT) which may be a manifestation of digoxin toxicity. This rare, life-threatening tachyarrhythmia is characterized by beat-to-beat changes in the polarity of consecutive premature ventricular complexes. Courtesy of Ary Goldberger, MD. Graphic 71796 Version 3.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 24/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Single-lead electrocardiogram (ECG) showing sinus rhythm with ventricular bigeminy Sinus rhythm with ventricular bigeminy. Each sinus beat is followed by a uniform premature complex with prolonged duration and no apparent P wave; these findings are indicative of ventricular ectopic beats. Courtesy of Ary Goldberger, MD. Graphic 72547 Version 4.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 25/26 7/5/23, 11:14 AM Cardiac arrhythmias due to digoxin toxicity - UpToDate Contributor Disclosures Ary L Goldberger, MD Other Financial Interest: Elsevier book royalties [Clinical electrocardiography]. All of the relevant financial relationships listed have been mitigated. Evan Schwarz, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cardiac-arrhythmias-due-to-digoxin-toxicity/print 26/26

7/5/23, 11:15 AM Cardiovascular effects of hyperthyroidism - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cardiovascular effects of hyperthyroidism : Irwin Klein, MD : Douglas S Ross, MD : Jean E Mulder, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 02, 2023. INTRODUCTION Thyroid hormone has important effects on cardiac muscle, the peripheral circulation, and the sympathetic nervous system that alter cardiovascular hemodynamics in a predictable way in patients with hyperthyroidism. The main changes are [1]: Increases in heart rate, cardiac contractility, systolic and mean pulmonary artery pressure, cardiac output, diastolic relaxation, and myocardial oxygen consumption Reductions in systemic vascular resistance and diastolic pressure The major cardiovascular manifestations of hyperthyroidism will be reviewed here. Other symptoms associated with this disorder are discussed separately. (See "Overview of the clinical manifestations of hyperthyroidism in adults".) PATHOPHYSIOLOGY The cellular actions of thyroid hormone are mediated by the binding of triiodothyronine (T3) to nuclear receptors. It is T3 and not thyroxine (T4) that is transported into the cardiac myocyte. The subsequent binding of the T3-receptor complexes to DNA regulates the expression of genes, specifically those regulating calcium cycling in the cardiac myocyte [1,2]. T3 may also have non- nuclear actions through mechanisms not yet fully understood [3]. https://www.uptodate.com/contents/cardiovascular-effects-of-hyperthyroidism/print 1/13 7/5/23, 11:15 AM Cardiovascular effects of hyperthyroidism - UpToDate Adrenergic effects Some actions of T3 on the heart produce clinical findings similar to those of beta-adrenergic stimulation [4]. The interaction between T3 and the adrenergic nervous system is best exemplified by the ability of essentially all beta blockers to alleviate many of the symptoms of hyperthyroidism (see "Beta blockers in the treatment of hyperthyroidism"). This may involve increased beta-adrenergic receptor density, increased expression of the stimulatory guanine nucleotide-binding protein (G protein), and downregulation of the cardiac-specific isoform of the adenylyl cyclase catalytic subunit [5-7]. Whether humans with hyperthyroidism have increased sensitivity to catecholamines is uncertain, but it seems clear that T3 effects on the heart can occur independently of beta-adrenergic receptor stimulation [8]. Chronotropic and inotropic stimulation Hyperthyroidism predictably increases heart rate and cardiac contractility [6,8]. Virtually all measures of cardiac function (including left ventricular ejection fraction [LVEF], the rate of ventricular pressure development, diastolic relaxation, and cardiac output) are increased [1]. As a result, cardiac output increases by as much as 250 percent and pulse pressure widens ( figure 1). These functional changes are most likely the result of an increase in expression of myocardial sarcoplasmic reticulum calcium-dependent adenosine triphosphatase, a decrease in the expression of its inhibitor, phospholamban, and a decline in systemic vascular resistance [6]. CLINICAL MANIFESTATIONS Cardiovascular symptoms and signs are common in patients with hyperthyroidism [9], and in some patients, these symptoms predominate ( table 1). They include: Tachycardia, at rest, during sleep, and exaggerated during exercise. Palpitations, due to both tachycardia and more forceful cardiac contractility. Hyperdynamic precordium, indicative of the increase in cardiac contractility and cardiac workload. Systolic hypertension with widened pulse pressure [10]. Exertional dyspnea, which is more due to respiratory and skeletal muscle weakness than cardiac dysfunction. Angina-like chest pain, with electrocardiogram (ECG) changes suggesting myocardial ischemia, which can occur especially in women; this appears to be the result of coronary vasospasm [11] and responds to treatment with orally administered calcium channel blockers and rendering the patients euthyroid. https://www.uptodate.com/contents/cardiovascular-effects-of-hyperthyroidism/print 2/13 7/5/23, 11:15 AM Cardiovascular effects of hyperthyroidism - UpToDate Increase in left ventricular (LV) mass index and LV hypertrophy [12,13]. Increased ventricular irritability, especially in amiodarone-treated patients with a prior history of ventricular ectopy (often in the setting of implanted cardiac defibrillators) [14]. Increased clearance of coagulation factors, leading to an increase in sensitivity to warfarin anticoagulation [15,16]. Hyperthyroidism is also associated with an increased risk of atrial fibrillation, heart failure, pulmonary hypertension, and angina, as described in the following sections. Atrial fibrillation Hyperthyroid patients with normal hearts have more premature supraventricular depolarizations, premature atrial complex (PAC; also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat), more nonsustained supraventricular tachycardias, increased heart rate, and reduced heart rate variability [17]. The latter is primarily the result of decreased parasympathetic tone. These electrical triggers may contribute to paroxysmal atrial tachycardia, atrial fibrillation, and atrial flutter. Among these arrhythmias, atrial fibrillation is the most common, occurring in 5 to 15 percent of patients, especially patients 60 years of age [6,18,19]. In a population-based study of 40,628 patients with clinical hyperthyroidism, 8.3 percent had atrial fibrillation or flutter [18]. Factors associated with increased risk included male sex, increasing age, coronary heart disease, heart failure, and valvular heart disease [4]. The association with increasing age presumably reflects the age-related reduction in the threshold for developing atrial fibrillation. Complications of atrial fibrillation in patients with hyperthyroidism include heart failure and thromboembolism, although it remains controversial whether atrial fibrillation in hyperthyroidism is associated with a higher thromboembolic risk than atrial fibrillation in other settings [1,6,19] (see "Atrial fibrillation in adults: Selection of candidates for anticoagulation"). Patients with overt thyrotoxicosis, especially females of East Asian descent (eg, Japanese, Chinese, and Korean), may present with focal neurologic findings, falsely suggesting central nervous system embolic events when indeed it is the result of central arterial vasospasm (moyamoya disease) [4,20,21]. (See 'Stroke' below.) Approximately 55 to 75 percent of patients with atrial fibrillation due to hyperthyroidism and no other underlying cardiac valvular disease will return to sinus rhythm within three to six months after treatment of the thyrotoxic state [1]. In patients with persistent atrial fibrillation, the question of additional forms of therapy needs to be addressed. (See "Management of atrial fibrillation: Rhythm control versus rate control".) https://www.uptodate.com/contents/cardiovascular-effects-of-hyperthyroidism/print 3/13 7/5/23, 11:15 AM Cardiovascular effects of hyperthyroidism - UpToDate The other atrial arrhythmias associated with hyperthyroidism are most likely to be detected by monitoring, because they do not often cause symptoms. The risk of ventricular arrhythmias in the non-ischemic (normal) heart is not increased [4]. Heart failure Heart failure is most commonly seen as a result of longstanding, often untreated disease with coexistent atrial fibrillation. In one study, only 6 percent of hyperthyroid patients had heart failure, average age was 66 years; 94 percent had coexistent atrial fibrillation and 47 percent had LV systolic dysfunction [22]. In others, it is a complication of prolonged marked sinus tachycardia. The signs and symptoms of heart failure almost always resolve when the ventricular rate is slowed, normal sinus rhythm is restored, and the patients are rendered euthyroid [4,5,22]. In one study, half had LV systolic dysfunction with LV ejection fraction <50 percent, and 85 percent had resolution of LV dysfunction after attaining euthyroidism [22]. Heart failure in the absence of underlying cardiac disease or arrhythmia is thought to reflect a rate-related cardiomyopathy, which disappears when the hyperthyroidism is treated. There is no clear histopathologic correlate of this cardiomyopathy, and treatment is primarily directed at rate control with beta-adrenergic blockade [5]. Pulmonary hypertension can also produce signs of isolated right heart failure with a rise in central venous pressure, neck vein distension, and hepatic congestion [4,23]. (See 'Pulmonary hypertension' below and "Arrhythmia-induced cardiomyopathy".) Hyperthyroidism is associated with an increase in N-terminal pro-B natriuretic peptide (NT- proBNP) in hyperthyroid patients without cardiac insufficiency [24]. NT-proBNP was positively correlated with LV end-diastolic diameter and interventricular septal thickness, and negatively correlated with LV ejection fraction [24]. Mild iatrogenic hyperthyroidism is also associated with an increase in NT-proBNP, without a measurable increase in systolic blood pressure or pulse pressure [24]. This may reflect the increased atrial size which results from increased renal sodium reabsorption, plasma volume, or pulmonary hypertension [25]. Tricuspid and/or mitral regurgitation have also been described in patients with hyperthyroidism of all causes [26-28]. Pulmonary hypertension Pulmonary hypertension has been reported with increasing frequency in patients with overt hyperthyroidism. Pulmonary artery pressures average twice normal values (10 mmHg) and may be as high as 30 to 50 mmHg. These changes reverse with treatment of the hyperthyroidism and may reflect the increase in cardiac output without the concomitant decline in pulmonary vascular resistance observed in the systemic circulation [26- 28]. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".) https://www.uptodate.com/contents/cardiovascular-effects-of-hyperthyroidism/print 4/13 7/5/23, 11:15 AM Cardiovascular effects of hyperthyroidism - UpToDate Angina pectoris Patients with angina may have chest pain more often when they become hyperthyroid, presumably because of the increase in cardiac oxygen consumption, due either to a direct effect of triiodothyronine (T3) on cardiac muscle or to an increase in peripheral oxygen demand. In the young patient with normal coronary anatomy, this may be due to coronary vasospasm (Prinzmetal angina). Other patients first develop angina when they become hyperthyroid. In a hospital-based study of 1049 patients who were admitted emergently, 6 percent had high serum T3 concentrations at the time of admission; these patients had a 2.6-fold higher risk of having angina pectoris or a myocardial infarction at that time, as compared with those patients with normal serum T3 concentrations [29]. Stroke Ischemic cerebrovascular disease is a rare complication of hyperthyroidism. In addition, neurologic findings similar to that seen in moyamoya disease have been described in several patients with Graves' disease (especially those of East Asian descent [eg, Japanese, Chinese, Korean]) and may simulate the clinical findings of embolic disease. It is important to distinguish these two entities since the treatment is different. (See "Neurologic manifestations of hyperthyroidism and Graves' disease".) SUBCLINICAL HYPERTHYROIDISM Patients with subclinical hyperthyroidism (normal serum thyroid hormone and low serum thyroid-stimulating hormone [TSH] concentrations) have more subtle cardiac findings. These include increases in heart rate and cardiac contractility and modest degrees of cardiac hypertrophy and, at least in older adults, an increase in risk of atrial fibrillation as compared with euthyroid subjects ( figure 2). Subclinical hyperthyroidism is reviewed in detail elsewhere. (See "Subclinical hyperthyroidism in nonpregnant adults", section on 'Cardiovascular effects'.) TREATMENT The cardiovascular manifestations of hyperthyroidism are best corrected by treating the hyperthyroidism, whether with radioiodine or an antithyroid drug. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment" and "Treatment of toxic adenoma and toxic multinodular goiter" and "Radioiodine in the treatment of hyperthyroidism" and "Thionamides in the treatment of Graves' disease".) Beta blockers, such as propranolol or atenolol, are also useful in relieving palpitations and in slowing the heart rate in patients with sinus tachycardia [30] (see "Beta blockers in the treatment https://www.uptodate.com/contents/cardiovascular-effects-of-hyperthyroidism/print 5/13 7/5/23, 11:15 AM Cardiovascular effects of hyperthyroidism - UpToDate of hyperthyroidism"). It is important to recognize that while calcium channel blockers of all types are commonly used in the acute treatment of atrial fibrillation, the intravenous use of these agents pose a potential risk in patients with underlying thyrotoxicosis. The vasodilatory and negative inotropic properties of these drugs can lead to hypotension and cardiovascular collapse [31,32]. Additional measures may be needed in patients with atrial fibrillation, marked palpitations, or severe tachycardia [1,5,33]. The management of atrial fibrillation is reviewed in detail elsewhere. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Among patients with overt heart failure, standard therapy should be given if the patient is older, known or suspected to have preexisting heart disease or hypertension, or the heart failure does not improve when the heart rate is slowed (see "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'). In certain circumstances, especially with severe hyperthyroidism or thyroid storm, intensive cardiovascular monitoring and treatment of other comorbid conditions (infection, trauma, acute psychiatric illness) is required [4,6]. (See "Thyroid storm".) SUMMARY Cardiovascular hemodynamics Thyroid hormone has important effects on cardiac muscle, the peripheral circulation, and the sympathetic nervous system. Some actions of triiodothyronine (T3) on the heart produce clinical findings similar to those of beta- adrenergic stimulation. Hyperthyroidism predictably increases heart rate and cardiac contractility. Virtually all measures of cardiac function (including left ventricular ejection fraction [LVEF], the rate of ventricular pressure development, diastolic relaxation, and cardiac output) are increased ( table 1). (See 'Chronotropic and inotropic stimulation' above.) Cardiac clinical manifestations Hyperthyroidism is also associated with an increased risk of atrial fibrillation, heart failure, pulmonary hypertension, and angina-like symptoms. (See 'Clinical manifestations' above.) Treatment of cardiovascular manifestations The cardiovascular manifestations of hyperthyroidism are best corrected by treating the hyperthyroidism, whether with radioiodine or an antithyroid drug. Beta blockers, such as propranolol or atenolol, are also useful in relieving palpitations and in slowing the heart rate in patients with sinus tachycardia. (See 'Treatment' above and "Radioiodine in the treatment of hyperthyroidism" https://www.uptodate.com/contents/cardiovascular-effects-of-hyperthyroidism/print 6/13 7/5/23, 11:15 AM Cardiovascular effects of hyperthyroidism - UpToDate and "Thionamides in the treatment of Graves' disease" and "Beta blockers in the treatment of hyperthyroidism".) Additional measures may be needed in patients with atrial fibrillation, marked palpitations, severe tachycardia, or heart failure. In certain circumstances, especially with severe hyperthyroidism or thyroid storm, intensive cardiovascular monitoring and treatment of other comorbid conditions (infection, trauma, acute psychiatric illness) is required. (See "Thyroid storm" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker' and "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001; 344:501. 2. Brent GA. The molecular basis of thyroid hormone action. N Engl J Med 1994; 331:847. 3. Davis PJ, Davis FB. Nongenomic actions of thyroid hormone on the heart. Thyroid 2002; 12:459. 4. Klein I, Biondi B. Endocrine disorders and cardiovascular disease. In: Braunwald's Heart Dise ase: A Textbook of Cardiovascular Medicine, Bonow RO, Mann DL, Tomaselli GF, Bhatt D (Ed s), Saunders Elsevier, Philadelphia 2019. p.1807. 5. Ventrella, S, Klein, I. Beta-adrenergic receptor blocking drugs in the management of hyperthyroidism. Endocrinologist 1994; 4:391. 6. Klein I, Danzi S. Thyroid disease and the heart. Circulation 2007; 116:1725. 7. Ojamaa K, Klein I, Sabet A, Steinberg SF. Changes in adenylyl cyclase isoforms as a mechanism for thyroid hormone modulation of cardiac beta-adrenergic receptor responsiveness. Metabolism 2000; 49:275. 8. Mintz G, Pizzarello R, Klein I. Enhanced left ventricular diastolic function in hyperthyroidism: noninvasive assessment and response to treatment. J Clin Endocrinol Metab 1991; 73:146. 9. Osman F, Franklyn JA, Holder RL, et al. Cardiovascular manifestations of hyperthyroidism before and after antithyroid therapy: a matched case-control study. J Am Coll Cardiol 2007; 49:71. 10. Iglesias P, Acosta M, S nchez R, et al. Ambulatory blood pressure monitoring in patients with hyperthyroidism before and after control of thyroid function. Clin Endocrinol (Oxf) https://www.uptodate.com/contents/cardiovascular-effects-of-hyperthyroidism/print 7/13 7/5/23, 11:15 AM Cardiovascular effects of hyperthyroidism - UpToDate 2005; 63:66. 11. Kim HJ, Jo SH, Lee MH, et al. Hyperthyroidism Is Associated with the Development of Vasospastic Angina, but Not with Cardiovascular Outcomes. J Clin Med 2020; 9. 12. Biondi B, Fazio S, Carella C, et al. Cardiac effects of long term thyrotropin-suppressive therapy with levothyroxine. J Clin Endocrinol Metab 1993; 77:334. 13. D rr M, Wolff B, Robinson DM, et al. The association of thyroid function with cardiac mass and left ventricular hypertrophy. J Clin Endocrinol Metab 2005; 90:673. 14. Dahl P, Danzi S, Klein I. Thyrotoxic cardiac disease. Curr Heart Fail Rep 2008; 5:170. 15. Kellett HA, Sawers JS, Boulton FE, et al. Problems of anticoagulation with warfarin in hyperthyroidism. Q J Med 1986; 58:43. 16. Kurnik D, Loebstein R, Farfel Z, et al. Complex drug-drug-disease interactions between amiodarone, warfarin, and the thyroid gland. Medicine (Baltimore) 2004; 83:107. 17. Wustmann K, Kucera JP, Zanchi A, et al. Activation of electrical triggers of atrial fibrillation in hyperthyroidism. J Clin Endocrinol Metab 2008; 93:2104. 18. Frost L, Vestergaard P, Mosekilde L. Hyperthyroidism and risk of atrial fibrillation or flutter: a population-based study. Arch Intern Med 2004; 164:1675. 19. Petersen P. Thromboembolic complications in atrial fibrillation. Stroke 1990; 21:4. 20. Malik S, Russman AN, Katramados AM, et al. Moyamoya syndrome associated with Graves' disease: a case report and review of the literature. J Stroke Cerebrovasc Dis 2011; 20:528. 21. Li D, Yang W, Xian P, et al. Coexistence of moyamoya and Graves' diseases: the clinical characteristics and treatment effects of 21 Chinese patients. Clin Neurol Neurosurg 2013; 115:1647. 22. Siu CW, Yeung CY, Lau CP, et al. Incidence, clinical characteristics and outcome of congestive heart failure as the initial presentation in patients with primary hyperthyroidism. Heart 2007; 93:483. 23. Ismail HM. Reversible pulmonary hypertension and isolated right-sided heart failure associated with hyperthyroidism. J Gen Intern Med 2007; 22:148. 24. Schultz M, Kistorp C, Langdahl B, et al. N-terminal-pro-B-type natriuretic peptide in acute hyperthyroidism. Thyroid 2007; 17:237. 25. Danzi S, Klein I. Treatment of hypertension and thyroid disease. In: Advanced Therapy in Hy pertension and Vascular Disease, Mohler ER, Townsend RR (Eds), BC Decker Inc., Ontario, Ca nada 2006. p.354. 26. Lozano HF, Sharma CN. Reversible pulmonary hypertension, tricuspid regurgitation and right-sided heart failure associated with hyperthyroidism: case report and review of the https://www.uptodate.com/contents/cardiovascular-effects-of-hyperthyroidism/print 8/13 7/5/23, 11:15 AM Cardiovascular effects of hyperthyroidism - UpToDate literature. Cardiol Rev 2004; 12:299. 27. Merc J, Ferr s S, Oltra C, et al. Cardiovascular abnormalities in hyperthyroidism: a prospective Doppler echocardiographic study. Am J Med 2005; 118:126. 28. Siu CW, Zhang XH, Yung C, et al. Hemodynamic changes in hyperthyroidism-related pulmonary hypertension: a prospective echocardiographic study. J Clin Endocrinol Metab 2007; 92:1736. 29. Peters A, Ehlers M, Blank B, et al. Excess triiodothyronine as a risk factor of coronary events. Arch Intern Med 2000; 160:1993. 30. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid 2016; 26:1343. 31. Clozel JP, Danchin N, Genton P, et al. Effects of propranolol and of verapamil on heart rate and blood pressure in hyperthyroidism. Clin Pharmacol Ther 1984; 36:64. 32. Subahi A, Ibrahim W, Abugroun A. Diltiazem-Associated Cardiogenic Shock in Thyrotoxic Crisis. Am J Ther 2018; 25:e666. 33. Featherstone HJ, Stewart DK. Angina in thyrotoxicosis. Thyroid-related coronary artery spasm. Arch Intern Med 1983; 143:554. Topic 7853 Version 19.0 https://www.uptodate.com/contents/cardiovascular-effects-of-hyperthyroidism/print 9/13 7/5/23, 11:15 AM Cardiovascular effects of hyperthyroidism - UpToDate GRAPHICS Thyroid hormone-mediated changes in cardiac output Effects of thyroid hormone on cardiovascular hemodynamics. T3 affects tissue thermogenesis, systemic vascular resistance, blood volume, cardiac contractility, heart rate, and cardiac output as indicated by the arrows. Hyper: hyperthyroidism; hypo: hypothyroidism; T3: triiodothyronine; T4: thyroxine. Reproduced with permission from: Klein I, Danzi S. Thyroid disease and the heart. Circulation 2007; 116:1725. Copyright 2007 Lippincott Williams & Wilkins. Graphic 85918 Version 6.0 https://www.uptodate.com/contents/cardiovascular-effects-of-hyperthyroidism/print 10/13 7/5/23, 11:15 AM Cardiovascular effects of hyperthyroidism - UpToDate Cardiovascular effects of hyperthyroidism Parameter Finding Heart rate Increased Pulmonary artery pressure Increased Systemic vascular resistance Decreased Cardiac output Increased Ejection fraction Increased Diastolic relaxation Increased Systolic blood pressure Increased Diastolic blood pressure Decreased Myocardial oxygen consumption Increased Anginal syndrome Can induce or worsen Graphic 56219 Version 3.0 https://www.uptodate.com/contents/cardiovascular-effects-of-hyperthyroidism/print 11/13 7/5/23, 11:15 AM Cardiovascular effects of hyperthyroidism - UpToDate Increased incidence of atrial fibrillation in subclinical hyperthyroidism Cumulative incidence of atrial fibrillation in subjects over age 60 years according to the serum concentration of TSH. The risk of atrial fibrillation was increased almost threefold in the subjects with marked suppression of TSH (left panel) as compared with those who had normal serum TSH concentrations and were presumably euthyroid (right panel); patients with slightly low serum TSH concentrations (middle panel) had a lesser increase in risk. TSH: thyroid-stimulating hormone. Data from: Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial brillation in older persons. N Engl J Med 1994; 331:1249. Graphic 55024 Version 4.0 https://www.uptodate.com/contents/cardiovascular-effects-of-hyperthyroidism/print 12/13 7/5/23, 11:15 AM Cardiovascular effects of hyperthyroidism - UpToDate Contributor Disclosures Irwin Klein, MD Consultant/Advisory Boards: Amneal Pharmaceuticals [Novel treatments of hypothyroidism]; Avion Pharmaceuticals [Novel treatments of hypothyroidism]. All of the relevant financial relationships listed have been mitigated. Douglas S Ross, MD Consultant/Advisory Boards: Medullary Thyroid Cancer Registry Consortium [Thyroid cancer]. All of the relevant financial relationships listed have been mitigated. Jean E Mulder, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cardiovascular-effects-of-hyperthyroidism/print 13/13

7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Enhanced cardiac automaticity : Philip J Podrid, MD, FACC : Bernard J Gersh, MB, ChB, DPhil, FRCP, MACC : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 02, 2021. INTRODUCTION Enhanced cardiac automaticity refers to the accelerated generation of an action potential by either normal pacemaker tissue (enhanced normal automaticity) or by abnormal tissue within the myocardium (abnormal automaticity). The discharge rate of normal or abnormal pacemakers may be accelerated by drugs, various forms of cardiac disease, reduction in extracellular potassium, or alterations of autonomic nervous system tone. Enhanced normal automaticity accounts for the occurrence of sinus tachycardia, while abnormal automaticity may result in various atrial or ventricular arrhythmias, for example, an accelerated idioventricular rhythm or an ectopic atrial tachycardia. This topic will review the physiologic principles underlying both enhanced normal automaticity and automatic automaticity. The diagnosis and treatment of arrhythmias resulting from enhanced cardiac automaticity are discussed separately. (See "Sinus tachycardia: Evaluation and management" and "Focal atrial tachycardia".) ENHANCED NORMAL AUTOMATICITY Enhanced normal automaticity is best understood by beginning with a brief review of the physiology and hierarchy of stimulation of normal cardiac automaticity. This will be followed by a discussion of the electrophysiologic principles underlying the normal and enhanced automaticity of the sinoatrial (SA) node, the subsidiary atrial pacemakers, the atrioventricular (AV) node, and the ventricles. https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 1/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Normal automaticity Normal automaticity involves the slow, progressive depolarization of the membrane potential (spontaneous diastolic depolarization or phase four depolarization) until a threshold potential is reached, at which point an action potential ( figure 1 and figure 2) is initiated. Although automaticity is an intrinsic property of all myocardial cells, the occurrence of spontaneous activity is prevented by the natural hierarchy of pacemaker function. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) The spontaneous discharge rate of the SA nodal complex exceeds that of all other subsidiary or latent pacemakers. As a result, the impulse initiated by the SA node depresses the activity of subsidiary pacemaker sites before they can spontaneously depolarize to threshold. However, slowly depolarizing and previously suppressed pacemakers in the atrium, AV node, or ventricle can become active and assume pacemaker control of the cardiac rhythm if the SA node pacemaker becomes slow or unable to generate an impulse or if impulses generated by the SA node are unable to activate the surrounding atrial myocardium. The emergence of subsidiary or latent pacemakers under such circumstances is an appropriate fail-safe mechanism which assures that ventricular activation is maintained. A subsidiary pacemaker may also become activated if there is sympathetic stimulation or increased catecholamines, resulting in a pacemaker discharge rate that is faster than the rate of sinus node discharge. This represents an accelerated rhythm. SA node The ionic mechanisms responsible for normal pacemaker activity in the SA node have not been conclusively defined, but are likely the result of a hyperpolarization-activated inward current and decay of outward potassium currents [1]. This progressive net gain of positive charge underlies the spontaneous diastolic depolarization of SA node cells which results from the following sequence of events ( figure 2) [2,3]: During the first third of diastolic depolarization, the inward leak of sodium ions is coupled with a time-dependent decrease in the outward potassium current. During the latter two thirds of depolarization, a slow inward movement of calcium ions occurs. This process moves the membrane potential to the threshold potential, at which time there is a more rapid inward calcium current, generating a slow action potential. Effects of drugs and autonomic tone on the SA node Drugs and autonomic neurotransmitters perturb these currents, thereby altering the SA node discharge rate. As an example, agents and neurotransmitters that accelerate the sinus node discharge rate bind to the beta adrenergic receptor, leading to an increase in the inward movement of calcium due to the phosphorylation of a protein that modulates the opening of calcium https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 2/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate channels ( figure 3) [4,5]. The ensuing influx of calcium accelerates the rate of diastolic depolarization [2]. Parasympathetic tone, on the other hand, reduces the spontaneous discharge rate of the SA node, while its withdrawal accelerates SA node automaticity. Acetylcholine, the principle neurotransmitter of the parasympathetic nervous system, inhibits spontaneous impulse generation in the SA node by increasing potassium conductance [3]. The resulting hyperpolarization of the membrane potential lengthens the time required for the membrane potential to depolarize to threshold, thereby decreasing the automaticity of the SA node. In addition to altering ionic conductance, changes in autonomic tone can also produce changes in the rate of the SA node by shifting the primary pacemaker region within the pacemaker complex, which is described as a cylindrical crescent [6]. Intrinsic discharge frequencies vary within different regions of the SA node; the discharge rate is faster in the cranial portion of the node, while it is slower in the caudal region. As a result, autonomically-mediated shifts of pacemaker regions may be accompanied by changes in the sinus rate [7,8]. Vagal fibers are more dense in the cranial portion of the SA node and stimulation of the parasympathetic nervous system shifts the pacemaker center to a more caudal region of the SA nodal complex, resulting in slowing of the heart rate, whereas stimulation of the sympathetic nervous system or withdrawal of vagal stimulation shifts the pacemaker center cranially, resulting in an increase in heart rate ( figure 4). The following are examples of stimuli which can alter the automaticity of the SA node: Exercise, which augments sympathetic tone, enhances normal automaticity in the SA node and can produce sinus tachycardia (heart rates exceeding 100 beats/minute). (See "Sinus tachycardia: Evaluation and management".) Respiratory sinus arrhythmia (respirophasic arrhythmia that is irregularly irregular) is primarily caused by withdrawal of vagal tone during inspiration (and hence a faster heart rate) and by reinstitution of vagal tone during expiration (and hence a slower heart rate). These alterations in vagal tone are mediated by peripheral sensors linked to arterial chemoreceptors and baroreceptors, intracardiac reflexes, and pulmonary stretch receptors [9-11]. (See "Normal sinus rhythm and sinus arrhythmia".) Digitalis has a well-known negative chronotropic effect on the SA node, caused by enhancement of vagal (parasympathetic) tone [9,12]. Digoxin does not appear to have any direct depressant effects on the intrinsic functions of the sinus node [13]. https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 3/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Beta blockers, which block the effect of sympathetic stimulation and circulating catecholamines on the SA node, result in a reduction in its normal automaticity. However, their effect at rest is less marked, as normal resting SA nodal function is not dependent upon sympathetic stimulation but is mediated more by vagal tone. However, during times of sympathetic stimulation, these agents will blunt the acceleration in heart rate. Calcium channel blockers, especially verapamil and diltiazem, reduce the influx of calcium ions, and therefore will reduce the rate of diastolic depolarization and hence the rate of SA nodal discharge. Ivabradine, which has a direct effect on SA automaticity and impulse discharge. Its action is unlike beta blockers, digoxin, or calcium channel blockers. It works by modulating the "f- current" (I ). Ivabradine slows the sinus rate by prolonging the slow depolarization phase. f Subsidiary atrial pacemakers Latent atrial pacemakers have been identified in the atrial myocardium (especially the crista terminalis), coronary sinus, and AV valves [14-18], while ectopic atrial pacemakers have been identified in the region around the pulmonary veins [19]. They may responsible for precipitating atrial fibrillation and their elimination or isolation with radiofrequency catheter ablation has been found to be effective for the prevention of paroxysmal atrial fibrillation [20]. (See "Atrial fibrillation: Catheter ablation".) Latent atrial pacemakers (located in the atrial myocardium) may be expected to contribute to impulse initiation in the atrium if the discharge rate of the SA node is reduced temporarily or permanently. In contrast to the normal pacemaker tissue, these latent or ectopic pacemakers usually generate a fast action potential, mediated by sodium ion fluxes. However, when severely damaged, the atrial tissue may not be able to generate a fast action potential (which is energy- dependent) but rather generates a slow, calcium ion-mediated action potential (which is energy- independent). Automaticity of subsidiary atrial pacemakers may also be enhanced by coronary disease and ischemia, chronic pulmonary disease, or drugs such as digitalis and alcohol, possibly overriding normal SA node activity [9,21,22]. AV node or junction It is uncertain if the AV node itself has pacemaker cells, but it is clear that the AV junction, which is an area that includes atrial tissue, the AV node and His-Purkinje tissue, does have pacemaker cells and is capable of exhibiting automaticity. Automaticity of the AV junction appears to arise via a mechanism similar to that which occurs in the SA node [23-25]. Diastolic depolarization is caused by a gradual decrease in the outward potassium current and an increase in the inward movement of calcium ions. Acceleration of AV nodal automaticity by https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 4/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate beta-adrenergic agonists is believed to result from activation of the calcium channel, resulting in an increased inward calcium current, similar to that induced in the SA node. Ectopic AV nodal tachycardias due to enhanced automaticity have the following clinical features: Marked sinus bradycardia or SA node exit block can result in an escape ectopic AV nodal or junctional rhythm. The emergence of an ectopic AV junctional rhythm is usually characterized by a gradual increase in spontaneous discharge rate (a warm-up phenomenon) until a reasonably regular rate of 35 to 60 beats per minute is attained [25]. Acceleration of the AV junctional rate to 70 to 130 beats per minute (ectopic junctional tachycardia) can occur with an inferior myocardial infarction, open heart surgery, myocarditis, digitalis intoxication (which is associated with an increase in outputs from the central sympathetic nervous system), or sympathetic activation. The onset and termination of accelerated junctional tachycardias are usually gradual (ie, nonparoxysmal). The tachycardia rate is slowed by enhanced vagal tone and is accelerated by vagolytic or sympathomimetic agents. Ventricle Isolated cells of the His-Purkinje system discharge spontaneously at rates of 15 to 60 beats per minute, whereas ventricular myocardial cells usually do not exhibit spontaneous diastolic depolarization or automaticity [26,27]. The relatively slow spontaneous discharge rate of Purkinje fibers ensures that pacemaker activity in the His-Purkinje system will be suppressed on a beat-to-beat basis by the more rapid discharge rate of the SA node [28,29]. Under normal conditions, the Purkinje fibers do not exhibit spontaneous automaticity because of "overdrive suppression" by more proximal pacemakers (ie, sinus and AV node) that have a faster discharge rate ( figure 5). However, enhanced Purkinje fiber automaticity can be induced by certain situations, such as a myocardial infarction. In this setting, some Purkinje fibers which survive the infarction have moderately reduced maximum diastolic membrane potentials and therefore accelerated spontaneous discharge rates [30-36]. In the presence of ischemia or myocardial infarction, myocardial cells may demonstrate spontaneous automaticity. ABNORMAL AUTOMATICITY https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 5/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Enhanced automaticity of the SA node, subsidiary atrial pacemakers, or the AV node due to a mechanism other than acceleration of normal automaticity has not been demonstrated clinically. However, abnormal automaticity of Purkinje fibers and atrial and ventricular tissue can occur. As noted above, isolated cardiac Purkinje fibers usually have relatively slow spontaneous discharge rates, whereas atrial and ventricular muscles are quiescent. However, depolarization of these tissues by a disease process, in particular acute myocardial ischemia, can induce spontaneous activity. With an acute myocardial infarction, there is loss of the normal energy- dependent fast sodium-mediated action potential (due to inactivation of the normal sodium- potassium ATPase pump, which requires energy and O to synthesize ATP). As a result, resting 2 membrane potential (which is normally -90 mV) becomes less negative and reaches the threshold potential of -60 mV. The normal rapid influx of sodium, which accounts for the fast action potential, is lost, and the fast action potential is no longer generated. However, the slow influx of calcium currents, which is energy independent and normally occurs during phase 2 of the action potential, still occurs. Hence, as a result of the loss of the fast inward sodium influx but maintenance of the slow influx of calcium ions, the fast action potential is converted to a slow action potential which has spontaneous automaticity. Thus, latent energy-independent slow action potential (mediated by calcium currents) is therefore exposed. This automaticity is not suppressed by overdrive pacing, is more easily suppressed by calcium channel blockade than by sodium channel blockade, and is accelerated by beta-adrenergic agonists [35-40]. Thus, abnormal automaticity in these tissues resembles normal automaticity in the sinus and AV nodes (ie, results from a time-dependent decay of outward potassium currents and progressive activation of inward calcium currents) [41,42]. Acceleration of Purkinje fiber automaticity can also be augmented by the elevated levels of catecholamines and increased sympathetic tone which occurs during ischemia [43]. Purkinje fibers surviving myocardial infarction appear to be more sensitive to the positive chronotropic effects of catecholamines than normal Purkinje fibers, perhaps because of denervation supersensitivity [44,45]. There appears to be an association between abnormal Purkinje fiber automaticity and the arrhythmias that occur during the acute phase of myocardial infarction, for example, an accelerated idioventricular rhythm. However, the role of abnormal automaticity in the development of ventricular arrhythmias associated with chronic ischemic heart disease is less certain. Isolated myocytes obtained from hypertrophied and failing hearts have been shown to manifest spontaneous diastolic depolarization and enhanced pacemaker currents, suggesting that https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 6/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate abnormal automaticity may contribute to the occurrence of some arrhythmias in heart failure and left ventricular hypertrophy [46,47]. It has been shown that stretch of the myocardium can increase its automaticity (ie, electromechanical feedback). This may account for arrhythmias that are seen with heart failure and acute dilation of the atrial or ventricular myocardium. (See "Left ventricular hypertrophy and arrhythmia".) Some of the arrhythmias that occur with digoxin toxicity may be related to suppression of sinus node activity by increased vagal tone as well as enhanced automaticity (resulting from an increase in central sympathetic neural outputs occurring with elevated digoxin levels), although this is not firmly established since delayed potentials (delayed after depolarizations [DADs]) and triggered automaticity are other potential mechanisms. It is likely that both mechanisms play a role as triggered automaticity may be enhanced by sympathetic stimulation. (See "Cardiac arrhythmias due to digoxin toxicity".) The role of abnormal automaticity in the genesis of other clinical arrhythmias has generally not been established. Although automaticity is not responsible for most clinical tachyarrhythmias, which are usually due to a reentry, it may certainly precipitate or trigger any reentrant arrhythmia. SUMMARY Enhanced cardiac automaticity refers to the accelerated generation of an action potential by either normal pacemaker tissue (enhanced normal automaticity) or by abnormal tissue within the myocardium (abnormal automaticity). (See 'Introduction' above.) The spontaneous discharge rate of the sinoatrial (SA) nodal complex exceeds that of all other subsidiary or latent pacemakers, thereby depressing the activity of subsidiary pacemaker sites before they can spontaneously depolarize to threshold. However, previously suppressed pacemakers in the atrium, atrioventricular (AV) node, or ventricle can assume pacemaker control of the cardiac rhythm if the SA node pacemaker becomes slow or unable to generate an impulse or if impulses generated by the SA node are unable to activate the surrounding atrial myocardium. (See 'Normal automaticity' above.) Drugs and autonomic neurotransmitters alter the SA node discharge rate (see 'Effects of drugs and autonomic tone on the SA node' above): Increased sympathetic input or withdrawal of parasympathetic input (eg, exercise, beta agonist medications) results in higher sinus rates. https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 7/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Decreased sympathetic input or increased parasympathetic input (eg, beta blockers, digoxin) leads to lower sinus rates. The AV junction, an area that includes atrial tissue, the AV node, and His-Purkinje tissue, contains pacemaker cells and is capable of exhibiting automaticity, which may result in ectopic AV nodal tachycardias. (See 'AV node or junction' above.) Isolated cells of the His-Purkinje system discharge spontaneously at rates of 15 to 60 beats per minute, whereas ventricular myocardial cells usually do not exhibit spontaneous diastolic depolarization or automaticity. Under normal conditions, the Purkinje fibers do not exhibit spontaneous automaticity because of suppression by more proximal pacemakers that have a faster discharge rate. However, enhanced Purkinje fiber automaticity can be induced by certain situations, such as a myocardial infarction. (See 'Ventricle' above.) There appears to be an association between abnormal Purkinje fiber automaticity and the arrhythmias that occur during the acute phase of myocardial infarction, for example, an accelerated idioventricular rhythm. However, the role of abnormal automaticity in the development of ventricular arrhythmias associated with chronic ischemic heart disease is less certain. (See 'Abnormal automaticity' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. DiFrancesco D. The pacemaker current (I(f)) plays an important role in regulating SA node pacemaker activity. Cardiovasc Res 1995; 30:307. 2. Irisawa, H, Hagiwara, N . Ionic current in sinoatrial node cells. J Cardiovasc Electrophysiol 1991; 2:531. 3. Brown HF. Electrophysiology of the sinoatrial node. Physiol Rev 1982; 62:505. 4. Reuter H. Calcium channel modulation by neurotransmitters, enzymes and drugs. Nature 1983; 301:569. 5. Kameyama M, Hofmann F, Trautwein W. On the mechanism of beta-adrenergic regulation of the Ca channel in the guinea-pig heart. Pflugers Arch 1985; 405:285. 6. Boineau JP, Canavan TE, Schuessler RB, et al. Demonstration of a widely distributed atrial pacemaker complex in the human heart. Circulation 1988; 77:1221. https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 8/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate 7. Bouman LN, Gerlings ED, Biersteker PA, Bonke FI. Pacemaker shift in the sino-atrial node during vagal stimulation. Pflugers Arch 1968; 302:255. 8. Goldberg JM. Intra-SA-nodal pacemaker shifts induced by autonomic nerve stimulation in the dog. Am J Physiol 1975; 229:1116. 9. Zipes DP. Specific arrhythmias: diagnosis and treatment. In: Heart Disease: A Textbook of Ca rdiovascular Medicine, Braunwald E (Ed), Saunders, Philadelphia 1992. p.667. 10. Eckberg DL. Human sinus arrhythmia as an index of vagal cardiac outflow. J Appl Physiol Respir Environ Exerc Physiol 1983; 54:961. 11. Grossman P, Kollai M. Respiratory sinus arrhythmia, cardiac vagal tone, and respiration: within- and between-individual relations. Psychophysiology 1993; 30:486. 12. Steinbeck G, Bonke FI, Allessie MA, Lammers WJ. The effect of ouabain on the isolated sinus node preparation of the rabbit studied with microelectrodes. Circ Res 1980; 46:406. 13. Alboni P, Shantha N, Filippi L, et al. Clinical effects of digoxin on sinus node and atrioventricular node function after pharmacologic autonomic blockade. Am Heart J 1984; 108:1255. 14. Wit AL, Cranefield PF. Triggered and automatic activity in the canine coronary sinus. Circ Res 1977; 41:434. 15. Jones SB, Euler DE, Randall WC, et al. Atrial ectopic foci in the canine heart: hierarchy of pacemaker automaticity. Am J Physiol 1980; 238:H788. 16. Wit AL, Fenoglio JJ Jr, Wagner BM, Bassett AL. Electrophysiological properties of cardiac muscle in the anterior mitral valve leaflet and the adjacent atrium in the dog. Possible implications for the genesis of atrial dysrhythmias. Circ Res 1973; 32:731. 17. Hogan PM, Davis LD. Evidence for specialized fibers in the canine right atrium. Circ Res 1968; 23:387. 18. James TN, Sherf L, Fine G, Morales AR. Comparative ultrastructure of the sinus node in man and dog. Circulation 1966; 34:139. 19. Ha ssaguerre M, Ja s P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998; 339:659. 20. Chen SA, Hsieh MH, Tai CT, et al. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation 1999; 100:1879. 21. Swerdlow CD, Liem LB. Atrial and junctional tachycardias: clinical presentation, course and t herapy. In: Cardiac Electrophysiology. From Cell to Bedside, Zipes,DP, Jalife J (Eds), Saunders, Philadelphia 1990. p.742. https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 9/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate 22. Goldreyer BN, Gallagher JJ, Damato AN. The electrophysiologic demonstration of atrial ectopic tachycardia in man. Am Heart J 1973; 85:205. 23. Kokubun S, Nishimura M, Noma A, Irisawa H. The spontaneous action potential of rabbit atrioventricular node cells. Jpn J Physiol 1980; 30:529. 24. Noma A, Irisawa H, Kokobun S, et al. Slow current systems in the A-V node of the rabbit heart. Nature 1980; 285:228. 25. Watanabe Y, Nishimura M, Noda T, et al. Atrioventricular junctional tachycardias. In: Cardiac Electrophysiology. From Cell to Bedside, Zipes DP, Jalife J (Eds), Saunders, Philadelphia 1990. p.564. 26. DiFrancesco D. A new interpretation of the pace-maker current in calf Purkinje fibres. J Physiol 1981; 314:359. 27. Hirano Y, Hiraoka M. Barium-induced automatic activity in isolated ventricular myocytes from guinea-pig hearts. J Physiol 1988; 395:455. 28. Vassalle M. The relationship among cardiac pacemakers. Overdrive suppression. Circ Res 1977; 41:269. 29. Vassalle M. Electrogenic suppression of automaticity in sheep and dog purkinje fibers. Circ Res 1970; 27:361. 30. Allen JD, Brennan FJ, Wit AL. Actions of lidocaine on transmembrane potentials of subendocardial Purkinje fibers surviving in infarcted canine hearts. Circ Res 1978; 43:470. 31. Friedman PL, Stewart JR, Wit AL. Spontaneous and induced cardiac arrhythmias in subendocardial Purkinje fibers surviving extensive myocardial infarction in dogs. Circ Res 1973; 33:612. 32. Lazzara R, el-Sherif N, Scherlag BJ. Electrophysiological properties of canine Purkinje cells in one-day-old myocardial infarction. Circ Res 1973; 33:722. 33. Dangman KH, Danilo P Jr, Hordof AJ, et al. Electrophysiologic characteristics of human ventricular and Purkinje fibers. Circulation 1982; 65:362. 34. Horowitz LN, Spear JF, Moore EN. Subendocardial origin of ventricular arrhythmias in 24- hour-old experimental myocardial infarction. Circulation 1976; 53:56. 35. Imanishi S. Calcium-sensitive discharges in canine Purkinje fibers. Jpn J Physiol 1971; 21:443. 36. Imanishi S, Surawicz B. Automatic activity in depolarized guinea pig ventricular myocardium. Characteristics and mechanisms. Circ Res 1976; 39:751. 37. Grant AO, Katzung BG. The effects of quinidine and verapamil on electrically induced automaticity in the ventricular myocardium of guinea pig. J Pharmacol Exp Ther 1976; 196:407. https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 10/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate 38. Elharrar V, Zipes DP. Voltage modulation of automaticity in cardiac Purkinje fibers. In: The sl ow inward current and cardiac arrhythmias, Zipes DP, Bailey JC, Elharrar V (Eds), Martinus Nij hoff, The Hague 1980. p.357. 39. Katzung BG. Effects of extracellular calcium and sodium on depolarization-induced automaticity in guinea pig papillary muscle. Circ Res 1975; 37:118. 40. Pappano AJ, Carmeliet EE. Epinephrine and the pacemaking mechanism at plateau potentials in sheep cardiac Purkinje fibers. Pflugers Arch 1979; 382:17. 41. Hauswirth O, Noble D, Tsien RW. The mechanism of oscillatory activity at low membrane potentials in cardiac Purkinje fibres. J Physiol 1969; 200:255. 42. Katzung BG, Morgenstern JA. Effects of extracellular potassium on ventricular automaticity and evidence for a pacemaker current in mammalian ventricular myocardium. Circ Res 1977; 40:105. 43. Ceremuzy ski L, Staszewska-Barczak J, Herbaczynska-Cedro K. Cardiac rhythm disturbances and the release of catecholamines after acute coronary occlusion in dogs. Cardiovasc Res 1969; 3:190. 44. Cameron JS, Han J. Effects of epinephrine on automaticity and the incidence of arrhythmias in Purkinje fibers surviving myocardial infarction. J Pharmacol Exp Ther 1982; 223:573. 45. Barber MJ, Mueller TM, Henry DP, et al. Transmural myocardial infarction in the dog produces sympathectomy in noninfarcted myocardium. Circulation 1983; 67:787. 46. Nuss HB, K b S, Kass DA, et al. Cellular basis of ventricular arrhythmias and abnormal automaticity in heart failure. Am J Physiol 1999; 277:H80. 47. Hoppe UC, Jansen E, S dkamp M, Beuckelmann DJ. Hyperpolarization-activated inward current in ventricular myocytes from normal and failing human hearts. Circulation 1998; 97:55. Topic 952 Version 19.0 https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 11/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate GRAPHICS Relationship between fast sodium-mediated myocardial action potential and surface electrocardiogram Each phase of the myocardial action potential (numbers, upper panel) corresponds to a deflection or interval on the surface ECG (lower panel). Phase 4, the resting membrane potential, is responsible for the TQ segment; this segment has a prominent role in the ECG manifestations of ischemia during exercise testing. ECG: electrocardiogram. Graphic 64133 Version 4.0 https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 12/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Spontaneous slow or calcium-mediated action potential generated by pacemaker structures - sinoatrial and atrioventricular nodes The normal sinoatrial node generates a spontaneous slow action potential (panel A), mediated primarily by calcium currents (panel B). The resting membrane potential is -65 mV and manifests spontaneous diastolic depolarization (phase 4), due to an inward leak of sodium ions via a hyperpolarization- dependent pacemaker current (If) and a gradual decline in the delayed rectifier current (Ik), resulting in a decline in the outward flow of potassium ions; these changes are superimposed upon a background current (Ib). The net result is an increase in intracellular positivity with the potential gradually reaching -40 mV, at which point a spontaneous action potential is generated, resulting from a marked increase in the influx of calcium (ICa), followed by a slow inward calcium current (Isi), and activation of Ik and the outward movement of potassium ions. Graphic 70961 Version 2.0 https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 13/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Interaction between sympathetic activation and the calcium channel Acceleration of sinus node automaticity by sympathetic stimulation results from an increase in the influx of sodium (If) during diastolic depolarization and an increase in calcium (Ca++) influx during phase 0; both are due to a direct stimulatory effect of the alpha subunit of the guanosine nucleotide binding protein (G protein) on the respective channels. In the resting nonstimulated state (panel A) guanosine diphosphate is bound to the alpha subunit of the G protein. With beta receptor activation (panel B), guanosine triphosphate (GTP) displaces GDP, stimulating adenyl cyclase; this generates cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP) (panel C). Generation of cAMP activates protein kinase A and phosphorylation of the regulatory component of the CA++ channel; the opening of the Ca++ channel in response to membrane depolarization is increased. Activation of the alpha subunit of the G protein may also activate the Ca++ channel. With deactivation of the beta receptor, an intrinsinc GTPase hydrolyzes GTP to GDP (panel D). Graphic 68194 Version 1.0 https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 14/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Location of pacemaker sites in the human sinus node Filled circles represent the location of sites under autonomic control, while the open circles are "escape" sites that are not under the control of the autonomic nervous system and are capable of generating ectopic impulses. There is a predominant clustering of all sites along the sulcus terminalis and superior vena caval (SVC)-right atrial (RA) junction in the upper posterior right atrium; a few escape sites are also located in the left atrium, below the pulmonary vein (PV). Stimulation of the parasympathetic nervous system shifts the dominant pacemaker site to a more caudal region of the sinus complex, while sympathetic stimulation shifts the site to a more cranial location. LAA: left atrial appendage; RAA: right atrial appendage. From Boineau, JP, Canavan, TE, Schuessler, RB, et al Circulation 1988; 77:1221. Graphic 55214 Version 1.0 https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 15/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Effect of overdrive pacing on spontaneous automaticity of Purkinje fiber The more rapid discharge from the sinus node produces overdrive suppression of Purkinje fiber automaticity. Microelectrode recording from a Purkinje fiber at baseline shows a maximum diastolic potential of -77 mV. During overdrive pacing, the membrane becomes hyperpolarized and maximum diastolic potential increases to -85 mV, resulting in part from the accumulation of sodium ions, activation of the sodium-potassium pump, and an increased influx of potassium as sodium is extruded. After the cessation of overdrive pacing, the onset of the next spontaneous action potential is delayed since the slow of phase 4 diastolic depolarization is reduced and the more negative diastolic potential increases in the time required to reach threshold. Graphic 61185 Version 2.0 https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 16/17 7/5/23, 11:15 AM Enhanced cardiac automaticity - UpToDate Contributor Disclosures Philip J Podrid, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Bernard J Gersh, MB, ChB, DPhil, FRCP, MACC Consultant/Advisory Boards: Bain Institute [CRO for trials involving Edwards percutaneous valve devices]; Cardiovascular Research Foundation [Data safety monitoring board (RELIEVE-HF Trial)]; Caristo Diagnostics Limited [Imaging and inflammation/atherosclerosis]; Philips Image Guided Therapy Corporation [Imaging]; Sirtex Med Limited [General consulting]; Thrombosis Research Institute [Data safety monitoring board (GARFIELD study)]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/enhanced-cardiac-automaticity/print 17/17

7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Epidemiology, risk factors, and prevention of atrial fibrillation : David Spragg, MD, FHRS : Peter J Zimetbaum, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 30, 2022. INTRODUCTION Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice. Patients are at increased risk for death, heart failure, hospitalization, and thromboembolic events [1-3]. The epidemiology of, disease associations with, and risk factors for AF will be reviewed here. An overview of the presentation and management of patients with AF is discussed elsewhere. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) EPIDEMIOLOGY Atrial fibrillation (AF) is a global health care problem with evidence suggesting an increasing prevalence and incidence worldwide [4-6]. A systematic review of worldwide population-based studies (n = 184) estimated that the number of individuals with AF in 2010 was 33.5 million. Most of the studies below have evaluated individuals living in North America or Europe, but other geographies will be specified. Prevalence The prevalence of AF depends upon population characteristics, with differences apparent due to age, sex, race, geography, and time period. The following data are primarily derived from studies in which an electrocardiogram was obtained during an office visit rather https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 1/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate than ambulatory monitoring. The prevalence of paroxysmal AF, which is more likely to be detected with ambulatory monitoring, is much higher. Age AF is uncommon in infants and children and when present, almost always occurs in association with structural heart disease. Healthy young adults are also at low risk [7]. The prevalence of AF increases with age ( figure 1) [2,8-11]. This relationship to age was demonstrated in the ATRIA study, a cross-sectional study of almost 1.9 million subjects in a health maintenance organization in the United States [11]. The overall prevalence of AF was 1 percent; 70 percent were at least 65 years old and 45 percent were 75 years old. The prevalence of AF ranged from 0.1 percent among adults less than 55 years of age to 9 percent in those 80 years of age ( figure 2). In the STROKESTOP study discussed below, the prevalence of AF in a 75- to 76-year-old population (2011) in Sweden was about 12 percent [12]. Similar patterns were reported in a European population-based prospective cohort study of 6808 subjects 55 years of age [10]. The prevalence of AF was 5.5 percent, ranging from 0.7 percent in those aged 55 to 59 years and 17.8 percent for those 85 years of age. Sex The prevalence was higher in men than women (1.1 versus 0.8 percent), a difference seen in every age group ( figure 2 and figure 1). In another study, the rates were 6 versus 5.1 percent, respectively [10]. Race/ethnicity In one study, AF was more frequent in Whites compared with Black Americans over the age of 50 years (2.2 versus 1.5 percent) [11]. It has not been determined whether those from a Black population are at lower risk or if those from a White population are at higher risk [13]. A study that included nearly 14,000,000 patients receiving hospital-based care in California (United States) between 2005 and 2009 evaluated the relationship between race and incident AF [14]. Adjustment was made for known AF risk factors and patient demographics. Compared with White Americans, Black (hazard ratio [HR] 0.84), Hispanic (HR 0.78), and Asian (HR 0.78) Americans each had a lower AF risk after adjustment. Geography In one study, the age-adjusted prevalence rate (per 100,000 population) was highest in North America (700 to 775) and lowest in Japan and South Korea (250 to 325) [6]. The rate in China was also relatively low (325 to 400). Time period The prevalence of AF in the population is increasing. In a community-based study of 1.4 million patients in England and Wales, the age-standardized prevalence of AF between 1994 and 1998 increased by 22 and 14 percent in men and women, respectively [8]. In the ATRIA study, it was estimated that 2.3 million adults in the United States had AF https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 2/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate in 1996 and 1997, and that this will increase to 5.6 million by the year 2050, with more than 50 percent being more than 80 years of age [11]. In a report from the United States, the prevalence of AF in 2005 was 3.03 million, and the projected prevalence for 2050 was 7.56 million [15]. In another study, the estimated age-adjusted prevalence rates (per 100,000 population) were 570 in men and 360 in women and 596 (men) and 373 (women) in 1990 and 2010, respectively [6]. Subclinical atrial fibrillation Subclinical AF refers to asymptomatic episodes in a patient without a prior history of AF, which are detected only by monitoring techniques. The prevalence of subclinical AF is presented separately. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Clinical presentation'.) Incidence The incidence of AF, similar to the prevalence, increases with advancing age [10,16- 18]. In a longitudinal study in which 3983 male Air Force recruits were followed for 44 years, 7.5 percent developed AF [18]. The risk increased with advancing age (from 0.5 per 1000 person- years before age 50 to 9.7 per 1000 person years after age 70). The lifetime risk for the development of AF was analyzed in a report from the Framingham Heart Study [19]. A total of 8725 patients were followed from 1968 to 1999 (176,166 person-years of follow-up); 936 developed AF. The risk of developing AF from age 40 to age 95 was 26 percent for men and 23 percent for women. Lifetime risk did not change substantially with increasing index age because AF incidence rose with age; the risk of developing AF from age 80 to age 95 was 23 percent for men and 22 percent for women. PATHOGENESIS Irrespective of the underlying risk factor(s), changes in the anatomy and electrophysiology of the atrial myocardium are likely important. Thus, atrial fibrillation (AF) is usually associated with some underlying heart disease. Atrial enlargement, an elevation in atrial pressure, or infiltration or inflammation of the atria are often seen. Premature atrial complex (PAC; also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat) appears to be most important as a trigger in patients with paroxysmal AF who have normal or near-normal hearts. The relative importance of PAC or other triggers versus an abnormal substrate is much less clear in patients with significant structural heart disease. (See "The electrocardiogram in atrial fibrillation".) The mechanisms of AF are presented in detail separately. (See "Mechanisms of atrial fibrillation".) https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 3/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate CHRONIC DISEASE ASSOCIATIONS Hypertensive heart disease and coronary heart disease (CHD) are the most common underlying chronic disorders in patients with atrial fibrillation (AF) in developed countries. Rheumatic heart disease, although now uncommon in developed countries, is associated with a much higher incidence of AF. Paroxysmal AF (PAF) is associated with the same disorders as chronic (permanent) AF. (See "Paroxysmal atrial fibrillation".) Hypertensive heart disease In a longitudinal study of male air crew recruits, a history of hypertension increased the risk of developing AF 1.42-fold [18]. Although this is a relatively small increase in risk, the high frequency of hypertension in the general population results in hypertensive heart disease being the most common underlying disorder in patients with AF [16]. Coronary disease AF is not commonly associated with CHD unless it is complicated by acute myocardial infarction (MI) or heart failure (HF). AF occurs transiently in 6 to 10 percent of patients with an acute MI, presumably due to atrial ischemia or atrial stretching secondary to HF [20-23]. These patients have a worse prognosis that is mostly due to comorbidities such as older age and HF. (See "Supraventricular arrhythmias after myocardial infarction", section on 'Atrial fibrillation'.) The incidence of AF is much lower in patients with chronic stable CHD [24,25]. In the Coronary Artery Surgical Study (CASS), which included over 18,000 patients with angiographically documented coronary artery disease, AF was present in only 0.6 percent [24]. These patients probably had chronic AF; the prevalence of PAF may be higher. AF was associated with age greater than 60, male sex, mitral regurgitation (MR), and HF; there was no association between AF and the number of coronary arteries involved. Valvular heart disease Almost any valvular lesion that leads to significant stenosis or regurgitation is associated with the development of AF. The following are representative frequencies: In a review of 89 patients with mitral valve prolapse (and grade 3 or 4 MR) and 360 with flail leaflets, the rate of development of AF was about 5 percent per year with both types of lesions [26]. The major independent risk factors were age 65 years and baseline left atrial dimension 50 mm. Rheumatic heart disease is now uncommon in developed countries. It is, however, associated with a high prevalence of AF [27,28]. In a study of approximately 1100 patients with rheumatic heart disease, the prevalence varied with the type of valve disease [28]: https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 4/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Mitral stenosis (MS), MR, and tricuspid regurgitation 70 percent MS and MR 52 percent Isolated MS 29 percent Isolated MR 16 percent Heart failure AF and HF often occur together, and each may predispose to the other [29]. Among patients with HF, the prevalence of AF is variable, depending in part upon the severity of HF. Issues related to AF in patients with HF and cardiomyopathy are discussed in detail separately. (See "The management of atrial fibrillation in patients with heart failure".) Hypertrophic cardiomyopathy AF has been reported in 10 to 28 percent of patients with hypertrophic cardiomyopathy [30-32]. The prognostic importance of AF in these patients is unclear, with some reports showing a worse prognosis [32] and others no increase in mortality [31]. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation".) Congenital heart disease AF has been reported in approximately 20 percent of adults with an atrial septal defect [33]. However, the incidence of AF is related to age, ranging in one series from 15 percent for those aged 40 to 60, to 61 percent for those over the age of 60 [34]. AF and/or atrial flutter also occurs in other forms of congenital heart disease that affect the atria, including Ebstein anomaly and patent ductus arteriosus, and after surgical correction of some other abnormalities, including ventricular septal defect, tetralogy of Fallot, pulmonic stenosis, and transposition of the great vessels. Venous thromboembolic disease Venous thromboembolic disease, which includes deep vein thrombosis and pulmonary embolism, is associated with an increased risk of AF. The mechanism is not known but has been speculated to be related to the increase in pulmonary vascular resistance and cardiac afterload, which may lead to right atrial strain [35,36]. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension", section on 'Diagnostic evaluation'.) The incidence of AF in patients with acute or chronic venous thromboembolic disease has not been well studied. It has been reported to be in the 10 to 14 percent range in patients with documented pulmonary embolism [37,38]. The impact of incident venous thromboembolism (VTE) on the future risk of AF was evaluated in a prospective population-based study of nearly 30,000 individuals of whom 1.8 percent had an incident VTE event and 5.4 percent were diagnosed with AF during 16-year follow-up [36]. The risk of AF was higher in those with VTE than in those without after multivariable adjustment (hazard ratio 1.63, 95% CI 1.22-2.17). This risk was particularly high in the first six months after the VTE event. https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 5/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Obstructive sleep apnea AF is associated with pulmonary disease and obstructive sleep apnea in particular [39-44]. In a 2020 study of 188 consecutive patients with AF and no prior diagnosis of sleep apnea who were scheduled to undergo AF ablation, home sleep apnea testing was positive in 155 (82.4 percent), and of these 82 percent had a predominant obstructive component [45]. Among the 155 patients, sleep apnea was considered severe in 23.2 percent, moderate in 32.9 percent, and mild in 43.8 percent. Continuous positive airway pressure therapy was prescribed in 85.9 percent of the patients with moderate or severe sleep apnea. There is a possible causal relationship between obstructive sleep apnea (OSA) and AF [46-49]. In a series of 39 patients diagnosed with both PAF and OSA, patients receiving treatment with continuous positive pressure ventilation had a lower incidence of AF recurrence at 12 months (42 versus 82 percent for patients who were not treated) [46]. In another observational study, the incidence of OSA was compared between 151 patients referred for cardioversion for AF and 312 controls without AF referred for general cardiology evaluation [47]. OSA was significantly more common in the patients with AF than in the control group (49 versus 32 percent). Finally, preoperative sleep studies were performed in a series of 121 patients referred for coronary artery bypass surgery [48]. Postoperative AF was significantly more common among the 49 patients with an abnormal sleep study (39 versus 18 percent in patients with normal sleep studies). (See "Obstructive sleep apnea and cardiovascular disease in adults", section on 'Atrial fibrillation'.) 2 Obesity Obese individuals (body mass index [BMI] >30 kg/m ) are significantly more likely to 2 develop AF than those with a normal BMI (<25 kg/m ) [50-52]. In the Framingham Heart Study, every unit increase in BMI was associated with an approximate 5 percent increase in risk [53]. (See "Overweight and obesity in adults: Health consequences".) A primary mechanism for the role of obesity may be an increase in the size of the left atrium. Increased left atrial pressure and volume, often associated with diastolic dysfunction, as well as a shortened effective refractory period in the left atrium and in the proximal and distal pulmonary veins have been identified as potential factors facilitating and perpetuating AF in obese patients [54]. Inflammation and pericardial fat may also play a role [50]. (See "Mechanisms of atrial fibrillation" and 'Other factors' below.) There is some evidence to suggest that long-term weight loss is associated with a reduction of AF burden [51,55]. Diabetes In a study of over 4700 individuals without valvular heart disease in the Framingham Heart Study, the presence of diabetes was associated with a significantly increased risk for the development of AF in multivariate analysis (odds ratio 1.1 for men and 1.5 for https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 6/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate women) [56]. Increased left ventricular mass and increased arterial stiffness have been put forth as possible mechanisms [57]. Metabolic syndrome As discussed above, the presence of hypertension, diabetes, or obesity is associated with an increased likelihood of the development of AF. The metabolic syndrome includes these three, as well as dyslipidemia. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Definition'.) The potential relationship between the metabolic syndrome and the development of AF was evaluated in a prospective, observational cohort study of 28,449 Japanese citizens [58]. Using the 2005 criteria for the metabolic syndrome approved by the American Heart Association and the National Heart, Lung, and Blood Institute, 4544 individuals met criteria for the metabolic syndrome at baseline [59]. During a mean follow-up for 4.5 years, AF developed in 265 patients. The risk of developing AF was significantly greater in those individuals with the metabolic syndrome (hazard ratio 1.61, 95% CI 1.21-2.15), as well as in those with individual components of hypertension, obesity, low high density lipoprotein cholesterol and impaired glucose tolerance, but not elevated triglycerides. Chronic kidney disease Chronic kidney disease (CKD) increases the risk of the development of AF. The following two prospective, cohort studies are representative: In a study of 235,818 individuals, the hazard ratio for the development of AF was 1.32 for 2 patients with estimated glomerular filtration rates (eGFRs) of 30 to 59 mL/min/1.73m compared with those with normal renal function [60]. The relationship between CKD and AF was evaluated in a report of 10,328 individuals free of AF participating in the Atherosclerosis Risk in Communities (ARIC) study who had a baseline cystatin C-based estimated glomerular filtration rate (eGFR ) [61]. Compared 2 cys with individuals with eGFR 90 mL/min/m , the multivariable hazard ratios for the cys development of AF were significantly increased at 1.3, 1.6, and 3.2 in those with eGFR 2 of cys 60 to 89, 30 to 59, and 15 to 29 mL/min/m , respectively, during a median follow-up of 10.1 years. In addition, macroalbuminuria and microalbuminuria were significantly associated with higher AF risk. The incidence and prevalence of AF in patients with CKD are presented separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Chronic kidney disease'.) POTENTIALLY REVERSIBLE TRIGGERS https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 7/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate The medical conditions listed above, which are associated with an increased risk of the development of atrial fibrillation (AF), are chronic. Historically, it has been assumed that the risk of AF decreases after a non-chronic (secondary) condition has been corrected. However, there is some evidence to suggest that the risk remains. In the Framingham Heart Study, 1409 individuals with new onset AF were evaluated for their risk of subsequent occurrences based on whether they had a secondary precipitant or not [62]. A precipitant was found in 439 (31 percent) and included cardiothoracic surgery (30 percent), infection (23 percent), non-cardiothoracic surgery (20 percent), and acute myocardial infarction (18 percent). Other secondary precipitants included acute alcohol consumption, thyrotoxicosis, acute pericardial disease, acute pulmonary embolism, and other acute pulmonary pathology. While the 15-year cumulative incidence of recurrent AF was significantly lower among those with secondary causes (62 versus 71 percent), the finding that AF recurred in the majority with secondary causes was unexpected. Surgery AF occurs in relation to a variety of different types of surgery, with the incidence greatest in patients undergoing cardiac surgery: Cardiac surgery AF has been reported in up to 30 to 40 percent of patients in the early postoperative period following coronary artery bypass graft surgery (CABG) [63-66], in 37 to 50 percent after valve surgery [63,66,67], and in as many as 60 percent undergoing valve replacement plus CABG [63,66]. This topic is discussed in detail separately. (See "Atrial fibrillation and flutter after cardiac surgery".) Cardiac transplantation AF has been described in 10 to 24 percent of patients with a denervated transplanted heart, often in the absence of significant rejection [66,68]. Most episodes occur within the first two weeks, while AF developing after two weeks may be associated with an increased risk of subsequent death [68,69]. (See "Heart transplantation in adults: Arrhythmias", section on 'Supraventricular arrhythmias'.) Noncardiac surgery AF is less common after noncardiac compared with cardiac surgery. The reported incidence of new onset AF in patients undergoing noncardiac surgery ranges from 1 and 40 percent. This broad range is likely due to variability in patient and surgical characteristics [70,71]. The largest experience comes from a review of 4181 patients over the age of 50 who were in sinus rhythm prior to major noncardiac surgery [72]. The incidence of perioperative AF was 4.1 percent; most episodes occurred within the first three days after surgery. The risk was greatest with intrathoracic surgery (odds ratio 9.2). In another series of 2588 undergoing noncardiac thoracic surgery, the incidence of AF was 12.3 percent [73]. https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 8/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Hyperthyroidism Patients with hyperthyroidism have an increased risk of developing AF [74]. In one population-based study of 40,628 patients with clinical hyperthyroidism, 8.3 percent had AF or atrial flutter [75]. AF occurred in 10 to 20 percent of patients over age 60 but in less than 1 percent of patients under age 40. Men were more likely to have AF than women (12.1 versus 7.6 percent). (See "Cardiovascular effects of hyperthyroidism", section on 'Atrial fibrillation'.) Increased beta adrenergic tone may be in part responsible for the development of AF in hyperthyroidism and may also contribute to the rapid ventricular response in this setting. In addition, excess thyroid hormone increases the likelihood of AF in experimental animals, even in the presence of beta receptor and vagal blockade [76]; it is likely that this observation applies to humans. The mechanism is unknown, but may be related to an increased automaticity and enhanced triggered activity of pulmonary vein cardiomyocytes, which can be a source of ectopic beats that initiate AF [77]. The risk of AF is also increased in patients with subclinical hyperthyroidism (defined as a low serum thyroid stimulating hormone concentration and normal serum thyroid hormone concentrations) [78-80]. The increase in risk is illustrated by the following observations: In a prospective study, 2007 subjects 60 years of age who did not have AF were followed for 10 years [78]. The subsequent age-adjusted incidence of AF was significantly higher among those with a low serum thyroid stimulating hormone concentration compared with those with a normal value (28 versus 10 per 1000 person-years). In a review of 23,638 subjects, the prevalence of AF in those with clinical and subclinical hyperthyroidism was similar (14 and 13 percent, respectively) and higher than that in euthyroid subjects (2.3 percent) [79]. A possible relationship between AF and hypothyroidism has been suggested but not proven [81,82]. Since hypothyroidism is present in 5 to 10 percent of the general population, it is not surprising that some patients with AF have hypothyroidism (7.7 percent with subclinical disease in one report [80]) that may not be causally related. OTHER FACTORS A number of risk factors not discussed above are associated with an increased risk for the development of atrial fibrillation (AF). Family history The presence of AF in a first-degree relative, particularly a parent, has long been associated with an increase in risk, independent of standard risk factors such as age, sex, https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 9/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate hypertension, diabetes, or clinically overt heart disease [83]. (See 'Epidemiology' above and 'Chronic disease associations' above.) In an analysis of over 4400 individuals in the Framingham Heart Study, the occurrence of AF in a first degree relative was associated with a significantly increased risk of incident AF (multivariable-adjusted hazard ratio [HR] 1.40, 95% CI 1.13-1.74) [84]. The strength of this relationship was greater when only first-degree relatives with premature onset (age 65 years) were considered. Genetic factors For the vast majority of AF patients, we do not suggest genetic screening as it does not change clinical management. Exceptions are when there is concern for a rare disorder that has a high stroke risk irrespective of CHA DS -VASc score such as AF in Emery 2 2 Dreifuss muscular dystrophy or Lamin disorder. For most patients with AF, one or more of the nongenetic disease associations discussed above are present. However, evidence suggests that AF is heritable, and in younger patients, there may be increased genetic susceptibility of AF [85]. Among 1300 participants who underwent whole genome sequencing, disease-associated rare variants in cardiomyopathy and arrhythmia genes were identified in 10 percent of participants younger than 66 years and 17 percent of those younger than 30 years. Disease-associated rare variants were more prevalent in genes associated with inherited cardiomyopathy syndromes than inherited arrhythmia syndromes. The heritability of AF is complex. For the majority of patients, genetic susceptibility, if present, is probably a polygenic phenomenon, meaning that it is due to the combined effects of a number of genes. Polygenic inheritance can explain why some diseases cluster in families, but do not demonstrate the classic Mendelian inheritance patterns of monogenic disorders. However, a small number of families demonstrate monogenic inheritance characteristics. Polygenic inheritance Polygenic inheritance appears to be more common and could explain the modest elevation in the relative risk of AF in first- and second-degree relatives of affected individuals. Evidence supporting a heritable component to AF susceptibility includes: In a review of 914 patients with AF, 50 (5 percent) had a family history of AF (one to nine additional relatives affected) [86]. In an analysis of 2243 offspring in the Framingham Heart Study, those with parental AF had a significantly higher incidence of developing AF than those without parental AF (4.1 versus 2.7 percent, adjusted odds ratio 1.85) [83]. This effect was more pronounced when the https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 10/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate analysis was limited to patients with age of AF onset less than 75 years and to those without prior myocardial infarction, heart failure, or valve disease (odds ratio 3.17). A population study in Iceland evaluated the heritability of AF in a cohort of 5269 patients diagnosed over a 16-year period [87]. Among patients with AF, the degree of relatedness was significantly greater than among matched controls. In addition, the relative risk of developing AF was higher in the relatives of patients than those of controls. Monogenic inheritance Some families have been identified in which AF inheritance follows more typical Mendelian patterns, consistent with a single disease-causing gene. Both autosomal dominant and autosomal recessive forms have been identified. Genetic linkage analysis has identified loci at 10q22-q24, 11p15.5, 6q14-16, 3p22-p25, and 4q25 [88-92]. At the 4q25 locus, several single-nucleotide polymorphisms have been identified [93]. In these individuals, penetrance is variable and the polymorphisms can affect the clinical expression of familial AF [94]. An autosomal recessive pattern of AF inheritance was reported in a large family from Uruguay [95]. Clinical manifestations included AF during fetal life, neonatal sudden death, ventricular tachyarrhythmias, and waxing and waning cardiomyopathy. A genetic locus on chromosome 5p13 was linked to disease in this family. Chromosomal loci are large areas with multiple genes, and a specific genetic defect is not yet known for most loci. Examples of a monogenic cause of AF include: The 11p15.5 locus is associated with a gain-of-function mutation in the KVLQT1 (KCNQ1) gene, the protein product of which is the alpha-subunit of the slowly acting component of the outward-rectifying potassium current (IKs) [89]. This mutation is thought to initiate and maintain AF by reducing the action potential duration and effective refractory period in atrial myocytes. A different gain-of-function mutation in this gene has been associated with the congenital short QT syndrome, while loss-of-function mutations are associated with long QT syndrome, type 1. (See "Congenital long QT syndrome: Pathophysiology and genetics", section on 'Type 1 LQTS (LQT1)'.) An autosomal dominant form of AF, usually in association with a dilated cardiomyopathy, has been associated with mutations in SCN5A, the cardiac sodium channel gene. In a report of individuals with SCN5A mutations, 27 percent had early features of dilated cardiomyopathy (mean age at diagnosis 20 years), 43 percent had AF (mean age at https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 11/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate diagnosis 28 years), and 38 percent had dilated cardiomyopathy (mean age at diagnosis 48 years) [91]. (See "Genetics of dilated cardiomyopathy".) Mutations in SCN5A have also been identified in several other cardiac disorders, including the long QT syndrome, the Brugada syndrome, familial atrioventricular conduction block, and familial sinus node dysfunction. (See "Brugada syndrome: Epidemiology and pathogenesis" and "Congenital long QT syndrome: Pathophysiology and genetics" and "Etiology of atrioventricular block" and "Sinus node dysfunction: Epidemiology, etiology, and natural history".) Birth weight A possible relationship between birth weight and the development of AF was evaluated in a prospective study of nearly 28,000 women over the age of 45 years, who were free of AF at baseline [96]. The age-adjusted HRs (with <2.5 kg [5.5 pounds] being the referent group) for incident AF increased significantly (1, 1.3, 1.28, 1.7, and 1.71) from the lowest to the highest birth weight category (<2.5 [5.5], 2.5 [5.5] to 3.2 [7.1], 3.2 [7.1] to 3.9 [8.6], 3.9 [8.6] to 4.5, and >4.5 [9.9] kg [pounds]), during a median follow-up of 14.5 years. Inflammation and infection Inflammatory processes may play a role in the genesis of AF. Measurement of serum C-reactive protein (CRP), an acute phase reactant, has been used to assess the relationship between AF and inflammation. Observational studies have reported elevated serum levels of CRP in patient populations with any of the following characteristics: later (after known high CRP) development of AF [97], history of atrial arrhythmias [98], failed cardioversion [99], recurrence of AF after cardioversion [100], and development of AF after cardiac surgery. (See "Atrial fibrillation and flutter after cardiac surgery".) However, inflammation is more likely a marker for other conditions associated with AF, as opposed to being a direct cause or a perpetuating agent. The strongest evidence against a direct causal role for inflammation, as detected by an elevation in CRP, comes from a Mendelian randomization study that evaluated nearly 47,000 individuals in two cohorts from Copenhagen, Demark [101]. (See "Mendelian randomization".) The following observations were made: After multifactorial adjustment, a CRP level in the upper versus lower quintile was associated with a significantly increased risk of the development of AF (hazard ratio 1.77, 95% CI 1.22-2.55). Genotype combinations of four CRP polymorphisms were significantly associated with up to a 63 percent increase in plasma CRP levels, but not with an increased risk of the development of AF. https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 12/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Thus, inflammation, as determined by CRP, is not likely to be causative of AF. In addition to inflammation as detected by serum CRP, new onset AF and other acute cardiac events have been associated with pneumococcal pneumonia [102]. (See "Pneumococcal pneumonia in patients requiring hospitalization", section on 'Cardiac events and other noninfectious complications'.) The risk of AF increases after infection with the influenza virus [103]. Pericardial (epicardial) fat Pericardial fat, also referred to as epicardial fat, is the fat depot within the pericardial sac, which is in between the visceral and parietal pericardium. It has inflammatory properties: both obesity and inflammation are risk factors for AF [104,105]. In a study of 126 patients with AF and 76 controls, those with AF had a significantly higher pericardial fat volume (102 versus 76 ml) [104]. This was true for patients with either paroxysmal or persistent AF, and was independent of other traditional predictors of AF, including left atrial enlargement. Autonomic dysfunction The autonomic nervous system may be involved in the initiation and maintenance of AF. It may be particularly important in patients with paroxysmal AF, as both heightened vagal and sympathetic tone can promote AF. Vagal tone is predominant in normal hearts, which may explain why vagally-mediated AF is often seen in athletic young men without apparent heart disease who have slow heart rates during rest or sleep; such patients may also have an electrocardiogram (ECG) pattern of typical atrial flutter alternating with AF [106,107]. In comparison, AF induced by increased sympathetic tone may be observed in patients with underlying heart disease or during exercise or other activity [107]. (See "Paroxysmal atrial fibrillation", section on 'Pathogenesis'.) Findings on the electrocardiogram Abnormal QT or P-wave duration are associated with an increased risk of AF: Corrected QT interval Individuals with either congenital long QT syndrome or short QT syndrome have an increased risk of AF [108,109]. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Short QT syndrome".) The issue of whether there is an association between the corrected QT interval (QTc) and the risk of AF in the general population was addressed in a study of 281,277 individuals without baseline AF in the greater Copenhagen region who were followed for a median st period of 5.7 years after a first ECG [110]. Individuals with a QTc <372 ms (1 percentile) or th 419 ms (60 percentile) had an increased risk (adjusted hazard ratios [HRs] 1.45 up to 1.44, respectively) compared with the reference group (411 to 419 ms). The risk increased in a dose-dependent manner above 419 ms and was strongest among individuals with lone AF. https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 13/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate P-wave duration The relationship between P-wave duration and the risk of AF was evaluated in a study of nearly 285,933 individuals, of whom 9550 developed AF during a median follow-up period of 6.7 years [111]. Compared with the reference group (100 to 105 milliseconds [ms]), individuals with very short ( 89 ms; HR 1.6), intermediate (112 to 119 ms; HR 1.22), long (120 to 129; HR 1.5), and very long P wave duration ( 130 ms; HR 2.06) had an increased risk. Premature atrial complex PAC is important as a trigger of PAF (see 'Pathogenesis' above). The issue of whether they are predictor of incident AF was evaluated in a study of 1260 adults without prevalent AF who underwent 24-hour ambulatory ECG (Holter) monitoring at baseline [112]. During a median follow-up of 13.0 years, 27 percent developed incident AF. After adjusting for other known predictors of AF, PAC count (by quartile) was significantly associated with incident AF; the adjusted HRs comparing quartile 2, 3, and 4 with quartile 1 were 2.17, 2.79, and 4.92, respectively. Other supraventricular tachyarrhythmias Spontaneous transition between typical atrial flutter and AF has been observed, although little is known about the mechanism of this conversion [113,114]. In addition, AF is, in some patients, associated with paroxysmal supraventricular tachycardia (PSVT) [115-117]. The most common causes of PSVT are atrioventricular nodal re-entrant tachycardia and atrioventricular reentrant tachycardia, which occurs in patients with the Wolff-Parkinson-White syndrome or concealed accessory pathways. (See "Atrioventricular nodal reentrant tachycardia" and "Atrioventricular reentrant tachycardia (AVRT) associated with an accessory pathway".) The association between AF and PSVT was illustrated in a report that evaluated 169 patients who presented with PSVT and were followed by clinic visits and transtelephonic ECG monitoring during symptomatic episodes [115]. Nineteen percent had an episode of AF during a mean follow-up of 31 months. Neither the mechanism nor the rate of the PSVT was associated with the time to occurrence of AF. Enhanced vagal tone, as determined by baroreflex sensitivity, or an increase in dispersion of right atrial refractory periods may contribute to the development of AF associated with PSVT [118]. Alternatively, an atrial premature beat can cause stable PSVT to degenerate into AF. Among patients with Wolff-Parkinson-White syndrome, the mechanism of AF may be retrograde conduction via the accessory pathway of a premature beat, stimulating the atrial myocardium during its vulnerable period [119]. Ablation of the accessory pathway reduces the incidence of subsequent AF [119,120]. https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 14/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate

group) for incident AF increased significantly (1, 1.3, 1.28, 1.7, and 1.71) from the lowest to the highest birth weight category (<2.5 [5.5], 2.5 [5.5] to 3.2 [7.1], 3.2 [7.1] to 3.9 [8.6], 3.9 [8.6] to 4.5, and >4.5 [9.9] kg [pounds]), during a median follow-up of 14.5 years. Inflammation and infection Inflammatory processes may play a role in the genesis of AF. Measurement of serum C-reactive protein (CRP), an acute phase reactant, has been used to assess the relationship between AF and inflammation. Observational studies have reported elevated serum levels of CRP in patient populations with any of the following characteristics: later (after known high CRP) development of AF [97], history of atrial arrhythmias [98], failed cardioversion [99], recurrence of AF after cardioversion [100], and development of AF after cardiac surgery. (See "Atrial fibrillation and flutter after cardiac surgery".) However, inflammation is more likely a marker for other conditions associated with AF, as opposed to being a direct cause or a perpetuating agent. The strongest evidence against a direct causal role for inflammation, as detected by an elevation in CRP, comes from a Mendelian randomization study that evaluated nearly 47,000 individuals in two cohorts from Copenhagen, Demark [101]. (See "Mendelian randomization".) The following observations were made: After multifactorial adjustment, a CRP level in the upper versus lower quintile was associated with a significantly increased risk of the development of AF (hazard ratio 1.77, 95% CI 1.22-2.55). Genotype combinations of four CRP polymorphisms were significantly associated with up to a 63 percent increase in plasma CRP levels, but not with an increased risk of the development of AF. https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 12/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Thus, inflammation, as determined by CRP, is not likely to be causative of AF. In addition to inflammation as detected by serum CRP, new onset AF and other acute cardiac events have been associated with pneumococcal pneumonia [102]. (See "Pneumococcal pneumonia in patients requiring hospitalization", section on 'Cardiac events and other noninfectious complications'.) The risk of AF increases after infection with the influenza virus [103]. Pericardial (epicardial) fat Pericardial fat, also referred to as epicardial fat, is the fat depot within the pericardial sac, which is in between the visceral and parietal pericardium. It has inflammatory properties: both obesity and inflammation are risk factors for AF [104,105]. In a study of 126 patients with AF and 76 controls, those with AF had a significantly higher pericardial fat volume (102 versus 76 ml) [104]. This was true for patients with either paroxysmal or persistent AF, and was independent of other traditional predictors of AF, including left atrial enlargement. Autonomic dysfunction The autonomic nervous system may be involved in the initiation and maintenance of AF. It may be particularly important in patients with paroxysmal AF, as both heightened vagal and sympathetic tone can promote AF. Vagal tone is predominant in normal hearts, which may explain why vagally-mediated AF is often seen in athletic young men without apparent heart disease who have slow heart rates during rest or sleep; such patients may also have an electrocardiogram (ECG) pattern of typical atrial flutter alternating with AF [106,107]. In comparison, AF induced by increased sympathetic tone may be observed in patients with underlying heart disease or during exercise or other activity [107]. (See "Paroxysmal atrial fibrillation", section on 'Pathogenesis'.) Findings on the electrocardiogram Abnormal QT or P-wave duration are associated with an increased risk of AF: Corrected QT interval Individuals with either congenital long QT syndrome or short QT syndrome have an increased risk of AF [108,109]. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Short QT syndrome".) The issue of whether there is an association between the corrected QT interval (QTc) and the risk of AF in the general population was addressed in a study of 281,277 individuals without baseline AF in the greater Copenhagen region who were followed for a median st period of 5.7 years after a first ECG [110]. Individuals with a QTc <372 ms (1 percentile) or th 419 ms (60 percentile) had an increased risk (adjusted hazard ratios [HRs] 1.45 up to 1.44, respectively) compared with the reference group (411 to 419 ms). The risk increased in a dose-dependent manner above 419 ms and was strongest among individuals with lone AF. https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 13/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate P-wave duration The relationship between P-wave duration and the risk of AF was evaluated in a study of nearly 285,933 individuals, of whom 9550 developed AF during a median follow-up period of 6.7 years [111]. Compared with the reference group (100 to 105 milliseconds [ms]), individuals with very short ( 89 ms; HR 1.6), intermediate (112 to 119 ms; HR 1.22), long (120 to 129; HR 1.5), and very long P wave duration ( 130 ms; HR 2.06) had an increased risk. Premature atrial complex PAC is important as a trigger of PAF (see 'Pathogenesis' above). The issue of whether they are predictor of incident AF was evaluated in a study of 1260 adults without prevalent AF who underwent 24-hour ambulatory ECG (Holter) monitoring at baseline [112]. During a median follow-up of 13.0 years, 27 percent developed incident AF. After adjusting for other known predictors of AF, PAC count (by quartile) was significantly associated with incident AF; the adjusted HRs comparing quartile 2, 3, and 4 with quartile 1 were 2.17, 2.79, and 4.92, respectively. Other supraventricular tachyarrhythmias Spontaneous transition between typical atrial flutter and AF has been observed, although little is known about the mechanism of this conversion [113,114]. In addition, AF is, in some patients, associated with paroxysmal supraventricular tachycardia (PSVT) [115-117]. The most common causes of PSVT are atrioventricular nodal re-entrant tachycardia and atrioventricular reentrant tachycardia, which occurs in patients with the Wolff-Parkinson-White syndrome or concealed accessory pathways. (See "Atrioventricular nodal reentrant tachycardia" and "Atrioventricular reentrant tachycardia (AVRT) associated with an accessory pathway".) The association between AF and PSVT was illustrated in a report that evaluated 169 patients who presented with PSVT and were followed by clinic visits and transtelephonic ECG monitoring during symptomatic episodes [115]. Nineteen percent had an episode of AF during a mean follow-up of 31 months. Neither the mechanism nor the rate of the PSVT was associated with the time to occurrence of AF. Enhanced vagal tone, as determined by baroreflex sensitivity, or an increase in dispersion of right atrial refractory periods may contribute to the development of AF associated with PSVT [118]. Alternatively, an atrial premature beat can cause stable PSVT to degenerate into AF. Among patients with Wolff-Parkinson-White syndrome, the mechanism of AF may be retrograde conduction via the accessory pathway of a premature beat, stimulating the atrial myocardium during its vulnerable period [119]. Ablation of the accessory pathway reduces the incidence of subsequent AF [119,120]. https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 14/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Low serum magnesium In an observational study of over 3500 participants in the Framingham Offspring Study, individuals in the lower quartile of serum magnesium were approximately 50 percent more likely to develop AF compared with those in the upper quartiles after multivariable adjustment [121]. Alcohol Alcohol is both a chronic risk factor for the development of new AF and also an acute trigger for AF episodes. AF occurs in up to 60 percent of binge drinkers with or without an underlying alcoholic cardiomyopathy [122]. Most cases occur during and following weekends or holidays when alcohol intake is increased, a phenomenon that has been termed "the holiday heart syndrome." However, even modest amounts of alcohol (one to two drinks) can trigger AF in some patients [123]. In a case-crossover study, 100 individuals free of alcohol dependence and with AF wore transdermal ethanol sensors and continuous ECG monitors for four weeks. Among the 56 persons who had an AF episode during this time period, having had one alcoholic drink doubled the odds of having AF (odds ratio [OR] 2.02 [95% CI 1.38-3.17]) and having two or more alcohol drinks tripled the odds of having an AF episode (OR 3.58 [CI 1.63-7.89]) in the next four hours. This study demonstrated a probable dose-response relationship between the amount of alcohol consumed and the likelihood of triggering an AF episode. The evidence is mixed for long-term alcohol consumption being a risk factor for developing new AF. Moderate, long-term alcohol consumption was not shown to be a risk factor for AF in relatively small studies [56,124,125]. However, a positive association was found in a 2014 study of 79,019 men and women free from AF at baseline [126]. Compared with current drinkers of <1 drink per week, the multivariable risk ratios of AF were 1.01 (95% CI 0.94-1.09) for one to six drinks per week, 1.07 (95% CI 0.98-1.17) for 7 to 14 drinks per week, 1.14 (95% CI 1.01-1.28) for 15 to 21 drinks per week, and 1.39 (95% CI 1.22-1.58) for >21 drinks per week. Heavy alcohol consumption is associated with a greater increase in incidence of AF. Two large cohort studies found an increased incidence among men with heavy alcohol consumption (HR 1.45 in both) [127,128]. Neither study found a correlation between heavy alcohol use and AF in women, but the ability to detect such a correlation was limited by the small numbers of women with alcohol consumption in this range. Another study of 1055 cases of AF occurring during long-term follow-up found an increased risk (relative risk 1.34, 95% CI 1.01-1.78) with consumption of more than 36 grams per day (approximately >3 drinks/day) [125]. Caffeine There is a widespread belief that caffeine, particularly at high doses, is associated with palpitations and a number of arrhythmias, including AF and supraventricular and ventricular ectopy. However, despite the theoretical relationship between caffeine and arrhythmogenesis, there is no evidence in humans that ingestion of caffeine in doses typically https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 15/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate consumed can provoke AF or any other spontaneous arrhythmia [129]. (See "Cardiovascular effects of caffeine and caffeinated beverages", section on 'Arrhythmias'.) Fish and fish oil supplements Observational data has suggested that dietary fish intake or fish oil supplements, particularly those rich in long-chain n-3 fatty acids, may reduce the incidence of arrhythmias, although evidence is mixed with regard to both atrial and ventricular arrhythmias. (See "Overview of sudden cardiac arrest and sudden cardiac death", section on 'Fish intake and fish oil'.) With regard to dietary fish intake and incident AF, three cohort studies (approximately 45,000, 48,000, and 5000 individuals) found no relationship [130-132], while one (approximately 5000 individuals) suggested a reduction in AF burden [133]. Medications Certain medications can cause or contribute to the development of AF [134]. These include theophylline [135], adenosine [136], and, since increased vagal tone can induce AF [107], drugs that enhance vagal tone, such as digitalis. (See 'Autonomic dysfunction' above.) Bisphosphonates (eg, alendronate, risedronate, etidronate) are widely used in the treatment of osteoporosis, and concern has been raised that these drugs can cause AF. The weight of evidence suggests that the risk of AF from oral bisphosphonates is small, if it exists at all. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Atrial fibrillation'.) Case-control studies have suggested a modest increased risk for the development of AF in patients taking nonsteroidal anti-inflammatory drugs [137-140]. However, the absence of an accepted biologic mechanism and the susceptibility of case-control studies to unmeasured confounders makes us cautious about the strength of this association [141]. Certain antiarrhythmic drugs may increase the risk of AF. A 2020 scientific statement from the American Heart Association details drugs associated with AF [142]. While exhaustive, this statement includes many medications for which the association with AF is likely relatively weak. Ivabradine, a selective blocker of the I channel that slows the sinus rate, has been associated f with a higher incidence of AF [143]. A meta-analysis of 11 studies suggests a 15 percent excess of AF in patients treated with ivabradine [144]. Regular physical activity The relationship between physical activity and the development of AF is uncertain. Some [145-147], but not all [148-150], studies have suggested that regular physical activity is associated with a risk of AF in the general population. In a 2013 meta-analysis of four prospective cohorts (n = 43,672), and after dividing subjects into four or five groups on the basis of cumulative physical activity per week, there was no difference in the risk of AF https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 16/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate comparing patients in the maximum and minimal groups (odds ratio 1.08, 95% CI 0.97-1.21) [151]. Air pollution Air pollution, and specifically fine particulate matter, is associated with increased cardiovascular disease mortality. (See "Overview of possible risk factors for cardiovascular disease", section on 'Air pollution'.) Whether air pollution is associated with episodes of AF was evaluated in a study of 176 patients with dual chamber implantable cardioverter-defibrillators that were capable of detecting episodes of AF. After follow-up of nearly two years, there were 328 episodes of AF lasting 30 seconds or more found in 49 patients [152]. The potential impact of multiple parameters of air pollution, (measured hourly) on the development of AF was examined. The odds of AF increased significantly as the concentration of particulate matter increased in the two hours prior to the event. Night shift work Data from The United Kingdom Biobank study showed that both current and lifetime night shift exposures were associated with increased AF risk, regardless of genetic AF risk [153]. This cohort had 283,657 participants with 5777 incident AF events over an approximately 10-year follow-up. Usual or permanent night shift workers (4 percent), compared with day workers (83 percent), had higher risks of AF (HR 1.16, 95% CI 1.02-1.32). Workers with a >10-year duration of night shifts (2.4 percent) had a higher AF risk compared with day workers (HR 1.18, 95% CI 0.99-1.40). Workers with three to eight night shifts per month but not <3 per month or >8 per month had an increased risk of developing AF (HR 1.22, 95% CI 1.02-1.45; HR 0.88, 95% CI 0.64 1.21; HR 1.05, 95% CI 0.86-12.8, respectively). A potential limitation of this study is the inability to fully account for underlying socioeconomic factors. A limitation of this sub-analysis was relatively low AF event rates in the group with <3 and >8 shifts per month. Whether decreasing or stopping shift work protects against later AF is uncertain. RISK PREDICTION MODELS Models that attempt to predict the risk of development of atrial fibrillation (AF) have been developed but are not widely employed. Using the Framingham Heart Study population, age, sex, systolic blood pressure, treatment for hypertension, PR interval, clinically significant cardiac murmur, body mass index, and heart failure were incorporated into a risk prediction model that predicts an individual's absolute risk over 10 years [154]. This model has been validated in two geographically and racially diverse cohorts in the age range of 45 to 95 years and predicted the five-year incidence of AF with https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 17/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate moderate accuracy (C statistic 0.66 to 0.68) [155]. Other models have been studied, including one in a racially diverse population [156]. However, the benefit of using risk prediction models in this setting has not been established. There are no studies linking this with improved outcomes. PREVENTION For many risk factors of AF, preventive strategies that significantly reduce risk of incident AF have not been identified. The following are possible preventive strategies: Healthy fats There is weak evidence that dietary modifications such as extra virgin olive oil or n-3 polyunsaturated fatty acids in fish oil lower the risk of the development of AF [157,158]. Mediterranean diet The PREDIMED primary prevention trial found that a Mediterranean diet enriched with either extra virgin olive oil or mixed nuts reduces the incidence of stroke, MI, and cardiovascular mortality [159] (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Diet'.) In a post-hoc analysis of PREDIMED, the group that received the Mediterranean diet supplemented with extra virgin olive oil had a lower risk of development of AF compared with the control group (hazard ratio [HR] 0.62; 95% CI 0.45-0.85) [160]. Blood pressure lowering Among patients with hypertension, a study suggests that lowering blood pressure reduced the risk of the development of AF. In the SPRINT trial, intensive compared with standard blood pressure lowering was associated with a lower risk of developing new AF (HR 0.74, 95% CI 0.56-0.98) [161]. (See "Goal blood pressure in adults with hypertension".) Cardiac pacing The role of pacing for the prevention of AF is discussed separately. (See "The role of pacemakers in the prevention of atrial fibrillation".) Although cardiac resynchronization therapy (CRT) improves some potential risk factors for AF. such as atrial size and left ventricular systolic function, CRT has not been shown to decrease the incidence of new or recurrent AF. This is discussed in detail separately. (See "Cardiac resynchronization therapy in atrial fibrillation".) https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 18/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate SUMMARY Epidemiology The incidence and prevalence of atrial fibrillation (AF) depends upon the population studied and the intensity of monitoring. Both increase significantly with increasing age. (See 'Epidemiology' above.) Chronic disease associations Hypertensive heart disease and coronary heart disease are the most common chronic disease associations in patients with AF in developed countries. Other frequent causes include alcohol excess, heart failure, valvular heart disease including both regurgitant and stenotic lesions, and hyperthyroidism. (See 'Chronic disease associations' above.) AF occurs in relation to a variety of different types of surgery; the incidence is greatest in patients undergoing coronary artery bypass graft or cardiac valve surgery. (See 'Chronic disease associations' above.) Chronic, heavy alcohol use does increase the risk of AF in men, while the impact of heavy alcohol use in women is less clear. Chronic moderate alcohol use does not appear to increase the incidence of AF in men or women. (See 'Chronic disease associations' above.) Genetic factors The heritability of AF is complex. For the majority of patients, genetic susceptibility, if present, is probably a polygenic phenomenon, meaning that it is due to the combined effects of a number of genes. (See 'Genetic factors' above.) Risk Prediction Models to predict the risk of subsequent AF have been developed. However, a benefit from using such models has not been established. (See 'Risk prediction models' above.) Prevention There is some evidence that dietary intake of healthy fats, a Mediterranean diet, and blood pressure lowering can prevent the onset of AF. (See 'Prevention' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 19/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate 1. Benjamin EJ, Wolf PA, D'Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98:946. 2. Chugh SS, Blackshear JL, Shen WK, et al. Epidemiology and natural history of atrial fibrillation: clinical implications. J Am Coll Cardiol 2001; 37:371. 3. Patel NJ, Deshmukh A, Pant S, et al. 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Effect of Intensive Blood Pressure Lowering on the Risk of Atrial Fibrillation. Hypertension 2020; 75:1491. Topic 1004 Version 58.0 https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 30/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate GRAPHICS Prevalence of atrial fibrillation by sex and age Lifetime risk for developing atrial fibrillation (AF) from the Framingham Heart Study. Men and women without AF at 40 years of age were determined to have a 26 and 23 percent likelihood of developing incident AF by 80 years of age. Reproduced with permission from: Magnani JW, Rienstra M, Lin H, et al. Atrial brillation: Current knowledge and future directions in epidemiology and genomics. Circulation 2011; 124:1982. Copyright Lippincott Williams & Wilkins. Graphic 82929 Version 4.0 https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 31/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Prevalence of atrial fibrillation with age In a cross-sectional study of almost 1.9 million men and women, the prevalence of atrial fibrillation increases with age, ranging from 0.1 for those <55 years of age to over 9 percent in those 85 years of age. At all ages, the prevalence is higher in men than women. Data from Go AS, Hylek EM, Phillips K, et al. Prevalence of diagnosed atrial brillation in adults: National implications for rhythm management and stroke prevention: The AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285:2370. Graphic 77268 Version 5.0 https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 32/33 7/5/23, 11:15 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Contributor Disclosures David Spragg, MD, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 33/33

7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Heart transplantation in adults: Arrhythmias : Howard J Eisen, MD, FACC, FAHA, FHFSA, FAST, Luke S Kusmirek, MD, FACC : Sharon A Hunt, MD : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 03, 2021. INTRODUCTION Cardiac arrhythmias are common in the orthotopic heart transplant recipient, particularly in the early postoperative period. Premature atrial complexes and premature ventricular complexes are especially frequent, with a reported incidence of over 60 percent. Fortunately, these arrhythmias have little clinical importance. However, other cardiac arrhythmias, such as sinus node dysfunction and ventricular tachycardia, may result in significant morbidity or mortality. Prognosis and other clinical issues following cardiac transplantation are discussed separately. (See "Heart transplantation in adults: Prognosis" and "Heart transplantation in adults: Induction and maintenance of immunosuppressive therapy" and "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy" and "Heart Transplantation: Prevention and treatment of cardiac allograft vasculopathy" and "Heart transplantation in adults: Graft dysfunction" and "Heart transplantation in adults: Diagnosis of allograft rejection" and "Heart transplantation in adults: Treatment of acute allograft rejection" and "Heart transplantation in adults: Exercise-based rehabilitation for transplant recipients" and "Heart transplantation in adults: Pregnancy after transplantation" and "Heart transplantation: Hyperlipidemia after transplantation" and "Malignancy after solid organ transplantation".) MECHANISMS There are several mechanisms for arrhythmogenesis in the transplanted heart, with early postoperative arrhythmias resulting from different mechanisms than those occurring later. https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 1/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate Surgical trauma to the sinoatrial and atrioventricular nodes, ischemia during preservation, surgical suture lines, and, over the long term, rejection and accelerated atherosclerosis may contribute to the formation of an arrhythmogenic substrate. As an example, one autopsy study of 18 hearts found that acute rejection involved the conduction system as severely as the myocardium [1]. With chronic rejection, there was often obstructive vasculopathy of the sinus node artery. In occasional cases, severe rejection isolated to the conduction system with sparing of the rest of the myocardium occurs and presents as bradycardia with syncope [2]. In addition, the denervated donor heart has increased sensitivity to sympathetic amines, adenosine, and acetylcholine, which may contribute to both tachyarrhythmias and bradyarrhythmias [3-5]. The sympathetic effect may be presynaptic in origin; it is not due to increased beta receptor density [3,4]. Because of this increased sinus node sensitivity, adenosine should generally not be used (as it often used is in other patient populations) to slow the rate in supraventricular tachyarrhythmias to elucidate the underlying arrhythmia mechanism. Such use can result in prolonged bradycardia or a period of asystole. Cautious use of IV adenosine in selected pediatric and young adult transplant patients was well tolerated in one single center study [6]. SINUS RATE In the denervated heart, the normal resting sinus rate is usually greater than 80 bpm and may exceed 100 bpm in hearts transplanted from young donors. The heart rate is higher than in normals because of the loss of vagal neural inputs, which have a negative chronotropic effect. (See "Sinus tachycardia: Evaluation and management".) Partial reinnervation of cardiac sympathetic nerves after transplantation occurs in about one- third of patients at one year [7-10]. The process of reinnervation continues gradually for up to 15 years but is regionally heterogeneous [10,11]. Reinnervation of the sinus node is accompanied by partial restoration of the normal heart rate response to exercise [8,9]. Vagal innervation appears to be absent in the majority of patients for up to 96 months after transplant [12]. Vagal reinnervation may depend upon surgical technique; it occurs more commonly with bicaval compared with the standard biatrial surgery [13]. Standard biatrial surgery transects about 50 percent of sympathetic fibers, but most recipient vagus nerve trunks remain intact. As a result, there is a stimulus for sympathetic fiber, but not vagal fiber, https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 2/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate regeneration. In contrast, bicaval surgery transects both sympathetic and parasympathetic fibers and regeneration may be stimulated in both branches. Persistent post-transplant sinus tachycardia is associated with decreased long-term survival. The role of agents to reduce heart rate (beta blocker or ivabradine) in this setting has not been established. A preliminary observational study found that 2 year survival was higher in patients treated with ivabradine compared to patients treated with metoprolol [14]. Further study is required to determine the efficacy of these drugs in this setting. SINUS NODE DYSFUNCTION Prevalence and causes Sinus node dysfunction (SND), which is usually manifested by a relative bradycardia, occurs in up to 50 percent of patients in the first several weeks following transplantation [15-17]. Although this early abnormality does not appear to affect mortality [18,19], sinus bradycardia may result in significant morbidity from decreased cardiac output. In a series of 1179 heart transplants (91 percent with biatrial technique) performed over 35 years, 11.5 percent required pacemaker implantation to treat bradycardia; 86 percent of patients requiring a pacemaker had SND [19]. Independent risk factors for pacemaker implantation were prolonged operative time and a biatrial anastomosis. (See "Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation" and "Sinus node dysfunction: Epidemiology, etiology, and natural history".) In cardiac transplant recipients with SND, intact atrioventricular nodal function is usually present; thus, atrial pacing is often sufficient but usually delivered with a dual chamber pacemaker capable of ventricular backup pacing if needed [20]. Lead dislodgement during endomyocardial biopsy rarely occurs. (See "Permanent cardiac pacing: Overview of devices and indications".) Potential causes of SND include ischemia during hypothermic preservation; surgical trauma to the sinus node, perinodal atrial tissue, or sinoatrial artery; pretransplant use of amiodarone; and immunologic processes such as rejection [17,21]. In one series, for example, patients who required permanent pacemakers for sinus bradycardia had a significantly higher prevalence of abnormal sinoatrial nodal arteries when compared to a control group of heart transplant recipients with normal sinus node function [22]. Surgical trauma to the sinoatrial artery can be avoided by performing a bicaval anastomosis rather than the standard biatrial anastomosis [19,23,24]; thus, the bicaval technique has become the most commonly used procedure in transplant centers [25]. This technique consists of total excision of the right atrium with a minimum cuff of left atrium remaining around the four https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 3/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate pulmonary veins, followed by direct anastomoses of the donor and recipient vena cavae. It appears to be associated with a decreased incidence of SND [26-28]. In a prospective series of 70 orthotopic heart transplant recipients undergoing either a standard biatrial or a bicaval anastomosis, the incidence of SND, as determined by atrial pacing techniques, was much lower with bicaval anastomosis (5 versus 44 percent) [28]. This finding was confirmed in a United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) database analysis of 20,999 recipients indicating that those transplanted utilizing bicaval anastomosis had lesser need for pacemaker therapy and improved long-term survival [29]. Several studies have suggested correlation of bradycardia with the donor ischemic time [16,30,31]; however, in other series, the donor ischemic time was not significantly different for orthotopic heart transplant recipients who required implantation of a permanent pacemaker for sinus bradycardia compared with those without this complication [19,22]. A separate UNOS/OPTN database analysis of 35,987 patients reported a 10.9 percent incidence of pacemaker-requiring bradyarrhythmias [32]. A biatrial anastomosis as well as greater recipient and donor age were the only factors associated with increased permanent pacemaker requirement. Pacemaker implantation had no adverse effect on survival; in fact, survival was better in pacemaker recipients as compared to those not receiving a pacemaker. Treatment of sinus bradycardia Normalization of post-transplant SND and bradyarrhythmias occurs spontaneously in up to 55 percent of patients during the first three postoperative months and a conservative strategy is reasonable in the early postoperative period [15]. The administration of theophylline [33,34] terbutaline [35], or albuterol has been advocated to increase the sinus rate and avoid implantation of a permanent pacemaker during the first three postoperative months. Studies comparing the acute effects of these agents, however, have demonstrated only a modest shortening of the sinus node cycle length and recovery time, with incomplete correction of the underlying sinus node abnormality [36,37]. Thus, these drugs are probably best reserved for patients with only mild or moderate SND or those with postoperative bradycardia due to prior amiodarone use. Atropine is not an effective treatment for bradycardia in the transplanted heart when vagal innervation is absent. Intravenous isoproterenol is suggested in the unlikely event that emergency treatment of bradycardia is needed in the heart transplant patient who does not have pacemaker wires in place. Patients with more severe bradycardia that persists for more than two weeks after transplantation usually require a permanent pacemaker; a rate-responsive dual chamber or https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 4/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate atrial pacemaker implanted in the donor right atrium (if intact atrioventricular conduction is present) is recommended [38]. (See "Modes of cardiac pacing: Nomenclature and selection".) The role of biventricular pacing is not known in cardiac transplant recipients who fulfill the criteria used for such therapy in nontransplant patients. Successful implementation of cardiac resynchronization therapy in heart transplant patients has been reported [39]. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) CONDUCTION DISTURBANCES The most common conduction abnormality following orthotopic heart transplant is a new right bundle branch delay not present on the donor electrocardiogram (ECG) prior to transplantation. This can occur in up to 70 percent of patients and is usually manifest as an incomplete right bundle branch block present immediately postoperatively [40]. The conduction abnormality may persist and, in one study, was associated with prolonged donor ischemic time and multiple episodes of rejection [41]. These findings were corroborated in a later report in which early RBBB was correlated with transpulmonary gradient before orthotopic heart transplant and late occurrence was correlated with higher rejection scores [42]. The incidence of RBBB was higher with biatrial versus bicaval anastomosis. Potential mechanisms for later right bundle branch block include right ventricular hypertrophy from elevated pulmonary pressures or damage to the right bundle from endomyocardial biopsy sampling of the right ventricular septal wall. (See "Right bundle branch block".) Although the transplanted heart is denervated, atrioventricular (AV) nodal function is intact and the ability of the AV node to adapt to exercise with a shortening of the PR interval is retained since it remains sensitive to circulating catecholamines [43]. High grade AV block is uncommon, particularly in the early postoperative period [16]. Although pacemaker implantation is performed in approximately 10 to 15 percent of cardiac transplant recipients, AV block accounts for less than 20 percent of these cases [22,44,45] and median time to pacemaker implantation is later for AV block than for sinus node dysfunction (eg, 1511 versus 27 days [19]). The late development of heart block has been associated with an increase in mortality, often from transplant arteriopathy [46]. (See "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy".) Indications for pacemaker placement are the same as for other patients with symptomatic bradyarrhythmias or chronotropic incompetence that are not expected to resolve. Patients who undergo bicaval cardiac transplants are less likely to require permanent cardiac pacing than https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 5/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate those who undergo biatrial cardiac transplants [47] (see "Permanent cardiac pacing: Overview of devices and indications"). SUPRAVENTRICULAR ARRHYTHMIAS Atrial premature beats Isolated premature atrial complex (PAC; also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat) and nonsustained atrial dysrhythmias are common in the early postoperative period, occurring in up to 76 percent of patients [16,48,49]. (See "Supraventricular premature beats".) The prevalence is lower at long-term follow-up, decreasing from 55 percent in the early postoperative period to 30 percent at mean of 24 months after transplantation in one report [48]. There are conflicting data on whether PACs occur with increased frequency during episodes of rejection [49,50]. Atrial fibrillation or flutter Reports of patients with atrial fibrillation (AF) or atrial flutter following cardiac transplantation have variably included perioperative and late arrhythmia. Atrial fibrillation has been described in 10 to 24 percent of patients [51-53], while atrial flutter has been described in 12 to 15 percent [49,53]. These arrhythmias often occur in the absence of significant rejection, although this has not been found in all reports [49,51,52,54]. Most episodes of AF occur within the first 30 to 60 days after transplantation with incidence ranging from 5 to 11 percent in large, single center experiences. This relatively low rate, compared to typical post-pericardiectomy AF incidence is postulated to be due to surgical pulmonary vein isolation and cardiac denervation, which occurs with the heart transplantation surgery. Patients treated with long-term amiodarone therapy prior to heart transplantation have less early postoperative atrial fibrillation with no adverse impact on mortality [55]. Late AF develops in 5 to 10 percent of patients and is associated with decrease in systolic function and increased overall mortality [51,53,56,57]. Atrial flutter may be a more common late arrhythmia [49]. Atrial flutter that occurs in the absence of rejection is a result of a macroreentrant circuit in a counterclockwise direction around the tricuspid ring, similar to that seen in typical atrial flutter in normal hearts [58-60]. This circuit includes the isthmus between the tricuspid valve and the inferior vena cava, referred to as the cavotricuspid isthmus. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) The cause of atrial dysrhythmias during rejection is not known. It is possible that the patchy nature of rejection results in heterogeneous impairment of atrial conduction and refractoriness, https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 6/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate allowing for the formation of multiple microreentrant circuits. In addition, atrial hemodynamics may be altered by the reduced ventricular function and compliance that occur during rejection. (See "The electrocardiogram in atrial fibrillation".) Treatment of these arrhythmias includes control of the ventricular response rate and, if warranted, immunosuppressive therapy for rejection. Overdrive pacing can be performed at the time of myocardial biopsy with more than a 90 percent success in terminating atrial flutter [54]. There are case reports and small series of successful radiofrequency ablation of atrial flutter in transplanted hearts [59,60]. Interestingly, the usual suture line between the donor and recipient heart lies within the cavo-tricuspid isthmus, which, as noted above, is a critical component of the circuit of typical atrial flutter. In a series of six cardiac transplant recipients undergoing cardiac electrophysiologic studies (EPS) for atrial flutter, only the tissue below the suture line from the donor heart was part of the macroreentrant circuit. In all of these cases, ablation from the tricuspid annulus to the suture line, rather than all the way to the inferior vena cava (IVC), successfully eliminated atrial flutter [60]. Macroreentry based on the gaps in the atrial anastomosis line and microreentrant/focal atrial tachycardias successfully treated with radiofrequency ablation have been described [61,62]. (See "Restoration of sinus rhythm in atrial flutter".) Heart transplant guidelines do not discuss anticoagulation in the setting of heart transplant patients with atrial fibrillation or atrial flutter. Standard guidelines for anticoagulation in patients with atrial fibrillation or atrial flutter should be followed in heart transplant patients. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Supraventricular tachycardias A variety of supraventricular arrhythmias can occur in orthotopic heart transplant recipients, including atrioventricular (AV) reentrant tachycardia involving a concealed AV bypass tract [63-65], Wolff-Parkinson-White syndrome [66,67], and sustained atrial tachycardias [52,68]. Radiofrequency catheter ablation has been performed in many of these patients with success and complication rates similar to nontransplant recipients [65,67,68]. (See "Narrow QRS complex tachycardias: Clinical manifestations, diagnosis, and evaluation" and "Overview of catheter ablation of cardiac arrhythmias", section on 'Introduction'.) Interaction of diltiazem with immunosuppressive agents Clinicians should be aware of drug interaction between diltiazem and immunosuppressive agents. Intravenous diltiazem is often used to control ventricular rates in patients with SVTs and/or atrial fibrillation. Diltiazem inhibits CYP3A, which metabolizes tacrolimus and cyclosporine. Consequently, heart transplant https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 7/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate patients receiving diltiazem often have elevated tacrolimus or cyclosporine levels which can result in renal dysfunction [69]. VENTRICULAR ARRHYTHMIAS Ventricular premature beats and nonsustained ventricular tachycardia Ventricular premature beats (VPBs) are common in the early post-transplant period, occurring in up to 100 percent of patients [16,49]. (See "Premature ventricular complexes: Clinical presentation and diagnostic evaluation".) The incidence of VPBs decreases after the early postoperative period and does not appear to be associated with rejection or other factors. The frequency of nonsustained ventricular tachycardia (NSVT) also decreases over time [48]. However, some studies have demonstrated an association with both rejection and coronary atherosclerosis (cardiac allograft vasculopathy) [16,70]. In one small series, for example, complex ventricular ectopy (multifocal VPBs and couplets) occurring in the late transplant period was also more prevalent in patients with severe cardiac allograft vasculopathy [50]. (See "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy".) Sustained ventricular arrhythmias and sudden cardiac death Standard recommendations for ICD therapy apply to cardiac transplant recipients. Antiarrhythmic drug therapy is based on safety, tolerability, and clinical experience as limited published evidence is available for these drugs in cardiac transplant recipients. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis".) Sustained ventricular arrhythmias are uncommon in the donor heart; when they occur, they are usually associated with either severe transplant cardiac allograft vasculopathy or allograft rejection [71]. Ventricular fibrillation has been reported in patients hospitalized for severe allograft rejection [72,73], while autopsy studies of patients with sudden cardiac death have demonstrated a high prevalence of severe cardiac allograft vasculopathy or recent myocardial infarctions [72,74]. Although ventricular tachyarrhythmias are thought to be the mode of sudden cardiac death, severe bradycardic events as well as electromechanical dissociation may also occur due to advanced atherosclerosis [75]. Limited outcome data exist for implantable cardioverter-defibrillator therapy (ICD) in heart transplant recipients. ICD therapy has been reported to effectively terminate ventricular arrhythmias in transplanted patients with severe left ventricular dysfunction, severe allograft https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 8/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate vasculopathy, or history of cardiac arrest [76]. The effect of ICD therapy on long-term survival and quality of life in this population is not known. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topic (see "Patient education: Heart transplantation (Beyond the Basics)") SUMMARY While most arrhythmias after orthotopic heart transplantation are benign, there are several clinical associations with which the physician must be familiar: Early postoperative bradyarrhythmias due to sinus node dysfunction (SND) are probably caused by surgical trauma to the sinoatrial node or its blood supply and can partly be avoided using a bicaval anastomosis technique. (See 'Sinus node dysfunction' above.) Atropine is not an effective treatment for bradycardia when vagal innervation is absent; intravenous isoproterenol is suggested in the unlikely event that emergency treatment of https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 9/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate bradycardia is needed in the heart transplant patient without pacemaker wires in place. (See 'Treatment of sinus bradycardia' above.) Sustained atrial flutter and fibrillation are commonly associated with allograft rejection. Thus, the presence of these arrhythmias should prompt a search for acute rejection by endomyocardial biopsy. Empiric steroid therapy should be considered in such patients prior to return of the biopsy results. Adenosine should not be used to try to elucidate the mechanism of supraventricular tachyarrhythmias since it can result in transient, but significant, bradyarrhythmias. (See 'Atrial fibrillation or flutter' above and "Heart transplantation in adults: Treatment of acute allograft rejection".) Complex ventricular ectopy or atrioventricular block may be caused by either acute rejection or severe cardiac allograft vasculopathy. Affected patients should undergo endomyocardial biopsy followed, if rejection is not present, by coronary angiography to diagnose cardiac allograft vasculopathy. (See 'Ventricular arrhythmias' above and 'Conduction disturbances' above and "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy".) Insertion of a permanent pacemaker should be considered in patients with significant bradyarrhythmias, either from SND or high grade atrioventricular (AV) block, that are associated with decreased cardiac output and occur in the absence of acute rejection. (See 'Treatment of sinus bradycardia' above and 'Conduction disturbances' above.) Patients with frequent and symptomatic supraventricular tachycardia may be treated with radiofrequency catheter ablation. (See 'Supraventricular tachycardias' above.) Standard recommendations for ICD therapy apply to cardiac transplant recipients. Antiarrhythmic drug therapy is based on safety, tolerability, and clinical experience as limited published evidence is available for these drugs in cardiac transplant recipients. (See 'Ventricular arrhythmias' above and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis".) Use of UpToDate is subject to the Terms of Use. 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Mechanism and location of atrial flutter in transplanted hearts: observations during transient entrainment from distant sites. J Am Coll Cardiol 1997; 30:539. 59. Pinski SL, Bredikis AJ, Winkel E, Trohman RG. Radiofrequency catheter ablation of atrial flutter after orthotopic heart transplantation: insights into the redefined critical isthmus. J Heart Lung Transplant 1999; 18:292. 60. Marine JE, Schuger CD, Bogun F, et al. Mechanism of atrial flutter occurring late after orthotopic heart transplantation with atrio-atrial anastomosis. Pacing Clin Electrophysiol 2005; 28:412.

21. Mason JW, Harrison DC. Electrophysiology and electropharmacology of the transplanted hu man heart. In: Cardiac Arrhythmias: Electrophysiology, Diagnosis and Management, Narula OS (Ed), Williams & Wilkins, Baltimore 1979. p.66. 22. DiBiase A, Tse TM, Schnittger I, et al. Frequency and mechanism of bradycardia in cardiac transplant recipients and need for pacemakers. Am J Cardiol 1991; 67:1385. 23. Dreyfus G, Jebara V, Mihaileanu S, Carpentier AF. Total orthotopic heart transplantation: an alternative to the standard technique. Ann Thorac Surg 1991; 52:1181. 24. Sarsam MA, Campbell CS, Yonan NA, et al. An alternative surgical technique in orthotopic cardiac transplantation. J Card Surg 1993; 8:344. 25. Aziz TM, Burgess MI, El-Gamel A, et al. Orthotopic cardiac transplantation technique: a survey of current practice. Ann Thorac Surg 1999; 68:1242. 26. Deleuze PH, Benvenuti C, Mazzucotelli JP, et al. Orthotopic cardiac transplantation with direct caval anastomosis: is it the optimal procedure? J Thorac Cardiovasc Surg 1995; 109:731. https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 12/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate 27. el Gamel A, Yonan NA, Grant S, et al. Orthotopic cardiac transplantation: a comparison of standard and bicaval Wythenshawe techniques. J Thorac Cardiovasc Surg 1995; 109:721. 28. Rothman SA, Jeevanandam V, Combs WG, et al. Eliminating bradyarrhythmias after orthotopic heart transplantation. Circulation 1996; 94:II278. 29. Davies RR, Russo MJ, Morgan JA, et al. Standard versus bicaval techniques for orthotopic heart transplantation: an analysis of the United Network for Organ Sharing database. J Thorac Cardiovasc Surg 2010; 140:700. 30. Heinz G, Ohner T, Laufer G, et al. Demographic and perioperative factors associated with initial and prolonged sinus node dysfunction after orthotopic heart transplantation. The impact of ischemic time. Transplantation 1991; 51:1217. 31. Miyamoto Y, Curtiss EI, Kormos RL, et al. Bradyarrhythmia after heart transplantation. Incidence, time course, and outcome. Circulation 1990; 82:IV313. 32. Cantillon DJ, Tarakji KG, Hu T, et al. Long-term outcomes and clinical predictors for pacemaker-requiring bradyarrhythmias after cardiac transplantation: analysis of the UNOS/OPTN cardiac transplant database. Heart Rhythm 2010; 7:1567. 33. Redmond JM, Zehr KJ, Gillinov MA, et al. Use of theophylline for treatment of prolonged sinus node dysfunction in human orthotopic heart transplantation. J Heart Lung Transplant 1993; 12:133. 34. Ellenbogen KA, Szentpetery S, Katz MR. Reversibility of prolonged chronotropic dysfunction with theophylline following orthotopic cardiac transplantation. Am Heart J 1988; 116:202. 35. Cook LS, Will KR, Moran J. Treatment of junctional rhythm after heart transplantation with terbutaline. J Heart Transplant 1989; 8:342. 36. Rothman SA, Jeevanandam V, Seeber CP, et al. Electrophysiologic effects of intravenous aminophylline in heart transplant recipients with sinus node dysfunction. J Heart Lung Transplant 1995; 14:429. 37. Rothman SA, Jeevanandam V, Hsia H, et al. A comparison of the electrophysiologic effects of aminophylline and terbutaline in heart transplant recipients with sinus node dysfunction (abstract). Circulation 1995; 92(Suppl 1):I. 38. Melton IC, Gilligan DM, Wood MA, Ellenbogen KA. Optimal cardiac pacing after heart transplantation. Pacing Clin Electrophysiol 1999; 22:1510. 39. Mariani JA, McDonald MA, Nanthakumar K, et al. Cardiac resynchronization therapy after atrioventricular node ablation for rapid atrial fibrillation in a heart transplant recipient with late allograft dysfunction. J Heart Lung Transplant 2010; 29:704. https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 13/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate 40. Villa AE, de Marchena EJ, Myerburg RJ, Castellanos A. Comparisons of paired orthotopic cardiac transplant donor and recipient electrocardiograms. Am Heart J 1994; 127:70. 41. Leonelli FM, Pacifico A, Young JB. Frequency and significance of conduction defects early after orthotopic heart transplantation. Am J Cardiol 1994; 73:175. 42. Ferretto S, Tafciu E, Giuliani I, et al. Interventricular conduction disorders after orthotopic heart transplantation: risk factors and clinical relevance. Ann Noninvasive Electrocardiol 2017; 22. 43. Koller-Strametz J, Kratochwill C, Grabenw ger M, et al. PR interval adaptation in the denervated transplanted heart. Pacing Clin Electrophysiol 1997; 20:1247. 44. Heinz G, Kratochwill C, Hirschl M, et al. Normal AV node function in patients with sinus node dysfunction after cardiac transplantation. J Card Surg 1993; 8:417. 45. Markewitz A, Schmoeckel M, Nollert G, et al. Long-term results of pacemaker therapy after orthotopic heart transplantation. J Card Surg 1993; 8:411. 46. Ruben S, Hsia H, Mather P, et al. Etiology and prognostic implications of post-transplant conduction system disease (abstract). J Heart Lung Transplant 1996; 15:S60. 47. Weiss ES, Nwakanma LU, Russell SB, et al. Outcomes in bicaval versus biatrial techniques in heart transplantation: an analysis of the UNOS database. J Heart Lung Transplant 2008; 27:178. 48. Little RE, Kay GN, Epstein AE, et al. Arrhythmias after orthotopic cardiac transplantation. Prevalence and determinants during initial hospitalization and late follow-up. Circulation 1989; 80:III140. 49. Scott CD, Dark JH, McComb JM. Arrhythmias after cardiac transplantation. Am J Cardiol 1992; 70:1061. 50. Romhilt DW, Doyle M, Sagar KB, et al. Prevalence and significance of arrhythmias in long- term survivors of cardiac transplantation. Circulation 1982; 66:I219. 51. Creswell LL, Schuessler RB, Rosenbloom M, Cox JL. Hazards of postoperative atrial arrhythmias. Ann Thorac Surg 1993; 56:539. 52. Pavri BB, O'Nunain SS, Newell JB, et al. Prevalence and prognostic significance of atrial arrhythmias after orthotopic cardiac transplantation. J Am Coll Cardiol 1995; 25:1673. 53. Ahmari SA, Bunch TJ, Chandra A, et al. Prevalence, pathophysiology, and clinical significance of post-heart transplant atrial fibrillation and atrial flutter. J Heart Lung Transplant 2006; 25:53. 54. Macdonald P, Hackworthy R, Keogh A, et al. Atrial overdrive pacing for reversion of atrial flutter after heart transplantation. J Heart Lung Transplant 1991; 10:731. https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 14/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate 55. Rivinius R, Helmschrott M, Ruhparwar A, et al. Long-term use of amiodarone before heart transplantation significantly reduces early post-transplant atrial fibrillation and is not associated with increased mortality after heart transplantation. Drug Des Devel Ther 2016; 10:677. 56. Cohn WE, Gregoric ID, Radovancevic B, et al. Atrial fibrillation after cardiac transplantation: experience in 498 consecutive cases. Ann Thorac Surg 2008; 85:56. 57. Dasari TW, Pavlovic-Surjancev B, Patel N, et al. Incidence, risk factors, and clinical outcomes of atrial fibrillation and atrial flutter after heart transplantation. Am J Cardiol 2010; 106:737. 58. Arenal A, Almendral J, Mu oz R, et al. Mechanism and location of atrial flutter in transplanted hearts: observations during transient entrainment from distant sites. J Am Coll Cardiol 1997; 30:539. 59. Pinski SL, Bredikis AJ, Winkel E, Trohman RG. Radiofrequency catheter ablation of atrial flutter after orthotopic heart transplantation: insights into the redefined critical isthmus. J Heart Lung Transplant 1999; 18:292. 60. Marine JE, Schuger CD, Bogun F, et al. Mechanism of atrial flutter occurring late after orthotopic heart transplantation with atrio-atrial anastomosis. Pacing Clin Electrophysiol 2005; 28:412. 61. Li YG, Gr nefeld G, Israel C, et al. Radiofrequency catheter ablation in patients with symptomatic atrial flutter/tachycardia after orthotopic heart transplantation. Chin Med J (Engl) 2006; 119:2036. 62. Nof E, Stevenson WG, Epstein LM, et al. Catheter ablation of atrial arrhythmias after cardiac transplantation: findings at EP study utility of 3-D mapping and outcomes. J Cardiovasc Electrophysiol 2013; 24:498. 63. Goy JJ, Kappenberger L, Turina M. Wolff-Parkinson-White syndrome after transplantation of the heart. Br Heart J 1989; 61:368. 64. Gallay P, Albat B, Thevenet A, Grolleau R. Direct current catheter ablation of an accessory pathway in a recipient with refractory reciprocal tachycardia. J Heart Lung Transplant 1992; 11:442. 65. Neuzner J, Friedl A, Pitschner HF. Radiofrequency catheter ablation of a concealed accessory atrioventricular pathway after heart transplantation. Pacing Clin Electrophysiol 1994; 17:1778. 66. Thompson E, Steinhaus D, Long N, Borkon AM. Preexcitation syndrome in a donor heart. J Heart Transplant 1989; 8:177. https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 15/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate 67. Rothman SA, Hsia HH, Bove AA, et al. Radiofrequency ablation of Wolff-Parkinson-White syndrome in a donor heart after orthotopic heart transplantation. J Heart Lung Transplant 1994; 13:905. 68. Ott P, Kelly PA, Mann DE, et al. Tachycardia-induced cardiomyopathy in a cardiac transplant recipient: treatment with radiofrequency catheter ablation. J Cardiovasc Electrophysiol 1995; 6:391. 69. Hebert MF, Lam AY. Diltiazem increases tacrolimus concentrations. Ann Pharmacother 1999; 33:680. 70. Park JK, Hsu DT, Hordof AJ, Addonizio LJ. Arrhythmias in pediatric heart transplant recipients: prevalence and association with death, coronary artery disease, and rejection. J Heart Lung Transplant 1993; 12:956. 71. Alexopoulos D, Yusuf S, Bostock J, et al. Ventricular arrhythmias in long term survivors of orthotopic and heterotopic cardiac transplantation. Br Heart J 1988; 59:648. 72. Berke DK, Graham AF, Schroeder JS, Harrison DC. Arrhythmias in the denervated transplanted human heart. Circulation 1973; 48:III112. 73. de Jonge N, Jambroes G, Lahpor JR, Woolley SR. Ventricular fibrillation during acute rejection after heart transplantation. J Heart Lung Transplant 1992; 11:797. 74. Uretsky BF, Kormos RL, Zerbe TR, et al. Cardiac events after heart transplantation: incidence and predictive value of coronary arteriography. J Heart Lung Transplant 1992; 11:S45. 75. Grinstead WC, Smart FW, Pratt CM, et al. Sudden death caused by bradycardia and asystole in a heart transplant patient with coronary arteriopathy. J Heart Lung Transplant 1991; 10:931. 76. Tsai VW, Cooper J, Garan H, et al. The efficacy of implantable cardioverter-defibrillators in heart transplant recipients: results from a multicenter registry. Circ Heart Fail 2009; 2:197. Topic 3518 Version 25.0 Contributor Disclosures Howard J Eisen, MD, FACC, FAHA, FHFSA, FAST No relevant financial relationship(s) with ineligible companies to disclose. Luke S Kusmirek, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Sharon A Hunt, MD No relevant financial relationship(s) with ineligible companies to disclose. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 16/17 7/5/23, 11:15 AM Heart transplantation in adults: Arrhythmias - UpToDate Conflict of interest policy https://www.uptodate.com/contents/heart-transplantation-in-adults-arrhythmias/print 17/17

7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Pathophysiology and etiology of sudden cardiac arrest : Philip J Podrid, MD, FACC : Brian Olshansky, MD, Scott Manaker, MD, PhD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 15, 2023. INTRODUCTION Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) refer to the sudden cessation of cardiac activity with hemodynamic collapse, typically due to sustained ventricular tachycardia/ventricular fibrillation. These events mostly occur in patients with structural heart disease (that may not have been previously diagnosed), particularly coronary heart disease. The event is referred to as SCA (or aborted SCD) if an intervention (eg, defibrillation) or spontaneous reversion restores circulation. The event is called SCD if the patient dies. However, the use of SCD to describe both fatal and nonfatal cardiac arrest persists by convention. (See "Overview of sudden cardiac arrest and sudden cardiac death", section on 'Definitions'.) The cardiac diseases that lead to the genesis of the arrhythmia resulting in cardiac collapse and sudden death are varied, and the association with sudden death in some cases is poorly understood [1]. Identification of the patient at risk for sudden death and identification of the factors that precipitate the fatal arrhythmia continue to represent a major challenge. This topic will review the mechanisms and etiology of SCA. Treatment for SCA, the evaluation of survivors, and the outcomes of SCA are discussed separately. (See "Advanced cardiac life support (ACLS) in adults" and "Cardiac evaluation of the survivor of sudden cardiac arrest" and "Prognosis and outcomes following sudden cardiac arrest in adults".) TYPES OF ARRHYTHMIAS LEADING TO SUDDEN CARDIAC DEATH https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 1/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate The exact mechanism of collapse in an individual patient is often impossible to establish since, for the vast majority of patients who die suddenly, cardiac activity is not being monitored at the time of their collapse. As a result, the mechanism can only be inferred based upon information obtained after the process has been initiated. However, there have been many cases in which the initiating event has been witnessed or recorded [2-4]. This has usually occurred in patients being continually monitored in the coronary care unit, those with a 24-hour ambulatory electrocardiogram (ECG) recording device, or those with an implantable cardioverter-defibrillator (ICD). Ventricular tachycardia (VT) or ventricular fibrillation (VF) account for the majority of episodes [2,4]. However, a bradyarrhythmia is responsible for some cases of SCD. A bradyarrhythmia and asystole were, in initial studies, less common causes of SCD, being observed in only about 10 percent of cases documented on an ambulatory monitor [2]. A bradyarrhythmia is more often associated with a nonischemic cardiomyopathy [5], while pulseless electrical activity, electromechanical dissociation, or asystole are the most common rhythms seen with a pulmonary embolism [6]. Other causes for pulseless electrical activity include myocardial rupture, tamponade, pneumothorax, hypoxemia, or drug overdose. In some cases, the bradyarrhythmia may result in a ventricular tachyarrhythmia as an escape mechanism. The distribution is different among patients with an ICD. Arrhythmic death accounts for 20 to 35 percent of deaths; post-shock or primary pulseless electrical activity (PEA, also called electromechanical dissociation) is a frequent cause of SCD in this setting [7]. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Epidemiology'.) The distribution of causes is also different with unmonitored out-of-hospital SCD. VF and pulseless VT appear to be responsible for 25 to 35 percent of episodes, although estimates vary widely. PEA accounts for as much as 25 percent of all cases of SCD. Among patients who collapse in an unmonitored setting in whom the exact time of onset and the etiologic arrhythmia are uncertain, asystole is often the first rhythm observed [8]. Asystole correlates with the duration of the arrest and may be the result of VF that has been present for several minutes or longer and then leads to loss of all electrical activity as a result of hypoxia, acidosis, and death of myocardial tissue ( waveform 1) [9]. ARRHYTHMIC MECHANISMS https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 2/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate Mechanism of ventricular tachycardia In approximately 80 percent of patients with VT/VF, the sustained ventricular arrhythmia is preceded by an increase in ventricular ectopy and the development of repetitive ventricular arrhythmia, particularly runs of nonsustained VT [2]. These spontaneous arrhythmias are present for a variable period of time prior to the development of VT/VF. Sustained monomorphic VT can accelerate to a rapid rate and then degenerate into VF. However, the relationship between monomorphic VT and SCD has been debated, with some studies suggesting that this arrhythmia is present in only a minority of patients with SCD [10,11]. Thus, sustained monomorphic VT may simply be the company kept by VF or, in the appropriate setting such as recurrent coronary ischemia, it may provide a rapid wavefront that becomes fractionated, leading to VF [11]. A sustained polymorphic VT can degenerate into VF. This is most often the result of underlying ischemia (ie, polymorphic VT without QT prolongation or a short QT interval of the sinus QRS complex), although it may also result from acquired or congenital QT prolongation or congenital short QT interval. A very rare cause of polymorphic VT without QT prolongation is a genetic abnormality associated with catecholaminergic polymorphic VT (a result of an abnormality of a ryanodine or calsequestrin gene). (See "Catecholaminergic polymorphic ventricular tachycardia" and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) VF can develop as a primary event. In approximately one-third of cases, the tachyarrhythmia is initiated by an early R on T premature ventricular complex/contraction (PVC; also referred to a premature ventricular beats or premature ventricular depolarizations); in the remaining two-thirds, the arrhythmia is initiated by a late cycle PVC [2]. Mechanism of ventricular fibrillation VF results from multiple localized areas of microreentry without any organized electrical activity [12]. The most likely mechanism is rotating spiral waves [13]. This almost always occurs in the setting of underlying myocardial disease (or abnormalities in repolarization as in the long QT syndrome) that is often diffuse, resulting in heterogeneity of depolarization and the dispersion of repolarization. This disparity of electrophysiologic properties is a precondition for reentry. A triggering event is usually necessary to precipitate the arrhythmia in a vulnerable heart [14]. The identification of a precipitating factor is more likely if there is less heart disease, and when there is more heart disease, a precipitating factor may be more difficult to define. (See "Reentry and the development of cardiac arrhythmias".) https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 3/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate The diversity in conduction and recovery parameters (myocardial heterogeneity) results in fragmentation of the impulse as it travels through the myocardium, producing multiple areas of localized reentry or multiple spiral wavelets of myocardial activation [12]. Since there is no organized electrical activity or myocardial depolarization, there is no uniform ventricular contraction resulting in failure of the heart to generate a cardiac output. With the development of global ischemia, the rate of VF decreases because of a reduction in the rotation period of the spiral waves which results from the increase in their core area [13]. The ECG in established VF shows high-frequency undulations or fibrillatory waves that are irregular in amplitude, morphology, and periodicity, occurring at a rate above 320/minute; organized QRS complexes are not seen ( waveform 1) [15]. However, at the very onset of VF, the irregular fibrillatory waves may be coarse with a tall amplitude (and may resemble polymorphic VT) or may occasionally appear to be regular ( waveform 2). The QRS complexes in this latter setting are indistinguishable from the T waves, and they appear to be sinusoidal in configuration. This finding may represent a brief period of an organized ventricular flutter, with a rate exceeding 260 beats per minute. In cases where the coarse fibrillatory waves resemble polymorphic VT, these initial ECG changes are collectively referred to as type I VF and may be associated with spontaneous defibrillation [16,17]. Importantly, polymorphic VT may spontaneously terminate, while VF never self-terminates but only responds to defibrillation. (See "Cardioversion for specific arrhythmias".) As the duration of VF increases, progressive cellular ischemia and acidosis develop, resulting in an electrophysiologic deterioration, manifested by an increase in fibrillation cycle length and prolonged diastole duration between fibrillation action potentials [9,17,18]. During this later (type II) VF, the fibrillatory waves rapidly become finer and more irregular in amplitude, duration, and cycle length; spontaneous resolution or reversion with an antiarrhythmic drug has not been observed [16,17]. Over a period of several minutes, the fibrillatory waves become so fine that there does not appear to be any electrical activity ( waveform 1) [15]. ETIOLOGY OF SCD There are many cardiac and noncardiac causes for a sustained ventricular tachyarrhythmia that can result in sudden cardiac death (SCD) ( table 1). Common causes of SCD The following approximate frequency of causes of out-of-hospital SCDs have been described [19-25]: Sixty-five to 70 percent of all SCDs are attributable to coronary heart disease (CHD) [19,20]. Most often, there is no evidence for an acute myocardial infarction, although acute https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 4/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate ischemia may be the precipitating cause. Cardiac biomarkers are often elevated as a result of ischemia due to the arrhythmia or the result of defibrillation, making the diagnosis of an acute myocardial infarction preceding the event difficult to establish. However, the frequency of CHD is much lower in SCDs occurring under the age of 30 to 40 (eg, 24 percent under the age of 30 in a review of SCDs in the United States in 1999, and 8 percent in a series of autopsies in military recruits) [19,26]. These observations were largely made from analyses of all reported SCDs in the United States using the diagnosis on the death certificate, which is of uncertain accuracy. A similar frequency of CHD was noted in a study of 84 consecutive survivors of out-of-hospital cardiac arrest [21]. Immediate coronary angiography revealed clinically significant coronary disease in 60 (71 percent) of the patients, 40 of whom (48 percent of all patients) had an occluded coronary artery. The absence of an occluded coronary artery in the other 20 patients does not preclude an acute coronary syndrome (or ischemia) since absence of occlusion on early angiography is seen in 60 to 85 percent of patients with a non-ST elevation acute coronary syndrome and in up to 28 percent of patients with an ST elevation MI. Ten percent of SCDs are due to other types of structural heart disease (eg, any type of cardiomyopathy, congenital coronary artery anomalies, myocarditis, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy) [19,20,26]. The frequency is much higher in subjects under the age of 30 (over 35 percent in a review of SCDs in the United States in 1999, and over 40 percent in a series of autopsies in military recruits) [19,26]. Five to 10 percent of SCDs are primary arrhythmogenic, occurring in the absence of structural heart disease (eg, long QT syndrome, Brugada syndrome, Wolff-Parkinson-White syndrome, catecholaminergic polymorphic ventricular tachycardia [VT]). In the absence of any structural abnormality or electrophysiologic abnormality on the ECG, these entities are often termed primary electrical disease [22-24]. Fifteen to 25 percent of cardiac arrests are noncardiac in origin [22,25]. The causes include trauma, bleeding, drug intoxication, intracranial hemorrhage, pulmonary embolism, near- drowning, and central airway obstruction. Although not specifically mentioned in most of these studies, heart failure (HF) is a relatively common cause of SCD. SCD accounts for 30 to 50 percent of deaths in patients with heart failure (HF) [27], and the incidence of SCD appears to be increased during periods of worsening HF symptoms [28]. Although the risk of both arrhythmic and nonarrhythmic death can be reduced https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 5/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate with appropriate chronic HF therapy, the SCD risk remains elevated. Thus, virtually all SCD survivors with HF receive an ICD. A detailed discussion of arrhythmic events and the effect of medical therapy in HF patients is presented separately. (See "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy".) The incidence of SCD increases with age in both men and women; however, at any level of multivariate risk, women are less vulnerable to sudden death than men and a higher fraction of sudden deaths in women occur in the absence of prior overt CHD ( figure 1) [18,29]. Transient or reversible causes A number of transient or reversible conditions may precipitate arrhythmic events and SCD. Identification of such conditions is critical both for the management of the underlying disorder and for determining the likelihood of recurrent SCD. (See "Cardiac evaluation of the survivor of sudden cardiac arrest", section on 'Initial evaluation'.) In some of these cases, management of the underlying disorder is all that is necessary to reduce the risk of recurrent events. However, despite an apparently reversible trigger for SCD, many patients have a persistent risk of recurrent events (due to the presence of irreversible structural heart disease) and may benefit from implantable cardioverter-defibrillator (ICD) therapy or, in some cases, pharmacologic therapy with an antiarrhythmic drug. (See "Prognosis and outcomes following sudden cardiac arrest in adults".) Potentially reversible triggers for SCD include the following: Acute cardiac ischemia and myocardial infarction Because CHD is the most common cause of SCD, acute coronary ischemia, even in the absence of evidence for an acute myocardial infarction, should be considered in all survivors of SCD. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features" and "Cardiac evaluation of the survivor of sudden cardiac arrest", section on 'Coronary angiography'.) Antiarrhythmic drugs All antiarrhythmic drugs have proarrhythmic properties, particularly in patients with underlying cardiac disease, especially when heart failure is present [30-32]. Among SCD survivors who have been taking antiarrhythmic medications, it is difficult to be certain if the arrest was provoked by the drug or occurred despite its use [33]. Thus, it is often difficult to know if antiarrhythmic medications should be discontinued, increased, or adjusted. In such patients, involvement of an arrhythmia specialist is recommended. Medication (eg, QT prolonging drugs), toxin, or illicit drug ingestion [34,35]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 6/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate Electrolyte abnormalities, most notably hypokalemia, hyperkalemia, and hypomagnesemia. pH changes, especially acidemia (respiratory or metabolic). Heart failure The incidence of SCD appears to be increased during periods of worsening HF symptoms [28]. However, HF is a chronic disease, and although acute episodes may be managed, the condition is not truly transient or reversible. Even with appropriate chronic HF therapy, the SCD risk remains elevated. (See "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy".) Severe hypoxemia. Autonomic nervous system activation, especially sympathetic neural inputs. Autopsy studies The distribution of cardiac causes of SCD varies with age, the population studied, and geography. While coronary heart disease (CHD) is listed as the underlying cause of SCD on 62 percent of death certificates among the general population in the United States [20], younger patients, athletes, and those without known prior disease have a different distribution of causes [22,36,37]: In an autopsy study of 902 persons with suspected SCD (mean age 38 years), 715 cases (79 percent) occurred in persons with underlying cardiac pathology [38]. CHD was felt to be the primary cause of SCD in 511 patients (57 percent); however, CHD was far more common in persons 35 years of age or older (73 percent versus 23 percent in those <35 years), whereas those under 35 years of age were significantly more likely to die from non-CHD causes such as sudden unexplained death (primary arrhythmic death, 41 versus 11 percent), hypertrophic cardiomyopathy (13 versus 3 percent), or myocarditis (6 versus 2 percent). An autopsy study from Israel evaluated 162 subjects aged 9 to 39 years with SCD; none had previously diagnosed underlying cardiac disease, and death occurred in the absence of trauma within 24 hours of onset of symptoms [22]. Approximately 15 percent of deaths were noncardiac (most often intracranial hemorrhage), and 73 percent were cardiac. Among those 20 to 29 years of age, CHD was found in 24 percent, myocarditis in 22 percent, and hypertrophic cardiomyopathy (HCM) in 13 percent. Among those 30 to 39 years of age, CHD was found in 58 percent, myocarditis in 11 percent, and HCM in 2 percent. An autopsy series from the United States evaluated 286 competitive athletes under age 35 in whom cardiovascular disease was shown to be the cause of SCD [36]. The most common underlying disorders were HCM (36 percent, with possible HCM in another 10 percent), an https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 7/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate anomalous origin of a coronary artery (13 percent), and myocarditis (7 percent). (See "Athletes: Overview of sudden cardiac death risk and sport participation".) A markedly different distribution was noted in a report from northern Italy where arrhythmogenic right ventricular cardiomyopathy or dysplasia (ARVC or ARVD) is relatively common [37]. Among 49 sudden deaths in young athletes, ARVC was most common (22 percent), followed by coronary atherosclerosis (18 percent), an anomalous origin of a coronary artery (12 percent), and HCM in only 2 percent. Myocardial ischemia and infarction Approximately 65 to 70 percent of SCDs are attributable to CHD [19,20], and it is estimated that SCD accounts for 30 to 50 percent of coronary deaths [18,39]. The incidence of SCD is related to the clinical manifestations of preexisting CHD, being highest in those with a prior myocardial infarction (MI) and intermediate in those who have angina without a prior infarction ( figure 2) [18]. However, SCD can occur in patients with silent (or discomfortless) ischemia and can be the initial manifestation of CHD. (See "Silent myocardial ischemia: Epidemiology, diagnosis, treatment, and prognosis".) Among SCD episodes that occur without warning, angiography demonstrates an occluded coronary artery in almost one-half of patients [21]. Clinical and ECG changes appear to correlate poorly with coronary occlusion. Furthermore, among patients with typical ECG changes or cardiac enzyme elevations after resuscitation, it may be difficult on clinical grounds alone to determine whether an acute MI caused ventricular fibrillation (VF), or if VF resulted in myocardial injury because of the absence of coronary artery blood flow and/or the result of defibrillation. Among patients who present with an acute MI rather than SCD, the incidence of VF varies with the type of infarct and time. This topic is discussed in detail separately but will be briefly reviewed here. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features", section on 'Incidence'.) The largest experience with acute ST elevation MI comes from the GUSTO-1 trial of 40,895 patients who were treated with thrombolytic therapy [40]. The overall incidence of VT or VF was 10.2 percent: 3.5 percent developed VT, 4.1 percent VF, and 2.7 percent both VT and VF. Approximately 80 to 85 percent of these arrhythmias occurred in the first 48 hours. The best data in non-ST elevation acute coronary syndrome come from a pooled analysis of four major trials of over 25,000 patients [41]. The overall incidence of VT or VF was 2.1 percent: VT occurred in 0.8 percent, VF in 1 percent, and VT and VF in 0.3 percent. The median time to arrhythmia was 78 hours, with the 25th and 75th percentiles being 16 hours and seven days. https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 8/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate A peak incidence of VF within the first 48 hours after acute MI has also been noted in other reports [42,43]. These episodes are presumably due to ischemia, while later onset VF may be related to healing of the infarct with the development of scar (and an increased risk of monomorphic VT) and associated with an increased risk of late SCD. Late SCD most often occurs in the first year, with the majority of events seen within the first few months and being due to a ventricular tachyarrhythmia [44,45]. The risk of late VT/VF appears to be equivalent in patients with ST elevation and non-ST elevation infarctions [44]. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features".) These data do not include patients with SCD who do not survive until hospitalization. It has been estimated that more than 50 percent of deaths due to acute MI occur out of the hospital, and most episodes occur within one hour of symptom onset [46]. Among patients with out-of- hospital cardiac arrest, the risk is greater in those with acute occlusion of the left anterior descending or left circumflex arteries (odds ratio 4.82 and 4.92, respectively, compared with those with a right coronary artery occlusion). In addition, there are patients who have unstable coronary lesions that may be responsible for acute ischemic events, short of infarction, and that can cause electrical instability [21,47,48]. The potential frequency of this effect was illustrated in a report of 84 resuscitated patients who underwent coronary angiography immediately upon admission: 76 percent had significant coronary disease, spasm, or an unstable lesion, and almost one-half had coronary occlusion [21]. (See "Cardiac evaluation of the survivor of sudden cardiac arrest".) The importance of unstable plaques has been confirmed in a number of autopsy studies of men and women with coronary disease who died suddenly [48-52]. (See "Mechanisms of acute coronary syndromes related to atherosclerosis".) In a report of 113 such men: 59 had an acute coronary thrombus and 54 had severe narrowing of the coronary artery by an atherosclerotic plaque without acute thrombosis (stable plaque) [48]. Among those with acute thrombosis, 41 resulted from rupture of a vulnerable plaque (a thin fibrous cap overlying a lipid-rich core) and 18 from erosion of a fibrous plaque rich in smooth-muscle cells and proteoglycans. The likelihood of plaque rupture may vary in different subgroups. In a review of 141 men with SCD associated with coronary artery disease, the 25 patients who died during exertion were significantly more likely to have plaque rupture (72 versus 23 percent in those who died at rest) and hemorrhage into the plaque (72 versus 41 percent) [50]. Among patients with SCD associated with unstable angina, the thrombi typically have a layered appearance indicative of episodic growth [51]. Episodic growth may alternate with https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 9/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate intermittent fragmentation of the thrombus, leading to distal embolization of both thrombus and platelet aggregates and microinfarction [51,52]. The presence of severe coronary disease alone in a survivor of SCD does not prove a cause-and- effect relationship. Among patients who are not in the acute phase of a myocardial infarction, an appreciable risk of recurrent VT/VF may persist despite successful revascularization as a result of underlying myocardial disease and fibrosis [53,54]. Heart failure The presence of heart failure (HF), regardless of etiology, increases overall mortality and the incidence of SCD in both men and women. This was illustrated in a 38-year follow-up of patients in the Framingham Heart Study: the incidence of SCD in those with HF, compared with those without HF, was increased fivefold in both sexes, although the absolute risk in women was only one-third that of men ( figure 3) [18]. The SCD death potential in men and women with HF was as great as that noted in patients with overt coronary heart disease (13.7 and 3.8 versus 12.9 and 2.4 per 1000 patients, respectively). (See "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy".) Published series suggest a relatively consistent pattern with 30 to 50 percent of all cardiac deaths in patients with HF being categorized as sudden deaths, with or without preceding symptoms. However, it is often difficult to distinguish those dying suddenly and unexpectedly from those experiencing terminal arrhythmias in the setting of progressive hemodynamic deterioration. It has been suggested that progressive pump failure, sudden arrhythmic death, and sudden death during episodes of clinical worsening each account for approximately one- third of deaths [27]. In the AIRE trial, for example, only 39 percent of sudden deaths were thought to be due to arrhythmia [28]. VT degenerating into VF is the most common cause of SCD; a bradyarrhythmia or PEA is responsible in 5 to 33 percent of cases [27]. An acute coronary event appears to be the precipitating factor in some patients with HF. The prevalence of coronary thrombus, ruptured plaque, or myocardial infarction and its relationship to SCD was examined in an autopsy study of 171 patients with HF in the ATLAS trial [55]. In patients with significant coronary artery disease, an acute coronary finding was found in 54 percent who died suddenly and in 32 percent who died of myocardial failure, although an acute coronary event had not been clinically diagnosed before death. In contrast, an acute coronary finding was uncommon in those without coronary disease, occurring in only 5 percent of those who died suddenly and in 10 percent of those who died of myocardial failure. Left ventricular hypertrophy Hypertension with left ventricular hypertrophy (LVH) appears to increase the risk of SCD. Myocardial hypertrophy due to hypertension is often associated with myocardial fibrosis and may be a precondition for ventricular arrhythmia. In addition, chronic https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 10/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate subendocardial ischemia (accounting for the ST-T wave changes that are often seen) is often present with the hypertrophy and the increased oxygen demands; the subendocardium, which is the last part of the myocardium to receive blood supply, may have a reduced oxygen supply resulting in ischemia. In addition, many patients with hypertension and LVH have underlying coronary artery disease. Such patients appear to be less likely to have coronary thrombi than normotensives who had SCD [56]. However, most such patients have severe coronary disease suggesting that the hypertrophied myocardium is more susceptible than normal myocardium to the effects of ischemia [56]. SCD also occurs more commonly in patients with hypertrophic cardiomyopathy. Among competitive athletes who die from SCD due to proven cardiac cause, hypertrophic cardiomyopathy may be one of the most common underlying disorders, accounting for 36 percent of 286 cases in an autopsy series [36]. (See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death".) Absence of known structural heart disease Sudden cardiac death can occur in patients who have no previous history of heart disease [22,29,57]. Other causes of death that could be misinterpreted as SCD (eg, acute drug overdose or intoxication) should also be excluded [58]. However, most of these patients with SCD have underlying structural heart disease. (See "General approach to drug poisoning in adults" and "Acute opioid intoxication in adults".) The frequency with which this occurs was illustrated in an autopsy study that evaluated 162 subjects aged 9 to 39 years with SCD; none had previously diagnosed underlying disease and death occurred in the absence of trauma and within 24 hours of onset of symptoms [22]. The following findings were noted: Approximately 15 percent of deaths were noncardiac (most often intracranial hemorrhage) and 73 percent were cardiac. The most common causes of heart disease were coronary disease (58 percent in those over age 30 compared with 22 percent in younger subjects), myocarditis (11 and 22 percent in the two age groups), hypertrophic cardiomyopathy (13 percent in younger subjects), sarcoidosis, and arrhythmogenic right ventricular cardiomyopathy. Approximately one-half had some prodromal symptoms, such as chest pain or dizziness. SCD occurred during routine activity in 49 percent, during sleep in 23 percent, and in relation to exercise in 23 percent. The association with exercise has also been described in competitive athletes. In a United States registry of SCD in 286 competitive athletes under age 35 in whom cardiovascular disease was https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 11/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate shown to be the cause at autopsy, the most common underlying disorders were hypertrophic cardiomyopathy (36 percent, with possible HCM in another 10 percent), an anomalous coronary artery of wrong sinus origin (13 percent), and myocarditis (7 percent) [36]. (See "Athletes: Overview of sudden cardiac death risk and sport participation".) A different distribution of causes was noted in a series of 49 athletes under age 35 with SCD from northern Italy [37]. The most common causes were arrhythmogenic right ventricular cardiomyopathy (22 percent, which occurs more frequently in this region), coronary atherosclerosis (18 percent), anomalous origin of a coronary artery (12 percent), mitral valve prolapse (10 percent), myocarditis (6 percent), and hypertrophic cardiomyopathy (2 percent). Absence of structural heart disease In different reports, 10 to 12 percent of younger patients have VF in the true absence of structural heart disease [22,59], while a lower value of approximately 5 percent has been described when older patients are included [23,24]. This can occur in a variety of settings: Brugada syndrome (see "Brugada syndrome: Clinical presentation, diagnosis, and evaluation") Commotio cordis (see "Commotio cordis") Idiopathic VF, also called primary electrical disease (see "Approach to sudden cardiac arrest in the absence of apparent structural heart disease", section on 'Idiopathic VF') Catecholaminergic polymorphic VT (see "Catecholaminergic polymorphic ventricular tachycardia") Congenital or acquired long QT syndrome (see "Congenital long QT syndrome: Diagnosis" and "Acquired long QT syndrome: Definitions, pathophysiology, and causes") Short QT syndrome (see "Short QT syndrome") Wolff-Parkinson-White syndrome (see "Wolff-Parkinson-White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis") INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 12/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Ventricular fibrillation (The Basics)") SUMMARY Background Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) refer to the sudden cessation of organized cardiac electrical activity with hemodynamic collapse. The event is referred to as SCA (or aborted SCD) if an intervention (eg, defibrillation, cardioversion, antiarrhythmic drug) or spontaneous reversion restores circulation. The event is called SCD if the patient dies. However, the use of SCD to describe both fatal and nonfatal cardiac arrest persists by convention. (See 'Introduction' above.) Mechanisms The exact mechanism of collapse in an individual patient is often impossible to establish since, for the vast majority of patients who die suddenly, cardiac electrical activity is not being monitored at the time of their collapse. However, in studies of patients who were having cardiac electrical activity monitored at the time of their event, ventricular tachycardia (VT) or ventricular fibrillation (VF) accounted for the majority of episodes, with bradycardia or asystole accounting for nearly all of the remainder. (See 'Arrhythmic mechanisms' above.) Arrhythmic mechanisms In the majority of patients with VT/VF, sustained ventricular arrhythmia is preceded by an increase in ventricular ectopy and the development of repetitive ventricular arrhythmia, particularly runs of nonsustained VT. In approximately one-third of cases, the tachyarrhythmia is initiated by an early R on T PVC; in the remaining two-thirds, the arrhythmia is initiated by a late cycle PVC. (See 'Arrhythmic mechanisms' above.) Common causes There are many cardiac and noncardiac causes for a sustained ventricular tachyarrhythmia that can result in SCD ( table 1). Among all SCD in all age groups, the majority (65 to 70 percent) are related to coronary heart disease, with other structural cardiac disease (approximately 10 percent), arrhythmias in the absence of structural heart disease (5 to 10 percent), and noncardiac causes (15 to 25 percent) responsible for the remaining deaths. (See 'Etiology of SCD' above.) https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 13/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate ACKNOWLEDGMENT The UpToDate editorial staff thank Dr. Jie Cheng for his past contributions as an author to prior versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kannel WB, Schatzkin A. Sudden death: lessons from subsets in population studies. J Am Coll Cardiol 1985; 5:141B. 2. Bay s de Luna A, Coumel P, Leclercq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J 1989; 117:151. 3. Dubner SJ, Pinski S, Palma S, et al. Ambulatory electrocardiographic findings in out-of- hospital cardiac arrest secondary to coronary artery disease. Am J Cardiol 1989; 64:801. 4. Wood MA, Stambler BS, Damiano RJ, et al. Lessons learned from data logging in a multicenter clinical trial using a late-generation implantable cardioverter-defibrillator. The Guardian ATP 4210 Multicenter Investigators Group. J Am Coll Cardiol 1994; 24:1692. 5. Luu M, Stevenson WG, Stevenson LW, et al. Diverse mechanisms of unexpected cardiac arrest in advanced heart failure. Circulation 1989; 80:1675. 6. K rkciyan I, Meron G, Sterz F, et al. Pulmonary embolism as a cause of cardiac arrest: presentation and outcome. Arch Intern Med 2000; 160:1529. 7. Mitchell LB, Pineda EA, Titus JL, et al. Sudden death in patients with implantable cardioverter defibrillators: the importance of post-shock electromechanical dissociation. J Am Coll Cardiol 2002; 39:1323. 8. Cummins RO, Ornato JP, Thies WH, Pepe PE. Improving survival from sudden cardiac arrest: the "chain of survival" concept. A statement for health professionals from the Advanced Cardiac Life Support Subcommittee and the Emergency Cardiac Care Committee, American Heart Association. Circulation 1991; 83:1832. 9. Tovar OH, Jones JL. Electrophysiological deterioration during long-duration ventricular fibrillation. Circulation 2000; 102:2886. 10. Weaver WD, Hill D, Fahrenbruch CE, et al. Use of the automatic external defibrillator in the management of out-of-hospital cardiac arrest. N Engl J Med 1988; 319:661. https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 14/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate 11. Raitt MH, Dolack GL, Kudenchuk PJ, et al. Ventricular arrhythmias detected after transvenous defibrillator implantation in patients with a clinical history of only ventricular fibrillation. Implications for use of implantable defibrillator. Circulation 1995; 91:1996.

Pathophysiology and etiology of sudden cardiac arrest - UpToDate shown to be the cause at autopsy, the most common underlying disorders were hypertrophic cardiomyopathy (36 percent, with possible HCM in another 10 percent), an anomalous coronary artery of wrong sinus origin (13 percent), and myocarditis (7 percent) [36]. (See "Athletes: Overview of sudden cardiac death risk and sport participation".) A different distribution of causes was noted in a series of 49 athletes under age 35 with SCD from northern Italy [37]. The most common causes were arrhythmogenic right ventricular cardiomyopathy (22 percent, which occurs more frequently in this region), coronary atherosclerosis (18 percent), anomalous origin of a coronary artery (12 percent), mitral valve prolapse (10 percent), myocarditis (6 percent), and hypertrophic cardiomyopathy (2 percent). Absence of structural heart disease In different reports, 10 to 12 percent of younger patients have VF in the true absence of structural heart disease [22,59], while a lower value of approximately 5 percent has been described when older patients are included [23,24]. This can occur in a variety of settings: Brugada syndrome (see "Brugada syndrome: Clinical presentation, diagnosis, and evaluation") Commotio cordis (see "Commotio cordis") Idiopathic VF, also called primary electrical disease (see "Approach to sudden cardiac arrest in the absence of apparent structural heart disease", section on 'Idiopathic VF') Catecholaminergic polymorphic VT (see "Catecholaminergic polymorphic ventricular tachycardia") Congenital or acquired long QT syndrome (see "Congenital long QT syndrome: Diagnosis" and "Acquired long QT syndrome: Definitions, pathophysiology, and causes") Short QT syndrome (see "Short QT syndrome") Wolff-Parkinson-White syndrome (see "Wolff-Parkinson-White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis") INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 12/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Ventricular fibrillation (The Basics)") SUMMARY Background Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) refer to the sudden cessation of organized cardiac electrical activity with hemodynamic collapse. The event is referred to as SCA (or aborted SCD) if an intervention (eg, defibrillation, cardioversion, antiarrhythmic drug) or spontaneous reversion restores circulation. The event is called SCD if the patient dies. However, the use of SCD to describe both fatal and nonfatal cardiac arrest persists by convention. (See 'Introduction' above.) Mechanisms The exact mechanism of collapse in an individual patient is often impossible to establish since, for the vast majority of patients who die suddenly, cardiac electrical activity is not being monitored at the time of their collapse. However, in studies of patients who were having cardiac electrical activity monitored at the time of their event, ventricular tachycardia (VT) or ventricular fibrillation (VF) accounted for the majority of episodes, with bradycardia or asystole accounting for nearly all of the remainder. (See 'Arrhythmic mechanisms' above.) Arrhythmic mechanisms In the majority of patients with VT/VF, sustained ventricular arrhythmia is preceded by an increase in ventricular ectopy and the development of repetitive ventricular arrhythmia, particularly runs of nonsustained VT. In approximately one-third of cases, the tachyarrhythmia is initiated by an early R on T PVC; in the remaining two-thirds, the arrhythmia is initiated by a late cycle PVC. (See 'Arrhythmic mechanisms' above.) Common causes There are many cardiac and noncardiac causes for a sustained ventricular tachyarrhythmia that can result in SCD ( table 1). Among all SCD in all age groups, the majority (65 to 70 percent) are related to coronary heart disease, with other structural cardiac disease (approximately 10 percent), arrhythmias in the absence of structural heart disease (5 to 10 percent), and noncardiac causes (15 to 25 percent) responsible for the remaining deaths. (See 'Etiology of SCD' above.) https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 13/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate ACKNOWLEDGMENT The UpToDate editorial staff thank Dr. Jie Cheng for his past contributions as an author to prior versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kannel WB, Schatzkin A. Sudden death: lessons from subsets in population studies. J Am Coll Cardiol 1985; 5:141B. 2. Bay s de Luna A, Coumel P, Leclercq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J 1989; 117:151. 3. Dubner SJ, Pinski S, Palma S, et al. Ambulatory electrocardiographic findings in out-of- hospital cardiac arrest secondary to coronary artery disease. Am J Cardiol 1989; 64:801. 4. Wood MA, Stambler BS, Damiano RJ, et al. Lessons learned from data logging in a multicenter clinical trial using a late-generation implantable cardioverter-defibrillator. The Guardian ATP 4210 Multicenter Investigators Group. J Am Coll Cardiol 1994; 24:1692. 5. Luu M, Stevenson WG, Stevenson LW, et al. Diverse mechanisms of unexpected cardiac arrest in advanced heart failure. Circulation 1989; 80:1675. 6. K rkciyan I, Meron G, Sterz F, et al. Pulmonary embolism as a cause of cardiac arrest: presentation and outcome. Arch Intern Med 2000; 160:1529. 7. Mitchell LB, Pineda EA, Titus JL, et al. Sudden death in patients with implantable cardioverter defibrillators: the importance of post-shock electromechanical dissociation. J Am Coll Cardiol 2002; 39:1323. 8. Cummins RO, Ornato JP, Thies WH, Pepe PE. Improving survival from sudden cardiac arrest: the "chain of survival" concept. A statement for health professionals from the Advanced Cardiac Life Support Subcommittee and the Emergency Cardiac Care Committee, American Heart Association. Circulation 1991; 83:1832. 9. Tovar OH, Jones JL. Electrophysiological deterioration during long-duration ventricular fibrillation. Circulation 2000; 102:2886. 10. Weaver WD, Hill D, Fahrenbruch CE, et al. Use of the automatic external defibrillator in the management of out-of-hospital cardiac arrest. N Engl J Med 1988; 319:661. https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 14/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate 11. Raitt MH, Dolack GL, Kudenchuk PJ, et al. Ventricular arrhythmias detected after transvenous defibrillator implantation in patients with a clinical history of only ventricular fibrillation. Implications for use of implantable defibrillator. Circulation 1995; 91:1996. 12. Kuo CS, Munakata K, Reddy CP, Surawicz B. Characteristics and possible mechanism of ventricular arrhythmia dependent on the dispersion of action potential durations. Circulation 1983; 67:1356. 13. Mandapati R, Asano Y, Baxter WT, et al. Quantification of effects of global ischemia on dynamics of ventricular fibrillation in isolated rabbit heart. Circulation 1998; 98:1688. 14. Kuo CS, Amlie JP, Munakata K, et al. Dispersion of monophasic action potential durations and activation times during atrial pacing, ventricular pacing, and ventricular premature stimulation in canine ventricles. Cardiovasc Res 1983; 17:152. 15. Bardy GH, Olson WH. Clinical characteristics of spontaneous-onset sustained ventricular tac hycardia and ventricular fibrillation in survivors of cardiac arrest. In: Cardiac Electrophysiolo gy: From Cell to Bedside, Zipes DP, Jalife J (Eds), WB Saunders, Philadelphia 1990. p.778. 16. Wu TJ, Lin SF, Weiss JN, et al. Two types of ventricular fibrillation in isolated rabbit hearts: importance of excitability and action potential duration restitution. Circulation 2002; 106:1859. 17. Chen PS, Wu TJ, Ting CT, et al. A tale of two fibrillations. Circulation 2003; 108:2298. 18. Kannel WB, Wilson PW, D'Agostino RB, Cobb J. Sudden coronary death in women. Am Heart J 1998; 136:205. 19. Centers for Disease Control and Prevention (CDC). State-specific mortality from sudden cardiac death United States, 1999. MMWR Morb Mortal Wkly Rep 2002; 51:123. 20. Zheng ZJ, Croft JB, Giles WH, Mensah GA. Sudden cardiac death in the United States, 1989 to 1998. Circulation 2001; 104:2158. 21. Spaulding CM, Joly LM, Rosenberg A, et al. Immediate coronary angiography in survivors of out-of-hospital cardiac arrest. N Engl J Med 1997; 336:1629. 22. Drory Y, Turetz Y, Hiss Y, et al. Sudden unexpected death in persons less than 40 years of age. Am J Cardiol 1991; 68:1388. 23. Chugh SS, Kelly KL, Titus JL. Sudden cardiac death with apparently normal heart. Circulation 2000; 102:649. 24. Survivors of out-of-hospital cardiac arrest with apparently normal heart. Need for definition and standardized clinical evaluation. Consensus Statement of the Joint Steering Committees of the Unexplained Cardiac Arrest Registry of Europe and of the Idiopathic Ventricular Fibrillation Registry of the United States. Circulation 1997; 95:265. https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 15/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate 25. Kuisma M, Alasp A. Out-of-hospital cardiac arrests of non-cardiac origin. Epidemiology and outcome. Eur Heart J 1997; 18:1122. 26. Eckart RE, Scoville SL, Campbell CL, et al. Sudden death in young adults: a 25-year review of autopsies in military recruits. Ann Intern Med 2004; 141:829. 27. Narang R, Cleland JG, Erhardt L, et al. Mode of death in chronic heart failure. A request and proposition for more accurate classification. Eur Heart J 1996; 17:1390. 28. Cleland JG, Erhardt L, Murray G, et al. Effect of ramipril on morbidity and mode of death among survivors of acute myocardial infarction with clinical evidence of heart failure. A report from the AIRE Study Investigators. Eur Heart J 1997; 18:41. 29. Albert CM, Chae CU, Grodstein F, et al. Prospective study of sudden cardiac death among women in the United States. Circulation 2003; 107:2096. 30. Velebit V, Podrid P, Lown B, et al. Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation 1982; 65:886. 31. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324:781. 32. Flaker GC, Blackshear JL, McBride R, et al. Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 1992; 20:527. 33. Ruskin JN, McGovern B, Garan H, et al. Antiarrhythmic drugs: a possible cause of out-of- hospital cardiac arrest. N Engl J Med 1983; 309:1302. 34. Kloner RA, Hale S, Alker K, Rezkalla S. The effects of acute and chronic cocaine use on the heart. Circulation 1992; 85:407. 35. Bauman JL, Grawe JJ, Winecoff AP, Hariman RJ. Cocaine-related sudden cardiac death: a hypothesis correlating basic science and clinical observations. J Clin Pharmacol 1994; 34:902. 36. Maron BJ, Carney KP, Lever HM, et al. Relationship of race to sudden cardiac death in competitive athletes with hypertrophic cardiomyopathy. J Am Coll Cardiol 2003; 41:974. 37. Corrado D, Basso C, Schiavon M, Thiene G. Screening for hypertrophic cardiomyopathy in young athletes. N Engl J Med 1998; 339:364. 38. Eckart RE, Shry EA, Burke AP, et al. Sudden death in young adults: an autopsy-based series of a population undergoing active surveillance. J Am Coll Cardiol 2011; 58:1254. 39. Gillum RF. Sudden coronary death in the United States: 1980-1985. Circulation 1989; 79:756. https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 16/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate 40. Newby KH, Thompson T, Stebbins A, et al. Sustained ventricular arrhythmias in patients receiving thrombolytic therapy: incidence and outcomes. The GUSTO Investigators. Circulation 1998; 98:2567. 41. Al-Khatib SM, Granger CB, Huang Y, et al. Sustained ventricular arrhythmias among patients with acute coronary syndromes with no ST-segment elevation: incidence, predictors, and outcomes. Circulation 2002; 106:309. 42. Volpi A, Cavalli A, Santoro L, Negri E. Incidence and prognosis of early primary ventricular fibrillation in acute myocardial infarction results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) database. Am J Cardiol 1998; 82:265. 43. Goldberg RJ, Gore JM, Haffajee CI, et al. Outcome after cardiac arrest during acute myocardial infarction. Am J Cardiol 1987; 59:251. 44. Berger CJ, Murabito JM, Evans JC, et al. Prognosis after first myocardial infarction. Comparison of Q-wave and non-Q-wave myocardial infarction in the Framingham Heart Study. JAMA 1992; 268:1545. 45. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)- Prevenzione. Circulation 2002; 105:1897. 46. Gheeraert PJ, Henriques JP, De Buyzere ML, et al. Out-of-hospital ventricular fibrillation in patients with acute myocardial infarction: coronary angiographic determinants. J Am Coll Cardiol 2000; 35:144. 47. Stevenson WG, Wiener I, Yeatman L, et al. Complicated atherosclerotic lesions: a potential cause of ischemic ventricular arrhythmias in cardiac arrest survivors who do not have inducible ventricular tachycardia? Am Heart J 1988; 116:1. 48. Burke AP, Farb A, Malcom GT, et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997; 336:1276. 49. Burke AP, Farb A, Malcom GT, et al. Effect of risk factors on the mechanism of acute thrombosis and sudden coronary death in women. Circulation 1998; 97:2110. 50. Burke AP, Farb A, Malcom GT, et al. Plaque rupture and sudden death related to exertion in men with coronary artery disease. JAMA 1999; 281:921. 51. Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation 1985; 71:699. https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 17/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate 52. Davies MJ, Thomas AC, Knapman PA, Hangartner JR. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation 1986; 73:418. 53. Natale A, Sra J, Axtell K, et al. Ventricular fibrillation and polymorphic ventricular tachycardia with critical coronary artery stenosis: does bypass surgery suffice? J Cardiovasc Electrophysiol 1994; 5:988. 54. Daoud EG, Niebauer M, Kou WH, et al. Incidence of implantable defibrillator discharges after coronary revascularization in survivors of ischemic sudden cardiac death. Am Heart J 1995; 130:277. 55. Uretsky BF, Thygesen K, Armstrong PW, et al. Acute coronary findings at autopsy in heart failure patients with sudden death: results from the assessment of treatment with lisinopril and survival (ATLAS) trial. Circulation 2000; 102:611. 56. Burke AP, Farb A, Liang YH, et al. Effect of hypertension and cardiac hypertrophy on coronary artery morphology in sudden cardiac death. Circulation 1996; 94:3138. 57. Viskin S, Belhassen B. Idiopathic ventricular fibrillation. Am Heart J 1990; 120:661. 58. Rodriguez RM, Montoy JCC, Repplinger D, et al. Occult Overdose Masquerading as Sudden Cardiac Death: From the POstmortem Systematic InvesTigation of Sudden Cardiac Death Study. Ann Intern Med 2020; 173:941. 59. Topaz O, Edwards JE. Pathologic features of sudden death in children, adolescents, and young adults. Chest 1985; 87:476. Topic 974 Version 31.0 https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 18/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate GRAPHICS Continuous electrocardigraphic (ECG) strip during an episode of ventricular fibrillation (VF) that progresses to fine VF and then asystole At the onset of ventricular fibrillation (VF), the QRS complexes are regular, widened, and of tall amplitude, suggesting a more organized ventricular tachyarrhythmia. Over a brief period of time, the rhythm becomes more disorganized with high amplitude fibrillatory waves; this is coarse VF. After a longer period of time, the fibrillatory waves become fine, culminating in asystole. Graphic 67777 Version 3.0 https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 19/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate ECG 12-lead ventricular fibrillation 12-lead ECG showing course ventricular fibrillation. ECG: electrocardiogram. Graphic 118944 Version 1.0 https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 20/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate Major causes of sudden death Ischemic heart disease Coronary artery disease with myocardial infarction or angina Coronary artery embolism Nonatherogenic coronary artery disease (arteritis, dissection, congenital coronary artery anomalies) Coronary artery spasm Nonischemic heart disease Hypertrophic cardiomyopathy Dilated cardiomyopathy Valvular heart disease Congenital heart disease Arrhythmogenic right ventricular dysplasia Myocarditis Acute pericardial tamponade Acute myocardial rupture Aortic dissection No structural heart disease Primary electrical disease (idiopathic ventricular fibrillation) Brugada syndrome (right bundle branch block and ST segment elevation in leads V1 to V3) Long QT syndrome Preexcitation syndrome Complete heart block Familial sudden cardiac death Chest wall trauma (commotio cordis) Noncardiac disease Pulmonary embolism Intracranial hemorrhage Drowning Pickwickian syndrome Drug-induced https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 21/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate Central airway obstruction Sudden infant death syndrome Sudden unexplained death in epilepsy (SUDEP) Graphic 62184 Version 3.0 https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 22/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate Incidence of sudden death in men and women increases with age During a 38-year follow-up of subjects in the Framingham Heart Study, the annual incidence of sudden death increased with age in both men and women. However, at each age, the incidence of sudden death is higher in men than women. Data from Kannel WB, Wilson PWF, D'Agostino RB, et al. Am Heart J 1998; 136:205. Graphic 59028 Version 4.0 https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 23/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate Risk of SCD is related to clinical manifestations of CHD During a 38-year follow-up of subjects in the Framingham Heart Study, the annual incidence of sudden cardiac death (SCD) in both men and women was related to the clinical manifestations of coronary heart disease (CHD). It was highest in those with a myocardial infarction, intermediate in those with angina and no prior infarction, and lowest in those without overt CHD. Data from: Kannel WB, Wilson PWF, D'Agostino RB, et al. Am Heart J 1998; 136:205. Graphic 52309 Version 2.0 https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 24/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate Heart failure predicts increased sudden cardiac death and overall mortality During a 38-year old follow-up of subjects in the Framingham Heart Study, the presence of heart failure (HF) significantly increased sudden death and overall mortality in both men and women. p <0.01. p <0.001. Data from: Kannel WB, Wilson PWF, D'Agostino RB, et al. Am Heart J 1998; 136:205. Graphic 58658 Version 4.0 https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 25/26 7/5/23, 11:16 AM Pathophysiology and etiology of sudden cardiac arrest - UpToDate Contributor Disclosures Philip J Podrid, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. Scott Manaker, MD, PhD Other Financial Interest: Expert witness in workers' compensation and in medical negligence matters [General pulmonary and critical care medicine]; National Board for Respiratory Care [Director]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/pathophysiology-and-etiology-of-sudden-cardiac-arrest/print 26/26

7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Reentry and the development of cardiac arrhythmias : Philip J Podrid, MD, FACC : Bernard J Gersh, MB, ChB, DPhil, FRCP, MACC : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 03, 2023. INTRODUCTION Cardiac arrhythmias are generally produced by one of three mechanisms: enhanced automaticity, triggered activity, or reentry. Reentry, due to a circuit within the myocardium, occurs when a propagating impulse fails to die out after normal activation of the heart and persists as a result of continuous activity around the circuit to re-excite the heart after the refractory period has ended; it is the electrophysiologic mechanism responsible for the majority of clinically important arrhythmias. Included among these arrhythmias are atrial fibrillation (where there are multiple small circuits in the left and right atria), atrial flutter (where there is a single circuit in the right atrium), atrioventricular (AV) nodal reentry (where the circuit is in the AV node as a result of dual AV nodal pathways), AV reentry (which involves a bypass tract and the normal AV node His-Purkinje system), ventricular tachycardia (with a circuit in the ventricular myocardium after myocardial infarction [MI] with the presence of left ventricular scar or in the presence of a cardiomyopathy due to fibrosis or infiltration), and ventricular fibrillation. The first demonstration of reentry in its simplest form (ie, the ring model) probably occurred in 1906 following the application of a stimulus to tissue from a jellyfish which initiated rhythmic contraction [1]. However, reentry was first conceived as a mechanism for arrhythmias in 1913 when it was recognized that reentrant tachycardias arise from circular electrical pathways, often initiated by a blocked impulse [2]. It was subsequently realized that reentry tachycardias may also be due to other mechanisms, including functional or leading circle circuits and abnormal electrical circuits caused by diseased myocardium. https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 1/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate The definition and characteristics of the different reentry circuits responsible for the most clinically significant arrhythmias are presented here, along with the electrophysiologic properties of these arrhythmias. The clinical presentation and management of the individual arrhythmias are discussed separately. (See "Overview of atrial flutter" and "Atrioventricular nodal reentrant tachycardia" and "Atrioventricular reentrant tachycardia (AVRT) associated with an accessory pathway" and "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis" and "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) DEFINITION AND CHARACTERISTICS Reentrant tachycardia (variously named reentrant excitation, reciprocating tachycardia, circus movement, and reciprocal or echo beats) is defined as a continuous repetitive propagation of an excitatory wave traveling in a circular path (reentrant circuit), returning to its site of origin to reactivate that site [1]. The one event crucial to the development of a reentrant tachycardia is the failure of a group of fibers to activate during a depolarization wave. The initiation of a reentrant arrhythmia also requires the presence of myocardial tissue with the following electrophysiologic properties ( figure 1) [3-6]: Adjacent tissue or pathways must have different electrophysiologic properties (conduction and refractoriness) and be joined proximally and distally, forming a circuit. These circuits may be fixed or stationary or may move within the myocardial substrate (as occurs with spiral waves). Each involved pathway of the circuit must be capable of conducting an impulse in an antegrade and retrograde direction. Transient or permanent unidirectional block of one pathway must exist as a result of heterogeneity of electrophysiologic properties of the myocardium. This event usually results when one electrical pathway has either a prolonged refractory period or a prolonged repolarization time, producing a wave which only travels down the remaining pathway. Conduction velocity in the normal unblocked pathway must be slow enough relative to the refractoriness of the blocked pathway to allow recovery of the previously blocked pathway. The impulse can then be conducted through the previously blocked but recovered pathway in a retrograde direction. https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 2/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Retrograde conduction in this previously blocked pathway must be slow enough to allow the normal pathway to recover, and again be capable of being excited. A sustained reentrant arrhythmia will occur if these conditions are present and maintained. In general, the onset and offset of the arrhythmia are abrupt. In contrast, when enhanced automaticity is the mechanism for the arrhythmia, there are often warm-up and cool-down phases (gradual increase and gradual decrease in the rate of the arrhythmia). Patients who develop reentrant arrhythmias usually have an anatomic or electrical (functional) abnormality, which could be caused by an accessory pathway, by an abnormal separation of adjacent fibers that may form two limbs of a reentrant circuit, or by juxtaposed fibers that possess different electrophysiologic characteristics, often resulting from abnormalities of the myocardium and Purkinje fibers as the result of a disease process. Susceptible patients with appropriate underlying abnormalities usually do not suffer from incessant tachycardia because the different electrophysiologic mechanisms required for the initiation and maintenance of a reentrant tachycardia are infrequently present at exactly the same time. However, changes in heart rate or autonomic tone, ischemia, electrolyte or pH abnormalities, or the occurrence of a premature beat (which results in transient changes in the electrophysiologic properties of the myocardium) may be sufficient to initiate a reentrant tachycardia. In fact, premature depolarizations frequently initiate these tachyarrhythmias when there are appropriate electrophysiologic conditions (ie, slow conduction and unidirectional block). They are associated with more rapid depolarization (as they are early or premature) that may block in one pathway (ie, unidirectional block), conduct through the second pathway, retrogradely enter the first pathway, and then reenter the second pathway. CRITERIA FOR DIAGNOSIS The initial criteria for the diagnosis of reentry proposed in the early 20th century are still valid, but are often difficult to prove [1]. As a result, the following twelve conditions in the electrophysiology laboratory were proposed to either prove or to identify the existence of a reentrant tachycardia [7]: Activation of the myocardium mapped in one direction around a continuous loop. Correlation of continuous electrical activity occurring when the tachycardia develops. Correlation of unidirectional block with initiation of reentry. Initiation and termination by premature stimulation. https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 3/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Dependence of initiation of the arrhythmia on the site of pacing. Inverse relationship between the coupling interval of the initiating premature beat and the interval to the first tachycardia beat. Resetting of the tachycardia by a premature beat with an inverse relationship between the coupling interval of the premature beat and the cycle length of the first or return beat of the tachycardia. Fusion between a premature beat and the tachycardia beat followed by resetting. Transient entrainment (with external overdrive pacing, the ability to enter the reentrant circuit and "capture" the circuit, resulting in a tachycardia at the pacing rate and having fused or paced complexes). Abrupt termination by premature stimulation or the termination of entrainment. Dependence of initiation on a critical slowing of conduction in the circuit. Similarity with experimental models in which reentry is proven and is the only mechanism of tachycardia. The segment of the reentrant circuit that is, at any given time, no longer refractory and is capable of being excited is called the excitable gap [6,8]. Slowing of impulse conduction or shortening of refractoriness will increase the excitable gap. The longer the excitable gap, the more likely it is for an extrastimulus to enter the reentrant circuit and initiate or terminate a reentrant arrhythmia. In addition, entrainment is more likely to occur when the excitable gap is longer. TYPES OF REENTRY Reentry tachycardias have been divided into two different forms based upon the type of anatomic substrate used for the development of the arrhythmia: anatomic or functional. The original ring model requires the presence of an anatomic obstruction (due to a structural abnormality). There are also several models of functional reentry (due to electrophysiologic abnormalities) including the leading circle, anisotropic conduction, figure of eight, and spiral wave ( figure 1 and figure 2). Anatomic reentry Anatomic reentrant tachycardia most closely resembles the original description of reentry arrhythmia because it requires an anatomic obstacle, such as an area of fibrosis [1]. This discrete anatomic block creates a surrounding circular pathway, resulting in a https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 4/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate fixed length and location of the reentrant circuit. A tachycardia is initiated when a depolarization wave splits into two limbs after going around this obstacle, creating a circus movement [9,10]. Tachycardia rates are determined both by the wavelength (defined as conduction velocity and refractory period) and the length of the circuit or the pathlength. Examples of anatomic reentry are supraventricular tachycardia associated with an accessory pathway (preexcitation syndromes) called atrioventricular reentrant tachycardia (AVRT), AV nodal reentrant tachycardia (AVNRT; associated with dual AV nodal pathways), typical atrial flutter originating in the right atrium due to an area of fibrosis in the lower portion of the atrium (termed isthmus), atrial fibrillation resulting from multiple reentrant circuits in the atria, ventricular tachycardia (VT) originating within the His-Purkinje system (bundle branch tachycardia), and VT originating at the terminal portion of the His-Purkinje system or around an area of infarcted tissue (scar mediated). There is often a long excitable gap associated with anatomic reentry. Functional reentry Functional reentry depends upon the intrinsic heterogeneity of the electrophysiologic properties of cardiac muscle (ie, dispersion of excitability or refractoriness) as well as anisotropic differences in intercellular resistances. There is no anatomic obstacle present. Examples of functional reentry include atypical atrial flutter, some cases of atrial fibrillation (AF), and VT in a structurally normal heart. Functional circuits have the following properties: They tend to be small, rapidly conducting, and unstable in that the waves they generate may fragment, establishing other areas of reentry. Circuit times and hence tachycardia rates are significantly dependent upon the refractory period of the involved tissue. The location and size of these tachycardias vary due to the absence of an anatomic block. There is usually a short excitable gap associated with functional reentry. One animal study reported the following additional properties [11]: A thin layer of activation near the core or central region of the circuit is responsible for the maintenance of reentry; the remaining portion of the tissue is activated passively by the outward propagation of wavefronts away from the core. Access to the tissue near the core is essential for termination of reentry by a point stimulation. https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 5/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate To terminate reentry with a stimulus applied away from the core, the stimulus must occur at certain critical coupling intervals and the line connecting the stimulus and the core must be roughly parallel to the fiber orientation. Leading circle concept In this model, functional reentry involves the propagation of an impulse around a functionally determined region of unexcitable tissue or a refractory core and among neighboring fibers with different electrophysiologic properties [4-6]. The excitation wave then travels in the smallest possible circuit with the head of the impulse having just enough strength to excite relatively refractory tissue ahead of it. Thus, the "head of the circulating wavefront is continuously biting its tail of refractoriness" ( figure 1) [6]. There is a small excitable gap in this setting. The circulating wave activates peripheral tissue but also gives rise to wavelets that collide at the center, rendering it refractory. Anisotropic reentry Anisotropic reentry is determined by the orientation of myocardial fibers and the manner in which these fibers and muscle bundles are connected to each other [12,13]. In general, the electrical resistances between cells is dependent upon fiber orientation (ie, cell- to-cell communication is more rapid between cell that are parallel to each other), while communication is slower when cells are transverse to each other [14,15]. Anisotropic reentry occurs in myocardium composed of tissue with structural features different from those of adjacent tissue, resulting in variations in conduction velocities and repolarization properties (referred to as anisotropic myocardium) ( figure 2) [16]. As an example, an impulse propagating parallel to the long axis of the myocardial tissue will typically travel three to five times faster than the same impulse traveling in the transverse direction. Therefore, anatomic anisotropy can cause heterogeneity of electrophysiologic properties which can result in blocked impulses and slowed conduction, thereby setting the stage for reentry [17]. Figure of eight reentry This model of reentry involves two counter rotating circuits around a center that is anatomically damaged, but is common to both circuits [18]. The reentrant beat produces a wavefront that circulates in both directions around a long line of functional conduction block and rejoins on the distal side of the block. This results in two concomitant circuits, forming a "figure of eight." Spiral wave (rotor) activity In this model of reentry, there are concentric circular waves that result in reverberators or rotating vortices of electrical activity [19-21]. Spiral waves, which typically describe reentry in two dimensions, can be initiated in an inhomogeneous, excitable medium whenever there is disruption of the wavefront. Spiral waves rotate around an organizing center or core, which includes cells with a transmembrane potential that has a reduced amplitude, duration and rate of depolarization (ie, slow upstroke velocity of phase 0); https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 6/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate these cells are potentially excitable, but remain unexcited [22]. Anisotropy and anatomic obstacles can modify the characteristics and spatiotemporal behavior of the spiral. In addition, the spiral waves may give rise to daughter spirals which can result in disorganized electrical activity; this may be the mechanism for ventricular fibrillation [23]. Spirals may be stationary (the possible mechanism for monomorphic VT), or may continuously drift or migrate away from their origin (possibly the mechanism for polymorphic VT or AF), or may be anchored, initially drifting and then becoming stationary by anchoring to a small obstacle ( waveform 1) [24]. Phase two reentry Phase 2 reentry is a phenomenon largely related to Brugada syndrome and is discussed separately. (See "Brugada syndrome: Epidemiology and pathogenesis", section on 'Ventricular arrhythmias and phase 2 reentry' and "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) CLINICAL ARRHYTHMIAS DUE TO REENTRY Reentry can cause many clinically significant arrhythmias including sinus node reentry, atrial flutter, atrial fibrillation (AF), AV nodal reentry (AVNRT), AV reentry using an accessory bypass tract (AVRT), and ventricular tachyarrhythmias ( figure 3). Sinus node reentry SA nodal reentrant tachycardia is due to a reentrant circuit that is in the area of the sinus node and involves this structure and the sinoatrial junction. Thus, electrophysiologic studies reveal atrial activation and conduction that is identical to sinus rhythm, with the earliest recorded atrial activation in the reentrant tachycardia being located near the sinus node [25]. As with any reentrant arrhythmia, SA nodal reentrant tachycardia is usually initiated by a premature atrial stimulus, but also rarely by a ventricular premature stimulus [26,27]. It is clinically and electrocardiographically difficult to distinguish this arrhythmia from sinus tachycardia. Both have identical P waves at a rate that is usually less than 150 beats/min. The abrupt onset and termination of the reentrant arrhythmia are the only clinical distinctions from sinus tachycardia, which results from enhanced sympathetic tone and has an onset and termination that are gradual and not abrupt ( waveform 2). (See "Sinoatrial nodal reentrant tachycardia (SANRT)".) Atrial flutter The reentrant circuit resulting in atrial flutter is typically localized within the right atrium. It results from a circuit that is due to an area of fibrosis and slow conduction (isthmus) that is located between the tricuspid annulus and area of the inferior vena caval https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 7/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate insertion. Details regarding the electrocardiographic and electrophysiologic features of atrial flutter are discussed separately. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) Atrial fibrillation AF is currently felt to be caused by multiple leading circle reentrant impulses (ie, the multiple wavelet theory) ( figure 4) [28,29]. Coarse AF, which is usually seen when the AF is more recent in onset, is thought to be caused by a relatively small number of large sized waves, while fine fibrillation (when usually indicated AF that has been present for a longer period of time) is caused by many small, fragmented waves ( waveform 3A-B). It has been estimated that a minimum of six circuits is needed to sustain AF [29]. (See "The electrocardiogram in atrial fibrillation".) AV nodal reentry AVNRT, one of the most frequent paroxysmal supraventricular tachycardias, is caused by a reentrant circuit located within the AV node. It is the result of dual AV nodal pathways (which are linked proximally and distally within the AV node), both of which conduct in an antegrade and retrograde direction [30-35]. The slow or alpha pathway typically has a slower conduction velocity and shorter refractory period (faster recovery) than the faster conducting beta pathway, which has a faster conduction velocity but a longer refractory period. These two pathways are linked proximally and distally within the AV junction. AVNRTs have been divided into two types based upon their mechanism of conduction [36]. (See "Atrioventricular nodal reentrant tachycardia".) The common type, comprising approximately 90 percent of all AVNRTs, is usually initiated by a premature atrial complex (also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat) that reaches the AV node when the fast pathway is still refractory and hence travels down the slow pathway to activate the ventricles in an antegrade fashion. If the impulse reaches the distal end of the circuit when the fast pathway has recovered, it enters the fast pathway and is conducted in a retrograde direction to activate the atrial in a retrograde direction and simultaneously with ventricular activation. If the slow pathway has recovered by the time the impulse reaches the proximally portion of the circuit, the impulse may also reenter the slow pathway. If this situation repeats, an AV nodal reentrant tachycardia results. As ventricular activation is via the slow pathway and retrograde atrial activation is via the fast pathway, this is termed "slow-fast" ( figure 5 and figure 6). The uncommon type of AVNRT uses the fast pathway in an antegrade manner and the slow pathway in the retrograde manner (fast-slow) ( figure 7 and figure 8). This may be initiated by a premature ventricular complex/contraction (PVC; also referred to a premature https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 8/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate ventricular beats or premature ventricular depolarizations) that is blocked in the fast pathway and hence travels up to the atrial via the slow pathway and then down to the ventricles via the fast pathway (fast-slow). Atrioventricular reentry using an accessory bypass tract The presence of an accessory bypass tract, which has electrophysiologic properties that are different from those of the normal AV node-His Purkinje system and resemble the properties of Purkinje fibers, favors the development of reentrant tachycardia by providing two limbs of a possible reentrant circuit: one limb is the AV node and His-Purkinje system; and the other is the bypass tract which directly connects an atrium and a ventricle, bypassing the AV node [37,38]. The circuit, known as a macroreentrant circuit, is formed by a proximal connection via the atria and a distal connection within the ventricular myocardium. Accessory bypass tracts can be found along the perimeter of both the mitral and tricuspid valves or within the ventricular myocardium (bundle of Kent, which links the atrium directly to the ventricular myocardium), may connect the atrium directly to the distal AV node or His Purkinje system (bundle of James), and may also connect the AV node to either the right bundle or the ventricle, termed nodofascicular and nodoventricular tracts, respectively. (See "Anatomy, pathophysiology, and localization of accessory pathways in the preexcitation syndrome".) Accessory bypass tracts may conduct reentrant impulses either in a retrograde or antegrade direction. Orthodromic AVRT is defined by conduction of the depolarization impulse to the ventricles down the AV node and His-Purkinje system in an antegrade manner and its return via the accessory tract in a retrograde manner ( waveform 4 and figure 9). The QRS complex is narrow (although it may have a typical right or left bundle branch block pattern if there is rate- related aberration) as ventricular activation is via the normal conduction pathway. Antidromic AVRT is characterized by the reverse sequence in which the depolarization wave travels down the bypass tract in an antegrade direction to activate the ventricular myocardium and returns to the atria via the His-Purkinje system and AV node ( waveform 5 and figure 10). In this situation, the QRS complex is maximally preexcited and has a wide and strange morphology as a result of direct myocardial activation via the accessory pathway. The complex has the same morphology in every lead as the preexcited complex during sinus rhythm, although it may be wider as it is maximally preexcited. Since it is wide, with a strange morphology, it may look like VT. Orthodromic AVRT is most common, occurring in approximately 90 percent of symptomatic patients with accessory bypass tracts [39]; antidromic AVRT accounts for the remaining 10 percent [40]. (See "Atrioventricular reentrant tachycardia (AVRT) associated with an accessory pathway".) The conduction characteristics of bypass tracts can vary significantly not only among patients, but also between retrograde and antegrade directions within the same tract in a given patient https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 9/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate [41]. As an example, a single bypass tract may be involved in both orthodromic and antidromic AVRTs. Ventricular tachycardia and fibrillation Ventricular tachycardia (VT; monomorphic) and ventricular fibrillation (VF), the two most lethal arrhythmias, are both caused by reentry ( waveform 6 and waveform 7) [42]. Pathologic changes associated with ischemic heart disease (infarction resulting in fibrosis) or cardiomyopathy (myocardial infiltration and/or fibrosis) most often produce the cardiac substrate necessary for reentrant ventricular arrhythmias: areas of unidirectional block and sufficiently slow conduction. The reentrant circuits are small, involving the distal Purkinje fibers within normal and abnormal myocardial tissue, and this has been termed "microreentry." Monomorphic VT can be initiated by appropriately timed premature ventricular impulses or by burst pacing and can be terminated by cardioversion, overdrive pacing, or antiarrhythmic drugs. VF can be initiated by appropriately timed premature ventricular impulses but can be terminated only with defibrillation. Although sustained VTs with different QRS morphologies (polymorphic VT without QT prolongation of the sinus complex) occur spontaneously (most commonly due to active ischemia) or during electrophysiologic study after a myocardial infarction, they most commonly arise from reentrant circuits located in the region of the infarction [43]. Factors responsible for different exit routes from circuits in the same region, leading to multiple morphologies include: Different direction of rotation around the same circuit Small differences in the reentrant circuit Reentrant circuits with different sizes and shapes Differences in the refractoriness of the ventricular myocardium and hence its ability to conduct the impulse While sustained VT generally involves one reentrant circuit, or perhaps a single spiral, VF results from multiple circuits simultaneously activating the ventricular myocardium. In an animal model, the most likely underlying mechanism was rotating spiral waves [44]. With the development of global ischemia during VF, the rate of VF decreases due to an increase in the rotation period of the spiral waves that results from an increase in the core area. It has frequently been observed that VF is often preceded by a variable period of VT (monomorphic or polymorphic). The transition from a sustained organized VT to disorganized VF probably involves the breakup of a single propagating wave or spiral into multiple daughter wavelets or spirals, a result of heterogeneity of myocardial electrophysiologic properties (functional block) or anatomic obstacles. This is identical to the process seen with AF. These wavelets rarely reenter themselves but can re-excite portions of the myocardium recently https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 10/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate activated by another wavefront, a process called random reentry. As a result, there are multiple wavefronts of activation that may collide with each other, extinguishing themselves or creating new wavelets or spiral and wavefronts, thereby perpetuating the arrhythmia [45,46]. Spontaneous wave breaks without apparent collision may also occur during VF; in an experimental model, procainamide can reduce the incidence of these events, decreasing the number of wavelets [46]. Spontaneously occurring reentrant arrhythmias are infrequent in a healthy ventricle, because the substrate for reentry is lacking. However, these tachyarrhythmias can occur in a normal heart in the right clinical setting. As an example, bundle branch reentry can be initiated by an early coupled premature impulse; VT may then develop based upon the difference in the refractory periods either between the two bundles or between one of the bundles and ventricular muscle ( figure 11) [47]. (See "Bundle branch reentrant ventricular tachycardia".) VF can also be induced in a healthy heart if a properly timed, strong stimulus is applied to the ventricle. The critical moment occurs immediately after the refractory period, generally at the downstroke of the T wave just after its peak, a period of time termed the vulnerable period, when a heterogeneous state of excitability and refractoriness exists [48]. A strong stimulus applied during the vulnerable period is postulated to set up a number of functional reentrant circuits. The amount of energy that provokes VF is termed the VF threshold. The VF threshold in a normal, nonischemic heart is high, while the VF threshold is low in the presence of active ischemia. In this situation, a premature ventricular complex or a pacing stimulus occurring at the downstroke of the T wave (R on T phenomenon) may have sufficient energy to provoke VF. SUMMARY Cardiac arrhythmias are generally produced by one of three mechanisms: enhanced automaticity, triggered activity, or reentry. Reentry, which occurs when a propagating impulse fails to die out after normal activation of the heart and persists to re-excite the heart after the refractory period has ended, is the electrophysiologic mechanism responsible for the majority of clinically important arrhythmias. (See 'Introduction' above.) While the one event which is crucial to the development of a reentrant tachycardia is the failure of a group of fibers to activate during a depolarization wave, the initiation of a reentrant arrhythmia also requires various electrophysiologic properties (eg, ability to conduct antegrade and retrograde, presence of unidirectional block, etc) to be present concurrently within the myocardial tissue making up the circuit. Changes in heart rate or autonomic tone, ischemia, electrolyte or pH abnormalities, or the occurrence of a https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 11/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate premature beat (which results in transient changes in the electrophysiologic properties of the myocardium) may be sufficient to initiate a reentrant tachycardia. (See 'Definition and characteristics' above.) Twelve conditions which may be seen during invasive electrophysiology study in the electrophysiology laboratory have been proposed to either prove or to identify the existence of a reentrant tachycardia. (See 'Criteria for diagnosis' above.) Reentry tachycardias have been divided into two different forms based upon the type of anatomic substrate used for the development of the arrhythmia: anatomic or functional. Anatomic reentrant tachycardia requires a discrete anatomic obstacle, such as an area of fibrosis, resulting in a fixed length and location of the reentrant circuit. Examples of anatomic reentry are supraventricular tachycardia associated with an accessory pathway (preexcitation syndromes), AV nodal reentrant tachycardia, atrial flutter, ventricular tachycardia originating within the His-Purkinje system (bundle branch tachycardia), and ventricular tachycardia originating at the terminal portion of the His- Purkinje system or around an area of infarcted tissue. (See 'Anatomic reentry' above.) Functional reentry depends upon the intrinsic heterogeneity of the electrophysiologic properties of cardiac muscle (ie, dispersion of excitability or refractoriness) as well as anisotropic differences in intercellular resistances. There is no anatomic obstacle present. Examples of functional reentry include type II (atypical) atrial flutter and atrial tachycardia. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Mayer AG. Rhythmical pulsation in scyphomedusae. Carnegie Institution of Washington Pub lication No. 47, 1906. 2. Mines GR. On dynamic equilibrium in the heart. J Physiol 1913; 46:349. 3. Lewis T. The Mechanism and Graphic Registration of the Heart Beat, & Sons, London 1925. 4. Allessie MA, Bonke FI, Schopman FJ. Circus movement in rabbit atrial muscle as a mechanism of trachycardia. Circ Res 1973; 33:54. 5. Allessie MA, Bonke FI, Schopman FJ. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. II. The role of nonuniform recovery of excitability in the https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 12/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate occurrence of unidirectional block, as studied with multiple microelectrodes. Circ Res 1976; 39:168. 6. Allessie MA, Bonke FI, Schopman FJ. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. III. The "leading circle" concept: a new model of circus movement in cardiac tissue without the involvement of an anatomical obstacle. Circ Res 1977; 41:9. 7. Hoffman BF. Circus movement in the AV ring. In: Cardiac Electrophysiology: A Textbook, Ros en MR, Janse MJ, Wi AL (Eds), Futura, Mt Kisco, NY 1990. p.573. 8. Waldo AL, MacLean WA, Karp RB, et al. Entrainment and interruption of atrial flutter with atrial pacing: studies in man following open heart surgery. Circulation 1977; 56:737. 9. Frame LH, Page RL, Hoffman BF. Atrial reentry around an anatomic barrier with a partially refractory excitable gap. A canine model of atrial flutter. Circ Res 1986; 58:495. 10. Gough WB, Mehra R, Restivo M, et al. Reentrant ventricular arrhythmias in the late myocardial infarction period in the dog. 13. Correlation of activation and refractory maps. Circ Res 1985; 57:432. 11. Kamjoo K, Uchida T, Ikeda T, et al. Importance of location and timing of electrical stimuli in terminating sustained functional reentry in isolated swine ventricular tissues: evidence in support of a small reentrant circuit. Circulation 1997; 96:2048. 12. Spach MS, Miller WT 3rd, Geselowitz DB, et al. The discontinuous nature of propagation in normal canine cardiac muscle. Evidence for recurrent discontinuities of intracellular resistance that affect the membrane currents. Circ Res 1981; 48:39. 13. Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. A model of reentry based on anisotropic discontinuous propagation. Circ Res 1988; 62:811. 14. Brugada J, Boersma L, Kirchhof CJ, et al. Reentrant excitation around a fixed obstacle in uniform anisotropic ventricular myocardium. Circulation 1991; 84:1296. 15. Spach MS, Dolber PC, Heidlage JF. Interaction of inhomogeneities of repolarization with anisotropic propagation in dog atria. A mechanism for both preventing and initiating reentry. Circ Res 1989; 65:1612. 16. Allessie MA, Schalij MJ, Kirchhof CJ, et al. Experimental electrophysiology and arrhythmogenicity. Anisotropy and ventricular tachycardia. Eur Heart J 1989; 10 Suppl E:2. 17. Allessie MA, Schalij MJ, Kirchhof CJ, et al. Electrophysiology of spiral waves in two dimensions: the role of anisotropy. Ann N Y Acad Sci 1990; 591:247. https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 13/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate 18. El-Sherif N, Smith RA, Evans K. Canine ventricular arrhythmias in the late myocardial infarction period. 8. Epicardial mapping of reentrant circuits. Circ Res 1981; 49:255. 19. Davidenko JM, Kent PF, Chialvo DR, et al. Sustained vortex-like waves in normal isolated ventricular muscle. Proc Natl Acad Sci U S A 1990; 87:8785. 20. Pertsov AM, Davidenko JM, Salomonsz R, et al. Spiral waves of excitation underlie reentrant activity in isolated cardiac muscle. Circ Res 1993; 72:631. 21. Davidenko JM, Pertsov AV, Salomonsz R, et al. Stationary and drifting spiral waves of excitation in isolated cardiac muscle. Nature 1992; 355:349. 22. Athill CA, Ikeda T, Kim YH, et al. Transmembrane potential properties at the core of functional reentrant wave fronts in isolated canine right atria. Circulation 1998; 98:1556. 23. Garfinkle A, Qu Z. Nonlinear dynamics of excitation and propagation in cardiac muscle. In: C ardiac Electrophysiology: From Cell to Bedside, Zipes DP, Jalife J (Eds), WB Saunders, Philadel phia 1999. p.515. 24. Davidenko JM. Spiral wave activity: a possible common mechanism for polymorphic and monomorphic ventricular tachycardias. J Cardiovasc Electrophysiol 1993; 4:730. 25. Wathen MS, Klein GJ, Yee R, Natale A. Classification and terminology of supraventricular tachycardia. Diagnosis and management of the atrial tachycardias. Cardiol Clin 1993; 11:109. 26. Narula OS. Sinus node re-entry: a mechanism for supraventricular tachycardia. Circulation 1974; 50:1114. 27. Wu D, Amat-y-leon F, Denes P, et al. Demonstration of sustained sinus and atrial re-entry as a mechanism of paroxysmal supraventricular tachycardia. Circulation 1975; 51:234. 28. Moe, GK . On the multiple wavelet hypothesis of atrial fibrillation. Arch Int Pharmacol Dyn Ther 1962; 140:183. 29. Allessie MA, Lammers WJEP, Bonke FIM, et al. Experimental evaluation of Moe's multiple wav elet hypothesis of atrial fibrillation. In: Cardiac Arrhythmias, Zipes DP, Jalife J (Eds), Grune & Stratton, New York 1985. p.265. 30. Denes P, Wu D, Amat-y-Leon F, et al. The determinants of atrioventricular nodal re-entrance with premature atrial stimulation in patients with dual A-V nodal pathways. Circulation 1977; 56:253. 31. Denes P, Wu D, Dhingra R, et al. Dual atrioventricular nodal pathways. A common electrophysiological response. Br Heart J 1975; 37:1069. 32. Denes P, Wu D, Dhingra RC, et al. Demonstration of dual A-V nodal pathways in patients with paroxysmal supraventricular tachycardia. Circulation 1973; 48:549. https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 14/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate 33. Rosen KM, Mehta A, Miller RA. Demonstration of dual atrioventricular nodal pathways in man. Am J Cardiol 1974; 33:291. 34. Sung RJ, Waxman HL, Saksena S, Juma Z. Sequence of retrograde atrial activation in patients with dual atrioventricular nodal pathways. Circulation 1981; 64:1059. 35. Wu D, Denes P, Dhingra R, et al. New manifestations of dual A-V nodal pathways. Eur J Cardiol 1975; 2:459.

existence of a reentrant tachycardia. (See 'Criteria for diagnosis' above.) Reentry tachycardias have been divided into two different forms based upon the type of anatomic substrate used for the development of the arrhythmia: anatomic or functional. Anatomic reentrant tachycardia requires a discrete anatomic obstacle, such as an area of fibrosis, resulting in a fixed length and location of the reentrant circuit. Examples of anatomic reentry are supraventricular tachycardia associated with an accessory pathway (preexcitation syndromes), AV nodal reentrant tachycardia, atrial flutter, ventricular tachycardia originating within the His-Purkinje system (bundle branch tachycardia), and ventricular tachycardia originating at the terminal portion of the His- Purkinje system or around an area of infarcted tissue. (See 'Anatomic reentry' above.) Functional reentry depends upon the intrinsic heterogeneity of the electrophysiologic properties of cardiac muscle (ie, dispersion of excitability or refractoriness) as well as anisotropic differences in intercellular resistances. There is no anatomic obstacle present. Examples of functional reentry include type II (atypical) atrial flutter and atrial tachycardia. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Mayer AG. Rhythmical pulsation in scyphomedusae. Carnegie Institution of Washington Pub lication No. 47, 1906. 2. Mines GR. On dynamic equilibrium in the heart. J Physiol 1913; 46:349. 3. Lewis T. The Mechanism and Graphic Registration of the Heart Beat, & Sons, London 1925. 4. Allessie MA, Bonke FI, Schopman FJ. Circus movement in rabbit atrial muscle as a mechanism of trachycardia. Circ Res 1973; 33:54. 5. Allessie MA, Bonke FI, Schopman FJ. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. II. The role of nonuniform recovery of excitability in the https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 12/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate occurrence of unidirectional block, as studied with multiple microelectrodes. Circ Res 1976; 39:168. 6. Allessie MA, Bonke FI, Schopman FJ. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. III. The "leading circle" concept: a new model of circus movement in cardiac tissue without the involvement of an anatomical obstacle. Circ Res 1977; 41:9. 7. Hoffman BF. Circus movement in the AV ring. In: Cardiac Electrophysiology: A Textbook, Ros en MR, Janse MJ, Wi AL (Eds), Futura, Mt Kisco, NY 1990. p.573. 8. Waldo AL, MacLean WA, Karp RB, et al. Entrainment and interruption of atrial flutter with atrial pacing: studies in man following open heart surgery. Circulation 1977; 56:737. 9. Frame LH, Page RL, Hoffman BF. Atrial reentry around an anatomic barrier with a partially refractory excitable gap. A canine model of atrial flutter. Circ Res 1986; 58:495. 10. Gough WB, Mehra R, Restivo M, et al. Reentrant ventricular arrhythmias in the late myocardial infarction period in the dog. 13. Correlation of activation and refractory maps. Circ Res 1985; 57:432. 11. Kamjoo K, Uchida T, Ikeda T, et al. Importance of location and timing of electrical stimuli in terminating sustained functional reentry in isolated swine ventricular tissues: evidence in support of a small reentrant circuit. Circulation 1997; 96:2048. 12. Spach MS, Miller WT 3rd, Geselowitz DB, et al. The discontinuous nature of propagation in normal canine cardiac muscle. Evidence for recurrent discontinuities of intracellular resistance that affect the membrane currents. Circ Res 1981; 48:39. 13. Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. A model of reentry based on anisotropic discontinuous propagation. Circ Res 1988; 62:811. 14. Brugada J, Boersma L, Kirchhof CJ, et al. Reentrant excitation around a fixed obstacle in uniform anisotropic ventricular myocardium. Circulation 1991; 84:1296. 15. Spach MS, Dolber PC, Heidlage JF. Interaction of inhomogeneities of repolarization with anisotropic propagation in dog atria. A mechanism for both preventing and initiating reentry. Circ Res 1989; 65:1612. 16. Allessie MA, Schalij MJ, Kirchhof CJ, et al. Experimental electrophysiology and arrhythmogenicity. Anisotropy and ventricular tachycardia. Eur Heart J 1989; 10 Suppl E:2. 17. Allessie MA, Schalij MJ, Kirchhof CJ, et al. Electrophysiology of spiral waves in two dimensions: the role of anisotropy. Ann N Y Acad Sci 1990; 591:247. https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 13/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate 18. El-Sherif N, Smith RA, Evans K. Canine ventricular arrhythmias in the late myocardial infarction period. 8. Epicardial mapping of reentrant circuits. Circ Res 1981; 49:255. 19. Davidenko JM, Kent PF, Chialvo DR, et al. Sustained vortex-like waves in normal isolated ventricular muscle. Proc Natl Acad Sci U S A 1990; 87:8785. 20. Pertsov AM, Davidenko JM, Salomonsz R, et al. Spiral waves of excitation underlie reentrant activity in isolated cardiac muscle. Circ Res 1993; 72:631. 21. Davidenko JM, Pertsov AV, Salomonsz R, et al. Stationary and drifting spiral waves of excitation in isolated cardiac muscle. Nature 1992; 355:349. 22. Athill CA, Ikeda T, Kim YH, et al. Transmembrane potential properties at the core of functional reentrant wave fronts in isolated canine right atria. Circulation 1998; 98:1556. 23. Garfinkle A, Qu Z. Nonlinear dynamics of excitation and propagation in cardiac muscle. In: C ardiac Electrophysiology: From Cell to Bedside, Zipes DP, Jalife J (Eds), WB Saunders, Philadel phia 1999. p.515. 24. Davidenko JM. Spiral wave activity: a possible common mechanism for polymorphic and monomorphic ventricular tachycardias. J Cardiovasc Electrophysiol 1993; 4:730. 25. Wathen MS, Klein GJ, Yee R, Natale A. Classification and terminology of supraventricular tachycardia. Diagnosis and management of the atrial tachycardias. Cardiol Clin 1993; 11:109. 26. Narula OS. Sinus node re-entry: a mechanism for supraventricular tachycardia. Circulation 1974; 50:1114. 27. Wu D, Amat-y-leon F, Denes P, et al. Demonstration of sustained sinus and atrial re-entry as a mechanism of paroxysmal supraventricular tachycardia. Circulation 1975; 51:234. 28. Moe, GK . On the multiple wavelet hypothesis of atrial fibrillation. Arch Int Pharmacol Dyn Ther 1962; 140:183. 29. Allessie MA, Lammers WJEP, Bonke FIM, et al. Experimental evaluation of Moe's multiple wav elet hypothesis of atrial fibrillation. In: Cardiac Arrhythmias, Zipes DP, Jalife J (Eds), Grune & Stratton, New York 1985. p.265. 30. Denes P, Wu D, Amat-y-Leon F, et al. The determinants of atrioventricular nodal re-entrance with premature atrial stimulation in patients with dual A-V nodal pathways. Circulation 1977; 56:253. 31. Denes P, Wu D, Dhingra R, et al. Dual atrioventricular nodal pathways. A common electrophysiological response. Br Heart J 1975; 37:1069. 32. Denes P, Wu D, Dhingra RC, et al. Demonstration of dual A-V nodal pathways in patients with paroxysmal supraventricular tachycardia. Circulation 1973; 48:549. https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 14/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate 33. Rosen KM, Mehta A, Miller RA. Demonstration of dual atrioventricular nodal pathways in man. Am J Cardiol 1974; 33:291. 34. Sung RJ, Waxman HL, Saksena S, Juma Z. Sequence of retrograde atrial activation in patients with dual atrioventricular nodal pathways. Circulation 1981; 64:1059. 35. Wu D, Denes P, Dhingra R, et al. New manifestations of dual A-V nodal pathways. Eur J Cardiol 1975; 2:459. 36. Sung RJ, Styperek JL, Myerburg RJ, Castellanos A. Initiation of two distinct forms of atrioventricular nodal reentrant tachycardia during programmed ventricular stimulation in man. Am J Cardiol 1978; 42:404. 37. Gallagher JJ, Sealy WC, Kasell J, Wallace AG. Multiple accessory pathways in patients with the pre-excitation syndrome. Circulation 1976; 54:571. 38. Wellens HJJ, Brugada P. Value of programmed stimulation of the heart in patients with the W olff-Parkinson-White syndrome. In: Tachycardias: Mechanisms, Diagnosis, Treatment, Josep hson ME, Wellens HJJ (Eds), Lea & Febiger, Philadelphia 1984. p.1991. 39. Newman BJ, Donoso E, Friedberg CK. Arrhythmias in the Wolff-Parkinson-White syndrome. Prog Cardiovasc Dis 1966; 9:147. 40. Bardy GH, Packer DL, German LD, Gallagher JJ. Preexcited reciprocating tachycardia in patients with Wolff-Parkinson-White syndrome: incidence and mechanisms. Circulation 1984; 70:377. 41. Wellens HJJ. Electrophysiologic properties of the accessory pathway in Wolff-Parkinson-Whit e syndrome. In: Conduction System of the Heart: Structure, Function, and Clinical Implicatio n, Wellens HJJ, Lie KI, Janse MJ (Eds), Stenfert Krose BV, Leiden 1976. p.567. 42. Josephson ME, Marchlinski FE, Buxton AE, et al. Electrophysiologic basis for sustained ventri cular tachycardia: The role of reentry. In: Tachycardias: Mechanisms, Diagnosis, Treatment, J osephson ME, Wellens HJJ (Eds), & Febiger, Philadelphia 1984. p.305. 43. Costeas C, Peters NS, Waldecker B, et al. Mechanisms causing sustained ventricular tachycardia with multiple QRS morphologies: results of mapping studies in the infarcted canine heart. Circulation 1997; 96:3721. 44. Mandapati R, Asano Y, Baxter WT, et al. Quantification of effects of global ischemia on dynamics of ventricular fibrillation in isolated rabbit heart. Circulation 1998; 98:1688. 45. Lee JJ, Kamjoo K, Hough D, et al. Reentrant wave fronts in Wiggers' stage II ventricular fibrillation. Characteristics and mechanisms of termination and spontaneous regeneration. Circ Res 1996; 78:660. https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 15/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate 46. Kwan YY, Fan W, Hough D, et al. Effects of procainamide on wave-front dynamics during ventricular fibrillation in open-chest dogs. Circulation 1998; 97:1828. 47. Akhtar M, Gilbert C, Wolf FG, Schmidt DH. Reentry within the His-Purkinje system. Elucidation of reentrant circuit using right bundle branch and His bundle recordings. Circulation 1978; 58:295. 48. Wiggers, CJ, Wegria, R . Ventricular fibrillation due to single, localized induction and condenser shocks applied during the vulnerable phase of ventricular systole. Am J Physiol 1940; 128:500. Topic 954 Version 22.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 16/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate GRAPHICS Mechanisms of reentry in cardiac arrhythmias Schematic representation of possible reentrant circuits. The thick black arrow represents the circulating impulse; thin black lines represent advancing wavefronts in completely refractory tissue; speckled areas are partially refractory tissue; white areas are fully excitable tissue. A is the original model of circus movement around a fixed obstacle. There is a fully excitable gap, and the length and location of the circuit are fixed. B represents circus movement around 2 fixed anatomic obstacles. A fully excitable gap is present. C represents rapidly conducting bundles forming closed loops that serve as preferential circuits through which the impulse may travel. D is the leading circle type of reentry which does not require an anatomic obstacle. Instead, the impulse propagates around a functionally refractory core and among neighboring fibers that have different electrophysiologic properties. Since the refractoriness of the core is variable, the circuit size changes but will be the smallest possible circuit that can continue to propagate an impulse. Functional circuits tend to be small, rapid, and unstable. E represents reentry around a fixed anatomic obstacle, but a fully excitable gap is absent. F demonstrates an area of slowed conduction (hatched lines) between anatomic boundaries, while in G all areas of slowed conduction neighbor an anatomic obstacle. H represents anisotropic reentry. There are differences in the conduction of a single impulse in various fibers as a result of differences in their orientation. https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 17/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Courtesy of Philip J Podrid, MD, FACC. Graphic 52134 Version 5.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 18/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Anisotropic reentry Panel A is an activation map of a single reentrant circuit at the epicardial border zone of a myocardial infarction. The large arrows represent the general activation pattern which occurs around a long line of block (blue arrow). Parallel isochrones 130 and 140 which are adjacent to the block suggest that activation is occurring across the block, resulting in a smaller circuit (shaded area) shown by the small black arrow. Panel B is an enlarged representation of this shaded area; the dark black rectangle represents an area of block around which there is a reentrant circuit (small arrows). Rapid activation occurs parallel to the long axis of the fiber orientation (isochrones 10-40 and 130-150), while in the transverse direction activation is slow (bunched isochrones 50-120). Graphic 54711 Version 2.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 19/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Mechanism of torsades de pointes The top panels A-F are examples of epicardial isochrone maps obtained from the surface of the anterior left ventricular (LV) wall and free wall of the right ventricle (RV) during an episode of quinidine-induced torsades de pointes. Each map corresponds to a QRS deflection of the surface ECG and simultaneous monophasic action potential (MAP). Early afterpotentials (EADs) result in triggered activity (panels A-C) which is followed by a long episode of spiral-like reentry (panels D-F). Panel C shows the first reentrant wave which is not stationary, but gradually shifts upward and to the right. This is associated with a gradual decrease in the QRS complex amplitude. Reprinted with permission from the American College of Cardiology. Journal of the American College of Cardiology, 1997; 29:831. Graphic 56857 Version 3.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 20/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Sites of reentry in supraventricular tachyarrhythmias Reentry may occur around a fixed anatomic obstacle or may be functional, developing in the absence of an anatomic obstacle and resulting from the intrinsic heterogeneity of electrophysiologic properties of the myocardial tissue. Reentrant circuits leading to a supraventricular tachyarrhythmia may develop in various parts of the heart: within and around the sinoatrial node (sinus node reentry); within the atrial myocardium (atrial tachycardia, atrial flutter, or atrial fibrillation); within the atrioventricular (AV) node due to the presence of a slow and fast pathway (atrioventricular nodal reentrant tachycardia); or involving the AV node and an accessory pathway (AP) (atrioventricular reentrant tachycardia). LAF: left anterior fascicle; LPF: left posterior fascicle. Graphic 82249 Version 4.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 21/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Single-lead electrocardiogram (ECG) showing sinoatrial (SA) nodal reentrant tachycardia Electrocardiogram showing SA nodal reentrant tachycardia. The first three beats are normal sinus beats at a rate of about 107 beats/min; the fourth beat is an atrial premature beat that is followed by a return to sinus rhythm. The eighth beat (arrow) represents the sudden onset of SA nodal reentrant tachycardia at a rate of about 145 beats/min. Since the P waves are similar to the sinus beats, the diagnosis is suggested only by the abrupt onset of the tachycardia. Courtesy of Morton F Arnsdorf, MD. Graphic 76364 Version 5.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 22/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Two types of reentry in atrial fibrillation The isochronal activation maps demonstrate two types of reentry in atrial fibrillation. Map A shows random reentry with three simultaneous wavefronts (black arrows) activating most of the recording area. Map B also shows three simultaneous wavefronts, but they are coming from different directions than those in map A. Maps C and D show two consecutive cycles of complete reentry. The wave of activation (black arrow) spreads clockwise in a circular fashion around a line of unexcited tissue. Reproduced with permission from Holm M, Johansson R, Brandt J, et al. Eur Heart J 1997; 18:290. Graphic 73931 Version 2.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 23/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Single-lead electrocardiogram (ECG) showing atrial fibrillation Lead V1 showing coarse AF with moderate ventricular response. The two characteristic findings in AF are present: the very rapid atrial fibrillatory waves (f waves), which are variable in appearance; and the irregularly irregular ventricular response as the R-R interval between beats is unpredictable. Coarse AF may appear similar to atrial flutter. However, the variable height and duration of the f waves differentiate them from atrial flutter (F) waves, which are identical in appearance and occur at a constant rate of about 250 to 350 beats/min. AF: atrial fibrillation. Courtesy of Ary Goldberger, MD. Graphic 73958 Version 6.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 24/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Single-lead electrocardiogram (ECG) showing atrial fibrillation with minimally apparent atrial activity F waves are not apparent in this lead, as the only finding suggestive of AF is the irregularly irrregular ventricular response. AF: atrial fibrillation. Courtesy of Morton Arnsdorf, MD. Graphic 53988 Version 4.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 25/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Typical atrioventricular nodal reentrant tachycardia The first two complexes are normal sinus beats with a normal P wave followed by a QRS complex. The third complex, an atrial premature beat (APB), has a prolonged PR interval; it initiates a common or typical atrioventricular nodal reentrant tachycardia (AVNRT) in which antegrade conduction to the ventricle is via the slow pathway and retrograde atrial activation is by the fast pathway. Although no distinct P wave is seen, the QRS complex has a small terminal deflection, known as a pseudo r', which is the P wave superimposed upon the terminal portion of the QRS complex. Graphic 54290 Version 3.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 26/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Slow-fast form of atrioventricular nodal reentrant tachycardia (AVNRT) Representation of dual pathway physiology involving the atrioventricular (AV) node and perinodal atrial tissue in the common form of AVNRT. Left panel: A normal sinus beat (A ) is conducted through the fast pathway (F) to the final common pathway (fcp) in the AV node and into the Bundle of His. The conduction through the slow pathway (S) runs into the refractory period of the impulse through the fast pathway and is extinguished. 1 Middle panel: A critically timed atrial premature beat (A ) finds the fast pathway refractory in the antegrade direction but is able to conduct antegrade through the slow pathway, which has a shorter refractory period. If excitability in the fast pathway has recovered by 2 the time the impulse reaches the fcp, there may be retrograde activation of the fast pathway. Right panel: The retrograde impulse throws off an echo to the atrium (A*), and, if the slow pathway has recovered its excitability, the impulse reenters the slow pathway and produces ventricular depolarization (V*). If the mechanism persists, a repetitive circuit is established that creates a sustained reentrant tachycardia. The sequence of antegrade (S) and retrograde (F) conduction is called the slow-fast form of AVNRT. Graphic 79760 Version 6.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 27/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Atypical atrioventricular nodal reentrant tachycardia Shown are three simultaneous ECG leads (I, II, and III) during an uncommon or atypical form of an atrioventricular nodal reentrant tachycardia (AVNRT) in which antegrade conduction to the ventricle is via the fast pathway and retrograde atrial activation is by the slow pathway. As a result of delayed atrial activation, there is a long RP and short PR interval and a negative P wave in the inferior leads II and III. Graphic 66828 Version 2.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 28/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Uncommon fast-slow variant of atrioventricular nodal reentrant tachycardia (AVNRT) Diagrammatic representation in the circuit (left panel) and the ladder diagram (right panel) of the uncommon form of AVNRT (fast-slow variant). Antegrade conduction is through the fast (F) pathway and retrograde conduction is through the slow (S) pathway. Because of slow retrograde activation of the atrium, the P wave occurs after the QRS complex with a long RP interval and relatively short PR interval before the next QRS complex. ECG: electrocardiogram. Graphic 56806 Version 4.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 29/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate 12-lead electrocardiogram (ECG) showing orthodromic atrioventricular reentrant tachycardia (AVRT) in a patient with an accessory AV pathway The 12-lead ECG from a patient with Wolff-Parkinson-White shows a regular tachycardia. However, in contrast to the QRS pattern during sinus rhythm, the QRS complexes are narrow, without evidence of a delta wave or pre-excitation; this is due to the fact that antegrade ventricular activation occurs via the normal atrioventricular node-His Purkinje pathway, while retrograde atrial activation is via the accessory pathway. Therefore, this is called an orthodromic atrioventricular reentrant tachycardia (OAVRT). Courtesy of Martin Burke, DO. Graphic 68804 Version 5.0 ECG in Wolff-Parkinson-White https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 30/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate The 12-lead ECG shows the typical features of Wolff-Parkinson-White; the PR interval is short (*) and the QRS duration prolonged as a result of a delta wave (arrow), indicating ventricular preexcitation. Courtesy of Martin Burke, DO. Graphic 67181 Version 3.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 31/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Orthodromic atrioventricular reentrant tachycardia (AVRT) in the setting of an accessory AV pathway The rhythm strip shows a sinus (S) beat that has a short PR interval and a wide QRS complex as a result of a delta wave (d). Panel A shows an atrial premature beat (APB,*) that is blocked in the accessory pathway (AP), which has a long refractory period but is conducted antegradely through the atrioventricular node (N) and the His-Purkinje system, resulting in a normal PR interval and a narrow and normal QRS complex, as seen on the rhythm strip. After normal myocardial activation, the impulse is conducted retrogradely along the AP, activating the atrium in a retrograde fashion (panel B), which results in a negative P wave. If this activation sequence repeats itself (panel C), an orthodromic atrioventricular reentrant (or reciprocating) tachycardia (AVRT) is established. Graphic 71302 Version 7.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 32/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate 12-lead electrocardiogram (ECG) showing antidromic atrioventricular reentrant tachycardia (AVRT) in a patient with an accessory AV pathway The 12-lead ECG of a patient with Wolff-Parkinson-White shows a regular tachycardia. The QRS complexes are widened and are identical to the QRS complexes seen in sinus rhythm; the antegrade conduction to the ventricle is via the accessory pathway and retrograde conduction is via the normal His- atrioventricular node pathway. This is, therefore, an antidromic atrioventricular reentrant tachycardia (AVRT). Courtesy of Martin Burke, DO. Graphic 54484 Version 20.0 ECG in Wolff-Parkinson-White https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 33/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate The 12-lead ECG shows the typical features of Wolff-Parkinson-White; the PR interval is short (*) and the QRS duration prolonged as a result of a delta wave (arrow), indicating ventricular preexcitation. Courtesy of Martin Burke, DO. Graphic 67181 Version 3.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 34/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Antidromic atrioventricular reentrant tachycardia (AVRT) in the setting of an accessory AV pathway The rhythm strip shows a sinus (S) beat that has a short PR interval and a wide QRS complex as a result of a delta wave (d). Panel A shows the activation sequence with an atrial premature beat (APB,*). The impulse reaches the atrioventricular node (N) before it has repolarized and hence is blocked in this structure. However, the accessory pathway (AP), which has a short refractory period, is able to conduct the impulse antegradely, resulting in an APB with a widened QRS morphology similar to the sinus beat. As seen in panel B, following myocardial activation, the impulse is conducted retrogradely along the His-Purkinje system and AV node, resulting in retrograde atrial activation, seen on the rhythm strip as an inverted P wave. If this activation sequence repeats itself (panel C), a wide QRS complex antidromic atrioventricular reentrant (or reciprocating) tachycardia (AVRT) is established. Graphic 50433 Version 4.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 35/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Single lead electrocardiogram (ECG) showing monomorphic ventricular tachycardia Three or more successive ventricular beats are defined as ventricular tachycardia (VT). This VT is monomorphic since all of the QRS complexes have an identical appearance. Although the P waves are not distinct, they can be seen altering the QRS complex and ST-T waves in an irregular fashion, indicating the absence of a relationship between the P waves and the QRS complexes (ie, AV dissociation is present). AV: atrioventricular. Graphic 63176 Version 7.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 36/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate ECG 12-lead ventricular fibrillation 12-lead ECG showing course ventricular fibrillation. ECG: electrocardiogram. Graphic 118944 Version 1.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 37/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Mechanism of bundle branch reentrant ventricular tachycardia Schematic representation of the reentrant circuit in bundle branch reentrant ventricular tachycardia (BBRVT) showing a ventricular premature beat that blocks in the right bundle branch (RBB), conducts slowly up the left bundle branch (LBB), activates the bundle of His, and returns antegradely down the RBB. If the RBB has recovered its excitability from the preceding beat, the circuit is completed, and the reentrant circuit may become repetitive. AV: atrioventricular; PVC: premature ventricular contraction. Graphic 75164 Version 5.0 https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 38/39 7/5/23, 11:16 AM Reentry and the development of cardiac arrhythmias - UpToDate Contributor Disclosures Philip J Podrid, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Bernard J Gersh, MB, ChB, DPhil, FRCP, MACC Consultant/Advisory Boards: Bain Institute [CRO for trials involving Edwards percutaneous valve devices]; Cardiovascular Research Foundation [Data safety monitoring board (RELIEVE-HF Trial)]; Caristo Diagnostics Limited [Imaging and inflammation/atherosclerosis]; Philips Image Guided Therapy Corporation [Imaging]; Sirtex Med Limited [General consulting]; Thrombosis Research Institute [Data safety monitoring board (GARFIELD study)]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/reentry-and-the-development-of-cardiac-arrhythmias/print 39/39

7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Sinus node dysfunction: Epidemiology, etiology, and natural history : Munther K Homoud, MD : Samuel L vy, MD : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jul 08, 2022. INTRODUCTION The sinoatrial (SA) node is normally the dominant pacemaker in the human heart. Originally described in 1907 as a subepicardial structure located at the junction of the right atrium and superior vena cava, the SA node represents the integrated activity of pacemaker cells in a compact region of the right atrium that depolarize and produce action potentials almost synchronously [1-3]. While the location of the primary pacemaker may move among groups of cells within the region of the SA node, only about 1 percent of the cells in the SA node act as the leading pacemaker [4]. Sinus node dysfunction (SND), also historically referred to as sick sinus syndrome, is the term used to describe the inability of the SA node to generate a heart rate that meets the physiologic needs of an individual. The initial clues to the diagnosis of SND are often derived from taking the history and obtaining a routine electrocardiogram (ECG), though the symptoms and ECG findings are frequently vague and nonspecific. The diagnostic evaluation should initially include a search for remediable causes of SA nodal depression such as drugs (eg, beta blockers, calcium channel blockers, digoxin) and metabolic diseases (eg, hypothyroidism). Treatment of SND is directed at symptoms and typically involves the implantation of a permanent pacemaker. The epidemiology, potential etiologies, and the natural history of SND will be reviewed here. The clinical manifestations, approach to diagnosis, and the treatment of SND are discussed in detail https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 1/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate separately. (See "Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation" and "Sinus node dysfunction: Treatment".) NORMAL PHYSIOLOGY OF THE SA NODE Cellular physiology Pacemaking activity that originates from the sinoatrial (SA) node is incompletely understood. There are two predominant mechanisms that are thought to serve as the initiation of sinus activity: The funny current (I ) f Spontaneous intracellular calcium release by sarcoplasmic reticulum The I current is the result of sodium and potassium ionic currents that allow for a steady f increase in the resting membrane potential of the cell ( figure 1). Once the resting membrane reaches the depolarization threshold of the cell, an action potential is generated, and electrical activity ensues. The rate of the steady increase of the resting membrane potential can be modulated by other ionic currents as well as beta-adrenergic activity. As the slope of the increase in resting membrane potential steepens, the rate of spontaneous sinus node activity increases. The second mechanism thought to be critical in SA node activity initiation is spontaneous sarcoplasmic reticulum calcium release within the SA nodal cells [5]. The release of calcium into the intracellular space results in activation of the sodium-calcium exchange current, eventually leading to phase 4 depolarization. These two mechanisms are not mutually exclusive, and evidence suggests that they may be complementary in their pacemaking actions. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs", section on 'Action potential in slow response tissues'.) While the calcium and potassium currents are the predominant determinants of SA nodal automaticity, there is evidence to suggest that the sodium channel may also play a role. Mutations in the human cardiac sodium channel (SCN5A) cause one type of long-QT syndrome (LQT3), and these individuals may also have sinus pauses and sinus bradycardia in addition to the characteristic prolongation of the QT interval. Studies in cells expressing either wild type or LQT3 channels showed that an increase in a persistent inward current in the mutated channels reduced the sinus rate directly and could also result in the failure to repolarize completely [6]. (See "Congenital long QT syndrome: Pathophysiology and genetics", section on 'Type 3 LQTS (LQT3)'.) https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 2/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate As mentioned above, pacemaking can originate from different areas within the sinus node. Mapping of sinus node activation indicates that at faster rates, the SA impulse originates in the superior portion of the SA node, or extranodally, while at slower rates, it arises from the inferior portion of the node or, once again, extranodally [7]. The SA node may be insulated from the surrounding atrial myocytes except at a limited number of preferential exit sites. Shifting pacemaker sites may select different exit pathways to the atria. Autonomic nervous system and the SA node The SA node is innervated by the parasympathetic and the sympathetic nervous systems, and the balance between these systems controls the pacemaker rate. The classic concept has been that of a reciprocally balanced relationship between sympathetic and parasympathetic inputs. More recent investigations, however, stress dynamic, demand-oriented interactions and the anatomic distribution of fibers that allows both autonomic systems to act quite selectively [8]. Muscarinic cholinergic and beta-1 adrenergic receptors are nonuniformly distributed in the SA node and modulate both the rate of depolarization and propagation [7]. Parasympathetic activity Parasympathetic input via the vagus nerves decreases the SA nodal pacemaker and is the dominant input at rest. The mediator of parasympathetic activity is acetylcholine (ACh) which, as a ligand gating agent, acts through the G-protein, G , to activate a i certain group of membrane channels called I channels ( figure 1) in tissues of the SA and KACh atrioventricular (AV) nodes as well as of the atria, Purkinje fibers, and ventricles [9]. Acetylcholine increases the outward potassium current, thereby slowing the SA nodal pacemaker, by at least two important mechanisms: The resting potential and the maximum diastolic potential become more negative; as a result, more current is required to reach threshold. The outward potassium current opposes the inward currents responsible for depolarizing the cell, resulting in a decrease in phase 4 depolarization. Acetylcholine also reduces the inward calcium current, I through the G-protein system. Ca Sympathetic activity Sympathetic nerve input, as well as the adrenal medullary release of catecholamines, increases the sinus rate during exercise and stress. The manner in which beta- receptor stimulation by catecholamines affects automaticity is complex and involves interactions of the beta-receptor/adenylate cyclase/G-protein systems. Catecholamines enhance the L-type of inward calcium current by increasing cyclic adenosine monophosphate (AMP) and activating the protein kinase A system; the increment in inward calcium current would be expected to increase the rate of phase 4 diastolic depolarization. The redistribution of calcium may also increase the completeness and the rate of I deactivation. Catecholamines may also enhance I . f K https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 3/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate SA nodal remodeling Atrial tachyarrhythmias can cause persistent changes in atrial electrophysiology that result in increased vulnerability to further dysrhythmia. This phenomenon is called "atrial remodeling." (See "Mechanisms of atrial fibrillation", section on 'Electrical remodeling'.) The SA node may also undergo electrophysiologic changes in response to atrial arrhythmias or other stimuli (see bullets below); these changes result in SA node dysfunction and are referred to as "SA nodal remodeling" [10,11]. Remodeling of the SA node may also occur in the setting of heart failure, even in the absence of a history of atrial fibrillation [12]. In a study of 18 patients with symptomatic heart failure and 18 age-matched controls, those with heart failure had significant prolongation of the intrinsic sinus cycle length, corrected sinus node recovery time, and sinoatrial conduction time, as well as caudal displacement of sinus activity and an increase in the number and duration of fractionated atrial electrograms [13]. After ablation for atrial fibrillation, reverse remodeling of the SA node may occur with elimination of the SA node depression and the prolonged sinus pauses [14]. Reverse remodeling of SA nodal function also occurs after the termination of atrial flutter [15] and after the catheter ablation of right atrial flutter [16]. As little as 10 to 15 minutes of atrial pacing causes SA nodal remodeling in humans [17]. Interestingly, asynchronous ventricular pacing has also been associated with SA nodal remodeling [18]. DEFINITION Sinus node dysfunction (SND) is characterized by dysfunction of the sinoatrial (SA) node that is often secondary to senescence of the node and surrounding atrial myocardium. The term "sinus node dysfunction" was first used in 1967 to describe the sluggish return of SA nodal activity in some patients following electrical cardioversion and is now commonly used to describe the inability of the SA node to generate a heart rate that meets the physiologic needs of an individual [19-21]. SND can present with numerous ECG abnormalities including: Sinus bradycardia Sinus pauses Sinus arrest SA nodal exit block Inadequate heart rate response to physiological demands during activity (chronotropic incompetence) https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 4/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate SND can also be accompanied by supraventricular tachycardias (atrial fibrillation, atrial flutter, and atrial tachycardia) as part of the tachycardia-bradycardia syndrome. (See "Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation", section on 'ECG findings'.) EPIDEMIOLOGY The epidemiology of SND is difficult to study, given the nature of SND and its varying manifestations, including nonspecific symptoms and ECG findings. However, patients with symptomatic SND are generally older (ie, seventh or eighth decade of life) with frequent comorbid diseases. In a pooled analysis of 20,572 patients from two large epidemiology studies (Atherosclerosis Risk in Communities [ARIC] and Cardiovascular Health Study [CHS]) who were followed for an average of 17 years, 291 incident cases of SND were noted, yielding in an incidence rate of 0.8 cases per 1000 person-years [22]. While several variables were associated with development of SND (eg, higher body mass index, hypertension, prior cardiovascular event), advancing age was the most significant risk factor for SND (hazard ratio 1.73 for each additional five years of age; 95% CI 1.47-2.05). In three major trials of pacing in this disorder, the median or mean age was 73 to 76 years [23-25]. Males and females appear equally affected, and although less common, SND can occur in younger adults and children. (See 'Childhood and familial disease' below.) ETIOLOGY Sinoatrial (SA) node dysfunction occurs as a result of disorders in automaticity, conduction, or both. Local cardiac pathology, systemic diseases that involve the heart, and medications/toxins can all be responsible for abnormal SA node function and result in SND. Most cases of sinus node dysfunction entail extrinsic and intrinsic components. Identification of an extrinsic component is important because it is often modifiable. Drug-induced SND (suppression) is transient and modifiable, whereas SND due to an infiltrative cardiomyopathy, surgical intervention, or a mutation in a number of genes identified to be associated with SND is not. Thus, it is important to identify and eliminate any aggravating (reversible) factors causing SND, given the absence of treatment of intrinsic SND other than pacemaker therapy with its associated limitations. (See "Sinus node dysfunction: Treatment".) https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 5/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate Abnormal automaticity, or sinus arrest, refers to a failure of sinus impulse generation. Abnormal conduction, or sinoatrial delay or block, is a failure of impulse transmission. In such cases, the sinus impulse is generated normally, but it is abnormally conducted to the neighboring atrial tissue. Both abnormal automaticity and abnormal conduction may result from one of several different mechanisms including fibrosis, atherosclerosis, and inflammatory/infiltrative myocardial processes. Sinus node fibrosis The most common cause of sinus node dysfunction is the replacement of sinus node tissue by fibrous tissue, which may be accompanied by degeneration and fibrosis of other parts of the conduction system as well, including the atrioventricular (AV) node [26-28]. The transitional junction between the sinus node and atrial tissue may also be involved, and there may be degeneration of nerve ganglia. Medications and toxins A number of medications and toxins can reversibly depress sinus node function, resulting in symptoms and ECG changes consistent with SND. The most commonly used prescription medications which alter myocardial conduction and can potentially result in SND include [29-34]: Beta blockers Nondihydropyridine calcium channel blockers Digoxin Antiarrhythmic medications Acetylcholinesterase inhibitors such as donepezil (Aricept) and rivastigmine used in the treatment of Alzheimer disease Other medications associated with depression of sinus node function include parasympathomimetic agents, sympatholytic drugs (eg, methyldopa, clonidine), cimetidine, lithium, and ivabradine [35,36]. In addition, poisoning by grayanotoxin, produced by some plants (eg, Rhododendron sp.) and found in certain varieties of honey, has been associated with depressed sinus node function [37]. Childhood and familial disease SND is rare in children, but when present it is most often seen in those with congenital and acquired heart disease, particularly after corrective cardiac surgery [38-41]. Familial sinus node dysfunction is rare, with mutations in the cardiac sodium channel gene SCN5A and the HCN4 gene (thought to contribute to the pacemaker current in the sinus node) responsible for some familial cases [42-48]. In a series of 30 children and young adults (ages 3 days to 25 years) with sinus node dysfunction, 22 had significant cardiac disease, and sinus node dysfunction developed after https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 6/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate cardiac surgery in 13 [38]. The causes of sinus node dysfunction were inappropriate sinus bradycardia, sinus arrest, and sinoatrial exit block. In a study of 10 children from seven families with familial SND, genomic DNA encoding the alpha subunit of the cardiac sodium channel was screened for mutations [42]. Compound heterozygous nucleotide changes were identified in five children from three families (but in none of over 75 control subjects). In a series of 38 patients with clinical evidence of Brugada syndrome, four had SCN5A mutations [45]. Three of these patients had SND with multiple affected family members. Mutations in SCN5A are not pathognomonic for sinus node disease, however, as different SCN5A mutations are associated with other cardiac abnormalities including Brugada syndrome, congenital long QT syndrome type 3, familial AV block, and familial dilated cardiomyopathy with conduction defects and susceptibility to atrial fibrillation (AF). (See "Congenital long QT syndrome: Pathophysiology and genetics" and "Etiology of atrioventricular block" and "Genetics of dilated cardiomyopathy" and "Brugada syndrome: Epidemiology and pathogenesis", section on 'SCN5A'.) Mutations in HCN4 can produce both symptomatic and asymptomatic sinus node dysfunction, as illustrated by numerous reports of sinus bradycardia in family members with such mutations [46-49]. Other SND is less often due to a variety of other disorders: Infiltrative diseases The SA node may be affected by infiltrative disease, such as amyloidosis, sarcoidosis, scleroderma [50], hemochromatosis, and rarely tumor. Inflammatory diseases Rheumatic fever, pericarditis, diphtheria, Chagas disease, and other disorders may depress SA nodal function. SA nodal artery disease The sinus node is perfused by branches of the right coronary artery in 55 to 60 percent and by the left circumflex artery in the remaining 40 to 45 percent. The SA nodal artery may be narrowed by atherosclerosis, inflammatory processes, or even emboli [28,50-52]. Approximately 5 percent of patients with myocardial infarction, usually inferior, show sinus node dysfunction that tends to be reversible [53-55]. In one study of 46 patients with prior inferior myocardial infarction (23 patients with and 23 without SND), the intrinsic heart rate was abnormal in almost all patients with more than a 75 percent narrowing of the SA nodal artery, but only 30 percent with less than 50 percent narrowing [56]. https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 7/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate Trauma Cardiac trauma during surgery may affect either the SA node directly or its blood supply. Miscellaneous Other disorders that can cause SND include hypothyroidism, hypothermia, hypoxia, and muscular dystrophies. Some infections (eg, leptospirosis, trichinosis, and Salmonella typhosa) are associated with relative sinus bradycardia, but permanent SND has not followed these [57-60]. NATURAL HISTORY The natural history of SND typically involves intermittent but progressive cardiac rhythm disorders, which have been associated with higher rates of other cardiovascular events and higher mortality. There is a tendency for the rhythm disturbances associated with SND to evolve over time, along with a higher likelihood of thromboembolic events and other cardiovascular events. Rhythm For many patients with SND, there are variable, and often long, periods of normal sinus node function [61]. Nevertheless, once present, sinus node dysfunction eventually progresses in most patients, along with a greater likelihood of developing atrial tachyarrhythmias [62]. However, it is very difficult to predict the time course of disease progression, which is why most patients with symptomatic SND will be treated earlier in an attempt to alleviate symptoms. (See "Sinus node dysfunction: Treatment".) Sinus node dysfunction progresses over time. In one cohort of 52 patients with sinus node dysfunction who presented with sinus bradycardia associated with sinoatrial (SA) block or SA arrest, it took an average of 13 years (range 7 to 29 years) for progression to complete SA arrest and an escape rhythm [61]. Atrial arrhythmias and conduction disturbances become more common over time, possibly the result of a progressive pathological process that affects the entire atrium and other parts of the heart [27,63,64]. As an example, among 213 patients with a history of symptomatic SND who were treated with atrial pacing and followed for a median of five years, 7 percent developed atrial fibrillation and 8.5 percent developed high-grade atrioventricular block [65]. Cardiovascular events Patients with SND, particularly those with alternating tachycardia and bradycardia, are at an increased risk for thromboembolic events even after pacemaker implantation. A possible contributor to cardiovascular events after pacemaker implantation is https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 8/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate asymptomatic episodes of atrial fibrillation resulting in thromboembolic events. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) In one prospectively-followed cohort of 35 patients aged 45 years with symptomatic SND manifested by a mean sinus rate at rest 50 beats/minute and/or intermittent SA block, who did not undergo immediate treatment but were followed for an average of 17 months, a cardiovascular event requiring treatment occurred in 57 percent of patients and included syncope (23 percent), overt heart failure (17 percent), chronic atrial fibrillation (11 percent), or poorly tolerated atrial arrhythmias (6 percent) [66]. Independent predictors of a cardiovascular event were age, left ventricular end-diastolic diameter, and left ventricular ejection fraction. In a study of 225 patients with SND who were randomized to single-chamber atrial or ventricular pacing, the annual risk of thromboembolism was approximately twofold higher for patients with SND and tachycardia/bradycardia syndrome compared with patients without tachycardia/bradycardia syndrome [67]. Mortality The relationship between SND and mortality is difficult to clearly understand as many individuals with SND have pre-existing comorbidities (hypertension, diabetes mellitus, atrial fibrillation) that are known to increase all-cause mortality. In one study of 19,893 persons from two prospective cohorts without atrial fibrillation or a pacemaker at baseline who were followed for an average of 17 years, 213 persons developed SND (0.6 events per 1000 person- years) [68]. While the development of SND was associated with a significantly higher mortality, this association was attenuated following adjustment for incident cardiovascular disease during follow-up. While SND certainly contributes to patient morbidity, if or how SND increases overall mortality is unclear. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 9/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Sinus node dysfunction (The Basics)" and "Patient education: Bradycardia (The Basics)") SUMMARY AND RECOMMENDATIONS Physiology of the SA node The sinoatrial (SA) node is innervated by the parasympathetic and the sympathetic nervous systems, and the balance between these systems controls the pacemaker rate. Parasympathetic input via the vagus nerves decreases the SA nodal pacemaker and is the dominant input at rest, while sympathetic nerve input, as well as the adrenal medullary release of catecholamines, increase the sinus rate during exercise and stress. (See 'Autonomic nervous system and the SA node' above.) Definition Sinus node dysfunction (SND) is characterized by dysfunction of the SA node that is often secondary to senescence of the SA node and surrounding atrial myocardium. Medications may also contribute and can often unmask subclinical sinoatrial dysfunction. (See 'Definition' above and "Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation", section on 'Clinical presentation'.) Epidemiology The epidemiology of SND is difficult to study, given the nature of SND and its varying manifestations, but patients with symptomatic SND are generally older (ie, seventh or eighth decade of life) with frequent comorbid diseases. Causes SA node dysfunction occurs as a result of disorders in automaticity, conduction, or both. Sinus node fibrosis is the most common cause of SND, although medications and toxins as well as systemic diseases that involve the heart can also be responsible for abnormal SA node function and result in SND. (See 'Etiology' above.) Natural history The natural history of SND caused by sinus node fibrosis typically involves intermittent but progressive cardiac rhythm disorders, which have been associated with higher rates of other cardiovascular events and higher mortality. There is a tendency for the rhythm disturbances associated with SND to evolve over time, along with a higher likelihood of thromboembolic events and other cardiovascular events. (See 'Natural history' above.) https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 10/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Alan Cheng, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Keith A, Flack M. The Form and Nature of the Muscular Connections between the Primary Divisions of the Vertebrate Heart. J Anat Physiol 1907; 41:172. 2. Bleeker WK, Mackaay AJ, Masson-P vet M, et al. Functional and morphological organization of the rabbit sinus node. Circ Res 1980; 46:11. 3. Boyett MR, Honjo H, Kodama I. The sinoatrial node, a heterogeneous pacemaker structure. Cardiovasc Res 2000; 47:658. 4. Boyett MR, Dobrzynski H, Lancaster MK, et al. Sophisticated architecture is required for the sinoatrial node to perform its normal pacemaker function. J Cardiovasc Electrophysiol 2003; 14:104. 5. Lakatta EG, Maltsev VA, Vinogradova TM. A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker. Circ Res 2010; 106:659. 6. Veldkamp MW, Wilders R, Baartscheer A, et al. Contribution of sodium channel mutations to bradycardia and sinus node dysfunction in LQT3 families. Circ Res 2003; 92:976. 7. Schuessler RB. Abnormal sinus node function in clinical arrhythmias. J Cardiovasc Electrophysiol 2003; 14:215. 8. Josephson, ME. Sinus Node Function. In: Clinical Cardiac Electrophysiology: Techniques and I nterpretations, 4th, Lippincott, Williams, & Wilkins, Philadelphia 2008. p.69-92. 9. Pappano AJ, Mubagwa K. Actions of muscarinic agents and adenosine on the heart. In: The Heart and Cardiovascular System, Fozzard HA, et al (Eds), Raven Press, New York 1992. p.176 5. 10. Sanders P, Morton JB, Davidson NC, et al. Electrical remodeling of the atria in congestive heart failure: electrophysiological and electroanatomic mapping in humans. Circulation 2003; 108:1461. 11. Morton JB, Sanders P, Vohra JK, et al. Effect of chronic right atrial stretch on atrial electrical remodeling in patients with an atrial septal defect. Circulation 2003; 107:1775. https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 11/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate 12. Yanni J, Tellez JO, Maczewski M, et al. Changes in ion channel gene expression underlying heart failure-induced sinoatrial node dysfunction. Circ Heart Fail 2011; 4:496. 13. Sanders P, Kistler PM, Morton JB, et al. Remodeling of sinus node function in patients with congestive heart failure: reduction in sinus node reserve. Circulation 2004; 110:897. 14. Hocini M, Sanders P, Deisenhofer I, et al. Reverse remodeling of sinus node function after catheter ablation of atrial fibrillation in patients with prolonged sinus pauses. Circulation 2003; 108:1172. 15. Sparks PB, Jayaprakash S, Vohra JK, Kalman JM. Electrical remodeling of the atria associated with paroxysmal and chronic atrial flutter. Circulation 2000; 102:1807. 16. Daoud EG, Weiss R, Augostini RS, et al. Remodeling of sinus node function after catheter ablation of right atrial flutter. J Cardiovasc Electrophysiol 2002; 13:20. 17. Hadian D, Zipes DP, Olgin JE, Miller JM. Short-term rapid atrial pacing produces electrical remodeling of sinus node function in humans. J Cardiovasc Electrophysiol 2002; 13:584. 18. Sparks PB, Mond HG, Vohra JK, et al. Electrical remodeling of the atria following loss of atrioventricular synchrony: a long-term study in humans. Circulation 1999; 100:1894. 19. Ferrer MI. The sick sinus syndrome in atrial disease. JAMA 1968; 206:645. 20. Lown B. Electrical reversion of cardiac arrhythmias. Br Heart J 1967; 29:469. 21. Dobrzynski H, Boyett MR, Anderson RH. New insights into pacemaker activity: promoting understanding of sick sinus syndrome. Circulation 2007; 115:1921. 22. Jensen PN, Gronroos NN, Chen LY, et al. Incidence of and risk factors for sick sinus syndrome in the general population. J Am Coll Cardiol 2014; 64:531. 23. Lamas GA, Lee KL, Sweeney MO, et al. Ventricular pacing or dual-chamber pacing for sinus- node dysfunction. N Engl J Med 2002; 346:1854. 24. Connolly SJ, Kerr CR, Gent M, et al. Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. Canadian Trial of Physiologic Pacing Investigators. N Engl J Med 2000; 342:1385. 25. Andersen HR, Thuesen L, Bagger JP, et al. Prospective randomised trial of atrial versus ventricular pacing in sick-sinus syndrome. Lancet 1994; 344:1523. 26. Kaplan BM, Langendorf R, Lev M, Pick A. Tachycardia-bradycardia syndrome (so-called "sick sinus syndrome"). Pathology, mechanisms and treatment. Am J Cardiol 1973; 31:497. 27. Thery C, Gosselin B, Lekieffre J, Warembourg H. Pathology of sinoatrial node. Correlations with electrocardiographic findings in 111 patients. Am Heart J 1977; 93:735. 28. HUDSON RE. The human pacemaker and its pathology. Br Heart J 1960; 22:153. https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 12/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate 29. Margolis JR, Strauss HC, Miller HC, et al. Digitalis and the sick sinus syndrome. Clinical and electrophysiologic documentation of severe toxic effect on sinus node function. Circulation 1975; 52:162. 30. Strauss HC, Gilbert M, Svenson RH, et al. Electrophysiologic effects of propranolol on sinus node function in patients with sinus node dysfunction. Circulation 1976; 54:452. 31. Breithardt G, Seipel L, Wiebringhaus E, Loogen F. Effects of verapamil on sinus node function in man. Eur J Cardiol 1978; 8:379. 32. Vera Z, Awan NA, Mason DT. Assessment of oral quinidine effects on sinus node function in sick sinus syndrome patients. Am Heart J 1982; 103:80. 33. LaBarre A, Strauss HC, Scheinman MM, et al. Electrophysiologic effects of disopyramide phosphate on sinus node function in patients with sinus node dysfunction. Circulation 1979; 59:226. 34. Kim HG, Friedman HS. Procainamide-induced sinus node dysfunction in patients with chronic renal failure. Chest 1979; 76:699. 35. Weintraub M, Hes JP, Rotmensch HH, et al. Extreme sinus bradycardia associated with lithium therapy. Isr J Med Sci 1983; 19:353. 36. Thormann J, Neuss H, Schlepper M, Mitrovic V. Effects of clonidine on sinus node function in man. Chest 1981; 80:201. 37. Lennerz C, Jilek C, Semmler V, et al. Sinus arrest from mad honey disease. Ann Intern Med 2012; 157:755. 38. Yabek SM, Jarmakani JM. Sinus node dysfunction in children, adolescents, and young adults. Pediatrics 1978; 61:593. 39. Hayes CJ, Gersony WM. Arrhythmias after the Mustard operation for transposition of the great arteries: a long-term study. J Am Coll Cardiol 1986; 7:133. 40. Beder SD, Gillette PC, Garson A Jr, et al. Symptomatic sick sinus syndrome in children and adolescents as the only manifestation of cardiac abnormality or associated with unoperated congenital heart disease. Am J Cardiol 1983; 51:1133. 41. Greenwood RD, Rosenthal A, Sloss LJ, et al. Sick sinus syndrome after surgery for congenital heart disease. Circulation 1975; 52:208. 42. Benson DW, Wang DW, Dyment M, et al. Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). J Clin Invest 2003; 112:1019. 43. Caralis DG, Varghese PJ. Familial sinoatrial node dysfunction. Increased vagal tone a possible aetiology. Br Heart J 1976; 38:951. https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 13/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate 44. Bharati S, Surawicz B, Vidaillet HJ Jr, Lev M. Familial congenital sinus rhythm anomalies: clinical and pathological correlations. Pacing Clin Electrophysiol 1992; 15:1720. 45. Makiyama T, Akao M, Tsuji K, et al. High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations. J Am Coll Cardiol 2005; 46:2100. 46. Schulze-Bahr E, Neu A, Friederich P, et al. Pacemaker channel dysfunction in a patient with sinus node disease. J Clin Invest 2003; 111:1537. 47. Ueda K, Nakamura K, Hayashi T, et al. Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. J Biol Chem 2004; 279:27194. 48. Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N Engl J Med 2006; 354:151. 49. Nof E, Luria D, Brass D, et al. Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia. Circulation 2007; 116:463. 50. James TN. The sinus node. Am J Cardiol 1977; 40:965. 51. James TN, Birk RE. Pathology of the cardiac conduction system in polyarteritis nodosa. Arch Intern Med 1966; 117:561. 52. JAMES TN, RUPE CE, MONTO RW. PATHOLOGY OF THE CARDIAC CONDUCTION SYSTEM IN SYSTEMIC LUPUS ERYTHEMATOSUS. Ann Intern Med 1965; 63:402. 53. Hatle L, Bathen J, Rokseth R. Sinoatrial disease in acute myocardial infarction. Long-term prognosis. Br Heart J 1976; 38:410. 54. Rokseth R, Hatle L. Sinus arrest in acute myocardial infarction. Br Heart J 1971; 33:639. 55. Simonsen E, Nielsen BL, Nielsen JS. Sinus node dysfunction in acute myocardial infarction. Acta Med Scand 1980; 208:463. 56. Alboni P, Baggioni GF, Scarf S, et al. Role of sinus node artery disease in sick sinus syndrome in inferior wall acute myocardial infarction. Am J Cardiol 1991; 67:1180. 57. Puljiz I, Beus A, Kuzman I, Seiwerth S. Electrocardiographic changes and myocarditis in trichinellosis: a retrospective study of 154 patients. Ann Trop Med Parasitol 2005; 99:403. 58. Assimakopoulos SF, Michalopoulou S, Papakonstantinou C, et al. A case of severe sinus bradycardia complicating anicteric leptospirosis. Am J Med Sci 2007; 333:381. 59. Cunha BA, Thermidor M, Mohan S, et al. Fever of unknown origin: subacute thyroiditis versus typhoid fever. Heart Lung 2005; 34:147. 60. Cunha BA. The diagnostic significance of relative bradycardia in infectious disease. Clin Microbiol Infect 2000; 6:633. https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 14/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate 61. Lien WP, Lee YS, Chang FZ, et al. The sick sinus syndrome: natural history of dysfunction of the sinoatrial node. Chest 1977; 72:628. 62. John RM, Kumar S. Sinus Node and Atrial Arrhythmias. Circulation 2016; 133:1892. 63. Ferrer MI. The etiology and natural history of sinus node disorders. Arch Intern Med 1982; 142:371. 64. Simonsen E, Nielsen JS, Nielsen BL. Sinus node dysfunction in 128 patients. A retrospective study with follow-up. Acta Med Scand 1980; 208:343. 65. Brandt J, Anderson H, F hraeus T, Sch ller H. Natural history of sinus node disease treated with atrial pacing in 213 patients: implications for selection of stimulation mode. J Am Coll Cardiol 1992; 20:633. 66. Menozzi C, Brignole M, Alboni P, et al. The natural course of untreated sick sinus syndrome and identification of the variables predictive of unfavorable outcome. Am J Cardiol 1998; 82:1205. 67. Andersen HR, Nielsen JC, Thomsen PE, et al. Arterial thromboembolism in patients with sick sinus syndrome: prediction from pacing mode, atrial fibrillation, and echocardiographic findings. Heart 1999; 81:412. 68. Alonso A, Jensen PN, Lopez FL, et al. Association of sick sinus syndrome with incident cardiovascular disease and mortality: the Atherosclerosis Risk in Communities study and Cardiovascular Health Study. PLoS One 2014; 9:e109662. Topic 940 Version 35.0 https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 15/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate GRAPHICS Action potential currents Major cardiac ion currents and channels responsible for a ventricular action potential are shown with their common name, abbreviation, and the gene and protein for the alpha subunit that forms the pore or transporter. The diagram on the left shows the time course of amplitude of each current during the action potential, but does not accurately reflect amplitudes relative to each of the other currents. This summary represents a ventricular myocyte, and lists only the major ion channels. The currents and their molecular nature vary within regions of the ventricles, and in atria, and other specialized cells such as nodal and Purkinje. Ion channels exist as part of multi-molecular complexes including beta subunits and other associated regulatory proteins which are also not shown. Courtesy of Jonathan C Makielski, MD, FACC. Graphic 70771 Version 4.0 https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 16/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate Contributor Disclosures

electrophysiologic documentation of severe toxic effect on sinus node function. Circulation 1975; 52:162. 30. Strauss HC, Gilbert M, Svenson RH, et al. Electrophysiologic effects of propranolol on sinus node function in patients with sinus node dysfunction. Circulation 1976; 54:452. 31. Breithardt G, Seipel L, Wiebringhaus E, Loogen F. Effects of verapamil on sinus node function in man. Eur J Cardiol 1978; 8:379. 32. Vera Z, Awan NA, Mason DT. Assessment of oral quinidine effects on sinus node function in sick sinus syndrome patients. Am Heart J 1982; 103:80. 33. LaBarre A, Strauss HC, Scheinman MM, et al. Electrophysiologic effects of disopyramide phosphate on sinus node function in patients with sinus node dysfunction. Circulation 1979; 59:226. 34. Kim HG, Friedman HS. Procainamide-induced sinus node dysfunction in patients with chronic renal failure. Chest 1979; 76:699. 35. Weintraub M, Hes JP, Rotmensch HH, et al. Extreme sinus bradycardia associated with lithium therapy. Isr J Med Sci 1983; 19:353. 36. Thormann J, Neuss H, Schlepper M, Mitrovic V. Effects of clonidine on sinus node function in man. Chest 1981; 80:201. 37. Lennerz C, Jilek C, Semmler V, et al. Sinus arrest from mad honey disease. Ann Intern Med 2012; 157:755. 38. Yabek SM, Jarmakani JM. Sinus node dysfunction in children, adolescents, and young adults. Pediatrics 1978; 61:593. 39. Hayes CJ, Gersony WM. Arrhythmias after the Mustard operation for transposition of the great arteries: a long-term study. J Am Coll Cardiol 1986; 7:133. 40. Beder SD, Gillette PC, Garson A Jr, et al. Symptomatic sick sinus syndrome in children and adolescents as the only manifestation of cardiac abnormality or associated with unoperated congenital heart disease. Am J Cardiol 1983; 51:1133. 41. Greenwood RD, Rosenthal A, Sloss LJ, et al. Sick sinus syndrome after surgery for congenital heart disease. Circulation 1975; 52:208. 42. Benson DW, Wang DW, Dyment M, et al. Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). J Clin Invest 2003; 112:1019. 43. Caralis DG, Varghese PJ. Familial sinoatrial node dysfunction. Increased vagal tone a possible aetiology. Br Heart J 1976; 38:951. https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 13/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate 44. Bharati S, Surawicz B, Vidaillet HJ Jr, Lev M. Familial congenital sinus rhythm anomalies: clinical and pathological correlations. Pacing Clin Electrophysiol 1992; 15:1720. 45. Makiyama T, Akao M, Tsuji K, et al. High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations. J Am Coll Cardiol 2005; 46:2100. 46. Schulze-Bahr E, Neu A, Friederich P, et al. Pacemaker channel dysfunction in a patient with sinus node disease. J Clin Invest 2003; 111:1537. 47. Ueda K, Nakamura K, Hayashi T, et al. Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. J Biol Chem 2004; 279:27194. 48. Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N Engl J Med 2006; 354:151. 49. Nof E, Luria D, Brass D, et al. Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia. Circulation 2007; 116:463. 50. James TN. The sinus node. Am J Cardiol 1977; 40:965. 51. James TN, Birk RE. Pathology of the cardiac conduction system in polyarteritis nodosa. Arch Intern Med 1966; 117:561. 52. JAMES TN, RUPE CE, MONTO RW. PATHOLOGY OF THE CARDIAC CONDUCTION SYSTEM IN SYSTEMIC LUPUS ERYTHEMATOSUS. Ann Intern Med 1965; 63:402. 53. Hatle L, Bathen J, Rokseth R. Sinoatrial disease in acute myocardial infarction. Long-term prognosis. Br Heart J 1976; 38:410. 54. Rokseth R, Hatle L. Sinus arrest in acute myocardial infarction. Br Heart J 1971; 33:639. 55. Simonsen E, Nielsen BL, Nielsen JS. Sinus node dysfunction in acute myocardial infarction. Acta Med Scand 1980; 208:463. 56. Alboni P, Baggioni GF, Scarf S, et al. Role of sinus node artery disease in sick sinus syndrome in inferior wall acute myocardial infarction. Am J Cardiol 1991; 67:1180. 57. Puljiz I, Beus A, Kuzman I, Seiwerth S. Electrocardiographic changes and myocarditis in trichinellosis: a retrospective study of 154 patients. Ann Trop Med Parasitol 2005; 99:403. 58. Assimakopoulos SF, Michalopoulou S, Papakonstantinou C, et al. A case of severe sinus bradycardia complicating anicteric leptospirosis. Am J Med Sci 2007; 333:381. 59. Cunha BA, Thermidor M, Mohan S, et al. Fever of unknown origin: subacute thyroiditis versus typhoid fever. Heart Lung 2005; 34:147. 60. Cunha BA. The diagnostic significance of relative bradycardia in infectious disease. Clin Microbiol Infect 2000; 6:633. https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 14/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate 61. Lien WP, Lee YS, Chang FZ, et al. The sick sinus syndrome: natural history of dysfunction of the sinoatrial node. Chest 1977; 72:628. 62. John RM, Kumar S. Sinus Node and Atrial Arrhythmias. Circulation 2016; 133:1892. 63. Ferrer MI. The etiology and natural history of sinus node disorders. Arch Intern Med 1982; 142:371. 64. Simonsen E, Nielsen JS, Nielsen BL. Sinus node dysfunction in 128 patients. A retrospective study with follow-up. Acta Med Scand 1980; 208:343. 65. Brandt J, Anderson H, F hraeus T, Sch ller H. Natural history of sinus node disease treated with atrial pacing in 213 patients: implications for selection of stimulation mode. J Am Coll Cardiol 1992; 20:633. 66. Menozzi C, Brignole M, Alboni P, et al. The natural course of untreated sick sinus syndrome and identification of the variables predictive of unfavorable outcome. Am J Cardiol 1998; 82:1205. 67. Andersen HR, Nielsen JC, Thomsen PE, et al. Arterial thromboembolism in patients with sick sinus syndrome: prediction from pacing mode, atrial fibrillation, and echocardiographic findings. Heart 1999; 81:412. 68. Alonso A, Jensen PN, Lopez FL, et al. Association of sick sinus syndrome with incident cardiovascular disease and mortality: the Atherosclerosis Risk in Communities study and Cardiovascular Health Study. PLoS One 2014; 9:e109662. Topic 940 Version 35.0 https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 15/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate GRAPHICS Action potential currents Major cardiac ion currents and channels responsible for a ventricular action potential are shown with their common name, abbreviation, and the gene and protein for the alpha subunit that forms the pore or transporter. The diagram on the left shows the time course of amplitude of each current during the action potential, but does not accurately reflect amplitudes relative to each of the other currents. This summary represents a ventricular myocyte, and lists only the major ion channels. The currents and their molecular nature vary within regions of the ventricles, and in atria, and other specialized cells such as nodal and Purkinje. Ion channels exist as part of multi-molecular complexes including beta subunits and other associated regulatory proteins which are also not shown. Courtesy of Jonathan C Makielski, MD, FACC. Graphic 70771 Version 4.0 https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 16/17 7/5/23, 11:18 AM Sinus node dysfunction: Epidemiology, etiology, and natural history - UpToDate Contributor Disclosures Munther K Homoud, MD Speaker's Bureau: Abbott [Live heart dissection]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/sinus-node-dysfunction-epidemiology-etiology-and-natural-history/print 17/17

7/5/23, 11:18 AM Supraventricular arrhythmias after myocardial infarction - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Supraventricular arrhythmias after myocardial infarction : David Spragg, MD, FHRS, Kapil Kumar, MD : Brian Olshansky, MD, Bernard J Gersh, MB, ChB, DPhil, FRCP, MACC, James Hoekstra, MD : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jul 28, 2022. INTRODUCTION Supraventricular arrhythmias, other than atrial fibrillation (AF) or flutter, are relatively uncommon in the periinfarction period. Their occurrence often indicates myocardial dysfunction and they may, by themselves, cause congestive heart failure or exacerbate ongoing myocardial ischemia. The incidence, mechanism, and treatment of supraventricular arrhythmias (particularly sinus bradycardia, sinus tachycardia, and AF) occurring after myocardial infarction (MI) will be reviewed here. The focus of the discussion here is on supraventricular arrhythmias in the setting of MI caused by acute atherothrombotic coronary artery disease. However, there are some clinical settings in which supraventricular arrhythmia may cause MI (such as when AF causes left atrial thrombus that embolizes to a coronary artery, or in the setting of a supraventricular tachycardia causing demand ischemia and MI). (See "Diagnosis of acute myocardial infarction" and "Diagnosis of acute myocardial infarction", section on 'Definitions'.) The following related topics are discussed separately: conduction disturbances after MI, ventricular arrhythmias during MI, and risk stratification of patients after MI. (See "Conduction abnormalities after myocardial infarction" and "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features" and "Risk stratification after acute ST- elevation myocardial infarction".) SINUS BRADYCARDIA https://www.uptodate.com/contents/supraventricular-arrhythmias-after-myocardial-infarction/print 1/12 7/5/23, 11:18 AM Supraventricular arrhythmias after myocardial infarction - UpToDate Sinus bradycardia, defined as less than 50 to 60 beats per minute (bpm), occurs in 15 to 25 percent of patients after acute MI [1-3]. It has the following clinical characteristics [1,2,4]: It is frequently seen with inferior wall infarctions, since the right coronary artery supplies the sinoatrial node (SA) in approximately 60 percent of people. It is most often transient, particularly for sinus bradycardia occurring within the first six hours; such arrhythmias typically resolve within 24 hours. It is usually caused by increased vagal tone, often seen with inferior MI. In some cases, this may be the result of diaphragmatic irritation. Other less common causes include ischemia of the SA node and as a reperfusion arrhythmia following fibrinolysis [5]. It is due to medications (beta blockade, calcium channel blocker, or digoxin). Treatment If therapy is necessary due to hemodynamic compromise or ischemia, sinus bradycardia following an acute MI usually responds well to intravenous atropine (0.6 to 1.0 mg in the majority of cases) [6,7]. Persistent bradycardia with hemodynamic compromise despite intravenous atropine warrants consideration of temporary cardiac pacing [6,7]. Atrial or sequential atrioventricular (AV) pacing is superior to ventricular pacing, particularly if there is an associated right ventricular MI [8]. Permanent pacing is not typically necessary in patients with sinus bradycardia after an MI, because in most cases the bradyarrhythmia is transient [7]. Any decision to implant a permanent cardiac pacemaker should be delayed for several days of observation. (See "Permanent cardiac pacing: Overview of devices and indications".) Mortality as a result of periinfarction sinus bradycardia is rare [1]. Its significance is related to the associated reduction in cardiac output and coronary perfusion, thereby exacerbating ischemia, and to the possible development of an escape rhythm with possible AV dissociation causing hemodynamic compromise [9]. SINUS TACHYCARDIA Sinus tachycardia occurs in approximately 30 to 40 percent of acute MIs [10]. Although this is seen on presentation, the heart rate usually declines over time to a level that reflects the degree of activation of the sympathetic nervous system. Patients with persistent sinus tachycardia usually have larger infarcts that are more often anterior [10] and a marked impairment in left ventricular (LV) function, which is associated with substantial morbidity, a high early mortality, and an increased 30-day mortality [10,11]. In addition, sinus tachycardia may increase the size of https://www.uptodate.com/contents/supraventricular-arrhythmias-after-myocardial-infarction/print 2/12 7/5/23, 11:18 AM Supraventricular arrhythmias after myocardial infarction - UpToDate ischemic injury and infarction due at least in part to increased oxygen consumption. In some cases, sinus tachycardia may be the result of associated pericarditis. Therapeutic efforts should be targeted at identification and management of the underlying cause. However, most patients will receive such therapy independent of the tachycardia since early beta blocker administration is part of routine management of acute MI. Care should be exercised in the utilization of beta blockers early in an infarction, especially in the presence of large anterior MIs, hypotension, or pulmonary congestion. (See "Acute myocardial infarction: Role of beta blocker therapy".) ATRIAL FIBRILLATION The following section will review the incidence, pathophysiology, clinical characteristics, and treatment of the atrial tachyarrhythmias that occur after acute MI. AF is the most common of these. The overall incidence of atrial tachyarrhythmias in the periinfarction period ranges from 6 to 20 percent [9,10,12-17]. These arrhythmias primarily occur within the first 72 hours after infarction; however, only 3 percent are noted in the very early (less than three-hour) phase [12]. AF is common both during hospitalization and after discharge for acute MI and in both time periods has prognostic significance. The incidence during hospitalization has been reported to be between 5 and 18 percent and is more likely in individuals with heart failure, kidney disease, hypertension, diabetes, and pulmonary disease [13,14,18]. As expected with these risk factors, 30-day mortality in patients who develop AF is increased [13]. Long-term mortality is also increased in patients with in-hospital AF compared to those without [9,13,15,16,19-22]. Information concerning the longer-term incidence and prognosis of patients who develop AF after discharge comes from the CARISMA study, which evaluated the long-term development of arrhythmias in 271 patients with acute MI and an LV ejection fraction less than 40 percent [18]. These individuals underwent placement of an insertable cardiac monitor (ICM; also sometimes referred to as implantable cardiac monitor or implantable loop recorder) and were monitored for the development of AF lasting more than 16 beats. (See "Ambulatory ECG monitoring", section on 'Insertable cardiac monitor' and "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features", section on 'Late arrhythmias'.) The following findings were noted during two years of follow-up: https://www.uptodate.com/contents/supraventricular-arrhythmias-after-myocardial-infarction/print 3/12 7/5/23, 11:18 AM Supraventricular arrhythmias after myocardial infarction - UpToDate Ninety-five individuals (39 percent) developed AF. Nearly half of these occurred by two months and nearly 80 percent by one year. Most of the AF events were asymptomatic. The duration of the AF event(s) was more than 30 seconds in slightly more than half of these. New onset AF was associated with a significantly increased risk of major cardiovascular events (Unadjusted hazard ratio [HR] 2.04). AF remained a significant predictor of adverse outcomes even after adjustment. The risk was significantly increased in those individuals whose duration of AF was more than 30 seconds (HR 2.73, 95% CI 1.25-5.50), but not in those with episodes lasting less than 30 seconds (HR 1.17, 95% CI 0.35-3.92). Pathophysiology The increase in the prevalence of AF during an acute MI has been ascribed to one or more of the following factors: atrial dysfunction (due to atrial ischemia, which is rare; infarction, which is rare; or atrial stretching due to heart failure with elevation in left atrial pressures, which is the most common etiology) [23], sympathetic stimulation, pericarditis [24], inflammatory state [25], atheromatous disease of the arteries supplying the sinoatrial (SA) and AV nodes and the left atrium (which is a rare cause for AF) [10,12,21,26], and iatrogenic factors such as positive inotropic agents. Prevention Statin therapy, possibly due to an antiinflammatory effect, has been associated with a reduction in AF recurrences in patients with lone AF, ischemic heart disease, and after cardiac bypass surgery. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Statins'.) In a retrospective study of over 3300 patients presenting with acute MI and in sinus rhythm, statin therapy (prescription within 48 hours of hospitalization) was associated with a reduced risk of AF (odds ratio 0.64, 95% CI 0.45-0.92) [27]. However, we do not recommend initiation of statin therapy in patients with MI to solely prevent AF. Almost all such patients should be on statin therapy for other reasons. (See "Low density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome", section on 'Summary and recommendations'.) Treatment The management of periinfarction atrial tachyarrhythmias is important, because tachycardia can increase myocardial oxygen demand, thereby exacerbating ischemia and possibly decreasing cardiac output. Atrial tachyarrhythmias may also induce or exacerbate heart failure, especially when associated with a rapid ventricular response. For sustained AF or atrial flutter that is of new onset after the MI and is associated with hemodynamic compromise, we make the following recommendations: https://www.uptodate.com/contents/supraventricular-arrhythmias-after-myocardial-infarction/print 4/12 7/5/23, 11:18 AM Supraventricular arrhythmias after myocardial infarction - UpToDate Initial treatment should consist of rate control. The first-line treatment is beta blockade. One option is intravenous metoprolol (2.5 to 5.0 mg every two to five minutes to a total of 15 mg over 10 to 15 minutes). If ineffective, intravenous calcium channel blockade (verapamil or diltiazem) should be considered. For unstable patients, synchronized direct current cardioversion should be considered. (See "Atrial fibrillation: Cardioversion" and "Atrial fibrillation: Cardioversion", section on 'Indications'.) For episodes of AF with hemodynamic compromise that do not respond to electrical cardioversion or that recur after a brief period of sinus rhythm, the use of intravenous followed by oral amiodarone to help control rate and help maintain sinus is indicated. The use of amiodarone or digoxin in the setting of hemodynamic compromise is recommended because these drugs are associated with less risk of worsening myocardial dysfunction than some other drugs (although some preparations of intravenous amiodarone can cause hypotension, which is the result of Tween 80, the detergent used to get amiodarone into aqueous solution) and have not been associated with increased risk of mortality post-infarction. However, in many patients hemodynamic compromise during AF is a result of the rapid ventricular rate. In such cases, amiodarone and digoxin, which slow AV conduction only gradually and after a long period of time, may not be as effective as other agents. We recommend the use of either an intravenous beta blocker or intravenous verapamil in this setting. Dofetilide is also an effective drug for long-term management of AF after MI to help maintain sinus rhythm. The DIAMOND-MI trial found that this drug had no effect on all- cause, cardiac, or total arrhythmic mortality compared to placebo [28]. However, dofetilide was better than placebo for reverting AF or flutter to sinus rhythm (42.3 versus 12.5 percent for placebo). For patients with sustained AF or atrial flutter without ongoing ischemia or hemodynamic compromise, rate control is indicated. Consideration should be given to cardioversion to sinus rhythm in patients without a history of AF or atrial flutter prior to MI. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy" and "Atrial fibrillation in adults: Use of oral anticoagulants".) Long-term antiarrhythmic therapy may not be necessary if factors associated with recurrent AF, such as moderate to severe LV systolic dysfunction or heart failure, are absent [16,22,29]. We suggest reassessment of the patient s rhythm status in one to two months after MI. If there is no https://www.uptodate.com/contents/supraventricular-arrhythmias-after-myocardial-infarction/print 5/12 7/5/23, 11:18 AM Supraventricular arrhythmias after myocardial infarction - UpToDate evidence of recurrent AF and if risk factors for recurrence are absent, antiarrhythmic therapy can be discontinued. The role of anticoagulation in these patients is discussed elsewhere. (See 'Anticoagulation' below and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Anticoagulation The optimal anticoagulation strategy for patients with MI who develop AF for the first time is unknown. With regard to intravenous heparin, most of our experts use it in patients who will be cardioverted prior to discharge. For patients who will not be cardioverted, some of our experts use intravenous heparin until such time as the patient is successfully anticoagulated with an oral agent while others do not use heparin (particularly in patients with a low CHA DS-VASc score) 2 prior to oral anticoagulation. Most of our experts recommend at least three to four weeks of oral anticoagulant, assuming the patient is not at high bleeding risk. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Summary and recommendations'.) For those patients who are discharged on anticoagulant therapy after one episode of AF, the optimal duration is unknown [30]. As the risk of bleeding is very high in patients on triple antithrombotic therapy (ie, antiplatelet therapy for those receive a stent along with anticoagulation), practitioners should carefully and repeatedly reassess the need for continued anticoagulation (and thienopyridine). This issue is discussed in detail elsewhere. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy".) Patients with recurrent episodes of AF, especially if persistent or permanent (which is often the result of LV dysfunction and heart failure post-MI), should be treated with oral anticoagulants long term. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Classification and terminology' and "Atrial fibrillation in adults: Use of oral anticoagulants" and "Acute coronary syndrome: Oral anticoagulation in medically treated patients".) PSVT Paroxysmal supraventricular tachycardia (PSVT) occurs in less than 10 percent of patients after an acute MI, but may require aggressive management due to a rapid ventricular rate [31]. We suggest the following sequence of therapeutic measures [7]: https://www.uptodate.com/contents/supraventricular-arrhythmias-after-myocardial-infarction/print 6/12 7/5/23, 11:18 AM Supraventricular arrhythmias after myocardial infarction - UpToDate Carotid sinus massage or a valsalva maneuver (both of which increase vagal tone and alter AV nodal properties). (See "Narrow QRS complex tachycardias: Clinical manifestations, diagnosis, and evaluation", section on 'Carotid sinus massage'.) Intravenous adenosine (6 mg over one to two seconds; if no response, 12 mg one to two minutes later; may repeat 12 mg dose if needed). We suggest adenosine be used only in patients who have been revascularized. An external defibrillator should be available since a small percentage of patients develop ventricular fibrillation from adenosine likely related to a coronary steal phenomenon. Intravenous beta blockade with metoprolol (2.5 to 5.0 mg every two to five minutes to a total of 15 mg over 10 to 15 minutes) or esmolol. Our authors and reviewers also suggest that either intravenous verapamil, amiodarone, diltiazem, or cardioversion may be considered. NONPAROXYSMAL JUNCTIONAL TACHYCARDIA Junctional tachycardia (or an accelerated junctional tachycardia) is an arrhythmia arising from a discrete focus within the AV node or His bundle. The mechanism is thought to be one of enhanced automaticity rather than reentry. In adults, this rhythm, generally called nonparoxysmal junctional tachycardia, and is an uncommon arrhythmia associated with acute MI [32-34]. The same arrhythmia may also be seen with digitalis intoxication [35,36]. Atrial activity during junctional tachycardia is variable. Retrograde atrial activation may occur, with a P wave that either follows each QRS complex or is concealed in the QRS complex, as with AV nodal reentrant tachycardia. If retrograde conduction does not occur, independent atrial activity may be seen, with complete AV dissociation that must be distinguished from AV dissociation due to complete heart block (in complete heart block, the atrial rate exceeds the ventricular rate, while with an accelerated junctional tachycardia the atrial rate is slower than the ventricular rate). (See "Narrow QRS complex tachycardias: Clinical manifestations, diagnosis, and evaluation", section on 'Undetectable P waves'.) Nonparoxysmal junctional tachycardia is typically transient, occurring within the first 48 hours of infarction and developing and terminating gradually. The rate of a junctional tachycardia is generally slightly above 100 bpm, whereas reentrant paroxysmal supraventricular tachycardias (PSVTs) are generally faster. No specific antiarrhythmic therapy is indicated [7]. https://www.uptodate.com/contents/supraventricular-arrhythmias-after-myocardial-infarction/print 7/12 7/5/23, 11:18 AM Supraventricular arrhythmias after myocardial infarction - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Non-ST-elevation acute coronary syndromes (non-ST-elevation myocardial infarction)" and "Society guideline links: ST- elevation myocardial infarction (STEMI)".) SUMMARY Supraventricular arrhythmias, other than atrial fibrillation (AF) or atrial flutter, are relatively uncommon in the periinfarction period. The incidence of in-hospital AF after myocardial infarction (MI) ranges from 5 to 18 percent. The development of AF is associated with a worse prognosis. Sinus bradycardia, defined as less than 50 to 60 beats per minute, occurs in 15 to 25 percent of patients after acute MI and is most often due to increased vagal tone. (See 'Sinus bradycardia' above.) Sinus tachycardia occurs in approximately 30 to 40 percent of acute MIs. Patients with persistent sinus tachycardia usually have larger infarcts that are more often anterior, associated with a marked impairment in left ventricular function, and a high, early, and 30- day mortality. (See 'Sinus tachycardia' above.) Paroxysmal supraventricular tachycardia (PSVT) occurs in less than 10 percent of patients after an acute MI, but may require aggressive management due to a rapid ventricular rate. (See 'PSVT' above.) Nonparoxysmal junctional tachycardia is typically transient, occurring within the first 48 hours of infarction and developing and terminating gradually. No specific antiarrhythmic therapy is indicated. ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Philip J Podrid, MD, FACC, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. https://www.uptodate.com/contents/supraventricular-arrhythmias-after-myocardial-infarction/print 8/12 7/5/23, 11:18 AM Supraventricular arrhythmias after myocardial infarction - UpToDate REFERENCES 1. Marks R, Beard RJ, Clark ML, et al. Gastrointestinal observations in rosacea. Lancet 1967; 1:739. 2. Adgey AA, Geddes JS, Mulholland HC, et al. Incidence, significance, and management of early bradyarrhythmia complicating acute myocardial infarction. Lancet 1968; 2:1097. 3. Rotman M, Wagner GS, Wallace AG. Bradyarrhythmias in acute myocardial infarction. Circulation 1972; 45:703. 4. Zimetbaum PJ, Josephson ME. Use of the electrocardiogram in acute myocardial infarction. N Engl J Med 2003; 348:933. 5. Goldberg S, Greenspon AJ, Urban PL, et al. Reperfusion arrhythmia: a marker of restoration of antegrade flow during intracoronary thrombolysis for acute myocardial infarction. Am Heart J 1983; 105:26. 6. Zipes DP. The clinical significance of bradycardic rhythms in acute myocardial infarction. Am J Cardiol 1969; 24:814. 7. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of pati ents with ST-elevation myocardial infarction. www.acc.org/qualityandscience/clinical/statem ents.htm (Accessed on August 24, 2006). 8. Topol EJ, Goldschlager N, Ports TA, et al. Hemodynamic benefit of atrial pacing in right ventricular myocardial infarction. Ann Intern Med 1982; 96:594. 9. Goldberg RJ, Seeley D, Becker RC, et al. Impact of atrial fibrillation on the in-hospital and long-term survival of patients with acute myocardial infarction: a community-wide perspective. Am Heart J 1990; 119:996. 10. Crimm A, Severance HW Jr, Coffey K, et al. 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The incidence and prognostic significance of new-onset atrial fibrillation in patients with acute myocardial infarction and left ventricular systolic dysfunction: a CARISMA substudy. Heart Rhythm 2011; 8:342. 19. Pedersen OD, Bagger H, K ber L, Torp-Pedersen C. The occurrence and prognostic significance of atrial fibrillation/-flutter following acute myocardial infarction. TRACE Study group. TRAndolapril Cardiac Evalution. Eur Heart J 1999; 20:748. 20. Behar S, Zahavi Z, Goldbourt U, Reicher-Reiss H. Long-term prognosis of patients with paroxysmal atrial fibrillation complicating acute myocardial infarction. SPRINT Study Group. Eur Heart J 1992; 13:45. 21. Hod H, Lew AS, Keltai M, et al. Early atrial fibrillation during evolving myocardial infarction: a consequence of impaired left atrial perfusion. Circulation 1987; 75:146. 22. Sakata K, Kurihara H, Iwamori K, et al. Clinical and prognostic significance of atrial fibrillation in acute myocardial infarction. Am J Cardiol 1997; 80:1522. 23. Celik S, Erd l C, Baykan M, et al. Relation between paroxysmal atrial fibrillation and left ventricular diastolic function in patients with acute myocardial infarction. Am J Cardiol 2001; 88:160. 24. Nagahama Y, Sugiura T, Takehana K, et al. The role of infarction-associated pericarditis on the occurrence of atrial fibrillation. Eur Heart J 1998; 19:287. 25. Zahler D, Merdler I, Rozenfeld KL, et al. C-Reactive Protein Velocity and the Risk of New Onset Atrial Fibrillation among ST Elevation Myocardial Infarction Patients. Isr Med Assoc J 2021; 23:169. 26. Kramer RJ, Zeldis SM, Hamby RI. Atrial fibrillation a marker for abnormal left ventricular function in coronary heart disease. Br Heart J 1982; 47:606. 27. Danchin N, Fauchier L, Marijon E, et al. Impact of early statin therapy on development of atrial fibrillation at the acute stage of myocardial infarction: data from the FAST-MI register. Heart 2010; 96:1809. https://www.uptodate.com/contents/supraventricular-arrhythmias-after-myocardial-infarction/print 10/12 7/5/23, 11:18 AM Supraventricular arrhythmias after myocardial infarction - UpToDate 28. K ber L, Bloch Thomsen PE, M ller M, et al. Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial. Lancet 2000; 356:2052. 29. Cameron A, Schwartz MJ, Kronmal RA, Kosinski AS. Prevalence and significance of atrial fibrillation in coronary artery disease (CASS Registry). Am J Cardiol 1988; 61:714. 30. Axelrod M, Gilutz H, Plakht Y, et al. Early Atrial Fibrillation During Acute Myocardial Infarction May Not Be an Indication for Long-Term Anticoagulation. Angiology 2020; 71:559. 31. Ganz LI, Friedman PL. Supraventricular tachycardia. N Engl J Med 1995; 332:162. 32. Konecke LL, Knoebel SB. Nonparoxysmal junctional tachycardia complicating acute myocardial infarction. Circulation 1972; 45:367. 33. Knoebel SB, Rasmussen S, Lovelace DE, Anderson GJ. Nonparoxysmal junctional tachycardia in acute myocardial infarction: computer-assisted detection. Am J Cardiol 1975; 35:825. 34. Berisso MZ, Ferroni A, Molini D, Vecchio C. [Supraventricular tachyarrhythmias during acute myocardial infarction: short- and mid-term clinical significance, therapy and prevention of relapse]. G Ital Cardiol 1991; 21:49. 35. Bigger JT Jr. Digitalis toxicity. J Clin Pharmacol 1985; 25:514. 36. Kastor JA, Yurchak PM. Recognition of digitalis intoxication in the presence of atrial fibrillation. Ann Intern Med 1967; 67:1045. Topic 82 Version 19.0 Contributor Disclosures David Spragg, MD, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Kapil Kumar, MD No relevant financial relationship(s) with ineligible companies to disclose. Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. Bernard J Gersh, MB, ChB, DPhil, FRCP, MACC Consultant/Advisory Boards: Bain Institute [CRO for trials involving Edwards percutaneous valve devices]; Cardiovascular Research Foundation [Data safety monitoring board (RELIEVE-HF Trial)]; Caristo Diagnostics Limited [Imaging and inflammation/atherosclerosis]; Philips Image Guided Therapy Corporation [Imaging]; Sirtex Med Limited [General consulting]; Thrombosis Research Institute [Data safety monitoring board (GARFIELD study)]. All of the relevant financial relationships listed have been mitigated. James Hoekstra, MD No relevant financial relationship(s) with ineligible companies to disclose. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. https://www.uptodate.com/contents/supraventricular-arrhythmias-after-myocardial-infarction/print 11/12 7/5/23, 11:18 AM Supraventricular arrhythmias after myocardial infarction - UpToDate Conflict of interest policy https://www.uptodate.com/contents/supraventricular-arrhythmias-after-myocardial-infarction/print 12/12

7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features : Philip J Podrid, MD, FACC : James Hoekstra, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 16, 2022. INTRODUCTION Sudden cardiac death in the setting of an acute myocardial infarction (MI) is most frequently the result of a ventricular tachyarrhythmia. The appearance of a sustained ventricular tachyarrhythmia following an MI, such as ventricular tachycardia (VT) or ventricular fibrillation (VF), in the early period post-MI may be the harbinger of ongoing myocardial ischemia, the development of proarrhythmic myocardial scar tissue, elevated sympathetic tone or increase in circulating catecholamines, or an electrolyte disturbance such as hypokalemia. In-hospital mortality approaches 20 percent or more in patients who develop VT or VF following an MI. As such, rapid identification and treatment of these arrhythmias can be life-saving. Although all patients with a prior MI have an elevated risk of malignant arrhythmias, the magnitude of risk varies from patient to patient, with reduced left ventricular ejection fraction being the most prominent risk stratifier. This topic will focus on the incidence, mechanisms, and clinical features of ventricular arrhythmias during and after acute MI. Treatment for established ventricular arrhythmias during acute MI and in the post-MI patient, using defibrillation with or without antiarrhythmic medications, is discussed separately. (See "Advanced cardiac life support (ACLS) in adults" and "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment".) https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 1/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate INCIDENCE While many studies have evaluated the incidence of ventricular arrhythmias in the peri-infarct period, comparison of these studies is difficult due to differences in populations (percutaneous intervention therapy versus fibrinolytic therapy versus no therapy), type of infarct (ST segment elevation MI [STEMI] versus non-ST segment elevation MI [NSTEMI] versus both), and arrhythmia reported (ventricular tachycardia [VT] versus ventricular fibrillation [VF] versus both). The clinical significance of different types of ventricular ectopy following MI also varies markedly. Ventricular arrhythmias, ranging from isolated premature ventricular complexes/contractions (PVCs; also referred to a premature ventricular beats, premature ventricular depolarizations, ventricular premature complexes, or ventricular premature beats) to VF, are common in the immediate post-infarction period (ie, within the first 48 hours). Observations in the pre- fibrinolytic era found the following range of incidence [1-3]: PVCs 10 to 93 percent VT 3 to 39 percent VF 4 to 20 percent Life-threatening ventricular arrhythmias, VT and VF, are infrequent but serious complications of an acute STEMI. The largest experience on the incidence of VT and VF during an acute STEMI comes from the GUSTO-1 trial of 40,895 patients who were treated with thrombolytic therapy [4]. The overall incidence of sustained VT or VF was 10.3 percent: 3.5 percent developed VT, 4.1 percent VF, and 2.7 percent both VT and VF. Approximately 80 to 85 percent of these arrhythmias occurred in the first 48 hours. Rates of VT and VF have declined with time. In a study of 11,825 patients with acute MI between 1986 and 2011, there was a decrease in the incidence of both VT (from 14.3 to 10.5 percent) and VF (from 8.2 to 1.7 percent) over the 25 years reviewed [3]. Sustained ventricular arrhythmias are less common in patients with an acute NSTEMI or unstable angina compared to patients with STEMI, as illustrated in a pooled analysis of four major trials of over 25,000 such patients [5]. The overall incidence of VT or VF was 2.1 percent, lower than the 10.3 percent incidence in GUSTO-1 in STEMI [6]. VT occurred in 0.8 percent, VF in 1 percent, and VT and VF in 0.3 percent. The median time to arrhythmia was 78 hours. Early versus late arrhythmias The definition of "early" versus "late" ventricular arrhythmias can vary among cardiologists and electrophysiologists and is also changing with time. Most now consider "late" arrhythmias to be those that occur beyond 24 to 48 hours post-MI onset. Late VT https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 2/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate is a predictor of a worse prognosis [4]. Among post-MI patients who survived for 30 days, subsequent one-year mortality was significantly higher among those who had late VT (24.7 percent) compared with those without sustained ventricular arrhythmia (2.7 percent) [4]. Pre-revascularization (fibrinolytic/PCI) era versus PCI era In the era of early percutaneous coronary intervention (PCI), VT (especially non-sustained VT) remains fairly common. In the MERLIN-TIMI 36 study of 6355 patients with non-ST elevation acute coronary syndromes who underwent seven days of continuous electrocardiographic (ECG) monitoring following their presentation to the hospital to assess for VT and ischemia, 25.3 percent were found to have VT (20 percent VT without ischemia, 5.3 percent VT with ischemia) [7]. Compared with patients with neither VT nor ischemia on continuous ECG monitoring, patients with VT without concurrent ischemia had a significantly increased risk of both cardiovascular death and sudden cardiac death (SCD; adjusted hazard ratio [HR] 2.2 and 2.3, respectively). Patients with VT and ischemia had an even higher risk of both cardiovascular death and SCD (adjusted HR 5.4 and 6.5, respectively). ST elevation MI Data regarding the incidence of ventricular arrhythmias at the time of acute STEMI come from studies of patients treated with either fibrinolysis or primary PCI. Although the incidence of ventricular arrhythmias is probably lower with contemporary therapies [4,5,8-11], these data are also probably underestimating the true incidence of arrhythmias because patients with prehospital SCD may not have been included in studies of fibrinolysis or primary PCI. The risk factors for and the prognosis of early VT or VF in patients with STEMI are discussed separately. (See 'Monomorphic ventricular tachycardia' below.) Fibrinolytic therapy Among patients with acute MI in the fibrinolytic era, the incidence of VF has ranged from 3.7 to 6.7 percent in large studies [4,5,10-13]. The largest experience in patients (40,895) with acute STEMI treated with fibrinolytic therapy comes from the GUSTO-1 trial [4]. The overall incidence of sustained VT or VF was 10.2 percent (3.5 percent developed VT, 4.1 percent VF, and 2.7 percent both VT and VF). Approximately 80 to 85 percent of these arrhythmias occurred in the first 48 hours. Two limitations of fibrinolytic trials are the exclusion of patients who died of SCD in the prehospital arena, which affects the total denominator of patients, as well as the fact that fibrinolysis and reperfusion may lead to reperfusion arrhythmias, falsely increasing the incidence of MI-associated arrhythmias. Primary PCI Reported rates of primary VF among patients with STEMI treated with primary PCI range from 6 to 9 percent in different studies. Among 5745 STEMI patients with planned PCI enrolled in the APEX AMI trial, VT or VF occurred in 329 (5.7 percent), with most events (282, or 86 percent) occurring within the https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 3/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate first 48 hours [14]. In a study of 13,253 patients with STEMI transported by ambulance in one city between 2006 and 2014, 749 patients (5.6 percent) had witnessed pre-hospital cardiac arrest [15]. In a study from the Spanish Codi AMI network which included 10.965 patients with STEMI treated with primary PCI between 2010 and 2014, 949 patients (8.7 percent) experienced primary VF [16]. Non-ST elevation MI The best data on the incidence of sustained ventricular arrhythmias in patients with acute NSTEMI or unstable angina come from a pooled analysis of four major trials of over 25,000 patients with a non-ST elevation acute coronary syndrome (NSTEMI or unstable angina) [5]. The overall incidence of sustained VT or VF was 2.1 percent, which is lower than the 10.2 percent STEMI incidence in GUSTO-1 [4]. VT occurred in 0.8 percent, VF in 1 percent, and VT and VF in 0.3 percent. The median time to arrhythmia was 78 hours. MECHANISMS OF ARRHYTHMOGENESIS Ventricular arrhythmias in the setting of acute MI result from an interplay among three basic components: The damaged myocardium, which produces a substrate capable of developing reentrant circuits or associated with enhanced automaticity Arrhythmia triggers, including variations in cycle length and heart rate Modulating factors, such as electrolyte imbalance (eg, hypokalemia), dysfunction of the autonomic nervous system (eg, increased sympathetic activity), continued ischemia, and impaired left ventricular (LV) function The proper milieu for the development and maintenance of ventricular arrhythmias is ultimately based upon the rapid and profound effects that acute myocardial ischemia has on the electrophysiologic characteristics of the myocyte. Changes in the resting membrane potential and in the inward and outward ionic fluxes during the action potential lead to alterations in conduction, refractoriness, and automaticity of cardiac muscle cells, all of which contribute to the occurrence of ventricular arrhythmias [17]. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) in the setting of MI result from the complex interaction of multiple factors, including: Myocardial ischemia (with resulting local electrolyte abnormalities) https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 4/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate Necrosis Reperfusion Healing Scar formation Autonomic changes (especially activation of the sympathetic nervous system and elevated levels of catecholamines) These events produce the mechanisms that initiate arrhythmias and the substrate for arrhythmia perpetuation. Arrhythmia pathogenesis varies at different stages in this process. For ventricular arrhythmias occurring more than 48 to 72 hours after an acute MI, scar formation is of primary importance. Acute phase (first 30 minutes) arrhythmias A distinction must be made between the acute phase of myocardial ischemia/MI (during the first 30 minutes) and the subacute phase (6 to 48 hours post-MI) when considering the mechanisms responsible for peri-infarction ventricular arrhythmias. Acute and delayed arrhythmias are distinguished by clinical arrhythmia type, cellular mechanisms, and immediate prognostic implications. Arrhythmias occurring within the first 30 minutes of experimental coronary artery occlusion demonstrate the following bimodal distribution [18]: Arrhythmias occurring after the first 2 to 10 minutes are known as "immediate" or phase 1a ventricular arrhythmias and have a peak incidence after five minutes of ischemia. Reentry is the likely dominant mechanism for these arrhythmias. "Delayed" or phase 1b arrhythmias occur after approximately 10 to 60 minutes of coronary artery occlusion. Abnormal automaticity as well as reentry are likely the dominant mechanisms for these arrhythmias. Delayed phase (6 to 48 hours) arrhythmias Delayed-phase arrhythmias generally occur between six hours and as long as one to two days after the onset of the MI. The most frequently observed ventricular arrhythmias are [19,20]: Premature ventricular complex/contraction (PVC; also referred to a premature ventricular beats or premature ventricular depolarizations) Nonsustained VT (NSVT; three or more sequential PVCs lasting less than 30 seconds) Accelerated idioventricular rhythm, which is generally felt to be due to reperfusion of the occluded artery but is neither sensitive nor specific for definitive reperfusion Chronic phase arrhythmias During the chronic, healing phase of an acute MI (more than 48 hours), the typical patient with sustained monomorphic VT (SMVT) has had a large, often https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 5/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate complicated infarct with an LV ejection fraction 30 percent [21,22]. The VT in this situation is usually reentrant and scar mediated. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis".) New ischemia can be superimposed upon this substrate with the appearance of a variety of ventricular arrhythmias, most commonly polymorphic VT or VF but also including NSVT and SMVT [23]. Thus, revascularization and anti-ischemic therapy may be part of the antiarrhythmic regimen. Autonomic imbalance, electrolyte abnormalities, and the proarrhythmic effects of antiarrhythmic drugs can also contribute to the appearance of SMVT or other ventricular arrhythmias. LV remodeling after an MI produces structural changes in the myocardium that may also be factors in the pathogenesis of ventricular arrhythmia. Reperfusion arrhythmias Ventricular arrhythmias in some patients have been thought to be related to reperfusion, which may be spontaneous or occurring within a period of minutes after reperfusion has been achieved via fibrinolysis or mechanical means [24-26]. The evidence is best for an accelerated idioventricular rhythm (AIVR) as a reperfusion arrhythmia [25-29], although AIVR is neither a sensitive nor very specific marker for successful reperfusion, as it may occur in other situations. (See "Diagnosis and management of failed fibrinolysis or threatened reocclusion in acute ST-elevation myocardial infarction", section on 'Primary failure'.) Serious ventricular arrhythmia induced by reperfusion does not appear to be a major clinical problem [29,30]. As an example, large trials of intravenous thrombolytic therapy did not demonstrate any increase in life-threatening arrhythmias that could be attributed to reperfusion, although frequent PVCs and AIVRs did occur [8,9]. Similar findings have been noted after primary percutaneous coronary intervention [29]. CLINICAL FEATURES Premature ventricular complex/contraction Premature ventricular complexes/contractions (PVC; also referred to a premature ventricular beats, premature ventricular depolarizations, ventricular premature complexes, or ventricular premature beats), which are typically asymptomatic, are common after acute MI with a reported incidence as high as 93 percent [1]. The early occurrence of PVCs does not predict short- or long-term mortality, but frequent and/or multiform PVCs that persist more than 48 to 72 hours after an MI may be associated with an increased long-term arrhythmic risk, especially in patients with reduced left ventricular ejection fraction (LVEF) [31,32]. In the GISSI-2 trial, which evaluated 8676 patients with ST elevation MI (STEMI) treated with thrombolytic therapy who underwent 24-hour Holter monitoring before https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 6/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate discharge, more than 10 PVCs per hour was a significant predictor for both total (relative risk [RR] 1.62, 95% CI 1.16-2.26) and sudden mortality (RR 2.24, 95% CI 1.22-4.08). [31]. (See "Incidence of and risk stratification for sudden cardiac death after myocardial infarction".) PVCs produce few or no symptoms in the vast majority of patients, although some individuals may be incapacitated by palpitations or dizziness. PVCs rarely cause true hemodynamic compromise, except when they occur frequently in a patient with severely depressed LV function or when they are associated with an underlying bradycardia. The most common symptoms resulting from PVCs are palpitations secondary to the hypercontractility of a post-PVC beat or a feeling that the heart has stopped secondary to a post-PVC pause. Less often, frequent PVCs can result in a pounding sensation in the neck, lightheadedness, or near syncope. Accelerated idioventricular rhythm An accelerated idioventricular rhythm (AIVR), which has also been called "slow ventricular tachycardia," arises below the atrioventricular (AV) node (within the ventricular myocardium) and has, by definition, a rate between 50 and 100 beats/minute ( waveform 1) [33]. It may be the result of pacemaker failure, and therefore be an escape rhythm, or it may represent an abnormal ectopic focus in the ventricle that is accelerated by sympathetic stimulation and circulating catecholamines. The clinical presentation of AIVR can vary, but given the relatively slow rate and transient nature patients are frequently asymptomatic. Some patients may notice palpitations or lightheadedness, and there may be some associated hypotension if the rate results in a drop in cardiac output. AIVR occurs in up to 50 percent of patients with acute MI, although it is not always documented on ECG as it may be transient. Some studies have suggested an association with reperfusion following fibrinolytic therapy [25]. However, AIVR is neither a sensitive nor very specific marker for successful reperfusion. Monomorphic ventricular tachycardia Ventricular tachycardia (VT) is defined as three or more consecutive PVCs lasting less than 30 seconds, originating below the AV node (within the ventricular myocardium), with a heart rate greater than 100 beats/minute ( waveform 2). VT is considered sustained if it lasts more than 30 seconds or is associated with hemodynamic collapse requiring prompt therapy. The presence of a single, consistent QRS morphology suggests that each beat arises from the same location (or the same reentrant circuit) and activates the ventricle in the same sequence. This uniformity should be present in all 12 ECG leads. As a result, a 12-lead ECG should be obtained in stable patients in order to fully characterize the VT morphology. https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 7/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate The clinical presentation may include palpitations, worsening ischemic symptoms due to the elevated heart rate, and hemodynamic compromise or collapse. Patients with faster tachycardias and worse LV systolic function are less likely to tolerate the arrhythmia. Another concern is that sustained monomorphic VT (SMVT) may produce ischemia, which may be an important concern for the degeneration of SMVT into ventricular fibrillation (VF). The impact of NSVT on mortality was evaluated in 6560 patients with non-ST-elevation acute coronary syndrome [34]. Only 1.2 percent of patients without VT experienced sudden cardiac death (SCD). Compared with patients with no VT, patients with four to seven beats of NSVT (2.9 percent SCD; adjusted hazard ratio [HR] 2.3, 95% CI 1.5-3.5) and patients with eight or more beats of NSVT (4.3 percent SCD; adjusted HR 2.8, 95% CI 1.5-4.9) had a higher risk of SCD. The probable mechanism and the prognostic significance of NSVT depend upon the time at which it occurs in relation to infarction. In the early stage of an evolving infarction (ie, the first 6 to as many as 48 hours), monomorphic VT may result from transient arrhythmogenic phenomena in ischemic and infarcting tissue, such as abnormal automaticity, triggered activity, and reentrant circuits created by heterogeneous conduction and repolarization. In the first 24 to 48 hours after an infarction, nonsustained VT (NSVT) is usually due to abnormal automaticity or triggered activity in the region of ischemia or infarction. In comparison, NSVT that occurs later is more often due to reentry. SMVT in any other setting is considered a marker of permanent arrhythmic substrate (ie, fibrosis and reentry) and an increased long-term risk of arrhythmia recurrence and SCD. Because of the physiologic and mechanistic link between SMVT and permanent substrate, it is not clear that SMVT at any point, even early after an MI, should be attributed to transient phenomena. Furthermore, SMVT in the setting of an acute MI may reflect permanent substrate from a prior infarction. As a result, the prognostic significance of SMVT in the early period after an MI is unclear. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis".) In fact, studies suggest that early SMVT is associated with higher in-hospital mortality due to cardiac arrest and possibly to exacerbation of ischemia and extension of the infarct [4,11,35-39], and may be a higher risk substrate than polymorphic VT [40]. Whether early SMVT is associated with an increased long-term mortality risk among contemporary patients undergoing revascularization who survive to hospital discharge is less well studied [4,11,14,35,37]. The SWEDEHEART registry included 2200 STEMI patients who underwent revascularization within 48 hours of presentation [40]. Among these patients, 150 had hemodynamically unstable VT, 35 had monomorphic VT, and 115 had nonmonomorphic VT https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 8/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate (ie, polymorphic VT or VF). Mortality at eight years was higher in those with monomorphic compared with the nonmonomorphic VT (63 versus 37 percent). Among patients who did not have early hemodynamically significant VT, mortality was 27 percent. Polymorphic VT Compared with monomorphic VT and VF, polymorphic VT (with changing QRS morphology and axis and irregularly irregular rate in the absence of QT prolongation) is much less common in the setting of an acute MI, occurring in 0.3 percent of patients in one report [41]. When polymorphic VT ( waveform 3) does occur early after an acute MI, usually within the first 12 hours after the onset of symptoms, it is typically associated with symptoms or signs of recurrent myocardial ischemia [41]. Even if signs and symptoms are absent, myocardial ischemia, which is the most common cause, should be suspected. Polymorphic VT frequently accompanies episodes of coronary vasospasm (Prinzmetal's angina). In some patients, the arrhythmia may be the only manifestation of ischemia (without angina or other more typical symptoms) [41]. The arrhythmia is not consistently related to electrolyte abnormalities, sinus bradycardia, preceding sinus pauses, or an abnormally long QT interval [41]. Polymorphic VT with prolonged QT interval of a sinus complex is termed "torsades de pointes," which has a different etiology and treatment. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) When polymorphic VT develops, the type and intensity of symptoms will vary depending upon the rate and duration of VT along with the presence or absence of significant comorbid conditions. Patients with polymorphic VT and symptoms typically present with one or more of the following: sudden cardiac arrest, syncope/presyncope, "seizure-like" activity, or palpitations. Importantly, polymorphic VT that persists for more than 10 to 15 seconds often degenerates into VF. Ventricular fibrillation VF is the most frequent mechanism of SCD. It is a rapid, disorganized ventricular arrhythmia, resulting in no uniform ventricular activation or contraction, no cardiac output, and no recordable blood pressure. As such, patients invariably present with sudden collapse (syncope and/or sudden cardiac arrest). The ECG in VF shows rapid (300 to 400 beats/minute), irregular, shapeless QRST undulations of variable amplitude, morphology, and interval ( waveform 4). Over time, these waveforms, which are initially coarse, decrease in amplitude and become finer undulations. Ultimately, asystole occurs. The majority of episodes of VF occur within the first 48 to 72 hours after the onset of symptoms [4,5,10]. It is presumably a manifestation of ischemia and is associated with lack of perfusion via the infarct-related artery [37,42]. Factors that are associated with an increased risk of VF include [5,10,14,43-46]: https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 9/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate STEMI Early repolarization (see "Early repolarization") Hypokalemia Hypotension Larger infarcts (based upon myocardial enzyme levels) Male gender History of smoking Preinfarction angina (see "Myocardial ischemic conditioning: Clinical implications") Pre-PCI Thrombolysis in MI (TIMI) flow grade 0 Inferior infarction Total baseline ST segment deviation Killip Class ( table 1) greater than I Prognosis after early VF The occurrence of VF among patients with an acute STEMI, if occurring within the first 48 hours, is associated with an increase in early mortality (eg, in- hospital mortality) but little or no increase in mortality at one to two years among patients who survive to hospital discharge [4,10,37-39,47]. These data are quite old; similar data do not exist in contemporary patients treated with early revascularization. Data are more limited in patients with a non-STEMI (NSTEMI). In a pooled analysis of patients with NSTEMI or unstable angina, VF was a significant predictor of increased mortality at both 30 days and six months (adjusted HR 23 and 15, respectively) [5]. The increase in risk was largely due to more deaths in the first 30 days. Late arrhythmias Late VT and VF are related to healing of the MI. Usually this reflects the development of scar tissue, which serves as an arrhythmogenic substrate that can promote the development of VT/VF. Fibrosis present in the scar leads to areas of conduction block with interdigitation of viable myocardium; the ensuing slowing of conduction at the border of the infarct can lead to stable reentry circuits and subsequent arrhythmias [48]. In general, late VT/VF is thought to portend risk of recurrent malignant arrhythmia and is usually treated specifically. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) In the CARISMA study, which prospectively observed 297 patients with a history of MI and LVEF of 40 percent or less (on excellent contemporary medical therapy) for late arrhythmias using an insertable cardiac monitor (also sometimes referred to as an implantable cardiac monitor or an implantable loop recorder), 13 percent of patients had at least one episode of NSVT (defined in this study as 16 or more beats, but less than 30 seconds in duration), 3 percent had an episode of sustained VT, and 3 percent had an episode of VF [49]. Over an average follow-up of two https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 10/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate years, there was a nonsignificant trend toward increased mortality in patients with any ventricular arrhythmia. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ventricular arrhythmias" and "Society guideline links: ST-elevation myocardial infarction (STEMI)" and "Society guideline links: Non-ST-elevation acute coronary syndromes (non-ST-elevation myocardial infarction)".) SUMMARY AND RECOMMENDATIONS Ventricular arrhythmias, ranging from isolated premature ventricular complexes/contractions (PVCs; also referred to a premature ventricular beats, premature ventricular depolarizations, ventricular premature complexes, or ventricular premature beats) to ventricular fibrillation (VF), are common in the immediate post-MI period. In the era of early percutaneous coronary intervention (PCI) and aggressive medical therapy, approximately 25 percent of patients with a non-ST elevation acute coronary syndrome experience ventricular tachycardia (VT) within the initial seven days, an event that portends a significantly greater risk of dying compared with patients without VT. (See 'Incidence' above.) VT and VF in the setting of MI result from the complex interaction of multiple factors, including myocardial ischemia, necrosis, reperfusion, healing, and scar formation. Ventricular arrhythmias in the setting of acute MI result from an interplay among three basic components: injured myocardium, which is capable of developing reentrant circuits; arrhythmia triggers (eg, spontaneous PVCs, variations in cycle length); and modulating factors (eg, electrolyte imbalance, ongoing ischemia, autonomic nervous system). (See 'Mechanisms of arrhythmogenesis' above.) PVCs are common after acute MI with a reported incidence as high as 93 percent. PVCs produce few or no symptoms in the vast majority of patients, although some individuals may be incapacitated by palpitations or dizziness. The early occurrence of PVCs does not predict short- or long-term mortality. (See 'Premature ventricular complex/contraction' above.) Accelerated idioventricular rhythm, which is generally felt to be due to reperfusion of the occluded artery, occurs in up to 50 percent of patients with acute MI. The clinical https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 11/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate presentation of AIVR can vary, but given the relatively slow rate and transient nature patients are frequently asymptomatic, although some patients may notice palpitations or lightheadedness, and there may be some associated hypotension if the rate results in a drop in cardiac output. (See 'Accelerated idioventricular rhythm' above.) VT is considered sustained if it lasts more than 30 seconds or is associated with hemodynamic collapse requiring prompt therapy. The clinical presentation may include palpitations, worsening ischemic symptoms due to the elevated heart rate, and hemodynamic compromise or collapse. Patients with faster tachycardias and worse LV systolic function are less likely to tolerate the arrhythmia. (See 'Monomorphic ventricular tachycardia' above.) Polymorphic VT (in the absence of QT prolongation of a sinus complex) is much less common in the setting of an acute MI, but when polymorphic VT occurs early after an acute MI, usually within the first 12 hours after the onset of symptoms, it is typically associated with symptoms or signs of recurrent myocardial ischemia. Patients with polymorphic VT and symptoms typically present with one or more of the following: sudden cardiac arrest, syncope/presyncope, "seizure-like" activity, or palpitations. Importantly, polymorphic VT that persists for more than 10 to 15 seconds often degenerates into VF. (See 'Polymorphic VT' above.) VF is the most frequent mechanism of SCD. It is a rapid, disorganized ventricular arrhythmia, resulting in no uniform ventricular contraction, no cardiac output, and no recordable blood pressure. As such, patients invariably present with sudden collapse (syncope and/or sudden cardiac arrest). (See 'Ventricular fibrillation' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Bigger JT Jr, Dresdale FJ, Heissenbuttel RH, et al. Ventricular arrhythmias in ischemic heart disease: mechanism, prevalence, significance, and management. Prog Cardiovasc Dis 1977; 19:255. https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 12/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate 2. O'Doherty M, Tayler DI, Quinn E, et al. Five hundred patients with myocardial infarction monitored within one hour of symptoms. Br Med J (Clin Res Ed) 1983; 286:1405. 3. Tran HV, Ash AS, Gore JM, et al. Twenty-five year trends (1986-2011) in hospital incidence and case-fatality rates of ventricular tachycardia and ventricular fibrillation complicating acute myocardial infarction. Am Heart J 2019; 208:1. 4. Newby KH, Thompson T, Stebbins A, et al. Sustained ventricular arrhythmias in patients receiving thrombolytic therapy: incidence and outcomes. The GUSTO Investigators. Circulation 1998; 98:2567. 5. Al-Khatib SM, Granger CB, Huang Y, et al. Sustained ventricular arrhythmias among patients with acute coronary syndromes with no ST-segment elevation: incidence, predictors, and outcomes. Circulation 2002; 106:309. 6. Sobel BE, Corr PB, Robison AK, et al. Accumulation of lysophosphoglycerides with arrhythmogenic properties in ischemic myocardium. J Clin Invest 1978; 62:546. 7. Harkness JR, Morrow DA, Braunwald E, et al. Myocardial ischemia and ventricular tachycardia on continuous electrocardiographic monitoring and risk of cardiovascular outcomes after non-ST-segment elevation acute coronary syndrome (from the MERLIN-TIMI 36 Trial). Am J Cardiol 2011; 108:1373. 8. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988; 2:349. 9. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI). Lancet 1986; 1:397. 10. Volpi A, Cavalli A, Santoro L, Negri E. Incidence and prognosis of early primary ventricular fibrillation in acute myocardial infarction results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) database. Am J Cardiol 1998; 82:265. 11. Henkel DM, Witt BJ, Gersh BJ, et al. Ventricular arrhythmias after acute myocardial infarction: a 20-year community study. Am Heart J 2006; 151:806. 12. Thompson CA, Yarzebski J, Goldberg RJ, et al. Changes over time in the incidence and case- fatality rates of primary ventricular fibrillation complicating acute myocardial infarction: perspectives from the Worcester Heart Attack Study. Am Heart J 2000; 139:1014. 13. Sarter BH, Finkle JK, Gerszten RE, Buxton AE. What is the risk of sudden cardiac death in patients presenting with hemodynamically stable sustained ventricular tachycardia after myocardial infarction? J Am Coll Cardiol 1996; 28:122. https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 13/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate 14. Mehta RH, Starr AZ, Lopes RD, et al. Incidence of and outcomes associated with ventricular tachycardia or fibrillation in patients undergoing primary percutaneous coronary intervention. JAMA 2009; 301:1779. 15. Karam N, Bataille S, Marijon E, et al. Incidence, Mortality, and Outcome-Predictors of Sudden Cardiac Arrest Complicating Myocardial Infarction Prior to Hospital Admission. Circ Cardiovasc Interv 2019; 12:e007081. 16. Garc a-Garc a C, Oliveras T, Rueda F, et al. Primary Ventricular Fibrillation in the Primary Percutaneous Coronary Intervention ST-Segment Elevation Myocardial Infarction Era (from the "Codi IAM" Multicenter Registry). Am J Cardiol 2018; 122:529. 17. Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev 1989; 69:1049. 18. Di Diego JM, Antzelevitch C. Ischemic ventricular arrhythmias: experimental models and their clinical relevance. Heart Rhythm 2011; 8:1963. 19. Campbell RW, Murray A, Julian DG. Ventricular arrhythmias in first 12 hours of acute myocardial infarction. Natural history study. Br Heart J 1981; 46:351. 20. Northover BJ. Ventricular tachycardia during the first 72 hours after acute myocardial infarction. Cardiology 1982; 69:149. 21. Marchlinski FE, Buxton AE, Waxman HL, Josephson ME. Identifying patients at risk of sudden death after myocardial infarction: value of the response to programmed stimulation, degree of ventricular ectopic activity and severity of left ventricular dysfunction. Am J Cardiol 1983; 52:1190. 22. DiMarco JP, Lerman BB, Kron IL, Sellers TD. Sustained ventricular tachyarrhythmias within 2 months of acute myocardial infarction: results of medical and surgical therapy in patients resuscitated from the initial episode. J Am Coll Cardiol 1985; 6:759. 23. Stambler BS, Akosah KO, Mohanty PK, et al. Myocardial ischemia and induction of sustained ventricular tachyarrhythmias: evaluation using dobutamine stress echocardiography- electrophysiologic testing. J Cardiovasc Electrophysiol 2004; 15:901. 24. Gressin V, Louvard Y, Pezzano M, Lardoux H. Holter recording of ventricular arrhythmias during intravenous thrombolysis for acute myocardial infarction. Am J Cardiol 1992; 69:152. 25. Gorgels AP, Vos MA, Letsch IS, et al. Usefulness of the accelerated idioventricular rhythm as a marker for myocardial necrosis and reperfusion during thrombolytic therapy in acute

presentation of AIVR can vary, but given the relatively slow rate and transient nature patients are frequently asymptomatic, although some patients may notice palpitations or lightheadedness, and there may be some associated hypotension if the rate results in a drop in cardiac output. (See 'Accelerated idioventricular rhythm' above.) VT is considered sustained if it lasts more than 30 seconds or is associated with hemodynamic collapse requiring prompt therapy. The clinical presentation may include palpitations, worsening ischemic symptoms due to the elevated heart rate, and hemodynamic compromise or collapse. Patients with faster tachycardias and worse LV systolic function are less likely to tolerate the arrhythmia. (See 'Monomorphic ventricular tachycardia' above.) Polymorphic VT (in the absence of QT prolongation of a sinus complex) is much less common in the setting of an acute MI, but when polymorphic VT occurs early after an acute MI, usually within the first 12 hours after the onset of symptoms, it is typically associated with symptoms or signs of recurrent myocardial ischemia. Patients with polymorphic VT and symptoms typically present with one or more of the following: sudden cardiac arrest, syncope/presyncope, "seizure-like" activity, or palpitations. Importantly, polymorphic VT that persists for more than 10 to 15 seconds often degenerates into VF. (See 'Polymorphic VT' above.) VF is the most frequent mechanism of SCD. It is a rapid, disorganized ventricular arrhythmia, resulting in no uniform ventricular contraction, no cardiac output, and no recordable blood pressure. As such, patients invariably present with sudden collapse (syncope and/or sudden cardiac arrest). (See 'Ventricular fibrillation' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Bigger JT Jr, Dresdale FJ, Heissenbuttel RH, et al. Ventricular arrhythmias in ischemic heart disease: mechanism, prevalence, significance, and management. Prog Cardiovasc Dis 1977; 19:255. https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 12/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate 2. O'Doherty M, Tayler DI, Quinn E, et al. Five hundred patients with myocardial infarction monitored within one hour of symptoms. Br Med J (Clin Res Ed) 1983; 286:1405. 3. Tran HV, Ash AS, Gore JM, et al. 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Henkel DM, Witt BJ, Gersh BJ, et al. Ventricular arrhythmias after acute myocardial infarction: a 20-year community study. Am Heart J 2006; 151:806. 12. Thompson CA, Yarzebski J, Goldberg RJ, et al. Changes over time in the incidence and case- fatality rates of primary ventricular fibrillation complicating acute myocardial infarction: perspectives from the Worcester Heart Attack Study. Am Heart J 2000; 139:1014. 13. Sarter BH, Finkle JK, Gerszten RE, Buxton AE. What is the risk of sudden cardiac death in patients presenting with hemodynamically stable sustained ventricular tachycardia after myocardial infarction? J Am Coll Cardiol 1996; 28:122. https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 13/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate 14. Mehta RH, Starr AZ, Lopes RD, et al. Incidence of and outcomes associated with ventricular tachycardia or fibrillation in patients undergoing primary percutaneous coronary intervention. JAMA 2009; 301:1779. 15. Karam N, Bataille S, Marijon E, et al. Incidence, Mortality, and Outcome-Predictors of Sudden Cardiac Arrest Complicating Myocardial Infarction Prior to Hospital Admission. Circ Cardiovasc Interv 2019; 12:e007081. 16. Garc a-Garc a C, Oliveras T, Rueda F, et al. Primary Ventricular Fibrillation in the Primary Percutaneous Coronary Intervention ST-Segment Elevation Myocardial Infarction Era (from the "Codi IAM" Multicenter Registry). Am J Cardiol 2018; 122:529. 17. Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev 1989; 69:1049. 18. Di Diego JM, Antzelevitch C. Ischemic ventricular arrhythmias: experimental models and their clinical relevance. Heart Rhythm 2011; 8:1963. 19. Campbell RW, Murray A, Julian DG. 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Myocardial ischemia and induction of sustained ventricular tachyarrhythmias: evaluation using dobutamine stress echocardiography- electrophysiologic testing. J Cardiovasc Electrophysiol 2004; 15:901. 24. Gressin V, Louvard Y, Pezzano M, Lardoux H. Holter recording of ventricular arrhythmias during intravenous thrombolysis for acute myocardial infarction. Am J Cardiol 1992; 69:152. 25. Gorgels AP, Vos MA, Letsch IS, et al. Usefulness of the accelerated idioventricular rhythm as a marker for myocardial necrosis and reperfusion during thrombolytic therapy in acute myocardial infarction. Am J Cardiol 1988; 61:231. 26. Goldberg S, Greenspon AJ, Urban PL, et al. Reperfusion arrhythmia: a marker of restoration of antegrade flow during intracoronary thrombolysis for acute myocardial infarction. Am https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 14/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate Heart J 1983; 105:26. 27. Miller FC, Krucoff MW, Satler LF, et al. Ventricular arrhythmias during reperfusion. Am Heart J 1986; 112:928. 28. Yoshida Y, Hirai M, Yamada T, et al. Antiarrhythmic efficacy of dipyridamole in treatment of reperfusion arrhythmias : evidence for cAMP-mediated triggered activity as a mechanism responsible for reperfusion arrhythmias. Circulation 2000; 101:624. 29. Wehrens XH, Doevendans PA, Ophuis TJ, Wellens HJ. A comparison of electrocardiographic changes during reperfusion of acute myocardial infarction by thrombolysis or percutaneous transluminal coronary angioplasty. Am Heart J 2000; 139:430. 30. Hackett D, McKenna W, Davies G, Maseri A. Reperfusion arrhythmias are rare during acute myocardial infarction and thrombolysis in man. Int J Cardiol 1990; 29:205. 31. Maggioni AP, Zuanetti G, Franzosi MG, et al. Prevalence and prognostic significance of ventricular arrhythmias after acute myocardial infarction in the fibrinolytic era. GISSI-2 results. Circulation 1993; 87:312. 32. Yap YG, Duong T, Bland JM, et al. Prognostic impact of demographic factors and clinical features on the mode of death in high-risk patients after myocardial infarction a combined analysis from multicenter trials. Clin Cardiol 2005; 28:471. 33. Rothfeld, EL, Zucker, et al. Idioventricular rhythm in acute myocardial infarction. Circulation 1968; 37:203. 34. Scirica BM, Braunwald E, Belardinelli L, et al. Relationship between nonsustained ventricular tachycardia after non-ST-elevation acute coronary syndrome and sudden cardiac death: observations from the metabolic efficiency with ranolazine for less ischemia in non-ST- elevation acute coronary syndrome-thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 2010; 122:455. 35. Eldar M, Sievner Z, Goldbourt U, et al. Primary ventricular tachycardia in acute myocardial infarction: clinical characteristics and mortality. The SPRINT Study Group. Ann Intern Med 1992; 117:31. 36. Mont L, Cinca J, Blanch P, et al. Predisposing factors and prognostic value of sustained monomorphic ventricular tachycardia in the early phase of acute myocardial infarction. J Am Coll Cardiol 1996; 28:1670. 37. Berger PB, Ruocco NA, Ryan TJ, et al. Incidence and significance of ventricular tachycardia and fibrillation in the absence of hypotension or heart failure in acute myocardial infarction treated with recombinant tissue-type plasminogen activator: results from the Thrombolysis in Myocardial Infarction (TIMI) Phase II trial. J Am Coll Cardiol 1993; 22:1773. https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 15/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate 38. Tofler GH, Stone PH, Muller JE, et al. Prognosis after cardiac arrest due to ventricular tachycardia or ventricular fibrillation associated with acute myocardial infarction (the MILIS Study). Multicenter Investigation of the Limitation of Infarct Size. Am J Cardiol 1987; 60:755. 39. Goldberg RJ, Gore JM, Haffajee CI, et al. Outcome after cardiac arrest during acute myocardial infarction. Am J Cardiol 1987; 59:251. 40. Demidova MM, lfarsson , Carlson J, et al. Relation of Early Monomorphic Ventricular Tachycardia to Long-Term Mortality in ST-Elevation Myocardial Infarction. Am J Cardiol 2022; 163:13. 41. Wolfe CL, Nibley C, Bhandari A, et al. Polymorphous ventricular tachycardia associated with acute myocardial infarction. Circulation 1991; 84:1543. 42. Zimetbaum PJ, Josephson ME. Use of the electrocardiogram in acute myocardial infarction. N Engl J Med 2003; 348:933. 43. Gheeraert PJ, Henriques JP, De Buyzere ML, et al. Preinfarction angina protects against out- of-hospital ventricular fibrillation in patients with acute occlusion of the left coronary artery. J Am Coll Cardiol 2001; 38:1369. 44. Gheeraert PJ, De Buyzere ML, Taeymans YM, et al. Risk factors for primary ventricular fibrillation during acute myocardial infarction: a systematic review and meta-analysis. Eur Heart J 2006; 27:2499. 45. Naruse Y, Tada H, Harimura Y, et al. Early repolarization is an independent predictor of occurrences of ventricular fibrillation in the very early phase of acute myocardial infarction. Circ Arrhythm Electrophysiol 2012; 5:506. 46. Tikkanen JT, Wichmann V, Junttila MJ, et al. Association of early repolarization and sudden cardiac death during an acute coronary event. Circ Arrhythm Electrophysiol 2012; 5:714. 47. Jensen GV, Torp-Pedersen C, Hildebrandt P, et al. Does in-hospital ventricular fibrillation affect prognosis after myocardial infarction? Eur Heart J 1997; 18:919. 48. de Bakker JM, van Capelle FJ, Janse MJ, et al. Slow conduction in the infarcted human heart. 'Zigzag' course of activation. Circulation 1993; 88:915. 49. Bloch Thomsen PE, Jons C, Raatikainen MJ, et al. Long-term recording of cardiac arrhythmias with an implantable cardiac monitor in patients with reduced ejection fraction after acute myocardial infarction: the Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) study. Circulation 2010; 122:1258. Topic 1060 Version 38.0 https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 16/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate GRAPHICS ECG 12-lead accelerated idioventricular rhythm 12-lead ECG showing idioventricular rhythm with AV dissociation and wide QRS complexes occurring at a rate faster than the sinus rate but slower than 100 bpm (hence not meeting the criteria for ventricular tachycardia). ECG: electrocardiogram. Graphic 118943 Version 2.0 https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 17/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate 12-lead ECG sustained monomorphic VT The electrocardiogram (ECG) hallmark for the diagnosis of sustained monomorphic ventricular tachycardia (S is a wide complex tachycardia with the obvious presence of atrioventricular (AV) dissociation. AV dissociation suggested by the presence of fusion complexes (which reflect a supraventricular impulse coming from above AV node fusing with an impulse generated in the ventricle) or captured complexes (which reflect an impulse coming from above the AV node that depolarizes the ventricles when they are no longer refractory but befor next ventricle-generated complex). Beats 12, 17, and 22 on this ECG likely represent capture beats. Graphic 111254 Version 1.0 https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 18/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate Single lead electrocardiogram (ECG) showing polymorphic ventricular tachycardia (VT) This is an atypical, rapid, and bizarre form of ventricular tachycardia that is characterized by a continuously changing axis of polymorphic QRS morphologies. Graphic 53891 Version 5.0 https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 19/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate ECG 12-lead ventricular fibrillation 12-lead ECG showing course ventricular fibrillation. ECG: electrocardiogram. Graphic 118944 Version 1.0 https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 20/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate Killip classification of acute myocardial infarction Class I No evidence of heart failure Class II Findings consistent with mild to moderate heart failure (eg, S3 gallop, lung rales less than one-half way up the posterior lung fields, or jugular venous distension) Class III Overt pulmonary edema Class IV Cardiogenic shock Graphic 65592 Version 7.0 https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 21/22 7/5/23, 11:18 AM Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features - UpToDate Contributor Disclosures Philip J Podrid, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. James Hoekstra, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-incidence-mechanisms-and-clinical-features/print 22/22

7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment : Philip J Podrid, MD, FACC : James Hoekstra, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 14, 2023. INTRODUCTION Sudden cardiac death (SCD) in the setting of an acute myocardial infarction (MI) is most frequently the result of a ventricular tachyarrhythmia. The appearance of a sustained ventricular tachyarrhythmia following an MI, such as ventricular tachycardia (VT) or ventricular fibrillation (VF), in the early period post-MI may be the harbinger of ongoing myocardial ischemia, the development of proarrhythmic myocardial scar tissue, elevated sympathetic tone or increase in circulating catecholamines, or an electrolyte disturbance such as hypokalemia. In-hospital mortality approaches 20 percent or more in patients who develop VT or VF following an MI. As such, rapid identification and treatment of these arrhythmias can be life-saving. Although all patients with a prior MI have an elevated risk of malignant arrhythmias, the magnitude of risk varies from patient to patient, with reduced left ventricular ejection fraction being the most prominent risk stratifier. This topic will focus on the prevention and treatment of ventricular arrhythmias during and immediately after acute MI. The incidence, mechanisms, and clinical features of ventricular arrhythmias during acute MI, as well as treatment of ventricular arrhythmias late post-MI (using defibrillation with or without antiarrhythmic medications) is discussed separately. (See "Advanced cardiac life support (ACLS) in adults" and "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features".) https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 1/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate PREVENTION Frequent ventricular premature beats (VPBs), VT, and ventricular fibrillation (VF) are all associated with increased long-term mortality following acute MI. An acute MI may be an ST- segment elevation MI (STEMI) or non-ST-segment elevation MI (NSTEMI). Most of the data available are in patients with a STEMI. While the data may also apply to patients with an NSTEMI, information in these patients is more limited. The following is a summary of the multi-modality approach to prevention of ventricular arrhythmias following MI (STEMI), which includes treatment of ischemia, electrolyte supplementation (if needed), and beta blockers. Treatment of symptomatic arrhythmias (should they arise) is discussed elsewhere. (See 'Treatment' below.) Revascularization/treatment of myocardial ischemia Patients with ventricular arrhythmias, especially polymorphic VT, in the setting of an acute MI should receive aggressive treatment for both the arrhythmia and myocardial ischemia. Therapy for ischemia usually includes drugs (eg, beta blockers, nitrates) and in most cases primary percutaneous coronary intervention or far less frequently, coronary artery bypass grafting for revascularization [1]. Fibrinolytic therapy is also effective but is used infrequently and generally only when PCI is not immediately available. The acute and long-term treatments of ischemic heart disease are discussed in detail separately. (See "Overview of the acute management of ST-elevation myocardial infarction" and "Overview of the acute management of non-ST-elevation acute coronary syndromes" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".) Electrolyte supplementation In the post-MI setting, we maintain levels of serum potassium 4 mEq/L and serum magnesium 2 mg/dL. The dose and route of potassium and/or magnesium are discussed elsewhere. (See "Clinical manifestations and treatment of hypokalemia in adults" and "Hypomagnesemia: Evaluation and treatment".) Hypokalemia is a risk factor for VF in the setting of an acute MI, and concomitant hypomagnesemia, which is detected in approximately 40 percent of cases of hypokalemia, prevents the correction of hypokalemia [2]. In the GISSI-2 trial, the likelihood of VF among patients with a serum potassium <3.6 mEq/L was almost twice as high as among patients with a higher serum potassium (odds ratio 1.97) [3]. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features", section on 'Ventricular fibrillation'.) The MAGIC trial showed no benefit to empiric magnesium supplementation in acute MI patients [4]. https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 2/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate Beta blockers Oral beta blockers are administered universally to all patients without contraindications who experience an acute MI [5]. In addition to other beneficial effects, the immediate administration of a beta blocker during an acute MI reduces the risk of VF. In a systematic review, the overall mortality in 31 long-term trials that included almost 25,000 patients was 9.7 percent; beta blockers reduced the odds of death by 23 percent (95% CI 15-31 percent) [6]. These benefits are seen following both STEMI and NSTEMI ( figure 1) [7]. The details of beta blocker use are discussed separately. (See "Acute myocardial infarction: Role of beta blocker therapy".) Beta blockers are of use as the etiology of ventricular arrhythmia in the early or acute stages of an MI is in part related to enhanced automaticity, resulting from elevated catecholamines and beta receptor stimulation. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features".) Antiarrhythmic drugs We do not administer prophylactic antiarrhythmic agents in the post- infarction period. The prophylactic administration of class IC antiarrhythmic agents (eg, encainide, flecainide) in the post-MI period is associated with increased mortality and is not recommended [8- 10]. Due to the suggestion of possible harm and unsure benefit, the routine prophylactic administration of lidocaine in the acute MI period is not recommended [11]. Unlike the other antiarrhythmic drugs, prophylactic amiodarone is not associated with an increase in mortality. However, its unselected use in all patients does not appear to improve outcomes. As such, we do not administer prophylactic amiodarone in the post-MI period. The use of these agents is reserved for patients with documented ventricular tachyarrhythmias. (See 'Treatment' below.) Heart failure therapy Although not considered antiarrhythmic drugs, angiotensin converting enzyme (ACE) inhibitors, aldosterone antagonists, angiotensin II receptor blockers (ARBs), and combination ARB and neprilysin inhibitor all reduce the incidence of SCD in patients with heart failure (HF). Reduced SCD rates have been reported specifically in post-MI populations with ACE inhibitors and aldosterone antagonists, and in a broader population of HF patients, approximately 50 percent of whom had a prior infarction, with an ARB. These topics are discussed separately. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials", section on 'Effect on sudden death'.) https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 3/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate Wearable defibrillator for primary prevention Among patients with left ventricular ejection fraction (LVEF) 35 percent who are less than 40 days post-MI, we discuss the potential benefits and risks of wearable cardioverter-defibrillator (WCD) use ( picture 1) and consider providing it to motivated patients with NYHA functional class II or III, or LVEF <30 percent and in NYHA class I, as these patients would be candidates for implantable cardioverter-defibrillator (ICD) implantation after 40 days. However, one study has not shown improvement in mortality in such patients as a result of WCD use [12]. In another analysis of this trial, it was reported that the lack of benefit might be in part related to poor compliance among patients prescribed the WCD [13]. The role of the WCD is discussed in detail separately. (See "Wearable cardioverter-defibrillator".) TREATMENT Ventricular premature beats In the post-MI patient with ventricular premature beats (VPBs) that cause significant or disabling symptoms (eg, palpitations, lightheadedness), beta blockers are administered, although most patients will already be taking them. In the rare circumstance that more aggressive antiarrhythmic therapy is considered for control of refractory symptoms, we prefer amiodarone, as it is likely to be effective and unlikely to cause significant harm, although there is an appreciable incidence of side effects with long-term amiodarone therapy. Mexiletine, which is a class IB agent that resembles lidocaine, also appears safe in the post-MI patient, and although there are no randomized trials in this population, it may be effective for arrhythmia suppression [14,15]. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) There is no role for chronic antiarrhythmic drug therapy to suppress asymptomatic VPBs. (See 'Prevention' above.) VPBs, particularly if frequent (more than 10 per hour) or complex (ie, couplets or non-sustained ventricular tachycardia) appear to be associated with a worse prognosis in patients with a prior MI. Based upon this association, trials of both class I and class III antiarrhythmic medications were conducted to determine if suppression of ventricular ectopy would reduce SCD. Patients with frequent asymptomatic VPBs post-MI were randomly assigned to receive suppressive antiarrhythmic therapy or placebo in an effort to suppress the ectopy [8,9]. The CAST study, which randomly assigned patients to treatment with encainide, flecainide, moricizine, or placebo, was prematurely terminated when it was noted that, despite suppression of VPBs, total mortality among the patients receiving encainide and flecainide was significantly increased compared with those on placebo (7.7 versus 3.0 percent); this was due primarily to an excess in arrhythmic deaths ( figure 2). https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 4/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate The CAST II study, which limited treatment to moricizine or placebo, was also terminated early due to an increased risk of death or cardiac arrest in the first 14 days of therapy among patients treated with moricizine (2.6 versus 0.5 percent with placebo) [9]. The CAMIAT study, which randomly assigned patients with frequent ( 10 per hour) or repetitive VPBs to amiodarone or placebo (approximately 60 percent were also treated with a beta blocker), showed that although arrhythmia suppression was more common with amiodarone (84 versus 35 percent with placebo), there was no significant difference in yearly all-cause or cardiac mortality (4.0 versus 5.2 percent) [16]. Nonsustained VT For patients with symptomatic (eg, palpitations, lightheadedness) nonsustained ventricular tachycardia (NSVT) after an MI, beta blockers are administered, although most patients should already be taking them. If antiarrhythmic drug therapy is considered due to persistent symptoms, we prefer amiodarone, as it is likely to be effective and unlikely to cause significant harm, although there is an appreciable incidence of side effects with long-term amiodarone therapy. An alternative agent is mexiletine as it is safe and has been found to be effective for arrhythmia suppression in other groups of patients [14,15]. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) In the absence of data specific to patients with NSVT, we do not prescribe chronic antiarrhythmic drug therapy to suppress asymptomatic NSVT. The presence of NSVT in post-MI patients with an LVEF 40 percent is an indication for further risk stratification, if the patient does not already meet criteria for ICD placement (LVEF 30 percent without heart failure symptoms, or LVEF 35 percent with NYHA class II or III heart failure). Electrophysiologic testing prior to hospital discharge may be appropriate in patients with late NSVT (ie, more than 24 to 48 hours into acute MI). (See "Incidence of and risk stratification for sudden cardiac death after myocardial infarction".) The development of NSVT one week or later post-MI carries at least a twofold increase in the risk of SCD [17]. The risk of NSVT is even further increased in post-MI patients with significantly diminished LV function (LVEF less than 40 percent). In this setting, the risk of SCD is increased more than fivefold [17,18]. Large randomized trials of antiarrhythmic drugs limited to patients with NSVT have not been performed. However, many of the patients included in the CAST and CAMIAT (39 percent) trials had NSVT. These trials showed an increased mortality in patients treated with class IC antiarrhythmic medications [8] and no significant reduction in overall mortality with amiodarone [16]. https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 5/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate Accelerated idioventricular rhythm An accelerated idioventricular rhythm (AIVR), which has also been called "slow VT," arises below the atrioventricular (AV) node and has, by definition, a rate between 50 and 100 beats/minute ( waveform 1). Most episodes are transient, benign, and require no treatment. Furthermore, pharmacologic therapy is contraindicated if there is complete heart block and an escape ventricular rhythm (which is not actually AIVR), since suppression of the pacemaker focus can result in profound bradycardia and possibly asystole. AIVR is most often seen in the peri-infarction period. AIVR often occurs after reperfusion therapy (PCI or fibrinolytic therapy) and is felt to be a reperfusion arrhythmia. It is likely the result of enhanced automaticity of ectopic foci in the ventricular myocardium. AIVR occurring after the peri-infarction period is uncommon. When it occurs, reversible causes should be sought such as digitalis toxicity, hypokalemia, or hypomagnesemia. There are no convincing data linking AIVR to sustained VT, ventricular fibrillation (VF), or a worse prognosis. Thus, no therapy is warranted for asymptomatic arrhythmias, while symptomatic arrhythmias can be treated with a beta blocker (if the patient is not already receiving this therapy), antiarrhythmic drugs, or perhaps ablation. Polymorphic VT Polymorphic VT associated with a normal QT interval is an uncommon arrhythmia following an acute MI ( waveform 2 and waveform 3). When it occurs, it is often associated with signs or symptoms of recurrent or ongoing myocardial ischemia [19]. Even if there are no signs or symptoms of myocardial ischemia, underlying myocardial ischemia is the most likely etiology. If polymorphic VT lasts for more than 8 to 10 seconds, it often degenerates into VF. This type of polymorphic VT generally fails to respond to class I antiarrhythmic drugs, magnesium, or overdrive pacing but may respond to intravenous amiodarone or lidocaine [19]. In patients treated with primary percutaneous coronary intervention who then manifest polymorphic ventricular tachycardia , revisualization of the coronary arteries is frequently warranted. An intraaortic balloon pump or other mechanical unloading therapy may help stabilize these patients. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features", section on 'Polymorphic VT'.) Revascularization has traditionally been considered to be adequate therapy for polymorphic VT due to ischemia in the absence of acute MI. However, more recent data suggest that ICD implantation in addition to revascularization may be optimal [20]. There is a second form of polymorphic VT that develops during the healing phase (at 3 to 11 days) and occurs in association with QT prolongation [21]. This arrhythmia resembles an acquired long QT syndrome and is treated in a similar fashion. One report of eight such patients found that defibrillation (if the arrhythmia is sustained), magnesium, lidocaine, beta blockers, and rapid overdrive pacing were effective therapies [21]. Mexiletine, which is similar to lidocaine https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 6/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate but is an oral medication, may be of benefit. In general, the QT interval shortened within 10 days, and long-term outcomes were uneventful. More commonly, polymorphic VT results from either acquired or congenital long QT interval and in this situation it is called torsades de pointes. Acquired QT prolongation may result from class IA or class III antiarrhythmic drugs, which can prolong the QT interval. An exception is amiodarone, which rarely produces torsades de pointes when used alone. Amiodarone should be discontinued if the burden of polymorphic VT increases, which is a possible sign of proarrhythmia. Many other drugs, including antibiotics, psychotropic agents, antihistamines, and GI medications may prolong the QT interval. Magnesium supplementation may be of benefit, even in the absence of hypomagnesemia. Bradycardia frequently facilitates the initiation of torsades de pointes VT in a susceptible patient with drug-induced QT prolongation as the QT interval lengthens further with slower heart rates. Increasing the heart rate, as with temporary pacing, may help prevent recurrent episodes. Although increasing the heart rate with intravenous isoproterenol or dobutamine may also be effective, this should be done with caution in the patient with an acute myocardial infarction. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes" and "Temporary cardiac pacing", section on 'Indications'.) Sustained monomorphic VT and VF Unstable, poorly-tolerated arrhythmias are a life- threatening emergency that are treated according to established advanced cardiac life support (ACLS) protocols [22]. VF is almost universally lethal if not treated. VF does not self-terminate nor does it revert with antiarrhythmic drugs. Defibrillation (nonsynchronized delivery of a shock) is the definitive therapy for VF. If available, a biphasic waveform defibrillator is preferable since the success rate for defibrillation is higher than with monophasic waveforms. The 2015 American Heart Association (AHA) guidelines for adult ACLS recommended that, for biphasic defibrillators, the initial shock should be at 120 to 200 joules, with subsequent shocks at the highest available biphasic energy level (200 joules for most devices) [22]. For monophasic defibrillators, nonescalating shocks beginning at 360 joules should be used. (See "Advanced cardiac life support (ACLS) in adults" and "Basic principles and technique of external electrical cardioversion and defibrillation".) Hemodynamically unstable or pulseless sustained monomorphic VT (SMVT) without identifying a distinct QRS should be treated with unsynchronized electrical shocks (ie, defibrillation and not cardioversion, which is the delivery of an electrical shock synchronized to the QRS complex). If available, a biphasic waveform defibrillator is preferable since the success rate for defibrillation is higher than with monophasic https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 7/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate waveforms. For biphasic defibrillators, the initial shock should be at 120 to 200 joules, with subsequent shocks at the highest available biphasic energy level (200 joules for most devices). For monophasic defibrillators, nonescalating shocks beginning at 360 joules should be used. (See "Cardioversion for specific arrhythmias", section on 'Ventricular tachycardia'.) SMVT (in which a distinct QRS complex can be identified) associated with angina, pulmonary edema, or hypotension (systolic blood pressure <90 mmHg) should be treated immediately with synchronized electrical cardioversion using an initial energy of 50 to 100 joules. Subsequent shocks at increasing energy can be given as necessary. Brief anesthesia is desirable if hemodynamically tolerable. SMVT that is hemodynamically tolerated and asymptomatic can be treated initially with intravenous amiodarone (or lidocaine or procainamide). Synchronized electrical cardioversion with brief anesthesia should be performed if VT persists after the administration of the initial 150 mg of amiodarone (or 100 to 300 mg of lidocaine). (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Stable patients' and "Cardioversion for specific arrhythmias", section on 'Ventricular tachycardia'.) Recurrent nonsustained and sustained VT, particularly polymorphic, should trigger consideration of investigation for ischemia, possibly (but not always) involving the infarct- related artery. (See 'Revascularization/treatment of myocardial ischemia' above.) Patients who manifest sustained VT or polymorphic VT more than 24 to 48 hours after acute MI should generally undergo ICD implantation prior to hospital discharge. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) The acute and long-term management of SMVT and VF in patients with a prior MI are discussed in detail separately. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Electrical storm Electrical storm is defined as multiple recurrent episodes of VF. The optimal therapy of electrical storm in patients with an acute MI is uncertain but is likely no different than in patients with electrical storm in any setting and includes defibrillation, antiarrhythmic medications, beta blockers, treatment of myocardial ischemia, and long-term therapies to prevent recurrent arrhythmias (eg, catheter ablation, cardiac sympathetic denervation, etc). (See "Electrical storm and incessant ventricular tachycardia".) https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 8/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Non-ST-elevation acute coronary syndromes (non-ST-elevation myocardial infarction)" and "Society guideline links: ST- elevation myocardial infarction (STEMI)" and "Society guideline links: Ventricular arrhythmias".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Ventricular tachycardia (The Basics)" and "Patient education: Ventricular fibrillation (The Basics)") SUMMARY AND RECOMMENDATIONS Revascularization Patients with ventricular arrhythmias, especially polymorphic VT, in the setting of an acute MI should receive aggressive treatment for both the arrhythmia and myocardial ischemia. Therapy for ischemia usually includes drugs (eg, beta blockers, nitrates) and either primary percutaneous coronary intervention or coronary artery bypass grafting for revascularization. (See 'Revascularization/treatment of myocardial ischemia' above.) Preventive therapies Other therapies that reduce ventricular arrhythmias during and immediately after acute MI include maintaining levels of serum potassium 4.0 mEq/L and https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 9/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate serum magnesium 2.0 mg/dL, administering beta blockers, and appropriate therapies for heart failure, when present. (See 'Prevention' above.) Antiarrhythmic drugs The prophylactic administration of antiarrhythmic agents to asymptomatic patients during and immediately after acute MI has at best no benefit and potentially can cause harm. The use of these agents is reserved for patients with documented ventricular tachyarrhythmias. (See 'Antiarrhythmic drugs' above and 'Treatment' above.) Ventricular premature beats In the post-MI patient with ventricular premature beats or nonsustained VT that cause significant or disabling symptoms (eg, palpitations, lightheadedness), beta blockers are administered, although most patients will already be taking them. In the rare circumstance that more aggressive antiarrhythmic therapy is considered for control of refractory symptoms, we prefer amiodarone, as it is likely to be effective and unlikely to cause significant harm. (See 'Ventricular premature beats' above.) Accelerated idioventricular rhythm Most episodes of accelerated idioventricular rhythm (AIVR) are transient, benign, and require no treatment. Furthermore, pharmacologic therapy is contraindicated if there is complete heart block and an escape ventricular rhythm (which is not actually AIVR), since suppression of the pacemaker focus can result in profound bradycardia and possibly asystole. (See 'Accelerated idioventricular rhythm' above.) Polymorphic VT This is associated with a normal QT interval, is an uncommon arrhythmia, and is often associated with signs or symptoms of recurrent or ongoing myocardial ischemia, in which case revisualization of the coronary arteries is usually warranted. Polymorphic VT that results from acquired long QT interval is called torsades de pointes and is usually related to medications. (See 'Polymorphic VT' above.) Poorly-tolerated arrhythmias Sustained monomorphic VT or VF is a life-threatening emergency that is treated according to established advanced cardiac life support (ACLS) protocols. (See "Advanced cardiac life support (ACLS) in adults" and 'Sustained monomorphic VT and VF' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 10/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 2. Whang R, Whang DD, Ryan MP. Refractory potassium repletion. A consequence of magnesium deficiency. Arch Intern Med 1992; 152:40. 3. Volpi A, Cavalli A, Santoro L, Negri E. Incidence and prognosis of early primary ventricular fibrillation in acute myocardial infarction results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) database. Am J Cardiol 1998; 82:265. 4. Magnesium in Coronaries (MAGIC) Trial Investigators. Early administration of intravenous magnesium to high-risk patients with acute myocardial infarction in the Magnesium in Coronaries (MAGIC) Trial: a randomised controlled trial. Lancet 2002; 360:1189. 5. American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, O'Gara PT, et al. 2013 ACCF/AHA guideline for the management of ST- elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61:e78. 6. Freemantle N, Cleland J, Young P, et al. beta Blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 1999; 318:1730. 7. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med 1998; 339:489. 8. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324:781. 9. Cardiac Arrhythmia Suppression Trial II Investigators. Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med 1992; 327:227. 10. Teo KK, Yusuf S, Furberg CD. Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction. An overview of results from randomized controlled trials. JAMA 1993; 270:1589. 11. Sadowski ZP, Alexander JH, Skrabucha B, et al. Multicenter randomized trial and a systematic https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 11/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate overview of lidocaine in acute myocardial infarction. Am Heart J 1999; 137:792. 12. Olgin JE, Pletcher MJ, Vittinghoff E, et al. Wearable Cardioverter-Defibrillator after Myocardial Infarction. N Engl J Med 2018; 379:1205. 13. Olgin JE, Lee BK, Vittinghoff E, et al. Impact of wearable cardioverter-defibrillator compliance on outcomes in the VEST trial: As-treated and per-protocol analyses. J Cardiovasc Electrophysiol 2020; 31:1009. 14. Stein J, Podrid PJ, Lampert S, et al. Long-term mexiletine for ventricular arrhythmia. Am Heart J 1984; 107:1091. 15. Mendes L, Podrid PJ, Fuchs T, Franklin S. Role of combination drug therapy with a class IC antiarrhythmic agent and mexiletine for ventricular tachycardia. J Am Coll Cardiol 1991; 17:1396. 16. Cairns JA, Connolly SJ, Roberts R, Gent M. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Lancet 1997; 349:675. 17. Bigger JT Jr, Fleiss JL, Rolnitzky LM. Prevalence, characteristics and significance of ventricular tachycardia detected by 24-hour continuous electrocardiographic recordings in the late hospital phase of acute myocardial infarction. Am J Cardiol 1986; 58:1151. 18. Mukharji J, Rude RE, Poole WK, et al. Risk factors for sudden death after acute myocardial infarction: two-year follow-up. Am J Cardiol 1984; 54:31. 19. Wolfe CL, Nibley C, Bhandari A, et al. Polymorphous ventricular tachycardia associated with acute myocardial infarction. Circulation 1991; 84:1543. 20. Natale A, Sra J, Axtell K, et al. Ventricular fibrillation and polymorphic ventricular tachycardia with critical coronary artery stenosis: does bypass surgery suffice? J Cardiovasc Electrophysiol 1994; 5:988. 21. Halkin A, Roth A, Lurie I, et al. Pause-dependent torsade de pointes following acute myocardial infarction: a variant of the acquired long QT syndrome. J Am Coll Cardiol 2001; 38:1168. 22. Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132:S444. Topic 118996 Version 15.0 https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 12/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate GRAPHICS Beta blockers are equally effective after a Q wave or non-Q wave MI Analysis of data from 201,752 patients with a myocardial infarction (MI) demonstrates that the reduction in mortality at two years with beta blockers is similar in those with a Q wave (14.2 versus 23.6 percent for those not receiving beta blockers) or non-Q wave MI (14.4 versus 23.9 percent). Data from Gottlieb SS, McCarter RJ, Vogel RA. N Engl J Med 1998; 339:489. Graphic 79592 Version 2.0 https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 13/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate Wearable cardioverter-defibrillator The wearable cardioverter-defibrillator consists of a vest incorporating two defibrillation electrodes and four sensing electrocardiographic electrodes connected to a waist unit containing the monitoring and defibrillation electronics. Reproduced with permission from: ZOLL Medical Corporation. Copyright 2012. All rights reserved. Graphic 60103 Version 3.0 https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 14/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate Encainide and flecainide increase cardiac mortality Results of the Cardiac Arrhythmia Suppression Trial (CAST) in patients with ventricular premature beats after myocardial infarction. Patients receiving encainide or flecainide had, when compared with those receiving placebo, a significantly lower rate of avoiding a cardiac event (death or resuscitated cardiac arrest) (left panel, p = 0.001) and a lower overall survival (right panel, p = 0.0006). The cause of death was arrhythmia or cardiac arrest. Data from Echt DS, Liebson PR, Mitchell B, et al. N Engl J Med 1991; 324:781. Graphic 59975 Version 5.0 https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 15/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate ECG 12-lead accelerated idioventricular rhythm 12-lead ECG showing idioventricular rhythm with AV dissociation and wide QRS complexes occurring at a rate faster than the sinus rate but slower than 100 bpm (hence not meeting the criteria for ventricular tachycardia). ECG: electrocardiogram. Graphic 118943 Version 2.0 https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 16/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate ECG_1 showing polymorphic ventricular tachycardia in ischemia Continuous rhythm strip revealing several episodes of nonsustained ventricular tachycardia (VT) occurring during an acute ischemic event. The QRS complexes are variable in morphology and RR intervals; thus, the VT is polymorphic. The QT interval is normal. This form of VT should be distinguished from torsade de pointes in which polymorphic VT is associated with QT interval prolongation. Graphic 54538 Version 3.0 https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 17/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate ECG_2 showing polymorphic ventricular tachycardia in ischemia Continuous rhythm strip showing an episode of very rapid polymorphic ventricular tachycardia which is often referred to as ventricular flutter. The QT interval is normal and the QRS complex morphology is highly variable. The patient had an underlying sinus tachycardia, suggesting increased sympathetic activity secondary to an ischemic event. Graphic 67322 Version 3.0 https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 18/19 7/5/23, 11:19 AM Ventricular arrhythmias during acute myocardial infarction: Prevention and treatment - UpToDate Contributor Disclosures Philip J Podrid, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. James Hoekstra, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/ventricular-arrhythmias-during-acute-myocardial-infarction-prevention-and-treatment/print 19/19

7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Ambulatory ECG monitoring : Christopher Madias, MD : Peter J Zimetbaum, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 29, 2022. INTRODUCTION In contrast to the standard electrocardiogram (ECG), which provides a brief sample of cardiac electrical activity over 10 seconds, ambulatory ECG monitoring provides a view of ECG data over an extended period of time, thereby permitting evaluation of dynamic and transient cardiac electrical phenomena. The most common ambulatory ECG application is in the diagnosis and assessment of cardiac arrhythmias or conduction abnormalities (symptomatic or asymptomatic) or the presence of potential arrhythmias (such as in patients with syncope or presyncope); however, ambulatory ECG also has a role in stratification of certain cardiomyopathies, in assessing the effectiveness of arrhythmia therapy, and in the evaluation of silent ischemia. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features" and "Silent myocardial ischemia: Epidemiology, diagnosis, treatment, and prognosis" and "Evaluation of heart rate variability".) Ambulatory ECG monitoring, which can be performed using a variety of techniques for as short as 24 to 48 hours and for as long as months to years ( table 1), offers the opportunity to review cardiac ECG data during routine activity, as well as during periods of physical and psychological stress. Ambulatory ECG monitoring for longer periods (when compared with standard ECG for a 10-second time period) is more sensitive for detecting spontaneous, often highly variable cardiac arrhythmias or conduction abnormalities [1,2]. Ambulatory monitoring, in conjunction with clinical and ECG findings, can be a useful component in the evaluation of the patient with unexplained syncope, presyncope, or palpitations. A detailed discussion of the evaluation of syncope and palpitations, including the https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 1/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate role of ambulatory monitors, is presented separately. (See "Syncope in adults: Clinical manifestations and initial diagnostic evaluation" and "Evaluation of palpitations in adults".) INDICATIONS Ambulatory ECG monitoring is the most widely employed technology for the evaluation of a patient with symptoms suggestive of cardiac arrhythmia or conduction abnormality. Professional society guidelines on ambulatory ECG recommend ambulatory ECG monitoring for the symptomatic patient with [3,4]: Unexplained syncope, near syncope, or episodic dizziness (see "Syncope in adults: Risk assessment and additional diagnostic evaluation", section on 'Introduction') Unexplained recurrent palpitations (see "Evaluation of palpitations in adults") The choice of initial ambulatory ECG monitoring for the symptomatic patient depends somewhat on the frequency and severity of symptoms. Continuous ECG (Holter) monitoring for 24 to 48 hours is most practical as the initial monitor for patients with daily or near daily symptoms, while those with less frequent symptoms are more likely to benefit from extended monitoring with an event monitor or an insertable cardiac monitor (sometimes referred to as an implantable cardiac monitor or an implantable loop recorder). (See 'Types of ambulatory ECG monitoring' below and 'Our approach to choosing an ambulatory ECG monitoring strategy' below.) In addition to being used for the evaluation of patients with unexplained symptoms suggestive of cardiac arrhythmia, ambulatory ECG monitors may also be used in risk stratification, in assessing the effectiveness of arrhythmia therapy, and in the evaluation of silent ischemia. As examples: To assess the average heart rate and adequacy of rate control in the patient with atrial fibrillation (AF). (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Additional cardiac testing'.) To evaluate for occult AF as a potential cause of cardioembolism in patients with cryptogenic stroke [5]. (See "Overview of the evaluation of stroke", section on 'Monitoring for subclinical atrial fibrillation'.) To screen for asymptomatic ventricular premature beats or nonsustained ventricular tachycardia in a patient with hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, dilated or restrictive cardiomyopathy, https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 2/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate congenital heart disease, or Brugada syndrome. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Ambulatory ECG monitoring' and "Congenital long QT syndrome: Diagnosis", section on 'Ambulatory ECG monitoring' and "Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis", section on 'Ambulatory monitoring'.) To evaluate prognosis following acute coronary syndrome. (See "Incidence of and risk stratification for sudden cardiac death after myocardial infarction".) To assess for silent myocardial ischemia in a patient with known or suspected coronary artery disease. (See "Silent myocardial ischemia: Epidemiology, diagnosis, treatment, and prognosis", section on 'Ambulatory monitoring'.) OUR APPROACH TO CHOOSING AN AMBULATORY ECG MONITORING STRATEGY The approach to choosing an ambulatory ECG monitoring strategy depends on the indication for the test in addition to the frequency and duration of symptoms ( table 1). When to choose continuous ECG (Holter) monitoring A Holter monitor is the preferred ambulatory ECG monitoring test for patients with daily or near daily symptoms, and for patients in whom a comprehensive/continuous assessment of all cardiac activity is required. Clinical scenarios in which a Holter monitor is a good choice include ( table 1): Patients with syncope, near syncope, or dizziness occurring on a daily or near daily basis. (See "Syncope in adults: Risk assessment and additional diagnostic evaluation", section on 'Ambulatory ECG monitoring'.) Patients with palpitations occurring on a daily or near daily basis. (See "Evaluation of palpitations in adults".) Patients with atrial fibrillation (AF) for assessment of ventricular rate control. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Additional cardiac testing'.) Patients with frequent ectopy (either ventricular premature beats [VPBs or premature atrial complexes [PAC; also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat]) requiring quantification of the ectopy burden. (See "Arrhythmia-induced cardiomyopathy".) https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 3/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate Patients with recent acute coronary syndrome (especially non-ST-segment elevation myocardial infarction [NSTEMI] or STEMI), hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, dilated or restrictive cardiomyopathy, congenital heart disease, or Brugada syndrome, in whom screening for ventricular ectopy or non-sustained ventricular arrhythmias might alter prognosis and therapy. (See "Incidence of and risk stratification for sudden cardiac death after myocardial infarction" and "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Ambulatory ECG monitoring' and "Congenital long QT syndrome: Diagnosis", section on 'Ambulatory ECG monitoring' and "Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis", section on 'Ambulatory monitoring'.) When to choose event monitoring An event monitor is the preferred ambulatory ECG monitoring test for patients with less frequent (ie, weekly to monthly) symptoms and for patients in whom a comprehensive assessment of all cardiac activity over a 24 to 48 hour interval is not required. Several types of event monitors are available with a gradation of features: Post Event Monitoring devices are generally small, lightweight devices that can be placed on the patient's chest upon the onset of symptoms. The patient's rhythm is stored for a specified amount of time after recording begins (eg, 30 to 150 seconds). Event/Loop Recorders are devices that constantly record for a pre-specified period, but do not save the data until they are triggered to do so by the patient pushing an event button. The device will record and save the patient's rhythm for a pre-specified amount of time before and after activation of the device (eg, 30 seconds prior to and 60 seconds after the event). Auto-triggered Event Recorders are more advanced devices. In addition to recording and saving symptomatic patient-triggered events, these devices have auto-detect features that will capture asymptomatic arrhythmias based on detection algorithms (eg, atrial fibrillation events or bradycardia events). Clinical scenarios in which an event monitor is a good choice include ( table 1): Patients with syncope, near syncope, or dizziness that occurs less frequently (ie, weekly to monthly). (See "Syncope in adults: Risk assessment and additional diagnostic evaluation", section on 'Ambulatory ECG monitoring'.) https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 4/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate Patients with palpitations that occur less frequently (ie, weekly to monthly). (See "Evaluation of palpitations in adults".) Patients with near syncope, dizziness, or palpitations that occur more frequently but in whom an initial Holter monitor was nondiagnostic. Patients undergoing evaluation for atrial fibrillation as a source of cryptogenic stroke. For this indication an event monitor with auto-triggered feature should be considered for the detection of asymptomatic atrial fibrillation events. (See "Overview of the evaluation of stroke", section on 'Monitoring for subclinical atrial fibrillation'.) When to choose mobile cardiac outpatient telemetry (MCOT) MCOT monitoring might be a preferred choice for patients with less frequent symptoms (ie, weekly to monthly) for whom comprehensive assessment of all cardiac activity is required. Clinical scenarios in which MCOT might be a good choice include ( table 1): Patients undergoing evaluation for atrial fibrillation as a source of cryptogenic stroke. (See "Overview of the evaluation of stroke", section on 'Monitoring for subclinical atrial fibrillation'.) Patients with syncope, near syncope, or dizziness that occurs less frequently (ie, weekly to monthly). (See "Syncope in adults: Risk assessment and additional diagnostic evaluation", section on 'Ambulatory ECG monitoring'.) Patients with palpitations that occur less frequently (ie, weekly to monthly). (See "Evaluation of palpitations in adults".) Patients in whom accurate information on arrhythmia burden is desired (eg, AF burden). Patients in whom information on nocturnal arrhythmias is desired, such as those associated with sleep apnea. When to choose insertable cardiac monitoring Intracardiac monitoring (ICM) can be a particularly useful diagnostic tool for patients with infrequent (ie, less than monthly) symptoms that are potentially injurious (eg, syncope). ICM can also be useful for patients with bothersome symptoms requiring a diagnosis, but whose prior assessments with Holter or event monitoring have been unrevealing of a diagnosis. ICM may also be helpful when searching for asymptomatic occult episodes of AF, such as following a cryptogenic stroke. (See "Overview of the evaluation of stroke", section on 'Monitoring for subclinical atrial fibrillation'.) https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 5/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate Other scenarios Occasionally, clinical circumstances will arise in which ambulatory ECG monitoring is not the optimal initial test ( table 1). Generally, if the patient has severe or potentially life-threatening symptoms (eg, syncope or presyncope with associated injury, sustained lightheadedness, etc), admission to the hospital for continuous in-hospital telemetry is warranted. TYPES OF AMBULATORY ECG MONITORING There are several different methods of performing ambulatory ECG monitoring ( table 2). Continuous ambulatory ECG (Holter) monitor The conventional continuous ambulatory ECG system, generally referred to as a Holter monitor, is most commonly performed for patients with frequent (ie, daily or near daily) symptoms of palpitations ( table 2). Continuous ambulatory ECG (Holter) monitoring includes a continuous recording of all ECG data for a period of 24 or 48 hours. This technology uses a small, lightweight, battery operated recorder ( figure 1) that typically records two or three channels of ECG data (although 12-lead monitors are also available) from electrodes placed on the patient's chest [6]. Holter monitoring devices have patient-activated event markers, and encoded time or time markers. The recorded data are analyzed with a playback instrument system that requires operator interaction with an arrhythmia analyzer, ST segment detector, RR interval analysis, signal-averaging computer, and a variety of audiovisual detection and review displays, as well as a printer for generating printouts of ECGs, trends, or a statistical summary. Holter monitors must be returned for analysis and, as such, do not provide real-time information on patient symptoms or arrhythmias. Holter monitor report A typical Holter monitor report includes the following information ( table 2): Total heart beats Average heart rate Maximum and minimum heart rates Number of premature beats (supraventricular and ventricular) Episodes of tachyarrhythmia and the etiology of the arrhythmias (eg, supraventricular or ventricular) https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 6/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate Longest R-R interval and any pauses greater than three seconds and etiology of the pauses (eg, sinus pauses versus AV block) ST segment changes Patient-reported symptoms and any associated ECG findings Representative samples of ECG tracings (eg, hourly samples) Event (loop) monitor Event monitors, historically referred to as loop monitors because the recording device continuously looped its recording tape, are most commonly used for patients with less frequent (ie, weekly to monthly) symptoms of palpitations, presyncope, or syncope ( table 2). Event monitors can be utilized for two to four weeks (although possibly up to three months). Similarly to Holter monitors, event monitors use a small, lightweight, battery operated recorder ( figure 1) that typically records two channels of ECG data from electrodes placed on the patient's chest. Typically, event monitors are worn continuously and are activated by patient trigger when symptoms arise. Alternatively, patients with longer lasting symptomatic episodes can be instructed to apply the event monitor during symptomatic events. Because these instruments store the ECG in continuous memory before activation, they are excellent for documenting transient symptomatic or incapacitating events, and often can display the antecedent onset and subsequent offset of a paroxysmal cardiac arrhythmia [7]. Several types of event monitors are available with a gradation of features: Post Event Monitoring devices are generally small, lightweight devices that can be placed on the patient s chest upon the onset of symptoms. The patient's rhythm is stored for a specified amount of time after recording begins (eg, 30 to 150 seconds). Event/Loop Recorders are devices that constantly record for a pre-specified period, but do not save the data until they are triggered to do so by the patient pushing an event button. The device will record and save the patient's rhythm for a pre-specified amount of time before and after activation of the device (eg, 30 seconds prior to and 60 seconds after the event). Auto-triggered Event Recorders are more advanced devices. In addition to recording and saving symptomatic patient-triggered events, these devices have auto-detect features that will capture asymptomatic arrhythmias based on detection algorithms (eg, atrial fibrillation events or bradycardia events). Real-time event monitors have been developed that transmit arrhythmic event data from an ambulatory patient to a continuously attended monitoring station [8,9]. Based on device specific algorithms and pre-specified alert criteria, these devices automatically record and transmit data https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 7/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate for review in real-time. Data can also be recorded through patient-triggered activation. (See 'Mobile cardiac outpatient telemetry (MCOT)' below.) The ECG data from event monitors are received at a base station equipped with a demodulator and an ECG strip chart recorder. Trained staff analyze live incoming patient data and can contact the patient's clinician if instructed to do so according to a prespecified set of alert criteria provided by the clinician. Event monitor report A typical event monitor report includes the following information ( table 2): ECG tracings for each patient-triggered (or auto-triggered) event Technician's interpretation of the tracing Reported symptoms and their duration Patch monitor Patch monitors ( picture 1) are all-in-one small adhesive devices that do not require separate leads, wires, or battery packs ( table 2). This makes them more convenient and less obtrusive than traditional Holter or event monitors. Patch monitors are capable of continuously recording an ECG for up to 14 days, although only a single lead is recorded [10,11]. Patch monitor report A typical patch monitor report includes the following information ( table 2): Average heart rate Maximum and minimum heart rates Number of premature beats (supraventricular and ventricular) Episodes of tachyarrhythmia and the etiology of the arrhythmias (eg, supraventricular or ventricular) Longest R-R interval and any pauses greater than three seconds and etiology of the pauses (eg, sinus pauses versus AV block) ECG tracings for each patient-triggered (or auto-triggered) event Mobile cardiac outpatient telemetry (MCOT) MCOT can be worn for up to 30 days ( table 2). Traditionally, a three-lead sensor transmits ECG telemetry data to a small portable monitor. The monitor transmits the ECG information to a monitoring center via built-in cell phone technology. The device can also be triggered to record symptomatic events by the patient or can be triggered automatically in response to programmed settings. Algorithms for https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 8/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate automatic arrhythmia detection analyze every heart beat and are based on rate, rhythm irregularity, P wave analysis, and QRS morphology. A single lead MCOT patch monitor is also available. As events occur, patient ECG data is automatically transmitted to the monitoring center for analysis. Certified technicians review the data and a daily report and service-summary report is made available for online review (or by fax) [12]. Immediate reports for potentially life- threatening arrhythmias can also be created and physicians are alerted to promptly review these episodes. MCOT has been shown to detect significantly more arrhythmias than standard patient triggered loop recorders and has been shown to be effective in diagnosing AF after cryptogenic stroke [13,14]. Daily reports on burden of arrhythmia (such as AF) are provided and MCOT can be useful to assess for possible nocturnal arrhythmias such as those associated with sleep apnea. Notably, prescribing physicians should be aware that MCOT can be more expensive than standard event monitoring. MCOT report A typical MCOT report includes the following information ( table 2): Daily and service-summary reports on heart rate and rhythm Daily and service-summary reports on classification, duration, and frequency of arrhythmic events ECG tracings for each patient-triggered (or auto-triggered) event Technician's interpretation of the tracing Reported symptoms and their duration Insertable cardiac monitor The insertable cardiac monitor (ICM) is a subcutaneous monitoring device ( picture 2) for the detection of cardiac arrhythmias ( table 2) [15]. ICMs are most commonly utilized in the evaluation of palpitations or syncope of undetermined etiology, particularly when symptoms are infrequent (eg, less than once per month) and/or other ambulatory monitoring has been unrevealing or inconclusive [16]. These devices are typically implanted in the left pectoral region and are MRI conditional. ICMs will store patient- triggered events and will also automatically store events according to programmed detection criteria (eg, a pause greater than four seconds). Depending on the manufacturer and the specific device, the battery longevity of ICMs can range between two to four years [17]. (See "Patient evaluation for metallic or electrical implants, devices, or foreign bodies before magnetic https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 9/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate resonance imaging", section on 'Safety labeling' and "Syncope in adults: Risk assessment and additional diagnostic evaluation", section on 'Ambulatory ECG monitoring'.) The ICM offers the ability to monitor for cardiac arrhythmias for prolonged periods of months to years. In one cohort of 312 patients who underwent ICM implantation at a single center between 2010 and 2015, ICM monitoring for a median of 12 months led to a diagnosis that changed management in 146 patients (47 percent) [18]. In one cohort of 157 patients with at least one episode of unexplained syncope who received an ICM, 70 (45 percent) were followed for greater than 18 months, some as long as four years [19]. Twenty-six percent of all diagnoses made in this cohort occurred more than 18 months following ICM implantation, indicating the utility of continued ICM monitoring in patients without a definitive diagnosis for their unexplained syncope. Among a registry cohort of 19,173 patients who underwent ICM implantation between 2007 and 2016 and were followed for an average of 2.1 years, syncope (54 percent) was the most common indication for ICM implantation; 25 percent of syncope patients ultimately had a diagnosis leading to implantation of a pacemaker or implantable cardioverter- defibrillator (ICD) [20]. Among patients with neurocardiogenic syncope, an ICM may more accurately establish a causative relationship between bradyarrhythmias and syncope than provocative tests (eg, upright tilt table testing or adenosine 5'-triphosphate [ATP] infusion). (See "Reflex syncope in adults and adolescents: Clinical presentation and diagnostic evaluation", section on 'Electrocardiographic monitoring'.) Implantation of the ICM is typically performed as an outpatient procedure using local anesthesia with few associated risks. Among 273 patients enrolled in a nonrandomized trial (151 patients) and an ICM registry (122 patients), device infections were noted in only four patients (1.5 percent), and serious adverse events (defined as procedure-related adverse events leading to death or serious deterioration in health) were noted in only three patients (1.1 percent) with no associated deaths [21]. ICM report A typical ICM report includes the following information ( table 2): Heart rate histograms, heart rate variability, and patient activity data Episode lists including classifications, frequency, and duration of arrhythmic events Single lead ECG tracings for each patient-triggered (or auto-triggered) event https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 10/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate Permanent pacemakers and implantable cardioverter-defibrillators Notably, permanent pacemakers and ICDs can also be used as a continuous monitoring devices, as these systems have built-in algorithms for the recognition of various arrhythmias (such as AF or VT) ( table 2). The devices can be interrogated to obtain data about arrhythmia frequency, duration, and atrial and ventricular rates. In addition, intracardiac ECGs meeting detection criteria can be recorded and stored for review. The data provided by such devices can be limited by the number and type of leads associated with the specific device (eg, a device with a single ventricular lead might not provide information on atrial arrhythmias) (see "Cardiac implantable electronic devices: Patient follow-up"). There are circumstances in which a patient with a PPM or ICD might be prescribed an external monitor to gain more clear and detailed information regarding a potential arrhythmia. For example, evaluation of a patient's single chamber defibrillator might reveal nonsustained ventricular tachycardia episodes that appear irregular. An external monitor can help differentiate if these episodes are atrial fibrillation or true nonsustained ventricular tachycardia events. Commercially available wearable heart rhythm monitors The use of commercially available, wearable heart rate and rhythm monitors is becoming more common ( table 2) [22]. These devices can be useful in the diagnosis of arrhythmia in certain patients. Many of these technologies come in the form of electronic wristbands and smartwatches. Optical sensors integrated into these devices use photoplethysmography to measure pulse rate [23]. Rapid rise in heart rate associated with symptoms can help detect arrhythmias such as supraventricular tachycardia or AF. In addition, some of these devices have automated algorithms to detect pulse irregularity and can notify the user regarding possible arrhythmia, such as AF. Photoplethysmographic algorithms for irregular heart rhythms in a number of smart watches and fitness trackers have been shown to have high positive predictive value for concurrent AF and to identify those who were likely to have AF demonstrated on subsequent traditional ECG monitoring [24-26]. Other commercially available devices use hand-held electrodes to record single or multiple-lead ECGs [23]. The ECGs are displayed and stored directly onto such devices or in another form, and are sent wirelessly to applications on the user's smartphone. Algorithms incorporated into these applications can also provide analysis for possible arrhythmia, including AF. Smartwatches are also now able to record single lead ECG by using electrodes built into the back of the watch and a finger from the opposite hand placed on the digital crown or onto an electrode built into the watch band to complete the circuit. Such devices can be useful in long term monitoring for arrhythmia recurrences, particularly in symptomatic patients with atrial fibrillation who have undergone rhythm control therapy (such as ablation). In addition to identifying cardiac rate and https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 11/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate rhythm, smartwatches have the potential to allow for QT interval measurement. In one study of 100 patients in which a single-lead ECG was recorded using a smartwatch in three different locations (left wrist, left ankle, left lateral chest wall), 94 percent of patients were able to obtain an accurate QT interval which correlated to the QT interval measured on 12-lead ECG [27]. As technology advances and arrhythmia detection algorithms further improve, the increased use of commercially available, wearable heart rhythm monitors is likely to prove valuable in the diagnosis and management of certain patients with arrhythmia. Data on how to best integrate such devices into optimal management of arrhythmia detection will be derived from ongoing clinical trials [28]. DIAGNOSTIC EFFICACY The ECG rhythm recorded using any ambulatory ECG monitoring modality must be correlated with the simultaneous occurrence of suggestive symptoms. Without this correlation in many cases, the detected rhythm abnormality is less likely to be clinically important. Bradycardia and sinus pauses are particularly common at night while the patient is asleep, as a result of enhanced vagal tone. Thus, the occurrence of such arrhythmias does not necessarily establish a causal mechanism for a transient disturbance in consciousness or for other symptoms. Among patients evaluated with 24-hour ambulatory monitoring, approximately 25 to 50 percent of patients will experience a symptom, between 2 and 15 percent will have an associated causal arrhythmia, and 35 percent will report symptoms without associated arrhythmias [29]. Extending the period of monitoring can increase the incidence of symptomatic events to approximately 50 percent at three days and 75 percent at 5 to 21 days (mean nine days) [30,31]. The diagnostic value of ambulatory monitoring seems to depend upon a number of variables: Hospitalized patients with symptoms are more likely to have a causal arrhythmia. In one study, which included 306 hospitalized patients and 278 outpatients, symptoms occurred far more frequently in the outpatients (55 versus 6 percent); however, symptomatic inpatients were significantly more likely to have symptoms that correlated with causal arrhythmias (95 versus 44 percent) [32]. The presenting symptom also may predict the findings of ambulatory ECG. In one report of 1010 hospitalized patients, those with syncope had a consistently higher rate of diary maintenance, of reporting symptoms during ambulatory ECG, and of a conclusive examination [33]. https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 12/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate When an insertable cardiac monitor (ICM) is implanted in patients with syncope of uncertain cause, transient bradycardia is frequently found to be responsible [34-38]. In the largest study of ICM use in the evaluation of patients with syncope of uncertain cause (The Place of Reveal In the Care pathway and Treatment of patients with Unexplained Recurrent Syncope, PICTURE registry) an ICM was implanted in 570 patients [39]. Patients were followed for at least one year or until their next syncopal episode (mean of 10 +/- 6 months). Recurrent syncope was noted in 218 patients (38 percent). Data acquired by the ICM during the syncopal event directly contributed to a diagnosis in 78 percent of patients. A cardiac etiology was found in 75 percent; however, a breakdown of specific cardiac arrhythmias noted on the ICM was not reported. (See "Syncope in adults: Risk assessment and additional diagnostic evaluation", section on 'Ambulatory ECG monitoring'.) Ambulatory ECG monitoring yields other potentially useful information regarding arrhythmias, including: Quantifying the number of ectopic morphologies (if multiple) and allowing qualitatively visual analysis of the different morphologies. Providing information regarding the onset and resolution of tachyarrhythmias and bradyarrhythmias. Providing information on a variety of arrhythmia characteristics such as coupling interval, rate dependence, and changes in QT interval. Ambulatory monitoring, typically with 24 to 48 hours of continuous ambulatory ECG, is useful for the evaluation of rate control of atrial fibrillation (AF) during daily activities or with exercise in patients who have permanent AF. Ambulatory monitoring may be used to assess AF burden (frequency or episodes and duration of episodes) in patients with paroxysmal or intermittent AF. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Evaluation and goal ventricular rate'.) FOLLOW-UP AFTER AMBULATORY ECG MONITORING After the diagnostic monitoring period, the following scenarios of patient symptoms and ECG findings might be encountered: The patient had symptoms with corresponding ECG abnormalities (ie, arrhythmia or conduction abnormality) Such patients should be treated appropriately and, in most https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 13/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate instances, do not require additional ambulatory ECG monitoring for diagnostic purposes (although additional monitoring to assess the efficacy of therapy might be indicated). The patient had symptoms without corresponding ECG abnormalities (ie, arrhythmia or conduction abnormality) In such instances, assuming that the monitor was functioning properly and the available ECG data are interpretable, the diagnosis is likely non-cardiac and there is generally no need for additional ambulatory ECG monitoring. The patient had no symptoms and no ECG abnormalities during the monitoring period The decision to pursue additional testing following a period of ambulatory ECG monitoring depends on the potential severity of the clinical conditions. As examples: A patient who experiences only infrequent and mild palpitations who had an unremarkable four-week event monitor can usually be managed conservatively. Conversely, a patient with more severe symptoms might require more prolonged ambulatory ECG monitoring to make a diagnosis (such as with an insertable cardiac monitor [ICM]). For a patient with history of cryptogenic stroke who had an unremarkable four-week event monitor for whom a diagnosis of atrial fibrillation would prompt the need for stroke prevention therapy (ie, initiation of oral anticoagulation), prolonged ambulatory ECG monitoring should be instituted (such as with an ICM). A patient who has suffered syncope (particularly abrupt syncope without warning symptoms that resulted in injury) but who did not have recurrent symptoms or ECG abnormalities during the initial monitoring should usually proceed with prolonged ambulatory ECG monitoring (such as with an ICM). SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Atrial fibrillation" and "Society guideline links: Supraventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS Background In contrast to the standard electrocardiogram (ECG), which provides a brief sample of cardiac electrical activity over 10 seconds, ambulatory ECG monitoring provides a https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 14/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate view of ECG data over an extended period of time, thereby permitting evaluation of dynamic and transient cardiac electrical phenomena. (See 'Introduction' above.) Indications Ambulatory ECG monitoring is the most widely employed technology to evaluate a patient with symptoms suggestive of a cardiac arrhythmia or a conduction abnormality (ie, unexplained syncope/near syncope or unexplained palpitations), but it is also used for a variety of other diagnostic and prognostic indications. (See 'Indications' above.) Types of monitors Ambulatory ECG monitoring is available in many forms ( table 2), including continuous (Holter) monitoring for 24 to 48 hours ( figure 1), event (loop) monitoring for several weeks, or insertable cardiac monitoring ( picture 2) for months to years. (See 'Types of ambulatory ECG monitoring' above.) The approach to choosing an ambulatory ECG monitoring strategy depends on the indication for the test along with the frequency and duration of symptoms ( table 1). If an ambulatory ECG monitor is being used for diagnostic purposes (ie, unexplained syncope or unexplained palpitations), extended duration monitoring might be required to increase the diagnostic yield. (See 'Diagnostic efficacy' above and 'Our approach to choosing an ambulatory ECG monitoring strategy' above.) Importance of symptom correlation The ECG rhythm recorded using any ambulatory ECG monitoring modality should be correlated with the simultaneous occurrence of suggestive symptoms. (See 'Diagnostic efficacy' above.) ACKNOWLEDGMENT The editorial staff at UpToDate acknowledge Philip Podrid, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Boudoulas H, Schaal SF, Lewis RP, Robinson JL. Superiority of 24-hour outpatient monitoring over multi-stage exercise testing for the evaluation of syncope. J Electrocardiol 1979; 12:103. 2. Poblete PF, Kennedy HL, Caralis DG. Detection of ventricular ectopy in patients with coronary heart disease and normal subjects by exercise testing and ambulatory electrocardiography. Chest 1978; 74:402. https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 15/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate 3. Steinberg JS, Varma N, Cygankiewicz I, et al. 2017 ISHNE-HRS expert consensus statement on ambulatory ECG and external cardiac monitoring/telemetry. Heart Rhythm 2017; 14:e55. 4. Crawford MH, Bernstein SJ, Deedwania PC, et al. ACC/AHA guidelines for ambulatory electrocardiography: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee to revise the guidelines for ambulatory electrocardiography). Circulation 1999; 100:886. 5. Afzal MR, Gunda S, Waheed S, et al. Role of Outpatient Cardiac Rhythm Monitoring in Cryptogenic Stroke: A Systematic Review and Meta-Analysis. Pacing Clin Electrophysiol 2015; 38:1236. 6. Barry J, Campbell S, Nabel EG, et al. Ambulatory monitoring of the digitized electrocardiogram for detection and early warning of transient myocardial ischemia in angina pectoris. Am J Cardiol 1987; 60:483. 7. Zimetbaum PJ, Josephson ME. The evolving role of ambulatory arrhythmia monitoring in general clinical practice. Ann Intern Med 1999; 130:848. 8. Joshi AK, Kowey PR, Prystowsky EN, et al. First experience with a Mobile Cardiac Outpatient Telemetry (MCOT) system for the diagnosis and management of cardiac arrhythmia. Am J Cardiol 2005; 95:878. 9. Olson JA, Fouts AM, Padanilam BJ, Prystowsky EN. Utility of mobile cardiac outpatient telemetry for the diagnosis of palpitations, presyncope, syncope, and the assessment of therapy efficacy. J Cardiovasc Electrophysiol 2007; 18:473. 10. Turakhia MP, Hoang DD, Zimetbaum P, et al. Diagnostic utility of a novel leadless arrhythmia monitoring device. Am J Cardiol 2013; 112:520. 11. Barrett PM, Komatireddy R, Haaser S, et al. Comparison of 24-hour Holter monitoring with 14-day novel adhesive patch electrocardiographic monitoring. Am J Med 2014; 127:95.e11. 12. Derkac WM, Finkelmeier JR, Horgan DJ, Hutchinson MD. Diagnostic yield of asymptomatic

Providing information regarding the onset and resolution of tachyarrhythmias and bradyarrhythmias. Providing information on a variety of arrhythmia characteristics such as coupling interval, rate dependence, and changes in QT interval. Ambulatory monitoring, typically with 24 to 48 hours of continuous ambulatory ECG, is useful for the evaluation of rate control of atrial fibrillation (AF) during daily activities or with exercise in patients who have permanent AF. Ambulatory monitoring may be used to assess AF burden (frequency or episodes and duration of episodes) in patients with paroxysmal or intermittent AF. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Evaluation and goal ventricular rate'.) FOLLOW-UP AFTER AMBULATORY ECG MONITORING After the diagnostic monitoring period, the following scenarios of patient symptoms and ECG findings might be encountered: The patient had symptoms with corresponding ECG abnormalities (ie, arrhythmia or conduction abnormality) Such patients should be treated appropriately and, in most https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 13/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate instances, do not require additional ambulatory ECG monitoring for diagnostic purposes (although additional monitoring to assess the efficacy of therapy might be indicated). The patient had symptoms without corresponding ECG abnormalities (ie, arrhythmia or conduction abnormality) In such instances, assuming that the monitor was functioning properly and the available ECG data are interpretable, the diagnosis is likely non-cardiac and there is generally no need for additional ambulatory ECG monitoring. The patient had no symptoms and no ECG abnormalities during the monitoring period The decision to pursue additional testing following a period of ambulatory ECG monitoring depends on the potential severity of the clinical conditions. As examples: A patient who experiences only infrequent and mild palpitations who had an unremarkable four-week event monitor can usually be managed conservatively. Conversely, a patient with more severe symptoms might require more prolonged ambulatory ECG monitoring to make a diagnosis (such as with an insertable cardiac monitor [ICM]). For a patient with history of cryptogenic stroke who had an unremarkable four-week event monitor for whom a diagnosis of atrial fibrillation would prompt the need for stroke prevention therapy (ie, initiation of oral anticoagulation), prolonged ambulatory ECG monitoring should be instituted (such as with an ICM). A patient who has suffered syncope (particularly abrupt syncope without warning symptoms that resulted in injury) but who did not have recurrent symptoms or ECG abnormalities during the initial monitoring should usually proceed with prolonged ambulatory ECG monitoring (such as with an ICM). SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Atrial fibrillation" and "Society guideline links: Supraventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS Background In contrast to the standard electrocardiogram (ECG), which provides a brief sample of cardiac electrical activity over 10 seconds, ambulatory ECG monitoring provides a https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 14/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate view of ECG data over an extended period of time, thereby permitting evaluation of dynamic and transient cardiac electrical phenomena. (See 'Introduction' above.) Indications Ambulatory ECG monitoring is the most widely employed technology to evaluate a patient with symptoms suggestive of a cardiac arrhythmia or a conduction abnormality (ie, unexplained syncope/near syncope or unexplained palpitations), but it is also used for a variety of other diagnostic and prognostic indications. (See 'Indications' above.) Types of monitors Ambulatory ECG monitoring is available in many forms ( table 2), including continuous (Holter) monitoring for 24 to 48 hours ( figure 1), event (loop) monitoring for several weeks, or insertable cardiac monitoring ( picture 2) for months to years. (See 'Types of ambulatory ECG monitoring' above.) The approach to choosing an ambulatory ECG monitoring strategy depends on the indication for the test along with the frequency and duration of symptoms ( table 1). If an ambulatory ECG monitor is being used for diagnostic purposes (ie, unexplained syncope or unexplained palpitations), extended duration monitoring might be required to increase the diagnostic yield. (See 'Diagnostic efficacy' above and 'Our approach to choosing an ambulatory ECG monitoring strategy' above.) Importance of symptom correlation The ECG rhythm recorded using any ambulatory ECG monitoring modality should be correlated with the simultaneous occurrence of suggestive symptoms. (See 'Diagnostic efficacy' above.) ACKNOWLEDGMENT The editorial staff at UpToDate acknowledge Philip Podrid, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Boudoulas H, Schaal SF, Lewis RP, Robinson JL. Superiority of 24-hour outpatient monitoring over multi-stage exercise testing for the evaluation of syncope. J Electrocardiol 1979; 12:103. 2. Poblete PF, Kennedy HL, Caralis DG. Detection of ventricular ectopy in patients with coronary heart disease and normal subjects by exercise testing and ambulatory electrocardiography. Chest 1978; 74:402. https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 15/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate 3. Steinberg JS, Varma N, Cygankiewicz I, et al. 2017 ISHNE-HRS expert consensus statement on ambulatory ECG and external cardiac monitoring/telemetry. Heart Rhythm 2017; 14:e55. 4. Crawford MH, Bernstein SJ, Deedwania PC, et al. ACC/AHA guidelines for ambulatory electrocardiography: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee to revise the guidelines for ambulatory electrocardiography). Circulation 1999; 100:886. 5. Afzal MR, Gunda S, Waheed S, et al. Role of Outpatient Cardiac Rhythm Monitoring in Cryptogenic Stroke: A Systematic Review and Meta-Analysis. Pacing Clin Electrophysiol 2015; 38:1236. 6. Barry J, Campbell S, Nabel EG, et al. Ambulatory monitoring of the digitized electrocardiogram for detection and early warning of transient myocardial ischemia in angina pectoris. Am J Cardiol 1987; 60:483. 7. Zimetbaum PJ, Josephson ME. The evolving role of ambulatory arrhythmia monitoring in general clinical practice. Ann Intern Med 1999; 130:848. 8. Joshi AK, Kowey PR, Prystowsky EN, et al. First experience with a Mobile Cardiac Outpatient Telemetry (MCOT) system for the diagnosis and management of cardiac arrhythmia. Am J Cardiol 2005; 95:878. 9. Olson JA, Fouts AM, Padanilam BJ, Prystowsky EN. Utility of mobile cardiac outpatient telemetry for the diagnosis of palpitations, presyncope, syncope, and the assessment of therapy efficacy. J Cardiovasc Electrophysiol 2007; 18:473. 10. Turakhia MP, Hoang DD, Zimetbaum P, et al. Diagnostic utility of a novel leadless arrhythmia monitoring device. Am J Cardiol 2013; 112:520. 11. Barrett PM, Komatireddy R, Haaser S, et al. Comparison of 24-hour Holter monitoring with 14-day novel adhesive patch electrocardiographic monitoring. Am J Med 2014; 127:95.e11. 12. Derkac WM, Finkelmeier JR, Horgan DJ, Hutchinson MD. Diagnostic yield of asymptomatic arrhythmias detected by mobile cardiac outpatient telemetry and autotrigger looping event cardiac monitors. J Cardiovasc Electrophysiol 2017; 28:1475. 13. Rothman SA, Laughlin JC, Seltzer J, et al. The diagnosis of cardiac arrhythmias: a prospective multi-center randomized study comparing mobile cardiac outpatient telemetry versus standard loop event monitoring. J Cardiovasc Electrophysiol 2007; 18:241. 14. Miller DJ, Khan MA, Schultz LR, et al. Outpatient cardiac telemetry detects a high rate of atrial fibrillation in cryptogenic stroke. J Neurol Sci 2013; 324:57. https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 16/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate 15. Krahn AD, Klein GJ, Skanes AC, Yee R. Insertable loop recorder use for detection of intermittent arrhythmias. Pacing Clin Electrophysiol 2004; 27:657. 16. Giada F, Gulizia M, Francese M, et al. Recurrent unexplained palpitations (RUP) study comparison of implantable loop recorder versus conventional diagnostic strategy. J Am Coll Cardiol 2007; 49:1951. 17. P rerfellner H, Sanders P, Pokushalov E, et al. Miniaturized Reveal LINQ insertable cardiac monitoring system: First-in-human experience. Heart Rhythm 2015; 12:1113. 18. Padmanabhan D, Kancharla K, El-Harasis MA, et al. Diagnostic and therapeutic value of implantable loop recorder: A tertiary care center experience. Pacing Clin Electrophysiol 2019; 42:38. 19. Furukawa T, Maggi R, Bertolone C, et al. Additional diagnostic value of very prolonged observation by implantable loop recorder in patients with unexplained syncope. J Cardiovasc Electrophysiol 2012; 23:67. 20. Mittal S, Rogers J, Sarkar S, et al. Real-World Incidence of Pacemaker and Defibrillator Implantation Following Diagnostic Monitoring With an Insertable Cardiac Monitor. Am J Cardiol 2019; 123:1967. 21. Mittal S, Sanders P, Pokushalov E, et al. Safety Profile of a Miniaturized Insertable Cardiac Monitor: Results from Two Prospective Trials. Pacing Clin Electrophysiol 2015; 38:1464. 22. Ip JE. Wearable Devices for Cardiac Rhythm Diagnosis and Management. JAMA 2019; 321:337. 23. Zungsontiporn N, Link MS. Newer technologies for detection of atrial fibrillation. BMJ 2018; 363:k3946. 24. Perez MV, Mahaffey KW, Hedlin H, et al. Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation. N Engl J Med 2019; 381:1909. 25. Guo Y, Wang H, Zhang H, et al. Mobile Photoplethysmographic Technology to Detect Atrial Fibrillation. J Am Coll Cardiol 2019; 74:2365. 26. Lubitz SA, Faranesh AZ, Selvaggi C, et al. Detection of Atrial Fibrillation in a Large Population Using Wearable Devices: The Fitbit Heart Study. Circulation 2022; 146:1415. 27. Strik M, Caillol T, Ramirez FD, et al. Validating QT-Interval Measurement Using the Apple Watch ECG to Enable Remote Monitoring During the COVID-19 Pandemic. Circulation 2020; 142:416. 28. Steinberg JS, Varma N, Cygankiewicz I, et al. 2017 ISHNE-HRS expert consensus statement on ambulatory ECG and external cardiac monitoring/telemetry. Ann Noninvasive Electrocardiol 2017; 22. https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 17/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate 29. Zeldis SM, Levine BJ, Michelson EL, Morganroth J. Cardiovascular complaints. Correlation with cardiac arrhythmias on 24-hour electrocardiographic monitoring. Chest 1980; 78:456. 30. Gibson TC, Heitzman MR. Diagnostic efficacy of 24-hour electrocardiographic monitoring for syncope. Am J Cardiol 1984; 53:1013. 31. Bass EB, Curtiss EI, Arena VC, et al. The duration of Holter monitoring in patients with syncope. Is 24 hours enough? Arch Intern Med 1990; 150:1073. 32. Surawicz, B, Pinto, RP . Symptoms in hospital patients and outpatients with ventricular arrhythmias during ambulatory ECG monitoring. J Ambul Monit 1991; 4:83. 33. Nwasokwa, ON, Wenger, NK . Diagnostic value of ambulatory electrocardiography: Dependence on presenting symptom, age and sex. Am J Noninvasive Cardiol 1988; 2:140. 34. Krahn AD, Klein GJ, Fitzpatrick A, et al. Predicting the outcome of patients with unexplained syncope undergoing prolonged monitoring. Pacing Clin Electrophysiol 2002; 25:37. 35. Krahn AD, Klein GJ, Yee R, Skanes AC. Randomized assessment of syncope trial: conventional diagnostic testing versus a prolonged monitoring strategy. Circulation 2001; 104:46. 36. Krahn AD, Klein GJ, Yee R, et al. Use of an extended monitoring strategy in patients with problematic syncope. Reveal Investigators. Circulation 1999; 99:406. 37. Farwell DJ, Freemantle N, Sulke AN. Use of implantable loop recorders in the diagnosis and management of syncope. Eur Heart J 2004; 25:1257. 38. Brignole M, Sutton R, Menozzi C, et al. Early application of an implantable loop recorder allows effective specific therapy in patients with recurrent suspected neurally mediated syncope. Eur Heart J 2006; 27:1085. 39. Edvardsson N, Frykman V, van Mechelen R, et al. Use of an implantable loop recorder to increase the diagnostic yield in unexplained syncope: results from the PICTURE registry. Europace 2011; 13:262. Topic 958 Version 40.0 https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 18/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate GRAPHICS Table ambulatory electrocardiographic monitoring clinical scenarios Ambulatory ECG monitor type Indications/patient selection Continuous ECG monitor (ie, Holter monitor) Daily or near daily symptoms (palpitations) Assessment for adequate rate control in atrial fibrillation Assessment of VPB or APB burden, NSVT in hypertrophic cardiomyopathy Heart rate assessment for inappropriate sinus tachycadia, postural orthostatic tachycardia syndrome, suspected chronotropic incompetence Event (loop) monitor Less frequent symptoms (weekly or biweekly) Assessment for arrhythmic source of palpitations Assessment for arrhythmic source of dizziness or pre- syncope/syncope Assessment for atrial fibrillation (though asymptomatic episodes could be missed unless an auto-triggered event monitor is used) Patch monitor Daily, near daily, or weekly frequency of symptoms Assess arrhythmia burden (eg, atrial fibrillation, VPBs) Assess for NSVT in hypertrophic cardiomyopathy Assessment for atrial fibrillation as a source of cryptogenic stroke (diagnosis limited by length of time the monitor is worn) Mobile cardiac outpatient telemetry (MCOT) Assess arrhythmia burden (eg, atrial fibrillation, VPBs) Assessment for arrhythmic source of palpitations Assessment for arrhythmic source of dizziness or pre- syncope/syncope Assessment for atrial fibrillation as a source of cryptogenic stroke (diagnosis limited by length of time the monitor is worn) Implantable loop recorder Infrequent (less than monthly) symptoms associated with syncope or other high risk features Assessment for atrial fibrillation as a source of cryptogenic stroke Assessment for recurrence of atrial fibrillation (eg, post- ablation) https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 19/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate Commercially available heart rate monitor (eg, wristbands, smartwatches) No approved indications Commercially available heart rhythm monitors (eg, smartwatches, hand held devices, smartphone based electrode cards, etc) No approved indications Can be considered for monitoring for arrhythmic source or palpitations Can be considered for monitoring for symptomatic atrial fibrillation recurrence Clinical monitoring scenarios Available monitoring options Symptoms (palpitations) daily or near daily Continuous ECG monitor (Holter) Patch monitor Symptoms (palpitations) weekly or biweekly Event (loop) monitor Patch monitor MCOT Symptoms infrequently (monthly or less) associated with syncope or high Implantable loop recorder risk features Assessment for occult atrial fibrillation* Event (loop) monitor, ideally an auto-triggered event monitor Patch monitor MCOT Implantable loop recorder Assessment for arrhythmia burden (eg, VPB burden) or average heart rate (eg, AF, inappropriate sinus tachycardia, etc) Continuous ECG monitor (Holter) Patch monitor MCOT ECG: electrocardiogram; VPB: ventricular premature beats; APB: atrial premature beats; NSVT: nonsustained ventricular tachycardia; AF: atrial fibrillation. Notably, the longer the monitoring duration, the higher the diagnostic yield. Adapted from: 1. Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2017; 70:e39. 2. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018. Graphic 120898 Version 3.0 https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 20/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate Table ambulatory electrocardiographic monitoring capabilities Ambulatory ECG Monitor capabilities monitor type Continuous ECG monitor (ie, Record all ECG data for 24 to 48 hours Holter monitor) Off-line analysis and review following completion of recording Typically 3 ECG leads but 12-lead options available Patient diary to record symptoms, with time correlation to ECG rhythm Event (loop) monitor Records one or two lead ECG data around time of arrhythmias May be triggered automatically in response to program settings or by patient following symptoms May be worn continuously or applied during symptoms May be worn for up to 30 days ECG data for triggered events can be sent wirelessly for real-time analysis to central monitoring station that can alert physicians and be made available for on-line review Patch monitor Records single-lead ECG data continuously (3, 7, 14, or 30 days) May be triggered automatically in response to program settings or by patient following symptoms Traditional off-line analysis at central monitoring station following completion of recording that is then available for on-line review by physicians Some models have capability to wirelessly transmit ECG data for triggered events for real-time analysis to central monitoring station that can alert physicians and be made available for on-line review Mobile cardiac outpatient telemetry (MCOT) Traditionally 3 leads but now also available in patch form (single lead) Can be worn for up to 30 days with continuous recording May be triggered automatically in response to program settings or by patient following symptoms Daily report is transmitted wirelessly to central monitoring station and is made available on-line for physician review ECG data for triggered events can be sent wirelessly for real-time analysis to central monitoring station that can alert physicians and be made available for on-line for review Implantable loop recorder Subcutaneously implanted, available for monitoring up to several years Triggered automatically or by patient/witness for symptomatic events https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 21/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate Commercially available heart Photoplethysmography technology records heart rate rate monitor (eg, wristbands, smartwatches) Data can be stored on smartphones, tablets/lap tops, or directly on devices Some devices have algorithms to detect rhythm/rate irregularities and alert for possible atrial fibrillation Commercially available heart rhythm monitors (eg, Single-lead ECG data that is recorded by patient during symptoms Some devices have algorithms to detect heart rhythm irregularities such as atrial fibrillation smartwatches, hand held devices, smartphone based electrode cards, etc) Rhythm strips can be stored on smart phones or directly on hand held devices and shared with physicians for review ECG: electrocardiogram Adapted from: 1. Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2017; 70:e39. 2. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018. Graphic 120899 Version 3.0 https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 22/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate Ambulatory (Holter) electrocardiography (ECG) monitor The ambulatory (Holter) monitor is a lightweight continuous electrocardiographic (ECG) monitoring system that uses three surface electrodes to continuously record all cardiac electrical activity, typically for 24 to 48 hours. Once the monitoring period is over, the patient returns the device, and all of the acquired data are analyzed (usually by a trained technician) and a summary report is generated for clinician review. Graphic 105244 Version 1.0 https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 23/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate Torso with Zio Reproduced with permission from: iRhythm Technologies, Inc. Copyright 2019. Available at: https://www.irhythmtech.com/products-services/zio-xt (Accessed on May 10, 2019). Graphic 121242 Version 1.0 https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 24/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate Insertable cardiac monitors (ICMs) for long- term electrocardiographic (ECG) monitoring Photograph showing two examples of insertable cardiac monitors used for long-term electrocardiographic (ECG) monitoring. The device is typically inserted under local anesthesia in the left anterior chest. Though not pictured, a third device from a different manufacturer (Biotronik) is available for clinical use. Graphic 104724 Version 4.0 https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 25/26 7/6/23, 10:40 AM Ambulatory ECG monitoring - UpToDate Contributor Disclosures Christopher Madias, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/ambulatory-ecg-monitoring/print 26/26

7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cardiac evaluation of the survivor of sudden cardiac arrest : Philip J Podrid, MD, FACC : Brian Olshansky, MD, Scott Manaker, MD, PhD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Aug 26, 2020. INTRODUCTION Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) refer to the sudden cessation of cardiac activity with hemodynamic collapse, typically due to sustained ventricular tachycardia/ventricular fibrillation. These events mostly occur in patients with structural heart disease (that may not have been previously diagnosed), particularly coronary heart disease. (See "Pathophysiology and etiology of sudden cardiac arrest".) The event is referred to as SCA (or aborted SCD) if an intervention (eg, defibrillation) or spontaneous reversion restores circulation. The event is called SCD if the patient dies. However, the use of SCD to describe both fatal and nonfatal cardiac arrest persists by convention. (See "Overview of sudden cardiac arrest and sudden cardiac death", section on 'Definitions'.) Evaluation of the survivor of SCD includes the following: Identification and treatment of acute reversible causes Evaluation for structural heart disease In patients without obvious arrhythmic triggers or cardiac structural abnormalities, an evaluation for primary electrical diseases Neurologic and psychologic assessment In selected patients with a suspected or confirmed heritable syndrome, evaluation of family members https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 1/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate The evaluation of the survivor of SCD will be reviewed here. The pathophysiology of SCD and the management of survivors of SCD are discussed separately. (See "Overview of sudden cardiac arrest and sudden cardiac death" and "Pathophysiology and etiology of sudden cardiac arrest" and "Approach to sudden cardiac arrest in the absence of apparent structural heart disease" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) ETIOLOGY OF SCD Accurate and precise measures of the relative frequencies of various causes of SCD are difficult to obtain. Case definitions are inconsistent and etiologies vary according to the population studied. Common causes of SCD include coronary heart disease, structural heart disease not related to CHD (eg, hypertrophic cardiomyopathy, nonischemic cardiomyopathy, etc), arrhythmias caused by primarily electrical disease (eg, Brugada syndrome, long QT syndrome, etc), and transient or reversible causes (eg, medication toxicity, electrolyte abnormalities, etc). A detailed review of the causes of SCD is presented separately. (See "Pathophysiology and etiology of sudden cardiac arrest", section on 'Etiology of SCD'.) INITIAL EVALUATION The evaluation begins immediately after resuscitation. The first concern is to exclude any obvious reversible factors that may have led to the event ( table 1). History and physical examination The patient (if awake) and family should be questioned, with particular attention to the following: Prior diagnoses of heart disease Use of any medications, especially antiarrhythmic drugs, diuretics, and drugs that might produce long QT syndrome Ingestion of toxins or illicit drugs Antecedent symptoms, especially evidence of ischemia Antecedent stressful events or activities Unfortunately, the cardiac arrest is frequently unwitnessed. In addition, the patient resuscitated from VF often has retrograde amnesia and is unable to remember what occurred prior to the cardiac arrest. Thus, a coherent history may not be ascertainable. Obtaining a history from an observer, when available, is important. https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 2/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate Laboratory testing Immediate evaluation should include standard laboratory testing and, in many cases, an arterial blood gas to exclude electrolyte abnormalities and acidosis. Any reversible metabolic abnormalities should be identified and corrected, particularly hypokalemia and hypomagnesemia which can predispose to ventricular tachyarrhythmias [1,2]. Toxicologic screening for drugs of abuse should be considered when relevant as drug overdose has been documented in significant numbers of patients with apparent sudden cardiac death [3]. When interpreting the test results, two important limitations should be considered: Electrolyte abnormalities during and shortly after resuscitation may be secondary to cardiac arrest and hypoperfusion as opposed to a cause of SCD [4]. Electrolyte abnormalities by themselves are usually insufficient to cause SCD. Clinical settings that increase the proarrhythmic effect of hypokalemia and hypomagnesemia include acute myocardial infarction [5], overt heart failure, and long QT syndrome. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Metabolic abnormalities'.) It is potentially hazardous to ascribe a cardiac arrest to an electrolyte or metabolic derangement alone, unless there is compelling evidence of an association. Mistaken attribution of a major arrhythmia to an innocent or merely potentiating laboratory abnormality can place the patient at high risk if appropriate therapy to prevent recurrent SCD is delayed or not given. Importantly, electrolyte and pH abnormalities may be secondary to the arrhythmia itself. This risk was illustrated in a review of 169 patients treated with an ICD for sustained ventricular arrhythmia in whom the plasma potassium concentration was measured on the day of the arrhythmia [6]. The likelihood of a recurrent sustained ventricular arrhythmia was 82 percent at five years. The long-term risk was similar in patients with low, normal, and high plasma potassium concentrations at presentation. Electrocardiogram The ECG can reveal evidence of both acute abnormalities and chronic conditions. It should be part of the immediate evaluation and repeated as necessary once the patient's cardiac, hemodynamic, and metabolic condition stabilizes. The ECG should be evaluated for evidence of the following: Ongoing ischemia or prior myocardial infarction. (See 'Coronary angiography' below and "Electrocardiogram in the diagnosis of myocardial ischemia and infarction".) Conduction system disease, including bundle branch block, second degree heart block, and third degree heart block. (See "Left bundle branch block" and "Right bundle branch block" https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 3/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate and "Second-degree atrioventricular block: Mobitz type II" and "Third-degree (complete) atrioventricular block".) Less common abnormalities that also may be evident include: Brugada syndrome, evidenced by a pseudo-RBBB and J point elevation with a downsloping ST segment to a negative T wave in lead V1 and often lead V2. In contrast, with an ST segment myocardial infarction the J point is elevated and the ST segment remains elevated as well ( waveform 1). (See "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) Wolff-Parkinson-White syndrome, evidenced by a short PR interval and a slurred QRS complex upstroke known as a delta wave (as a result the QRS complex has a broad base and narrow peak) ( waveform 2). (See "Wolff-Parkinson-White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis", section on 'Electrocardiographic findings'.) Arrhythmogenic right ventricular cardiomyopathy (ARVC), suggested by VT or ventricular ectopy with a left bundle branch block configuration and an inferior axis. In addition, abnormalities of the baseline QRS may be present, including an epsilon wave in the right precordial leads (ie, leads V1-V2) ( waveform 3A-B). Long QT syndrome ( waveform 4), possibly with torsades de pointes ( waveform 5). (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Hypertrophic cardiomyopathy. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation".) EVALUATION FOR STRUCTURAL HEART DISEASE Excluding patients with an obvious noncardiac etiology (eg, trauma, hemorrhage, or pulmonary embolus), structural heart disease is present in up to 90 percent of patients with SCD ( table 2) [7-13]. (See "Pathophysiology and etiology of sudden cardiac arrest".) It is essential that all survivors of SCD undergo a complete cardiac examination to determine the nature and extent of underlying heart disease. The initial history, physical examination, and laboratory tests may provide evidence of one of these disorders, but further testing is usually necessary to confirm a diagnosis. https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 4/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate The standard evaluation typically includes: ECG (see 'Electrocardiogram' above) Cardiac catheterization with coronary angiography Echocardiography In the appropriate clinical setting, coronary angiography and echocardiography may be part of the urgent initial evaluation. In selected patients, cardiac magnetic resonance imaging (MRI) and, rarely, myocardial biopsy are performed. (See 'Cardiac MR' below.) Coronary angiography Coronary angiography is performed in most survivors of SCD for one of two indications: management of an acute coronary syndrome or diagnosis of chronic CHD. Acute coronary syndrome Patients with evidence of STEMI following resuscitation from SCD should undergo urgent cardiac catheterization and, when indicated by the anatomy, revascularization with primary PCI or surgical revascularization [14]. Similarly, patients with a confirmed NSTEMI and those with a high suspicion of ongoing myocardial ischemia should also undergo cardiac catheterization with revascularization as indicated. (See "Primary percutaneous coronary intervention in acute ST elevation myocardial infarction: Determinants of outcome" and "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization".) SCD may be the presenting manifestation of an acute coronary syndrome (ACS). Among patients with an ACS, malignant arrhythmias are significantly more common in the setting of an acute ST elevation MI (STEMI), but are also seen in approximately 2 percent of patients with a non-ST elevation MI (NSTEMI). In patients with an ACS and ischemia, the arrhythmia is usually polymorphic VT, rapid VT (ventricular flutter), or VF. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features".) Patients who experience SCD during the first 48 hours after an STEMI have a higher in-hospital mortality compared with STEMI patients who do not experience sustained VT or VF. However, among patients who survive to hospital discharge there is little or no difference in mortality at one to two years. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features".) Diagnostic angiography In SCD survivors without an ACS, angiography is still considered to exclude stable, chronic CHD, which, as indicated above, is the leading cause for SCD [15]. Malignant arrhythmias and SCD occur in such patients, usually those who have had a prior infarction with residual myocardial scar. In contrast to patients with an ACS, the culprit arrhythmia is usually scar-related monomorphic VT, which is not the result of ischemia. However, https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 5/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate monomorphic VT can ultimately degenerate to VF, particularly if the arrhythmia induces ischemia. Because SCD may be the first clinical evidence of chronic CHD, most SCD survivors undergo diagnostic angiography prior to discharge. Even for patients arriving at the hospital in refractory VT/VF who are receiving ongoing cardiopulmonary resuscitation (CPR), immediate coronary angiography appears beneficial in a carefully selected group of patients (18 to 75 years of age with VT/VF as initial rhythm who received three shocks and amiodarone loading dose and who can be in the catheterization lab in <30 minutes post-arrest) [16]. Among a cohort of 55 patients who met these criteria (after excluding 7 of 62 who were declared deceased on arrival to the catheterization lab), all of whom were started on extracorporeal life support and underwent immediate coronary angiography, 46 patients (84 percent) had significant obstructive CHD, including 35 patients (64 percent) with acute thrombus, all of whom underwent percutaneous coronary intervention [16]. Among the cohort, 26 patients (42 percent) were discharged alive with favorable neurologic function, compared with 15 percent of historical controls. Diagnostic coronary angiography may not be necessary in selected patients without signs or symptoms of CHD if another clear cause for SCD is identified (eg, long QT syndrome, WPW, Brugada, hypertrophic cardiomyopathy, left ventricular noncompaction, or arrhythmogenic right ventricular cardiomyopathy). Angiography is suggested in younger patients without an apparent cause for SCD in whom angiography may also detect an anomalous origin of a coronary artery. Among competitive athletes under age 35, anomalous origin of a coronary artery was present in 13 percent of SCD survivors in one series [17]. (See "Athletes: Overview of sudden cardiac death risk and sport participation", section on 'Etiology of sudden death'.) Patients with stable CHD who experience an episode of primary SCD without evidence of simultaneous ischemia are at high risk for recurrent malignant arrhythmias, even after percutaneous or surgical revascularization [18-21]. As a result, such patients are treated with an ICD. (See "Risk stratification after acute ST-elevation myocardial infarction".) Echocardiography Echocardiography can detect abnormalities that suggest or confirm the diagnosis of many of the important causes of SCD. Since global left ventricular dysfunction due to myocardial stunning can be induced by cardiac arrest and cardiopulmonary resuscitation, evaluation of left ventricular function should be performed at least 48 hours after resuscitation [22]. Detailed review of the diagnostic criteria for each disorder is presented separately. Potential causes of SCD that can be detected with echocardiography include the following: https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 6/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate CHD Left ventricular dysfunction with wall motion abnormalities suggest prior myocardial infarction. Dyskinetic wall motion is consistent with an aneurysm. Hypertrophic cardiomyopathy (see "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation") Arrhythmogenic right ventricular cardiomyopathy Aortic stenosis (see "Echocardiographic evaluation of the aortic valve") Dilated cardiomyopathy (see "Echocardiographic recognition of cardiomyopathies" and "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy") Cardiac MR Cardiac magnetic resonance imaging (CMR) is indicated for selected patients in whom a diagnosis is uncertain after the above evaluation. (See "Clinical utility of cardiovascular magnetic resonance imaging".) CMR is useful in the evaluation of the following disorders: Hypertrophic cardiomyopathy (see "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation") Myocarditis Arrhythmogenic right ventricular cardiomyopathy Dilated cardiomyopathy Congenital heart disease, including anomalous origin of coronary arteries (see "Congenital and pediatric coronary artery abnormalities" and "Cardiac imaging with computed tomography and magnetic resonance in the adult") Cardiac sarcoidosis Cardiac amyloidosis (see "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Cardiovascular magnetic resonance') The utility of CMR angiography as an alternative to invasive coronary angiography is not well defined. Alternatively, cardiac computed tomography angiography may be used to assess both congenital and acquired coronary abnormalities. (See "Cardiac imaging with computed tomography and magnetic resonance in the adult".) https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 7/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate Summary In 1997, the Joint steering committees of the Unexplained Cardiac Arrest Registry of Europe and of the Idiopathic Ventricular Fibrillation Registry of the United States published recommendations for the evaluation of SCD survivors [12]. These recommendations included the following tests, all of which are described above: History and physical examination Blood biochemistries ECG Echocardiography Coronary angiography Since the publication of these recommendations, cardiac MR has come into wider use and is now a common component of this evaluation when standard tests are inconclusive. When this evaluation has not provided a diagnosis, the patient is evaluated for primary electrical disease. EVALUATION FOR PRIMARY ELECTRICAL DISEASES General issues Approximately 5 to 10 percent of SCD survivors have no evidence of a noncardiac etiology or of structural heart disease after the above evaluation. Such patients are considered to have a primary electrical disorder. A detailed discussion of SCD in patients with a structurally normal heart is presented separately. (See "Approach to sudden cardiac arrest in the absence of apparent structural heart disease".) The majority of these patients do not actually have "normal" hearts, but historically our diagnostic tools have been unable to identify the structural or functional derangement. In the past, the etiology of many of these deaths was unknown and deemed "idiopathic." Subsequent discoveries have identified the cause of death in many of these patients [11,23,24]. As our understanding of the mechanisms of primary electrical disorders has improved, so have our diagnostic capabilities, with important benefits for both the victims of SCD and their families. These disorders are often detected by characteristic changes on the ECG. (See 'Electrocardiogram' above.) Several of the disorders that cause SCD in the absence of structural heart disease are due to abnormalities of cardiac ion channels, including the following: https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 8/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate Brugada syndrome (see "Brugada syndrome: Clinical presentation, diagnosis, and evaluation") Long QT syndrome (see "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Acquired long QT syndrome: Definitions, pathophysiology, and causes") Short QT syndrome (see "Short QT syndrome") Catecholaminergic polymorphic VT (see "Catecholaminergic polymorphic ventricular tachycardia") Disorders associated with SCD that are not due to ion channel abnormalities include: Wolff-Parkinson-White syndrome (see "Wolff-Parkinson-White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis") Commotio cordis (see "Commotio cordis") Patients without evidence of any of the above structural or electrical abnormalities are said to have idiopathic VF or primary electrical disease. Identification of a primary electrical disorder in a SCD survivor has two important benefits: Directing medical treatment to prevent arrhythmia recurrence (eg, beta blockers for catecholaminergic polymorphic VT). Although medical therapy alone is now uncommon in SCD survivors (the vast majority of patients receive an ICD), adjunctive medical therapy can be useful to reduce the frequency of ICD shocks. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Other treatment options'.) Guiding the evaluation and management of family members. EP study Electrophysiologic (EP) testing is not usually performed in patients with an established etiology of SCD. However, EP study can be valuable in those whose initial evaluation reveals no etiology, and in selected patients with a previously identified disorder. In SCD survivors with an apparently normal heart, EP testing may reveal the following: Abnormalities of atrioventricular conduction The presence of severe conducting system disease suggests that a serious bradyarrhythmia may have contributed to the SCD event. However, such patients typically present with syncope rather than SCD. Furthermore, even when conduction disease is identified, VT/VF may be the real culprit and ventricular stimulation to induce ventricular arrhythmias may be warranted. https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 9/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate An accessory pathway in patients with Wolff-Parkinson-White syndrome An accessory pathway can result in rapid conduction to the ventricle of a supraventricular arrhythmia, primarily atrial fibrillation, producing a very rapid ventricular rate that can degenerate to VF. Such patients usually have evidence of preexcitation on their ECG. If preexcitation is evident on an ECG in a survivor of SCD, EP study and ablation of the accessory pathway are usually indicated. (See "Wolff-Parkinson-White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis", section on 'Ventricular fibrillation and sudden death'.) Inducible ventricular arrhythmias VT and VF may be induced in patients with a number of underlying cardiac abnormalities. The prognostic value of inducible arrhythmias is best established in patients with prior myocardial infarction and reduced LV systolic function. (See "Incidence of and risk stratification for sudden cardiac death after myocardial infarction", section on 'Inducible VT/VF'.) There is evidence that inducible VF, particularly when induced repeatedly with nonaggressive protocols, suggests the diagnosis of idiopathic VF and may predict recurrent arrhythmic events [25,26]. In a review of the literature, 69 percent of patients with idiopathic VF had a sustained ventricular tachyarrhythmia induced with a nonaggressive protocol; induced arrhythmia was generally polymorphic in configuration and poorly tolerated [25]. In some other conditions it is not clear that inducible VT or VF has prognostic significance (eg, Brugada syndrome, infiltrative diseases, HCM). Furthermore, aggressive stimulation protocols can induce polymorphic VT or VF in some individuals without cardiac disease. Thus, inducible arrhythmias can be a nonspecific finding. For this reason, the significance of inducible ventricular arrhythmias in patients with apparently normal hearts is unclear. On the other hand, the absence of inducible VT/VF may not preclude ICD implantation since lack of inducibility does not predict low risk. Myocardial scar Substrate mapping may identify areas of scar indicating abnormal substrate and a predisposition to ventricular arrhythmia. These abnormalities are more commonly seen in patients with CHD, HCM, ARVC, or infiltrative diseases, but also occur in some cases of idiopathic VF [27]. In addition, some patients with idiopathic VF have other electrophysiologic abnormalities, including areas of slow conduction, regionally delayed repolarization, or dispersion in repolarization [28]. Supraventricular arrhythmias Patients in whom VT or VF was not well documented at the time of SCD may have another culprit arrhythmia, usually a supraventricular tachycardia (SVT). In such patients, SVT may be inducible during EP study [29]. https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 10/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate Exercise testing Exercise testing is not usually part of the CHD evaluation in SCD survivors, since most undergo coronary angiography. However, it may be of importance for the SCD survivor in whom the sudden death episode occurred during exercise or physical activity. In addition, the provocation of ischemia with exercise, independently of coronary anatomy, is of importance in the evaluation of the SCD survivor. Although angiography alone does not prove a causal relationship to SCD or the presence of ischemia, the observation that revascularization appears to improve outcomes [9,20,21] means that a negative exercise test in a patient with significant coronary disease on angiography is not likely to affect the decision on revascularization. Also of great importance is the provocation of VT or VF in these patients, which would predict a higher recurrence rate. It is also a target for adjunctive antiarrhythmic therapy, particularly a beta blocker, in addition to an ICD. While VT (which is often scar mediated and provoked by catecholamines) may be provoked during exercise, VF most commonly occurs after exercise in the recovery period (when ischemia is more common). In patients with apparently normal hearts, exercise testing can assist in the diagnosis of long QT syndrome (QT interval fails to shorten or may even lengthen with an increase in heart rate) and catecholaminergic polymorphic VT. It is also useful in patients with Wolff-Parkinson-White pattern as the resolution of the delta wave with exercise generally correlates with low likelihood of a rapid ventricular rate with atrial fibrillation which is the etiology for VF and SCD in these patients. (See "Congenital long QT syndrome: Diagnosis", section on 'Exercise testing' and "Catecholaminergic polymorphic ventricular tachycardia" and "Wolff-Parkinson-White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis", section on 'Evaluation'.) Ambulatory monitoring In patients without a clear etiology for SCD, ambulatory monitoring may reveal recurrent sustained or nonsustained arrhythmias. However, most patients without an established diagnosis will have an ICD placed prior to discharge, and the memory features in these devices may preclude the need for ambulatory monitoring. Pharmacologic challenge As noted above, some of the primary electrical disorders may still be present despite no evidence of abnormalities on any of the preceding tests. ECG abnormalities may be intermittent or latent, and genetic testing is not yet comprehensive enough to exclude all possible disorders. Investigators have evaluated the role of pharmacologic challenge to elicit diagnostic ECG changes or arrhythmias in selected SCD survivors. One report included 18 SCD survivors with no evidence of structural heart disease [30]. All patients had a normal ECG, echocardiogram, coronary angiography, and cardiac MR. Patients were infused with epinephrine (0.05 to 0.5 microg/kg per minute) and then procainamide (1 g over 30 minutes). Epinephrine was intended to induce catecholaminergic polymorphic VT and procainamide to induce the characteristic ECG https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 11/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate abnormalities of Brugada syndrome. (See "Catecholaminergic polymorphic ventricular tachycardia" and "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) The following findings were noted: Ten patients were diagnosed with catecholaminergic polymorphic VT based upon an abnormal response to epinephrine infusion (frequent or polymorphic ventricular ectopy, nonsustained VT, or sustained VT). Four of these patients had ventricular ectopy during exercise testing, but none had sustained or nonsustained VT. Two patients were diagnosed with Brugada syndrome. Six patients were left with a diagnosis of idiopathic VF. Among 55 family members who were tested, eight affected members from one family were diagnosed with catecholaminergic polymorphic VT, and one relative was diagnosed with Brugada syndrome. In summary, two-thirds of patients whose standard evaluation provided no etiology for SCD had a diagnosis established with pharmacologic provocative testing. This allowed for the addition of appropriate adjunctive therapy (beta blockers for catecholaminergic polymorphic VT) and the identification of nine additional affected family members. MINOR CARDIAC ABNORMALITIES NOT ASSOCIATED WITH SCD During the course of the cardiac evaluation, minor cardiac abnormalities are often detected that do not have a clear causal relationship to SCD. These findings do not preclude the diagnosis of idiopathic VF; however, their severity must be considered and monitoring is warranted since these disorders may be the initial manifestations of an underlying structural heart disease that will become clinically apparent at a later date [12]. Disorders such as first degree atrioventricular (AV) block, transient second degree Mobitz type II AV block without bradycardia, and isolated bundle branch block do not exclude idiopathic VF. Thickening of the left ventricle less than 10 percent above normal and hypertension without LV hypertrophy are not clearly associated with SCD. A direct link between mitral valve prolapse and SCD has not been established unless there is valve redundancy or thickening, a family history of SCD, or perhaps significant mitral https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 12/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate regurgitation, QT interval prolongation, or ST-T waves changes. (See "Arrhythmic complications of mitral valve prolapse".) AF in the absence of ventricular preexcitation or hyperthyroidism is associated with an increase in total mortality, but not SCD [12,31]. (See "Epidemiology, risk factors, and prevention of atrial fibrillation".) Isolated ventricular premature beats, and more importantly repetitive forms (ie, couplets or nonsustained ventricular tachycardia), are associated with an increased risk of subsequent SCD only in patients with structural heart disease or with risk factors for CHD. (See "Premature ventricular complexes: Treatment and prognosis", section on 'Prognosis'.) EVALUATION OF FAMILY MEMBERS Some causes of SCD are familial, including a genetic predisposition to premature coronary heart disease, a cardiomyopathy or an electrophysiologic abnormality (eg, long QT syndrome or Brugada), and the risk of cardiovascular disease appears significantly higher in first- and second- degree relatives of the SCD victims, particularly young victims. In a nationwide Danish study from 2000 to 2006, 470 victims of SCD were identified who were 35 years of age or younger [32]. Among a cohort of 3073 first- and second-degree relatives of the SCD victims who were followed for up to 11 years, cardiovascular disease (CVD) was significantly more likely to be present than in the general population (standardized incidence ratio [SIR] for CVD 3.5, 95% CI 2.7-4.7). In contrast, among relatives of elderly (greater than 60 years of age) victims of SCD, there was no difference in the rates of CVD compared with the general population (SIR 0.9, 95% CI 0.8-1.1). A general cardiologic evaluation of first- and second-degree relatives of victims of unexplained SCD can yield the diagnosis of a heritable disease in up to 40 percent of families as illustrated by the following observations [33-35]. In a study of 32 families of victims of unexplained SCD, a general cardiologic evaluation (ECG, echocardiogram, Holter monitor and, less commonly, stress testing) was completed in 107 first-degree relatives [33]. Seven families (22 percent) were diagnosed with a heritable disease: four with long QT syndrome, one with nonstructural cardiac disease, one with myotonic dystrophy, and one with HCM. These findings were extended in a second report that evaluated 43 families with 183 surviving first- and second-degree relatives of victims of unexplained SCD at age 40 [34]. Careful history identified 26 additional cases of unexplained SCD at age 40. Cardiology evaluation included ECG, echocardiogram, exercise tolerance testing (ETT), and https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 13/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate measurement of serum lipids. Additional testing, as indicated, included flecainide challenge for suspected Brugada syndrome or cardiac MR for suspected ARVC. (See "Brugada syndrome or pattern: Management and approach to screening of relatives".) When a clinical diagnosis was established, genetic testing for the suspected disease was performed. Where a genetic abnormality was confirmed, additional screening was done in another 150 family members. The following findings were noted: A heritable disease was identified in 17 families (40 percent): five with catecholaminergic polymorphic VT, four with long QT syndrome, two with Brugada syndrome, one with Brugada/long QT syndrome, three with ARVC, one with HCM, and one with familial hypercholesterolemia. Genetic analysis confirmed the diagnosis in 10 families. An average of 8.9 asymptomatic carriers per family was identified, many through the secondary genetic analysis. Identification of a specific disease was more likely if 2 unexplained SCD events occurred in the family, and if more family members underwent evaluation. The increased yield in the second study may reflect the more extensive evaluation, including ETT, and the inclusion of more family members. Consistent with these findings, it has been recommended that first-degree family members of patients with SCD in the absence of structural heart disease be informed of the potentially increased risk and that an assessment should be offered at a center with experience in the diagnosis and management of inherited cardiac diseases [24]. Routine genetic screening for inherited disorders is not feasible although, in the presence of an identifiable condition, the genetic evaluation of family members may be undertaken at some centers. NEUROLOGIC AND PSYCHOLOGIC ASSESSMENT Patients who have been resuscitated from sudden death should be given a complete neurologic examination to establish the nature and extent of impairment resulting from the arrest. The physical examination, rather than imaging studies or other testing, is the most useful way of elucidating the patient's degree of neurologic function, mental impairment, and of determining prognosis. A 2004 meta-analysis of 11 studies found that the following clinical signs predicted a poor clinical outcome following cardiac arrest with 97 percent specificity [36]: Absence of pupillary light response after 24 hours Absence of corneal reflex after 24 hours https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 14/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate Absent motor responses to pain after 24 hours Absent motor responses after 72 hours (See "Hypoxic-ischemic brain injury in adults: Evaluation and prognosis".) Equally important is an assessment of the patient's psychologic state. Posttraumatic stress disorder (PTSD) may occur in SCD survivors. This was suggested in a study of 143 patients who had been resuscitated and discharged with no or only moderate neurologic disability [37]. All patients completed a self-rating questionnaire at a mean of 45 months after cardiac arrest: 39 (27 percent) fulfilled criteria for PTSD. (See "Posttraumatic stress disorder in adults: Epidemiology, pathophysiology, clinical manifestations, course, assessment, and diagnosis" and "Management of posttraumatic stress disorder in adults".) MANAGEMENT At present, most survivors of SCD are treated with an ICD. The use of ICDs in SCD survivors, the role of adjunctive antiarrhythmic medications and catheter ablation, and exceptions to the use of ICDs are discussed in detail separately. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) SUMMARY AND RECOMMENDATIONS Evaluation of the survivor of SCD includes the following: Identification and treatment of acute reversible causes, including (see 'Etiology of SCD' above and "Pathophysiology and etiology of sudden cardiac arrest", section on 'Etiology of SCD'): Acute cardiac ischemia and myocardial infarction Antiarrhythmic drugs or other medication (eg, QT prolonging drugs), toxin, or illicit drug ingestion Electrolyte abnormalities, most notably hypokalemia, hyperkalemia, and hypomagnesemia Heart failure Autonomic nervous system factors, especially sympathetic activation (eg, physical or psychologic stress) https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 15/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate Evaluation for structural heart disease Initial evaluation including history, physical examination, laboratory testing (eg, electrolytes, blood gas, toxin screen, etc), and electrocardiogram (see 'Initial evaluation' above) Evaluation for structural heart disease, which may include one or more of echocardiography, coronary angiography, cardiac magnetic resonance imaging, depending of the clinical scenario (see 'Evaluation for structural heart disease' above) In patients without obvious arrhythmic triggers or cardiac structural abnormalities, an evaluation for primary electrical diseases Primary electrical diseases include Brugada syndrome, long QT syndrome, short QT syndrome, Wolff-Parkinson-White, catecholaminergic polymorphic VT, commotio cordis, and idiopathic ventricular fibrillation (see 'General issues' above) The evaluation for primary electrical disease may include one or more of electrophysiology studies, exercise testing, ambulatory ECG monitoring, and pharmacologic challenge (see 'Evaluation for primary electrical diseases' above) Neurologic and psychologic assessment (see 'Neurologic and psychologic assessment' above) In selected patients with a suspected or confirmed heritable syndrome, evaluation of family members (see 'Evaluation of family members' above) ACKNOWLEDGMENT The editorial staff at UpToDate acknowledges Jie Cheng, MD, who contributed to an earlier version of this topic review.

degree relatives of the SCD victims, particularly young victims. In a nationwide Danish study from 2000 to 2006, 470 victims of SCD were identified who were 35 years of age or younger [32]. Among a cohort of 3073 first- and second-degree relatives of the SCD victims who were followed for up to 11 years, cardiovascular disease (CVD) was significantly more likely to be present than in the general population (standardized incidence ratio [SIR] for CVD 3.5, 95% CI 2.7-4.7). In contrast, among relatives of elderly (greater than 60 years of age) victims of SCD, there was no difference in the rates of CVD compared with the general population (SIR 0.9, 95% CI 0.8-1.1). A general cardiologic evaluation of first- and second-degree relatives of victims of unexplained SCD can yield the diagnosis of a heritable disease in up to 40 percent of families as illustrated by the following observations [33-35]. In a study of 32 families of victims of unexplained SCD, a general cardiologic evaluation (ECG, echocardiogram, Holter monitor and, less commonly, stress testing) was completed in 107 first-degree relatives [33]. Seven families (22 percent) were diagnosed with a heritable disease: four with long QT syndrome, one with nonstructural cardiac disease, one with myotonic dystrophy, and one with HCM. These findings were extended in a second report that evaluated 43 families with 183 surviving first- and second-degree relatives of victims of unexplained SCD at age 40 [34]. Careful history identified 26 additional cases of unexplained SCD at age 40. Cardiology evaluation included ECG, echocardiogram, exercise tolerance testing (ETT), and https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 13/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate measurement of serum lipids. Additional testing, as indicated, included flecainide challenge for suspected Brugada syndrome or cardiac MR for suspected ARVC. (See "Brugada syndrome or pattern: Management and approach to screening of relatives".) When a clinical diagnosis was established, genetic testing for the suspected disease was performed. Where a genetic abnormality was confirmed, additional screening was done in another 150 family members. The following findings were noted: A heritable disease was identified in 17 families (40 percent): five with catecholaminergic polymorphic VT, four with long QT syndrome, two with Brugada syndrome, one with Brugada/long QT syndrome, three with ARVC, one with HCM, and one with familial hypercholesterolemia. Genetic analysis confirmed the diagnosis in 10 families. An average of 8.9 asymptomatic carriers per family was identified, many through the secondary genetic analysis. Identification of a specific disease was more likely if 2 unexplained SCD events occurred in the family, and if more family members underwent evaluation. The increased yield in the second study may reflect the more extensive evaluation, including ETT, and the inclusion of more family members. Consistent with these findings, it has been recommended that first-degree family members of patients with SCD in the absence of structural heart disease be informed of the potentially increased risk and that an assessment should be offered at a center with experience in the diagnosis and management of inherited cardiac diseases [24]. Routine genetic screening for inherited disorders is not feasible although, in the presence of an identifiable condition, the genetic evaluation of family members may be undertaken at some centers. NEUROLOGIC AND PSYCHOLOGIC ASSESSMENT Patients who have been resuscitated from sudden death should be given a complete neurologic examination to establish the nature and extent of impairment resulting from the arrest. The physical examination, rather than imaging studies or other testing, is the most useful way of elucidating the patient's degree of neurologic function, mental impairment, and of determining prognosis. A 2004 meta-analysis of 11 studies found that the following clinical signs predicted a poor clinical outcome following cardiac arrest with 97 percent specificity [36]: Absence of pupillary light response after 24 hours Absence of corneal reflex after 24 hours https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 14/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate Absent motor responses to pain after 24 hours Absent motor responses after 72 hours (See "Hypoxic-ischemic brain injury in adults: Evaluation and prognosis".) Equally important is an assessment of the patient's psychologic state. Posttraumatic stress disorder (PTSD) may occur in SCD survivors. This was suggested in a study of 143 patients who had been resuscitated and discharged with no or only moderate neurologic disability [37]. All patients completed a self-rating questionnaire at a mean of 45 months after cardiac arrest: 39 (27 percent) fulfilled criteria for PTSD. (See "Posttraumatic stress disorder in adults: Epidemiology, pathophysiology, clinical manifestations, course, assessment, and diagnosis" and "Management of posttraumatic stress disorder in adults".) MANAGEMENT At present, most survivors of SCD are treated with an ICD. The use of ICDs in SCD survivors, the role of adjunctive antiarrhythmic medications and catheter ablation, and exceptions to the use of ICDs are discussed in detail separately. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) SUMMARY AND RECOMMENDATIONS Evaluation of the survivor of SCD includes the following: Identification and treatment of acute reversible causes, including (see 'Etiology of SCD' above and "Pathophysiology and etiology of sudden cardiac arrest", section on 'Etiology of SCD'): Acute cardiac ischemia and myocardial infarction Antiarrhythmic drugs or other medication (eg, QT prolonging drugs), toxin, or illicit drug ingestion Electrolyte abnormalities, most notably hypokalemia, hyperkalemia, and hypomagnesemia Heart failure Autonomic nervous system factors, especially sympathetic activation (eg, physical or psychologic stress) https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 15/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate Evaluation for structural heart disease Initial evaluation including history, physical examination, laboratory testing (eg, electrolytes, blood gas, toxin screen, etc), and electrocardiogram (see 'Initial evaluation' above) Evaluation for structural heart disease, which may include one or more of echocardiography, coronary angiography, cardiac magnetic resonance imaging, depending of the clinical scenario (see 'Evaluation for structural heart disease' above) In patients without obvious arrhythmic triggers or cardiac structural abnormalities, an evaluation for primary electrical diseases Primary electrical diseases include Brugada syndrome, long QT syndrome, short QT syndrome, Wolff-Parkinson-White, catecholaminergic polymorphic VT, commotio cordis, and idiopathic ventricular fibrillation (see 'General issues' above) The evaluation for primary electrical disease may include one or more of electrophysiology studies, exercise testing, ambulatory ECG monitoring, and pharmacologic challenge (see 'Evaluation for primary electrical diseases' above) Neurologic and psychologic assessment (see 'Neurologic and psychologic assessment' above) In selected patients with a suspected or confirmed heritable syndrome, evaluation of family members (see 'Evaluation of family members' above) ACKNOWLEDGMENT The editorial staff at UpToDate acknowledges Jie Cheng, MD, who contributed to an earlier version of this topic review. 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Topic 970 Version 35.0 https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 19/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate GRAPHICS Treatable conditions associated with cardiac arrest Condition Common associated clinical settings Acidosis Diabetes, diarrhea, drug overdose, renal dysfunction, sepsis, shock Anemia Gastrointestinal bleeding, nutritional deficiencies, recent trauma Cardiac Post-cardiac surgery, malignancy, post-myocardial infarction, pericarditis, trauma tamponade Hyperkalemia Drug overdose, renal dysfunction, hemolysis, excessive potassium intake, rhabdomyolysis, major soft tissue injury, tumor lysis syndrome Hypokalemia* Alcohol abuse, diabetes mellitus, diuretics, drug overdose, profound gastrointestinal losses Hypothermia Alcohol intoxication, significant burns, drowning, drug overdose, elder patient, endocrine disease, environmental exposure, spinal cord disease, trauma Hypovolemia Significant burns, diabetes, gastrointestinal losses, hemorrhage, malignancy, sepsis, trauma Hypoxia Upper airway obstruction, hypoventilation (CNS dysfunction, neuromuscular disease), pulmonary disease Myocardial infarction Cardiac arrest Poisoning History of alcohol or drug abuse, altered mental status, classic toxidrome (eg, sympathomimetic), occupational exposure, psychiatric disease Pulmonary embolism Immobilized patient, recent surgical procedure (eg, orthopedic), peripartum, risk factors for thromboembolic disease, recent trauma, presentation consistent with acute pulmonary embolism Tension pneumothorax Central venous catheter, mechanical ventilation, pulmonary disease (eg, asthma, chronic obstructive pulmonary disease), thoracentesis, thoracic trauma CNS: central nervous system. Hypomagnesemia should be assumed in the setting of hypokalemia, and both should be treated. Adapted from: Eisenberg MS, Mengert TJ. Cardiac resuscitation. N Engl J Med 2001; 344:1304. Graphic 52416 Version 8.0 https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 20/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate 12-lead electrocardiogram (ECG) from a patient with the Brugada syndrome shows downsloping ST elevation ST segment elevation and T wave inversion in the right precordial leads V1 and V2 (arrows); the QRS is normal. The widened S wave in the left lateral leads (V5 and V6) that is characteristic of right bundle branch block is absent. Courtesy of Rory Childers, MD, University of Chicago. Graphic 64510 Version 10.0 https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 21/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate 12-lead electrocardiogram showing the Wolff-Parkinson- White pattern The 2 main electrocardiographic features of Wolff-Parkinson-White pattern include a short PR interval (<0.12 seconds) and a delta wave (arrows). The QRS complex is wide (>0.12 seconds) and represents a fusion beat; the initial portion (delta wave) results from rapid ventricular activation via the accessory pathway (preexcitation), while the termination of ventricular activation is via the normal conduction system, leading to a fairly normal terminal portion of the QRS. Graphic 75578 Version 10.0 ECG of sinus rhythm to Normal electrocardiogram (ECG) Normal sinus rhythm at a rate of 71 beats/minute, a P wave axis of 45 , and a PR interval of 0.15 seconds. https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 22/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate ECG: electrocardiogram. Courtesy of Morton Arnsdorf, MD. Graphic 58149 Version 5.0 https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 23/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate 12-lead electrocardiogram showing ventricular tachycardia in arrhythmogenic right ventricular cardiomyopathy Ventricular tachycardia in arrhythmogenic right ventricular cardiomyopathy usually arises from the free wall of the right ventricle, resulting in a left bundle branch morphology. With permission from Podrid PJ, Kowey PR (Eds), Cardiac Arrhythmia - Mechanisms, Diagnosis, and Management, Williams & Wilkins, Baltimore, 1995. Graphic 56591 Version 9.0 Normal ECG https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 24/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate Normal electrocardiogram showing normal sinus rhythm at a rate of 75 beats/minute, a PR interval of 0.14 seconds, a QRS interval of 0.10 seconds, and a QRS axis of approximately 75 . Courtesy of Ary Goldberger, MD. Graphic 76183 Version 4.0 https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 25/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate 12-lead electrocardiogram showing epsilon wave and T wave inversions in arrhythmogenic right ventricular cardiomyopathy 12-lead electrocardiogram in a patient with arrhythmogenic right ventricular cardiomyopathy showing deep T wave inversions in V2 to V4, compatible with right ventricular disease, and epsilon waves representing delayed right ventricular depolarization just after the QRS complex (arrows). Data from: Jaoude S, Leclercq JF, Coumel P. Eur Heart J 1996; 17:1717. Graphic 60781 Version 9.0 https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 26/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate Single-lead electrocardiogram showing a prolonged QT interval The corrected QT interval (QTc) is calculated by dividing the QT interval (0.60 seconds) by the square root of the preceding RR interval (0.92 seconds). In this case, the QTc is 0.625 seconds (625 milliseconds). Graphic 77018 Version 7.0 https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 27/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate Single lead electrocardiogram (ECG) showing polymorphic ventricular tachycardia (VT) This is an atypical, rapid, and bizarre form of ventricular tachycardia that is characterized by a continuously changing axis of polymorphic QRS morphologies. Graphic 53891 Version 5.0 https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 28/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate Major causes of sudden death Ischemic heart disease Coronary artery disease with myocardial infarction or angina Coronary artery embolism Nonatherogenic coronary artery disease (arteritis, dissection, congenital coronary artery anomalies) Coronary artery spasm Nonischemic heart disease Hypertrophic cardiomyopathy Dilated cardiomyopathy Valvular heart disease Congenital heart disease Arrhythmogenic right ventricular dysplasia Myocarditis Acute pericardial tamponade Acute myocardial rupture Aortic dissection No structural heart disease Primary electrical disease (idiopathic ventricular fibrillation) Brugada syndrome (right bundle branch block and ST segment elevation in leads V1 to V3) Long QT syndrome Preexcitation syndrome Complete heart block Familial sudden cardiac death Chest wall trauma (commotio cordis) Noncardiac disease Pulmonary embolism Intracranial hemorrhage Drowning Pickwickian syndrome Drug-induced https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 29/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate Central airway obstruction Sudden infant death syndrome Sudden unexplained death in epilepsy (SUDEP) Graphic 62184 Version 3.0 https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 30/31 7/6/23, 10:41 AM Cardiac evaluation of the survivor of sudden cardiac arrest - UpToDate Contributor Disclosures Philip J Podrid, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. Scott Manaker, MD, PhD Other Financial Interest: Expert witness in workers' compensation and in medical negligence matters [General pulmonary and critical care medicine]; National Board for Respiratory Care [Director]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cardiac-evaluation-of-the-survivor-of-sudden-cardiac-arrest/print 31/31

7/6/23, 10:41 AM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Embolic risk and the role of anticoagulation in atrial flutter : Warren J Manning, MD, Jordan M Prutkin, MD, MHS, FHRS : Bradley P Knight, MD, FACC, Scott E Kasner, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 11, 2022. INTRODUCTION Most patients with atrial flutter should be considered for chronic anticoagulation in a manner similar to those with atrial fibrillation (AF). This recommendation is based not only on the fact atrial flutter carries a risk for systemic embolization but also that these patients usually have episodes of AF. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Summary and recommendations'.) Our approach to anticoagulation applies to all types of atrial flutter, whether it is typical or atypical. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) PREVALENCE OF THROMBUS Many patients with atrial flutter have alternating periods of atrial fibrillation (AF) making it difficult to know the exact risk of thrombus formation (and subsequent embolization) specifically attributable to atrial flutter [1]. Atrial mechanical function is not normal in patients with atrial flutter. However, transmitral and left atrial appendage Doppler echocardiography commonly demonstrate more organized atrial and atrial appendage mechanical function with sustained atrial flutter, as opposed to AF, in which organized atrial contraction is absent. One study performed transesophageal https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 1/13 7/6/23, 10:41 AM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate echocardiography (TEE) immediately before and after cardioversion in 19 patients with atrial flutter and 44 patients with AF with the following findings [2]: Prior to cardioversion, patients with atrial flutter had greater left atrial appendage peak ejection velocities and shear rates compared to those with AF. After cardioversion, left atrial appendage peak ejection velocities and shear rates decreased in both groups of patients, but the impaired left atrial appendage function was less pronounced in patients with atrial flutter. New or increased spontaneous echo contrast, a marker of blood stasis, occurred significantly less often in patients with atrial flutter (21 versus 50 percent for AF). Like AF, the vast majority of thrombi among patients with atrial flutter are located in the left atrial appendage. TEE evidence of atrial thrombi has been documented in a number of reports of patients with atrial flutter not receiving chronic anticoagulation [3-8]. As with AF, the thrombi overwhelmingly involve or are exclusively within the left atrial appendage. The frequency with which this occurs may vary with the duration of the arrhythmia and other risk factors (similar to AF) as illustrated by the following observations: Two series evaluated patients with atrial flutter for a mean duration of 33 to 36 days who did not have a history of AF, rheumatic heart disease, or a prosthetic heart valve [3,4]. A left atrial thrombus was found in 1 to 1.6 percent, a right atrial thrombus in 1 percent, and left atrial spontaneous echo contrast in 11 to 13 percent [3,4]. In one of these reports, there was a close correlation between a history of thromboembolism and periods of AF during atrial flutter [4]. Atrial thrombi and spontaneous echo contrast may be more common in patients with atrial flutter of longer duration. In a TEE study of 30 patients with persistent atrial flutter (duration 6.4 months), two patients (7 percent) had thrombus in the left atrial appendage, and 25 percent had spontaneous echo contrast prior to cardioversion [5]. As described below in more depth (see 'Cardioversion' below) and mentioned above, left atrial contractile function (as measured by peak atrial appendage ejection velocity) transiently declines after cardioversion in many patients and is considered a manifestation of atrial "stunning." Left atrial thrombus was present in 5 of 47 consecutive patients (11 percent) with atrial flutter for a mean duration of 28 days who did not have a history of AF or mitral stenosis [6]. https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 2/13 7/6/23, 10:41 AM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate EMBOLIC RISK The risk of embolization in atrial flutter is related to risk factors and the need for cardioversion or ablation. Risk factors and lone atrial flutter Risk factors for clinical thromboembolism include valvular heart disease (eg, rheumatic valve disease, prosthetic valves), increasing age, depressed left ventricular systolic function or heart failure, hypertension, diabetes, vascular disease, and a history of thromboembolism. Atrial flutter without an identifiable risk factor is called lone atrial flutter. It is relatively uncommon, occurring in only 3 of 181 adults with atrial flutter in a population-based study (1.7 percent) [9] and in 8 percent of children and young adults with atrial flutter in a multicenter series [10]. The embolic risk associated with lone atrial flutter was evaluated in a review of 59 mostly elderly patients with lone atrial flutter (mean age at diagnosis 70 years); 75 percent developed recurrent episodes or persistent atrial flutter [11]. At presentation, these patients did not have coronary heart disease, hyperthyroidism, heart failure, valvular heart disease, congenital heart disease, obstructive lung disease, uncontrolled hypertension, or known antecedent atrial fibrillation (AF). At the time of diagnosis, 25 were treated with aspirin and six with warfarin; at last follow-up, 28 were treated with aspirin and 13 with warfarin. The following observations were noted at an average follow-up of 10 years: AF developed in 33 patients (56 percent), which was paroxysmal in 25 and permanent in eight, highlighting the rationale for managing anticoagulation in patients with atrial flutter in a manner similar to AF. One or more ischemic cerebrovascular events occurred in 19 patients (32 percent) at a mean age of 80 years, including six who were in AF at the time of the event. Compared to age- and sex-adjusted expected rates of thromboembolism, the thromboembolic risk was significantly increased in the patients with lone atrial flutter (hazard ratio 5.2 in patients with controlled hypertension and 2.5 in patients without a history of hypertension). When compared with patients with lone AF, the patients with lone atrial flutter had, after adjustment for age and sex, a significantly higher rate of thromboembolism (hazard ratio 2.6). The risk was lower and no longer significant when only patients without a history of hypertension were included (hazard ratio 1.9). (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Classification and terminology'.) https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 3/13 7/6/23, 10:41 AM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate Long-term flutter There is an increased risk for clinical thromboembolism in patients with persistent atrial flutter compared to the general population without atrial arrhythmias [1,12-14]. In a systematic review based upon limited data, the long-term embolic risk in patients with sustained atrial flutter (with varying risk factors) was estimated to be approximately 3 percent per year [12]. For comparison, the rate of thromboembolism in patients with AF <1 percent per year in patients with no risk factors, with the rate increasing with increasing CHA DS -VASc score 2 2 ( table 1). One problem with interpreting these data, as mentioned previously, is that many patients with persistent atrial flutter also have episodes of AF (34 percent in the preceding report [13]) also have episodes of AF. In a review of the Medicare database, the risk of stroke was significantly increased in patients with atrial flutter (relative risk 1.41 compared to a control group). In these patients, the relative risk was 1.56 in patients who subsequently had an episode of AF (similar to the risk with AF alone), while those with isolated atrial flutter had a stroke risk not significantly different from the control population (relative risk 1.11) ( figure 1) [1]. Cardioversion Although the risk of clinical thromboembolization at the time of cardioversion is increased compared to individuals not undergoing cardioversion, the absolute thromboembolism risk of cardioversion for pure atrial flutter is not known with a high degree of confidence due to the fact that many patients included in reports of atrial flutter cardioversion related events also had episodes of AF (but happened to be in atrial flutter at the time of cardioversion) [3,13,15-17]. The studies that have attempted to evaluate the risk at the time of cardioversion studied different populations. Some included patients with a prior history of thromboembolism and were thus more likely to report high event rates, while studies in which at least some patients were anticoagulated or underwent precardioversion transesophageal echocardiography (TEE) to assess for thrombus were more likely to report low event rates [3,12-17]. Three early studies found no embolic events in a total of 314 patients with atrial flutter (and without AF) who underwent elective cardioversion for atrial flutter without anticoagulation prior to or after cardioversion [4,18,19]. However, the overall incidence is 0.6 to 1.0 percent [16,17] with a higher risk in patients with a history of AF or underlying heart disease [13,15]. In a meta- analysis of these studies, the rate of short-term emboli ranged from 0 to 7.3 percent [12]. Embolization may be related to a transient reduction in atrial mechanical function leading to post-cardioversion thrombus formation, referred to as atrial "stunning," and is present after successful cardioversion of atrial flutter [2,5,6,20,21]. In one report, left atrial appendage peak ejection velocity fell by 26 percent within 15 minutes of cardioversion and almost 50 percent of https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 4/13 7/6/23, 10:41 AM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate subjects had new or more pronounced spontaneous echo contrast [5]. These changes predispose to de novo thrombus formation [15]. Similar observations have been made in patients with AF. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Atrial stunning'.) The severity of atrial stunning appears to be somewhat less pronounced in atrial flutter than in AF, which could explain the lower embolic risk after cardioversion in atrial flutter. In a report that compared 19 patients with atrial flutter with 44 patients with AF, the left atrial appendage peak ejection velocity was significantly higher in the patients with atrial flutter at baseline (42 versus 28 cm/sec in atrial fibrillation) and after cardioversion (27 versus 15 cm/sec) [2]. In addition, new or more pronounced spontaneous echo contrast was significantly less likely in those with atrial flutter (21 versus 50 percent). Radiofrequency catheter ablation Atrial stunning (see 'Cardioversion' above) also occurs after radiofrequency catheter ablation [21,22]. The likelihood of developing atrial stunning and its duration were assessed in a review of 15 patients with persistent atrial flutter (mean duration 17 months) and seven with paroxysmal atrial flutter who underwent radiofrequency catheter ablation [21]. Significant left atrial appendage stunning and spontaneous echo contrast on TEE were observed after ablation in 80 percent of those with persistent flutter but in none with paroxysmal atrial flutter, suggesting that, like AF, left atrial stunning in atrial flutter is related to the duration of the arrhythmia and not the mode of reversion. These changes resolved after three weeks of sustained sinus rhythm. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'RF catheter ablation'.) PREVENTION OF EMBOLIZATION Patients with long-term atrial flutter Patients with persistent or recurrent atrial flutter who also have periods of atrial flutter-fibrillation should be treated in the same manner as those with pure atrial fibrillation (AF) [23,24]. This recommendation also applies to patients with atrial flutter who have a prior history of AF. Though the optimal management of atrial flutter without any history of AF is uncertain and may be more limited ( figure 1) [1], we and others recommend that patients with pure atrial flutter be managed similar to those with AF [25]. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Summary and recommendations'.) Anticoagulation with warfarin (goal international normalized ratio [INR] between 2.0 and 3.0) has been recommended to prevent embolization in patients with atrial flutter, similar to patients with AF (eg, using CHA DS -VASc criteria for nonvalvular AF). Of the non-vitamin K oral 2 2 https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 5/13 7/6/23, 10:41 AM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate anticoagulants tested for stroke prevention in AF, in the large clinical trials, only apixaban enrolled patients with atrial flutter [26]. It is likely, however, that there is similar efficacy of all the non-vitamin K oral anticoagulants (eg, apixaban, dabigatran, edoxaban, and rivaroxaban) for atrial flutter as well as AF. At the time of cardioversion We and others recommend that anticoagulation leading to, at the time of, and after cardioversion of atrial flutter be managed in a manner similar to that for AF [23,24]. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Patients presenting with an initial episode of atrial flutter should be treated in a manner similar to those presenting with their first episode of AF, including a transthoracic echocardiogram (TTE) to evaluate for congenital heart disease, valve disease, and left ventricular systolic function. After radiofrequency catheter ablation Anticoagulation recommendations following catheter ablation of AF are discussed separately. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'Anticoagulation after RF catheter ablation'.) RECOMMENDATIONS OF OTHERS The 2016 European Society of Cardiology guidelines for the management of atrial fibrillation, the 2015 American Heart Association/American College of Cardiology/Heart Rhythm Society guideline on the management of adult patient with supraventricular tachycardia, and the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guideline on the management of patients with atrial fibrillation (and its 2019 focused update) similarly recommend managing anticoagulation in patients with atrial flutter in a manner similar to those in atrial fibrillation [23,27-31], recognizing that no report has been sufficiently large to accurately define both the risk of embolization and benefit of antithrombotic therapy in a pure atrial flutter population. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) SUMMARY AND RECOMMENDATIONS https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 6/13 7/6/23, 10:41 AM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate The risk of embolization in atrial flutter is related to clinical risk factors and underlying cardiac disease (eg, valve disease). However, the exact rates are not known, in part due to the presence of atrial fibrillation (AF) in most cohorts studied and the coexistence of AF and atrial flutter in most individuals. (See 'Long-term flutter' above.) For patients with atrial flutter, with or without AF, we recommend an anticoagulant strategy identical to that used in patients with AF (Grade 1B). (See 'Prevention of embolization' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Biblo LA, Yuan Z, Quan KJ, et al. Risk of stroke in patients with atrial flutter. Am J Cardiol 2001; 87:346. 2. Grimm RA, Stewart WJ, Arheart K, et al. Left atrial appendage "stunning" after electrical cardioversion of atrial flutter: an attenuated response compared with atrial fibrillation as the mechanism for lower susceptibility to thromboembolic events. J Am Coll Cardiol 1997; 29:582. 3. Corrado G, Sgalambro A, Mantero A, et al. Thromboembolic risk in atrial flutter. The FLASIEC (FLutter Atriale Societ Italiana di Ecografia Cardiovascolare) multicentre study. Eur Heart J 2001; 22:1042. 4. Schmidt H, von der Recke G, Illien S, et al. Prevalence of left atrial chamber and appendage thrombi in patients with atrial flutter and its clinical significance. J Am Coll Cardiol 2001; 38:778. 5. Weiss R, Marcovitz P, Knight BP, et al. 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January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 29. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 30. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 31. Page RL, Joglar JA, Caldwell MA, et al. 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2016; 67:e27. Topic 1066 Version 30.0 https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 9/13 7/6/23, 10:41 AM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate GRAPHICS Clinical risk factors for stroke, transient ischemic attack, and systemic embolism in the CHA DS -VASc score 2 2 (A) The risk factor-based approach expressed as a point based scoring system, with the acronym CHA DS -VASc 2 2 (NOTE: maximum score is 9 since age may contribute 0, 1, or 2 points) CHA DS -VASc risk factor Points 2 2 Congestive heart failure +1 Signs/symptoms of heart failure or objective evidence of reduced left ventricular ejection fraction Hypertension +1 Resting blood pressure >140/90 mmHg on at least 2 occasions or current antihypertensive treatment Age 75 years or older +2 Diabetes mellitus +1 Fasting glucose >125 mg/dL (7 mmol/L) or treatment with oral hypoglycemic agent and/or insulin Previous stroke, transient ischemic attack, or thromboembolism +2 Vascular disease +1 Previous myocardial infarction, peripheral artery disease, or aortic plaque Age 65 to 74 years +1 Sex category (female) +1 (B) Adjusted stroke rate according to CHA DS -VASc score 2 2 CHA DS -VASc score Patients (n = 73,538) Stroke and thromboembolism event 2 2 rate at 1-year follow-up (%) 0 6369 0.78 1 8203 2.01 2 12,771 3.71 3 17,371 5.92 4 13,887 9.27 https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 10/13 7/6/23, 10:41 AM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate 5 8942 15.26 6 4244 19.74 7 1420 21.50 8 285 22.38 9 46 23.64 CHA DS -VASc: Congestive heart failure, Hypertension, Age ( 75; doubled), Diabetes, Stroke (doubled), Vascular disease, Age (65 to 74), Sex. 2 2 Part A from: Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial brillation developed in collaboration with EACTS. Europace 2016; 18(11):1609-1678. By permission of Oxford University Press on behalf of the European Society of Cardiology. Copyright 2016 Oxford University Press. Available at: www.escardio.org/. Graphic 83272 Version 29.0 https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 11/13 7/6/23, 10:41 AM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate Stroke risk in atrial flutter is related to concomitant atrial fibrillation Among 395,147 patients over 65 years of age, the risk of stroke in those with chronic atrial flutter is increased when atrial fibrillation (AF) is also present and is equivalent to the risk associated with only AF. The incidence of stroke in those with isolated atrial flutter is the same as the risk in the control patients who have no atrial arrhythmia. Data from Biblo LA, Yuan Z, Quan KJ, et al. Am J Cardiol 2001; 87:346. Graphic 67382 Version 2.0 https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 12/13 7/6/23, 10:41 AM Embolic risk and the role of anticoagulation in atrial flutter - UpToDate Contributor Disclosures Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Jordan M Prutkin, MD, MHS, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/embolic-risk-and-the-role-of-anticoagulation-in-atrial-flutter/print 13/13

7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Evaluation of heart rate variability : Ary L Goldberger, MD, Phyllis K Stein, PhD : N A Mark Estes, III, MD : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Aug 08, 2022. INTRODUCTION Evaluation of beat-to-beat heart rate dynamics as a noninvasive, albeit indirect, probe of autonomic nervous system function is of interest from a number of basic perspectives, along with having potential translational applications in cardiology and other clinical areas. For example, a large body of clinical and experimental evidence indicates a central role for the autonomic nervous system in the triggering or sustaining of malignant ventricular arrhythmias [1]. Higher sympathetic activity unopposed by vagal activity promotes arrhythmia in a variety of ways: Reducing ventricular refractory period and the ventricular fibrillation threshold Promoting triggered activity afterpotentials Enhancing automaticity (see "Enhanced cardiac automaticity") Vagal stimulation opposes these changes and reduces the effects of sympathetic stimulation by prolonging refractoriness, elevating the ventricular fibrillation threshold, and reducing automaticity. Furthermore, the fundamental role of the autonomic nervous system in regulating inflammation, believed to underlie many disease processes, is increasingly being appreciated. Increased sympathetic activity promotes inflammation, and increased vagal activity moderates it [2,3]. There are three major noninvasive or minimally invasive assessment approaches to evaluating the functioning of the autonomic nervous system which provide complementary information https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 1/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate about autonomic as well as nonautonomic regulatory mechanisms in health and disease: RR interval (RRI) or heart rate variability (HRV) from short-term or longer-term monitoring Baroreflex sensitivity (BRS) testing Bedside autonomic function tests (eg, Valsalva maneuver, tilt testing, and other orthostatic challenges) The utility of HRV measures for prediction of outcome or detection of changes in clinical status depends on their stability over time. HRV is influenced significantly by age, race, sex, physical fitness, clinical conditions, sleep/wake cycles and drug treatment, but most 24-hour HRV measures appear to be stable when measured on a day-to-day basis and over periods of days to weeks when there are no major intervening clinical events. This topic will briefly review selected technical aspects and some clinical applications of HRV testing in adults. Although measurements are actually based on the RR intervals (cardiac interbeat interval obtained from a continuous ECG recording and usually from the normal sinus to normal sinus [NN] intervals), the term "HRV," instead of "RRV," has entered the lexicon and will be used here. AUTONOMIC NERVOUS SYSTEM INTERACTIONS WITH CARDIAC RATE AND RHYTHM Modulation of heart rate and the autonomic nervous system The autonomic nervous system is the primary regulator of heart rate in the presence of sinus rhythm ( figure 1). The intrinsic sinus node rate at rest (ie, the rate after pharmacologic or surgical denervation of the sinus node) is about 95 to 110 beats per minute [4]. Under normal supine resting conditions, there is little efferent sympathetic neural input to the sinoatrial node, and the concentration of circulating catecholamines is low; however, there is substantial efferent parasympathetic traffic on the vagus nerves, which slows the resting sinus node rate to about 55 to 75 beats per minute in healthy adults. Clinicians should keep in mind that resting heart rate is determined by both sympathetic and parasympathetic tone (ie, the basic firing rate of the nerves). The classical range given for "normal sinus rhythm" at rest of 60 to 100 beats per minute excludes some of the fittest individuals who have resting rates <60 beats per minute but includes some individuals with relatively higher rates (especially >85 to 90 per minute) associated with a variety of adverse outcomes in large population studies [5]. Heart rate variability (HRV) metrics quantify the fluctuations in the sequential output of RR intervals (also referred to as NN intervals when applied to presumed sinus beats), which are https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 2/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate related primarily to autonomic control mechanisms. However, these mathematical HRV measures do not quantify autonomic "tone" per se, despite claims to the contrary [6]. Instead, HRV reflects the extraordinarily complex, nonlinear interplay of all of the feedback loops, autonomic and nonautonomic, which regulate sinus node pacemaker activity and help facilitate the matching of cardiac output to the needs of the body. Therefore, interpretations that attempt to equate specific HRV measures with explicit neuroautonomic mechanisms are, of necessity, likely to be oversimplifications. One particularly notable example is the misinterpretation of the so-called low- to high-frequency power ratio (LF/HF) as a reliable index of "sympatho-vagal" balance [7]. Analysis of HRV patterns from continuous electrocardiograms (ECGs) permits the identification and quantification of underlying physiologic rhythms. The strength of these rhythms is expressed by the magnitude of various frequency-domain HRV measures. When recordings of at least 24 hours are available, the predominant physiologic rhythm that accounts for the most HRV is the circadian rhythm, with relatively increased sympathetic activity associated with higher heart rates during the daytime and increased vagal activity associated with lower heart rates during the night [8]. During normal sleep, there are also prominent physiologic rhythms associated with each approximately 90-minute sleep cycle, and there is evidence that these rhythms persist during wake time, possibly in association with neuroendocrine rhythms, but such "ultradian" HRV measures have not found clinical applications at this point. (See 'HRV methodology, definitions, and normal values' below.) Baroreflex activity (oscillations at relatively low frequencies that include so-called Mayer waves) also causes concomitant fluctuations in heart rate [9]. These baroreflex changes are most apparent with sudden standing or during tilt in healthy young adults. Finally, rhythmic fluctuations in the frequency of impulse conduction along the vagus nerves, modulated by the rate and depth of breathing, result, among supine subjects with intact autonomic functioning, in substantial variations in RR intervals at higher frequencies, known as respiratory sinus arrhythmia (RSA) [10,11]. RSA can be increased during metronomic breathing or with meditation-related slow breathing rates. The use of the term "arrhythmia" in this context is potentially misleading since RSA is usually a physiologic finding that is attenuated or absent with advanced aging and severe heart disease, among other pathologies. RR interval fluctuations are also affected by mental or physical activities and responses to environmental stressors, which reduce the average frequency of impulses conducted along the vagus nerves and, as effort increases, increase the activity of the sympathetic nervous system. In some individuals, changes related to sleep-disordered breathing events, periodic limb movements, restless legs syndrome, or poor sleep can increase HRV during sleep [12-15]. Nonautonomic factors (eg, neuroendocrine function) also play an important role in modulating https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 3/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate HRV, and some HRV can be increased by an abnormally irregular sinus rhythm due to sinus node dysfunction or subtle atrial ectopy (termed erratic or fragmented supraventricular rhythm) that is often missed in routine assessments, especially in older individuals [16,17]. (See "Normal sinus rhythm and sinus arrhythmia".) Triggering of cardiac arrhythmias and the autonomic nervous system Both branches of the autonomic nervous system have an important role in the triggering or sustaining of malignant ventricular arrhythmias, particularly post-myocardial infarction (MI). This relationship partly explains the predictive value of abnormal HR variability for such events when the arrhythmogenesis is a consequence of alterations in autonomic functioning. The sympathetic nervous system Chronically increased sympathetic activity and elevated plasma catecholamines can be found in the setting of myocardial dysfunction [18,19]. These alter the electrophysiologic properties of the myocardium and promote arrhythmogenesis, regardless of the mechanism involved (enhanced automaticity, triggered activity, or reentry) [20,21]. Some of the arrhythmogenic effects of high sympathetic activity are related to the adverse effects of tachycardia, such as ischemia, while others result from heterogeneity of ventricular repolarization. Increased sympathetic activity can cause tachycardia, which can result in myocardial ischemia, but myocardial ischemia, especially in the anterior wall, independent of the underlying mechanism, usually increases sympathetic activity while decreasing efferent vagal activity [22,23]. Additionally, myocardial ischemia triggers a release of norepinephrine from epicardial sympathetic nerves and an increase in its local myocardial concentrations due to the high extracellular potassium concentrations in the ischemic regions, resulting in regional heterogeneity of depolarization and repolarization, which is an important precondition for the development of reentrant activity and the precipitation of ventricular fibrillation [24]. Myocardial infarction can also involve the epicardial sympathetic nerves, producing regional sympathetic denervation of the myocardium distal to the infarct and further enhancing heterogeneity of repolarization and increasing the potential for reentry during times of enhanced sympathetic activity [25,26]. The noninfarcted tissue responds normally to sympathetic stimulation with a shortening of the ventricular refractory period, while denervated tissue fails to respond. The parasympathetic nervous system The parasympathetic nervous system, through vagal innervation, may exert important antiarrhythmic effects by reducing the heart rate and counteracting the proarrhythmic effects of sympathetic nervous system activity [27-30]. Furthermore, the parasympathetic nervous system appears to play a large role in regulating the https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 4/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate inflammatory response, and RR variability is inversely related to the production of many inflammatory markers [31,32]. Our prior understanding of the actions of the vagus nerve, however, is likely simplistic, including the common assumption of a reciprocal relationship between the activation of the sympathetic component and a dampening of that activation by the vagus in response to internal and external demands. Discussion of evolutionary models of vagus development, as well as central neuroanatomic nuclei involved in autonomic regulation and controversies in this field, are outside the scope of this brief overview [33-35]. Clinicians should be aware that higher parasympathetic activity as measured using HRV is not always better, since excess vagal activation can result in syncope, heart block, and, potentially, in some cases, increase dispersion of atrial refractoriness resulting in paroxysmal atrial fibrillation [36]. Also, traditional time and frequency domain HRV measures of parasympathetic activity do not distinguish between higher levels of RSA, associated with ventral vagal activity, and increased beat-to-beat variability that can be associated with pathologic conditions, including inferior-posterior type MIs, vasovagal syncope and its variants, and anorexia nervosa [37]. (See "Sinus bradycardia", section on 'Etiology' and "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department", section on 'Cardiac arrhythmias during ACS'.) HRV METHODOLOGY, DEFINITIONS, AND NORMAL VALUES Heart rate variability (HRV) is derived from intervals between normal sinus heart beats (NNs) and can be quantified by many methods ( table 1) [6,20,38-43], primarily comprising: Time domain measures Frequency domain measures Heart rate turbulence In addition, newer methods based on nonlinear dynamics (complexity science) have been developed that are discussed elsewhere ( www.physionet.org) [44]. It should be noted, however, that because the term "RR interval" is often used, closer scrutiny is needed to determine if results of a particular study are in fact based on NN intervals only. This understanding is increasingly relevant as more wearable devices become commercially available that purport to measure HRV, but may, in fact, derive this measurement indirectly from the pulse waveform. Furthermore, most clinical HRV measures are only interpretable for autonomic assessment purposes if the patient is predominantly in normal sinus rhythm and if the detection of the R-wave peaks and beat morphology is accurate, which can be problematic in a Holter https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 5/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate recording ordered for clinical purposes and scanned by a technician who can only allocate limited time to beat annotation efforts before generating a clinical Holter report [17,45]. HRV measurements Most Holter scanner manufacturers provide an HRV analysis feature; however, such analysis may not be included in the clinical report unless specifically requested by the ordering clinician. In addition, some manufacturers use different names for the same HRV variables. However, Holter scanners also can export a version of a "beat file," which is a list of the individual heart beats in the recording by morphology (eg, normal, premature ventricular or supraventricular, etc) and the time between them. The beat file can be used to accurately calculate HRV. It should be noted that the RR interval file, often available from pulse-based devices, is not equivalent to a beat file because it is not linked to an actual ECG signal, is heavily influenced by "noise" generated during physical activity, and lacks beat labels or independent ways to check on the accuracy and consistency of each beat's detection. For more information on HRV measurement, open source software for HRV analysis and open access databases are freely available at the website of the NIH/NCRR Research Resource for Complex Physiologic Signals ( www.physionet.org/), along with tutorial material. Also, free HRV software is available for download from The Biosignal and Medical Analysis Group in Finland [46]. In 2015, the European Society of Cardiology, along with the European Heart Rhythm Association and the Asia Pacific Heart Rhythm Association, published a position statement that provides a compact summary of HRV techniques and applications [43]. Those who use HRV measures should also be aware that short-term variability of NN intervals does not necessarily reflect intact vagal modulation of the sinoatrial node. Indeed, anomalous (nonrespiratory) sinus rhythm may confound measures of high frequency fluctuations in HRV, which are generally interpreted as due to healthy cardiac vagal modulation. Erratic sinus rhythm, described above, especially in older individuals and those with organic heart disease, may be a form of short-term HRV that is a marker of adverse cardiovascular risk [16,17]. An alternative conceptual construct, in concert with a set of metrics to quantify potentially nonvagal sources of short-term HRV, has been proposed [47-51]. The utility of this quantitative approach remains to be further validated. Time domain HRV Average NN in milliseconds (and/or heart rate in beats per minute) Not a measure of variability per se, but average heart rate is an important marker for cardiac autonomic function that is available from any commercial Holter software. Daytime and nighttime average heart rates are also generally available, and often hourly heart rates can be obtained as well, providing potential insights into circadian rhythms. https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 6/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate SDNN in milliseconds Standard deviation of NN (normal-to-normal RR) intervals over a 24- hour period reflects total HRV, but in the literature, SDNN is often reported over a brief (often five minutes) measurement period and results are erroneously interpreted by referring to studies from 24-hour measures. SDANN in milliseconds Standard deviation of the average NN intervals for all of the five- minute intervals in a 24-hour continuous ECG recording. However, this measure is not meaningful in a brief recording, but because it is based on five-minute averaged heart rates, which are not affected by short-term variations. pNN50 and related Percent NN intervals >50 ms different from the prior interval is often available on commercial Holter HRV reports. pNN50 is extremely sensitive to uneven beat detection and/or incorrect beat morphology labeling. Similar pNN statistics with lower thresholds (eg, pNN20) have also been described [52]. pNN625 is a heart rate corrected version of pNN50 where 625 represents 6.25 percent of the local average NN. pNN50, therefore, would be identical to pNN625 at an average NN of 800 ms, which corresponds to a heart rate of 75 bpm. rMSSD in milliseconds Root mean square of differences between successive NN intervals; essentially the average absolute value of the change in NN interval between beats. rMSSD is also sensitive to uneven beat detection and/or incorrect beat morphology labeling. It should be noted that when time domain measures are compared between individuals, neither the pNN statistics nor rMSSD tend to be normally distributed and natural log (in) transformation may be needed to permit parametric statistical comparisons. Moreover, especially in older individuals and patients with significant autonomic neuropathy (eg, severe diabetes), the pNN statistic can approach zero, creating major problems when log transformation is performed. Generally, in this situation, adding one to all values of pNN statistics solves that problem and permits parametric statistical analysis. Frequency domain HRV 2 Total power (TP) in ms TP captures the total variance in HRV. TP is sometimes reported as the total variance over 24 hours and sometimes as the 24-hour average of five-minute variances, an important distinction. 2 Ultra-low frequency power (ULF) in ms ULF captures the magnitude of underlying rhythms in heart rate at frequencies of every five minutes to once in 24 hours and is not meaningful in a short recording. https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 7/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate 2 Very low frequency power (VLF) in ms VLF captures the magnitude of underlying oscillations in the heart rate pattern at frequencies between every 25 seconds and every five minutes (0.003 to 0.04 Hz). VLF power at night is increased in the case of sleep- disordered breathing or periodic limb movements, both of which cause oscillations of heart rate patterns at frequencies within the VLF band. 2 Low-frequency power (LF) in ms LF captures the magnitude of heart rate oscillations in the range of three to nine cycles per minute (0.04 to 0.15 Hz). 2 High-frequency power (HF) in ms HF captures heart rate oscillations in the range of 9 to 24 cycles per minute, which is the range of typical adult respiratory frequencies (0.15 to 0.40 Hz). The HF band limits would need to be adjusted in recordings of infants and small children who normally have higher respiratory rates than adults. LF/HF ratio (unitless) Often referred to as the "sympathovagal" balance. However, this term is something of a misnomer since lower frequency fluctuations may be related to both sympathetic and parasympathetic activity [7]. Also, during exercise, overall heart rate variability (including LF) decreases, yet sympathetic activity is high. The LF/HF ratio may be most useful during maneuvers like standing and tilt testing, or at rest during metronomic breathing. Normalized LF power (NLF) in percent NLF captures the proportion of HRV accounted for by low frequency power. A similar and complemental measure, normalized HF power (NHF), can be calculated in the same manner. For measures like VLF, LF, HF, LF/HF, and NLF, 24-hour HRV can be viewed as the averaged HRV from multiple shorter recording periods. Note that for statistical reasons, most frequency domain HRV, which is not normally distributed in the population, is natural log (ln) transformed. NLF and NHF are exceptions. Ln transformation normalizes the distribution and tends to bring outlier values back to the middle of the distribution, so at times, frequency domain HRV values can appear to provide better parametric statistical discrimination between normal and abnormal HRV than time domain HRV. Heart rate turbulence Heart rate "turbulence" (HRT) is an HRV parameter designed to evaluate the oscillation (shortening then lengthening) in NN intervals associated with a temporary decrease in cardiac output associated with a premature ventricular complex/contraction (PVC; also referred to a premature ventricular beat or premature ventricular depolarization) [53]. Thus, HRT can be thought of as a measure of the resilience of the autonomic nervous system in the face of such a perturbation. As such, HRT has been proposed as a useful marker for cardiac autonomic neuropathy in some populations. Two https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 8/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate measures have been calculated, turbulence onset (TO) and turbulence slope (TS), using a composite of the responses to all PVCs on the recording. TO measures whether or not there is a brief tachycardia in the average of two normal heartbeat intervals after, compared with before, the PVC. The absence of this response (zero or positive TO) would indicate a lack of vagally-modulated autonomic adaptation to the PVC. TS measures the degree to which there is a predominantly baroreflex-mediated slower oscillation in heart rate (bradycardia, tachycardia, and return to baseline) after the PVC. A low value for TS (<2.5 ms/beat) is a strong marker for autonomic dysfunction among cardiac patients and suggests a potential inability of the cardiovascular system to recover appropriately after challenges [54]. Abnormal HRT has also been shown to be a risk marker in older adults without cardiac disease, although cut points for TS and elevated risk appear to be higher [55]. Although HRT measures, which generally require 24-hour Holter monitoring or at least five PVCs for calculation, are not available on most commercial Holter systems, abnormal heart rate turbulence may help identify autonomic dysfunction and increased risk of cardiovascular events among both cardiac patients and in low-risk population-dwelling older adults [54,56-58]. As an example, in a prospective cohort study of 1455 acute myocardial infarction survivors with HRT measurements who were followed for an average of 22 months, patients with abnormal TO and TS were at significantly greater risk of death (hazard ratio 5.9, 95% CI 2.9-12.2) [58]. Although abnormal HRT has been strongly associated with risk of sudden death, a more complete review of research findings for HRT in 2013 concluded that "to enhance its predictive value HRT should be evaluated in combination with other markers" [59]. The results of SCD-HeFT, in which abnormal TS was found to be one of several Holter-based risk factors for sudden cardiac death among patients with CHF, support this conclusion [60]. Physiologic interpretation of HRV measures When HRV is measured over a five-minute period, SDNN, VLF, LF, and HF power, the LF/HF ratio, normalized LF power, rMSSD, and pNN50 values can be generated. In this case, SDNN is a measure of HRV over only five minutes and, thus, does not reflect circadian rhythm and is not comparable with SDNN measured over 24 hours (as noted above). HRV measures from five-minute or other short-term recordings, in some cases as brief as one minute, have similar physiologic meanings to those from 24-hour recordings, which can be seen as the average of multiple short recordings, but they reflect only a very limited snapshot of autonomic function. Clinicians should be aware that there are considerable circadian changes in autonomic function within a single 24-hour cycle [61]. https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 9/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate Heart rate should be the first number to be evaluated to give the rest of the values some context. As noted, the same names are often used for variables derived both short-term (typically five-minute) and longer term (usually 24-hour) recordings, so it is important to remember the origin of the data. Thus, it is obvious that a mean heart rate of 80 bpm over 24 hours would not be the same as a mean heart rate of 80 bpm while sitting in the office. SDNN SDNN captures total HRV, and low values on a 24-hour recording reflect a lack of circadian rhythm, a concerning sign. Higher values usually, though not necessarily, mean all is well, although a patient in atrial fibrillation might have very high values of SDNN, as would a patient whose heart rate increased throughout the recording rather than following a circadian rhythm. However, among cardiac patients, SDNN >100 ms has been associated with a markedly lower risk of mortality. For example, in the UK-heart study, among patients with CHF, annual mortality was 5.5 percent for SDNN >100 ms versus 51.4 percent in patients with SDNN <50 ms [62]. SDANN SDANN is only meaningful in a longer recording and also captures circadian rhythm in a 24-hour recording [63]. The same is true of ULF power, which measures nearly the same thing. SDNN and SDANN measured over 24 hours are usually of a similar magnitude because of the predominant contribution of circadian rhythm to total HRV. Thus, SDNN and the smoothed-out SD of five minutes averaged NN version, SDANN, should be within approximately 20 or 30 ms of each other, with SDANN usually lower, and a wider discrepancy could raise questions about the underlying rhythm or the quality of scanning. Since 24-hour SDNN, SDANN, TP, and ULF are all primarily influenced by the magnitude of the circadian rhythm, they tend to provide very similar information to the clinician, but SDNN is the best known and the most intuitively obvious. VLF power The physiologic interpretation of VLF power has not been well-studied. In healthy adults, VLF appears to reflect parasympathetic activity since it is abolished by atropine administration and unaffected by beta-blockade. It also appears to reflect the activity of the renin-angiotensin system since it is reduced by ACE inhibition [64,65]. At the same time, decreased VLF power has been strongly related to adverse outcomes. As is the case for most HRV measures, context is important. Numbers alone do not carry enough information. Thus, because it captures oscillations in the range of every 25 seconds to every five minutes, VLF power is also increased by abnormalities such as sleep disordered breathing events (although it could be argued that the ability to mount a strong autonomic response to them is a better clinical sign than being unable to mount such a response). LF power LF power reflects the combined modulation of efferent parasympathetic (vagal) and efferent sympathetic nervous system activity and is modulated by baroreflex activity https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 10/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate [66]. HF power HF power, under normal conditions, reflects modulation of efferent parasympathetic (vagal) activity by ventilation (respiratory sinus arrhythmia), but only in the presence of true sinus rhythm. When the power spectrum is plotted with the subject supine, HF power has a clearly visible peak, the center frequency of which reflects the predominant respiratory frequency. In the presence of very low respiratory rates (ie, below 10 per minute), respiration can actually modulate LF power, and the amount of HRV can increase dramatically because respiration is affecting both sympathetic and parasympathetic control of heart rate [67-69]. Also, very rapid respiration, like that seen among CHF patients, sharply decreases HF power amplitude, paradoxically reflecting loss of vagal function because there is not enough time for the full effect of increased parasympathetic activity during the exhalation phase to slow the heart rate even among healthy people [70]. However, across the usual range of breathing frequencies, changes in respiratory rate appear to have little effect on the amplitude of the HF peak [70]. LF/HF ratio The LF/HF ratio is often claimed to characterize "sympathovagal balance" or "relative sympathetic activity" because the LF band reflects modulation by both the sympathetic and parasympathetic arms of the autonomic nervous system and the HF band reflects parasympathetic activity. Although there are selected situations where this concept might usefully be applied, far too many situations exist where it cannot (eg, exercise, heart failure, the cold pressor test, etc), and claims about the meaning of this ratio should be interpreted with extreme caution [7,71]. Several caveats apply to the interpretation of HRV measures. The position of the patient during a five-minute recording will dramatically affect HRV since parasympathetic activity is markedly increased for most people when they are supine. The limitations of this five-minute resting assessment must also be appreciated. Just as a resting ECG can yield information about clear ECG abnormalities, it provides no information about abnormalities or adaptations when the patient is active. A similar limitation applies to supine five-minute HRV [6]. If it is markedly depressed, then certainly there is some autonomic abnormality present, but the effect of activity on HRV or whether circadian rhythm is abnormal, etc, will be much more informative than a resting snapshot. Two other metrics defined in the table, rMSSD and pNN measures ( table 1), are also usually reported from both five-minute and longer recordings [38,52]. Both characterize heart rate changes on a beat-to-beat basis and, since beat-to-beat changes in heart rate as opposed to longer-term trends are mediated by changes in parasympathetic activity, the magnitude of either of these measures is taken as a surrogate of parasympathetic modulation of heart rate. https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 11/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate For this reason, these measures should correlate strongly with each other and with HF power, which also measures parasympathetic activity as expressed by changes in the respiratory frequency band. Normal values for HRV One of the complicating factors in using HRV clinically, aside from the technical issues discussed above, is that unlike, for example, a blood pressure measurement, there is a considerable range of normal values even in people of the same age and sex, and considerable ranges of normal change with age. A review of existing studies of normal values for short-term HRV found huge discrepancies in values [72]. More is known about 24-hour HRV measures, which have been collected in a large number of clinical populations and in some nonclinical ones as well. One study compared HRV in healthy middle-aged adults, recent post-MI patients (from the 1980s), and patients who were one-year post-MI [73]. SDNN was highest in the healthy adults, intermediate in the one-year post-MI group, and lowest in the recent MI group, but there were no differences between groups in time domain measures of beat-to-beat HRV (rMSSD and pNN50), potentially because the organization of the heart rate patterns (true RSA versus erratic sinus rhythm) cannot be determined from traditional time domain measures. Importantly, the study reported that at the upper end of the distribution for the three groups, HRV did not separate healthy subjects from patients with either recent MI or one year post-MI. Thus, clinically, it is possible to find normal circadian HRV in a cardiac patient, probably reflecting the ability to sleep well. Conversely, consistent with the notion that very low HRV reflects a significant abnormality, only 2 of 274 normal adults had values for ULF power previously reported to identify CHD patients at high risk of death, and only three had values for LF power below the cut-point for increased risk of mortality in CHD patients, thus supporting the possibility that finding a presumably healthy adult with very low 24-hour HRV would be clinically meaningful but also underscoring the fact the "normal" HRV values may be found in patients with known CVD. A 1998 study of HRV in 260 healthy adults found that HRV was both age and sex- dependent, with 95 percent confidence intervals reported for each decade [74]. Unfortunately, these limits are so broad as to be unusable clinically. For example, among adults in their 60's, normal limits for SDNN were defined as between 68 and 186 ms, and normal limits for 24-hour averaged heart rate were 52 to 99 bpm. The Cardiovascular Health Study examined changes in 24-hour-based frequency domain HRV over five years in 585 adults >65 years old [75]. HRV declined more in the group that was aged 65 to 69 at baseline, less in the group that was 70 to 74, and almost not at all in the group that was 75 years old. Although most HRV was slightly but significantly lower in https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 12/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate the group with prevalent cardiovascular disease, there was no difference in the magnitude of the age-related change in HRV among those with or without CVD. However, heart rate, ratio-based and nonlinear HRV values continued to decline with advancing age [75]. Reproducibility of HRV measures The utility of HRV measures for prediction of outcome or detection of changes in clinical status depends on their stability over time. HRV is influenced significantly by age, race, sex, physical fitness, clinical comorbidities and drug treatment, but most 24-hour HRV appears to be stable when measured on a day-to-day basis and over periods of days to weeks when there are no major intervening events [76-78]. Less is known about serial changes in HRV in the same individuals over longer periods of time, but as previously mentioned, these changes might be age- and measure-dependent [79]. Finally, the limitation of 24-hour recordings is being overcome by advances in technology. Whereas in the early days of clinical HRV data collection, subjects were asked to wear a somewhat cumbersome Holter device that recorded their ECG on reel-to-reel or later cassette tapes (two channels over 24 hours at a sampling rate of 128 Hz), technology permits collection of multichannel, high-resolution ECGs via a small patch attached to the chest, over several days in a row, either using a built-in SSD card or uploaded to a web server. HRV can also be measured from stored signals from inpatient ICU monitoring. This has greatly expanded potential applications of inpatient and outpatient HRV to interventions, eg, dialysis or chemotherapy. Reproducibility in patients with cardiac disease The reproducibility of HR variability measurements in patients with cardiac disease has been found to be comparable to the high stability observed in normal subjects. The stability of measures of HRV makes it possible to distinguish real changes due to progression or regression of cardiac disease or drug effects from apparent changes due to random variation. Unfortunately, criteria for real and significant changes in HRV have not been established. However, if a patient goes from apparently normal HRV (eg, SDNN >120 ms) to markedly decreased HRV (eg SDNN <70 ms) on serial recordings, this would be a matter of concern. As examples: Patients with ventricular arrhythmias In a study that evaluated the day-to-day stability of HRV in two groups of arrhythmia patients (a random sample of 40 patients in the ESVEM study who had sustained ventricular arrhythmias, and a random sample of 40 patients in the placebo group of CAPS who had nonsustained ventricular arrhythmias), there were no significant differences in measures of HRV between the two 24-hour recording sessions in either group [80]. Patients with stable angina In a study of 261 patients with chronic stable angina followed for three years, most HRV measures remained largely unchanged over time, although pNN50 and LF/HF were less stable [81]. Declines in most HRV measures, although not HF https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 13/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate power, were seen in those who suffered a myocardial infarction during that period. However, as previously stated, the magnitude of traditional time and frequency domain HRV measures fails to capture changes in the organization of heart rate patterns, which may be captured by nonlinear measures that were not determined in this study. CLINICAL USES OF HRV IN CARDIOLOGY The traditional clinical applications of HRV are based on a Task Force report published in 1996, in which the Task Force recommended two applications of HRV testing [38]: Prediction of risk of cardiac death or arrhythmic events post-myocardial infarction (MI) Detection and quantification of autonomic neuropathy in patients with diabetes mellitus A 2015 position statement reiterated the potential role for HRV in post-MI patients and also suggested a role in patients with heart failure [43]. While HRV has been investigated and shows potential for risk stratification in a variety of clinical conditions, and HRV can be derived from a Holter recording ordered for other clinical indications, there remains no clear indication for the test in the routine management of most patients. However, the ability of HRV from Holter monitoring to identify patients with sleep-disordered breathing, and the high and increasing

longer-term trends are mediated by changes in parasympathetic activity, the magnitude of either of these measures is taken as a surrogate of parasympathetic modulation of heart rate. https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 11/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate For this reason, these measures should correlate strongly with each other and with HF power, which also measures parasympathetic activity as expressed by changes in the respiratory frequency band. Normal values for HRV One of the complicating factors in using HRV clinically, aside from the technical issues discussed above, is that unlike, for example, a blood pressure measurement, there is a considerable range of normal values even in people of the same age and sex, and considerable ranges of normal change with age. A review of existing studies of normal values for short-term HRV found huge discrepancies in values [72]. More is known about 24-hour HRV measures, which have been collected in a large number of clinical populations and in some nonclinical ones as well. One study compared HRV in healthy middle-aged adults, recent post-MI patients (from the 1980s), and patients who were one-year post-MI [73]. SDNN was highest in the healthy adults, intermediate in the one-year post-MI group, and lowest in the recent MI group, but there were no differences between groups in time domain measures of beat-to-beat HRV (rMSSD and pNN50), potentially because the organization of the heart rate patterns (true RSA versus erratic sinus rhythm) cannot be determined from traditional time domain measures. Importantly, the study reported that at the upper end of the distribution for the three groups, HRV did not separate healthy subjects from patients with either recent MI or one year post-MI. Thus, clinically, it is possible to find normal circadian HRV in a cardiac patient, probably reflecting the ability to sleep well. Conversely, consistent with the notion that very low HRV reflects a significant abnormality, only 2 of 274 normal adults had values for ULF power previously reported to identify CHD patients at high risk of death, and only three had values for LF power below the cut-point for increased risk of mortality in CHD patients, thus supporting the possibility that finding a presumably healthy adult with very low 24-hour HRV would be clinically meaningful but also underscoring the fact the "normal" HRV values may be found in patients with known CVD. A 1998 study of HRV in 260 healthy adults found that HRV was both age and sex- dependent, with 95 percent confidence intervals reported for each decade [74]. Unfortunately, these limits are so broad as to be unusable clinically. For example, among adults in their 60's, normal limits for SDNN were defined as between 68 and 186 ms, and normal limits for 24-hour averaged heart rate were 52 to 99 bpm. The Cardiovascular Health Study examined changes in 24-hour-based frequency domain HRV over five years in 585 adults >65 years old [75]. HRV declined more in the group that was aged 65 to 69 at baseline, less in the group that was 70 to 74, and almost not at all in the group that was 75 years old. Although most HRV was slightly but significantly lower in https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 12/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate the group with prevalent cardiovascular disease, there was no difference in the magnitude of the age-related change in HRV among those with or without CVD. However, heart rate, ratio-based and nonlinear HRV values continued to decline with advancing age [75]. Reproducibility of HRV measures The utility of HRV measures for prediction of outcome or detection of changes in clinical status depends on their stability over time. HRV is influenced significantly by age, race, sex, physical fitness, clinical comorbidities and drug treatment, but most 24-hour HRV appears to be stable when measured on a day-to-day basis and over periods of days to weeks when there are no major intervening events [76-78]. Less is known about serial changes in HRV in the same individuals over longer periods of time, but as previously mentioned, these changes might be age- and measure-dependent [79]. Finally, the limitation of 24-hour recordings is being overcome by advances in technology. Whereas in the early days of clinical HRV data collection, subjects were asked to wear a somewhat cumbersome Holter device that recorded their ECG on reel-to-reel or later cassette tapes (two channels over 24 hours at a sampling rate of 128 Hz), technology permits collection of multichannel, high-resolution ECGs via a small patch attached to the chest, over several days in a row, either using a built-in SSD card or uploaded to a web server. HRV can also be measured from stored signals from inpatient ICU monitoring. This has greatly expanded potential applications of inpatient and outpatient HRV to interventions, eg, dialysis or chemotherapy. Reproducibility in patients with cardiac disease The reproducibility of HR variability measurements in patients with cardiac disease has been found to be comparable to the high stability observed in normal subjects. The stability of measures of HRV makes it possible to distinguish real changes due to progression or regression of cardiac disease or drug effects from apparent changes due to random variation. Unfortunately, criteria for real and significant changes in HRV have not been established. However, if a patient goes from apparently normal HRV (eg, SDNN >120 ms) to markedly decreased HRV (eg SDNN <70 ms) on serial recordings, this would be a matter of concern. As examples: Patients with ventricular arrhythmias In a study that evaluated the day-to-day stability of HRV in two groups of arrhythmia patients (a random sample of 40 patients in the ESVEM study who had sustained ventricular arrhythmias, and a random sample of 40 patients in the placebo group of CAPS who had nonsustained ventricular arrhythmias), there were no significant differences in measures of HRV between the two 24-hour recording sessions in either group [80]. Patients with stable angina In a study of 261 patients with chronic stable angina followed for three years, most HRV measures remained largely unchanged over time, although pNN50 and LF/HF were less stable [81]. Declines in most HRV measures, although not HF https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 13/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate power, were seen in those who suffered a myocardial infarction during that period. However, as previously stated, the magnitude of traditional time and frequency domain HRV measures fails to capture changes in the organization of heart rate patterns, which may be captured by nonlinear measures that were not determined in this study. CLINICAL USES OF HRV IN CARDIOLOGY The traditional clinical applications of HRV are based on a Task Force report published in 1996, in which the Task Force recommended two applications of HRV testing [38]: Prediction of risk of cardiac death or arrhythmic events post-myocardial infarction (MI) Detection and quantification of autonomic neuropathy in patients with diabetes mellitus A 2015 position statement reiterated the potential role for HRV in post-MI patients and also suggested a role in patients with heart failure [43]. While HRV has been investigated and shows potential for risk stratification in a variety of clinical conditions, and HRV can be derived from a Holter recording ordered for other clinical indications, there remains no clear indication for the test in the routine management of most patients. However, the ability of HRV from Holter monitoring to identify patients with sleep-disordered breathing, and the high and increasing prevalence of this disorder in the population (eg, an estimated 17 percent and increasing among males 50 to 70 years of age, the same age group that is likely to be tested for cardiovascular disease) support the possibility that Holter monitoring could be indicated as a screening tool in cardiac patients [82]. In some research labs, where HRV is measured in various clinical studies, significant and unsuspected sleep-disordered breathing is frequently seen and findings reported to the primary investigator, who then notifies the patient and suggests further evaluation by a sleep lab [83]. Prediction of mortality in the early post-MI period The impact of HRV on prognosis post- MI, initially reported in the era prior to treatment with thrombolysis, has also been validated in patients with an MI treated with thrombolytic therapy [84-86]. Patients with reduced indices of HRV measured early following an MI (within 14 days) have a three- to fourfold greater risk of death within three years following an MI. However, the sensitivity of measures like SDNN <50 ms as predictors of mortality, originally estimated to be approximately 30 percent, has declined simply because improvements in post-MI treatment have resulted in markedly fewer patients having SDNN at those levels. In a later study of 412 post-MI patients treated in the era of percutaneous revascularization and followed for 4.3 years, SDNN <50 ms was seen in only 7 percent of patients, and only 31 patients died in the entire cohort [87]. Even though an SDNN measurement of <50 ms was associated https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 14/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate with a doubling of risk of mortality compared with SDNN >50 ms in the earlier landmark study, in the latter study, SDNN <50 ms was only found in 3 of the 31 who died [84,87]. Another open question in this era of lower post-MI mortality is that of the optimal recording time after the event. It is possible that an early recording shortly after MI would identify one set of higher risk patients, and a later one, perhaps six weeks after MI, when patients have or have not recovered well, would provide more useful information. Prediction of mortality in the late post-MI period While reduced HRV in the early post-MI period is clearly associated with a worse prognosis among patients from the pre-PCI era, the substantial recovery of HR variability within the three months after myocardial infarction, particularly following an inferior infarct, raises a question as to whether recovery values for HR variability predict death [73,88]. Among the 68 placebo-treated patients entered into the Cardiac Arrhythmia Pilot Study (CAPS) who had 24-hour ECG recordings at baseline and at 3, 6, and 12 months after MI, there was a substantial increase in all measures of HRV between three weeks and three months [89]. On average, recovery of HRV was completed by three months post-MI; between 3 and 12 months, the values were stable for the group as a whole and for individual patients. Several older studies suggested that reduced HRV months or years post-MI remains a predictor of adverse outcomes [90-93]. As an example, in a study of 292 patients admitted with an acute coronary syndrome between 1991 and 1994, reduced HRV seen on 24-hour Holter recordings three to six months after their event continued to have prognostic value [93]. Patients with stable CHD An association between decreased HRV and the presence of significant coronary heart disease (CHD) has been suggested. Among 470 consecutive patients undergoing elective coronary angiography, patients with obstructive CHD (>50 percent stenosis) had significantly reduced HRV based on five-minute supine measurement, especially in the low 2 frequency (LF) band (180 with versus 267 ms without obstructive CHD) [94]. In a multivariate 2 2 analysis using a cutoff of LF power = 250 ms , persons with LF power below 250 ms were at significantly greater risk of obstructive CHD (adjusted OR 2.4, 95% CI 1.3-4.4) independent of baseline Framingham Risk Scores. Patients with heart failure Several studies have shown that patients with heart failure and/or cardiomyopathy have reduced HRV compared with controls, and that reduced HRV was associated with disease severity measures such as NYHA functional class, left ventricular diastolic dimension, reduced left ventricular ejection fraction, and peak O consumption [62,95- 2 101]. Prognostically, reductions in HRV have been shown to be independent predictors of overall https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 15/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate mortality, mortality from heart failure, sudden cardiac death, ventricular arrhythmias, and the need for transplant [62,100]. Improvements in HRV are seen with effective heart failure therapy (eg cardiac resynchronized therapy [CRT]). Patients with improved HRV after CRT have been shown to have better outcomes than those in whom HRV is not improved [102,103]. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT'.) A detailed review of studies of HRV applications to heart failure patients is available elsewhere [104]. Patients with atrial fibrillation Though the presence of atrial fibrillation (AF) precludes the use of standard NN variability measures, analysis of the variability and irregularity of the ventricular response interval (VRI) may provide useful information regarding prognosis of patients with chronic AF and likelihood of AF recurrence following cardioversion [105,106]. In a series of 107 patients with chronic atrial fibrillation who underwent 24-hour ambulatory monitoring for VRI variability and irregularity and were followed for 33 months, reductions in all VRI variability and irregularity measures were associated with an increased risk for cardiac death [105]. In a series of 93 patients who underwent cardioversion for AF and had RR variability measured in sinus rhythm, the AF recurrence rate at two weeks was significantly higher (73 versus 9 percent) in patients with reduced RR variability [106]. (See "Paroxysmal atrial fibrillation", section on 'Natural history'.) Furthermore, despite the apparent lack of beat-to-beat autonomic control in AF, a circadian rhythm, measurable by SDANN which averages out the extreme short-term variability in RR intervals, persists and can be assessed, and there is evidence that decreased SDANN is an adverse sign in AF [63]. The clinical applicability of this, like other potential applications of HRV, has not yet been evaluated. Reduced HRV in the general population Reduced HRV has been associated with increased mortality and a greater risk of cardiac events in several population studies [55,107-110]. As examples: In a random sample of 900 patients enrolled in the ARIC (Atherosclerosis Risk in Communities) study who had time-domain measures of RR variability determined from a two-minute ECG rhythm strip, those with low RR variability had a significantly higher risk of cardiovascular death (adjusted relative risk [RR] 1.98, 95% CI 1.06-3.70) and all-cause death https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 16/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate (adjusted RR 1.50, 95% CI ) compared with patients with an intermediate RR variability (SDNN 23.9 to 35.4 ms) [108]. Among 1172 patients aged 65 years or greater from the CHS (Cardiovascular Health Study), even in the lowest stratum of Framingham Risk Score, abnormal values for HRV and HR turbulence identified a group with a significantly increased relative risk of mortality (RR 7.7 compared with those with normal HRV, 95% CI 3.7-16.0) [57]. Among 4652 patients in the MESA (Multi-Ethnic Study of Atherosclerosis) population who had time-domain measures of RR variability determined from a 30-second ECG rhythm strip and who were followed for a median of 7.6 years, patients in the lowest tertile of HRV had a significantly greater risk of developing heart failure (adjusted hazard ratio 2.4, 95% CI 1.4-4.2) [109]. In a 2013 meta-analysis of eight studies involving 21,988 patients, patients with the lowest HRV as measured by SDNN had a significantly higher risk of first cardiovascular events compared with patients with the greatest HRV measurements (RR 1.35, 95% CI 1.1-1.7) [110]. Furthermore, combinations of HRV measures from different domains (time domain, frequency domain, nonlinear, or HRT) may have better predictive value than HRV from a single domain because they capture different aspects of cardiac autonomic activity. HRV in combination with other risk factors By itself, HRV has limited sensitivity and specificity to sufficiently identify high-risk patients, although as previously suggested, normal HRV has been shown to be found in low risk patients. At the same time, correlations between time or frequency domain measures of HRV and previously-identified postinfarction risk factors such as left ventricular ejection fraction (LVEF) and ventricular arrhythmias are remarkably weak [84]. This lack of correlation and the fact that measures of HRV are independent predictors of patients at high risk after myocardial infarction suggest the potential utility of combining abnormal HRV with other risk stratifiers to improve risk prediction, although doing so clearly limits the proportion of patients to whom this applies [73,85,111]. As an example, among 1284 patients with a recent MI (within 28 days) followed for an average of 21 months in the ATRAMI study in whom baroreflex sensitivity and SDNN were used for risk stratification, patients with abnormal values for both had a 17 percent risk of mortality, whereas patients with normal values for both had a 2 percent risk (of note, mortality for the entire cohort was only 3.5 percent) [85]. The small number of patients with reduced HRV and LVEF less than 35 percent had nearly a sevenfold increase in mortality compared with patients with preserved HRV and LVEF of 35 percent or greater. (RR 6.7, 95% CI 3.1-14.6). HRV has also been shown to add to existing risk scores for prediction of HF and of stroke in asymptomatic older adults [112]. https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 17/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate In addition, many other conditions are associated with autonomic abnormalities, including alcoholism, chronic kidney disease, depression, severe hypertension, chemotherapy and other chemotoxins, and sleep apnea. So, if the question is whether the patient has significant autonomic neuropathy, absent or very diminished HRV may provide useful adjunctive information. The ability of serial HRV measures to identify patients with adverse responses to an intervention (eg, cardiotoxic chemotherapy) before they manifest clear deficits in cardiac function as reflected, for example, in reduced LVEF, is being investigated. As a final example, in infants, quantification of relative bradycardia and decreased heart rate variability, likely due to activation of the dorsal branch of the vagus, may provide early warning of infection-related conditions in very low birth weight infants. In preterm babies, the myelinated vagus has not yet become active, and RSA is minimal [113]. OUR APPROACH Guidelines for the routine use of ambulatory monitoring to determine heart rate variability (HRV), based on the original Task Force recommendations from 1996, were also published in 1999 by the American College of Cardiology/American Heart Association [114]. While HRV has been used for risk stratification of all-cause, cardiac, and arrhythmic death post-MI, the role for HRV testing in clinical practice remains undefined [38,115]. Based on the evidence available, we do not recommend the routine use of HRV testing outside of the clinical trial settings. We also believe that to further the field, existing and prospective datasets need to be analyzed with the goal of developing understandable and replicable algorithms that capture the rich and full clinical picture obtainable from these recordings. The diagnostic and prognostic utility of so-called ultra-short ECGs (eg, 10 to 30 seconds) or recordings for reliable estimates of short-term HRV parameters requires further study [116]. Finally, a number of articles have discussed the potential utility of HRV metrics in the diagnosis and prognosis of coronavirus disease 2019 (COVID-19) infections (eg, [117]). However, no specific or sensitive findings have yet emerged from prospective evaluations to guide clinical use of HRV in this syndrome and its associated neuroautonomic effects. (See "COVID-19: Cardiac manifestations in adults" and "COVID-19: Arrhythmias and conduction system disease".) SUMMARY AND RECOMMENDATIONS There are three major noninvasive or minimally invasive assessment approaches to evaluating the autonomic nervous system which provide complementary information https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 18/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate about autonomic as well as nonautonomic regulatory mechanisms in health and disease: heart rate variability (HRV), baroreflex sensitivity, and bedside autonomic function tests. (See 'Introduction' above.) The autonomic nervous system, including the sympathetic and parasympathetic components, has an important role in the triggering or sustaining of malignant ventricular arrhythmias. (See 'Triggering of cardiac arrhythmias and the autonomic nervous system' above.) HRV (derived from intervals between normal sinus beats NN intervals) can be measured by many methods, which can be categorized as time domain measures, frequency domain measures, nonlinear/complexity-based measures, and heart rate turbulence. (See 'HRV methodology, definitions, and normal values' above.) HRV appears to be highly consistent over 24 hours, despite marked differences among the five-minute intervals during a day. The same stability in HRV appears to be true for patients with ventricular arrhythmias, angina, and heart failure. (See 'Reproducibility of HRV measures' above.) HRV has been shown to be significantly decreased, compared with normal values, among post-myocardial infarction patients, although there is considerable inter-individual difference in this. This decreased HRV is a likely marker for autonomic dysregulation and likely reflects both decreased parasympathetic and increased sympathetic activity. Reduced HRV has also been associated with worse outcomes in patients with stable coronary heart disease, heart failure, and atrial fibrillation. Also, however, without accurate ECG analysis and an understanding of what HRV represents, HRV, especially short-term measures, can appear to be higher in the presence of either uneven beat detection or an erratic (fragmented) sinus rhythm. (See 'Clinical uses of HRV in cardiology' above.) We do not recommend the routine use of HRV testing based on clinical Holter scanning. Refinement of the conceptual framework and algorithms by which HRV is interpreted and measured lend support to the anticipation that HRV will have translational value in a variety of clinical settings. (See 'Our approach' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to earlier versions of this topic review. https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 19/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lown B, Verrier RL. Neural activity and ventricular fibrillation. N Engl J Med 1976; 294:1165. 2. Zhao M, Sun L, Liu JJ, et al. Vagal nerve modulation: a promising new therapeutic approach for cardiovascular diseases. Clin Exp Pharmacol Physiol 2012; 39:701. 3. Hask G. Receptor-mediated interaction between the sympathetic nervous system and immune system in inflammation. Neurochem Res 2001; 26:1039. 4. Jose AD, Taylor RR. Autonomic blockade by propranolol and atropine to study intrinsic myocardial function in man. J Clin Invest 1969; 48:2019. 5. Zhang D, Shen X, Qi X. 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48. Costa MD, Goldberger AL. Heart rate fragmentation: using cardiac pacemaker dynamics to probe the pace of biological aging. Am J Physiol Heart Circ Physiol 2019; 316:H1341. 49. Costa MD, Redline S, Davis RB, et al. Heart Rate Fragmentation as a Novel Biomarker of Adverse Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis. Front Physiol 2018; 9:1117. 50. Costa MD, Redline S, Soliman EZ, et al. Fragmented sinoatrial dynamics in the prediction of atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis. Am J Physiol Heart Circ Physiol 2021; 320:H256. 51. Costa MD, Redline S, Hughes TM, et al. Prediction of Cognitive Decline Using Heart Rate Fragmentation Analysis: The Multi-Ethnic Study of Atherosclerosis. Front Aging Neurosci 2021; 13:708130. 52. Mietus JE, Peng CK, Henry I, et al. The pNNx files: re-examining a widely used heart rate variability measure. Heart 2002; 88:378. 53. Schmidt G, Malik M, Barthel P, et al. 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Diurnal variation of ventricular response to atrial fibrillation in patients with advanced heart failure. Am Heart J 1995; 129:58. 64. Taylor JA, Carr DL, Myers CW, Eckberg DL. Mechanisms underlying very-low-frequency RR- interval oscillations in humans. Circulation 1998; 98:547. 65. Tripathi KK. Very low frequency oscillations in the power spectra of heart rate variability during dry supine immersion and exposure to non-hypoxic hypobaria. Physiol Meas 2011; 32:717. 66. Akselrod S, Gordon D, Ubel FA, et al. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science 1981; 213:220. 67. Peng CK, Mietus JE, Liu Y, et al. Exaggerated heart rate oscillations during two meditation techniques. Int J Cardiol 1999; 70:101. 68. Bernardi L, Sleight P, Bandinelli G, et al. Effect of rosary prayer and yoga mantras on autonomic cardiovascular rhythms: comparative study. BMJ 2001; 323:1446. 69. Peng CK, Henry IC, Mietus JE, et al. 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Topic 993 Version 33.0 https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 28/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate GRAPHICS Autonomic innervation of the heart The heart, especially the pacemaker tissue, is innervated by fibers from both the parasympathetic and sympathetic nervous systems. Graphic 69693 Version 1.0 https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 29/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate Definitions for time and frequency domain measures of heart period variability Variable Units Definition Time Domain - Statistical measures Night-day ms Difference between the average of all the normal RR intervals at night difference (24:00 to 05:00) and the average of all the normal RR intervals during the day (07:30 to 21:30). SDNN ms Standard deviation of all normal RR intervals in the entire 24-hour ECG recording. SDANN ms Standard deviation of the average normal RR intervals for all 288 5- minute segments of a 24-hour ECG recording (each average is weighted by the fraction of the 5 minutes that has normal RR intervals). ASDNN ms Average of the standard deviations of normal RR intervals for all 288 5-minute segments of a 24-hour ECG recording. r-MSSD ms Root mean square successive difference, the square root of the mean of the squared differences between adjacent normal RR intervals over the entire 24-hour ECG recording. pNN50 percent Percent of differences between adjacent normal RR intervals that are greater than 50 ms computed over the entire 24-hour ECG recording. NN50 none Number of adjacent normal RR intervals that are greater than 50 ms counted over the entire 24-hour ECG recording. Time Domain - Geometric measures HRV triangular none Total number of NN intervals divided by the number of NN intervals in index the modal bin of a histogram of all NN intervals with a bin width of 7.8125 msec (for a sampling rate of 128/sec). TINN ms Baseline width of the minimum square difference triangular interpolation of the highest peak of the histogram of all NN intervals. Frequency Domain Measures 2 Total power ms The energy in the heart period power spectrum up to 0.40 Hz. 2 Ultra low ms The energy in the heart period power spectrum up to 0.0033 Hz. frequency (ULF) power 2 Very low frequency (VLF) ms The energy in the heart period power spectrum between 0.0033 and 0.04 Hz. power https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 30/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate 2 Low frequency ms The energy in the heart period power spectrum between 0.04 and (LF) power 0.15 Hz. 2 High frequency (HF) power ms The energy in the heart period power spectrum between 0.15 and 0.40 Hz. LF/HF ratio none The ratio of low to high frequency power. beta none Slope of log (power) on log (frequency) between 0.01 and 0.0001 Hz on a log-log plot. Graphic 79145 Version 4.0 https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 31/32 7/6/23, 10:42 AM Evaluation of heart rate variability - UpToDate Contributor Disclosures Ary L Goldberger, MD Other Financial Interest: Elsevier book royalties [Clinical electrocardiography]. All of the relevant financial relationships listed have been mitigated. Phyllis K Stein, PhD No relevant financial relationship(s) with ineligible companies to disclose. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/evaluation-of-heart-rate-variability/print 32/32

7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Invasive diagnostic cardiac electrophysiology studies : Munther K Homoud, MD : Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Aug 19, 2022. INTRODUCTION Invasive cardiac electrophysiology (EP) is a collection of clinical techniques for the investigation and treatment of cardiac rhythm disorders. These techniques permit a detailed analysis of the mechanism(s) underlying the cardiac arrhythmia, precise location of the site of origin, and, when applicable, definitive treatment via catheter-based ablation techniques. An overview of invasive cardiac EP studies will be presented here. Issues related to its use in the evaluation of specific arrhythmias are discussed separately. (See "Overview of catheter ablation of cardiac arrhythmias" and "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists" and "Atrial fibrillation: Catheter ablation".) INDICATIONS AND CONTRAINDICATIONS Indications Broadly speaking, the indications for invasive EP studies can be broken down to two categories: diagnosis and risk stratification [1]. EP studies suffer from limited sensitivity and specificity. The significance of the findings is often determined by the underlying cardiac disease and the patient's clinical presentation. Diagnosis EP studies can be helpful to diagnose the etiology of syncope, sudden cardiac death, wide complex tachyarrhythmia, and atrioventricular conduction delay or disease. Syncope In many cases of syncope, an EP study can serve as a useful diagnostic test. Specific scenarios are described below: https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 1/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Syncope and ischemic or other structural heart disease The concurrent diagnosis of cardiac disease can be based on history, physical examination, electrocardiography, and/or echocardiography. The aim of an EP study for such patients would be to determine if sustained ventricular arrhythmias (or atrial tachyarrhythmias in the case of adults with congenital heart disease such as transposition of the great arteries with atrial switch) or bradyarrhythmias may be the underlying cause of heart disease [2-4]. If a patient with syncope undergoes an EP study and is induced into a clinically relevant and hemodynamically significant sustained ventricular tachycardia (VT) or ventricular fibrillation (VF), the implantation of an implantable cardioverter-defibrillator (ICD) is indicated. Syncope with suspected sinus node dysfunction Often, this is suspected based on inappropriate sinus bradycardia. The detection of a prolonged corrected sinus node recovery time may predict future recurrence of syncope [3]. Syncope in patients with bifascicular block This includes patients who have syncope with left bundle branch block, or right bundle branch block with a fascicular block when noninvasive evaluation has been unrevealing [3]. The causes of syncope in patients with bifascicular block can be multifactorial. An EP study can help delineate the cause, define the prognosis, and determine the therapy [5]. The induction of infra-Hisian block in patients with bifascicular block can predict future adverse cardiovascular events [6]. Syncope in patients who are employed in high-risk occupations (eg, airline pilots, school bus drivers, police officers) An EP study can be helpful when all other noninvasive diagnostic tools have failed to arrive at a cause for syncope. Syncope immediately following palpitations [3]. Unexplained syncope [7]. Other diagnostic indications Sudden cardiac death (SCD) with no established cause In this case, an EP study is considered a step in the diagnostic cascade recommended to try to establish a diagnosis [2,8]. Patients with wide complex tachyarrhythmias In patients in whom a diagnosis cannot be established by noninvasive means or who are suspected of harboring a life- threatening arrhythmia, an EP study can define the mechanism of the arrhythmia to help determine therapy and prognosis [9]. https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 2/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Abnormal atrioventricular (AV) conduction An EP study in such patients can help determine the site of block when clinical and electrocardiographic information fail to help localize the site of block. Rare cases of AV conduction abnormalities may be due to concealed junctional beats that can only be demonstrated through an invasive EP study [4,10]. Patients with documented tachyarrhythmias who are undergoing catheter ablation These patients will automatically undergo a diagnostic EP study, usually directed at the putative tachyarrhythmia, before catheter ablation is performed. The purpose of this EP study is to define the diagnosis and localize the pathway responsible for the arrhythmia. In the pediatric population, the role of programmed electrical stimulation is limited and is not expected to confer value beyond what has already been collected noninvasively. While a diagnostic EP study is employed in conjunction with a preplanned catheter ablation for a documented arrhythmia, it is rarely used to risk stratify patients with nonsustained polymorphic ventricular arrhythmias or to define endocardial scar [11]. Risk stratification EP studies may be helpful to risk stratify in the following conditions. Selected patients with ischemic cardiomyopathy and nonsustained VT Among patients with an ischemic cardiomyopathy due to a prior myocardial infarction or revascularization and who have left ventricular ejection fraction (LVEF) <40 percent with nonsustained VT on ambulatory cardiac rhythm monitoring, the induction of sustained VT or VF constitutes a class I indication for the implantation of an ICD [12]. The MUSTT trial enrolled patients with recent myocardial infarction or revascularization, LVEF <40 percent, and asymptomatic nonsustained VT [13]. All patients underwent an EP study. Patients in whom sustained ventricular tachyarrhythmias were induced by programmed stimulation were randomly assigned to receive either antiarrhythmic therapy, including drugs and implantable defibrillators, as indicated by the results of EP testing, or no antiarrhythmic therapy. The patients who were assigned an ICD had a lower risk of sudden cardiac death. Asymptomatic second-degree AV block, if the site of block cannot be determined reliably AV conduction abnormalities below the level of the AV node may progress to complete AV block with catastrophic consequences [14]. The site of block in patients with Mobitz type II second degree AV block is infranodal (intra- or infra-Hisian), and this constitutes an indication for pacing even if the patient is asymptomatic. An EP study is indicated if the site of block cannot be determined reliably in an asymptomatic individual with second degree AV block. If the site is infranodal, pacing is indicated [4]. https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 3/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Asymptomatic young (8 to 21 years) patients with electrocardiographic evidence of preexcitation Such patients may be at high risk of SCD due to atrial fibrillation progressing to VF. These patients are advised to undergo exercise stress testing. The clear and sudden loss of preexcitation with exercise stress testing predicts a favorable prognosis. If clear loss of preexcitation is not seen or the data are uninterpretable, invasive risk stratification via transesophageal pacing or EP studies is recommended [15]. Programmed electrical stimulation for risk stratification of a manifest accessory bypass tract is a class I indication in a symptomatic patient and a class IIa indication in an asymptomatic patient if the noninvasive measures described cannot be met [16]. (See "Wolff-Parkinson-White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis", section on 'Risk stratification of asymptomatic patients with WPW pattern'.) Cardiac sarcoidosis In patients with cardiac sarcoidosis and an LVEF >35 percent despite optimal medical therapy and immunosuppression, an EP study can be helpful. In such patients, programmed electrical stimulation can be considered to help risk stratify sudden cardiac death [12,17]. Arrhythmogenic right ventricular cardiomyopathy In patients who are asymptomatic, programmed electrical stimulation is occasionally used to help risk stratify them [12,18]. (See "Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis", section on 'Electrophysiologic testing and electroanatomic mapping'.) Tetralogy of Fallot EP studies are used for risk stratification of adults with tetralogy of Fallot with high-risk factors for sudden cardiac death, such as left ventricular systolic and diastolic dysfunction, QRS 180 milliseconds, extensive right ventricular scarring, pulmonary regurgitation or stenosis, and nonsustained VT (class IIa indication). EP studies should not be used as a screening test on patients with tetralogy of Fallot who do not have high-risk factors or in patients with repaired tetralogy of Fallot [2]. Adult patients with congenital heart disease of moderate to severe complexity who display high-risk features such as syncope and ventricular arrhythmias should undergo invasive EP studies to determine if they are at risk for sudden cardiac death and may benefit from an ICD (class IIa indication) [12]. Brugada syndrome The role of EP studies in Brugada syndrome is controversial. Patients with Brugada syndrome who have had a history of syncope or have survived sudden cardiac death are more likely to be inducible. However, the role of EP studies in predicting future events is controversial [8]. The implantation of an ICD may be considered in a patient with Brugada syndrome who is induced into VF. One study analyzed the role of clinical factors and programmed ventricular stimulation in determining the risk of https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 4/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate arrhythmic events in patients with Brugada syndrome. The investigators concluded that clinical factors such as syncope and spontaneous type 1 Brugada pattern and the induction of ventricular arrhythmias by programmed ventricular stimulation all portend a higher risk of events. The value of programmed ventricular stimulation was greater if ventricular arrhythmias were induced with single or double extrastimuli. A negative study did not predict arrhythmia-free survival [19]. Professional society guidelines allow the use of invasive programmed electrical stimulation with one to two premature ventricular extrastimuli for risk stratification of asymptomatic patients with class I Brugada pattern (class IIb) [12]. (See "Brugada syndrome or pattern: Management and approach to screening of relatives".) Contraindications Absolute contraindications to EP study include [20]: Unstable angina Bacteremia or septicemia Acute decompensated congestive heart failure not caused by the arrhythmia Major bleeding diathesis Acute lower extremity venous thrombosis if femoral vein cannulation is desired PREPROCEDURAL EVALUATION In all patients undergoing invasive EP study, the preprocedure evaluation includes a thorough history and physical examination and review of the available electrocardiograms (ECGs), both at baseline and, if available, during the tachycardia. The history should focus on the appropriateness of invasive EP study for the particular patient and screen for any potential contraindications to the procedure. Additional evaluation prior to the procedure in select patients may include: Event monitoring for up to four weeks in an effort to document the tachycardia. Event monitoring for longer periods is typically more useful than short-term (24 to 48 hours) Holter monitoring in documenting the tachycardia. (See "Ambulatory ECG monitoring".) Transthoracic echocardiography to assess for structural heart disease. Cardiac magnetic resonance imaging may also be considered for special situations (eg, suspicion of arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, etc). Exercise testing, if there is a history of exercise-induced arrhythmia. https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 5/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Cardiac catheterization and coronary angiography, if indicated by the patient's clinical presentation and symptoms suggesting coronary heart disease. If the clinical presentation is prehospital cardiac arrest or ventricular tachycardia causing hemodynamic collapse, coronary angiography and an assessment of ventricular function (eg, echocardiography, ventriculography) should usually be obtained prior to invasive EP studies with programmed cardiac stimulation. In most patients, all atrioventricular (AV) nodal blocking agents, including beta blockers, calcium blockers, digoxin, and class I and III antiarrhythmic drugs ( table 1) are discontinued several days prior to the scheduled procedure. In general, beta blockers should be gradually tapered and discontinued, while other agents can be discontinued without tapering. Because radiation exposure is a necessary component of an invasive EP study, it is reasonable to obtain a pregnancy test on all women of childbearing capacity on the morning of the procedure. (See 'Fluoroscopy' below.) PREPARATION AND MONITORING Invasive EP studies are typically performed in a dedicated EP laboratory [20]. In addition to the electrophysiologist, several other staff members are required. Intravenous conscious sedation is typically used to ensure patient comfort, although in some situations (ie, prolonged catheter ablation procedures) general anesthesia can be used. Standard electrocardiogram (ECG) leads are applied to the patient, as well as "hands-off" defibrillation pads. Arterial pressure may be monitored invasively or noninvasively, depending upon the complexity of the procedure. Oxygen saturation, as well as in some cases end-tidal CO , is monitored. 2 The following are considered part of the routine preparation and monitoring involved in invasive EP studies: Patients should be fasting after midnight on the day of the procedure, except for oral medications with sips of water. Patients should hold their normal cardiovascular medications, particularly medications which affect atrioventricular (AV) node conduction (ie, beta blockers, dihydropyridine calcium channel blockers, and digoxin) and antiarrhythmic medications ( table 1). (See 'Preprocedural evaluation' above.) Standard cardiorespiratory monitoring should include blood pressure (noninvasively or via arterial monitoring), pulse, oxygen saturation, and cardiac telemetry. https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 6/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Defibrillation pads should be placed on the patient prior to beginning the procedure ( figure 1). Intravenous access is required for administration of sedation and for management of any rhythm-related complications (ie, ventricular fibrillation, sinus bradycardia, etc). Supplemental oxygen, a suction device, and intubation equipment should be immediately available for management of respiratory complications (though supplemental oxygen should be removed prior to delivery of any electrical shocks). (See "Cardioversion for specific arrhythmias", section on 'Supplemental oxygen'.) A code cart with medications used in advanced cardiac life support should be immediately available in the event of life-threatening arrhythmias that do not respond to defibrillation. (See "Advanced cardiac life support (ACLS) in adults".) While many cardiologists are trained in the administration of procedural sedation, sedation may also be administered by an anesthesiologist who can immediately assist in the management of respiratory complications should any develop. (See "Procedural sedation in adults: General considerations, preparation, monitoring, and mitigating complications", section on 'Anticipating and mitigating Complications'.) FLUOROSCOPY Fluoroscopy is required for anatomic orientation throughout the EP study, including vascular access, catheter positioning, etc. Operators should make every effort to minimize radiation exposure to the patient as well as the procedural staff. (See "Radiation-related risks of imaging".) VASCULAR ACCESS AND ELECTRODE CATHETER PLACEMENT In nearly all EP studies, venous vascular access is required, often from multiple sites. The Seldinger technique is employed to place multiple venous accesses. The femoral approach is most common, but the subclavian, internal jugular, or brachial approach may be used, most often for placement of a catheter in the coronary sinus. Multipolar electrode catheters are positioned in the heart. Typical positions include: The right atrium (high right atrium [HRA]) Anterior tricuspid valve annulus to record the bundle of His The right ventricle (right ventricular apex [RVA]) https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 7/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate A catheter may be placed in the coronary sinus to record left atrial activation, particularly in studies of patients with supraventricular tachycardia (SVT). When mapping and ablation are performed, electrodes may be placed in the left heart. Left heart access may be obtained via either a transseptal or retrograde aortic approach. Intracardiac recordings and programmed electrical stimulation (PES) are performed via the electrode catheters. Typically, for evaluation of ventricular arrhythmias requiring LV mapping, a retrograde aortic approach is employed, while the transseptal approach is preferred for left-sided SVTs. Either approach may be used for patients with a suspected left-sided accessory pathway. When catheters are placed into left-sided cardiac chambers, systemic anticoagulation is required to prevent thromboembolic complications. Typically intravenous heparin is initiated at the time of the procedure and continued until the catheters are removed from the left-sided cardiac chambers. At the conclusion of the procedure, the access sheaths are pulled and hemostasis is achieved using manual or mechanical pressure or a vascular closure device. The patient is generally kept on bed rest for four to six more hours to ensure adequate hemostasis has been achieved. (See "Complications of diagnostic cardiac catheterization", section on 'Hemostasis at the access site' and "Percutaneous arterial access techniques for diagnostic or interventional procedures", section on 'Hemostasis at the access site'.) ELECTROCARDIOGRAPHIC AND ELECTROPHYSIOLOGIC RECORDINGS Baseline recordings Baseline recordings obtained during a typical invasive EP study include several surface electrocardiograms (ECGs) to time events from the body's surface and several intracardiac electrograms, all of which are recorded simultaneously. The intracardiac electrograms are generally displayed in the order of normal cardiac activation ( waveform 1). The first intracardiac tracing is a recording from the high right atrium (HRA) close to the sinus node. Pacing at this position allows evaluation of sinoatrial node function and atrioventricular (AV) conduction; the addition of premature atrial complex (also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat) or burst atrial pacing may result in the induction of supraventricular tachyarrhythmias. Sinus node function is determined by measuring the sinus node recovery time (SNRT), a reflection of the node's automaticity, and the sinoatrial conduction time (SACT), a reflection of peri-sinus node conduction properties. Great care must be exercised in interpreting the findings from EP studies due to limited sensitivity and specificity. https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 8/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate The next intracardiac tracing is the His bundle recording (HBE), obtained from a catheter positioned at the bundle of His (in the area of the tricuspid annulus). One to three recordings may be obtained from the coronary sinus (CS) in patients with supraventricular tachyarrhythmias or preexcitation. Since the coronary sinus runs in the mitral annulus, these recordings reflect left atrial activation. The next is a recording from a right ventricular apex (RVA) electrode catheter. The stability and reproducibility of the right ventricle apex position (during a given study as well as from one study to the next) makes it a useful site for adding premature stimuli during programmed ventricular stimulation. (See 'Programmed electrical stimulation' below.) Depending upon the particular study, other required recordings may include right bundle branch recording, left ventricular recording, transseptal left-atrial recording, and atrial and ventricular mapping catheter tracings for EP mapping and ablation. AH interval The AH interval is measured on the His bundle electrogram and represents the interval from the earliest rapid deflection of the atrial recording (activation of the lowest part of the right atrium) to the earliest onset of the His bundle deflection. This interval approximates AV nodal conduction. More precisely, however, it is the sum of conduction through the low right atrial inputs into the atrioventricular node, the atrioventricular node proper, and the proximal His bundle. The AH interval has a wide range in normal subjects (50 to 120 milliseconds) and is markedly influenced by the autonomic nervous system [21,22]. Short AH intervals may be seen in the following circumstances [23]: Increased sympathetic tone Enhanced AV nodal conduction, which may be due in some patients to steroid use or pregnancy Preferential left-atrial input into the atrioventricular node Long AH intervals are most commonly due to: Impaired or delayed AV node conduction from drugs such as digoxin, beta blockers, calcium channel blockers, and antiarrhythmic drugs, particularly amiodarone Increase parasympathetic (vagal) tone Intrinsic disease of the atrioventricular node https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 9/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Artifactually prolonged AH intervals may result from an improperly positioned catheter and the incorrect identification of a right bundle branch potential as a His bundle potential. This situation needs to be distinguished from true AH prolongation. His bundle electrogram duration The His bundle electrogram duration reflects conduction through the short length of compact His bundle that penetrates the fibrous septum. This interval is normally short (15 to 25 milliseconds), with fractionation and prolongation or even splitting of the His bundle potential, seen with disturbances of His bundle conduction ( waveform 2) [24,25]. HV interval The HV interval is measured from the earliest onset of the His bundle deflection to the earliest registered surface or intracardiac ventricular activation anywhere. This measurement reflects conduction time through the distal His-Purkinje system. Unlike the AV node, the His-Purkinje system is far less influenced by the autonomic nervous system, and the range in normal subjects is narrow (35 to 55 milliseconds) [26]. A prolonged HV interval is consistent with diseased distal conduction in all fascicles [27]. In patients with symptoms suggesting a bradyarrhythmia, a prolonged HV interval (>55 milliseconds) warrants pacemaker therapy. In asymptomatic patients with an HV interval >100 milliseconds, a pacemaker is also indicated [28,29]. In asymptomatic patients with an HV interval >70 milliseconds, pacemakers are more controversial [27,28,30]. A validated short HV interval suggests one of two situations: Ventricular preexcitation via an AV bypass tract Ventricular origin for the beats, such as ventricular premature beats (VPBs) or an accelerated idioventricular rhythm that is isorhythmic with the sinus rhythm A spurious explanation for a short HV interval is the inadvertent recording of a right bundle branch potential rather than a His potential. VA conduction The assessment of ventriculoatrial (VA) conduction is also important in the EP study, particularly for patients with a supraventricular tachycardia (SVT). This is performed by ventricular extrastimulus and incremental ventricular pacing. Absence of VA conduction makes certain SVTs less likely (ie, atrioventricular reciprocating tachycardia and atrioventricular nodal reentrant tachycardia) and suggests an atrial tachycardia (AT), since AT is independent of retrograde VA conduction. Sinoatrial conduction time The usual method of calculating sinoatrial conduction time (SACT), which is a measure of sinus node function, is an indirect measure. This approach involves the placement of a catheter in the superior aspect of the right atrium approximating the main https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 10/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate intrinsic pacemaker site of the SA node. Progressively premature atrial extrastimuli are introduced by way of that catheter after every 8th to 10th beat of either a stable sinus rhythm (Strauss method) [31] or atrial pacing (Narula method) [32]. Due to the limitations of indirect methods in assessing the SACT, techniques for direct recording of the sinus electrogram (EGM) have been developed [33-38]. Endocardial recordings demonstrate diastolic phase 4 activity followed by a slow upstroke culminating in a rapid atrial EGM. The directly measured SACT was defined as the interval between the local EGM and the rapid atrial deflection. Normal SACT times generally range from 40 to 150 milliseconds, depending upon the laboratory [39,40]. Studies have shown a good correlation between indirect and direct methods of measuring SACT [35,37,38,41]. However, SACT is a relatively insensitive test for SA node dysfunction. Sinus node recovery time The sinus node recovery time (SNRT) is performed by placing a catheter near the SA node and pacing (overdrive suppression) for at least 30 seconds at a fixed cycle length starting slightly faster than the intrinsic sinus rate. This is repeated at progressively shorter cycle lengths. Pacing rates up to 200 beats per minute may be employed for improved sensitivity [42]. It is important to wait at least one minute between pacing sequences to allow full recovery of the SN. Confirmation that the escape beat is sinus by examining P-wave morphology and atrial activation sequence is essential to exclude a shift in pacemaker site [43]. The maximum SNRT is the longest pause from the last pacing stimulus to the first spontaneously occurring sinus beat at any paced cycle length. As the sinus cycle length (SCL) affects the SNRT, it is often normalized or corrected: The SNRT is normalized by dividing this value by the SCL. The corrected sinus node recovery time (CSNRT) is determined by subtracting the SCL from the SNRT ( waveform 3). A total recovery time (TRT) can also be calculated, which is the time required to return to the basal sinus rate. Normal values have generally been estimated as follows [43]: SNRT/SCL <150 percent CSNRT <550 milliseconds TRT less than five seconds https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 11/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate There are several limitations to the use of overdrive suppression in determining SN function, which include changes in autonomic tone due to the effects of pacing, changes in P-wave morphology or atrial activation suggesting a pacemaker shift, sinoatrial entrance block, and secondary pauses. PROGRAMMED ELECTRICAL STIMULATION After baseline measurements are recorded, pacing is performed via the intracardiac electrode catheters. Burst pacing at various fixed cycle lengths as well as programmed electrical stimulation (PES) is administered. With PES, a number of stimuli at a fixed cycle length are delivered (eg, eight beats at a rate of 100 beats per minute), followed by a premature beat. The coupling interval of the premature beat is progressively shortened until the refractory period of the tissue being paced is reached. Multiple premature stimuli can be introduced. The technique of PES is used to assess the atrioventricular (AV) conducting system and to induce supraventricular and ventricular arrhythmias. Premature beats can be introduced during a tachyarrhythmia to probe the mechanism of the tachycardia. Programmed atrial stimulation is usually from the high right atrium, although a second atrial site such as coronary sinus pacing is also employed in certain situations ( waveform 4A-B) [44,45]. One or sometimes two atrial extrastimuli with progressively shorter coupling intervals are delivered following a train of eight or more drive beats at several cycle lengths until atrial refractoriness is encountered [45,46]. Incremental atrial pacing in steps of 10 milliseconds is also performed until second degree AV block develops. Programmed atrial extrastimuli can be used to determine the effective refractory period of the His-Purkinje system (HPS), which should be <450 milliseconds. However, the response of refractory periods to pacing may reveal severe HPS disease. As the refractory period of the HPS should shorten with the cycle length, an increasing refractory period with shorter cycle lengths indicates abnormal HPS conduction [29]. MEDICATIONS USED FOR DIAGNOSTIC PURPOSES DURING EPS Administration of pharmacologic agents may be of help in certain settings. Selective blocking of antegrade atrioventricular (AV) nodal conduction with adenosine, for example, may unmask latent accessory pathway conduction. Atropine or isoproterenol may be used to facilitate the induction of AV nodal reentrant tachycardia (AVNRT) or AV reentrant tachycardia (AVRT) by enhancing ventriculoatrial (VA) conduction in patients with poorer AV nodal conduction https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 12/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate characteristics [47] or by widening the tachycardia zone or the section of the cardiac cycle during which extrastimuli cause the necessary block and the critical delay to initiate reentrant activation. Procainamide normally prolongs the HV interval by 10 to 20 percent [48]. Doubling of the HV interval, an HV interval >100 milliseconds, or the development of infra-Hisian block after administering procainamide represent poor HPS reserve and probably mandates permanent pacing ( waveform 5) [29,49]. Evaluation of His-Purkinje system (HPS) conduction can be limited by AV nodal conduction (ie, block in the AV node preventing evaluation of the HPS). In these instances, atropine is often used to shorten the refractory period of the AV node without affecting HPS conduction [50]. MAPPING AND ABLATION In many cases, catheter ablation immediately follows the diagnostic EP study. Cardiac mapping refers to careful movement of a mapping or ablation catheter in the area of interest, probing for the site at which radiofrequency ablation will be successful at curing the arrhythmia. Cardiac mapping during EP testing identifies the temporal and spatial distributions of electrical potentials generated by the myocardium during normal and abnormal rhythms. This process allows description of the spread of activation from its initiation to its completion within a region of interest and, in its usual application, is focused toward the identification of the site of origin or a critical site of conduction for an arrhythmia. Multiple techniques for mapping have been developed. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Mapping and localization of the arrhythmia'.) COMPLICATIONS OF INVASIVE CARDIAC ELECTROPHYSIOLOGY STUDIES Complications of invasive cardiac EP studies are rare, with reported complication rates of approximately 2 percent [51,52]. Serious complications of these procedures are generally related to the catheterization process itself, including vascular injury, tricuspid valve damage, pulmonary embolism, hemorrhage requiring transfusion therapy, cardiac chamber perforation resulting in pericardial tamponade, sepsis from catheterization site abscess, myocardial infarction, stroke, and death ( table 2). The induction of serious ventricular tachyarrhythmias occurs frequently during diagnostic EP testing. Such arrhythmias can usually be promptly terminated, either by overdrive pacing or https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 13/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate external defibrillation. However, if the arrhythmia is difficult to revert and is of long duration, there may be complications related to the prolonged hypotension and, rarely, sudden death. Complications with concomitant catheter ablation Catheter-based radiofrequency (RF) ablation procedures are typically much longer studies with more radiation exposure, administration of higher doses of sedative and analgesic agents, more frequent catheterization of the left heart, and more frequent change of catheters. The duration of some of the RF ablation procedures may raise morbidity from vascular complications, thromboembolic complications, cardiac chamber rupture, or radiation exposure including skin injuries and a possible increased risk for malignancy ( table 2). These issues are discussed in detail separately. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Complications'.) With the rapid expansion of clinical cardiac EP beginning in the 1990s, the complexity of the procedures performed in the EP laboratory has greatly increased, and, along with the increased complexity, the risks involved have increased. To meet the expanding demands and help provide patients and staff with the safest possible and most productive environment, guidelines concerning the staffing and qualifications of the EP laboratory personnel, as well as the design of the laboratory itself, have been issued [53]. SUMMARY AND RECOMMENDATIONS Background Invasive cardiac electrophysiology (EP) study permits a detailed analysis of the mechanism underlying the cardiac arrhythmia and precise location of the site of origin. (See 'Introduction' above and 'Indications and contraindications' above.) Preprocedural evaluation This occurs prior to catheter ablation and includes a history and physical examination along with an electrocardiogram (ideally during the arrhythmia) or strips from ambulatory monitoring that document the arrhythmia in every patient. Consideration of other testing prior to the ablation should be based on the patient's clinical presentation and symptoms but may include echocardiography, stress testing, cardiac magnetic resonance imaging, or coronary angiography to evaluate for underlying structural heart disease. (See 'Preprocedural evaluation' above.) Catheter placement and baseline recordings Multipolar electrode catheters are positioned in the heart. Typical positions include the right atrium (high right atrium) and right ventricle (right ventricular apex); a catheter is also positioned across the tricuspid annulus to record a potential from the bundle of His https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 14/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate (His). A catheter may be placed in the coronary sinus to record left-atrial activation, particularly in studies of patients with supraventricular tachycardia (SVT). These electrodes allow for the measurement of several intervals with diagnostic implications. (See 'Vascular access and electrode catheter placement' above.) Baseline recordings obtained during a typical invasive EP study include several surface electrocardiograms to time events from the body's surface and several intracardiac electrograms, all of which are recorded simultaneously. The intracardiac electrograms are generally displayed in the order of normal cardiac activation ( waveform 1). (See 'Electrocardiographic and electrophysiologic recordings' above.) Programmed electrical stimulation After baseline measurements are recorded, pacing is performed via the intracardiac electrode catheters. Burst pacing at various fixed cycle lengths as well as programmed electrical stimulation (PES) is administered. The technique of PES is used to assess the atrioventricular (AV) conducting system and to induce supraventricular and ventricular arrhythmias. Administration of pharmacologic agents may be of help in certain settings. (See 'Programmed electrical stimulation' above and 'Medications used for diagnostic purposes during EPS' above.) Mapping and ablation Cardiac mapping refers to careful movement of a mapping or ablation catheter in the area of interest, probing for the site at which radiofrequency ablation will be successful at curing the arrhythmia. Cardiac mapping during EP testing identifies the temporal and spatial distributions of electrical potentials generated by the myocardium during normal and abnormal rhythms. This process allows description of the spread of activation from its initiation to its completion within a region of interest. Multiple techniques for mapping have been developed. (See 'Mapping and ablation' above.) Complications These are rare but can be potentially life threatening ( table 2). (See 'Complications of invasive cardiac electrophysiology studies' above.) ACKNOWLEDGMENT The authors and UpToDate thank Dr. Philip Podrid, Dr. Leonard Ganz, Dr. Joseph Germano, Dr. Peter Zimetbaum, and Dr. Brian Olshansky who contributed to earlier versions of this content. Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 15/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate 1. Muresan L, Cismaru G, Martins RP, et al. Recommendations for the use of

activation. Procainamide normally prolongs the HV interval by 10 to 20 percent [48]. Doubling of the HV interval, an HV interval >100 milliseconds, or the development of infra-Hisian block after administering procainamide represent poor HPS reserve and probably mandates permanent pacing ( waveform 5) [29,49]. Evaluation of His-Purkinje system (HPS) conduction can be limited by AV nodal conduction (ie, block in the AV node preventing evaluation of the HPS). In these instances, atropine is often used to shorten the refractory period of the AV node without affecting HPS conduction [50]. MAPPING AND ABLATION In many cases, catheter ablation immediately follows the diagnostic EP study. Cardiac mapping refers to careful movement of a mapping or ablation catheter in the area of interest, probing for the site at which radiofrequency ablation will be successful at curing the arrhythmia. Cardiac mapping during EP testing identifies the temporal and spatial distributions of electrical potentials generated by the myocardium during normal and abnormal rhythms. This process allows description of the spread of activation from its initiation to its completion within a region of interest and, in its usual application, is focused toward the identification of the site of origin or a critical site of conduction for an arrhythmia. Multiple techniques for mapping have been developed. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Mapping and localization of the arrhythmia'.) COMPLICATIONS OF INVASIVE CARDIAC ELECTROPHYSIOLOGY STUDIES Complications of invasive cardiac EP studies are rare, with reported complication rates of approximately 2 percent [51,52]. Serious complications of these procedures are generally related to the catheterization process itself, including vascular injury, tricuspid valve damage, pulmonary embolism, hemorrhage requiring transfusion therapy, cardiac chamber perforation resulting in pericardial tamponade, sepsis from catheterization site abscess, myocardial infarction, stroke, and death ( table 2). The induction of serious ventricular tachyarrhythmias occurs frequently during diagnostic EP testing. Such arrhythmias can usually be promptly terminated, either by overdrive pacing or https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 13/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate external defibrillation. However, if the arrhythmia is difficult to revert and is of long duration, there may be complications related to the prolonged hypotension and, rarely, sudden death. Complications with concomitant catheter ablation Catheter-based radiofrequency (RF) ablation procedures are typically much longer studies with more radiation exposure, administration of higher doses of sedative and analgesic agents, more frequent catheterization of the left heart, and more frequent change of catheters. The duration of some of the RF ablation procedures may raise morbidity from vascular complications, thromboembolic complications, cardiac chamber rupture, or radiation exposure including skin injuries and a possible increased risk for malignancy ( table 2). These issues are discussed in detail separately. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Complications'.) With the rapid expansion of clinical cardiac EP beginning in the 1990s, the complexity of the procedures performed in the EP laboratory has greatly increased, and, along with the increased complexity, the risks involved have increased. To meet the expanding demands and help provide patients and staff with the safest possible and most productive environment, guidelines concerning the staffing and qualifications of the EP laboratory personnel, as well as the design of the laboratory itself, have been issued [53]. SUMMARY AND RECOMMENDATIONS Background Invasive cardiac electrophysiology (EP) study permits a detailed analysis of the mechanism underlying the cardiac arrhythmia and precise location of the site of origin. (See 'Introduction' above and 'Indications and contraindications' above.) Preprocedural evaluation This occurs prior to catheter ablation and includes a history and physical examination along with an electrocardiogram (ideally during the arrhythmia) or strips from ambulatory monitoring that document the arrhythmia in every patient. Consideration of other testing prior to the ablation should be based on the patient's clinical presentation and symptoms but may include echocardiography, stress testing, cardiac magnetic resonance imaging, or coronary angiography to evaluate for underlying structural heart disease. (See 'Preprocedural evaluation' above.) Catheter placement and baseline recordings Multipolar electrode catheters are positioned in the heart. Typical positions include the right atrium (high right atrium) and right ventricle (right ventricular apex); a catheter is also positioned across the tricuspid annulus to record a potential from the bundle of His https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 14/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate (His). A catheter may be placed in the coronary sinus to record left-atrial activation, particularly in studies of patients with supraventricular tachycardia (SVT). These electrodes allow for the measurement of several intervals with diagnostic implications. (See 'Vascular access and electrode catheter placement' above.) Baseline recordings obtained during a typical invasive EP study include several surface electrocardiograms to time events from the body's surface and several intracardiac electrograms, all of which are recorded simultaneously. The intracardiac electrograms are generally displayed in the order of normal cardiac activation ( waveform 1). (See 'Electrocardiographic and electrophysiologic recordings' above.) Programmed electrical stimulation After baseline measurements are recorded, pacing is performed via the intracardiac electrode catheters. Burst pacing at various fixed cycle lengths as well as programmed electrical stimulation (PES) is administered. The technique of PES is used to assess the atrioventricular (AV) conducting system and to induce supraventricular and ventricular arrhythmias. Administration of pharmacologic agents may be of help in certain settings. (See 'Programmed electrical stimulation' above and 'Medications used for diagnostic purposes during EPS' above.) Mapping and ablation Cardiac mapping refers to careful movement of a mapping or ablation catheter in the area of interest, probing for the site at which radiofrequency ablation will be successful at curing the arrhythmia. Cardiac mapping during EP testing identifies the temporal and spatial distributions of electrical potentials generated by the myocardium during normal and abnormal rhythms. This process allows description of the spread of activation from its initiation to its completion within a region of interest. Multiple techniques for mapping have been developed. (See 'Mapping and ablation' above.) Complications These are rare but can be potentially life threatening ( table 2). (See 'Complications of invasive cardiac electrophysiology studies' above.) ACKNOWLEDGMENT The authors and UpToDate thank Dr. Philip Podrid, Dr. Leonard Ganz, Dr. Joseph Germano, Dr. Peter Zimetbaum, and Dr. Brian Olshansky who contributed to earlier versions of this content. Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 15/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate 1. Muresan L, Cismaru G, Martins RP, et al. Recommendations for the use of electrophysiological study: Update 2018. Hellenic J Cardiol 2019; 60:82. 2. Khairy P, Van Hare GF, Balaji S, et al. PACES/HRS Expert Consensus Statement on the Recognition and Management of Arrhythmias in Adult Congenital Heart Disease: developed in partnership between the Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS). 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Zipes DP, Calkins H, Daubert JP, et al. 2015 ACC/AHA/HRS Advanced Training Statement on Clinical Cardiac Electrophysiology (A Revision of the ACC/AHA 2006 Update of the Clinical Competence Statement on Invasive Electrophysiology Studies, Catheter Ablation, and Cardioversion). J Am Coll Cardiol 2015; 66:2767. https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 17/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate 21. Narula OS, Cohen LS, Samet P, et al. Localization of A-V conduction defects in man by recording of the His bundle electrogram. Am J Cardiol 1970; 25:228. 22. Castellanos A Jr, Castillo CA, Agha AS. Symposium on Electophysiologic Correlates of Clinical Arrhythmias. 3. Contribution of His bundle recordings to the understanding of clinical arrhythmias. Am J Cardiol 1971; 28:499. 23. Benditt DG, Klein GJ, Kriett JM, et al. Enhanced atrioventricular nodal conduction in man: electrophysiologic effects of pharmacologic autonomic blockade. Circulation 1984; 69:1088. 24. Amat-y-Leon F, Dhingra R, Denes P, et al. The clinical spectrum of chronic His bundle block. Chest 1976; 70:747. 25. Bharati S, Lev M, Wu D, et al. Pathophysiologic correlations in two cases of split His bundle potentials. Circulation 1974; 49:615. 26. Kupersmith J, Krongrad E, Waldo AL. Conduction intervals and conduction velocity in the human cardiac conduction system. Studies during open-heart surgery. Circulation 1973; 47:776. 27. Dhingra RC, Palileo E, Strasberg B, et al. Significance of the HV interval in 517 patients with chronic bifascicular block. Circulation 1981; 64:1265. 28. Scheinman MM, Peters RW, Suav MJ, et al. Value of the H-Q interval in patients with bundle branch block and the role of prophylactic permanent pacing. Am J Cardiol 1982; 50:1316. 29. Josephson ME. Intraventricular Conduction Disturbances. In: Clinical Cardiac Electrophysiolo gy. Techniques and Interpretations, 3rd ed, Josephson ME (Ed), Lippincott, Philadelphia 200 2. p.110. 30. McAnulty JH, Rahimtoola SH, Murphy E, et al. Natural history of "high-risk" bundle-branch block: final report of a prospective study. N Engl J Med 1982; 307:137. 31. Strauss HC, Bigger JT, Saroff AL, Giardina EG. Electrophysiologic evaluation of sinus node function in patients with sinus node dysfunction. Circulation 1976; 53:763. 32. Narula OS, Shantha N, Vasquez M, et al. A new method for measurement of sinoatrial conduction time. Circulation 1978; 58:706. 33. Cramer M, Hariman RJ, Boxer R, Hoffman BF. Electrograms from the canine sinoatrial pacemaker recorded in vitro and in situ. Am J Cardiol 1978; 42:939. 34. Cramer M, Siegal M, Bigger JT Jr, Hoffman BF. Characteristics of extracellular potentials recorded from the sinoatrial pacemaker of the rabbit. Circ Res 1977; 41:292. 35. Gomes JA, Kang PS, El-Sherif N. The sinus node electrogram in patients with and without sick sinus syndrome: techniques and correlation between directly measured and indirectly estimated sinoatrial conduction time. Circulation 1982; 66:864. https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 18/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate 36. Hariman RJ, Krongrad E, Boxer RA, et al. Method for recording electrical activity of the sinoatrial node and automatic atrial foci during cardiac catheterization in human subjects. Am J Cardiol 1980; 45:775. 37. Reiffel JA, Bigger JT Jr. Current status of direct recordings of the sinus node electrogram in man. Pacing Clin Electrophysiol 1983; 6:1143. 38. Reiffel JA, Gang E, Gliklich J, et al. The human sinus node electrogram: a transvenous catheter technique and a comparison of directly measured and indirectly estimated sinoatrial conduction time in adults. Circulation 1980; 62:1324. 39. Dhingra RC, Wyndham C, Amat-Y-Leon, et al. Sinus nodal responses to atrial extrastimuli in patients without apparent sinus node disease. Am J Cardiol 1975; 36:445. 40. Strauss HC, Saroff AL, Bigger JT Jr, Giardina EG. Premature atrial stimulation as a key to the understanding of sinoatrial conduction in man. Presentation of data and critical review of the literature. Circulation 1973; 47:86. 41. Rakovec P, Jakopin J, Rode P, et al. Clinical comparison of indirectly and directly determined sinoatrial conduction time. Am Heart J 1981; 102:292. 42. Heddle, W, Dorveaux, et al. Use of rapid atrial pacing to assess sinus node function. Clin Prog Electrophysiol Pacing 1985; 3:299. 43. Josephson ME. Sinus Node Dysfunction. In: Clinical Cardiac Electrophysiology. Techniques an d Interpretations, 3rd ed, Josephson ME (Ed), Lippincott, Philadelphia 2002. p.68. 44. Wellens HJ, Brugada P, B r FW. Indications for use of intracardiac electrophysiologic studies for the diagnosis of site of origin and mechanism of tachycardias. Circulation 1987; 75:III110. 45. Brugada P, Farr J, Green M, et al. Observations in patients with supraventricular tachycardia having a P-R interval shorter than the R-P interval: differentiation between atrial tachycardia and reciprocating atrioventricular tachycardia using an accessory pathway with long conduction times. Am Heart J 1984; 107:556. 46. Denes P, Wu D, Amat-y-Leon F, et al. The determinants of atrioventricular nodal re-entrance with premature atrial stimulation in patients with dual A-V nodal pathways. Circulation 1977; 56:253. 47. Yu WC, Chen SA, Chiang CE, et al. Effects of isoproterenol in facilitating induction of slow- fast atrioventricular nodal reentrant tachycardia. Am J Cardiol 1996; 78:1299. 48. Josephson ME, Caracta AR, Ricciutti MA, et al. Electrophysiologic properties of procainamide in man. Am J Cardiol 1974; 33:596. https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 19/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate 49. Tonkin AM, Heddle WF, Tornos P. Intermittent atrioventricular block: procainamide administration as a provocative test. Aust N Z J Med 1978; 8:594. 50. Akhtar M, Damato AN, Caracta AR, et al. Electrophysiologic effects of atropine on atrioventricular conduction studied by His bundle electrogram. Am J Cardiol 1974; 33:333. 51. Dimarco JP, Garan H, Ruskin JN. Complications in patients undergoing cardiac electrophysiologic procedures. Ann Intern Med 1982; 97:490. 52. Horowitz LN, Kay HR, Kutalek SP, et al. Risks and complications of clinical cardiac electrophysiologic studies: a prospective analysis of 1,000 consecutive patients. J Am Coll Cardiol 1987; 9:1261. 53. Haines DE, Beheiry S, Akar JG, et al. Heart Rythm Society expert consensus statement on electrophysiology laboratory standards: process, protocols, equipment, personnel, and safety. Heart Rhythm 2014; 11:e9. Topic 980 Version 32.0 https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 20/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 21/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 22/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Options for hands-free pacemaker/defibrillator pad positioning Positioning options for hands-free pacemaker/defibrillator pads showing anterior/lateral positioning (left) and anterior/posterior positioning (right). Graphic 103268 Version 2.0 https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 23/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Normal intracardiac electrograms obtained during invasive electrophysiologic study (EPS) The normal intracardiac electrograms, during sinus rhythm, obtained during an electrophysiologic study are shown. Three surface electrocardiogram (ECG) leads are monitored (I, aVF, and V1); intracardiac electrograms are obtained from the high right atrium (HRA); the proximal (p), mid (m), and distal (d) bundle of His (HBE); the p, m, and d coronary sinus (CS); and right ventricular apex (RVA). For an ablation procedure, an exploratory catheter (exp) is also used for more extensive mapping. The electrogram obtained includes those from the atrium (A), bundle of His (H), and ventricle (V). Graphic 64875 Version 4.0 https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 24/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Electrophysiologic study (EPS) in advanced conduction disease showing intra-Hisian block The tracing, obtained during an electophysiologic study, records three surface electrocardiogram (ECG) leads (1, 2, and V1) and the bundle of His electrogram (HBE). The first two sinus beats (SB) are conducted normally from the atrium to the ventricle, but the HBE manifests a split bundle of His electrograms (H and H'). The proximal component (H) is present following a nonconducted P wave (P*), but the distal bundle of His (H') is not activated. The level of atrioventricular block is sharply defined as being intra-Hisian, indicating advanced conduction system disease. A: atrial electrogam; V: ventricular electrogram. Graphic 80538 Version 7.0 https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 25/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Electrophysiology study (EPS) tracings used in the determination of the corrected sinus node recovery time (SNRT) This tracing is from a 76-year-old male with paroxysmal atrial fibrillation and recurrent near syncope associated with palpitations. Surface leads represented are I, II, III, V1, and V6. Intracardiac tracings shown are the high right atrium (HRA d), the proximal His bundle electrogram (HIS p), the mid His bundle electrogram (HIS m), the distal His bundle electrogram (HIS d), and the right ventricular apex (RVa d). High right atrial pacing at 400 milliseconds (150 beats per minute) is performed for 30 seconds. Upon termination of pacing, a sinus node recovery time of 2150 milliseconds is observed (arrow). The basal sinus cycle length was 1200 milliseconds, giving a corrected sinus node recovery time of 950 milliseconds, consistent with severe sinus node dysfunction. Note the significant secondary pause extending beyond the end of the tracing providing additional evidence of sinus node dysfunction. ms: milliseconds. Courtesy of Joseph J Germano, DO. Graphic 58763 Version 5.0 https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 26/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Initiation and termination of an atrioventricular reentrant tachycardia captured during invasive electrophysiology studies (EPS) During atrial pacing (S1), a premature atrial beat (S2) is blocked antegradely in the accessory pathway and conducts through the atrioventricular node with a long delay (A2H2 interval), which allows for the recovery of the accessory pathway before retrograde conduction (panel A). The mechanism is an orthodromic atrioventricular reentrant tachycardia (AVRT) using a left- sided pathway, suggested by the atrial activation sequence; earliest retrograde atrial activation during the first echo beat of AVRT (Ae) is in the https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 27/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate mid coronary sinus (CSm). A single ventricular premature beat (VPB) terminates the AVRT (panel B). The VPB conducts to the left atrium but encounters the refractory period of the AV node and is blocked, interrupting conduction in the antegrade limb and terminating the arrhythmia. V: ventricular electrogram; A: atrial electrogram; NSR: normal sinus rhythm; d: distal; p: proximal. Graphic 81938 Version 7.0 https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 28/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Electrophysiology study (EPS) tracing during mapping of atrial tachycardia Shown are three surface electrocardiogram (ECG) leads (I, aVF, V1) and intracardiac recordings from the high posterior right atrium (HRA); posterior left atrium (USER1 and USER 3); proximal, mid, and distal coronary sinuses (CS9-10, CS5-6, CS1-2); and right ventricular apex (RVA). The patient had an incessant atrial tachycardia and dilated cardiomyopathy (left ventricular ejection fraction 9 percent) referred for cardiac transplant evaluation. The P wave (*) falls at the end of the T wave in the surface ECG; its onset is difficult to discern. However, the intracardiac electrograms demonstrate obvious atrial (A) and ventricular (V) activity. Activation mapping involves positioning the mapping catheters in the right (HRA) and left atria (USER) to record earliest electrical activity during the tachycardia. The left atrial catheter records earlier electrical activity (arrow) than the right atrial catheter, but the timing with respect to the surface P wave is obscured because of the T wave of the preceding QRS complex. Graphic 58120 Version 7.0 https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 29/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Electrophysiology study (EPS) tracing showing the effects of procainamide on an abnormal His-Purkinje conduction system These tracings were taken from a 58-year-old male with syncope. The baseline 12-lead electrocardiogram demonstrated sinus rhythm with prolonged atrioventricular (AV) conduction and a left bundle branch block with left axis deviation. Surface leads represented are I, II, III, and V1. Intracardiac tracings shown are the high right atrium (HRA), the distal His bundle electrogram (HIS d), the proximal His bundle electrogram (HIS 2), and the right ventricular apex (RVa). The left side of Panel A shows a baseline HV interval of 68 milliseconds. The right side of Panel A demonstrates prolongation of the HV interval to 100 milliseconds after the administration of procainamide indicating severe His-Purkinje conduction disease. Panel B (same lead schema) demonstrates high right atrial pacing at 400 milliseconds (150 beats per minute) with infra-Hisian block (arrow) after the administration of procainamide, confirming severe His-Purkinje disease. A: atrial depolarization; H: His bundle depolarization; msec: milliseconds; V: ventricular depolarization. Courtesy of Joseph J Germano, DO. Graphic 56786 Version 5.0 https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 30/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Complications of invasive cardiac electrophysiology studies Associated with percutaneous catheterization of veins and arteries Pain Adverse drug reaction Infection/abscess at the catheterization site, sepsis Excessive bleeding, hematoma formation Thrombophlebitis Pulmonary thromboembolism Arterial damage, aortic dissection Systemic thromboembolism Transient ischemic attack/stroke Associated with intracardiac catheters and programmed cardiac stimulation Cardiac chamber or coronary sinus perforation Hemopericardium, cardiac tamponade Atrial fibrillation Ventricular tachycardia/ventricular fibrillation Myocardial infarction Right or left bundle branch block Associated with transcatheter ablation Complete heart block Thromboembolism Vascular access problems (bleeding, infection, hematoma, vascular injury) Cardiac trauma (myocardial perforation, tamponade, valvular damage) Coronary artery thrombosis/myocardial infarction Cardiac arrhythmias Pericarditis Pulmonary vein stenosis Phrenic nerve paralysis Radiation skin burns Possible late malignancy Atrioesophageal fistula https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 31/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Death resulting from one of the above complications Graphic 63157 Version 4.0 https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 32/33 7/6/23, 10:42 AM Invasive diagnostic cardiac electrophysiology studies - UpToDate Contributor Disclosures Munther K Homoud, MD Speaker's Bureau: Abbott [Live heart dissection]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/invasive-diagnostic-cardiac-electrophysiology-studies/print 33/33

7/6/23, 10:42 AM Role of echocardiography in atrial fibrillation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Role of echocardiography in atrial fibrillation : Warren J Manning, MD : Bradley P Knight, MD, FACC : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 03, 2023. INTRODUCTION Atrial fibrillation (AF) is the most common treated arrhythmia. Echocardiography plays a key role in evaluation and management of patients with AF. The topic will review the use of echocardiography in evaluating patients with AF. An overview of AF is presented separately. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) OBJECTIVES The role of echocardiographic imaging among patients with AF can be divided into two main categories: Assessment of cardiac chamber sizes and function, the atrial contribution to left ventricular filling, the pericardium, and valvular function. This information may be helpful in determining the conditions associated with AF, the risk for recurrent AF following cardioversion, and the hemodynamic benefit of maintaining sinus rhythm. This information is generally obtained from transthoracic echocardiography (TTE), with moderately invasive transesophageal echocardiography (TEE) generally reserved for assessment of the left atrial appendage for thrombus prior to cardioversion. (See "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) https://www.uptodate.com/contents/role-of-echocardiography-in-atrial-fibrillation/print 1/16 7/6/23, 10:42 AM Role of echocardiography in atrial fibrillation - UpToDate Identification of patients at increased risk for thromboembolic complications of AF before cardioversion and in patients with chronic AF. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) INDICATIONS Nearly all patients presenting with their first episode of AF will benefit from transthoracic (surface) echocardiographic (TTE) evaluation of left atrial size, left ventricular cavity size and regional/global systolic function, and mitral valve morphology and function. Examination of prior TTE data (if available) may allow for assessment of the atrial contribution to left ventricular filling (transmitral Doppler peak A wave velocity) when the patient is in sinus rhythm so as to have an assessment of the atrial contribution to ventricular filling. (See 'Transthoracic echocardiography' below.) A more selected subgroup may benefit from the additional information obtained from transesophageal echocardiographic (TEE) evaluation for left atrial thrombi to allow for early cardioversion if no thrombi are identified. (See 'Transesophageal echocardiography' below and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) TRANSTHORACIC ECHOCARDIOGRAPHY TTE provides detailed information about cardiac anatomy and function. In comparison to TEE, TTE is less useful for the detection of atrial thrombus, especially thrombus in the right atrial appendage or left atrial appendage (LAA), which is better detected by TEE. (See 'Left atrial thrombi' below.) Left atrial size TTE is particularly helpful in assessing the size of the body of the left atrium. 2 The normal left atrial dimension in adults is less than 4.0 cm (or less than 2.0 cm/m body 2 surface area) or biplane derived left atrial volume index of less than 34 mL/m body surface area. Left atrial enlargement is common in AF, particularly in patients with mitral valve disease (both stenosis and regurgitation), left ventricular cavity dilation, annular calcification, or hypertension [1]. In addition, sustained AF itself can lead to a further increase in left atrial size [2], an effect that is reversible after cardioversion and maintenance of sinus rhythm [3]. Pulsed Doppler studies have shown that the time to recovery of atrial mechanical function is directly related to the duration of AF (eg, within 24 hours in patients with AF for less than 2 weeks; up to a week for patients who have been in AF for two to six weeks; and up to a month for patients https://www.uptodate.com/contents/role-of-echocardiography-in-atrial-fibrillation/print 2/16 7/6/23, 10:42 AM Role of echocardiography in atrial fibrillation - UpToDate with sustained AF for more than six weeks) [4]. However, the routine serial assessment of atrial mechanical function recovery is not recommended and TTE Doppler assessment of atrial recovery does not predict long term maintenance of sinus rhythm. (See "Echocardiographic evaluation of the atria and appendages".) Regardless of the mechanism, left atrial enlargement is important prognostically. It decreases the probability that long-term maintenance of sinus rhythm will be successful [5-7]. Patients with chronic (more than one year) AF, rheumatic mitral valve disease, or severe left atrial 2 enlargement (dimension greater than 6.0 cm or left atrial volume greater than 48 mL/m ) are at greatest risk for recurrent AF [7]. If, however, the duration of AF is brief, an attempt at cardioversion is reasonable for most patients regardless of absolute left atrial size. (See "Atrial fibrillation: Cardioversion".) Although TTE can provide anatomic imaging of the body of the left atrium, TEE is preferred when looking for left atrial thrombi and assessing LAA and right atrial appendage anatomy and function (abnormalities of which predispose to the thrombus formation), as these areas are not well seen on TTE. Few data are known regarding the impact of AF on atrial appendage anatomy, though sustained AF does lead to progressively more impaired LAA ejection velocity. (See 'Transesophageal echocardiography' below.) Mitral valve function TTE is quite useful in the assessment of mitral valve anatomy and function, which can influence the risk of thrombus formation. As an example, occult mitral stenosis in the adult may initially present with AF, often in the setting of acute thromboembolism. In this setting, long-term oral anticoagulation is indicated even if cardioversion to sinus rhythm is successful and independent of CHA DS -VASc score (these 2 2 clinical thromboembolism scores were derived from non-valvular AF populations). Long-term maintenance of sinus rhythm is unlikely unless the mitral stenosis (by surgery or percutaneous balloon mitral valvuloplasty) or severe mitral regurgitation (surgical repair or replacement) is corrected. (See "Surgical and investigational approaches to management of mitral stenosis" and "Percutaneous mitral balloon commissurotomy in adults".) Mitral regurgitation is commonly found among patients with AF. More than moderate mitral regurgitation appears to protect against clinical thromboembolism in chronic AF, presumably by minimized stasis in the left atrium and LAA [8-11] (see "Mechanisms of thrombogenesis in atrial fibrillation"). However, mitral regurgitation does not appear to protect from the formation of LAA thrombus as identified on TEE. As mentioned, examination of a prior TTE when the patient is in sinus rhythm (if available) will provide useful information on the relative atrial contribution to total left ventricular filling by https://www.uptodate.com/contents/role-of-echocardiography-in-atrial-fibrillation/print 3/16 7/6/23, 10:42 AM Role of echocardiography in atrial fibrillation - UpToDate examining the transmitral peak A wave velocity or peak E to peak A wave ratio. For those patients with a relatively high/large transmitral A wave, the contribution of left atrial systole to left ventricular filling is greater. Thus, these patients may derive greater hemodynamic benefit from rhythm control. Left ventricular function All patients with newly discovered AF should have a TTE to assess for LV size and function and other structural cardiac conditions that may impact treatment. TTE assessment of left ventricular systolic function helps to guide the choice of pharmacologic therapy for ventricular rate control in chronic AF. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) TTE can also detect left ventricular hypertrophy, focal wall motion abnormalities suggestive of myocardial infarction, and conditions less frequently associated with AF, including pericarditis (pericardial effusion), pulmonary embolus (dilated and poorly functioning right ventricle), and aortic stenosis (AF is generally poorly tolerated in this disorder and does not occur until very late in the disease). (See "Medical management of asymptomatic aortic stenosis in adults", section on 'Atrial fibrillation'.) Left ventricular dysfunction, as determined from the TTE, independently predicts an increased risk of a stroke in patients with AF. Analysis of 1066 patients entered into three prospective clinical trials evaluating the role of anticoagulation in nonvalvular AF (BAATAF, SPINAF, and SPAF) found that, among patients in the placebo or control groups, the incidence of a stroke was 9.3 percent per year in patients with moderate to severe left ventricular dysfunction compared with 4.4 percent per year in those with normal or mildly abnormal left ventricular systolic function ( figure 1) [12]. The predictive value of left ventricular dysfunction for thromboembolic risk has been confirmed in many other studies. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'CHA2DS2-VASc score'.) While TTE is recommended for all patients presenting with their first episode of AF, repeated TTE is not indicated when the patient has recurrent episodes unless there is a concern that the clinical situation has changed (eg, new heart failure). TRANSESOPHAGEAL ECHOCARDIOGRAPHY The preceding observations provide the rationale for the performance of TTE in all patients presenting with their first episode of AF. On the other hand, TEE should be reserved for patients in whom the diagnostic information will lead to alterations in therapy. It is a moderately invasive imaging technique that provides superior visualization of posterior structures, such as the left atrium and left atrial appendage (LAA). https://www.uptodate.com/contents/role-of-echocardiography-in-atrial-fibrillation/print 4/16 7/6/23, 10:42 AM Role of echocardiography in atrial fibrillation - UpToDate TEE has particular value in estimating thromboembolic risk in different clinical settings: It can detect LAA and right atrial appendage thrombi ( movie 1 and movie 2) for patients being considered for early cardioversion. In this setting, there is little additional benefit from TTE prior to TEE, as most of the necessary information can be derived from the TEE with its superior assessment of both appendages. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) While data suggest a role of TEE for patients who have not received a full month of therapeutic anticoagulation prior to cardioversion, there does not appear to be a role for routine TEE prior to cardioversion in patients who have been adequately anticoagulated with warfarin or direct oral anticoagulant (DOAC) for at least four weeks prior to cardioversion. However, TEE immediately prior to elective cardioversion should be considered for those patients at increased risk for left atrial thrombi (eg, rheumatic mitral valve disease, recent/prior thromboembolism, severe left ventricular systolic dysfunction) or those with a transiently subtherapeutic international normalized ratio (INR) or who have missed doses of DOAC in the month prior to elective cardioversion. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Among patients in paroxysmal or chronic AF, abnormalities in the LAA (thrombus, dense spontaneous echo contrast, or flow velocity 20 cm/s) or the presence of a complex aortic plaque increases the risk of a thromboembolic event and are more likely in patients with clinical risk factors for thromboembolism ( figure 2) [13]. Another role of TEE is for assessment of the adequacy of complete exclusion of the LAA for those undergoing surgical or percutaneous (eg, Watchman device) LAA occlusion. This assessment is helpful in determining the duration of anticoagulation following LAA occlusion. (See "Atrial fibrillation: Left atrial appendage occlusion".) Left atrial thrombi A main advantage of TEE is that it provides superior visualization of posterior structures, such as the left atrium and LAA as well as the anterior right atrial appendage. This is particularly important for the detection of thrombi, spontaneous echocontrast (a precursor to thrombus), and depressed atrial appendage ejection velocities as these metrics are not assessable with TTE. The ability of TTE to identify or exclude left atrial or atrial appendage thrombi (as well as right atrial appendage thrombi) is quite limited, with a reported sensitivity of 39 to 63 percent, due largely to poor visualization of the LAA [14,15]. By contrast, TEE permits detection of thrombus in both the left atrium ( movie 3 and movie 4) and the LAA ( movie 1 and movie 2). https://www.uptodate.com/contents/role-of-echocardiography-in-atrial-fibrillation/print 5/16 7/6/23, 10:42 AM Role of echocardiography in atrial fibrillation - UpToDate TEE evidence of thrombus in the body of the left atrium is very uncommon. The vast majority of thrombi are seen in the LAA with thrombi seen in approximately 13 percent of patients presenting with nonrheumatic AF of more than three days duration [16-18]. The prevalence is increased in high-risk patients with mitral stenosis (33 percent in one series) [19], left ventricular systolic dysfunction, enlargement of the left atrium or LAA, spontaneous echo contrast, a recent thromboembolic event (43 percent in one report) [20], and CHADS2 score [21]. Recurrent embolization in the last setting may be due to migration of the residual thrombus. On the other hand, the apparent lack of atrial thrombi in 57 percent of these patients probably reflects migration of the entire thrombus during the embolic event, a thrombus not visualized by TEE due to its small size, or another source for the embolus. Thrombus in the right atrial appendage is far less common. The sensitivity and specificity of TEE for left atrial thrombi (in patients in whom the left atrium was directly examined at surgery) are 93 to 100 percent and 99 to 100 percent, respectively [14,15]. In a review of 231 patients in whom only 5.2 percent had a left atrial thrombus, TEE has a positive and negative predictive value of 86 and 100 percent, respectively [14]. For patients who are not candidates for TEE due to esophageal stricture or another contraindication, intracardiac echocardiography with the catheter in the main pulmonary artery has been shown to be at least as efficacious as TEE for identifying atrial appendage thrombi [22]. One potential limitation of these studies is that they were performed by experienced operators and the accuracy may not be replicable at all institutions. Additionally, the complementary role of three-dimension real-time TEE for atrial appendage thrombus is unknown. The use of an endocardial border definition echocontrast agent may help define small thrombi in the atrial appendage [23]. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Studies from the Stroke Prevention in Atrial Fibrillation (SPAF) investigators confirmed the usefulness of TEE for predicting thromboembolism [13,24]. This study involved 786 patients with nonrheumatic AF, 382 of whom were at high clinical risk for a thromboembolism (eg, women >75 years of age and patients with systolic blood pressure >160 mmHg or a history of previous thromboembolism, impaired left ventricular function, or recent congestive heart failure). The rate of stroke was increased over threefold when TEE evidence of dense spontaneous echo contrast was present, increased by threefold for reduced (<20 cm/second) LAA peak ejection velocity and for LAA thrombus, and increased by fourfold by complex aortic plaque. Spontaneous echo contrast Spontaneous echo contrast (SEC or "smoke") refers to the presence of dynamic, smoke-like echoes seen during TEE in the left atrium or atrial appendage https://www.uptodate.com/contents/role-of-echocardiography-in-atrial-fibrillation/print 6/16 7/6/23, 10:42 AM Role of echocardiography in atrial fibrillation - UpToDate ( movie 3 and movie 2). Although most widely studied in the left atrium, SEC also occurs in the right atrium [16,25]. (See 'Right atrial thrombi' below.) SEC is thought to reflect increased erythrocyte aggregation caused by low shear rate due to altered atrial flow dynamics and uncoordinated atrial systole [26,27]. Erythrocyte aggregation is mediated by plasma proteins, especially fibrinogen, which promotes red cell rouleaux formation by moderating the normal electrostatic forces (due to negatively charged membranes) which keep erythrocytes from aggregating [28]. SEC is a strong risk factor for and may be the preceding stage to thrombus formation and thromboembolic events [13,24,29,30]. The following clinical characteristics of SEC have been identified: SEC is present in over 50 percent of all patients with AF and in over 80 percent of those with LAA thrombi or a recent thromboembolic event [12,13,20,24,25,29,30]. Furthermore, serial TEE studies have shown that SEC subsequently develops in many patients with chronic AF (44 percent in one report) who do not have SEC on their initial TEE [29]. The LAA peak outflow velocity can be estimated by TEE and SEC semiquantitatively graded as marked or dense if present throughout the entire cardiac cycle, or faint when intermittent [24,29]. The risk of thromboembolism increases as these parameters worsen [24]. SEC is associated with clinical risk factors for thromboembolism, including a prior thromboembolic event, left ventricular systolic dysfunction, and hypertension ( figure 2) [24,31] as well as CHADS2 risk score. On the other hand, it is less common in patients with mitral regurgitation [29] which, as noted above, appears to protect against clinical thromboembolism in chronic AF, presumably by minimized stasis in the left atrium and atrial appendage [8-11]. Warfarin, which leads to thrombus resolution and a lower incidence of thromboembolism, does not affect the presence of SEC, since it does not change the underlying hemodynamic abnormality [28,30,32]. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Blood flow velocity The ability to estimate blood flow velocity in the left or right atrium and left and right atrial appendage permits a more quantifiable measure of stasis. A low LAA blood flow velocity (less than 20 cm/second) is associated with the presence of appendage thrombus [25,29,33] and with denser SEC [24,29]. The risk of stroke increases sharply with marked reductions in blood flow velocity (<15 cm/sec), particularly in the LAA or posterior left atrium [34]. https://www.uptodate.com/contents/role-of-echocardiography-in-atrial-fibrillation/print 7/16 7/6/23, 10:42 AM Role of echocardiography in atrial fibrillation - UpToDate It has been suggested that left atrial blood flow velocity also may be a predictor of the likelihood of maintaining sinus rhythm after cardioversion. In one report, a high peak LAA blood flow velocity (>40 cm/sec) identified patients with an increased likelihood of remaining in sinus rhythm one year after cardioversion [35]. In comparison, low blood velocity was of limited predictive value. Other reports have been conflicting on the predictive value of low LAA blood flow velocity for the maintenance of sinus rhythm [36,37]. An explanation for ongoing thromboembolism in patients with paroxysmal AF and apparently maintained sinus rhythm may be related to a mechanical discordance between the body of the left atrium and the LAA (ie, an AF LAA pulse wave Doppler phenotype with sinus rhythm electrocardiogram and body of the left atrium motion) [38]. The reproducibility and consistency of this finding are unknown, but retrospective data suggest a discordance in up to 25 percent of patients with paroxysmal AF. Right atrial thrombi Few data are available comparing the sensitivity, specificity, and accuracy of TTE and TEE for right atrial and right atrial appendage thrombi, but the right atrial appendage is rarely seen by TTE. By contrast, right atrial or atrial appendage thrombi are also easily seen by TEE ( image 1). They are much less common than left atrial thrombi in patients in AF, occurring in 3 to 6 percent of cases (versus 15 to 20 percent for left atrial thrombi) [16,25]. The majority of patients with right atrial thrombi also have markedly depressed right ventricular systolic function, rheumatic tricuspid stenosis or prosthetic valve, or left atrial thrombi [12]. Cardioversion should be deferred even if patients have isolated right atrial thrombi. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation".) SUMMARY AND RECOMMENDATIONS Routine performance of transthoracic echocardiography is suggested for all patients presenting with their first episode of atrial fibrillation (AF) to obtain information regarding atrial size, ventricular function, valvular function, and possible pericardial effusion. Repeated transthoracic echocardiographic examinations for recurrent presentations of AF are not necessary unless the clinical presentation has changed. If available, data from prior transthoracic echocardiography (TTE) when the patient was in sinus rhythm is useful to https://www.uptodate.com/contents/role-of-echocardiography-in-atrial-fibrillation/print 8/16 7/6/23, 10:42 AM Role of echocardiography in atrial fibrillation - UpToDate determine the patient's relative dependence on sinus rhythm/atrial contribution to total left ventricular filling. (See 'Indications' above and 'Transthoracic echocardiography' above.) The main advantage of moderately invasive transesophageal echocardiography (TEE) is its ability to detect left and right atrial appendage thrombi and patients at risk for thrombi because of the presence of spontaneous echo contrast or reduced left atrial appendage (LAA) blood flow velocity as well as aortic plaque. The main clinical use of TEE for AF is in the management of early cardioversion in patients with AF of more than 48 hours or high- risk patients with AF of shorter duration who are candidates for cardioversion. (See 'Indications' above and 'Transesophageal echocardiography' above and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) There does not appear to be a role for routine TEE prior to cardioversion in patients who have been adequately anticoagulated with warfarin or direct oral anticoagulant (DOAC) for at least four weeks prior to cardioversion. However, TEE immediately prior to elective cardioversion should be considered for those patients at increased risk for left atrial thrombi (eg, rheumatic mitral valve disease, recent/prior thromboembolism, severe left ventricular systolic dysfunction) or those with a transiently subtherapeutic international normalized ratio (INR) or who have missed doses of DOAC in the month prior to elective cardioversion. 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Ayirala S, Kumar S, O'Sullivan DM, Silverman DI. Echocardiographic predictors of left atrial appendage thrombus formation. J Am Soc Echocardiogr 2011; 24:499. 22. Anter E, Silverstein J, Tschabrunn CM, et al. Comparison of intracardiac echocardiography and transesophageal echocardiography for imaging of the right and left atrial appendages. Heart Rhythm 2014; 11:1890. 23. Jung PH, Mueller M, Schuhmann C, et al. Contrast enhanced transesophageal echocardiography in patients with atrial fibrillation referred to electrical cardioversion improves atrial thrombus detection and may reduce associated thromboembolic events. Cardiovasc Ultrasound 2013; 11:1. 24. Transesophageal echocardiographic correlates of thromboembolism in high-risk patients with nonvalvular atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Ann Intern Med 1998; 128:639. 25. de Divitiis M, Omran H, Rabahieh R, et al. Right atrial appendage thrombosis in atrial fibrillation: its frequency and its clinical predictors. Am J Cardiol 1999; 84:1023. 26. Black IW, Chesterman CN, Hopkins AP, et al. Hematologic correlates of left atrial spontaneous echo contrast and thromboembolism in nonvalvular atrial fibrillation. J Am Coll Cardiol 1993; 21:451. 27. Fatkin D, Herbert E, Feneley MP. Hematologic correlates of spontaneous echo contrast in patients with atrial fibrillation and implications for thromboembolic risk. Am J Cardiol 1994; 73:672. 28. Fatkin D, Loupas T, Low J, Feneley M. Inhibition of red cell aggregation prevents spontaneous echocardiographic contrast formation in human blood. Circulation 1997; 96:889. 29. Fatkin D, Kelly RP, Feneley MP. Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. J Am Coll Cardiol 1994; 23:961. 30. Black IW, Hopkins AP, Lee LC, Walsh WF. Left atrial spontaneous echo contrast: a clinical and echocardiographic analysis. J Am Coll Cardiol 1991; 18:398. https://www.uptodate.com/contents/role-of-echocardiography-in-atrial-fibrillation/print 11/16 7/6/23, 10:42 AM Role of echocardiography in atrial fibrillation - UpToDate 31. Puwanant S, Varr BC, Shrestha K, et al. Role of the CHADS2 score in the evaluation of thromboembolic risk in patients with atrial fibrillation undergoing transesophageal echocardiography before pulmonary vein isolation. J Am Coll Cardiol 2009; 54:2032. 32. Tsai LM, Chen JH, Lin LJ, Teng JK. Natural history of left atrial spontaneous echo contrast in nonrheumatic atrial fibrillation. Am J Cardiol 1997; 80:897. 33. Santiago D, Warshofsky M, Li Mandri G, et al. Left atrial appendage function and thrombus formation in atrial fibrillation-flutter: a transesophageal echocardiographic study. J Am Coll Cardiol 1994; 24:159. 34. Shively BK, Gelgand EA, Crawford MH. Regional left atrial stasis during atrial fibrillation and flutter: determinants and relation to stroke. J Am Coll Cardiol 1996; 27:1722. 35. Antonielli E, Pizzuti A, P link s A, et al. Clinical value of left atrial appendage flow for prediction of long-term sinus rhythm maintenance in patients with nonvalvular atrial fibrillation. J Am Coll Cardiol 2002; 39:1443. 36. Verhorst PM, Kamp O, Welling RC, et al. Transesophageal echocardiographic predictors for maintenance of sinus rhythm after electrical cardioversion of atrial fibrillation. Am J Cardiol 1997; 79:1355. 37. P rez Y, Duval AM, Carville C, et al. Is left atrial appendage flow a predictor for outcome of cardioversion of nonvalvular atrial fibrillation? A transthroacic and transesophageal echocardiographic study. Am Heart J 1997; 134:745. 38. Warraich HJ, Gandhavadi M, Manning WJ. Mechanical discordance of the left atrium and appendage: a novel mechanism of stroke in paroxysmal atrial fibrillation. Stroke 2014; 45:1481. Topic 908 Version 19.0 https://www.uptodate.com/contents/role-of-echocardiography-in-atrial-fibrillation/print 12/16 7/6/23, 10:42 AM Role of echocardiography in atrial fibrillation - UpToDate GRAPHICS Significant left ventricular dysfunction predicts stroke in AF In a prospective study of 1066 patients entered into three clinical trials evaluating the role of anticoagulation in nonvalvular AF (BAATAF, SPINAF, and SPAF), the incidence of a stroke was 9.3 percent per year in patients with moderate to severe left ventricular dysfunction compared with 4.4 percent per year in those with normal or mildly abnormal left ventricular function. Data from: Atrial Fibrillation Investigators, Arch Intern Med 1998; 158:1316. Graphic 70244 Version 4.0 https://www.uptodate.com/contents/role-of-echocardiography-in-atrial-fibrillation/print 13/16 7/6/23, 10:42 AM Role of echocardiography in atrial fibrillation - UpToDate Left atrial abnormalities and complex aortic plaque correlate with the risk of thromboembolism in atrial fibrillation Correlation of clinical risk for thromboembolism (TE) and transesophageal echocardiographic (TEE) findings in 786 patients with atrial fibrillation. Patients were deemed to be at high risk if they had one or more of the following clinical features: prior TE, women >75 years of age, systolic blood pressure >160 mmHg, and heart failure or poor left ventricular function. Patients with none of these features were either at low risk or, if they had a history of hypertension, moderate risk. Panel A: There was an increasing incidence of a left atrial appendage (LAA) abnormality (thrombus, dense spontaneous echo contrast, or flow velocity 20 cm/s) or a complex aortic plaque risk with increasing clinical risk of TE. Panel B: The frequency of LAA abnormalities and complex aortic plaque in patients with a single high risk factor. Redrawn from: Zabalgoitia M, Halperin JL, Pearce LA, et al. for the Stroke Prevention in Atrial Fibrillation III Investigators. J Am Coll Cardiol 1998; 31:1622. Graphic 55452 Version 3.0 https://www.uptodate.com/contents/role-of-echocardiography-in-atrial-fibrillation/print 14/16 7/6/23, 10:42 AM Role of echocardiography in atrial fibrillation - UpToDate Apical 4 chamber echocardiogram showing right atrial thrombus The apical four chamber view show a thrombus that was in transit from the lower extremities and temporarily became lodged in the right atrium (RA). Additionally, the right ventricle (RV) is enlarged, implying that other emboli have reached the pulmonary circulation, resulting in raised pulmonary vascular resistance. LV: left ventricle; LA: left atrium. Graphic 68756 Version 4.0 https://www.uptodate.com/contents/role-of-echocardiography-in-atrial-fibrillation/print 15/16 7/6/23, 10:42 AM Role of echocardiography in atrial fibrillation - UpToDate Contributor Disclosures Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/role-of-echocardiography-in-atrial-fibrillation/print 16/16

7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications : Sanjiv M Narayan, MD, PhD, Michael E Cain, MD : Ary L Goldberger, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 10, 2021. INTRODUCTION Over 300,000 individuals succumb to sudden cardiac death (SCD) per year in the United States alone, with the single biggest cause being ventricular tachycardia (VT) or ventricular fibrillation (VF). The approach to the prevention of SCD depends upon the identification of those patients who are most likely to have a VT or VF and the effectiveness of the available preventive measures. (See "Pathophysiology and etiology of sudden cardiac arrest" and "Incidence of and risk stratification for sudden cardiac death after myocardial infarction".) The signal-averaged electrocardiogram (SAECG) is a noninvasive signal-processing technique to detect subtle abnormalities in the surface ECG, not visible to the naked eye, that are related to the pathophysiology underlying reentrant arrhythmias such as VT. The SAECG has most often been used to identify low-amplitude signals at the terminus of the QRS complex, referred to as "ventricular late potentials." These late potentials represent delayed ventricular activation, which may reflect the presence of myocardial scar tissue and identify patients at increased risk for reentrant ventricular tachyarrhythmias. The SAECG has been studied in an effort to identify individuals at risk for SCD, particularly in the context of coronary artery disease, acute myocardial infarction (MI), and left ventricular dysfunction. However, the SAECG can also be useful in evaluating the risk for atrial arrhythmias, with a prolonged SAECG P wave, equivalent to "atrial late potentials," which may potentially identify patients at risk for atrial fibrillation. https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 1/23 7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate In patients with the substrates for VT, slow conduction through myocardium disrupted by inflammation, edema, fibrosis, or scar tissue results in electrical potentials that extend beyond the activation time of normal surrounding myocardium but that are too small for detection on the surface ECG. The SAECG uses computerized averaging of ECG complexes during sinus rhythm to facilitate the detection of these small microvolt-level signals, which occur later than rapid ventricular activation and are termed late potentials. (See 'Techniques' below.) The SAECG is particularly useful in understanding the arrhythmic substrate and stratifying risk for ventricular tachyarrhythmias in patients with cardiomyopathies of various etiologies, most commonly in association with arrhythmogenic (right) ventricular cardiomyopathy [1], but also in the context of coronary heart disease, healed MI, or left ventricular dysfunction. The clinical uses and technical aspects of the SAECG and the characteristics of late potentials will be reviewed here. Specific conditions in which the SAECG is more regularly used are discussed separately. (See "Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis", section on 'Signal-averaged ECG' and "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation", section on 'Signal-averaged electrocardiogram' and "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) DEFINITIONS AND EPIDEMIOLOGY Definition Late potentials are low-amplitude, high-frequency signals that are thought to reflect slow and fragmented myocardial conduction ( figure 1). Late potentials are defined by three criteria ( waveform 1): Total filtered QRS duration Voltage in the terminal portion of the QRS (usually the last 40 milliseconds) Duration of the terminal QRS that is below a particular amplitude (usually 40 microvolts), called the late potential duration This definition of late potentials is empiric, yet has become validated over time by clinical observations. Notably, values for each parameter depend upon the type and frequency response of the filters used in the signal-averaging system. The most commonly used algorithms employ a 40- or 25-Hz high-pass filter. Using the 40-Hz filter, a Task Force Committee of the European Society of Cardiology, the American Heart Association, and the American College of Cardiology suggested the following definition of late potentials: Filtered QRS duration >114 milliseconds Terminal (last 40 milliseconds) QRS root mean square voltage <20 microvolts Low-amplitude (<40 microvolts) late potentials with duration >38 milliseconds https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 2/23 7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate Despite this attempt at standardization, authors have used variations of these criteria, and definitions for spectral (frequency-domain) analysis of late potentials have not been formalized. Epidemiology This abnormal conduction, which may occur in regions of prior infarction, nonischemic scar, or fibrosis, provides a substrate for reentrant ventricular tachycardia (VT) ( figure 2). Late potentials are present in 6 percent of asymptomatic normal subjects, but their incidence increases progressively when examining patients with a recent myocardial infarction (MI) without VT, patients with a remote MI who have not had VT, and patients with a remote MI who have had sustained monomorphic VT. Accordingly, the prevalence of late potentials in patients with documented VT and coronary artery disease ranges from 70 to 92 percent, and the predictive value of late potentials for VT increases with the number of other clinical risk factors. MECHANISM OF VENTRICULAR ARRHYTHMIAS DUE TO LATE POTENTIALS Late potentials are primarily used to reflect the presence of substrates for ventricular tachycardia (VT) rather than a dynamic predisposition to form a reentrant circuit. This is because reentrant arrhythmias require a critical balance between conduction delay and heterogeneous recovery of excitability. (See "Reentry and the development of cardiac arrhythmias".) Therefore, while late potentials reflect slow conduction related to arrhythmogenic substrates, episodes of VT initiation in such patients are uncommon in the absence of additional triggers such as ventricular premature beats, electrolyte abnormalities, increased circulating catecholamines, or ischemia. (See "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation", section on 'Additional diagnostic evaluation'.) Despite their link with structural substrates, there is also evidence to suggest that late potentials may indicate dynamic predisposition to ventricular arrhythmias: Diurnal variations in late potentials correspond to those reported in both the incidence of myocardial infarction (MI) and in the relative resistance of acute MI to thrombolysis. Despite variability in the characteristics of late potentials, they consistently correlate with the subsequent induction of VT. There has been ongoing debate about whether variability in late potentials reflects a dynamic susceptibility to VT or influences such as autonomic tone without direct arrhythmogenic impact. The synergy between slow conduction and additional clinical triggers in initiating VT is supported by the improvement in predictive accuracy for VT when combining the SAECG with assessments of left ventricular ejection fraction, autonomic tone, the presence of complex https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 3/23 7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate ventricular ectopy on ambulatory ECG recordings, or ischemia on exercise testing. An evolving area of study is in correlating late potential on the ECG with intracardiac ventricular late potentials that are increasingly used as targets for the ablation of VT [2]. TECHNIQUES The electrical signals of interest that reflect delayed conduction through ventricular or atrial scar are minute (in the microvolt range) compared with the size of the QRS complex or P wave seen on a surface ECG. Although simple amplification of the ECG may reveal these signals, it also amplifies ambient noise, which typically masks the useful low-amplitude signals. The SAECG is derived by computing the arithmetic mean of multiple ECG complexes. This process requires consistent signals between complexes while diminishing the more variable noise components, thus increasing the signal-to-noise ratio of cardiac potentials to enable detection of smaller (ie, microvolt-level) signals than would otherwise be discernible on visual inspection of the surface ECG. Signals from the His bundle as well as subtle abnormalities of atrial or ventricular complexes, anomalies not visualized on a surface ECG, are detectable using the SAECG. The ECG can be averaged over time ("temporal averaging") or spatially, and this process has been further enhanced by digital filtering and spectral analysis. Acquiring the data The ideal number and configuration of ECG leads used to record the SAECG is unclear, but the most commonly used lead set uses three bipolar leads in a standard X, Y, and Z (orthogonal) arrangement ( figure 3). In most cases, the averaging of 200 to 400 QRS complexes with the same morphology, over approximately three to seven minutes, is sufficient to record an adequate SAECG. Signal filtering further augments signal detection of the SAECG and minimizes random noise that is not synchronized to the QRS complex. As an example, filters facilitate easy recognition of QRS onset and offset. They may also help with the detection of low-amplitude, high-frequency signals, such as late potentials or atrial activity, during the otherwise low-frequency or isoelectric ST segment. The most commonly used filters are bidirectional filters. In this setup, the high-pass component removes low-frequency activity, such as that due to baseline drift of the ECG signal and low- frequency components of the ST segment and T waves. The low-pass components remove high- frequency noise, such as pectoral muscle components. Temporal signal averaging The most commonly applied SAECG method, temporal signal averaging, averages a number of QRS complexes over time. Beats are detected by computer https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 4/23 7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate algorithms, based on voltage thresholds or other criteria, then aligned by a constant feature of the signal, the "fiducial" ( figure 3 and waveform 1). Once beats have been aligned, their arithmetic mean is taken. This process diminishes random noise that is not synchronized to the QRS complex. The disadvantage of this process is that oscillating, transient, or other signals that are not present in each beat are diluted by temporal averaging. An approach to retain this information is spatial averaging. (See 'Spatial signal averaging' below.) Since averaging is performed until a "noise floor" is reached, the lower the initial baseline noise level, the fewer the number of beats required to generate the SAECG, and the better the resultant signal. However, in order to obtain a reliable averaged signal, only QRS complexes of similar beat-to-beat morphology should be analyzed. Thus, premature ventricular beats, aberrantly conducted beats, or grossly "noisy" beats are excluded from the analysis. An automated algorithm typically generates an "acceptable" template from the first few QRS complexes, then compares each successive beat for "closeness of fit" with the template before incorporating the beat into the average. Temporal signal averaging has some inherent limitations: This technique can only enhance signals that occur in a fixed relationship to the fiducial point. If there is significant variability in the morphology of late potentials from beat to beat, they may actually be considered to be "noise" and diminished by averaging. Ventricular late potentials can only be detected from the body surface when the fragmented activity outlasts the normal ventricular activation. Thus, in patients with bundle branch block, late potentials may be obscured by the delayed activation of normal ventricular myocardium. Spatial signal averaging ECG spatial averaging involves the summation and averaging of electrical potentials simultaneously recorded from multiple pairs of closely spaced electrodes. This process allows a real-time, beat-by-beat analysis of individual QRS complexes but requires electrical shielding of the patient and equipment. The advantage of this technique over temporal signal averaging is that it allows assessment of irregular rhythms with changing conduction or signals that may oscillate or otherwise vary between beats. The disadvantage is that by averaging across spatial locations, it dilutes information specific to any one location. Although often considered distinct from the SAECG, spatial averaging is the basis of Laplacian filtering embodied in electrodes used to record beat-to-beat dynamics of T-wave alternans. The principle of spatial averaging is also the basis for high-resolution body surface potential mapping that may detect the risk for sudden cardiac arrest or other arrhythmias. Finally, spatial averaging also allows dynamic changes to be evaluated after drug therapy, after ectopic beats, https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 5/23 7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate or after the onset of ischemia. (See "T wave (repolarization) alternans: Overview of technical aspects and clinical applications".) Other techniques Spectral analysis Spectral analysis considers the QRS complex (or P wave) to be composed of multiple, simple waveforms, typically sinusoids. Spectral analysis thus decomposes the QRS complex or P wave into these constituent signals, represented by component frequencies and corresponding phase and amplitudes. Spectral decomposition is typically performed using Fourier analysis, although methods such as wavelet transform have also been successfully applied. Spectrotemporal analysis Spectrotemporal analysis is the combination of time- and frequency-domain techniques. This procedure presents the Fourier transform of multiple segments of the ECG signal, shifted in time as a three-dimensional plot of the magnitude of individual signal frequencies against time. Thus, this technique may overcome the disadvantages of temporal signal averaging by allowing identification of fractionated activity occurring within the QRS complex (eg, in patients with an intraventricular conduction delay or a bundle branch block). CLINICAL SETTINGS SAECG abnormalities are associated with an increased risk of ventricular arrhythmias and cardiac and sudden death mortality in the following clinical settings: Ischemic heart disease ( table 1), including post-myocardial infarction (MI) and ischemic cardiomyopathy. (See 'Ischemic heart disease' below.) Nonischemic cardiomyopathies. (See 'Dilated cardiomyopathy' below.) Arrhythmogenic right ventricular cardiomyopathy (ARVC) [3]. Brugada syndrome. (See "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) Noninvasive diagnosis of transplant rejection in cardiac allograft recipients. (See "Heart transplantation in adults: Diagnosis of allograft rejection".) Identification of individuals with paroxysmal atrial fibrillation (AF) prone to frequent recurrences based upon abnormalities in the P-wave SAECG. (See 'P-wave SAECG and atrial fibrillation' below.) https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 6/23 7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate Although abnormalities in the SAECG have been identified in divergent populations with a number of other cardiac diseases, there is little or no clinical role for SAECG in their management. Patients with an abnormal SAECG appear to be at prognostically greater risk of ventricular tachycardia (VT) or sudden cardiac arrest (SCA), but the SAECG is only one of many prognosticating factors for VT and has a limited role for guiding therapy in modern cardiology practice. We concur with the 2008 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) scientific statement on noninvasive risk stratification [4] and the 2006 ACC/AHA/European Society of Cardiology guidelines for management of patients with ventricular arrhythmias [5], which concluded that the SAECG may be useful to identify patients at low risk for sudden cardiac death (SCD), but its routine use to identify patients at high risk for SCD is not yet adequately supported. Ischemic heart disease Patients with prior VT Most patients with sustained VT or ventricular fibrillation (VF), with or without coronary heart disease, will be treated with an implantable cardioverter-defibrillator (ICD) for secondary prevention of SCD. In such patients, further risk stratification testing including the SAECG is not likely to impact management. Because of this, we do not routinely perform SAECG in all patients with ischemic heart disease and documented VT or VF. Abnormalities on the SAECG are common among patients with ischemic heart disease and prior MI, with a notable difference between patients with and without VT. SAECG abnormalities are present in up to 93 percent of those with a history of VT, compared with only 18 to 33 percent without prior VT. This observation has inspired efforts to use the SAECG to predict future arrhythmic risk. Abnormalities in both time- and frequency-domain analyses are common in patients with a history of VT. Such abnormalities may occur at the terminal QRS, within the ST segment, or throughout the entire cardiac cycle. By contrast to time-domain analysis, the predictive accuracy of frequency-domain abnormalities is not affected by bundle branch block. This implies that the physiologic substrate critical to the initiation or maintenance of reentrant arrhythmias is independent of the deranged sequence or total duration of ventricular activation. SAECG abnormalities are less common in patients with a history of VF, demonstrable in only 21 to 65 percent of patients, which may reflect pathophysiologic differences compared with VT. Patients without prior VT Due to the reduced rates of arrhythmic events in patients treated with contemporary reperfusion and medical therapies, the utility of the SAECG is limited in low- risk, unselected post-MI populations. As such, we do not routinely perform SAECG for risk https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 7/23 7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate stratification in all patients with ischemic heart disease without documented VT or VF. However, there may be a role for the SAECG in selected higher-risk, post-MI cohorts defined in conjunction with additional risk stratification tests, or for patients at high risk of complications from an ICD, in whom the absence of late potentials would impart a better prognosis and potentially shift the risk/benefit ratio. (See "Incidence of and risk stratification for sudden cardiac death after myocardial infarction".) Following an acute MI, the absence of late potentials on SAECG has a very high negative predictive accuracy (95 to 99 percent), but the presence of late potentials is associated with a low positive predictive accuracy (14 to 29 percent). Although the absence of late potentials on the SAECG indicates an excellent arrhythmia-free prognosis, their positive predictive accuracy is too low to guide therapy. Another limitation is that most of the data predate the use of contemporary therapies for acute MI that have been shown to improve outcome and reduce the rates of SCD (eg, rapid reperfusion, beta blockers, angiotensin converting enzyme inhibitors, statins). (See "Incidence of and risk stratification for sudden cardiac death after myocardial infarction".) The positive predictive value of the SAECG is modest but improves considerably when combined with other risk factors including reduced left ventricular ejection fraction (LVEF), attenuated heart rate variability, high-grade ventricular ectopy, or inducible VT on electrophysiologic study ( table 1). In one series of 102 post-MI patients, the combination of an abnormal T-wave alternans study and an abnormal SAECG had a positive predictive value for ventricular arrhythmias of 50 percent ( figure 4). In the MUSTT trial, which enrolled 1925 patients with chronic coronary disease, left ventricular dysfunction, and asymptomatic nonsustained VT, an abnormal SAECG (filtered QRS duration >114 milliseconds) was associated with a significantly increased risk of arrhythmic death or cardiac arrest, cardiac death, and total mortality. The combination of an abnormal SAECG and LVEF <30 percent identified patients at highest risk for arrhythmic or cardiac death ( figure 5). The optimal time at which to obtain the SAECG post-MI is uncertain, although it should be at least two to three weeks following the index MI. Late potentials are present within three hours of an acute MI in up to 52 percent of patients, and the incidence increases during the electrically unstable initial 24 to 48 hours post-MI. Although their prevalence decreases after this initial phase, late potentials recorded as early as 24 to 72 hours post-MI may portend increased risk for VT and VF. At 6 to 14 days post-MI, late potentials are detectable in up to 93 percent of patients https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 8/23 7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate who eventually develop VT or VF, particularly in the first six months. The detectability of late potentials falls over time, and when measured five years post-MI, late potentials are no longer seen in up to 50 percent of patients in whom they were detectable early after the infarction. It is uncertain whether the arrhythmic risk of these individuals diminishes compared with those in whom late potentials persist. Among patients treated with thrombolytic therapy or primary percutaneous coronary intervention (PCI), the prevalence of SAECG abnormalities is lower (5 to 24 percent) than in patients with MI who are not reperfused (18 to 43 percent). In a substudy of a randomized trial of thrombolytic therapy in which 310 patients had an SAECG prior to discharge, the incidence of late potentials was 37 percent lower in patients assigned to thrombolytic therapy compared with placebo. In a cohort of 1800 survivors of acute MI, among whom 99 percent underwent primary reperfusion therapy (91 percent primary PCI), only 90 of 968 patients who had an SAECG (9.3 percent) were identified as having late potentials (ie, abnormal SAECG). Over a mean follow-up of 34 months, SAECG abnormalities did not correlate with the primary combined end point of cardiac death and arrhythmic events. Although primary reperfusion does not affect the physiologic basis of the SAECG, it is not known if the lower prevalence is due to reductions in infarct size or restoration of patency in the infarct- related artery. Nonischemic heart disease Dilated cardiomyopathy There are conflicting data on the predictive value of the SAECG in patients with dilated nonischemic cardiomyopathy, with the SAECG being predictive of total mortality, cardiac death, and/or arrhythmic events in some studies but not others. Given the inconsistent data, we do not routinely use the SAECG for risk stratification of patients with nonischemic cardiomyopathy. As examples of the mixed data on SAECG in patients with dilated nonischemic cardiomyopathy: In a prospective study of 114 patients with nonischemic dilated cardiomyopathy, in which 20 of the 86 patients without bundle branch block had an abnormal SAECG, one-year survival free of VT was markedly better in patients with a normal SAECG (95 percent) compared with those with late potentials on the SAECG (39 percent). Similarly, a study of 131 patients with dilated cardiomyopathy followed for 54 months found that those with late potentials had an increased risk of all-cause cardiac death (relative risk [RR] 3.3, 95% CI 1.5-7.5) and arrhythmic events (RR 7.2, 95% CI 2.6-19.4). https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 9/23 7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate Conversely, in a study of 343 patients with idiopathic dilated cardiomyopathy followed for 52 months, late potential on the SAECG did not predict arrhythmia risk or transplantation- free survival. Some studies have found that SAECG abnormalities are predictive of progressive heart failure in patients with dilated cardiomyopathy. Detection of cardiac allograft rejection Cardiac allograft rejection is characterized by myocardial inflammation followed by necrosis. Early studies suggested that the SAECG may be sensitive to disruptions in myocardial conduction caused by rejection, in addition to reductions in ECG voltage, conduction delay, and other ECG abnormalities that may occur despite immunosuppression. However, the SAECG is rarely used for this purpose in clinical practice. Arrhythmogenic right ventricular cardiomyopathy In the past, SAECG was considered a standard diagnostic test for ARVC [6]. However, the importance of SAECG testing has declined considerably due to its limited sensitivity and specificity. Furthermore, SAECG testing is not available in many medical centers. However, when available, the SAECG is still considered a standard part of the diagnostic evaluation for ARVC. A detailed discussion of the role of SAECG in the diagnosis of ARVC is presented separately. (See "Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis", section on 'Signal-averaged ECG'.) Brugada syndrome SAECG is not performed in all patients with Brugada-pattern ECG findings, but it can be helpful when there is a high suspicion of Brugada syndrome but the diagnosis remains uncertain after other testing. Additionally, SAECG may be helpful in identifying a subset of patients at higher risk for VT and SCD. This is discussed in detail separately. (See "Brugada syndrome: Clinical presentation, diagnosis, and evaluation", section on 'Initial steps to diagnose Brugada syndrome'.) Late potentials and catheter ablation for ventricular tachycardia We do not routinely perform SAECG in all patients with VT going for catheter ablation, but in select patients it can provide prognostic information. Some data support the prognostic utility of intracardiac late potentials in patients undergoing percutaneous catheter ablation, particularly in the SMASH-VT study, in which catheter ablation at regions of intraventricular late potentials reduced the incidence of ICD therapy on long-term follow-up [7]. In a study of 18 patients with ARVC, elimination of late ventricular potentials by radiofrequency ablation predicted freedom from ventricular arrhythmias after a mean follow-up of five years [8]. In two other studies, abnormal SAECG indices of ventricular depolarization were associated with cardiomyopathy in patients with right ventricular outflow tract-related ventricular arrhythmias, while epsilon waves in late depolarization and negative T waves were associated with the extent of ventricular scar on electroanatomic mapping [9,10]. The clinical role of ventricular late potentials in these contexts is being actively investigated, with some more modern studies using novel high resolution https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 10/23 7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate mapping also increasingly identifying late potentials as targets for ablation [11,12] (See "Invasive diagnostic cardiac electrophysiology studies".) P-wave SAECG and atrial fibrillation Reentrant arrhythmias in the atrium, analogous to those in the ventricle, also likely require heterogeneities in slow conduction and repolarization. This provides a theoretical basis for prediction of the propensity for AF by SAECG by examining slow conduction in the atrium, analogous to the detection of ventricular late potentials. However, further data are needed to clarify the role of P-wave SAECG before its widespread use can be recommended. (See "Reentry and the development of cardiac arrhythmias" and "The electrocardiogram in atrial fibrillation".) Patients with paroxysmal AF may be identified by P-wave prolongation on the SAECG during sinus rhythm, although the threshold P-wave duration that best discriminates such patients is controversial. A vector P-wave duration of 155 milliseconds predicted AF with a sensitivity, specificity, and positive predictive accuracy of 80, 93, and 92 percent, respectively. Unlike the ventricle, the utility of atrial late potentials in the terminal 10 to 20 milliseconds of the P wave remains controversial. It is also unclear whether low root mean square voltage at the P-wave terminus indicates AF risk independent of structural heart disease or left atrial dilatation. A biatrial mapping study showed that the site of AF initiation typically shows slow conduction at rapid rates, but not at baseline, just prior to AF onset [13]. Data suggest that the development of AF can be predicted using analyses of the P wave from the SAECG in certain patient populations; for example, patients undergoing cardiac surgery, patients with a recent MI, and patients with hypertrophic cardiomyopathy ( figure 6). A substudy analysis of MADIT II found that abnormalities of P-wave shape in orthogonal X, Y, and Z axis ECGs predicted AF onset and SCA in 802 patients with ischemic cardiomyopathy and LVEF 30 percent [14]. However, the traditional SAECG indices of P-wave duration and terminal amplitude did not predict AF onset or SCA. These results suggest a wider significance of the P wave than is generally recognized, perhaps as an indicator of atrial enlargement from ventricular dysfunction, and warrant further study. In a related study, P-wave morphology changed over time in patients from the MADIT II study who later developed AF, but remained unchanged in those who did not [15]. SUMMARY AND RECOMMENDATIONS Late potentials are primarily used to reflect the presence of substrates for ventricular tachycardia (VT) rather than a dynamic, time-varying predisposition to reentry. Although late potentials reflect slow conduction related to arrhythmogenic substrates, episodes of https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 11/23 7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate VT initiation in such patients are uncommon in the absence of additional triggers such as ventricular premature beats, electrolyte abnormalities, increased circulating catecholamines, or ischemia. (See 'Definitions and epidemiology' above.) The signal-averaged electrocardiogram (SAECG) is useful for detecting subtle abnormalities in the surface ECG that are not visible to the naked eye. One example of such an abnormality is the "ventricular late potential," a low-amplitude signal near the end of the QRS complex that can be used to stratify risk for ventricular tachyarrhythmias in patients with cardiomyopathies of various etiologies. (See "Reentry and the development of cardiac arrhythmias".) The SAECG can be acquired by one of three methods (temporal signal averaging, spatial signal averaging, or spectral analysis), all with inherent benefits and limitations (see 'Techniques' above): Temporal signal averaging, the most common method for obtaining the SAECG, averages a number of QRS complexes over time. Spatial signal averaging analyzes electrical potentials simultaneously recorded from multiple pairs of closely spaced electrodes. Spectral analysis considers the QRS complex (or P wave) to be composed of multiple simple waveforms, typically sinusoids. Spectral analysis thus decomposes the QRS complex (or P wave) into these constituent signals for analysis. The following time analyses, derived from temporal signal averaging, are the most frequently used criteria to define an abnormal SAECG (see 'Definition' above): Filtered QRS duration >114 milliseconds Terminal (last 40 milliseconds) QRS root mean square voltage <20 microvolts Low-amplitude (<40 microvolts) late potentials with duration >38 milliseconds SAECG abnormalities are associated with an increased risk of ventricular arrhythmias and cardiac and sudden death mortality in various clinical settings including post-myocardial infarction, ischemic cardiomyopathy, nonischemic cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and the Brugada syndrome. (See 'Clinical settings' above.) Ventricular late potentials on the intracardiac electrogram may represent critical sustaining mechanisms for VT and may be targeted for catheter ablation with successful arrhythmia elimination. (See 'Late potentials and catheter ablation for ventricular tachycardia' above.) https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 12/23 7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate The P-wave SAECG may indicate slow conduction in the atrium and in early work has been used to predict the propensity for atrial fibrillation. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Liao YC, Lin YJ, Chung FP, et al. Risk stratification of arrhythmogenic right ventricular cardiomyopathy based on signal averaged electrocardiograms. Int J Cardiol 2014; 174:628. 2. Ja s P, Maury P, Khairy P, et al. Elimination of local abnormal ventricular activities: a new end point for substrate modification in patients with scar-related ventricular tachycardia. Circulation 2012; 125:2184. 3. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 4. Goldberger JJ, Cain ME, Hohnloser SH, et al. American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society scientific statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death: a scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention. Circulation 2008; 118:1497. 5. European Heart Rhythm Association, Heart Rhythm Society, Zipes DP, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol 2006; 48:e247. 6. Kamath GS, Zareba W, Delaney J, et al. Value of the signal-averaged electrocardiogram in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm 2011; 8:256. 7. Reddy VY, Reynolds MR, Neuzil P, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med 2007; 357:2657. 8. Nogami A, Sugiyasu A, Tada H, et al. Changes in the isolated delayed component as an endpoint of catheter ablation in arrhythmogenic right ventricular cardiomyopathy: https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 13/23 7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate predictor for long-term success. J Cardiovasc Electrophysiol 2008; 19:681. 9. Santangeli P, Di Biase L, Horton R, et al. Ablation of atrial fibrillation under therapeutic warfarin reduces periprocedural complications: evidence from a meta-analysis. Circ Arrhythm Electrophysiol 2012; 5:302. 10. Zorzi A, Migliore F, Elmaghawry M, et al. Electrocardiographic predictors of electroanatomic scar size in arrhythmogenic right ventricular cardiomyopathy: implications for arrhythmic risk stratification. J Cardiovasc Electrophysiol 2013; 24:1321. 11. Lackermair K, Kellner S, Kellnar A, et al. Initial single centre experience with the novel Rhythmia high density mapping system in an all comer collective of 400 electrophysiological patients. Int J Cardiol 2018; 272:168. 12. Jamil-Copley S, Vergara P, Carbucicchio C, et al. Application of ripple mapping to visualize slow conduction channels within the infarct-related left ventricular scar. Circ Arrhythm Electrophysiol 2015; 8:76. 13. Lalani GG, Schricker A, Gibson M, et al. Atrial conduction slows immediately before the onset of human atrial fibrillation: a bi-atrial contact mapping study of transitions to atrial fibrillation. J Am Coll Cardiol 2012; 59:595. 14. Holmqvist F, Platonov PG, McNitt S, et al. Abnormal P-wave morphology is a predictor of atrial fibrillation development and cardiac death in MADIT II patients. Ann Noninvasive Electrocardiol 2010; 15:63. 15. Holmqvist F, Platonov PG, Carlson J, et al. Altered interatrial conduction detected in MADIT II patients bound to develop atrial fibrillation. Ann Noninvasive Electrocardiol 2009; 14:268. Topic 984 Version 27.0

generally recognized, perhaps as an indicator of atrial enlargement from ventricular dysfunction, and warrant further study. In a related study, P-wave morphology changed over time in patients from the MADIT II study who later developed AF, but remained unchanged in those who did not [15]. SUMMARY AND RECOMMENDATIONS Late potentials are primarily used to reflect the presence of substrates for ventricular tachycardia (VT) rather than a dynamic, time-varying predisposition to reentry. Although late potentials reflect slow conduction related to arrhythmogenic substrates, episodes of https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 11/23 7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate VT initiation in such patients are uncommon in the absence of additional triggers such as ventricular premature beats, electrolyte abnormalities, increased circulating catecholamines, or ischemia. (See 'Definitions and epidemiology' above.) The signal-averaged electrocardiogram (SAECG) is useful for detecting subtle abnormalities in the surface ECG that are not visible to the naked eye. One example of such an abnormality is the "ventricular late potential," a low-amplitude signal near the end of the QRS complex that can be used to stratify risk for ventricular tachyarrhythmias in patients with cardiomyopathies of various etiologies. (See "Reentry and the development of cardiac arrhythmias".) The SAECG can be acquired by one of three methods (temporal signal averaging, spatial signal averaging, or spectral analysis), all with inherent benefits and limitations (see 'Techniques' above): Temporal signal averaging, the most common method for obtaining the SAECG, averages a number of QRS complexes over time. Spatial signal averaging analyzes electrical potentials simultaneously recorded from multiple pairs of closely spaced electrodes. Spectral analysis considers the QRS complex (or P wave) to be composed of multiple simple waveforms, typically sinusoids. Spectral analysis thus decomposes the QRS complex (or P wave) into these constituent signals for analysis. The following time analyses, derived from temporal signal averaging, are the most frequently used criteria to define an abnormal SAECG (see 'Definition' above): Filtered QRS duration >114 milliseconds Terminal (last 40 milliseconds) QRS root mean square voltage <20 microvolts Low-amplitude (<40 microvolts) late potentials with duration >38 milliseconds SAECG abnormalities are associated with an increased risk of ventricular arrhythmias and cardiac and sudden death mortality in various clinical settings including post-myocardial infarction, ischemic cardiomyopathy, nonischemic cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and the Brugada syndrome. (See 'Clinical settings' above.) Ventricular late potentials on the intracardiac electrogram may represent critical sustaining mechanisms for VT and may be targeted for catheter ablation with successful arrhythmia elimination. (See 'Late potentials and catheter ablation for ventricular tachycardia' above.) https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 12/23 7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate The P-wave SAECG may indicate slow conduction in the atrium and in early work has been used to predict the propensity for atrial fibrillation. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Liao YC, Lin YJ, Chung FP, et al. Risk stratification of arrhythmogenic right ventricular cardiomyopathy based on signal averaged electrocardiograms. Int J Cardiol 2014; 174:628. 2. Ja s P, Maury P, Khairy P, et al. Elimination of local abnormal ventricular activities: a new end point for substrate modification in patients with scar-related ventricular tachycardia. Circulation 2012; 125:2184. 3. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 4. Goldberger JJ, Cain ME, Hohnloser SH, et al. American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society scientific statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death: a scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention. Circulation 2008; 118:1497. 5. European Heart Rhythm Association, Heart Rhythm Society, Zipes DP, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol 2006; 48:e247. 6. Kamath GS, Zareba W, Delaney J, et al. Value of the signal-averaged electrocardiogram in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm 2011; 8:256. 7. Reddy VY, Reynolds MR, Neuzil P, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med 2007; 357:2657. 8. Nogami A, Sugiyasu A, Tada H, et al. Changes in the isolated delayed component as an endpoint of catheter ablation in arrhythmogenic right ventricular cardiomyopathy: https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 13/23 7/6/23, 10:42 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate predictor for long-term success. J Cardiovasc Electrophysiol 2008; 19:681. 9. Santangeli P, Di Biase L, Horton R, et al. Ablation of atrial fibrillation under therapeutic warfarin reduces periprocedural complications: evidence from a meta-analysis. Circ Arrhythm Electrophysiol 2012; 5:302. 10. Zorzi A, Migliore F, Elmaghawry M, et al. Electrocardiographic predictors of electroanatomic scar size in arrhythmogenic right ventricular cardiomyopathy: implications for arrhythmic risk stratification. J Cardiovasc Electrophysiol 2013; 24:1321. 11. Lackermair K, Kellner S, Kellnar A, et al. Initial single centre experience with the novel Rhythmia high density mapping system in an all comer collective of 400 electrophysiological patients. Int J Cardiol 2018; 272:168. 12. Jamil-Copley S, Vergara P, Carbucicchio C, et al. Application of ripple mapping to visualize slow conduction channels within the infarct-related left ventricular scar. Circ Arrhythm Electrophysiol 2015; 8:76. 13. Lalani GG, Schricker A, Gibson M, et al. Atrial conduction slows immediately before the onset of human atrial fibrillation: a bi-atrial contact mapping study of transitions to atrial fibrillation. J Am Coll Cardiol 2012; 59:595. 14. Holmqvist F, Platonov PG, McNitt S, et al. Abnormal P-wave morphology is a predictor of atrial fibrillation development and cardiac death in MADIT II patients. Ann Noninvasive Electrocardiol 2010; 15:63. 15. Holmqvist F, Platonov PG, Carlson J, et al. Altered interatrial conduction detected in MADIT II patients bound to develop atrial fibrillation. Ann Noninvasive Electrocardiol 2009; 14:268. Topic 984 Version 27.0 https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 14/23 7/6/23, 10:43 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate GRAPHICS Late potentials on the signal-averaged ECG suggesting possible substrate for reentrant ventricular arrhythmias Signal-averaged electrocardiogram (SAECG) showing a QRS complex after a first and second myocardial infarction (MI) in the same patient. Left panel: After a first MI, no late potentials are present on the SAECG. Right panel: After a second MI, late potentials are seen as low amplitude signals at the end of the QRS complex (arrow). The filtered QRS duration is increased to >120 milliseconds. Graphic 72380 Version 3.0 https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 15/23 7/6/23, 10:43 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate Computation of the signal averaged ECG Successive QRS complexes meeting a predetermined coefficient of similarity are aligned (within the window indicated by dashed lines) on an ongoing basis. Their rolling arithmetic mean is computed until a predetermined noise threshold is achieved (shown as the typical criterion of the standard deviation of the TP segment <1 microvolts). The QRS complex is then filtered and analyzed for late potentials, defined when the filtered QRS duration is >114 milliseconds, root mean square (RMS) voltage in the terminal 40 milliseconds is <20 microvolts, and low amplitude signal (LAS) duration (the terminal signal duration from 40 mV to isopotential) is >38 milliseconds. Graphic 67428 Version 5.0 https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 16/23 7/6/23, 10:43 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate Late potentials bridging diastole Shown are surface ECG leads I, II, III, V1, V4, and V6 and electrograms (a to h) recorded from the endocardial surface of the myocardium during ventricular tachycardia. There are presystolic signals in the area of slow myocardial conduction that can be traced through diastole to the preceding QRS complex. During sinus rhythm, late potentials can be recorded from these sites. Graphic 82329 Version 1.0 https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 17/23 7/6/23, 10:43 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate QRS alignment methods Optimal beat alignment permits the averaging of signals at physiologically corresponding timepoints. Sliding template alignment provides the greatest precision and may be computed by maximizing the dot-product between candidate beats and a template. QRS peak and upstroke fiducial methods are less precise but still used. The P-wave triggered signal averaged ECG requires P- wave alignment, typically with a sliding template approach. Graphic 75403 Version 1.0 https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 18/23 7/6/23, 10:43 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate Incidence of sustained ventricular arrhythmias or sudden cardiac death in patients after myocardial infarction Percent adverse outcomes Test For normal test For abnormal test results results SAECG and ejection fraction 0-1 31-38 SAECG and Holter monitor 0-1 27-35 Ejection fraction and Holter monitor 7 29 SAECG, ejection fraction, and Holter monitor 0 50 SAECG and programmed stimulation 2 27 SAECG and HRV 7 33 SAECG, HRV, and Holter monitor 4 43 SAECG: signal-averaged electrocardiogram; HRV: heart rate variability. Adapted from Cain, et al. J Am Coll Cardiol 1996; 27:238. Graphic 53211 Version 2.0 https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 19/23 7/6/23, 10:43 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate Repolarization alternans (RPA) and late potentials (LP) predict arrhythmic events following myocardial infarction In a study of 102 patients with a prior myocardial infarction (MI) followed for 13 months, the combination of repolarization alternans (RPA) and late potentials (LP) on a signal averaged ECG had a specificity and negative predictive value for an arrhythmic event of 91 and 92 percent, respectively. However, the positive predictive value was only 50 percent. The very low event rate in the group "RPA negative and LP positive" may be due to the small number of patients in this subset (n = 5). Data from Ikeda T, Sakata T, Takami M, et al, J Am Coll Cardiol 2000; 35:722. Graphic 51831 Version 3.0 https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 20/23 7/6/23, 10:43 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate The signal averaged ECG predicts outcome in patients with nonsustained ventricular tachycardia In a trial of 1925 patients with coronary artery disease, asymptomatic nonsustained ventricular tachycardia, and left ventricular dysfunction, the signal averaged ECG (SAECG) predicted outcome, particularly in those with a left ventricular ejection fraction (LVEF) <30 percent. The two- and five-year event rates for patients with filtered QRS duration >114 milliseconds were 17 and 36 percent, respectively, compared with 10 and 23 percent, respectively, with a QRS 114 milliseconds (p = 0.0001). In patients with an LVEF 30 percent, the two- and five-year event rates were 6 and 13 percent, respectively and 11 and 22 percent, respectively, for a QRS or >114 milliseconds (p = 0.01). Data from: Gomes JA, Cain ME, et al. Circulation 2001; 104:436. Graphic 66009 Version 6.0 https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 21/23 7/6/23, 10:43 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate Signal averaged electrocardiogram predicts atrial fibrillation after coronary artery bypass graft (CABG) surgery The incidence of atrial fibrillation (AF) after coronary artery bypass graft surgery is directly related to the duration of the P wave on a signal averaged ECG. Data from Zaman AG, Archbold RA, Helft G, et al. Circulation 2000; 101:1403. Graphic 60431 Version 4.0 https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 22/23 7/6/23, 10:43 AM Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications - UpToDate Contributor Disclosures Sanjiv M Narayan, MD, PhD Patent Holder: Stanford University [Atrial fibrillation, machine learning, arrhythmias]; University of California [Atrial fibrillation, machine learning, arrhythmias]. Grant/Research/Clinical Trial Support: NIH [Atrial fibrillation]. Consultant/Advisory Boards: Abbott [Cardiac arrhythmias]; Life Signals Inc [Ambulatory monitoring for general health including COVID-19]; TDK Inc [Magnetocardiography]. All of the relevant financial relationships listed have been mitigated. Michael E Cain, MD No relevant financial relationship(s) with ineligible companies to disclose. Ary L Goldberger, MD Other Financial Interest: Elsevier book royalties [Clinical electrocardiography]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/signal-averaged-electrocardiogram-overview-of-technical-aspects-and-clinical-applications/print 23/23

7/6/23, 10:43 AM Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation : Munther K Homoud, MD : Samuel L vy, MD : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 30, 2022. INTRODUCTION Sinus node dysfunction (SND), also historically referred to as sick sinus syndrome (SSS) is characterized by dysfunction of the sinoatrial (SA) node that is often secondary to senescence of the SA node and surrounding atrial myocardium. Patients with SND are typically symptomatic with fatigue, lightheadedness, palpitations, presyncope, and/or syncope, although the occasional patient may be identified during electrocardiography (ECG) or ambulatory ECG monitoring performed for another indication. The clinical manifestations, evaluation, and approach to diagnosis of SND will be reviewed here. The causes, natural history, and management of SND, along with the appropriate timing of referral to a specialist, are discussed in detail separately. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history" and "Sinus node dysfunction: Treatment" and "Arrhythmia management for the primary care clinician", section on 'Referral to a specialist'.) DEFINITION SND is a clinical syndrome characterized by chronic sinoatrial (SA) node dysfunction, a sluggish or absent SA nodal pacemaker after electrical cardioversion, and/or depressed escape pacemakers in the presence or absence of atrioventricular (AV) nodal conduction disturbances [1-3]. SND may also manifest as chronotropic incompetence with inappropriate heart rate responses to physiological demands during activity. SND can also be accompanied by AV nodal https://www.uptodate.com/contents/sinus-node-dysfunction-clinical-manifestations-diagnosis-and-evaluation/print 1/16 7/6/23, 10:43 AM Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation - UpToDate conduction disturbances and by atrial tachyarrhythmias as part of the tachycardia-bradycardia syndrome. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history", section on 'Definition'.) CLINICAL PRESENTATION SND is defined by electrocardiogram (ECG) abnormalities (eg, bradycardia, sinus pauses, sinus arrest) that occur in association with clinical signs and symptoms. Most patients with SND present with one or more of the following nonspecific symptoms: fatigue, lightheadedness, palpitations, presyncope, syncope, dyspnea on exertion, or chest discomfort. Symptoms are frequently intermittent with gradual progression in frequency and severity, although some patients may present with profound, persistent symptoms at the initial visit. Rarely, SND may be asymptomatic and identified on routine ECG or ambulatory ECG monitoring. Symptoms Patients with symptomatic SND are primarily older and frequently have comorbid diseases. Patients with SND often seek medical attention with symptoms of lightheadedness, presyncope, syncope, and, in patients with alternating periods of bradycardia and tachycardia, palpitations and/or other symptoms associated with a rapid heart rate. Patients with coexisting cardiac pathology may notice increasing dyspnea on exertion or worsening chest discomfort related to lower heart rate and the resulting reduction in cardiac output. Because symptoms may be variable in nature, nonspecific, and frequently transient, it may be challenging at times to establish this symptom-rhythm relationship. Prior to any testing beyond an ECG, a thorough evaluation should be performed for potentially reversible causes, which include medication use (eg, beta blockers, calcium channel blockers, digoxin, antiarrhythmics), myocardial ischemia, systemic illness (eg, hypothyroidism), and autonomic imbalance. (See 'Approach to the diagnosis' below.) SND is defined by ECG abnormalities (eg, bradycardia, sinus pauses, sinus arrest) that occur in association with clinical signs and symptoms. Of note, ECG abnormalities alone, in particular sinus bradycardia, do not always denote the presence of SND. As an example, highly conditioned athletes often have a pronounced increase in vagal tone at rest with heart rates well below 60 beats per minute in the absence of symptoms. ECG findings The diagnosis of SND in persons with suggestive symptoms is often made from the surface ECG. ECG manifestations can include: Periods of inappropriate, and often severe (less than 50 beats per minutes), bradycardia [1,3]. https://www.uptodate.com/contents/sinus-node-dysfunction-clinical-manifestations-diagnosis-and-evaluation/print 2/16 7/6/23, 10:43 AM Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation - UpToDate Sinus pauses, arrest, and sinoatrial (SA) exit block with, and often without, appropriate atrial and junctional escape rhythms. The failure of escape pacemakers may lead to symptoms including syncope [1,3]. (See "Sinoatrial nodal pause, arrest, and exit block".) Alternating bradycardia and atrial tachyarrhythmias in over 50 percent of cases [1,4-9]. Atrial fibrillation is most common, but atrial flutter and paroxysmal supraventricular tachycardias (ie, due to atrial tachycardia) may also occur. Atrial arrhythmias seem to develop slowly over time, possibly the result of a progressive pathological process that affects the SA node and the atrium [10-12]. Various examples of the ECG findings that may be seen are shown in the accompanying figures ( waveform 1 and waveform 2 and waveform 3). APPROACH TO THE DIAGNOSIS There are no standardized criteria for establishing a diagnosis of SND, and the initial clues to the diagnosis of SND are most often gleaned from the patient s history. However, the symptoms of SND are nonspecific and the electrocardiogram (ECG) findings may not be diagnostic. Hence, the key to making a diagnosis of SND is to establish a correlation between the patient's symptoms and the underlying rhythm at the time of the symptoms. Patients may present with symptoms of fatigue, lightheadedness, presyncope, syncope, dyspnea on exertion, chest discomfort, and/or palpitations. A routine ECG and/or ambulatory ECG monitoring may confirm the diagnosis if typical ECG findings (eg, one or more of sinus bradycardia; sinus pauses, arrest, and sinoatrial [SA] exit block; or alternating bradycardia and atrial tachyarrhythmias) can be correlated with symptoms. In some patients, however, additional diagnostic testing may be required, and SND should not be diagnosed until any potentially reversible causes have been identified and treated. Our approach is as follows ( algorithm 1): Comprehensive history and physical examination, resting 12-lead ECG, review of prior records and ECG tracings, and exercise stress testing The key to making a diagnosis of SND is establishing a symptom-rhythm correlation. Hence, a good history and ECG findings during symptoms are often sufficient to diagnose SND. Careful review of prior records, in particular previous ECG tracings, can provide subtle clues to changes in the ECG over time. For patients with clinically suspected SND in whom the diagnosis remains uncertain following the initial ECG, we perform exercise stress testing. https://www.uptodate.com/contents/sinus-node-dysfunction-clinical-manifestations-diagnosis-and-evaluation/print 3/16 7/6/23, 10:43 AM Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation - UpToDate Exercise stress testing can aid in identifying abnormal sinus node function, excluding myocardial ischemia, and can help guide device programming for patients who ultimately receive a permanent pacemaker (eg, rate responsiveness). A subnormal increase in heart rate after exercise (ie, chronotropic incompetence) can help identify individuals with abnormal sinus node function who may benefit from a pacemaker implantation [13,14]. While there are various definitions on what is considered subnormal, most clinicians diagnose chronotropic incompetence as the inability of achieving at least 80 percent of the maximum predicted heart rate with exercise testing [15]. The sensitivity and specificity of this latter approach, however, are uncertain, and the results obtained may not be reproducible [16]. (See "Exercise ECG testing: Performing the test and interpreting the ECG results".) Careful review for potentially reversible causes and medication use should be performed to exclude remediable causes for apparent SND [15]. In patients with medication use (eg, beta blockers, calcium channel blockers, digoxin, antiarrhythmics, and acetylcholine esterase inhibitors) suspected to result in symptomatic bradycardia, the patient should remain on an ECG monitor while the medications are withdrawn. If symptoms and ECG abnormalities persist following the withdrawal of the medications (ie, after three to five half-lives), then SND can be diagnosed. Similarly, patients with symptomatic bradycardia suspected to be due to myocardial ischemia, hypothyroidism, or another condition should receive treatment directed at that condition while ECG monitoring continues. If SND cannot be definitively diagnosed following history, physical, and initial 12-lead ECG, ambulatory ECG monitoring (with a continuous monitor [Holter] for 1 to 14 days and/or event monitor for up to four weeks) should be performed to identify symptomatic episodes of arrhythmias and average heart rates over extended periods of surveillance [15]. (See "Ambulatory ECG monitoring".) In patients with suspected SND but without a confirmed diagnosis following ambulatory ECG monitoring, additional testing may include: Extended ambulatory ECG monitoring with an insertable cardiac monitor (also sometimes called an implantable cardiac monitor or an implantable loop recorder). (See 'Ambulatory ECG monitoring and event recording' below.) Electrophysiology studies (EPS) have historically been used, but the very limited sensitivity of EPS in detecting evidence of SND has limited the usefulness of EPS. In symptomatic patients with suspected SND but no ECG documentation, EPS may be considered. https://www.uptodate.com/contents/sinus-node-dysfunction-clinical-manifestations-diagnosis-and-evaluation/print 4/16 7/6/23, 10:43 AM Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation - UpToDate Referral to a cardiac electrophysiologist should be considered at any point in the diagnostic approach, but is most helpful if SND is suspected but not confirmed following the initial period of ambulatory ECG monitoring (up to four weeks). Once SND is confirmed, treatment typically involves referral for implantation of a pacemaker. Management of SND is discussed in detail separately. (See "Sinus node dysfunction: Treatment".) DIAGNOSTIC TESTING For patients in whom SND is clinically suspected but not confirmed by electrocardiogram (ECG) and/or exercise stress test findings, a number of different modalities may be helpful. In most patients, ambulatory ECG monitoring for an extended period of time (typically two to four weeks but potentially longer) has the greatest yield and allows for correlation with symptoms. In select patients where the diagnosis remains uncertain, other diagnostic testing options include adenosine administration, carotid sinus massage, and invasive electrophysiology studies. Ambulatory ECG monitoring and event recording For patients with clinically suspected SND in whom the initial ECG and monitoring are non-diagnostic, we perform additional ambulatory ECG monitoring [15]. We most frequently use an ambulatory event monitor for two to four weeks to try to capture the ECG during a symptomatic episode. Rare patients with frequent symptoms may be successfully diagnosed with an ambulatory Holter monitor worn for 24 to 48 hours, while patients with less frequent symptoms may require extended monitoring for months to years with an implantable cardiac monitor. The introduction of the insertable cardiac monitor into the diagnostic armamentarium has enhanced the diagnostic yield of the clinical evaluation [17]. The challenge of evaluating patients with SND remains the nonspecificity of symptoms, apart from syncope, and the inconsistency of electrocardiographic clues. Management requires correlation between symptoms and electrocardiographic findings. The insertable cardiac monitor is uniquely suited to achieve this goal and is becoming more frequently and earlier in the cascade of diagnostic tools. (See "Ambulatory ECG monitoring".) Ambulatory ECG monitoring with a 24-hour Holter monitor may provide important clues in 50 to 70 percent of patients with suspected SND [18-20]. However, the sensitivity and specificity of a 24-hour continuous monitor is relatively low due to the variable nature of symptoms and short duration of monitoring [21]. The use of cardiac event monitors, ambulatory ECG monitors which are typically worn for two to four weeks, has been shown to be more effective than 24-hour continuous monitors in establishing a diagnosis [22,23]. In some instances where the symptoms are very infrequent, the use of implantable event monitors have been used that allow for monitoring periods of greater than one year [24]. Variable patient compliance and sensitivity to https://www.uptodate.com/contents/sinus-node-dysfunction-clinical-manifestations-diagnosis-and-evaluation/print 5/16 7/6/23, 10:43 AM Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation - UpToDate the adhesive electrode patches further limits the utility of two- to four-week week monitoring. The enhanced diagnostic utility of insertable cardiac monitoring has significantly reduced the role of pharmacological challenge, determining the intrinsic heart rate and invasive electrophysiological studies. The latter tests are of limited diagnostic yield lacking both sensitivity and specificity. Pharmacologic challenge A number of drugs have been used in aiding the diagnosis of SND, but none are used in routine clinical practice. Atropine and isoproterenol Atropine (1 or 2 mg) and isoproterenol (2 to 3 mcg/minute) may be useful, since both agents normally increase the sinus rate [25,26]. A suggested abnormal response is an increase in the sinus rate of less than 25 percent, or to a rate below 90 beats per minute. Since in most cases the diagnosis of SND can be achieved by establishing a symptom-rhythm correlation with the use of ambulatory monitor and a comprehensive history and physical exam, testing with these agents is rarely necessary. Adenosine Adenosine has been proposed as an alternative to invasive electrophysiology studies, but its routine use is not yet established [27-29]. (See "Invasive diagnostic cardiac electrophysiology studies", section on 'Electrocardiographic and electrophysiologic recordings'.) Calculating the intrinsic heart rate The intrinsic heart rate (IHR) is the heart rate in the presence of complete pharmacological denervation of the sinus node [30]. This is achieved with the simultaneous use of beta blockers and atropine. The calculation of the IHR following simultaneous administration of beta blockers and atropine is largely of historical interest and is rarely performed in the modern evaluation of patients with suspected SND. Electrophysiologic testing Invasive electrophysiologic studies (EPS) are rarely used for the evaluation of SND (eg, symptomatic patient who has no electrocardiographic findings suggestive of SND but no other evident cause for the symptoms) because of their limited sensitivity in eliciting bradyarrhythmic abnormalities as well as the widespread availability of diagnostic options for long-term monitoring. However, EPS may be helpful in patients with suspected SND who also describe sustained episodes of tachyarrhythmias in an effort to identify a tachycardia (eg, atrial tachycardia) that would be potentially curable with ablation [15]. The 2018 ACC/AHA/HRS guidelines do not support performing invasive EP studies for the sole purpose of establishing a diagnosis of SND [15]. The function of the sinus node can be evaluated invasively (ie, EP studies) within the context of evaluating a patient with other conditions such as a life-threatening arrhythmia that may warrant an implantable cardioverter defibrillator. Establishing a diagnosis of SND under such circumstances may lead the operator to consider https://www.uptodate.com/contents/sinus-node-dysfunction-clinical-manifestations-diagnosis-and-evaluation/print 6/16 7/6/23, 10:43 AM Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation - UpToDate implanting an ICD with atrial pacing capabilities. These guidelines have conferred a Class IIb indication for invasive EP studies for establishing the diagnosis of SND. The salient aspects of electrophysiology studies that aid in eliciting a bradyarrhythmic abnormality include assessment of the SA node recovery time, SA conduction time, and the sinus node and atrial tissue refractory periods. A more detailed discuss of invasive EPS is presented separately. (See "Invasive diagnostic cardiac electrophysiology studies".) DIFFERENTIAL DIAGNOSIS While SND is common, other conditions should also be considered in the differential diagnosis, including carotid sinus hypersensitivity, neurocardiogenic syncope with a predominant cardioinhibitory component, and physiologically normal bradycardia especially among highly conditioned athletes. Carotid sinus massage is typically not employed in diagnosing SND but is often used to establish the presence of carotid sinus hypersensitivity that may elucidate a cause for syncope. Some have advocated for its use in the assessment of SND due to previous reports describing an association between carotid sinus hypersensitivity and SND [31]. With carotid sinus massage, a pause longer than three seconds and/or a symptomatic drop in blood pressure are indicative of carotid sinus hypersensitivity. This study has limited specificity in establishing a diagnosis of carotid sinus hypersensitivity as the reason for syncope. Occasionally, otherwise asymptomatic older adult individuals may exhibit sinus pauses greater than three seconds in duration. Hence, interpretation of the results of carotid sinus massage must be made in the proper clinical context. The technique for performing this test and contraindications are discussed in detail elsewhere. (See "Vagal maneuvers", section on 'Carotid sinus massage'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Syncope" and "Society guideline links: Cardiac implantable electronic devices" and "Society guideline links: Supraventricular arrhythmias".) INFORMATION FOR PATIENTS https://www.uptodate.com/contents/sinus-node-dysfunction-clinical-manifestations-diagnosis-and-evaluation/print 7/16 7/6/23, 10:43 AM Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation - UpToDate UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Sinus node dysfunction (The Basics)") SUMMARY AND RECOMMENDATIONS Definition Sinus node dysfunction (SND) is characterized by dysfunction of the sinoatrial (SA) node that is often secondary to senescence of the SA node and surrounding atrial myocardium. SND is characterized by chronic sinoatrial (SA) node dysfunction, a sluggish or absent SA nodal pacemaker after electrical cardioversion, and/or depressed escape pacemakers in the presence or absence of atrioventricular (AV) nodal conduction disturbances. SND may also manifest as chronotropic incompetence with inappropriate heart rate responses to physiological demands during activity. (See 'Definition' above.) Clinical presentation SND is defined by ECG abnormalities that occur in association with clinical signs and symptoms. Most patients with SND with present with one or more of the following nonspecific symptoms: fatigue, lightheadedness, palpitations, presyncope, syncope, dyspnea on exertion, or angina. Symptoms are frequently intermittent with gradual progression in frequency and severity. (See 'Clinical presentation' above.) ECG findings Typical ECG findings in patients with SND include one or more of sinus bradycardia; sinus pauses, arrest, and SA exit block; and alternating bradycardia and atrial tachyarrhythmias ( waveform 1 and waveform 2 and waveform 3). (See 'ECG findings' above.) Diagnosis There are no standardized criteria for making a diagnosis of SND, and the key is to establish a symptom-rhythm correlation. The initial clues to the diagnosis of SND are most often gleaned from the patient s history. However, the symptoms of SND are https://www.uptodate.com/contents/sinus-node-dysfunction-clinical-manifestations-diagnosis-and-evaluation/print 8/16 7/6/23, 10:43 AM Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation - UpToDate nonspecific and the ECG findings may not be diagnostic. Hence, the key to making a diagnosis of SND is to establish a correlation between the patient's symptoms and the underlying rhythm at the time of the symptoms. Our approach to the diagnosis of SND is summarized in the text ( algorithm 1). (See 'Approach to the diagnosis' above.) Role of ambulatory monitoring Patients with clinically suspected SND in whom the initial ECG and monitoring are non-diagnostic should undergo ambulatory ECG monitoring. We most frequently use an ambulatory event monitor for two to four weeks to try to capture the ECG during a symptomatic episode. (See 'Ambulatory ECG monitoring and event recording' above.) Role of additional evaluation For patients in whom the diagnosis remains uncertain following ambulatory ECG monitoring, additional diagnostic options include the insertion of an insertable cardiac monitor that may last as long as three years. Pharmacologic challenge and invasive electrophysiology testing are rarely employed. Referral to a cardiac electrophysiologist should be considered. (See 'Diagnostic testing' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Alan Cheng, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Ferrer MI. The sick sinus syndrome in atrial disease. JAMA 1968; 206:645. 2. Lown B. Electrical reversion of cardiac arrhythmias. Br Heart J 1967; 29:469. 3. Ferrer MI. The Sick Sinus Syndrome, Futura Press, New York 1974. 4. SHORT DS. The syndrome of alternating bradycardia and tachycardia. Br Heart J 1954; 16:208. 5. BIRCHFIELD RI, MENEFEE EE, BRYANT GD. Disease of the sinoatrial node associated with bradycardia, asystole, syncope, and paroxysmal atrial fibrillation. Circulation 1957; 16:20. 6. Rubenstein JJ, Schulman CL, Yurchak PM, DeSanctis RW. Clinical spectrum of the sick sinus syndrome. Circulation 1972; 46:5. 7. Kaplan BM, Langendorf R, Lev M, Pick A. Tachycardia-bradycardia syndrome (so-called "sick sinus syndrome"). Pathology, mechanisms and treatment. Am J Cardiol 1973; 31:497. https://www.uptodate.com/contents/sinus-node-dysfunction-clinical-manifestations-diagnosis-and-evaluation/print 9/16 7/6/23, 10:43 AM Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation - UpToDate 8. Gomes JA, Kang PS, Matheson M, et al. Coexistence of sick sinus rhythm and atrial flutter- fibrillation. Circulation 1981; 63:80. 9. Lamas GA, Lee KL, Sweeney MO, et al. Ventricular pacing or dual-chamber pacing for sinus- node dysfunction. N Engl J Med 2002; 346:1854. 10. Ferrer MI. The etiology and natural history of sinus node disorders. Arch Intern Med 1982; 142:371. 11. Simonsen E, Nielsen JS, Nielsen BL. Sinus node dysfunction in 128 patients. A retrospective study with follow-up. Acta Med Scand 1980; 208:343. 12. Thery C, Gosselin B, Lekieffre J, Warembourg H. Pathology of sinoatrial node. Correlations with electrocardiographic findings in 111 patients. Am Heart J 1977; 93:735. 13. Eraut D, Shaw DB. Sinus bradycardia. Br Heart J 1971; 33:742. 14. Kay GN. Quantitation of chronotropic response: comparison of methods for rate- modulating permanent pacemakers. J Am Coll Cardiol 1992; 20:1533. 15. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74:e51. 16. Josephson, ME. Sinus Node Function. In: Clinical Cardiac Electrophysiology: Techniques and I nterpretations, 4th, Lippincott, Williams, & Wilkins, Philadelphia 2008. p.69-92. 17. Furukawa T, Maggi R, Bertolone C, et al. Additional diagnostic value of very prolonged observation by implantable loop recorder in patients with unexplained syncope. J Cardiovasc Electrophysiol 2012; 23:67. 18. Lipski J, Cohen L, Espinoza J, et al. Value of Holter monitoring in assessing cardiac arrhythmias in symptomatic patients. Am J Cardiol 1976; 37:102. 19. Reiffel JA, Bigger JT Jr, Cramer M, Reid DS. Ability of Holter electrocardiographic recording and atrial stimulation to detect sinus nodal dysfunction in symptomatic and asymptomatic patients with sinus bradycardia. Am J Cardiol 1977; 40:189. 20. Gibson TC, Heitzman MR. Diagnostic efficacy of 24-hour electrocardiographic monitoring for syncope. Am J Cardiol 1984; 53:1013. 21. Kerr CR, Strauss HC. The measurement of sinus node refractoriness in man. Circulation 1983; 68:1231. 22. Kinlay S, Leitch JW, Neil A, et al. Cardiac event recorders yield more diagnoses and are more cost-effective than 48-hour Holter monitoring in patients with palpitations. A controlled https://www.uptodate.com/contents/sinus-node-dysfunction-clinical-manifestations-diagnosis-and-evaluation/print 10/16 7/6/23, 10:43 AM Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation - UpToDate clinical trial. Ann Intern Med 1996; 124:16. 23. Zimetbaum PJ, Josephson ME. The evolving role of ambulatory arrhythmia monitoring in general clinical practice. Ann Intern Med 1999; 130:848. 24. Vavetsi S, Nikolaou N, Tsarouhas K, et al. Consecutive administration of atropine and isoproterenol for the evaluation of asymptomatic sinus bradycardia. Europace 2008; 10:1176. 25. Dhingra RC, Amat-Y-Leon F, Wyndham C, et al. Electrophysiologic effects of atropine on sinus node and atrium in patients with sinus nodal dysfunction. Am J Cardiol 1976; 38:848. 26. Talano JV, Euler D, Randall WC, et al. Sinus node dysfunction. An overview with emphasis on autonomic and pharmacologic consideration. Am J Med 1978; 64:773. 27. Burnett D, Abi-Samra F, Vacek JL. Use of intravenous adenosine as a noninvasive diagnostic test for sick sinus syndrome. Am Heart J 1999; 137:435. 28. Fragakis N, Iliadis I, Sidopoulos E, et al. The value of adenosine test in the diagnosis of sick sinus syndrome: susceptibility of sinus and atrioventricular node to adenosine in patients with sick sinus syndrome and unexplained syncope. Europace 2007; 9:559. 29. Viskin S, Justo D, Halkin A. Should the 'adenosine-challenge test' be part of the routine work- up for syncope? Europace 2007; 9:557. 30. Opthof T. The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res 2000; 45:177. 31. Thormann J, Schwarz F, Ensslen R, Sesto M. Vagal tone, significance of electrophysiologic findings and clinical course in symptomatic sinus node dysfunction. Am Heart J 1978; 95:725. Topic 896 Version 35.0 https://www.uptodate.com/contents/sinus-node-dysfunction-clinical-manifestations-diagnosis-and-evaluation/print 11/16 7/6/23, 10:43 AM Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation - UpToDate GRAPHICS Single lead electrocardiogram (ECG) showing sick sinus syndrome and atrial fibrillation Rhythm strip showing sick sinus syndrome. The initial part (left) of the tracing reveals coarse atrial fibrillation with irregular ventricular response in the absence of drugs that slow AV nodal conduction. The atrial fibrillation terminates and is followed by a sinus beat with a prolonged sinus node recovery time of nearly four seconds. Courtesy of Ary Goldberger, MD. Graphic 51193 Version 7.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/sinus-node-dysfunction-clinical-manifestations-diagnosis-and-evaluation/print 12/16 7/6/23, 10:43 AM Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation - UpToDate Single-lead electrocardiogram (ECG) showing manifestations of sick sinus syndrome (SSS) with sinus arrest Example of sick sinus syndrome (SSS). In this example, sinus arrest is seen with a junctional escape beat, a premature atrial complex, and eventual resumption of sinus activity. Courtesy of Alan Cheng, MD, FACC, FAHA, FHRS. Graphic 91605 Version 1.0 https://www.uptodate.com/contents/sinus-node-dysfunction-clinical-manifestations-diagnosis-and-evaluation/print 13/16 7/6/23, 10:43 AM Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation - UpToDate Single lead electrocardiogram (ECG) showing sick sinus syndrome (SSS) with ectopic atrial and junctional beats Example of sick sinus syndrome (SSS). In this example, sinus rhythm abruptly pauses, followed by two ectopic atrial beats, a junctional escape beat, and resumption of sinus activity. Courtesy of Alan Cheng, MD, FACC, FAHA, FHRS. Graphic 91606 Version 1.0 https://www.uptodate.com/contents/sinus-node-dysfunction-clinical-manifestations-diagnosis-and-evaluation/print 14/16 7/6/23, 10:43 AM Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation - UpToDate Algorithm for evaluation of the patient with suspected sick sinus syndrome (SSS) H&P: history and physical; ECG: electrocardiogram; ETT: exercise treadmill test; PPM: permanent pacemaker; SSS: sick sinus syndrome. Graphic 103295 Version 1.0 https://www.uptodate.com/contents/sinus-node-dysfunction-clinical-manifestations-diagnosis-and-evaluation/print 15/16 7/6/23, 10:43 AM Sinus node dysfunction: Clinical manifestations, diagnosis, and evaluation - UpToDate Contributor Disclosures Munther K Homoud, MD Speaker's Bureau: Abbott [Live heart dissection]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/sinus-node-dysfunction-clinical-manifestations-diagnosis-and-evaluation/print 16/16

7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation : Alfred Buxton, MD : N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 06, 2023. INTRODUCTION Sustained monomorphic ventricular tachycardia (SMVT) is defined by the following characteristics: A regular (<50 msec beat-to-beat cycle length variation) wide QRS complex ( 120 milliseconds) tachycardia at a rate greater than 100 beats per minute The consecutive beats have a uniform and stable QRS morphology The arrhythmia lasts 30 seconds or causes hemodynamic collapse in <30 seconds In patients with coronary heart disease (CHD) or other structural heart disease, a wide QRS complex tachycardia (WCT) should be considered to be ventricular tachycardia until proven otherwise. (See "Wide QRS complex tachycardias: Approach to the diagnosis".) This topic will focus on the clinical presentation, diagnosis, and evaluation of SMVT. The approach to treatment of SMVT, the approach to patients with monomorphic VT and no apparent heart disease, and the management of non-sustained VT are discussed separately. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis" and "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features" and "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management" and "Ventricular tachycardia in the absence of apparent structural heart disease".) https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 1/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate EPIDEMIOLOGY AND RISK FACTORS Cardiovascular disease (CVD) is common in the general population, affecting the majority of adults past the age of 60 years. In 2012 and 2013, CVD was estimated to result in 17.3 million deaths worldwide on an annual basis [1,2]. Many patients who die from CVD experience unexpected sudden cardiac death (SCD), with more than 50 percent of SCD episodes occurring as a first event in persons thought to be at low risk [3]. Along with ventricular fibrillation, SMVT is responsible for nearly all of the arrhythmic SCD, although ventricular arrhythmias are fairly uncommon in the general population populations. Among a prospective cohort of more than half a million United Kingdom residents, the prevalence of ventricular arrhythmias (which included ventricular premature beats, as well as ventricular tachycardia [VT] and ventricular fibrillation [VF]) was approximately 12 per 10,000 persons under age 55 and increased to between 20 (females) and 59 (males) per 10,000 persons 65 years of age [4]. These data are most likely weight toward VPBs rather than VT or VF in this cross-sectional community population. (See "Overview of sudden cardiac arrest and sudden cardiac death" and "Overview of established risk factors for cardiovascular disease".) SMVT may be idiopathic but occurs most frequently in patients with underlying heart disease of various types including: Coronary heart disease (CHD), especially with prior myocardial infarction Dilated cardiomyopathy Infiltrative cardiomyopathy Chagas heart disease Complex congenital heart disease Cardiac sarcoidosis Arrhythmogenic right ventricular cardiomyopathy Left ventricular noncompaction CHD is responsible for the majority of cases of SMVT. Approximately 70 percent of the cases of SCD in the United States are due to CHD, resulting in hundreds of thousands of deaths. However, SCD can result from VT that occurs in the absence of known heart disease. Monomorphic VT occurring in the absence of apparent structural heart disease is discussed in detail separately. (See "Ventricular tachycardia in the absence of apparent structural heart disease".) Drugs Flecainide and encainide have been associated with ventricular proarrhythmia in patients with prior infarct. By extension, propafenone is usually not recommended in this setting. Antiarrhythmic drugs in general can lead to more frequent (and at times incessant, albeit slower) SMVT. Inotropes, sympathomimetic agents, and other stimulants have been https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 2/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate associated with SMVT. A number of other agents have been implicated in SMVT but at very low frequencies. A 2020 scientific statement from the American Heart Association details drugs associated with SMVT [5]. CLINICAL MANIFESTATIONS AND ECG FINDINGS The history, physical examination, and 12-lead electrocardiogram (ECG) during SMVT and in sinus rhythm can all provide information to help confirm the diagnosis of SMVT. Because time may not allow for extensive questioning or examination, identifying a history of coronary heart disease (CHD) or other structural heart disease is the most important piece of historical information, along with obtaining an accurate list of medications and potential intoxicants (eg, flecainide, digoxin, etc) to identify any potential triggers for SMVT. (See "Wide QRS complex tachycardias: Approach to the diagnosis".) History and associated symptoms The clinical presentation of SMVT is highly variable, ranging from sudden cardiac arrest to mild symptoms. Although most patients with SMVT experience symptoms, in the occasional patient, symptoms may be minimal. Most patients with SMVT will have a history of underlying structural heart disease (eg, CHD, heart failure, hypertrophic cardiomyopathy, congenital heart disease, etc), although SMVT can also be seen in patients without known structural heart disease. Although SMVT is most commonly related to the development of reentrant circuits that follow healing of a prior myocardial infarction (MI), patients with prior MI may also develop SMVT due to non-reentrant mechanisms. (See "Ventricular tachycardia in the absence of apparent structural heart disease".) In the most severe instances, when SMVT significantly impairs cardiac output and results in immediate hemodynamic collapse, patients may briefly experience the onset of symptoms prior to the abrupt loss of consciousness and sudden cardiac arrest. Patients with faster ventricular rates, underlying heart disease, and decompensated heart failure with reduced left ventricular systolic function are more likely to develop hemodynamic instability. In such cases, prompt defibrillation and resuscitation to restore a perfusing heart rhythm is required. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Unstable patients'.) For patients without immediate sudden cardiac arrest, the type and intensity of symptoms will vary depending upon the rate and duration of SMVT along with the presence or absence of significant comorbid conditions. Patients with SMVT typically present with one or more of the following symptoms: Shortness of breath/dyspnea https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 3/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate Chest discomfort Palpitations Syncope or presyncope General malaise Most commonly, symptomatic patients will report chest discomfort and/or shortness of breath. Palpitations are less common during VT in persons with significant ventricular dysfunction because the heart does not contract with enough vigor to cause palpitations. If the associated rate of SMVT is rapid enough to result in hemodynamic compromise, patients may experience presyncope or even syncope and further deterioration into cardiac arrest. On occasion, patients may experience syncope at the onset of SMVT and then recover consciousness while remaining in VT. The patient's medication list should be reviewed carefully, with special attention for rate- controlling drugs and antiarrhythmic drugs, to assess potential proarrhythmic effects and to guide therapy. QT-prolonging drugs, however, typically cause torsades de pointes (ie, polymorphic VT). (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Physical examination Few physical examination findings in patients with SMVT are unique and specific. By definition, patients will have a pulse exceeding 100 beats per minute during the episode. In addition, if the physical examination is performed while SMVT persists, this can reveal evidence of atrioventricular (AV) dissociation, although it is not always easy to detect [6]. During AV dissociation, the normal coordination of atrial and ventricular contraction is lost, which may produce characteristic physical examination findings including (see "Wide QRS complex tachycardias: Approach to the diagnosis", section on 'AV dissociation'): Marked fluctuations in the blood pressure because of the variability in the degree of left atrial contribution to left ventricular filling, stroke volume, and cardiac output. Variability in the occurrence and intensity of heart sounds, especially S1, which is heard more frequently when the rate of the tachycardia is slower. Cannon "A" waves Cannon A waves are intermittent and irregular jugular venous pulsations of greater amplitude than normal waves. They reflect simultaneous atrial and ventricular activation, resulting in contraction of the right atrium against a closed tricuspid valve. Prominent A waves can also be seen during some SVTs. Such prominent waves result from simultaneous atrial and ventricular contraction occurring with every beat. (See "Examination of the jugular venous pulse".) Electrocardiogram In patients with sudden cardiac arrest or hemodynamically unstable SMVT, often the only ECG available is a single-lead assessment from the telemetry monitor or defibrillator showing a wide QRS complex tachycardia (WCT); in such instances, a full 12-lead ECG https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 4/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate is not typically obtained until the patient has been stabilized. However, for patients with suspected SMVT who are hemodynamically stable, a 12-lead ECG should be performed as this provides the maximal ECG information for making an accurate diagnosis and determining a possible etiology and may help to direct future therapy. If available, a previous ECG when the patient was in normal sinus rhythm is very helpful for comparison. For example, if a patient with underlying bundle branch block develops wide QRS complex tachycardia with a bundle branch block pattern opposite to the baseline bundle branch block (ie, a left bundle branch block pattern in a patient with right bundle branch block during NSR), the tachycardia is very likely to be VT, not SVT with aberrant conduction. SMVT typically generates a WCT, usually with a QRS width >0.12 seconds ( waveform 1). WCT occurring in patients with prior MI is almost always SMVT. In rare instances, SMVT may present as a relatively narrow complex tachycardia ( algorithm 1). Such an arrhythmia may be incorrectly diagnosed and treated as a supraventricular tachycardia [7]. Although uncommon, a QRS complex that is narrower during tachycardia than during sinus rhythm (usually in patients with chronic bundle branch block or intraventricular conduction delay during sinus rhythm) is diagnostic of SMVT. (See "Ventricular tachycardia in the absence of apparent structural heart disease", section on 'Idiopathic left ventricular tachycardia'.) A detailed discussion of the ECG characteristics of SMVT is found elsewhere (see "Wide QRS complex tachycardias: Approach to the diagnosis", section on 'Evaluation of the electrocardiogram'). Summarized briefly: The ECG hallmark for the diagnosis of SMVT is a wide complex tachycardia with the obvious presence of AV dissociation ( waveform 2). If not obvious, AV dissociation is suggested by the presence of fusion complexes (which reflect a supraventricular impulse coming from above the AV node fusing with an impulse generated in the ventricle) or sinus capture complexes (which reflect an impulse coming from above the AV node that depolarizes the ventricles when they are no longer refractory but before the next VT-generated complex). The occurrence of persistent or intermittent retrograde block is virtually diagnostic of SMVT. However, up to 40 percent of patients have intact ventriculoatrial (VA) conduction during SMVT, and AV dissociation is not seen ( waveform 3) [8]. VA conduction may occur in a 1:1 pattern or with second-degree VA block (eg, 2:1 or 3:1). Variability in the ST and T waves may be present, reflecting superimposed P waves as well as changes in ventricular repolarization. The tachycardia rate is usually constant but may warm up at start and may exhibit some subtle variability. https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 5/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate While concordance, or the presence of monophasic QRS complexes with the same polarity in leads V1 through V6, has been reported to have a specificity of greater than 90 percent for VT, positive concordance can also be present in preexcited tachyarrhythmias, specifically antidromic reciprocating tachycardia, which occur less frequently than VT [9]. Negative concordance is rarely seen but is consistent with VT. The specific QRS morphology, particularly when a shift in QRS axis occurs during WCT, may be helpful. Given the number of exceptions and the need to establish the correct diagnosis, ECG criteria may only be suggestive of SMVT. Confirmation sometimes requires other means, such as intracardiac ECGs from an implantable cardioverter-defibrillator (ICD) or pacemaker or invasive electrophysiologic testing. If a patient with sustained tachycardia has an ICD or pacemaker, interrogation and review of intracardiac electrograms are often diagnostic. DIAGNOSIS The diagnosis of SMVT should be suspected in a patient who presents with either sudden cardiac arrest, syncope, or sustained palpitations, particularly in a patient with a known history of structural heart disease. The diagnosis of SMVT is typically confirmed following review of an ECG, acquired during the arrhythmia, showing a wide QRS complex tachycardia with the presence of AV dissociation (manifest as an atrial rate slower than the ventricular rate). Frequently, however, it is not possible to identify P waves and the atrial rate amongst the wide QRS complexes, so other evidence of AV dissociation (ie, fusion and capture beats) is helpful in confirming the diagnosis of VT. Additional ECG features (eg, QRS axis, concordance, QRS morphology, etc) can provide additional supportive evidence for a diagnosis of VT versus supraventricular tachycardia ( table 1). (See "Wide QRS complex tachycardias: Approach to the diagnosis", section on 'Evaluation of the electrocardiogram'.) DIFFERENTIAL DIAGNOSIS The differential diagnosis for a wide QRS complex tachycardia (WCT) includes SMVT, supraventricular tachycardia with aberrant conduction (either preexistent or rate-related), supraventricular tachycardia with preexcitation, and tachycardia with ventricular pacing ( algorithm 1). Differentiating SMVT from other causes of WCT may be difficult, particularly if a high-quality 12-lead ECG is not available during the time of the arrhythmia. The presence of a https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 6/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate WCT in a patient with prior myocardial infarction (MI) or other structural heart disease probably represents SMVT. By contrast, a WCT in a patient without coronary heart disease (CHD) or structural heart disease more likely represents supraventricular tachycardia. Bundle branch reentry Bundle branch reentrant tachycardia (BBRT) should always be considered in patients presenting with SMVT in the setting of nonischemic cardiomyopathy because it is eminently curable by catheter ablation. While the most common ECG appearance is that of a left bundle branch block with left axis pattern, rarely, it may have a right bundle branch block pattern. BBRT has rarely been reported in persons without apparent structural heart disease or persons with coronary disease. These patients usually display an IVCD on the standard ECG, usually a left bundle branch block type pattern. Supraventricular tachycardia A patient with an underlying bundle branch block, or someone that is dependent on a ventricular pacemaker, who then develops tachycardia will, by definition, have a WCT. Review of a baseline ECG showing bundle branch block or ventricular paced rhythm with a similar QRS morphology to that seen during WCT suggests a higher likelihood of supraventricular tachycardia with aberrancy, but does not exclude ventricular tachycardia. In patients who present with symptomatic WCT, where time may be limited, a history of prior MI or other structural heart disease (or absence thereof) is the most important piece of historical information helping the clinician to distinguish supraventricular tachycardia from SMVT. While the absence of CHD or other structural heart disease does not exclude SMVT, supraventricular tachycardia is much more likely in patients without CHD or structural heart disease. (See 'History and associated symptoms' above and "Wide QRS complex tachycardias: Approach to the diagnosis".) Electrocardiogram artifact ECG artifact, particularly when observed on a rhythm strip, can be misdiagnosed as VT ( waveform 4). Artifact is highly probable, and a true WCT excluded, if narrow-complex beats can be identified regularly "marching" through the rhythm strip, particularly if there is a one-to-one association between P waves and QRS complexes. (See "Wide QRS complex tachycardias: Causes, epidemiology, and clinical manifestations", section on 'Artifact mimicking ventricular tachycardia'.) ADDITIONAL DIAGNOSTIC EVALUATION Following acute treatment for SMVT, reversible causes of arrhythmia should be sought. These include myocardial ischemia and adverse drug effects. Neither anemia nor electrolyte disturbances cause SMVT, hypotension, and heart failure, which may, with the appropriate https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 7/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate substrate, facilitate the induction of SMVT or contribute to its persistence but are rarely the primary cause for the arrhythmia. Thereafter, a thorough diagnostic evaluation to exclude associated structural heart disease is warranted. Even young, otherwise healthy patients need a thorough evaluation to exclude entities such as undiagnosed cardiomyopathy, anomalous origin of a coronary artery, hypertrophic cardiomyopathy, or arrhythmogenic right ventricular cardiomyopathy. (See "Congenital and pediatric coronary artery abnormalities" and "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death" and "Arrhythmogenic right ventricular cardiomyopathy: Anatomy, histology, and clinical manifestations".) The diagnostic evaluation to establish the presence and type of heart disease generally includes various invasive and noninvasive techniques, depending in part upon the clinical history and presentation. Cardiac imaging (with echocardiography and preferably cardiac magnetic resonance [CMR] imaging) and continuous ECG monitoring (for 24 hours or longer while hospitalized) should be performed in all patients. Invasive electrophysiology studies (EPS) can frequently be helpful but are not routinely performed in most patients, unless catheter ablation is being considered or there is persistent diagnostic uncertainty. Signal-averaged ECG (SAECG) is rarely helpful in evaluating patients with SMVT. In patients presenting with SMVT without known structural heart disease, stress testing can be helpful as a screen for coronary heart disease (CHD), and may help elicit VT in patients with idiopathic VT, arrhythmogenic right ventricular cardiomyopathy, or other unusual structural abnormalities. In patients with SMVT and history of prior myocardial infarction [MI], revascularization is rarely adequate as monotherapy to prevent recurrent VT, as SMVT is usually due to a reentrant circuit emanating from a prior infarct scar. CPVT is classically triggered by exertion, but condition is usually associated with frequent PVCs and PMVT on stress testing, not SMVT. Cardiac imaging All patients with SMVT should undergo cardiac imaging to evaluate for structural heart disease [10-12]. Echocardiography has long been the preferred method for evaluation of structural heart disease because of its widespread availability, accuracy in diagnosing a variety of structural cardiac defects (myocardial, valvular, congenital), safety to the patients, and relatively low expense. However, CMR imaging generally provides superior image quality and also allows for tissue characterization, making it an important imaging option for certain diagnoses (eg, arrhythmogenic right ventricular cardiomyopathy, cardiac sarcoidosis, other infiltrative cardiomyopathies, etc) and for patients with poor quality or nondiagnostic echocardiographic images [13-15]. In addition, if ablation is contemplated, CMR findings (areas of delayed gadolinium enhancement) may help guide ablation. (See "Tests to evaluate left ventricular systolic function" and "Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis", section on 'Cardiovascular magnetic resonance'.) https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 8/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate Continuous ECG monitoring Following acute treatment for SMVT, hospitalized patients should have continuous ECG monitoring while any potential reversible causes are identified and corrected. Typically the duration of continuous ECG monitoring should be at least 24 hours following the last episode of SMVT, but additional monitoring may be useful if patients have reversible causes that have not been fully remedied (eg, ongoing myocardial ischemia, heart failure, hypokalemia, etc). Since SMVT generally occurs infrequently and sporadically, we do not routinely perform outpatient ambulatory ECG monitoring [16,17]. However, in patients with syncope suspected of having SMVT, but in whom the diagnosis has not been, extended ambulatory ECG monitoring with an event (loop) monitor, extended Holter monitor, or insertable cardiac monitor (also sometimes referred to as an implantable cardiac monitor or implantable loop recorder) can successfully aid in establishing the diagnosis [18-20]. (See "Ambulatory ECG monitoring".) Signal-averaged electrocardiogram We do not routinely perform a signal-averaged ECG (SAECG) for diagnostic purposes in patients with documented SMVT. The rationale for not routinely obtaining a SAECG is that, while the SAECG often demonstrates late potentials (low amplitude oscillations occurring after the QRS complex) in patients with SMVT and ischemic heart disease, the presence of late potentials provides only indirect data that are suggestive, but not diagnostic, of SMVT [21-23]. Although the SAECG has a prognostic role for predicting the risk of SMVT in patients with ischemic heart disease, it has a limited role in the evaluation of patients who have already experienced SMVT and is rarely used in current cardiology practice [24-26]. (See "Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications".) The rare patients in whom the SAECG can aid in the diagnosis of underlying heart disease include patients with suspected arrhythmogenic right ventricular cardiomyopathy, in whom the SAECG findings are part of the diagnostic criteria for the disorder, as well as patients with suspected Brugada syndrome. The diagnostic approaches to these conditions are discussed in detail separately. (See "Brugada syndrome: Clinical presentation, diagnosis, and evaluation", section on 'Diagnostic evaluation' and "Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis", section on 'Diagnostic evaluation'.) Exercise testing Exercise stress testing, or pharmacologic stress testing if the patient cannot exercise, is an important component of the diagnostic approach in patients presenting with SMVT and suspected myocardial ischemia. For patients with SMVT and evidence of an acute coronary syndrome, stress testing is typically deferred in favor of prompt coronary angiography (with or without https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 9/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate revascularization as indicated). (See "Overview of the acute management of ST-elevation myocardial infarction" and "Overview of the acute management of non-ST-elevation acute coronary syndromes".) For patients with SMVT in whom CHD is a possible contributing factor to SMVT (eg, patients with numerous risk factors for atherosclerotic cardiovascular disease, patients with cardiac imaging findings suggesting CHD, etc), we proceed with stress testing primarily for prognostic purposes. The choice of the optimal stress test should be based upon the patient's ability to exercise, the ability to interpret the patient's baseline ECG, and the pre- test probability of CHD [27]. (See "Selecting the optimal cardiac stress test".) In patients in whom significant myocardial ischemia is identified, the decision to proceed with revascularization should primarily be based on the presence or absence of symptoms attributable to the ischemia. However, treatment of myocardial ischemia does not eliminate the risk of recurrent SMVT, particularly in patients with prior MI and the presence of myocardial scar. Electrophysiologic studies EPS is the most definitive means of establishing the diagnosis of SMVT [28]. (See "Invasive diagnostic cardiac electrophysiology studies".) There are a number of potential uses for EPS in the evaluation of patients with SMVT: To establish the diagnosis of SMVT when the diagnosis is uncertain. To establish the mechanism of the SMVT. When combined with mapping, the location of the arrhythmogenic focus can be identified, which is useful in cases where ablation is being considered. (See "Invasive diagnostic cardiac electrophysiology studies", section on 'Mapping and ablation'.) Prior to catheter ablation of SMVT, EPS should be performed to assess whether the clinical VT is inducible and also to assess the extensiveness of scar tissue. When BBRT is suspected, EPS can confirm the diagnosis, and ablation is highly effective. While EPS can be helpful in the diagnosis of VT, it is not without limitations: Patients with a prior MI and a history of SMVT almost always (90+ percent) have inducible SMVT with EPS. However, in some studies of patients with ischemic heart disease, up to 5 percent of patients with clinically documented SMVT are not inducible; thus, noninducibility does not exclude this diagnosis [28,29]. The clinically occurring morphology of SMVT is frequently not the same as the morphology of the induced VT during EPS and may have consequences for eventual catheter ablation. https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 10/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate This is in part related to the limited number of induction attempts during routine diagnostic studies. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials: "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching for "patient info" and the keyword[s] of interest.) Basics topics (see "Patient education: Ventricular tachycardia (The Basics)") SUMMARY AND RECOMMENDATIONS Background Sustained monomorphic ventricular tachycardia (SMVT) is a potentially life- threatening arrhythmia which requires urgent attention and evaluation. Clinical manifestations Patients with structural heart disease, especially coronary artery disease and a prior myocardial infarction, who present with a wide QRS complex tachycardia (WCT) should be presumed to have VT. All available telemetry recordings and surface electrocardiograms (ECGs), including prior ECGs, should be reviewed for clues to the diagnosis of VT which include (see 'Electrocardiogram' above and "Wide QRS complex tachycardias: Approach to the diagnosis", section on 'Evaluation of the electrocardiogram'): Atrioventricular (AV) dissociation with P waves appearing independently of the QRS complexes. If not obvious, AV dissociation is suggested by the presence of fusion or captured complexes. Variability of ST and T waves from superimposed P waves or from changes in repolarization. https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 11/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate QRS axis shift from baseline ECG axis. Morphology of QRS complex, especially in leads V1-V6. Differential diagnosis The differential diagnosis of SMVT includes supraventricular tachycardia with aberrant conduction (preexisting or rate-related), supraventricular tachycardia with preexcitation, supraventricular tachycardia in a pacemaker dependent patient, and ECG artifact ( waveform 4). (See 'Differential diagnosis' above.) Cardiac imaging Echocardiography should be performed to evaluate for structural heart disease. If the echocardiographic evaluation is inconclusive, cardiac computed tomography (CT) or magnetic resonance imaging (MRI) should be performed. (See 'Cardiac imaging' above.) Exercise testing All patients should be evaluated for ischemic heart disease. We typically proceed with exercise stress testing (or pharmacologic stress testing if the patient is unable to exercise) with or without cardiac imaging, as clinically appropriate, and coronary angiography when indicated. (See 'Exercise testing' above.) Electrophysiologic studies Invasive electrophysiologic studies can provide a more definitive diagnosis in instances where the diagnosis of ventricular tachycardia (VT) remains uncertain, or in cases where catheter ablation is being considered. However, if the diagnosis of VT is certain, and therapy with an implantable cardiac defibrillator (ICD) placement is planned, electrophysiologic studies are unlikely to affect further management and are not recommended unless catheter ablation is also being planned. (See 'Electrophysiologic studies' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Philip J. Podrid, MD, FACC and Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age- sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015; 385:117. https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 12/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate 2. Roth GA, Huffman MD, Moran AE, et al. Global and regional patterns in cardiovascular mortality from 1990 to 2013. Circulation 2015; 132:1667. 3. Myerburg RJ. Sudden cardiac death: exploring the limits of our knowledge. J Cardiovasc Electrophysiol 2001; 12:369. 4. Khurshid S, Choi SH, Weng LC, et al. Frequency of Cardiac Rhythm Abnormalities in a Half Million Adults. Circ Arrhythm Electrophysiol 2018; 11:e006273. 5. Tisdale JE, Chung MK, Campbell KB, et al. Drug-Induced Arrhythmias: A Scientific Statement From the American Heart Association. Circulation 2020; 142:e214. 6. Gupta AK, Thakur RK. Wide QRS complex tachycardias. Med Clin North Am 2001; 85:245. 7. Hayes JJ, Stewart RB, Green HL, Bardy GH. Narrow QRS ventricular tachycardia. Ann Intern Med 1991; 114:460. 8. Militianu A, Salacata A, Meissner MD, et al. Ventriculoatrial conduction capability and prevalence of 1:1 retrograde conduction during inducible sustained monomorphic ventricular tachycardia in 305 implantable cardioverter defibrillator recipients. Pacing Clin Electrophysiol 1997; 20:2378. 9. Miller JM, Das MK. Differential diagnosis of wide complex tachycardia. In: Cardiac electrophy siology: from cell to bedside, 4th, Zipes DP, Jalife J (Eds), Saunders, 2004. p.751. 10. European Heart Rhythm Association, Heart Rhythm Society, Zipes DP, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol 2006; 48:e247. 11. American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, et al. ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 Appropriate Use Criteria for Echocardiography. A Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Critical Care Medicine, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance Endorsed by the American College of Chest Physicians. J Am Coll Cardiol 2011; 57:1126. https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 13/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate 12. Priori SG, Blomstr m-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015; 36:2793. 13. Ki s P, Bootsma M, Bax J, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: screening, diagnosis, and treatment. Heart Rhythm 2006; 3:225. 14. Marcus F, Towbin JA, Zareba W, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C): a multidisciplinary study: design and protocol. Circulation 2003; 107:2975. 15. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J 2010; 31:806. 16. Bay s de Luna A, Coumel P, Leclercq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J 1989; 117:151. 17. Gradman AH, Batsford WP, Rieur EC, et al. Ambulatory electrocardiographic correlates of ventricular inducibility during programmed electrical stimulation. J Am Coll Cardiol 1985; 5:1087. 18. Linzer M, Pritchett EL, Pontinen M, et al. Incremental diagnostic yield of loop electrocardiographic recorders in unexplained syncope. Am J Cardiol 1990; 66:214. 19. Krahn AD, Klein GJ, Yee R, et al. Use of an extended monitoring strategy in patients with problematic syncope. Reveal Investigators. Circulation 1999; 99:406. 20. Kadish AH, Buxton AE, Kennedy HL, et al. ACC/AHA clinical competence statement on electrocardiography and ambulatory electrocardiography. A report of the ACC/AHA/ACP- ASIM Task Force on Clinical Competence (ACC/AHA Committee to Develop a Clinical Competence Statement on Electrocardiography and Ambulatory Electrocardiography). J Am Coll Cardiol 2001; 38:2091. 21. Denniss AR, Richards DA, Cody DV, et al. Prognostic significance of ventricular tachycardia and fibrillation induced at programmed stimulation and delayed potentials detected on the signal-averaged electrocardiograms of survivors of acute myocardial infarction. Circulation 1986; 74:731. 22. Vaitkus PT, Kindwall KE, Marchlinski FE, et al. Differences in electrophysiological substrate in patients with coronary artery disease and cardiac arrest or ventricular tachycardia. Insights https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 14/22 7/6/23, 10:43 AM

Morphology of QRS complex, especially in leads V1-V6. Differential diagnosis The differential diagnosis of SMVT includes supraventricular tachycardia with aberrant conduction (preexisting or rate-related), supraventricular tachycardia with preexcitation, supraventricular tachycardia in a pacemaker dependent patient, and ECG artifact ( waveform 4). (See 'Differential diagnosis' above.) Cardiac imaging Echocardiography should be performed to evaluate for structural heart disease. If the echocardiographic evaluation is inconclusive, cardiac computed tomography (CT) or magnetic resonance imaging (MRI) should be performed. (See 'Cardiac imaging' above.) Exercise testing All patients should be evaluated for ischemic heart disease. We typically proceed with exercise stress testing (or pharmacologic stress testing if the patient is unable to exercise) with or without cardiac imaging, as clinically appropriate, and coronary angiography when indicated. (See 'Exercise testing' above.) Electrophysiologic studies Invasive electrophysiologic studies can provide a more definitive diagnosis in instances where the diagnosis of ventricular tachycardia (VT) remains uncertain, or in cases where catheter ablation is being considered. However, if the diagnosis of VT is certain, and therapy with an implantable cardiac defibrillator (ICD) placement is planned, electrophysiologic studies are unlikely to affect further management and are not recommended unless catheter ablation is also being planned. (See 'Electrophysiologic studies' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Philip J. Podrid, MD, FACC and Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age- sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015; 385:117. https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 12/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate 2. Roth GA, Huffman MD, Moran AE, et al. Global and regional patterns in cardiovascular mortality from 1990 to 2013. Circulation 2015; 132:1667. 3. Myerburg RJ. Sudden cardiac death: exploring the limits of our knowledge. J Cardiovasc Electrophysiol 2001; 12:369. 4. Khurshid S, Choi SH, Weng LC, et al. Frequency of Cardiac Rhythm Abnormalities in a Half Million Adults. Circ Arrhythm Electrophysiol 2018; 11:e006273. 5. Tisdale JE, Chung MK, Campbell KB, et al. Drug-Induced Arrhythmias: A Scientific Statement From the American Heart Association. Circulation 2020; 142:e214. 6. Gupta AK, Thakur RK. Wide QRS complex tachycardias. Med Clin North Am 2001; 85:245. 7. Hayes JJ, Stewart RB, Green HL, Bardy GH. Narrow QRS ventricular tachycardia. Ann Intern Med 1991; 114:460. 8. Militianu A, Salacata A, Meissner MD, et al. Ventriculoatrial conduction capability and prevalence of 1:1 retrograde conduction during inducible sustained monomorphic ventricular tachycardia in 305 implantable cardioverter defibrillator recipients. Pacing Clin Electrophysiol 1997; 20:2378. 9. Miller JM, Das MK. Differential diagnosis of wide complex tachycardia. In: Cardiac electrophy siology: from cell to bedside, 4th, Zipes DP, Jalife J (Eds), Saunders, 2004. p.751. 10. European Heart Rhythm Association, Heart Rhythm Society, Zipes DP, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol 2006; 48:e247. 11. American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, et al. ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 Appropriate Use Criteria for Echocardiography. A Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Critical Care Medicine, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance Endorsed by the American College of Chest Physicians. J Am Coll Cardiol 2011; 57:1126. https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 13/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate 12. Priori SG, Blomstr m-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015; 36:2793. 13. Ki s P, Bootsma M, Bax J, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: screening, diagnosis, and treatment. Heart Rhythm 2006; 3:225. 14. Marcus F, Towbin JA, Zareba W, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C): a multidisciplinary study: design and protocol. Circulation 2003; 107:2975. 15. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J 2010; 31:806. 16. Bay s de Luna A, Coumel P, Leclercq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J 1989; 117:151. 17. Gradman AH, Batsford WP, Rieur EC, et al. Ambulatory electrocardiographic correlates of ventricular inducibility during programmed electrical stimulation. J Am Coll Cardiol 1985; 5:1087. 18. Linzer M, Pritchett EL, Pontinen M, et al. Incremental diagnostic yield of loop electrocardiographic recorders in unexplained syncope. Am J Cardiol 1990; 66:214. 19. Krahn AD, Klein GJ, Yee R, et al. Use of an extended monitoring strategy in patients with problematic syncope. Reveal Investigators. Circulation 1999; 99:406. 20. Kadish AH, Buxton AE, Kennedy HL, et al. ACC/AHA clinical competence statement on electrocardiography and ambulatory electrocardiography. A report of the ACC/AHA/ACP- ASIM Task Force on Clinical Competence (ACC/AHA Committee to Develop a Clinical Competence Statement on Electrocardiography and Ambulatory Electrocardiography). J Am Coll Cardiol 2001; 38:2091. 21. Denniss AR, Richards DA, Cody DV, et al. Prognostic significance of ventricular tachycardia and fibrillation induced at programmed stimulation and delayed potentials detected on the signal-averaged electrocardiograms of survivors of acute myocardial infarction. Circulation 1986; 74:731. 22. Vaitkus PT, Kindwall KE, Marchlinski FE, et al. Differences in electrophysiological substrate in patients with coronary artery disease and cardiac arrest or ventricular tachycardia. Insights https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 14/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate from endocardial mapping and signal-averaged electrocardiography. Circulation 1991; 84:672. 23. Martinez-Rubio A, Shenasa M, Borggrefe M, et al. Electrophysiologic variables characterizing the induction of ventricular tachycardia versus ventricular fibrillation after myocardial infarction: relation between ventricular late potentials and coupling intervals for the induction of sustained ventricular tachyarrhythmias. J Am Coll Cardiol 1993; 21:1624. 24. Ommen SR, Hammill SC, Bailey KR. Failure of signal-averaged electrocardiography with use of time-domain variables to predict inducible ventricular tachycardia in patients with conduction defects. Mayo Clin Proc 1995; 70:132. 25. Steinberg JS, Prystowsky E, Freedman RA, et al. Use of the signal-averaged electrocardiogram for predicting inducible ventricular tachycardia in patients with unexplained syncope: relation to clinical variables in a multivariate analysis. J Am Coll Cardiol 1994; 23:99. 26. Cain, ME, Anderson, et al. Signal-averaged electrocardiography. ACC Expert Consensus Document. J Am Coll Cardiol 1996; 27:238. 27. Hendel RC, Berman DS, Di Carli MF, et al. ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 Appropriate Use Criteria for Cardiac Radionuclide Imaging: A Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the American Society of Nuclear Cardiology, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the Society of Cardiovascular Computed Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society of Nuclear Medicine. J Am Coll Cardiol 2009; 53:2201. 28. Volgman AS, Zheutlin TA, Mattioni TA, et al. Reproducibility of programmed electrical stimulation responses in patients with ventricular tachycardia or fibrillation associated with coronary artery disease. Am J Cardiol 1992; 70:758. 29. Bhandari AK, Hong R, Kulick D, et al. Day to day reproducibility of electrically inducible ventricular arrhythmias in survivors of acute myocardial infarction. J Am Coll Cardiol 1990; 15:1075. Topic 1029 Version 35.0 https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 15/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate GRAPHICS ECG of sustained monomorphic ventricular tachycardia Shown are the six precordial electrocardiogram (ECG) leads (V1-V6). The QRS complex is wide and bizarre and the rhythm is ventricular tachycardia (VT). The sixth (+) and seventh (*) QRS complexes show a change in morphology, resembling a normal QRS complex; these represent fusion beats, with partial (+) or complete (*) normalization of the QRS complex. The seventh QRS complex (*) is preceded by a distinct P wave, which is probably conducted, capturing the ventricle for one beat, but not terminating the VT; this is also known as a Dressler beat. Reproduced with permission by Samuel Levy, MD. Graphic 69201 Version 3.0 https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 16/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate Algorithm for the initial ECG review and differential diagnosis of tachycardia ECG: electrocardiogram; AVNRT: atrioventricular nodal reentrant tachycardia; AVRT: atrioventricular reciprocating (bypass-tract mediated) tachycardia; AT: atrial tachycardia; SANRT: sinoatrial nodal reentrant tachycardia; AF: atrial fibrillation; AV: atrioventricular; VT: ventricular tachycardia; SVT: supraventricular tachycardia; WPW: Wolff-Parkinson-White. A narrow QRS complex is <120 milliseconds in duration, whereas a wide QRS complex is 120 milliseconds duration. Refer to UpToDate topic reviews for additional details on specific ECG findings and management of individu arrhythmias. Monomorphic VT accounts for 80% of wide QRS complex tachycardias; refer to UpToDate topic on diagnosi wide QRS complex tachycardias for additional information on discriminating VT from SVT. Graphic 117571 Version 3.0 https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 17/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate Atrioventricular dissociation Independent activation of the atria and ventricles results in no fixed relationship between the P waves (arrows) and the QRS complexes; the PR intervals are variable in a random fashion. Graphic 52123 Version 2.0 Normal rhythm strip Normal rhythm strip in lead II. The PR interval is 0.15 sec and the QRS duration is 0.08 sec. Both the P and T waves are upright. Courtesy of Morton F Arnsdorf, MD. Graphic 59022 Version 3.0 https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 18/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate 12-lead ECG sustained monomorphic VT The electrocardiogram (ECG) hallmark for the diagnosis of sustained monomorphic ventricular tachycardia (S is a wide complex tachycardia with the obvious presence of atrioventricular (AV) dissociation. AV dissociation suggested by the presence of fusion complexes (which reflect a supraventricular impulse coming from above AV node fusing with an impulse generated in the ventricle) or captured complexes (which reflect an impulse coming from above the AV node that depolarizes the ventricles when they are no longer refractory but befor next ventricle-generated complex). Beats 12, 17, and 22 on this ECG likely represent capture beats. Graphic 111254 Version 1.0 https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 19/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate ECG features of ventricular tachycardia QRS width >120 milliseconds Shift in QRS axis, particularly to a "northwest" axis (between 90 and 180 degrees) AV dissociation (including the presence of fusion complexes and/or capture beats) Negative concordance in leads V1 to V6 RS >100 milliseconds in any of leads V1 to V6 Morphology: VT with RBBB-like morphology in V1: R/S <1 in V6 VT with LBBB-like morphology in V1: Any Q wave in V6 ECG: electrocardiogram; AV: atrioventricular; VT: ventricular tachycardia; RBBB: right bundle branch block; LBBB: left bundle branch block. Graphic 111307 Version 2.0 https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 20/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate Ventricular tachycardia artifact Courtesy of Alfred Buxton, MD. Graphic 140806 Version 1.0 https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 21/22 7/6/23, 10:43 AM Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation - UpToDate Contributor Disclosures Alfred Buxton, MD No relevant financial relationship(s) with ineligible companies to disclose. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/sustained-monomorphic-ventricular-tachycardia-clinical-manifestations-diagnosis-and-evaluation/print 22/22

7/6/23, 10:44 AM Vagal maneuvers - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Vagal maneuvers : Daniel R Frisch, MD, Peter J Zimetbaum, MD : Brian Olshansky, MD : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 15, 2023. INTRODUCTION The autonomic nervous system is composed of the sympathetic and parasympathetic divisions. This system innervates and regulates most visceral functions including electrophysiological and hemodynamic cardiovascular responses. Various physical maneuvers can elicit autonomic responses (see 'Types of vagal maneuvers' below). Many of these maneuvers can be performed at the bedside or in an office setting with minimal risk. These maneuvers can be both diagnostic (eg, in confirming carotid sinus hypersensitivity) and therapeutic (eg, terminating supraventricular tachycardia [SVT]). Understanding the indications, techniques, and complications of various vagal maneuvers is necessary to safe and effective clinical application. Vagal maneuvers to evaluate and treat cardiac arrhythmias and conduction abnormalities are reviewed here. The evaluation of carotid sinus hypersensitivity and SVT are presented separately. (See "Carotid sinus hypersensitivity and carotid sinus syndrome" and "Narrow QRS complex tachycardias: Clinical manifestations, diagnosis, and evaluation".) CARDIAC RESPONSES TO VAGAL STIMULATION In the heart, parasympathetic (vagal) stimulation causes local release of acetylcholine, with the following effects: https://www.uptodate.com/contents/vagal-maneuvers/print 1/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate In the sinus node, there is slowing of the rate of impulse formation. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history", section on 'Autonomic nervous system and the SA node'.) In the atrioventricular (AV) node, conduction velocity slows and the refractory period lengthens [1,2]. In atrial tissue, there is no change in conduction velocity, while the refractory period shortens [1]. The electrophysiologic properties of the His-Purkinje system do not change significantly. In ventricular myocardium, vagal nerve stimulation has been shown to decrease ventricular inotropy [3]. The effects on the sinus node are often more manifest with right vagus activation and the effects on the AV node by left vagus activation. Manual pressure on the carotid sinus can elicit an intense activation of the vagus nerve on that side. The intensity of the response is directly related to the ambient blood pressure, the sensitivity of the vagus nerve, the underlying sympathetic activation, and the expertise of applying manual pressure to the correct spot. The direct role of acute increases in vagus nerve activation in stopping supraventricular tachycardias is supported by the following observations: Successful arrhythmia termination with vagal maneuvers is associated with a greater degree of bradycardic response to vagal maneuvers while in sinus rhythm [4]. Arrhythmia termination is often preceded by gradual slowing of the tachycardia, suggesting progressive prolongation of AV conduction during the maneuver [2,5,6]. CLINICAL USES Vagal maneuvers can be performed in a variety of clinical settings for diagnostic and/or therapeutic purposes ( table 1): Vagal maneuvers are a safe and easily performed diagnostic test as well as an effective first-line therapeutic intervention for patients with SVT. The 2015 American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines recommend vagal maneuvers (Class IA LOE B-R) for acute treatment of SVT of unknown mechanism, for treatment of AV reentrant tachycardia, and for treatment of AV nodal reentrant tachycardia [7]. (See "Narrow QRS complex tachycardias: Clinical manifestations, diagnosis, and https://www.uptodate.com/contents/vagal-maneuvers/print 2/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate evaluation" and "Atrioventricular nodal reentrant tachycardia" and "Atrioventricular reentrant tachycardia (AVRT) associated with an accessory pathway".) Vagal maneuvers, in particular carotid sinus massage, can be helpful in determining the location of the conduction abnormality in a patient with 2:1 AV block (eg, within the AV node or in the His-Purkinje system). Increased vagal tone slows conduction through the AV node but has little effect on conduction properties of the His-Purkinje system. (See "Second-degree atrioventricular block: Mobitz type I (Wenckebach block)" and "Second- degree atrioventricular block: Mobitz type II".) Carotid sinus massage is employed in the evaluation of potential carotid sinus hypersensitivity as a cause of syncope. This maneuver should not be performed in patients with carotid artery disease, as discussed below. (See 'Contraindications' below and 'Carotid sinus massage' below.) The Valsalva maneuver can also be useful in the evaluation of cardiac murmurs. (See "Auscultation of cardiac murmurs in adults".) Historical case reports and small series have documented termination of atrial fibrillation and hemodynamically stable ventricular tachycardia initiated during cardiac electrophysiological studies by vagal maneuvers [8-10]. TYPES OF VAGAL MANEUVERS A wide variety of physical maneuvers can have intended or unintended influence on increasing vagal tone. These include: Carotid sinus massage (see 'Carotid sinus massage' below) Valsalva maneuver (standard or modified technique) (see 'Valsalva maneuver' below) Water immersion, especially cold water immersion (diving reflex) (see 'Diving reflex' below) Eyeball pressure (oculocardiac reflex) (see 'Oculocardiac reflex' below) Breath holding Rectal examination Coughing Deep respirations Gagging and/or vomiting Swallowing Intracardiac catheter placement Nasogastric tube placement https://www.uptodate.com/contents/vagal-maneuvers/print 3/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Squatting Trendelenburg position Although only a small number of these maneuvers are used clinically for diagnostic or therapeutic purposes (eg, carotid sinus massage and the Valsalva maneuver), it is useful to be aware of the potential autonomic impact of the others. CHOICE OF MANEUVER The choice of a particular vagal maneuver is dependent on the clinical scenario and the patient's ability to successfully perform some of the maneuvers. Our approach to choosing a vagal maneuver for the most commonly encountered clinical scenarios is as follows: For diagnostic and/or therapeutic use in a patient with SVT, we typically start with the Valsalva maneuver and employ the modified Valsalva when possible, as the Valsalva maneuver appears to be more effective in terminating SVT than other vagal maneuvers. For diagnostic evaluation of a patient with suspected carotid sinus hypersensitivity, we use carotid sinus massage. For diagnostic evaluation of a cardiac murmur, we use the Valsalva maneuver. (See "Physiologic and pharmacologic maneuvers in the differential diagnosis of heart murmurs and sounds", section on 'Valsalva maneuver'.) Successful termination of SVT by vagal maneuvers has been noted in as many as 72 percent of cases, although likelihood of success diminishes as the duration of the arrhythmia increases [4- 6,11,12]. In the largest randomized trial of vagal maneuvers for the treatment of SVT, patients performing the modified Valsalva maneuver with supine repositioning and passive leg raise were significantly more likely to have restoration of sinus rhythm at one minute (43 versus 17 percent in the standard Valsalva group; adjusted odds ratio 3.7; 95% CI 2.3-5.8) [11]. The relative efficacy of four different vagal maneuvers (Valsalva maneuver, right carotid sinus massage, left carotid massage, and the diving reflex) was evaluated in a series of 35 patients with SVT inducible by programmed electrical stimulation [4]. The supine Valsalva maneuver was most successful in terminating SVT (54 percent), with significantly lower efficacy right and left carotid sinus massage (17 and 5 percent, respectively) and the diving reflex (17 percent). https://www.uptodate.com/contents/vagal-maneuvers/print 4/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Another study evaluated the standard Valsalva maneuver, modified Valsalva maneuver, and carotid sinus massage and found that the success rate for SVT termination was 43.7 percent (14 of 32 cases) for the modified Valsalva maneuver, 24.2 percent (8 of 33) for the standard Valsalva maneuver, and 9.1 percent (3 of 33) for carotid sinus massage (p <0.05) [12]. VALSALVA MANEUVER For both diagnostic and therapeutic purposes, the Valsalva maneuver is commonly used in patients with suspected SVTs. Because of its greater efficacy in terminating SVT, we perform a modified Valsalva maneuver involving passive leg raising whenever feasible. (See "Atrioventricular nodal reentrant tachycardia", section on 'Vagal maneuvers' and "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'Acute treatment of symptomatic arrhythmias'.) A.M. Valsalva is credited with describing the maneuver that bears his name [13]. In the original 1704 reporting, the use of the maneuver, essentially a forceful expiration against a closed mouth and nose, was beneficial in rapid expulsion of pus from the middle ear. Subsequent investigation of the Valsalva maneuver has focused on its cardiovascular and autonomic nervous properties [14,15]. Currently, the Valsalva maneuver is primarily used in clinical practice in the diagnosis and treatment of SVTs and, occasionally, for the assessment of heart failure and left ventricular dysfunction [7]. Valsalva maneuver technique Various descriptions of the technique of performing a Valsalva maneuver exist ( figure 1). Most commonly, the patient is placed in a supine or semirecumbent position and instructed to exhale forcefully against a closed glottis after a normal inspiratory effort (ie, at tidal volume). Signs of adequacy include neck vein distension, increased tone in the abdominal wall muscles, and a flushed face. The patient should maintain the strain for 10 to 15 seconds and then release it and resume normal breathing. A modified Valsalva maneuver, which involves the standard strain (40 mmHg pressure for 15 seconds in the semirecumbent position) followed by supine repositioning with 15 seconds of passive leg raise at a 45 degree angle, has been shown to be more successful in restoring sinus rhythm for patients with SVT [11]. While some descriptions have required patients to blow into a manometer to generate a certain amount of pressure (eg, 40 mmHg), this is not generally required. https://www.uptodate.com/contents/vagal-maneuvers/print 5/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate In the largest randomized trial of vagal maneuvers for the treatment of SVT, patients performing the modified Valsalva maneuver with supine repositioning and passive leg raise were significantly more likely to have restoration of sinus rhythm at one minute (43 versus 17 percent in the standard Valsalva group; adjusted odds ratio 3.7; 95% CI 2.3-5.8) [11]. When feasible, the modified Valsalva maneuver should be performed given the greater likelihood of successful restoration of sinus rhythm. (See "Atrioventricular nodal reentrant tachycardia", section on 'Vagal maneuvers'.) Valsalva maneuver monitoring When the Valsalva maneuver is performed in a medical environment (eg, hospital, clinic, etc), all patients should have vital signs monitored before and after the maneuver, with some variation in monitoring during the maneuver depending upon the indication (ie, paroxysmal SVT versus heart failure). Patients who are performing the Valsalva maneuver for either diagnostic and/or therapeutic purposes in the setting of SVT should have continuous heart rate monitoring. Ideally, the continuous monitoring is performed with 12-lead electrocardiography, yielding the most information about the heart rhythm and tachycardia, but if this is not available or practical then continuous single-lead telemetry monitoring should be performed. Although seldom used in current practice, alterations in the systemic arterial blood pressure response to the Valsalva maneuver have been described in patients with heart failure and/or left ventricular dysfunction [16]. Patients who are performing the Valsalva maneuver for diagnostic purposes in this setting should have continuous blood pressure monitoring along with continuous heart rate monitoring (single-lead telemetry is adequate here) during the maneuver. When noninvasively monitoring blood pressure responses using a blood pressure cuff, the cuff should be inflated to approximately 15 mmHg above the patient's resting systolic blood pressure, and the examiner should auscultate the brachial artery throughout the maneuver and for 15 to 30 seconds afterward. Blood pressure responses following a Valsalva maneuver The expected blood pressure response in normal subjects is divided into four phases ( figure 2) [14]. Phases 1 and 2 occur during the active strain phase of the Valsalva maneuver, while phases 3 and 4 occur after the strain phase has been completed. The normal pattern of systolic blood pressure has been named the "sinusoidal" response. Phase 1 is characterized by a >15 mmHg rise in the patient's systolic blood pressure that occurs at the onset of straining and typically lasts less than five seconds. Phase 1 occurs because of increased intrathoracic pressure. https://www.uptodate.com/contents/vagal-maneuvers/print 6/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Phase 2 is typified by a return of the systolic blood pressure to baseline (below the 15 mmHg increase) during the remainder of the straining phase. Phase 2 occurs due to decreased venous return (leading to a decrease in stroke volume) and an increase in systemic vascular resistance. Relative tachycardia may occur during this phase [17]. Phase 3 occurs after release of the strain and is distinguished by an abrupt fall in systolic blood pressure below baseline. Phase 3 occurs due to an acute decrease in intrathoracic pressure. Phase 4 follows and is identified by a secondary rise in systolic blood pressure >15 mmHg above baseline. Phase 4 occurs because of a reflex sympathetic response to the decrease in systolic blood pressure encountered during phase 3. Relative bradycardia may occur during this phase. In addition to the normal sinusoidal response to Valsalva, two abnormal response patterns have been described in patients not taking beta-blocking agents [17,18]. The "absent overshoot" response is characterized by an absence of the expected rise in systolic blood pressure during phase 4. This response is associated with a moderately decreased left ventricular ejection fraction. The "square wave" response is characterized by the presence of Korotkoff sounds during the entire straining phase (indicating a sustained rise in blood pressure following phase 1) and an absence of the expected rise in systolic blood pressure during phase 4. This response is associated with a severely decreased ejection fraction. Patients taking beta-blockers typically show a blunted blood pressure response to the Valsalva maneuver. Heart rate responses for patients with SVT For a patient with SVT in whom the Valsalva maneuver is performed for both diagnostic and/or therapeutic purposes, the potential heart rate and rhythm responses are similar to those that can be seen following any vagal maneuver or the administration of adenosine. Potential outcomes include slowing of sinoatrial nodal activity, block at the AV node "unmasking" atrial activity, termination of the SVT, or no response (generally indicating inadequate performance of the technique). These responses are discussed in detail separately. (See "Narrow QRS complex tachycardias: Clinical manifestations, diagnosis, and evaluation", section on 'Possible outcomes following vagal maneuvers or adenosine administration'.) https://www.uptodate.com/contents/vagal-maneuvers/print 7/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate CAROTID SINUS MASSAGE The cerebrovascular and cardiovascular effects of carotid artery compression were documented at least as early as the 18th century [19]. Early theories suggested that pressure on the carotid sinus directly stimulated the vagus nerve. However, later work demonstrated that distinct afferent nerve fibers are present in the carotid sinus and that these fibers join the glossopharyngeal nerve (cranial nerve IX) to directly stimulate medullary centers [19]. Carotid sinus massage (CSM) is commonly used in a variety of settings, most commonly in the evaluation of SVTs as well as the evaluation of patients with suspected reflex syncope or carotid sinus hypersensitivity [1,4,20,21]. Use of CSM in the diagnosis of syncope and carotid sinus hypersensitivity is discussed separately. (See "Reflex syncope in adults and adolescents: Clinical presentation and diagnostic evaluation" and "Carotid sinus hypersensitivity and carotid sinus syndrome".) Carotid sinus massage technique Carotid sinus massage is performed as follows [22]: Patients are first screened for contraindications to carotid sinus massage. In those without known carotid disease, auscultation for carotid bruits should be performed first to avoid inadvertent carotid artery injury. (See 'Contraindications' below.) The patient is placed in the supine position with the neck extended (ie, raising the chin away from the chest) to maximize access to the carotid artery. The carotid sinus is usually located inferior to the angle of the mandible at the level of the thyroid cartilage near the arterial impulse ( figure 3). Pressure is applied to one carotid sinus for 5 to 10 seconds. Although pulsatile pressure via vigorous circular motion may be more effective, steady pressure is recommended because it may be more reproducible [6]. If the expected response is not obtained, the procedure is repeated on the other side after a one- to two-minute delay. (See 'Responses to carotid sinus massage' below.) Carotid sinus massage monitoring When carotid sinus massage is performed in a medical environment (eg, hospital, clinic, etc), all patients should have vital signs monitored before and after the maneuver, with some variation in monitoring during carotid sinus massage depending upon the indication (ie, paroxysmal SVT versus carotid sinus hypersensitivity) [22]. Patients undergoing carotid sinus massage for either diagnostic and/or therapeutic purposes in the setting of SVT should have continuous heart rate monitoring. Ideally, the https://www.uptodate.com/contents/vagal-maneuvers/print 8/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate continuous monitoring is performed with 12-lead electrocardiography, yielding the most information about the heart rhythm and tachycardia, but if this is not available or practical then continuous single-lead telemetry monitoring should be performed. Patients undergoing carotid sinus massage for diagnostic purposes in the setting of suspected carotid sinus hypersensitivity should have frequent blood pressure monitoring along with continuous heart rate monitoring (single-lead telemetry is adequate here) during the massage. (See "Carotid sinus hypersensitivity and carotid sinus syndrome".) Responses to carotid sinus massage Changes in heart rate or rhythm, as well as blood pressure, occur following carotid sinus massage. The expected responses vary somewhat depending upon the indication (ie, paroxysmal SVT versus carotid sinus hypersensitivity) [8]. For a patient with SVT in whom carotid sinus massage is performed for both diagnostic and/or therapeutic purposes, the potential heart rate and rhythm responses are similar to those that can be seen following any vagal maneuver or the administration of adenosine. Potential outcomes include slowing of sinoatrial nodal activity, block at the AV node "unmasking" atrial activity, termination of the SVT, or no response (generally indicating inadequate performance of the technique). These responses are discussed in detail separately. (See "Narrow QRS complex tachycardias: Clinical manifestations, diagnosis, and evaluation", section on 'Possible outcomes following vagal maneuvers or adenosine administration'.) Criteria for abnormal responses suggestive of carotid sinus hypersensitivity (and carotid sinus syndrome if clinical symptoms are reproduced) are discussed separately. (See "Carotid sinus hypersensitivity and carotid sinus syndrome", section on 'Diagnostic evaluation'.) Contraindications Injury to the carotid artery, with its attendant consequences, can occur with direct pressure on the carotid artery. Carotid sinus massage should be avoided in patients with known carotid artery stenosis, prior transient ischemia attack, or stroke within the past three months and in patients with carotid bruits (unless carotid Doppler studies have excluded significant stenosis) [21-23]. As noted above, in those without known carotid disease, auscultation for carotid bruits should be performed first to avoid inadvertent carotid artery injury. Additional exclusion criteria have been used in some studies including recent myocardial infarction, history of ventricular arrhythmia, immobility, blindness, and cognitive impairment [20,24]. (See 'Complications' below.) For patients in whom carotid sinus massage is needed as part of an evaluation (ie, in the evaluation of carotid sinus hypersensitivity), there are few data on screening for carotid disease with any means other than auscultation for carotid bruits (eg, carotid ultrasound, etc). (See "Screening for asymptomatic carotid artery stenosis".) https://www.uptodate.com/contents/vagal-maneuvers/print 9/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate For patients with SVT in whom there is concern about increased risk of stroke due to carotid sinus massage, alternative vagal maneuvers (eg, Valsalva maneuver) should be utilized. (See 'Valsalva maneuver' above.) DIVING REFLEX The diving reflex was first described in chickens and ducks and has also been observed as an oxygen-conserving maneuver in diving mammals. In humans, the diving reflex has been studied as a tool to assess the autonomic nervous system [25,26]. Similar to other vagal maneuvers, the diving reflex can potentially terminate paroxysmal SVT. The diving reflex is commonly used to terminate SVT in infants, but it is rarely used in older children or adults. A variety of techniques to elicit a diving reflex have been tried [25-27]. Infants In infants, the vagal maneuver most commonly used is application of a bag filled with ice and cold water over the face for 15 to 30 seconds. This successfully terminates SVT in 60 to 90 percent of cases. (See "Management of supraventricular tachycardia (SVT) in children", section on 'Vagal maneuvers'.) Adults and older children Most commonly, the patient is seated in front of a basin of water (at a temperature of 10 to 20 C) and is attached to continuous electrocardiographic monitoring (ideally, continuous 12-lead electrocardiography, but if this is not available or practical then continuous single-lead telemetry monitoring). The patient takes a moderate breath, holds it, and then submerges his or her face in water for 20 to 30 seconds. A bradycardic response usually occurs within 10 to 30 seconds of breath holding. If the inspiration is too deep, increased intrathoracic pressure may attenuate the bradycardic response. Contact of the area innervated by the ophthalmic division of the trigeminal nerve seems to be particularly important in eliciting a response. The expected response in normal subjects results from a combination of facial immersion and breath holding. The expected effect is parasympathetic-mediated bradycardia and sympathetic-mediated peripheral vasoconstriction, ideally resulting in termination of the SVT. Although its role is limited, this maneuver may be preferred in patients who should not be performing a Valsalva maneuver (eg, pregnant women with SVT). OCULOCARDIAC REFLEX https://www.uptodate.com/contents/vagal-maneuvers/print 10/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate As a clinical tool, the oculocardiac reflex is poorly defined and rarely used. It has been used to terminate supraventricular tachycardias and in the diagnostic evaluation of syncope [28-30]. However, due to limited utility, risk of injury to the eyes and other associated risks, and the availability of alternative maneuvers, we do not perform this test in clinical practice. The oculocardiac reflex involves a decrease in heart rate and/or blood pressure in response to eyeball pressure. The reflex is thought to originate from the ophthalmic portion of the trigeminal nerve. Afferent stimuli move through the reticular formation and nuclei of the vagus nerve output and proceed via an efferent link through the vagus nerve to cardiovascular structures [28]. This oculocardiac reflex is most often recognized in the context of ophthalmic surgery. Pressure or traction on the orbital contents, globe, or extra-ocular muscles can produce unwanted and sometimes dangerous consequences, which on rare occasions can include lethal arrhythmias [28]. COMPLICATIONS In appropriately selected patients, vagal maneuvers are generally safe. However, there are potential complications to performing vagal maneuvers ( table 2): Cardiac In general, the potential cardiac complications following a vagal maneuver are simply exaggerations of the expected response from the procedure. Patients may develop prolonged sinus pauses/asystole, AV block, and/or hypotension, all of which are transient and typically resolve within seconds to minutes. Less commonly, tachyarrhythmias such as atrial fibrillation can be provoked following a vagal maneuver. Neurologic Neurologic complications are rare (less than 1 percent) and are usually related to stroke or transient ischemia attack following carotid sinus massage [20,24,31]. (See 'Contraindications' above.) Miscellaneous In addition to the potential cardiac and neurologic complications, there are some maneuver-specific potential complications, including the following: Valsalva maneuver Rupture of the round window of the ear, induction of labor in pregnant women Diving reflex (ice-water immersion) Aspiration, drowning, induction of labor in pregnant women Oculocardiac reflex Ocular injury https://www.uptodate.com/contents/vagal-maneuvers/print 11/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Vagal maneuvers and their responses (The Basics)") SUMMARY AND RECOMMENDATIONS Role of autonomic nervous system The autonomic nervous system is composed of the sympathetic and parasympathetic divisions. Various physical maneuvers can elicit autonomic responses, including a wide variety that can have intended or unintended influence on increasing vagal tone. (See 'Introduction' above.) Cardiac response to vagal stimulation In the heart, parasympathetic (vagal) stimulation causes local release of acetylcholine, which results in slowing of sinus node impulse formation and slowed conduction with lengthening of the refractory period in the atrioventricular (AV) node. (See 'Cardiac responses to vagal stimulation' above.) Clinical uses Vagal maneuvers can be performed in a variety of clinical settings for diagnostic and/or therapeutic purposes ( table 1), including the evaluation and/or treatment of patients with supraventricular tachycardia (SVT), AV block, syncope, and cardiac murmurs. (See 'Clinical uses' above.) Choice of vagal maneuver The choice of a particular vagal maneuver is dependent on the clinical scenario and the patient's ability to successfully perform the maneuvers. Our approach to choosing a vagal maneuver for the most commonly encountered clinical scenarios is as follows (see 'Choice of maneuver' above): https://www.uptodate.com/contents/vagal-maneuvers/print 12/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate For diagnostic and/or therapeutic use in a patient with SVT, we typically start with the Valsalva maneuver and employ the modified Valsalva when possible, as the Valsalva maneuver appears to be more effective in terminating SVT than other vagal maneuvers. (See 'Valsalva maneuver' above.) For diagnostic evaluation of a patient with suspected carotid sinus hypersensitivity, we use carotid sinus massage. (See 'Carotid sinus massage' above.) For diagnostic evaluation of a cardiac murmur, we use the Valsalva maneuver. Contraindications and complications In appropriately selected patients, vagal maneuvers are generally safe. However, there are potential contraindications and complications to performing vagal maneuvers. While noncardiac side effects are rare ( table 2), interventions that alter cardiac conduction properties can result in adverse events, including sinus pauses, AV block, and, rarely, tachyarrhythmias. (See 'Contraindications' above and 'Complications' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kirchhof CJ, Gorgels AP, Wellens HJ. Carotid sinus massage as a diagnostic and therapeutic tool for atrial flutter-fibrillation. Pacing Clin Electrophysiol 1998; 21:1319. 2. Klein HO, Hoffman BF. Cessation of paroxysmal supraventricular tachycardias by parasympathomimetic interventions. Ann Intern Med 1974; 81:48. 3. Yamakawa K, So EL, Rajendran PS, et al. Electrophysiological effects of right and left vagal nerve stimulation on the ventricular myocardium. Am J Physiol Heart Circ Physiol 2014; 307:H722. 4. Mehta D, Wafa S, Ward DE, Camm AJ. Relative efficacy of various physical manoeuvres in the termination of junctional tachycardia. Lancet 1988; 1:1181. 5. Josephson ME, Seides SE, Batsford WB, et al. The effects of carotid sinus pressure in re- entrant paroxysmal supraventricular tachycardia. Am Heart J 1974; 88:694. 6. Waxman MB, Wald RW, Sharma AD, et al. Vagal techniques for termination of paroxysmal supraventricular tachycardia. Am J Cardiol 1980; 46:655. 7. Page RL, Joglar JA, Caldwell MA, et al. 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of https://www.uptodate.com/contents/vagal-maneuvers/print 13/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation 2016; 133:e506. 8. Schweitzer P, Teichholz LE. Carotid sinus massage. Its diagnostic and therapeutic value in arrhythmias. Am J Med 1985; 78:645. 9. Hess DS, Hanlon T, Scheinman M, et al. Termination of ventricular tachycardia by carotid sinus massage. Circulation 1982; 65:627. 10. Wei JY, Greene HL, Weisfeldt ML. Cough-facilitated conversion of ventricular tachycardia. Am J Cardiol 1980; 45:174. 11. Appelboam A, Reuben A, Mann C, et al. Postural modification to the standard Valsalva manoeuvre for emergency treatment of supraventricular tachycardias (REVERT): a randomised controlled trial. Lancet 2015; 386:1747. 12. Ceylan E, Ozpolat C, Onur O, et al. Initial and Sustained Response Effects of 3 Vagal Maneuvers in Supraventricular Tachycardia: A Randomized, Clinical Trial. J Emerg Med 2019; 57:299. 13. DERBES VJ, KERR A Jr. Valsalva's maneuver and Weber's experiment. N Engl J Med 1955; 253:822. 14. IRVIN CW Jr. Valsalva maneuver as a diagnostic aid. J Am Med Assoc 1959; 170:787. 15. Smith G, Morgans A, Boyle M. Use of the Valsalva manoeuvre in the prehospital setting: a review of the literature. Emerg Med J 2009; 26:8. 16. Zema MJ. Diagnosing Heart Failure by the Valsalva Maneuver: Isn't it Finally Time? JACC Heart Fail 2018; 6:969. 17. Zema MJ, Restivo B, Sos T, et al. Left ventricular dysfunction bedside Valsalva manoeuvre. Br Heart J 1980; 44:560. 18. Zema MJ, Masters AP, Margouleff D. Dyspnea: the heart or the lungs? Differentiation at bedside by use of the simple Valsalva maneuver. Chest 1984; 85:59. 19. LOWN B, LEVINE SA. The carotid sinus. Clinical value of its stimulation. Circulation 1961; 23:766. 20. Richardson DA, Bexton R, Shaw FE, et al. Complications of carotid sinus massage a prospective series of older patients. Age Ageing 2000; 29:413. 21. Brignole M, Moya A, de Lange FJ, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J 2018; 39:1883. 22. Pasquier M, Clair M, Pruvot E, et al. Carotid Sinus Massage. N Engl J Med 2017; 377:e21. 23. Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: A Report of the American College of https://www.uptodate.com/contents/vagal-maneuvers/print 14/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. J Am Coll Cardiol 2017. 24. Davies AJ, Kenny RA. Frequency of neurologic complications following carotid sinus massage. Am J Cardiol 1998; 81:1256. 25. Reyners AK, Tio RA, Vlutters FG, et al. Re-evaluation of the cold face test in humans. Eur J Appl Physiol 2000; 82:487. 26. Duprez D, De Buyzere M, Trouerbach J, et al. Continuous monitoring of haemodynamic parameters in humans during the early phase of simulated diving with and without breathholding. Eur J Appl Physiol 2000; 81:411. 27. Gooden BA. The diving response in clinical medicine. Aviat Space Environ Med 1982; 53:273. 28. Van Brocklin MD, Hirons RR, Yolton RL. The oculocardiac reflex: a review. J Am Optom Assoc 1982; 53:407. 29. Brignole M, Menozzi C, Gianfranchi L, et al. Carotid sinus massage, eyeball compression, and head-up tilt test in patients with syncope of uncertain origin and in healthy control subjects. Am Heart J 1991; 122:1644. 30. Allison CE, De Lange JJ, Koole FD, et al. A comparison of the incidence of the oculocardiac and oculorespiratory reflexes during sevoflurane or halothane anesthesia for strabismus surgery in children. Anesth Analg 2000; 90:306. 31. Puggioni E, Guiducci V, Brignole M, et al. Results and complications of the carotid sinus massage performed according to the "method of symptoms". Am J Cardiol 2002; 89:599. Topic 1034 Version 31.0 https://www.uptodate.com/contents/vagal-maneuvers/print 15/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate GRAPHICS Conditions in which vagal maneuvers may be useful diagnostically or therapeutically Tachyarrhythmias Narrow, regular supraventricular tachycardias Sinus tachycardia Conduction abnormalities 2:1 atrioventricular block Bundle branch blocks Preexcitation Other cardiovascular uses Carotid sinus hypersensitivity Pulmonary edema Courtesy of Peter J Zimetbaum, MD and Daniel Frisch, MD. Graphic 67134 Version 4.0 https://www.uptodate.com/contents/vagal-maneuvers/print 16/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Valsalva maneuver The Valsalva maneuver is performed with the patient supine or in a semirecumbent position and instructed to exhale forcefully against a closed glottis after a normal inspiratory effort (ie, at tidal volume). Signs of adequacy include neck vein distension, increased tone in the abdominal wall muscles, and a flushed face. The patient should maintain the strain for 10 to 15 seconds and then release it and resume normal breathing. A modified Valsalva maneuver involves the standard strain (40 mmHg pressure for 15 seconds in the semirecumbent position at 45 degrees) immediately followed by lowering the trunk to a supine position with passive leg raise at a 45 degree angle for 15 seconds. The modified Valsalva maneuver has been shown to be more successful in restoring sinus rhythm for patients with supraventricular tachycardia. Modi ed from: Hunter C. Slow down, you re going too fast: SVT and The Modi ed Valsalva Maneuver. CPR Seattle 2019. Graphic 130499 Version 1.0 https://www.uptodate.com/contents/vagal-maneuvers/print 17/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Normal blood pressure responses to the Valsalva maneuver Normal Valsalva response: Normal changes in systolic blood pressure during 10 seconds of straining (shaded). Phase 1 - systolic blood pressure rises with initiation of the maneuver. Phase 2 - systolic blood pressure returns to baseline after several seconds. Phase 3 - systolic blood pressure drops below normal after strain is released. Phase 4 - systolic blood pressure rises transiently before returning to baseline. Graphic 78776 Version 4.0 https://www.uptodate.com/contents/vagal-maneuvers/print 18/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Anatomy of the carotid sinus The carotid sinus is located at the base of the internal carotid artery just superior to its bifurcation from the external carotid artery. Graphic 139405 Version 1.0 https://www.uptodate.com/contents/vagal-maneuvers/print 19/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Potential complications of selected vagal maneuvers Vagal maneuver Potential complication Valsalva maneuver Rupture of the round window of the ear Carotid sinus massage Decreased cerebral perfusion, cerebral embolism Ice-water immersion Aspiration, drowning, pregnancy complications Eyeball compression Ocular injury Courtesy of Peter J Zimetbaum, MD and Daniel Frisch, MD. Graphic 79543 Version 5.0 https://www.uptodate.com/contents/vagal-maneuvers/print 20/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Contributor Disclosures Daniel R Frisch, MD Other Financial Interest: Abbott [Arrhythmias speaking engagement]; St Jude Medical [Arrhythmias speaking engagement]. All of the relevant financial relationships listed have been mitigated. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose.

https://www.uptodate.com/contents/vagal-maneuvers/print 13/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation 2016; 133:e506. 8. Schweitzer P, Teichholz LE. Carotid sinus massage. Its diagnostic and therapeutic value in arrhythmias. Am J Med 1985; 78:645. 9. Hess DS, Hanlon T, Scheinman M, et al. Termination of ventricular tachycardia by carotid sinus massage. Circulation 1982; 65:627. 10. Wei JY, Greene HL, Weisfeldt ML. Cough-facilitated conversion of ventricular tachycardia. Am J Cardiol 1980; 45:174. 11. Appelboam A, Reuben A, Mann C, et al. Postural modification to the standard Valsalva manoeuvre for emergency treatment of supraventricular tachycardias (REVERT): a randomised controlled trial. Lancet 2015; 386:1747. 12. Ceylan E, Ozpolat C, Onur O, et al. Initial and Sustained Response Effects of 3 Vagal Maneuvers in Supraventricular Tachycardia: A Randomized, Clinical Trial. J Emerg Med 2019; 57:299. 13. DERBES VJ, KERR A Jr. Valsalva's maneuver and Weber's experiment. N Engl J Med 1955; 253:822. 14. IRVIN CW Jr. Valsalva maneuver as a diagnostic aid. J Am Med Assoc 1959; 170:787. 15. Smith G, Morgans A, Boyle M. Use of the Valsalva manoeuvre in the prehospital setting: a review of the literature. Emerg Med J 2009; 26:8. 16. Zema MJ. Diagnosing Heart Failure by the Valsalva Maneuver: Isn't it Finally Time? JACC Heart Fail 2018; 6:969. 17. Zema MJ, Restivo B, Sos T, et al. Left ventricular dysfunction bedside Valsalva manoeuvre. Br Heart J 1980; 44:560. 18. Zema MJ, Masters AP, Margouleff D. Dyspnea: the heart or the lungs? Differentiation at bedside by use of the simple Valsalva maneuver. Chest 1984; 85:59. 19. LOWN B, LEVINE SA. The carotid sinus. Clinical value of its stimulation. Circulation 1961; 23:766. 20. Richardson DA, Bexton R, Shaw FE, et al. Complications of carotid sinus massage a prospective series of older patients. Age Ageing 2000; 29:413. 21. Brignole M, Moya A, de Lange FJ, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J 2018; 39:1883. 22. Pasquier M, Clair M, Pruvot E, et al. Carotid Sinus Massage. N Engl J Med 2017; 377:e21. 23. Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: A Report of the American College of https://www.uptodate.com/contents/vagal-maneuvers/print 14/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. J Am Coll Cardiol 2017. 24. Davies AJ, Kenny RA. Frequency of neurologic complications following carotid sinus massage. Am J Cardiol 1998; 81:1256. 25. Reyners AK, Tio RA, Vlutters FG, et al. Re-evaluation of the cold face test in humans. Eur J Appl Physiol 2000; 82:487. 26. Duprez D, De Buyzere M, Trouerbach J, et al. Continuous monitoring of haemodynamic parameters in humans during the early phase of simulated diving with and without breathholding. Eur J Appl Physiol 2000; 81:411. 27. Gooden BA. The diving response in clinical medicine. Aviat Space Environ Med 1982; 53:273. 28. Van Brocklin MD, Hirons RR, Yolton RL. The oculocardiac reflex: a review. J Am Optom Assoc 1982; 53:407. 29. Brignole M, Menozzi C, Gianfranchi L, et al. Carotid sinus massage, eyeball compression, and head-up tilt test in patients with syncope of uncertain origin and in healthy control subjects. Am Heart J 1991; 122:1644. 30. Allison CE, De Lange JJ, Koole FD, et al. A comparison of the incidence of the oculocardiac and oculorespiratory reflexes during sevoflurane or halothane anesthesia for strabismus surgery in children. Anesth Analg 2000; 90:306. 31. Puggioni E, Guiducci V, Brignole M, et al. Results and complications of the carotid sinus massage performed according to the "method of symptoms". Am J Cardiol 2002; 89:599. Topic 1034 Version 31.0 https://www.uptodate.com/contents/vagal-maneuvers/print 15/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate GRAPHICS Conditions in which vagal maneuvers may be useful diagnostically or therapeutically Tachyarrhythmias Narrow, regular supraventricular tachycardias Sinus tachycardia Conduction abnormalities 2:1 atrioventricular block Bundle branch blocks Preexcitation Other cardiovascular uses Carotid sinus hypersensitivity Pulmonary edema Courtesy of Peter J Zimetbaum, MD and Daniel Frisch, MD. Graphic 67134 Version 4.0 https://www.uptodate.com/contents/vagal-maneuvers/print 16/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Valsalva maneuver The Valsalva maneuver is performed with the patient supine or in a semirecumbent position and instructed to exhale forcefully against a closed glottis after a normal inspiratory effort (ie, at tidal volume). Signs of adequacy include neck vein distension, increased tone in the abdominal wall muscles, and a flushed face. The patient should maintain the strain for 10 to 15 seconds and then release it and resume normal breathing. A modified Valsalva maneuver involves the standard strain (40 mmHg pressure for 15 seconds in the semirecumbent position at 45 degrees) immediately followed by lowering the trunk to a supine position with passive leg raise at a 45 degree angle for 15 seconds. The modified Valsalva maneuver has been shown to be more successful in restoring sinus rhythm for patients with supraventricular tachycardia. Modi ed from: Hunter C. Slow down, you re going too fast: SVT and The Modi ed Valsalva Maneuver. CPR Seattle 2019. Graphic 130499 Version 1.0 https://www.uptodate.com/contents/vagal-maneuvers/print 17/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Normal blood pressure responses to the Valsalva maneuver Normal Valsalva response: Normal changes in systolic blood pressure during 10 seconds of straining (shaded). Phase 1 - systolic blood pressure rises with initiation of the maneuver. Phase 2 - systolic blood pressure returns to baseline after several seconds. Phase 3 - systolic blood pressure drops below normal after strain is released. Phase 4 - systolic blood pressure rises transiently before returning to baseline. Graphic 78776 Version 4.0 https://www.uptodate.com/contents/vagal-maneuvers/print 18/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Anatomy of the carotid sinus The carotid sinus is located at the base of the internal carotid artery just superior to its bifurcation from the external carotid artery. Graphic 139405 Version 1.0 https://www.uptodate.com/contents/vagal-maneuvers/print 19/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Potential complications of selected vagal maneuvers Vagal maneuver Potential complication Valsalva maneuver Rupture of the round window of the ear Carotid sinus massage Decreased cerebral perfusion, cerebral embolism Ice-water immersion Aspiration, drowning, pregnancy complications Eyeball compression Ocular injury Courtesy of Peter J Zimetbaum, MD and Daniel Frisch, MD. Graphic 79543 Version 5.0 https://www.uptodate.com/contents/vagal-maneuvers/print 20/21 7/6/23, 10:44 AM Vagal maneuvers - UpToDate Contributor Disclosures Daniel R Frisch, MD Other Financial Interest: Abbott [Arrhythmias speaking engagement]; St Jude Medical [Arrhythmias speaking engagement]. All of the relevant financial relationships listed have been mitigated. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/vagal-maneuvers/print 21/21

7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment : Mark S Link, MD : N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 22, 2023. INTRODUCTION While there has always been concern about the potential for electromagnetic interference (EMI) with pacemaker, implantable cardioverter-defibrillator (ICD), and cardiac resynchronization devices function due to interaction between the device and an electromagnetic field, the risk is generally low, unless there is a strong magnet or electrical field close to the generator ( table 1) [1,2]. EMI can occur in a variety of settings, but overall is more likely in the hospital environment than in the nonhospital environment [3]. There are reports of cardiac implantable electronic devices (CIEDs) being impacted by sources of EMI in the nonhospital environment (eg, strong magnets, cellular phones, slot machines, laptop computers, etc). There are also disclaimers that wireless sources could be the source of EMI with CIEDs, even though no published data exists (eg, automobile manufacturers providing "caution" for device patients purchasing automobiles with "keyless" entry mechanisms, hybrid engines, etc). Nonetheless, most sources of EMI in the nonhospital environment are not concerning [4,5]. However, with the proliferation of wireless technology, any new device which operates on a new frequency or new technology platform should be assessed for the likelihood of clinically significant EMI. Electromagnetic interference with medical sources is discussed separately. (See "Pacing system malfunction: Evaluation and management", section on 'Electromagnetic interference' and https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 1/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate "Cardiac implantable electronic devices: Long-term complications", section on 'Electromagnetic interference'.) HOUSEHOLD APPLIANCES Although there are no studies that have systematically evaluated the effect of household microwave ovens on implanted devices, it is widely accepted that contemporary pacemakers and ICDs are adequately shielded from microwave energy produced by modern appliances [3]. Manufacturers do not recommend any special precautions when using common household appliances, such as televisions, radios, toasters, microwave ovens, and electric blankets; UpToDate experts agree with this approach. As a new appliance that uses a new or different energy source reaches the market, the appliance needs to be tested to determine whether there is any potential for device interference. There are circumstances in which a device may be affected by specific sources of energy under narrow circumstances. This was illustrated in a study assessing the potential for induction cook tops to interfere with pacemaker function. Patients with a unipolar, left-sided implant could experience interference if the pot was not concentrically placed on the induction coil and if the patient stood as close as possible to the cook top. The most common response to interference was a reset to an asynchronous interference mode [6]. Most contemporary devices utilize bipolar pacing and sensing configuration, which minimizes the chance of device malfunction from electromagnetic interference. CELLULAR TELEPHONES The widespread use of cellular telephones requires a heightened awareness of their potential for adverse effects on cardiac device function. Equipment with high-strength magnets Patients with a pacemaker or an ICD should be aware that strong magnetic fields in close proximity to their device generator can alter normal cardiac device function [7-10]. Electronic equipment (eg, cellular phones with strong magnets for wireless charging) and accessories with powerful magnets (eg, watch bands) should be stored at least 15 inches away from pacemaker or ICD generators ( figure 1 and picture 1). In general, we advise all patients to use cellular telephones at the ear on the side opposite the cardiac device and carry cellular telephones in a pocket below the waist. Similar warnings apply to magnets included in clothing, accessories, and elsewhere. (See 'Small magnets incorporated into clothing, furniture, and identification badges' below.) https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 2/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate When equipment with a strong magnetic field is in close proximity to an ICD or pacemaker generator, the cardiac device defaults to magnet mode. Generally, magnet mode causes ICDs to suspend tachyarrhythmia therapies (eg, shocks and antitachycardia pacing) until the magnet is removed. Magnet mode causes pacemakers to asynchronously pace at rates and modes determined by the type of device and manufacturer ( table 2). (See "Perioperative management of patients with a pacemaker or implantable cardioverter-defibrillator", section on 'Magnet application' and "Pacing system malfunction: Evaluation and management", section on 'Magnet application'.) While there are too many devices and magnet applications to provide a complete list of equipment and scenarios to avoid, the following case reports highlight specific devices and use scenarios that may induce magnet mode in an ICD or pacemaker: Working with a laptop on the chest while recumbent [7]. Using a wristwatch with a magnetic band [11]. Using a cellular phone with a magnetic array for wireless charging (eg, iPhone 12) [8]. Large interrogation studies describe the rate of unintended magnet mode induction (events) as between 7 and 11 events per 100 patient years [9,12]. Neither study recorded malignant arrythmias during magnet mode induction, suggesting that most magnet mode activations were short-lived. Equipment without high-strength magnets Cellular telephone equipment without strong magnets is unlikely to cause clinically significant interference with pacemakers or ICDs [13-18]. However, cellular phones may disrupt telemetry, and patients should avoid using the cellular phone during telemetry [19]. In addition, patients should use the telephone at the ear on the side opposite the cardiac device and carry the telephone in a pocket below the waist. Use on the contralateral side will maximally reduce the risk of interference [20,21]. SECURITY SYSTEMS Electromagnetic security systems (eg, antishoplifting gates, metal detectors) are in widespread use, and are often present in or near the workplace, in shopping malls, and at airports. Although device interference is possible, it is unlikely that any clinically significant interference would occur with the transient exposure associated with walking through such a field. There are case reports of inappropriate shocks and pacemaker inhibition associated with continued close exposure to electromagnetic security systems [22]. The best recommendation for patients is to move through the detection and do not stop close to the detectors (ie, be aware of the location https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 3/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate of security systems and simply move through them at a normal pace) [1]. Single-beat inhibition of a device by anti-theft equipment would not be of clinical concern. Permanent pacemakers Electronic security systems can potentially interfere with pacemakers [23-25]. The frequency and type of complications were evaluated in a study of 204 patients who were exposed to an electronic security system for up to 30 seconds [23]. One or more episodes of pacemaker function interference developed in 17 percent of patients. Sensing abnormalities were the most common type of interference, and they were typically transient, lasting only for the duration of exposure. In patients with dual chamber pacemakers, interference at the atrial level was more common than at the ventricular level. In another report, the most common complications were asynchronous pacing, atrial oversensing (producing a tachycardia in the ventricle), ventricular oversensing (with pacemaker inhibition), and paced beats due to direct induction of current in the pacemaker [24]. Symptoms such as palpitations and presyncope occurred in some patients while they were in the security system field. Interference with pacemaker function can occur at a distance of 50 cm from the security system [25]. This is of particular concern for those who are fully pacemaker-dependent; such patients should avoid remaining in close proximity to a security system. General consensus is that it is safe for airport personnel to use a hand held metal detector or 'wand' for patients with a permanent pacemaker, even for those who are pacemaker-dependent. Additionally, a manual or pat-down search can be performed [1]. Implantable cardioverter-defibrillators There are case reports of a patient with an ICD in whom interference from an electronic antitheft-surveillance device resulted in the delivery of multiple shocks due to oversensing [22,26]. In contrast, no interference was noted in another report of 25 patients with an ICD who were exposed to the fields of six different electronic article surveillance systems using three modes of operation (magnetic audio frequency, radiofrequency, or acoustomagnetic) [24]. The duration of exposure is an important determinant of risk as illustrated in a study of 170 patients with variable exposure to three common systems [27]. This again emphasizes the basic principle of "move through the detection and do not stop close to the detectors." General consensus is that it is safe for airport personnel to use a hand held metal detector or 'wand' for patients with a ICD. Additionally, a manual or pat-down search can be performed [1]. EXTERNAL ELECTRICAL EQUIPMENT https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 4/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate Potential causes of concern in the workplace are welders, industrial welding machines, electric motors, and degaussing coils [1,28]. Functional evaluation of pacemakers and ICDs in the work place has rarely demonstrated oversensing of an external electrical field. Nevertheless, since interference remains a concern, it is recommended that assessment of potential electromagnetic sources in the workplace be considered when the patient returns to work. For the non-pacemaker dependent patient this should rarely, if ever, be a problem. For the pacemaker-dependent and/or ICD patient it may be necessary to monitor the patient with an ambulatory monitor to determine if proximity to and/or use of specific equipment results in any interference. Rarely, for patients that are felt to be at higher risk or using equipment that is known to generate higher electromagnetic fields, it may be necessary to have the work environment assessed by an occupational safety officer or engineer prior to return to work [1]. LEAKAGE OF CURRENT FROM ELECTRICAL EQUIPMENT DRIVEN BY A POWER LINE Depending on the environment the patient is in, several scenarios could be considered. There has been concern raised regarding the potential for interference in CIED patients living under or near commercial power-lines. There is no sound evidence that any significant interference occurs in this situation [29]. For monitoring or therapeutic purposes, a patient may be connected to electromechanical equipment that is connected to a power-line. Such connections may permit accidental flow or leakage of weak alternating current through patients to ground. Similarly, an intracardiac catheter may provide a low-resistance path to ground through the patient's heart and thereby place the patient at risk for electrically induced ventricular tachyarrhythmia [30]. As previously noted, faulty household appliances have the potential for causing interference in patients with a CIED. Similarly, there have been multiple reports of CIED interference from a nongrounded or current-leaking light in swimming pools [31]. TRANSCUTANEOUS MUSCLE/NERVE STIMULATORS There are several case reports of electromagnetic interference resulting from transcutaneous muscle or nerve stimulation which caused inappropriate ICD discharges [32]. However, for many patients with implantable devices a transcutaneous stimulator can be used. For the pacemaker dependent and/or ICD patient, a monitored in-clinic assessment while operating the stimulator in the desired location should be considered prior to allowing the patient to use the equipment. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 5/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate It should be noted that commercial transcutaneous stimulators such as those used in doctor and chiropractor offices use larger currents and thus are more likely to cause interference. SMALL MAGNETS INCORPORATED INTO CLOTHING, FURNITURE, AND IDENTIFICATION BADGES Patients occasionally ask about the use of magnets that have been incorporated into clothing, jewelry, furniture (specifically mattresses), and identification badges. While there could be potential for electromagnetic interference with a CIED, it would be dependent on the strength of the magnet. There is a relative paucity of published literature, although there are case reports of small magnets in a variety of devices (eg, snaps sewn inside a patient's jacket, continuous positive airway pressure mask for sleep apnea, etc) resulting in interference and audible alerts from an ICD [33-36]. In general, there is minimal to no concern unless a strong magnet is positioned directly adjacent to the CIED; strong magnets can induce magnet mode in pacemakers and ICDs. (See 'Equipment with high-strength magnets' above.) MAGNETIC RESONANCE IMAGING Issues relating to magnetic resonance imaging and cardiac devices are discussed separately. (See "Patient evaluation for metallic or electrical implants, devices, or foreign bodies before magnetic resonance imaging", section on 'Cardiovascular implantable electronic device'.) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 6/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate Basics topic (see "Patient education: Pacemakers (The Basics)") Beyond the Basics topic (see "Patient education: Pacemakers (Beyond the Basics)") Basics topic (See "Patient education: Implantable cardioverter-defibrillators (The Basics)".) Beyond the Basics topic (See "Patient education: Implantable cardioverter-defibrillators (Beyond the Basics)".) SUMMARY AND RECOMMENDATIONS Background While there is the potential for electromagnetic interference with pacemaker, implantable cardioverter-defibrillator (ICD), and cardiac resynchronization devices function in the nonhospital environment, the risk of a clinically significant problem is generally low. (See 'Introduction' above.) Household appliances Pacemaker manufacturers do not recommend any special precautions when using normally functioning common household appliances, such as televisions, radios, toasters, microwave ovens, and electric blankets. UpToDate experts agree with this approach. (See 'Household appliances' above.) Cellular telephones Patients with a pacemaker or an ICD should be aware that strong magnetic fields (eg, selected cellular phones [iPhone 12], magnetic accessories) in close proximity to their device generator ( figure 1 and picture 1) can alter normal cardiac device function. Cellular telephone equipment without strong magnets is unlikely to cause clinically significant interference with pacemakers or ICDs. The safest strategy is for all patients to use cellular telephones at the ear on the side opposite the cardiac device and carry the telephones in a pocket below the waist. (See 'Cellular telephones' above.) Security systems While inappropriate ICD shocks and pacemaker inhibition have been associated with prolonged exposure to electromagnetic security systems (eg, antishoplifting gates, metal detectors), similar problems are only rarely seen in brief exposure. Patients should be advised to be aware of the location of security systems and to move through them at a normal pace (ie, "don't linger, don't lean"). (See 'Security systems' above.) Issues relating to magnetic resonance imaging and cardiac devices are discussed separately. (See "Patient evaluation for metallic or electrical implants, devices, or foreign bodies before magnetic resonance imaging", section on 'Cardiovascular implantable electronic device'.) https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 7/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate ACKNOWLEDGMENT The UpToDate editorial staff thank David L Hayes, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Pinski SL, Trohman RG. Interference in implanted cardiac devices, Part I. Pacing Clin Electrophysiol 2002; 25:1367. 2. Kolb C, Zrenner B, Schmitt C. Incidence of electromagnetic interference in implantable cardioverter defibrillators. Pacing Clin Electrophysiol 2001; 24:465. 3. Goldschlager N, Epstein A, Friedman P, et al. Environmental and drug effects on patients with pacemakers and implantable cardioverter/defibrillators: a practical guide to patient treatment. Arch Intern Med 2001; 161:649. 4. Napp A, Stunder D, Maytin M, et al. Are patients with cardiac implants protected against electromagnetic interference in daily life and occupational environment? Eur Heart J 2015; 36:1798. 5. Misiri J, Kusumoto F, Goldschlager N. Electromagnetic interference and implanted cardiac devices: the nonmedical environment (part I). Clin Cardiol 2012; 35:276. 6. Irnich W, Bernstein AD. Do induction cooktops interfere with cardiac pacemakers? Europace 2006; 8:377. 7. Tiikkaja M, Aro A, Alanko T, et al. Inappropriate implantable cardioverter-defibrillator magnet-mode switch induced by a laptop computer. Pacing Clin Electrophysiol 2012; 35:e177. 8. Greenberg JC, Altawil MR, Singh G. Letter to the Editor-Lifesaving therapy inhibition by phones containing magnets. Heart Rhythm 2021; 18:1040. 9. von Olshausen G, Schorr J, Grebmer C, et al. Incidence of magnet mode in patients with implantable cardioverter defibrillators. J Interv Card Electrophysiol 2019; 56:335. 10. Shea JB, Aguilar M, Sauer WH, Tedrow U. Unintentional magnet reversion of an implanted cardiac defibrillator by an electronic cigarette. HeartRhythm Case Rep 2020; 6:121. 11. Asher EB, Panda N, Tran CT, Wu M. Smart wearable device accessories may interfere with implantable cardiac devices. HeartRhythm Case Rep 2021; 7:167. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 8/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate 12. Kolb C, Deisenhofer I, Weyerbrock S, et al. Incidence of antitachycardia therapy suspension due to magnet reversion in implantable cardioverter defibrillators. Pacing Clin Electrophysiol 2004; 27:221. 13. Irnich W, Batz L, M ller R, Tobisch R. Electromagnetic interference of pacemakers by mobile phones. Pacing Clin Electrophysiol 1996; 19:1431. 14. Hayes DL, Wang PJ, Reynolds DW, et al. Interference with cardiac pacemakers by cellular telephones. N Engl J Med 1997; 336:1473. 15. Ismail MM, Badreldin AM, Heldwein M, Hekmat K. Third-generation mobile phones (UMTS) do not interfere with permanent implanted pacemakers. Pacing Clin Electrophysiol 2010; 33:860. 16. Barbaro V, Bartolini P, Bellocci F, et al. Electromagnetic interference of digital and analog cellular telephones with implantable cardioverter defibrillators: in vitro and in vivo studies. Pacing Clin Electrophysiol 1999; 22:626. 17. Chiladakis JA, Davlouros P, Agelopoulos G, Manolis AS. In-vivo testing of digital cellular telephones in patients with implantable cardioverter-defibrillators. Eur Heart J 2001; 22:1337. 18. Lacour P, Parwani AS, Schuessler F, et al. Are Contemporary Smartwatches and Mobile Phones Safe for Patients With Cardiovascular Implantable Electronic Devices? JACC Clin Electrophysiol 2020; 6:1158. 19. Occhetta E, Plebani L, Bortnik M, et al. Implantable cardioverter defibrillators and cellular telephones: is there any interference? Pacing Clin Electrophysiol 1999; 22:983. 20. Hayes DL, Carrillo RG, Findlay GK, Embrey M. State of the science: pacemaker and defibrillator interference from wireless communication devices. Pacing Clin Electrophysiol 1996; 19:1419. 21. Fetter JG, Ivans V, Benditt DG, Collins J. Digital cellular telephone interaction with implantable cardioverter-defibrillators. J Am Coll Cardiol 1998; 31:623. 22. Gimbel JR, Cox JW Jr. Electronic article surveillance systems and interactions with implantable cardiac devices: risk of adverse interactions in public and commercial spaces. Mayo Clin Proc 2007; 82:318. 23. Mugica J, Henry L, Podeur H. Study of interactions between permanent pacemakers and electronic antitheft surveillance systems. Pacing Clin Electrophysiol 2000; 23:333. 24. McIvor ME, Reddinger J, Floden E, Sheppard RC. Study of Pacemaker and Implantable Cardioverter Defibrillator Triggering by Electronic Article Surveillance Devices (SPICED TEAS). Pacing Clin Electrophysiol 1998; 21:1847. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 9/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate 25. Wilke A, Kruse T, Hesse H, et al. Interactions between pacemakers and security systems. Pacing Clin Electrophysiol 1998; 21:1784. 26. Santucci PA, Haw J, Trohman RG, Pinski SL. Interference with an implantable defibrillator by an electronic antitheft-surveillance device. N Engl J Med 1998; 339:1371. 27. Groh WJ, Boschee SA, Engelstein ED, et al. Interactions between electronic article surveillance systems and implantable cardioverter-defibrillators. Circulation 1999; 100:387. 28. Fetter JG, Benditt DG, Stanton MS. Electromagnetic interference from welding and motors on implantable cardioverter-defibrillators as tested in the electrically hostile work site. J Am Coll Cardiol 1996; 28:423. 29. Korpinen L, Kuisti H, Elovaara J, Virtanen V. Cardiac pacemakers in electric and magnetic fields of 400-kV power lines. Pacing Clin Electrophysiol 2012; 35:422. 30. Verma KP, Adam D. An unusual source of electromagnetic interference. Pacing Clin Electrophysiol 2018; 41:1381. 31. Roberto ES, Aung TT, Hassan A, Wase A. Electromagnetic Interference from Swimming Pool Generator Current Causing Inappropriate ICD Discharges. Case Rep Cardiol 2017; 2017:6714307. 32. Marbach JA, Yeo C, Green MS, Nair GM. Multiple inappropriate implantable cardiac defibrillator therapies in rapid succession. Clin Case Rep 2017; 5:1972. 33. Wolber T, Ryf S, Binggeli C, et al. Potential interference of small neodymium magnets with cardiac pacemakers and implantable cardioverter-defibrillators. Heart Rhythm 2007; 4:1. 34. Schwartz Y, Wasserlauf J, Sahakian AV, Knight B. Inappropriate activation of pacemaker magnet response mode by CPAP masks. Pacing Clin Electrophysiol 2019; 42:1158. 35. Zaphiratos V, Donati F, Drolet P, et al. Magnetic interference of cardiac pacemakers from a surgical magnetic drape. Anesth Analg 2013; 116:555. 36. Beinart R, Guy ML, Ellinor PT. Intermittent, erratic behaviour of an implantable cardioverter defibrillator secondary to a hidden magnetic source of interference. Europace 2011; 13:1508. Topic 964 Version 28.0 https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 10/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate GRAPHICS Documented sources of electromagnetic interference (EMI) in patients with implanted cardiac devices Source Examples Electromagnetic fields Daily life* Faulty home appliances Metal detectors Anti-theft equipment Slot machines Cellular phones and accessories with strong magnets (eg, wireless charging, [1] magnetic fasteners) Work and industrial High voltage power lines environment Welding equipment Electronic motors while "on" Induction furnaces Degaussing coils Medical/hospital Magnetic resonance imaging environment Defibrillation or cardioversion Device-device interaction (eg, pacemaker and neural stimulator) Radiofrequency ablation Electrocautery Transcutaneous nerve stimulation Therapeutic diathermy Lithotripsy Radiation therapy There are many potential sources of single-beat inhibition. However, single-beat inhibition is not clinically significant and does not merit specific mention. If working at or near the level of the power line. There is no convincing evidence that being under the power lines at ground level will cause interference. Although all welding equipment is capable of causing interference, it most commonly occurs with equipment that operates at 150 amps. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 11/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate Radiation therapy may cause electromagnetic interference but may also result in direct damage to the pulse generator resulting in sudden no output or "runaway." Reference: 1. Greenberg JC, Altawail MR, Singh G. Life saving therapy inhibition by phones containing magnets. Heart Rhythm; 2021. Reproduced with permission from: Pinski SL, Trohman RG. Interference in implanted cardiac devices, Part I. Pacing Clin Electrophysiol 2002; 25:1367. Copyright 2002 Blackwell Publishing. Graphic 51277 Version 8.0 https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 12/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate Implantable cardioverter-defibrillator (ICD) An ICD sits under the skin near a person's heart. Graphic 129613 Version 2.0 https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 13/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate Subcutaneous implantable cardioverter-defibrillator Modi ed from: 1. Al-Khatib SM, Friedman P, Ellenbogen KA. De brillators: Selecting the Right Device for the Right Patient. Circulation 2016; 134:1390. 2. Mayo Clinic. Subcutaneous implantable cardioverter-de brillator (S-ICD). https://www.mayoclinic.org/diseases-conditions/ventricular-tachycardia/multimedia/img- 20303862 (Accessed on March 31, 2021). Graphic 130973 Version 1.0 https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 14/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate Pacemaker response to magnet placement Pacemaker Magnet mode Explanation manufacturer designation Biotronik AUTO (DEFAULT) If normal conditions, 10 asynchronous events at 90 bpm, then returns to original programmed mode (ie, synchronous pacing) at the lower rate limit. If battery is at ERI, 10 asynchronous events at 80 bpm in VOO mode, then either VDD (dual- chamber) or VVI (single-chamber) with pacing at 11% below the lower rate limit. For any dual- chamber mode, the AVd shortens to 100 milliseconds for the 10 asynchronous events. ASYNCH Asynchronous pacing at 90 bpm if normal conditions. At ERI, 80 bpm (single-step change) in VOO mode regardless of original programming. For any dual-chamber pacing mode, the AVd shortens to 100 milliseconds while the magnet is in place. SYNCH If normal conditions, pacing in original programmed mode, without rate responsiveness. Pacing is at lowest available rate (LRL, sleep rate, or hysteresis rate). If battery is at ERI, then either VDD (dual chamber) or VVI (single chamber) with pacing at 11% below the lower rate limit. Boston Scientific ASYNCH If normal conditions, asynchronous pacing with (includes Guidant Medical CPI) (DEFAULT) 100 millisecond AVd at 100 bpm. If ERI, 85 bpm (single-step change). The Insignia and Altrua models have an intermediate step (90 bpm) at ERN. Most models shorten the pulse width to 50% on the third paced ventricular event (TMT). For Triumph and Prelude models, refer to Medtronic pacemakers, below. OFF No change; magnet is ignored. OFF is also the magnet mode after a "power on reset," or activation of "safety core," which can occur secondary to EMI. EGM mode No change in pacing. Magnet application initiates data collection. Intermedics (purchased by Guidant in 1998, now Boston Scientific, Five asynchronous events at 90 bpm (regardless of battery voltage), then 60 additional asynchronous events at LRL if normal conditions, https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 15/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate but special programmer needed) 90 bpm if ERI, and 80 bpm if EOL. The fifth paced event is emitted at 50% of the originally programmed pulse width (TMT). After the 64th asynchronous event, the magnet is ignored. Medtronic Conventional transvenous pacemakers (including cardiac resynchronization Asynchronous pacing based on programmed mode at 85 bpm if normal conditions*, 65 bpm if at ERI. therapy pacemakers) Leadless intra- cardiac pacemakers (ie, Micra and Micra AV ) No magnet response. MicroPort (Sorin / ELA Medical) Asynchronous pacing at 96 bpm gradually declining to 80 bpm at ERI. Sorin/ELA pacemakers take eight additional pacing cycles (the final two cycles are at LRL with long AVd) upon magnet removal. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 16/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate Abbott (St. Jude Medical "SJM" radiograph Battery test (DEFAULT) Asynchronous pacing at 100 bpm (older models 98.6 bpm) gradually decreasing to 85 bpm (older [SJM], Pacesetter) logo; standard transvenous pacemaker models 86.3) at ERI. OFF No magnet response. Event snapshots No change in pacing. Magnet application causes pacemaker to collect data. Identity and Entity models lack this feature. Event snapshots + battery test For a magnet placed on the device for two seconds, pacing mode and rate are unchanged, and the device stores an electrogram. If the magnet is placed for =5 seconds, the battery test mode (refer to above) is activated. Identity and Entity models lack this feature. Pacesetter radiograph Battery test (DEFAULT) Asynchronous pacing, and the rate depends upon specific model. In general, a pacing rate of less logo; standard transvenous pacemaker than 90 bpm should prompt further evaluation. OFF No magnet response. VARIO mode VARIO results in a series of 32 asynchronous (present in some models) pacing events. The rate of the first 16 paces reflects battery voltage, gradually declining from 100 bpm to 85 bpm at ERI. The next 15 paces are used to document ventricular pacing capture safety margin. The rate will be 119 bpm with gradually declining pacing voltage. The 16th pace of this group is at no output. The next pace restarts the 32-event sequence. The 32-event sequence repeats while the magnet remains in place. "Nanostim" leadless intra-cardiac pacemaker On (DEFAULT) Asynchronous pacing at 100 bpm for eight cycles, then 90 bpm if normal conditions; 65 bpm if ERI. OFF No magnet response. The effect(s) of appropriately placing a magnet over a pacemaker are shown, assuming normal battery and lead function. Column 1 shows the pacemaker manufacturer. Where a manufacturer has multiple responses, Column 1 is subdivided. If the magnet response is programmable, then Column 2 shows the various magnet modes available. The first mode shown is the default. A device reset from EMI might produce some other mode (ie, magnet mode disabled). Column 3 shows the effect on pacing therapy for the magnet mode shown in Column 2. Unless otherwise specified, asynchronous pacing takes place, without rate responsiveness, in the chambers originally programmed. Thus, a dual-chamber program would result in DOO pacing; a single-chamber program would result in VOO (unless an atrial device, which would be AOO) pacing; and a biventricular, dual- chamber device would be DOOOV. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 17/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate Caution for Medtronic transvenous pacemakers: All Medtronic transvenous pacemakers except Enrhythm P1501, EMDR series, Revo, Advisa, and Ensura suspend magnet detection for up to 60 minutes following removal of the programming head after an interrogation session, unless specific programming action (which requires multiple "button" depressions) is taken prior to removing the programming head. Caution for all dual-chamber pacemakers: An electrical fault or exposure to strong EMI could cause a "power on reset" or "safety core event" (BSC - Boston-labeled devices), causing the pacemaker to switch to VVI pacing only, regardless of prior pacing programming. For a dual-chamber pacemaker with a bad RV lead and programmed to atrial pacing only (AAI, AOO) in a pacing-dependent patient, this event could result in patient injury or death. For further explanation of terms, refer to UpToDate topics on modes of cardiac pacing and cardiac pacing nomenclature. bpm: beats/minute; ERI: elective replacement indicator (the device should be replaced promptly - the US Food and Drug Administration [FDA] requires pacemakers to perform safely for at least three months from onset of ERI); VOO: ventricular asynchronous pacing, no sensing; VDD: ventricle paced, atrium and ventricle sensed, and either inhibition or tracking of the pacemaker in response to a sensed beat; VVI: ventricle paced, ventricle sensed, and pacemaker inhibited in response to a sensed beat; AVd: atrioventricular delay (for dual-chamber pacing; note that this is a programmed value, although the AVd can be shortened during the first 3 to 15 events upon magnet placement; note that a short AVd can reduce stroke volume and produce untoward hemodynamics in some patients); LRL: lower rate limit (the programmed lower rate, or set point, of the pacemaker); ERN: elective replacement near (the device should be undergoing monthly checks [IFI]); TMT: threshold margin test (This is the emission of a single pacing pulse [except VARIO - refer to St. Jude Medical Pacesetter Logo] at a lower amplitude or pulse width to demonstrate adequacy of pacing output relative to pacing threshold. Typically, this is the third or fifth pacing pulse, and failure to capture [pace] on this event suggests an inadequate safety margin for capture. Properly programmed atrial- only pacemakers are unlikely to demonstrate this feature.); EMI: electromagnetic interference; EGM: electrogram; EOL: end of life (the device should be replaced immediately); AOO: asynchronous A pacing; AAI: atrium paced, atrium sensed, and pacemaker inhibited in response to sensed atrial beat; ERT: elective replacement time (Same as ERI for Boston Scientific pacemakers [Guidant, CPI labels also]. At ERT, rate-responsive programming is cancelled. At three months post-ERT, only single- chamber operation continues.); SSI: single-chamber, inhibited mode (If implanted for ventricular pacing, then SSI = VVI. For an atrial pacemaker, SSI = AAI.). Some Medtronic pacemakers deliver the first three or five asynchronous beats in magnet operation at 100 bpm. The first three asynchronous paces of the Adapta, Versa, Sensia, and Relia models are at 100 bpm (the amplitude of the last of the three 100 bpm paced beats is reduced by 20%). The first

pacemakers, below. OFF No change; magnet is ignored. OFF is also the magnet mode after a "power on reset," or activation of "safety core," which can occur secondary to EMI. EGM mode No change in pacing. Magnet application initiates data collection. Intermedics (purchased by Guidant in 1998, now Boston Scientific, Five asynchronous events at 90 bpm (regardless of battery voltage), then 60 additional asynchronous events at LRL if normal conditions, https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 15/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate but special programmer needed) 90 bpm if ERI, and 80 bpm if EOL. The fifth paced event is emitted at 50% of the originally programmed pulse width (TMT). After the 64th asynchronous event, the magnet is ignored. Medtronic Conventional transvenous pacemakers (including cardiac resynchronization Asynchronous pacing based on programmed mode at 85 bpm if normal conditions*, 65 bpm if at ERI. therapy pacemakers) Leadless intra- cardiac pacemakers (ie, Micra and Micra AV ) No magnet response. MicroPort (Sorin / ELA Medical) Asynchronous pacing at 96 bpm gradually declining to 80 bpm at ERI. Sorin/ELA pacemakers take eight additional pacing cycles (the final two cycles are at LRL with long AVd) upon magnet removal. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 16/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate Abbott (St. Jude Medical "SJM" radiograph Battery test (DEFAULT) Asynchronous pacing at 100 bpm (older models 98.6 bpm) gradually decreasing to 85 bpm (older [SJM], Pacesetter) logo; standard transvenous pacemaker models 86.3) at ERI. OFF No magnet response. Event snapshots No change in pacing. Magnet application causes pacemaker to collect data. Identity and Entity models lack this feature. Event snapshots + battery test For a magnet placed on the device for two seconds, pacing mode and rate are unchanged, and the device stores an electrogram. If the magnet is placed for =5 seconds, the battery test mode (refer to above) is activated. Identity and Entity models lack this feature. Pacesetter radiograph Battery test (DEFAULT) Asynchronous pacing, and the rate depends upon specific model. In general, a pacing rate of less logo; standard transvenous pacemaker than 90 bpm should prompt further evaluation. OFF No magnet response. VARIO mode VARIO results in a series of 32 asynchronous (present in some models) pacing events. The rate of the first 16 paces reflects battery voltage, gradually declining from 100 bpm to 85 bpm at ERI. The next 15 paces are used to document ventricular pacing capture safety margin. The rate will be 119 bpm with gradually declining pacing voltage. The 16th pace of this group is at no output. The next pace restarts the 32-event sequence. The 32-event sequence repeats while the magnet remains in place. "Nanostim" leadless intra-cardiac pacemaker On (DEFAULT) Asynchronous pacing at 100 bpm for eight cycles, then 90 bpm if normal conditions; 65 bpm if ERI. OFF No magnet response. The effect(s) of appropriately placing a magnet over a pacemaker are shown, assuming normal battery and lead function. Column 1 shows the pacemaker manufacturer. Where a manufacturer has multiple responses, Column 1 is subdivided. If the magnet response is programmable, then Column 2 shows the various magnet modes available. The first mode shown is the default. A device reset from EMI might produce some other mode (ie, magnet mode disabled). Column 3 shows the effect on pacing therapy for the magnet mode shown in Column 2. Unless otherwise specified, asynchronous pacing takes place, without rate responsiveness, in the chambers originally programmed. Thus, a dual-chamber program would result in DOO pacing; a single-chamber program would result in VOO (unless an atrial device, which would be AOO) pacing; and a biventricular, dual- chamber device would be DOOOV. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 17/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate Caution for Medtronic transvenous pacemakers: All Medtronic transvenous pacemakers except Enrhythm P1501, EMDR series, Revo, Advisa, and Ensura suspend magnet detection for up to 60 minutes following removal of the programming head after an interrogation session, unless specific programming action (which requires multiple "button" depressions) is taken prior to removing the programming head. Caution for all dual-chamber pacemakers: An electrical fault or exposure to strong EMI could cause a "power on reset" or "safety core event" (BSC - Boston-labeled devices), causing the pacemaker to switch to VVI pacing only, regardless of prior pacing programming. For a dual-chamber pacemaker with a bad RV lead and programmed to atrial pacing only (AAI, AOO) in a pacing-dependent patient, this event could result in patient injury or death. For further explanation of terms, refer to UpToDate topics on modes of cardiac pacing and cardiac pacing nomenclature. bpm: beats/minute; ERI: elective replacement indicator (the device should be replaced promptly - the US Food and Drug Administration [FDA] requires pacemakers to perform safely for at least three months from onset of ERI); VOO: ventricular asynchronous pacing, no sensing; VDD: ventricle paced, atrium and ventricle sensed, and either inhibition or tracking of the pacemaker in response to a sensed beat; VVI: ventricle paced, ventricle sensed, and pacemaker inhibited in response to a sensed beat; AVd: atrioventricular delay (for dual-chamber pacing; note that this is a programmed value, although the AVd can be shortened during the first 3 to 15 events upon magnet placement; note that a short AVd can reduce stroke volume and produce untoward hemodynamics in some patients); LRL: lower rate limit (the programmed lower rate, or set point, of the pacemaker); ERN: elective replacement near (the device should be undergoing monthly checks [IFI]); TMT: threshold margin test (This is the emission of a single pacing pulse [except VARIO - refer to St. Jude Medical Pacesetter Logo] at a lower amplitude or pulse width to demonstrate adequacy of pacing output relative to pacing threshold. Typically, this is the third or fifth pacing pulse, and failure to capture [pace] on this event suggests an inadequate safety margin for capture. Properly programmed atrial- only pacemakers are unlikely to demonstrate this feature.); EMI: electromagnetic interference; EGM: electrogram; EOL: end of life (the device should be replaced immediately); AOO: asynchronous A pacing; AAI: atrium paced, atrium sensed, and pacemaker inhibited in response to sensed atrial beat; ERT: elective replacement time (Same as ERI for Boston Scientific pacemakers [Guidant, CPI labels also]. At ERT, rate-responsive programming is cancelled. At three months post-ERT, only single- chamber operation continues.); SSI: single-chamber, inhibited mode (If implanted for ventricular pacing, then SSI = VVI. For an atrial pacemaker, SSI = AAI.). Some Medtronic pacemakers deliver the first three or five asynchronous beats in magnet operation at 100 bpm. The first three asynchronous paces of the Adapta, Versa, Sensia, and Relia models are at 100 bpm (the amplitude of the last of the three 100 bpm paced beats is reduced by 20%). The first five asynchronous paces of the Azure, Astra, Percepta, Serena, and Solara models are at 100 bpm. Other models (ie, EnRythm, Revo, Advisa, Ensura, Viva) deliver all asynchronous beats in magnet response at 85 bpm (or 65 bpm if at ERI). In Azure, Astra, Percepta, Serena, Solara, EnRythm, Revo, Advisa, Ensura, and Viva devices, a magnet suspends tachyarrhythmia detection. When the magnet is removed, the device returns to its programmed operation. Original gure modi ed for this publication. Rozner MA. Implantable cardiac pulse generators: Pacemakers and cardioverter- de brillators. In: Miller's Anesthesia, 8th ed, Miller RD (Ed), Saunders, Philadelphia 2015. Table used with the permission of https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 18/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate Elsevier Inc. All rights reserved. Graphic 105468 Version 7.0 https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 19/20 7/6/23, 10:47 AM Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment - UpToDate Contributor Disclosures Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cardiac-implantable-electronic-device-interactions-with-electromagnetic-fields-in-the-nonhospital-environment/print 20/20

7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cardiac implantable electronic device lead removal : Jay A Montgomery, MD : Jonathan Piccini, MD, MHS, FACC, FAHA, FHRS : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 24, 2022. INTRODUCTION Cardiac implantable electronic devices (CIEDs), a term that includes permanent pacemakers (PPMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) pacemakers, are used to treat a broad array of cardiac conditions. Occasionally, infection, venous occlusion, mechanical lead failure, or other complications that involve or are caused by a CIED result in the need to remove the entire CIED system or one of its components (eg, leads, pulse generator). CIED lead removal is particularly difficult and can result in fatal complications such as pericardial effusion or tearing of the superior vena cava. Thus, the patient-specific and device-specific risks must be carefully assessed for each proposed CIED removal. This topic will discuss the indications for lead removal, lead removal procedure requirements, outcomes, and potential complications of lead removal. Comprehensive discussions of CIED infection, complications of CIED implantation, and device malfunction are found separately. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis".) (See "Cardiac implantable electronic devices: Long-term complications".) (See "Pacing system malfunction: Evaluation and management".) (See "Cardiac implantable electronic devices: Periprocedural complications".) https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 1/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate DEFINITIONS Standardized definitions related to lead removal have been proposed [1]. Lead removal is a general term that encompasses removal of a CIED lead using any technique, while lead explantation and lead extraction are terms with more specific definitions. Lead explantation Lead explantation is defined as removal of a lead that has been implanted for less than one year via the implant vein using only the tools typically supplied for lead implantation in combination with manual traction. Lead extraction Lead extraction is a more complicated procedure that meets one of the following criteria: The lead is removed with the assistance of specialized equipment (eg, laser sheaths) regardless of the implant duration. (See 'Lead removal procedure' below.) The lead is removed via a site other than the implant vein. The lead being removed has been implanted for more than one year. INDICATIONS The most common indications for lead removal are infection, venous occlusion, mechanical lead failure (often resulting in improper pacemaker function or inappropriate ICD shocks), or recalls related to potential lead malfunction [1-3]. As a result of the complex nature of these cases, recommendations for lead removal apply only to those patients in whom the benefits outweigh the risks when assessed on individual patient factors and operator-specific experience and outcomes [4,5]. Infection Infections, which can result in CIED device and lead removal, can generally grouped into two major categories: CIED-associated endocarditis with bacteremia without an alternative source (particularly Staphylococcus aureus) or bacteremia that persists or recurs despite appropriate antimicrobial therapy. Both situations are associated with challenging management and often require CIED device and lead removal [1,6]. A full discussion of the management of infections involving CIEDs is presented separately. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Infections involving cardiac implantable electronic devices: Treatment and prevention".) https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 2/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate Venous thrombosis/stenosis Upper extremity venous thrombosis and venous stenosis are not absolute indications for lead removal. However, CIED-related thrombosis or stenosis that causes significant symptoms (eg, superior vena cava [SVC] syndrome, ongoing thromboembolic events) or prevents device upgrade is generally an appropriate circumstance for CIED lead removal. Several clinical studies have revealed that venous stenosis and/or occlusion following endovascular pacing and defibrillator lead placement are common occurrences; in most cases, patients remain asymptomatic and do not require specific therapy [7-9]. However, there are situations in which a thrombosis may cause symptoms: The most concerning, albeit least common, is SVC syndrome. If the patient is to undergo stent deployment as treatment, lead removal should be performed prior to stent placement to avoid entrapment of the lead between the stent and the vessel wall [10-15]. (See "Malignancy-related superior vena cava syndrome", section on 'Patients without life- threatening symptoms'.) Lead removal is recommended in rare cases of clinically significant thromboembolic events caused by a lead that cannot be treated in any other way. The more common circumstance in which venous occlusion would necessitate lead removal is when the occlusion does not allow upgrade of an existing device. Under this circumstance, possible approaches include: Contralateral lead placement and tunneling across the chest, which is not advised in some situations (eg, contralateral atrioventricular fistula/shunt, vascular access port, or prior mastectomy). Ipsilateral venoplasty. Lead removal with specialized tools, such as laser sheath, to allow for regaining/retaining venous access. The approach should be individualized based on the patient's circumstances, the desire to decrease lead burden and/or preserve contralateral venous access, and operator experience. As an example, an older adult patient undergoing upgrade to a cardiac resynchronization therapy device may sometimes be a reasonable candidate for contralateral lead placement and tunneling. By contrast, a younger patient is almost always better served by extraction for ipsilateral implantation, due to the additive risks of having leads indwelling in bilateral subclavian veins with several decades of remaining life. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 3/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate Leads causing harm Lead removal should be performed in patients with leads that pose an immediate risk to the patient s life. Such situations include cardiac perforation or inadvertent placement of a lead in the arterial system, left atrium, or left ventricle. These scenarios are separate from malfunctioning leads in which require careful consideration of abandonment versus removal. Removal of chronically placed leads from the arterial circulation requires specialized procedural techniques to minimize the risk of cerebral embolization. (See 'Lead upgrade and abandonment' below.) Advisory/recall The decision to remove an apparently normally functioning lead or leads in response to a manufacturer's or regulatory body's warning is complex and includes the use of available data that describe the risk of device failure, the patient's clinical status, and the remaining lifespan [1]. Nonetheless, when the response to an advisory or recall results in lead removal, we can learn from the resulting treatment. Data accumulated following several prominent advisories and recalls of CIED leads have provided valuable information for clinicians: In October 2007, Medtronic suspended distribution of the Sprint Fidelis lead due to growing concerns regarding an abnormally high fracture rate [16]. In a retrospective, multicenter review of 3169 patients with Sprint Fidelis leads, the reported failure rates (failure defined as a sudden rise in impedance or inappropriate shocks) were 5, 11, and 17 percent at three, four, and five years postimplantation, respectively [17]. Predictors of higher risk of lead failure were female sex, axillary or subclavian venous access, and previous lead failure. The clinician response to this has been variable, with some only removing leads that demonstrate malfunction, while others have prophylactically removed the lead even without evidence of malfunction. In December 2011, St. Jude Medical announced that the US Food and Drug Administration (FDA) classified its voluntary medical device advisory letter to clinicians regarding the performance of Riata and Riata ST Silicone Defibrillation Leads as a Class I Recall [18]. The incidence rate of conductor externalization is around 5 per 100 patient-years and is notably higher in 8-French compared with 7-French leads [19]. Externalized leads have a higher rate of electrical failure [20]. The decision to pursue conservative monitoring versus lead extraction in this situation is challenging and multifactorial without any firm evidence to guide the decision. In the cases in which lead extraction was pursued and cable externalization was noted, externalization predicted more complex extraction with more frequent use of laser sheaths (71 versus 55 percent) [21]. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 4/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate Notably, any Riata or Fidelis leads that remain in service have now been intravascular significantly longer than most of those previously studied. As such, extraction of these leads may be more complex than published reports suggest. Lead upgrade and abandonment The placement of new leads or CIED equipment may require extraction or abandonment of existing leads. Some factors that favor extraction rather than abandonment include: A high likelihood of future intravascular device/lead exchanges (eg, young age) High risk of future lead infection (eg, immunosuppression, history of endocarditis) [22,23] Intravascular crowding (eg, four or more leads in the target vessel or five or more leads in the SVC) Inability to place a new lead regardless of the number of leads Electrical interference between a superfluous lead and new leads [1,4] Shorter dwell time of the superfluous lead (eg, less than two years) [24] CONTRAINDICATIONS In most patients, lead removal is associated with benefits that exceed the potential risks of the procedure. However, there are some relative contraindications to percutaneous transvenous lead removal, which include [4]: Lack of required personnel or equipment. Known anomalous placement of leads through structures other than normal venous and cardiac structures (eg, subclavian artery, aorta, pleura, or mediastinum). Lead placement through a systemic venous atrium or systemic ventricle. Concomitant need to remove epicardial lead components. Large vegetations (eg, larger than 2.5 cm), where open extraction or preemptive use of a suction catheter should be considered [1,25,26]. (See 'Embolism' below.) LEAD REMOVAL PROCEDURE Lead removal generally requires a significant amount of advance preparation [1,3]. Knowledge of the patient's comorbidities, prior invasive/surgical history (eg, prior cardiac surgery or presence of an inferior vena cava filter), and lead characteristics such as lead length, diameter, https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 5/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate dwell time, special fixation mechanism (eg, Medtronic Starfix lead), and adapter information are required. The need for pacemaker support (ie, in a pacemaker-dependent patient) and ongoing device therapy must be assessed. Our approach Extraction of leads is technically more challenging than generator removal and carries a risk of vascular and/or cardiac injury. This risk is largely due to the fibrous connections that develop between the leads and the vascular wall or endocardial surface. As the lead is separated from adhesions to veins and endocardial surfaces, these structures can tear, sometimes resulting in immediate hemodynamic collapse. Our approach is as follows: All patients should undergo preprocedural evaluation, which includes a complete history and physical exam, electrocardiogram (ECG), chest radiograph with posterior-anterior and lateral views, and assessment of device function and pacemaker dependency. If doubt exists as to whether the course and position of the lead(s) are normal, a cardiac-gated computed tomography (CT) scan can be helpful. A detailed review of the risks and benefits should be undertaken with the patient, and shared decision-making is paramount. Due to the risk of endovascular injury, lead extraction procedures should be performed with cardiothoracic surgical backup available. Preprocedural pretransfusion testing (typing and crossmatching) for red blood cells should be routinely performed, and we maintain four units of packed red blood cells within the operating room during the procedure. We routinely obtain femoral vein and artery access to ensure rapid access for fluid volume resuscitation, temporary pacing, and access for emergency stabilization procedures such as superior vena cava (SVC) balloon occlusion and cardiopulmonary bypass. While radial arterial access may substitute for femoral arterial access in some low-risk scenarios, patients with a previous sternotomy should have femoral arterial access due to the risk of mediastinal adhesions that can complicate or prevent rapid sternal entry for cardiopulmonary bypass. There is no specific lead removal technique that can maximize efficacy and minimize risk in every individual patient. The choice depends upon a variety of factors, centered around the risk attributed to the lead itself and the risks associated with the patient's clinical condition. Periprocedural sedation is required, along with local anesthesia at the superficial site. Specific choice of sedation should be based on the relative risk of the extraction. In our practice, most extractions are performed under general anesthesia. We recommend having an echocardiography machine in the operating room, turned on, plugged in, and with a cardiac probe (transthoracic echocardiogram [TTE] or https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 6/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate transesophageal echocardiogram [TEE]) in place for emergency use to rapidly recognize pericardial or pleural effusions. In more complex cases or for those with vegetations, continuous intraprocedural ultrasound imaging (intracardiac echocardiography [ICE] or TEE) can be helpful to guide the procedural strategy [27]. Postprocedural management includes routine postoperative monitoring for hemodynamic changes suggestive of internal complications, as well as observation for bleeding at the pocket or vascular access sites. In addition, a postprocedure chest radiograph is performed to document hardware removal and/or new lead implant. If unexpected hypotension or other signs of internal bleeding or tamponade arises, a TTE is warranted. The duration of postprocedural observation depends on the likelihood of postprocedural complications and the need for ongoing inpatient management (eg, temporary pacing, intravenous antibiotics). Preprocedural evaluation Preprocedural evaluation helps to plan the extraction procedure. The evaluation includes an assessment of the CIED components to be removed (eg, dwell time, anatomic course on radiography) and patient characteristics that may require management prior to extraction (eg, anticoagulation, heart failure). For patients taking long-term anticoagulation therapy, providers will need to discuss the optimal approach to periprocedural management, including risks of bleeding versus thromboembolic risk of interrupting therapy. We instruct almost all patients to discontinue long-term oral anticoagulation therapy to reduce the risk of catastrophic bleeding. Techniques The choice of a specific lead removal technique depends upon a variety of factors, centered around the risk attributed to the lead itself and the risks associated with the patient's clinical condition. There is no single technique that will be most effective in every patient. There are a variety of techniques for lead removal [1,28]: Direct (manual) traction A stylet is inserted into the hollow center of the lead, extending close to the distal electrode, and the helix is typically retracted, if possible. If needed, a stylet designed for lead extraction locks into place, providing support and allowing the application of direct traction to remove the lead. Leads that are isodiametric (the same diameter along the length of the lead) and less than one year old can often be removed by manual traction alone. Significant traction should not be placed on a lead without a locking stylet, as unraveling of the lead makes it impossible to advance a locking stylet. Similarly, a locking stylet or other lead extender is a prerequisite for most other extraction techniques. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 7/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate Telescoping sheaths Specially designed sheaths extend over the lead, dissecting it away from the vascular wall and endocardium. Complete lead removal success can be as high as 97 percent [29]. Excimer laser sheaths The laser in these sheaths dissolves, rather than tears, the fibrous attachments to the vasculature. Rotational cutting tool sheaths Mechanical sheaths with rotational cutting blades are used to cut fibrous adhesions. Snares A variety of snares inserted via the femoral vein serve as an adjunct to tools utilized from the implant site to allow for lead removal, removal of lead fragments, or to provide additional traction on the lead. Surgical removal Cardiotomy with surgical removal is usually reserved for cases in which transcutaneous approaches have failed or are impossible (epicardial leads). In some patients with large vegetations attached to the lead (eg, >2.5 cm with globular shape), surgical removal may be required in order to minimize the risk of pulmonary embolism (PE), though we currently favor use of a suction catheter as the initial approach. Suction catheters Large vegetations can potentially be removed with suction catheters, which can then allow a safer percutaneous extraction without the need for open cardiac surgery. (See 'Embolism' below.) Factors that increase the likelihood of adhesion formation between endovascular structures and CIED leads include lead placement for more than two years, ICD leads (especially ICD coils located in the SVC), and younger patient age [30-33]. In patients who have any of these features or in whom the lead is suspected to be adherent to an endovascular structure, extraction is performed with specialized techniques and equipment that breaks fibrous adhesions and provides countertraction, which improves the success and safety of the procedure [28,34]. Facility and operator requirements Lead removal is performed under intravenous sedation or general anesthesia in the electrophysiology laboratory or operating room with high-quality fluoroscopy. A complete array of extraction tools as well as surgical instruments should be at hand. The ability to perform TTE and TEE must be immediately available. Because of the potential for serious complications, personnel and resources to perform emergency sternotomy and cardiopulmonary bypass should be immediately available [35]. A multidisciplinary approach involving cardiac surgery, electrophysiology, and cardiac anesthesiology allows for a rapid and successful response to major complications [36]. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 8/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate Lead extraction should be performed by trained and experienced clinician staff using specialized equipment and only following appropriate patient preparation [1,4]. There is an inverse relationship between complication rates and operator experience [37-40]. Complications have been shown to be 1.5 times more likely to occur during the first 10 cases, with the steepest decline in complication rates during the first 30 cases, and slower but continued decline with further experience, up to 400 cases [39,41]. In a 2014 systematic review and meta-analysis, which included 18,433 patients from 66 observational studies, there was no significant difference in major complication rates depending on center volume [40]. However, a significant inverse association was noted between center volume and rate of minor complications, with centers performing <15 lead extractions annually having significantly higher minor complication rates (7.2 versus 2.1 percent in hospitals performing >30 extractions per year). The informed consent process should include a discussion of the center-specific procedural success and complication rates. (See 'Complications' below.) Outcomes Success rates for lead removal are variable as a result of case selection as well as differences in reporting (ie, complete versus partial removal). Large studies of patients who have undergone lead extraction report relatively high success rates (95 to 99 percent) and low complication rates (<1 percent), although major complications do occur, including cardiac tamponade, vessel laceration, traumatic tricuspid regurgitation (TR), and death [42-51]. However, the likelihood of complications varies with operator experience [28,39,43]. Thus, the results of individual studies, which often reflect the outcomes of experienced operators with high volumes in tertiary/quaternary care centers, are not generalizable to all settings. In the LExICon study, in which 2405 leads in 1449 consecutive patients at 13 centers were extracted via a laser between 2004 and 2007, complete lead removal was reported in 96.5 percent of patients [47]. Procedure failure was higher in leads implanted for greater than 10 years and when performed in low-volume centers. All-cause in-hospital mortality was 1.86 percent and increased to 4.3 percent when lead removal was associated with endocarditis. In 279 procedures involving the removal of 445 leads between 2000 and 2009 at a single center where all leads were removed via manual traction (without the assistance of extraction sheaths), clinical success was approximately 85 percent [52]. This success rate is similar to published data on lead removal using direct traction or telescoping sheaths from a decade prior [53]. The highest clinical success (approximately 95 percent) was observed in patients with leads in place for less than 2.6 years [52]. Comparative data come from a randomized trial of 301 patients with 465 leads in place for an average of 65 to 69 months [45]. Complete lead extraction was achieved significantly https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 9/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate more often using a laser sheath compared with traction through a nonpowered telescoping sheath (94 versus 64 percent). Major complications occurred in 5 of 244 laser lead extractions and in 2 of 221 nonlaser lead extractions. Similar success rates have been reported for the extraction of coronary sinus leads used for cardiac resynchronization therapy. In a single-center, retrospective review of 145 patients undergoing extraction of coronary sinus leads (147 leads total), 99 percent of leads were successfully extracted, 70 percent using manual traction alone [54]. Cardiac tamponade in one patient (0.7 percent) was the only major complication reported. Limited data are available regarding the risks of lead extraction in pediatric patients or adults with congenital heart disease [55,56]. In the international PLEASE registry of 878 patients (mean age 18.6 years) with an ICD implanted between 2005 and 2010, lead extraction was required in 137 patients (involving 143 leads) [55]. All leads were successfully extracted, with major complications, but no deaths, occurring in 6 of 137 patients (4 percent). Complications While CIED lead removal is performed safely in most patients, complications can occur. Most of the complications are traumatic and related to the lead itself (eg, vascular injury, cardiac tear or perforation resulting in cardiac tamponade, TR), although embolization of thrombus or vegetation from the lead is also a concern. When performed by experienced operators, mortality is usually less than 1 percent of patients, with major complications seen in 2 to 4 percent of patients, though risk varies with patient and lead factors [51,57-60]. (See 'Outcomes' above.) In general, ICD leads are more challenging to remove than pacemaker leads as a result of the presence of coils, which tend to be more adherent to vasculature and myocardium. In turn, dual- coil ICD leads are more difficult to remove than single-coil ICD leads. Leads with a passive fixation mechanism may be more difficult to extract than those that are active [42,45]. Lead dwell time is another factor independently associated with adherences, with older leads being more adherent [61]. Additional risk factors for a complication during lead removal include [42,43,62,63]: Pediatric and geriatric age groups Female sex Presence of calcification involving the leads on chest radiograph Presence of multiple leads Death Estimates of mortality following CIED lead removal are highly variable depending on how the variable is defined (eg, procedural mortality, in-hospital mortality, 30-day mortality, etc). https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 10/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate Most published estimates of immediate procedure-related mortality are less than 1 percent, but 30-day mortality is higher, ranging from 2 to 3 percent [51,64,65]. Advancing age, renal failure, device-related infection, and very large (>2 cm) vegetations have been associated with a higher risk of death [65-67]. In a single-center review of 5521 leads extracted during 2999 procedures (mean age 67 years, mean lead implant duration 4.7 years) over a 15-year period (1996 to 2011), 67 patients (2.2 percent) died within 30 days of the procedure [51]. The investigators developed a nomogram incorporating the variable associated with mortality (age, body mass index, hemoglobin, end-stage kidney disease, left ventricular ejection fraction, New York Heart Association functional class, infection, number of previous extractions performed by the operator, and dual-coil ICD leads), and a risk calculator based on the nomogram is available online [68]. In another single-center review of 1006 leads extracted from 510 patients (mean age 64 years, median lead implant duration 47 months) over a 20-year period (1992 to 2012), all- cause mortality was 3.3 percent at 30 days, 7.7 percent at six months, and 10 percent at one year [64]. In a study of 11,304 patients in the NCDR ICD registry who underwent lead extraction (leads in place >1 year) between 2010 and 2012, 258 patients (2.3 percent) had a major complication, among whom 41 (0.36 percent) required urgent cardiac surgery and 14 (0.16 percent) died during the lead extraction [66]. Vascular trauma Though relatively rare, vascular trauma can lead to rapid hemodynamic compromise. Vascular trauma is most likely to occur in patients with multiple or long-standing leads, in particular leads that are adherent to the wall of the SVC or innominate vein, requiring excimer laser or mechanical dilator sheaths to aid in removing the lead [60]. In response to the concern for vascular laceration, specifically SVC tear and its associated morbidity and mortality (approximately 50 percent), an SVC occlusion device received FDA approval in February 2016. Several small series have suggested that the occlusion device can be rapidly deployed and may improve the likelihood of surviving an SVC tear [69,70]. In the largest reported series of 114 cases of confirmed SVC tears identified through search of the FDA database, 51 patients (44 percent) were initially treated with the balloon device; survival to hospital discharge was significantly higher among patients treated with balloon occlusion (88 versus 57 percent in patients without use of the balloon device) [71]. Tricuspid regurgitation Between 5 and 10 percent of patients develop significant traumatic TR following right ventricular lead removal [72-74]. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 11/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate In a prospective study over a five-year period during which 237 leads were removed from 208 patients using a variety of techniques, traumatic TR occurred in 19 patients (9 percent) and was severe in 14 (7 percent) [72]. Nine of these 14 patients developed new right-sided heart failure. Multivariate analysis identified three independent risk factors for traumatic TR: use of a laser sheath, use of both a laser sheath and snare, and female sex. However, it is possible that laser and snare use identified more complex extractions rather than being causative for TR. In a prospective single-center study in which 266 leads were removed from 208 patients (90 percent with laser extraction) between 2014 and 2016, 24 patients (11.5 percent) developed an acute worsening of TR by TEE assessment, although no long-term follow up data were reported [75]. Embolism In spite of concern that percutaneous lead extraction of large vegetations or thrombus might precipitate PE, clinically relevant acute PE is uncommon even with vegetations >10 mm in size [5,76-81]. However, septic pulmonary emboli are more likely in patients with vegetations >1 cm and are associated with an increased risk of mortality among patients with CIED endocarditis [53,82,83]. In addition, among patients with vegetations >2 cm, a globular shape (rather than linear) is associated with increased mortality [84]. Based upon this data and the high 30-day mortality of patients with CIED endocarditis, we attempt to debulk vegetations that are 1.5 cm or that have a globular shape using suction catheters. Though data from randomized trials are not currently available, the high morbidity and mortality of CIED endocarditis seem to suggest that outcomes may be improved if effective vegetation debulking can be achieved with low procedural risk. Open surgical extraction can be considered in the case of very large vegetations, but we no longer employ this technique due to the availability of suction-catheter systems, which were designed to retrieve thrombi from the vasculature. Observational data suggest that suction- catheter systems are safe and effective at removing vegetations [25,26]. The decision to debulk a vegetation prior to extraction is made on a case-by-case basis [5], but the risk of clinically relevant acute PE was rare in several cohort studies: In a retrospective study of 53 cases of pacemaker-lead endocarditis, 29 patients with 49 leads bearing vegetations with a mean size of 17.8 mm underwent successful transvenous removal using locking stylets and sheaths with no clinically apparent PEs [80]. Pacemaker leads with larger vegetations (mean size 22.4 mm) were removed by open cardiac surgery in 24 patients, three of whom died. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 12/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate In a single-center study of percutaneous lead removal (215 leads in 100 patients) in the setting of intracardiac vegetations, either on the leads or on the valves and ranging in size from 0.2 to 4.0 cm (mean 1.6 cm) in diameter, embolization of vegetation material, which measured >2 cm before extraction, was witnessed in only two cases with a third case that was presumed to have embolized (97 percent overall success rate for removal without embolization) [82]. In spite of the apparent embolization, all three patients recovered completely. [82] Paradoxical embolization of vegetation or thrombus into the systemic circulation at the time of lead extraction is possible, albeit rare, in patients with a patent foramen ovale (PFO). Among a cohort of 774 patients undergoing transvenous CIED lead extraction in the Mayo Clinic system over 17.5 years, postprocedural stroke occurred in 1 percent of patients and was significantly more likely among patients with PFO and right-to-left shunting [85]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac implantable electronic devices".) SUMMARY AND RECOMMENDATIONS Lead removal is a general term that encompasses removal of a cardiac implantable electronic device (CIED) lead using any technique, while lead explantation and lead extraction are terms with more specific definitions. (See 'Definitions' above.) The most common indications for lead removal are infection, venous occlusion, mechanical lead failure (often resulting in improper pacemaker function or inappropriate implantable cardioverter-defibrillator [ICD] shocks), or advisory or recall as a result of (potential) lead malfunction. As a result of the complex nature of these cases, recommendations for lead extraction apply only to those patients in whom the benefits outweigh the risks when assessed on individual patient factors and operator-specific experience and outcomes. (See 'Indications' above.) Relative contraindications to percutaneous transvenous lead removal include unavailability of required personnel or equipment, the patient not being a candidate for emergency https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 13/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate thoracotomy, or anomalous lead placement. (See 'Contraindications' above.) Lead removal generally requires a significant amount of advance preparation. Knowledge of the patient's comorbidities, prior invasive/surgical history (eg, prior cardiac surgery or presence of an inferior vena cava filter), and lead characteristics such as lead length, diameter, and adapter information are required. The need for pacemaker support (ie, in a pacemaker-dependent patient) and ongoing device therapy must be assessed. Due to the risk of endovascular injury, lead extraction procedures should be performed with cardiothoracic surgical backup available. (See 'Lead removal procedure' above.) On occasion, previously placed leads may be capped and abandoned during CIED upgrade. Abandoned leads, however, pose a risk of interference with the placement or operation of another CIED and may need to be removed. In the absence of contraindications, we suggest removal of abandoned leads at the time of an indicated CIED procedure if implantation of the new device would result in greater than four unilateral leads or greater than five leads through the superior vena cava (Grade 2C). (See 'Lead upgrade and abandonment' above.) There are a variety of techniques and equipment used for lead removal, including direct (manual) traction, locking stylets, nonpowered "mechanical" sheaths, excimer laser powered sheaths, rotational cutting blade sheaths, and endovascular snares. (See 'Techniques' above.) Success rates for lead removal are variable and often reported in terms of complete versus partial removal. Large series of patients who have undergone lead extraction have reported high success rates (95 to 99 percent). Most of the complications are traumatic and related to the lead itself (eg, vascular injury, cardiac perforation resulting in cardiac tamponade, tricuspid regurgitation), although embolization of thrombus or vegetation from the lead is also a concern. When performed by experienced operators, mortality is usually less than 1 percent of patients, with major complications seen in 2 to 4 percent of patients. (See 'Outcomes' above and 'Complications' above.) ACKNOWLEDGMENTS The UpToDate editorial staff acknowledges Brian Olshansky, MD, and Jonathan Weinstock, MD, FACC, FHRS, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 14/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate REFERENCES 1. Kusumoto FM, Schoenfeld MH, Wilkoff BL, et al. 2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction. Heart Rhythm 2017; 14:e503. 2. Joy PS, Kumar G, Poole JE, et al. Cardiac implantable electronic device infections: Who is at greatest risk? Heart Rhythm 2017; 14:839. 3. Lewis RK, Pokorney SD, Hegland DD, Piccini JP. Hands on: How to approach patients undergoing lead extraction. J Cardiovasc Electrophysiol 2020; 31:1801. 4. Wilkoff BL, Love CJ, Byrd CL, et al. Transvenous lead extraction: Heart Rhythm Society expert consensus on facilities, training, indications, and patient management: this document was endorsed by the American Heart Association (AHA). Heart Rhythm 2009; 6:1085. 5. Baddour LM, Epstein AE, Erickson CC, et al. Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association. Circulation 2010; 121:458. 6. Nakajima I, Narui R, Tokutake K, et al. Staphylococcus bacteremia without evidence of cardiac implantable electronic device infection. Heart Rhythm 2021; 18:752. 7. Da Costa SS, Scalabrini Neto A, Costa R, et al. Incidence and risk factors of upper extremity deep vein lesions after permanent transvenous pacemaker implant: a 6-month follow-up prospective study. Pacing Clin Electrophysiol 2002; 25:1301. 8. Korkeila P, Ylitalo A, Koistinen J, Airaksinen KE. Progression of venous pathology after pacemaker and cardioverter-defibrillator implantation: A prospective serial venographic study. Ann Med 2009; 41:216. 9. Haghjoo M, Nikoo MH, Fazelifar AF, et al. Predictors of venous obstruction following pacemaker or implantable cardioverter-defibrillator implantation: a contrast venographic study on 100 patients admitted for generator change, lead revision, or device upgrade. Europace 2007; 9:328. 10. Gula LJ, Ames A, Woodburn A, et al. Central venous occlusion is not an obstacle to device upgrade with the assistance of laser extraction. Pacing Clin Electrophysiol 2005; 28:661.

catheter systems are safe and effective at removing vegetations [25,26]. The decision to debulk a vegetation prior to extraction is made on a case-by-case basis [5], but the risk of clinically relevant acute PE was rare in several cohort studies: In a retrospective study of 53 cases of pacemaker-lead endocarditis, 29 patients with 49 leads bearing vegetations with a mean size of 17.8 mm underwent successful transvenous removal using locking stylets and sheaths with no clinically apparent PEs [80]. Pacemaker leads with larger vegetations (mean size 22.4 mm) were removed by open cardiac surgery in 24 patients, three of whom died. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 12/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate In a single-center study of percutaneous lead removal (215 leads in 100 patients) in the setting of intracardiac vegetations, either on the leads or on the valves and ranging in size from 0.2 to 4.0 cm (mean 1.6 cm) in diameter, embolization of vegetation material, which measured >2 cm before extraction, was witnessed in only two cases with a third case that was presumed to have embolized (97 percent overall success rate for removal without embolization) [82]. In spite of the apparent embolization, all three patients recovered completely. [82] Paradoxical embolization of vegetation or thrombus into the systemic circulation at the time of lead extraction is possible, albeit rare, in patients with a patent foramen ovale (PFO). Among a cohort of 774 patients undergoing transvenous CIED lead extraction in the Mayo Clinic system over 17.5 years, postprocedural stroke occurred in 1 percent of patients and was significantly more likely among patients with PFO and right-to-left shunting [85]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac implantable electronic devices".) SUMMARY AND RECOMMENDATIONS Lead removal is a general term that encompasses removal of a cardiac implantable electronic device (CIED) lead using any technique, while lead explantation and lead extraction are terms with more specific definitions. (See 'Definitions' above.) The most common indications for lead removal are infection, venous occlusion, mechanical lead failure (often resulting in improper pacemaker function or inappropriate implantable cardioverter-defibrillator [ICD] shocks), or advisory or recall as a result of (potential) lead malfunction. As a result of the complex nature of these cases, recommendations for lead extraction apply only to those patients in whom the benefits outweigh the risks when assessed on individual patient factors and operator-specific experience and outcomes. (See 'Indications' above.) Relative contraindications to percutaneous transvenous lead removal include unavailability of required personnel or equipment, the patient not being a candidate for emergency https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 13/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate thoracotomy, or anomalous lead placement. (See 'Contraindications' above.) Lead removal generally requires a significant amount of advance preparation. Knowledge of the patient's comorbidities, prior invasive/surgical history (eg, prior cardiac surgery or presence of an inferior vena cava filter), and lead characteristics such as lead length, diameter, and adapter information are required. The need for pacemaker support (ie, in a pacemaker-dependent patient) and ongoing device therapy must be assessed. Due to the risk of endovascular injury, lead extraction procedures should be performed with cardiothoracic surgical backup available. (See 'Lead removal procedure' above.) On occasion, previously placed leads may be capped and abandoned during CIED upgrade. Abandoned leads, however, pose a risk of interference with the placement or operation of another CIED and may need to be removed. In the absence of contraindications, we suggest removal of abandoned leads at the time of an indicated CIED procedure if implantation of the new device would result in greater than four unilateral leads or greater than five leads through the superior vena cava (Grade 2C). (See 'Lead upgrade and abandonment' above.) There are a variety of techniques and equipment used for lead removal, including direct (manual) traction, locking stylets, nonpowered "mechanical" sheaths, excimer laser powered sheaths, rotational cutting blade sheaths, and endovascular snares. (See 'Techniques' above.) Success rates for lead removal are variable and often reported in terms of complete versus partial removal. Large series of patients who have undergone lead extraction have reported high success rates (95 to 99 percent). Most of the complications are traumatic and related to the lead itself (eg, vascular injury, cardiac perforation resulting in cardiac tamponade, tricuspid regurgitation), although embolization of thrombus or vegetation from the lead is also a concern. When performed by experienced operators, mortality is usually less than 1 percent of patients, with major complications seen in 2 to 4 percent of patients. (See 'Outcomes' above and 'Complications' above.) ACKNOWLEDGMENTS The UpToDate editorial staff acknowledges Brian Olshansky, MD, and Jonathan Weinstock, MD, FACC, FHRS, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 14/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate REFERENCES 1. Kusumoto FM, Schoenfeld MH, Wilkoff BL, et al. 2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction. Heart Rhythm 2017; 14:e503. 2. Joy PS, Kumar G, Poole JE, et al. Cardiac implantable electronic device infections: Who is at greatest risk? Heart Rhythm 2017; 14:839. 3. Lewis RK, Pokorney SD, Hegland DD, Piccini JP. Hands on: How to approach patients undergoing lead extraction. J Cardiovasc Electrophysiol 2020; 31:1801. 4. Wilkoff BL, Love CJ, Byrd CL, et al. Transvenous lead extraction: Heart Rhythm Society expert consensus on facilities, training, indications, and patient management: this document was endorsed by the American Heart Association (AHA). Heart Rhythm 2009; 6:1085. 5. Baddour LM, Epstein AE, Erickson CC, et al. Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association. Circulation 2010; 121:458. 6. Nakajima I, Narui R, Tokutake K, et al. Staphylococcus bacteremia without evidence of cardiac implantable electronic device infection. Heart Rhythm 2021; 18:752. 7. Da Costa SS, Scalabrini Neto A, Costa R, et al. Incidence and risk factors of upper extremity deep vein lesions after permanent transvenous pacemaker implant: a 6-month follow-up prospective study. Pacing Clin Electrophysiol 2002; 25:1301. 8. Korkeila P, Ylitalo A, Koistinen J, Airaksinen KE. Progression of venous pathology after pacemaker and cardioverter-defibrillator implantation: A prospective serial venographic study. Ann Med 2009; 41:216. 9. Haghjoo M, Nikoo MH, Fazelifar AF, et al. Predictors of venous obstruction following pacemaker or implantable cardioverter-defibrillator implantation: a contrast venographic study on 100 patients admitted for generator change, lead revision, or device upgrade. Europace 2007; 9:328. 10. Gula LJ, Ames A, Woodburn A, et al. Central venous occlusion is not an obstacle to device upgrade with the assistance of laser extraction. Pacing Clin Electrophysiol 2005; 28:661. 11. Cooper JM, Stephenson EA, Berul C, et al. Implantable Cardioverter-Defibrillator Lead Complications and Laser Extraction in Children and Young Adults with Congenital heart Disease. J Cardiovasc Electrophys 2003; 14:344. 12. Fischer A, Love B, Hansalia R, Mehta D. Transfemoral snaring and stabilization of pacemaker and defibrillator leads to maintain vascular access during lead extraction. Pacing Clin Electrophysiol 2009; 32:336. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 15/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate 13. Chan AW, Bhatt DL, Wilkoff BL, et al. Percutaneous treatment for pacemaker-associated superior vena cava syndrome. Pacing Clin Electrophysiol 2002; 25:1628. 14. Worley SJ, Gohn DC, Pulliam RW. Over the wire lead extraction and focused force venoplasty to regain venous access in a totally occluded subclavian vein. J Interv Card Electrophysiol 2008; 23:135. 15. Henrikson CA, Alexander D, Ringel RE, Brinker JA. Laser recanalization of the subclavian vein. Pacing Clin Electrophysiol 2006; 29:436. 16. Medtronic, Inc. Sprint Fidelis Model 6949 Lead Performance Physician Letter, dated October 15, 2007 http:// www.medtronic.com/product-advisories/physician/sprint-fidelis/ PROD-ADV PHYS-OCT.htm (Accessed on February 02, 2012). 17. Birnie DH, Parkash R, Exner DV, et al. Clinical predictors of Fidelis lead failure: report from the Canadian Heart Rhythm Society Device Committee. Circulation 2012; 125:1217. 18. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalPro ducts/ucm284390.htm (Accessed on January 26, 2012). 19. Theuns DAMJ, van Erven L, Kimman GP, et al. 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Safety of Transvenous Lead Removal in Patients 70 Years of Age in the United States from 2005 to 2012. Am J Cardiol 2018; 122:799. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 19/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate 68. http://www.r-calc.com/administrator/calculatorPreview.aspx?isGrid=0&mobile=0&isTemp=0 &calculator_id=cb78c47a-72d6-4fd0-a72a-43b44941759d (Accessed on January 15, 2016). 69. Boyle TA, Wilkoff BL, Pace J, et al. Balloon-assisted rescue of four consecutive patients with vascular lacerations inflicted during lead extraction. Heart Rhythm 2017; 14:757. 70. Azarrafiy R, Tsang DC, Boyle TA, et al. Compliant endovascular balloon reduces the lethality of superior vena cava tears during transvenous lead extractions. Heart Rhythm 2017; 14:1400. 71. Azarrafiy R, Tsang DC, Wilkoff BL, Carrillo RG. Endovascular Occlusion Balloon for Treatment of Superior Vena Cava Tears During Transvenous Lead Extraction: A Multiyear Analysis and an Update to Best Practice Protocol. Circ Arrhythm Electrophysiol 2019; 12:e007266. 72. Franceschi F, Thuny F, Giorgi R, et al. Incidence, risk factors, and outcome of traumatic tricuspid regurgitation after percutaneous ventricular lead removal. J Am Coll Cardiol 2009; 53:2168. 73. Rodriguez Y, Mesa J, Arguelles E, Carrillo RG. Tricuspid insufficiency after laser lead extraction. Pacing Clin Electrophysiol 2013; 36:939. 74. Coffey JO, Sager SJ, Gangireddy S, et al. The impact of transvenous lead extraction on tricuspid valve function. Pacing Clin Electrophysiol 2014; 37:19. 75. Park SJ, Gentry JL 3rd, Varma N, et al. Transvenous Extraction of Pacemaker and Defibrillator Leads and the Risk of Tricuspid Valve Regurgitation. JACC Clin Electrophysiol 2018; 4:1421. 76. Klug D, Lacroix D, Savoye C, et al. Systemic infection related to endocarditis on pacemaker leads: clinical presentation and management. Circulation 1997; 95:2098. 77. Sohail MR, Uslan DZ, Khan AH, et al. Infective endocarditis complicating permanent pacemaker and implantable cardioverter-defibrillator infection. Mayo Clin Proc 2008; 83:46. 78. Victor F, De Place C, Camus C, et al. Pacemaker lead infection: echocardiographic features, management, and outcome. Heart 1999; 81:82. 79. Nguyen KT, Neese P, Kessler DJ. Successful laser-assisted percutaneous extraction of four pacemaker leads associated with large vegetations. Pacing Clin Electrophysiol 2000; 23:1260. 80. Ruttmann E, Hangler HB, Kilo J, et al. Transvenous pacemaker lead removal is safe and effective even in large vegetations: an analysis of 53 cases of pacemaker lead endocarditis. Pacing Clin Electrophysiol 2006; 29:231. 81. P rez Baztarrica G, Gariglio L, Salvaggio F, et al. Transvenous extraction of pacemaker leads in infective endocarditis with vegetations 20 mm: our experience. Clin Cardiol 2012; 35:244. https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 20/21 7/6/23, 10:48 AM Cardiac implantable electronic device lead removal - UpToDate 82. Grammes JA, Schulze CM, Al-Bataineh M, et al. Percutaneous pacemaker and implantable cardioverter-defibrillator lead extraction in 100 patients with intracardiac vegetations defined by transesophageal echocardiogram. J Am Coll Cardiol 2010; 55:886. 83. Narui R, Nakajima I, Norton C, et al. Risk Factors for Repeat Infection and Mortality After Extraction of Infected Cardiovascular Implantable Electronic Devices. JACC Clin Electrophysiol 2021; 7:1182. 84. Arora Y, Perez AA, Carrillo RG. Influence of vegetation shape on outcomes in transvenous lead extractions: Does shape matter? Heart Rhythm 2020; 17:646. 85. Lee JZ, Agasthi P, Pasha AK, et al. Stroke in patients with cardiovascular implantable electronic device infection undergoing transvenous lead removal. Heart Rhythm 2018; 15:1593. Topic 971 Version 40.0 Contributor Disclosures Jay A Montgomery, MD No relevant financial relationship(s) with ineligible companies to disclose. Jonathan Piccini, MD, MHS, FACC, FAHA, FHRS Grant/Research/Clinical Trial Support: Abbott [Atrial fibrillation, catheter ablation]; AHA [Atrial fibrillation, cardiovascular disease]; Bayer [Atrial fibrillation]; Boston Scientific [Cardiac mapping, pacemaker/ICD, atrial fibrillation care]; iRhythm [Atrial fibrillation]; NIA [Atrial fibrillation]; Philips [Lead management]. Consultant/Advisory Boards: Abbott [Atrial fibrillation, catheter ablation]; Abbvie [Atrial fibrillation]; Bayer [Atrial fibrillation]; Boston Scientific [Cardiac mapping, atrial fibrillation, pacemaker/ICD]; ElectroPhysiology Frontiers [Atrial fibrillation, catheter ablation]; Element Science [DSMB]; Medtronic [Atrial fibrillation, pacemaker/ICDs]; Milestone [Supraventricular tachycardia]; Pacira [Atrial fibrillation]; Philips [Lead extraction]; ReCor [Cardiac arrhythmias]; Sanofi [Atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cardiac-implantable-electronic-device-lead-removal/print 21/21

7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cardiac implantable electronic devices: Long-term complications : Jonathan Piccini, MD, MHS, FACC, FAHA, FHRS : N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 22, 2021. INTRODUCTION As more people are living longer with more medical comorbidities including significant cardiac disease, the number of permanent pacemakers (PPMs) and implantable cardioverter- st defibrillators (ICDs) inserted continues to increase. Beginning early in the 21 century, there has also been an expansion in the indications for cardiac implantable electronic devices (CIED, a term which includes PPMs and ICDs), resulting in device therapy becoming more complex and more prolonged over the patient's lifetime. As such, therapy with a CIED frequently involves multiple leads and multiple pulse generators per patient over each patient's lifetime with the device, exposing the patient to greater operative risk as well as ongoing risk related to the CIED. There are a variety of potential complications associated with CIED use, both at and around the time of implantation as well as long-term over the life of the patient and his/her device [1-3]. Efforts to avoid some of these complications have led to the development of new technologies (ie, leadless pacemakers, subcutaneous ICDs). The long-term complications associated with a CIED will be reviewed here. Procedural and peri-procedural complications associated with CIED implantation, as well as basic principles associated with PPMs, ICDs, and alternative technologies, are discussed separately. (See "Cardiac implantable electronic devices: Periprocedural complications" and "Permanent cardiac pacing: Overview of devices and indications" and "Implantable cardioverter-defibrillators: Overview of indications, components, and functions" and "Permanent cardiac pacing: Overview of devices and indications", section on 'Leadless systems' and "Subcutaneous implantable cardioverter defibrillators".) https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 1/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate INCIDENCE Major complications requiring reoperation or hospitalization were analyzed in a cohort of 114,484 patients aged 65 years or greater (mean age 74.8 years, 72 percent male) who were enrolled in the National Cardiovascular Data Registry (NCDR) ICD registry and received a first ICD between 2006 and 2010 [4]. Over a median follow-up of 2.7 years, ICD-related complications requiring hospitalization or reoperation occurred at a rate of 6.1 per 100 patient-years. Patients who experienced a complication within the first 90 days following ICD implantation were at greater risk of all-cause mortality at one (hazard ratio [HR] 1.13, 95% CI 1.05-1.20) and three (HR 1.09, 95% CI 1.05-1.13) years [5]. A higher reoperation rate was seen in a Canadian study of 3410 first-time ICD recipients (implanted between 2003 and 2012, median follow-up 34 months), in which 12 percent of patients per year required reoperation [6]. Pulse generator malfunctions are a rare but significant long-term complication, particularly for patients who are pacemaker-dependent. In a 2006 meta-analysis which included patients from three registries, including 475,618 PPMs and 20,633 ICDs implanted between 1974 and 2004, rates of device malfunction (pulse generator only, no data on lead malfunctions were reported) were 1.3 per 1000 person-years for PPMs and 26.5 per 1000 person-years for ICDs, although the complication rates fell significantly over time [7]. Lead malfunctions, another rare but significant potential long-term complication, are more common in ICD leads, with significant variability in the rates of malfunction in certain leads. Reported lead failure rates have varied from 1 to 9 percent at two years, 2 to 15 percent at five years and 5 to 40 percent at 8 to 10 years [8-10]. Comparison of rates are confounded by varying definitions of lead failure, differences among lead models, varying patient and clinician characteristics, and limitations of methods for detection of lead malfunction [9]. MRI COMPATIBILITY Contemporary CIED and lead systems are generally labeled magnetic resonance imaging (MRI) compatible or MRI conditional, though management and behavior are variable among manufacturers/models and require some evaluation prior to scanning. Systems with older leads, abandoned leads, and some unusual features may not be strictly labeled MRI compatible. Several observational studies have shown that most patients can be safely scanned if appropriate precautions are taken [11,12]. Evaluation of patients with CIEDs for possible MRI imaging is discussed separately. (See "Patient evaluation for metallic or electrical implants, https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 2/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate devices, or foreign bodies before magnetic resonance imaging", section on 'Cardiovascular implantable electronic device'.) LEAD COMPLICATIONS Lead-related problems include infection, lead failure (resulting in failure to pace, failure to shock, or inappropriate shocks), tricuspid valve regurgitation and/or damage, implant vein occlusion, and increased defibrillation thresholds (DFT). Abandoned leads also represent another type of lead-related complication insofar that they represent a contraindication to magnetic resonance imaging (MRI) scanning, which can be an impediment to medical care in some instances. Rarely, abandoned leads can affect device function by causing electrical artifacts. Venous thrombosis causes upper extremity swelling and discomfort in 5 to 10 percent of patients with chronic leads and may interfere with placement of additional leads [13]. Infection Infection of the generator pocket or leads can occur at the time of CIED implantation or at any subsequent time. Because infection of a CIED can be a life-threatening problem, complete hardware removal, including the CIED pulse generator and all leads, along with antibiotic therapy, are strongly recommended unless there is a reason to pursue palliative antibiotic therapy (eg, very short life-expectancy) [14]. These issues are discussed in detail separately. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Cardiac implantable electronic device lead removal".) Lead failure The frequency of lead failure and the types of problems that occur have been evaluated in a number of studies [2,8-10,15-18]. Certain lead models and sizes have been identified as prone to failure [10,17,19]. Additionally, ICD leads seem more prone to failure compared with pacemaker leads, due to the increased complexity of the design to allow for both pacing and defibrillation functions. However, it is difficult to separate the relative contribution of materials, lead diameter, lead design, patient factors (eg, younger age, female sex, lower BMI, submuscular pectoral implant, etc) or other as yet unidentified factors with respect to failure rates. In a series of 1317 consecutive patients with an ICD placed between 1993 and 2004 who were followed for a median of 6.4 years, 38 patients (2.9 percent) experienced a lead malfunction requiring lead revision, with 29 of the 38 patients (76 percent) experiencing inappropriate ICD therapies [8]. The main reasons for lead malfunction were insulation defects (26 percent), artifact oversensing (24 percent), and lead fractures (24 percent). The rate of recurrent ICD lead- https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 3/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate related problems was 20 percent at five years. Deaths related to ICD lead failure have been reported but are exceedingly rare [20]. Detecting lead failure Lead failure has traditionally most commonly been diagnosed when a patient presents with symptoms related to the failed lead (eg, inappropriate ICD shocks, dizziness or syncope due to failure to pace, etc) and the device parameters are interrogated. Evidence of lead fracture is rarely identified on a chest radiograph. With modern systems, remote CIED follow-up has frequently revealed evidence of lead malfunction before it is manifested clinically. Patients with known hardware under advisory should be followed with remote monitoring in order to detect potential lead failure as soon as possible [21]. Devices often have software designed to detect emerging lead problems [22]. For example, one manufacturer's algorithm that combines oversensing and impedance measurements to detect coaxial ICD lead failure found a sensitivity of 83 percent (24 of 29) and a specificity of 100 percent in 667 patients when tested in a population with various lead models [23]. The algorithm was subsequently modified to add features beyond lead failure detection, including a more extensive alerting system and the implementation of real-time, automatic changes to the ventricular fibrillation (VF) detection parameters of the ICD when a lead failure is detected [24]. (See "Cardiac implantable electronic device lead removal", section on 'Advisory/recall'.) Lead extraction When mechanical lead failure has been identified, lead replacement is indicated. The decision to remove a failed lead, versus capping the lead and leaving it in site (ie, abandoning the lead), is made on a case by case basis, with the decision largely dependent on the perceived risk/benefit ratio, both peri-procedural and long-term, in the individual patient. Indications and outcomes for lead extraction are discussed separately. Unfortunately, long-term follow-up data comparing outcomes in patients who undergo lead extraction versus capping and abandoning are not currently available. (See "Cardiac implantable electronic devices: Periprocedural complications" and "Cardiac implantable electronic device lead removal" and "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis".) Tricuspid regurgitation Severe tricuspid regurgitation (TR) can result from the placement of CIED leads causing damage to the tricuspid valve or impeding the appropriate closure of the valve during systole [25-27]. The frequency of developing significant TR is approximately 10 to 20 percent of persons receiving a CIED device with transvenous leads, ultimately resulting in heart failure symptoms in approximately 50 percent of those with severe TR [25]. In a single-center cohort study of 58,556 patients (including 634 with PPMs; patients with ICDs were excluded from this study) who underwent echocardiograms over a seven-year period from 2005 to 2011, 16 percent of patients with a PPM had severe TR, compared with 2 percent of patients without a https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 4/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate PPM [28]. After adjusting for baseline comorbidities, significant TR remained significantly more likely in patients with a PPM (adjusted odds ratio 2.3, 95% CI 1.5-3.5). Tricuspid regurgitation has also been reported amongst recipients of bioprosthetic tricuspid valves who subsequently undergo implantation of a permanent pacemaker (PPM) or ICD with a transvenous ventricular lead. In a retrospective cohort study of 323 patients who received a bioprosthetic tricuspid valve (58 patients with a PPM/ICD lead, 265 patients without a lead) and were followed for a mean of over two years, there was a non-significant increase in the rate of moderate or severe TR in patients with a device lead (9 versus 5 percent), rates which compare favorably with the rate of TR development following transvenous lead placement through native tricuspid valves [29]. While the study is limited due to its retrospective, non-randomized nature, these results suggest that transvenous device leads are relatively safe and feasible in patients with a bioprosthetic tricuspid valve. As an alternative, leadless cardiac pacemakers can be considered in this population. (See "Permanent cardiac pacing: Overview of devices and indications", section on 'Leadless systems'.) Management of TR is discussed in detail separately. (See "Management and prognosis of tricuspid regurgitation", section on 'Management of pacemaker therapy'.) Increased defibrillation threshold The safety threshold values for pacing and defibrillation may change over time. Causes of both increased pacing and DFT include lead dislodgement/micro-dislodgement, inflammation around the tip, exit block, lead failure, progression of left ventricular dysfunction and left ventricle (LV) dilatation, and the effects of certain drugs. The DFT (also called defibrillation energy requirement for an ICD) is usually 15 joules and often <10 joules with biphasic shocks and improved lead systems. Routine DFT testing has not shown a clinical benefit in patients receiving an ICD for primary prevention. However, when the DFT is high, higher energy devices, reversed energy polarity, other waveform modifications, and/or alternative lead placements can be used to achieve an adequate safety margin. When these measures fail, an additional defibrillation lead can be placed in the azygous vein (posterior to the heart) to improve the shocking vector. Very rarely, placement of a tunneled subcutaneous array or an epicardial lead is required. Manipulation of pharmacologic therapy can also be helpful in selected cases; amiodarone is known to increase the defibrillation energy requirement (see below), while sotalol and dofetilide tend to lower this parameter. Frequent ICD discharges may produce a secondary increase in DFT due to intense fibrosis and cumulative damage at the ICD electrode-myocardial interface [30,31]. However, in the absence of any changes in the clinical status of the patient, DFTs with current transvenous lead systems are generally stable over time [32,33]. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 5/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate A more common problem is that patients with frequent appropriate shocks may be treated with amiodarone, which can increase the DFT and also alter the pacing threshold [34]. Older professional society guidelines for amiodarone therapy recommended that, whenever amiodarone was initiated in a patient with an ICD, a noninvasive ICD evaluation or an electrophysiology study should be performed to test for adverse drug-device interactions once loading is complete [35]. However, a 2015 expert consensus statement did not specifically address the role of DFT testing in patients treated with amiodarone; however, the consensus statement did indicate that it was "reasonable" to omit routine DFT testing for most newly implanted left pectoral ICD systems with right ventricular apical lead position as well as for high- risk patients with cardiac comorbidities such as severe pulmonary hypertension or severely depressed left ventricular function (eg, LVEF <20 percent) [36]. Data supporting this move away from DFT testing in patients receiving amiodarone were reported from the OPTIC trial, in which the increase in DFT related to amiodarone was quite small, calling into question the necessity of verifying the defibrillation safety margin [37]. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions", section on 'Defibrillation threshold testing'.) PULSE GENERATOR COMPLICATIONS Long-term complications related to the CIED pulse generator are relatively uncommon, occurring in less than 2 percent of patients, and include skin erosion/infection, device and/or lead migration, tissue necrosis (due to the size and weight of the generator) and electromechanical interference/damage [2]. In addition, peri-procedural complications (eg, hematomas, infection) can occur in the pulse generator pocket [38]. (See "Cardiac implantable electronic devices: Periprocedural complications".) Pocket erosion/infection Infection involving the pulse generator pocket can occur at the time of CIED implantation or at any subsequent time. Because infection of a CIED can be a life- threatening problem, complete removal of the CIED pulse generator and all leads, along with antibiotic therapy, are strongly recommended. In rare instances, a patient may elect to pursue palliative antibiotic therapy; however, such an approach is not curative. These issues are discussed in detail separately. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Cardiac implantable electronic device lead removal".) Pulse generator infection occurring late (more than six months post-implantation) may be due a chronic, smoldering infection, which can be subclinical for a prolonged period of time. These infections are more common with low virulence organisms such as coagulase negative https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 6/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate Staphylococcus species. This can be associated with device erosion through the skin. Though rare, this particular complication is more common amongst thin patients with minimal subcutaneous fat and other tissue overlying the device. Significant weight loss after implant predisposes to this complication. Once the integrity of the skin overlying the device has been compromised, system infection should be assumed, even in the absence of symptoms, and the device (and frequently leads) will need to be removed and replaced. Repeated device infection should also raise concern for potential allergy to device components, which can rarely occur. In cases of suspected device component allergies, skin testing with specialized panels should be performed by a dermatologist or allergist. In patients who are at high risk for pocket infection, prophylactic use of a dissolving antibiotic pouch around the device may be useful. Randomized clinical trials are underway to test the efficacy of such an approach [39]. Twiddler's syndrome Twiddler's syndrome is a condition in which twisting or rotating the CIED pulse generator within its pocket results in lead dislodgement and device malfunction [40,41]. Affected patients most often present with an increase in bradycardic pacing threshold or lead impedance, although pacemaker-dependent patients may present with symptoms related to bradyarrhythmia (eg, syncope, lightheadedness, etc). In patients with ventricular lead dislodgement and retraction, it is also possible that an ICD will fail to sense and treat an arrhythmia. Careful suturing of the lead suture sleeves, suturing the device to the fascia, using a nonabsorbable antimicrobial pouch, warning the patient not to manipulate the device, and ensuring appropriate pocket size are important proactive steps to reduce the likelihood of this complication [42]. Electronic circuit damage Device failures are uncommon, with reports estimating an incidence between 0.01 and 0.1 percent [43]. Electronic circuit failure can result from electrical overstress damage to the high voltage hybrid circuit and other electronic components [44]. Signs of such failure include loss of telemetry and inability to deliver therapy. Electrical overstress damage may occur during capacitor reformation or charging and the delivery of a shock, after cardioversion, or rarely with the use of electrocautery. It is recommended that routine follow-up examination of device function be performed in these settings. Radiation therapy can damage circuitry as well. Current recommendations include shielding the device from the radiation beam and careful follow-up, particularly in pacemaker-dependent patients. In some instances, it may be required to relocate the pulse generator outside of the radiation field. Electromagnetic interference Since reliable function of any CIED depends upon proper sensing of the electrical activity of the heart, a potential concern is electromagnetic interference from external sources, including cellular telephones containing magnets, welding equipment, https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 7/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate motor-generator systems, and surveillance systems ( table 1). These issues are discussed in detail separately. (See "Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment".) Interference with ICD function can occur during noncardiac surgery as a result of electrical current generated by electrocautery, as well as during magnetic resonance imaging (MRI). Issues related to electrosurgery and MRI scanning and potential interactions with implanted cardiac devices are discussed in detail separately. (See "Perioperative management of patients with a pacemaker or implantable cardioverter-defibrillator".) Advisories/recalls Occasionally, CIED manufacturers will issue an "advisory" or "recall" due to concerns about device performance or safety. In most instances following a notification, CIED failure rates are quite low, but some patients/physicians choose to electively replace generators on a case by case basis. ARRHYTHMIC COMPLICATIONS A variety of arrhythmia-related problems can occur in patients with an ICD. Arrhythmic complications include both inappropriate shocks, usually due to the treatment of supraventricular tachycardias, and appropriate shocks. Additionally, while not caused by an arrhythmia, the perception of a shock when one has not been delivered, termed a "phantom shock," should be considered in patients with symptoms but no evidence of shock on device interrogation. Inappropriate shocks Inappropriate shocks (ie, shocks delivered by an ICD for any rather other than ventricular tachyarrhythmia) occur in up to 40 percent of patients with an ICD [45-50]. However, contemporary device programming, including delayed detection and use of discriminator functions, is associated with lower risks of inappropriate shocks [51]. The most common cause of inappropriate shocks is a supraventricular tachyarrhythmia (SVT), which results in a ventricular heart rate that falls within a programmed treatment zone [46,50]. The most common supraventricular arrhythmia causing inappropriate therapies is atrial fibrillation, although sinus tachycardia and other SVTs may also result in inappropriate shocks. Other causes of inappropriate shocks include electrical noise, inappropriate sensing (ie, T wave oversensing), and ICD malfunction (typically due to lead fracture). Patients who receive inappropriate shocks may become quite anxious or uncomfortable since the most common causes of inappropriate shocks (ie, SVT and lead fracture) often result in the delivery of multiple shocks. Rarely, multiple inappropriate (or even appropriate) shocks can result in a posttraumatic-stress-disorder-like syndrome. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 8/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate While inappropriate shocks due to lead fracture or other device malfunction are difficult to predict (and therefore prevent), the frequency of inappropriate shocks not related to lead malfunction (ie, those related to SVT) can usually be reduced with modern ICD programming strategies. The recommended modern approach to ICD programming is discussed in detail separately. In addition to modern device programming (eg, high rate cutoffs, longer delays prior to initiating treatment), other device features such as arrhythmia discrimination and the placement of an atrial lead may reduce the frequency of inappropriate shocks [21,52]. Dual-chamber devices have an atrial lead for sensing, which allows for more effective discrimination between atrial and ventricular arrhythmias, with appropriate programming, dual-chamber ICDs have been shown to decrease inappropriate detection compared with single-chamber devices [53]. However, device programming to limit unnecessary therapies may be more important than dual-chamber devices [54]. Modern devices nearly universally contain proprietary arrhythmia discrimination software, which aims to accurately discriminate between various atrial tachyarrhythmias (eg, atrial tachycardia, atrial flutter, and atrial fibrillation) and ventricular tachyarrhythmias. While there are conflicting data on an association between inappropriate shocks and mortality, most studies suggest a 1.5-to-2-fold increase in mortality among recipients of an inappropriate shock [46-48,55]. As an example, among patients in the ALTITUDE study who received inappropriate shocks, those who were shocked for atrial fibrillation or atrial flutter had significantly increased mortality (hazard ratio [HR] 1.6 compared with those without any ICD shock), while those who were shocked for other supraventricular tachyarrhythmias or sinus tachycardia had no difference in mortality (HR 1.0 compared with no ICD shock) [50]. Appropriate shocks Appropriately-delivered ICD shocks for ventricular tachyarrhythmias are not technically a complication but rather the intended response of the device. While potentially life-saving, appropriate shocks can also have an adverse effect on quality of life, including emotional problems and driving restriction. (See 'Quality of life' below and "Driving restrictions in patients with an implantable cardioverter-defibrillator", section on 'Overall incidence of ventricular arrhythmias and ICD shocks'.) In a systematic review of seven trials of primary and secondary prevention of sudden cardiac death (SCD), appropriate ICD therapies outnumbered SCD events in the control groups by a factor of two to three [56]. Subsequent studies have clarified that the likely reason for this discrepancy in outcomes relates to the treatment of arrhythmias that would have been hemodynamically tolerated and/or terminated spontaneously (ie, nonfatal events). Strategies to https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 9/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate reduce the number of appropriate shocks include high rate cutoffs for delivering a shock, longer delays prior to initiating treatment, and antitachycardia pacing (ATP), which should terminate at least 90 percent of episodes of persistent VT [57,58]. Antitachycardia pacing as well as the recommended modern approach to ICD programming are discussed in detail separately. Phantom shocks The perception of having received an ICD shock when no shock was delivered is called a "phantom shock." In the prospective COPE-ICD trial, 9 percent of patients reported phantom shocks [59]. While the underlying reason for experiencing a phantom shock is not known, patients who do report phantom shocks are more likely to have received an actual ICD shock (and thus may have continued worry about receiving another shock) or to suffer from unrelated anxiety or depression [60,61]. The optimal strategy to manage phantom shocks depends on the patient. For those who have continued worry about phantom shocks, counseling or pharmacotherapy may be necessary to address the patient's anxiety. For some patients, careful follow-up or transtelephonic monitoring may be valuable. Frequent follow-up and further discussions with the electrophysiologist may be necessary, but over time, symptoms tend to abate without the need for unnecessary interventions or the need to turn the device off. MISCELLANEOUS COMPLICATIONS Heart failure CIEDs may worsen left ventricular function and/or precipitate symptomatic heart failure (HF), particularly in patients with preexisting systolic dysfunction, by one of two mechanisms: Right ventricular pacing, producing ventricular dyssynchrony. Improved long-term survival in patients with advanced cardiac disease can result in patients living long enough for HF to develop or progress. These issues are discussed in detail separately. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Modes to minimize ventricular pacing' and "Overview of pacemakers in heart failure", section on 'Implantable cardioverter-defibrillators'.) Quality of life The ICD is often associated with deleterious psychosocial effects, with as many as 50 percent of recipients reporting elevated levels of anxiety and depression resulting from the fear of receiving a shock, device failure, decrease in physical activity, and negative lifestyle changes (such as the inability to drive or to return to work) [62-70]. Some patients develop severe psychiatric problems after receiving appropriate shocks [71]. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 10/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate The frequency and severity of these psychosocial effects can be illustrated by the following findings: In a report of 119 patients, most described the shocks from the ICD as severe [62]. Common descriptions were a blow to the body or a spasm causing the body to jump. Twenty-three percent dreaded the shocks, and 5 percent said they would prefer to be without the ICD and take their chances. However, most patients tolerated the shocks because they are lifesaving. Another study of 70 patients noted an association between the number of shocks received and the likelihood of mood disturbances, ranging from 9 percent among those with less than four shocks to 55 percent in those with more than 10 shocks [63]. In an analysis of 800 patients from the AVID trial of secondary prevention, the ICD and amiodarone were associated with similar alterations in quality of life [66]. A reduction in physical functioning and mental well-being was largely related to the occurrence of any shocks from the ICD and to adverse side effects from the ICD or drug. Efforts should be made to reduce the frequency of both appropriate and inappropriate shocks if they are common enough to interfere with the quality of life. The degree of anxiety and depression can also be reduced by the use of group and individual support and behavioral, cognitive, and relaxation therapies [72,73]. (See 'Appropriate shocks' above and 'Inappropriate shocks' above.) The safety of driving in patients with an ICD is discussed separately. (See "Driving restrictions in patients with an implantable cardioverter-defibrillator".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 11/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Sudden cardiac arrest (The Basics)") Beyond the Basics topics (see "Patient education: Implantable cardioverter-defibrillators (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Lead-related problems include infection, lead failure (resulting in failure to pace, failure to shock, or inappropriate shocks), tricuspid valve damage, venous thrombosis, and increased defibrillation thresholds. Infection of the generator pocket or leads can occur at the time of CIED implantation or at any subsequent time. Because infection of a CIED can be a life-threatening problem, complete removal of the CIED pulse generator and all leads, along with antibiotic therapy, are strongly recommended for nearly all patients. (See 'Infection' above and "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Cardiac implantable electronic device lead removal".) Lead failure, which has had a highly variable frequency from lead to lead, has traditionally most commonly been diagnosed when a patient presents with symptoms related to the failed lead (eg, inappropriate implantable cardioverter-defibrillator [ICD] shocks, dizziness or syncope due to failure to pace, etc) and the device parameters are interrogated. When mechanical lead failure has been identified, lead replacement is indicated. (See 'Lead failure' above.) Severe tricuspid regurgitation (TR) can result from the placement of CIED leads causing damage to the tricuspid valve or impeding the appropriate closure of the valve during systole. (See 'Tricuspid regurgitation' above.) The safety threshold values for pacing and defibrillation may change over time. Causes of both increased pacing and defibrillation threshold include lead dislodgement/micro- dislodgement, inflammation around the tip, exit block, lead failure, progression of left ventricular dysfunction and dilatation, and the effects of certain drugs. (See 'Increased defibrillation threshold' above.) https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 12/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate Long-term complications related to the CIED pulse generator are relatively uncommon, occurring in less than 2 percent of patients, and include skin erosion/infection, device and/or lead migration, tissue necrosis (due to the size and weight of the generator) and electromechanical interference/damage. (See 'Pulse generator complications' above and "Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment", section on 'Equipment with high-strength magnets'.) A variety of arrhythmia-related problems can occur in patients with an ICD. Arrhythmic complications include both inappropriate shocks, usually due to the treatment of supraventricular tachycardias, as well as appropriate shocks and "phantom" shocks. Inappropriate shocks (ie, shocks delivered by an ICD for any rather other than ventricular tachyarrhythmia) occur in up to 40 percent of patients with an ICD. The frequency of inappropriate shocks not related to lead malfunction (ie, those related to supraventricular tachycardia [SVT]) can usually be reduced with modern ICD programming strategies. (See 'Inappropriate shocks' above.) Appropriately-delivered ICD shocks for ventricular tachyarrhythmias are not technically a complication but rather the intended response of the device. While potentially life- saving, appropriate shocks can also have an adverse effect on quality of life, including emotional problems and driving restriction. (See 'Appropriate shocks' above.) The perception of having received an ICD shock when no shock was delivered is called a "phantom shock." The optimal strategy to manage phantom shocks depends on the patient, but typically involves close follow-up and reassurance. (See 'Phantom shocks' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Pfeiffer D, Jung W, Fehske W, et al. Complications of pacemaker-defibrillator devices: diagnosis and management. Am Heart J 1994; 127:1073. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 13/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate 2. Kron J, Herre J, Renfroe EG, et al. Lead- and device-related complications in the antiarrhythmics versus implantable defibrillators trial. Am Heart J 2001; 141:92. 3. DiMarco JP. Implantable cardioverter-defibrillators. N Engl J Med 2003; 349:1836. 4. Ranasinghe I, Parzynski CS, Freeman JV, et al. Long-Term Risk for Device-Related Complications and Reoperations After Implantable Cardioverter-Defibrillator Implantation: An Observational Cohort Study. Ann Intern Med 2016. 5. Kipp R, Hsu JC, Freeman J, et al. Long-term morbidity and mortality after implantable cardioverter-defibrillator implantation with procedural complication: A report from the National Cardiovascular Data Registry. Heart Rhythm 2018; 15:847. 6. Hawkins NM, Grubisic M, Andrade JG, et al. Long-term complications, reoperations and survival following cardioverter-defibrillator implant. Heart 2018; 104:237. 7. Maisel WH. Pacemaker and ICD generator reliability: meta-analysis of device registries. JAMA 2006; 295:1929. 8. Eckstein J, Koller MT, Zabel M, et al. Necessity for surgical revision of defibrillator leads implanted long-term: causes and management. Circulation 2008; 117:2727. 9. Maisel WH, Kramer DB. Implantable cardioverter-defibrillator lead performance. Circulation 2008; 117:2721. 10. van Rees JB, van Welsenes GH, Borleffs CJ, et al. Update on small-diameter implantable cardioverter-defibrillator leads performance. Pacing Clin Electrophysiol 2012; 35:652. 11. Nazarian S, Hansford R, Rahsepar AA, et al. Safety of Magnetic Resonance Imaging in Patients with Cardiac Devices. N Engl J Med 2017; 377:2555. 12. Russo RJ, Costa HS, Silva PD, et al. Assessing the Risks Associated with MRI in Patients with a Pacemaker or Defibrillator. N Engl J Med 2017; 376:755. 13. Zuber M, Huber P, Fricker U, et al. Assessment of the subclavian vein in patients with transvenous pacemaker leads. Pacing Clin Electrophysiol 1998; 21:2621. 14. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017; 70:252.

th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 11/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Sudden cardiac arrest (The Basics)") Beyond the Basics topics (see "Patient education: Implantable cardioverter-defibrillators (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Lead-related problems include infection, lead failure (resulting in failure to pace, failure to shock, or inappropriate shocks), tricuspid valve damage, venous thrombosis, and increased defibrillation thresholds. Infection of the generator pocket or leads can occur at the time of CIED implantation or at any subsequent time. Because infection of a CIED can be a life-threatening problem, complete removal of the CIED pulse generator and all leads, along with antibiotic therapy, are strongly recommended for nearly all patients. (See 'Infection' above and "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Cardiac implantable electronic device lead removal".) Lead failure, which has had a highly variable frequency from lead to lead, has traditionally most commonly been diagnosed when a patient presents with symptoms related to the failed lead (eg, inappropriate implantable cardioverter-defibrillator [ICD] shocks, dizziness or syncope due to failure to pace, etc) and the device parameters are interrogated. When mechanical lead failure has been identified, lead replacement is indicated. (See 'Lead failure' above.) Severe tricuspid regurgitation (TR) can result from the placement of CIED leads causing damage to the tricuspid valve or impeding the appropriate closure of the valve during systole. (See 'Tricuspid regurgitation' above.) The safety threshold values for pacing and defibrillation may change over time. Causes of both increased pacing and defibrillation threshold include lead dislodgement/micro- dislodgement, inflammation around the tip, exit block, lead failure, progression of left ventricular dysfunction and dilatation, and the effects of certain drugs. (See 'Increased defibrillation threshold' above.) https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 12/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate Long-term complications related to the CIED pulse generator are relatively uncommon, occurring in less than 2 percent of patients, and include skin erosion/infection, device and/or lead migration, tissue necrosis (due to the size and weight of the generator) and electromechanical interference/damage. (See 'Pulse generator complications' above and "Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment", section on 'Equipment with high-strength magnets'.) A variety of arrhythmia-related problems can occur in patients with an ICD. Arrhythmic complications include both inappropriate shocks, usually due to the treatment of supraventricular tachycardias, as well as appropriate shocks and "phantom" shocks. Inappropriate shocks (ie, shocks delivered by an ICD for any rather other than ventricular tachyarrhythmia) occur in up to 40 percent of patients with an ICD. The frequency of inappropriate shocks not related to lead malfunction (ie, those related to supraventricular tachycardia [SVT]) can usually be reduced with modern ICD programming strategies. (See 'Inappropriate shocks' above.) Appropriately-delivered ICD shocks for ventricular tachyarrhythmias are not technically a complication but rather the intended response of the device. While potentially life- saving, appropriate shocks can also have an adverse effect on quality of life, including emotional problems and driving restriction. (See 'Appropriate shocks' above.) The perception of having received an ICD shock when no shock was delivered is called a "phantom shock." The optimal strategy to manage phantom shocks depends on the patient, but typically involves close follow-up and reassurance. (See 'Phantom shocks' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Pfeiffer D, Jung W, Fehske W, et al. Complications of pacemaker-defibrillator devices: diagnosis and management. Am Heart J 1994; 127:1073. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 13/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate 2. Kron J, Herre J, Renfroe EG, et al. Lead- and device-related complications in the antiarrhythmics versus implantable defibrillators trial. Am Heart J 2001; 141:92. 3. DiMarco JP. Implantable cardioverter-defibrillators. N Engl J Med 2003; 349:1836. 4. Ranasinghe I, Parzynski CS, Freeman JV, et al. Long-Term Risk for Device-Related Complications and Reoperations After Implantable Cardioverter-Defibrillator Implantation: An Observational Cohort Study. Ann Intern Med 2016. 5. Kipp R, Hsu JC, Freeman J, et al. Long-term morbidity and mortality after implantable cardioverter-defibrillator implantation with procedural complication: A report from the National Cardiovascular Data Registry. Heart Rhythm 2018; 15:847. 6. Hawkins NM, Grubisic M, Andrade JG, et al. Long-term complications, reoperations and survival following cardioverter-defibrillator implant. Heart 2018; 104:237. 7. Maisel WH. Pacemaker and ICD generator reliability: meta-analysis of device registries. JAMA 2006; 295:1929. 8. Eckstein J, Koller MT, Zabel M, et al. Necessity for surgical revision of defibrillator leads implanted long-term: causes and management. Circulation 2008; 117:2727. 9. Maisel WH, Kramer DB. Implantable cardioverter-defibrillator lead performance. Circulation 2008; 117:2721. 10. van Rees JB, van Welsenes GH, Borleffs CJ, et al. Update on small-diameter implantable cardioverter-defibrillator leads performance. Pacing Clin Electrophysiol 2012; 35:652. 11. Nazarian S, Hansford R, Rahsepar AA, et al. Safety of Magnetic Resonance Imaging in Patients with Cardiac Devices. N Engl J Med 2017; 377:2555. 12. Russo RJ, Costa HS, Silva PD, et al. Assessing the Risks Associated with MRI in Patients with a Pacemaker or Defibrillator. N Engl J Med 2017; 376:755. 13. Zuber M, Huber P, Fricker U, et al. Assessment of the subclavian vein in patients with transvenous pacemaker leads. Pacing Clin Electrophysiol 1998; 21:2621. 14. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017; 70:252. 15. Ellenbogen KA, Wood MA, Shepard RK, et al. Detection and management of an implantable cardioverter defibrillator lead failure: incidence and clinical implications. J Am Coll Cardiol 2003; 41:73. 16. Kleemann T, Becker T, Doenges K, et al. Annual rate of transvenous defibrillation lead defects in implantable cardioverter-defibrillators over a period of >10 years. Circulation https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 14/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate 2007; 115:2474. 17. Hauser RG, Kallinen LM, Almquist AK, et al. Early failure of a small-diameter high-voltage implantable cardioverter-defibrillator lead. Heart Rhythm 2007; 4:892. 18. Kallinen LM, Hauser RG, Lee KW, et al. Failure of impedance monitoring to prevent adverse clinical events caused by fracture of a recalled high-voltage implantable cardioverter- defibrillator lead. Heart Rhythm 2008; 5:775. 19. Groves R. Urgent medical device information. Medtronic, Inc. October 15, 2007. 20. Hauser RG, Abdelhadi R, McGriff D, Retel LK. Deaths caused by the failure of Riata and Riata ST implantable cardioverter-defibrillator leads. Heart Rhythm 2012; 9:1227. 21. Slotwiner D, Varma N, Akar JG, et al. HRS Expert Consensus Statement on remote interrogation and monitoring for cardiovascular implantable electronic devices. Heart Rhythm 2015; 12:e69. 22. Kusumoto FM, Schoenfeld MH, Wilkoff BL, et al. 2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction. Heart Rhythm 2017; 14:e503. 23. Gunderson BD, Patel AS, Bounds CA, et al. An algorithm to predict implantable cardioverter- defibrillator lead failure. J Am Coll Cardiol 2004; 44:1898. 24. Swerdlow CD, Gunderson BD, Ousdigian KT, et al. Downloadable algorithm to reduce inappropriate shocks caused by fractures of implantable cardioverter-defibrillator leads. Circulation 2008; 118:2122. 25. Lin G, Nishimura RA, Connolly HM, et al. Severe symptomatic tricuspid valve regurgitation due to permanent pacemaker or implantable cardioverter-defibrillator leads. J Am Coll Cardiol 2005; 45:1672. 26. Chang JD, Manning WJ, Ebrille E, Zimetbaum PJ. Tricuspid Valve Dysfunction Following Pacemaker or Cardioverter-Defibrillator Implantation. J Am Coll Cardiol 2017; 69:2331. 27. Cho MS, Kim J, Lee JB, et al. Incidence and predictors of moderate to severe tricuspid regurgitation after dual-chamber pacemaker implantation. Pacing Clin Electrophysiol 2019; 42:85. 28. Delling FN, Hassan ZK, Piatkowski G, et al. Tricuspid Regurgitation and Mortality in Patients With Transvenous Permanent Pacemaker Leads. Am J Cardiol 2016; 117:988. 29. Eleid MF, Blauwet LA, Cha YM, et al. Bioprosthetic tricuspid valve regurgitation associated with pacemaker or defibrillator lead implantation. J Am Coll Cardiol 2012; 59:813. 30. Epstein AE, Kay GN, Plumb VJ, et al. Gross and microscopic pathological changes associated with nonthoracotomy implantable defibrillator leads. Circulation 1998; 98:1517. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 15/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate 31. Martin DT, John R, Venditti FJ Jr. Increase in defibrillation threshold in non-thoracotomy implantable defibrillators using a biphasic waveform. Am J Cardiol 1995; 76:263. 32. Newman D, Barr A, Greene M, et al. A population-based method for the estimation of defibrillation energy requirements in humans. Assessment of time-dependent effects with a transvenous defibrillation system. Circulation 1997; 96:267. 33. Rashba EJ, Olsovsky MR, Shorofsky SR, et al. Temporal decline in defibrillation thresholds with an active pectoral lead system. J Am Coll Cardiol 2001; 38:1150. 34. Zhou L, Chen BP, Kluger J, et al. Effects of amiodarone and its active metabolite desethylamiodarone on the ventricular defibrillation threshold. J Am Coll Cardiol 1998; 31:1672. 35. Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med 2000; 160:1741. 36. Wilkoff BL, Fauchier L, Stiles MK, et al. 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. Heart Rhythm 2016; 13:e50. 37. Hohnloser SH, Dorian P, Roberts R, et al. Effect of amiodarone and sotalol on ventricular defibrillation threshold: the optimal pharmacological therapy in cardioverter defibrillator patients (OPTIC) trial. Circulation 2006; 114:104. 38. Mittal S, Shaw RE, Michel K, et al. Cardiac implantable electronic device infections: incidence, risk factors, and the effect of the AigisRx antibacterial envelope. Heart Rhythm 2014; 11:595. 39. Kolek MJ, Patel NJ, Clair WK, et al. Efficacy of a Bio-Absorbable Antibacterial Envelope to Prevent Cardiac Implantable Electronic Device Infections in High-Risk Subjects. J Cardiovasc Electrophysiol 2015; 26:1111. 40. Chaara J, Sunthorn H. Twiddler syndrome. J Cardiovasc Electrophysiol 2014; 25:659. 41. Weir RA, Murphy CA, O'Rourke B, Petrie CJ. Twiddler's syndrome: a rare cause of implantable cardioverter defibrillator malfunction. Eur Heart J 2016; 37:3439. 42. Osoro M, Lorson W, Hirsh JB, Mahlow WJ. Use of an antimicrobial pouch/envelope in the treatment of Twiddler's syndrome. Pacing Clin Electrophysiol 2018; 41:136. 43. Gould PA, Gula LJ, Champagne J, et al. Outcome of advisory implantable cardioverter- defibrillator replacement: one-year follow-up. Heart Rhythm 2008; 5:1675. 44. Hauser RG, Hayes DL, Almquist AK, et al. Unexpected ICD pulse generator failure due to electronic circuit damage caused by electrical overstress. 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Long-term outcome after ICD and CRT implantation and influence of remote device follow-up: the ALTITUDE survival study. Circulation 2010; 122:2359. 49. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008; 359:1009. 50. Powell BD, Saxon LA, Boehmer JP, et al. Survival after shock therapy in implantable cardioverter-defibrillator and cardiac resynchronization therapy-defibrillator recipients according to rhythm shocked. The ALTITUDE survival by rhythm study. J Am Coll Cardiol 2013; 62:1674. 51. Gasparini M, Proclemer A, Klersy C, et al. Effect of long-detection interval vs standard- detection interval for implantable cardioverter-defibrillators on antitachycardia pacing and shock delivery: the ADVANCE III randomized clinical trial. JAMA 2013; 309:1903. 52. Moss AJ, Schuger C, Beck CA, et al. Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med 2012; 367:2275. 53. 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Psychological indices and phantom shocks in patients with ICD. J Interv Card Electrophysiol 2006; 15:185. 61. Jacob S, Panaich SS, Zalawadiya SK, et al. Phantom shocks unmasked: clinical data and proposed mechanism of memory reactivation of past traumatic shocks in patients with implantable cardioverter defibrillators. J Interv Card Electrophysiol 2012; 34:205. 62. Ahmad M, Bloomstein L, Roelke M, et al. Patients' attitudes toward implanted defibrillator shocks. Pacing Clin Electrophysiol 2000; 23:934. 63. Herrmann C, von zur M hen F, Schaumann A, et al. Standardized assessment of psychological well-being and quality-of-life in patients with implanted defibrillators. Pacing Clin Electrophysiol 1997; 20:95. 64. Sears SF, Todaro JF, Urizar G, et al. Assessing the psychosocial impact of the ICD: a national survey of implantable cardioverter defibrillator health care providers. Pacing Clin Electrophysiol 2000; 23:939. 65. Burgess ES, Quigley JF, Moran G, et al. Predictors of psychosocial adjustment in patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol 1997; 20:1790. 66. Schron EB, Exner DV, Yao Q, et al. Quality of life in the antiarrhythmics versus implantable defibrillators trial: impact of therapy and influence of adverse symptoms and defibrillator shocks. Circulation 2002; 105:589. 67. Namerow PB, Firth BR, Heywood GM, et al. Quality-of-life six months after CABG surgery in patients randomized to ICD versus no ICD therapy: findings from the CABG Patch Trial. Pacing Clin Electrophysiol 1999; 22:1305. 68. Passman R, Subacius H, Ruo B, et al. Implantable cardioverter defibrillators and quality of life: results from the defibrillators in nonischemic cardiomyopathy treatment evaluation study. Arch Intern Med 2007; 167:2226. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 18/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate 69. Atwater BD, Daubert JP. Implantable cardioverter defibrillators: risks accompany the life- saving benefits. Heart 2012; 98:764. 70. Kamphuis HC, de Leeuw JR, Derksen R, et al. Implantable cardioverter defibrillator recipients: quality of life in recipients with and without ICD shock delivery: a prospective study. Europace 2003; 5:381. 71. Bourke JP, Turkington D, Thomas G, et al. Florid psychopathology in patients receiving shocks from implanted cardioverter-defibrillators. Heart 1997; 78:581. 72. Kohn CS, Petrucci RJ, Baessler C, et al. The effect of psychological intervention on patients' long-term adjustment to the ICD: a prospective study. Pacing Clin Electrophysiol 2000; 23:450. 73. Tchou PJ, Piasecki E, Gutmann M, et al. Psychological support and psychiatric management of patients with automatic implantable cardioverter defibrillators. Int J Psychiatry Med 1989; 19:393. Topic 989 Version 53.0 https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 19/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate GRAPHICS Documented sources of electromagnetic interference (EMI) in patients with implanted cardiac devices Source Examples Electromagnetic fields Daily life* Faulty home appliances Metal detectors Anti-theft equipment Slot machines Cellular phones and accessories with strong magnets (eg, wireless charging, magnetic fasteners) [1] Work and industrial environment High voltage power lines Welding equipment Electronic motors while "on" Induction furnaces Degaussing coils Medical/hospital environment Magnetic resonance imaging Defibrillation or cardioversion Device-device interaction (eg, pacemaker and neural stimulator) Radiofrequency ablation Electrocautery Transcutaneous nerve stimulation Therapeutic diathermy Lithotripsy Radiation therapy There are many potential sources of single-beat inhibition. However, single-beat inhibition is not clinically significant and does not merit specific mention. If working at or near the level of the power line. There is no convincing evidence that being under the power lines at ground level will cause interference. Although all welding equipment is capable of causing interference, it most commonly occurs with equipment that operates at 150 amps. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 20/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate Radiation therapy may cause electromagnetic interference but may also result in direct damage to the pulse generator resulting in sudden no output or "runaway." Reference: 1. Greenberg JC, Altawail MR, Singh G. Life saving therapy inhibition by phones containing magnets. Heart Rhythm; 2021. Reproduced with permission from: Pinski SL, Trohman RG. Interference in implanted cardiac devices, Part I. Pacing Clin Electrophysiol 2002; 25:1367. Copyright 2002 Blackwell Publishing. Graphic 51277 Version 8.0 https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 21/22 7/6/23, 10:48 AM Cardiac implantable electronic devices: Long-term complications - UpToDate Contributor Disclosures Jonathan Piccini, MD, MHS, FACC, FAHA, FHRS Grant/Research/Clinical Trial Support: Abbott [Atrial fibrillation, catheter ablation]; AHA [Atrial fibrillation, cardiovascular disease]; Bayer [Atrial fibrillation]; Boston Scientific [Cardiac mapping, pacemaker/ICD, atrial fibrillation care]; iRhythm [Atrial fibrillation]; NIA [Atrial fibrillation]; Philips [Lead management]. Consultant/Advisory Boards: Abbott [Atrial fibrillation, catheter ablation]; Abbvie [Atrial fibrillation]; Bayer [Atrial fibrillation]; Boston Scientific [Cardiac mapping, atrial fibrillation, pacemaker/ICD]; ElectroPhysiology Frontiers [Atrial fibrillation, catheter ablation]; Element Science [DSMB]; Medtronic [Atrial fibrillation, pacemaker/ICDs]; Milestone [Supraventricular tachycardia]; Pacira [Atrial fibrillation]; Philips [Lead extraction]; ReCor [Cardiac arrhythmias]; Sanofi [Atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-long-term-complications/print 22/22

7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cardiac implantable electronic devices: Patient follow-up : Bradley P Knight, MD, FACC : Samuel L vy, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 24, 2023. INTRODUCTION As more people are living longer with more significant cardiac disease, permanent pacemakers (PPMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy st (CRT) devices are being implanted more frequently. Beginning early in the 21 century, there has also been an expansion in the indications for cardiac implantable electronic devices (CIEDs, a term which includes PPMs, ICDs, and CRT devices, as well as other devices such as insertable cardiac monitors [also sometimes referred to as implantable cardiac monitors or implantable loop recorders]), and device therapy has become more commonplace. Issues related to follow-up of patients with a CIED (PPM, ICD, or CRT devices only) will be reviewed here. The indications for PPM, ICD, and CRT use, as well as general issues related these devices, are discussed separately. (See "Permanent cardiac pacing: Overview of devices and indications" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Implantable cardioverter-defibrillators: Overview of indications, components, and functions" and "Modes of cardiac pacing: Nomenclature and selection".) (See "Permanent cardiac pacing: Overview of devices and indications".) (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 1/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) (See "Modes of cardiac pacing: Nomenclature and selection".) METHODS AND FREQUENCY OF CIED FOLLOW-UP For several decades, follow-up evaluation of cardiac implantable electronic devices (CIEDs) required in-person assessment for device interrogation on a recurring basis. Subsequently, transtelephonic monitoring (TTM) became available for some types of permanent pacemakers (PPMs). Current technology, however, has evolved to enable comprehensive and safe remote monitoring for nearly all types of CIEDs [1-3]. Remote monitoring provides alerts in real-time (or on a daily basis), but is not as comprehensive as a complete device interrogation. A major difference between remote monitoring and an in-person interrogation is that a CIED cannot be adjusted or reprogrammed remotely. The equipment required for remote monitoring, which is proprietary and unique to each manufacturer just as the in-person programmers are, along with requirements (eg, internet connection) and instructions for use, should be discussed with the patient as part of the implantation process. Office-based versus remote follow-up For most patients, the majority of CIED follow-up device interrogations can be done either in person or remotely ( table 1) [3-5]. Following the immediate post-implant check, an initial in-person evaluation (IPE) should occur within weeks to three months post-implantation, and ideally one IPE annually for the duration of therapy with a CIED [6]. With the exception of these initial and annual IPEs, all other CIED follow-up assessments may be done either in person or remotely (if available) ( table 2), an approach consistent with the 2015 Heart Rhythm Society expert consensus statement on the remote device interrogation and monitoring [6]. Remote monitoring is strongly encouraged for patients. Multiple prospective randomized trials have demonstrated the feasibility and safety of remote CIED monitoring as well as identified a greater number of clinically significant issues and shortened the time to clinical action [7-15]. Multiple nonrandomized observational studies have suggested improved survival for patients with remote CIED monitoring; however, this has not been universally replicated in prospective randomized trials [16-18]. In a 2015 systematic review and meta-analysis of nine randomized trials involving 6469 ICD recipients who were randomized to either remote monitoring (3496 patients) or in-office follow-up (2973 patients), patients assigned to remote monitoring had nonsignificant reductions in total mortality (odds ratio [OR] 0.83; 95% CI 0.58-1.17), cardiovascular mortality (OR 0.66; 95% CI 0.41-1.09), and hospitalizations (OR 0.83; 95% CI 0.63- 1.10) along with significantly fewer inappropriate shocks (OR 0.55; 95% CI 0.38-0.80) [19]. Further evidence of improvements in mortality was seen in a 2017 analysis using patient-level data from https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 2/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate only three of the nine randomized trials included in the 2015 meta-analysis (IN-TIME, ECOST, and TRUST) [7,11,13], in which the absolute risk of overall mortality was reduced by 1.9 percent (95% CI 0.1-3.8 percent) [20]. In the 2019 RM-ALONE trial, which included 445 patients with CIEDs (151 ICDs and 294 PPMs including 54 percent pacemaker-dependent patients), participants were randomized to in-office device interrogation or remote device interrogation every six months; all patients in both groups were remotely monitored with daily transmission of alerts with unscheduled office visits at the provider's discretion following an alert [21]. Over a mean follow-up of 21 months, there was no significant difference between the two groups in major adverse cardiac events (20 percent in each group). More patients in the remote interrogation group had an unscheduled office visit (55 percent versus 45 percent of office interrogation patients); however, the remote interrogation group had 79 percent fewer total office visits (136 versus 653 in the office interrogation group). Overall, a strategy of remote-only device monitoring and interrogation appears to be as safe and efficacious as a strategy that includes twice yearly in-office visits. Important limitations include the relatively small sample size and the absence of CRT devices. Additional data from a multi-center randomized trial of remote-only versus periodic IPE, published after the RM-ALONE trial, suggest that remote-only follow-up for up to two years is safe and associated with significantly fewer office visits [22]. While most patients find remote follow-up more convenient, some may find in-office follow-up preferable for a variety of reasons (eg, the desire to be seen in-person more frequently for reassurance, social interaction, etc). With this in mind, the approach to CIED follow-up must be tailored to each individual patient. At present, standard practice continues to include at least an annual office visit, which is felt to be adequate for most patients. (See 'Frequency of CIED follow- up visits' below.) In some instances, an IPE may be associated with significant risks to patients and healthcare providers. For example, during the COVID-19 pandemic, when the risk of viral transmission was very high, it was recommended by experts to substitute IPEs with remote checks. In April of 2020, the Heart Rhythm Society COVID-19 Task Force recommended that every effort be made to perform CIED interrogation via remote monitoring rather than via IPE [23]. The recommendations stated that IPEs for CIEDs should be limited to potentially hazardous lead or generator issues not adequately assessed by remote monitoring, absolute need for reprogramming, or other issues per physician judgment. A creative response to the COVID-19 pandemic was the creation of drive-through pacing clinics [24]. Frequency of CIED follow-up visits The frequency of follow-up visits for patients with a CIED will vary according to the type of device, age of the device, and clinical status of the patient https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 3/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate ( table 2) [4,5]. In general, however, most patients with a CIED should have an annual IPE, with one or more additional follow-up assessments (either remotely or in-person) throughout the year. Patients who have received therapies (eg, ICD shocks or antitachycardia pacing), as well as those whose devices are approaching the end of battery life, may require more frequent follow- up. Furthermore, patients with advisory generators and/or leads may require more frequent follow-up, or additional testing (eg, lead fluoroscopy) during follow-up. Patients who have an ICD which was placed for primary prevention may require less frequent follow-up. In the REFORM trial of 155 patients receiving a primary prevention ICD based on MADIT II criteria, patients were randomized (following a routine 3-month post-implant visit in all patients) to either 3-month or 12-month follow-up intervals and followed for 24 months [25]. Patients in the 12-month interval group had significantly fewer in-office follow-up visits (1.6 versus 3.9 visits per year), with no significant differences in mortality or hospitalization. While these findings are encouraging regarding the potential for reduced frequency of follow-up in stable recipients of primary prevention ICDs, our recommendations for follow-up will remain unchanged until these data are replicated in other larger patient populations and/or until professional societies alter follow-up guidelines. (See 'Summary and recommendations' below.) FOLLOW-UP OF THE PATIENT WITH A PACEMAKER All patients with a permanent pacemaker (PPM) require routine follow-up on a periodic basis. Both office-based and remote follow-up strategies are available, safe, and effective for monitoring of PPM function ( table 1). For most stable patients with a PPM, follow-up should occur every three to four months ( table 2). However, the frequency of these follow-up visits may increase in certain clinical situations (eg, device nearing battery depletion or a suspected device infection). PPM evaluation Whether the system involves a single-chamber or dual-chamber pacemaker, the evaluation is similar. Device interrogation includes the evaluation of several aspects of device function (see "Pacing system malfunction: Evaluation and management"): Assessment of the presenting and underlying rhythms Programmed pacing parameters Pacing and sensing thresholds and lead impedance Evaluation of pacing capture Review of recorded episodes of arrhythmia detection, if the device is capable of storing these data Review of battery status and estimation of time until the pulse generator must be replaced https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 4/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate Review of all additional data collected Establish programmed parameters Interrogate the pacemaker so that the programmed parameters as well as measured data of lead and battery function are obtained. Evaluate capture To evaluate capture, the paced electrocardiogram (ECG) should be carefully examined. Contemporary pacemakers have automatic pacing threshold testing algorithms. The following points may be helpful when there is difficulty interpreting the auto- threshold tracings or when capture thresholds are determined manually. If the native rate is faster than the paced rate, thereby inhibiting the system, the rate and/or atrioventricular (AV) interval should be reprogrammed so that stimuli are visible. Capture is intact if there is a distinct change in the morphology of the QRS or P wave that follows each stimulus and if this morphology is stable and different from the native complexes. If this is not seen, there is noncapture, and the differential diagnosis for failure to capture should be considered. (See "Pacing system malfunction: Evaluation and management", section on 'Causes of loss of capture'.) If initial evaluation shows a pacing stimulus that is simultaneous with the native QRS complex, changing the rate and AV intervals will be helpful to distinguish capture from fusion. It may be necessary to assess the capture threshold by adjusting the output and demonstrating loss of capture before it is certain that capture was intact on the initial tracings. If there is loss of capture, one should also consider whether this is true failure to capture or functional loss of capture (ie, failure to sense a native QRS complex followed by the release of the pacing stimulus at a time when the myocardium is physiologically refractory and incapable of being stimulated). Evaluate sensing To evaluate sensing, intrinsic complexes must be present. Most contemporary pacemakers have automatic sensing threshold testing algorithms. Similar to capture determination, the following points may be helpful when there is difficulty interpreting the automatic sensing determination or when sensing thresholds are determined manually. If the rhythm is totally paced, the paced rate can be decreased, the AV delay increased, or the unit programmed to a non-tracking mode in order to evaluate ventricular sensing. If the system is then inhibited and the native rhythm appears, sensing is intact. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 5/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate To evaluate atrial sensing, it may be necessary to reduce the base pacing rate and shorten the AV interval. This will result in P wave tracking in the presence of in-tact atrial sensing. If sensing is not present or consistent, the etiology should be evaluated and appropriate corrective actions taken. Event markers Event markers are indicators of pacing and sensing reported directly by the pacemaker. However, the fact that the pacemaker released an output pulse does not mean that the pacing stimulus effectively captured the heart muscle and resulted in a depolarization. In addition, the fact that the system reports that it sensed an event does not mean that this was an appropriate complex to be sensed. Thus, the event markers need to be correlated with the surface ECG recordings and/or intracardiac electrogram, and are most valuable when the event markers are printed along with a simultaneously recorded surface ECG or intracardiac electrogram. A sense marker coinciding with a native P or R wave confirms proper sensing, unless there is a P marker over a native R wave or vice versa, in which case there may be a problem such as a dislodged atrial lead, inappropriate connection of the atrial and ventricular leads into the pulse generator, or far-field sensing. If the event markers indicated that the pacemaker is sensing an event that is not visible on the surface ECG, further evaluation is required. Electrogram assessment Endocardial electrograms can be particularly helpful in examining the morphology of the native complexes to determine capture as well as why a given signal may not have been sensed. It is also useful in examining the signals that are being sensed when these are not readily identified from the surface ECG. Electrogram telemetry will greatly facilitate the evaluation, allowing it to be completed more expeditiously and provide information that may not be easily acquired. FOLLOW-UP OF THE PATIENT WITH AN ICD All patients with an implantable cardioverter-defibrillator (ICD) require routine follow-up on a periodic basis as well as semi-urgent or urgent follow-up after receiving a shock from the ICD ( table 2). Both office-based and remote follow-up strategies are available, safe, and effective for monitoring of ICD function ( table 1) [6]. For most stable patients with an ICD who have not received a shock, follow-up should occur every three months. For most visits, follow-up may be in person or remote (if available) according to local protocol, but at least one follow-up per year should be an IPE. However, the frequency of these follow-up visits may increase in certain clinical situations https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 6/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate (eg, device nearing end of battery life or a CIED or lead that has been placed on a medical advisory). (See 'Routine ICD follow-up' below.) Patients with an ICD who have received a single ICD shock and who otherwise feel well should have follow-up within 24 to 48 hours. This follow-up may be done in person or remotely (if available). Patients who receive multiple ICD shocks within a short period of time (minutes to hours), or the patient who receives a single shock and feels unwell, require more urgent evaluation. (See 'Follow-up after ICD discharge' below.) Routine ICD follow-up Device interrogation and a detailed review of device function should be performed with each visit [26]. Monitoring for evidence of device complications should also be performed. (See "Cardiac implantable electronic devices: Long-term complications", section on 'Pulse generator complications' and "Cardiac implantable electronic devices: Long-term complications".) Device interrogation includes the evaluation of several aspects of device function: Programmed detection criteria and programmed therapy for ventricular tachycardia and fibrillation (VT and VF). Pacing and sensing thresholds. Pacing and shocking lead impedance. Signal amplitudes and morphologies. Review of recorded episodes of arrhythmia detection and device activation, including pacing and shocks. Current devices include the date and time of each episode and store the electrograms from the event. In systems containing an atrial lead, review of diagnostic information regarding atrial arrhythmias. Review of battery status and estimation of time until the pulse generator must be replaced. Review of all additional data collected DFT testing as part of routine ICD follow-up In the past, many centers did defibrillation threshold (DFT) testing at the time of initial implant and at some periodic basis during follow-up. However, the induction and termination of a ventricular tachyarrhythmia has potential complications, is unpleasant for the patient, and adds additional cost, with a benefit to the patient that has not been proven. Although DFT testing at the time of the initial implant remains somewhat controversial, we do not recommend performing DFT testing as part of routine follow-up. The need for routine DFT testing has been assessed in large randomized clinical trials [27,28]. Both the SAFE-ICD and SIMPLE trials demonstrated that DFT testing does not improve shock https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 7/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate efficacy or reduce arrhythmic death. Follow-up after ICD discharge Patients who receive one or more shocks from their ICD require review of the episode and either remote or in-clinic follow-up depending on the clinical situation and the institutional guidelines. The timing and urgency of the follow-up varies according to the clinical scenario: Patients who receive a single ICD shock without loss of consciousness should have office- based or remote follow-up within 24 to 48 hours. If remote review of the data reveals a single appropriate ICD shock and the patient is feeling well, an IPE may not be required. However, if neither office-based nor remote follow-up is available for longer than 24 to 48 hours, the patient may need to be seen in the emergency department. For patients who receive a single ICD shock with loss of consciousness or near syncope, the decision as to whether the patient needs to be seen in clinic or in the emergency department will vary according to the clinical situation and the guidelines followed by a specific follow-up center. If a patient has a single appropriate shock as determined by review of remote data, or if the patient is feeling well and was not injured with loss of consciousness, some centers may not recommend a face-to-face visit. If the clinical situation is uncertain and/or if the patient is concerned or has been injured during the loss of consciousness, then the patient should be seen in the clinic or emergency department. Patients who receive multiple ICD shocks within a short period of time (minutes to hours) should have more urgent evaluation in the emergency department. Patients who are seen in the emergency department should all have a brief history and physical examination, 12- lead electrocardiogram (ECG), and additional laboratory testing as the clinical presentation dictates: Troponin level in a patient with suspected acute myocardial ischemia Potassium and magnesium in a patient with suspected electrolyte depletion Toxin screen in a patient with suspected intentional or inadvertent drug overdose Because ICDs are placed in patients felt to be at an increased risk of ventricular arrhythmias or sudden cardiac death, ICD discharge is an anticipated event during the long-term follow-up of such patients. Because a single ICD shock frequently represents the appropriate termination of a sustained ventricular tachyarrhythmia, patients who receive only a single ICD shock without loss of consciousness may have follow-up (either office-based or remotely) within 24 to 48 hours to ascertain that the device is functioning properly, to exclude other causes of the ICD shock (eg, supraventricular tachyarrhythmias, device malfunction) and to provide patient reassurance. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 8/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate Even though a single ICD shock often represents the appropriate termination of a sustained ventricular tachyarrhythmia, ICD discharges that are accompanied by loss of consciousness or near syncope should be promptly reviewed. These patients may need to have programming changes or, in the event of injury related to syncope, more immediate follow-up, usually in the clinic or the emergency department. Patients who receive multiple ICD shocks or clusters of shocks within minutes to hours require immediate evaluation in the emergency department to determine the cause. Such recurrent discharges may be either appropriate (due to recurrent VT and electrical storm) or inappropriate (due to a supraventricular tachycardia with a rapid rate, or to device malfunction). If frequent discharges are due to recurrent VT and electrical storm, additional therapy (such as an antiarrhythmic drug or catheter ablation) may be required. These therapies are discussed in detail elsewhere. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Other treatment options' and "Electrical storm and incessant ventricular tachycardia".) Prognosis following ICD shocks Several clinical trials have shown that patients who receive appropriate ICD therapy have a higher mortality than patients who do not. In the SCD-HeFT trial, both appropriate and inappropriate ICD therapy were associated with a higher mortality during follow-up [29]. The delivery of therapy by an ICD, therefore, should prompt clinicians to re- evaluate the patient's overall clinical status and therapeutic plan. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Driving following ICD shocks Guidelines for driving following ICD shocks have been developed by professional societies [30,31]. Legal restrictions on driving in such patients vary widely between municipalities, and each clinician and patient should be aware of his/her own local guidelines. A more extensive discussion of driving restrictions in patients with an ICD is presented separately. (See "Driving restrictions in patients with an implantable cardioverter-defibrillator".) FOLLOW-UP OF THE PATIENT WITH A CRT DEVICE Cardiac resynchronization therapy (CRT) is a device-based therapy which involves simultaneous pacing of both ventricles (biventricular or BiV pacing) or left ventricular pacing in an effort to optimize cardiac synchrony and function. CRT may involve pacing only (CRT-P) or may be combined with the typically therapeutic functions of an ICD (CRT-D). https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 9/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate All patients with a CRT device (either CRT-P or CRT-D) require routine follow-up on a periodic basis, and patients with a CRT-D device require semi-urgent or urgent follow-up after receiving one or more shocks from the ICD ( table 2). Both office-based and remote follow-up strategies are available, safe, and effective for monitoring of CRT function ( table 1). In general, the protocol for follow-up evaluation for CRT-P or CRT-D devices is similar to that for standard PPMs or ICDs. For most stable patients with a CRT-P (or CRT-D device with no ICD shocks), follow-up should occur every three to four months. For most visits, follow-up may be in person or remote (if available) according to local protocol, but at least one follow-up per year should be an IPE. However, the frequency of these follow-up visits may increase in certain clinical situations (eg, device nearing battery depletion or a suspected device infection). (See 'PPM evaluation' above and 'Routine ICD follow-up' above.) Patients with a CRT-D device who have received a single ICD shock should have follow-up within 24 to 48 hours. This follow-up may be done in person or remotely (if available). Patients who receive multiple ICD shocks within a short period of time (minutes to hours) require more urgent evaluation. (See 'Follow-up after ICD discharge' above.) The optimal approach to programming CRT devices is discussed in greater detail separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Concerns have been raised regarding the potential for cyber interference with CIEDs. Generally, this has not been shown to be a clinical concern. However, manufacturers are exploring ways to better protect devices from any hacking potential [32-34]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 10/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Sudden cardiac arrest (The Basics)") Beyond the Basics topic (see "Patient education: Implantable cardioverter-defibrillators (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS The frequency of follow-up visits for patients with a cardiac implantable electronic device (CIED) will vary according to the type of device, age of the device, and clinical status of the patient ( table 2). Follow-up after pacemaker For most stable patients with a permanent pacemaker (PPM), follow-up should occur every three to four months. (See 'Follow-up of the patient with a pacemaker' above.) Follow-up after implantable cardioverter-defibrillator (ICD) For most stable patients with an ICD who have not received a shock, follow-up should occur every three months. (See 'Follow-up of the patient with an ICD' above.) Frequency of visits For stable patients with either a PPM or ICD, follow-up may be in person or remote (if available) according to local protocol, but at least one follow-up per year should be an in-person evaluation (IPE) ( table 1). The frequency of these follow-up visits may increase in certain clinical situations (eg, device nearing end of battery life or a suspected device infection). (See 'Follow-up of the patient with a pacemaker' above and 'Routine ICD follow-up' above.) Follow-up post-ICD shock Single shock Patients who receive a single ICD shock without loss of consciousness, and who otherwise feel well, should have office-based or remote follow-up within 24 to 48 hours. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 11/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate If remote review of the data reveals a single appropriate ICD shock and the patient is feeling well, an IPE may not be required. However, if neither office-based nor remote follow-up is available for longer than 24 to 48 hours, the patient may need to be seen in the emergency department. If the clinical situation is uncertain and/or if the patient is concerned or has been injured during the loss of consciousness, then the patient should be seen in the clinic or emergency department. Multiple shocks Patients who receive multiple ICD shocks within a short period of time (minutes to hours), or the patient who receives a single shock and feels unwell, should have more urgent evaluation in the emergency department. Patients who are seen in the emergency department should all have a brief history and physical examination, 12-lead electrocardiogram, and additional laboratory testing as the clinical presentation dictates. (See "Cardiac implantable electronic devices: Long-term complications".) ACKNOWLEDGMENT The UpToDate editorial staff thank David L. Hayes, MD, and Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. The author would like to thank Carrie Baumann-Matta, RN, for valuable input on this review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lampert R. Managing with pacemakers and implantable cardioverter defibrillators. Circulation 2013; 128:1576. 2. Al-Khatib SM, Friedman P, Ellenbogen KA. Defibrillators: Selecting the Right Device for the Right Patient. Circulation 2016; 134:1390. 3. Ploux S, Varma N, Strik M, et al. Optimizing implantable cardioverter-defibrillator remote monitoring: a practical guide. J Am Coll Cardiol EP 2017; 3:315. 4. Dubner S, Auricchio A, Steinberg JS, et al. ISHNE/EHRA expert consensus on remote monitoring of cardiovascular implantable electronic devices (CIEDs). Europace 2012; 14:278. 5. Wilkoff BL, Auricchio A, Brugada J, et al. HRS/EHRA expert consensus on the monitoring of cardiovascular implantable electronic devices (CIEDs): description of techniques, indications, https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 12/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate personnel, frequency and ethical considerations. Heart Rhythm 2008; 5:907. 6. Slotwiner D, Varma N, Akar JG, et al. HRS Expert Consensus Statement on remote interrogation and monitoring for cardiovascular implantable electronic devices. Heart Rhythm 2015; 12:e69. 7. Gu don-Moreau L, Lacroix D, Sadoul N, et al. A randomized study of remote follow-up of implantable cardioverter defibrillators: safety and efficacy report of the ECOST trial. Eur Heart J 2013; 34:605. 8. Mabo P, Victor F, Bazin P, et al. A randomized trial of long-term remote monitoring of pacemaker recipients (the COMPAS trial). Eur Heart J 2012; 33:1105. 9. Crossley GH, Chen J, Choucair W, et al. Clinical benefits of remote versus transtelephonic monitoring of implanted pacemakers. J Am Coll Cardiol 2009; 54:2012. 10. Crossley GH, Boyle A, Vitense H, et al. The CONNECT (Clinical Evaluation of Remote Notification to Reduce Time to Clinical Decision) trial: the value of wireless remote monitoring with automatic clinician alerts. J Am Coll Cardiol 2011; 57:1181. 11. Varma N, Epstein AE, Irimpen A, et al. Efficacy and safety of automatic remote monitoring for implantable cardioverter-defibrillator follow-up: the Lumos-T Safely Reduces Routine Office Device Follow-up (TRUST) trial. Circulation 2010; 122:325. 12. Gu don-Moreau L, Kouakam C, Klug D, et al. Decreased delivery of inappropriate shocks achieved by remote monitoring of ICD: a substudy of the ECOST trial. J Cardiovasc Electrophysiol 2014; 25:763. 13. Hindricks G, Taborsky M, Glikson M, et al. Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial. Lancet 2014; 384:583. 14. Al-Khatib SM, Piccini JP, Knight D, et al. Remote monitoring of implantable cardioverter defibrillators versus quarterly device interrogations in clinic: results from a randomized pilot clinical trial. J Cardiovasc Electrophysiol 2010; 21:545. 15. Landolina M, Perego GB, Lunati M, et al. Remote monitoring reduces healthcare use and improves quality of care in heart failure patients with implantable defibrillators: the evolution of management strategies of heart failure patients with implantable defibrillators (EVOLVO) study. Circulation 2012; 125:2985. 16. Saxon LA, Hayes DL, Gilliam FR, et al. Long-term outcome after ICD and CRT implantation and influence of remote device follow-up: the ALTITUDE survival study. Circulation 2010; 122:2359. 17. Akar JG, Bao H, Jones PW, et al. Use of Remote Monitoring Is Associated With Lower Risk of Adverse Outcomes Among Patients With Implanted Cardiac Defibrillators. Circ Arrhythm https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 13/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate Electrophysiol 2015; 8:1173. 18. Varma N, Piccini JP, Snell J, et al. The Relationship Between Level of Adherence to Automatic Wireless Remote Monitoring and Survival in Pacemaker and Defibrillator Patients. J Am Coll Cardiol 2015; 65:2601. 19. Parthiban N, Esterman A, Mahajan R, et al. Remote Monitoring of Implantable Cardioverter- Defibrillators: A Systematic Review and Meta-Analysis of Clinical Outcomes. J Am Coll Cardiol 2015; 65:2591. 20. Hindricks G, Varma N, Kacet S, et al. Daily remote monitoring of implantable cardioverter- defibrillators: insights from the pooled patient-level data from three randomized controlled trials (IN-TIME, ECOST, TRUST). Eur Heart J 2017; 38:1749. 21. Garc a-Fern ndez FJ, Osca Asensi J, Romero R, et al. Safety and efficiency of a common and simplified protocol for pacemaker and defibrillator surveillance based on remote monitoring only: a long-term randomized trial (RM-ALONE). Eur Heart J 2019; 40:1837. 22. Watanabe E, Yamazaki F, Goto T, et al. Remote Management of Pacemaker Patients With Biennial In-Clinic Evaluation: Continuous Home Monitoring in the Japanese At-Home Study: A Randomized Clinical Trial. Circ Arrhythm Electrophysiol 2020; 13:e007734. 23. Heart Rhythm Society COVID-19 Task Force Update. Management of cardiac implantable ele ctronic devices (CIED). 2020. https://www.hrsonline.org/COVID19-Challenges-Solutions/hrs-c ovid-19-task-force-update-april-15-2020 (Accessed on December 13, 2022). 24. Akhtar Z, Montalbano N, Leung LWM, et al. Drive-Through Pacing Clinic: A Popular Response to the COVID-19 Pandemic. JACC Clin Electrophysiol 2021; 7:128. 25. Hindricks G, Elsner C, Piorkowski C, et al. Quarterly vs. yearly clinical follow-up of remotely monitored recipients of prophylactic implantable cardioverter-defibrillators: results of the REFORM trial. Eur Heart J 2014; 35:98. 26. Winters SL, Packer DL, Marchlinski FE, et al. Consensus statement on indications, guidelines for use, and recommendations for follow-up of implantable cardioverter defibrillators. North American Society of Electrophysiology and Pacing. Pacing Clin Electrophysiol 2001; 24:262. 27. Brignole M, Occhetta E, Bongiorni MG, et al. Clinical evaluation of defibrillation testing in an unselected population of 2,120 consecutive patients undergoing first implantable cardioverter-defibrillator implant. J Am Coll Cardiol 2012; 60:981. 28. Healey JS, Hohnloser SH, Glikson M, et al. Cardioverter defibrillator implantation without induction of ventricular fibrillation: a single-blind, non-inferiority, randomised controlled trial (SIMPLE). Lancet 2015; 385:785. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 14/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate 29. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008; 359:1009. 30. Bleakley JF, Akiyama T, Canadian Cardiovascular Society, et al. Driving and arrhythmias: implications of new data. Card Electrophysiol Rev 2003; 7:77. 31. Task force members, Vijgen J, Botto G, et al. Consensus statement of the European Heart Rhythm Association: updated recommendations for driving by patients with implantable cardioverter defibrillators. Europace 2009; 11:1097. 32. Ransford B, Kramer DB, Foo Kune D, et al. Cybersecurity and medical devices: A practical guide for cardiac electrophysiologists. Pacing Clin Electrophysiol 2017; 40:913. 33. Kramer DB, Fu K. Cybersecurity Concerns and Medical Devices: Lessons From a Pacemaker Advisory. JAMA 2017; 318:2077. 34. Pycroft L, Aziz TZ. Security of implantable medical devices with wireless connections: The dangers of cyber-attacks. Expert Rev Med Devices 2018; 15:403. Topic 1015 Version 39.0 https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 15/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate GRAPHICS

Baumann-Matta, RN, for valuable input on this review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lampert R. Managing with pacemakers and implantable cardioverter defibrillators. Circulation 2013; 128:1576. 2. Al-Khatib SM, Friedman P, Ellenbogen KA. Defibrillators: Selecting the Right Device for the Right Patient. Circulation 2016; 134:1390. 3. Ploux S, Varma N, Strik M, et al. Optimizing implantable cardioverter-defibrillator remote monitoring: a practical guide. J Am Coll Cardiol EP 2017; 3:315. 4. Dubner S, Auricchio A, Steinberg JS, et al. ISHNE/EHRA expert consensus on remote monitoring of cardiovascular implantable electronic devices (CIEDs). Europace 2012; 14:278. 5. Wilkoff BL, Auricchio A, Brugada J, et al. HRS/EHRA expert consensus on the monitoring of cardiovascular implantable electronic devices (CIEDs): description of techniques, indications, https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 12/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate personnel, frequency and ethical considerations. Heart Rhythm 2008; 5:907. 6. Slotwiner D, Varma N, Akar JG, et al. HRS Expert Consensus Statement on remote interrogation and monitoring for cardiovascular implantable electronic devices. Heart Rhythm 2015; 12:e69. 7. Gu don-Moreau L, Lacroix D, Sadoul N, et al. A randomized study of remote follow-up of implantable cardioverter defibrillators: safety and efficacy report of the ECOST trial. Eur Heart J 2013; 34:605. 8. Mabo P, Victor F, Bazin P, et al. A randomized trial of long-term remote monitoring of pacemaker recipients (the COMPAS trial). Eur Heart J 2012; 33:1105. 9. Crossley GH, Chen J, Choucair W, et al. Clinical benefits of remote versus transtelephonic monitoring of implanted pacemakers. J Am Coll Cardiol 2009; 54:2012. 10. Crossley GH, Boyle A, Vitense H, et al. The CONNECT (Clinical Evaluation of Remote Notification to Reduce Time to Clinical Decision) trial: the value of wireless remote monitoring with automatic clinician alerts. J Am Coll Cardiol 2011; 57:1181. 11. Varma N, Epstein AE, Irimpen A, et al. Efficacy and safety of automatic remote monitoring for implantable cardioverter-defibrillator follow-up: the Lumos-T Safely Reduces Routine Office Device Follow-up (TRUST) trial. Circulation 2010; 122:325. 12. Gu don-Moreau L, Kouakam C, Klug D, et al. Decreased delivery of inappropriate shocks achieved by remote monitoring of ICD: a substudy of the ECOST trial. J Cardiovasc Electrophysiol 2014; 25:763. 13. Hindricks G, Taborsky M, Glikson M, et al. Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial. Lancet 2014; 384:583. 14. Al-Khatib SM, Piccini JP, Knight D, et al. Remote monitoring of implantable cardioverter defibrillators versus quarterly device interrogations in clinic: results from a randomized pilot clinical trial. J Cardiovasc Electrophysiol 2010; 21:545. 15. Landolina M, Perego GB, Lunati M, et al. Remote monitoring reduces healthcare use and improves quality of care in heart failure patients with implantable defibrillators: the evolution of management strategies of heart failure patients with implantable defibrillators (EVOLVO) study. Circulation 2012; 125:2985. 16. Saxon LA, Hayes DL, Gilliam FR, et al. Long-term outcome after ICD and CRT implantation and influence of remote device follow-up: the ALTITUDE survival study. Circulation 2010; 122:2359. 17. Akar JG, Bao H, Jones PW, et al. Use of Remote Monitoring Is Associated With Lower Risk of Adverse Outcomes Among Patients With Implanted Cardiac Defibrillators. Circ Arrhythm https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 13/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate Electrophysiol 2015; 8:1173. 18. Varma N, Piccini JP, Snell J, et al. The Relationship Between Level of Adherence to Automatic Wireless Remote Monitoring and Survival in Pacemaker and Defibrillator Patients. J Am Coll Cardiol 2015; 65:2601. 19. Parthiban N, Esterman A, Mahajan R, et al. Remote Monitoring of Implantable Cardioverter- Defibrillators: A Systematic Review and Meta-Analysis of Clinical Outcomes. J Am Coll Cardiol 2015; 65:2591. 20. Hindricks G, Varma N, Kacet S, et al. Daily remote monitoring of implantable cardioverter- defibrillators: insights from the pooled patient-level data from three randomized controlled trials (IN-TIME, ECOST, TRUST). Eur Heart J 2017; 38:1749. 21. Garc a-Fern ndez FJ, Osca Asensi J, Romero R, et al. Safety and efficiency of a common and simplified protocol for pacemaker and defibrillator surveillance based on remote monitoring only: a long-term randomized trial (RM-ALONE). Eur Heart J 2019; 40:1837. 22. Watanabe E, Yamazaki F, Goto T, et al. Remote Management of Pacemaker Patients With Biennial In-Clinic Evaluation: Continuous Home Monitoring in the Japanese At-Home Study: A Randomized Clinical Trial. Circ Arrhythm Electrophysiol 2020; 13:e007734. 23. Heart Rhythm Society COVID-19 Task Force Update. Management of cardiac implantable ele ctronic devices (CIED). 2020. https://www.hrsonline.org/COVID19-Challenges-Solutions/hrs-c ovid-19-task-force-update-april-15-2020 (Accessed on December 13, 2022). 24. Akhtar Z, Montalbano N, Leung LWM, et al. Drive-Through Pacing Clinic: A Popular Response to the COVID-19 Pandemic. JACC Clin Electrophysiol 2021; 7:128. 25. Hindricks G, Elsner C, Piorkowski C, et al. Quarterly vs. yearly clinical follow-up of remotely monitored recipients of prophylactic implantable cardioverter-defibrillators: results of the REFORM trial. Eur Heart J 2014; 35:98. 26. Winters SL, Packer DL, Marchlinski FE, et al. Consensus statement on indications, guidelines for use, and recommendations for follow-up of implantable cardioverter defibrillators. North American Society of Electrophysiology and Pacing. Pacing Clin Electrophysiol 2001; 24:262. 27. Brignole M, Occhetta E, Bongiorni MG, et al. Clinical evaluation of defibrillation testing in an unselected population of 2,120 consecutive patients undergoing first implantable cardioverter-defibrillator implant. J Am Coll Cardiol 2012; 60:981. 28. Healey JS, Hohnloser SH, Glikson M, et al. Cardioverter defibrillator implantation without induction of ventricular fibrillation: a single-blind, non-inferiority, randomised controlled trial (SIMPLE). Lancet 2015; 385:785. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 14/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate 29. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008; 359:1009. 30. Bleakley JF, Akiyama T, Canadian Cardiovascular Society, et al. Driving and arrhythmias: implications of new data. Card Electrophysiol Rev 2003; 7:77. 31. Task force members, Vijgen J, Botto G, et al. Consensus statement of the European Heart Rhythm Association: updated recommendations for driving by patients with implantable cardioverter defibrillators. Europace 2009; 11:1097. 32. Ransford B, Kramer DB, Foo Kune D, et al. Cybersecurity and medical devices: A practical guide for cardiac electrophysiologists. Pacing Clin Electrophysiol 2017; 40:913. 33. Kramer DB, Fu K. Cybersecurity Concerns and Medical Devices: Lessons From a Pacemaker Advisory. JAMA 2017; 318:2077. 34. Pycroft L, Aziz TZ. Security of implantable medical devices with wireless connections: The dangers of cyber-attacks. Expert Rev Med Devices 2018; 15:403. Topic 1015 Version 39.0 https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 15/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate GRAPHICS Remote monitoring recommendations for cardiac implantable electronic devices (CIEDs) Class of recommendation Level of evidence Device follow-up paradigm A strategy of remote CIED monitoring and interrogation, combined with at least annual in-person examination, is recommended over a calendar-based schedule of in-person CIED evaluation alone (when technically feasible). I A All patients with CIEDs should be offered RM as part of the standard follow-up management strategy. I A Before implementing RM, it is recommended that each patient be educated about the nature of RM, their responsibilities and expectations, potential benefits, and limitations. The I E occurrence of this discussion should be documented in the medical record. It is recommended that all CIEDs be checked through direct patient contact 2 to 12 weeks postimplantation. I E It may be beneficial to initiate RM within the two weeks of CIED implantation. IIa C All patients with an implantable loop recorder with wireless data transfer capability should be enrolled in an RM program, given the daily availability of diagnostic data. I E It is recommended that allied health care professionals responsible for interpreting RM transmissions and who are involved in subsequent patient management decisions have the same qualifications as those performing in-clinic I E assessments and should ideally possess IBHRE certification for device follow-up or equivalent experience. It is recommended that RM programs develop and document appropriate policies and procedures to govern program operations, the roles and responsibilities of those involved in the program, and the expected timelines for providing service. I E CIED: cardiac implantable electronic device; HRS: Heart Rhythm Society; IBHRE: International Board of Heart Rhythm Examiners; RM: remote monitoring. Reproduced from: Slotwiner D, Varma N, Akar JG, et al. HRS Expert Consensus Statement on remote interrogation and monitoring for cardiovascular implantable electronic devices. Heart Rhythm 2015; 12:e69. Illustration used with the https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 16/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate permission of Elsevier Inc. All rights reserved. Graphic 108755 Version 1.0 https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 17/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate Minimum frequency of cardiac implantable electronic device (CIED) follow- up Type Frequency Delivery method Immediate post-implant check Within 72 hours In person Early post-implant check 2 to 12 weeks In person Routine PPM/CRT-PPM check Every 3 to 12 months In person or remote Routine ICD/CRT-D Every 3 to 6 months In person or remote Following one ICD/CRT-D shock Within 24 to 48 hours In person or remote Following >1 ICD/CRT-D shocks Immediately In person Any CIED until signs of battery depletion Annually In person Any CIED following signs of battery depletion Every 1 to 3 months In person or remote CIED: cardiac implantable electronic device; CRT: cardiac resynchronization therapy; ICD: implantable cardioverter-defibrillator; PPM: permanent pacemaker. Adapted from: Wilko BL, Auricchio A, Brugada J, et al. HRS/EHRA expert consensus on the monitoring of cardiovascular implantable electronic devices (CIEDs): description of techniques, indications, personnel, frequency and ethical considerations. Heart Rhythm 2008; 5:907. Graphic 91502 Version 3.0 https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 18/19 7/6/23, 10:48 AM Cardiac implantable electronic devices: Patient follow-up - UpToDate Contributor Disclosures Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-patient-follow-up/print 19/19

7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cardiac implantable electronic devices: Periprocedural complications : Kevin F Kwaku, MD, PhD : Jonathan Piccini, MD, MHS, FACC, FAHA, FHRS : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 22, 2023. INTRODUCTION As more people are living longer with more significant cardiac disease, the number of permanent pacemakers (PPMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices in clinical practice continues to increase. Beginning early st in the 21 century, there has also been an expansion in the indications for cardiac implantable electronic devices (CIED, a term that includes PPMs, ICDs, insertable [or implantable] cardiac [or loop] monitors [ICMs]) and intravascular devices such as pulmonary artery pressure monitors (eg, Cardiomems), resulting in device therapy becoming more complex and more prolonged over the patient's lifetime. As such, therapy with a CIED frequently involves multiple leads and multiple pulse generators per patient over each patient's lifetime with the device, exposing the patient to greater operative risk as well as ongoing risk related to the CIED. There are a variety of potential complications associated with CIED use, both at and around the time of implantation as well as long-term over the life of the patient and his/her device [1-3]. Procedural and periprocedural complications associated with CIED implantation will be reviewed here; the focus will be on CIED systems utilizing implantable leads. The long-term complications associated with a CIED, as well as basic principles associated with both PPMs and ICDs, are discussed separately. (See "Cardiac implantable electronic devices: Long-term complications".) (See "Permanent cardiac pacing: Overview of devices and indications".) https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 1/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions".) (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Our approach'.) INCIDENCE Overall, reported implant complication rates have ranged from 3 to >10 percent, although the exact incidence of periprocedural CIED complications varies significantly depending upon the type of device (eg, PPM, ICD, CRT) and is difficult to determine due to inconsistent definitions and the lack of mandatory reporting [4-9]. However, following the establishment of the National Cardiovascular Data Registry (NCDR) ICD Registry by the American College of Cardiology, information became available for a majority of ICDs implanted in the United States [10]. Unfortunately, there is no contemporary nationwide registry of pacemaker, CRT, or ICM devices, although some pacemaker complications can be estimated from ICD data, such as pneumothorax rates in single- and dual-lead systems [11-13]. Major complications requiring reoperation or hospitalization were analyzed in a cohort of 114,484 patients aged 65 years or greater (mean age 74.8 years, 72 percent male) who were enrolled in the NCDR ICD registry and received a first ICD between 2006 and 2010 [10]. Within the initial 90 days following implantation, approximately 5.4 percent of patients experience an ICD-related complication requiring hospitalization and/or reoperation. Most but not all studies have suggested a decline in the overall rate of complications with increasing experience and contemporary devices and practices, although rates remain somewhat higher in elderly populations and female patients [6]. In an observational study of 367,153 new ICD recipients between April 2006 and March 2010, in-hospital complications and mortality significantly decreased from 3.7 percent during year 1 of the study to 2.8 percent during year 4 (odds ratio [OR] 0.75, 95% CI 0.71- 0.79) [5]. Among a cohort of 83,792 ICD recipients over age 65 who received an initial primary prevention ICD between 2006 and 2009, significantly higher one-year mortality rates were seen among patients with dementia or frailty (27 and 22 percent, respectively, compared with 12 percent in the total cohort) [14]. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 2/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate In an observational study of 38,912 patients ages 65 years or older who received an ICD for primary prevention between January 2006 and December 2009, 5.4 percent of patients experienced a device-related complication within the first six months [6]. Rates of complications were significantly higher in women (7.2 percent compared with 4.8 percent in men, adjusted OR 1.4, 95% CI 1.3-1.5). In an observational cohort study of patients with 11,924 ICDs, 33,519 pacemakers and 4472 CRT devices were implanted (both de novo and replacements) by cardiologists, surgeons, and electrophysiologists across six United States geographical regions within a single integrated healthcare organization between 2007 and 2013 [15]. The 30-day serious complication rate (including tamponade, hematoma, pneumothorax, and deep infection) was 1.23, 1.48, and 1.74 percent for ICDs, pacemakers, and CRT devices, respectively. In a retrospective review of more than 3.7 million CIED implantations over the period from 1998 to 2013, a post-procedure pneumothorax developed in 1.3 percent of patients and was more common in patients >80 years old, women, patients with chronic obstructive pulmonary disease, and dual-chamber CIEDs [16]. An earlier systematic review, which included less than 5000 patients, reported a slightly lower incidence of 0.9 percent [17]. The risk of pneumothorax appears dependent on the implant technique used, with a meta- analysis of 23 studies including 35,722 patients finding an increased risk of pneumothorax using a subclavian puncture technique as compared with a cephalic vein cut down (odds ratio 4.88), but this difference disappeared when comparing axillary vein puncture with cephalic vein access [18]. In a retrospective cohort study (which acquired data from linked administrative databases) of 81,304 adult patients who received their first CIED (81 percent PPMs, 19 percent ICDs) at one of 174 hospitals in Australia or New Zealand between 2010 and 2015, 6664 patients (8.2 percent) experienced a major complication (a composite of death, device-related re- operation, or hospitalization for device-related complication) within the first 90 days [19]. Complication rates were higher with ICDs compared with PPMs (10 versus 7.8 percent), with significant variation from hospital to hospital (complication rates ranging from 5.3 to 14.3 percent). In a retrospective cohort study of 14,293 patients who underwent de novo CIED implantation between 2008 and 2021 in Poland, 400 patients aged 60 or older experienced lead dislodgement requiring reoperation [20]. In both women and men, a frailty score was independently predictive of lead dislodgement (odds ratios 2.12 and 1.63, respectively). https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 3/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate Complications can also occur during generator replacement procedures, lead revision procedures (changing or adding a lead), or lead extraction procedures. The rate of complications associated with these procedures, including infections, is an important issue for patients as well as for clinicians and patients considering early generator change due to a device advisory or recall. The reported rates of device failure in the case of an advisory or recall are usually very low, often well under one percent. As an example, in one study of 2915 patients with an ICD subject to an advisory, of whom 533 patients had a device replaced and were followed for an average of 2.7 months, 8 percent of the patients who underwent replacement had a complication, including major complications requiring reoperation in 5 percent [21]. In comparison, during the study period, three of the devices subject to advisories experienced a malfunction (0.1 percent), with none of these malfunctions resulting in adverse clinical sequelae. Thus, even low procedure-related complication rates could outweigh the benefit of changing the device. On the other hand, several studies have shown that proactive management of these advisory components can lead to improved outcomes. As such, these types of decisions are best approached on a case-by-case basis, taking into account the individual patient scenario and the patient's preference [22,23]. (See "Cardiac implantable electronic device lead removal", section on 'Advisory/recall'.) PROCEDURAL COMPLICATIONS Implantation of a CIED system involves placement of the lead system and the pulse generator. Both transvenous and epicardial leads are generally attached to a pulse generator in the pectoral region, although some pacemakers and ICDs implanted at the time of surgery are implanted in an abdominal position (with tunneled epicardial leads). Modern CIED lead systems are most commonly placed via the axillary, subclavian, or cephalic vein. Increasingly rarely, permanent pacemaker (PPM) or ICD leads may be placed on the epicardial surface (via thoracotomy). In addition to transvenous and epicardial systems, a subcutaneous ICD (S-ICD) is also available in which the pulse generator is placed in the mid-axillary region with the lead tunneled subcutaneously and placed along the left parasternal region. Leadless pacemakers, in which a pulse generator is placed in direct contact with the right ventricular endocardium without external leads, have their own unique risks which are different than standard transvenous devices and are discussed separately. (See "Permanent cardiac pacing: Overview of devices and indications", section on 'Leadless systems'.) https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 4/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate Each option for pulse generator and lead placement carries its own set of unique potential complications. The discussion in this topic will focus on CIED systems with transvenous and epicardial leads, while information on S-ICDs and leadless pacemakers is presented separately. (See "Subcutaneous implantable cardioverter defibrillators", section on 'Potential complications' and "Permanent cardiac pacing: Overview of devices and indications", section on 'Leadless systems'.) Given the potential for transvenous lead-related complications, a patient's candidacy for nontraditional devices should be considered at the time of initial implantation. Operator characteristics As indications for CIED implantation expand and more patients are receiving CIEDs during their lifetimes, devices are being implanted by increasing numbers of clinicians with a wide range of procedural volumes and with different board certifications. In general, complications and mortality decrease as the implanting provider's volume of implantations increases, regardless of specialty [24]. In a cohort of 9854 Medicare patients who underwent ICDs implantation by 1672 clinicians, the annual implant volume ranged from 1 to 87 devices (median seven implants per year) [25]. While there was no correlation between operator volume and periprocedural mortality, 90-day rates of mechanical complications (7 versus 4.4 percent) and ICD infection (1.3 versus 0.6 percent) were significantly higher among clinicians in the lowest quartile of implant volume compared with those in the highest. However, once a threshold of 11 implants per year was reached, the overall complication rate was no longer dependent upon volume. In a retrospective cohort study using data from a national ICD registry, which included 111,293 patients who underwent initial transvenous ICD placement by 2128 clinicians in 1062 hospitals between January 2006 and June 2007, implanting providers were classified according to one of four categories of board certification: electrophysiologists, non- electrophysiologist cardiologists, thoracic surgeons, and other specialists [26]. Notably, patients were excluded if their clinician submitted fewer than 10 ICD procedures, if they were 18 years old or younger, if they had a prior ICD implantation, or if they had an epicardial lead placed. Clinicians who were board certified in electrophysiology placed 71 percent of ICDs and had the lowest rates of overall and major complications (3.5 and 1.3 percent, respectively), while thoracic surgeons placed 1.7 percent of ICDs and had significantly higher rates of overall and major complications (5.8 and 2.5 percent). Some of the higher rates of complications in the surgical cases may be due to the tendency of surgical cases to be sicker patients. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 5/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate Initial (or de novo) implantation Transvenous lead systems Various lead systems approved for use involve one to three transvenous leads [17]. Reported complication rates range from 3 to 6 percent, with up to one- half of these complications considered serious [4-6]. Complications associated with transvenous CIED lead implantation include bleeding, infections, lead dislodgement, pneumothorax, air embolism, cardiac perforation, thrombosis of the implant vein, and rarely death. Most lead dislodgements and infections occur in the first three months, while lead fractures continue to occur during follow-up [17]. The risk of pneumothorax is a function of the venous access method; traditional subclavian access has a higher pneumothorax risk than the extrathoracic axillary vein micropuncture technique or cephalic vein access [18]. The use of periprocedural venography to guide access can reduce the risk of complications. Mortality Perioperative mortality with transvenous CIED implantation is rare but does occasionally occur. Estimates of periprocedural mortality have ranged from 0.2 to 0.4 percent [4,11,17,24,27]. Higher in-hospital (rather than periprocedural) mortality rates have been reported: In an analysis of over 800,000 patients from the NCDR database who underwent initial CIED implantation procedure between 2010 and 2014, the observed in-hospital mortality rate was 0.9 percent [28]. In a cohort of 26,887 heart failure patients undergoing ICD and/or cardiac resynchronization therapy (CRT) implantation, complications were more common in older adults with rates ranging from 0.7 to 1.2 to 2.2 percent in patients aged <80, 80 to 85, and >85 years [29]. When compared with those receiving a single-chamber ICD, patients receiving a dual-chamber ICD have a greater risk of complications (3.2 versus 2.1 percent, adjusted odds ratio [OR] 1.40, 95% CI 1.28-1.52) and in-hospital mortality (0.4 versus 0.23 percent, adjusted OR 1.45, 95% CI 1.20-1.74) [27]. Using data from the REPLACE Registry, a prospective multicenter study of patients undergoing CIED reimplantation with two distinct cohorts (patients undergoing generator change only and patients undergoing generator change plus the placement of at least one additional lead), no significant association was identified between the rate of complications and risk of death during the initial six months post-procedure [30]. However, several patient characteristics (admission for heart failure within preceding 12 months, NYHA class III or IV status, antiarrhythmic drug use, chronic kidney disease, cerebrovascular disease, and advancing age) were identified that predicted mortality. Using these risk markers, the investigators created the REPLACE DARE Mortality Risk Score to predict mortality, with increasingly higher scores associated with greater https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 6/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate risk of mortality. It is notable that in the REPLACE registry, replacement of a CRT device was associated with the highest risk of complications (19 percent). Cardiac perforation Cardiac perforation at the time of CIED implantation, a rare complication with most estimates ranging between 0.1 and 0.4 percent of CIED procedures, is associated with significant morbidity and mortality [31-33]. Among 440,251 first-time ICD recipients enrolled in the National Cardiovascular Data Registry between January 2006 and September 2011, only 625 cardiac perforations (0.14 percent) were reported [31]. However, patients with cardiac perforation had a significantly greater risk of other major complications (OR 27.5, 95% CI 19.9-38.0) and in-hospital mortality (OR 17.7, 95% CI 12.2-25.6). Bleeding While most patients who undergo transvenous CIED insertion have minimal blood loss or postoperative bleeding, serious bleeding can sometimes occur. In addition to the risks associated with a drop in hemoglobin and discomfort associated with a pocket hematoma, patients who develop a significant pocket hematoma are at higher risk of developing device- related infection [34,35]. Reported bleeding rates have varied widely depending on the presence or absence of concomitant antithrombotic therapy [17,36-38]. In patients who are taking dual antiplatelet therapy, bleeding complications are more frequent (between two- and fourfold increase in bleeding compared with those on no antiplatelet therapy) [38-40]. To minimize the risk of bleeding at the time of transvenous CIED insertion, we proceed as follows: For patients requiring transvenous CIED insertion who have the highest risk of thromboembolic events (greater than 5 percent per year), in whom the risk of discontinuing antithrombotic therapy is thought to exceed the risks of post-procedural bleeding [41], we recommend continuation of chronic antithrombotic therapy rather than a bridging strategy using heparin. For patients with a lower risk of thromboembolic events (5 percent per year or less) who require transvenous CIED insertion, there are no outcomes data to guide the decision to continue or temporarily suspend antithrombotic therapy at the time of the procedure. Our experts typically use the following approach, which is based on individualized assessment of risks and benefits: In general, warfarin should be continued, and if it is temporarily stopped in a patient with low risk of thromboembolic complications and/or a high risk of bleeding complications, bridging anticoagulation should not be provided given the increased risk of bleeding and adverse outcomes associated with bridging anticoagulation strategies. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 7/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate If the clinical scenario is consistent with a short-term increased risk of thromboembolism (eg, cardioversion as part of the procedure, or performed recently) in a patient who is otherwise not at chronically high risk of thromboembolism, we continue uninterrupted NOAC (or warfarin) therapy. If the clinical scenario is not consistent with a short-term increased risk of thromboembolism, or if there is a history of bleeding or frailty, we perform the procedure with interrupted NOAC. The NOAC can be held 24 to 48 hours before and resumed 24 to 48 hours after the procedure if there are no bleeding issues. Given the short half-lives of NOAC agents, there is no rationale for bridging therapy. In patients who are taking antiplatelet therapy with either one or two antiplatelet medications, the optimal management strategy is not as clearly defined. In spite of the association of antiplatelet drugs with increased risks of bleeding, many patients are prescribed these drugs for important reasons (eg, prior cerebrovascular events, recent acute coronary syndrome or cardiac stenting procedure, etc) [40]. Additionally, stopping antiplatelet therapy requires five days (for clopidogrel) and seven days (for aspirin) advanced notice, which may make temporarily stopping them impractical. Therefore, we typically continue antiplatelet therapy for CIED procedures, even when prescribed concurrently with antithrombotic medications, unless the indication for therapy is no longer present. The BRUISE CONTROL investigators performed the largest randomized trial of antithrombotic treatment strategies in patients undergoing transvenous CIED insertion. Among 681 patients with an annualized risk of thromboembolic events of 5 percent or greater and taking long-term warfarin, those randomized to device insertion while on continued warfarin therapy had a significantly lower incidence of the primary outcome (clinically significant pocket hematoma requiring prolonged hospital stay, interruption of anticoagulation therapy, or surgery for hematoma removal) compared with those whose warfarin was stopped and heparin-bridging therapy used (3.5 versus 16 percent, relative risk 0.19, 95% CI 0.10-0.36) [41]. Two subsequent meta-analyses have shown findings consistent with BRUISE CONTROL, including a 2014 meta- analysis that included 3744 patients from 14 studies (including BRUISE CONTROL and four other prospective randomized trials) and found that heparin bridging was associated with a significantly higher risk of bleeding compared with continuation of anticoagulation (hazard ratio 3.1, 95% CI 2.0-4.8) with no significant reduction in thromboembolic events [42,43]. Based on this, we recommend continuation of chronic warfarin therapy rather than a bridging strategy using heparin for patients at high risk of thromboembolic events who undergo transvenous CIED insertion. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 8/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate Dabigatran, an oral direct thrombin inhibitor, along with apixaban and rivaroxaban, factor Xa inhibitors, have limited data available regarding bleeding risk during transvenous CIED insertion, but the available data does not suggest a higher rate of bleed complications with uninterrupted NOAC therapy [44-47]. The BRUISE CONTROL-2 investigators performed the largest randomized trial of antithrombotic treatment strategies in patients taking an NOAC and undergoing transvenous CIED insertion. Among 662 patients with CHA DS -VASc scores 2 and 2 2 taking a NOAC for chronic anticoagulation, those randomized to device insertion while on continued NOAC therapy had no significant difference in the incidence of the primary outcome (clinically significant pocket hematoma requiring prolonged hospital stay, interruption of anticoagulation therapy, or surgery for hematoma removal) compared with those whose NOAC was stopped (2.1 percent in both treatment arms) [47]. While these data are promising that transvenous CIED implantation can be performed with uninterrupted direct thrombin or factor Xa inhibitors, additional studies are needed prior to routinely recommending this in practice. In a 2019 analysis of the 1343 patients from the two BRUISE CONTROL studies, there was no difference in clinically significant hemorrhage between patients maintained on warfarin compared with NOAC therapy at the time of CIED implantation [40]. However, patients who underwent CIED implantation while on antiplatelet medication had more than twofold greater risk of bleeding (9.8 versus 4.3 percent in patients not taking an antiplatelet agent). There are limited data evaluating the optimal approach to anticoagulation in patients receiving an S-ICD, but the risk of hematoma appears higher when compared with transvenous insertion. In a single-center retrospective study of 137 patients undergoing S-ICD implantation, 6 of 24 patients maintained on warfarin developed pocket hematoma (25 percent), compared with 2 of 113 patients (2 percent) not taking warfarin [48]. Additional data are needed prior to making recommendations on the management of anticoagulation around the time of S-ICD placement. Similarly, there are limited data assessing the optimal approach to anticoagulation in patients receiving a leadless pacemaker, but small studies have suggested that the risk of significant bleeding events is small among patients on oral antithrombotic therapy [49]. Additional data are needed prior to making recommendations specific to the management of anticoagulation around the time of leadless pacemaker placement. Infection Infection of the generator pocket or leads can occur at the time of CIED implantation or at any subsequent time. Because infection of a CIED can be a life-threatening problem, complete removal of the CIED pulse generator and all leads, along with antibiotic therapy, are strongly recommended for essentially all patients. In very rare instances, a patient may elect to proceed with antibiotic therapy without hardware removal. These issues are discussed in detail separately. (See "Infections involving cardiac implantable electronic devices: https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 9/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Cardiac implantable electronic device lead removal".) In contemporary practice, the rate of infection within one year post-CIED implantation is approximately 1 percent. Among 19,603 patients who underwent CIED implantation between 2012 and 2016, the overall rate of infection was 0.9 percent, with a slightly higher rate (1.1 percent) among "high risk" patients (defined as patients undergoing any repeat procedure or a new CRT implantation) [50]. Among an earlier "real world" cohort of 200,909 patients enrolled in an ICD registry with implant between 2006 and 2009, 1.7 percent (3390 patients) developed an infection within six months post-implantation, with a higher incidence in pulse generator replacements than in initial implantation [51]. The rate of CIED infection appears to be significantly higher among patients on dialysis, estimated at 8 percent of all patients with an indwelling CIED (including pacemakers and ICDs) who were receiving dialysis between 2005 and 2009 [52]. The incidence of early CIED infection appears to be lower with preoperative antibiotic prophylaxis [53], with the transvenous rather than the epicardial approach, and with pectoral implantation rather than abdominal implantation. The use of an antibiotic-impregnated absorbable envelope at the time of CIED implantation has been shown to reduce major CIED infections in certain higher-risk populations [54]. (See "Infections involving cardiac implantable electronic devices: Treatment and prevention", section on 'Use of antibiotic-impregnated envelopes'.) Lead malposition and lead terminal switches Unintended cardiac chambers can be sensed and paced in an unintended sequence as a result of lead malposition at initial implant or incorrect connection of the proximal lead terminals to the CIED header at either initial implant or generator replacement. While rare, each of these scenarios can lead to serious consequences if left unrecognized at the time of implant. Ventricular lead placement into the atrial port and vice- versa can lead to pacemaker syndrome and left ventricular systolic dysfunction [55]. A recent systematic review identified 157 cases of inadvertent lead malposition in the left heart [56]. The malposition was not diagnosed until an average of 365 days after CIED implantation; 31 percent had a transient ischemic attack or stroke at time of diagnosis, whereas 15 percent had heart failure. Over a nine-month mean follow-up, four patients experienced transient ischemic attack or stroke (three treated with oral anticoagulants and one following percutaneous lead extraction). Inadvertent lead malposition in the left heart can be avoided (or recognized) intraoperatively by visualizing a guide wire going below the diaphragm, evaluating the paced QRS morphology in V1 or its equivalent, and imaging in both the right and (steep) left anterior oblique projections. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 10/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate Epicardial lead systems In the vast majority of patients, transvenous CIED leads can be placed quickly, without general anesthesia, and with relatively little morbidity. Because of this, transvenous lead placement has largely replaced epicardial lead placement, which requires a thoracotomy, general anesthesia, and a longer recovery. However, epicardial leads remain an option for patients with complicated vascular access or active bloodstream infection in which the placement of transvenous leads may be contraindicated. In these patients, nonleaded systems (ie, subcutaneous ICD and leadless pacemaker) should be considered. (See "Permanent cardiac pacing: Overview of devices and indications", section on 'Leadless systems'.) Given the relative infrequency with which epicardial leads are placed, there are no data available on the frequency of complications from epicardial lead placement with modern devices. Epicardial lead placement is associated with appreciable mortality and with complications that are unique to thoracotomy and epicardial lead systems, such as the postpericardiotomy syndrome (postcardiac injury syndrome), pleural effusion, erosion of epicardial patches, constrictive pericarditis, and atrial arrhythmias [57]. Additionally, epicardial leads do tend to have higher pacing capture thresholds. (See "Post-cardiac injury syndromes" and "Constrictive pericarditis: Diagnostic evaluation".) Shoulder-related problems Shoulder-related problems due to pulse generator placement (utilizing either transvenous or epicardial leads) include decreased shoulder motility, pain, reduced function, and insertion tendinitis. These complaints, more common with sub-pectoral CIED placement rather than subcutaneous CIED placement, usually do not require additional intervention or surgical revision and often abate by 12 months after insertion [58]. Furthermore, the smaller size of modern pulse generators has made device-related shoulder problems extremely rare. Reuse of explanted ICDs Many CIED pulse generators have useful battery life remaining at the time of a patient's death or when the CIED is explanted due to infection or device upgrade. Because of concerns regarding the transmission of infectious disease from patient to patient, and because of the lack of data regarding device reliability when used in such a fashion, reuse of explanted CIEDs has not been approved by any governing or regulatory body. However, due to the large numbers of patients in resource-limited settings who have indications for a CIED but are unable to afford the device, there is a potential for compassionate reuse of CIEDs if sterility and reliability can be assured. From a single-center cohort of 81 indigent patients with indications for an ICD who received 106 explanted ICD pulse generators (cleaned and sterilized using a protocol involving hydrogen peroxide, povidone-iodine, and ethylene oxide gas) with a projected battery life of three or more years, the following findings were reported [59]: https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 11/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate No infectious complications One lead dislodgement and one lead fracture Mean time to subsequent ICD replacement 1287 days Appropriate ICD therapy (shocks or antitachycardia pacing) in 64 out of 106 devices (60 percent) In 2003, the Montreal Heart Institute developed a prospective registry to enroll patients receiving resterilized CIEDs. In 2020, investigators from this group published a case-control study of 1051 patients who had received a reused/resterilized CIED (85 percent PPMs, 15 percent ICDs), who were matched with 3153 matched controls who received their CIED in Canada [60]. Over a follow-up of two years, CIED infection rates were not significantly different between recipients of reused or new CIEDs (2.0 versus 1.2 percent, respectively), with no device-related deaths. While additional data will be helpful in validating this practice on a larger scale and for longer follow-up, reuse of resterilized CIEDs appears safe and feasible, particularly in resource- limited settings. CIED generator changes and revision procedures The risks associated with CIED generator change and/or lead revision are different from those of initial implantation, with the absolute risk differing significantly depending on whether the procedure involves only a generator change or whether lead revision is also involved. If extraction of a chronic lead(s) is performed concurrently, the procedural risk is higher. (See 'Infection' above and "Cardiac implantable electronic device lead removal".) The REPLACE Registry was a prospective multicenter study of patients undergoing CIED reimplantation with two distinct cohorts, patients undergoing generator change only (1031 patients) and patients undergoing generator change plus the placement of at least one additional lead (713 patients), who were followed for six months post-procedure to assess for complications [61]. Major complications occurred in only 41 patients (4 percent) of the generator-only cohort as compared with 109 patients (15 percent) of the generator plus lead cohort. Subsequently, investigators reevaluated the patients from the REPLACE Registry in an effort to identify risk factors related to mortality within the six months post-procedure, ultimately identifying several patient characteristics (admission for heart failure within preceding 12 months, NYHA class III or IV status, antiarrhythmic drug use, chronic kidney disease, cerebrovascular disease, and advancing age) were identified that predicted mortality [30]. PERIPROCEDURAL MONITORING https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 12/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate All patients who undergo CIED implantation will have the device placed using local anesthesia at the site of the pulse generator insertion, with procedural sedation or higher level of anesthesia provided for patients in whom anxiety or pain control is needed. The monitoring associated with procedural sedation is discussed in detail separately. (See "Procedural sedation in adults: General considerations, preparation, monitoring, and mitigating complications", section on 'Monitoring'.) Following CIED implantation, a posteroanterior (PA) and lateral chest radiograph should be obtained to document the position of the pulse generator and the associated lead(s) and to exclude any apparent complications, including pneumothorax and lead dislodgment [62]. Patients should also have a 12-lead electrocardiogram (ECG) recorded post implant. This is particularly helpful in the case of cardiac resynchronization therapy to verify biventricular capture. Following CIED implantation, patients have traditionally been observed overnight in a hospitalized environment with continuous ECG monitoring, and discharged the following day if doing well without any apparent complications. However, accumulating reports support the feasibility and safety of sending patients home the same day as their implant if there are no apparent early complications [63-65]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 13/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Sudden cardiac arrest (The Basics)" and "Patient education: Pacemakers (The Basics)" and "Patient education: Cardiac resynchronization therapy (The Basics)") Beyond the Basics topics (see "Patient education: Implantable cardioverter-defibrillators (Beyond the Basics)" and "Patient education: Pacemakers (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Background and incidence There are a variety of potential complications associated with cardiac implantable electronic device (CIED) use, both at and around the time of implantation as well as long-term over the life of the patient and his/her device. Reported implant complication rates range from 2 to 6 percent, although the exact incidence of periprocedural CIED complications is difficult to determine due to inconsistent definitions and the lack of mandatory reporting. (See 'Incidence' above.) Procedural complications Complications associated with transvenous CIED lead implantation include bleeding, infections, lead dislodgement, pneumothorax, cardiac perforation, and rarely death. Perioperative mortality This is rare with transvenous CIED implantation, but it occurs occasionally, with estimates of periprocedural mortality ranging from 0.2 to 0.4 percent. (See 'Mortality' above.)

Because of concerns regarding the transmission of infectious disease from patient to patient, and because of the lack of data regarding device reliability when used in such a fashion, reuse of explanted CIEDs has not been approved by any governing or regulatory body. However, due to the large numbers of patients in resource-limited settings who have indications for a CIED but are unable to afford the device, there is a potential for compassionate reuse of CIEDs if sterility and reliability can be assured. From a single-center cohort of 81 indigent patients with indications for an ICD who received 106 explanted ICD pulse generators (cleaned and sterilized using a protocol involving hydrogen peroxide, povidone-iodine, and ethylene oxide gas) with a projected battery life of three or more years, the following findings were reported [59]: https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 11/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate No infectious complications One lead dislodgement and one lead fracture Mean time to subsequent ICD replacement 1287 days Appropriate ICD therapy (shocks or antitachycardia pacing) in 64 out of 106 devices (60 percent) In 2003, the Montreal Heart Institute developed a prospective registry to enroll patients receiving resterilized CIEDs. In 2020, investigators from this group published a case-control study of 1051 patients who had received a reused/resterilized CIED (85 percent PPMs, 15 percent ICDs), who were matched with 3153 matched controls who received their CIED in Canada [60]. Over a follow-up of two years, CIED infection rates were not significantly different between recipients of reused or new CIEDs (2.0 versus 1.2 percent, respectively), with no device-related deaths. While additional data will be helpful in validating this practice on a larger scale and for longer follow-up, reuse of resterilized CIEDs appears safe and feasible, particularly in resource- limited settings. CIED generator changes and revision procedures The risks associated with CIED generator change and/or lead revision are different from those of initial implantation, with the absolute risk differing significantly depending on whether the procedure involves only a generator change or whether lead revision is also involved. If extraction of a chronic lead(s) is performed concurrently, the procedural risk is higher. (See 'Infection' above and "Cardiac implantable electronic device lead removal".) The REPLACE Registry was a prospective multicenter study of patients undergoing CIED reimplantation with two distinct cohorts, patients undergoing generator change only (1031 patients) and patients undergoing generator change plus the placement of at least one additional lead (713 patients), who were followed for six months post-procedure to assess for complications [61]. Major complications occurred in only 41 patients (4 percent) of the generator-only cohort as compared with 109 patients (15 percent) of the generator plus lead cohort. Subsequently, investigators reevaluated the patients from the REPLACE Registry in an effort to identify risk factors related to mortality within the six months post-procedure, ultimately identifying several patient characteristics (admission for heart failure within preceding 12 months, NYHA class III or IV status, antiarrhythmic drug use, chronic kidney disease, cerebrovascular disease, and advancing age) were identified that predicted mortality [30]. PERIPROCEDURAL MONITORING https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 12/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate All patients who undergo CIED implantation will have the device placed using local anesthesia at the site of the pulse generator insertion, with procedural sedation or higher level of anesthesia provided for patients in whom anxiety or pain control is needed. The monitoring associated with procedural sedation is discussed in detail separately. (See "Procedural sedation in adults: General considerations, preparation, monitoring, and mitigating complications", section on 'Monitoring'.) Following CIED implantation, a posteroanterior (PA) and lateral chest radiograph should be obtained to document the position of the pulse generator and the associated lead(s) and to exclude any apparent complications, including pneumothorax and lead dislodgment [62]. Patients should also have a 12-lead electrocardiogram (ECG) recorded post implant. This is particularly helpful in the case of cardiac resynchronization therapy to verify biventricular capture. Following CIED implantation, patients have traditionally been observed overnight in a hospitalized environment with continuous ECG monitoring, and discharged the following day if doing well without any apparent complications. However, accumulating reports support the feasibility and safety of sending patients home the same day as their implant if there are no apparent early complications [63-65]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 13/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Sudden cardiac arrest (The Basics)" and "Patient education: Pacemakers (The Basics)" and "Patient education: Cardiac resynchronization therapy (The Basics)") Beyond the Basics topics (see "Patient education: Implantable cardioverter-defibrillators (Beyond the Basics)" and "Patient education: Pacemakers (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Background and incidence There are a variety of potential complications associated with cardiac implantable electronic device (CIED) use, both at and around the time of implantation as well as long-term over the life of the patient and his/her device. Reported implant complication rates range from 2 to 6 percent, although the exact incidence of periprocedural CIED complications is difficult to determine due to inconsistent definitions and the lack of mandatory reporting. (See 'Incidence' above.) Procedural complications Complications associated with transvenous CIED lead implantation include bleeding, infections, lead dislodgement, pneumothorax, cardiac perforation, and rarely death. Perioperative mortality This is rare with transvenous CIED implantation, but it occurs occasionally, with estimates of periprocedural mortality ranging from 0.2 to 0.4 percent. (See 'Mortality' above.) Cardiac perforation At the time of CIED implantation, this is rare, occurring in only 0.1 to 0.2 percent of patients, but it is associated with significant morbidity and mortality. (See 'Cardiac perforation' above.) Bleeding While most patients who undergo transvenous CIED insertion have minimal blood loss or post-operative bleeding, serious bleeding can sometimes occur. To minimize the risk of bleeding, chronic antithrombotic therapy should be discontinued prior to device insertion when reasonable to do so, although this may not be an option for those at the highest risk of thromboembolic events. (See 'Bleeding' above.) Infection An infection of the generator pocket or leads can occur at the time of CIED implantation or at any subsequent time, having been reported in up to 2 percent of https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 14/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate patients within six months post-procedure. The incidence of early CIED infection is lower with perioperative antibiotics (with the transvenous rather than the epicardial approach) and with pectoral implantation, and higher with increasing number of leads, in replacement versus de novo implants, and in patients on hemodialysis. (See 'Infection' above.) Periprocedural monitoring Following CIED implantation, a posteroanterior (PA) and lateral chest radiograph should be obtained to document the position of the pulse generator and the associated lead(s) and to exclude any apparent complications, including pneumothorax and lead dislodgment. Patients should also have a 12-lead ECG recorded post implant. (See 'Periprocedural monitoring' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Pfeiffer D, Jung W, Fehske W, et al. Complications of pacemaker-defibrillator devices: diagnosis and management. Am Heart J 1994; 127:1073. 2. Kron J, Herre J, Renfroe EG, et al. Lead- and device-related complications in the antiarrhythmics versus implantable defibrillators trial. Am Heart J 2001; 141:92. 3. DiMarco JP. Implantable cardioverter-defibrillators. N Engl J Med 2003; 349:1836. 4. 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Pacemaker and ICD generator malfunctions: analysis of Food and Drug Administration annual reports. JAMA 2006; 295:1901. 13. Maisel WH. Pacemaker and ICD generator reliability: meta-analysis of device registries. JAMA 2006; 295:1929. 14. Green AR, Leff B, Wang Y, et al. Geriatric Conditions in Patients Undergoing Defibrillator Implantation for Prevention of Sudden Cardiac Death: Prevalence and Impact on Mortality. Circ Cardiovasc Qual Outcomes 2016; 9:23. 15. Gupta N, Kiley ML, Anthony F, et al. Multi-Center, Community-Based Cardiac Implantable Electronic Devices Registry: Population, Device Utilization, and Outcomes. J Am Heart Assoc 2016; 5:e002798. 16. Ogunbayo GO, Charnigo R, Darrat Y, et al. Incidence, predictors, and outcomes associated with pneumothorax during cardiac electronic device implantation: A 16-year review in over 3.7 million patients. Heart Rhythm 2017; 14:1764. 17. van Rees JB, de Bie MK, Thijssen J, et al. Implantation-related complications of implantable cardioverter-defibrillators and cardiac resynchronization therapy devices: a systematic review of randomized clinical trials. J Am Coll Cardiol 2011; 58:995. 18. Atti V, Turagam MK, Garg J, et al. Subclavian and Axillary Vein Access Versus Cephalic Vein Cutdown for Cardiac Implantable Electronic Device Implantation: A Meta-Analysis. JACC Clin Electrophysiol 2020; 6:661. 19. Ranasinghe I, Labrosciano C, Horton D, et al. Institutional Variation in Quality of Cardiovascular Implantable Electronic Device Implantation: A Cohort Study. Ann Intern Med 2019; 171:309. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 16/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate 20. Mlynarski R, Mlynarska A, Joniec M, et al. Predictors of Early Cardiac Implantable Electronic Device Lead Dislodgement in the Elderly. 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The relation between patients' outcomes and the volume of cardioverter-defibrillator implantation procedures performed by physicians treating Medicare beneficiaries. J Am Coll Cardiol 2005; 46:1536. 26. Curtis JP, Luebbert JJ, Wang Y, et al. Association of physician certification and outcomes among patients receiving an implantable cardioverter-defibrillator. JAMA 2009; 301:1661. 27. Dewland TA, Pellegrini CN, Wang Y, et al. Dual-chamber implantable cardioverter- defibrillator selection is associated with increased complication rates and mortality among patients enrolled in the NCDR implantable cardioverter-defibrillator registry. J Am Coll Cardiol 2011; 58:1007. 28. Pasupula DK, Rajaratnam A, Rattan R, et al. Trends in Hospital Admissions for and Readmissions After Cardiac Implantable Electronic Device Procedures in the United States: An Analysis From 2010 to 2014 Using the National Readmission Database. Mayo Clin Proc 2019; 94:588. 29. Swindle JP, Rich MW, McCann P, et al. Implantable cardiac device procedures in older patients: use and in-hospital outcomes. Arch Intern Med 2010; 170:631. 30. Chung MK, Holcomb RG, Mittal S, et al. REPLACE DARE (Death After Replacement Evaluation) score: determinants of all-cause mortality after implantable device replacement or upgrade from the REPLACE registry. Circ Arrhythm Electrophysiol 2014; 7:1048. 31. Hsu JC, Varosy PD, Bao H, et al. Cardiac perforation from implantable cardioverter- defibrillator lead placement: insights from the national cardiovascular data registry. Circ Cardiovasc Qual Outcomes 2013; 6:582. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 17/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate 32. Migliore F, Zorzi A, Bertaglia E, et al. Incidence, management, and prevention of right ventricular perforation by pacemaker and implantable cardioverter defibrillator leads. Pacing Clin Electrophysiol 2014; 37:1602. 33. Vamos M, Erath JW, Benz AP, et al. Incidence of Cardiac Perforation With Conventional and With Leadless Pacemaker Systems: A Systematic Review and Meta-Analysis. J Cardiovasc Electrophysiol 2017; 28:336. 34. Balla C, Brieda A, Righetto A, et al. Predictors of infection after "de novo" cardiac electronic device implantation. Eur J Intern Med 2020; 77:73. 35. Calder n-Parra J, S nchez-Chica E, Asensio-Vegas , et al. Proposal for a Novel Score to Determine the Risk of Cardiac Implantable Electronic Device Infection. Rev Esp Cardiol (Engl Ed) 2019; 72:806. 36. Bernard ML, Shotwell M, Nietert PJ, Gold MR. Meta-analysis of bleeding complications associated with cardiac rhythm device implantation. Circ Arrhythm Electrophysiol 2012; 5:468. 37. Nichols CI, Vose JG. Incidence of Bleeding-Related Complications During Primary Implantation and Replacement of Cardiac Implantable Electronic Devices. J Am Heart Assoc 2017; 6. 38. Notaristefano F, Angeli F, Verdecchia P, et al. Device-Pocket Hematoma After Cardiac Implantable Electronic Devices. Circ Arrhythm Electrophysiol 2020; 13:e008372. 39. Tompkins C, Cheng A, Dalal D, et al. Dual antiplatelet therapy and heparin "bridging" significantly increase the risk of bleeding complications after pacemaker or implantable cardioverter-defibrillator device implantation. J Am Coll Cardiol 2010; 55:2376. 40. Essebag V, Healey JS, Joza J, et al. Effect of Direct Oral Anticoagulants, Warfarin, and Antiplatelet Agents on Risk of Device Pocket Hematoma: Combined Analysis of BRUISE CONTROL 1 and 2. Circ Arrhythm Electrophysiol 2019; 12:e007545. 41. Birnie DH, Healey JS, Wells GA, et al. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med 2013; 368:2084. 42. Du L, Zhang Y, Wang W, Hou Y. Perioperative anticoagulation management in patients on chronic oral anticoagulant therapy undergoing cardiac devices implantation: a meta- analysis. Pacing Clin Electrophysiol 2014; 37:1573. 43. Sant'anna RT, Leiria TL, Nascimento T, et al. Meta-analysis of continuous oral anticoagulants versus heparin bridging in patients undergoing CIED surgery: reappraisal after the BRUISE study. Pacing Clin Electrophysiol 2015; 38:417. https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 18/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate 44. Jennings JM, Robichaux R, McElderry HT, et al. Cardiovascular implantable electronic device implantation with uninterrupted dabigatran: comparison to uninterrupted warfarin. J Cardiovasc Electrophysiol 2013; 24:1125. 45. Rowley CP, Bernard ML, Brabham WW, et al. Safety of continuous anticoagulation with dabigatran during implantation of cardiac rhythm devices. Am J Cardiol 2013; 111:1165. 46. Kosiuk J, Koutalas E, Doering M, et al. Treatment with novel oral anticoagulants in a real- world cohort of patients undergoing cardiac rhythm device implantations. Europace 2014; 16:1028. 47. Birnie DH, Healey JS, Wells GA, et al. Continued vs. interrupted direct oral anticoagulants at the time of device surgery, in patients with moderate to high risk of arterial thrombo- embolic events (BRUISE CONTROL-2). Eur Heart J 2018; 39:3973. 48. Afzal MR, Mehta D, Evenson C, et al. Perioperative management of oral anticoagulation in patients undergoing implantation of subcutaneous implantable cardioverter-defibrillator. Heart Rhythm 2018; 15:520. 49. San Antonio R, Chipa-Ccasani F, Apolo J, et al. Management of anticoagulation in patients undergoing leadless pacemaker implantation. Heart Rhythm 2019; 16:1849. 50. Krahn AD, Longtin Y, Philippon F, et al. Prevention of Arrhythmia Device Infection Trial: The PADIT Trial. J Am Coll Cardiol 2018; 72:3098. 51. Prutkin JM, Reynolds MR, Bao H, et al. Rates of and factors associated with infection in 200 909 Medicare implantable cardioverter-defibrillator implants: results from the National Cardiovascular Data Registry. Circulation 2014; 130:1037. 52. Guha A, Maddox WR, Colombo R, et al. Cardiac implantable electronic device infection in patients with end-stage renal disease. Heart Rhythm 2015; 12:2395. 53. de Oliveira JC, Martinelli M, Nishioka SA, et al. Efficacy of antibiotic prophylaxis before the implantation of pacemakers and cardioverter-defibrillators: results of a large, prospective, randomized, double-blinded, placebo-controlled trial. Circ Arrhythm Electrophysiol 2009; 2:29. 54. Tarakji KG, Mittal S, Kennergren C, et al. Antibacterial Envelope to Prevent Cardiac Implantable Device Infection. N Engl J Med 2019; 380:1895. 55. Khurwolah MR, Vezi BZ. Pacemaker syndrome with sub-acute left ventricular systolic dysfunction in a patient with a dual-chamber pacemaker: consequence of lead switch at the header. Cardiovasc J Afr 2017; 28:134. 56. Spighi L, Notaristefano F, Piraccini S, et al. Inadvertent Lead Malposition in the Left Heart during Implantation of Cardiac Electric Devices: A Systematic Review. J Cardiovasc Dev Dis https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 19/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate 2022; 9. 57. Kuck KH, Cappato R, Siebels J, R ppel R. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest : the Cardiac Arrest Study Hamburg (CASH). Circulation 2000; 102:748. 58. Korte T, Jung W, Schlippert U, et al. Prospective evaluation of shoulder-related problems in patients with pectoral cardioverter-defibrillator implantation. Am Heart J 1998; 135:577. 59. Pavri BB, Lokhandwala Y, Kulkarni GV, et al. Reuse of explanted, resterilized implantable cardioverter-defibrillators: a cohort study. Ann Intern Med 2012; 157:542. 60. Khairy TF, Lupien MA, Nava S, et al. Infections Associated with Resterilized Pacemakers and Defibrillators. N Engl J Med 2020; 382:1823. 61. Poole JE, Gleva MJ, Mela T, et al. Complication rates associated with pacemaker or implantable cardioverter-defibrillator generator replacements and upgrade procedures: results from the REPLACE registry. Circulation 2010; 122:1553. 62. Kusumoto FM, Schoenfeld MH, Wilkoff BL, et al. 2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction. Heart Rhythm 2017; 14:e503. 63. Choudhuri I, Desai D, Walburg J, et al. Feasibility of early discharge after implantable cardioverter-defibrillator procedures. J Cardiovasc Electrophysiol 2012; 23:1123. 64. Darda S, Khouri Y, Gorges R, et al. Feasibility and safety of same-day discharge after implantable cardioverter defibrillator placement for primary prevention. Pacing Clin Electrophysiol 2013; 36:885. 65. Archontakis S, Oikonomou E, Sideris K, et al. Safety of same-day discharge versus overnight stay strategy following cardiac device implantations: a high-volume single-centre experience. J Interv Card Electrophysiol 2023; 66:471. Topic 108919 Version 29.0 Contributor Disclosures Kevin F Kwaku, MD, PhD Grant/Research/Clinical Trial Support: Boston Scientific [ICD anti-tachycardia pacing (APPRAISE-ATP) trial]. Other Financial Interest: Medtronic [Travel expenses]. All of the relevant financial relationships listed have been mitigated. Jonathan Piccini, MD, MHS, FACC, FAHA, FHRS Grant/Research/Clinical Trial Support: Abbott [Atrial fibrillation, catheter ablation]; AHA [Atrial fibrillation, cardiovascular disease]; Bayer [Atrial fibrillation]; Boston Scientific [Cardiac mapping, pacemaker/ICD, atrial fibrillation care]; iRhythm [Atrial fibrillation]; NIA [Atrial fibrillation]; Philips [Lead management]. Consultant/Advisory Boards: Abbott [Atrial fibrillation, catheter ablation]; Abbvie [Atrial fibrillation]; Bayer [Atrial fibrillation]; Boston Scientific [Cardiac mapping, atrial fibrillation, pacemaker/ICD]; ElectroPhysiology Frontiers [Atrial fibrillation, catheter ablation]; Element Science [DSMB]; Medtronic [Atrial fibrillation, pacemaker/ICDs]; Milestone [Supraventricular tachycardia]; Pacira [Atrial fibrillation]; Philips https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 20/21 7/6/23, 10:49 AM Cardiac implantable electronic devices: Periprocedural complications - UpToDate [Lead extraction]; ReCor [Cardiac arrhythmias]; Sanofi [Atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cardiac-implantable-electronic-devices-periprocedural-complications/print 21/21

7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cardiac resynchronization therapy in heart failure: Indications and choice of system : Evan Adelstein, MD, Samir Saba, MD : Frederick Masoudi, MD, MSPH, FACC, FAHA : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 14, 2023. INTRODUCTION Cardiac resynchronization therapy (CRT) is a modality of cardiac pacing used in patients with left ventricular (LV) systolic dysfunction and dyssynchronous ventricular activation that provides simultaneous or nearly simultaneous electrical activation of the LV and right ventricle (RV) via stimulation of the LV and RV (biventricular pacing) or LV alone. This is performed by either a CRT- pacemaker (CRT-P) or by a combined CRT-implantable cardioverter-defibrillator (CRT-D). CRT devices include a transvenous pacing lead placed in a branch of the coronary sinus (or, less commonly, an epicardial or endocardial LV lead) for LV pacing, in addition to leads in the RV and right atrium. These leads are attached to a pulse generator typically located in the subcutaneous tissue of the upper chest. (See "Cardiac resynchronization therapy in heart failure: System implantation and programming".) Many of the indications for implantable cardioverter-defibrillators (ICDs) overlap with those for CRT. The indications and evidence for ICD use are discussed separately. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis".) https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 1/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate CRT and ICD therapy are key components of the management of heart failure (HF) with reduced ejection fraction in addition to pharmacologic therapy, as discussed separately. (See "Overview of the management of heart failure with reduced ejection fraction in adults".) Use of CRT in patients with atrial fibrillation is discussed separately. (See "Cardiac resynchronization therapy in atrial fibrillation".) RATIONALE FOR CRT CRT involves pacing the LV and usually simultaneous or nearly simultaneous pacing of the RV to restore ventricular synchrony and thus improve LV systolic function and clinical outcomes for selected patients with LV systolic dysfunction and electrocardiographic evidence of electrical dyssynchrony. (See 'Evidence' below.) Observational studies suggest that electrical dyssynchrony (manifest as a prolonged QRS complex on the surface electrocardiogram [ECG]) is associated with adverse clinical outcomes. Approximately one-third of patients with HF with reduced ejection fraction (HFrEF) have a "wide" QRS complex, defined as >120 ms [1]. Mortality among patients with HFrEF increases with increasing QRS complex duration [2,3]. Left bundle branch block (LBBB) is itself associated with increased mortality among patients with HFrEF of any etiology, whereas right bundle branch block is not [4]. These observations prompted studies demonstrating that LV electromechanical activation in patients with native or pacing-induced LBBB is hemodynamically disadvantageous. In the cardiomyopathic state, this inefficiency further reduces cardiac output, exacerbates functional mitral regurgitation, and worsens adverse LV remodeling (ie, dilatation) [5]. Electroanatomic mapping of the LV demonstrates that LBBB is associated with delayed activation of the basal posterolateral wall compared with nearly simultaneous electrical activation in the setting of normal His-Purkinje activation. This mechanical "dyssynchrony" was first observed with echocardiographic M-mode imaging, followed by tissue Doppler imaging and, later, speckle- tracking strain imaging. In the presence of LBBB, mechanical activation of the posterolateral LV is typically delayed compared with the interventricular septum, mirroring the findings from electroanatomic mapping. MECHANISMS OF BENEFIT Among those who respond to CRT, therapy induces immediate hemodynamic benefits, improves LV systolic function, and promotes LV reverse remodeling, whereby the LV decreases in size and https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 2/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate becomes less spherical. Acute hemodynamic benefits of CRT include increased systolic blood pressure, increased cardiac output, and increased contractility (dP/dt). In the CARE-HF trial, CRT therapy was associated with increases in LV ejection fraction of 3.7 percent at three months and 6.9 percent at 18 months and decreases in LV end-systolic volume index by 16.7 percent at three months and 29.6 percent at 18 months [6]. These findings highlight the fact that CRT confers progressive structural benefits. Unlike inotrope therapy, CRT enhances myocardial contractility without increasing myocardial oxygen consumption. The molecular mechanisms of CRT are poorly understood; this therapy is associated with potentially beneficial upregulation of HF-related genes, including sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a), phospholamban, and the beta-1 adrenergic receptor [7]. The clinical benefits of CRT are discussed below. (See 'Evidence' below.) INDICATIONS FOR REFERRAL FOR CRT Our approach Our approach to referral for CRT is presented here. The evidence to support this approach is presented below. (See 'Evidence' below.) When to consider CRT Patients with HF with reduced ejection fraction (HFrEF) with LV ejection fraction (LVEF) 35 percent should be evaluated for indications for CRT. This assessment should be performed after patients have received optimal (maximum tolerated up to target doses) evidence-based medical therapy for at least three months after initial diagnosis of HFrEF (or for at least 40 days after myocardial infarction) and after identification and treatment of any reversible causes of LV systolic dysfunction (such as myocardial ischemia or tachycardia-induced cardiomyopathy) [8]. In addition, some patients with LVEF between 35 and 50 percent may be candidates for CRT, including those anticipated to require frequent ventricular pacing (generally >40 percent of the time) or who have a QRS 150 ms with left bundle branch block (LBBB) and refractory symptoms of HF despite optimal medical therapy. Determine if an indication is present Indications for CRT and the evidence supporting these indications are discussed below. Candidacy for CRT is based upon LVEF, QRS duration, QRS pattern, New York Heart Association (NYHA) functional class, and need for ventricular pacing ( algorithm 1 and algorithm 2). (See 'CRT indications in sinus rhythm' below and 'Evidence for general indications' below.) https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 3/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate Perform an individualized risk-benefit assessment For patients with an indication for CRT, an individualized risk-benefit assessment is performed to determine whether and how to proceed with CRT. Factors associated with less expected benefit or increased periprocedural and long-term risks are described below. For patients with less compelling indications for CRT, the threshold to proceed with therapy is higher in patients who already have a pacemaker or implantable cardioverter-defibrillator (ICD), particularly if upgrade to CRT would require a stand-alone procedure (ie, considered outside the setting of a generator that has reached end-of-service). (See 'Individualized risk-benefit assessment' below.) Assess for contraindications The above individualized risk-benefit assessment includes evaluation of any contraindications as described below. (See 'Contraindications' below.) CRT indications in sinus rhythm Indications for CRT for patients in sinus rhythm are based upon LVEF, QRS duration, QRS morphology, NYHA functional class, and need for ventricular pacing as described in this section. CRT is indicated in selected patients with HFrEF with LVEF 35 percent and wide QRS (see 'For patients with LVEF 35 percent' below). CRT is also indicated in selected patients with LVEF between 35 and 50 percent who are anticipated to require frequent ventricular pacing or who have a QRS 150 ms with LBBB and symptoms of HF despite optimal medical therapy. (See 'For patients with LVEF between 35 and 50 percent' below.) Indications for CRT in patients in sinus rhythm are presented here. Recommendations for patients with persistent atrial fibrillation are discussed separately. (See "Cardiac resynchronization therapy in atrial fibrillation".) Major society guidelines that include indications for CRT include the 2012 American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) focused update of the 2008 guidelines for device-based therapy for cardiac rhythm abnormalities, the 2013 ACC/AHA HF guidelines and the 2016 European Society of Cardiology (ESC) HF guidelines, and the 2021 ESC guidelines on cardiac pacing and CRT [8-11]. (See 'Society guideline links' below.) For patients with LVEF 35 percent The following general indications apply to patients in sinus rhythm with LVEF 35 percent on optimal evidence-based medical therapy for at least three months after initial diagnosis (or for at least 40 days after myocardial infarction) and after treatment of any reversible causes of persistent HF (such as myocardial ischemia or tachycardia- induced cardiomyopathy) ( algorithm 1) [8]. Evidence supporting these recommendations is presented below. (See 'Evidence for general indications' below.) QRS 150 ms with LBBB (See 'For QRS duration 150 ms' below.) https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 4/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate For patients with QRS 150 ms with LBBB and NYHA class II to ambulatory class IV HF, we recommend referral for CRT. These patients also meet criteria for ICD therapy for primary prevention of sudden cardiac death. (See 'NYHA class III or ambulatory class IV HF' below and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) We also suggest referral for CRT in patients with NYHA class I HF and ischemic cardiomyopathy (ICM). Patients with ICM with LVEF 30 percent on medical therapy also meet criteria for ICD placement. (See 'NYHA class I or II' below.) Based on indirect evidence from patients with ICM, some experts (including the authors of this topic) also refer patients with NYHA class I HF and nonischemic cardiomyopathy (NICM) for an individualized risk-benefit assessment of CRT. These patients do not generally meet criteria for ICD placement. (See 'Individualized risk-benefit assessment' below and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) QRS 150 ms with non-LBBB (See 'For QRS duration 150 ms' below.) For patients with QRS 150 ms with non-LBBB pattern and NYHA functional class III or ambulatory class IV HF symptoms, we suggest referral for CRT. (See 'NYHA class III or ambulatory class IV HF' below.) For patients with mild (NYHA class II) HF symptoms, we refer for an individualized risk- benefit assessment of CRT including acknowledgment of the limited evidence of benefit. (See 'For QRS duration 120 to 149 ms and/or non-LBBB morphology' below and 'Individualized risk-benefit assessment' below.) QRS <150 ms (See 'For QRS duration 120 to 149 ms and/or non-LBBB morphology' below.) For patients with QRS 130 to 149 ms with LBBB and NYHA class II to ambulatory class IV HF, we suggest referral for CRT. For patients with QRS 120 to 149 ms with non-LBBB pattern, persistent NYHA functional class III or ambulatory class IV HF, and recurrent HF hospitalizations despite optimal medical therapy, we refer for an individualized risk-benefit assessment of CRT. (See 'Individualized risk-benefit assessment' below.) For patients with LVEF between 35 and 50 percent Additional recommendations apply to selected patients in sinus rhythm with LVEF >35 and <50 percent ( algorithm 2). Evidence https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 5/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate supporting these recommendations is presented below. (See 'Evidence for patients with LVEF between 35 and 50 percent' below.) For patients who require a pacemaker (including patients undergoing atrioventricular [AV] junction ablation), have an LVEF <50 percent, and are anticipated to require frequent ventricular pacing (>40 percent of the time), we suggest referral for CRT. (See 'Evidence for patients with LVEF between 35 and 50 percent' below.) For patients with QRS duration 150 ms with LBBB (native or paced) and persistent severe HF (NYHA functional class III or IV) despite optimal evidence-based medical therapy for at least three months, we refer for an individualized risk-benefit assessment of CRT- pacemaker (CRT-P). The efficacy of CRT in this population is not established. The rationale for CRT in this setting is based upon indirect evidence from trials in patients with LVEF 35 percent and a single trial in pacemaker candidates. (See 'Evidence for patients with LVEF between 35 and 50 percent' below.) Choice between CRT-D versus CRT-P Most patients with LVEF 35 percent and an indication for CRT have an indication for a concomitant ICD. Thus, a key component of the initial consultation for CRT includes a discussion with patients of both CRT-P and CRT-defibrillator (CRT- D). Generally, with a concomitant indication for an ICD, CRT-D therapy is recommended. Importantly, there are no prospective data demonstrating a survival benefit of CRT-D over CRT-P. In observational studies [12], those less likely to benefit from CRT-D compared with CRT-P include older patients (age 75 years), patients without coronary artery disease particularly if they are without dilated LV or midwall fibrosis, and pacemaker-dependent patients without coronary artery disease. (See 'Evidence for general indications' below.) Compared with CRT-D devices, CRT-P devices are smaller, less expensive, possibly incur less risk of infection, and have been subject to fewer recalls and advisories. Only CRT-D devices provide antitachycardia pacing or high-energy shocks to terminate potentially lethal ventricular arrhythmias; their use also risks the possibility of inappropriate shocks. Additionally, the high- voltage leads used in the RV for CRT-D devices historically have been less reliable than low- voltage pacing leads, which is particularly relevant to patients with pacemaker dependency [13]. Evidence Evidence for general indications For QRS duration 150 ms Randomized clinical trials have demonstrated that CRT reduces mortality, reduces hospitalizations, and improves functional status in patients with LVEF https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 6/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate 35 percent and QRS duration 150 ms (largely with LBBB) with NYHA functional class II, III, or ambulatory IV HF. NYHA class III or ambulatory class IV HF In a meta-analysis of 14 randomized trials including 4420 patients (nearly all with NYHA class III or IV symptoms, mean QRS range 155 to 209 ms), CRT increased the likelihood of improving by at least one NYHA class (59 versus 37 percent, relative risk [RR] 1.6, 95% CI 1.3-1.9). Hospitalizations for HF were reduced 37 percent, and all-cause mortality was reduced 22 percent, primarily because of a lower risk of HF-related death (RR 0.64, 95% CI 0.49-0.84) [14]. This meta-analysis included early crossover and randomized trials that demonstrated significant improvement in patients with NYHA class III to IV HF symptoms, six-minute walk distance, and NYHA functional class (MUSTIC, MIRACLE, VENTAK-CHF, CONTAK-CD) [15,16], as well as longer-term trials that corroborated these findings (COMPANION, CARE-HF) [6,17]. Additional support comes from imaging data demonstrating that CRT improves LVEF and reduces LV end-systolic volume (LVESV). For example, in the MIRACLE trial at six months, LVEF increased 3.6 percent in CRT patients versus 0.4 percent in controls, and LVESV decreased 25.6 mL compared with no change in controls [18]. Reduction in LVESV at six months by 10 percent, or "reverse remodeling," is associated with improved survival [19]. This relationship is graded; as LVESV decreases, survival improves incrementally [20]. NYHA class I or II A meta-analysis that included six trials with 4572 patients with QRS 150 ms and NYHA class I or II HFrEF (including patients with ICM and class I symptoms) found that CRT reduced HF events and improved functional status [21]. CRT significantly reduced the risk of death for patients with class II but not for class I HF [22]. There are limited data for CRT in patients with NYHA class I HF with NICM. Patients with NYHA class I and II HF were included in MADIT-CRT, REVERSE, and RAFT randomized trials [17,19,23,24]. These trials demonstrated a reduction in HF hospitalizations, improved LVEF, and reverse remodeling in patients who received CRT. Long-term follow-up (average of 2.4 years) of patients enrolled in the MADIT-CRT trial (85 percent with NYHA class II HF at baseline) demonstrated improved survival among patients receiving CRT with LBBB, LVEF 30 percent, and QRS duration 150 ms [25,26]. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 7/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate For QRS duration 120 to 149 ms and/or non-LBBB morphology For patients with LVEF 35 percent and either LBBB with QRS duration 120 to 149 ms or non-LBBB with QRS duration 150 ms, the benefits of CRT are less clear [6,16,17,23,25,27,28]. While subgroup analyses should be interpreted with some caution, a frequent finding in the trials and meta-analyses is that subgroups with shorter QRS durations or non-LBBB morphology appeared to benefit less from CRT than patients meeting more stringent QRS duration and morphology criteria [29-31]. However, a patient-level meta-analysis of randomized trials found that CRT reduced the risk of all-cause mortality in patients with a nonspecific intraventricular conduction delay >150 ms (all- cause mortality 32 versus 35 percent without CRT; adjusted hazard ratio [HR] 0.5, 95% CI 0.29- 0.89) [32]. However, the applicability of these findings to modern practice is limited by the small numbers of patients with non-LBBB and absence of modern medical and device therapies for HFrEF (eg, sodium-glucose co-transporter 2 inhibitors, multisite CRT pacing). The evidence for clinical benefit from CRT is stronger in patients with native QRS duration of 150 ms or greater than in patients with QRS duration between 120 and 149 ms [28,30,32-36]. A meta- analysis demonstrated that the risk of death or HF hospitalization was 42 percent lower (HR 0.58, 95% CI 0.50-0.68) in patients with QRS duration 150 ms or greater who received CRT-D compared with a standard ICD, whereas there was no difference in those with QRS duration 120 to 149 ms who received CRT-D (HR 0.95, 95% CI 0.83-1.10) [28]. Some experts have suggested that a true complete LBBB requires a QRS duration of at least 130 ms in women and 140 ms in men [34]. Evidence of lack of benefit and possible harm in patients with QRS duration <120 or <130 ms is discussed below. (See 'Groups unlikely to benefit' below.) Among patients treated with CRT, patients with non-LBBB QRS patterns, particularly right bundle branch block (RBBB), have less reverse remodeling and higher mortality compared with patients with LBBB [26,37,38]. There are inconsistent findings from post hoc studies and meta-analyses on the benefit of CRT in patients with RBBB regardless of QRS duration; a large patient-level meta-analysis of randomized trials found no clear benefit of CRT in this population [32,39,40]. There are limited data suggesting a benefit of CRT in patients with LVEF 35 percent and non- LBBB with QRS duration 120 to 149 ms. Meta-analyses of clinical trials have generated conflicting results on whether QRS morphology (LBBB versus non-LBBB) is a predictor of clinical benefit from CRT in patients with a QRS between 120 to 149 ms. [29,30,32,41]. Evidence for patients with LVEF between 35 and 50 percent The evidence to support use of CRT in selected patients with LVEF >35 and <50 percent is limited. The following studies support use of CRT to prevent adverse outcomes in patients with LVEF between 35 and 50 percent [42] and in patients who are anticipated to require frequent https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 8/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate ventricular pacing (>40 percent) [42,43]. The BLOCK-HF trial demonstrated that in HF patients (NYHA class I, II, and III symptoms and an LVEF between 30 and 50 percent) with AV block, CRT was superior to conventional RV pacing for the composite end point of death, HF event requiring intervention, or ventricular remodeling (45.8 versus 55.6 percent; HR 0.74, 95% CI 0.60-0.90) [42]. A similar effect was seen for the secondary end points of death or urgent HF visit (HR 0.73, 95% CI 0.57-0.92) and hospitalization for HF (HR 0.70, 95% CI 0.52-0.93). There was no significant difference in the risk of death (HR 0.83, 95% CI 0.61-1.14). The PAVE randomized trial demonstrated that patients undergoing AV junction ablation for atrial fibrillation had a better six-minute walk and LVEF with CRT compared with RV pacing, particularly in those with baseline HF symptoms and impaired systolic function [43]. Additional evidence on the effects of CRT in patients with atrial fibrillation is discussed separately. (See "Cardiac resynchronization therapy in atrial fibrillation".) For patients with an LVEF >35 and <50 percent with QRS duration 150 ms with LBBB (native or paced) and persistent severe HF (NYHA functional class III or IV) despite optimal evidence-based medical therapy for at least three months, the efficacy of CRT is not established. The rationale for CRT in this setting is based upon indirect evidence from trials in patients with LVEF 35 percent as well as the results of the BLOCK-HF trial in candidates for a pacemaker. We refer such patients for an individualized risk-benefit assessment of CRT-P. Groups unlikely to benefit CRT is unlikely to provide benefit and is probably associated with harm in the following clinical settings. Patients with a QRS duration <120 ms should not receive CRT based upon several randomized clinical trials showing no benefit from CRT-D compared with ICD in patients without QRS prolongation with NYHA class II to IV HF and echocardiographic evidence of mechanical dyssynchrony (RethinQ, Echo-CRT) [44,45]. In the EchoCRT trial in patients with a QRS duration <130 ms, overall mortality and cardiovascular mortality were higher with CRT-D compared with ICD [45]. Thus, for patients with QRS duration <120 ms, mechanical dyssynchrony should not be assessed with the objective of determining candidacy for CRT [45]. Patients with LVEF 50 percent should not receive CRT, as there are no clinical trials demonstrating CRT benefit in this context. For example, the PACE study demonstrated that while CRT was associated with the preservation of LVEF compared with RV pacing among https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 9/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate 177 patients with bradycardia, there were no differences in six-minute walk distance or quality of life at 12 months [46] or two years [47]. Nonrandomized, single-center studies suggest that CRT should not be used in nonambulatory NYHA class IV HF patients. Patients on chronic inotropic therapy for HF who receive CRT-D therapy have a poor prognosis and may not experience greater survival from CRT-D compared with ICD alone [48,49]. Evidence on CRT-D versus CRT-P Major society guidelines do not delineate the role of CRT-D versus CRT-P due to limited evidence. Only one randomized trial evaluated outcomes in separate arms for CRT-D and CRT-P (COMPANION) [17] but did not have adequate power to exclude clinically important differences. In an analysis not included in the original COMPANION report, all-cause mortality was nominally lower for CRT-D compared with CRT-P, but the difference was not significant (odds ratio 0.79, 95% CI 0.60-1.06) [50]. Other evidence is more circumstantial: The CARE-HF trial in patients with LVEF 35 percent, QRS prolongation, and NYHA class III or IV HF (nearly all class III) almost exclusively employed CRT-P. This therapy resulted in significantly lower risks of death compared with medical therapy alone at mean 29 months follow-up (20 versus 30 percent, HR 0.64, 95% CI 0.48-0.85) [6]. Most patients (62 percent) enrolled in CARE-HF had NICM. The trial provides strong evidence for use of CRT-P in this population with the objective of increasing survival but does not provide comparison with CRT-D. The DANISH trial in patients with NICM with LVEF 35 percent and NYHA class II to IV HF found no difference in mortality between those who received an ICD versus no ICD [51]. A sizable proportion of patients in both arms of the study (58 percent in both) received CRT (ie, CRT-D or CRT-P), suggesting that the benefit of CRT-P may be similar to that of CRT-D in this population. Some patient populations without prior sustained ventricular tachyarrhythmias may derive similar benefit from CRT-P compared with CRT-D. However, there are no randomized clinical trials addressing this issue, and there are no official recommendations in this respect in either European or United States guidelines. Older adults Most clinical trials did not enroll many older adult patients, particularly those 80 years old. Observational studies suggest that the frequency of ICD therapies decreases with age; among CRT recipients in the ALTITUDE registry, ICD shocks were 50 percent less common in CRT-D patients 80 years old compared with those <50 years old [52]. In https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 10/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate another study, appropriate CRT-D shocks were infrequent in patients 80 years of age (8 percent among 258 patients followed for 52 months) and were significantly less frequent than in CRT-D recipients <80 years of age [53,54]. NICM and LBBB This population may derive adequate benefit from CRT to obviate the need for defibrillator functionality [55]. The previously discussed DANISH trial provides indirect evidence of this hypothesis [51]. In an analysis from our center, smaller LV dimensions at CRT implant in NICM patients with "strictly defined" LBBB [34] were associated with lower risk of appropriate CRT-D shocks, and no patients with indexed LV 2 end-diastolic dimension (LVEDD) <3.36 cm/m height received a shock over 59 months follow-up [53,54]. NICM and pacemaker dependency These patients may also derive a benefit from CRT; in fact, many normalize LV function. In a study from our center, smaller LV dimensions (LVEDD <58 mm, LV end-systolic dimension <48 mm) and shorter time from cardiomyopathy diagnosis (<24 months) were associated with a higher likelihood of normalization of LVEF [56]. These findings are particularly relevant in patients who develop LV dysfunction with RV pacing in the setting of spontaneous or iatrogenic complete heart block. Pacemaker-dependent patients with NICM undergoing CRT upgrade had a much lower risk of device therapies for ventricular tachyarrhythmias than similar patients with known coronary artery disease in another small study [57]. NICM and lack of ventricular midwall fibrosis An observational study suggested that patients with NICM and without significant ventricular midwall fibrosis on cardiovascular magnetic resonance imaging may be a low-risk group in whom there may be no benefit from CRT-D compared with CRT-P, so some experts may favor CRT-P in this population [58]. Early implantation in new cardiomyopathy with LBBB There are data suggesting that, unlike patients with new cardiomyopathy and narrow QRS, patients with new cardiomyopathy and LBBB often do not achieve LVEF improvement with initial medical therapy [59]. Whether these patients should receive CRT-P before awaiting the outcome of medical therapy for three to nine months is unclear. Patients with congenital heart block who require ventricular pacing may also benefit from CRT. In a study of 42 patients with congenital heart block, patients who received a standard pacemaker were more likely to develop a cardiomyopathy than patients who did not require a pacemaker [60]. In four patients who subsequently underwent placement of a CRT device, LV dysfunction improved or stabilized. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 11/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate Patients with normalized or nearly normalized LVEF, with NICM who have no history of recorded ventricular tachyarrhythmias, should be counseled on whether to continue with a CRT-D device or switch to a CRT-P device at the time of generator change provided that switching hardware does not require insertion of new leads. In a meta-analysis of patients with significant improvement in LVEF ( 45 percent) after CRT and no secondary indication for ICD implantation, the incidence of appropriate ICD therapy during follow-up was significantly lower. Similarly, in a study from our group, patients who normalized their LV dimensions with CRT had a very low incidence of appropriate ICD therapy [61,62]. However, a MADIT-CRT post hoc analysis demonstrated that although the risk of ventricular tachyarrhythmias among CRT patients who had improved LVEF and no longer met a primary prevention ICD indication was reduced by over 50 percent, there remained a significant risk of arrhythmias during the ensuing two years [63]. Risks The risks of CRT are greater than those of single- or dual-chamber devices, as LV lead implantation increases procedural complexity, increases risk of infection, and reduces battery longevity, necessitating more frequent generator changes. In addition, there are reports of LV pacing inducing ventricular arrhythmias in a minority of CRT recipients [64]. Complications of CRT are discussed separately. (See "Cardiac resynchronization therapy in heart failure: System implantation and programming".) SHARED DECISION MAKING FOR CRT General considerations Because of the heterogeneity of benefit conferred by treatment as a function of patient factors, the lack of compelling data in some patient populations, and the frequency of comorbidities in patients with HF, decision making around CRT is often complex. Ultimately, the decision to pursue the therapy should be informed by best estimates of both benefits and risks in the context of shared decision making, which is defined as selecting therapy from the reasonable options that is aligned with the patient s values, goals, and preferences [65]. Indeed, the ACC/AHA/HRS guidelines specifically recommend informed shared decision making as integral to the provision of implantable cardioverter-defibrillator (ICD) and CRT therapy. Because many patients considered for CRT have advanced symptomatic HF, the discussion about device therapy will be part of a larger discussion about prognosis. (See "Palliative care for patients with advanced heart failure: Indications and systems of care", section on 'Disease course and prognosis'.) The capacity to estimate the benefits of CRT varies substantially based upon patient characteristics. In cases where benefits are not well established, the limitations of existing data should be openly acknowledged in the decision-making process. A patient-level analysis of five randomized trials of CRT found that quality of life (QoL) benefits at three months were predicted https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 12/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate by patient age, baseline QoL, and QRS duration [66]. Such statistical models may be useful in determining the likely advantages of undergoing CRT implantation. Further, clinicians must also elicit and consider the patient's care-related goals and preferences in order to achieve shared decision making [67]. Individualized risk-benefit assessment Because CRT is associated with risk, both acutely during implantation and chronically, the risk-benefit ratio of CRT implant must be considered in each individual patient, particularly in those with less compelling indications. The CRT implantation procedure is longer, entails more procedural risk, and may increase the risk of infection compared with standard ICD or pacemaker implantations. LV leads have an increased risk of dislodgment or pacing the phrenic nerve compared with traditional RV leads. Battery longevity is generally shorter for CRT devices compared with conventional ICDs or pacemakers. Another consideration is that not all patients with similar indications for CRT derive similar benefits, but a means of identifying patients with indications for CRT who will fail to benefit has not been established. Approximately one-third of CRT recipients are deemed "nonresponders" [68], although the definition of "response" is not standardized [69]. Definitions of response include improvement in exercise capacity, improved QoL via standardized assessments, improvement in New York Heart Association (NYHA) status by at least one class, prevention of HF hospitalizations, and LV reverse remodeling. A subset of patients may be "negative responders" and become worse with CRT. Increased risk with an upgrade procedure Intervening on a device system already in place (ie, CRT "upgrade") entails increased risk of infection and complications compared with de novo implant or generator change only. In the REPLACE registry, the six-month major complication rate for CRT upgrades was 18.7 percent, compared with 4.0 percent for patients undergoing generator change only [70]. The threshold for upgrading an existing device to CRT is thus higher than for a de novo implant. A stand-alone "upgrade" procedure in patients with an existing pacemaker or ICD should be considered only after careful consideration of the risk-benefit balance. Factors associated with less benefit from CRT Greater scar burden, as assessed by either myocardial perfusion or cardiovascular magnetic resonance imaging, is associated with less improvement in LV ejection fraction, less reverse remodeling, and higher mortality among patients treated with CRT [71]. However, there are no randomized trials assessing whether patients with high scar burden benefit less from CRT. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 13/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate As discussed above, among patients treated with CRT, non-left bundle branch block (LBBB) QRS patterns, particularly right bundle branch block, are associated with less reverse remodeling and higher mortality compared with LBBB. (See 'Groups unlikely to benefit' above.) As discussed above, a native QRS duration between 120 and 149 ms predicts less clinical benefit from CRT than QRS duration 150 ms or greater. (See 'Groups unlikely to benefit' above.) Because milder HF symptoms are associated with a lower baseline risk of morbidity and mortality, the estimated absolute risk reduction from CRT is lower in those with less severe symptoms. For patients with less compelling indications and in patients for whom CRT would be a stand-alone upgrade procedure rather than a de novo implant, NYHA functional class is an important factor in decision making, as the risk-benefit balance may favor CRT in more advanced HF symptoms and not favor CRT in those patients with less severe symptoms. Competing causes of cardiopulmonary morbidity and mortality Patients with severe chronic obstructive pulmonary disease (COPD) may not derive symptomatic benefit from CRT if their symptoms are predominantly caused by COPD [72]. Clinically, identifying the cause of dyspnea in patients with both HF and COPD can be challenging. Patients with severe renal insufficiency may benefit less from CRT and may also not benefit from ICDs [73,74]. Median survival after an appropriate CRT-D shock in patients with severe renal insufficiency was only 90 days in one observational study [75]. The risk of device- related infection is also higher in this population [24]. Hemodialysis is associated with a high rate of device complications, including hematoma, pocket infection, bacteremia with endovascular lead infection, and compromise of hemodialysis access [76]. Patients on hemodialysis also may have limited access for intravascular lead placement. There are no randomized trials demonstrating mortality benefit in older adult patients, particularly those over 80 years of age. The risk of sudden cardiac death decreases with advancing age, whereas the risk of progressive pump failure increases. CRT-pacemaker may be a better option in clinically eligible older patients with significant symptoms of HF compared with CRT-defibrillator. (See 'Indications for referral for CRT' above.)

incidence of appropriate ICD therapy [61,62]. However, a MADIT-CRT post hoc analysis demonstrated that although the risk of ventricular tachyarrhythmias among CRT patients who had improved LVEF and no longer met a primary prevention ICD indication was reduced by over 50 percent, there remained a significant risk of arrhythmias during the ensuing two years [63]. Risks The risks of CRT are greater than those of single- or dual-chamber devices, as LV lead implantation increases procedural complexity, increases risk of infection, and reduces battery longevity, necessitating more frequent generator changes. In addition, there are reports of LV pacing inducing ventricular arrhythmias in a minority of CRT recipients [64]. Complications of CRT are discussed separately. (See "Cardiac resynchronization therapy in heart failure: System implantation and programming".) SHARED DECISION MAKING FOR CRT General considerations Because of the heterogeneity of benefit conferred by treatment as a function of patient factors, the lack of compelling data in some patient populations, and the frequency of comorbidities in patients with HF, decision making around CRT is often complex. Ultimately, the decision to pursue the therapy should be informed by best estimates of both benefits and risks in the context of shared decision making, which is defined as selecting therapy from the reasonable options that is aligned with the patient s values, goals, and preferences [65]. Indeed, the ACC/AHA/HRS guidelines specifically recommend informed shared decision making as integral to the provision of implantable cardioverter-defibrillator (ICD) and CRT therapy. Because many patients considered for CRT have advanced symptomatic HF, the discussion about device therapy will be part of a larger discussion about prognosis. (See "Palliative care for patients with advanced heart failure: Indications and systems of care", section on 'Disease course and prognosis'.) The capacity to estimate the benefits of CRT varies substantially based upon patient characteristics. In cases where benefits are not well established, the limitations of existing data should be openly acknowledged in the decision-making process. A patient-level analysis of five randomized trials of CRT found that quality of life (QoL) benefits at three months were predicted https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 12/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate by patient age, baseline QoL, and QRS duration [66]. Such statistical models may be useful in determining the likely advantages of undergoing CRT implantation. Further, clinicians must also elicit and consider the patient's care-related goals and preferences in order to achieve shared decision making [67]. Individualized risk-benefit assessment Because CRT is associated with risk, both acutely during implantation and chronically, the risk-benefit ratio of CRT implant must be considered in each individual patient, particularly in those with less compelling indications. The CRT implantation procedure is longer, entails more procedural risk, and may increase the risk of infection compared with standard ICD or pacemaker implantations. LV leads have an increased risk of dislodgment or pacing the phrenic nerve compared with traditional RV leads. Battery longevity is generally shorter for CRT devices compared with conventional ICDs or pacemakers. Another consideration is that not all patients with similar indications for CRT derive similar benefits, but a means of identifying patients with indications for CRT who will fail to benefit has not been established. Approximately one-third of CRT recipients are deemed "nonresponders" [68], although the definition of "response" is not standardized [69]. Definitions of response include improvement in exercise capacity, improved QoL via standardized assessments, improvement in New York Heart Association (NYHA) status by at least one class, prevention of HF hospitalizations, and LV reverse remodeling. A subset of patients may be "negative responders" and become worse with CRT. Increased risk with an upgrade procedure Intervening on a device system already in place (ie, CRT "upgrade") entails increased risk of infection and complications compared with de novo implant or generator change only. In the REPLACE registry, the six-month major complication rate for CRT upgrades was 18.7 percent, compared with 4.0 percent for patients undergoing generator change only [70]. The threshold for upgrading an existing device to CRT is thus higher than for a de novo implant. A stand-alone "upgrade" procedure in patients with an existing pacemaker or ICD should be considered only after careful consideration of the risk-benefit balance. Factors associated with less benefit from CRT Greater scar burden, as assessed by either myocardial perfusion or cardiovascular magnetic resonance imaging, is associated with less improvement in LV ejection fraction, less reverse remodeling, and higher mortality among patients treated with CRT [71]. However, there are no randomized trials assessing whether patients with high scar burden benefit less from CRT. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 13/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate As discussed above, among patients treated with CRT, non-left bundle branch block (LBBB) QRS patterns, particularly right bundle branch block, are associated with less reverse remodeling and higher mortality compared with LBBB. (See 'Groups unlikely to benefit' above.) As discussed above, a native QRS duration between 120 and 149 ms predicts less clinical benefit from CRT than QRS duration 150 ms or greater. (See 'Groups unlikely to benefit' above.) Because milder HF symptoms are associated with a lower baseline risk of morbidity and mortality, the estimated absolute risk reduction from CRT is lower in those with less severe symptoms. For patients with less compelling indications and in patients for whom CRT would be a stand-alone upgrade procedure rather than a de novo implant, NYHA functional class is an important factor in decision making, as the risk-benefit balance may favor CRT in more advanced HF symptoms and not favor CRT in those patients with less severe symptoms. Competing causes of cardiopulmonary morbidity and mortality Patients with severe chronic obstructive pulmonary disease (COPD) may not derive symptomatic benefit from CRT if their symptoms are predominantly caused by COPD [72]. Clinically, identifying the cause of dyspnea in patients with both HF and COPD can be challenging. Patients with severe renal insufficiency may benefit less from CRT and may also not benefit from ICDs [73,74]. Median survival after an appropriate CRT-D shock in patients with severe renal insufficiency was only 90 days in one observational study [75]. The risk of device- related infection is also higher in this population [24]. Hemodialysis is associated with a high rate of device complications, including hematoma, pocket infection, bacteremia with endovascular lead infection, and compromise of hemodialysis access [76]. Patients on hemodialysis also may have limited access for intravascular lead placement. There are no randomized trials demonstrating mortality benefit in older adult patients, particularly those over 80 years of age. The risk of sudden cardiac death decreases with advancing age, whereas the risk of progressive pump failure increases. CRT-pacemaker may be a better option in clinically eligible older patients with significant symptoms of HF compared with CRT-defibrillator. (See 'Indications for referral for CRT' above.) https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 14/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate CONTRAINDICATIONS General contraindications to placement of a cardiac implantable electronic device such as active bloodstream infection and anesthetic concerns also apply to potential candidates for CRT implantation. (See "Anesthetic considerations for electrophysiology procedures", section on 'Procedures for cardiac implantable electronic devices'.) For patients in whom transvenous placement of CRT is not feasible, including those lacking subclavian access, a surgical approach may be an alternative. (See 'Choice of CRT system' below.) We concur with guidelines that CRT is not indicated in patients whose frailty or comorbidities limit expected survival with good functional capacity to less than one year [8]. We avoid CRT in the following clinical settings in which CRT is unlikely to be of benefit: Although there are no high-quality studies that examine the use of CRT in patients receiving mechanical circulatory support (eg, LV assist devices [LVAD]), the benefit of CRT in this group of patients is likely low given that the LVAD subsumes much of the cardiac output generated by the LV. De novo CRT should not be provided to these patients. The role of preexisting CRT in this population has not been conclusively studied, although a small study suggests that RV pacing alone is equivalent if not superior to CRT in terms of functional status and ventricular tachyarrhythmia burden [77]. This study supports our practice of deactivating CRT in patients with LVADs, which has the added benefit of battery preservation. If patients with a history of ventricular arrhythmias have recurrences with CRT deactivation, anecdotal experience suggests that reactivation may reduce the risk of recurrent arrhythmias. (See "Treatment of advanced heart failure with a durable mechanical circulatory support device".) Inotrope-dependent patients have a markedly increased risk of death, need for cardiac transplant, or transition to LVAD support even with CRT as compared with non-inotrope- dependent patients. The benefits of CRT in this population appear to be limited [48]. We avoid CRT in these patients unless a strong indication exists. Patients who possibly should not receive CRT include those in whom the procedure or presence of multiple intravascular leads are associated with increased complications. The role of CRT in patients with end-stage kidney disease is uncertain given the risk of complications and uncertain benefit. (See 'Groups unlikely to benefit' above.) https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 15/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate CHOICE OF CRT SYSTEM Initial approach In patients with HF with reduced ejection fraction (HFrEF) who have an indication for CRT, we suggest placement of a coronary sinus lead as the initial approach to establishing CRT, rather than conduction system pacing. Epicardial lead placement is reserved for patients who cannot undergo coronary sinus lead placement or who have an indication for cardiac surgery, such as coronary artery bypass grafting or valve replacement [78]. (See 'Epicardial lead placement' below.) Professional society guidelines also have a weak preference for CRT with a coronary sinus lead compared with conduction system pacing [79]. Our approach is influenced by our experience with coronary sinus lead placement, the higher likelihood of successful coronary sinus lead placement (>95 percent versus approximately 85 percent with conduction system pacing), and the greater amount of data on the efficacy and safety of coronary sinus leads. Conduction system pacing may have higher rates of significant complications at implantation (eg, coronary artery injury, LV cavity perforation), and the long- term complications of conduction system leads (eg, battery drain, ability to extract the lead) are unknown. The evidence includes: In trials that established the benefit of CRT therapy in patients with HFrEF, the initial approach to lead placement was via the coronary sinus, and conduction system pacing was not an option [15-19]. These studies are described in detail elsewhere in this topic. (See 'For QRS duration 150 ms' above.) In a trial that included 40 patients with nonischemic cardiomyopathy and left bundle branch block, random assignment to CRT with a left bundle branch area pacing (LBBAP) lead was associated with a greater increase in LVEF at six months compared with CRT using a coronary sinus lead (difference in LVEF at six months 5.6 percent; 95% CI 0.3-10.9), but other important markers of CRT effectiveness (eg, LV end-diastolic dimension, six-minute walk time) were similar between the two groups [80]. Lead dislodgement occurred in one patient assigned to LBBAP and none of the patients assigned to coronary sinus pacing. Though this direct comparison between coronary sinus pacing and conduction system pacing did not show large differences between the two methods, the sample size was too low and follow-up too short to conclusively establish the safety of conduction system pacing. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 16/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate In a registry that included 2533 patients who underwent CRT with an LBBAP lead, placement of the lead was successful in 84 percent of the 696 patients with HF [81]. In the overall sample, complications related to LBBAP lead placement included intraprocedural perforation into the LV cavity (4 percent), ST-segment elevation in multiple leads (1 percent), and lead dislodgement (1.5 percent). In a study that included 100 patients with HF who underwent CRT using a coronary sinus lead (n = 51) or an LBBAP lead (n = 49), HF hospitalization and mortality were similar between the two groups [82]. The rate of improvement in LVEF of >5 percent was similar between the two groups (86 versus 80 percent). One patient had a coronary sinus lead dislodgement. Alternative approaches In patients who cannot undergo placement of a coronary sinus lead, the approach to placement of a conduction system pacing lead or an epicardial lead is individualized to the patient s characteristics and experience with alternative lead placement. Conduction system pacing Pacing of the His bundle or left bundle branch via a lead in the right ventricle fixed to the septum (ie, conduction system pacing) can be used to resynchronize the right and left ventricle. Leads placed in this position may be more unstable, may injure the septal coronary arteries, and may be more difficult to extract, particularly left bundle branch area pacing leads [83]. In patients who cannot undergo placement of a coronary sinus lead, the decision to implant a CRT system with a conduction system pacing lead (ie, His bundle lead, LBBAP lead) is individualized to the patient and depends on the implanting center's experience with conduction system lead placement. Conduction system pacing is a reasonable option for CRT in patients in whom epicardial lead placement via a surgical approach is undesirable. Professional guidelines describe a similar approach to conduction system pacing [84]. Epicardial lead placement A CRT lead can be placed on the epicardial surface of the lateral LV via a lateral thoracotomy or during cardiac surgery performed for a separate indication. Patients in whom epicardial lead placement should be considered include: Failed placement of a percutaneous lead In patients who cannot undergo traditional coronary sinus lead placement and in whom the benefits of CRT outweigh the risk of lead placement, epicardial lead placement is an option for CRT pacing. However, the efficacy and safety of this approach are determined by the patient's suitability for surgery and institutional surgical experience. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 17/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate The evidence on epicardial lead placement includes small studies and one trial, which describe variable rates of morbidity, mortality, and successful lead implantation [85-88]. As examples: In a randomized trial that included 80 patients with HFrEF from 2008, patients randomly assigned to epicardial lead placement had a longer length of intensive care unit stay (3.8 versus 0.34 days) and longer ventilation time (3.2 versus 0.3 hours) compared with those with coronary venous lead placement [88]. Notably, one study described unfavorable anterior lead placement in 44 percent of patients undergoing epicardial lead placement and 5 percent of patients undergoing coronary sinus lead placement [87]. Patients who will undergo cardiac surgery for a separate indication In patients with HFrEF who will undergo cardiac surgery (eg, coronary artery bypass grafting) and who have an indication for CRT, it is reasonable to place an epicardial lead at the time of surgery rather than attempting coronary sinus lead placement after surgery. This approach is motivated by the desire to avoid the need for a subsequent thoracotomy if placement of a coronary sinus lead is not technically feasible, which occurs in approximately 3 to 5 percent of patients [89]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Heart failure in adults" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 18/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Cardiac resynchronization therapy (The Basics)") SUMMARY AND RECOMMENDATIONS Rationale for CRT Cardiac resynchronization therapy (CRT) involves pacing of the left and right ventricles to restore ventricular synchrony and thus improve left ventricular (LV) systolic function, symptoms of heart failure (HF), survival for selected patients with LV systolic dysfunction, and electrocardiographic evidence of dyssynchrony. (See 'Rationale for CRT' above.) CRT for patients in sinus rhythm Indications for CRT for patients in sinus rhythm are based upon LV ejection fraction (LVEF), QRS duration, QRS morphology, New York Heart Association (NYHA) functional class, and need for ventricular pacing. The recommendations are predicated on a discussion with the patient about the risks and benefits of the procedure in the context of shared decision making. The approach is as follows (see 'CRT indications in sinus rhythm' above): For patients with LVEF 35 percent The following general indications apply to patients with LVEF 35 percent on optimal evidence-based medical therapy for at least three months after initial diagnosis (or for at least 40 days after myocardial infarction) and after identification and treatment of any reversible causes of persistent HF (such as myocardial ischemia or tachycardia-induced cardiomyopathy) ( algorithm 1) (see 'For patients with LVEF 35 percent' above and 'Evidence for general indications' above): QRS 150 ms with LBBB For patients with QRS 150 ms with left bundle branch block (LBBB) and NYHA class II to ambulatory class IV HF, we recommend referral for CRT (Grade 1A). These patients also meet criteria for implantable cardioverter- defibrillator (ICD) therapy for primary prevention of sudden cardiac death. (See 'For QRS duration 150 ms' above and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) We also suggest referral for CRT in patients with NYHA class I HF and ischemic cardiomyopathy (ICM) (Grade 2B). Patients with ICM with LVEF 30 percent on medical therapy also meet criteria for ICD placement. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 19/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate Based on indirect evidence from patients with ICM, some experts (including the authors of this topic) also refer patients with NYHA class I HF and nonischemic cardiomyopathy for an individualized risk-benefit assessment of CRT. These patients do not generally meet criteria for ICD placement. (See 'For QRS duration 150 ms' above and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) QRS 150 ms with non-LBBB For patients with QRS 150 ms with non-LBBB pattern and NYHA functional class III or ambulatory class IV HF symptoms, we suggest referral for CRT (Grade 2B). For patients with mild (NYHA class II) HF symptoms, we refer for an individualized risk-benefit assessment of CRT. QRS <150 ms For patients with QRS 130 to 149 ms with LBBB and NYHA class II to ambulatory class IV HF, we suggest referral for CRT (Grade 2B). (See 'For QRS duration 120 to 149 ms and/or non-LBBB morphology' above.) For patients with QRS 120 to 149 ms with non-LBBB pattern, persistent NYHA functional class III or ambulatory class IV HF, and recurrent HF hospitalizations despite optimal medical therapy, we refer for an individualized risk-benefit assessment of CRT. (See 'For QRS duration 120 to 149 ms and/or non-LBBB morphology' above.) For patients with LVEF between 35 and 50 percent For most patients with LVEF >35 and <50 percent, the benefits of CRT are not likely to outweigh the risks. However, CRT may be of benefit in the following select circumstances ( algorithm 2) (see 'For patients with LVEF between 35 and 50 percent' above): For patients who require a pacemaker (including patients undergoing atrioventricular junction ablation), have an LVEF <50 percent, and are anticipated to require frequent ventricular pacing (>40 percent of the time), we suggest referral for CRT (Grade 2B). (See 'Evidence for patients with LVEF between 35 and 50 percent' above.) For patients with QRS duration 150 ms with LBBB (native or paced) and persistent severe HF (NYHA functional class III or IV) despite optimal evidence-based medical therapy for at least three months, we refer for an individualized risk-benefit assessment of CRT-pacemaker (CRT-P). The efficacy of CRT in this population is not established. The rationale for CRT in this setting is based upon indirect evidence https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 20/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate from trials in patients with LVEF 35 percent and a single trial in pacemaker candidates. (See 'Evidence for patients with LVEF between 35 and 50 percent' above.) CRT for patients not in sinus rhythm Recommendations for patients with persistent atrial fibrillation are discussed separately. (See "Cardiac resynchronization therapy in atrial fibrillation".) Choice of CRT with or without defibrillator functionality CRT-P and CRT-defibrillator (CRT-D) should be discussed with all patients referred for CRT. Those populations with less likelihood of incremental benefit from CRT-D compared with CRT-P include older patients, patients without coronary artery disease (particularly if the LV is not dilated), and pacemaker-dependent patients. (See 'Choice between CRT-D versus CRT-P' above.) Contraindications General contraindications to placement of a cardiac implantable electronic device (such as active bloodstream infection) apply to potential candidates for CRT implantation. We also avoid CRT implantation in patients unlikely to benefit from it, such as patients whose comorbidities or frailty limit survival with good functional capacity to less than one year. (See 'Contraindications' above.) Choice of CRT system In patients with HF with reduced ejection fraction (HFrEF) who have an indication for CRT, we suggest placement of a coronary sinus lead as the initial approach to establishing CRT, rather than conduction system pacing (eg, left bundle branch area pacing [LBBAP], His bundle pacing) (Grade 2C). (See 'Alternative approaches' above and 'Conduction system pacing' above.) Epicardial lead placement is reserved for patients who cannot undergo coronary sinus lead placement or who have an indication for cardiac surgery, such as coronary artery bypass grafting or valve replacement. (See 'Epicardial lead placement' above.) ACKNOWLEDGMENTS The editorial staff at UpToDate acknowledges Leslie Saxon, MD, Teresa DeMarco, MD, and Wilson Colucci, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. 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The benefit of cardiac resynchronization therapy and QRS duration: a meta-analysis. J Cardiovasc Electrophysiol 2012; 23:163. 29. Sipahi I, Chou JC, Hyden M, et al. Effect of QRS morphology on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials. Am Heart J 2012; 163:260. 30. Cleland JG, Abraham WT, Linde C, et al. An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure. Eur Heart J 2013; 34:3547. 31. Kang SH, Oh IY, Kang DY, et al. Cardiac resynchronization therapy and QRS duration: systematic review, meta-analysis, and meta-regression. J Korean Med Sci 2015; 30:24. 32. Friedman DJ, Al-Khatib SM, Dalgaard F, et al. Cardiac Resynchronization Therapy Improves Outcomes in Patients With Intraventricular Conduction Delay But Not Right Bundle Branch Block: A Patient-Level Meta-Analysis of Randomized Controlled Trials. Circulation 2023; 147:812. 33. Sipahi I, Carrigan TP, Rowland DY, et al. Impact of QRS duration on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials. Arch Intern Med 2011; 171:1454. 34. Strauss DG, Selvester RH, Wagner GS. Defining left bundle branch block in the era of cardiac resynchronization therapy. Am J Cardiol 2011; 107:927. 35. Woods B, Hawkins N, Mealing S, et al. Individual patient data network meta-analysis of mortality effects of implantable cardiac devices. Heart 2015; 101:1800. 36. Zusterzeel R, Selzman KA, Sanders WE, et al. Cardiac resynchronization therapy in women: US Food and Drug Administration meta-analysis of patient-level data. JAMA Intern Med 2014; 174:1340. 37. Peterson PN, Greiner MA, Qualls LG, et al. QRS duration, bundle-branch block morphology, and outcomes among older patients with heart failure receiving cardiac resynchronization therapy. JAMA 2013; 310:617. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 24/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate 38. Leong DP, H ke U, Delgado V, et al. Predictors of long-term benefit of cardiac resynchronization therapy in patients with right bundle branch block. Eur Heart J 2012; 33:1934. 39. Birnie DH, Ha A, Higginson L, et al. Impact of QRS morphology and duration on outcomes after cardiac resynchronization therapy: Results from the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT). Circ Heart Fail 2013; 6:1190. 40. Fantoni C, Kawabata M, Massaro R, et al. 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Combined resynchronisation and implantable defibrillator therapy in left ventricular dysfunction: Bayesian network meta-analysis of randomised controlled trials. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 25/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate BMJ 2007; 335:925. 51. K ber L, Thune JJ, Nielsen JC, et al. Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure. N Engl J Med 2016; 375:1221. 52. Saba S, Adelstein E, Wold N, et al. Influence of patients' age at implantation on mortality and defibrillator shocks. Europace 2017; 19:802. 53. Adelstein EC, Jain S, Wang NC, et al. Left Ventricular Dimensions Predict Risk of Appropriate Shocks but Not Mortality in Cardiac Resynchronization Therapy-Defibrillator Recipients with Left Bundle-Branch Block and Non-Ischemic Cardiomyopathy. Europace 2016. 54. 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heart failure. N Engl J Med 2010; 363:2385. 24. Bloom H, Heeke B, Leon A, et al. Renal insufficiency and the risk of infection from pacemaker or defibrillator surgery. Pacing Clin Electrophysiol 2006; 29:142. 25. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009; 361:1329. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 23/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate 26. Biton Y, Kutyifa V, Cygankiewicz I, et al. Relation of QRS Duration to Clinical Benefit of Cardiac Resynchronization Therapy in Mild Heart Failure Patients Without Left Bundle Branch Block: The Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy Substudy. Circ Heart Fail 2016; 9:e002667. 27. Linde C, Abraham WT, Gold MR, et al. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol 2008; 52:1834. 28. Stavrakis S, Lazzara R, Thadani U. The benefit of cardiac resynchronization therapy and QRS duration: a meta-analysis. J Cardiovasc Electrophysiol 2012; 23:163. 29. Sipahi I, Chou JC, Hyden M, et al. Effect of QRS morphology on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials. Am Heart J 2012; 163:260. 30. Cleland JG, Abraham WT, Linde C, et al. An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure. Eur Heart J 2013; 34:3547. 31. Kang SH, Oh IY, Kang DY, et al. Cardiac resynchronization therapy and QRS duration: systematic review, meta-analysis, and meta-regression. J Korean Med Sci 2015; 30:24. 32. Friedman DJ, Al-Khatib SM, Dalgaard F, et al. Cardiac Resynchronization Therapy Improves Outcomes in Patients With Intraventricular Conduction Delay But Not Right Bundle Branch Block: A Patient-Level Meta-Analysis of Randomized Controlled Trials. Circulation 2023; 147:812. 33. Sipahi I, Carrigan TP, Rowland DY, et al. Impact of QRS duration on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials. Arch Intern Med 2011; 171:1454. 34. Strauss DG, Selvester RH, Wagner GS. Defining left bundle branch block in the era of cardiac resynchronization therapy. Am J Cardiol 2011; 107:927. 35. Woods B, Hawkins N, Mealing S, et al. Individual patient data network meta-analysis of mortality effects of implantable cardiac devices. Heart 2015; 101:1800. 36. Zusterzeel R, Selzman KA, Sanders WE, et al. Cardiac resynchronization therapy in women: US Food and Drug Administration meta-analysis of patient-level data. JAMA Intern Med 2014; 174:1340. 37. Peterson PN, Greiner MA, Qualls LG, et al. QRS duration, bundle-branch block morphology, and outcomes among older patients with heart failure receiving cardiac resynchronization therapy. JAMA 2013; 310:617. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 24/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate 38. Leong DP, H ke U, Delgado V, et al. Predictors of long-term benefit of cardiac resynchronization therapy in patients with right bundle branch block. Eur Heart J 2012; 33:1934. 39. Birnie DH, Ha A, Higginson L, et al. Impact of QRS morphology and duration on outcomes after cardiac resynchronization therapy: Results from the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT). Circ Heart Fail 2013; 6:1190. 40. Fantoni C, Kawabata M, Massaro R, et al. Right and left ventricular activation sequence in patients with heart failure and right bundle branch block: a detailed analysis using three- dimensional non-fluoroscopic electroanatomic mapping system. J Cardiovasc Electrophysiol 2005; 16:112. 41. Cunnington C, Kwok CS, Satchithananda DK, et al. Cardiac resynchronisation therapy is not associated with a reduction in mortality or heart failure hospitalisation in patients with non- left bundle branch block QRS morphology: meta-analysis of randomised controlled trials. Heart 2015; 101:1456. 42. Curtis AB, Worley SJ, Adamson PB, et al. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med 2013; 368:1585. 43. Doshi RN, Daoud EG, Fellows C, et al. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc Electrophysiol 2005; 16:1160. 44. Beshai JF, Grimm RA, Nagueh SF, et al. Cardiac-resynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med 2007; 357:2461. 45. Ruschitzka F, Abraham WT, Singh JP, et al. Cardiac-resynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med 2013; 369:1395. 46. Yu CM, Chan JY, Zhang Q, et al. Biventricular pacing in patients with bradycardia and normal ejection fraction. N Engl J Med 2009; 361:2123. 47. Chan JY, Fang F, Zhang Q, et al. Biventricular pacing is superior to right ventricular pacing in bradycardia patients with preserved systolic function: 2-year results of the PACE trial. Eur Heart J 2011; 32:2533. 48. Bhattacharya S, Abebe K, Simon M, et al. Role of cardiac resynchronization in end-stage heart failure patients requiring inotrope therapy. J Card Fail 2010; 16:931. 49. Adelstein E, Bhattacharya S, Simon MA, et al. Comparison of outcomes for patients with nonischemic cardiomyopathy taking intravenous inotropes versus those weaned from or never taking inotropes at cardiac resynchronization therapy. Am J Cardiol 2012; 110:857. 50. Lam SK, Owen A. Combined resynchronisation and implantable defibrillator therapy in left ventricular dysfunction: Bayesian network meta-analysis of randomised controlled trials. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 25/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate BMJ 2007; 335:925. 51. K ber L, Thune JJ, Nielsen JC, et al. Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure. N Engl J Med 2016; 375:1221. 52. Saba S, Adelstein E, Wold N, et al. Influence of patients' age at implantation on mortality and defibrillator shocks. Europace 2017; 19:802. 53. Adelstein EC, Jain S, Wang NC, et al. Left Ventricular Dimensions Predict Risk of Appropriate Shocks but Not Mortality in Cardiac Resynchronization Therapy-Defibrillator Recipients with Left Bundle-Branch Block and Non-Ischemic Cardiomyopathy. Europace 2016. 54. Adelstein EC, Liu J, Jain S, et al. Clinical outcomes in cardiac resynchronization therapy- defibrillator recipients 80 years of age and older. Europace 2016; 18:420. 55. Witt CT, Kronborg MB, Nohr EA, et al. Adding the implantable cardioverter-defibrillator to cardiac resynchronization therapy is associated with improved long-term survival in ischaemic, but not in non-ischaemic cardiomyopathy. Europace 2016; 18:413. 56. Adelstein E, Schwartzman D, Gorcsan J 3rd, Saba S. Predicting hyperresponse among pacemaker-dependent nonischemic cardiomyopathy patients upgraded to cardiac resynchronization. J Cardiovasc Electrophysiol 2011; 22:905. 57. Adelstein E, Schwartzman D, Bazaz R, et al. Outcomes in pacemaker-dependent patients upgraded from conventional pacemakers to cardiac resynchronization therapy- defibrillators. Heart Rhythm 2014; 11:1008. 58. Leyva F, Zegard A, Acquaye E, et al. Outcomes of Cardiac Resynchronization Therapy With or Without Defibrillation in Patients With Nonischemic Cardiomyopathy. J Am Coll Cardiol 2017; 70:1216. 59. Wang NC, Singh M, Adelstein EC, et al. New-onset left bundle branch block-associated idiopathic nonischemic cardiomyopathy and left ventricular ejection fraction response to guideline-directed therapies: The NEOLITH study. Heart Rhythm 2016; 13:933. 60. Rangavajla G, Mulukutla S, Thoma F, et al. Ventricular pacing and myocardial function in patient with congenital heart block. J Cardiovasc Electrophysiol 2021; 32:2684. 61. Chatterjee NA, Roka A, Lubitz SA, et al. Reduced appropriate implantable cardioverter- defibrillator therapy after cardiac resynchronization therapy-induced left ventricular function recovery: a meta-analysis and systematic review. Eur Heart J 2015; 36:2780. 62. Adelstein EC, Schwartzman D, Jain S, et al. Left ventricular dimensions predict risk of appropriate shocks but not mortality in cardiac resynchronization therapy-defibrillator recipients with left bundle-branch block and non-ischemic cardiomyopathy. Europace 2017; 19:1689. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 26/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate 63. Sherazi S, Shah F, Kutyifa V, et al. Risk of Ventricular Tachyarrhythmic Events in Patients Who Improved Beyond Guidelines for a Defibrillator in MADIT-CRT. JACC Clin Electrophysiol 2019; 5:1172. 64. Bradfield JS, Shivkumar K. Cardiac resynchronization therapy-induced proarrhythmia: understanding preferential conduction within myocardial scars. Circ Arrhythm Electrophysiol 2014; 7:1000. 65. Allen LA, Stevenson LW, Grady KL, et al. Decision making in advanced heart failure: a scientific statement from the American Heart Association. Circulation 2012; 125:1928. 66. Nassif ME, Tang Y, Cleland JG, et al. Precision Medicine for Cardiac Resynchronization: Predicting Quality of Life Benefits for Individual Patients-An Analysis From 5 Clinical Trials. Circ Heart Fail 2017; 10. 67. Cardiac Resynchronization Therapy with Defibrillation (CRT-D). Colorado Program for Patient Centered Decisions. https://patientdecisionaid.org/icd-crt-2/ (Accessed on June 14, 2023). 68. Gorcsan J 3rd. Finding pieces of the puzzle of nonresponse to cardiac resynchronization therapy. Circulation 2011; 123:10. 69. Fornwalt BK, Sprague WW, BeDell P, et al. Agreement is poor among current criteria used to define response to cardiac resynchronization therapy. Circulation 2010; 121:1985. 70. Poole JE, Gleva MJ, Mela T, et al. Complication rates associated with pacemaker or implantable cardioverter-defibrillator generator replacements and upgrade procedures: results from the REPLACE registry. Circulation 2010; 122:1553. 71. Adelstein EC, Tanaka H, Soman P, et al. Impact of scar burden by single-photon emission computed tomography myocardial perfusion imaging on patient outcomes following cardiac resynchronization therapy. Eur Heart J 2011; 32:93. 72. Razak E, Kamireddy S, Saba S. Implantable cardioverter-defibrillators confer survival benefit in patients with chronic obstructive pulmonary disease. Pacing Clin Electrophysiol 2010; 33:1125. 73. Pun PH, Al-Khatib SM, Han JY, et al. Implantable cardioverter-defibrillators for primary prevention of sudden cardiac death in CKD: a meta-analysis of patient-level data from 3 randomized trials. Am J Kidney Dis 2014; 64:32. 74. Goldenberg I, Vyas AK, Hall WJ, et al. Risk stratification for primary implantation of a cardioverter-defibrillator in patients with ischemic left ventricular dysfunction. J Am Coll Cardiol 2008; 51:288. 75. Adelstein EC, Saba S, Jain S, Wang NC. Severe chronic kidney disease is associated with poor survival after initial CRT-defibrillator tachyarrhythmia therapy. Pacing Clin Electrophysiol https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 27/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate 2020; 43:78. 76. Dasgupta A, Montalvo J, Medendorp S, et al. Increased complication rates of cardiac rhythm management devices in ESRD patients. Am J Kidney Dis 2007; 49:656. 77. Chung BB, Grinstein JS, Imamura T, et al. Biventricular Pacing Versus Right Ventricular Pacing in Patients Supported With LVAD. JACC Clin Electrophysiol 2021; 7:1003. 78. European Heart Rhythm Association, European Society of Cardiology, Heart Rhythm Society, et al. 2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management. Heart Rhythm 2012; 9:1524. 79. Chung MK, Patton KK, Lau CP, et al. 2023 HRS/APHRS/LAHRS guideline on cardiac physiologic pacing for the avoidance and mitigation of heart failure. Heart Rhythm 2023. 80. Wang Y, Zhu H, Hou X, et al. Randomized Trial of Left Bundle Branch vs Biventricular Pacing for Cardiac Resynchronization Therapy. J Am Coll Cardiol 2022; 80:1205. 81. Jastrz bski M, Kie basa G, Cano O, et al. Left bundle branch area pacing outcomes: the multicentre European MELOS study. Eur Heart J 2022; 43:4161. 82. Chen X, Ye Y, Wang Z, et al. Cardiac resynchronization therapy via left bundle branch pacing vs. optimized biventricular pacing with adaptive algorithm in heart failure with left bundle branch block: a prospective, multi-centre, observational study. Europace 2022; 24:807. 83. Vijayaraman P. Extraction of Left Bundle Branch Pacing Lead. JACC Clin Electrophysiol 2020; 6:903. 84. 2023 HRS/APHRS/LAHRS Guideline on Cardiac Physiologic Pacing for the Avoidance and Miti gation of Heart Failure https://www.hrsonline.org/2023-hrsaphrslahrs-guideline-cardiac-phy siologic-pacing-avoidance-and-mitigation-heart-failure (Accessed on June 05, 2023). 85. Ezelsoy M, Bayram M, Yazici S, et al. Surgical placement of left ventricular lead for cardiac resynchronisation therapy after failure of percutaneous attempt. Cardiovasc J Afr 2017; 28:19. 86. McALOON CJ, Anderson BM, Dimitri W, et al. Long-Term Follow-Up of Isolated Epicardial Left Ventricular Lead Implant Using a Minithoracotomy Approach for Cardiac Resynchronization Therapy. Pacing Clin Electrophysiol 2016; 39:1052. 87. Koos R, Sinha AM, Markus K, et al. Comparison of left ventricular lead placement via the coronary venous approach versus lateral thoracotomy in patients receiving cardiac resynchronization therapy. Am J Cardiol 2004; 94:59. 88. Doll N, Piorkowski C, Czesla M, et al. Epicardial versus transvenous left ventricular lead placement in patients receiving cardiac resynchronization therapy: results from a https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 28/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate randomized prospective study. Thorac Cardiovasc Surg 2008; 56:256. 89. Hummel JD, Coppess MA, Osborn JS, et al. Real-World Assessment of Acute Left Ventricular Lead Implant Success and Complication Rates: Results from the Attain Success Clinical Trial. Pacing Clin Electrophysiol 2016; 39:1246. Topic 3475 Version 41.0 https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 29/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate GRAPHICS Indications for referral for CRT for patients in sinus rhythm with LVEF 35% CRT: cardiac resynchronization therapy; LVEF: left ventricular ejection fraction; LBBB: left bundle branch block than LBBB; NYHA: New York Heart Association. Most patients with an LVEF 35% with an indication for CRT also have an indication for an implantable card choosing between a pacemaker (CRT-P) and a combined CRT-ICD (CRT-D). Graphic 115693 Version 2.0 https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 30/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate Indications for CRT in patients in sinus rhythm with LVEF between 35 and 50% CRT: cardiac resynchronization therapy; LVEF: left ventricular ejection fraction; LBBB: left bundle branch block QRS pattern on ECG; NYHA: New York Heart Association. Graphic 115692 Version 1.0 https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 31/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate Contributor Disclosures Evan Adelstein, MD No relevant financial relationship(s) with ineligible companies to disclose. Samir Saba, MD Grant/Research/Clinical Trial Support: Abbott [Implantable cardiac monitors in post-MI patients]. Consultant/Advisory Boards: Boston Scientific [Design of devices and clinical trials around AF ablation]; Medtronic [Use of temporary pacemakers in specific patient populations (eg, post-TAVR)]. All of the relevant financial relationships listed have been mitigated. Frederick Masoudi, MD, MSPH, FACC, FAHA Consultant/Advisory Boards: Bristol Meyers Squibb [Hypertrophic cardiomyopathy]; Colorado Prevention Center [Diabetes trial steering committee, study sponsor, Better Therapeutics]; TurningPoint [Utilization policy review]. Other Financial Interest: American College of Cardiology [Cardiovascular disease]; Massachusetts Medical Society [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 32/32

7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cardiac resynchronization therapy in heart failure: System implantation and programming : Bradley P Knight, MD, FACC : Jonathan Piccini, MD, MHS, FACC, FAHA, FHRS : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 22, 2023. INTRODUCTION Cardiac resynchronization therapy (CRT) is a treatment for select patients with chronic heart failure (HF) with both reduced ejection fraction and bundle branch block [1-3]. The traditional definition of CRT involves biventricular or left ventricular (LV)-only pacing. However, CRT can also be accomplished with His bundle pacing (HBP) or left bundle pacing (LBP), which are broadly referred to as conduction system pacing [4,5]. CRT can be achieved with a device designed only for pacing (CRT-P) or with the added capability of defibrillation (CRT-D) ( image 1). This topic will review implantation techniques for CRT, LBP, and HBP systems, as well as the approach to programming. The rationale and indications for CRT in patients with HF are discussed separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT' and "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in atrial fibrillation", section on 'Heart failure'.) TRADITIONAL CRT WITH A CORONARY SINUS LEAD System overview Most CRT implantations are performed via a transvenous approach with placement of a right atrial (RA) lead, right ventricular (RV) lead, and LV lead ( image 1). https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 1/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate Right atrial lead An atrial lead allows sensing and tracking of the atrial rhythm (either intrinsic or paced atrial rhythm) to appropriately time ventricular activation (ie, allow for atrial contraction before ventricular activation). The RA lead provides atrial pacing as needed. In patients with indications for CRT and cardioverter-defibrillator function but who do not require atrial pacing, there are defibrillation leads with floating atrial electrodes with sensing-only function. Devices that use this type of lead are programmed to the VDD pacing mode. Patients with atrial fibrillation or flutter who have indications for CRT may not require an atrial lead; the absence of functional atrial contraction obviates the need for pacing. The details on CRT in patients with atrial fibrillation are discussed separately. (See "Cardiac resynchronization therapy in atrial fibrillation".) Right ventricular lead The RV lead is an essential component for biventricular pacing systems; its role is to sense the intrinsic ventricular rhythm, pace the RV, and provide tachyarrhythmia therapy in devices capable of such therapy. The optimal programming of the RV lead is described elsewhere in this topic. (See 'Approach to programming' below.) Most RV leads are placed transvenously. The RV lead tip is usually placed in the septum; greater separation from the LV lead improves the ability to synchronize the ventricles [6]; in the case of CRT-D, this position also provides an optimal shocking vector. Epicardial placement via a direct surgical approach is another option for RV lead placement; this method of placement is reserved for patients who cannot undergo transvenous placement (eg, due to venous thrombosis) or who require concomitant cardiac surgery (eg, coronary artery bypass grafting). Further details on epicardial lead placement are discussed elsewhere in this topic. (See 'Surgical placement of an epicardial lead' below.) Left ventricular lead In most patients, the cause of dyssynchrony is electrical delay or block in the left-sided His-Purkinje conduction system. Placement of an LV lead via the coronary sinus allows for pacing of the LV, which can restore electrical and mechanical synchrony of ventricular contractions ( image 1). Pulse generator The pulse generator connects to the leads to provide pacing stimuli and regulation of the rhythm according to a number of settings and algorithms. The pulse generator contains the battery and the interface for programming changes and is typically placed in the region medial to the deltopectoral groove. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 2/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate Procedure for placement During the placement of a traditional CRT system, the steps include: Appropriate anesthesia is established. (See "Anesthetic considerations for electrophysiology procedures", section on 'Procedures for cardiac implantable electronic devices'.) Ipsilateral upper extremity contrast venography of the central venous system is obtained to facilitate venous access. A pocket for the device is surgically created within the plane of the prepectoral fascia below the clavicle. Venous access is obtained from the pocket to the axillary, subclavian, or cephalic vein, and the leads are extended to the RA and RV. Once in place, the leads are anchored to the pectoral muscle. The LV lead is placed similarly to the RA and RV leads but is placed in the coronary sinus instead of within a cardiac chamber. The placement of the LV lead is typically the most complicated aspect of CRT implantation. The placement of the LV lead consists of the following: Contrast injections through the guide sheath, fluoroscopic landmarks, or electrophysiologic signals are used to identify the ostium of the coronary sinus. The operator may also identify anatomy such as abnormal position of the coronary sinus ostium, presence of venous valves (eg, Thebesian valve, Valve of Vieussens), or coronary sinus strictures [7]. The coronary ostium is then accessed with a wire or catheter and the coronary sinus guide sheath is advanced into the coronary sinus. The lead is advanced through the sheath into one of the venous branches for LV pacing based on criteria. Further details on optimal coronary sinus lead placement are discussed elsewhere in this topic. (See 'Coronary sinus lead positioning' below.) The success of de novo CRT system placement is high and associated with the experience of the implanting center. In approximately 5 to 10 percent of implantation attempts, the LV lead cannot be placed. In a study of de novo transvenous CRT implants among 2014 patients from 114 centers, the overall success rate was 97.1 percent, median fluoroscopic time was 17 minutes, median dye use was 25 mL, and adverse events occurred in 2.6 percent [8]. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 3/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate In an analysis of the National Inpatient Sample Database involving 410,104 de novo CRT implants between 2003 and 2011, lower hospital volume was associated with higher rates of in-hospital mortality [9]. Placement issues with preexisting pacing systems For patients with a preexisting transvenous pacing or defibrillation system, most patients can undergo addition of a coronary sinus lead by opening the existing pocket, adding a coronary sinus lead, and upgrading the pacing generator as appropriate. However, patients who require addition of a coronary sinus lead (ie, device "upgrade") are more likely to have venous obstruction (prevalence 10 to 30 percent) caused by the existing system that may prevent placement of a coronary sinus lead (10 to 30 percent) [10-14]. In patients undergoing device upgrade, regardless of the absence of symptoms suggesting venous stenosis (eg, arm edema), we routinely obtain contrast venography prior to CRT upgrade to aid in procedural planning and execution [13,15]. If contrast venography suggests that typical left-sided transvenous coronary sinus lead placement is not feasible, the following strategies may be used to place a coronary sinus lead. The approach to such patients is controversial and depends on local experience with treating the obstruction and the risks of any alternative placement strategy: Lead extraction and coronary sinus lead placement One common approach is transvenous lead extraction followed by transvenous coronary sinus lead placement [16]. (See "Cardiac implantable electronic device lead removal".) In the LEXICON study of 2405 extracted leads, this approach was associated with clinically successful lead extraction in 97.7 percent, a major adverse event rate of 1.4 percent, and procedural death in 0.28 percent [17]. Risk factors for complications include body mass 2 index <25 kg/m and procedures performed at low volume extraction centers. Treatment of venous obstruction prior to lead placement Treatment of venous obstruction with percutaneous venoplasty prior to lead implantation may allow for successful CRT upgrade [11]. Venous cannulation beyond the obstruction This approach requires "deep" transvenous access beyond the point of obstruction in a more central or medial point. The risks of this approach include vascular or thoracic trauma, pneumothorax, and increased risk of lead fracture on follow-up [18,19]. A related strategy is parasternal or paraclavicular lead tunneling to an alternate point of venous entry. The sites for entry include the ipsilateral internal jugular vein or the https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 4/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate contralateral axillary-subclavian venous system [20]. Concerns include risk for skin erosion over bony sternal or clavicular prominences where there is typically minimal subcutaneous tissue, which may lead to subsequent transvenous extraction. For these reasons, this approach is rarely utilized. Surgical placement of an epicardial LV lead Surgical placement of an epicardial LV pacing lead is discussed elsewhere in this topic. (See 'Surgical placement of an epicardial lead' below.) Contralateral implant of a coronary sinus lead or de novo system If upgrade of a left- or right-sided system is not feasible, a new system can be placed on the contralateral side with full or partial abandonment of the preexisting system. To minimize the number of new leads when using the contralateral side, a lone coronary sinus lead can be implanted on the contralateral side and tunneled subcutaneously across the chest to connect to the device in the pocket. Disadvantages of abandoned leads include increased risks of venous occlusive disease (eg, superior vena cava stenosis), device-device or lead-lead interactions, and bloodstream infection [21]. In aggregate, the ability to safely place a coronary sinus lead in patients with preexisting transvenous cardiac implantable electronic device systems at experienced centers is high: In a contemporary comparative study of 1496 patients at a high-volume tertiary center who were undergoing de novo or upgrade CRT procedures, the rates of procedural success were similar (97 versus 96 percent), as were the rates of complications at 90 days (5.1 versus 4.6 percent) [15]. In an analysis comparing 19,546 CRT upgrades with 464,246 de novo procedures in the United States between 2003 and 2013, the upgrades were independently associated with increased mortality (odds ratio [OR] 1.91), cardiac perforation (OR 3.2), and need for lead revision (OR 2.09) [22]. In the REPLACE registry, the complication rates for procedures involving lead additions were greater than those for generator replacement alone [23]. Coronary sinus lead positioning General principles The optimal LV lead location is that at which the lead effectively paces the site of greatest electromechanical delay while avoiding phrenic nerve stimulation. However, the patient s coronary sinus and LV venous anatomy ( image 2) determine where the LV lead can be placed. The most common LV venous anatomy is composed of an anterior vein coursing in the interventricular groove, an anterolateral branch coursing diagonally from the LV apex to https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 5/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate the base of the LV, a midlateral and/or posterolateral vein that often shares a common trunk, and the middle cardiac vein coursing posteriorly to the LV apex. The available evidence suggests that the optimal position for the LV lead is generally the lateral or posterolateral wall ( image 2). In the presence of left bundle branch block (LBBB), the basal posterolateral wall is often the last segment to contract in a dyssynchronous LV. In the follow-up results of the MADIT CRT study, only patients with lateral and posterior LV lead locations derived long-term mortality benefit from CRT over implantable cardioverter-defibrillator (ICD) alone [24]. Additionally, a more basal placement has also been associated with better rates of CRT response. Strategies for optimal lead placement In general, the usual strategy for initial LV placement is guided by anatomy; the lead tip is positioned near the basal position of the lateral wall at a stable site with acceptable pacing parameters and where there is no left phrenic nerve capture. Some implanting clinicians also use electrical or mechanical information including the Q-LV interval ( figure 1) to further direct lead placement and the optimal pacing site. Site of greatest electrical delay In patients with LBBB, we often target the site of greatest LV electrical delay for pacing stimulation ( figure 1). In patients without LBBB, we do not select the pacing site using the Q-LV interval [25]. The following studies illustrate the importance of LV electrical delay as measured by Q-LV as a predictor of improvement in hemodynamic improvement: In a prospective acute hemodynamic studies of 31 and 32 patients undergoing CRT implant, Q-LV was strongly associated with hemodynamic improvement as measured by dP/dt max independent of the pacing mode [26,27]. In a prospective study of 156 patients, Q-LV was the only independent predictor of improvement in LV ejection fraction (LVEF) and decrease in LV end-systolic volume in follow-up [28]. In an analysis of the SMART AV trial involving 426 patients, Q-LV was associated with greater improvement in mitral regurgitation, suggesting an additional physiologic mechanism for targeting the site of greatest electrical delay [29]. Other methods of pacing site selection Other methods of pacing site selection may play a role but are used less frequently: Right to left interelectrical delay The presence of LBBB causes overall delayed LV activation compared with the RV, leading some operators to measure the interlead https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 6/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate electrical delay (IED) time, which is the time between sensing of the native impulse at the RV and sensing of the native impulse at the LV lead. In a study of 68 patients, IED was independently associated with CRT response (reverse remodeling), even when accounting for the presence of myocardial scar (OR 3.99, 95% CI 1.02-15.7) [30]. In another study involving 160 patients, an IED 100 ms was associated with more pronounced LV reverse remodeling when lead implantation site was guided by identification of the latest mechanical delay in a nonscarred myocardial segment [31]. Site of greatest mechanical delay After optimizing the site of pacing using the site of greatest electrical delay, some experts evaluate for the site of greatest mechanical delay. Targeting the site of greatest mechanical delay for pacing stimulation has been associated with improved CRT outcomes in some studies: Echocardiographic-based imaging and magnetic resonance imaging have been utilized to evaluate the value of LV pacing at or near the area of greatest mechanical delay [32-34]. Tissue Doppler imaging has been the most widely studied and utilized method in clinical practice [35-42]. Tissue Doppler imaging was initially assessed in a series of 54 patients, and a greater reduction in end-systolic volume was associated with LV pacing at the site of greatest mechanical delay [43]. An additional echocardiographic-based method is myocardial strain imaging [44,45]. (See "Tissue Doppler echocardiography", section on 'Use in heart failure and resynchronization therapy'.) Although direct measures of mechanical dyssynchrony have been investigated as a means of identifying responders to CRT [46-50], the clinical utility of such assessment has not been established. Avoiding LV scar The optimal position for the LV lead is in the vicinity of viable myocardium that is not in or immediately adjacent to scar tissue. Pacing in regions of LV scar has been associated with lower response rates. In addition, pacing in a densely scarred region may require higher pacing outputs, which can lead to premature battery drain. The burden of scar may influence the efficacy of CRT pacing [32,51-53]. Placement of a quadripolar lead We typically place a quadripolar LV pacing lead. These leads reduce the incidence of phrenic nerve stimulation and improve the likelihood of CRT response by providing an array of options for the site of pacing [54]. Selecting the site for https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 7/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate optimal pacing and algorithms that make use of multiple coronary sinus pacing sites are discussed elsewhere in this topic. (See 'Other parameters for optimization' below.) Approach to programming Initial settings In general, we optimize device settings for the best clinical response and lowest battery use. The optimal device settings at the time of implant are not clearly defined and may be patient specific. The following principles influence our choice of initial programming: Program the atrioventricular delay to optimize resynchronization For patients who are in sinus rhythm, the pacing mode is typically programmed DDD, DDDR, or VDD depending on the need for atrial pacing. For patients in sinus rhythm and with intact atrioventricular (AV) conduction, the AV delay should be set to a value that minimizes the QRS duration. Increase the frequency of pacing In patients with relatively high resting heart rate or continuous atrial fibrillation, we increase the lower rate limit to target 100 percent CRT pacing. Choose the optimal site of pacing We pace the LV at a site with the greatest electrical delay (measured by the Q-LV interval) ( figure 1) that does not result in a wider QRS morphology, LBBB morphology, or apical QRS morphology. The site of pacing should not stimulate the phrenic nerve. Minimize power consumption We program CRT devices to promote battery longevity by choosing pacing sites with the lowest possible electrical thresholds, lowest impedance measurements, and shortest pulse width. Minimizing RV pacing stimulation with fusion pacing can extend battery longevity. Ancillary settings Other pacing settings are available, but routine selection of one method over another is controversial. (See 'Other parameters for optimization' below.) Identification of and approach to nonresponders Most experts define nonresponse to CRT as lack of improvement in LVEF or New York Heart Association class. However, other criteria that can be used to identify nonresponders include other measures of LV function (eg, global longitudinal strain), LV dimensions, exercise capacity and functional status, and quality of life [55]. For most patients with HF with reduced ejection fraction who do not initially respond to CRT, we evaluate for causes of nonresponse (eg, progressive HF, nonadherence to medical therapy) and adjust settings as described above. In most patients, the initial approach to nonresponse is to https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 8/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate change pacing parameters based on the surface electrocardiogram (ECG). Pacing vectors (ie, sites) are adjusted until the narrowest QRS duration is achieved and there are no signs of an apical pacing morphology (ie, LBBB appearance in V1 with a superior axis that is negative in limbs leads II, III, and aVF with a widened QRS >200 ms). However, optimizing pacing with electrophysiologic parameters does not always translate to a clinical response or improved mechanical synchrony. For example, ventricular scar patterns can create "balanced delay" in which the overall right and left ventricular activations are relatively simultaneous (ie, paced QRS appears narrow) but remain mechanically dyssynchronous due to nonhomogenous conduction through and around intrinsic LV scar. Mismatch between the surrogates for mechanical synchronization (eg, surface ECG parameters) and true mechanical resynchronization likely explain the discrepancy: In patients with little or no intrinsic AV conduction (ie, complete heart block), achieving a more narrowly paced QRS duration was associated with reduction of LV end-systolic volume of 15 percent from baseline [56]. In a substudy of the PROSPECT trial, greater shortening of the paced QRS over the intrinsic QRS duration was also associated with significantly increased likelihood of clinical and echocardiographic response (OR 0.89) [57]. In an analysis of the MADIT CRT trial, shortened paced QRS duration was not associated with better outcomes, while apical pacing demonstrated worse outcomes [58]. Other parameters for optimization Options for programming that are used in specific scenarios include: Fusion pacing In patients with intact AV conduction and LBBB, fusion pacing can be used rather than standard biventricular pacing. Fusion pacing entails timing LV pacing to coincide with normal RV activation ( figure 2). The timing of LV pacing is determined from the sensed time between RA depolarization and RV activation [59]. Thus, fusion-pacing algorithms commonly result in a more narrowly paced QRS than either traditional biventricular pacing or LV-only pacing; the intact right bundle and/or septal His-Purkinje allows more rapid electrical depolarization. Fusion pacing is not the same as "LV-only" CRT pacing; the latter ignores RA-RV conduction. A similar algorithm allows for dynamic adjustment of the AV delay to accommodate ventricular remodeling while allowing the option of using varying combinations of LV pacing, RV pacing, and intrinsic conduction (ie, so-called "triple fusion") [60,61]. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 9/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate In the Adaptive CRT trial, 478 patients were randomized in a 2:1 ratio to fusion pacing (LV pacing synchronized to RV contraction using a proprietary algorithm) versus standard CRT with echocardiographic-guided optimization [62]. At a mean of 20 months of follow-up, the fusion pacing group demonstrated a lower likelihood of all-cause hospitalizations (OR 0.54, 95% CI 0.31-0.94). Multisite pacing In patients with a quadripolar lead, some experts use the multisite pacing programming (MPP) algorithm. This is typically done at the time of implant. MPP is a proprietary algorithm that simultaneously uses two or more LV pacing configurations to overcome transmyocardial conduction delay or improve intraventricular dyssynchrony. In an observational study of 110 patients comparing standard with multisite pacing, the one-year echocardiographic response rate with optimally positioned leads was 72 percent with standard programming and 90 percent with MPP [63]. In a meta-analysis of studies comparing MPP with conventional CRT, the use of MPP was associated with decreased HF hospitalizations, improved LVEF, increased CRT response, and decreased all-cause mortality [64]. LV-only pacing LV-only pacing is infrequently used in modern practice. Randomized trials that compared LV-only pacing with standard LV pacing (PATH-CHF, DECREASE-HF, B-LEFT HF, GREATER EARTH) showed no advantage of LV-only pacing in patients with LBBB [65-68]. Echocardiographic optimization We do not routinely perform echocardiographic optimization of CRT pacing. There is limited evidence to support routine optimization of CRT pacing with echocardiographic parameters. The approaches to echocardiographic optimization include: AV optimization For CRT pacing, a shortened AV delay (ie, 90 to 120 ms) reduces the likelihood of native AV conduction and increases the percentage of biventricular pacing. In patients who fail to experience improvement in symptoms or cardiac function following CRT implantation, postprocedural adjustment in the AV delay ("AV optimization") with Doppler echocardiographic assessment may be helpful in highly selected individuals. The typical strategy is to program the AV delay such that the end of atrial contraction (marked by the end of the A wave) is timed to coincide with the onset of ventricular contraction (marked by the onset of systolic mitral regurgitant flow) [69]. However, the clinical efficacy of AV optimization has not been established, as randomized clinical trials have failed to demonstrate benefit [70]. In a post hoc analysis of the MADIT CRT study involving 1235 patients, sensed AV delays less than 120 ms demonstrated overall better https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 10/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate clinical outcomes when compared with longer sensed AV delays, likely attributable to a greater percentage of biventricular pacing in place of intrinsic activation via the native diseased His-Purkinje system [71]. VV optimization With CRT devices, the timing between the right and left ventricular pacing stimulus (VV timing) can be adjusted, but the optimal programming strategies for VV timing have not been fully defined and may be patient specific. There is limited evidence to support routine adjustment of VV timing using echocardiographic parameters. Complications The complications of CRT pacing include coronary sinus or coronary vein trauma, pneumothorax, pocket hematoma, infection, and phrenic nerve pacing [72-75]. There are also specific concerns with LV lead placement, such as prolonged radiation exposure due to the complexity of the transvenous implantation procedure, which may have acute skin effects and contribute to long-term radiation-related risks [76]. Postoperative CRT implantation complication rates varied among studies but appear to be higher with CRT upgrades [22] and lower among high-volume centers [9]: In a study of 2014 patients from 114 centers undergoing de novo transvenous CRT implant, the composite complication rate was 2.6 percent at three months, most commonly involving LV lead dislodgement in 1.7 percent of patients and phrenic nerve stimulation not amenable to reprogramming in 0.5 percent of patients [8]. A meta-analysis of clinical trials, albeit among older studies, reported an overall acute complication rate of 14 percent that is largely driven by lead-related complications but also includes 0.8 percent perioperative mortality [77]. One study looking exclusively at CRT upgrades found an acute complication rate of 11 percent [78]. Higher in-hospital mortality rates were observed in a cohort of 26,887 patients undergoing ICD and/or CRT implantation that included older adults with rates ranging from 0.7 to 1.2 to 2.2 percent in patients aged <80, 80 to 85, and >85 years [79]. While patients over 80 years old undergoing CRT implantation may face higher complication rates than younger patients, longer-term data suggest that mortality rates for these patients are only slightly higher than in the general octogenarian population. Long-term The long-term complications of CRT include device malfunction and infection. The incidence of late complications is illustrated by the following results from a review of https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 11/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate implantation success rates and safety outcomes in studies of patients undergoing CRT or CRT-D implantation [74]: In 54 studies (6123 patients) of CRT-alone devices, 5 percent of CRT devices malfunctioned, and 2 percent of patients were hospitalized for infections in the implant site over six months of follow-up. During a median follow-up of 11 months, lead problems occurred in 7 percent of CRT devices. While there is a theoretical risk that pacing from an LV lead may be proarrhythmic due to alterations in depolarization and repolarization sequences (eg, "dispersion of refractoriness"), a pooled analysis from 14 randomized controlled trials did not demonstrate any excess risk of sudden death or noncardiac death in CRT device recipients, on average [80]. However, there are cases of individual patients who experience ventricular tachycardia storm after CRT is activated. In 36 studies (5199 patients) of combined CRT-D devices, 5 percent of CRT-D devices malfunctioned, 1 percent of patients developed site infection, and lead problems were detected in 7 percent of patients over 12 months of follow-up. SURGICAL PLACEMENT OF AN EPICARDIAL LEAD System overview Epicardial CRT systems are composed of transvenous leads in the RA and RV and a lead placed directly on the lateral LV epicardium via a thoracotomy. These leads are joined to a pulse generator that provides pulse stimuli and programming. Epicardial lead placement is reserved for patients in whom a coronary sinus lead cannot be placed (eg, venous occlusive disease, anatomy incompatible with coronary sinus lead placement). In rare cases, patients with an indication for CRT may undergo surgical lead placement at the time of concomitant cardiac surgery (eg, valve surgery, coronary artery bypass grafting). Additional details on the indications for epicardial lead placement are discussed separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Alternative approaches'.) Procedure and lead placement The technique for surgical LV lead placement includes a mini-thoracotomy approach in the fourth or fifth intercostal space anterior to the midaxillary line. Typically, single lung ventilation is performed to allow dissection into the pericardial space for implantation of the epicardial LV lead [81]. It is important that the lead be placed at a basal https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 12/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate lateral location. The lead is fixed directly to the cardiac tissue using a specifically designed instrument and tested in the same manner as leads placed via a transvenous approach. A key advantage of surgical epicardial lead placement is that lead placement is not confined to the anatomic branches of the LV venous circulation as is the case with transvenous placement. (See 'General principles' above.) Programming In nearly all cases, the programming of epicardial CRT systems is the same as coronary sinus systems. (See 'Approach to programming' above.) Complications Epicardial lead placement entails an increased risk of adverse events and provides no greater benefit compared with transvenous placement. The risk of surgical lead placement is variable; some centers report complication rates similar to transvenous lead placement, while others report a much higher mortality rate than expected with transvenous lead placement: In a study of 30 patients who underwent cardiac surgery for isolated LV lead placement via a mini-thoracotomy following failed transvenous placement, the epicardial lead placement was successful in all patients and perioperative mortality was zero. However, this study did not report electrical lead testing data, rate of bleeding, or infectious complication rate [82]. In a series of 42 patients with "stand-alone" LV epicardial lead placement using a mini- thoracotomy approach, the mean length of stay was 3.4 days, and the 30-day adverse event rate was 17.5 percent; the adverse events included 4.8 percent mortality, 7.5 percent LV lead noncapture, and 5 percent infection [83]. A study that compared patients with surgically placed epicardial LV leads with transvenously placed leads found no difference over a mean five years of follow-up in which the overall clinical response rate to CRT pacing was 65 percent [84]. In this study, major adverse events occurred in 5 percent of patients undergoing stand-alone LV lead placement and 14 percent of patients with concomitant LV lead placement. HIS BUNDLE PACING Components of His bundle pacing systems The goal of His bundle pacing is to capture the His-Purkinje system to improve ventricular synchrony. His bundle pacing (HBP) either "directly" (ie, selectively) stimulates the His-Purkinje system or results in para-Hisian (ie, nonselective) stimulation that captures both the His-Purkinje system and adjacent RV myocardium [85]. The use of His bundle pacing in patients in who cannot undergo coronary sinus lead placement is https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 13/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate discussed separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Alternative approaches'.) In a HBP system, the RV lead is placed directly into the proximal septum at the location of the bundle of His. If indicated, an RA lead is placed in a manner similar to coronary sinus systems. (See 'System overview' above.) Lead placement His bundle leads are placed in the septum and are guided by pacing maneuvers to confirm His capture. After establishing anesthesia and transvenous access similar to coronary sinus leads, placement of a His bundle lead consists of the following: A pacing lead is advanced through a delivery system to a site on the atrial side of the tricuspid valve annulus or beyond the annulus in the anteroseptal RV. Next, the His bundle pacing site is evaluated using electrograms recorded from the candidate lead [4,86]. Published criteria suggest that the His Bundle pacing should result in a QRS duration less than 120 ms and ideally include a 20 to 40 ms isoelectric segment between the pacing stimulus and the QRS complex. Variants of this HBP technique include the use of a diagnostic electrophysiology catheter as a fluoroscopic reference, injection of intravenous contrast, or the use of an electroanatomic mapping system [86]. Placement of a His pacing system is successful in approximately 50 to 80 percent of attempts, though experience with this approach continues to develop: In a meta-analysis of retrospective studies, HBP for CRT had an average implant success rate of 80 percent and was associated with mean paced QRS duration 122.9 12.0 ms [4]. Compared with baseline values, there were improvements in LVEF, LV volumes, and HF symptoms. The most common complication was an increase in capture thresholds during follow-up. In the His-SYNC pilot trial that included 41 patients with HF and left bundle branch block (LBBB), patients assigned to HBP and biventricular CRT (ie, CRT with a coronary sinus lead) had similar New York Heart Association class and Kansas City Cardiomyopathy Questionnaire scores during follow-up [87]. However, many patients (48 percent) randomized to HBP crossed over to biventricular CRT due to inability to correct the native LBBB with HBP, and many patients (26 percent) randomized to biventricular CRT crossed over to HBP due to anatomic difficulties, which limits the external validity of the results. Programming Programming is guided by the underlying indication for the pacemaker. During evaluation and programming, it is important to distinguish between septal capture, nonselective His capture, and His bundle capture during threshold testing. However, studies https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 14/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate have shown that programming the pacemaker outputs to achieve selective His bundle capture does not provide better outcomes compared with nonselective capture [88]. Complications Limited comparative data exist on the complications associated with CRT among patients undergoing biventricular CRT versus either left bundle pacing (LBP) or HBP. Uncommon but unique complications of conduction system pacing include [89,90]: Atrial oversensing. Septal perforation. Tricuspid regurgitation. Coronary artery injury to septal perforator branches of the left anterior descending artery. High pacing thresholds. Uncertainty about the ability to safely extract HBP and LBP leads without injury to septal arteries or the septum or without creation of retained intramyocardial fragments. LEFT BUNDLE AREA PACING Components of left bundle area pacing systems The goal of left bundle area pacing (LBAP) is to provide CRT by stimulating the native cardiac conduction system to partially overcome intrinsic bundle branch block or interventricular conduction delay. The indications for LBAP pacing systems are discussed separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Choice of CRT system'.) LBAP systems are composed of an RV lead that paces in the area of the left bundle and, if indicated, a standard RA lead.

"Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Alternative approaches'.) Procedure and lead placement The technique for surgical LV lead placement includes a mini-thoracotomy approach in the fourth or fifth intercostal space anterior to the midaxillary line. Typically, single lung ventilation is performed to allow dissection into the pericardial space for implantation of the epicardial LV lead [81]. It is important that the lead be placed at a basal https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 12/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate lateral location. The lead is fixed directly to the cardiac tissue using a specifically designed instrument and tested in the same manner as leads placed via a transvenous approach. A key advantage of surgical epicardial lead placement is that lead placement is not confined to the anatomic branches of the LV venous circulation as is the case with transvenous placement. (See 'General principles' above.) Programming In nearly all cases, the programming of epicardial CRT systems is the same as coronary sinus systems. (See 'Approach to programming' above.) Complications Epicardial lead placement entails an increased risk of adverse events and provides no greater benefit compared with transvenous placement. The risk of surgical lead placement is variable; some centers report complication rates similar to transvenous lead placement, while others report a much higher mortality rate than expected with transvenous lead placement: In a study of 30 patients who underwent cardiac surgery for isolated LV lead placement via a mini-thoracotomy following failed transvenous placement, the epicardial lead placement was successful in all patients and perioperative mortality was zero. However, this study did not report electrical lead testing data, rate of bleeding, or infectious complication rate [82]. In a series of 42 patients with "stand-alone" LV epicardial lead placement using a mini- thoracotomy approach, the mean length of stay was 3.4 days, and the 30-day adverse event rate was 17.5 percent; the adverse events included 4.8 percent mortality, 7.5 percent LV lead noncapture, and 5 percent infection [83]. A study that compared patients with surgically placed epicardial LV leads with transvenously placed leads found no difference over a mean five years of follow-up in which the overall clinical response rate to CRT pacing was 65 percent [84]. In this study, major adverse events occurred in 5 percent of patients undergoing stand-alone LV lead placement and 14 percent of patients with concomitant LV lead placement. HIS BUNDLE PACING Components of His bundle pacing systems The goal of His bundle pacing is to capture the His-Purkinje system to improve ventricular synchrony. His bundle pacing (HBP) either "directly" (ie, selectively) stimulates the His-Purkinje system or results in para-Hisian (ie, nonselective) stimulation that captures both the His-Purkinje system and adjacent RV myocardium [85]. The use of His bundle pacing in patients in who cannot undergo coronary sinus lead placement is https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 13/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate discussed separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Alternative approaches'.) In a HBP system, the RV lead is placed directly into the proximal septum at the location of the bundle of His. If indicated, an RA lead is placed in a manner similar to coronary sinus systems. (See 'System overview' above.) Lead placement His bundle leads are placed in the septum and are guided by pacing maneuvers to confirm His capture. After establishing anesthesia and transvenous access similar to coronary sinus leads, placement of a His bundle lead consists of the following: A pacing lead is advanced through a delivery system to a site on the atrial side of the tricuspid valve annulus or beyond the annulus in the anteroseptal RV. Next, the His bundle pacing site is evaluated using electrograms recorded from the candidate lead [4,86]. Published criteria suggest that the His Bundle pacing should result in a QRS duration less than 120 ms and ideally include a 20 to 40 ms isoelectric segment between the pacing stimulus and the QRS complex. Variants of this HBP technique include the use of a diagnostic electrophysiology catheter as a fluoroscopic reference, injection of intravenous contrast, or the use of an electroanatomic mapping system [86]. Placement of a His pacing system is successful in approximately 50 to 80 percent of attempts, though experience with this approach continues to develop: In a meta-analysis of retrospective studies, HBP for CRT had an average implant success rate of 80 percent and was associated with mean paced QRS duration 122.9 12.0 ms [4]. Compared with baseline values, there were improvements in LVEF, LV volumes, and HF symptoms. The most common complication was an increase in capture thresholds during follow-up. In the His-SYNC pilot trial that included 41 patients with HF and left bundle branch block (LBBB), patients assigned to HBP and biventricular CRT (ie, CRT with a coronary sinus lead) had similar New York Heart Association class and Kansas City Cardiomyopathy Questionnaire scores during follow-up [87]. However, many patients (48 percent) randomized to HBP crossed over to biventricular CRT due to inability to correct the native LBBB with HBP, and many patients (26 percent) randomized to biventricular CRT crossed over to HBP due to anatomic difficulties, which limits the external validity of the results. Programming Programming is guided by the underlying indication for the pacemaker. During evaluation and programming, it is important to distinguish between septal capture, nonselective His capture, and His bundle capture during threshold testing. However, studies https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 14/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate have shown that programming the pacemaker outputs to achieve selective His bundle capture does not provide better outcomes compared with nonselective capture [88]. Complications Limited comparative data exist on the complications associated with CRT among patients undergoing biventricular CRT versus either left bundle pacing (LBP) or HBP. Uncommon but unique complications of conduction system pacing include [89,90]: Atrial oversensing. Septal perforation. Tricuspid regurgitation. Coronary artery injury to septal perforator branches of the left anterior descending artery. High pacing thresholds. Uncertainty about the ability to safely extract HBP and LBP leads without injury to septal arteries or the septum or without creation of retained intramyocardial fragments. LEFT BUNDLE AREA PACING Components of left bundle area pacing systems The goal of left bundle area pacing (LBAP) is to provide CRT by stimulating the native cardiac conduction system to partially overcome intrinsic bundle branch block or interventricular conduction delay. The indications for LBAP pacing systems are discussed separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Choice of CRT system'.) LBAP systems are composed of an RV lead that paces in the area of the left bundle and, if indicated, a standard RA lead. Lead placement LBAP leads are placed in the proximal RV septum and are tested to confirm left bundle branch capture. Left bundle lead placement also requires 12-lead procedural ECG recording and a delivery sheath or catheter and should only be implanted by experienced operators and in accordance with published techniques, criteria, and applicable equipment [91]. The delivery system is first advanced into the RV over a guidewire. A transvenous pacing lead with either an extendable-retractable or fixed screw is then advanced through the delivery system to the appropriate location on the RV septum. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 15/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate The candidate location is selected beginning approximately 1 to 1.5 cm distal (apical) and inferior of the location of the His bundle. Unipolar pacing from the initial candidate endocardial location allows recording of the baseline impedance, 12-lead ECG of the paced QRS morphology, and LV activation time (LVAT) as measured from the pacing stimulus to the peak depolarization in leads V5 to V6. Initial pacing prior to screw fixation is expected to yield an overall left bundle branch block (LBBB)-pattern QRS complex with characteristic "w" pattern in lead V1. The lead is then advanced into the septum with periodic pacing to evaluate for the presence of left bundle capture. Contrast venography and impedance measurements can help identify the depth in the septum and whether the lead has penetrated into the LV cavity ( image 3). The final location is accepted in accordance with published standards, but generally involving evidence of left bundle capture as assessed by QRS duration and morphology in V1, and LVAT 80 ms in V5 or V6. In a prospective study of 63 patients with HF and complete LBBB, CRT was successfully achieved in 97 percent with LBP, resulting in QRS narrowing to mean 118 12 ms associated with improvements in LVEF, volumes, and HF symptoms. Normalization of LVEF 50 percent occurred in 75 percent of patients [5]. Programming Programming is guided by the underlying indication for the pacemaker. During evaluation and programming, it is important to distinguish between septal capture and left bundle capture [92]. Complications The complications of LBAP leads are similar to those of His bundle pacing (HBP) leads (see 'Complications' above), but LBAP usually has better pacing thresholds and lower risk of atrial oversensing. Because LBAP pacing leads are placed more distally and deeper in the septum, the risks of septal perforation are higher than those observed with HBP leads [93]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Cardiac implantable electronic devices".) https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 16/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Cardiac resynchronization therapy (The Basics)") SUMMARY AND RECOMMENDATIONS Types of cardiac resynchronization pacing: Traditional resynchronization systems with a coronary sinus lead Most cardiac resynchronization therapy (CRT) implantations are performed via a transvenous approach in which leads are placed in the right atrium (RA), right ventricle (RV), and coronary sinus (ie, left ventricular [LV] pacing lead) ( image 1). (See 'Traditional crt with a coronary sinus lead' above.) The coronary sinus lead is typically placed at the site of greatest electromechanical delay while avoiding phrenic nerve stimulation. (See 'General principles' above.) Surgical placement of an epicardial lead Epicardial CRT systems are composed of transvenous leads in the RA and RV and a lead placed directly on the lateral LV epicardium via a thoracotomy. (See 'Surgical placement of an epicardial lead' above.) The indications for epicardial lead placement are discussed elsewhere. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Alternative approaches'.) https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 17/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate His bundle pacing The goal of His bundle pacing (HBP) is to enable pacing and capture of the His-Purkinje system, which can improve synchrony and ventricular activation. His bundle leads are placed in the septum and are guided by pacing maneuvers to confirm His capture. (See 'Components of His bundle pacing systems' above.) The use of HBP in patients in whom a coronary sinus lead cannot be placed is discussed separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Alternative approaches'.) Left bundle area pacing The goal of left bundle area pacing (LBAP) is to provide CRT by stimulating the native cardiac conduction system to partially overcome intrinsic bundle branch block or interventricular conduction delay. LBAP systems are composed of an RV lead that paces in the area of the left bundle and, if indicated, a standard RA lead. (See 'Components of left bundle area pacing systems' above.) The indications for LBAP pacing systems are discussed separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Choice of CRT system'.) Initial program settings In general, we optimize device settings for the best clinical response and lowest battery use. The optimal program settings at the time of implant have not been fully defined and may be patient specific. Initial programming includes (see 'Initial settings' above): Program the atrioventricular delay to optimize resynchronization For patients who are in sinus rhythm, the pacing mode is typically programmed DDD, DDDR, or VDD depending on the need for atrial pacing. For patients in sinus rhythm and with intact atrioventricular (AV) conduction, the AV delay should be set to a value that minimizes the QRS duration. Increase the frequency of pacing In patients with relatively high resting heart rate or continuous atrial fibrillation, we increase the lower rate limit to target 100 percent CRT pacing. Choose the optimal site of pacing We pace the LV at a site with the greatest electrical delay (measured by the Q-LV interval) ( figure 1) that does not result in a wider QRS morphology, left bundle branch block (LBBB) morphology, or apical QRS morphology. The site of pacing should not stimulate the phrenic nerve. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 18/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate Minimize power consumption We program CRT devices to promote battery longevity by choosing pacing sites with the lowest possible electrical thresholds, lowest impedance measurements, and shortest pulse width. Ancillary settings Other pacing settings are available, but routine selection of one method over another is controversial. (See 'Other parameters for optimization' above.) CRT nonresponse Most experts define nonresponse to CRT as lack of improvement in LV ejection fraction (LVEF) or New York Heart Association class. (See 'Identification of and approach to nonresponders' above.) Initial approach to nonresponders For most patients with HF with reduced ejection fraction who do not initially respond to CRT, we evaluate for causes of nonresponse and adjust settings as appropriate. In most patients, the initial approach to nonresponse is to change pacing parameters based on the surface ECG. (See 'Identification of and approach to nonresponders' above.) Additional programming If a response to CRT is not achieved with optimization of the surface ECG, other parameters may be adjusted on an individual basis (eg, fusion pacing, multisite pacing, echocardiographic optimization). (See 'Other parameters for optimization' above.) ACKNOWLEDGMENTS The UpToDate editorial staff acknowledges Leslie A Saxon, MD, Teresa DeMarco, MD, Wilson Colucci, MD, and Daniel J Cantillon, MD, FACC, HRS, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Leclercq C, Kass DA. 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Intraventricular dyssynchrony predicts mortality and morbidity after cardiac resynchronization therapy: a study using cardiovascular magnetic resonance tissue synchronization imaging. J Am Coll Cardiol 2007; 50:243. 35. Bax JJ, Bleeker GB, Marwick TH, et al. Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. J Am Coll Cardiol 2004; 44:1834. 36. Kapetanakis S, Kearney MT, Siva A, et al. Real-time three-dimensional echocardiography: a novel technique to quantify global left ventricular mechanical dyssynchrony. Circulation 2005; 112:992. 37. Cho GY, Song JK, Park WJ, et al. Mechanical dyssynchrony assessed by tissue Doppler imaging is a powerful predictor of mortality in congestive heart failure with normal QRS duration. J Am Coll Cardiol 2005; 46:2237. 38. Penicka M, Bartunek J, De Bruyne B, et al. Improvement of left ventricular function after cardiac resynchronization therapy is predicted by tissue Doppler imaging echocardiography. 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Clinical outcomes with synchronized left ventricular pacing: analysis of the adaptive CRT trial. Heart Rhythm 2013; 10:1368. 60. Varma N, O'Donnell D, Bassiouny M, et al. Programming Cardiac Resynchronization Therapy for Electrical Synchrony: Reaching Beyond Left Bundle Branch Block and Left Ventricular Activation Delay. J Am Heart Assoc 2018; 7. 61. Thibault B, Ritter P, Bode K, et al. Dynamic programming of atrioventricular delay improves electrical synchrony in a multicenter cardiac resynchronization therapy study. Heart Rhythm 2019; 16:1047. 62. Starling RC, Krum H, Bril S, et al. Impact of a Novel Adaptive Optimization Algorithm on 30- Day Readmissions: Evidence From the Adaptive CRT Trial. JACC Heart Fail 2015; 3:565. 63. Zanon F, Marcantoni L, Baracca E, et al. Optimization of left ventricular pacing site plus multipoint pacing improves remodeling and clinical response to cardiac resynchronization therapy at 1 year. Heart Rhythm 2016; 13:1644. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 24/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate 64. Hu F, Zheng L, Ding L, et al. Clinical outcome of left ventricular multipoint pacing versus conventional biventricular pacing in cardiac resynchronization therapy: a systematic review and meta-analysis. Heart Fail Rev 2018; 23:927. 65. Auricchio A, Stellbrink C, Sack S, et al. Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J Am Coll Cardiol 2002; 39:2026. 66. Rao RK, Kumar UN, Schafer J, et al. Reduced ventricular volumes and improved systolic function with cardiac resynchronization therapy: a randomized trial comparing simultaneous biventricular pacing, sequential biventricular pacing, and left ventricular pacing. Circulation 2007; 115:2136. 67. Boriani G, Kranig W, Donal E, et al. A randomized double-blind comparison of biventricular versus left ventricular stimulation for cardiac resynchronization therapy: the Biventricular versus Left Univentricular Pacing with ICD Back-up in Heart Failure Patients (B-LEFT HF) trial. Am Heart J 2010; 159:1052. 68. Thibault B, Ducharme A, Harel F, et al. Left ventricular versus simultaneous biventricular pacing in patients with heart failure and a QRS complex 120 milliseconds. Circulation 2011; 124:2874. 69. Meluz n J, Nov k M, M llerov J, et al. A fast and simple echocardiographic method of determination of the optimal atrioventricular delay in patients after biventricular stimulation. Pacing Clin Electrophysiol 2004; 27:58. 70. Ellenbogen KA, Gold MR, Meyer TE, et al. Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial: a randomized trial comparing empirical, echocardiography- guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy. Circulation 2010; 122:2660. 71. Brenyo A, Kutyifa V, Moss AJ, et al. Atrioventricular delay programming and the benefit of cardiac resynchronization therapy in MADIT-CRT. Heart Rhythm 2013; 10:1136. 72. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004; 350:2140. 73. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005; 352:1539. 74. McAlister FA, Ezekowitz J, Hooton N, et al. Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: a systematic review. JAMA 2007; 297:2502. 75. Le n AR, Abraham WT, Curtis AB, et al. Safety of transvenous cardiac resynchronization system implantation in patients with chronic heart failure: combined results of over 2,000 https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 25/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate patients from a multicenter study program. J Am Coll Cardiol 2005; 46:2348. 76. Perisinakis K, Theocharopoulos N, Damilakis J, et al. Fluoroscopically guided implantation of modern cardiac resynchronization devices: radiation burden to the patient and associated risks. J Am Coll Cardiol 2005; 46:2335. 77. Fox M, Mealing S, Anderson R, et al. The clinical effectiveness and cost-effectiveness of cardiac resynchronisation (biventricular pacing) for heart failure: systematic review and economic model. Health Technol Assess 2007; 11:iii. 78. Duray GZ, Israel CW, Pajitnev D, Hohnloser SH. Upgrading to biventricular pacing/defibrillation systems in right ventricular paced congestive heart failure patients: prospective assessment of procedural parameters and response rate. Europace 2008; 10:48. 79. Swindle JP, Rich MW, McCann P, et al. Implantable cardiac device procedures in older patients: use and in-hospital outcomes. Arch Intern Med 2010; 170:631. 80. Fish JM, Brugada J, Antzelevitch C. Potential proarrhythmic effects of biventricular pacing. J Am Coll Cardiol 2005; 46:2340. 81. Navia JL, Atik FA. Minimally invasive surgical alternatives for left ventricle epicardial lead implantation in heart failure patients. Ann Thorac Surg 2005; 80:751. 82. Ezelsoy M, Bayram M, Yazici S, et al. Surgical placement of left ventricular lead for cardiac resynchronisation therapy after failure of percutaneous attempt. Cardiovasc J Afr 2017; 28:19. 83. McALOON CJ, Anderson BM, Dimitri W, et al. Long-Term Follow-Up of Isolated Epicardial Left Ventricular Lead Implant Using a Minithoracotomy Approach for Cardiac Resynchronization Therapy. Pacing Clin Electrophysiol 2016; 39:1052. 84. Rickard J, Johnston DR, Price J, et al. Reverse ventricular remodeling and long-term survival in patients undergoing cardiac resynchronization with surgically versus percutaneously placed left ventricular pacing leads. Heart Rhythm 2015; 12:517. 85. Vijayaraman P, Dandamudi G, Zanon F, et al. Permanent His bundle pacing: Recommendations from a Multicenter His Bundle Pacing Collaborative Working Group for standardization of definitions, implant measurements, and follow-up. Heart Rhythm 2018; 15:460. 86. Hua W, Zhang S, Huang D. The implantation technique in His-bundle pacing: evolution and perspectives. Europace 2020; 22:ii3. 87. Upadhyay GA, Vijayaraman P, Nayak HM, et al. On-treatment comparison between corrective His bundle pacing and biventricular pacing for cardiac resynchronization: A secondary analysis of the His-SYNC Pilot Trial. Heart Rhythm 2019; 16:1797. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 26/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate 88. Beer D, Sharma PS, Subzposh FA, et al. Clinical Outcomes of Selective Versus Nonselective His Bundle Pacing. JACC Clin Electrophysiol 2019; 5:766. 89. Zhang S, Zhou X, Gold MR. Left Bundle Branch Pacing: JACC Review Topic of the Week. J Am Coll Cardiol 2019; 74:3039. 90. Su L, Wang S, Wu S, et al. Long-Term Safety and Feasibility of Left Bundle Branch Pacing in a Large Single-Center Study. Circ Arrhythm Electrophysiol 2021; 14:e009261. 91. Huang W, Chen X, Su L, et al. A beginner's guide to permanent left bundle branch pacing. Heart Rhythm 2019; 16:1791. 92. Wu S, Chen X, Wang S, et al. Evaluation of the Criteria to Distinguish Left Bundle Branch Pacing From Left Ventricular Septal Pacing. JACC Clin Electrophysiol 2021; 7:1166. 93. Ponnusamy SS, Basil W, Vijayaraman P. Electrophysiological characteristics of septal perforation during left bundle branch pacing. Heart Rhythm 2022; 19:728. Topic 3500 Version 31.0 https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 27/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate GRAPHICS Chest radiographs of CRT-P and CRT-D Representative chest radiographs of (A) CRT-P and (B) CRT-D systems. The arrows in (B) denote the presence of a larger pulse generator and associated shocking coil on the right ventricular pacing lead required for

Day Readmissions: Evidence From the Adaptive CRT Trial. JACC Heart Fail 2015; 3:565. 63. Zanon F, Marcantoni L, Baracca E, et al. Optimization of left ventricular pacing site plus multipoint pacing improves remodeling and clinical response to cardiac resynchronization therapy at 1 year. Heart Rhythm 2016; 13:1644. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 24/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate 64. Hu F, Zheng L, Ding L, et al. Clinical outcome of left ventricular multipoint pacing versus conventional biventricular pacing in cardiac resynchronization therapy: a systematic review and meta-analysis. Heart Fail Rev 2018; 23:927. 65. Auricchio A, Stellbrink C, Sack S, et al. Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J Am Coll Cardiol 2002; 39:2026. 66. Rao RK, Kumar UN, Schafer J, et al. Reduced ventricular volumes and improved systolic function with cardiac resynchronization therapy: a randomized trial comparing simultaneous biventricular pacing, sequential biventricular pacing, and left ventricular pacing. Circulation 2007; 115:2136. 67. Boriani G, Kranig W, Donal E, et al. A randomized double-blind comparison of biventricular versus left ventricular stimulation for cardiac resynchronization therapy: the Biventricular versus Left Univentricular Pacing with ICD Back-up in Heart Failure Patients (B-LEFT HF) trial. Am Heart J 2010; 159:1052. 68. Thibault B, Ducharme A, Harel F, et al. Left ventricular versus simultaneous biventricular pacing in patients with heart failure and a QRS complex 120 milliseconds. Circulation 2011; 124:2874. 69. Meluz n J, Nov k M, M llerov J, et al. A fast and simple echocardiographic method of determination of the optimal atrioventricular delay in patients after biventricular stimulation. Pacing Clin Electrophysiol 2004; 27:58. 70. Ellenbogen KA, Gold MR, Meyer TE, et al. Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial: a randomized trial comparing empirical, echocardiography- guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy. Circulation 2010; 122:2660. 71. Brenyo A, Kutyifa V, Moss AJ, et al. Atrioventricular delay programming and the benefit of cardiac resynchronization therapy in MADIT-CRT. Heart Rhythm 2013; 10:1136. 72. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004; 350:2140. 73. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005; 352:1539. 74. McAlister FA, Ezekowitz J, Hooton N, et al. Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: a systematic review. JAMA 2007; 297:2502. 75. Le n AR, Abraham WT, Curtis AB, et al. Safety of transvenous cardiac resynchronization system implantation in patients with chronic heart failure: combined results of over 2,000 https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 25/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate patients from a multicenter study program. J Am Coll Cardiol 2005; 46:2348. 76. Perisinakis K, Theocharopoulos N, Damilakis J, et al. Fluoroscopically guided implantation of modern cardiac resynchronization devices: radiation burden to the patient and associated risks. J Am Coll Cardiol 2005; 46:2335. 77. Fox M, Mealing S, Anderson R, et al. The clinical effectiveness and cost-effectiveness of cardiac resynchronisation (biventricular pacing) for heart failure: systematic review and economic model. Health Technol Assess 2007; 11:iii. 78. Duray GZ, Israel CW, Pajitnev D, Hohnloser SH. Upgrading to biventricular pacing/defibrillation systems in right ventricular paced congestive heart failure patients: prospective assessment of procedural parameters and response rate. Europace 2008; 10:48. 79. Swindle JP, Rich MW, McCann P, et al. Implantable cardiac device procedures in older patients: use and in-hospital outcomes. Arch Intern Med 2010; 170:631. 80. Fish JM, Brugada J, Antzelevitch C. Potential proarrhythmic effects of biventricular pacing. J Am Coll Cardiol 2005; 46:2340. 81. Navia JL, Atik FA. Minimally invasive surgical alternatives for left ventricle epicardial lead implantation in heart failure patients. Ann Thorac Surg 2005; 80:751. 82. Ezelsoy M, Bayram M, Yazici S, et al. Surgical placement of left ventricular lead for cardiac resynchronisation therapy after failure of percutaneous attempt. Cardiovasc J Afr 2017; 28:19. 83. McALOON CJ, Anderson BM, Dimitri W, et al. Long-Term Follow-Up of Isolated Epicardial Left Ventricular Lead Implant Using a Minithoracotomy Approach for Cardiac Resynchronization Therapy. Pacing Clin Electrophysiol 2016; 39:1052. 84. Rickard J, Johnston DR, Price J, et al. Reverse ventricular remodeling and long-term survival in patients undergoing cardiac resynchronization with surgically versus percutaneously placed left ventricular pacing leads. Heart Rhythm 2015; 12:517. 85. Vijayaraman P, Dandamudi G, Zanon F, et al. Permanent His bundle pacing: Recommendations from a Multicenter His Bundle Pacing Collaborative Working Group for standardization of definitions, implant measurements, and follow-up. Heart Rhythm 2018; 15:460. 86. Hua W, Zhang S, Huang D. The implantation technique in His-bundle pacing: evolution and perspectives. Europace 2020; 22:ii3. 87. Upadhyay GA, Vijayaraman P, Nayak HM, et al. On-treatment comparison between corrective His bundle pacing and biventricular pacing for cardiac resynchronization: A secondary analysis of the His-SYNC Pilot Trial. Heart Rhythm 2019; 16:1797. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 26/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate 88. Beer D, Sharma PS, Subzposh FA, et al. Clinical Outcomes of Selective Versus Nonselective His Bundle Pacing. JACC Clin Electrophysiol 2019; 5:766. 89. Zhang S, Zhou X, Gold MR. Left Bundle Branch Pacing: JACC Review Topic of the Week. J Am Coll Cardiol 2019; 74:3039. 90. Su L, Wang S, Wu S, et al. Long-Term Safety and Feasibility of Left Bundle Branch Pacing in a Large Single-Center Study. Circ Arrhythm Electrophysiol 2021; 14:e009261. 91. Huang W, Chen X, Su L, et al. A beginner's guide to permanent left bundle branch pacing. Heart Rhythm 2019; 16:1791. 92. Wu S, Chen X, Wang S, et al. Evaluation of the Criteria to Distinguish Left Bundle Branch Pacing From Left Ventricular Septal Pacing. JACC Clin Electrophysiol 2021; 7:1166. 93. Ponnusamy SS, Basil W, Vijayaraman P. Electrophysiological characteristics of septal perforation during left bundle branch pacing. Heart Rhythm 2022; 19:728. Topic 3500 Version 31.0 https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 27/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate GRAPHICS Chest radiographs of CRT-P and CRT-D Representative chest radiographs of (A) CRT-P and (B) CRT-D systems. The arrows in (B) denote the presence of a larger pulse generator and associated shocking coil on the right ventricular pacing lead required for https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 28/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate the system to provide defibrillation capability. These elements are not present on the CRT-P system shown in (A). CRT-P: cardiac resynchronization therapy pacemaker; CRT-D: cardiac resynchronization therapy defibrillator. Graphic 116571 Version 1.0 https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 29/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate Contrast venography in the LAO and RAO Contrast venography in the LAO (A) and RAO (B) projections depicting expected venous branches of the coronary sinus. These images were obtained from a patient with a mechanical MV prosthesis in order to provide anatomic orientation. These images also demonstrate both pacing and ICD leads fixed in the right ventricular apex. The RAO image (B) also includes the presence of a pacing lead fixed in the right atrial appendage. The AIV courses in the interventricular groove between the https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 30/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate right and left ventricles. The MCV courses posteriorly over the left ventricle. Venous branches commonly selected for left ventricular lead placement include (1) the anterolateral branch, (2) the midlateral branch, and (3) the posterolateral branch. LAO: left anterior oblique view; RAO: right anterior oblique view; AIV: anterior interventricular vein; MV: mitral valve; MCV: middle cardiac vein; ICD: implantable cardioverter-defibrillator. Graphic 116573 Version 2.0 https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 31/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate Strategies for optimizing cardiac resynchronization therapy Optimization of CRT can be achieved by avoiding scar (B), targeting a Q-LV interval 95 ms (C), employing algorithms to maximize fusion of LV pacing with native conduction (D), and pacing at multiple LV sites (E). LV: left ventricular; CRT: cardiac resynchronization therapy. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography 2018-2019. All Rights Reserved. Graphic 120743 Version 1.0 https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 32/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate Conceptual overview of electrical activation of the cardiac His-Purkinje fibers Conceptual overview of electrical activation of the cardiac His-Purkinje fibers for (A) normal conduction, (B) with left bundle branch block, (C) with biventricular pacing, and (D) with fusion pacing. In all 4 panels, the length of the x-axis is the biventricular activation time reflected by the width of the QRS complex recorded on a surface electrocardiogram. (A) With normal conduction, biventricular activation is rapid (ie, 90 ms) when impulses propagate antegrade over intact right and left bundles. (B) In a patient with complete left bundle branch block, electrical activation is blocked antegrade due to the underlying disease state and proceeds more slowly following transseptal activation via the right bundle occurring via cell-to-cell connections. The total biventricular activation time of 170 ms is a typical intrinsic QRS duration for a patient with complete left bundle branch block. (C) The grey thunderbolts depict left and right ventricular pacing stimulation resulting in electrical activation largely along myocardial cell-to-cell connections that are typically slower than intact His- Purkinje fibers. The total activation time of 140 ms is a typical paced QRS duration for a patient with biventricular pacing. (D) The concept of fusion pacing is that intrinsic electrical activation proceeds antegrade over an intact right bundle and collides with electrical activation resultant from the left ventricular pacing stimulus https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 33/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate depicted by the grey thunderbolt. The total activation time of 110 ms is afforded by rapid physiologic conduction over the native right bundle. The white thunderbolt depicts the optional delivery of right ventricular pacing stimulation that is delayed and offset from the left ventricular stimulus according to vendor-specific algorithms. As an example, such pacing stimulation could be applied in scenarios when the native His-Purkinje disease is more complicated than an isolated left bundle branch block. RV: right ventricular. Graphic 116574 Version 2.0 https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 34/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate Fluoroscopic view of left bundle branch area pacing lead placement Fluoroscopic view of the heart during implantation of a left bundle branch area pacing lead. A delivery sheath was extended from the left subclavian vein access site to the RV septum. Then, an active fixation pacing lead with a fixed helix at the tip was advanced and fixed deep in the RV septum. The position of the lead was confirmed with iodinated contrast injection, which is seen here at the right of the edge of the spine. The proximal pacing electrode is still within the sheath near the tip. Pacing from the distal electrode resulted in capture of the left bundle branch that travels along the left side of the ventricular septum. Also seen is a J-tip guidewire that was used subsequently to place the atrial lead. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 35/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate RV: right ventricular. Graphic 141249 Version 2.0 https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 36/37 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: System implantation and programming - UpToDate Contributor Disclosures Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Jonathan Piccini, MD, MHS, FACC, FAHA, FHRS Grant/Research/Clinical Trial Support: Abbott [Atrial fibrillation, catheter ablation]; AHA [Atrial fibrillation, cardiovascular disease]; Bayer [Atrial fibrillation]; Boston Scientific [Cardiac mapping, pacemaker/ICD, atrial fibrillation care]; iRhythm [Atrial fibrillation]; NIA [Atrial fibrillation]; Philips [Lead management]. Consultant/Advisory Boards: Abbott [Atrial fibrillation, catheter ablation]; Abbvie [Atrial fibrillation]; Bayer [Atrial fibrillation]; Boston Scientific [Cardiac mapping, atrial fibrillation, pacemaker/ICD]; ElectroPhysiology Frontiers [Atrial fibrillation, catheter ablation]; Element Science [DSMB]; Medtronic [Atrial fibrillation, pacemaker/ICDs]; Milestone [Supraventricular tachycardia]; Pacira [Atrial fibrillation]; Philips [Lead extraction]; ReCor [Cardiac arrhythmias]; Sanofi [Atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-system-implantation-and-programming/print 37/37

7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Driving restrictions in patients with an implantable cardioverter-defibrillator : Kapil Kumar, MD : N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 15, 2023. INTRODUCTION The implantable cardioverter-defibrillator (ICD) has been instrumental in improving survival in patients resuscitated from ventricular fibrillation or unstable ventricular tachycardia (ie, secondary prevention of sudden cardiac death). There are compelling data that the ICD is also effective in the primary prevention of sudden cardiac death (SCD) in select high-risk patients. Since many patients with an ICD may be healthy enough to drive an automobile, this topic will review the concerns regarding the risk of ventricular arrhythmias and ICD shocks in this patient population while driving. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Overview of sudden cardiac arrest and sudden cardiac death".) INCREASED RISK WITH DRIVING For patients with ICDs, driving could lead to losing control of the vehicle if there are symptomatic ventricular arrythmias or ICD shocks. Loss of vehicle control not only poses a risk to the patient, but also to other occupants of the vehicle and persons outside of the vehicle. The extension of risk to others makes this issue a public health concern. Data regarding the risks associated with driving with an ICD are primarily retrospective, with no prospective trials that have randomized patients to driving with or without restrictions. Recommendations are based primarily on expert opinion and public policy. https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 1/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate Causes of accidents Both ventricular arrhythmias and ICD-delivered shock therapies can interfere with driving and lead to accidents. In patients with ICDs, causes of accidents include: Sudden cardiac death Although ICDs have been shown to improve survival, they do not entirely eliminate the risk of sudden cardiac death (SCD). Data from major trials indicate that the residual rate of SCD among patients who receive an ICD for secondary prevention is one to two percent per year [1-3]. Similar or slightly lower SCD rates have been reported in major primary prevention trials [4-6]. Syncope Syncope may occur due to arrhythmic and nonarrhythmic causes in ICD recipients. Even rapid treatment of a ventricular arrhythmia by an ICD may not protect against driving impairment, since syncope or altered states of consciousness can still occur. In the MADIT-RIT study, which included 1500 patients who received a primary prevention ICD and who were followed for an average of 1.4 years, 64 patients (4.3 percent) experienced syncope, with similar frequency regardless of the programmed device settings [7]. (See 'Syncope' below.) Transient incapacitation from the shock Even if therapy is successful and the patient remains conscious, the discomfort from an ICD discharge, either appropriate or inappropriate, may startle or briefly incapacitate the patient and disrupt safe motor vehicle operation. Overall incidence of ventricular arrhythmias and ICD shocks A higher incidence of ventricular arrhythmias and ICD shocks increases the likelihood of that an incident may occur during driving. In patients treated for secondary prevention Data on the incidence of recurrent ventricular arrhythmias and ICD therapies among patients treated with an ICD for secondary prevention comes primarily from studies performed in the 1990s and early 2000s. As such, estimates of recurrent arrhythmia from those trials are presumably higher than what is seen in contemporary practice; this likely reflects the impact of contemporary medical therapy and ICD programming strategies, which appear to significantly reduce the rates of arrhythmias and inappropriate device therapy. In the AVID trial, among the 449 patients assigned to ICD therapy, 35 percent of patients had an arrhythmic event (arrhythmic death, sustained ventricular arrhythmia, shock, or antitachycardia pacing) at three months, 53 percent had an event at one year, and 68 percent at two years [8]. First shocks or antitachycardia pacing after the second year were uncommon. https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 2/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate Among a cohort of 256 patients who received a subcutaneous ICD (S-ICD) for secondary prevention and who were followed for an average of 21 months, 12 percent of patients received an appropriate ICD shock [9]. In the Danish Pacemaker and ICD Register, 4580 patients with ICDs placed for secondary prevention were followed for an average of 3.6 years [10]. Thirty percent experienced appropriate ICD therapies, of which 16.8 percent were ICD shocks, and 4.6 percent of patients had an inappropriate ICD shock. There was a reduction in appropriate (28.2 to 7.9 per 100 person-years) and inappropriate (10 to 1 per 100 person-years) ICD therapy over the study period 2007 to 2016. Another study of patients with ICD for secondary prevention is the DREAM-ICD-II Study [11]. This study observed patients from Canada from 2016 to 2020. The incidence of recurrent ventricular arrhythmia was greatest during the first three months following ICD implantation (34.4 percent) and decreased over time to 10.6 percent between months 3 and 6 and 11.7 percent between months 6 and 12. The authors also observed that the cumulative rate of sudden incapacitation resulting from syncope was 1.8 percent during the first 90 days after ICD insertion and then reduced to 0.4 percent between three to six months. Among patients treated with an ICD for secondary prevention, single device therapy has an increased risk of additional events. In one study, the mean time to first ICD therapy was 138 days; among those with a first event, the mean time to second ICD therapy was only 66 days [12]. Patients with an initial ICD therapy had a 79 percent likelihood of another ICD therapy within one year. Patients who do not have an ICD therapy within the first year appear to have a lower, but still appreciable, risk of future events [13,14]. One report, for example, identified 14 patients who had not received an appropriate shock at 24 months [13]. The actuarial risk of an appropriate shock in the next 24 months was still 29 percent. In patients treated for primary prevention Patients receiving an ICD for primary prevention have a lower risk of ventricular arrhythmias when compared with those in whom an ICD was placed for secondary prevention. Patients with primary prevention ICDs have variable rates of ICD discharge, which may be influenced by ICD programming, underlying cardiac diagnosis, and other factors [5,15-17]. (See "Implantable cardioverter-defibrillators: Optimal programming", section on 'Tachycardia therapies'.) As examples: https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 3/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate In the MADIT-RIT trial of 1500 patients with a primary prevention ICD placed between 2009 and 2011 who were randomly assigned to one of three ICD programming strategies, appropriate ICD therapy occurred in 12.4 percent over 1.4 years [16]. When compared with conventional programming, delayed therapy programming and high-rate programming reduced the risk of inappropriate and appropriate shocks without increasing the risk of death or syncope [16,18]. In a study of 803 patients who had a primary prevention ICD placed between 2016 and 2019, the rate of ICD-delivered therapy (anti-tachycardia pacing or ICD shock) was 0.4 percent at 30 days, 1 percent at 90 days, and 1.7 percent at 180 days [17]. There were no episodes of syncope after six months of observation. Among 1111 patients with a low ejection fraction who underwent an S-ICD implant between 2015 and 2018 for primary prevention, 9 percent had received a shock at 18 months [19]. Predictors of events A number of clinical features are associated with an increased risk of arrhythmic events and ICD therapies. These include the following: Reduced left ventricular ejection fraction (LVEF) [12,20,21] New York Heart Association Functional Class III or IV heart failure [12,21,22] Sustained monomorphic VT rather than VF as the presenting arrhythmia [12,21] Absence of revascularization in patients with coronary heart disease [12,21] Absence of beta blocker therapy after hospital discharge [12,21] Syncope When considering the risks associated with driving by patients with ICDs, the incidence of ventricular arrhythmias and ICD discharge are less important than the actual incidence of syncope during an arrhythmic event (since not all events lead to impaired consciousness). The incidence of syncope among patients treated with an ICD for secondary prevention ranges from 15 to 46 percent [12,23-25]. The frequency, causes of, and risk factors for syncope were evaluated in a review of 421 patients with an ICD for secondary prevention [23]. At a mean follow-up of 26 months, 62 had syncope (15 percent of all patients and 27 percent of those with recurrent ventricular arrhythmia). Syncopal episodes occurred in the following settings: Shortly after rapid and successful delivery of a first 34 joule shock; the mean ICD capacitor charge time was 9.4 sec (55 percent of syncopal episodes) https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 4/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate VT that was initially treated with antitachycardia pacing, which may then lead to acceleration of the VT after pacing (16 percent of episodes) Incessant or clusters of VT (VT storm) (8 percent) Failure of a first shock (7 percent) No cause could be identified in three patients. Risk factors for syncope Several clinical features predict an increased likelihood of syncope in patients treated with an ICD, including the following: Syncope during a prior episode of VT [23,26]. In one series, among ICD patients with syncope during a prior episode of VT, the median time to a first recurrent syncopal event was 376 days, suggesting that patients who present with syncope during VT are more likely to have syncope with recurrent episodes of VT, and the standard six-month driving restriction may be inadequate [26]. Very rapid VT (cycle length less than 300 msec) [23]. Reduced LVEF [23]. Chronic atrial fibrillation [23]. The authors suggested that these risk factors may be used to risk-stratify ICD patients for future syncopal events. In the study discussed above, overall actuarial survival free of syncope was 90, 85, and 81 percent at one, two, and three years after implantation; in comparison, event-free survival was better in patients with none of the above risk factors (96, 92, and 92 percent) [23]. Effect of therapy on recurrent ventricular arrhythmias In many patients with chronic ventricular tachycardia, ventricular tachyarrhythmias can be suppressed by antiarrhythmic medications and catheter ablation, thereby preventing syncope or ICD shocks. A meta-analysis suggests that amiodarone is the most effective antiarrhythmic medication for suppression of ventricular arrhythmia [27]. Amiodarone modestly reduced the incidence of SCD in patients with or without an ICD (relative risk 0.76; 95% CI 0.66-0.88) and was superior to other antiarrhythmics with low to moderate quality of evidence. Catheter ablation of VT has emerged as an effective treatment modality in patients with a prior documented history of VT or VF. One of the first studies to demonstrate the ability of substrate- based VT ablation to reduce future ICD therapy was the SMASH-VT study [28]. Appropriate ICD therapy occurred in 12 percent of the patients randomized to ICD implantation plus catheter ablation versus 33 percent in the ICD-implantation-alone arm over a mean follow-up of 22.5 https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 5/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate months. Other randomized studies have also shown superiority of VT ablation over antiarrhythmic drugs to minimize outcomes of composite endpoints, which included appropriate ICD therapy [29,30]. Given the relatively high recurrence of ventricular tachyarrhythmias and ICD shocks after antiarrhythmic medications or catheter ablation over the ensuing months, these therapies may not sufficiently reduce the risk of impairment while driving. Inappropriate ICD shocks Inappropriate shocks, which may predispose to an accident by startling or briefly incapacitating the patient, occur less frequently with modern generations and contemporary programming of ICDs. Thus, patients who have inappropriate ICD therapies without loss of consciousness may not require restriction. Again, official recommendations vary according to location. Examples of trials and studies that report the rate of inappropriate shocks include: Among 1500 patients who received an ICD for primary prevention in MADIT-RIT (average follow up 1.4 years), the annual incidence of inappropriate shocks was only 2.9 percent. The main cause is supraventricular tachyarrhythmia, in particular atrial fibrillation with rapid ventricular response. Such patients may often receive multiple inappropriate shocks. Other causes of inappropriate shocks include electrical noise from conditions such as lead fracture or external electromagnetic interference and ICD. (See "Cardiac implantable electronic devices: Long-term complications".) In a cohort of 4089 patients, 417 patients (65 percent with a secondary prevention indication) experienced an inappropriate shock. Less than 1 percent of patients experienced an episode of syncope associated with the inappropriate shock. The estimated maximum annual risk of harm is calculated well below the established acceptable risk threshold of 5 in 100,000 [31]. Among 1111 patients with a low ejection fraction who underwent an S-ICD implant between 2015 and 2018 for primary prevention, 4.1 percent experienced an inappropriate shock at 18 months [19]. INCIDENCE OF ICD SHOCKS WHILE DRIVING AND ACCIDENTS Although information regarding the general incidence of arrhythmic events and the risk factors for such events are useful, there is now increasing evidence that directly addresses the incidence of such events while driving. https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 6/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate ICD shocks while driving The incidence of ICD shocks associated with driving was assessed in an analysis from the TOVA study [32]. A total of 1,188 patients treated with an ICD for a range of primary and secondary prevention indications were followed for a median of 562 days. The following findings were noted: The estimated risk of an ICD shock within one hour of driving was one shock per 25,000 person-hours of driving. The relative risk for ICD shocks for VT/VF within one hour of driving compared to other times was 2.24. However, the elevated risk was limited to the 30 minutes after driving (relative risk 4.46 compared to other times), rather than during the driving episode itself (relative risk 1.05 compared to other times). Accidents Among patients with an ICD, the rate of motor vehicle accidents is highest immediately following ICD implantation and then decreases over months to years. However, accidents are typically underreported and may not be properly attributed to an arrhythmia or ICD-delivered therapy, which leads to potentially inaccurate measurements of the rate and cause of accidents in this population. The following studies illustrate the range of findings: In a Danish registry study that included 2741 patients with an ICD implanted for any indication between 2013 and 2016, 0.2 percent of patients received a shock while driving, and there was one traffic accident [33]. The authors estimated that the risk of harm was 0.0002 percent per person-year of ICD therapy. In another study of 14,230 patients who received an ICD for any indication between 2008 and 2013 and who experienced at least one shock, the risk of harm while driving after the initial shock (as determined by a formula that estimates the annual risk to other road users posed by a driver with an ICD, assuming a probability of loss of consciousness with an ICD shock of 32 percent) was 12.5 events per 100,000 ICD recipients at one month and 2.7 events per 100,00 recipients at one year [34]. Among patients enrolled in a trial of ICD placement for secondary prevention (AVID) between 1993 and 1997, 50 patients reported having at least one accident, and there were a total of 55 accidents during 1619 patient-years of follow-up after the resumption of driving (3.4 events per 100 patient-years) [35]. Of these accidents, 11 percent (0.4 events per 100 patient-years) were preceded by symptoms of arrhythmia. RECOMMENDATIONS OF OTHERS AND GOVERNMENT LAWS https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 7/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate Patients with an ICD placed for secondary prevention Guidelines for driving after an episode of sudden cardiac death (SCD) have been published by various professional societies and local governments [36-39]. The general approaches to driving restriction in 4 different regions are summarized in the table ( table 1) [37]: Noncommercial drivers are generally advised to not drive for the first six months postimplantation (first three months in the European Union), the time of greatest risk for recurrent events [8]. If there has been no discharge from the ICD during this period, driving can be resumed ( table 1). If highway or long-distance travel is anticipated, patients should be encouraged to have an adult companion drive, and cruise control driving should be avoided. The six-month driving restriction restarts if an ICD discharge occurs with or without syncope. For commercial drivers, the risk of harm to the public as a consequence of ICD discharge or syncope is much higher. As a result, it was recommended that all commercial driving be prohibited permanently after a life-threatening ventricular arrhythmia whether the patient is treated with an ICD or antiarrhythmic drugs. Some patients with an ICD have frequent episodes of hemodynamically well-tolerated, asymptomatic VT that are consistently terminated (and without acceleration) by antitachycardia pacing. The guidelines recommend that decisions on noncommercial driving in such patients be made on a case-by-case basis. However, some have considered these guidelines too conservative in light of subsequently published data and advances in the treatment of arrhythmia [40]. In a report from the AVID trial described above, 57 percent of patients resumed driving within three months; the rate of patient-reported accidents preceded by symptoms suggestive of an arrhythmia was only 0.4 percent per patient-year, which is less than the accident rate in the general driving population (0.7 percent per year) [35]. Patients in the AVID registry who were not randomized had similar clinical characteristics to those who were, suggesting that these observations can be generalized to all patients who would be eligible [41]. Reporting bias is a potential problem since patients may underreport accidents or near-accidents. These observations have led to the suggestion that low-risk patients (LVEF >40 percent, no persistent medical condition predisposing to recurrent arrhythmia, and no recurrent ventricular arrhythmia) can begin driving after three months [40]. https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 8/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate The 1997 ESC guidelines reached similar conclusions ( table 1), although it was emphasized that, because of limited data, the recommendations do not represent practice standards [38]. Thus, clinical judgment should be considered with a given patient [42,43]. As noted above, patients with frequent ICD shocks for recurrent arrhythmia may benefit from antiarrhythmic drug therapy or catheter ablation. (See "Pharmacologic therapy in survivors of sudden cardiac arrest", section on 'Treatment of breakthrough arrhythmias'.) Patients with an ICD placed for primary prevention The 2007 addendum to the AHA/NASPE guidelines provided the following driving recommendations ( table 1) for patients with ICDs implanted for primary prevention [39]: Noncommercial driving should be restricted for at least one week following ICD implantation. In the absence of symptoms potentially related to an arrhythmia, driving privileges thereafter should not be restricted. Patients should be instructed that impairment of consciousness is a possible future event. Patients who have received an ICD for primary prevention who subsequently receive an appropriate therapy for VT or VF, especially with symptoms of cerebral hypoperfusion, should be managed according to the recommendations for patients with ICDs for secondary prevention. These recommendations do not apply to the licensing of commercial drivers. The ESC guidelines recommended no restriction for noncommercial driving, beyond the two- week restriction immediately following implantation to allow for wound healing, but total restriction for commercial driving when an ICD was implanted for primary prevention ( table 1) [38,43]. As in low-risk patients who receive an ICD for secondary prevention, resumption of driving may be safe after three months in patients who receive an ICD for primary prevention if they have had no sustained ventricular tachyarrhythmias [40,44]. Patients with nonsustained arrhythmias but without an ICD The 1996 AHA/NASPE guidelines also made recommendations for driving in patients with ventricular tachyarrhythmias (nonsustained VT and idiopathic VT) not associated with loss of consciousness not treated with ICDs [37]: No restrictions for either noncommercial or commercial driving for patients with nonsustained VT without impaired consciousness. https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 9/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate Noncommercial driving should be restricted for three months and commercial driving for six months in patients with nonsustained VT and impaired consciousness or with idiopathic VT (ie, no apparent structural heart disease) without impaired consciousness. Driving must cease if there are disabling symptoms. Driving is only allowed after specialist assessment and satisfactory control of the arrhythmia. If there is an indication for an ICD, the respective rules apply. (See "Ventricular tachycardia in the absence of apparent structural heart disease" and "Catecholaminergic polymorphic ventricular tachycardia".) Governmental laws Legal restrictions on driving for patients with a history of cardiac arrhythmias, non-seizure syncope, and seizure syncope differ among local, regional, and national governments ( table 1), and there is generally no distinction between patients managed medically or with an ICD [25,43]. It has been estimated that, as of 1992, only about 30 percent of clinicians who implanted an ICD were aware of governmental regulations regarding driving [45]. Furthermore, among those aware of governmental regulations, 20 percent admitted to making recommendations that were not consistent with the regulations. Clinicians must be aware of and adhere to the strictest legal regulations covering the area in which they practice (and also the areas in which their patients reside, if different from the practice location). It may be helpful for the clinician to point out to the patient that the issue affects public safety as well as patient safety. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 10/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Implantable cardioverter-defibrillators (The Basics)" and "Patient education: Time to stop driving? (The Basics)") Beyond the Basics topic (see "Patient education: Implantable cardioverter-defibrillators (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Background Data regarding the risks associated with driving with an ICD are primarily retrospective, and there are no trials of driving with or without restrictions. Recommendations are based primarily on expert opinion and public policy. Although restricting driving for a short period of time after implantable cardioverter-defibrillator (ICD) implantation may be necessary, excessive restrictions or a total ban may be unwarranted. (See 'Increased risk with driving' above.) Predictors of events We consider the following factors when deciding about driving restrictions (see 'Predictors of events' above): Number of arrhythmic events Presence of syncope Low left ventricular ejection fraction (LVEF) Other cardiac diagnosis Treatment with antiarrhythmic drug or catheter ablation treatment Treatment of underlying factors All reversible factors that might cause or exacerbate ventricular arrhythmia should be corrected (eg, coronary ischemia, drug toxicity, and electrolyte imbalance, particularly hypokalemia or hypomagnesemia). (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Treatment of associated conditions'.) Shared decision-making discussions When making therapeutic decisions for life- threatening ventricular arrhythmias, the clinician should make it clear to the patient and family members that driving restrictions may be independent of whether the patient is treated with an ICD or antiarrhythmic drugs as other medical conditions may also contribute to the need to restrict driving. Such discussions can be difficult because of the https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 11/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate importance of driving for both independence and quality of life. (See 'Recommendations of others and government laws' above.) Knowledge of legal considerations Clinicians must be aware of and adhere to the strictest legal regulations covering the area in which they practice (and also the areas in which their patients reside, if different from the practice location) ( table 1). It may be helpful for the clinician to point out to the patient that the issue affects public safety as well as patient safety. (See 'Governmental laws' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Ann Garlitski, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Causes of death in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. J Am Coll Cardiol 1999; 34:1552. 2. Grubman EM, Pavri BB, Shipman T, et al. Cardiac death and stored electrograms in patients with third-generation implantable cardioverter-defibrillators. J Am Coll Cardiol 1998; 32:1056. 3. Mitchell LB, Pineda EA, Titus JL, et al. Sudden death in patients with implantable cardioverter defibrillators: the importance of post-shock electromechanical dissociation. J Am Coll Cardiol 2002; 39:1323. 4. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996; 335:1933. 5. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004; 350:2151. 6. Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of an implantable cardioverter- defibrillator after acute myocardial infarction. N Engl J Med 2004; 351:2481. 7. Ruwald MH, Okumura K, Kimura T, et al. Syncope in high-risk cardiomyopathy patients with implantable defibrillators: frequency, risk factors, mechanisms, and association with https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 12/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate mortality: results from the multicenter automatic defibrillator implantation trial-reduce inappropriate therapy (MADIT-RIT) study. Circulation 2014; 129:545. 8. Klein RC, Raitt MH, Wilkoff BL, et al. Analysis of implantable cardioverter defibrillator therapy in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. J Cardiovasc Electrophysiol 2003; 14:940. 9. Boersma LV, Barr CS, Burke MC, et al. Performance of the subcutaneous implantable cardioverter-defibrillator in patients with a primary prevention indication with and without a reduced ejection fraction versus patients with a secondary prevention indication. Heart Rhythm 2017; 14:367. 10. Ruwald MH, Ruwald AC, Johansen JB, et al. Temporal Incidence of Appropriate and Inappropriate Therapy and Mortality in Secondary Prevention ICD Patients by Cardiac Diagnosis. JACC Clin Electrophysiol 2021; 7:781. 11. Steinberg C, Dognin N, Sodhi A, et al. DREAM-ICD-II Study. Circulation 2022; 145:742. 12. Freedberg NA, Hill JN, Fogel RI, et al. Recurrence of symptomatic ventricular arrhythmias in patients with implantable cardioverter defibrillator after the first device therapy: implications for antiarrhythmic therapy and driving restrictions. CARE Group. J Am Coll Cardiol 2001; 37:1910. 13. Fogoros RN, Elson JJ, Bonnet CA. Actuarial incidence and pattern of occurrence of shocks following implantation of the automatic implantable cardioverter defibrillator. Pacing Clin Electrophysiol 1989; 12:1465. 14. Curtis JJ, Walls JT, Boley TM, et al. Time to first pulse after automatic implantable cardioverter defibrillator implantation. Ann Thorac Surg 1992; 53:984. 15. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352:225. 16. Moss AJ, Schuger C, Beck CA, et al. Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med 2012; 367:2275. 17. Steinberg C, Cheung CC, Wan D, et al. Driving Restrictions and Early Arrhythmias in Patients Receiving a Primary-Prevention Implantable Cardioverter-Defibrillator (DREAM-ICD) Study. Can J Cardiol 2020; 36:1269. 18. Ruwald AC, Schuger C, Moss AJ, et al. Mortality reduction in relation to implantable cardioverter defibrillator programming in the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT). Circ Arrhythm Electrophysiol 2014; 7:785. 19. Gold MR, Lambiase PD, El-Chami MF, et al. Primary Results From the Understanding Outcomes With the S-ICD in Primary Prevention Patients With Low Ejection Fraction https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 13/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate (UNTOUCHED) Trial. Circulation 2021; 143:7. 20. Larsen GC, Stupey MR, Walance CG, et al. Recurrent cardiac events in survivors of ventricular fibrillation or tachycardia. Implications for driving restrictions. JAMA 1994; 271:1335. 21. Levine JH, Mellits ED, Baumgardner RA, et al. Predictors of first discharge and subsequent survival in patients with automatic implantable cardioverter-defibrillators. Circulation 1991; 84:558. 22. Whang W, Mittleman MA, Rich DQ, et al. Heart failure and the risk of shocks in patients with implantable cardioverter defibrillators: results from the Triggers Of Ventricular Arrhythmias (TOVA) study. Circulation 2004; 109:1386. 23. B nsch D, Brunn J, Castrucci M, et al. Syncope in patients with an implantable cardioverter- defibrillator: incidence, prediction and implications for driving restrictions. J Am Coll Cardiol 1998; 31:608. 24. Kou WH, Calkins H, Lewis RR, et al. Incidence of loss of consciousness during automatic implantable cardioverter-defibrillator shocks. Ann Intern Med 1991; 115:942. 25. Strickberger SA, Cantillon CO, Friedman PL. When should patients with lethal ventricular arrhythmia resume driving? An analysis of state regulations and physician practices. Ann Intern Med 1991; 115:560. 26. Abello M, Merino JL, Peinado R, et al. Syncope following cardioverter defibrillator implantation in patients with spontaneous syncopal monomorphic ventricular tachycardia. Eur Heart J 2006; 27:89. 27. Claro JC, Candia R, Rada G, et al. Amiodarone versus other pharmacological interventions for prevention of sudden cardiac death. Cochrane Database Syst Rev 2015; :CD008093. 28. Reddy VY, Reynolds MR, Neuzil P, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med 2007; 357:2657. 29. Parkash R, Nault I, Rivard L, et al. Effect of Baseline Antiarrhythmic Drug on Outcomes With Ablation in Ischemic Ventricular Tachycardia: A VANISH Substudy (Ventricular Tachycardia Ablation Versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease). Circ Arrhythm Electrophysiol 2018; 11:e005663. 30. Arenal , vila P, Jim nez-Candil J, et al. Substrate Ablation vs Antiarrhythmic Drug Therapy for Symptomatic Ventricular Tachycardia. J Am Coll Cardiol 2022; 79:1441. 31. Watanabe E, Okajima K, Shimane A, et al. Inappropriate implantable cardioverter defibrillator shocks-incidence, effect, and implications for driver licensing. J Interv Card Electrophysiol 2017; 49:271. https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 14/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate 32. Albert CM, Rosenthal L, Calkins H, et al. Driving and implantable cardioverter-defibrillator shocks for ventricular arrhythmias: results from the TOVA study. J Am Coll Cardiol 2007; 50:2233. 33. Bjerre J, Rosenkranz SH, Schou M, et al. Driving following defibrillator implantation: a nationwide register-linked survey study. Eur Heart J 2021; 42:3529. 34. Merchant FM, Hoskins MH, Benser ME, et al. Time Course of Subsequent Shocks After Initial Implantable Cardioverter-Defibrillator Discharge and Implications for Driving Restrictions. JAMA Cardiol 2016; 1:181. 35. Akiyama T, Powell JL, Mitchell LB, et al. Resumption of driving after life-threatening ventricular tachyarrhythmia. N Engl J Med 2001; 345:391. 36. Assessment of the cardiac patient for fitness to drive. Can J Cardiol 1992; 8:406. 37. Epstein AE, Miles WM, Benditt DG, et al. Personal and public safety issues related to arrhythmias that may affect consciousness: implications for regulation and physician recommendations. A medical/scientific statement from the American Heart Association and the North American Society of Pacing and Electrophysiology. Circulation 1996; 94:1147. 38. Jung W, Anderson M, Camm AJ, et al. Recommendations for driving of patients with implantable cardioverter defibrillators. Study Group on 'ICD and Driving' of the Working Groups on Cardiac Pacing and Arrhythmias of the European Society of Cardiology. Eur Heart J 1997; 18:1210. 39. Epstein AE, Baessler CA, Curtis AB, et al. Addendum to "Personal and public safety issues related to arrhythmias that may affect consciousness: implications for regulation and physician recommendations: a medical/scientific statement from the American Heart Association and the North American Society of Pacing and Electrophysiology": public safety issues in patients with implantable defibrillators: a scientific statement from the American Heart Association and the Heart Rhythm Society. Circulation 2007; 115:1170. 40. Bleakley JF, Akiyama T, Canadian Cardiovascular Society, et al. Driving and arrhythmias: implications of new data. Card Electrophysiol Rev 2003; 7:77. 41. Kim SG, Hallstrom A, Love JC, et al. Comparison of clinical characteristics and frequency of implantable defibrillator use between randomized patients in the Antiarrhythmics Vs Implantable Defibrillators (AVID) trial and nonrandomized registry patients. Am J Cardiol 1997; 80:454. 42. Task force members, Vijgen J, Botto G, et al. Consensus statement of the European Heart Rhythm Association: updated recommendations for driving by patients with implantable cardioverter defibrillators. Europace 2009; 11:1097. https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 15/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate

reduced ejection fraction versus patients with a secondary prevention indication. Heart Rhythm 2017; 14:367. 10. Ruwald MH, Ruwald AC, Johansen JB, et al. Temporal Incidence of Appropriate and Inappropriate Therapy and Mortality in Secondary Prevention ICD Patients by Cardiac Diagnosis. JACC Clin Electrophysiol 2021; 7:781. 11. Steinberg C, Dognin N, Sodhi A, et al. DREAM-ICD-II Study. Circulation 2022; 145:742. 12. Freedberg NA, Hill JN, Fogel RI, et al. Recurrence of symptomatic ventricular arrhythmias in patients with implantable cardioverter defibrillator after the first device therapy: implications for antiarrhythmic therapy and driving restrictions. CARE Group. J Am Coll Cardiol 2001; 37:1910. 13. Fogoros RN, Elson JJ, Bonnet CA. Actuarial incidence and pattern of occurrence of shocks following implantation of the automatic implantable cardioverter defibrillator. Pacing Clin Electrophysiol 1989; 12:1465. 14. Curtis JJ, Walls JT, Boley TM, et al. Time to first pulse after automatic implantable cardioverter defibrillator implantation. Ann Thorac Surg 1992; 53:984. 15. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352:225. 16. Moss AJ, Schuger C, Beck CA, et al. Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med 2012; 367:2275. 17. Steinberg C, Cheung CC, Wan D, et al. Driving Restrictions and Early Arrhythmias in Patients Receiving a Primary-Prevention Implantable Cardioverter-Defibrillator (DREAM-ICD) Study. Can J Cardiol 2020; 36:1269. 18. Ruwald AC, Schuger C, Moss AJ, et al. Mortality reduction in relation to implantable cardioverter defibrillator programming in the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT). Circ Arrhythm Electrophysiol 2014; 7:785. 19. Gold MR, Lambiase PD, El-Chami MF, et al. Primary Results From the Understanding Outcomes With the S-ICD in Primary Prevention Patients With Low Ejection Fraction https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 13/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate (UNTOUCHED) Trial. Circulation 2021; 143:7. 20. Larsen GC, Stupey MR, Walance CG, et al. Recurrent cardiac events in survivors of ventricular fibrillation or tachycardia. Implications for driving restrictions. JAMA 1994; 271:1335. 21. Levine JH, Mellits ED, Baumgardner RA, et al. Predictors of first discharge and subsequent survival in patients with automatic implantable cardioverter-defibrillators. Circulation 1991; 84:558. 22. Whang W, Mittleman MA, Rich DQ, et al. Heart failure and the risk of shocks in patients with implantable cardioverter defibrillators: results from the Triggers Of Ventricular Arrhythmias (TOVA) study. Circulation 2004; 109:1386. 23. B nsch D, Brunn J, Castrucci M, et al. Syncope in patients with an implantable cardioverter- defibrillator: incidence, prediction and implications for driving restrictions. J Am Coll Cardiol 1998; 31:608. 24. Kou WH, Calkins H, Lewis RR, et al. Incidence of loss of consciousness during automatic implantable cardioverter-defibrillator shocks. Ann Intern Med 1991; 115:942. 25. Strickberger SA, Cantillon CO, Friedman PL. When should patients with lethal ventricular arrhythmia resume driving? An analysis of state regulations and physician practices. Ann Intern Med 1991; 115:560. 26. Abello M, Merino JL, Peinado R, et al. Syncope following cardioverter defibrillator implantation in patients with spontaneous syncopal monomorphic ventricular tachycardia. Eur Heart J 2006; 27:89. 27. Claro JC, Candia R, Rada G, et al. Amiodarone versus other pharmacological interventions for prevention of sudden cardiac death. Cochrane Database Syst Rev 2015; :CD008093. 28. Reddy VY, Reynolds MR, Neuzil P, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med 2007; 357:2657. 29. Parkash R, Nault I, Rivard L, et al. Effect of Baseline Antiarrhythmic Drug on Outcomes With Ablation in Ischemic Ventricular Tachycardia: A VANISH Substudy (Ventricular Tachycardia Ablation Versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease). Circ Arrhythm Electrophysiol 2018; 11:e005663. 30. Arenal , vila P, Jim nez-Candil J, et al. Substrate Ablation vs Antiarrhythmic Drug Therapy for Symptomatic Ventricular Tachycardia. J Am Coll Cardiol 2022; 79:1441. 31. Watanabe E, Okajima K, Shimane A, et al. Inappropriate implantable cardioverter defibrillator shocks-incidence, effect, and implications for driver licensing. J Interv Card Electrophysiol 2017; 49:271. https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 14/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate 32. Albert CM, Rosenthal L, Calkins H, et al. Driving and implantable cardioverter-defibrillator shocks for ventricular arrhythmias: results from the TOVA study. J Am Coll Cardiol 2007; 50:2233. 33. Bjerre J, Rosenkranz SH, Schou M, et al. Driving following defibrillator implantation: a nationwide register-linked survey study. Eur Heart J 2021; 42:3529. 34. Merchant FM, Hoskins MH, Benser ME, et al. Time Course of Subsequent Shocks After Initial Implantable Cardioverter-Defibrillator Discharge and Implications for Driving Restrictions. JAMA Cardiol 2016; 1:181. 35. Akiyama T, Powell JL, Mitchell LB, et al. Resumption of driving after life-threatening ventricular tachyarrhythmia. N Engl J Med 2001; 345:391. 36. Assessment of the cardiac patient for fitness to drive. Can J Cardiol 1992; 8:406. 37. Epstein AE, Miles WM, Benditt DG, et al. Personal and public safety issues related to arrhythmias that may affect consciousness: implications for regulation and physician recommendations. A medical/scientific statement from the American Heart Association and the North American Society of Pacing and Electrophysiology. Circulation 1996; 94:1147. 38. Jung W, Anderson M, Camm AJ, et al. Recommendations for driving of patients with implantable cardioverter defibrillators. Study Group on 'ICD and Driving' of the Working Groups on Cardiac Pacing and Arrhythmias of the European Society of Cardiology. Eur Heart J 1997; 18:1210. 39. Epstein AE, Baessler CA, Curtis AB, et al. Addendum to "Personal and public safety issues related to arrhythmias that may affect consciousness: implications for regulation and physician recommendations: a medical/scientific statement from the American Heart Association and the North American Society of Pacing and Electrophysiology": public safety issues in patients with implantable defibrillators: a scientific statement from the American Heart Association and the Heart Rhythm Society. Circulation 2007; 115:1170. 40. Bleakley JF, Akiyama T, Canadian Cardiovascular Society, et al. Driving and arrhythmias: implications of new data. Card Electrophysiol Rev 2003; 7:77. 41. Kim SG, Hallstrom A, Love JC, et al. Comparison of clinical characteristics and frequency of implantable defibrillator use between randomized patients in the Antiarrhythmics Vs Implantable Defibrillators (AVID) trial and nonrandomized registry patients. Am J Cardiol 1997; 80:454. 42. Task force members, Vijgen J, Botto G, et al. Consensus statement of the European Heart Rhythm Association: updated recommendations for driving by patients with implantable cardioverter defibrillators. Europace 2009; 11:1097. https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 15/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate 43. https://ec.europa.eu/transport/road_safety/sites/roadsafety/files/pdf/behavior/driving_and_ cardiovascular_disease_final.pdf (Accessed on February 20, 2019). 44. Mylotte D, Sheahan RG, Nolan PG, et al. The implantable defibrillator and return to operation of vehicles study. Europace 2013; 15:212. 45. Curtis AB, Conti JB, Tucker KJ, et al. Motor vehicle accidents in patients with an implantable cardioverter-defibrillator. J Am Coll Cardiol 1995; 26:180. Topic 948 Version 27.0 https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 16/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate GRAPHICS Driving restrictions in patients with ICD and pacemaker in four countries/regions License Japan UK USA EU type Pacemaker implant Class 1 Cease driving for 1 week. Cease driving for 1 week. Cease driving for 1 week. Cease driving for 1 week. Class 2 Disqualified Cease driving for 6 Cease driving Disqualified if until pacemaker integrity is ascertained. weeks. for 4 weeks. persistent symptoms. ICD implant for VT/VF with incapacity (secondary prevention) Class 1 Cease for 6 months after first implant. Cease for 6 months after first implant. Cease for 6 months after first implant. Cease for 3 months. Class 2 Permanently bars. Permanently bars. Permanently bars. Permanently bars. ICD implant for sustained VT without Class 1 Cease for 6 months after first implant. Cease for 1 month after first implant provided all of the Cease for 6 months after implant. Cease for 3 months after implant. incapacity (secondary prevention) following are met: a. LVEF >35%. b. No fast VT on EPS. c. Any induced VT could be pace- terminated by the ICD twice, without acceleration, during the post- implantation study. Class 2 Permanently Permanently bars. Permanently Permanently bars. bars. bars. https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 17/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate Prophylactic ICD implantation (primary prevention) Class 1 Cease for 1 week. Cease for 1 month. Cease for 1 week. Cease For 4 weeks. Class 2 Permanently bars. Permanently bars. Permanently bars. Permanently bars. ICD and lead Class 1 Cease For 1 Cease for 1 month No specific Cease For 4 system replacement week after replacement of the lead system or replacement of the ICD. after a revision of the leads or antiarrhythmic drug change. guidance. weeks after replacement of the ICD and lead system or the lead system alone. Cease For 1 week after replacement of ICD. Delivery of ICD therapy Class 1 Cease for 3 months after appropriate therapy. Appropriate shock plus symptomatic ATP: Cease for 6 months with corrective Cease for 6 months after appropriate therapy. Cease for 3 months after appropriate therapy. Inappropriate Inappropriate Inappropriate measures to prevent recurrence provided no further symptomatic therapy. therapy: no restrictions for asymptomatic episodes. Cease for 3 therapy: no distinction made from appropriate therapy. therapy: cease until cause of inappropriate therapy was corrected. months in case of syncope. Inappropriate therapy: cease for 1 month after the cause of the inappropriate therapy was corrected. Driving restrictions in various countries/regions. A class 1 license is a license to operate one's own vehicle for personal use, while a class 2 license is a commercial license for those who drive a vehicle for work. ICD: implantable cardioverter-defibrillator; VT: ventricular fibrillation; VF: ventricular fibrillation; LVEF: left ventricular ejection fraction; EPS: electrophysiologic test; ATP: antitachycardia pacing. Reproduced from: Watanabe E, Abe H, Watanabe S. Driving restrictions in patients with implantable cardioverter https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 18/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate de brillators and pacemakers. J Arrhythm 2017; 33:594. Table used with the permission of Elsevier, Inc. All rights reserved. Graphic 120456 Version 1.0 https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 19/20 7/6/23, 10:51 AM Driving restrictions in patients with an implantable cardioverter-defibrillator - UpToDate Contributor Disclosures Kapil Kumar, MD No relevant financial relationship(s) with ineligible companies to disclose. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/driving-restrictions-in-patients-with-an-implantable-cardioverter-defibrillator/print 20/20

7/6/23, 10:51 AM Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management : Brian Olshansky, MD : N A Mark Estes, III, MD : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 26, 2019. INTRODUCTION Periodic evaluations are required to maintain optimal pacemaker programming as well as to identify any system problems. A review of the common pacing system problems of dual chamber pacemakers and the methods of evaluation and therapy are reviewed here. The malfunctions presented will be limited to those that are manifest on the electrocardiogram. Other complications, such as infections, venous thrombosis and emboli, pacemaker syndrome, and tricuspid regurgitation are discussed elsewhere. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Cardiac implantable electronic devices: Long-term complications", section on 'Tricuspid regurgitation'.) A more general review of the evaluation and management of single and dual chamber pacemakers and of the modes of cardiac pacing and indications for pacemaker therapy are presented separately. (See "Pacing system malfunction: Evaluation and management" and "Modes of cardiac pacing: Nomenclature and selection" and "Permanent cardiac pacing: Overview of devices and indications".) PACING SYSTEM COMPONENTS The pacing system is comprised of the pulse generator ( picture 1), also called the pacemaker, and the lead or leads that connect the pulse generator to the heart [1]. Either component may https://www.uptodate.com/contents/dual-chamber-pacing-system-malfunctions-of-timing-sensing-and-capture-evaluation-and-management/print 1/15 7/6/23, 10:51 AM Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management - UpToDate be the source of a clinical malfunction. (See "Permanent cardiac pacing: Overview of devices and indications", section on 'Types of permanent pacemaker systems'.) The phrase "pacing system malfunction" includes problems that might arise from any of the components of the system. Inappropriately programmed pacemaker parameters, although not representing abnormal pacing system function, may yield suboptimal results for the patient. The normal characteristics and unique timing systems and algorithms of a given pacemaker should be examined, as they may be interpreted as malfunction by a clinician who is unfamiliar with the specific pulse generator. Recording system artifacts must always be considered in the differential diagnosis of a pacing system malfunction. DUAL CHAMBER PACING MODES A pacemaker programmed to the DDD mode is capable of pacing and sensing in both the right atrium and right ventricle. Virtually all of the dual-chamber rate-modulated pacing systems can also be programmed to any of the available modes, including DDI, DVI, VDD, and all of the single-chamber modes ( table 1). A review of the normal pacing modes is presented in detail separately. (See "Modes of cardiac pacing: Nomenclature and selection".) LIMITING THE MAXIMAL PACED RATE In dual chamber pacing systems that are capable of tracking P waves, there is a programmable limit placed upon the maximum paced ventricular rate that can occur in response to sensed atrial activity. This is essential because, if there was no limit, the pacemaker could potentially track atrial flutter at the rate of the flutter waves or track atrial fibrillation resulting in a rapid ventricular response. In addition, there may be clinical and physiologic reasons to limit the fastest rate of the pacing system, such as active ischemic heart disease. Total atrial refractory period The total atrial refractory period (TARP) is comprised of the AV interval, during which the atrial sensing circuit is refractory and the post ventricular atrial refractory period (PVARP). The PVARP is a second refractory period that is initiated on the atrial channel by a sensed or paced ventricular event. With early generation dual-chamber unipolar pacing systems, far-field oversensing was relatively common. To prevent this, paced events in one chamber initiated periods of refractoriness in the opposite channel of the pacemaker. In addition, a ventricular depolarization could potentially be sensed in the atrium and, thus, when an R wave is sensed in the ventricle, the PVARP is initiated. https://www.uptodate.com/contents/dual-chamber-pacing-system-malfunctions-of-timing-sensing-and-capture-evaluation-and-management/print 2/15 7/6/23, 10:51 AM Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management - UpToDate When the interval between successive native atrial complexes is shorter than the TARP, some P waves will not be sensed. Since the pacemaker can only track those atrial depolarizations that are sensed, as the intrinsic atrial rate increases, eventually the device will only track every other P wave (a fixed 2:1 block response). The occurrence of abrupt 2:1 upper rate behavior may sometimes result in symptoms, most commonly sudden fatigue during exercise or strenuous exertion, in those patients who can exercise to a sufficient degree to achieve atrial rates in excess of the 2:1 block point. Contemporary pacemakers are capable of recognizing rapid atrial rates for the purpose of reverting from a tracking to a nontracking mode when the rapid rate is felt to be secondary to a pathologic atrial rhythm. The change in mode is called mode switching. Mode switching requires that the pacemaker be able to detect atrial events occurring within the PVARP even though it does not track these complexes. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Mode switching'.) When the sensed atrial rate exceeds the trigger rate, there is an automatic change in pacing mode from an atrial tracking mode to a mode incapable of atrial tracking, for example from DDD to VVI or DDI, or DDDR to VVIR or DDIR. To prevent the pacemaker from detecting a paced or sensed ventricular signal on the atrial channel (called a far field R wave), there is a separate timing interval within the PVARP called the post ventricular atrial blanking (PVAB) period during which the atrial sensing circuit is disabled. It is initiated by the ventricular output or ventricular sensed event. Maximum tracking rate timer In an effort to modulate the upper rate behavior, the maximum tracking rate timer is initiated by a paced or sensed ventricular event and must be completed before another ventricular output pulse can be released. Thus, even when a P wave occurs and the AV interval, which was initiated by that sensed atrial event, times out, the release of the ventricular output pulse is delayed until the maximum tracking rate timing period ends. While this limits the maximum tracking rate, it also effectively lengthens the interval from the sensed P wave to the ventricular output pulse (PV interval). If the atrial rate is stable, the next sensed P wave occurs closer to the preceding ventricular paced complex; if sensed, the same series of timers is initiated, and another ventricular paced beat occurs at an even longer PV interval. Eventually, a P wave will coincide with the PVARP, not be sensed, and, hence, not be tracked, resulting in a relative pause. The net effect is group beating at a fixed ventricular rate with a progressively increasing PV interval. The group beating and increasing PV interval are similar to AV nodal Wenckebach second degree AV block. As a result, this form of pacing system function is called pseudo-Wenckebach upper rate behavior [2]. https://www.uptodate.com/contents/dual-chamber-pacing-system-malfunctions-of-timing-sensing-and-capture-evaluation-and-management/print 3/15 7/6/23, 10:51 AM Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management - UpToDate Other techniques Other techniques are used to modulate the upper rate behavior of the pacemaker, including rate smoothing and fallback [3,4]. RATE MODULATED (RESPONSIVE) PACEMAKERS Rate-modulation capabilities in dual-chamber pacemakers may result in a number of interesting rhythms since the pacing rate will be controlled by either the sensed P wave or the sensor-input to the pacemaker [5-9]. Rate modulated pacing is of particular value to patients with chronotropic incompetence due to either concomitant pharmacologic therapy or intrinsic conduction system disease; these patients will not increase their native heart rate in response to a physiologic stress. Sensors most commonly incorporated to achieve rate-modulation are an accelerometer (activity sensing) or minute-ventilation sensor. With regard to upper rate behavior, there are three definitions: The upper rate limit (URL) is the maximum paced ventricular rate that can occur in any setting. The maximum tracking rate (MTR) is the maximum paced ventricular rate that can occur in response to sensed atrial activity, defined by the total atrial refractory period (TARP). The maximum sensor rate (MSR) is the maximum paced ventricular rate that can occur in response to the sensor input to the pacing system. Both the MTR and MSR are subsets of the URL. While these two timers are often programmed to identical rates, most contemporary pacemakers allow them to be programmed independently. TRUE DUAL CHAMBER SYSTEM MALFUNCTION True pacemaker system malfunctions occur when there is loss of capture at a time when the myocardium is capable of being depolarized, loss of sensing when an appropriate signal occurs during an alert period, or oversensing. (See "ECG tutorial: Pacemakers", section on 'Pacer malfunction'.) Loss of atrial capture True loss of atrial capture in a dual-chamber pacemaker results in effective ventricular pacing only. With complete loss of atrial capture, the patient may experience symptoms of pacemaker syndrome. If an atrial stimulus fails to depolarize the atrium and following the subsequent ventricular paced depolarization if retrograde conduction is intact, this may lead to sustained retrograde conduction or even induction of an endless loop https://www.uptodate.com/contents/dual-chamber-pacing-system-malfunctions-of-timing-sensing-and-capture-evaluation-and-management/print 4/15 7/6/23, 10:51 AM Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management - UpToDate tachycardia (ELT). If there is retrograde block, the lack of atrial capture will allow the native atrial rhythm to occur, which will be intermittently tracked, typically appearing as if there were an premature atrial complex (also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat) simply by juxtaposition of the native atrial rate with the paced rhythm. (See "Pacing system malfunction: Evaluation and management", section on 'Pacing stimuli present with loss of capture'.) Loss of atrial sensing The ECG manifestation of a loss of atrial sensing depends on the status of AV nodal conduction and the intrinsic atrial rate. In the presence of complete heart block, loss of atrial sensing will result in AV sequential pacing at the programmed base rate of the pacemaker. P waves will march through the tracing, occasionally being reset when there is atrial capture; at other times, they will render the atrial stimulus ineffective due to functional noncapture resulting in the appearance of fixed AV sequential pacing. In the absence of complete heart block, the intrinsic atrial rate will determine the presentation. If P waves were able to be sensed normally then the ECG would demonstrate consistent intrinsic P wave to V-paced intervals (so called PV or P synchronous pacing). A lack of PV pacing would therefore suggest loss of atrial sensing. If the PR interval is normal, however, the loss of atrial sensing may not be readily apparent from the surface ECG since the pacemaker will be appropriately inhibited by the sensed ventricular events. Safety pacing, in dual-chamber pacemakers, is the delivery of a ventricular output pulse at an abbreviated AV interval, following atrial pacing, if a signal is sensed by the ventricular channel during the early portion of the AV interval (ie, the cross-talk sensing window or ventricular safety pacing interval which follows the relatively short post-atrial ventricular blanking period). It is used to ensure that ventricular depolarization occurs if the sensed event was something other than an intrinsic ventricular depolarization. The abbreviated AV interval is usually in the range of 100 to 110 ms. If the sensed event was indeed an intrinsic ventricular event, the abbreviated AV interval delivers the pacing artifact early enough to prevent the pacing artifact from being delivered in the vulnerable portion of the cardiac cycle. (See "Pacing system malfunction: Evaluation and management", section on 'Pacing stimulus present with failure to sense'.) Loss of ventricular capture Loss of ventricular capture is obvious in the presence of high- grade AV block. Loss of ventricular capture is not as apparent when AV conduction is intact, because the ventricular stimulus may coincide with the onset of the conducted QRS. If the QRS is narrow, it will probably be interpreted as a fusion beat. If the QRS is wide, as with a bundle branch block, one may easily be misled into believing that capture is intact. In either case, if the https://www.uptodate.com/contents/dual-chamber-pacing-system-malfunctions-of-timing-sensing-and-capture-evaluation-and-management/print 5/15 7/6/23, 10:51 AM Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management - UpToDate pacing artifact coincides with the native depolarization but does not contribute to the activation of that chamber these events would be designated pseudofusion beats. (See "Pacing system malfunction: Evaluation and management", section on 'Pacing stimuli present with loss of capture'.) Loss of ventricular sensing Undersensing on the ventricular channel may not be obvious when high-grade AV block is present, as each P wave is tracked and triggers a ventricular output. Even when AV conduction is intact, undersensing may not be recognized unless the ventricular stimulus occurs well after each native QRS. If the AV interval allows the ventricular stimulus to coincide with the conducted R wave, which may be normal depending upon where sensing actually occurs within the QRS, loss of ventricular sensing cannot readily be identified from the surface ECG. (See "Pacing system malfunction: Evaluation and management", section on 'Pacing stimulus present with failure to sense'.) Ventricular oversensing Oversensing on the ventricular channel will result in inappropriate pacemaker inhibition and rates that are below the programmed base rate. Depending upon where the oversensing occurs, the sensed ventricular event will also initiate both a ventricular refractory period as well as a PVARP. This may result in functional atrial and ventricular undersensing with failure to recognize intrinsic P waves and R waves. Atrial oversensing In the DDD mode, oversensing on the atrial channel will be interpreted by the pacemaker as the occurrence of multiple P waves. This may result in periods of more rapidly paced ventricular rhythms as the pacemaker attempts to track what it believes are atrial depolarizations. Symptoms include palpitations from the loss of AV synchrony and salvos of rapid paced ventricular rates or pacemaker syndrome as a result of the effective ventricular pacing. It may also be the initiating trigger for an ELT. Far field R wave sensing (ventricular paced or sensed events) may result in the pacing system interpreting a normal rhythm as a pathological atrial rhythm, and it may initiate the mode switching algorithm with loss of atrial tracking. Examination of the markers and atrial electrogram will help to identify the presence of far field R waves. When these are present, the atrial refractory period and/or the PVAB should be reprogrammed such that detection of these events are prevented. Inappropriate mode switching in the patient with high grade AV block may result in symptoms of pacemaker syndrome. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Pacemaker syndrome'.) BIVENTRICULAR PACEMAKERS https://www.uptodate.com/contents/dual-chamber-pacing-system-malfunctions-of-timing-sensing-and-capture-evaluation-and-management/print 6/15 7/6/23, 10:51 AM Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management - UpToDate In patients with significant dyssynchrony due to intrinsic conduction disease, cardiac resynchronization therapy (CRT) with biventricular (BiV) pacing can improve intraventricular synchrony. This is accomplished with an additional pacemaker lead usually implanted via the coronary sinus to stimulate the left ventricle (LV), most commonly its lateral or posterolateral surface. Simultaneous (or sequential) stimulation of the LV and RV pacing leads provides more synchronous activation of the heart than RV pacing alone, which may actually cause dyssynchronous contraction. Among patients with heart failure who are in sinus rhythm, restoration of ventricular synchrony improves cardiac performance, symptoms, and overall survival. The efficacy of CRT in patients with heart failure and chronic AF is less well established, although available evidence suggests a benefit. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in atrial fibrillation".) Dual-chamber biventricular pacemakers are prone to the same problems as dual chamber pacing systems. However, the specific features of device malfunction are in some respects distinct, and therefore merit separate discussion. Pacing system components and pacing mode The components of a BiV pacing system typically include an atrial lead in the right atrium, a right ventricular lead in the right ventricle, and a left ventricular lead that is most often placed in a cardiac vein by way of the coronary sinus ( figure 1). Biventricular pacemakers are usually programmed in DDD or DDDR mode if the patient is in normal sinus rhythm. Atrial events that are sensed or paced trigger an AV interval that is intended to be long enough to optimize the atrial contribution to ventricular filling but short enough to ensure ventricular pacing for the vast majority of the time and ideally near 100 percent. Pacing is necessary if resynchronization is to be achieved. Proper timing of the AV delay may require echocardiographic assessment to maximize the left ventricular outflow tract velocity time integral and left ventricular filling and ejection times. CRT often results in a QRS complex that is narrower than the native QRS complex because of fusion between the two paced signals. However, QRS duration does not always normalize, and some studies have shown a poor correlation between the width of the paced QRS complex and the clinical benefit of BiV pacing. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) CRT malfunction Biventricular pacing systems are prone to the same system malfunctions seen with other types of pacemakers. (See 'True dual chamber system malfunction' above.) https://www.uptodate.com/contents/dual-chamber-pacing-system-malfunctions-of-timing-sensing-and-capture-evaluation-and-management/print 7/15 7/6/23, 10:51 AM Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management - UpToDate In addition, there are other system problems that are specific to the CRT setting. Since many patients with BiV pacemakers do not require pacing for the standard indications, pacemaker malfunction will not be associated clinically with syncope or "pacemaker syndrome." Instead, loss of ventricular synchrony may result in exacerbation of heart failure. Loss of capture The coronary sinus (left ventricular) lead of a BiV pacing system is separated from the myocardium by the full thickness of the vein wall and by any epicardial fat that may be encasing the vein. The capture threshold of the left ventricular lead may be higher than that of the right ventricular lead. In contemporary CRT devices, the right and left ventricular leads can be assessed independently if loss of capture is suspected. Loss of capture may be manifested by widening of the QRS complex or by a more subtle change in QRS morphology [10]. It is not always possible to recognize loss of capture based upon the surface ECG alone ( waveform 1). An intracardiac electrogram obtained by interrogating the pacemaker will commonly demonstrate an obvious change. Oversensing Oversensing is the detection of an inappropriate physiologic or nonphysiologic electrical signal. Skeletal muscle potentials generated by isometric contraction of the muscles in close proximity to the pulse generator are the most common etiology of oversensing, although inappropriate sensing of electrical activity in another cardiac chamber is also a potential problem. In a BiV pacing system, oversensing of atrial activity on the ventricular channel results in ventricular inhibition and loss of resynchronization [11]. This can be a result of malposition of the left ventricular lead too close to the AV valve ring. Mechanical lead failure All major electrical malfunctions, including loss of capture, undersensing, and oversensing, can be associated with a breach in lead insulation or conductor failure. A breach in lead insulation causes a marked drop in the measured stimulation impedance, while a conductor coil fracture causes a marked increase in impedance. PACING SYSTEM EVALUATION Whether the system involves a single chamber or dual chamber pacemaker, the process for evaluating the pacing system is similar. A detailed discussion of pacing system evaluation is presented separately. (See "Cardiac implantable electronic devices: Patient follow-up", section on 'PPM evaluation'.) https://www.uptodate.com/contents/dual-chamber-pacing-system-malfunctions-of-timing-sensing-and-capture-evaluation-and-management/print 8/15 7/6/23, 10:51 AM Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management - UpToDate PACEMAKER DIAGNOSTICS In addition to interrogation of programmed and measured data, which is absolutely essential, all contemporary systems can provide telemetered event markers and endocardial electrograms. When these are available, the clinician should take advantage of them, since they will greatly facilitate the evaluation. A detailed discussion of pacemaker diagnostics is presented separately. (See "Cardiac implantable electronic devices: Patient follow-up", section on 'Follow-up of the patient with a pacemaker'.) SUMMARY AND RECOMMENDATIONS The phrase "pacing system malfunction" includes problems that might arise from any of the components of the system, including the pulse generator ( picture 1), also called the pacemaker, and the lead or leads that connect the pulse generator to the heart. (See 'Pacing system components' above.) True pacemaker system malfunctions occur when there is loss of capture at a time when the myocardium is capable of being depolarized, loss of sensing when an appropriate signal occurs during an alert period, or oversensing. The pacemaker cannot unpredictably alter its manner of function unless there is a component malfunction. Given the overall reliability of the pulse generators, if a bizarre behavior is encountered, one should consider a device eccentricity, a lead problem, or a recording artifact before entertaining the diagnosis of a pulse generator failure. In these more unusual circumstances, if a definitive diagnosis is not reached, it is always helpful to contact the manufacturer's "help-line" prior to invasive troubleshooting. (See 'True dual chamber system malfunction' above.) Biventricular pacemakers are prone to the same problems as dual chamber pacing systems. However, since many patients with biventricular pacemakers do not require pacing for the standard indications, pacemaker malfunction will not be associated clinically with syncope or "pacemaker syndrome." Instead, loss of ventricular synchrony may result in exacerbation of heart failure. (See 'Biventricular pacemakers' above.) ACKNOWLEDGMENT The UpToDate editorial staff thank Dr. David L. Hayes for his past contributions as an author to prior versions of this topic review. https://www.uptodate.com/contents/dual-chamber-pacing-system-malfunctions-of-timing-sensing-and-capture-evaluation-and-management/print 9/15 7/6/23, 10:51 AM Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Ellenbogen A, Wilkoff BL, Kay GN, Lau CP. Pacemaker troubleshooting and follow-up. In: Clin ical Cardiac Pacing, Defibrillation and Resynchronization Therapy, 3rd ed, Saunders, Philadel phia 2007. p.1005. 2. Barold SS. Upper rate of DDD pacemakers. The view from the atrial side. Pacing Clin Electrophysiol 1988; 11:2149. 3. Papp, MA, Mason, et al. Use of rate smoothing to treat pacemaker-mediated tachycardias and symptoms due to upper rate response of a DDD pacemaker. Clin Proc Pacing Electrophysiol 1984; 2:547. 4. van Mechelen R, Ruiter J, de Boer H, Hagemeijer F. Pacemaker electrocardiography of rate smoothing during DDD pacing. Pacing Clin Electrophysiol 1985; 8:684. 5. Higano ST, Hayes DL. P wave tracking above the maximum tracking rate in a DDDR pacemaker. Pacing Clin Electrophysiol 1989; 12:1044. 6. Higano ST, Hayes DL, Eisinger G. Sensor-driven rate smoothing in a DDDR pacemaker. Pacing Clin Electrophysiol 1989; 12:922. 7. Higano ST, Hayes DL, Eisinger G. Advantage of discrepant upper rate limits in a DDDR pacemaker. Mayo Clin Proc 1989; 64:932. 8. Hayes DL, Higano ST, Eisinger G. Electrocardiographic manifestations of a dual-chamber, rate-modulated (DDDR) pacemaker. Pacing Clin Electrophysiol 1989; 12:555. 9. Pitney MR, May CD, Davis MJ. Undesirable mode switching with a dual chamber rate responsive pacemaker. Pacing Clin Electrophysiol 1993; 16:729. 10. Yong P, Duby C. A new and reliable method of individual ventricular capture identification during biventricular pacing threshold testing. Pacing Clin Electrophysiol 2000; 23:1735. 11. Lipchenca I, Garrigue S, Glikson M, et al. Inhibition of biventricular pacemakers by oversensing of far-field atrial depolarization. Pacing Clin Electrophysiol 2002; 25:365. Topic 1018 Version 20.0 https://www.uptodate.com/contents/dual-chamber-pacing-system-malfunctions-of-timing-sensing-and-capture-evaluation-and-management/print 10/15 7/6/23, 10:51 AM Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management - UpToDate GRAPHICS Examples of cardiac pacemaker pulse generators Examples of cardiac pacemaker pulse generators commonly used in practice in 2015. Graphic 104720 Version 1.0 https://www.uptodate.com/contents/dual-chamber-pacing-system-malfunctions-of-timing-sensing-and-capture-evaluation-and-management/print 11/15 7/6/23, 10:51 AM Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management - UpToDate Types of cardiac pacemakers and NBG codes Code Meaning VOO Asynchronous ventricular pacemaker; no adaptive rate control or antitachyarrhythmia functions VVI Ventricular "demand" pacemaker with electrogram-waveform telemetry; no adaptive rate control or antitachyarrhythmia functions DVI Multiprogrammable atrioventricular-sequential pacemaker; no adaptive rate control DDD Multiprogrammable "physiologic" dual-chamber pacemaker; no adaptive rate control or antitachyarrhythmia functions DDI Multiprogrammable DDI pacemaker (with dual-chamber pacing and sensing but without atrial-synchronous ventricular pacing); no adaptive rate control or antitachycardia functions VVIR Adaptive-rate VVI pacemaker with escape interval controlled adaptively by one or more unspecified variables DDDR Programmable DDD pacemaker with escape interval controlled adaptively by one or more unspecified variables Graphic 79459 Version 1.0 https://www.uptodate.com/contents/dual-chamber-pacing-system-malfunctions-of-timing-sensing-and-capture-evaluation-and-management/print 12/15 7/6/23, 10:51 AM Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management - UpToDate Pacing leads for cardiac resynchronization therapy Two leads (right atrial and right ventricular leads) permit pacing of the right atrium and right ventricle. The third lead (coronary sinus lead), which is advanced through the coronary sinus into a venous branch that runs along the free wall of the left ventricle, paces the lateral wall and enables synchronized left ventricular contraction. Graphic 79450 Version 5.0 https://www.uptodate.com/contents/dual-chamber-pacing-system-malfunctions-of-timing-sensing-and-capture-evaluation-and-management/print 13/15 7/6/23, 10:51 AM Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management - UpToDate Loss of LV capture with BiV pacing The top line of this tracing shows one lead from the surface electrocardiogram (ECG). The middle portion of the tracing shows the pacemaker event markers obtained by telemetry. The bottom line of the tracing shows the intracardiac electrogram. The arrow above the tracing indicates the time point at which capture of the left ventricle (LV) by the biventricular (BiV) pacemaker is lost. The changes with loss of capture are subtle in the surface ECG tracing. The event markers and the intracardiac electrogram document the loss of capture. Graphic 71566 Version 2.0 https://www.uptodate.com/contents/dual-chamber-pacing-system-malfunctions-of-timing-sensing-and-capture-evaluation-and-management/print 14/15 7/6/23, 10:51 AM Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management - UpToDate Contributor Disclosures Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/dual-chamber-pacing-system-malfunctions-of-timing-sensing-and-capture-evaluation-and-management/print 15/15

7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Implantable cardioverter-defibrillators: Optimal programming : Martin K Stiles, MB ChB, PhD, FRACP, FHRS : Jonathan Piccini, MD, MHS, FACC, FAHA, FHRS : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 11, 2022. INTRODUCTION Ventricular tachyarrhythmia is a common cause of sudden cardiac arrest (SCA) and sudden cardiac death (SCD). Although cardiopulmonary resuscitation, including chest compressions and assisted ventilation, can provide transient circulatory support for the patient with SCA, the only effective approach for terminating pulseless ventricular tachycardia (VT) or ventricular fibrillation (VF) is electrical defibrillation. Success with external defibrillation led to the development of an implantable defibrillator in the mid-1960s. It was not until 1980 that the first automatic internal defibrillator was implanted in humans [1,2]. (See "Pathophysiology and etiology of sudden cardiac arrest".) Because of its high success rate in terminating VF rapidly, along with the results of multiple clinical trials showing improvement in survival, implantable cardioverter-defibrillator (ICD) implantation is generally considered the first-line treatment option for the secondary prevention of SCD and for primary prevention in certain populations at high risk of SCD due to VT/VF. Alternatives to ICD implantation include antiarrhythmic drugs, ablative surgery, catheter ablation, and, in rare individuals, cardiac transplantation. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Radiofrequency catheter ablation' and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Pharmacologic therapy in survivors of sudden cardiac arrest".) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 1/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate This topic will review the approach to optimal ICD programming. The general indications for ICD implantation as well as the components and functionalities of the ICD, the clinical trials documenting the efficacy of an ICD in different clinical settings (including both secondary and primary prevention), complications of ICD placement, and follow-up care of patients with ICDs are discussed separately. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Cardiac implantable electronic devices: Long-term complications" and "Cardiac implantable electronic devices: Patient follow- up" and "Cardiac implantable electronic devices: Periprocedural complications".) OVERVIEW OF ICD PROGRAMMING AND THERAPIES General approach to programming Our approach to optimal ICD programming seeks to emphasize that, while the decision to implant the ICD and perioperative management are important factors in patient outcome, much of the risk/benefit ratio of these devices is determined by the way they are programmed. When recommending ICD programming settings, we are often guided in our general approach by randomized trials. However, specific patient circumstances may mandate a different approach from that of generic programming recommendations. In particular, evidence for ICD programming is often gleaned from adult populations, and direct translation to pediatric patients may not always be appropriate; this is particularly pertinent for rate cutoff settings in children, teenagers, and young adults. Thus, programming guidelines are simply that: guidelines. They are not always applicable to every patient, and care must be taken to tailor therapy to the individual. Fortunately, most patients do not have such specific requirements, and an empiric approach to programming is reasonable for the majority. Readers who wish for a more comprehensive overview on ICD programming are directed to the 2015 HRS/EHRA/APHRS/SOLAECE Expert Consensus Statement on Optimal Implantable Cardioverter-Defibrillator Programming and Testing and the 2019 focused update discussing manufacturer-specific programming [3,4]. Types of ICD programming and therapies As ICD technology has evolved, the number and variety of available programming and therapeutic options have dramatically increased [3]. Contemporary ICDs have a variety of flexible programming and therapeutic options [5]: Bradycardia settings While ICDs are implanted for the treatment of tachyarrhythmias, patients occasionally have a need for bradycardia support also. In addition, the pacemaker settings of an ICD may influence patient outcome even when an indication for bradycardia https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 2/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate pacing does not exist [6,7]. A general principle of ICD bradycardia pacing settings is to minimize the percentage of right ventricular pacing. (See "Overview of pacemakers in heart failure".) Cardiac resynchronization therapy (CRT) The indications for ICD implantation and CRT overlap to a degree. A general principle of ICD bradycardia pacing settings in patients with CRT-defibrillators is to maximize the percentage of biventricular pacing. A detailed discussion of CRT devices is presented separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Arrhythmia detection At their most basic, ICDs detect arrhythmias based on duration criteria (an arrhythmia must be of sufficient length to be significant) and rate criteria (an arrhythmia must exceed a programmed rate cutoff to be significant). Therefore, an episode must be both sufficiently long and sufficiently rapid to trigger therapy. Recommendations for rate criteria and duration have evolved over time and are further refined by the addition of supraventricular tachycardia (SVT) discriminators and algorithms to reduce detection of noise (both physiological and nonphysiological sources of noise). Arrhythmia discrimination The ability to distinguish arrhythmias requiring ICD therapy from other heart rhythms is crucial to appropriate ICD function. ICDs can be programmed to assess heart rate, suddenness of onset, atrioventricular (AV) dissociation, interval stability, QRS templates, and other parameters to help identify ventricular tachyarrhythmias requiring therapy. Noise discrimination Algorithms to avoid signal noise being detected as an arrhythmia have evolved over time. These aim to prevent physiological noise (eg, T-wave oversensing) and nonphysiological noise (eg, electromagnetic interference) from being falsely detected as ventricular arrhythmia and triggering inappropriate therapy. (See "Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment".) Multiple available therapies ICDs can treat ventricular tachyarrhythmias with antitachycardia pacing (ATP) and/or shocks. These therapies have parameters that can be varied and adjusted (eg, the number, rate, and duration of ATP cycles and the delivered energy for cardioversion and defibrillation). In each therapy zone, a sequence of therapies (ATP, cardioversion, or defibrillation) can be delivered. After each therapy, the device reevaluates the rhythm, and if the tachyarrhythmia persists, the next therapy is delivered. These therapies are discussed in detail below. (See 'Tachycardia therapies' below.) Multiple zones ICDs can be programmed to provide different therapies to tachyarrhythmias in up to three heart rate zones. The rationale for this approach is that https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 3/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate relatively slow ventricular tachyarrhythmias (eg, ventricular tachycardia [VT] with a heart rate <180 beats per minute) may not lead to loss of consciousness or other unstable symptoms for at least several minutes. Additionally, VT can often be terminated with ATP, which can be delivered quickly and with no pain and minimal battery drainage. By contrast, faster VTs (eg, heart rate >250 beats per minute) are more likely to be unstable and poorly tolerated; they can require high-energy defibrillation and can become increasingly difficult to terminate if definitive therapy is delayed. Thus, the most successful approach for such fast VTs is high-energy defibrillation. However, there is some evidence that ATP can be effective even for very fast VTs and that self-termination is not uncommon. This has led to strategies employing longer detection times and attempts to terminate VT with ATP before or during capacitor charging. (See 'Duration criteria for ventricular arrhythmia detection' below.) Avoidable therapy A relatively new concept to ICD programming is to recognize therapy as not just appropriate (delivered for ventricular arrhythmia) or inappropriate (delivered for SVT or noise), but to recognize that any given therapy may be avoidable. It is increasingly accepted that self-terminating arrhythmias are common and that programming to treat slower or short duration arrhythmias tends to overtreat patients, often with negative consequences. Thus, eliminating avoidable therapy is one of the aims of modern ICD programming. (See 'Our approach to tachycardia therapies' below.) TACHYCARDIA DETECTION Modern ICD programming for the detection of arrhythmias utilizes higher detection rates, longer detection durations, antitachycardia pacing (ATP), algorithms that discriminate supraventricular tachycardia (SVT) from ventricular tachycardia (VT), and specific electrocardiographic (ECG) features to minimize the sensing of noise. All these strategies combined provide the patient with the security of ICD therapy when needed with the aim of eliminating inappropriate and avoidable therapies. ICDs detect arrhythmias based on two primary criteria (both must be satisfied): Duration criteria An arrhythmia must be of sufficient length to be significant Rate criteria An arrhythmia must exceed a programmed rate cutoff With early generation ICDs in clinical practice, the focus was on rapid detection and treatment of VT/ventricular fibrillation (VF). This was necessary due to the inherent limitations of the devices: long charge times, potential for undersensing, monophasic waveforms, and the knowledge that https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 4/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate defibrillation thresholds increased with VF duration. Therefore, early generation ICDs were programmed to detect and treat arrhythmia rapidly. With subsequent technological improvements in ICDs, resulting in the advent of stored electrograms, improved electrogram sensing, and the move toward primary prevention of sudden cardiac death, there has been a gradual appreciation of the adverse effects of an ICD shock. Initially, the focus was mainly on inappropriate shocks (ie, shocks delivered for nonlife- threatening arrhythmias or because of oversensing). Oversensing is divided into physiological oversensing (eg, T-wave oversensing or double counting of QRS) or nonphysiological oversensing (eg, electromagnetic interference or lead fracture noise). More recently, there has been an appreciation that ventricular arrhythmias may self-terminate without therapy and that slower arrhythmias need not necessarily be treated. Early shock therapies for benign or self- terminating ventricular arrhythmias may appear to be appropriate shocks, but if they were not going to be absolutely necessary, then shocks for these rhythms are avoidable shocks. Our approach to tachycardia detection Our recommendations for tachycardia detection programming in patients with an ICD are generally in agreement with the 2015 HRS/EHRA/APHRS/SOLAECE Expert Consensus Statement on Optimal Implantable Cardioverter- Defibrillator Programming and Testing and the 2019 focused update discussing manufacturer- specific programming [3,4]. For patients with any ICD (primary or secondary prevention), we recommend that tachyarrhythmia detection duration criteria be programmed to require the tachycardia to continue for at least 6 to 12 seconds (or for 30 intervals), rather than a shorter duration, before completing detection. For patients with a primary prevention ICD (and for secondary prevention patients in whom the VT rate is not known), we recommend that the slowest tachycardia therapy zone limit should be programmed between 185 and 200 beats per minute. For secondary prevention ICD patients for whom the clinical VT rate is known, we program the slowest tachycardia therapy zone at least 10 beats per minute below the documented tachycardia rate but not faster than 200 beats per minute. The aim of the above three recommendations is to reduce the total number of ICD therapies. Faster minimum rates for detection may be appropriate in young patients or those in whom SVT- VT discriminators cannot reliably distinguish SVT from VT, provided no clinical VT exists below this rate. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 5/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Programming multiple tachycardia detection zones can be useful to allow effective use of tiered therapy and/or SVT-VT discriminators. This may allow a shorter delay for faster (and potentially unstable) arrhythmias while allowing slower (and potentially stable) arrhythmias a longer time to self-terminate and/or more attempts at ATP. Discrimination algorithms to distinguish SVT from VT should be programmed to include rhythms with rates faster than 200 beats per minute and potentially up to 230 beats per minute to reduce inappropriate therapies. Discriminator time-out functions should generally be programmed OFF. T-wave oversensing algorithms should usually be ON. Lead-failure alerts should be activated to detect potential lead problems. Duration criteria for ventricular arrhythmia detection For the vast majority of patients with modern ICDs, the devices should be programmed to a longer duration interval. This will allow for a greater number of nonsustained arrhythmias to terminate spontaneously, without any ICD therapy, thereby reducing avoidable shocks ( table 1). Early ICDs used short duration "detection" criteria of up to five seconds (variable depending on manufacturer and tachycardia rate) before either ATP or charging to shock. This time period was comprised of detection time plus duration or number of intervals. More recently, awareness of potential harm from avoidable shocks has led to strategies of prolonged detection settings, with data derived from numerous studies, initially from the nonrandomized PREPARE and RELEVANT studies but subsequently from three randomized trials [8-12]: MADIT-RIT, a randomized trial of three different ICD programming and therapy strategies, assigned 1500 patients receiving an ICD for primary prevention (both ischemic and nonischemic cardiomyopathy) to one of three programming strategies [10]: "Conventional" therapy programming 2.5-second delay at rates of 170 to 199 beats per minute; 1-second delay at rates of 200 or more beats per minute. Delayed therapy programming 60-second delay at rates of 170 to 199 beats per minute; 12-second delay at rates of 200 to 249 beats per minute; 2.5-second delay at rates of 250 or more beats per minute. High-rate therapy programming No therapy at rates of 170 to 199 beats per minutes; 2.5-second delay at rates of 200 or more beats per minute. Patients were followed for an average of 1.4 years, with the primary outcome being the time to first delivery of inappropriate therapy and two prespecified secondary outcomes (all-cause mortality and first syncopal episode). While relatively few patients received https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 6/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate appropriate ICD therapy (242 patients, or 16 percent, with 70 percent of appropriate therapies being ATP), the primary outcome occurred in 152 patients (11 percent). When compared with conventional programming: Inappropriate therapies were lower in both high-rate therapy (hazard ratio [HR] 0.21, 95% CI 0.13-0.34) and the delayed therapy (HR 0.24, 95% CI 0.15-0.40) groups. All-cause mortality was lower in the high-rate therapy group (HR 0.45, 95% CI 0.24-0.85), and there was a trend toward lower mortality in the delayed therapy group that was not statistically significant (HR 0.56, 95% CI 0.30-1.02). The ADVANCE III trial, a randomized, single blind trial of 1902 patients receiving an ICD for primary (1425 patients, 75 percent) or secondary (477 patients, 25 percent) prevention, assigned patients to "standard" detection (18/24) or long detection (30/40) strategies for ventricular rates >187 beats per minute (cycle length 320 milliseconds) [11]. Programming for treatment options of ATP and shocks was the same for all participants. Long detection was associated with a highly significant reduction of overall therapies (appropriate and inappropriate ATP and/or shocks), inappropriate shocks, and all-cause hospitalizations. In the PROVIDE trial, which randomized 1670 patients to experimental programming (two VT and one VF zone requiring 25-, 18-, and 12-beat detections, respectively) or conventional programming (12-beat detection in each of two zones), there was a 36 percent reduction in two-year all-cause shock rate and reduction in mortality with a prolonged detection interval (HR 0.7, 95% CI 0.50-0.98) [12]. These studies (PREPARE, RELEVANT, MADIT-RIT, ADVANCE III, and PROVIDE) consistently showed that programming a prolonged detection algorithm benefited the patient without compromising safety. Importantly, ADVANCE III included a subset of secondary prevention patients (published separately) in whom similar findings were reported [13]. Subsequent meta-analyses of these trials have demonstrated a mortality benefit in the combined therapy-reduction arms without an increased risk of syncope [14,15]. However, there are some limitations to be acknowledged, including that not all ICD manufacturers are represented in these trials [16], there are no data from aging devices in which charge times can be long, and there will always be specific situations in which prolonged detection times may be deleterious (eg, ventricular undersensing). Rate criteria for ventricular arrhythmia detection Ventricular tachyarrhythmia detection by implantable devices is primarily based on rate. For the vast majority of patients with modern ICDs, the devices should be programmed to a higher rate at which therapies should be provided. This will prevent inappropriate shocks for slower supraventricular tachyarrhythmias and allow https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 7/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate for slower nonsustained arrhythmias to terminate spontaneously, thereby reducing avoidable shocks. Heart rates can be extremely rapid during ventricular tachyarrhythmias, and it is less likely that such rates are achieved during supraventricular tachyarrhythmias, thus making rate a powerful component of arrhythmia discrimination. However, VT can also have slower rates in the range of those of supraventricular tachyarrhythmias or even of sinus tachycardia. Therefore, any rate cutoff will always imply a trade-off between maximizing sensitivity for ventricular tachyarrhythmia detection at the expense of inappropriate detection of fast supraventricular tachyarrhythmias and maximizing specificity at the expense of some slow VTs going undetected [17]. The recognition of a significant number of inappropriate therapies in ICD patients, as well as their potentially deleterious consequences, prompted the development of studies that tested if programming faster rate criteria would reduce avoidable ICD therapies and, particularly, shocks. In the MADIT-RIT trial, the primary end point of first occurrence of inappropriate therapy was observed in 20 percent of the conventional group and in 4 percent of the high-rate group over a mean follow-up of 1.4 years. ICD shocks occurred in 4 and 2 percent in the conventional and high-rate groups, respectively. Importantly, all-cause mortality was approximately double in the conventional group (6.6 percent) than in the high-rate group (3.2 percent). Observational studies have demonstrated that even a rate cutoff of 220 beats per minute has been shown to be safe and reduce avoidable shocks [18]. (See 'Duration criteria for ventricular arrhythmia detection' above.) Supraventricular tachyarrhythmia discrimination SVTs are common in patients with ventricular arrhythmias [19-21]. If the ICD interprets an SVT incorrectly as VT, the patient may experience inappropriate shocks, which occur in up to 20 to 25 percent of patients [22-25]. The majority of inappropriate shocks for SVT occur within the range of 181 to 213 beats per minute. Therefore, adjustment of rate criteria and the deployment of SVT discriminators are most likely to be successful at around these rates. Once the duration and rate criteria for VT/VF have been satisfied, SVT discriminators aim to classify the rhythm as SVT (therapies for VT withheld) or VT (therapies delivered). Examples of algorithms used to distinguish SVT from VT include: AV dissociation Identification of different and distinct rhythms in the atrium and the ventricle, particularly when the ventricular rate exceeds the atrial rate, is consistent with AV dissociation seen with VT. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 8/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Atrial rate exceeds ventricular rate In dual-chamber devices (and those with an atrial sensing ring on the ventricular lead), information from the atrial electrode may help differentiate VT from atrial tachyarrhythmias [19-21,26]. The primary discriminator is heart rate; if the atrial rate is greater than the ventricular rate, the arrhythmia is almost certainly SVT, usually atrial fibrillation (AF) or atrial flutter. However, care must be taken not to withhold therapy in the case of a "dual tachycardia" (eg, VT with coexisting AF). QRS templates Many devices record templates of the ventricular electrogram during intrinsic rhythm. During a tachyarrhythmia, the device compares the electrograms during the tachycardia with the baseline recording. Deviations in shape, duration, and polarity all increase the likelihood that the device will categorize the tachycardia as VT or VF. An interval stability criterion detects irregularity in cycle length and can distinguish AF from VT. Obvious pitfalls with this are regularization of AF (perhaps from antiarrhythmic drugs) and irregular VT [27,28]. An onset criterion monitors the cycle length for the sudden or abrupt onset of a high ventricular rate (indicative of a VT) rather than a gradually increasing heart rate (as might be seen in exercise-induced sinus tachycardia). As this discriminator is applied "once only," care should be taken not to allow this discriminator to withhold therapy indefinitely (in case of VT/VF occurring after the rate threshold is crossed gradually). Some dual-chamber devices have "chamber of onset" as a discriminator. Each of these discrimination features is designed to help prevent SVT from being erroneously categorized as VT or VF; therefore, they reduce the likelihood of inappropriate shocks. However, as none of these discriminators are 100 percent specific for SVT, these discriminators can be programmed to "time out" so that the ICD eventually treats the arrhythmia as VT/VF. As discriminator reliability has improved, recommendations have moved away from endorsing the use of the "time out" feature [29]. In addition to discrimination criteria, most contemporary ICDs have a "second look" feature designed to help prevent or limit inappropriate shocks. Once the criteria for delivering a shock are met, the capacitors charge. This takes several seconds (more as the device ages). Following charging, the device reevaluates the heart rhythm to confirm that the tachycardia persists and has not spontaneously terminated. If the tachycardia has resolved, the shock will be diverted. Dual-chamber ICDs can be programmed for mode switching to prevent inappropriate tracking of atrial arrhythmias. In addition, some devices can deliver therapy for atrial tachyarrhythmias such as pace termination of atrial flutter or AF [20,21]. (See "The role of pacemakers in the prevention of atrial fibrillation".) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 9/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Therapeutic alternatives for patients who continue to have frequent inappropriate shocks for atrial tachyarrhythmias include antiarrhythmic drugs and catheter ablation. (See "Pharmacologic therapy in survivors of sudden cardiac arrest", section on 'Treatment of breakthrough arrhythmias'.) Noise discriminators Noise detected by an ICD can lead to inappropriate shocks. The source of noise may be physiological or nonphysiological. Although less common than inappropriate shocks due to SVT, noise-related therapies can be repetitive and cause serious harm to a patient. Physiological noise can be due to T-wave oversensing, double counting of QRS events, or P wave oversensing. Displacement of the ICD lead into the fibrillating atrium is also possible in the immediate post-implant period. The problem of T-wave oversensing has led to several methods to identify this, including high bandpass filters, altering the sensing bipole, reducing sensitivity, and looking for specific repetitive patterns consistent with T-wave oversensing. Additionally, physiological noise due to T-wave oversensing can often be remedied with reprogramming (eg, adjusting sensitivity, etc). Nonphysiological noise is most commonly related to ICD lead failure. Several high-profile lead recalls have brought this issue to the forefront and led to the development of algorithms designed to alert the clinician early to a potential lead failure and to delay or divert therapy if noise is the likely reason for the episode detected. Generally, the following features are identified when detecting lead noise: Intervals are very short; so short as to be physiologically unlikely Such short intervals are transient and repetitive If noise is present on the lead distal bipole, it is absent on the wide bipole (shock coil electrogram) The first two of these are used to provide alerts (vibratory, audible, or via home monitor). The third may be used to withhold shocks. Many of the algorithms are designed for particular lead failure (eg, Lead Integrity Alert on Medtronic Devices are designed to detect Fidelis fractures, SecureSense on St. Jude Medical Devices to detect Riata failures). Accompanying data, such as a change in lead impedance, sensing, or threshold, are frequently available from remote monitoring and may assist in diagnosing lead failure. TACHYCARDIA THERAPIES https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 10/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Modern ICD programming for the treatment of arrhythmias utilizes antitachycardia pacing (ATP) as the initial therapy for many patients with ventricular tachycardia (VT), given the high rates of successful VT termination following ATP. If ATP is unsuccessful, or if the presenting rhythm is ventricular fibrillation (VF), ICDs can deliver one or more defibrillatory shocks in an effort to terminate VT/VF. Although therapies delivered by the ICD aim to abort sudden cardiac death, both appropriate and inappropriate ICD shocks have been associated with a considerable increase in the risk of mortality [30-35]. In the SCD-HeFT trial, the risk of mortality was fivefold higher in patients who received appropriate ICD shocks and twofold higher in patients who received inappropriate shocks [31]. Likewise, in pooled data from four studies of 2135 ICD patients, shocked VT was associated with a 32 percent increase in the risk of mortality, and patients receiving a shock had lower survival rates than patients treated with ATP only [32]. ICD shocks are likely to be a marker of advanced heart disease, but defibrillation therapies have been associated with troponin release and increased left ventricular dysfunction. Additionally, ICD shocks deplete the battery and are painful for the patient. Our approach to tachycardia therapies Our recommendations for tachycardia therapy programming in patients with an ICD are generally in agreement with the 2015 HRS/EHRA/APHRS/SOLAECE Expert Consensus Statement on Optimal Implantable Cardioverter- Defibrillator Programming and Testing and the 2019 focused update discussing manufacturer- specific programming [3,4]. For all patients with structural heart disease and ATP-capable devices, ATP therapy should be active for all ventricular tachyarrhythmia detection zones to include arrhythmias up to 230 beats per minute (except when ATP is documented to be ineffective or proarrhythmic). This aims to reduce total shocks. ATP therapy should be programmed to deliver at least one ATP attempt with a minimum of eight stimuli and a cycle length 84 to 88 percent of the tachycardia cycle length for ventricular tachyarrhythmias. Burst ATP therapy is preferred to ramp ATP therapy. We activate shock therapy in all ventricular tachyarrhythmia therapy zones to improve the termination rate of ventricular tachyarrhythmias, except in rare cases where ATP only might be prescribed for hemodynamically stable monomorphic VT. We program the initial shock energy to the maximal available energy in the highest rate detection zone to improve the first shock termination of ventricular arrhythmias, unless specific defibrillation testing demonstrates efficacy at lower energies. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 11/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Antitachycardia pacing VT, particularly reentrant VT associated with scar from a prior myocardial infarction, can often be terminated by pacing the ventricle at a rate slightly faster than the VT. When a paced impulse enters the reentrant circuit during a tachycardia, it can depolarize a segment of the circuit, leaving that segment refractory when the reentrant wave returns, thus terminating the tachycardia. ATP, or overdrive pacing, refers to the delivery of short bursts (eg, eight beats) of rapid ventricular pacing to terminate VT. Although a variety of algorithms exist, ATP is usually programmed to be delivered at a rate that is slightly faster (eg, commencing at a cycle length 10 to 15 percent shorter) than the rate of the detected tachycardia [36-39]. In several studies, as many as 95 percent of episodes of spontaneous VT were successfully terminated with ATP [36,38-41]. Utilization of ATP therapy has evolved from tailored therapy used only if shown to be effective in the electrophysiology (EP) lab to empiric programming as routine therapy. Delivery of ATP has been shown to reduce inappropriate shocks and appropriate shocks and improve quality of life [8-11,42-46]. This programming may improve survival [10]. Indeed, several studies have shown that ATP is effective at terminating slow and fast VT with very low rates of adverse events [41,47- 52]. In the PainFREE Rx II trial, 634 patients with ICDs were randomly assigned to empiric ATP or shock for initial therapy of spontaneous rapid VT (188 to 250 beats per minute) [47]. After a mean follow-up of 11 months, 431 episodes of rapid VT occurred in 98 patients. Pacing was successful in terminating 229 of 284 such episodes in the ATP arm (81 percent). The incidence of VT acceleration, syncope, and sudden death was the same in the ATP and shock arms (seven versus five episodes). The use of ATP during ICD capacitor charging has been clinically validated as safe and effective [51]. It is important to recognize that inappropriate therapies, including inappropriate ATP, delivered primarily in the setting of supraventricular arrhythmias have been associated with increased mortality in the MADIT-RIT and MADIT-CRT trials [33,53]. However, the overall safety of ATP and its value in preventing avoidable ICD shocks are well established. One concern with ATP is that rapid pacing can cause VT to degenerate into VF. For this reason, all ICDs also have high-energy defibrillation, which can be used after ATP as a backup therapy if necessary. However, this theoretical problem associated with ATP appears to be uncommon [23,37,47,48,54,55]. ATP programming Although the ideal number of ATP attempts (ie, bursts) has not been definitively determined, we advocate for two or more attempts, recognizing that a law of https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 12/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate diminishing returns applies as the number of attempts increase, and that as ATP becomes more aggressive, proarrhythmia is more likely. The most effective ATP duration is likewise uncertain; however, most clinicians program eight-pulse bursts of ATP. While one study reported that up to five ATP attempts was safe [56], most data support the use of up to two ATP attempts, as additional attempts yield very little additional efficacy [41,47-52,56,57]. The 2015 HRS/EHRA/APHRS/SOLAECE Expert Consensus Statement on Optimal Implantable Cardioverter-Defibrillator Programming and Testing advocates for "at least one ATP attempt" [3]. In the ADVANCE-D Trial, a prospective randomized clinical trial of 925 patients, eight-pulse ATP was as effective and safe as fifteen-pulse ATP [58]. In the PITAGORA ICD clinical trial, which randomized 206 patients with an ICD to two ATP strategies (interval burst versus interval ramp), burst pacing was more effective for terminating fast VT episodes (between cycle lengths of 240 and 320 milliseconds), although ramp ATP appears more proarrhythmic than burst ATP [59]. In primary prevention ICD patients, the VT cycle length is unknown, so empiric programming is necessary. For secondary prevention patients with recorded VT, the programming can be tailored to the rate of the VT and other clinical features, such as hemodynamic tolerability. Slow monomorphic VT that is well tolerated favors an approach using ATP termination with at least two to three sequences of eight pulses or more. The use of a second burst of ATP has also been shown to increase effectiveness from 64 to 83 percent even in the fast VT range of 188 to 250 beats per minute [57]. Although a second burst has clear value, value beyond two bursts is limited to uncommon clinical situations [42]. However, recent data have shown programming up to six-burst ATP therapies for VTs 150 to 200 beats per minute can avoid ICD shocks in most (88 percent) patients. There is incremental benefit for up to six ATP attempts with a risk of accelerating the VT in nearly 7 percent. Ramp ATP after three failed bursts were shown to be similarly effective [60]. Cardioversion A shock that is synchronized to be delivered at the peak of the R wave is referred to as cardioversion. Because VT is an organized electrical rhythm, the delivery of an electrical shock during the vulnerable period of repolarization can cause VT to degenerate into VF. Synchronized cardioversion prevents shock delivery during the vulnerable period. (See "Basic principles and technique of external electrical cardioversion and defibrillation".) Although ICDs can be programmed to deliver synchronized shocks at a range of energies up to the maximum output of the device (usually 30 to 40 joules), synchronized cardioversion can https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 13/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate often terminate VT with relatively low energy (eg, 10 joules or less). However, low-energy shocks have been shown to be less effective and more arrhythmogenic compared with high-energy shocks [60]. Defibrillation An unsynchronized shock (ie, a shock delivered randomly during the cardiac cycle) is referred to as defibrillation. Because VF is not an organized rhythm, synchronized cardioversion is neither possible nor necessary. Defibrillation can be delivered across a range of energies. Initial shocks are sometimes programmed for lower energies to reduce capacitor charge time and save battery (although all shocks should be at least 10 joules above the defibrillation threshold). Subsequent shocks are usually delivered at higher energies, often at the maximum output of the ICD (eg, 30 to 40 joules), to optimize efficacy. If the defibrillation threshold is determined, the first shock should be 10 joules above this value. In the absence of defibrillation testing, maximum output shocks are programmed. Defibrillation threshold testing was once a routine part of ICD implantation, with the aim of confirming the correct connection of high voltage components and the ability of the system to detect and terminate VF. However, with stepwise technological innovation (eg, biphasic shocks, high-output devices), failure to defibrillate is increasingly rare. Risks of defibrillation testing include hypoperfusion from the VT/VF, failure to defibrillate, the consequences of the shock, and the sedation required to render the patient amnestic of the shock. Therefore, the risk to benefit ratio of routine defibrillation testing is seen by many to be unfavorable. When the defibrillation threshold is not established, defibrillation is programmed to maximum energy from the first shock. The advantages and disadvantages of defibrillation threshold testing are discussed separately. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions", section on 'Defibrillation threshold testing'.) BRADYCARDIA PROGRAMMING While ICDs are implanted primarily for the treatment of tachyarrhythmias, some patients require pacing for bradycardia at the time of implantation, while others will develop a need for

returns, thus terminating the tachycardia. ATP, or overdrive pacing, refers to the delivery of short bursts (eg, eight beats) of rapid ventricular pacing to terminate VT. Although a variety of algorithms exist, ATP is usually programmed to be delivered at a rate that is slightly faster (eg, commencing at a cycle length 10 to 15 percent shorter) than the rate of the detected tachycardia [36-39]. In several studies, as many as 95 percent of episodes of spontaneous VT were successfully terminated with ATP [36,38-41]. Utilization of ATP therapy has evolved from tailored therapy used only if shown to be effective in the electrophysiology (EP) lab to empiric programming as routine therapy. Delivery of ATP has been shown to reduce inappropriate shocks and appropriate shocks and improve quality of life [8-11,42-46]. This programming may improve survival [10]. Indeed, several studies have shown that ATP is effective at terminating slow and fast VT with very low rates of adverse events [41,47- 52]. In the PainFREE Rx II trial, 634 patients with ICDs were randomly assigned to empiric ATP or shock for initial therapy of spontaneous rapid VT (188 to 250 beats per minute) [47]. After a mean follow-up of 11 months, 431 episodes of rapid VT occurred in 98 patients. Pacing was successful in terminating 229 of 284 such episodes in the ATP arm (81 percent). The incidence of VT acceleration, syncope, and sudden death was the same in the ATP and shock arms (seven versus five episodes). The use of ATP during ICD capacitor charging has been clinically validated as safe and effective [51]. It is important to recognize that inappropriate therapies, including inappropriate ATP, delivered primarily in the setting of supraventricular arrhythmias have been associated with increased mortality in the MADIT-RIT and MADIT-CRT trials [33,53]. However, the overall safety of ATP and its value in preventing avoidable ICD shocks are well established. One concern with ATP is that rapid pacing can cause VT to degenerate into VF. For this reason, all ICDs also have high-energy defibrillation, which can be used after ATP as a backup therapy if necessary. However, this theoretical problem associated with ATP appears to be uncommon [23,37,47,48,54,55]. ATP programming Although the ideal number of ATP attempts (ie, bursts) has not been definitively determined, we advocate for two or more attempts, recognizing that a law of https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 12/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate diminishing returns applies as the number of attempts increase, and that as ATP becomes more aggressive, proarrhythmia is more likely. The most effective ATP duration is likewise uncertain; however, most clinicians program eight-pulse bursts of ATP. While one study reported that up to five ATP attempts was safe [56], most data support the use of up to two ATP attempts, as additional attempts yield very little additional efficacy [41,47-52,56,57]. The 2015 HRS/EHRA/APHRS/SOLAECE Expert Consensus Statement on Optimal Implantable Cardioverter-Defibrillator Programming and Testing advocates for "at least one ATP attempt" [3]. In the ADVANCE-D Trial, a prospective randomized clinical trial of 925 patients, eight-pulse ATP was as effective and safe as fifteen-pulse ATP [58]. In the PITAGORA ICD clinical trial, which randomized 206 patients with an ICD to two ATP strategies (interval burst versus interval ramp), burst pacing was more effective for terminating fast VT episodes (between cycle lengths of 240 and 320 milliseconds), although ramp ATP appears more proarrhythmic than burst ATP [59]. In primary prevention ICD patients, the VT cycle length is unknown, so empiric programming is necessary. For secondary prevention patients with recorded VT, the programming can be tailored to the rate of the VT and other clinical features, such as hemodynamic tolerability. Slow monomorphic VT that is well tolerated favors an approach using ATP termination with at least two to three sequences of eight pulses or more. The use of a second burst of ATP has also been shown to increase effectiveness from 64 to 83 percent even in the fast VT range of 188 to 250 beats per minute [57]. Although a second burst has clear value, value beyond two bursts is limited to uncommon clinical situations [42]. However, recent data have shown programming up to six-burst ATP therapies for VTs 150 to 200 beats per minute can avoid ICD shocks in most (88 percent) patients. There is incremental benefit for up to six ATP attempts with a risk of accelerating the VT in nearly 7 percent. Ramp ATP after three failed bursts were shown to be similarly effective [60]. Cardioversion A shock that is synchronized to be delivered at the peak of the R wave is referred to as cardioversion. Because VT is an organized electrical rhythm, the delivery of an electrical shock during the vulnerable period of repolarization can cause VT to degenerate into VF. Synchronized cardioversion prevents shock delivery during the vulnerable period. (See "Basic principles and technique of external electrical cardioversion and defibrillation".) Although ICDs can be programmed to deliver synchronized shocks at a range of energies up to the maximum output of the device (usually 30 to 40 joules), synchronized cardioversion can https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 13/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate often terminate VT with relatively low energy (eg, 10 joules or less). However, low-energy shocks have been shown to be less effective and more arrhythmogenic compared with high-energy shocks [60]. Defibrillation An unsynchronized shock (ie, a shock delivered randomly during the cardiac cycle) is referred to as defibrillation. Because VF is not an organized rhythm, synchronized cardioversion is neither possible nor necessary. Defibrillation can be delivered across a range of energies. Initial shocks are sometimes programmed for lower energies to reduce capacitor charge time and save battery (although all shocks should be at least 10 joules above the defibrillation threshold). Subsequent shocks are usually delivered at higher energies, often at the maximum output of the ICD (eg, 30 to 40 joules), to optimize efficacy. If the defibrillation threshold is determined, the first shock should be 10 joules above this value. In the absence of defibrillation testing, maximum output shocks are programmed. Defibrillation threshold testing was once a routine part of ICD implantation, with the aim of confirming the correct connection of high voltage components and the ability of the system to detect and terminate VF. However, with stepwise technological innovation (eg, biphasic shocks, high-output devices), failure to defibrillate is increasingly rare. Risks of defibrillation testing include hypoperfusion from the VT/VF, failure to defibrillate, the consequences of the shock, and the sedation required to render the patient amnestic of the shock. Therefore, the risk to benefit ratio of routine defibrillation testing is seen by many to be unfavorable. When the defibrillation threshold is not established, defibrillation is programmed to maximum energy from the first shock. The advantages and disadvantages of defibrillation threshold testing are discussed separately. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions", section on 'Defibrillation threshold testing'.) BRADYCARDIA PROGRAMMING While ICDs are implanted primarily for the treatment of tachyarrhythmias, some patients require pacing for bradycardia at the time of implantation, while others will develop a need for bradycardia support at a later time. In addition, the pacemaker settings of an ICD may influence patient outcome even when an indication for bradycardia pacing does not exist [6]. In general, single- and dual-chamber ICDs should be programmed to avoid ventricular pacing, whenever feasible; cardiac resynchronization therapy-defibrillator (CRT-D) devices should be programmed to encourage biventricular pacing. (See "Permanent cardiac pacing: Overview of devices and indications" and "Overview of pacemakers in heart failure".) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 14/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Our approach to bradycardia programming Our recommendations for bradycardia programming in patients with an ICD are generally in agreement with the 2015 HRS/EHRA/APHRS/SOLAECE Expert Consensus Statement on Optimal Implantable Cardioverter- Defibrillator Programming and Testing and the 2019 focused update discussing manufacturer- specific programming [3,4]. For patients who also have sinus node disease and guideline-supported indications for a pacemaker, we provide dual-chamber (right atrial [RA] and right ventricular [RV]) pacing along with the ICD, rather than RV pacing alone, to reduce the risk of atrial fibrillation (AF) and stroke, to avoid pacemaker syndrome, and to improve quality of life. For patients with a single- or dual-chamber ICD without guideline-supported indications for a pacemaker, we adjust the pacing parameters to minimize ventricular stimulation in an effort to improve survival and reduce heart failure (HF) hospitalization. For patients who are in sinus rhythm, with no or only mild left ventricular (LV) dysfunction, and AV block where ventricular pacing is expected, we provide dual-chamber (RA and RV) pacing rather than RV pacing alone, in order to avoid pacemaker syndrome and to improve quality of life. For patients with sinus rhythm, mild to moderate LV dysfunction, and AV block where frequent RV pacing is expected (>50 percent), we suggest biventricular pacing (ie, cardiac resynchronization therapy [CRT]) rather than dual-chamber (RA and RV) pacing in order to improve the combination of HF hospitalization, LV enlargement, and death. For patients who have chronotropic incompetence, we program the ICD to provide sensor augmented physiological rate-responsive pacing, especially if the patient is young and physically active. For patients with a dual-chamber ICD and native PR intervals of 230 milliseconds or less, the mode, automatic mode change, and rate response should be set so that the patient s native AV conduction is favored and minimizes RV pacing. For patients with biventricular pacing, the device should be programmed to produce the highest achievable percentage of ventricular pacing, preferably above 98 percent, in order to improve survival and reduce HF hospitalization. Additionally, the algorithms providing automatic adjustment of AV delay and/or LV-RV offset should be activated, in order to obtain a high percentage of LV synchronized pacing and to reduce the incidence of clinical events. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 15/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Pacing modes and rates for bradycardia in ICD patients The knowledge concerning the most suitable pacing modes and rates for patients with bradycardia is mostly gained from trials involving patients with a pacemaker. Although similar, there are some distinct differences among patients with an ICD that influence best programming practice for bradycardia. In patients with a pacemaker but no ICD, dual-chamber (ie, AV) pacing has been associated with lower rates of atrial fibrillation (AF) and stroke [61]; however, no difference in mortality has been shown between dual-chamber AV pacing and ventricular-only pacing modes. Among ICD recipients in the DAVID trial, patients without symptomatic bradycardia fared worse with DDDR pacing than with back-up VVI pacing, most likely due to unnecessary RV pacing associated with DDDR mode [7]. In patients with persistent sinus bradycardia, atrial pacing (AAI) with back-up ventricular pacing (eg, AAI-DDD) is the mode of choice. This is particularly true for patients with sinus node disease where the greatest benefits in AF reduction and stroke have been seen. In AV node disease, large randomized trials have failed to show superiority of dual- chamber pacing modes for clinical end points [62]. Therefore, the benefit of dual-chamber pacing modes is largely confined to improved exercise capacity and the avoidance of pacemaker syndrome, which occurs when single-chamber ventricular pacing conducts retrogradely to the atria resulting in atrial contraction against closed AV valves. This can cause symptoms such as dyspnea, dizziness, palpitations, and chest pain. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Pacemaker syndrome'.) Evidence supporting the superiority of dual-chamber pacing modes in exercise capacity and the avoidance of pacemaker syndrome is tempered by the lack of improvement demonstrated in hard clinical end points. Taken together with the increased complication risk and expense of dual-chamber ICDs, patients for whom no indication for bradycardia pacing exists generally undergo implantation of single-chamber ICDs over dual-chamber ICDs. In these patients, care should be taken to avoid ventricular pacing if possible. Further information on algorithms designed to minimize ventricular pacing is presented separately. (See "Overview of pacemakers in heart failure", section on 'Pacing modes to limit RV pacing'.) THE SUBCUTANEOUS ICD The novel subcutaneous ICD (S-ICD) follows many of the same principles as intravascular ICDs but is considered here separately for duration criteria, rate criteria, and discrimination https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 16/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate algorithms. A full discussion of the S-ICD is presented separately. (See "Subcutaneous implantable cardioverter defibrillators".) Programming is simpler with the S-ICD compared with transvenous ICDs. The programming choices in S-ICDs are limited to detection rate, one- or two-zone detection, post-shock pacing, and therapies on or off. Some automatic features may be manually overridden. As the S-ICD does not act as a pacemaker, bradycardia programming recommendations do not apply. Candidates for the S-ICD must initially be screened with a modified trichannel surface ECG that mimics the sensing vectors of the S-ICD system. This test is designed to assess the R wave to T wave ratio for appropriate signal characteristics and relationships. If the screening is not satisfactory for at least one of the three vectors both supine and standing, an S-ICD should not be implanted. Some patients (those with hypertrophic cardiomyopathy in particular) may benefit from additional screening during exercise [63]. At implant, the S-ICD automatically analyzes and selects the optimal sensing vector. Detection of ventricular tachycardia (VT) or ventricular fibrillation (VF) by the S-ICD is programmable utilizing a single or dual zone. In the single-zone configuration, shocks are delivered for detected heart rates above the programmed rate threshold: the "shock zone" [64]. In the dual-zone configuration, arrhythmia discrimination algorithms are active from the lower rate: the "conditional shock zone." In this latter zone, a unique discrimination algorithm is used to classify rhythms as either shockable or nonshockable. If they are classified as supraventricular arrhythmias or nonarrhythmic oversensing, therapy is withheld. The system utilizes an initial 18 of 24 duration criteria (nonprogrammable) prior to capacitor charging commencement; however, this duration is automatically extended following nonsustained ventricular tachyarrhythmia events. A confirmation algorithm is also utilized at the end of capacitor charging to ensure persistence of the ventricular arrhythmia prior to shock delivery. Shocks for spontaneous (noninduced) episodes are delivered at a nonprogrammable 80 joules regardless of the therapy zone of origination. The S-ICD VT detection algorithm, when programmed to include a conditional shock zone, has been demonstrated to be as effective as transvenous ICD system detection algorithms for the prevention of detection of induced supraventricular arrhythmias [65]. Furthermore, in the clinical evaluation of the conditional shock zone, it was strongly associated with a reduction in inappropriate shocks and did not result in prolongation of detection times or increased syncope [66]. The Praetorian trial showed the S-ICD to be noninferior to transvenous ICDs for patients without a pacing indication for the composite endpoint of inappropriate shocks and device-related https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 17/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate complications [67]. However, this trial has come under some criticism for event adjudication and for combining outcomes trending in opposite directions (which favors noninferiority) in the composite endpoint [68]. PRACTICAL PROGRAMMING GUIDANCE With the number of device companies and models available, together with the complexity of programming permutations, attempts have been made to give practical programming guidance. With the publication of the 2015 HRS/EHRA/APHRS/SOLAECE Expert Consensus Statement on Optimal Implantable Cardioverter-Defibrillator Programming and Testing and the 2019 focused update, manufacturer-specific programming recommendations were published online with the aim of providing a practical framework within which to optimally program ICDs as per the recommendations of that document [3,4]. The "Manufacturer-Specific Programming Guidelines" are hosted on the Heart Rhythm Society website. It is hoped that this will keep pace with new technology as it is released so as to become a living document of ICD programming best practice. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 18/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Implantable cardioverter-defibrillators (The Basics)" and "Patient education: Sudden cardiac arrest (The Basics)") Beyond the Basics topic (see "Patient education: Implantable cardioverter-defibrillators (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Background Implantable cardioverter-defibrillator (ICD) implantation is usually the preferred option for the secondary prevention of sudden cardiac death (SCD) and for primary prevention in certain populations at high risk of SCD due to ventricular tachycardia/fibrillation (VT/VF). (See 'Introduction' above.) General approach Our approach to optimal ICD programming seeks to emphasize that much of the risk/benefit ratio of these devices is determined by the way they are programmed. When recommending ICD programming settings, we are often guided in our general approach by randomized trials. However, specific patient circumstances may mandate a different approach from that of generic programming recommendations. (See 'General approach to programming' above.) Tachycardia detection Modern ICD programming utilizes higher arrythmia detection rates, longer detection durations, algorithms that discriminate supraventricular tachycardia (SVT) from VT, and specific electrocardiographic (ECG) features to minimize the sensing of noise. All these strategies combined provide the patient with the security of ICD therapy when needed with the aim of eliminating inappropriate and avoidable therapies. (See 'Tachycardia detection' above and 'Our approach to tachycardia detection' above.) For patients with any ICD (primary or secondary prevention), we recommend that tachyarrhythmia detection duration criteria be programmed to require the tachycardia to continue for at least 6 to 12 seconds (or for 30 intervals), rather than a shorter duration, before completing detection (Grade 1B). For patients with a primary prevention ICD (and for secondary prevention patients in whom the VT rate is not known), we recommend that the slowest tachycardia therapy zone limit should be programmed between 185 and 200 beats per minute (Grade 1B). For secondary prevention ICD patients for whom the clinical VT rate is known, we program the slowest tachycardia therapy zone at least 10 beats per minute below the https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 19/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate documented tachycardia rate but not faster than 200 beats per minute. Tachycardia therapies Modern ICD programming for the treatment of arrhythmias utilizes ATP as the initial therapy for many patients with VT, given the high rates of successful VT termination following ATP. If ATP is unsuccessful, or if the presenting rhythm is VF, ICDs can deliver one or more defibrillatory shocks in an effort to terminate VT/VF. (See 'Tachycardia therapies' above and 'Our approach to tachycardia therapies' above.) Bradycardia programming While ICDs are implanted primarily for the treatment of tachyarrhythmias, some patients require pacing for bradycardia at the time of implantation or at a later time. In general, single- and dual-chamber ICDs should be programmed to avoid ventricular pacing, whenever feasible; cardiac resynchronization therapy-defibrillator (CRT-D) devices should be programmed to encourage biventricular pacing. (See 'Bradycardia programming' above and 'Our approach to bradycardia programming' above.) Subcutaneous ICD Programming is simpler with the subcutaneous ICD (S-ICD). The programming choices in S-ICDs are limited to detection rate, one- or two-zone detection, post-shock pacing, and therapies on or off. Some automatic features may be manually overridden. As the S-ICD does not act as a pacemaker, bradycardia programming recommendations do not apply. (See 'The subcutaneous ICD' above.) Adjunctive therapies These include antiarrhythmic medication and/or catheter ablation and are important in the management of patients treated with an ICD, particularly as an effort to prevent recurrent ICD shocks in patients who have received multiple ICD shocks. Additionally, many other therapies such as those indicated for heart failure or in specific conditions (eg, cervical sympathectomy for long QT syndrome) are complementary to ICD therapy. Thus, a multidisciplinary approach is warranted for the management of ICD patients. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Other treatment options' and "Overview of the management of heart failure with reduced ejection fraction in adults".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. 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Toff WD, Camm AJ, Skehan JD, United Kingdom Pacing and Cardiovascular Events Trial

Cardiol 2008; 51:1357. 31. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008; 359:1009. 32. Sweeney MO, Sherfesee L, DeGroot PJ, et al. Differences in effects of electrical therapy type for ventricular arrhythmias on mortality in implantable cardioverter-defibrillator patients. Heart Rhythm 2010; 7:353. 33. Sood N, Ruwald AC, Solomon S, et al. Association between myocardial substrate, implantable cardioverter defibrillator shocks and mortality in MADIT-CRT. Eur Heart J 2014; 35:106. 34. Powell BD, Saxon LA, Boehmer JP, et al. Survival after shock therapy in implantable cardioverter-defibrillator and cardiac resynchronization therapy-defibrillator recipients according to rhythm shocked. The ALTITUDE survival by rhythm study. J Am Coll Cardiol 2013; 62:1674. 35. van Rees JB, Borleffs CJ, de Bie MK, et al. Inappropriate implantable cardioverter-defibrillator shocks: incidence, predictors, and impact on mortality. J Am Coll Cardiol 2011; 57:556. 36. Schaumann A, von zur M hlen F, Herse B, et al. Empirical versus tested antitachycardia pacing in implantable cardioverter defibrillators: a prospective study including 200 patients. Circulation 1998; 97:66. 37. Trappe HJ, Klein H, Kielblock B. Role of antitachycardia pacing in patients with third generation cardioverter defibrillators. Pacing Clin Electrophysiol 1994; 17:506. 38. Saksena S, Chandran P, Shah Y, et al. Comparative efficacy of transvenous cardioversion and pacing in patients with sustained ventricular tachycardia: a prospective, randomized, https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 23/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate crossover study. Circulation 1985; 72:153. 39. Bardy GH, Poole JE, Kudenchuk PJ, et al. A prospective randomized repeat-crossover comparison of antitachycardia pacing with low-energy cardioversion. Circulation 1993; 87:1889. 40. Clinical outcome of patients with malignant ventricular tachyarrhythmias and a multiprogrammable implantable cardioverter-defibrillator implanted with or without thoracotomy: an international multicenter study. PCD Investigator Group. J Am Coll Cardiol 1994; 23:1521. 41. Sullivan RM, Russo AM, Berg KC, et al. Arrhythmia rate distribution and tachyarrhythmia therapy in an ICD population: results from the INTRINSIC RV trial. Heart Rhythm 2012; 9:351. 42. Wilkoff BL, Ousdigian KT, Sterns LD, et al. A comparison of empiric to physician-tailored programming of implantable cardioverter-defibrillators: results from the prospective randomized multicenter EMPIRIC trial. J Am Coll Cardiol 2006; 48:330. 43. Sweeney MO, Wathen MS, Volosin K, et al. Appropriate and inappropriate ventricular therapies, quality of life, and mortality among primary and secondary prevention implantable cardioverter defibrillator patients: results from the Pacing Fast VT REduces Shock ThErapies (PainFREE Rx II) trial. Circulation 2005; 111:2898. 44. Gilliam FR, Hayes DL, Boehmer JP, et al. Real world evaluation of dual-zone ICD and CRT-D programming compared to single-zone programming: the ALTITUDE REDUCES study. J Cardiovasc Electrophysiol 2011; 22:1023. 45. Fischer A, Ousdigian KT, Johnson JW, et al. The impact of atrial fibrillation with rapid ventricular rates and device programming on shocks in 106,513 ICD and CRT-D patients. Heart Rhythm 2012; 9:24. 46. Gonz lez-Enr quez S, Rodr guez-Entem F, Exp sito V, et al. Single-chamber ICD, single-zone therapy in primary and secondary prevention patients: the simpler the better? J Interv Card Electrophysiol 2012; 35:343. 47. Wathen MS, DeGroot PJ, Sweeney MO, et al. Prospective randomized multicenter trial of empirical antitachycardia pacing versus shocks for spontaneous rapid ventricular tachycardia in patients with implantable cardioverter-defibrillators: Pacing Fast Ventricular Tachycardia Reduces Shock Therapies (PainFREE Rx II) trial results. Circulation 2004; 110:2591. 48. Wathen MS, Sweeney MO, DeGroot PJ, et al. Shock reduction using antitachycardia pacing for spontaneous rapid ventricular tachycardia in patients with coronary artery disease. Circulation 2001; 104:796. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 24/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate 49. Saeed M, Neason CG, Razavi M, et al. Programming antitachycardia pacing for primary prevention in patients with implantable cardioverter defibrillators: results from the PROVE trial. J Cardiovasc Electrophysiol 2010; 21:1349. 50. Sivagangabalan G, Eshoo S, Eipper VE, et al. Discriminatory therapy for very fast ventricular tachycardia in patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol 2008; 31:1095. 51. Schoels W, Steinhaus D, Johnson WB, et al. Optimizing implantable cardioverter-defibrillator treatment of rapid ventricular tachycardia: antitachycardia pacing therapy during charging. Heart Rhythm 2007; 4:879. 52. Gasparini M, Anselme F, Clementy J, et al. BIVentricular versus right ventricular antitachycardia pacing to terminate ventricular tachyarrhythmias in patients receiving cardiac resynchronization therapy: the ADVANCE CRT-D Trial. Am Heart J 2010; 159:1116. 53. Ruwald AC, Schuger C, Moss AJ, et al. Mortality reduction in relation to implantable cardioverter defibrillator programming in the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT). Circ Arrhythm Electrophysiol 2014; 7:785. 54. Nasir N Jr, Pacifico A, Doyle TK, et al. Spontaneous ventricular tachycardia treated by antitachycardia pacing. Cadence Investigators. Am J Cardiol 1997; 79:820. 55. Pinski SL, Fahy GJ. The proarrhythmic potential of implantable cardioverter-defibrillators. Circulation 1995; 92:1651. 56. Martins RP, Blangy H, Muresan L, et al. Safety and efficacy of programming a high number of antitachycardia pacing attempts for fast ventricular tachycardia: a prospective study. Europace 2012; 14:1457. 57. Anguera I, Dallaglio P, Sabat X, et al. The benefit of a second burst antitachycardia sequence for fast ventricular tachycardia in patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol 2014; 37:486. 58. Santini M, Lunati M, Defaye P, et al. Prospective multicenter randomized trial of fast ventricular tachycardia termination by prolonged versus conventional anti-tachyarrhythmia burst pacing in implantable cardioverter-defibrillator patients-Atp DeliVery for pAiNless ICD thErapy (ADVANCE-D) Trial results. J Interv Card Electrophysiol 2010; 27:127. 59. Gulizia MM, Piraino L, Scherillo M, et al. A randomized study to compare ramp versus burst antitachycardia pacing therapies to treat fast ventricular tachyarrhythmias in patients with implantable cardioverter defibrillators: the PITAGORA ICD trial. Circ Arrhythm Electrophysiol 2009; 2:146. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 25/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate 60. Strik M, Ramirez FD, Welte N, et al. Progressive implantable cardioverter-defibrillator therapies for ventricular tachycardia: The efficacy and safety of multiple bursts, ramps, and low-energy shocks. Heart Rhythm 2020; 17:2072. 61. Castelnuovo E, Stein K, Pitt M, et al. The effectiveness and cost-effectiveness of dual- chamber pacemakers compared with single-chamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation. Health Technol Assess 2005; 9:iii, xi. 62. Toff WD, Camm AJ, Skehan JD, United Kingdom Pacing and Cardiovascular Events Trial Investigators. Single-chamber versus dual-chamber pacing for high-grade atrioventricular block. N Engl J Med 2005; 353:145. 63. Francia P, Adduci C, Palano F, et al. Eligibility for the Subcutaneous Implantable Cardioverter-Defibrillator in Patients With Hypertrophic Cardiomyopathy. J Cardiovasc Electrophysiol 2015; 26:893. 64. Weiss R, Knight BP, Gold MR, et al. Safety and efficacy of a totally subcutaneous implantable- cardioverter defibrillator. Circulation 2013; 128:944. 65. Gold MR, Theuns DA, Knight BP, et al. Head-to-head comparison of arrhythmia discrimination performance of subcutaneous and transvenous ICD arrhythmia detection algorithms: the START study. J Cardiovasc Electrophysiol 2012; 23:359. 66. Gold MR, Weiss R, Theuns DA, et al. Use of a discrimination algorithm to reduce inappropriate shocks with a subcutaneous implantable cardioverter-defibrillator. Heart Rhythm 2014; 11:1352. 67. Knops RE, Olde Nordkamp LRA, Delnoy PHM, et al. Subcutaneous or Transvenous Defibrillator Therapy. N Engl J Med 2020; 383:526. 68. Mandrola J, Enache B, Redberg RF. Subcutaneous or Transvenous Defibrillator Therapy. N Engl J Med 2021; 384:676. Topic 113776 Version 15.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 26/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate GRAPHICS Tachycardia detection evidence Short detection controls Prolonged detection intervention Participants (n) Study Findings PREPARE 1391 12 of 16 (58%) 30 of 40 beats Reduction in Nonrandomized beats inappropriate shocks (SVT), Primary prevention 18 of 24 (42%) beats avoidable shocks (VT), and "morbidity index" RELEVANT 324 Nonrandomized 12 of 16 beats 30 of 40 beats Reduction in inappropriate shocks (SVT), Primary prevention avoidable shocks (VT), and HF hospitalizations MADIT-RIT 1500 Randomized 2.5 seconds (170 to 199 bpm) 60 seconds (170 to 199 bpm) Reduction in first inappropriate Primary prevention therapy, first 1 second ( 200 bpm) 12 seconds (200 appropriate therapy, to 249 bpm) 2.5 seconds ( 250 bpm) appropriate ATP, and inappropriate ATP; improved survival ADVANCE-III 1902 Randomized 18 of 24 beats 30 of 40 beats Reduction in overall therapies, inappropriate Primary and secondary shocks, and all- prevention cause hospitalizations PROVIDE 1670 Randomized 12 beats 25 beats (180 to Reduction in all- 214 bpm) cause shock rate; improved survival Primary prevention 18 beats (214 to 250 bpm) 12 beats (>250 bpm) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 27/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate SVT: supraventricular tachycardia; VT: ventricular tachycardia; HF: heart failure; bpm: beats per minute; ATP: antitachycardia pacing. Reproduced from: Wilko BL, Fauchier L, Stiles MK, et al. 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-de brillator programming and testing. Heart Rhythm 2016; 13:e50. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 115226 Version 1.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 28/29 7/6/23, 10:51 AM Implantable cardioverter-defibrillators: Optimal programming - UpToDate Contributor Disclosures Martin K Stiles, MB ChB, PhD, FRACP, FHRS Consultant/Advisory Boards: Ceryx Medical [Novel pacemaker device]. Speaker's Bureau: Medtronic [AF ablation]. All of the relevant financial relationships listed have been mitigated. Jonathan Piccini, MD, MHS, FACC, FAHA, FHRS Grant/Research/Clinical Trial Support: Abbott [Atrial fibrillation, catheter ablation]; AHA [Atrial fibrillation, cardiovascular disease]; Bayer [Atrial fibrillation]; Boston Scientific [Cardiac mapping, pacemaker/ICD, atrial fibrillation care]; iRhythm [Atrial fibrillation]; NIA [Atrial fibrillation]; Philips [Lead management]. Consultant/Advisory Boards: Abbott [Atrial fibrillation, catheter ablation]; Abbvie [Atrial fibrillation]; Bayer [Atrial fibrillation]; Boston Scientific [Cardiac mapping, atrial fibrillation, pacemaker/ICD]; ElectroPhysiology Frontiers [Atrial fibrillation, catheter ablation]; Element Science [DSMB]; Medtronic [Atrial fibrillation, pacemaker/ICDs]; Milestone [Supraventricular tachycardia]; Pacira [Atrial fibrillation]; Philips [Lead extraction]; ReCor [Cardiac arrhythmias]; Sanofi [Atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-optimal-programming/print 29/29

7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Implantable cardioverter-defibrillators: Overview of indications, components, and functions : Jonathan Piccini, MD, MHS, FACC, FAHA, FHRS, Cara Pellegrini, MD : N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 20, 2023. INTRODUCTION Ventricular fibrillation (VF) is a common cause of sudden cardiac death (SCD) and is sometimes preceded by monomorphic or polymorphic ventricular tachycardia (VT). All sustained ventricular arrhythmias have the potential to be lethal arrhythmias. Although cardiopulmonary resuscitation, including chest compressions and assisted ventilation, can provide transient circulatory support for the patient with cardiac arrest, the only effective approach for terminating VF is electrical defibrillation. Implantable cardioverter-defibrillator (ICD) implantation is generally considered the first-line treatment option for the secondary prevention of SCD and for primary prevention in certain populations at high risk of SCD due to VT/VF. This topic will review the general indications for ICD implantation as well as the components and functionalities of the ICD. The clinical trials documenting the efficacy of an ICD in different clinical settings (including both secondary and primary prevention), complications of ICD placement, optimal ICD programming, and follow-up care of patients with ICDs are discussed separately. (See "Implantable cardioverter-defibrillators: Optimal programming".) (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) (See "Cardiac implantable electronic devices: Long-term complications".) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 1/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate (See "Cardiac implantable electronic devices: Patient follow-up".) (See "Cardiac implantable electronic devices: Periprocedural complications".) Alternatives and adjunctive therapies to ICD implantation include antiarrhythmic drugs; ablative surgery; catheter ablation; and in advanced cases stellate ganglion resection, noninvasive cardiac radiation, and cardiac transplantation; and are discussed separately. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Radiofrequency catheter ablation'.) (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) (See "Pharmacologic therapy in survivors of sudden cardiac arrest".) INDICATIONS The main indications for use of an ICD are as follows [1,2]: Secondary prevention of sudden cardiac death (SCD) in patients with prior sustained ventricular tachycardia (VT), ventricular fibrillation (VF), or resuscitated SCD thought to be due to VT/VF. Primary prevention of SCD in patients at increased risk of life-threatening VT/VF. Secondary prevention Implantation of an ICD is recommended for the secondary prevention of SCD due to life-threatening VT/VF in the following settings [2]: Patients with a prior episode of resuscitated VT/VF or sustained hemodynamically unstable VT in whom a completely reversible cause cannot be identified. This includes patients with a variety of underlying heart diseases and those with idiopathic VT/VF and congenital long QT syndrome, but not patients who have VT/VF limited to the first 48 hours after an acute myocardial infarction (MI). (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Secondary prevention of SCD'.) (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features".) (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Treatment of associated conditions'.) Patients with episodes of spontaneous sustained VT in the presence of heart disease (valvular, ischemic, hypertrophic, dilated, or infiltrative cardiomyopathies) and other https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 2/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate settings (eg, channelopathies). (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'ICD therapy' and "Catecholaminergic polymorphic ventricular tachycardia".) Patients with unexplained syncope and high suspicion of VT/VF as the etiology. (See "Syncope in adults: Management and prognosis", section on 'Documented, suspected, or induced ventricular tachycardia'.) A key issue is the prevention of total mortality (not arrhythmic or sudden death). Simply correcting VT/VF may not improve overall mortality. Therefore, patient selection for ICD implantation should take into account both the known risk of SCD due to VT/VF for a specific condition and the risk of total mortality from underlying medical conditions as well. Primary prevention Implantation of an ICD is recommended for the primary prevention of SCD due to life-threatening VT/VF in patients who have received optimal guideline-directed medical therapy. While guideline-directed medical therapy used to be relatively simple and included beta-blocker therapy and use of an angiotensin receptor blocker or ACE inhibitor, guideline-directed medical therapy now includes several other medications. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction".) Patients on guideline-directed medical therapy who have high risk of SCD include the following groups of patients [2]: Patients with a prior MI (at least 40 days ago) and left ventricular ejection fraction (LVEF) 30 percent. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) Patients with a cardiomyopathy, New York Heart Association (NYHA) functional class II to III table 1), and LVEF 35 percent. Patients with a nonischemic cardiomyopathy generally ( require optimal medical therapy for three months with documentation of persistent LVEF 35 percent at that time. However, the DANISH trial calls into question the role of prophylactic ICDs in some patients with nonischemic cardiomyopathy. It is recommended that patients be evaluated at least three months after revascularization (coronary artery bypass graft surgery [CABG] or stent placement). (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF", section on 'Use of an ICD'.) Some patients with heart failure who are candidates for an ICD also have intraventricular conduction delay ( 120 milliseconds) and are candidates for cardiac resynchronization therapy (CRT) with a biventricular pacemaker. Such patients could be treated with a device https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 3/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate with combined ICD and biventricular pacing functions (cardiac resynchronization therapy- defibrillator [CRT-D]). (See 'Cardiac resynchronization therapy' below and "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Patients with a prior MI, nonsustained VT, and LVEF 40 percent who have VF or sustained VT-induced during electrophysiology study. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) Select patients with certain underlying disorders who are deemed to be at high risk for life- threatening VT/VF. This includes: Patients with congenital long QT syndrome who have recurrent symptoms and/or torsades de pointes despite therapy with beta blockers or other high-risk patients. (See "Congenital long QT syndrome: Treatment", section on 'Implantable cardioverter- defibrillator'.) High-risk patients with hypertrophic cardiomyopathy, arrhythmogenic right ventricular (RV) cardiomyopathy, or cardiac sarcoidosis. (See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death", section on 'Risk stratification' and "Management and prognosis of cardiac sarcoidosis", section on 'Implantable cardioverter-defibrillator'.) High-risk patients with Brugada syndrome, catecholaminergic polymorphic VT, and other channelopathies. (See "Catecholaminergic polymorphic ventricular tachycardia", section on 'Implantable cardioverter-defibrillators' and "Brugada syndrome or pattern: Management and approach to screening of relatives".) ICD not recommended ICD therapy is NOT recommended in the following settings [2]: Patients with ventricular tachyarrhythmias due to a completely reversible disorder in the absence of structural heart disease (eg, electrolyte imbalance, drugs, or trauma). Patients who do not have a reasonable expectation of survival with an acceptable functional status for at least one year, even if they otherwise meet ICD implantation criteria. Patients with incessant VT or VF in whom other therapies (eg, catheter ablation) should be considered first. (See "Electrical storm and incessant ventricular tachycardia", section on 'Catheter ablation'.) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 4/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Patients with severe psychiatric illnesses that may be aggravated by device implantation. In clinical practice, this situation is very rarely encountered and may apply more to primary prevention than secondary prevention settings. Patients with NYHA Class IV heart failure that is refractory to optimal medical treatment who are not candidates for cardiac transplantation or CRT. (See "Heart transplantation in adults: Indications and contraindications" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Patients with syncope without inducible ventricular tachyarrhythmias and without structural heart disease. Patients with VF or VT amenable to surgical or catheter ablation in whom the risk of sudden cardiac death is normalized after successful ablation (eg, pre-excited atrial fibrillation and subsequent ventricular arrhythmias associated with the Wolff-Parkinson- White syndrome, RV or LV outflow tract VT, idiopathic VT, or fascicular VT in the absence of structural heart disease). (See "Treatment of arrhythmias associated with the Wolff- Parkinson-White syndrome", section on 'Catheter ablation' and "Ventricular tachycardia in the absence of apparent structural heart disease".) ICD implantation should be delayed in patients with active infections or other acute medical issues. If necessary, the patient can be bridged with a wearable cardioverter- defibrillator (WCD) until ICD implantation can be carried out. (See "Wearable cardioverter- defibrillator".) ELEMENTS OF THE ICD The ICD system is comprised of the following elements [3]: Pacing/sensing electrodes Defibrillation electrodes Pulse generator ( picture 1) In contemporary transvenous ICDs, both the pace/sense electrodes and the defibrillation electrodes are located on a single ventricular lead. Decades ago, ICD systems were implanted epicardially, requiring major surgery to affix separate shocking and sensing electrodes to the epicardial surface of the heart. Generators were typically placed in the upper abdomen. The need for epicardial electrodes and abdominal pulse generators has become vanishingly rare. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 5/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate There is also a subcutaneous ICD (S-ICD) which requires no transvenous leads. (See "Subcutaneous implantable cardioverter defibrillators".) Electrodes Pacing and sensing functions require a pair of electrodes. Contemporary pacemakers and defibrillators usually use leads with two electrodes on the ventricular lead: the distal electrode at the tip of the lead and a second electrode in the shape of a ring, several millimeters back from the tip (ie, true bipolar leads). These bipolar leads provide accurate sensing, with high amplitude, narrow electrograms. Some ICD leads utilize integrated bipolar sensing in which the bipole consists of a single tip electrode and the distal shocking coil electrode. In addition to improved sensing capabilities, bipolar leads reduce the risk of extraneous interference, which could lead to inappropriate device function (eg, inappropriate shocks delivered due to sensing of muscular activity). The defibrillation function of the electrodes requires a relatively large surface area and positioning of the lead to maximize the density of current flow through the ventricular myocardium. Contemporary ICD systems use a "coil" of wire that extends along the ventricular lead as the primary defibrillation electrode. Thus, a single transvenous lead can accomplish all pacing, sensing, and defibrillation functions. In the distant past (and in some unique cases, in persons without vascular access options), epicardial patches were used for defibrillation, but placement required a thoracotomy. Additional defibrillation electrodes improve defibrillation efficacy and reduce the defibrillation threshold. Most contemporary ICD systems have two or three defibrillation electrodes. Along with the distal coil in the right ventricle (RV) on the transvenous lead, some ICD leads have a second defibrillation coil proximal to the RV coil. In addition, with "active can" technology, the metal housing of the ICD serves as one of the shocking electrodes. This configuration requires that the pulse generator be implanted in the pectoral region ( figure 1). The active can and transvenous lead systems can be combined to achieve adequate defibrillation thresholds (minimum energy required for successful defibrillation, which should generally be 10 joules less than the maximum output of the device). (See 'Defibrillation threshold testing' below.) There are three types of pacing offered by current transvenous systems. Single-chamber systems have only an RV lead. Dual-chamber systems have right atrial (RA) and RV leads. Cardiac resynchronization therapy (CRT, also called biventricular) systems have RA, RV, and left ventricular (LV) leads, or in some patients with permanent atrial fibrillation, RV and LV leads. Pulse generator The pulse generator ( picture 1) contains the sensing circuitry as well as the high voltage capacitors and battery. While the initial pulse generators were located in the abdomen, the development of small pulse generators (eg, thickness 15 mm) has permitted https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 6/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate placement in the infraclavicular region of the anterior chest wall in nearly all patients [4]. The majority are placed in a prepectoral (ie, subcutaneous) position, but in some cases, a subpectoral position is advantageous. For most patients with the pulse generator in this location, the impulses generated are transmitted to the myocardium via transvenous leads. Epicardial systems are still available and may be necessary as a result of anatomical limitations to placing a transvenous lead(s). Additionally, a subcutaneous ICD (S-ICD) system is now available in which the pulse generator is placed overlying the left lower lateral ribs. (See 'Choosing the optimal pulse generator location' below.) Battery life in ICD pulse generators has improved over time. For example, devices implanted after 2002 have significantly longer battery lives (5.6 versus 4.9 years) [5]. Single-chamber ICDs implanted since 2002 had the longest battery life (mean 6.7 years). Contemporary ICD devices generally have an expected longevity greater than eight years and CRT- D devices greater than six years, although some ICDs have estimated battery longevity >10 years [6,7]. IMPLANTATION Prior to implanting an ICD, the provider must determine the optimal position for placement of the leads and the pulse generator. Most current ICD systems utilize one or two transvenous leads placed via the axillary, subclavian, or cephalic vein, with attachment to a pulse generator in the subcutaneous tissue in the infraclavicular anterior chest wall. In more recent years, there has been a trend toward single coils rather than dual-coil defibrillation leads. Dual-coil leads were favored earlier in the era of transvenous ICD systems. However, a proximal coil is rarely needed for defibrillation and single-coil leads pose less risk in the future if lead extraction is necessary. An additional defibrillation lead can be placed in the azygos vein, coronary sinus, or subcutaneous tissue if necessary to improve defibrillation. Choosing the optimal pulse generator location Modern devices are small enough to be implanted in the pectoral region of the anterior chest wall; the devices are implanted either subcutaneously or submuscularly, similar to a pacemaker implantation. Although implantation on the left side is preferred, a right-sided implant can be performed [8,9]. The left pectoral position is usually chosen for three reasons: The defibrillation energy requirement is usually lower on the left because of the location of the heart in the left chest Ipsilateral arm movement restrictions shortly after implant are less impactful for the nondominant hand (which for most people is the left) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 7/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate There is a small risk of arm swelling due to venous occlusion; this is less impactful on the nondominant hand (which for most people is the left hand). Additionally, a subcutaneous ICD (S-ICD) system is available that allows for defibrillation (though no backup pacing aside from immediately post-shock or antitachycardia pacing) without the insertion of a transvenous lead. The pulse generator for the S-ICD system ( picture 2) is implanted in a subcutaneous pocket in the left lateral, mid-axillary thoracic position ( picture 3 and picture 4). (See 'Subcutaneous ICD' below and "Subcutaneous implantable cardioverter defibrillators".) Choosing the optimal lead placement In most de novo ICD implantations, the lead with the pace/sense electrodes is placed transvenously, with the distal electrode positioned on the right ventricular (RV) apical endocardium. Defibrillation energy requirement is generally optimized (ie, lowest) with an RV apical lead position. RV septal lead placement is also an option. In rare cases, usually due to limitations of the venous anatomy and/or a high risk of bacteremia and endovascular infection, the pace/sense electrodes are placed on the epicardium during surgery ( image 1). The electrodes should record a ventricular electrogram of at least 5 mV. These signals should be sufficiently large such that detection of lower amplitude ventricular tachycardia (VT) and ventricular fibrillation (VF) is straight-forward. Dual-chamber ICDs have an additional lead with another pair of pace/sense electrodes in the right atrium for atrial sensing and pacing [10]. Not all patients require an atrial lead. Whether use of an atrial lead reduces the risk of inappropriate shocks for supraventricular rhythms is controversial and debated. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Pacing modes'.) An S-ICD has been developed with no leads placed in the heart. The subcutaneous lead, which toward its terminal end contains an 8 cm shocking coil electrode, is tunneled from a small midline incision and the pulse generator in the left mid axillary line on the lateral chest wall to a position along the left parasternal margin ( image 2). The S-ICD can sense VT/VF and deliver therapeutic shocks but cannot deliver antitachycardia pacing or pacing for bradycardias. (See 'Subcutaneous ICD' below.) Defibrillation threshold testing Defibrillation threshold testing (DFT) has historically been performed at the time of device implantation, although the necessity for this evaluation with modern devices and randomized trials to date has failed to identify clear benefit [11-17]. Among patients who have had DFT testing, only a small fraction need DFT testing. The following 2015 consensus statement on optimal ICD programming and testing counsels that the following groups may be considered for DFT testing [11]: https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 8/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate DFT testing is reasonable to consider in patients undergoing an initial right pectoral ICD implantation or an ICD pulse generator replacement. The rationale for testing right-sided implants is that defibrillation may be more difficult with a right pectoral pulse generator, given the fact that the heart lies in the left chest. For generator changes, there may be concerns about the integrity of the chronic leads. DFT testing should not be performed in patients with a documented nonchronic cardiac thrombus, atrial fibrillation/flutter without adequate anticoagulation, severe aortic stenosis, unstable angina, recent stroke or transient ischemic attack, or hemodynamic instability. Additionally, many centers avoid DFT testing in patients with very low left ventricular ejection fractions (<15 percent) or severe pulmonary hypertension. Furthermore, the 2015 statement counsels that: DFT testing can performed in patients receiving an S-ICD. (See "Subcutaneous implantable cardioverter defibrillators".) DFT testing can be omitted in patients undergoing a left pectoral transvenous ICD implantation with a RV apical lead that is functioning appropriately. Some electrophysiologists feel that universally omitting DFT testing might compromise the safety within certain subsets of patients, especially those patients with high DFTs who would benefit from a higher energy device and/or additional leads. A distinction should be made, however, between DFT testing at initial implantation and at the time of generator replacement. DFT testing at the time of generator replacement is useful in subsets of patients with leads that have a hazard alert or in patients at higher risk of DFT changes (eg, obese patients, patients with heart failure symptoms, patients on amiodarone, etc) [18]. Early ICD systems frequently required lead system adjustment at the time of implantation in order to achieve an adequate safety margin (arbitrarily set at 10 joules or greater). As technology improved, thresholds were substantially reduced [19]. As a result, it is very unusual for defibrillator systems to require modification at the time of implantation ( figure 1). Data regarding DFT testing on the more modern single-coil systems are limited since the available cohort and registry data predate the development of single-coil systems. One paired randomized study of 216 patients with a mix of ICD indications and ICD manufacturers found no difference in first shock efficacy, which was >90 percent for either system [20]. On average, omitting the proximal coil in a single-coil system likely increases the DFT a few joules, which usually does not impact the safety margin but could be significant in some patients [21]. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 9/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Several studies have illustrated the impact of DFT testing at the time of ICD implantation with the current generation of devices, generally showing no significant difference in outcomes [14- 17,22,23]. In the Shockless Implant Evaluation (SIMPLE) trial, a single-blind, multicenter, noninferiority study of 2500 patients receiving an initial ICD in the left pectoral region for standard primary or secondary prevention indications, patients were randomized 1:1 to either have or not have DFT testing at the time of ICD implantation and were followed for an average of 3.1 years [22]. For the composite primary outcome of arrhythmic death or failed appropriate shock, no DFT testing was identified as noninferior to DFT testing (with a trend toward superiority), as patients in the no DFT testing group had a lower incidence of the primary outcome (7 percent per year versus 8 percent per year in the DFT testing group), with no significant differences in the secondary safety outcomes noted between the two groups. Similarly, in the NORDIC ICD trial, which also randomized patients receiving a first ICD to have or not have DFT testing at the time of ICD implantation, no DFT testing was identified as noninferior to DFT testing (also with a trend toward superiority) and was also associated with a trend toward fewer procedure-related adverse events [23]. In a systematic review and meta- analysis of 13 studies involving 9740 patients undergoing initial ICD implantation, there was no significant difference in mortality or adverse outcomes between patients with and without DFT testing [24]. In the absence of randomized data or society guidelines, many electrophysiologists perform DFT for most S-ICD implantations; it is also strongly encouraged for S-ICD generator replacement procedures. However, observational data have not shown that DFT at the time of initial S-ICD implantation is associated with a lower rate of ineffective shocks or cardiovascular mortality [25,26]. Among 566 propensity-matched patients with S-ICDs implanted across 17 European centers, there was no significant difference in the composite of ineffective shocks and cardiovascular mortality in those who underwent or did not undergo defibrillation testing [25]. Similarly, a multi-center Italian study of 650 propensity-matched patients found no significant difference in the composite of all-cause death and ineffective S-ICD therapy, as well as a secondary composite endpoint of all-cause death, ineffective shock, inappropriate shock, and complication [26]. Periprocedural monitoring Nearly all patients who undergo ICD implantation will have the device placed using local anesthesia at the site of the pulse generator insertion, with intravenous sedation provided most commonly by nurse anesthetists and/or anesthesiologists. If patients undergo DFT testing following device implantation, a "deeper" level of sedation may be required, but in most cases DFT testing can be performed without requiring general anesthesia. Following ICD implantation, a posteroanterior (PA) and lateral chest radiograph should be obtained to establish the position of the pulse generator and the associated lead(s) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 10/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate and to exclude any apparent complications, including pneumothorax and lead dislodgment. Patients should also have a 12-lead electrocardiogram (ECG) recorded during pacing to document the ECG appearance of the QRS complex. The monitoring associated with procedural sedation, as well as additional periprocedural observation and timing of discharge post-procedure, is discussed in detail separately. (See "Procedural sedation in adults: General considerations, preparation, monitoring, and mitigating complications", section on 'Monitoring' and "Cardiac implantable electronic devices: Periprocedural complications", section on 'Periprocedural monitoring'.) Complications There are a variety of potential complications associated with ICDs, both at and around the time of implantation as well as long-term over the life of patients and their device(s). Both the periprocedural and long-term complications associated with ICDs are discussed in detail separately. (See "Cardiac implantable electronic devices: Periprocedural complications" and "Cardiac implantable electronic devices: Long-term complications".) ICD FUNCTIONS ECG monitoring and storage Contemporary ICDs have more extensive storage and monitoring capacities, thereby allowing more expedient patient management, often without requiring a face-to-face visit. Some examples: Recording and display of stored electrograms from tachyarrhythmia events. This can be very helpful for the detection of "silent" or asymptomatic arrhythmias where management of the patient is likely to change (eg, brief episodes of rate-controlled atrial fibrillation). Telemetry capabilities that permit easier analysis when patients receive shocks. Remote monitoring capabilities via telephone or internet that allow clinicians to review ICD parameters and events without requiring the patient to come to the office or hospital. (See "Cardiac implantable electronic devices: Patient follow-up".) Antitachycardia pacing Ventricular tachycardia (VT), particularly reentrant VT associated with scar from a prior myocardial infarction, can sometimes be terminated by pacing the ventricle. When a paced impulse enters the reentrant circuit during a tachycardia, it can depolarize a segment of the circuit, leaving that segment refractory when the reentrant wave returns, thus terminating the tachycardia. Antitachycardia pacing, or overdrive pacing, refers to the delivery of short bursts (eg, eight beats) of rapid ventricular pacing to terminate VT ( waveform 1). Although a variety of https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 11/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate algorithms exist, antitachycardia pacing is usually programmed to be delivered at a rate that is slightly faster (eg, at a cycle length 10 to 12 percent shorter) than the rate of the detected tachycardia. Subcutaneous ICDs (S-ICDs) cannot deliver antitachycardic pacing. (See "Implantable cardioverter-defibrillators: Optimal programming", section on 'Antitachycardia pacing'.) Though employed substantially less frequently, antitachycardia pacing can also terminate some atrial tachyarrhythmias, and these features have been incorporated in some contemporary ICD systems. Cardioversion/defibrillation A shock that is synchronized to be delivered at the peak of the R wave is referred to as cardioversion. Because VT is an organized electrical rhythm, the delivery of an electrical shock during the vulnerable period of repolarization can cause VT to degenerate into ventricular fibrillation (VF). Synchronized cardioversion prevents shock delivery during the vulnerable period. Although ICDs can be programmed to deliver synchronized shocks at a range of energies up to the maximum output of the device (usually 30 to 40 joules), synchronized cardioversion can often terminate VT with relatively low energy (eg, 10 joules or less). (See "Implantable cardioverter-defibrillators: Optimal programming", section on 'Cardioversion'.) An unsynchronized shock (ie, a shock delivered randomly during the cardiac cycle) is referred to as defibrillation. Clinicians can program ICDs to deliver unsynchronized shocks for very rapid ventricular arrhythmias (eg, heart rate greater than 200 beats/min). Because VF is not an organized rhythm, synchronized cardioversion is neither possible nor necessary. Similarly, it can be difficult to synchronize with very rapid VTs, and such rapid rhythms are unlikely to be hemodynamically tolerated. ICDs are typically programmed to deliver synchronized shocks at energies approaching the maximum output of the device (usually 30 to 40 joules) ( waveform 2). (See "Implantable cardioverter-defibrillators: Optimal programming", section on 'Defibrillation'.) Bradycardia pacing All contemporary transvenous ICDs are capable of pacing; however, current S-ICDs can deliver pacing for only 30 seconds post shock delivery and not standard bradycardia pacing. Many patients with an ICD have a conventional indication for cardiac pacing [27]. Separate ICDs and pacemakers can lead to device-to-device interactions, particularly with older models, potentially resulting in inappropriate shocks and underdetection of VT/VF [28-31]. With rare exceptions, patients should have only one transvenous or epicardial device, although the combined use of a leadless pacemaker with an S-ICD is under investigation. Generally, however, when a patient with a pacemaker develops an indication for ICD implantation, the pacemaker is removed and replaced with an ICD. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 12/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate For patients with known atrioventricular (AV) block or sinus node dysfunction, or those who are receiving left ventricular (LV) pacing as part of cardiac resynchronization therapy (CRT), the device will be programmed accordingly. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Pacing modes'.) For those without pre-existing AV block or sinus node dysfunction and who presumably do not require regular ventricular pacing, the ICD will typically be programmed to minimize the amount of pacing provided (eg, pace only for intrinsic rates less than 40 beats/min). (See "Overview of pacemakers in heart failure" and "Modes of cardiac pacing: Nomenclature and selection", section on 'Modes to minimize ventricular pacing'.) In addition to the usual indications for pacing, the ability to provide pacing also protects against bradyarrhythmias that can follow a tachycardia or shock, and also against ventricular arrhythmias that are bradycardia-dependent [32]. Because of the unique physiology following a ventricular tachyarrhythmia and device shock, ICDs allow for distinct post-shock pacing programming (usually at higher outputs). S-ICDs are able to provide this brief pacing function. Cardiac resynchronization therapy CRT, which utilizes biventricular pacing, is an effective treatment for symptomatic heart failure in some patients with LV dyssynchrony. CRT is currently recommended in patients with advanced heart failure (usually NYHA class III or IV), severe systolic dysfunction (LV ejection fraction 35 percent), and intraventricular conduction delay (QRS >120 milliseconds). The evidence of benefit is greatest in patients with left bundle branch block and a QRS duration >150 milliseconds. Pacing of the LV is most frequently achieved by transvenous insertion of an electrode into a cardiac vein via the coronary sinus. Surgical placement of an epicardial lead is also an option in patients following failed efforts at transvenous lead placement, or in patients undergoing cardiac surgery for another reason. Conduction system pacing is another means of synchronizing ventricular stimulation; its impact, compared with traditional CRT with an coronary sinus lead, is being actively investigated. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in heart failure: System implantation and programming" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT'.) Improvement in heart failure can reduce the frequency of ventricular arrhythmias, raising the possibility that biventricular pacing may have an adjunctive role with an ICD by reducing the need for ICD therapy. Although an initial series of 32 patients found such an effect [33], this benefit was not confirmed in the much larger MIRACLE ICD trial of 369 patients [34]. Although the addition of biventricular pacing to ICD therapy was associated with significant improvements https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 13/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate in symptoms and quality of life, there was no reduction in the number of appropriate or inappropriate shocks. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT'.) Perioperative ICD functioning During surgical procedures, the function of ICDs may be affected by electromagnetic interference (EMI), most commonly due to use of an electrosurgery unit (ESU). ICDs with integrated bipolar sensing configuration may be more susceptible to EMI than those with true bipolar sensing. Very rarely, direct damage from cautery to the ICD may alter its ability to deliver pacing or shocks or reset the ICD to an alternate or backup mode. The much more common concern is that the device might misinterpret the cautery as tachyarrhythmia, leading to withholding of bradycardia pacing and perhaps inappropriate ICD shocks. A full discussion regarding the perioperative management of patients with an ICD, including optimal monitoring and cardiac implantable electronic device programming, is presented separately. (See "Perioperative management of patients with a pacemaker or implantable cardioverter-defibrillator".) NONVASCULAR CARDIOVERTER-DEFIBRILLATOR Transvenous ICDs have a number of short- and long-term complications that may potentially be avoided with nonvascular systems. (See "Cardiac implantable electronic devices: Periprocedural complications", section on 'Transvenous lead systems' and "Cardiac implantable electronic devices: Long-term complications".) Wearable cardioverter-defibrillator Some patients who are at risk for sudden cardiac death do not meet established criteria for implantation of an ICD or may require only short-term protection (such as patients awaiting subsequent ICD insertion or cardiac transplantation). In

atrial tachyarrhythmias, and these features have been incorporated in some contemporary ICD systems. Cardioversion/defibrillation A shock that is synchronized to be delivered at the peak of the R wave is referred to as cardioversion. Because VT is an organized electrical rhythm, the delivery of an electrical shock during the vulnerable period of repolarization can cause VT to degenerate into ventricular fibrillation (VF). Synchronized cardioversion prevents shock delivery during the vulnerable period. Although ICDs can be programmed to deliver synchronized shocks at a range of energies up to the maximum output of the device (usually 30 to 40 joules), synchronized cardioversion can often terminate VT with relatively low energy (eg, 10 joules or less). (See "Implantable cardioverter-defibrillators: Optimal programming", section on 'Cardioversion'.) An unsynchronized shock (ie, a shock delivered randomly during the cardiac cycle) is referred to as defibrillation. Clinicians can program ICDs to deliver unsynchronized shocks for very rapid ventricular arrhythmias (eg, heart rate greater than 200 beats/min). Because VF is not an organized rhythm, synchronized cardioversion is neither possible nor necessary. Similarly, it can be difficult to synchronize with very rapid VTs, and such rapid rhythms are unlikely to be hemodynamically tolerated. ICDs are typically programmed to deliver synchronized shocks at energies approaching the maximum output of the device (usually 30 to 40 joules) ( waveform 2). (See "Implantable cardioverter-defibrillators: Optimal programming", section on 'Defibrillation'.) Bradycardia pacing All contemporary transvenous ICDs are capable of pacing; however, current S-ICDs can deliver pacing for only 30 seconds post shock delivery and not standard bradycardia pacing. Many patients with an ICD have a conventional indication for cardiac pacing [27]. Separate ICDs and pacemakers can lead to device-to-device interactions, particularly with older models, potentially resulting in inappropriate shocks and underdetection of VT/VF [28-31]. With rare exceptions, patients should have only one transvenous or epicardial device, although the combined use of a leadless pacemaker with an S-ICD is under investigation. Generally, however, when a patient with a pacemaker develops an indication for ICD implantation, the pacemaker is removed and replaced with an ICD. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 12/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate For patients with known atrioventricular (AV) block or sinus node dysfunction, or those who are receiving left ventricular (LV) pacing as part of cardiac resynchronization therapy (CRT), the device will be programmed accordingly. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Pacing modes'.) For those without pre-existing AV block or sinus node dysfunction and who presumably do not require regular ventricular pacing, the ICD will typically be programmed to minimize the amount of pacing provided (eg, pace only for intrinsic rates less than 40 beats/min). (See "Overview of pacemakers in heart failure" and "Modes of cardiac pacing: Nomenclature and selection", section on 'Modes to minimize ventricular pacing'.) In addition to the usual indications for pacing, the ability to provide pacing also protects against bradyarrhythmias that can follow a tachycardia or shock, and also against ventricular arrhythmias that are bradycardia-dependent [32]. Because of the unique physiology following a ventricular tachyarrhythmia and device shock, ICDs allow for distinct post-shock pacing programming (usually at higher outputs). S-ICDs are able to provide this brief pacing function. Cardiac resynchronization therapy CRT, which utilizes biventricular pacing, is an effective treatment for symptomatic heart failure in some patients with LV dyssynchrony. CRT is currently recommended in patients with advanced heart failure (usually NYHA class III or IV), severe systolic dysfunction (LV ejection fraction 35 percent), and intraventricular conduction delay (QRS >120 milliseconds). The evidence of benefit is greatest in patients with left bundle branch block and a QRS duration >150 milliseconds. Pacing of the LV is most frequently achieved by transvenous insertion of an electrode into a cardiac vein via the coronary sinus. Surgical placement of an epicardial lead is also an option in patients following failed efforts at transvenous lead placement, or in patients undergoing cardiac surgery for another reason. Conduction system pacing is another means of synchronizing ventricular stimulation; its impact, compared with traditional CRT with an coronary sinus lead, is being actively investigated. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in heart failure: System implantation and programming" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT'.) Improvement in heart failure can reduce the frequency of ventricular arrhythmias, raising the possibility that biventricular pacing may have an adjunctive role with an ICD by reducing the need for ICD therapy. Although an initial series of 32 patients found such an effect [33], this benefit was not confirmed in the much larger MIRACLE ICD trial of 369 patients [34]. Although the addition of biventricular pacing to ICD therapy was associated with significant improvements https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 13/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate in symptoms and quality of life, there was no reduction in the number of appropriate or inappropriate shocks. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT'.) Perioperative ICD functioning During surgical procedures, the function of ICDs may be affected by electromagnetic interference (EMI), most commonly due to use of an electrosurgery unit (ESU). ICDs with integrated bipolar sensing configuration may be more susceptible to EMI than those with true bipolar sensing. Very rarely, direct damage from cautery to the ICD may alter its ability to deliver pacing or shocks or reset the ICD to an alternate or backup mode. The much more common concern is that the device might misinterpret the cautery as tachyarrhythmia, leading to withholding of bradycardia pacing and perhaps inappropriate ICD shocks. A full discussion regarding the perioperative management of patients with an ICD, including optimal monitoring and cardiac implantable electronic device programming, is presented separately. (See "Perioperative management of patients with a pacemaker or implantable cardioverter-defibrillator".) NONVASCULAR CARDIOVERTER-DEFIBRILLATOR Transvenous ICDs have a number of short- and long-term complications that may potentially be avoided with nonvascular systems. (See "Cardiac implantable electronic devices: Periprocedural complications", section on 'Transvenous lead systems' and "Cardiac implantable electronic devices: Long-term complications".) Wearable cardioverter-defibrillator Some patients who are at risk for sudden cardiac death do not meet established criteria for implantation of an ICD or may require only short-term protection (such as patients awaiting subsequent ICD insertion or cardiac transplantation). In such settings, a wearable cardioverter-defibrillator (WCD) may be preferable to either ICD insertion or bystander resuscitation. The indications for use, efficacy, and limitations of the WCD are discussed separately. (See "Wearable cardioverter-defibrillator".) Subcutaneous ICD Some patients who are at risk for sudden cardiac death and require an ICD will have compelling reasons for avoiding the indwelling transvenous leads associated with a standard ICD (eg, other indwelling leads or catheters, high risk for systemic infection, relatively young age at implant with numerous device implants anticipated over a lifetime, high risk for lead fracture, etc). An entirely subcutaneous ICD (S-ICD) can provide an effective alternative means of defibrillation. The S-ICD is discussed separately. (See "Subcutaneous implantable cardioverter defibrillators".) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 14/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Extravascular ICD The extravascular ICD is not yet approved for use in the United States but if found to be safe and efficacious may provide benefits of antitachycardia pacing that are lacking in S-ICDs. The extravascular ICD has a single lead implanted substernally, and in addition to defibrillation it can deliver pause-prevention and antitachycardia pacing. A preliminary single- arm study in 316 selected patients with indications for an ICD suggests the extravascular ICD can be successfully implanted (in 94.6 percent) and can detect and terminate ventricular arrythmia (98.7 percent) at the time of implantation; there was a moderate but comparable rate of major complications up to six months post-implantation (7.3 percent) with lead dislodgement and wound infection necessitating system removal being the most common [35]. SUMMARY AND RECOMMENDATIONS Indications Because of its high success rate in terminating ventricular tachycardia (VT) and ventricular fibrillation (VF) rapidly, along with the results of multiple clinical trials showing improvement in survival, implantable cardioverter-defibrillator (ICD) implantation is generally considered the first-line treatment option for the secondary prevention of sudden cardiac death (SCD) and for primary prevention in certain populations at high risk of SCD due to VT/VF. However, there are some situations in which ICD therapy is not recommended, including but not limited to patients with VT/VF from a completely reversible disorder and patients without a reasonable expectation of survival with an acceptable functional status for at least one year. (See 'Introduction' above and 'Indications' above and 'ICD not recommended' above.) Components of the ICD The ICD system is comprised of pacing/sensing electrodes, defibrillation electrodes, and a pulse generator ( picture 1). Contemporary ICDs use leads with pace-sense electrodes and shock coils on a single ventricular lead. Most current ICD systems utilize one, two, or three transvenous leads placed via the axillary, subclavian, or cephalic vein, with attachment to a pulse generator in the subcutaneous tissue in the infraclavicular anterior chest wall. Subcutaneous ICD (S-ICD) systems are an effective alternative that avoid indwelling transvenous lead(s) but lack some of the standard capabilities of a traditional transvenous ICD. (See 'Elements of the ICD' above.) Defibrillation threshold (DFT) While DFT used to be very common, in contemporary EP practice, it is infrequently performed due to the results of randomized trials and the performance of contemporary ICD systems. However, DFT testing is generally performed at the time of device implantation in patients receiving an S-ICD and is reasonable in patients undergoing a right pectoral ICD implantation or ICD pulse generator replacement or those with multiple high-risk features for an elevated DFT (ie, patient with high body mass index https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 15/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate on amiodarone with a nonischemic cardiomyopathy). However, DFT testing is commonly omitted in patients undergoing a left pectoral transvenous ICD implantation with a right ventricular apical lead that is functioning appropriately. (See 'Defibrillation threshold testing' above.) ICD functions Contemporary ICDs have extensive storage and monitoring capacities, the ability to deliver antitachycardia pacing (ie, overdrive pacing) to terminate VT, the ability to deliver synchronized and unsynchronized shocks for VT/VF, and the option of bradycardia pacing. (See 'ICD functions' above.) Nonvascular cardioverter defibrillators Transvenous ICDs have a number of short- and long-term complications that may potentially be avoided with nonvascular systems (including wearable cardioverter-defibrillators, subcutaneous, and extravascular ICDs). (See 'Nonvascular cardioverter-defibrillator' above.) The optimal approach to programming of modern ICDs is discussed in detail separately. (See "Implantable cardioverter-defibrillators: Optimal programming".) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Russo AM, Stainback RF, Bailey SR, et al. ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR 2013 appropriate use criteria for implantable cardioverter-defibrillators and cardiac resynchronization therapy: a report of the American College of Cardiology Foundation appropriate use criteria task force, Heart Rhythm Society, American Heart Association, American Society of Echocardiography, Heart Failure Society of America, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol 2013; 61:1318. 2. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 16/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 3. DiMarco JP. Implantable cardioverter-defibrillators. N Engl J Med 2003; 349:1836. 4. Fenelon G, Huvelle E, Brugada P. Initial clinical experience with a new small sized third- generation implantable cardioverter defibrillator: results of a multicenter study. European Ventak Mini Investigator Group. Pacing Clin Electrophysiol 1997; 20:2967. 5. Thijssen J, Borleffs CJ, van Rees JB, et al. Implantable cardioverter-defibrillator longevity under clinical circumstances: an analysis according to device type, generation, and manufacturer. Heart Rhythm 2012; 9:513. 6. Boriani G, Merino J, Wright DJ, et al. Battery longevity of implantable cardioverter- defibrillators and cardiac resynchronization therapy defibrillators: technical, clinical and economic aspects. An expert review paper from EHRA. Europace 2018; 20:1882. 7. Zanon F, Martignani C, Ammendola E, et al. Device Longevity in a Contemporary Cohort of ICD/CRT-D Patients Undergoing Device Replacement. J Cardiovasc Electrophysiol 2016; 27:840. 8. Flaker GC, Tummala R, Wilson J. Comparison of right- and left-sided pectoral implantation parameters with the Jewel active can cardiodefibrillator. The World Wide Jewel Investigators. Pacing Clin Electrophysiol 1998; 21:447. 9. Gold MR, Shih HT, Herre J, et al. Comparison of defibrillation efficacy and survival associated with right versus left pectoral placement for implantable defibrillators. Am J Cardiol 2007; 100:243. 10. Israel CW, Gr nefeld G, Iscolo N, et al. Discrimination between ventricular and supraventricular tachycardia by dual chamber cardioverter defibrillators: importance of the atrial sensing function. Pacing Clin Electrophysiol 2001; 24:183. 11. Wilkoff BL, Fauchier L, Stiles MK, et al. 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. Heart Rhythm 2016; 13:e50. 12. Strickberger SA, Klein GJ. Is defibrillation testing required for defibrillator implantation? J Am Coll Cardiol 2004; 44:88. 13. Day JD, Doshi RN, Belott P, et al. Inductionless or limited shock testing is possible in most patients with implantable cardioverter- defibrillators/cardiac resynchronization therapy defibrillators: results of the multicenter ASSURE Study (Arrhythmia Single Shock Defibrillation Threshold Testing Versus Upper Limit of Vulnerability: Risk Reduction Evaluation With Implantable Cardioverter-Defibrillator Implantations). Circulation 2007; 115:2382. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 17/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate 14. Healey JS, Gula LJ, Birnie DH, et al. A randomized-controlled pilot study comparing ICD implantation with and without intraoperative defibrillation testing in patients with heart failure and severe left ventricular dysfunction: a substudy of the RAFT trial. J Cardiovasc Electrophysiol 2012; 23:1313. 15. Guenther M, Rauwolf T, Br ggemann B, et al. Pre-hospital discharge testing after implantable cardioverter defibrillator implantation: a measure of safety or out of date? A retrospective analysis of 975 patients. Europace 2012; 14:217. 16. Brignole M, Occhetta E, Bongiorni MG, et al. Clinical evaluation of defibrillation testing in an unselected population of 2,120 consecutive patients undergoing first implantable cardioverter-defibrillator implant. J Am Coll Cardiol 2012; 60:981. 17. Arnson Y, Suleiman M, Glikson M, et al. Role of defibrillation threshold testing during implantable cardioverter-defibrillator placement: data from the Israeli ICD Registry. Heart Rhythm 2014; 11:814. 18. Phan K, Kabunga P, Kilborn MJ, Sy RW. Defibrillator Threshold Testing at Generator Replacement: Is it Time to Abandon the Practice? Pacing Clin Electrophysiol 2015; 38:777. 19. Kopp DE, Blakeman BP, Kall JG, et al. Predictors of defibrillation energy requirements with nonepicardial lead systems. Pacing Clin Electrophysiol 1995; 18:253. 20. Larsen JM, Heath FP, Riahi S, et al. Single and dual coil shock efficacy and predictors of shock failure in patients with modern implantable cardioverter defibrillators-a single-center paired randomized study. J Interv Card Electrophysiol 2019; 54:65. 21. Sunderland N, Kaura A, Murgatroyd F, et al. Outcomes with single-coil versus dual-coil implantable cardioverter defibrillators: a meta-analysis. Europace 2018; 20:e21. 22. Healey JS, Hohnloser SH, Glikson M, et al. Cardioverter defibrillator implantation without induction of ventricular fibrillation: a single-blind, non-inferiority, randomised controlled trial (SIMPLE). Lancet 2015; 385:785. 23. B nsch D, Bonnemeier H, Brandt J, et al. Intra-operative defibrillation testing and clinical shock efficacy in patients with implantable cardioverter-defibrillators: the NORDIC ICD randomized clinical trial. Eur Heart J 2015; 36:2500. 24. Phan K, Ha H, Kabunga P, et al. Systematic Review of Defibrillation Threshold Testing at De Novo Implantation. Circ Arrhythm Electrophysiol 2016; 9:e003357. 25. Forleo GB, Gasperetti A, Breitenstein A, et al. Subcutaneous implantable cardioverter- defibrillator and defibrillation testing: A propensity-matched pilot study. Heart Rhythm 2021; 18:2072. https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 18/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate 26. Bianchi V, Bisignani G, Migliore F, et al. Safety of Omitting Defibrillation Efficacy Testing With Subcutaneous Defibrillators: A Propensity-Matched Case-Control Study. Circ Arrhythm Electrophysiol 2021; 14:e010381. 27. Best PJ, Hayes DL, Stanton MS. The potential usage of dual chamber pacing in patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol 1999; 22:79. 28. Calkins H, Brinker J, Veltri EP, et al. Clinical interactions between pacemakers and automatic implantable cardioverter-defibrillators. J Am Coll Cardiol 1990; 16:666. 29. Ellenbogen KA, Edel T, Moore S, et al. A prospective randomized-controlled trial of ventricular fibrillation detection time in a DDDR ventricular defibrillator. Ventak AV II DR Study Investigators. Pacing Clin Electrophysiol 2000; 23:1268. 30. Glikson M, Trusty JM, Grice SK, et al. A stepwise testing protocol for modern implantable cardioverter-defibrillator systems to prevent pacemaker-implantable cardioverter- defibrillator interactions. Am J Cardiol 1999; 83:360. 31. Mattke S, Markewitz A, M ller D, et al. The combined transvenous implantation of cardioverter defibrillators and permanent pacemakers. Pacing Clin Electrophysiol 1997; 20:2775. 32. Fisher JD, Teichman SL, Ferrick A, et al. Antiarrhythmic effects of VVI pacing at physiologic rates: a crossover controlled evaluation. Pacing Clin Electrophysiol 1987; 10:822. 33. Higgins SL, Yong P, Sheck D, et al. Biventricular pacing diminishes the need for implantable cardioverter defibrillator therapy. Ventak CHF Investigators. J Am Coll Cardiol 2000; 36:824. 34. Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA 2003; 289:2685. 35. Friedman P, Murgatroyd F, Boersma LVA, et al. Efficacy and Safety of an Extravascular Implantable Cardioverter-Defibrillator. N Engl J Med 2022; 387:1292. Topic 921 Version 53.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 19/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate GRAPHICS NYHA and other classifications of cardiovascular disability Canadian NYHA functional [1] Cardiovascular Specific activity Class [3] classification Society functional scale [2] classification I Patients with cardiac Ordinary physical Patients can perform to disease but without activity, such as completion any activity requiring 7 metabolic equivalents (ie, can resulting limitations of physical activity. walking and climbing stairs, does not cause Ordinary physical angina. Angina with carry 24 lb up 8 steps; activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. strenuous or rapid prolonged exertion at work or recreation. do outdoor work [shovel snow, spade soil]; do recreational activities [skiing, basketball, squash, handball, jog/walk 5 mph]). II Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Slight limitation of ordinary activity. Walking or climbing stairs rapidly, walking uphill, walking or stair- Patients can perform to completion any activity requiring 5 metabolic equivalents (eg, have sexual intercourse Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. climbing after meals, in cold, in wind, or when under emotional stress, or only during the few hours after without stopping, garden, rake, weed, roller skate, dance foxtrot, walk at 4 mph on level ground) but awakening. Walking more than 2 blocks on cannot and do not perform to completion activities requiring 7 metabolic equivalents. the level and climbing more than 1 flight of ordinary stairs at a normal pace and in normal conditions. III Patients with cardiac Marked limitation of Patients can perform to disease resulting in marked limitation of ordinary physical activity. Walking 1 to 2 completion any activity requiring 2 metabolic equivalents (eg, shower physical activity. They blocks on the level and are comfortable at rest. Less-than-ordinary climbing 1 flight in normal conditions. without stopping, strip and make bed, clean https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 20/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate physical activity causes windows, walk 2.5 fatigue, palpitation, mph, bowl, play golf, dyspnea, or anginal pain. dress without stopping) but cannot and do not perform to completion any activities requiring >5 metabolic equivalents. IV Patients with cardiac disease resulting in Inability to carry on any physical activity Patients cannot or do not perform to inability to carry on any physical activity without discomfort. Anginal syndrome may completion activities requiring >2 metabolic without discomfort. Symptoms of cardiac be present at rest. equivalents. Cannot carry out activities insufficiency or of the listed above (specific anginal syndrome may be present even at rest. If any physical activity activity scale III). is undertaken, discomfort is increased. NYHA: New York Heart Association. References: 1. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the th Heart and Great Vessels, 9 ed, Little, Brown & Co, Boston 1994. p.253. 2. Campeau L. Grading of angina pectoris. Circulation 1976 54:522. 3. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: Advantages of a new speci c activity scale. Circulation 1981; 64:1227. Graphic 52683 Version 19.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 21/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Examples of transvenous ICD pulse generators Examples of implantable cardioverter-defibrillator pulse generators commonly used in practice in 2015. ICD: implantable cardioverter-defibrillator. Graphic 104721 Version 2.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 22/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Transvenous ICD shock lead configurations With the active can electrode, current flows between the coil(s) right ventricular (RV) electrode and the housing (active can) of the pulse generator. For transvenous leads with two coils, current also flows between two transvenous coils (RV and superior vena cava). ICD: implantable cardioverter-defibrillator. Graphic 113994 Version 1.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 23/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Subcutaneous ICD pulse generator Example of subcutaneous implantable cardioverter-defibrillator pulse generator commonly used in practice in 2015. ICD: implantable cardioverter-defibrillator. Graphic 104722 Version 3.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 24/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Subcutaneous implantable cardioverter-defibrillator Modi ed from: 1. Al-Khatib SM, Friedman P, Ellenbogen KA. De brillators: Selecting the Right Device for the Right Patient. Circulation 2016; 134:1390. 2. Mayo Clinic. Subcutaneous implantable cardioverter-de brillator (S-ICD). https://www.mayoclinic.org/diseases-conditions/ventricular-tachycardia/multimedia/img- 20303862 (Accessed on March 31, 2021). Graphic 130973 Version 1.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 25/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Lateral view of a patient with a subcutaneous implantable cardioverter-defibrillator (S-ICD) Lateral view of a patient with an S-ICD. S-ICD: subcutaneous implantable cardioverter-defibrillator. Reproduced with permission from: Magnusson P, Pergolizzi JV, LeQuang JA. The Subcutaneous Implantable Cardioverter-De brillator. In: Cardiac Pacing and Monitoring, Min M (Ed), IntechOpen, 2019. Copyright Peter Magnusson, MD, PhD. Graphic 131058 Version 2.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 26/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Different ICD lead systems Chest radiographs of two different implantable cardioverter-defibrillator (ICD) systems. Left panel shows an ICD epicardial lead system. Epicardial sensing electrodes are located on the left ventricle (arrow) and the three epicardial patch electrodes are located on the right atrium, and the inferior and lateral walls of the left ventricle. Right panel shows a dual coil transvenous ICD lead system with a pulse generator in the pectoral region. Courtesy of Douglas Kopp, MD. Graphic 56923 Version 3.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 27/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Posteroanterior (PA) and lateral chest radiographs of a subcutaneous implantable cardioverter-defibrillator (S-ICD) Posteroanterior (PA) and lateral chest radiographs of a subcutaneous implantable cardioverter-defibrillator (S-ICD) with the defibrillation lead visible adjacent to the sternum and the pulse generator in the axilla. Graphic 97372 Version 2.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 28/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Implantable cardioverter-defibrillator (ICD) electrogram anti-tachycardia pacin monomorphic ventricular tachycardia (VT) https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 29/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Stored intracardiac electrogram from an ICD showing the development of monomorphic ventricular tachycar which is successfully terminated by a burst of anti-tachycardia pacing delivered by the ICD. This tachycardia i monomorphic VT, but is labeled VF by the device because it was detected in the VF zone due to the rapid rate RA: right atrial; RV: right ventricular; VT: ventricular tachycardia; VF: ventricular fibrillation; ATP: anti-tachycar pacing; AS: atrium sensed; VS: ventricle sensed. Graphic 114829 Version 2.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 30/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Implantable cardioverter-defibrillator (ICD) electrogram shock for ventricular f (VF) Stored intracardiac electrogram from an ICD showing the development of ventricular fibrillation, which is suc terminated by a single shock from the ICD. RA: right atrium; RV: right ventricle; AS: atrium sensed; AP: atrium paced; A pacing: atrial pacing; VF: ventricu fibrillation; PVC: premature ventricular contraction; VPB: ventricular premature beats. Graphic 114831 Version 1.0 https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 31/32 7/6/23, 10:53 AM Implantable cardioverter-defibrillators: Overview of indications, components, and functions - UpToDate Contributor Disclosures Jonathan Piccini, MD, MHS, FACC, FAHA, FHRS Grant/Research/Clinical Trial Support: Abbott [Atrial fibrillation, catheter ablation]; AHA [Atrial fibrillation, cardiovascular disease]; Bayer [Atrial fibrillation]; Boston Scientific [Cardiac mapping, pacemaker/ICD, atrial fibrillation care]; iRhythm [Atrial fibrillation]; NIA [Atrial fibrillation]; Philips [Lead management]. Consultant/Advisory Boards: Abbott [Atrial fibrillation, catheter ablation]; Abbvie [Atrial fibrillation]; Bayer [Atrial fibrillation]; Boston Scientific [Cardiac mapping, atrial fibrillation, pacemaker/ICD]; ElectroPhysiology Frontiers [Atrial fibrillation, catheter ablation]; Element Science [DSMB]; Medtronic [Atrial fibrillation, pacemaker/ICDs]; Milestone [Supraventricular tachycardia]; Pacira [Atrial fibrillation]; Philips [Lead extraction]; ReCor [Cardiac arrhythmias]; Sanofi [Atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Cara Pellegrini, MD Consultant/Advisory Boards: Abbott [Atrial fibrillation and supraventricular tachycardia]; Biosense Webster [Ablation]; Cook Medical [Lead extraction tools and techniques]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/implantable-cardioverter-defibrillators-overview-of-indications-components-and-functions/print 32/32

7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis : Adolf W Karchmer, MD, Vivian H Chu, MD, MHS, Jay A Montgomery, MD : Stephen B Calderwood, MD : Elinor L Baron, MD, DTMH, Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 07, 2023. INTRODUCTION Traditionally, cardiac implantable electronic devices (CIEDs), including pacemakers (PPMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices with or without defibrillation capacity (CRT-D or CRT-P, respectively), have included pulse generators to provide the electrical stimulus and either transvenous or epicardial leads to deliver the stimulus to the heart. Additional novel devices have been developed which operate effectively without the requirement for a transvenous or epicardial lead system; leadless pacemakers are percutaneously placed directly inside the heart, while subcutaneous ICDs and implantable loop recorders function effectively in an extrathoracic pocket without direct attachment to the heart. The clinical presentation and management of CIED infections vary according to the location and extent of infection and the clinical characteristics of the patient [1]. This topic focuses on the epidemiology, microbiology, clinical manifestations, and diagnosis of CIED infections involving PPMs, ICDs, and CRT devices. CIED infections are generally considered in two categories: pocket infection and systemic infection. These categories are not mutually exclusive, and the two forms may coexist. An alternative approach to classification of CIED infection is by mode of infection (eg, primary or https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-and 1/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up secondary). Primary infection occurs when the device and/or pocket itself is the source of infection; this is the most common form of CIED infection and occurs as a result of contamination at the time of CIED implantation. Secondary infection occurs when the leads (and sometimes the device and the pocket) are seeded due to bacteremia from a remote source. Issues related to treatment and prevention of CIED infections, as well as noninfectious complications of PPMs and ICDs, are discussed separately. (See "Infections involving cardiac implantable electronic devices: Treatment and prevention".) (See "Cardiac implantable electronic devices: Long-term complications" and "Cardiac implantable electronic devices: Periprocedural complications".) EPIDEMIOLOGY Incidence The true incidence of CIED infection is difficult to determine due to the lack of a comprehensive registry or mandatory reporting. A range of values has been reported in a number of observational series [2-8]. In one review including 21 studies of CIED recipients with variable follow-up, the rate of infections ranged from 0.8 to 5.7 percent [9]. Data also suggest that increasing use of CIEDs has been associated with an increased incidence of device infection [7,10]. The following observations illustrate the range of findings: The incidence of infection was studied among 97,750 patients who underwent a total of 128,045 implantation or replacement procedures (100,374 pacemaker [PPM], 16,718 implantable cardioverter-defibrillator [ICD], 4630 cardiac resynchronization therapy-PPM [CRT-P], and 6323 cardiac resynchronization therapy-defibrillator [CRT-D] procedures) in Denmark between 1982 and 2018. After 566,275 device-years of surveillance, the following infection risks were identified [11]: PPM 1.2 percent lifetime risk ICD 1.9 percent lifetime risk CRT-P 2.2 percent lifetime risk CRT-D 3.4 percent lifetime risk Infection rates were lowest during the initial implantation, with infection rates 1.5 to 3-fold higher during revision or replacement procedures. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-and 2/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Data from the United States National Inpatient Sample from 1993 to 2008 indicate an overall infection incidence of 1.6 percent; rates were stable until 2004, whereupon the incidence was noted to increase significantly [10]. Between 2000 and 2012, the average annual incidence of CIED infection in this database was 2.06 percent per patient-year [12]. Between 2003 and 2017, the annual proportion with CIED-related infectious endocarditis (CIED-IE) increased from 1.7 to 4.8 percent [13]. In a cohort of more than 200,000 patients enrolled in a CIED registry, 1.7 percent (3390 patients) developed an infection within six months post-implantation; the incidence was higher among patients who underwent pulse-generator replacement than among those who underwent initial implantation [14]. Patients admitted for CIED infection experience significant mortality: Among the 27,257 with CIED-IE in the 2003-2017 United States National Inpatient Sample, the overall in-hospital mortality was 9.2 percent; mortality for those with native valve or prosthetic valve endocarditis was 12 percent each. The longitudinal analysis revealed a significant reduction in CIED-IE mortality from 15 to 9.7 percent in 2003 and 2017, respectively [13]. Another study including 416 patients admitted with CIED infection noted mortality rates of 5.5 and 14.6 percent at 30 days and 1 year after admission, respectively [15]. Among more than 3,400 Medicare recipients undergoing initial CIED implantation or replacement who experienced device infection during the following year, 1-year mortality was noted in 17 percent of 2,109 patients treated with device extraction and replacement and 34 percent of 1,355 patients treated with device extraction in the absence of replacement [16]. Risk factors A number of risk factors and comorbid conditions have been associated with CIED infection [3,9,17-21]. The most clearly identified risk factor is recent manipulation of the device (eg, newly implanted device, device revision or generator change). Other risk factors include the number of prior procedures, the lack of antibiotic prophylaxis at the time of implantation, immunocompromised state, renal dysfunction, younger age, and postprocedure hematoma [21,22]. Devices that have been in place for longer periods of time are less likely to become secondarily infected in the setting of bacteremia. Approximately 63 to 77 percent of infections occur within one year, and 23 to 37 percent occur after one year [23]. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-and 3/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up In one systematic review and meta-analysis, three major categories of risk factors were defined [24]: Patient-related risk factors End-stage kidney disease Previous device infection Corticosteroid use Chronic obstructive lung disease Malignancy Diabetes mellitus Heart failure Anticoagulant use Skin disorders Older age with comorbidities Pre-procedure fever Procedure-related risk factors Procedure duration Postoperative hematoma Reintervention for lead dislodgement Operator inexperience Temporary pacing Device replacement/revision Lack of antibiotic prophylaxis Device-related characteristics: Epicardial leads Abdominal pocket Positioning of two or more leads ICD, CRT-P, or CRT-D greater risk than PPM [11,25] MICROBIOLOGY Causative organisms Staphylococcus aureus and coagulase-negative staphylococci (often Staphylococcus epidermidis) cause the majority of generator pocket infections and up to 89 percent of device-related endocarditis (CIED-IE) [5,26-29]. The likelihood of S. aureus infection is https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-and 4/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up high for CIED infections arising within two weeks of implantation [30,31]. Other organisms implicated in CIED infections include streptococci, enterococci, Corynebacterium spp, Cutibacterium (formerly Propionibacterium) acnes, gram-negative bacilli, and Candida spp. In one study including more than 600 CIED infections, only 5 percent were caused by gram- negative bacilli (Pseudomonas aeruginosa and Serratia species being most common). Of these 31 patients, infection was limited to the pocket in 24 cases; and in the 7 patients with bloodstream infection, 6 had concurrent pocket infection [32]. In another study that included 412 patients with infected CIEDs (241 localized pocket infections and 171 endovascular infections without pocket inflammation); staphylococcal infections were the most common ( table 1) [33]. Among 162 episodes of precisely defined pacemaker endocarditis from four studies, coagulase-negative staphylococci caused 61 percent and S. aureus caused 30 percent [2,3,34,35]. Methicillin resistance was common among the staphylococci. Polymicrobial infection occurred in 18 patients, and cultures were negative in 7 patients. In the Spanish Collaboration on Endocarditis that included 3,966 cases of endocarditis, 424 patients had CIED-IE. S. aureus and coagulase negative staphylococci each caused 30 percent of cases; other causes included enterococci (5 percent), streptococci (8 percent), gram negative bacilli (7 percent), Candida species (2 percent). In contrast, the major causes for valvular endocarditis were S. aureus (18 percent), coagulase negative staphylococci (21 percent), enterococci (19 percent), streptococci (22 percent), Candida species (2 percent), and gram negative bacilli (7 percent) [36]. Bacteremia S. aureus bacteremia in patients with a CIED is associated with a relatively high rate of CIED infection, morbidity, and mortality [13,37-39]. It is likely that many of these patients have a primary infection of the CIED, particularly when bacteremia occurs in the initial three months after device manipulation. In addition, a significant number of individuals with S. aureus CIED lead infection also have concurrent valvular infection. Furthermore, secondary bacteremic seeding of the CIED from S. aureus infection occurring at a remote site is common. Given the morbidity and mortality associated with S. aureus bacteremia generally and with CIED infection particularly, it is important that patients with a CIED who develop S. aureus bacteremia are carefully evaluated for CIED infection. (See 'CIED systemic infection' below.) In one study that applied the European Heart Rhythm Association s CIED-IE diagnostic criteria [1] to 110 patients with a CIED and S. aureus bacteremia (inclusive of those with a https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-and 5/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up pocket infections), definite and possible CIED-IE were diagnosed in 52 and 28 percent of cases, respectively [40]. In another study including more than 360 patients with a CIED and S. aureus bacteremia, CIED infection was observed in 51 percent of patients. Among those without evidence of CIED infection who did not undergo empiric CIED removal, 19 percent had recurrent bacteremia. The risk of relapse correlated with the duration of bacteremia (>1 day of bacteremia OR 9.99) [41]. Enterococcus faecalis is a less common cause of CIED infection (compared with S. aureus and S. epidermidis); development of E. faecalis bacteremia in the context of CIED placement should prompt consideration of device infection: In one population-based cohort study including 72 patients with a CIED and monomicrobial E. faecalis bacteremia between 2014 and 2018, 4 underwent device extraction [42]. Of the 68 patients whose device was retained, recurrent of E. faecalis bacteremia occurred in 10 percent of cases. Similarly, a prospective international observational registry of CIED infection including 433 patients noted enterococcal bacteremia in 4.8 percent of cases, most of whom had definite endocarditis [43]. The onset of infection was distant from the most recent device manipulation, suggesting that CIED infection likely arose by hematogenous seeding from a remote focus of infection. Native valve endocarditis can occur independently or concurrently with CIED endocarditis/lead infection. This is of particular concern when patients have endocarditis-predisposing valvular lesions (native or prosthetic valve). In one study, 12 of 45 bacteremic patients with a CIED had only valvular endocarditis; in 6 of the 12 patients, the causative organism was a streptococcus [3]. Thus, in patients with unexplained bacteremia due to streptococcus or enterococcus (eg, organisms that commonly causes endocarditis), evidence of independent valvular infection should be sought. (See 'Endocarditis' below.). CIED lead/valve infection caused by gram-negative organisms is rare [44,45]. Occasionally, gram- negative bacilli cause pocket infection due to direct introduction during device implantation or revision, and such an infection could give rise to bacteremia. However, gram-negative bacteremia from sources other than the CIED pocket rarely seed the device pocket or leads. Thus, in the absence of evidence of pocket infection or CIED-IE, patients with gram-negative bacteremia from a remote site can be managed initially with device retention [44,46]. However, in patients managed with CIED retention, recurrence of bacteremia with the same species after appropriate antimicrobial therapy and in the absence of an alternative source for bacteremia https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-and 6/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up should prompt careful evaluation for CIED infection. (See "Infections involving cardiac implantable electronic devices: Treatment and prevention".) Fungemia Data on fungemia in patients with CIED are sparse. One systematic review of case reports and case series suggests that 90 percent of fungemias were associated with valve or lead involvement (as seen on echocardiography); CIED extraction was associated with increased survival to hospital discharge among cases where the device was removed versus retained (92 versus 54 percent) [47]. In another study including 12 patients with CIED and candidemia, mortality was higher among those who did not undergo CIED removal (88 versus 25 percent) [48]. However, because these patients are often immunosuppressed and chronically ill, the treatment strategy was likely confounded by the severity of illness. FORMS OF INFECTION CIED pocket infection Definition CIED pocket infection refers to infection involving the subcutaneous pocket containing the pulse generator and the subcutaneous segment of the leads, but not the transvenous segment of the leads ( figure 1). Such patients generally have negative blood cultures and no evidence of a lead/valve vegetation on transesophageal echocardiogram (TEE). Extension of CIED pocket infection to involve intravascular lead(s) can occur, leading to systemic infection (eg, concurrent positive blood cultures and/or evidence of a lead/valve vegetation on TEE). (See 'CIED systemic infection' below.) Pathogenesis The most common source of pocket infection is perioperative contamination with skin flora, which can result in acute or delayed-onset infection. This was illustrated in a prospective study including 103 patients undergoing elective pacemaker (PPM) implantation [49]: Swab specimens (obtained from the pulse-generator pocket before and after insertion) yielded bacteria from 48 and 37 percent of specimens, respectively; the organisms were predominantly coagulase-negative staphylococci. Subsequent PPM infection developed in five patients (4.8 percent). Staphylococcus schleiferi (a coagulase-negative species) caused three of these infections at 4, 16, and 29 months after implantation, respectively. Based upon molecular typing, the S. schleiferi isolates recovered at insertion and at the time of the infection appeared identical. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-and 7/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Clinical manifestations Infections involving the generator pocket typically develop soon after CIED implantation or pulse generator change. However, pocket infections can also arise many months after implantation due to a chronic, smoldering infection related to contamination at the time of implantation. Patients with acute or subacute pocket infection may present with pocket discomfort, erythema of the overlying skin (eg, cellulitis), swelling, and occasionally drainage through a dehisced incision. Fever and systemic symptoms are often absent when infection is limited to the generator pocket [50]. However, patients with evident pocket infection who manifest a systemic inflammatory response (tachycardia, tachypnea, fever or hypothermia, and leukocytosis or leukopenia) and/or hypotension are at risk for concurrent blood stream infection [51] (see 'CIED systemic infection' below). In some patients, part of the device or lead erodes through the overlying skin ( picture 1); this can occur in acute or delayed infection. Patients with delayed pocket infection may present with the above findings or may present with minimal local inflammatory changes; in some cases, the sole clinical manifestation may be the erosion itself. In the setting of erosion of the pulse generator or lead due to physical factors, site contamination is unavoidable; erosion of any part of the CIED unequivocally indicates that the device is contaminated and infected. Therefore, such cases should be managed as a pocket infection (even in the absence of overt evidence for infection or inflammation). Diagnosis The diagnosis of CIED pocket infection should be suspected when there is inflammation overlying the implanted device (including erythema, swelling, warmth, pain, or tenderness), purulent drainage from the pocket, deformation of the pocket, adherence or threatened erosion ( picture 1), or erosion of the device or lead through the skin. The absence of systemic symptoms does not exclude the possibility of a CIED pocket infection. The diagnosis of isolated CIED pocket infection is established by the presence of one or more of these manifestations in the setting of negative blood cultures and negative TEE [52]. The approach to evaluation of suspected pocket infection is summarized in the algorithm ( algorithm 1). In the absence of clinical signs of local inflammation, percutaneous aspiration of a pocket is not warranted; the diagnostic yield is generally low and there is a potential risk of introducing microorganisms. In the setting of prior antibiotic therapy, pocket infection may be obvious clinically, but pocket and blood cultures may be falsely negative. In the absence of prior antimicrobial therapy, negative Gram stains or culture of drainage may indicate infection due to an unusual organism (mycobacteria, fungi, etc); in such cases, detection might require assessment using special histopathologic and culture techniques. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-and 8/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up In patients with overt pocket infection, draining purulent fluid should be cultured and blood cultures should be drawn (at least two or three sets), particularly if the patient manifests a systemic inflammatory response syndrome or is hypotensive. Thereafter, empiric antimicrobial therapy can be initiated. At the time of device removal, the pocket swabs and tissue should be cultured. Sonication of the device with culture of the sonicate fluid has been found to be more sensitive than swab cultures of the device or pocket tissue. In addition, polymerase chain reaction (PCR) testing of the sonicate fluid further enhances sensitivity. While not widely available nor routine, sonicate fluid PCR may be diagnostic for patients who have received recent antibiotics or for circumstances in which difficult to-culture organisms are anticipated [53,54]. In addition, chest radiography should be obtained to evaluate for evidence of septic pulmonary emboli, and a TEE should be obtained to evaluate for lead/valve vegetations. These studies are particularly important in evaluating patients in whom prior antibiotic therapy may have led to false-negative blood cultures. In settings with suspected but less obvious pocket infection, fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) or radiolabeled autologous white blood cell single-photon emission computed tomogram with CT (SPECT/CT) scanning may be helpful to define pocket infection. (See 'Diagnosis' below.) Of note, TEE imaging of chronic leads may demonstrate fibrous stranding arising from the lead [55,56]. In the absence of positive blood cultures, such findings should not be interpreted as infected vegetations. The approach to empiric antibiotic therapy is discussed separately. (See "Infections involving cardiac implantable electronic devices: Treatment and prevention", section on 'Empiric therapy'.) Differential diagnosis Pocket infection must be distinguished from: Early superficial site infection Early superficial site infection, such as a superficial stitch abscess, occurs within the initial 30 days after implantation and is localized to the superficial aspect of the wound (ie, does not extend to involve the pocket). In the absence of a stitch abscess, superficial infection may be difficult to distinguish from early pocket infection or early postimplantation inflammation (see below). Early postimplantation inflammation Early postimplantation inflammation, a very rare event, occurs within the initial 30 days after implantation; it is associated with erythema of the skin abutting the incision but no purulent exudate, dehiscence, fluctuance, or systemic signs of infection. This entity does not represent infection; it may occur due to local https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-and 9/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up bleeding, reaction to a wound dressing, or skin preparation. The manifestations generally resolve within two weeks. Pocket hematoma A CIED pocket hematoma consists of a blood collection within the pocket or, occasionally, collecting in the subpectoral space. Because the bleeding is due to the procedure, it usually occurs within the first 24 hours after implantation. A hematoma within either space typically leads to swelling and minimal discoloration of the skin, more suggestive of bruising than inflammation. Late occurrence of CIED pocket swelling (especially when remote from any procedure) should raise suspicion for pocket infection. The difficulty in distinguishing the above entities from one another and from pocket infection may prompt evaluation using 18F-FDG-PET/CT, SPECT/CT or even empiric antimicrobial therapy (including coverage for S. aureus). On the assumption that the pocket is not infected in this situation, the device may be retained. If this strategy is pursued, very careful follow-up is essential to detect failure to respond or recurrence, which would suggest pocket and device infection. CIED systemic infection Definition CIED systemic infection refers to infection involving the transvenous portion of the lead (with involvement of the contiguous endocardium or tricuspid valve) or an epicardial electrode (with involvement of the epicardium). CIED systemic infection can occur with or without involvement of the generator pocket. Patients with systemic infection generally have positive blood cultures and/or vegetation on TEE. Synonyms for CIED systemic infection include lead infection and device-related endocarditis (CIED-IE). Pathogenesis Infection of the intravascular component of a CIED system (manifesting as an endocarditis-like vegetation) occurs primarily on the intracardiac portion of the lead along the right atrium, the tricuspid valve, or the right ventricular contact point. Occasionally, vegetations may be seen on the lead as it traverses from the superior vena cava into the right atrium. These infections may track intravascularly along the device lead from the subcutaneous pocket and device component or arise by bacteremic seeding from a remote site [2,34,35,46]. Seeding of the CIED from bacteremia primarily involves the intracardiac lead and is caused most commonly by S. aureus. (See 'Bacteremia' above.) The host response to placement of the intravenous lead can provide protection from late bacteremic seeding. Approximately one week after placement, the portion of the lead in contact with the vein intima becomes partially incorporated into the vein wall by connective tissue and https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 10/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up an endothelial covering. Fibrous tissue proliferation at some sites in the vena cava and right atrium results in a fibrotic attachment of the pacing lead to these points [57,58]. The endothelial covering may protect the lead against the adherence of bacteria and subsequent infection during episodes of bacteremia. While protective, these changes make subsequent extraction of pacing leads difficult. (See "Cardiac implantable electronic device lead removal".) Epicardial electrodes may be infected at the cardiac attachment point as a result of intraoperative contamination or, less likely, by spread of infection along pacing electrodes from an infected pulse-generator pocket. Clinical presentations Endocarditis (manifested as a lead vegetation and/or adjacent valve vegetation) is an important feature of CIED systemic infection [34]. The presence of vegetation(s) attached to the device lead (and/or contiguous endocardium) is termed device-related endocarditis (CIED-IE); these infections primarily involve the intracardiac portion of the lead and essentially represent a right-sided endocarditis. (See 'Endocarditis' below and 'Lead vegetation' below and 'Valve vegetation' below.) Patients with infection of epicardial leads, particularly when those leads have been implanted at cardiac surgery, may present with concurrent mediastinitis or pericarditis. (See 'Other presentations' below.) Endocarditis Up to half of patients with CIED-IE also have echocardiographic or intraoperative evidence of a vegetation on a valve (usually the tricuspid valve) [3,33,59]. Occasionally, echocardiography demonstrates isolated left-sided endocarditis or fails to demonstrate a vegetation in patients with CIED lead infection and high-grade bacteremia. In one study including 45 patients with PPMs and endocarditis who underwent TEE, the following findings were observed [3]: PPM endocarditis was observed in 33 patients. Concurrent valve involvement occurred in 16 patients (10 tricuspid, 6 aortic or mitral valves). The median interval from implantation to infection was 0.75 years (range 0.01 to 8 years). Multiple PPM procedures (generator changes) were common. Infection was caused by staphylococci in 70 percent of cases. Valve infection (primarily left sided) without PPM involvement was observed in 12 patients. The median interval from implantation to infection was 2.2 years (range 0.08 to 7.2). Multiple PPM procedures were infrequent in this group. Infection was caused by staphylococci (42 percent) and less virulent organisms more typically associated with endocarditis such as streptococci, enterococci, and HACEK (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella; 58 percent). https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 11/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up In another series of CIED infections including 51 patients with prosthetic valves, infection involved the pocket in 20 patients and the lead or valve in 31 (lead only in 15, valve only in 4, lead plus valve in 7, and occult bacteremia in 5) [60]. Similarly, in a study including 44 episodes of CIED-IE, 38 patients had device infection with or without valve leaflet involvement, and 6 had infection confined to the aortic or mitral valves [59]. Given that the TEE is not 100 percent sensitive for the detection of endocarditis, some patients with high-grade bacteremia due to typical endocarditis-causing organisms (defined as multiple [two or more] separate blood cultures positive for the same organism, drawn 1 hour apart) and a negative TEE will satisfy the modified Duke criteria for possible endocarditis and should be treated accordingly ( algorithm 2 and algorithm 3). By further evaluation with an alternative imaging technology (eg, electrocardiogram-gated cardiac computed tomography angiography [CTA], 18F-FDG-PET/CT, or SPECT/CT]) infection or endocarditis may be confirmed in some of these patients. The choice of a particular diagnostic modality will be guided by local availability and expertise. (See 'Diagnosis' below and "Infections involving cardiac implantable electronic devices: Treatment and prevention".) Lead vegetation Presence of a vegetation on the intracardiac lead seen on TEE (as opposed to fibrin stranding, which is found commonly on longstanding uninfected leads) may indicate infection of the CIED lead. Because of significant overlap in the appearance of infectious and noninfectious lead-adherent echodensities, the clinical scenario often determines the diagnosis and approach to treatment. For example, an echodensity found by TEE or intracardiac echo performed for an unrelated reason is unlikely to represent CIED infection or CIED-IE [56]. The clinical manifestations of lead infection are similar to those of right-sided endocarditis [34]. (See "Right-sided native valve infective endocarditis", section on 'Clinical manifestations'.) Usually the presentation is subacute, but occasional patients present with sepsis syndrome and shock. The acute presentations are associated with more virulent organisms (eg, S. aureus). Manifestations overall include: Fever 84 to 100 percent. Chills 75 to 84 percent. Pulmonary abnormalities Clinical and/or radiographic findings consistent with pneumonia, bronchitis, lung abscess, or embolism occur in 20 to 45 percent of patients [34,35]. In particular, pulmonary embolism occurs in 11 to 40 percent of cases [3,27,34,35,59]. Abnormalities on chest imaging may provide indirect evidence of intracardiac lead or tricuspid valve infection. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 12/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Tricuspid abnormalities Tricuspid regurgitation develops in about 25 percent of patients; occasionally tricuspid stenosis results from an obstructing vegetation [2,61]. Metastatic seeding of mitral or aortic valve, bone, joints, liver, and spleen [59]. Systemic emboli Systemic emboli, including stroke, are rare but can occur in the setting of a patent foramen ovale, atrial septal defect, or unrecognized left-sided valve infection [13]. The clinical presentation of lead infection may be early onset (within three to six months of CIED implantation or generator change; approximately one-third of cases) or late onset (more than six months after CIED manipulation; approximately two-thirds of cases) [3,33-35]. In general, patients with early-onset CIED infection are recognized promptly because of the frequent concurrence of systemic symptoms and associated generator pocket infection [3,34,35]. Among patients with late-onset CIED infection, the average interval from device manipulation to the onset of symptoms is 25 months, and the symptoms are often protean and consistent with endocarditis, resulting in a delayed diagnosis [34,35]. Clinical manifestations of endocarditis are discussed further separately. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Prosthetic valve endocarditis: Epidemiology, clinical manifestations, and diagnosis" and "Right-sided native valve infective endocarditis".) Valve vegetation CIED infection can occur in association with concomitant infection of the right (or, less commonly, left) heart valves [3,59,62]. In addition, patients with a CIED may present with valvular endocarditis in the absence of device infection. The most common symptoms of valvular endocarditis are fever and chills; other symptoms include malaise, headache, myalgias, arthralgias, night sweats, abdominal pain, dyspnea, cough, and pleuritic pain. Cardiac murmurs are observed in approximately 85 percent of patients. Signs specifically suggestive of left-sided valve infection include cutaneous manifestations such as petechiae or splinter hemorrhages and systemic emboli. (See "Right-sided native valve infective endocarditis" and "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Prosthetic valve endocarditis: Epidemiology, clinical manifestations, and diagnosis".) Other presentations Other presentations of CIED systemic infection include bacteremia with infection of remote sites, and in patients with epicardial leads, mediastinitis, and pericarditis. Bacteremia associated with CIED lead infection may occur in the absence of clinical evidence for endocarditis. Occasionally, remote extravascular sites (eg, bone or joint) are seeded. In patients https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 13/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up with a CIED who present with hematogenously seeded deep infection, the potential for concurrent CIED lead infection must be considered. Symptoms of mediastinitis or pericarditis may occur in the setting of patients with infection of epicardial electrodes. Both are usually associated with bacteremia: Clinical manifestations of mediastinitis include fever and chest pain. (See "Postoperative mediastinitis after cardiac surgery".) Clinical manifestations of pericarditis include fever, pleuritic chest pain, and pericardial friction rub. Pericardial effusion may be observed on echocardiogram or radiographic imaging and be accompanied by hemodynamic complications. (See "Acute pericarditis: Clinical presentation and diagnosis".) Diagnostic evaluation The clinical presentation and results of initial tests determine the need to test for a CIED systemic infection as follows: Patients who require evaluation for CIED infection Diagnostic testing for CIED systemic infection should be obtained in patients with a CIED who present with any of the following characteristics: Fever or other systemic signs of infection Overt pocket infection Pulmonary nodular infiltrates (eg, suspected septic emboli) Unexplained bacteremia Bacteremia with S. aureus The absence of signs or symptoms of CIED pocket infection does not rule out CIED systemic infection. Patients who may not require evaluation for a CIED infection - Diagnostic testing for CIED systemic infection may not be necessary for all patients with a CIED and bacteremia. Patients with a CIED and bacteremia from a clearly defined infection remote from the CIED (eg, pneumococcal pneumonia, pyelonephritis due to Enterobacteriaceae) caused by an organism not typically associated with intravascular infection are at low risk of CIED infection. In such patients, the infection can be treated and the patient can be monitored for signs of CIED infection during follow-up. Evaluation for CIED infection The approach to evaluation of suspected CIED systemic infection is summarized in the algorithms ( algorithm 2 and algorithm 3) and includes the following tests: https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 14/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Blood cultures At least two sets of blood cultures should be obtained from separate venipuncture sites prior to initiation of empiric antimicrobial therapy [1,52]. If bacteremia is detected, follow-up blood cultures should be obtained daily after antimicrobial therapy is begun and continued until 48 to 72 hours after clearance of bacteremia is documented. Frequent blood cultures may provide additional prognostic information in those with staphylococcal bacteremia and possible CIED infection; notably the risk of recurrence is associated with the duration of staphylococcal bacteremia [41]. The approach to empiric antibiotic therapy is discussed separately. (See "Infections involving cardiac implantable electronic devices: Treatment and prevention", section on 'Empiric therapy'.) Echocardiography In all patients with suspected CIED infection, echocardiography

and noninfectious lead-adherent echodensities, the clinical scenario often determines the diagnosis and approach to treatment. For example, an echodensity found by TEE or intracardiac echo performed for an unrelated reason is unlikely to represent CIED infection or CIED-IE [56]. The clinical manifestations of lead infection are similar to those of right-sided endocarditis [34]. (See "Right-sided native valve infective endocarditis", section on 'Clinical manifestations'.) Usually the presentation is subacute, but occasional patients present with sepsis syndrome and shock. The acute presentations are associated with more virulent organisms (eg, S. aureus). Manifestations overall include: Fever 84 to 100 percent. Chills 75 to 84 percent. Pulmonary abnormalities Clinical and/or radiographic findings consistent with pneumonia, bronchitis, lung abscess, or embolism occur in 20 to 45 percent of patients [34,35]. In particular, pulmonary embolism occurs in 11 to 40 percent of cases [3,27,34,35,59]. Abnormalities on chest imaging may provide indirect evidence of intracardiac lead or tricuspid valve infection. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 12/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Tricuspid abnormalities Tricuspid regurgitation develops in about 25 percent of patients; occasionally tricuspid stenosis results from an obstructing vegetation [2,61]. Metastatic seeding of mitral or aortic valve, bone, joints, liver, and spleen [59]. Systemic emboli Systemic emboli, including stroke, are rare but can occur in the setting of a patent foramen ovale, atrial septal defect, or unrecognized left-sided valve infection [13]. The clinical presentation of lead infection may be early onset (within three to six months of CIED implantation or generator change; approximately one-third of cases) or late onset (more than six months after CIED manipulation; approximately two-thirds of cases) [3,33-35]. In general, patients with early-onset CIED infection are recognized promptly because of the frequent concurrence of systemic symptoms and associated generator pocket infection [3,34,35]. Among patients with late-onset CIED infection, the average interval from device manipulation to the onset of symptoms is 25 months, and the symptoms are often protean and consistent with endocarditis, resulting in a delayed diagnosis [34,35]. Clinical manifestations of endocarditis are discussed further separately. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Prosthetic valve endocarditis: Epidemiology, clinical manifestations, and diagnosis" and "Right-sided native valve infective endocarditis".) Valve vegetation CIED infection can occur in association with concomitant infection of the right (or, less commonly, left) heart valves [3,59,62]. In addition, patients with a CIED may present with valvular endocarditis in the absence of device infection. The most common symptoms of valvular endocarditis are fever and chills; other symptoms include malaise, headache, myalgias, arthralgias, night sweats, abdominal pain, dyspnea, cough, and pleuritic pain. Cardiac murmurs are observed in approximately 85 percent of patients. Signs specifically suggestive of left-sided valve infection include cutaneous manifestations such as petechiae or splinter hemorrhages and systemic emboli. (See "Right-sided native valve infective endocarditis" and "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Prosthetic valve endocarditis: Epidemiology, clinical manifestations, and diagnosis".) Other presentations Other presentations of CIED systemic infection include bacteremia with infection of remote sites, and in patients with epicardial leads, mediastinitis, and pericarditis. Bacteremia associated with CIED lead infection may occur in the absence of clinical evidence for endocarditis. Occasionally, remote extravascular sites (eg, bone or joint) are seeded. In patients https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 13/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up with a CIED who present with hematogenously seeded deep infection, the potential for concurrent CIED lead infection must be considered. Symptoms of mediastinitis or pericarditis may occur in the setting of patients with infection of epicardial electrodes. Both are usually associated with bacteremia: Clinical manifestations of mediastinitis include fever and chest pain. (See "Postoperative mediastinitis after cardiac surgery".) Clinical manifestations of pericarditis include fever, pleuritic chest pain, and pericardial friction rub. Pericardial effusion may be observed on echocardiogram or radiographic imaging and be accompanied by hemodynamic complications. (See "Acute pericarditis: Clinical presentation and diagnosis".) Diagnostic evaluation The clinical presentation and results of initial tests determine the need to test for a CIED systemic infection as follows: Patients who require evaluation for CIED infection Diagnostic testing for CIED systemic infection should be obtained in patients with a CIED who present with any of the following characteristics: Fever or other systemic signs of infection Overt pocket infection Pulmonary nodular infiltrates (eg, suspected septic emboli) Unexplained bacteremia Bacteremia with S. aureus The absence of signs or symptoms of CIED pocket infection does not rule out CIED systemic infection. Patients who may not require evaluation for a CIED infection - Diagnostic testing for CIED systemic infection may not be necessary for all patients with a CIED and bacteremia. Patients with a CIED and bacteremia from a clearly defined infection remote from the CIED (eg, pneumococcal pneumonia, pyelonephritis due to Enterobacteriaceae) caused by an organism not typically associated with intravascular infection are at low risk of CIED infection. In such patients, the infection can be treated and the patient can be monitored for signs of CIED infection during follow-up. Evaluation for CIED infection The approach to evaluation of suspected CIED systemic infection is summarized in the algorithms ( algorithm 2 and algorithm 3) and includes the following tests: https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 14/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Blood cultures At least two sets of blood cultures should be obtained from separate venipuncture sites prior to initiation of empiric antimicrobial therapy [1,52]. If bacteremia is detected, follow-up blood cultures should be obtained daily after antimicrobial therapy is begun and continued until 48 to 72 hours after clearance of bacteremia is documented. Frequent blood cultures may provide additional prognostic information in those with staphylococcal bacteremia and possible CIED infection; notably the risk of recurrence is associated with the duration of staphylococcal bacteremia [41]. The approach to empiric antibiotic therapy is discussed separately. (See "Infections involving cardiac implantable electronic devices: Treatment and prevention", section on 'Empiric therapy'.) Echocardiography In all patients with suspected CIED infection, echocardiography should be performed using an approach similar to the evaluation for valvular endocarditis (ie, initial transthoracic echocardiography [TTE] with a subsequent transesophageal echo [TEE] if the TTE is negative or additional information is required to direct management) ( movie 1) [1]. TEE is better than transthoracic echocardiography for detection of lead and valve vegetations and also provides images of the lead in the proximal superior vena cava. In several studies, TEE identified vegetations on the tricuspid valve or device lead in 90 to 96 percent of patients with endocarditis; in contrast, TTE identified such findings in only 22 to 43 percent [2,27,34,35,63]. However, TEE cannot fully exclude the presence of CIED infection or endocarditis. Accordingly, when intracardiac infection is highly suspected and the TEE is negative, further testing is necessary (eg, repeat echocardiography or alternative imaging as described below) ( algorithm 3). The limitations of TEE for discriminating between infectious lead vegetations and thrombus were demonstrated in small studies: In a small case-control study that blinded echocardiographers to all clinical data, infectious and noninfectious echodensities did not differ in their echocardiographic characteristics (eg, diameter, mobility), and the reviewers' ability to correctly diagnose infectious vegetations was low (sensitivity 34 percent) [64]. Another study showed that 17 percent of patients undergoing TEE for noninfectious indications were found to have lead-based echodensities, and none of these patients manifested bacteremia during follow-up [56]. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 15/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Alternative imaging When intracardiac infection is highly suspected in patients with a negative or nondiagnostic TEE, alternative imaging with SPECT [65-67] or FDG-PET/CT to support the diagnosis may be warranted [67-73]. These technologies can assess the entire device and may also detect infected sites remote from the device. These alternative imaging modalities are not routinely used in assessing CIED infection; they may be useful for situations when CIED infection has not been confirmed (but is strongly suspected) [1,74]. The choice of a particular diagnostic modality is guided by local availability and expertise: 18F 18 FDG-PET/CT scan PET positivity depends upon uptake of F-FDG by inflammatory cells at the site of infection; its utility is uncertain in patients with leukopenia or after 18 prolonged administration of antibiotics. F-FDG-PET/CT technology may be useful for distinguishing infection of soft tissues overlying the generator from generator pocket infection and can define infection along the extracardiac course of electronic leads and 18 within the heart [67,69-72,75]. In addition, F-FDG-PET/CT can detect septic pulmonary emboli as a manifestation of lead-related endocarditis. Occasionally, this imaging may also demonstrate infection involving other sites due to bacteremia (such as vertebral osteomyelitis/discitis) or embolic events suggesting concurrent left-sided endocarditis (such as splenic or renal infarcts) [67-71,73,74]. A meta-analysis including 340 patients noted a high overall sensitivity and specificity of 18 F-FDG-PET/CT for diagnosis of CIED infection (87 and 94 percent, respectively) [73]. However, the sensitivity and specificity were higher for pocket/generator infection (93 and 98 percent, respectively) compared with lead-associated endocarditis (65 and 88 percent, respectively). The findings of another meta-analysis including 492 patients were very similar [76]. Thus, radionuclide imaging, particularly FDG-PET/CT, is uniquely useful in assessing pocket infection but can also supplement diagnostic efforts for CIED- IE when echocardiography is equivocal. 99m Tagged WBC scan Scintigraphy ( Tc-labeled white blood cell) and SPECT/CT have been used for the detection and localization of CIED infections [66]. SPECT/CT is able to locate inflammation better than scintigraphy, which has poor spatial resolution. SPECT/CT has good sensitivity for pocket infection. In patients with a suspected CIED 18 infection and recent cardiac surgery, scintigraphy may be more specific than F-FDG- PET/CT, which may be positive, particularly around implanted material, for two to three months after surgery due to sterile inflammation (false positive) [68]. Cardiac CT angiography (CCTA) CCTA (with or without EKG gating), has poorer sensitivity than echocardiography for lead vegetations. It can be combined with https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 16/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up enhanced chest CT to evaluate for pocket infection or hematogenous pulmonary findings which would indirectly support a diagnosis of CIED infection. Use of CCTA should be limited to situations in which radionuclide imaging is unavailable [74]. Evaluation for associated endocarditis Patients with a CIED who are undergoing evaluation for a CIED infection or who have unexplained bacteremia caused by an organism that commonly causes endocarditis are at high risk for right-sided or left-sided endocarditis; these patients should be evaluated for endocarditis, which typically includes a TEE. The approach to testing and interpretation of tests for endocarditis are discussed separately. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis", section on 'Diagnosis'.) Diagnosis Our approach The diagnosis of CIED systemic infection is established if a patient with a CIED has a fever or systemic signs of infection and one of the following ( algorithm 2): Clinically evident pocket infection and positive blood cultures. TEE with valve or lead vegetation in the context of other signs and symptoms of systemic infection (as distinguished from fibrin stranding, which can be found on leads that have been in place over an extended period). Because of significant overlap in appearance between infectious and noninfectious vegetations, the clinical history, physical examination, and microbiology results supporting CIED infection should inform the interpretation of lead-based echodensities. In patients with nondiagnostic TEE or in whom TEE cannot be done, an alternative imaging modality (such as FDG-PET/CT, SPECT/CT, or CCTA) can identify evidence of CIED infection or endocarditis. The choice of a particular diagnostic modality will be guided by local availability and expertise. (See 'Evaluation for CIED infection' above.) Blood cultures demonstrate (see 'Bacteremia' above): Any isolation of the following organisms: S. aureus (especially in the absence of a clear portal of entry, occurring within three months of device manipulation, or persisting or recurring in spite of appropriate antimicrobial therapy) (see 'Bacteremia' above) Candida species https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 17/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up High-grade bacteremia (defined as 2 or more separate blood cultures positive for the same organism, drawn 1 hour apart) with the following organisms: Coagulase-negative staphylococci. Cutibacterium (formerly Propionibacterium) species. Other high-grade bacteremia without clear portal of entry (especially due to an organism that commonly causes endocarditis, such as alpha-hemolytic streptococci, beta-hemolytic streptococci, enterococci). A single positive blood culture for coagulase-negative staphylococci or Cutibacterium species may represent skin contamination. In such cases, blood cultures should be repeated to evaluate for high grade bacteremia. If repeat cultures are confounded by antibiotic therapy and clinical suspicion for CIED infection persists, consider pursuing further imaging (FDG-PET/CT) if available; further management should be guided by consultation with infectious disease expertise. Culture and histopathology of the vegetation/lead tip consistent with infection. Proposed diagnostic criteria The European Heart Rhythm Association proposed diagnostic criteria for CIED-IE modeled after the modified Duke Criteria for infective endocarditis; these criteria categorize cases into definite, possible, and rejected groups [1]. The criteria have not been validated, given the absence of a diagnostic "gold standard," but they provide a tool for systematic assessment for CIED-IE. The criteria use the above alternate imaging modalities as components of the classification schema; we agree with this approach. Differential diagnosis The differential diagnosis of CIED-IE includes other causes of septic pulmonary emboli and causes of bacteremia in patients with a CIED that include: Septic jugular thrombophlebitis Septic jugular thrombophlebitis is characterized by infectious involvement of the carotid sheath vessels with bacteremia (often with Fusobacterium spp); it should be suspected in patients with antecedent pharyngitis or parapharyngeal infection, septic pulmonary emboli, and persistent fever despite antimicrobial therapy. The diagnosis is established by computed tomography of the neck and upper thorax. (See "Catheter-related septic thrombophlebitis".) Lower extremity or pelvic vein thrombophlebitis Patients with septic pelvic thrombophlebitis usually present shortly after delivery or surgery with fever in the absence of localizing symptoms, which persists despite antibiotics. Radiographic studies may or https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 18/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up may not demonstrate thrombus and the diagnosis is often one of exclusion. (See "Septic pelvic thrombophlebitis".) Bacteremia associated with a remote site of infection Bacteremia (without involvement of the CIED) may occur from noncardiac sites such as the abdomen, pelvis, soft tissues, bone, or any prosthetic implant. Blood culture contamination Positive blood cultures do not always represent a true bacteremia; contamination with skin flora must be considered, particularly if the entire clinical picture does not suggest a systemic infection. Fibrous material associated with longstanding CIED leads TEE may demonstrate fibrous material, clot, or stranding; these findings do not always represent infection [55,56]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infections involving cardiac implantable electronic devices".) SUMMARY AND RECOMMENDATIONS Cardiac implantable electronic devices (CIEDs) include pacemakers, implantable cardioverter-defibrillators, and cardiac resynchronization therapy (CRT) devices with or without defibrillation capacity. The most important risk factor for CIED infection is recent manipulation of the device. The most common causes of CIED infection are Staphylococcus aureus and coagulase-negative staphylococci. (See 'Epidemiology' above and 'Microbiology' above.) Forms of CIED infection include pocket infection and systemic infection. These categories are not mutually exclusive, and the two forms may coexist. (See 'Forms of infection' above.) CIED pocket infection refers to infection involving the subcutaneous pocket containing the pulse generator and the subcutaneous segment of the leads, but not the transvenous segment of the leads. (See 'Definition' above.) CIED pocket infection should be suspected when there is inflammation overlying the implanted device (including erythema, swelling, warmth, pain, and tenderness), purulent https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 19/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up drainage from the pocket, deformation of the pocket, or erosion of the device or lead through the skin, in the absence of systemic symptoms. The diagnosis of isolated pocket infection is established by the presence of one or more of these manifestations in the setting of negative blood cultures and negative transesophageal echocardiography. The approach to evaluation of suspected pocket infection is summarized in the algorithm ( algorithm 1). (See 'Clinical manifestations' above and 'Diagnosis' above.) CIED systemic infection refers to infection involving the transvenous portion of the lead (particularly infection of the endocardial portion of the lead with involvement of the contiguous endocardium or tricuspid valve) or an epicardial electrode (with involvement of the epicardium). Endocarditis (due to lead vegetation and/or valve vegetation) is an important presentation of CIED systemic infection. Other presentations include bacteremia with infection of remote sites and, in patients with epicardial leads, mediastinitis and pericarditis. (See 'Definition' above and 'Clinical presentations' above.) The diagnosis of CIED systemic infection should be suspected in patients with a CIED who present with fever or other systemic symptoms of infection and have signs of a pocket infection, pulmonary nodular infiltrates (eg, suspected septic emboli), unexplained bacteremia, or bacteremia caused by S. aureus. The approach to evaluation of suspected CIED systemic infection is summarized in the algorithms ( algorithm 2 and algorithm 3). (See 'Diagnosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Blomstr m-Lundqvist C, Traykov V, Erba PA, et al. 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40. Chesdachai S, Baddour LM, Sohail MR, et al. Evaluation of European Heart Rhythm Association consensus in patients with cardiovascular implantable electronic devices and Staphylococcus aureus bacteremia. Heart Rhythm 2022; 19:570. 41. Nakajima I, Narui R, Tokutake K, et al. Staphylococcus bacteremia without evidence of cardiac implantable electronic device infection. Heart Rhythm 2021; 18:752. 42. Berge A, Arkel L, Nilson B, Rasmussen M. Enterococcus faecalis bacteremia, cardiac implantable electronic device, extraction, and the risk of recurrence. Infection 2022; 50:1517. 43. Oh TS, Le K, Baddour LM, et al. Cardiovascular implantable electronic device infections due to enterococcal species: Clinical features, management, and outcomes. Pacing Clin Electrophysiol 2019; 42:1331. 44. Uslan DZ, Sohail MR, Friedman PA, et al. Frequency of permanent pacemaker or implantable cardioverter-defibrillator infection in patients with gram-negative bacteremia. Clin Infect Dis 2006; 43:731. 45. Chesdachai S, Baddour LM, Sohail MR, et al. Risk of Cardiovascular Implantable Electronic Device Infection in Patients Presenting With Gram-Negative Bacteremia. Open Forum Infect Dis 2022; 9:ofac444. 46. Camus C, Leport C, Raffi F, et al. Sustained bacteremia in 26 patients with a permanent endocardial pacemaker: assessment of wire removal. Clin Infect Dis 1993; 17:46. 47. Baman JR, Medhekar AN, Jain SK, et al. Management of systemic fungal infections in the presence of a cardiac implantable electronic device: A systematic review. Pacing Clin Electrophysiol 2021; 44:159. 48. Nakamura T, Narui R, Holmes B, et al. Candidemia in patients with cardiovascular implantable electronic devices. J Interv Card Electrophysiol 2021; 60:69. 49. Da Costa A, Leli vre H, Kirkorian G, et al. Role of the preaxillary flora in pacemaker infections: a prospective study. Circulation 1998; 97:1791. 50. Chua JD, Wilkoff BL, Lee I, et al. Diagnosis and management of infections involving implantable electrophysiologic cardiac devices. Ann Intern Med 2000; 133:604. 51. Esquer Garrigos Z, George MP, Khalil S, et al. Predictors of Bloodstream Infection in Patients Presenting With Cardiovascular Implantable Electronic Device Pocket Infection. Open Forum Infect Dis 2019; 6:ofz084. 52. Baddour LM, Epstein AE, Erickson CC, et al. Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association. Circulation 2010; 121:458. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 24/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up 53. Nagpal A, Patel R, Greenwood-Quaintance KE, et al. Usefulness of sonication of cardiovascular implantable electronic devices to enhance microbial detection. Am J Cardiol 2015; 115:912. 54. Esquer Garrigos Z, Sohail MR, Greenwood-Quaintance KE, et al. Molecular Approach to Diagnosis of Cardiovascular Implantable Electronic Device Infection. Clin Infect Dis 2020; 70:898. 55. Downey BC, Juselius WE, Pandian NG, et al. Incidence and significance of pacemaker and implantable cardioverter-defibrillator lead masses discovered during transesophageal echocardiography. Pacing Clin Electrophysiol 2011; 34:679. 56. Patel NJ, Singleton MJ, Brunetti R, et al. Evaluation of lead-based echodensities on transesophageal echocardiogram in patients with cardiac implantable electronic devices. J Cardiovasc Electrophysiol 2023; 34:7. 57. Cox JN. Pathology of cardiac pacemakers and central catheters. Curr Top Pathol 1994; 86:199. 58. Spittell PC, Hayes DL. Venous complications after insertion of a transvenous pacemaker. Mayo Clin Proc 1992; 67:258. 59. Sohail MR, Uslan DZ, Khan AH, et al. Infective endocarditis complicating permanent pacemaker and implantable cardioverter-defibrillator infection. Mayo Clin Proc 2008; 83:46. 60. Huang XM, Fu HX, Zhong L, et al. Outcomes of Transvenous Lead Extraction for Cardiovascular Implantable Electronic Device Infections in Patients With Prosthetic Heart Valves. Circ Arrhythm Electrophysiol 2016; 9. 61. Voet JG, Vandekerckhove YR, Muyldermans LL, et al. Pacemaker lead infection: report of three cases and review of the literature. Heart 1999; 81:88. 62. Schulze MR, Ostermaier R, Franke Y, et al. Images in cardiovascular medicine. Aortic endocarditis caused by inadvertent left ventricular pacemaker lead placement. Circulation 2005; 112:e361. 63. Victor F, De Place C, Camus C, et al. Pacemaker lead infection: echocardiographic features, management, and outcome. Heart 1999; 81:82. 64. George MP, Esquer Garrigos Z, Vijayvargiya P, et al. Discriminative Ability and Reliability of Transesophageal Echocardiography in Characterizing Cases of Cardiac Device Lead Vegetations Versus Noninfectious Echodensities. Clin Infect Dis 2021; 72:1938. 65. Sohns JM, Bavendiek U, Ross TL, Bengel FM. Targeting Cardiovascular Implant Infection: Multimodality and Molecular Imaging. Circ Cardiovasc Imaging 2017; 10. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 25/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up 66. Erba PA, Sollini M, Conti U, et al. Radiolabeled WBC scintigraphy in the diagnostic workup of patients with suspected device-related infections. JACC Cardiovasc Imaging 2013; 6:1075. 67. Ahmed FZ, James J, Memmott MJ, Arumugam P. Radionuclide Imaging of Cardiovascular Infection. Cardiol Clin 2016; 34:149. 68. Chen W, Sajadi MM, Dilsizian V. Merits of FDG PET/CT and Functional Molecular Imaging Over Anatomic Imaging With Echocardiography and CT Angiography for the Diagnosis of Cardiac Device Infections. JACC Cardiovasc Imaging 2018; 11:1679. 69. Sarrazin JF, Philippon F, Tessier M, et al. Usefulness of fluorine-18 positron emission tomography/computed tomography for identification of cardiovascular implantable electronic device infections. J Am Coll Cardiol 2012; 59:1616. 70. Brinker J. Imaging for infected cardiac implantable electronic devices: a new trick for your pet. J Am Coll Cardiol 2012; 59:1626. 71. Pizzi MN, Roque A, Fern ndez-Hidalgo N, et al. Improving the Diagnosis of Infective Endocarditis in Prosthetic Valves and Intracardiac Devices With 18F-Fluordeoxyglucose Positron Emission Tomography/Computed Tomography Angiography: Initial Results at an Infective Endocarditis Referral Center. Circulation 2015; 132:1113. 72. Calais J, Touati A, Grall N, et al. Diagnostic Impact of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography and White Blood Cell SPECT/Computed Tomography in Patients With Suspected Cardiac Implantable Electronic Device Chronic Infection. Circ Cardiovasc Imaging 2019; 12:e007188. 73. Juneau D, Golfam M, Hazra S, et al. Positron Emission Tomography and Single-Photon Emission Computed Tomography Imaging in the Diagnosis of Cardiac Implantable Electronic Device Infection: A Systematic Review and Meta-Analysis. Circ Cardiovasc Imaging 2017; 10. 74. Galea N, Bandera F, Lauri C, et al. Multimodality Imaging in the Diagnostic Work-Up of Endocarditis and Cardiac Implantable Electronic Device (CIED) Infection. J Clin Med 2020; 9. 75. Jer nimo A, Olmos C, Vilacosta I, et al. Accuracy of 18F-FDG PET/CT in patients with the suspicion of cardiac implantable electronic device infections. J Nucl Cardiol 2022; 29:594. 76. Mahmood M, Kendi AT, Farid S, et al. Role of 18F-FDG PET/CT in the diagnosis of cardiovascular implantable electronic device infections: A meta-analysis. J Nucl Cardiol 2019; 26:958. Topic 2146 Version 44.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 26/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up GRAPHICS Microbiology of cardiac implantable electronic device (CIED) infections Pacemaker All CIED infections (pocket endocarditis and bloodstream) Organism Number of patients Number of pathogens [1] [2] (percent) (percent) Coagulase-negative staphylococci 99 (61) 183 (44) Staphylococcus aureus 49 (30) 148 (36) Enterobacteriaceae 8 (5) 18 (4) Streptococci 7 (4) 12 (3) Pseudomonas 6 (4) 12 (3) Other gram-negative bacteria 8 (2) Candida 3 (2) 2 (<1) Enterococci 3 (2) 20 (5) Corynebacterium 2 (1) 2 (<1) Cutibacterium (formerly Propionibacterium) acnes 1 (<1) 1 (<1) Listeria 1 (<1) Anaerobes 5 (1) Micrococci 1 (<1) Mycobacterium spp 2 (<1) Apergillus 1 (<1) Polymicrobial infection occurred in 11 percent of cases. References: 1. Arber N, Pras E, Copperman Y, et al. Medicine (Baltimore) 1994; 73:299; Duval X, Selton-Suty C, Alla F, et al. Clin Infect Dis 2004; 39:68; Klug D, Lacroix D, Savoye C, et al. Circulation 1997; 95:2098; and Cacoub P, Leprince P, Nataf P, et al. Am J Cardiol 1998; 82:480. 2. Tarakji KG, Chan EJ, Cantillon DJ, et al. Cardiac implantable electronic device infections: Presentation, management, and patient outcomes. Heart Rhythm 2010; 7:1043. Graphic 55942 Version 5.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 27/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Transvenous cardiac implantable electronic device (CIED) lead and pulse generator Transvenous CIED demonstrating the pulse generator in the left pectoral region with three transvenous leads in the right atrium, right ventricle, and coronary sinus/left ventricle as would be seen in a patient receiving cardiac resynchronization therapy. Used with permission of Mayo Foundation for Medical Education and Research. All rights reserved. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 28/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Graphic 118356 Version 2.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 29/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Pacemaker pocket erosion The pacemaker generator, implanted several years prior to presentation, is clearly visible beneath the skin and is on the verge of complete erosion (arrow). The patient was asymptomatic. The device and leads were easily removed. Although purulent material was present, cultures of the pocket obtained at the time of explant were negative. A new pacing system was placed on the contralateral side. Courtesy of Margaret Lloyd, MD. Graphic 74725 Version 3.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 30/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Approach to evaluation and management of suspected infection limited to cardiac implantable electronic device (CIED) pocket in adults https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 31/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up TEE: transesophageal echocardiogram; FDG PET/CT: fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography; SPECT/CT: radiolabeled autologous white blood cell single-photon emission computed tomography with computed tomography; MRSA: methicillin- resistant Staphylococcus aureus. Refer to separate UpToDate algorithm for approach to patients with systemic symptoms, positive blood cultures, and/or vegetation on TEE. FDG PET/CT may be useful to distinguish between CIED pocket infection and superficial site infection in some circumstances; refer to the UpToDate topic on diagnosis of CIED infection for further discussion. Oral antibiotic dosing as follows: Cephalexin 500 mg orally 4 times daily Clindamycin 300 to 450 mg orally 4 times daily (use higher dose for patients with weight >120 kg) Dicloxacillin 500 mg orally 4 times daily Doxycycline 100 mg orally twice daily Linezolid 600 mg orally twice daily Minocycline 200 mg orally once, then 100 mg orally every 12 hours Trimethoprim-sulfamethoxazole 1 to 2 double-strength tablets orally every 12 hours We favor initial therapy with vancomycin (15 to 20 mg/kg/dose intravenously every 8 to 12 hours [not to exceed 2 g per dose]); refer to UpToDate text for discussion of alternative agents. Graphic 117258 Version 5.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 32/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Approach to evaluation and management of suspected infection of a cardiac implantable electronic device (CIED) in adults TTE: transthoracic echocardiogram; TEE: transesophageal echocardiogram. Signs and symptoms of an isolated CIED pocket infection include pocket erythema, discomfort, swelling, incision dehiscence, deformation, and erosion. Signs and symptoms of endocarditis include new murmur, new regurgitation, vegetation, paravalvular leak, evidence of pulmonary or systemic emboli, and immune phenomena. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 33/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Vancomycin dosing consists of 15 to 20 mg/kg/dose intravenously every 8 to 12 hours (not to exceed 2 g per dose); in patients presenting with severe sepsis, broadening of parenteral therapy to include gram-negative bacteria is appropriate. Refer to UpToDate text for further discussion. The choice of antibiotic regimen is guided by blood culture results (refer to UpToDate text). The duration of antibiotic therapy (4 to 6 weeks) should be counted from the day of device explantation, if warranted. Graphic 117257 Version 7.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 34/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Approach to management of adults with suspected CIED infection and negative UpToDate algorithm for approach to initial diagnostic evaluation) CIED: cardiac implantable electronic device; TEE: transesophageal echocardiogram; FDG PET/CT: fluorine-18 f tomography/computed tomography; SPECT/CT: single photon emission computed tomography/computed to High-grade bacteremia is defined as multiple (2 or more) separate blood cultures positive for the same org for coagulase-negative staphylococci or Cutibacterium species may represent skin contamination. In such cas grade bacteremia. If repeat cultures are confounded by antibiotic therapy and clinical suspicion for CIED infe PET/CT) if available; further management should be guided by consultation with infectious disease expertise Clinical suspicion is increased for organisms that commonly cause endocarditis. FDG PET/CT may be useful to establish a diagnosis of CIED infection in some circumstances. Other potentia https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 35/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up The choice and duration of antibiotic therapy is based on regimens for treatment of endocarditis caused by implicated (refer to UpToDate text and related topics). The duration of antibiotic therapy (usually 4 to 6 weeks warranted. The choice of antibiotic therapy is guided by culture results. Graphic 131691 Version 2.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 36/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis - Up Contributor Disclosures Adolf W Karchmer, MD Equity Ownership/Stock Options: AbbVie [Pharmaceuticals]; Johnson and Johnson [Pharmaceuticals]; Lilly [Pharmaceuticals]; Merck [Pharmaceuticals]; Pfizer [Pharmaceuticals]. Grant/Research/Clinical Trial Support: Karius [Endocarditis]. Consultant/Advisory Boards: Debio International [Antibiotic development]; Pfizer [Rheumatologic diseases, ulcerative colitis]. Other Financial Interest: Board of Directors [Winter Course in Infectious Diseases]. All of the relevant financial relationships listed have been mitigated. Vivian H Chu, MD, MHS No relevant financial relationship(s) with ineligible companies to disclose. Jay A Montgomery, MD No relevant financial relationship(s) with ineligible companies to disclose. Stephen B Calderwood, MD Consultant/Advisory Boards: Day Zero Diagnostics [Whole genome sequencing for microbial identification and determination of antimicrobial susceptibility]. All of the relevant financial relationships listed have been mitigated. Elinor L Baron, MD, DTMH No relevant financial relationship(s) with ineligible companies to disclose. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-epidemiology-microbiology-clinical-manifestations-an 37/37

7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Infections involving cardiac implantable electronic devices: Treatment and prevention : Adolf W Karchmer, MD, Vivian H Chu, MD, MHS, Jay A Montgomery, MD : Stephen B Calderwood, MD : Elinor L Baron, MD, DTMH, Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 10, 2023. INTRODUCTION Traditionally, cardiac implantable electronic devices (CIEDs), including pacemakers, implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices with or without defibrillation capacity, have included pulse generators to provide the electrical stimulus and either transvenous or epicardial leads to deliver the stimulus to the heart. Newer devices have been developed which operate effectively without the requirement for a transvenous or epicardial lead system; leadless pacemakers are percutaneously placed directly inside the heart, thus avoiding a subcutaneous pocket and transvenous leads. Subcutaneous ICDs with an extrathoracic tunneled electrode have no transvenous component. Implantable loop recorders function effectively to monitor cardiac rhythm from a subcutaneous pocket without direct attachment to the heart. The clinical presentation and management of CIED infections varies according to the location and extent of infection and the clinical characteristics of the patient [1-5]. This topic focuses on treatment and prevention of infection involving traditional CIEDs, those with subcutaneous pockets and transvenous leads. The epidemiology, microbiology, clinical manifestations, and diagnosis of CIED infections, as well as noninfectious complications of CIEDs, are discussed separately. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 1/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis".) (See "Cardiac implantable electronic devices: Long-term complications" and "Cardiac implantable electronic devices: Periprocedural complications".) TREATMENT General principles In general, successful management of a CIED infection (systemic infection or pocket infection) requires ( algorithm 1 and algorithm 2 and algorithm 3 and algorithm 4) [2,5,6]: Antibiotic therapy Explantation of the entire CIED (leads, including residual leads that are non-functional, and pulse generator) Reimplantation of a new device (through an uninfected route), if indication for CIED persists The details of the therapeutic approach depend upon the extent of infection, the pathogen, and individual clinical circumstances (eg, the general health of the patient, the potential complexity of device removal). Consultation with physicians with expertise in the care of patients with CIED infection is desirable. Antibiotic therapy The antibiotic regimen is based upon the extent of infection and the causative organism, if identified. In general, initial antibiotic empiric therapy assumes systemic infection and utilizes regimens designed to treat endocarditis. Once the extent and etiology of infection are defined, antibiotic therapy should be tailored accordingly. Empiric therapy Empiric intravenous antibiotic therapy should be initiated following collection of blood cultures (at least two or three sets) and culture of pocket drainage, if present. Obtaining blood cultures prior to initiating empiric therapy is particularly important in patients who present with hypotension or criteria for a systemic inflammatory syndrome response (tachycardia, tachypnea, fever or hypothermia, leukocytosis or leukopenia) because these features are associated with bloodstream infection [7]. Once a causative organism is identified (via blood and/or pocket wound cultures), the antibiotic regimen should be tailored accordingly. Empiric antibiotic therapy for patients with suspected CIED infection should consist of antistaphylococcal therapy. Given the high incidence of methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis infection, initial therapy with vancomycin ( table 1) is reasonable. In patients presenting with hemodynamic instability, broadening of https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 2/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate therapy to include gram-negative bacteria is appropriate (reasonable additions to vancomycin include piperacillin-tazobactam, cefepime, a carbapenem, or gentamicin) [4]. High-dose daptomycin (8 to 10 mg/kg ideal body weight, which is higher than the US Food and Drug Administration approved dose) is an acceptable alternative to vancomycin for treatment of device infection. However, caution is required in the setting of foreign-body infection or vancomycin failure. S. aureus that are nonsusceptible to daptomycin have been detected when the organism has persisted in spite of vancomycin therapy or when there is breakthrough bacteremia during daptomycin therapy [8]. Accordingly, susceptibility testing must be performed on these persisting organisms to ensure continued susceptibility to daptomycin. Use of daptomycin as an alternative for treatment of CIED infection is supported by a study of 25 cases of device-related infection in which high-dose daptomycin (mean 8.3 mg/kg [range 6.4 to 10.7 mg/kg]) resulted in cure or improvement in 92 percent of cases [8]. Devices were explanted in 22 patients; 2 patients with retained devices remained bacteremic during therapy. (See "Methicillin- resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia".) Data for use of other alternative antistaphylococcal agents (such as teicoplanin, ceftaroline, and telavancin) in treatment of CIED infections are lacking. Ceftaroline and telavancin likely retain activity against MRSA with reduced susceptibility to vancomycin and daptomycin. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia".) Definitive therapy Bacterial infection Once a causative organism is identified (via blood and/or pocket wound cultures), the antibiotic regimen should be tailored accordingly. Definitive antibiotic therapy is based on the antibiotic susceptibility of the implicated pathogen(s) and is derived from pathogen-specific regimens recommended for treatment of endocarditis. The duration of antimicrobial infection is determined by the pathogen and the extent of infection (pocket versus systemic) ( algorithm 4 and algorithm 1 and algorithm 3). (See "Antimicrobial therapy of left-sided native valve endocarditis" and "Antimicrobial therapy of prosthetic valve endocarditis".) Imaging with a lead or valve vegetation For patients with echocardiography demonstrating a valve or lead vegetation, we favor presumptive treatment for endocarditis; the antibiotic choice and duration of therapy is based upon the organism recovered from blood cultures. In these settings, we treat with four to six weeks of parenteral therapy, depending on the implicated pathogen. This approach is particularly important when implantation of a new device is anticipated. (See "Antimicrobial therapy of left-sided native valve endocarditis" and "Antimicrobial therapy of prosthetic valve endocarditis" and "Infections involving cardiac https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 3/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Diagnostic evaluation'.) In patients with bacteremia with an organism typically associated with endocarditis, with transesophageal echocardiography (TEE) demonstrating a lead vegetation in the absence of valve vegetation, we still favor treatment as for endocarditis; this is in contrast to some others (including some guideline committees) who favor a shorter duration of therapy in such cases [1,2,4,5]. We favor this approach given the less than perfect sensitivity of TEE for excluding valvular endocarditis (or mural endocarditis at the lead implantation site). If the TEE is nondiagnostic or cannot be done, we pursue an alternative imaging modality (eg, computed tomography [CT] angiography, fluorodeoxyglucose [FDG] positron emission tomography [PET], or single-photon emission CT) in an attempt to establish a diagnosis. The choice of a particular diagnostic modality will be guided by local availability and expertise. Imaging with no lead or valve vegetation For patients with no lead or valve vegetation on TEE (or other imaging) and bacteremia due to S. aureus, Candida species coagulase-negative Staphylococcus (high grade), Cutibacterium (formerly Propionibacterium) species (high grade), or high-grade bacteremia due to another organism with a propensity to cause endocarditis (in the absence of clear alternative source), we favor presumptive treatment for endocarditis, four to six weeks of pathogen-specific parenteral antibiotic. High-grade bacteremia is defined as two or more separate blood cultures positive for the same organism, drawn 1 hour apart. A single positive blood culture for coagulase-negative staphylococci or Cutibacterium species may represent skin contamination. In such cases, blood cultures should be repeated to evaluate for high grade bacteremia. If repeat cultures are confounded by antibiotic therapy and clinical suspicion for CIED infection persists, consider pursuing further imaging (FDG-PET/CT) if available; further management should be guided by consultation with infectious disease expertise. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Diagnostic evaluation'.) The above approach is preferred because approximately half of patients with CIED infection have concurrent valvular infection, and because the sensitivity of TEE (or other imaging) to exclude valve infection is limited [9,10]. Furthermore, S. aureus bacteremia (community onset or nosocomial) among patients with a CIED, even limited to a single positive blood culture, is associated with a significant risk of complicated infection, which mandates additional imaging (such as fluorine-18-FDG-PET/CT, if available) as well as intensive antimicrobial therapy [11,12]. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Diagnostic evaluation'.) https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 4/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate In the setting of additional sites of infectious involvement (such as discitis and/or vertebral osteomyelitis), extension of duration of therapy may be warranted. (See "Antimicrobial therapy of left-sided native valve endocarditis" and "Antimicrobial therapy of prosthetic valve endocarditis" and "Vertebral osteomyelitis and discitis in adults".) For patients with no lead or valve vegetation on TEE (or other imaging) and bacteremia due to alpha-hemolytic streptococci, non-Group A beta-hemolytic streptococci, or enterococcus (high grade and/or no clear alternative source), we favor presumptive treatment for endocarditis. This approach is based on the predilection of these organisms to cause endocarditis and the significant frequency of endocarditis when these organisms cause bloodstream infection in patients with anatomic predispositions for endocarditis, recognizing that TEE (or other imaging technologies) are not 100 percent sensitive for detection of vegetations [13-16]. This approach is supported by one study including 12 patients with pacemakers who had valve infection in the absence of pacemaker involvement; besides S. aureus, pathogens included other organisms typically associated with endocarditis (such as streptococci, enterococci, and HACEK [Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella]) in more than half of the cases [17]. For patients with no lead or valve vegetation on TEE and gram-negative bacteremia (non- Pseudomonas aeruginosa/non-Serratia), Streptococcus pneumoniae, or transient bacteremia from a clear alternative source due to an organism that does not commonly cause endocarditis, antibiotics should be administered for at least two weeks using a regimen appropriate for the organism and primary site of infection [5,18]. After completion of antibiotic therapy, blood cultures (two sets) should be obtained, with close follow-up. (See "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia in adults" and "Gram-negative bacillary bacteremia in adults".) For patients with an isolated CIED pocket infection (eg, TEE negative for lead or valve vegetation, sterile blood cultures, and no symptoms to suggest systemic infection) ( algorithm 1), antibiotics should be administered for two weeks following device removal [1,2,4]. Empiric intravenous antibiotic therapy should be initiated until bacteremia has been excluded. Upon clarification of the pathogens causing pocket infection, device removal, and control of infection, pathogen-specific antibiotic treatment may be completed orally. If antibiotics have been administered prior to obtaining blood cultures, clinicians should be cognizant that recent antibiotic therapy can render blood cultures falsely negative. Fungal infection The approach to selection of antifungal therapy for treatment of systemic Candida CIED infection is the same as that of native valve endocarditis ( table 2) https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 5/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate [19,20]. This is discussed further separately. (See "Candida endocarditis and suppurative thrombophlebitis".) We are in agreement with guidelines which recommend prompt removal of the entire device in the setting of Candida infection involving any component of the CIED [1,5,21,22]. Systemic CIED fungal infection has been associated with a very high mortality rate and occasional relapse after therapy, and medical therapy alone has been associated with treatment failure [23-27]. The duration of antifungal therapy for CIED pocket infection is four weeks following device removal. The duration of therapy for CIED systemic infection is at least six weeks following device removal. Relapse after completion of therapy should prompt repeat assessment for CIED or cardiac valve infection. We are in agreement with some experts who favor lifelong suppressive antifungal therapy for patients with systemic Candida CIED infection following new CIED implantation (even in the absence of detectable valve involvement), particularly in older adults or those with multiple comorbidities. This approach merits consideration because of the risk for recurrent CIED Candida infection and its associated high mortality rate and is supported by descriptions of delayed onset IE in patients with prosthetic valves who experience candidemia [28] and descriptions of relapsed CIED fungal infection despite antifungal therapy plus device explantation [29]. In addition, cardiac imaging is not sufficiently sensitive to fully exclude intracardiac infection. Device removal versus retention Removal indications Removal of the entire CIED, as well as any residual nonfunctional leads, is indicated in any of the following circumstances ( algorithm 4 and algorithm 1 and algorithm 3) [1,2,5]: TEE demonstrating valve or lead vegetation in the presence of known or suspected bacteremia (as distinguished from noninfected fibrin stranding, which is often seen with long-duration leads) [30,31] Blood cultures demonstrate: Any isolation of the following organisms: S. aureus (especially in the absence of a clear portal of entry, occurring within three months of device manipulation, or persisting or recurring in spite of appropriate antimicrobial therapy) (see "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Bacteremia') https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 6/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Candida species High-grade bacteremia (defined as two or more separate blood cultures positive for the same organism, drawn 1 hour apart) with the following organisms: Coagulase-negative staphylococci. Cutibacterium (formerly Propionibacterium) species. Other high-grade bacteremia without clear portal of entry (especially due to an organism that commonly causes endocarditis, such as alpha-hemolytic streptococci, beta-hemolytic streptococci, enterococci). A single positive blood culture for coagulase-negative staphylococci or Cutibacterium species may represent skin contamination. In such cases, blood cultures should be repeated to evaluate for high grade bacteremia. If repeat cultures are confounded by antibiotic therapy and clinical suspicion for CIED infection persists, consider pursuing further imaging (FDG-PET/CT) if available; further management should be guided by consultation with infectious disease expertise. Presence of pocket infection (based on clinical manifestations of pain or tenderness, erythema, swelling, purulent drainage, pocket deformation, adherence or threatened erosion, and/or percutaneous exposure/erosion of the generator and/or leads), with or without positive culture of pocket drainage or bacteremia. The preferred approach for CIED removal consists of transvenous extraction of all leads (including previously abandoned leads, if present), in conjunction with removal of the generator. Major complications are infrequent (<2 percent), and extraction-related in-hospital mortality is <1 percent [4]. Presence of large lead vegetation(s) (>2 cm) prompt concern for development of pulmonary embolism (PE) in association with transvenous CIED removal. Surgical removal may be warranted to avoid PE; the threshold vegetation size for surgical removal is uncertain. In small observational studies, transvenous removal of CIED leads with large vegetations was associated with hemodynamically significant PEs relatively infrequently [32-34], and surgical removal is associated with greater morbidity than transvenous extraction. However, subclinical septic emboli may also occur, which may impact long-term outcomes. Accordingly, consideration of surgical management requires careful risk-benefit assessment [4,35]. To reduce the risk of PE while avoiding cardiac surgery, percutaneous suction removal of large lead vegetations prior to transvenous lead extraction has been used increasingly in recent years https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 7/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate [36,37]. The technical aspects of vegetation debulking and lead removal are discussed separately; arrangements should be made for managing arrhythmias until a new device can be reasonably reimplanted. (See "Cardiac implantable electronic device lead removal" and "Wearable cardioverter-defibrillator", section on 'Bridge to indicated or interrupted ICD therapy'.) In addition to device explantation, the pocket, if infected, should be meticulously debrided including removal of the fibrous capsule and any foreign material. The pocket should be irrigated with sterile saline. Removal of other intravascular devices, where feasible, is indicated as well. The above approach to device removal in patients with S. aureus bacteremia is supported by the following studies: In a retrospective cohort including 360 patients with CIED and staphylococcal bacteremia (329 due to S. aureus), CIED infection was confirmed on initial evaluation in 182 patients; among the remaining 178 patients, 36 died or underwent empiric device removal [12]. Of the surviving 142 patients, 27 patients (of whom 25 had S. aureus infection), experienced relapsed bacteremia within 6 months. The risk of relapse was greater among those with >1 day of bacteremia than among those with a single day of bacteremia (35 versus 5 percent). In a multivariable analysis, the hazard of death at one year was reduced among those who underwent empiric device removal (hazard ratio [HR] 0.28, 95% CI 0.08-0.95). In a study of 110 patients with a CIED and S. aureus bacteremia [38], patients were classified using the European Heart Rhythm Association 2019 definition for CIED infection [5,38]. Device infection was definite in 57 patients, possible in 31 patients, and rejected in 22 patients. The median duration of bacteremia was four days, three days, and two days, respectively; device removal occurred in 80, 39, and 33 percent of patients respectively. Recurrence of S. aureus bacteremia recurred in two patients with definite or possible infection (both of whom underwent device removal) and two patients with rejected device infection (neither of whom underwent device removal). Device removal was associated with a significant survival benefit at one year among those with definite infection (HR 0.17 [0.06- 0.47]), but not among those with possible infection (HR 0.33 [0.07-1.51]) or rejected infection (HR 0.83 [0.17-4.03]). In most cases, the risks of recurrent infection and mortality significantly outweigh the risks of immediate extraction [39,40]. Alternative approaches (such as device retention with antibiotic therapy or generator removal with lead retention and antibiotic therapy) are associated with increased risk of mortality [39,40]. In one study including 415 patients with CIED infection, patients who did not undergo device removal experienced a sevenfold increase in 30-day mortality relative to those who https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 8/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate underwent device removal (HR 6.97, 95% CI 1.36-35.6) [39]. Immediate CIED removal (in contrast with removal after failure of antimicrobial therapy or no removal) was associated with a threefold reduction in mortality at one year (HR 0.35, 95% CI 0.16-0.75). In another study of 177 patients with CIED infection, device removal during the index hospitalization was associated with decreased mortality at one year (20 versus 38 percent) [40]. In a study including 80 patients with an isolated pocket infection who were not candidates for CIED extraction (or who elected not to undergo CIED extraction) who were treated with pocket debridement and infusion of antibiotics directly into the pocket for at least 14 days, 85 percent of patients had clinical resolution of infection [41]. There are circumstances in which CIED removal addresses only one of multiple possible sites of intravascular infection. While removing the CIED site of infection may increase the probability of a cure, presence of any other retained intravascular device or prosthesis raises the possibility of residual infection. As an example, in the setting of prosthetic valve endocarditis, CIED removal may increase the probability of cure of PVE without valve removal, but this cannot be considered definitive. Such situations require consultation with physicians who have experience treating complex patients with intravascular infection in the setting of intravascular devices or prostheses. In general, ease of lead extraction is inversely related to lead dwell time; leads that have been in place for more than two years are more difficult to extract than newer leads, and the risk seems to continue to increase with increased time. However, such leads can be removed safely by experienced operators in most cases. The degree of explant difficulty also depends on the lead type; implantable cardioverter-defibrillator (ICD) leads (particularly dual coil designs) tend to have more extensive adhesions and therefore are more difficult to explant than pacemaker leads. In such cases, the decision to attempt lead removal must be individualized. (See 'Removal warranted but not feasible' below and "Cardiac implantable electronic device lead removal".) Rarely, CIED infection may be complicated by stroke or systemic embolus in the apparent absence of concurrent left-sided endocarditis. In such cases, or in cases in which there are other suggestions of right to left shunting, evaluation for a patent foramen ovale should be undertaken; if found, efforts to prevent paradoxical embolization at the time of device extraction should be considered [42]. (See "Cardiac implantable electronic device lead removal", section on 'Embolism'.) Removal warranted but not feasible CIED removal may not be feasible for patients in whom the intervention would pose significant risks (for example, patients with major https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 9/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate comorbidities and limited life expectancy who have longstanding devices and who require continuous pacemaker support). In such cases, or if patients refuse CIED removal, an aggressive approach to antibiotic therapy is warranted, although evidence to guide therapy is lacking. We favor a six-week course of therapy as would be used for prosthetic valve endocarditis caused by the implicated organism. (See "Antimicrobial therapy of prosthetic valve endocarditis".) This approach is associated with a high risk of relapse [43] and no way to test for cure before discontinuing antibiotics: Among patients who are candidates for CIED removal if the infection relapses, close monitoring following completion of antibiotic therapy is indicated [2,4]. If there is evidence of persistent or progressive infection or relapse despite appropriate intravenous antibiotic therapy, the device should be removed. Among patients for whom CIED removal is not an option, long-term suppressive antibiotic therapy can be used, but this is a last resort [2,4]. These patients are at high risk of failure with subsequent relapse and increased mortality [2,43]. In one retrospective study including 37 patients with CIED infection managed with chronic antibiotic suppression, the estimated median overall survival was 1.43 years (95% CI 0.27-2.14); relapse within one year occurred in 18 percent of cases [43]. Retention criteria Device retention may be reasonably attempted in the following circumstances, since such patients may not have CIED infection ( algorithm 4 and algorithm 1 and algorithm 3): Bacteremia due to a pathogen other than S. aureus from a defined source other than the device or valvular infection, if: There is no clinical, TEE, or other imaging (if available) evidence of lead or valve infection There is no evidence of pocket infection The device has not been manipulated recently (ie, within three months) Gram-negative bacteremia (other than that caused by P. aeruginosa or Serratia), pneumococcal bacteremia, and transient bacteremia due to organisms that do not commonly cause endocarditis may be managed with device retention when there is a clear alternative source or portal of entry and no evidence of CIED infection. However patients managed with device retention who have continued unexplained bacteremia despite https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 10/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate appropriate antibiotic therapy or who relapse after appropriate antibiotic therapy likely have CIED infection and warrant device removal [2,17,44]. Presence of superficial cellulitis or a stitch abscess at the incision site, typically shortly after implant or generator replacement, with no involvement of the generator pocket [2]. This distinction is often difficult to make, and patients managed with device retention require close observation for subsequent evidence of device infection. Device reimplantation The optimal timing for CIED reimplantation is uncertain; an approach is summarized in the algorithm ( algorithm 2) [2]. For patients who require reimplantation of a new CIED, the risk of infection of a new device must be balanced with the risk of monitoring with no device in place. Approximately 23 to 30 percent of patients with CIED infection do not require a new device [4]. If necessary, a temporary device can be placed, although these are also associated with risk of infection. The techniques for temporary pacing are discussed separately. (See "Temporary cardiac pacing".) For patients with systemic CIED infection, the approach depends on TEE, blood culture results, and the presence of systemic infection: CIED infection and valvular endocarditis In patients with a CIED infection and TEE evidence of valve vegetation, the new CIED may be implanted once surveillance blood cultures following device removal are negative for at least 14 days. By that time, the valve infection should be sufficiently treated such that seeding of the new lead is unlikely. This is a generally accepted practice with limited data to support it. In one study including 109 patients with CIED-related infectious endocarditis (CIED-IE; defined as echocardiographically reported device lead or valve vegetation), patients with a reimplantation interval <14 days had the lowest 12-month survival (58 percent), particularly if there was a valve vegetation [45]. CIED infection and with extracardiac infection In patients with a CIED infection and extracardiac sites of infection, treatment prior to reimplantation should be sufficient to make relapse and recurrent bacteremia highly unlikely. For patients with TEE demonstrating only lead vegetation and for patients with bacteremia but no vegetation on TEE (ie, patients with no valve or extracardiac sites of infection), the new CIED may be implanted once surveillance blood cultures following device removal are negative for at least 72 hours of therapy. Isolated pocket infection For patients with isolated pocket CIED infection (no vegetation on TEE and negative blood cultures), the new CIED may be implanted once there is sufficient control of the local infection. For patients with pocket infection with minimal https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 11/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate inflammation or device exposure due to erosion, same-day reimplantation on the contralateral side place has been performed in small numbers of pacer dependent patients [1,46]; however, published experience with this approach is limited, and the severity of infection and other clinical factors (eg, pacemaker dependence) should be considered carefully in deciding on timing of reimplantation. The new CIED should not be placed at the site of the previously infected device if any alternative exists. Contralateral CIED implant is reasonable in many scenarios. In addition to intravascular CIEDs, subcutaneous ICDs or leadless pacemakers, when clinically appropriate, pose a lower risk of intravascular infection [47-49]. (See "Subcutaneous implantable cardioverter defibrillators", section on 'When to consider the S-ICD' and "Permanent cardiac pacing: Overview of devices and indications", section on 'Leadless systems'.) PREVENTION Implantation of CIEDs (ie, pacemakers or implantable cardioverter-defibrillators [ICDs]) should be performed with assiduous aseptic and surgical techniques in a controlled environment; the same is true of changing pulse-generator units [2,5,50]. CIED implantation should be deferred in the setting of active infection elsewhere [1]. Efforts to prevent CIED infection have been reviewed in detail; the major considerations are noted below [51]. Operator experience affects outcome; ideally, the procedure should be performed by an individual who has done many CIED implantations [5,52,53]. (See "Cardiac implantable electronic devices: Periprocedural complications", section on 'Operator characteristics' and "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Risk factors'.) Anticoagulation or antiplatelet therapy Pocket hematomas are associated with a significantly increased risk of CIED infection. Accordingly, careful attention should be directed to current anticoagulation or antiplatelet therapy. For patients with CHA DS -VASc <4 (calculator 1) 2 2 (eg, those not at high risk for embolic events), anticoagulation should be held prior to the procedure. Bridging anticoagulation with heparin is not recommended. Ideally, antiplatelet therapy should be held for 5 to 10 days before the procedure [5]. (See "Cardiac implantable electronic devices: Periprocedural complications", section on 'Bleeding'.) Antibiotic prophylaxis at device implantation Systemic antibiotic prophylaxis is warranted for surgical implantation of foreign devices. We are in agreement with the American Heart Association and the Heart Rhythm Society, which recommend prophylaxis with antistaphylococcal antimicrobial drugs at the time CIEDs are implanted or generator units https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 12/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate exchanged [1,2,5]. The dosing regimens are similar to those used for cardiac surgery (eg, cefazolin 2 g [3 g for those weighing >120 kg] intravenously within 60 minutes of surgical incision or, if there is concern about cephalosporin allergy or colonization by methicillin-resistant staphylococci, vancomycin 1 g intravenously within 90 to 120 minutes before the incision) ( table 3) [2,54]. For patients who cannot tolerate beta-lactam antibiotics or vancomycin, daptomycin or linezolid are alternatives [2]. (See "Antimicrobial prophylaxis for prevention of surgical site infection in adults", section on 'Antibiotic selection'.) Contamination with skin flora is responsible for a significant proportion of CIED infections; antibiotic prophylaxis reduces risk for device infection [55-59]. In a randomized trial including 1000 patients randomized to receive either cefazolin or placebo prior to CIED implantation, those who received cefazolin had a lower infection rate than those who received placebo (0.6 versus 3.3 percent) [58]. Administration of incremental perioperative antibiotics does not appear to confer benefit over conventional administration of preoperative antibiotic therapy for prevention of CIED infection. In the PADIT (Prevention of Arrhythmia Device Infection Trial) trial, a cluster randomized trial including 19,603 patients undergoing CIED procedures at 28 centers (including 12,842 "high risk" patients undergoing any repeat CIED procedure or cardiac resynchronization therapy procedure), patients were randomized to incremental treatment (which included preprocedural cefazolin plus vancomycin, intraprocedural bacitracin pocket wash, and oral cephalexin for two days following the procedure) or conventional therapy (preprocedural cefazolin) [59]. Compared with cefazolin prior to the procedure, there was no significant difference in the hospitalization rate for CIED infection within one year overall (odds ratio [OR] 0.77, 95% CI 0.56-1.05) or within the risk-related subpopulations (high-risk patients: OR 0.82, 95% CI 0.59-1.15; low-risk patients: OR 0.77, 95% CI 0.56-1.05). Antibiotic prophylaxis for other clinical procedures There is no role for routine prophylaxis at times of mucosal trauma or manipulation for patients with CIEDs, unless there is another independent indication for endocarditis prophylaxis [2,60]. Transient bacteremia associated with mucosal trauma rarely results in CIED infection. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".) Some experts favor deferring elective procedures that pose a risk for bacteremia (such as colonoscopy or dental work) for 8 to 12 weeks following CIED implantation if possible; however, there are no data regarding the benefit of this practice. Use of antibiotic-impregnated envelopes We suggest using an antibiotic-impregnated absorbable envelope at the time of CIED implantation or generator replacement in patients at increased risk for CIED infection wherein benefit has been established in a prospective https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 13/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate randomized trial [5,61]. This approach is based on the reduction in major CIED infections in certain higher-risk populations in the WRAP-IT trial [62]. Utilizing an antibiotic-impregnated absorbable envelope consists of placing the CIED pulse generator in an absorbable mesh envelope that is impregnated with minocycline and rifampin such that these antibiotics are slowly released in the generator pocket. All CIED recipients, including those whose device is placed in an envelope, should still receive preprocedure systemic antibiotic prophylaxis. Data regarding the efficacy of antibiotic-impregnated envelopes are derived from one randomized trial and nonrandomized cohort studies [62-65]. Published in 2019, the WRAP-IT trial randomized 6983 patients who were considered at increased risk for major CIED infection to either have the device encased in an antibiotic- impregnated absorbable envelope or not (control group) [62]. The study population was comprised of patients undergoing CIED generator replacement, system upgrade, pocket or lead revision, or those undergoing initial cardiac resynchronization-defibrillator (CRT-D). Standard-of-care infection prevention was provided to all patients. During the 12-month postprocedure follow-up, the primary end point of a major device infection (defined as

https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 11/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate inflammation or device exposure due to erosion, same-day reimplantation on the contralateral side place has been performed in small numbers of pacer dependent patients [1,46]; however, published experience with this approach is limited, and the severity of infection and other clinical factors (eg, pacemaker dependence) should be considered carefully in deciding on timing of reimplantation. The new CIED should not be placed at the site of the previously infected device if any alternative exists. Contralateral CIED implant is reasonable in many scenarios. In addition to intravascular CIEDs, subcutaneous ICDs or leadless pacemakers, when clinically appropriate, pose a lower risk of intravascular infection [47-49]. (See "Subcutaneous implantable cardioverter defibrillators", section on 'When to consider the S-ICD' and "Permanent cardiac pacing: Overview of devices and indications", section on 'Leadless systems'.) PREVENTION Implantation of CIEDs (ie, pacemakers or implantable cardioverter-defibrillators [ICDs]) should be performed with assiduous aseptic and surgical techniques in a controlled environment; the same is true of changing pulse-generator units [2,5,50]. CIED implantation should be deferred in the setting of active infection elsewhere [1]. Efforts to prevent CIED infection have been reviewed in detail; the major considerations are noted below [51]. Operator experience affects outcome; ideally, the procedure should be performed by an individual who has done many CIED implantations [5,52,53]. (See "Cardiac implantable electronic devices: Periprocedural complications", section on 'Operator characteristics' and "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Risk factors'.) Anticoagulation or antiplatelet therapy Pocket hematomas are associated with a significantly increased risk of CIED infection. Accordingly, careful attention should be directed to current anticoagulation or antiplatelet therapy. For patients with CHA DS -VASc <4 (calculator 1) 2 2 (eg, those not at high risk for embolic events), anticoagulation should be held prior to the procedure. Bridging anticoagulation with heparin is not recommended. Ideally, antiplatelet therapy should be held for 5 to 10 days before the procedure [5]. (See "Cardiac implantable electronic devices: Periprocedural complications", section on 'Bleeding'.) Antibiotic prophylaxis at device implantation Systemic antibiotic prophylaxis is warranted for surgical implantation of foreign devices. We are in agreement with the American Heart Association and the Heart Rhythm Society, which recommend prophylaxis with antistaphylococcal antimicrobial drugs at the time CIEDs are implanted or generator units https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 12/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate exchanged [1,2,5]. The dosing regimens are similar to those used for cardiac surgery (eg, cefazolin 2 g [3 g for those weighing >120 kg] intravenously within 60 minutes of surgical incision or, if there is concern about cephalosporin allergy or colonization by methicillin-resistant staphylococci, vancomycin 1 g intravenously within 90 to 120 minutes before the incision) ( table 3) [2,54]. For patients who cannot tolerate beta-lactam antibiotics or vancomycin, daptomycin or linezolid are alternatives [2]. (See "Antimicrobial prophylaxis for prevention of surgical site infection in adults", section on 'Antibiotic selection'.) Contamination with skin flora is responsible for a significant proportion of CIED infections; antibiotic prophylaxis reduces risk for device infection [55-59]. In a randomized trial including 1000 patients randomized to receive either cefazolin or placebo prior to CIED implantation, those who received cefazolin had a lower infection rate than those who received placebo (0.6 versus 3.3 percent) [58]. Administration of incremental perioperative antibiotics does not appear to confer benefit over conventional administration of preoperative antibiotic therapy for prevention of CIED infection. In the PADIT (Prevention of Arrhythmia Device Infection Trial) trial, a cluster randomized trial including 19,603 patients undergoing CIED procedures at 28 centers (including 12,842 "high risk" patients undergoing any repeat CIED procedure or cardiac resynchronization therapy procedure), patients were randomized to incremental treatment (which included preprocedural cefazolin plus vancomycin, intraprocedural bacitracin pocket wash, and oral cephalexin for two days following the procedure) or conventional therapy (preprocedural cefazolin) [59]. Compared with cefazolin prior to the procedure, there was no significant difference in the hospitalization rate for CIED infection within one year overall (odds ratio [OR] 0.77, 95% CI 0.56-1.05) or within the risk-related subpopulations (high-risk patients: OR 0.82, 95% CI 0.59-1.15; low-risk patients: OR 0.77, 95% CI 0.56-1.05). Antibiotic prophylaxis for other clinical procedures There is no role for routine prophylaxis at times of mucosal trauma or manipulation for patients with CIEDs, unless there is another independent indication for endocarditis prophylaxis [2,60]. Transient bacteremia associated with mucosal trauma rarely results in CIED infection. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".) Some experts favor deferring elective procedures that pose a risk for bacteremia (such as colonoscopy or dental work) for 8 to 12 weeks following CIED implantation if possible; however, there are no data regarding the benefit of this practice. Use of antibiotic-impregnated envelopes We suggest using an antibiotic-impregnated absorbable envelope at the time of CIED implantation or generator replacement in patients at increased risk for CIED infection wherein benefit has been established in a prospective https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 13/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate randomized trial [5,61]. This approach is based on the reduction in major CIED infections in certain higher-risk populations in the WRAP-IT trial [62]. Utilizing an antibiotic-impregnated absorbable envelope consists of placing the CIED pulse generator in an absorbable mesh envelope that is impregnated with minocycline and rifampin such that these antibiotics are slowly released in the generator pocket. All CIED recipients, including those whose device is placed in an envelope, should still receive preprocedure systemic antibiotic prophylaxis. Data regarding the efficacy of antibiotic-impregnated envelopes are derived from one randomized trial and nonrandomized cohort studies [62-65]. Published in 2019, the WRAP-IT trial randomized 6983 patients who were considered at increased risk for major CIED infection to either have the device encased in an antibiotic- impregnated absorbable envelope or not (control group) [62]. The study population was comprised of patients undergoing CIED generator replacement, system upgrade, pocket or lead revision, or those undergoing initial cardiac resynchronization-defibrillator (CRT-D). Standard-of-care infection prevention was provided to all patients. During the 12-month postprocedure follow-up, the primary end point of a major device infection (defined as infection causing CIED removal or revision without removal, prolonged antibiotic therapy in lieu of removal, or death) occurred in 25 (0.7 percent) of envelope recipients and 42 patients (1.2 percent) in the control group (hazard ratio [HR] 0.60, 95% CI 0.36-0.95). Among the major infections, pocket infections were the predominant clinical event (occurring in 14 [0.4 percent] of the envelope patients and 35 patients [1.0 percent] in the control patients [HR 0.30, 95% CI 0.21-0.72]); the rate of bacteremia or endocarditis did not differ significantly between the groups. In subgroup analyses, the only significant difference in major infections was noted among the ICD or CRT-D recipients. An in-depth analysis of the microbiology of infections in the WRAP-IT trial demonstrated that patients who received an envelope had a 76 percent reduction in staphylococcus- related pocket infection (HR 0.24, 95% CI 0.08-0.71) with no major difference in staphylococcal systemic infections (HR 4.0, 95% CI 0.87-19.32) [66]. Subsequent publication of longer-term follow-up (mean 21 months) demonstrated a sustained reduction in major CIED infections (HR 0.66) among recipients of the antibiotic-impregnated envelope, an effect that was driven mostly by a reduction in major pocket infections [67]. Further support of the WRAP-IT trial is seen in systematic reviews and meta-analyses. In a meta-analysis of six studies including 11,899 patients, the 5844 who underwent implantations with an antibiotic-impregnated envelope experienced significantly fewer major CIED infections in both the pooled and propensity matched analyses (OR 0.34 [95% https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 14/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate CI 0.13-0.86] and OR 0.29 [95% CI 0.10-0.82], respectively) [61]. Mortality rates were not significantly reduced in envelope recipients. The efficacy of antibiotic-impregnated envelopes accrues in high infection risk patients; in fact, there is no benefit in subgroup analyses when envelope recipients are compared to a low-risk population. Cost considerations have prompted further efforts to better define the patient population at greatest likelihood of benefit from these envelopes [68]. In addition to the device- related factors mentioned above, some of highest risks for CIED infection include end-stage kidney disease, prior CIED infection, fever prior to implantation, and immune suppression [68]. It is not fully known if antibiotic envelopes would reduce infection in all of these scenarios, particularly those in which the infection is bloodborne rather than via the skin or surgical site. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infections involving cardiac implantable electronic devices".) SUMMARY AND RECOMMENDATIONS Cardiac implantable electronic devices (CIEDs) include pacemakers and implantable cardioverter-defibrillators (ICDs). Management of CIED infection includes antibiotic therapy, CIED explantation (leads and pulse generator), and, if indication for CIED persists, CIED reimplantation (through an uninfected route) ( algorithm 4 and algorithm 1 and algorithm 2 and algorithm 3). (See 'General principles' above.) Antibiotic therapy In general, initial empiric antibiotic therapy assumes systemic infection and utilizes regimens designed to treat endocarditis. Subsequently, antibiotic therapy should be tailored to the extent and etiology of infection once defined (via blood and/or pocket wound cultures). (See 'Antibiotic therapy' above.) Empiric antibiotic therapy for patients with suspected CIED infection should consist of antistaphylococcal therapy. Given the high incidence of methicillin resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis, initial therapy with vancomycin is reasonable. In patients presenting with hemodynamic instability, broadening of therapy to include gram-negative bacteria is appropriate. (See 'Empiric therapy' above.) https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 15/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Once a causative organism is identified (via blood and/or pocket wound cultures), the antibiotic regimen should be tailored accordingly. Definitive antibiotic therapy is based on the recovered pathogen and its antibiotic susceptibility. The antibiotic selection and duration (generally four to six weeks) are based on pathogen-specific regimens for treatment of endocarditis ( algorithm 4 and algorithm 1 and algorithm 3). (See 'Definitive therapy' above.) We favor four to six weeks of parenteral antibiotic therapy for definitive or presumptive endocarditis in the following circumstances (see "Antimicrobial therapy of left-sided native valve endocarditis" and "Antimicrobial therapy of prosthetic valve endocarditis"): Patients with transesophageal echocardiography (TEE) or other imaging demonstrating a valve or lead vegetation. Patients with bacteremia due to S. aureus, coagulase-negative Staphylococcus (high grade), Cutibacterium (formerly Propionibacterium) species (high grade), Candida species; high-grade bacteremia is defined as multiple (two or more) separate blood cultures positive for the same organism, drawn 1 hour apart. Patients with bacteremia due to alpha-hemolytic streptococci, non-Group A beta- hemolytic streptococci, or enterococcus (high grade and/or no clear alternative source). A two-week course of antibiotic therapy is reasonable in the following circumstances (see 'Definitive therapy' above): Patients with no lead or valve vegetation on TEE and bacteremia due to a gram-negative organism, Streptococcus pneumoniae, or transient bacteremia from a clear alternative source due to an organism that does not commonly cause endocarditis Patients with CIED pocket infection only (no lead or valve vegetation on TEE, sterile blood cultures, and no clinical evidence suggesting systemic infection) Device management We recommend CIED removal (leads, including residual non-functional leads, and pulse generator ( algorithm 4 and algorithm 1 and algorithm 3) (Grade 1B) (see 'Device removal versus retention' above). These include: Patients with TEE or other imaging demonstrating valve or lead vegetation with suspicion or confirmation of bloodstream infection https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 16/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Patients with bacteremia due to S. aureus, coagulase-negative Staphylococcus (high grade), Cutibacterium (formerly Propionibacterium) species (high grade), Candida species, or high-grade bacteremia due to another organism with propensity to cause endocarditis Patients with CIED pocket infection (based on clinical manifestations of pain or tenderness, erythema, swelling, purulent drainage, pocket deformation, and/or percutaneous exposure/erosion of the generator and/or leads) or imaging studies Device retention may be reasonably attempted in a few limited circumstances. These include absence of vegetation on TEE in the setting of bacteremia due to a gram-negative organism or S. pneumoniae, or transient bacteremia from a clear alternative source due to an organism that does not commonly cause endocarditis. (See 'Retention criteria' above.) An approach to device reimplantation is summarized in the algorithm ( algorithm 2). (See 'Device reimplantation' above.) Prevention At the time of all CIED implantations, generator exchanges, or upgrades, we recommend systemic preprocedure antimicrobial prophylaxis ( table 3) (Grade 1A). Additionally, in patients at increased risk of CIED infection (eg, patients undergoing CIED generator replacement, lead revision, system upgrade, or CRT-D placement), we suggest using an antibiotic-impregnated absorbable envelope at the time of CIED implantation (Grade 2B). (See 'Antibiotic prophylaxis at device implantation' above and 'Use of antibiotic- impregnated envelopes' above.) Unless there is an independent indication for endocarditis prophylaxis, we suggest not administering antimicrobial prophylaxis at times of mucosal trauma or manipulation (Grade 2C). (See 'Antibiotic prophylaxis for other clinical procedures' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kusumoto FM, Schoenfeld MH, Wilkoff BL, et al. 2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction. Heart Rhythm 2017; 14:e503. 2. Baddour LM, Epstein AE, Erickson CC, et al. Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 17/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Association. Circulation 2010; 121:458. 3. Baddour LM, Cha YM, Wilson WR. Clinical practice. Infections of cardiovascular implantable electronic devices. N Engl J Med 2012; 367:842. 4. Sandoe JA, Barlow G, Chambers JB, et al. Guidelines for the diagnosis, prevention and management of implantable cardiac electronic device infection. Report of a joint Working Party project on behalf of the British Society for Antimicrobial Chemotherapy (BSAC, host organization), British Heart Rhythm Society (BHRS), British Cardiovascular Society (BCS), British Heart Valve Society (BHVS) and British Society for Echocardiography (BSE). J Antimicrob Chemother 2015; 70:325. 5. Blomstr m-Lundqvist C, Traykov V, Erba PA, et al. European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2020; 41:2012. 6. DeSimone DC, Sohail MR, Mulpuru SK. Contemporary management of cardiac implantable electronic device infection. Heart 2019; 105:961. 7. Esquer Garrigos Z, George MP, Khalil S, et al. Predictors of Bloodstream Infection in Patients Presenting With Cardiovascular Implantable Electronic Device Pocket Infection. Open Forum Infect Dis 2019; 6:ofz084. 8. van Hal SJ, Paterson DL, Gosbell IB. Emergence of daptomycin resistance following vancomycin-unresponsive Staphylococcus aureus bacteraemia in a daptomycin-na ve patient a review of the literature. Eur J Clin Microbiol Infect Dis 2011; 30:603. 9. Baddour LM, Wilson WR. Infections of prosthetic valves and intravascular devices. In: Princip les and Practice of Infectious Diseases, 6th ed, Mandell GL, Bennett JE, Dolin R (Eds), Churchil l Livingstone, Philadelphia 2005. p.1022. 10. Tarakji KG, Chan EJ, Cantillon DJ, et al. Cardiac implantable electronic device infections: presentation, management, and patient outcomes. Heart Rhythm 2010; 7:1043. 11. Kaasch AJ, Fowler VG Jr, Rieg S, et al. Use of a simple criteria set for guiding echocardiography in nosocomial Staphylococcus aureus bacteremia. Clin Infect Dis 2011; 53:1. 12. Nakajima I, Narui R, Tokutake K, et al. Staphylococcus bacteremia without evidence of cardiac implantable electronic device infection. Heart Rhythm 2021; 18:752. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 18/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate 13. stergaard L, Bruun NE, Voldstedlund M, et al. Prevalence of infective endocarditis in patients with positive blood cultures: a Danish nationwide study. Eur Heart J 2019; 40:3237. 14. Sunnerhagen T, T rnell A, Vikbrant M, et al. HANDOC: A Handy Score to Determine the Need for Echocardiography in Non- -Hemolytic Streptococcal Bacteremia. Clin Infect Dis 2018; 66:693. 15. Berge A, Krantz A, stlund H, et al. The DENOVA score efficiently identifies patients with monomicrobial Enterococcus faecalis bacteremia where echocardiography is not necessary. Infection 2019; 47:45. 16. Berge A, Kronberg K, Sunnerhagen T, et al. Risk for Endocarditis in Bacteremia With Streptococcus-Like Bacteria: A Retrospective Population-Based Cohort Study. Open Forum Infect Dis 2019; 6:ofz437. 17. Duval X, Selton-Suty C, Alla F, et al. Endocarditis in patients with a permanent pacemaker: a 1-year epidemiological survey on infective endocarditis due to valvular and/or pacemaker infection. Clin Infect Dis 2004; 39:68. 18. Maskarinec SA, Thaden JT, Cyr DD, et al. The Risk of Cardiac Device-Related Infection in Bacteremic Patients Is Species Specific: Results of a 12-Year Prospective Cohort. Open Forum Infect Dis 2017; 4:ofx132. 19. Joly V, Belmatoug N, Leperre A, et al. Pacemaker endocarditis due to Candida albicans: case report and review. Clin Infect Dis 1997; 25:1359. 20. Tascini C, Bongiorni MG, Tagliaferri E, et al. Micafungin for Candida albicans pacemaker- associated endocarditis: a case report and review of the literature. Mycopathologia 2013; 175:129. 21. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 62:e1. 22. Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio- Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015; 36:3075. 23. Halawa A, Henry PD, Sarubbi FA. Candida endocarditis associated with cardiac rhythm management devices: review with current treatment guidelines. Mycoses 2011; 54:e168. 24. Glavis-Bloom J, Vasher S, Marmor M, et al. Candida and cardiovascular implantable electronic devices: a case of lead and native aortic valve endocarditis and literature review. Mycoses 2015; 58:637. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 19/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate 25. Roger PM, Boissy C, Gari-Toussaint M, et al. Medical treatment of a pacemaker endocarditis due to Candida albicans and to Candida glabrata. J Infect 2000; 41:176. 26. Baman JR, Medhekar AN, Jain SK, et al. Management of systemic fungal infections in the presence of a cardiac implantable electronic device: A systematic review. Pacing Clin Electrophysiol 2021; 44:159. 27. Nakamura T, Narui R, Holmes B, et al. Candidemia in patients with cardiovascular implantable electronic devices. J Interv Card Electrophysiol 2021; 60:69. 28. Nasser RM, Melgar GR, Longworth DL, Gordon SM. Incidence and risk of developing fungal prosthetic valve endocarditis after nosocomial candidemia. Am J Med 1997; 103:25. 29. Rivera NT, Bray N, Wang H, et al. Rare infection of implantable cardioverter-defibrillator lead with Candida albicans: case report and literature review. Ther Adv Cardiovasc Dis 2014; 8:193. 30. Patel NJ, Singleton MJ, Brunetti R, et al. Evaluation of lead-based echodensities on transesophageal echocardiogram in patients with cardiac implantable electronic devices. J Cardiovasc Electrophysiol 2023; 34:7. 31. George MP, Esquer Garrigos Z, Vijayvargiya P, et al. Discriminative Ability and Reliability of Transesophageal Echocardiography in Characterizing Cases of Cardiac Device Lead Vegetations Versus Noninfectious Echodensities. Clin Infect Dis 2021; 72:1938. 32. Grammes JA, Schulze CM, Al-Bataineh M, et al. Percutaneous pacemaker and implantable cardioverter-defibrillator lead extraction in 100 patients with intracardiac vegetations defined by transesophageal echocardiogram. J Am Coll Cardiol 2010; 55:886. 33. P rez Baztarrica G, Gariglio L, Salvaggio F, et al. Transvenous extraction of pacemaker leads in infective endocarditis with vegetations 20 mm: our experience. Clin Cardiol 2012; 35:244. 34. Meier-Ewert HK, Gray ME, John RM. Endocardial pacemaker or defibrillator leads with infected vegetations: a single-center experience and consequences of transvenous extraction. Am Heart J 2003; 146:339. 35. Mulpuru SK, Pretorius VG, Birgersdotter-Green UM. Device infections: management and indications for lead extraction. Circulation 2013; 128:1031. 36. Richardson TD, Lugo RM, Crossley GH, Ellis CR. Use of a clot aspiration system during transvenous lead extraction. J Cardiovasc Electrophysiol 2020; 31:718. 37. Starck CT, Schaerf RHM, Breitenstein A, et al. Transcatheter aspiration of large pacemaker and implantable cardioverter-defibrillator lead vegetations facilitating safe transvenous lead extraction. Europace 2020; 22:133. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 20/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate 38. Chesdachai S, Baddour LM, Sohail MR, et al. Evaluation of European Heart Rhythm Association consensus in patients with cardiovascular implantable electronic devices and Staphylococcus aureus bacteremia. Heart Rhythm 2022; 19:570. 39. Le KY, Sohail MR, Friedman PA, et al. Impact of timing of device removal on mortality in patients with cardiovascular implantable electronic device infections. Heart Rhythm 2011; 8:1678. 40. Athan E, Chu VH, Tattevin P, et al. Clinical characteristics and outcome of infective endocarditis involving implantable cardiac devices. JAMA 2012; 307:1727. 41. Topaz M, Chorin E, Schwartz AL, et al. Regional Antibiotic Delivery for Implanted Cardiovascular Electronic Device Infections. J Am Coll Cardiol 2023; 81:119. 42. Lee JZ, Agasthi P, Pasha AK, et al. Stroke in patients with cardiovascular implantable electronic device infection undergoing transvenous lead removal. Heart Rhythm 2018; 15:1593. 43. Tan EM, DeSimone DC, Sohail MR, et al. Outcomes in Patients With Cardiovascular Implantable Electronic Device Infection Managed With Chronic Antibiotic Suppression. Clin Infect Dis 2017; 64:1516. 44. Uslan DZ, Dowsley TF, Sohail MR, et al. Cardiovascular implantable electronic device infection in patients with Staphylococcus aureus bacteremia. Pacing Clin Electrophysiol 2010; 33:407. 45. Arshad V, Baddour LM, Lahr BD, et al. Impact of delayed device re-implantation on outcomes of patients with cardiovascular implantable electronic device related infective endocarditis. Pacing Clin Electrophysiol 2021; 44:1303. 46. Mountantonakis SE, Tschabrunn CM, Deyell MW, Cooper JM. Same-day contralateral implantation of a permanent device after lead extraction for isolated pocket infection. Europace 2014; 16:252. 47. El-Chami MF, Soejima K, Piccini JP, et al. Incidence and outcomes of systemic infections in patients with leadless pacemakers: Data from the Micra IDE study. Pacing Clin Electrophysiol 2019; 42:1105. 48. Burke MC, Gold MR, Knight BP, et al. Safety and Efficacy of the Totally Subcutaneous Implantable Defibrillator: 2-Year Results From a Pooled Analysis of the IDE Study and EFFORTLESS Registry. J Am Coll Cardiol 2015; 65:1605. 49. Boersma L, Burke MC, Neuzil P, et al. Infection and mortality after implantation of a subcutaneous ICD after transvenous ICD extraction. Heart Rhythm 2016; 13:157. 50. Padfield GJ, Steinberg C, Bennett MT, et al. Preventing cardiac implantable electronic device infections. Heart Rhythm 2015; 12:2344. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 21/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate 51. Blomstrom-Lundqvist C, Ostrowska B. Prevention of cardiac implantable electronic device infections: guidelines and conventional prophylaxis. Europace 2021; 23:iv11. 52. Harcombe AA, Newell SA, Ludman PF, et al. Late complications following permanent pacemaker implantation or elective unit replacement. Heart 1998; 80:240. 53. Byrd CL, Wilkoff BL, Love CJ, et al. Intravascular extraction of problematic or infected permanent pacemaker leads: 1994-1996. U.S. Extraction Database, MED Institute. Pacing Clin Electrophysiol 1999; 22:1348. 54. Antimicrobial prophylaxis for surgery. Treat Guidel Med Lett 2012; 10:73. 55. Bertaglia E, Zerbo F, Zardo S, et al. Antibiotic prophylaxis with a single dose of cefazolin during pacemaker implantation: incidence of long-term infective complications. Pacing Clin Electrophysiol 2006; 29:29. 56. Klug D, Balde M, Pavin D, et al. Risk factors related to infections of implanted pacemakers and cardioverter-defibrillators: results of a large prospective study. Circulation 2007; 116:1349. 57. Sohail MR, Uslan DZ, Khan AH, et al. Risk factor analysis of permanent pacemaker infection. Clin Infect Dis 2007; 45:166. 58. de Oliveira JC, Martinelli M, Nishioka SA, et al. Efficacy of antibiotic prophylaxis before the implantation of pacemakers and cardioverter-defibrillators: results of a large, prospective, randomized, double-blinded, placebo-controlled trial. Circ Arrhythm Electrophysiol 2009; 2:29. 59. Krahn AD, Longtin Y, Philippon F, et al. Prevention of Arrhythmia Device Infection Trial: The PADIT Trial. J Am Coll Cardiol 2018; 72:3098. 60. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116:1736. 61. Callahan TD, Tarakji KG, Wilkoff BL. Antibiotic eluting envelopes: evidence, technology, and defining high-risk populations. Europace 2021; 23:iv28. 62. Tarakji KG, Mittal S, Kennergren C, et al. Antibacterial Envelope to Prevent Cardiac Implantable Device Infection. N Engl J Med 2019; 380:1895. 63. Koerber SM, Turagam MK, Winterfield J, et al. Use of antibiotic envelopes to prevent cardiac implantable electronic device infections: A meta-analysis. J Cardiovasc Electrophysiol 2018; 29:609. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 22/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate 64. Hirsh DS, Bloom HL. Clinical use of antibacterial mesh envelopes in cardiovascular electronic device implantations. Med Devices (Auckl) 2015; 8:71. 65. Ullah W, Nadeem N, Haq S, et al. Efficacy of antibacterial envelope in prevention of cardiovascular implantable electronic device infections in high-risk patients: A systematic review and meta-analysis. Int J Cardiol 2020; 315:51. 66. Sohail MR, Corey GR, Wilkoff BL, et al. Clinical Presentation, Timing, and Microbiology of CIED Infections: An Analysis of the WRAP-IT Trial. JACC Clin Electrophysiol 2021; 7:50. 67. Mittal S, Wilkoff BL, Kennergren C, et al. The World-wide Randomized Antibiotic Envelope Infection Prevention (WRAP-IT) trial: Long-term follow-up. Heart Rhythm 2020; 17:1115. 68. Traykov V, Blomstr m-Lundqvist C. Antibiotic-Eluting Envelopes for the Prevention of Cardiac Implantable Electronic Device Infections: Rationale, Efficacy, and Cost-Effectiveness. Front Cardiovasc Med 2022; 9:855233. Topic 116021 Version 18.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 23/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate GRAPHICS Approach to evaluation and management of suspected infection limited to cardiac implantable electronic device (CIED) pocket in adults https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 24/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate TEE: transesophageal echocardiogram; FDG PET/CT: fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography; SPECT/CT: radiolabeled autologous white blood cell single-photon emission computed tomography with computed tomography; MRSA: methicillin- resistant Staphylococcus aureus. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 25/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Refer to separate UpToDate algorithm for approach to patients with systemic symptoms, positive blood cultures, and/or vegetation on TEE. FDG PET/CT may be useful to distinguish between CIED pocket infection and superficial site infection in some circumstances; refer to the UpToDate topic on diagnosis of CIED infection for further discussion. Oral antibiotic dosing as follows: Cephalexin 500 mg orally 4 times daily Clindamycin 300 to 450 mg orally 4 times daily (use higher dose for patients with weight >120 kg) Dicloxacillin 500 mg orally 4 times daily Doxycycline 100 mg orally twice daily Linezolid 600 mg orally twice daily Minocycline 200 mg orally once, then 100 mg orally every 12 hours Trimethoprim-sulfamethoxazole 1 to 2 double-strength tablets orally every 12 hours We favor initial therapy with vancomycin (15 to 20 mg/kg/dose intravenously every 8 to 12 hours [not to exceed 2 g per dose]); refer to UpToDate text for discussion of alternative agents. Graphic 117258 Version 5.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 26/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Approach to reimplantation of cardiac implanted electronic device (CIED) following removal of an infected device (for patients who require CIED reimplantation) TEE: transesophageal echocardiogram. Refer to separate UpToDate algorithms for approach to diagnosis and antibiotic therapy for management of CIED infection. Temporary pacing may be required; refer to the UpToDate text for further discussion. Graphic 117259 Version 1.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 27/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Approach to management of adults with suspected CIED infection and negative UpToDate algorithm for approach to initial diagnostic evaluation) CIED: cardiac implantable electronic device; TEE: transesophageal echocardiogram; FDG PET/CT: fluorine-18 f tomography/computed tomography; SPECT/CT: single photon emission computed tomography/computed to High-grade bacteremia is defined as multiple (2 or more) separate blood cultures positive for the same orga for coagulase-negative staphylococci or Cutibacterium species may represent skin contamination. In such cas grade bacteremia. If repeat cultures are confounded by antibiotic therapy and clinical suspicion for CIED infec PET/CT) if available; further management should be guided by consultation with infectious disease expertise. Clinical suspicion is increased for organisms that commonly cause endocarditis. FDG PET/CT may be useful to establish a diagnosis of CIED infection in some circumstances. Other potentia https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 28/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate The choice and duration of antibiotic therapy is based on regimens for treatment of endocarditis caused by implicated (refer to UpToDate text and related topics). The duration of antibiotic therapy (usually 4 to 6 weeks warranted. The choice of antibiotic therapy is guided by culture results. Graphic 131691 Version 2.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 29/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Approach to evaluation and management of suspected infection of a cardiac implantable electronic device (CIED) in adults TTE: transthoracic echocardiogram; TEE: transesophageal echocardiogram. Signs and symptoms of an isolated CIED pocket infection include pocket erythema, discomfort, swelling, incision dehiscence, deformation, and erosion. Signs and symptoms of endocarditis include new murmur, new regurgitation, vegetation, paravalvular leak, evidence of pulmonary or systemic emboli, and immune phenomena. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 30/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Vancomycin dosing consists of 15 to 20 mg/kg/dose intravenously every 8 to 12 hours (not to exceed 2 g per dose); in patients presenting with severe sepsis, broadening of parenteral therapy to include gram-negative bacteria is appropriate. Refer to UpToDate text for further discussion. The choice of antibiotic regimen is guided by blood culture results (refer to UpToDate text). The duration of antibiotic therapy (4 to 6 weeks) should be counted from the day of device explantation, if warranted. Graphic 117257 Version 7.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 31/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Approach to vancomycin dosing for adults with normal kidney function* Loading dose (for patients with known or Load 20 to 35 mg/kg (based on actual body suspected severe Staphylococcus aureus weight, rounded to the nearest 250 mg infection) increment; not to exceed 3000 mg). Within this range, we use a higher dose for critically ill patients; we use a lower dose for patients who are obese and/or are receiving vancomycin via continuous infusion. Initial maintenance dose and interval Typically 15 to 20 mg/kg every 8 to 12 hours for most patients (based on actual body weight, rounded to the nearest 250 mg increment). In general, the approach to establishing the vancomycin dose/interval is guided by a nomogram. Subsequent dose and interval adjustments Based on AUC-guided (preferred for severe [1]

66. Sohail MR, Corey GR, Wilkoff BL, et al. Clinical Presentation, Timing, and Microbiology of CIED Infections: An Analysis of the WRAP-IT Trial. JACC Clin Electrophysiol 2021; 7:50. 67. Mittal S, Wilkoff BL, Kennergren C, et al. The World-wide Randomized Antibiotic Envelope Infection Prevention (WRAP-IT) trial: Long-term follow-up. Heart Rhythm 2020; 17:1115. 68. Traykov V, Blomstr m-Lundqvist C. Antibiotic-Eluting Envelopes for the Prevention of Cardiac Implantable Electronic Device Infections: Rationale, Efficacy, and Cost-Effectiveness. Front Cardiovasc Med 2022; 9:855233. Topic 116021 Version 18.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 23/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate GRAPHICS Approach to evaluation and management of suspected infection limited to cardiac implantable electronic device (CIED) pocket in adults https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 24/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate TEE: transesophageal echocardiogram; FDG PET/CT: fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography; SPECT/CT: radiolabeled autologous white blood cell single-photon emission computed tomography with computed tomography; MRSA: methicillin- resistant Staphylococcus aureus. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 25/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Refer to separate UpToDate algorithm for approach to patients with systemic symptoms, positive blood cultures, and/or vegetation on TEE. FDG PET/CT may be useful to distinguish between CIED pocket infection and superficial site infection in some circumstances; refer to the UpToDate topic on diagnosis of CIED infection for further discussion. Oral antibiotic dosing as follows: Cephalexin 500 mg orally 4 times daily Clindamycin 300 to 450 mg orally 4 times daily (use higher dose for patients with weight >120 kg) Dicloxacillin 500 mg orally 4 times daily Doxycycline 100 mg orally twice daily Linezolid 600 mg orally twice daily Minocycline 200 mg orally once, then 100 mg orally every 12 hours Trimethoprim-sulfamethoxazole 1 to 2 double-strength tablets orally every 12 hours We favor initial therapy with vancomycin (15 to 20 mg/kg/dose intravenously every 8 to 12 hours [not to exceed 2 g per dose]); refer to UpToDate text for discussion of alternative agents. Graphic 117258 Version 5.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 26/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Approach to reimplantation of cardiac implanted electronic device (CIED) following removal of an infected device (for patients who require CIED reimplantation) TEE: transesophageal echocardiogram. Refer to separate UpToDate algorithms for approach to diagnosis and antibiotic therapy for management of CIED infection. Temporary pacing may be required; refer to the UpToDate text for further discussion. Graphic 117259 Version 1.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 27/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Approach to management of adults with suspected CIED infection and negative UpToDate algorithm for approach to initial diagnostic evaluation) CIED: cardiac implantable electronic device; TEE: transesophageal echocardiogram; FDG PET/CT: fluorine-18 f tomography/computed tomography; SPECT/CT: single photon emission computed tomography/computed to High-grade bacteremia is defined as multiple (2 or more) separate blood cultures positive for the same orga for coagulase-negative staphylococci or Cutibacterium species may represent skin contamination. In such cas grade bacteremia. If repeat cultures are confounded by antibiotic therapy and clinical suspicion for CIED infec PET/CT) if available; further management should be guided by consultation with infectious disease expertise. Clinical suspicion is increased for organisms that commonly cause endocarditis. FDG PET/CT may be useful to establish a diagnosis of CIED infection in some circumstances. Other potentia https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 28/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate The choice and duration of antibiotic therapy is based on regimens for treatment of endocarditis caused by implicated (refer to UpToDate text and related topics). The duration of antibiotic therapy (usually 4 to 6 weeks warranted. The choice of antibiotic therapy is guided by culture results. Graphic 131691 Version 2.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 29/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Approach to evaluation and management of suspected infection of a cardiac implantable electronic device (CIED) in adults TTE: transthoracic echocardiogram; TEE: transesophageal echocardiogram. Signs and symptoms of an isolated CIED pocket infection include pocket erythema, discomfort, swelling, incision dehiscence, deformation, and erosion. Signs and symptoms of endocarditis include new murmur, new regurgitation, vegetation, paravalvular leak, evidence of pulmonary or systemic emboli, and immune phenomena. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 30/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Vancomycin dosing consists of 15 to 20 mg/kg/dose intravenously every 8 to 12 hours (not to exceed 2 g per dose); in patients presenting with severe sepsis, broadening of parenteral therapy to include gram-negative bacteria is appropriate. Refer to UpToDate text for further discussion. The choice of antibiotic regimen is guided by blood culture results (refer to UpToDate text). The duration of antibiotic therapy (4 to 6 weeks) should be counted from the day of device explantation, if warranted. Graphic 117257 Version 7.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 31/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Approach to vancomycin dosing for adults with normal kidney function* Loading dose (for patients with known or Load 20 to 35 mg/kg (based on actual body suspected severe Staphylococcus aureus weight, rounded to the nearest 250 mg infection) increment; not to exceed 3000 mg). Within this range, we use a higher dose for critically ill patients; we use a lower dose for patients who are obese and/or are receiving vancomycin via continuous infusion. Initial maintenance dose and interval Typically 15 to 20 mg/kg every 8 to 12 hours for most patients (based on actual body weight, rounded to the nearest 250 mg increment). In general, the approach to establishing the vancomycin dose/interval is guided by a nomogram. Subsequent dose and interval adjustments Based on AUC-guided (preferred for severe [1] infection) or trough-guided serum concentration monitoring. AUC: area under the 24-hour time-concentration curve. Refer to the UpToDate topic on vancomycin dosing for management of patients with abnormal kidney function. For patients with known or suspected severe S. aureus infection, we suggest administration of a loading dose to reduce the likelihood of suboptimal initial vancomycin exposure. Severe S. aureus infections include (but are not limited to) bacteremia, endocarditis, osteomyelitis, prosthetic joint infection, pneumonia warranting hospitalization, infection involving the central nervous system, or infection causing critical illness. If possible, the nomogram should be developed and validated at the institution where it is used to best reflect the regional patient population. Refer to the UpToDate topic on vancomycin dosing for sample nomogram. Refer to the UpToDate topic on vancomycin dosing for discussion of AUC-guided and trough- guided vancomycin dosing. For patients with nonsevere infection who receive vancomycin for <3 days (in the setting of stable kidney function and absence of other risk factors for altered vancomycin kinetics), vancomycin concentration monitoring is often omitted; the value of such monitoring prior to achieving steady state (usually around treatment day 2 to 3) is uncertain. Reference: 1. Rybak MJ, Le J, Lodise TP, et al. Therapeutic Monitoring of Vancomycin for Serious Methicillin-Resistant Staphylococcus Aureus Infections: A Revised Consensus Guideline and Review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2020; 77:835. Graphic 128911 Version 5.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 32/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Management of Candida infections involving cardiac implantable electronic devices in adults Condition or treatment Therapy group Primary Step-down Comments Candida infections involving cardiac implantable electronic devices Implantable A lipid formulation of For patients who are Removal of the entire cardiac amphotericin B (3 to 5 clinically stable, have device is strongly defibrillator mg/kg IV daily) with or isolates that are recommended. or pacemaker without flucytosine* susceptible to For infections limited (25 mg/kg orally four fluconazole, and have to generator pockets, times daily); negative repeat blood 4 weeks of antifungal cultures following therapy following OR initiation of a lipid device removal is High-dose formulation of recommended. echinocandin amphotericin B or For infections (caspofungin 150 mg high-dose involving device wires, IV daily, micafungin echinocandin therapy, antifungal therapy 150 mg IV daily, or transition to oral should continue for at anidulafungin 200 mg fluconazole 400 to least 6 weeks after IV daily). 800 mg (6 to 12 wire removal. Some mg/kg) daily is specialists prefer appropriate. lifelong oral Oral voriconazole suppressive therapy 200 to 300 mg (3 to 4 after lead removal, mg/kg) twice daily or especially if there is posaconazole possible endocardial delayed-release infection or if a new tablets 300 mg daily device is implanted. can be used for step- down therapy in clinically stable patients who have isolates susceptible to these agents but not susceptible to fluconazole. The doses above are intended for adults with normal organ function. The dose of fluconazole and flucytosine must be adjusted in the setting of renal insufficiency; the caspofungin and voriconazole dose may require adjustment in hepatic insufficiency. Refer to the Lexicomp drug-specific monographs for additional information including specific dose adjustment recommendations. https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 33/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate IV: intravenous; VAD: ventricular assist device. Toxic effects on bone marrow and liver require careful monitoring preferably with frequent serum flucytosine levels; refer to accompanying text for discussion of benefits and risks of combined flucytosine and amphotericin B therapy. Since fluconazole is highly bioavailable, oral therapy is appropriate for most patients. IV therapy (at the same dose) should be given to patients who are unable to take oral medications, who are not expected to have good gastrointestinal absorption, or who are severely ill. Therapeutic drug monitoring should be considered; refer to the topic review on pharmacology of azoles for details. In patients with endocarditis caused by a Candida species that is not susceptible to fluconazole, oral voriconazole (200 or 300 mg [3 to 4 mg/kg] twice daily) or delayed-release posaconazole tablets (300 mg daily) should be used for chronic suppressive therapy if the organism is susceptible. Data from: Pappas PG, Kau man CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2015; 62:e1. Graphic 107269 Version 1.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 34/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Antimicrobial prophylaxis for cardiac surgery in adults Usual adult Nature of operation Recommended antimicrobials Redose interval Common pathogens dose* Cardiac Staphylococcus Cefazolin <120 kg: 2 4 hours procedures: aureus, Staphylococcus epidermidis g IV coronary artery 120 kg: 3 g IV bypass, cardiac device insertion OR cefuroxime 1.5 g IV 4 hours procedures (eg, pacemaker OR vancomycin 15 mg/kg N/A implantation), IV (max 2 placement of g) ventricular OR clindamycin 900 mg IV 6 hours assist devices IV: intravenous. Parenteral prophylactic antimicrobials can be given as a single IV dose begun within 60 minutes before the procedure. If vancomycin is used, the infusion should be started within 60 to 120 minutes before the initial incision to have adequate tissue levels at the time of incision and to minimize the possibility of an infusion reaction close to the time of induction of anesthesia. For prolonged procedures (>3 hours) or those with major blood loss or in patients with extensive burns, additional intraoperative doses should be given at intervals 1 to 2 times the half-life of the drug for the duration of the procedure in patients with normal renal function. Cefazolin is preferred over cefuroxime, given increasing resistance to second-generation cephalosporins. Indications for vancomycin are summarized in footnote . Clindamycin may be used for patients unable to tolerate the other agents listed. Some experts recommend an additional dose when patients are removed from bypass during open-heart surgery. Use of vancomycin is appropriate in hospitals in which methicillin-resistant S. aureus (MRSA) and S. epidermidis are a frequent cause of postoperative wound infection, in patients previously colonized with MRSA, or for those who are allergic to penicillins or cephalosporins. Rapid IV administration may cause hypotension, which could be especially dangerous during induction of anesthesia. Even when the drug is given over 60 minutes, hypotension may occur; treatment with diphenhydramine and further slowing of the infusion rate may be helpful. For procedures in which enteric gram-negative bacilli are common pathogens, many experts would add another drug such as an aminoglycoside (gentamicin 5 mg/kg IV), aztreonam (2 g IV), or a fluoroquinolone (ciprofloxacin 400 mg IV or levofloxacin 500 mg IV). https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 35/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Adapted from: 1. Antimicrobial prophylaxis for surgery. Med Lett Drugs Ther 2016; 58:63. 2. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surg Infect (Larchmt) 2013; 14:73. Graphic 76499 Version 16.0 https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 36/37 7/6/23, 10:53 AM Infections involving cardiac implantable electronic devices: Treatment and prevention - UpToDate Contributor Disclosures Adolf W Karchmer, MD Equity Ownership/Stock Options: AbbVie [Pharmaceuticals]; Johnson and Johnson [Pharmaceuticals]; Lilly [Pharmaceuticals]; Merck [Pharmaceuticals]; Pfizer [Pharmaceuticals]. Grant/Research/Clinical Trial Support: Karius [Endocarditis]. Consultant/Advisory Boards: Debio International [Antibiotic development]; Pfizer [Rheumatologic diseases, ulcerative colitis]. Other Financial Interest: Board of Directors [Winter Course in Infectious Diseases]. All of the relevant financial relationships listed have been mitigated. Vivian H Chu, MD, MHS No relevant financial relationship(s) with ineligible companies to disclose. Jay A Montgomery, MD No relevant financial relationship(s) with ineligible companies to disclose. Stephen B Calderwood, MD Consultant/Advisory Boards: Day Zero Diagnostics [Whole genome sequencing for microbial identification and determination of antimicrobial susceptibility]. All of the relevant financial relationships listed have been mitigated. Elinor L Baron, MD, DTMH No relevant financial relationship(s) with ineligible companies to disclose. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/infections-involving-cardiac-implantable-electronic-devices-treatment-and-prevention/print 37/37

7/6/23, 10:54 AM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Management of cardiac implantable electronic devices in patients receiving palliative care : Kapil Kumar, MD : R Sean Morrison, MD, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 22, 2023. INTRODUCTION Discontinuation of cardiac implantable electronic device (CIED) therapy, including both permanent pacemakers (PPMs) and implantable cardioverter-defibrillators (ICDs), is a complicated issue. For many patients, these are often life-sustaining therapies, with many ethical, legal, and religious principles that underlie the decision-making process to withdraw CIEDs. The issues related to changes in CIED therapy, including specific issues related to palliative care, will be discussed here. A more extensive discussion of palliative care planning and ethical issues which arise in palliative care are presented separately. (See "Palliative care: The last hours and days of life".) (See "Overview of comprehensive patient assessment in palliative care".) (See "Ethical issues in palliative care".) KEY CONCEPTS IN PALLIATIVE CARE A few key concepts specifically relevant to the management of CIEDs in patients receiving palliative care will be reviewed here ( algorithm 1). Advance care planning Patients at any stage of health or illness should be encouraged to engage in advance care planning to identify their goals of care, articulate wishes in the setting of serious illness, and name a surrogate decision maker. Advance care plans should also https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 1/16 7/6/23, 10:54 AM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate specifically address CIED management when the patient has one. Advance care plans and proxy designations can always be subsequently modified in the event of a change in clinical status or change in the patient's goals of care. (See "Advance care planning and advance directives" and "Discussing goals of care".) Patients and advance directives Advance care planning should be an important part of every patient's care plan regardless of underlying illness, but such advance directives take on additional importance for patients with significant medical comorbidities who are being considered for palliative care. Advance-care planning for patients with CIEDs however, still needs improvement, as evidenced by the following observational data [1-4]. In a retrospective study of the prevalence of an advanced directive among 420 patients with an implantable cardioverter-defibrillator (ICD), only 28 percent had an advance directive in place at the time of ICD implantation, with only 1 percent specifically addressing the issue of ICD deactivation at end of life [1]. In a survey of 278 patients with an ICD, more than half of the patients had executed an advance directive, but only 1 percent had included a plan for the management of the ICD [2]. In a nationwide survey of 3067 participants with CIEDs from the Swedish ICD and Pacemaker Registry which asked patients 11 questions (true or false type questions) about their knowledge of the ICD and its function in relation to end-of-life issues, 29 percent of patients were able to answer only five or fewer questions correctly, indicating a significant lack of understanding of the ICD and how it might impact quality of life in an end-of-life situation [3]. Clinicians and advance care planning Advance care plans should be an integral part of the clinical care plan for all patients, especially when caring for patients who are being considered for palliative care. However, patient and clinician understandings regarding the role of advanced directives and the capabilities of CIED programming can be vastly different [5-10]. As examples: In a survey of United States clinicians, one-third of internists and two-thirds of electrophysiologists who responded believed patients knew they could deactivate the shocking function of an ICD [5]. However, in a separate survey, nearly 50 percent of patients indicated that they had never considered ICD deactivation in the context of end-of- life situations [6]. Clinicians who believe that patients know the options for device management at the end of life may be less likely to discuss deactivation [5]. https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 2/16 7/6/23, 10:54 AM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate In a survey of 294 patients in the Netherlands, 68 percent believed that it is possible to turn the ICD off [7]. In contrast, in a 54 patient study in the United States, only 3 percent recalled receiving information about deactivation when providing consent for implantation, and 38 percent became aware later [8]. In one chart review of 150 patients who underwent device deactivation at a tertiary care center, 42 percent of patients with device deactivation had a palliative care consultation, and of those, 68 percent specifically addressed device deactivation, indicating the potential value of a palliative care consult regarding goals of care [9]. A separate study revealed that only 10 percent of hospice providers have a device deactivation policy [10]. When differing opinions or beliefs are present Although patients have the right to request withdrawal of therapy, it is possible that the personal and professional values of the provider and the patient may differ. Various professional society guidelines stipulate that clinicians in this position have an obligation to arrange for alternative provisions of care in cases of conscientious objection that cannot be resolved by ethics or clerical consultation [11-13]. Additionally, while ethicists are not routinely involved in decisions regarding withdrawal of CIED therapy, there are select occasions in which an ethics committee may be helpful, namely when the patient is unable to provide consent and there is a difference of opinion among family members and/or health care providers. Separate topic reviews on discussing goals of care and handling requests for potentially futile or inappropriate therapies are available. (See "Discussing goals of care" and "Palliative care: Medically futile and potentially inappropriate therapies of questionable benefit".) Withholding versus withdrawing therapy Withholding therapy refers to not providing a therapy that may be indicated, in contrast to withdrawing therapy which generally refers to removal of a previously instituted and indicated therapy. Withholding a life-sustaining therapy is sometimes seen as emotionally easier for clinicians and families to accept compared with withdrawing a previously instituted life-sustaining therapy, probably because there is a perception of less involvement in the patient's death. However, in multiple countries, including the United States and United Kingdom, there is no ethically meaningful distinction between withholding and withdrawing life-sustaining treatments. A more extensive discussion of the ethical issues in palliative care as well as the distinction between withholding and withdrawing therapy is presented separately. (See "Withholding and withdrawing ventilatory support in adults in the intensive care unit", section on 'Ethical misperceptions about foregoing ventilatory support' and "Ethical issues in palliative care".) FREQUENCY OF LATE-LIFE ICD THERAPIES https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 3/16 7/6/23, 10:54 AM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate Patients and providers should engage in early and frequent discussions regarding how the CIED fits in with the patient s goals of care and advance care planning. Patient opinions regarding their end-of-life implantable cardioverter-defibrillator (ICD) therapy can vary widely. Some patients choose to deactivate their ICD when nearing end of life. Others wish to have all possible efforts at prolonging life; they may choose to maintain ICD therapies and accept the potentially negative side effects (eg, shock-related pain, anxiety, etc). For these patients, receiving ICD shocks near the end of life can have a profoundly negative impact on quality of life and may also negatively impact family and friends. Unfortunately, patient and provider discussions regarding ICD deactivation occur much less frequently than do discussions regarding living wills and health care proxy assignment. In a prospective study of 51 patients with ICDs and significant medical comorbidities who were followed for up to 18 months, living wills and health care proxy assignment were completed 88 and 98 percent of the time, whereas communication about patient prognosis and ICD deactivation occurred only 10 and 23 percent of the time [14]. These low rates of discussions regarding ICD deactivation likely result in low rates of ICD deactivation near the end of life. A retrospective chart review of 98 patients with ICDs from the MADIT II who later died found that 15 percent chose to have their ICDs deactivated [15]. This is consistent with studies from other countries. In a study from Sweden, 52 percent of the patients had a do-not-resuscitate order, yet 65 percent of them still had the ICD activated 24 hours before death [16]. Unfortunately, ICD shocks are common at the end of life. Last month of life Interviews with family members of deceased patients in a single practice found that approximately 20 percent of patients with ICDs had the device discharge in the last month of life [5]. A separate clinical cohort study from Japan studied 27 patients with do-not-resuscitate orders. Twenty-seven percent of patients experienced an ICD shock, and 24 percent experienced electrical storm [17]. Last 24 hours of life In the MADIT II trial, 83 patients had terminal illnesses and active ICDs; 12 percent of these patients had a device discharge within 24 hours of death [15]. In an autopsy study from Sweden, 125 ICDs were explanted from patients who had died. The study showed that 31 percent of patients received shock treatment during the last 24 hours of their lives. However, arrhythmic death was the primary cause of death in only 13 percent [16]. Most notably, 52 percent of the patients had a do-not-resuscitate order, yet 65 percent of them still had the ICD activated 24 hours before death [16]. https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 4/16 7/6/23, 10:54 AM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate INDICATIONS FOR DISCONTINUING CIED THERAPY The discussion around discontinuation of CIED therapy is different depending on whether the device in question is a permanent pacemaker (PPM) or an ICD ( algorithm 1). In general, however, a discussion regarding the discontinuation of CIED therapy typically arises in one or more of the following settings: The goals of care have changed As examples: The patient and/or the healthcare proxy have decided (patient preference) that a patient with an advanced serious life-threatening illness should not be resuscitated by either external or internal (ie, ICD) defibrillation. The patient and/or the healthcare proxy have decided (patient preference) to withdraw treatments in a patient who is pacemaker-dependent. A CIED complication has occurred Most commonly due to infection or device component malfunction necessitating CIED removal. Patient-directed change in goals of care The concept of patient autonomy underlies both the ethical and legal principles surrounding CIED deactivation, with these ethical and legal principles having been well established. Patients with capacity (or the patient's legally designated surrogate) can request discontinuation of any medical or device treatment, including therapies such as pacemaker treatment in a pacemaker-dependent patient. When made by a patient with capacity or the relevant surrogate, such a decision falls within the spectrum of "withdrawal of treatment", is ethically sound, and should be distinguished from an act of euthanasia or physician-assisted suicide. No patient is committed to therapy that he or she no longer wishes to receive [18]. In addition, it is not necessary for patients to be terminally ill to make these requests. (See "Ethical issues in palliative care".) Device complications necessitating CIED removal Occasionally, it becomes necessary to remove a CIED system, the generator, and accompanying lead(s) due to a complication, most commonly CIED system infection or structural failure of a CIED component such as lead fracture. When a pacemaker is removed, the indication for pacing versus the risks of reimplantation should be addressed. When an ICD is removed, the patient is no longer protected from sudden cardiac death, and a decision must be made about if and when to place a new ICD. (See "Cardiac implantable electronic devices: Long-term complications" and "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis".) https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 5/16 7/6/23, 10:54 AM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate WHAT TO EXPECT AFTER DEVICE DISCONTINUATION Discontinuation of ICD therapy All modern ICD systems have the ability to treat ventricular tachyarrhythmias and provide for backup pacing functionality (ie, serve as a pacemaker). Each of these functions can be turned off individually. For most patients with an ICD, discontinuing antitachycardia therapies (including antitachycardia pacing and shocks) by reprogramming the device will not have any immediate impact on comfort or quality of life ( algorithm 1). The only exception would be in a patient who is receiving, or has recently received, one or more ICD shocks. In this case, quality of life may improve by reducing painful shocks, but a recurrent ventricular arrhythmia would be untreated and potentially fatal. When discontinuation of ICD therapy is requested because of a change in the goals of care, the role of the clinician is to fully explain the implications of the decision. Some issues that may be important include: Shock-related pain and anxiety Among patients with a terminal illness and a poor prognosis, the pain from an ICD shock, or the anxiety of potentially receiving an ICD shock, can be contrary to a primary goal of maintaining the patient's comfort [19]. When a patient with a preexisting ICD has a new diagnosis of a terminal illness, the option of disabling ICD therapies should be included in broader discussions of end-of-life care. Many patients will choose to disable ICD therapies, resulting in fewer shocks (and greater comfort) in the final days of a terminal illness [20]. Long-term recovery Patients in all states of health, ranging from those with a terminal- illness to active and healthy patients without an advanced life-threatening illness, may request that they not be resuscitated due to a fear of recovery to an incapacitated state requiring long-term mechanical support. Because an ICD treats potentially lethal arrhythmias quite rapidly, patients may recover to their baseline condition after the device has discharged. However, it should be noted that recurrence of ventricular arrhythmias is high, and their presence may not only be a manifestation but also a driver of worsening cardiac status. Discontinuing pacemaker therapy in the nonpacemaker-dependent patient For patients who are not pacemaker-dependent, discontinuing pacemaker therapy (either by reprogramming or removing the device) would not be expected to immediately result in death ( algorithm 1). In nearly all cases, the device may be noninvasively reprogrammed such that device removal is not typically required to accomplish withdrawal of therapy. https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 6/16 7/6/23, 10:54 AM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate While potentially controversial to some patients and providers, the discontinuation of a permanent pacemaker (PPM) in patients who are not PPM-dependent is generally considered reasonable if desired by the patient; this decision amounts to withholding rather than withdrawing therapy. Among 658 respondents to a survey regarding the withdrawal of PPM therapy at the end of life, legal professionals (89 percent), medical professionals (87 percent), and patients (79 percent) were consistent in their opinion that withdrawal of PPM therapy in a patient who was not PPM-dependent was appropriate if requested by the patient [21]. Discontinuing pacemaker therapy in the pacemaker-dependent patient More challenging and controversial is the decision to withdraw PPM therapy in a patient who is PPM- dependent, which would generally be considered a withdrawal of therapy. For patients who are pacemaker-dependent, discontinuing pacemaker therapy (either by reprogramming or removing the device) will almost certainly result in symptomatic bradycardia or asystole ( algorithm 1). Clinicians should notify the patient (or the patient's proxy) of the likelihood of loss of consciousness related to bradycardia or asystole and may wish to consider administering additional sedation to the patient at the time the pacemaker is reprogrammed should that decision ultimately be made. The 2018 American College of Cardiology/American Heart Association/Heart Rhythm Society Guidelines support shared decision-making regarding discontinuation of PPM therapy; these guidelines state patients with decision-making capacity or his/her/their legally defined surrogate have the right to refuse or request withdrawal of pacemaker therapy, even if the patient is pacemaker dependent [22]. It should be noted that turning off the pacing function of a pacemaker may not lead to the immediate demise of the patient. Many patients have an underlying junctional or ventricular escape rhythm that may sustain life for several hours, days, or even longer. During this time, a patient may have worse quality of life due to syncope or significant lightheadedness. For patients who have cardiac resynchronization therapy (biventricular pacemaker), their underlying heart failure symptoms may also worsen after withdrawal of pacing. Among the same 658 respondents to the survey discussed above regarding the withdrawal of PPM therapy at the end of life, greater numbers of legal professionals (85 percent) than patients (66 percent) and medical professionals (63 percent) thought that a pacemaker could be turned off in a pacemaker-dependent patient [21]. In a separate survey, an even larger proportion of electrophysiologists (318 of 384 respondents; 83 percent) responded that deactivation of antitachycardia therapies in an ICD was ethically and morally different than discontinuing pacemaker therapy in a pacemaker-dependent patient [23]. However, given the competent patient's ultimate autonomous right to medical decision-making, the patient retains an absolute right to request turning off a PPM in a pacemaker-dependent https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 7/16 7/6/23, 10:54 AM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate patient if an informed discussion has taken place between the patient (or proxy) and clinician. In the context of an ethical discussion, regardless of the fact that a patient is pacemaker dependent, the pacemaker still represents an artificial life-sustaining treatment that the patient has the right to refuse at any time [12,18]. Patient autonomy as well as the clinician's ability to withdraw or withhold treatment considered to be futile or otherwise inappropriate are highly important components of any discussion regarding the withdrawal of PPM therapy in a PPM- dependent patient. (See "Ethical issues in palliative care".) On occasion, the clinician who is asked to withdraw pacemaker therapy in a pacemaker- dependent patient may disagree with the decision to withdraw pacemaker therapy or may have a conscientious objection to performing this function. In this situation, the patient should be referred for another opinion to a clinician with expertise in pacemakers, or a consultation with the hospital ethics committee may be requested. LOGISTICS OF CIED DEACTIVATION Important logistic considerations include documentation of the care plan, choice of the appropriate environment for CIED reprogramming, and the appropriate CIED settings. Discussion and documentation Prior to any changes in CIED programming, there should be adequate discussion between the patient (or proxy) and clinician regarding the process and expected clinical progression with or without device deactivation, along with documentation of the discussion and the wishes of the patient (or proxy) [24,25]. With the exception of urgent or emergent situations (ie, recurrent ICD shocks delivered to the patient), reprogramming of the CIED, particularly in hospitalized patients, should not occur until an order and/or a note documenting the discussion has been placed in the patient's record. Choosing the proper location Choice of the most appropriate location for device deactivation is most relevant for pacemaker-dependent patients, as in most instances these are the only patients likely to experience an abrupt change in clinical status. Because of the high likelihood of symptomatic bradycardia or asystole following PPM deactivation in a pacemaker-dependent patient, these patients should have their device deactivated in a setting in which additional sedation can be administered prior to the PPM being reprogrammed. Typically, this occurs in a health care environment (eg, hospital, nursing home) or at home with hospice care. Since most non-pacemaker-dependent patients and patients with an ICD typically experience few, if any, immediate consequences following device deactivation, these https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 8/16 7/6/23, 10:54 AM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate patients can have their devices reprogrammed anywhere that is feasible for the patient and the clinician. Device reprogramming Typically, the reprogramming of the CIED can be handled by the clinician who routinely follows the patient for CIED-related issues, but any clinician who is trained in the management of CIEDs can reprogram the device. The following are examples of the types of reprogramming: For patients with an ICD, tachycardia therapies (ie, antitachycardia pacing and ICD shocks) can be disabled. If pacemaker support is necessary and remains consistent with the goals of care, contemporary ICDs can be programmed to maintain functionality as a pacemaker. If planned ICD inactivation has not yet been performed, emergent deactivation of antitachycardia therapies, including antitachycardia pacing and shocks, can be accomplished for most devices by placing a magnet over the ICD generator. While the magnet is in place, the ICD will withhold antitachycardia therapy while continuing with pacing functions. When the magnet is removed, the original parameters are restored. For patients with a permanent pacemaker (PPM), some devices may be programmed to an OOO mode. Alternatively, the lower rate limit or output may be reprogrammed so that the device is functionally programmed "off." SUMMARY AND RECOMMENDATIONS Discontinuing therapy Discontinuation of cardiac implantable electronic device (CIED) therapy, including both permanent pacemakers (PPMs) and implantable cardioverter- defibrillators (ICDs), is a complicated issue. Patients at any stage of health or illness should be encouraged to engage in advance care planning to identify their goals of care, specifically addressing CIED management when the patient has an active device. (See "Advance care planning and advance directives" and "Discussing goals of care".) Key concepts in palliative care The utility of late-life ICD therapies will be viewed differently according to the wishes of the patient or proxy. Patients who wish to have all possible efforts at prolonging life will likely desire to maintain ICD therapies and accept the potentially negative side effects (eg, shock-related pain, anxiety, etc). However, for those patients who decline life-prolonging therapies, receiving ICD shocks near the end of life can have a profoundly negative impact on quality of life and may also impact family and friends. (See 'Key concepts in palliative care' above.) https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 9/16 7/6/23, 10:54 AM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate Indications for discontinuation A discussion regarding the discontinuation of CIED therapy should typically arise when the goals of care have changed or a CIED complication has occurred. Patients with capacity (or the patient's legally designated surrogate) can request discontinuation of any medical or device treatment, including therapies such as pacemaker treatment in a pacemaker-dependent patient. (See 'Indications for discontinuing CIED therapy' above.) What the patient and family should expect following CIED discontinuation varies depending on the device and clinical scenario ( algorithm 1). (See 'What to expect after device discontinuation' above.) For most patients with an ICD, discontinuing antitachycardia therapies (including antitachycardia pacing and shocks) by reprogramming the device will not have any immediate impact on comfort or quality of life. The only exception would be in a patient who is receiving, or has recently received, one or more ICD shocks. In this case, quality of life may improve by reducing painful shocks, but a recurrent ventricular arrhythmia would be untreated and potentially fatal. For patients who are not pacemaker-dependent, discontinuing pacemaker therapy (either by reprogramming or removing the device) would not be expected to immediately result in death or have an immediate impact on comfort or quality of life. For patients who are pacemaker-dependent, discontinuing pacemaker therapy (either by reprogramming or removing the device) will almost certainly result in symptomatic bradycardia or asystole. Clinicians should notify the patient (or the patient's proxy) of the likelihood of loss of consciousness related to bradycardia or asystole and may wish to consider administering additional sedation to the patient at the time the pacemaker is reprogrammed. Logistics of deactivation Following discussion between the patient (and/or the patient's healthcare proxy) and the clinician and decision-making regarding deactivation of cardiac implantable electronic device (CIED) therapies, the CIED can usually be reprogrammed to provide or withhold the desired therapies. Important logistic considerations including documentation of the care plan, choice of the appropriate setting for CIED reprogramming, and the appropriate environs in which to make the programming changes. (See 'Logistics of CIED deactivation' above.) ACKNOWLEDGMENT https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 10/16 7/6/23, 10:54 AM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate The UpToDate editorial staff acknowledges Ann Garlitski, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Tajouri TH, Ottenberg AL, Hayes DL, Mueller PS. The use of advance directives among patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol 2012; 35:567. 2. Kirkpatrick JN, Gottlieb M, Sehgal P, et al. Deactivation of implantable cardioverter defibrillators in terminal illness and end of life care. Am J Cardiol 2012; 109:91. 3. Str mberg A, Fluur C, Miller J, et al. ICD recipients' understanding of ethical issues, ICD function, and practical consequences of withdrawing the ICD in the end-of-life. Pacing Clin Electrophysiol 2014; 37:834. 4. Stoevelaar R, Brinkman-Stoppelenburg A, van Driel AG, et al. Implantable cardioverter defibrillator deactivation and advance care planning: a focus group study. Heart 2020; 106:190. 5. Goldstein N, Bradley E, Zeidman J, et al. Barriers to conversations about deactivation of implantable defibrillators in seriously ill patients: results of a nationwide survey comparing cardiology specialists to primary care physicians. J Am Coll Cardiol 2009; 54:371. 6. Herman D, Stros P, Curila K, et al. Deactivation of implantable cardioverter-defibrillators: results of patient surveys. Europace 2013; 15:963. 7. Pedersen SS, Chaitsing R, Szili-Torok T, et al. Patients' perspective on deactivation of the implantable cardioverter-defibrillator near the end of life. Am J Cardiol 2013; 111:1443. 8. Raphael CE, Koa-Wing M, Stain N, et al. Implantable cardioverter-defibrillator recipient attitudes towards device deactivation: how much do patients want to know? Pacing Clin Electrophysiol 2011; 34:1628. 9. Pasalic D, Gazelka HM, Topazian RJ, et al. Palliative Care Consultation and Associated End-of- Life Care After Pacemaker or Implantable Cardioverter-Defibrillator Deactivation. Am J Hosp Palliat Care 2016; 33:966. 10. Goldstein N, Carlson M, Livote E, Kutner JS. Brief communication: Management of implantable cardioverter-defibrillators in hospice: A nationwide survey. Ann Intern Med 2010; 152:296. 11. Pitcher D, Soar J, Hogg K, et al. Cardiovascular implanted electronic devices in people towards the end of life, during cardiopulmonary resuscitation and after death: guidance https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 11/16 7/6/23, 10:54 AM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate from the Resuscitation Council (UK), British Cardiovascular Society and National Council for Palliative Care. Heart 2016; 102 Suppl 7:A1. 12. Lampert R, Hayes DL, Annas GJ, et al. HRS Expert Consensus Statement on the Management of Cardiovascular Implantable Electronic Devices (CIEDs) in patients nearing end of life or requesting withdrawal of therapy. Heart Rhythm 2010; 7:1008. 13. Wilkoff BL, Auricchio A, Brugada J, et al. HRS/EHRA expert consensus on the monitoring of cardiovascular implantable electronic devices (CIEDs): description of techniques, indications, personnel, frequency and ethical considerations. Heart Rhythm 2008; 5:907. 14. Kramer DB, Habtemariam D, Adjei-Poku Y, et al. The Decisions, Interventions, and Goals in ImplaNtable Cardioverter-DefIbrillator TherapY (DIGNITY) Pilot Study. J Am Heart Assoc 2017; 6. 15. Sherazi S, McNitt S, Aktas MK, et al. End-of-life care in patients with implantable cardioverter defibrillators: a MADIT-II substudy. Pacing Clin Electrophysiol 2013; 36:1273. 16. Kinch Westerdahl A, Sj blom J, Mattiasson AC, et al. Implantable cardioverter-defibrillator therapy before death: high risk for painful shocks at end of life. Circulation 2014; 129:422. 17. Nakazawa M, Suzuki T, Shiga T, et al. Deactivation of implantable cardioverter defibrillator in Japanese patients with end-stage heart failure. J Arrhythm 2021; 37:196. 18. Kramer DB, Mitchell SL, Brock DW. Deactivation of pacemakers and implantable cardioverter-defibrillators. Prog Cardiovasc Dis 2012; 55:290. 19. Palacios-Ce a D, Losa-Iglesias ME, Alvarez-L pez C, et al. Patients, intimate partners and family experiences of implantable cardioverter defibrillators: qualitative systematic review. J Adv Nurs 2011; 67:2537. 20. Lewis WR, Luebke DL, Johnson NJ, et al. Withdrawing implantable defibrillator shock therapy in terminally ill patients. Am J Med 2006; 119:892. 21. Kapa S, Mueller PS, Hayes DL, Asirvatham SJ. Perspectives on withdrawing pacemaker and implantable cardioverter-defibrillator therapies at end of life: results of a survey of medical and legal professionals and patients. Mayo Clin Proc 2010; 85:981. 22. Writing Committee Members, Kusumoto FM, Schoenfeld MH, et al. 2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2019; 16:e128. 23. Daeschler M, Verdino RJ, Caplan AL, Kirkpatrick JN. Defibrillator Deactivation against a Patient's Wishes: Perspectives of Electrophysiology Practitioners. Pacing Clin Electrophysiol https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 12/16 7/6/23, 10:54 AM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate 2015; 38:917. 24. Hadler RA, Goldstein NE, Bekelman DB, et al. "Why Would I Choose Death?": A Qualitative Study of Patient Understanding of the Role and Limitations of Cardiac Devices. J Cardiovasc Nurs 2019; 34:275. 25. Goldstein NE, Mehta D, Siddiqui S, et al. "That's like an act of suicide" patients' attitudes toward deactivation of implantable defibrillators. J Gen Intern Med 2008; 23 Suppl 1:7. Topic 91204 Version 22.0 https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 13/16 7/6/23, 10:54 AM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate GRAPHICS Approach to cardiac implantable electronic device management (permanent pacemakers and implantable cardioverter-defibrillators) in patients receiving palliative care* CIED: cardiac implantable electronic device; ICD: implantable cardioverter-defibrillator; PPM: permanent pacemaker. There is no inherent code status among patients receiving palliative care. Patients may opt for a status of do not resuscitate (DNR), but may continue to choose active CIED therapies. Clarification of code status and the establishment of advanced directives, including CIED management, is an important component of the care plan. in patients without a health care proxy, decisions regarding capacity may require evaluation by psychiatric experts, legal review for determining guardianship, etc. In general, CIED reprogramming occurs in a controlled setting on an elective basis. The one exception may be for a patient who is receiving repetitive ICD shocks in whom placing a magnet over the ICD will terminate the delivery of shocks. https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 14/16 7/6/23, 10:54 AM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate On occasion, the clinician who is asked to withdraw pacemaker therapy in a pacemaker- dependent patient may disagree with the decision to withdraw pacemaker therapy or may have a conscientious objection to performing this. In this situation, the patient should be referred for another opinion by a clinician with expertise in pacemakers, or a consultation with the hospital ethics committee may be requested. Expected clinical course will vary based on type of CIED. In most cases, deactivation of an ICD or a PPM in a non-pacemaker dependent patient will not immediately impact the patient's clinical condition. Deactivating a PPM in a patient who is pacemaker dependent may lead to an immediate deterioration of clinical condition and/or fairly rapid demise depending upon the patient's underlying cardiac rhythm and overall hemodynamic status. Graphic 126133 Version 1.0 https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 15/16 7/6/23, 10:54 AM Management of cardiac implantable electronic devices in patients receiving palliative care - UpToDate Contributor Disclosures Kapil Kumar, MD No relevant financial relationship(s) with ineligible companies to disclose. R Sean Morrison, MD No relevant financial relationship(s) with ineligible companies to disclose. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/management-of-cardiac-implantable-electronic-devices-in-patients-receiving-palliative-care/print 16/16

7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Modes of cardiac pacing: Nomenclature and selection : Mark S Link, MD : N A Mark Estes, III, MD : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 07, 2022. INTRODUCTION Once it has been established that bradycardia or a conduction disorder warrants permanent pacing, the most appropriate pacing mode for the patient must be selected. The choice depends upon the specific abnormality that is present, since a wide range of pacemaker functions have been developed to accommodate specific clinical needs ( table 1). (See "Permanent cardiac pacing: Overview of devices and indications".) To facilitate the use and understanding of pacemakers, a standardized classification code has been developed. Most patients can be managed with one of two or three common modes (AAI, VVI, or DDD), with or without rate responsiveness. Contemporary pacemakers are versatile and capable of the most commonly used pacing modes and basic functions (ie, mode switching and rate responsiveness). Some advanced features are available in selected devices. Pacemaker nomenclature and the clinical application of common pacing modes and functions will be reviewed here. NOMENCLATURE Five position code A three-letter code describing the basic function of the various pacing systems was first proposed in 1974 by a combined task force from the American Heart Association and the American College of Cardiology and subsequently updated by a committee from the North American Society of Pacing and Electrophysiology (NASPE) and the British Pacing https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 1/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate and Electrophysiology Group (BPEG). The code, which has five positions, is designated the NBG code for pacing nomenclature ( table 2) [1]. The code is generic and does not describe specific or unique functional characteristics for each device. When a code includes only three or four characters, it can be assumed that the positions not mentioned are "O" or absent. Position I The first position reflects the chamber(s) paced. "A" indicates the atrium, "V" indicates the ventricle, and "D" means dual chamber (ie, both the atrium and the ventricle). Position II The second position refers to the chamber(s) sensed. The letters are the same as those for the first position: "A" for atrium, "V" for ventricle, "D" for dual. An additional option "O" indicates an absence of sensing. Programmed in this mode, a device will pace automatically at a specified rate, ignoring any intrinsic rhythm. (See 'Asynchronous pacing' below.) Manufacturers sometimes use "S" in the first and second positions to indicate that the device is capable of pacing only a single cardiac chamber. Once the device is implanted and connected to a lead in either the atrium or the ventricle, "S" should be changed to "A" or "V" in the clinical record to reflect the chamber in which pacing and sensing are occurring. Position III The third position refers to how the pacemaker responds to a sensed event. "I" indicates that a sensed event inhibits the output pulse and causes the pacemaker to recycle for one or more timing cycles. "T" indicates that an output pulse is triggered in response to a sensed event. "D" indicates that there are dual modes of response. This designation is restricted to dual- chamber systems. An event sensed in the atrium inhibits the atrial output but triggers a ventricular output. There is a programmable delay between the sensed atrial event and the triggered ventricular output to mimic the normal PR interval. If the ventricular lead senses a native ventricular signal during the programmed delay, it will inhibit the ventricular output. "O" indicates no response to sensed input; it is most commonly used in conjunction with an "O" in the second position. Position IV The fourth position reflects rate modulation, also referred to as rate responsive or rate adaptive pacing. (See 'Rate responsiveness' below.) "R" in the fourth position indicates that the pacemaker has rate modulation and incorporates a sensor to adjust its programmed paced heart rate in response to patient https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 2/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate activity. From a practical standpoint, "R" is the only indicator commonly used in the fourth position. "O" indicates that rate modulation is either unavailable or disabled. "O" is often omitted from the fourth position (ie, DDD is the same as DDDO). Position V The fifth position is rarely ever utilized but specifies the location or absence of multisite pacing, defined as stimulation sites in both atria, both ventricles, more than one stimulation site in any single chamber, or a combination of these. The fifth position of the code is rarely used. "O" means no multisite pacing "A" indicates multisite pacing in the atrium or atria "V" indicates multisite pacing in the ventricle or ventricles "D" indicates dual multisite pacing in both atrium and ventricle The most common application of multisite pacing is biventricular pacing for the management of heart failure. This issue is discussed in detail separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) ADDITIONAL FEATURES In addition to the above basic pacing modes, modern pacemakers have additional features to improve performance in a variety of specific clinical settings. Mode switching and rate responsiveness are available in all contemporary pacemakers. Some features are available in select devices and can be utilized as specific clinical situations demand. Mode switching In dual-chamber pacing systems (DDD/DDDR or less commonly, VDD/VDDR), the ventricle will be paced following every sensed atrial event, up to a programmed maximum ventricular rate. If the patient develops a paroxysmal atrial tachyarrhythmia (eg, atrial fibrillation [AF]), the ventricle would then be paced at this maximum programmed rate for the duration of the arrhythmia, which is obviously undesirable. Mode switching refers to automatic reprogramming of a pacemaker to a mode that no longer tracks the intrinsic atrial rate, usually VVI, DDI, or DVI with or without rate responsiveness. When the sensed atrial rate again falls below the mode switching cutoff and the device assumes that a physiologic rhythm has been restored (ie, with termination of the arrhythmia), the pacing mode automatically reverts to the original programming. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 3/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate All contemporary dual-chamber pacemakers have mode switching capabilities. This feature can be activated or disabled, depending upon the clinical situation. Rate responsiveness As described above, rate responsiveness, also referred to as rate modulation or rate adaptation, refers to the ability of a pacemaker to adjust its programmed paced rate based upon patient activity. A variety of sensors have been designed to determine when a patient is physically active (eg, vibration, minute ventilation, change in right ventricular impedance). The range of heart rates, the pace of acceleration and deceleration, and the degree of activity required to initiate this response are all programmable in rate-adaptive pacing modes. Modes to minimize ventricular pacing Right ventricular (RV) pacing causes the right ventricle to contract before the left ventricle (LV), and causes the septum to contract before the lateral wall of the LV, simulating the effects of left bundle branch block. This phenomenon is referred to as ventricular dyssynchrony or asynchrony. Whether due to RV pacing or intrinsic conduction abnormalities, dyssynchrony can cause or exacerbate heart failure in some patients and increase the frequency of AF. (See "Overview of pacemakers in heart failure" and "The role of pacemakers in the prevention of atrial fibrillation".) Native atrioventricular (AV) conduction is hemodynamically preferable to RV pacing. With an increased understanding of the detrimental effects of RV pacing, efforts have been made to develop pacing modes that minimize ventricular pacing [2-7]. Examples of novel pacing strategies for this purpose include the following: Ventricular avoidance pacing algorithms A dual-chamber device can be programmed to pace AAI (allowing native conduction), but if specific criteria are met that signify a loss of AV conduction, the pacemaker will automatically switch to DDD pacing for some period of time until the algorithm once again determines the presence of intrinsic AV conduction. This approach has been associated with a markedly lower rate of frequency of ventricular pacing compared with conventional dual-chamber pacing (9 versus 99 percent and 4 versus 74 percent in two studies) [3,4,7]. AV search hysteresis Algorithms exist that will prolong the programmed AV delay in a dual-chamber device to allow native conduction when present. The mechanism and frequency with which the algorithm allows AV prolongation to determine the presence of intrinsic AV conduction and the degree to which the AV delay can be extended are variable depending on manufacturer and model [5]. If native conduction with a long PR or AR is present, the device will allow this to continue until the allowed interval is exceeded and there is no intrinsic QRS. This will generally reset the algorithm to the original programmed AV interval. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 4/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate Biventricular pacing In some patients, ventricular dyssynchrony is unavoidable due to intrinsic conduction disease or inevitable ventricular pacing. If such a patient also has heart failure and LV dysfunction, synchrony may be restored with biventricular pacing, or cardiac resynchronization therapy (CRT), which improves outcomes in selected patients. Cardiac resynchronization therapy is discussed in detail elsewhere. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Patients with LV dysfunction and a mildly reduced ejection fraction (EF; eg, 36 to 49 percent) who have an indication for permanent pacing have traditionally received a standard dual-chamber pacemaker. However, given the potential for ventricular pacing (especially RV apical pacing) to cause or exacerbate LV dysfunction, it is believed that patients might have better outcomes if cardiac resynchronization therapy (ie, biventricular pacing) was the initially implanted device. One trial, BLOCK-HF, demonstrated that in patients with AV block and LV systolic dysfunction (LVEF <50 percent) with NYHA class I, II, or III heart failure, biventricular pacing was superior to conventional RV pacing for the primary outcome of time to death from any cause, urgent IV therapy for heart failure, or 15 percent or greater increase in LV end-systolic volume index [8]. In a post hoc analysis of the BLOCK-HF trial, patients in the biventricular pacing arm were more likely to have improvement in NYHA functional status and in a clinical composite score incorporating various clinical outcomes [9]. Additional randomized clinical trials are needed to assess conventional pacing versus biventricular stimulation in patients with mildly reduced LV function. His bundle pacing His bundle pacing is an alternative approach to reduce the risk of dyssynchrony, as discussed separately. (See "Permanent cardiac pacing: Overview of devices and indications", section on 'His bundle pacing'.) PACING MODES In selecting the ideal pacing mode, the patient's overall physical condition, associated medical problems, exercise capacity, left ventricular function, and chronotropic response to exercise must be considered along with the underlying rhythm disturbance. Some of the various ventricular and atrial pacing systems available and their NBG codes are shown in the table ( table 3). Single-chamber pacing Early pacemakers were designed to sense and pace in a single chamber. Ventricular pacing can prevent ventricular bradyarrhythmias or asystole of any etiology. Atrial pacing can be used in patients with isolated sinus node dysfunction (SND) and intact AV conduction. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 5/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate VVI or VVIR pacing Ventricular demand pacing (ventricle paced, ventricle sensed, and pacemaker inhibited in response to a sensed beat) remains the most commonly used pacing mode. Advantages of ventricular demand pacing include the requirement for only a single lead and the ability to protect the patient from dangerous bradycardias of any etiology. However, ventricular demand pacing cannot maintain AV synchrony, and lack of AV synchrony can result in pacemaker syndrome. (See 'Pacemaker syndrome' below.) Virtually all devices currently in use are capable of VVIR pacing. VVIR pacing is primarily indicated in patients with chronic atrial fibrillation with a slow ventricular response. By contrast, in a patient with normal sinus rhythm, VVIR pacing should not be used as an excuse to forego attempts at placing an atrial lead. If sinus node function is intact, dual-chamber (DDD) pacing preserves AV synchrony and maintains the patient's natural heart rate response to activity. This approach is optimal and should be used whenever possible. (See 'Physiologic pacing' below.) AAI or AAIR pacing Atrial demand pacing (atrium paced, atrium sensed, and pacemaker inhibited in response to sensed atrial beat) is appropriate for patients with SND who have intact AV nodal function. Patients with symptomatic sinus bradycardia or sinus pauses, but with an intact ability to accelerate their heart rate with exertion, can be programmed in an AAI mode. Those who cannot adequately accelerate their heart rate should have rate responsive capability available (ie, AAIR). As with ventricular demand pacemakers, these devices have the benefit of requiring only a single lead. However, unlike ventricular single-chamber pacemakers, they will not protect patients from ventricular bradyarrhythmias due to AV conduction block. Due to this limitation, atrial demand pacemakers are infrequently used. Many clinicians are concerned that a patient who already has sinus node disease will later develop AV conduction disease. Although it would be uncommon for AV block to develop precipitously and result in a catastrophic event, gradual development of AV conduction system disease may require upgrade of the pacemaker to a dual- chamber device. Pacemaker upgrade can be technically more difficult than original placement of a dual-chamber pacemaker, and the second procedure obviously entails additional cost and patient risk. However, if the patient with SND is assessed carefully and does not have AV node disease at the time of pacemaker implant, the occurrence of clinically significant AV nodal disease is very low (less than 2 percent per year) [10]. Assessment prior to use of an AAI system should include incremental atrial pacing at the time of pacemaker implant. Although criteria vary among https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 6/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate institutions and implanting clinicians, the adult patient should be capable of 1:1 AV nodal conduction to rates of 120 to 140 beats/minute. Dual-chamber pacing DDD or DDDR pacing The dual-chamber (DDD) pacing system provides physiologic pacing (see 'Physiologic pacing' below), with sensing and pacing capabilities in both the atrium and the ventricle. The pacemaker will be totally inhibited in the presence of sinus rhythm with normal AV conduction if the sinus rate is faster than the programmed lower rate of the pacemaker and the intrinsic AV conduction is faster than the programmed AV interval. If there is sinus bradycardia but normal AV conduction with the intrinsic QRS occurring before the end of the programmed AV interval, there will be atrial pacing with a native QRS complex following each paced atrial beat. Both the atrium and ventricle will be paced if there is sinus bradycardia and delayed or absent AV conduction. The ventricle will be paced synchronously with the atrium if there is normal sinus rhythm with delayed or absent AV conduction. As a result, there are four different rhythms that can be seen with normal pacemaker function ( waveform 1): Normal sinus rhythm Atrial pacing, normally conducted to the ventricle with a native QRS AV sequential pacing Atrial sensing and ventricular pacing The DDD pacing mode is appropriate for patients with AV block who have normal sinus node function. DDD pacing is also considered by some to be the mode of choice in carotid sinus hypersensitivity with symptomatic cardioinhibition. However, most patients should receive a pacemaker capable of DDDR pacing, even if rate response is not initially programmed "on." The ideal patient for DDDR pacing is one with combined sinus nodal and AV nodal dysfunction in whom DDDR pacing would restore rate responsiveness and AV synchrony. DDDR pacing is also appropriate for patients with SND and normal AV conduction. As noted above, many practitioners are not comfortable with AAIR pacing. Use of DDDR pacing mode with an algorithm that will minimize ventricular pacing is often preferred. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 7/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate DDI or DDIR pacing In the DDI pacing mode, there is atrial sensing and pacing, and ventricular sensing and pacing; however, the pacemaker will not track intrinsic atrial activity. When there is a sensed native atrial rate, the pacemaker will inhibit both atrial and ventricular output, thereby allowing native conduction to the ventricle. If AV block develops, ventricular pacing will occur at a programmed rate, but will not be synchronized with the atrium. As an example, if a device is programmed DDI at 50 beats per minute, and the patient has sinus rhythm at 60 with 1:1 AV conduction, the device will be fully inhibited. If AV block develops, the pacemaker will pace the ventricle at 50 beats per minute. If sinus bradycardia develops, the pacemaker will pace the atrium and ventricle synchronously at 50 beats per minute. In the DDI mode, if the sinus rate is below the programmed rate, the pacemaker will pace the atrium and ventricle sequentially. There are few, if any, advantages of DDI or DDIR pacing at this time. At one time, this mode was helpful for the patient with atrial tachyarrhythmias. Since DDI does not "track," this mode would alleviate the concern of fast ventricular rates in response to the atrial tachyarrhythmia. However, this has become much less important since essentially all dual-chamber devices now have mode switching capability. (See 'Mode switching' above.) Less common modes VDD and DVI mode remain programmable options in most pacemakers but are rarely used. VDD pacing VDD pacing (ventricle paced, atrium and ventricle sensed, and either inhibition or tracking of the pacemaker in response to a sensed beat) may be appropriate for the patient with normal sinus node function and conduction disease of the AV node. Dual-chamber (two lead) VDD pacing systems have largely been supplanted by DDD pacemakers. However, a single-lead VDD pacing system, now available for many years, has increased interest in the use of VDD as the initial pacing mode in patients with AV block but normal sinus node function [11-13]. In these systems, atrial sensing is accomplished from "floating" sensing electrodes on the atrial portion of the ventricular pacing lead. One limitation to the use of a single-lead VDD pacemaker is that patients with initially normal SA node function may develop SND. This would then require a second procedure to place an atrial lead capable of pacing in order to maintain AV synchrony and chronotropic competence. However, this is an infrequent occurrence [14,15]. DVI pacing DVI pacemakers (atrium and ventricle paced, ventricular sensing only, and inhibition of pacemaker in response to sensed ventricular beat) are now of historical interest only. DVI pacing is, by definition, limited by the absence of atrial sensing, which prevents the https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 8/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate restoration of rate responsiveness in the chronotropically competent patient. In addition, lack of atrial sensing may lead to competitive atrial pacing and initiation of atrial rhythm disturbances. Asynchronous pacing Pacemakers may be programmed to pace at a fixed rate, without attempting to sense or react to native cardiac activity. These modes are referred to as asynchronous pacing. AOO, VOO, or DOO mode In these modes, the atrium, ventricle, or both are paced, but the pacemaker has no sensing capability and hence there is no sensing response of the pacemaker. Asynchronous pacing modes are rarely used long-term. These modes, however, may be temporarily necessary for patients who are undergoing a surgical procedure, especially if the patient is pacemaker-dependent. Electrocautery could be sensed by the pacemaker and misinterpreted as native cardiac activity, thereby inhibiting pacing output. This could produce significant bradycardia or asystole in a pacemaker-dependent patient. Thus, prior to surgery, the pacemaker could be reprogrammed to an asynchronous mode that turns off its sensing capability. After surgery, the pacemaker should be reprogrammed to its prior mode. Alternatively, a magnet placed over the pacemaker will deactivate its ability to sense and, while left in place, will result in asynchronous pacing. Although this approach has been used for many years there are some concerns that are likely more theoretical than real. Pacing in an asynchronous mode can be associated with competition between the native and the paced rhythms, with the possibility that a paced impulse will occur during a native T wave (or the vulnerable period). To reduce this risk, asynchronous pacing could be programmed to a relatively higher rate ( 80 beats/minute). PHYSIOLOGIC PACING Physiologic pacing is a term that has been used to describe pacing systems that most closely approximate normal cardiac behavior. It most commonly refers to systems that maintain AV synchrony (eg, AAI or DDD systems, in contrast to VVI systems), but has also been applied to rate responsive pacemakers. (See 'AAI or AAIR pacing' above and 'Dual-chamber pacing' above and 'Rate responsiveness' above.) Potential advantages Physiologic pacing has several potential hemodynamic and clinical advantages compared with VVI pacing [16]. These include: Reduced incidence of atrial fibrillation (AF) The incidence of atrial tachyarrhythmias, particularly AF, is reduced by physiologic compared with VVI pacing. (See "The role of https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 9/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate pacemakers in the prevention of atrial fibrillation".) Reduced incidence of thromboembolic events A lower rate of thromboembolic events is suggested in the meta-analysis of physiologic pacing discussed below, and may be secondary to the lower incidence of AF [17]. Improved hemodynamics The maintenance of AV synchrony and "atrial kick" is hemodynamically favorable and physiologic pacing improves cardiac output, arterial pressure, and coronary blood flow [18-21]. The magnitude of these improvements is small, and their clinical significance is not clear but, in some studies, physiologic pacing has resulted in a lower incidence of heart failure [22]. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Atrial systole'.) Avoidance of pacemaker syndrome VVI pacing is associated with the development of "pacemaker syndrome." This syndrome is due to AV dyssynchrony or retrograde ventricular-to-atrial conduction. It is prevented by physiologic pacing [23,24]. (See 'Pacemaker syndrome' below.) Effects on outcomes Several trials and a meta-analysis have compared physiologic and VVI pacing [17,24-29]. In the aggregate, these reports demonstrate that across the spectrum of patients with bradycardic indications for pacemakers, physiologic pacing does not improve survival or the incidence of heart failure, but does reduce the incidence of AF and may reduce the incidence of stroke. The meta-analysis included data from five randomized trials [17]: A Danish trial of 225 patients with sinus node dysfunction (SND) and normal AV conduction [22,25,30]. The MOST trial of 2010 patients with SND, 20 percent of whom also had AV conduction disease [26,31]. The CTOPP trial of 2568 patients with both SND and AV conduction disease (42 percent with SND) [27,29,32,33]. The PASE trial of 407 patients, 43 percent with SND [24,34]. The UKPACE trial of 2021 older adult patients, all of whom had AV conduction disease [28]. The meta-analysis included 7231 patients and over 35,000 patient-years of follow-up. The average patient age was 76. Most patients randomly assigned to physiologic pacing received a https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 10/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate dual-chamber (DDD) pacemaker, while all of those in the Danish trial and some in CTOPP received an AAI pacemaker. The following findings were noted: There was no difference in the incidence of heart failure or in all-cause mortality between physiologic and VVI pacing (31 versus 33 percent all-cause mortality). Physiologic pacing significantly reduced the incidence of AF (17 versus 22 percent). Physiologic pacing appeared to reduce the incidence of stroke (5.2 versus 6.3 percent). However, the authors suggested cautious interpretation of this finding, due to borderline statistical significance (95% CI 0.67-0.99, p = 0.035) and the lack of adjustment for multiple hypothesis testing. Subgroup analysis suggested that physiologic pacing may be more beneficial in patients with SND than those with AV block. Among patients with SND, physiologic pacing appeared to reduce the combined endpoint of stroke or cardiovascular death. However, the authors suggested caution in the interpretation of this subgroup analysis, because of heterogeneity in the populations of the included trials (ie, different percentages of patients with SND). Issues specifically related to physiologic pacing and SND are discussed separately. There was no additional advantage in several other subgroups that are often considered to derive a greater benefit from physiologic pacing (eg, those with left ventricular dysfunction or heart failure). Patients appear to prefer physiologic pacing, suggested by relatively high crossover rates from VVI to dual-chamber pacing in the two trials in which this was easy to do. (See 'Patient preference' below.) The results of the meta-analysis are broadly consistent with those of the individual trials. However, due to some differences in the patient populations (eg, SND versus AV block, older adult patients), and the pacemakers used (eg, AAI versus DDD), some points from individual studies are worth consideration: As in the subgroup analysis, results from the Danish trial suggested a greater benefit of physiologic pacing in patients with SND than in those with AV block, which we now understand to be a function of maintaining intrinsic AV conduction in the SND group [30]. In adults with advanced age, the rates of AF and stroke are high regardless of pacing mode. The value of physiologic pacing may be less significant in this group, particularly those with AV block [28,35]. This was best illustrated in the UKPACE trial of 2021 older adult https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 11/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate patients (average age 80), all of whom had AV block [28]. In this population, physiologic pacing did not reduce the rates of mortality, AF, or thromboembolism. Pacemaker syndrome Pacemaker syndrome is a phenomenon associated with the loss of AV synchrony and is seen most commonly with single-chamber VVI pacing. It is defined as the adverse hemodynamics associated with a normally functioning pacing system, resulting in overt symptoms or limitation of the patient's ability to achieve optimal functional status [23]. The development of the pacemaker syndrome with VVI pacing may require upgrade from a VVI pacemaker to a dual-chamber system in some patients. Symptoms most commonly include general malaise, easy fatigability, dyspnea, orthopnea, cough, dizziness, atypical chest discomfort, and a sensation of throat fullness and, less commonly, may result in pre-syncope or syncope. Physical examination may reveal hypotension, rales, increased jugular venous pressure with cannon A waves, peripheral edema, and murmurs of tricuspid and/or mitral regurgitation [23,36]. Patient preference Although no consistent mortality benefit has been identified in randomized clinical trials with physiologic pacing, patients seem to prefer physiologic pacing as illustrated by the following observations: In a double-blind crossover study of different pacing modes, 86 percent of patients preferred physiologic pacing [37]. In PASE and MOST, quality of life scores were higher in patients with SND randomly assigned to physiologic pacing [24,26]. In the clinical trials comparing physiologic and VVI pacing, when crossing over from VVI to physiologic pacing was easy, up to 38 percent of patients chose to cross over. In PASE and MOST, all patients received dual-chamber pacemakers, and randomization to physiologic or VVI pacing occurred after implantation [24,26]. Thus, crossover required only device reprogramming (as opposed to a second procedure). The crossover rates in these two trials were 26 and 38 percent (compared with less than 5 percent in the other trials). The high crossover rate in MOST led to questions about the validity of the results. However, in a later study, the results of intention-to-treat and on-treatment analyses were similar [31]. As in the original report from MOST [26], the on-treatment analysis showed no difference in the primary endpoint between the two pacing modes, but there was a significant reduction in the incidence of AF with physiologic pacing. Based upon the reduced incidence of AF and patient preference, we suggest that physiologic pacing should be used in most patients who require a pacemaker. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 12/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate MODE SELECTION ALGORITHMS A number of guidelines and algorithms are available for determining the appropriate pacing mode for patients with sinus node disease and AV node disease [38]. The indications and contraindications for the various types of pacing modes are listed in the accompanying tables ( table 4) [38]. In this listing, chronotropically competent refers to the ability of a patient to achieve an appropriate heart rate for a given physiologic activity. Several algorithms are also available: General algorithms for all bradycardic indications ( algorithm 1 and figure 1) An algorithm for sick sinus syndrome ( algorithm 2) An algorithm for AV block ( algorithm 3) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Pacemakers (The Basics)") Beyond the Basics topic (see "Patient education: Pacemakers (Beyond the Basics)") https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 13/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate SUMMARY AND RECOMMENDATIONS Nomenclature For permanent cardiac pacing, the five position NBG code indicates the chamber(s) paced, the chamber(s) sensed, the response to sensing, presence or absence of rate modulation, and location or absence of multisite pacing ( table 2). (See 'Nomenclature' above.) Selection of pacing mode In selecting a pacing mode, the patient's overall physical condition, associated medical problems, exercise capacity, left ventricular (LV) function, and chronotropic response to exercise must be considered along with the underlying rhythm disturbance. Some commonly used pacing modes are shown in the table ( table 3). (See 'Pacing modes' above.) Most patients with a standard bradycardic indication for pacing can be managed with one of three common pacing modes (with or without rate responsive pacing): AAI(R), VVI(R), or DDD(R). At the time of implantation, one should consider how many leads will be necessary and which additional features, if any, will be of potential value. Choice of single- or dual-chamber pacemaker The most important choice in most patients with a bradycardic indication for pacing is whether to place a single- or dual- chamber pacemaker (see "Permanent cardiac pacing: Overview of devices and indications" and 'Pacing modes' above). The choice varies with the clinical setting: Atrial fibrillation In patients with chronic atrial fibrillation (AF) who require a pacemaker due to slow ventricular response, we recommend a single-chamber ventricular pacemaker (VVI or VVIR) (Grade 1B). (See 'VVI or VVIR pacing' above.) Sinus rhythm In patients in sinus rhythm with conditions that could be managed with either a single- or a dual-chamber pacemaker (eg, atrioventricular [AV] block, sinus node dysfunction [SND]), we suggest a dual-chamber pacemaker (Grade 2B). (See 'Physiologic pacing' above and 'Dual-chamber pacing' above.) Exception for advanced age or difficult two lead implantation A single- chamber pacemaker is a reasonable alternative in patients who are adults with advanced age or whose anatomy and physical condition make the implantation of two leads more difficult than usual. In such cases, the additional costs and risks of a dual-chamber physiologic pacemaker may outweigh the potential benefits of the reduced risk of AF and patient preference. VVI(R) pacing will be effective in all such patients. (See 'VVI or VVIR pacing' above.) https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 14/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate Possible exception for SND with intact AV conduction An AAI(R) pacemaker is a reasonable alternative to VVI(R) pacing in the subset of patients with SND in whom AV conduction is intact and meets intra-implant testing criteria (see "Sinus node dysfunction: Treatment"). However, effective AAIR pacing is more commonly accomplished with a dual-chamber pacemaker with a ventricular pacing avoidance option. (See 'AAI or AAIR pacing' above and 'Modes to minimize ventricular pacing' above.) Additional features The following additional features are appropriate for selected patients: Rate responsiveness This feature can be programmed for patients who are active, but not chronotropically competent. (See 'Rate responsiveness' above.) Mode switching This feature can be programmed for patients with paroxysmal atrial arrhythmias. (See 'Mode switching' above.) Ventricular pacing avoidance Algorithms to avoid ventricular pacing are appropriate for most patients with PR prolongation or type II AV block. Some parameter to minimize ventricular pacing is available in most contemporary devices. (See 'Modes to minimize ventricular pacing' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges David L Hayes, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Bernstein AD, Daubert JC, Fletcher RD, et al. The revised NASPE/BPEG generic code for antibradycardia, adaptive-rate, and multisite pacing. North American Society of Pacing and Electrophysiology/British Pacing and Electrophysiology Group. Pacing Clin Electrophysiol 2002; 25:260. 2. Sweeney MO, Prinzen FW. A new paradigm for physiologic ventricular pacing. J Am Coll Cardiol 2006; 47:282. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 15/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate 3. Sweeney MO, Bank AJ, Nsah E, et al. Minimizing ventricular pacing to reduce atrial fibrillation in sinus-node disease. N Engl J Med 2007; 357:1000. 4. Sweeney MO, Ellenbogen KA, Casavant D, et al. Multicenter, prospective, randomized safety and efficacy study of a new atrial-based managed ventricular pacing mode (MVP) in dual chamber ICDs. J Cardiovasc Electrophysiol 2005; 16:811. 5. Olshansky B, Day JD, Moore S, et al. Is dual-chamber programming inferior to single- chamber programming in an implantable cardioverter-defibrillator? Results of the INTRINSIC RV (Inhibition of Unnecessary RV Pacing With AVSH in ICDs) study. Circulation 2007; 115:9. 6. Ricci RP, Botto GL, B n zet JM, et al. Association between ventricular pacing and persistent atrial fibrillation in patients indicated to elective pacemaker replacement: Results of the Prefer for Elective Replacement MVP (PreFER MVP) randomized study. Heart Rhythm 2015; 12:2239.

https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 12/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate MODE SELECTION ALGORITHMS A number of guidelines and algorithms are available for determining the appropriate pacing mode for patients with sinus node disease and AV node disease [38]. The indications and contraindications for the various types of pacing modes are listed in the accompanying tables ( table 4) [38]. In this listing, chronotropically competent refers to the ability of a patient to achieve an appropriate heart rate for a given physiologic activity. Several algorithms are also available: General algorithms for all bradycardic indications ( algorithm 1 and figure 1) An algorithm for sick sinus syndrome ( algorithm 2) An algorithm for AV block ( algorithm 3) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Pacemakers (The Basics)") Beyond the Basics topic (see "Patient education: Pacemakers (Beyond the Basics)") https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 13/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate SUMMARY AND RECOMMENDATIONS Nomenclature For permanent cardiac pacing, the five position NBG code indicates the chamber(s) paced, the chamber(s) sensed, the response to sensing, presence or absence of rate modulation, and location or absence of multisite pacing ( table 2). (See 'Nomenclature' above.) Selection of pacing mode In selecting a pacing mode, the patient's overall physical condition, associated medical problems, exercise capacity, left ventricular (LV) function, and chronotropic response to exercise must be considered along with the underlying rhythm disturbance. Some commonly used pacing modes are shown in the table ( table 3). (See 'Pacing modes' above.) Most patients with a standard bradycardic indication for pacing can be managed with one of three common pacing modes (with or without rate responsive pacing): AAI(R), VVI(R), or DDD(R). At the time of implantation, one should consider how many leads will be necessary and which additional features, if any, will be of potential value. Choice of single- or dual-chamber pacemaker The most important choice in most patients with a bradycardic indication for pacing is whether to place a single- or dual- chamber pacemaker (see "Permanent cardiac pacing: Overview of devices and indications" and 'Pacing modes' above). The choice varies with the clinical setting: Atrial fibrillation In patients with chronic atrial fibrillation (AF) who require a pacemaker due to slow ventricular response, we recommend a single-chamber ventricular pacemaker (VVI or VVIR) (Grade 1B). (See 'VVI or VVIR pacing' above.) Sinus rhythm In patients in sinus rhythm with conditions that could be managed with either a single- or a dual-chamber pacemaker (eg, atrioventricular [AV] block, sinus node dysfunction [SND]), we suggest a dual-chamber pacemaker (Grade 2B). (See 'Physiologic pacing' above and 'Dual-chamber pacing' above.) Exception for advanced age or difficult two lead implantation A single- chamber pacemaker is a reasonable alternative in patients who are adults with advanced age or whose anatomy and physical condition make the implantation of two leads more difficult than usual. In such cases, the additional costs and risks of a dual-chamber physiologic pacemaker may outweigh the potential benefits of the reduced risk of AF and patient preference. VVI(R) pacing will be effective in all such patients. (See 'VVI or VVIR pacing' above.) https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 14/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate Possible exception for SND with intact AV conduction An AAI(R) pacemaker is a reasonable alternative to VVI(R) pacing in the subset of patients with SND in whom AV conduction is intact and meets intra-implant testing criteria (see "Sinus node dysfunction: Treatment"). However, effective AAIR pacing is more commonly accomplished with a dual-chamber pacemaker with a ventricular pacing avoidance option. (See 'AAI or AAIR pacing' above and 'Modes to minimize ventricular pacing' above.) Additional features The following additional features are appropriate for selected patients: Rate responsiveness This feature can be programmed for patients who are active, but not chronotropically competent. (See 'Rate responsiveness' above.) Mode switching This feature can be programmed for patients with paroxysmal atrial arrhythmias. (See 'Mode switching' above.) Ventricular pacing avoidance Algorithms to avoid ventricular pacing are appropriate for most patients with PR prolongation or type II AV block. Some parameter to minimize ventricular pacing is available in most contemporary devices. (See 'Modes to minimize ventricular pacing' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges David L Hayes, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Bernstein AD, Daubert JC, Fletcher RD, et al. The revised NASPE/BPEG generic code for antibradycardia, adaptive-rate, and multisite pacing. North American Society of Pacing and Electrophysiology/British Pacing and Electrophysiology Group. Pacing Clin Electrophysiol 2002; 25:260. 2. Sweeney MO, Prinzen FW. A new paradigm for physiologic ventricular pacing. J Am Coll Cardiol 2006; 47:282. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 15/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate 3. Sweeney MO, Bank AJ, Nsah E, et al. Minimizing ventricular pacing to reduce atrial fibrillation in sinus-node disease. N Engl J Med 2007; 357:1000. 4. Sweeney MO, Ellenbogen KA, Casavant D, et al. Multicenter, prospective, randomized safety and efficacy study of a new atrial-based managed ventricular pacing mode (MVP) in dual chamber ICDs. J Cardiovasc Electrophysiol 2005; 16:811. 5. Olshansky B, Day JD, Moore S, et al. Is dual-chamber programming inferior to single- chamber programming in an implantable cardioverter-defibrillator? Results of the INTRINSIC RV (Inhibition of Unnecessary RV Pacing With AVSH in ICDs) study. Circulation 2007; 115:9. 6. Ricci RP, Botto GL, B n zet JM, et al. Association between ventricular pacing and persistent atrial fibrillation in patients indicated to elective pacemaker replacement: Results of the Prefer for Elective Replacement MVP (PreFER MVP) randomized study. Heart Rhythm 2015; 12:2239. 7. Stockburger M, Boveda S, Moreno J, et al. Long-term clinical effects of ventricular pacing reduction with a changeover mode to minimize ventricular pacing in a general pacemaker population. Eur Heart J 2015; 36:151. 8. Curtis AB, Worley SJ, Adamson PB, et al. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med 2013; 368:1585. 9. Curtis AB, Worley SJ, Chung ES, et al. Improvement in Clinical Outcomes With Biventricular Versus Right Ventricular Pacing: The BLOCK HF Study. J Am Coll Cardiol 2016; 67:2148. 10. Hayes DL, Furman S. Stability of AV conduction in sick sinus node syndrome patients with implanted atrial pacemakers. Am Heart J 1984; 107:644. 11. Antonioli, G, Ansani, et al. Single-Lead VDD Pacing. In: New Perspectives in Cardiac Pacing, 3, Barold, S, Mugica, J (Eds), Futura Publishing, Mount Kisco 1993. 12. Rey JL, Tribouilloy C, Elghelbazouri F, Otmani A. Single-lead VDD pacing: long-term experience with four different systems. Am Heart J 1998; 135:1036. 13. Huang M, Krahn AD, Yee R, et al. Optimal pacing for symptomatic AV block: a comparison of VDD and DDD pacing. Pacing Clin Electrophysiol 2004; 27:19. 14. Wiegand UK, Bode F, Schneider R, et al. Development of sinus node disease in patients with AV block: implications for single lead VDD pacing. Heart 1999; 81:580. 15. Morsi A, Lau C, Nishimura S, Goldman BS. The development of sinoatrial dysfunction in pacemaker patients with isolated atrioventricular block. Pacing Clin Electrophysiol 1998; 21:1430. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 16/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate 16. Lamas GA, Ellenbogen KA. Evidence base for pacemaker mode selection: from physiology to randomized trials. Circulation 2004; 109:443. 17. Healey JS, Toff WD, Lamas GA, et al. Cardiovascular outcomes with atrial-based pacing compared with ventricular pacing: meta-analysis of randomized trials, using individual patient data. Circulation 2006; 114:11. 18. Stewart WJ, Dicola VC, Harthorne JW, et al. Doppler ultrasound measurement of cardiac output in patients with physiologic pacemakers. Effects of left ventricular function and retrograde ventriculoatrial conduction. Am J Cardiol 1984; 54:308. 19. Rediker DE, Eagle KA, Homma S, et al. Clinical and hemodynamic comparison of VVI versus DDD pacing in patients with DDD pacemakers. Am J Cardiol 1988; 61:323. 20. Boon NA, Frew AJ, Johnston JA, Cobbe SM. A comparison of symptoms and intra-arterial ambulatory blood pressure during long term dual chamber atrioventricular synchronous (DDD) and ventricular demand (VVI) pacing. Br Heart J 1987; 58:34. 21. Takeuchi M, Nohtomi Y, Kuroiwa A. Effect of ventricular pacing on coronary blood flow in patients with normal coronary arteries. Pacing Clin Electrophysiol 1997; 20:2463. 22. Nielsen JC, Andersen HR, Thomsen PE, et al. Heart failure and echocardiographic changes during long-term follow-up of patients with sick sinus syndrome randomized to single- chamber atrial or ventricular pacing. Circulation 1998; 97:987. 23. Ausubel K, Furman S. The pacemaker syndrome. Ann Intern Med 1985; 103:420. 24. Lamas GA, Orav EJ, Stambler BS, et al. Quality of life and clinical outcomes in elderly patients treated with ventricular pacing as compared with dual-chamber pacing. Pacemaker Selection in the Elderly Investigators. N Engl J Med 1998; 338:1097. 25. Andersen HR, Thuesen L, Bagger JP, et al. Prospective randomised trial of atrial versus ventricular pacing in sick-sinus syndrome. Lancet 1994; 344:1523. 26. Lamas GA, Lee KL, Sweeney MO, et al. Ventricular pacing or dual-chamber pacing for sinus- node dysfunction. N Engl J Med 2002; 346:1854. 27. Connolly SJ, Kerr CR, Gent M, et al. Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. Canadian Trial of Physiologic Pacing Investigators. N Engl J Med 2000; 342:1385. 28. Toff WD, Camm AJ, Skehan JD, United Kingdom Pacing and Cardiovascular Events Trial Investigators. Single-chamber versus dual-chamber pacing for high-grade atrioventricular block. N Engl J Med 2005; 353:145. 29. Kerr CR, Connolly SJ, Abdollah H, et al. Canadian Trial of Physiological Pacing: Effects of physiological pacing during long-term follow-up. Circulation 2004; 109:357. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 17/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate 30. Andersen HR, Nielsen JC, Thomsen PE, et al. Long-term follow-up of patients from a randomised trial of atrial versus ventricular pacing for sick-sinus syndrome. Lancet 1997; 350:1210. 31. Hellkamp AS, Lee KL, Sweeney MO, et al. Treatment crossovers did not affect randomized treatment comparisons in the Mode Selection Trial (MOST). J Am Coll Cardiol 2006; 47:2260. 32. Skanes AC, Krahn AD, Yee R, et al. Progression to chronic atrial fibrillation after pacing: the Canadian Trial of Physiologic Pacing. CTOPP Investigators. J Am Coll Cardiol 2001; 38:167. 33. Tang AS, Roberts RS, Kerr C, et al. Relationship between pacemaker dependency and the effect of pacing mode on cardiovascular outcomes. Circulation 2001; 103:3081. 34. Ellenbogen KA, Stambler BS, Orav EJ, et al. Clinical characteristics of patients intolerant to VVIR pacing. Am J Cardiol 2000; 86:59. 35. Jahangir A, Shen WK, Neubauer SA, et al. Relation between mode of pacing and long-term survival in the very elderly. J Am Coll Cardiol 1999; 33:1208. 36. Link MS, Hellkamp AS, Estes NA 3rd, et al. High incidence of pacemaker syndrome in patients with sinus node dysfunction treated with ventricular-based pacing in the Mode Selection Trial (MOST). J Am Coll Cardiol 2004; 43:2066. 37. Sulke N, Chambers J, Dritsas A, Sowton E. A randomized double-blind crossover comparison of four rate-responsive pacing modes. J Am Coll Cardiol 1991; 17:696. 38. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74:e51. Topic 950 Version 30.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 18/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate GRAPHICS Guidelines for choice of pacemaker generator in selected indications for pacing Neurally-mediated Type of Sinus node syncope or carotid AV block pacemaker dysfunction sinus hypersensitivity Single-chamber No suspected Not appropriate Not appropriate (unless atrial abnormality of AV AV block systematically conduction and not at increased risk for excluded) future AV block Maintenance of AV synchrony during pacing desired Rate response available if desired Single-chamber ventricular Maintenance of AV synchrony during pacing not necessary Chronic atrial fibrillation or other atrial tachyarrhythmia or maintenance of AV synchrony during pacing not necessary Chronic atrial fibrillation or other atrial tachyarrhythmia Rate response available if desired Rate response available if desired Rate response available if desired Dual-chamber AV synchrony during pacing desired AV synchrony during pacing desired Sinus mechanism present Rate response available if Suspected abnormality of AV conduction or Atrial pacing desired desired increased risk for future AV block Rate response available if desired Rate response available if desired Single-lead, Not appropriate Normal sinus node function Not appropriate atrial-sensing ventricular and no need for atrial pacing https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 19/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate Desire to limit number of pacemaker leads AV: atrioventricular. Data from Gregoratos G, Cheitlin MD, Conill A, et al. Circulation 1998; 97:1325. Graphic 51504 Version 3.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 20/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate Revised NBG code for pacing nomenclature I II III IV V Position Chamber(s) paced Chamber(s) sensed Response to sensing Rate modulation Multisite pacing Category O = None O = None O = None O = None O = None A = Atrium A = Atrium T = R = Rate A = Atrium Triggered modulation V = Ventricle V = Ventricle V = I = Inhibited Ventricle D = Dual (A+V) D = Dual (A+V) D = Dual (T+I) D = Dual (A+V) S = Single (A S = Single (A Manufacturer's or V) or V) designation only: Note: Positions I through III are used exclusively for antibradyarrythmia function. Adapted from Bernstein AD, Daubert JC, Fletcher RD, et al. Pacing Clin Electrophysiol 2002; 25:260. Graphic 68327 Version 3.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 21/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate Types of cardiac pacemakers and NBG codes Code Meaning VOO Asynchronous ventricular pacemaker; no adaptive rate control or antitachyarrhythmia functions VVI Ventricular "demand" pacemaker with electrogram-waveform telemetry; no adaptive rate control or antitachyarrhythmia functions DVI Multiprogrammable atrioventricular-sequential pacemaker; no adaptive rate control DDD Multiprogrammable "physiologic" dual-chamber pacemaker; no adaptive rate control or antitachyarrhythmia functions DDI Multiprogrammable DDI pacemaker (with dual-chamber pacing and sensing but without atrial-synchronous ventricular pacing); no adaptive rate control or antitachycardia functions VVIR Adaptive-rate VVI pacemaker with escape interval controlled adaptively by one or more unspecified variables DDDR Programmable DDD pacemaker with escape interval controlled adaptively by one or more unspecified variables Graphic 79459 Version 1.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 22/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate Rhythms seen with a normal DDD pacemaker The rhythms that occur in a patient with a DDD pacemaker depend upon the underlying heart rate and atrioventricular (AV) nodal conduction. The pacemaker spike is represented in blue. First panel: The pacemaker may be completely inhibited when the sinus rate is greater than the lower rate limit of the pacemaker. Second panel: P- wave synchronous pacing occurs when there is intrinsic AV nodal delay which is greater than the AV delay in the pacemaker. Third panel: Atrial pacing occurs when the sinus rate falls below the lower limit of the pacemaker and AV nodal conduction is intact. Fourth panel: If there is sinus bradycardia and AV nodal conduction delay, the pacemaker paces both atrium and ventricle, known as AV sequential pacing. Graphic 52858 Version 3.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 23/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate Pacing modes indications and contraindications Generally agreed Controversial Mode Contraindications upon indications indications VVI/VVIR Fixed atrial arrhythmias (atrial Symptomatic bradycardia in the Patients with known pacemaker syndrome or fibrillation or flutter) patient with associated hemodynamic with symptomatic bradycardia in the CC patient (VVI) or CI terminal illness or other medical conditions from which deterioration with ventricular pacing at the time of implant patient (VVIR) recovery is not CI patient who will benefit from rate anticipated and pacing is life-sustaining only response Patients with hemodynamic need for dual-chamber pacing AAI/AAIR Symptomatic bradycardia as a result Sinus node dysfunction with associated AV block of sinus node dysfunction; used when AV conduction can be proven normal in the otherwise CC patient (AAI) or CI either demonstrated spontaneously or during pre-implant testing When adequate atrial sensing cannot be patient (AAIR) attained DVI* VDD /VDDR Congenital AV block Sinus node dysfunction AV block when sinus node function can be AV block when accompanied by sinus proven normal in the CC patient (VDD) or CI node dysfunction When adequate atrial patient (VDDR) sensing cannot be attained AV block when accompanied by PSVT DDI/DDIR Need for dual-chamber Sinus node dysfunction CI patient with a pacing in the presence of significant PSVT in in the absence of AV block in the presence demonstrated need or improvement with rate the CC patient (DDI) or CI patient (DDIR) of significant PSVT in the CC patient (DDI) or responsiveness CI patient (DDIR) https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 24/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate DDD/DDDR AV block and sinus For any rhythm Presence of chronic node dysfunction in the CC patient (DDD) or disturbance when atrial sensing and atrial fibrillation, atrial flutter, giant inexcitable CI patient (DDDR) capture is possible for atrium or other the potential purpose of minimizing future frequent PSVTs Need for AV synchrony to maximize cardiac output in CC active When adequate atrial sensing cannot be atrial fibrillation and improved morbidity patients (DDD) attained and survival Previous pacemaker syndrome CC: chronotropically competent (ie, the ability to achieve an appropriate heart rate for a given physiologic activity); CI: chronotropically incompetent (ie, the inability to achieve an appropriate heart rate for a given physiologic activity); AV: atrioventricular; PSVT: paroxysmal supraventricular tachycardia. DVI as a stand-alone pacing mode (ie, a pacemaker capable of DVI as the only dual-chamber mode of operation) is obsolete. All primary uses of this mode should be considered individually. VDD as a stand-alone pacing mode (ie, a pacemaker capable of VDD as the only dual-chamber mode of operation) is currently used primarily as a single-lead VDD system. If a dual-lead system is implanted, then the capability of DDD pacing is desirable. In current single-lead VDDR pacemakers, P-wave tracking occurs as long as the sinus rate is appropriate. However, in the presence of sinus bradycardia or chronotropic incompetence, the pacemaker operates in the VVIR mode. DDIR has been supplanted by DDD or DDDR pacemakers with the capability of mode-switching (ie, the pacemaker automatically reprograms to a mode incapable of tracking the atrial rhythm in the presence of an atrial rhythm that the pacemaker classifies as a pathological rhythm). When the pacemaker recognizes the atrial rhythm as being physiological, the pacemaker reprograms to the previously programmed mode. Graphic 120148 Version 1.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 25/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate Pacemaker algorithm Algorithm for the use of the different types of pacemakers depending upon the need for atrioventricular (AV) sequential pacing, the presence of sinoatrial (SA) node chronotropic competence, the AV conduction rate, and the need for rate-responsiveness. Refer to UpToDate content on modes of cardiac pacing: nomenclature and selection. Courtesy of MD McGoon, MD. Graphic 64626 Version 3.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 26/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate Simplified pacemaker algorithm for use with rate adaptive pacemakers Simplified algorithm for the choice of pacemaker mode assuming that a rate-responsive pacemaker (DDDR or VVIR) will be used. Courtesy of MD McGoon, MD. Graphic 76446 Version 2.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 27/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate Selection of pacemaker systems for patients with sinus node dysfunction Decisions are illustrated by diamonds. Shaded boxes indicate type of pacemaker. AV: atrioventricular. Reproduced with permission from: Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2008; 51(21):e1-e62. Illustration used with permission of Elsevier Inc. All rights reserved. Copyright 2008 Elsevier Inc. Graphic 77929 Version 5.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 28/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate Selection of pacemaker systems for patients with atrioventricular block Decisions are illustrated by diamonds. Shaded boxes indicate type of pacemaker. AV: atrioventricular. Reproduced with permission from: Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2008; 51(21):e1-e62. Illustration used with permission of Elsevier Inc. All rights reserved. Copyright 2008 Elsevier Inc. https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 29/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate Graphic 71370 Version 4.0 https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 30/31 7/6/23, 10:54 AM Modes of cardiac pacing: Nomenclature and selection - UpToDate Contributor Disclosures Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/modes-of-cardiac-pacing-nomenclature-and-selection/print 31/31

7/6/23, 10:57 AM Overview of pacemakers in heart failure - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Overview of pacemakers in heart failure : E Kevin Heist, MD, PhD : Frederick Masoudi, MD, MSPH, FACC, FAHA : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 03, 2023. INTRODUCTION Cardiac implantable electronic devices (CIEDs), such as cardiac pacemakers and implantable cardioverter-defibrillators (ICDs), are increasingly used in patients with heart failure (HF) and at risk for HF. The impact of CIEDs on the incidence and progression of HF is complex and depends upon both the nature of the device (eg, ICD and/or single chamber, dual chamber, or biventricular pacemaker), and device programming. The role and effects of cardiac implantable electronic devices in patients with HF will be reviewed here. Indications for cardiac resynchronization therapy (CRT), ICD, permanent pacemakers, and the various modes of cardiac pacing are discussed separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in atrial fibrillation" and "Cardiac resynchronization therapy in heart failure: System implantation and programming" and "Implantable cardioverter-defibrillators: Overview of indications, components, and functions" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Permanent cardiac pacing: Overview of devices and indications" and "Modes of cardiac pacing: Nomenclature and selection".) Use of pacemakers and ICDs as continuous monitoring devices is discussed separately. (See "Ambulatory ECG monitoring", section on 'Permanent pacemakers and implantable cardioverter- defibrillators'.) https://www.uptodate.com/contents/overview-of-pacemakers-in-heart-failure/print 1/13 7/6/23, 10:57 AM Overview of pacemakers in heart failure - UpToDate Secondary mitral regurgitation is common in patients with HF. The effects of atrioventricular (AV) optimization in patients with dual chamber pacemakers and CRT on mitral regurgitation are discussed separately. (See "Management and prognosis of chronic secondary mitral regurgitation".) ROLE OF PACING IN HEART FAILURE Approach to pacemaker or ICD use In patients with HF (or at risk for HF due to systolic dysfunction), pacing that may worsen HF is avoided while CIEDs likely to provide clinical benefit are prescribed. While right ventricular (RV) pacing can exacerbate or precipitate HF in patients with left ventricular (LV) systolic dysfunction, evidence-based device therapy (including cardiac resynchronization therapy [CRT] and ICDs) improves clinical outcomes in selected patients with HF and/or LV systolic dysfunction. (See 'Clinical effects of pacing' below.) Our approach is in general agreement with the 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA) guidelines on the management of HF [1], the 2021 European Society of Cardiology HF guidelines [2], and the 2018 ACC/AHA/Heart Rhythm Society guidelines on the evaluation and management of patients with bradycardia and cardiac conduction delay [3]. For patients with HF (or at risk for HF due to systolic dysfunction): Determine if an indication for a pacemaker, CRT, and/or ICD is present. Indications for pacing include symptomatic sinus node dysfunction or AV block, as presented separately. (See "Permanent cardiac pacing: Overview of devices and indications".) Indications for CRT with biventricular pacing for patients in sinus rhythm or with atrial fibrillation are presented separately. These devices are appropriate for selected HF patients with systolic dysfunction and ventricular dyssynchrony. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in atrial fibrillation".) CRT is performed with a pacemaker that simultaneously paces the right and left ventricles (biventricular pacemaker). CRT can improve cardiac function, symptoms, and survival in selected patients with HF with LV systolic dysfunction (particularly those with LV ejection fraction [LVEF] 35 percent, very wide QRS, and left bundle branch block). In addition, CRT can improve outcomes in selected patients with LV systolic dysfunction https://www.uptodate.com/contents/overview-of-pacemakers-in-heart-failure/print 2/13 7/6/23, 10:57 AM Overview of pacemakers in heart failure - UpToDate (LVEF 35 percent) who require a pacemaker with anticipated requirement for significant (>40 percent) ventricular pacing (thus avoiding the detrimental effects of isolated RV pacing). The role of cardiac contractility modulation in patients with HF is discussed separately. (See "Investigational therapies for management of heart failure", section on 'Cardiac contractility modulation'.) Indications for an ICD are presented separately. The impact of an ICD on HF outcomes is discussed below. (See 'Implantable cardioverter-defibrillators' below and "Implantable cardioverter-defibrillators: Overview of indications, components, and functions" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) For patients who have an indication for a CIED that may include RV pacing, the adverse effects of isolated RV pacing can be minimized by appropriate device selection and programming. (See 'Device selection and programming' below and "Permanent cardiac pacing: Overview of devices and indications" and "Modes of cardiac pacing: Nomenclature and selection".) If a standard indication for CIED is not present, cardiac pacing does not play a role in treating or preventing HF. (See 'Clinical effects of pacing' below.) Device selection and programming For patients with HF and/or systolic dysfunction who require a pacemaker or an ICD, ventricular dyssynchrony should be minimized, either by utilizing CRT (with biventricular pacing or conduction system pacing) or by minimizing RV pacing. Determine if CRT is indicated, as discussed separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in atrial fibrillation" and "Cardiac resynchronization therapy in heart failure: System implantation and programming".) Many candidates for ICD therapy also have indications for CRT and should receive a device with both functions (CRT-D). (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Conduction system (His bundle or left bundle branch) pacing is another pacing option that can be used for resynchronization or to minimize the effects of isolated RV pacing. (See https://www.uptodate.com/contents/overview-of-pacemakers-in-heart-failure/print 3/13 7/6/23, 10:57 AM Overview of pacemakers in heart failure - UpToDate "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Conduction system pacing' and "Permanent cardiac pacing: Overview of devices and indications", section on 'His bundle pacing' and "Permanent cardiac pacing: Overview of devices and indications", section on 'Left bundle pacing'.) For patients who are not candidates for CRT (by biventricular pacing or conduction system pacing), the following methods may be used to minimize RV pacing (see 'Pacing modes to limit RV pacing' below): Managed ventricular pacing Devices with this capability allow native conduction to occur, even in the setting of substantial PR prolongation or second-degree AV block. If high-grade AV block develops, the device will switch modes to dual-chamber pacing. These devices are appropriate for patients with first- or second-degree AV block, for whom they can substantially reduce the frequency of ventricular pacing. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Modes to minimize ventricular pacing'.) Standard devices programmed to minimize RV pacing Many patients with HF and systolic dysfunction do not have a pacemaker or an ICD with a managed ventricular pacing (or comparable) programming option. However, in patients with intact AV conduction, the following device programming options can reduce the frequency of ventricular pacing (see "Modes of cardiac pacing: Nomenclature and selection") ( table 1): - - Prolonged programmed AV intervals Eliminating rate responsive AV delay DDI (dual-chamber sequential AV pacing with atrial sensing but not tracking) or DDIR (DDI rate-responsive) pacing AAI (atrial demand) pacing (see "Sinus node dysfunction: Treatment") However, these programming options also have limitations, and, in many patients with conduction system disease, it is difficult to effectively minimize ventricular pacing. CLINICAL EFFECTS OF PACING Data from both retrospective analyses and a randomized trial show that RV pacing can exacerbate HF, hypothesized to result from the following: https://www.uptodate.com/contents/overview-of-pacemakers-in-heart-failure/print 4/13 7/6/23, 10:57 AM Overview of pacemakers in heart failure - UpToDate When the native conduction system is normal, the QRS duration is 120 ms, and ventricular contraction is synchronized. Synchronous ventricular contraction optimizes cardiac function. Standard RV pacing causes the RV to contract before the LV (interventricular dyssynchrony). In addition, RV pacing simulates the effect of left bundle branch block, causing the septum to contract before the lateral wall (intraventricular dyssynchrony). Ventricular dyssynchrony can reduce cardiac efficiency. Additionally, asynchronous ventricular pacing can impede cardiac pump function by inducing asynchrony in atrial and ventricular contraction. Although such alterations in cardiac pump function may be clinically imperceptible in patients without an underlying cardiomyopathy, it can be important in the setting of a failing ventricle, resulting in increased HF symptoms [4]. The relationships between ventricular dyssynchrony, HF, and resynchronization therapy are discussed in detail separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT'.) Greater RV pacing worsens outcomes Although it had been proposed that dual-chamber (right atrial and RV) pacing might be beneficial in patients with HF, a randomized trial (DAVID) and observational studies found that DDD (dual-chamber paced and sensed) pacing can exacerbate HF, likely due to the detrimental effect of RV pacing. The hypothesis that dual-chamber pacing might improve cardiac function in patients with HF was based upon the following observations [5]. Pacing permits more aggressive beta blocker therapy for HF, which may be limited by symptomatic bradycardia. Dual-chamber pacing allows optimization of the AV interval, thereby improving coordination between atria and ventricles, optimizing valve closure, and minimizing mitral regurgitation. In addition, atrial pacing has been reported to reduce the frequency of atrial fibrillation in some studies (see "The role of pacemakers in the prevention of atrial fibrillation"). A potential benefit of dual-chamber pacing was suggested in an initial uncontrolled study of 17 patients with idiopathic dilated cardiomyopathy who had medically refractory HF and severe symptoms [6,7]. These findings provided the rationale for the DAVID trial, which did not confirm any benefit. The DAVID trial studied dual-chamber (right atrial and RV) pacing in patients with HF with LV systolic dysfunction [8]. The trial found that rate-responsive dual-chamber (DDDR) pacing increased HF admissions and mortality compared to ventricular demand pacing (VVI), likely due to the RV component of dual chamber pacing ( table 1) [9]. https://www.uptodate.com/contents/overview-of-pacemakers-in-heart-failure/print 5/13 7/6/23, 10:57 AM Overview of pacemakers in heart failure - UpToDate The trial enrolled 506 patients with an LVEF 40 percent and an indication for ICD implantation but no indication for antibradycardia pacing [8]. The patients were randomly assigned to VVI pacing with a lower rate limit of 40 beats per minute (VVI-40) or to DDDR pacing with a lower rate limit of 70 beats per minute (DDDR-70). The frequency of RV pacing was substantially higher in the DDDR-70 compared to the VVI-40 group (60 versus 1 percent) due to a relatively short programmed AV interval (typically 180 ms) in the DDDR group. Thus, the trial effectively compared DDDR pacing with sinus rhythm. At one-year follow-up, there was a detrimental effect of DDDR-70 pacing. Survival free of the primary composite end point of death or hospitalization for HF was significantly lower in the DDDR-70 group (73 versus 84 percent in the VVI-40 group). There were nominally higher rates of both components of the primary end point in the DDDR-70 group: mortality (10.1 versus 6.4 percent) and HF hospitalization (22.6 versus 13.3 percent), but these differences were not statistically significant. In a post-hoc analysis, the detrimental effects of DDDR-70 pacing were more pronounced in patients with a baseline QRS 110 ms [10]. Patients with QRS prolongation were more likely than those with a normal QRS to have other markers of poor outcome (eg, worse systolic function and a history of HF). Thus, it is not clear if baseline conduction abnormalities themselves or associated cardiac abnormalities predisposed patients to the adverse consequences of RV pacing. A post-hoc analysis of data from the MOST trial of pacing modes in patients with sinus node dysfunction further supports the deleterious effects associated with RV pacing [11]. This analysis was restricted to the 1339 of 2010 participants with a normal QRS duration (120 ms). In this subgroup, 707 had been assigned to DDDR and 632 to VVIR pacing. Regardless of pacing mode, patients with a higher cumulative proportion of ventricular pacing had significantly higher rates of subsequent HF hospitalization and atrial fibrillation. Pacing modes to limit RV pacing Given the results of these studies, later randomized trials studied pacing modes selected to avoid or limit RV pacing. Settings that avoided or limited RV pacing led to similar outcomes to those with back-up ventricular pacing. The DAVID II trial found that atrial pacing and back-up ventricular pacing produced similar rates of event-free survival and quality of life [12]. The trial randomly assigned 600 patients with LVEF 40 percent and an indication for ICD implantation but no indication for antibradycardia pacing to AAI (atrial demand) pacing at 70 beats/min or VVI (ventricular demand) pacing at 40 beats/min. The primary combined end point of time to HF hospitalization or death was similar in the two treatment groups, with overall incidence of https://www.uptodate.com/contents/overview-of-pacemakers-in-heart-failure/print 6/13 7/6/23, 10:57 AM Overview of pacemakers in heart failure - UpToDate 11.1, 16.9, and 24.6 percent at one, two, and three years, respectively. The incidence of atrial fibrillation, syncope, appropriate or inappropriate shocks, and quality-of-life measures were also similar. The INTRINSIC RV trial found that dual-chamber rate-responsive pacing with the AV Search Hysteresis algorithm to minimize ventricular pacing (DDDR AVSH at 60 to 130 beats per minute) produced similar outcomes as back-up ventricular (VVI at 40 beats per minute) pacing. Individualized programming with attention to the PR interval is important since very long programmed AV delay using the AV Search Hysteresis algorithm can result in significant bradycardia or pacemaker syndrome in the presence of more advanced or progressive AV block [13]. IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS ICDs are recommended for the primary and secondary prevention of sudden cardiac death (SCD) in selected patients with ischemic and nonischemic cardiomyopathy. By reducing the incidence of arrhythmic death, ICDs may result in more patients surviving to advanced stages of heart failure (HF). (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) ICDs can influence the incidence and progression of HF by two mechanisms: Contemporary transvenous ICDs also function as cardiac pacemakers. As an example, the DAVID trial, discussed above, involved dual-chamber ICDs. Thus, the detrimental impact of RV pacing also applies to ICDs. Because many patients with an ICD do not have a standard indication for pacing, efforts to minimize ventricular pacing are particularly important in these patients. The programming and device selection options discussed above are also available in ICDs. (See 'Role of pacing in heart failure' above.) By aborting arrhythmic deaths, ICDs prolong survival in patients with substantial cardiac disease. Such patients may later progress to more advanced HF. This phenomenon was illustrated in a post-hoc analysis from the MADIT II trial [14]. In this trial, 1218 patients with a prior myocardial infarction and an LVEF 30 percent were randomly assigned to ICD implantation or conventional medical therapy. The patients assigned to ICD therapy had significantly lower risks of death. At a mean follow-up of 20 https://www.uptodate.com/contents/overview-of-pacemakers-in-heart-failure/print 7/13 7/6/23, 10:57 AM Overview of pacemakers in heart failure - UpToDate months, patients assigned to ICD therapy were significantly more likely to be hospitalized for HF than those assigned to conventional therapy (23 versus 17 percent). Among patients assigned to ICD therapy, the incidence of HF was significantly greater after appropriate ICD therapy compared to before such therapy (23 versus 16 events per 100 person years). Both the incidence of initial HF admissions and the intensity of recurrent admissions increased after appropriate ICD therapies. In contrast, there was no difference in the incidence of HF after inappropriate device therapies. These data suggest that appropriate ICD therapies are more common in patients who have or will soon experience worsening HF. Thus, life-prolonging ICD therapies may transform SCD risk to subsequent HF risk, although short-term mortality is improved. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Heart failure in adults" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient education: Cardiac resynchronization therapy (The Basics)") SUMMARY AND RECOMMENDATIONS https://www.uptodate.com/contents/overview-of-pacemakers-in-heart-failure/print 8/13 7/6/23, 10:57 AM Overview of pacemakers in heart failure - UpToDate The impact of cardiac implantable electronic devices (CIEDs) on the incidence and progression of heart failure (HF) depends upon the type of device and device programming. In patients with HF (or at risk for HF due to systolic dysfunction), right ventricular (RV) pacing can exacerbate or precipitate HF. In contrast, evidence-based device therapy (cardiac resynchronization therapy [CRT], conduction system pacing, and implantable cardioverter-defibrillator [ICD] use) improves clinical outcomes in selected patients with HF and/or systolic dysfunction. (See 'Approach to pacemaker or ICD use' above.) Patients with HF (or at risk for HF due to systolic dysfunction) are evaluated to determine if standard indications one or more of the following CIEDs are present, which are discussed separately (see 'Approach to pacemaker or ICD use' above): Permanent pacemaker therapy. (See "Permanent cardiac pacing: Overview of devices and indications" and "Modes of cardiac pacing: Nomenclature and selection".) CRT. Many candidates for ICD therapy also have indications for CRT and should receive a combined device (CRT-D), as discussed separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in atrial fibrillation".) ICD. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) If a standard indication for CIED is not present, cardiac pacing does not play a role in treating or preventing HF. (See 'Approach to pacemaker or ICD use' above and 'Clinical effects of pacing' above.) For patients with HF (or at risk for HF due to systolic dysfunction) who require a pacemaker or an ICD, ventricular dyssynchrony should be minimized, either by utilizing CRT (with biventricular pacing or conduction system pacing) or by minimizing RV pacing. (See 'Device selection and programming' above.) CRT with biventricular pacing is indicated for selected HF patients and for some patients with left ventricular systolic dysfunction at risk for developing HF. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in atrial fibrillation".) https://www.uptodate.com/contents/overview-of-pacemakers-in-heart-failure/print 9/13 7/6/23, 10:57 AM Overview of pacemakers in heart failure - UpToDate Conduction system (His bundle or left bundle branch) pacing is another pacing option that can be used for resynchronization or to minimize the effects of isolated RV pacing. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Conduction system pacing' and "Permanent cardiac pacing: Overview of devices and indications", section on 'His bundle pacing' and "Permanent cardiac pacing: Overview of devices and indications", section on 'Left bundle pacing'.) For patients who are not candidates for CRT (by biventricular pacing or conduction system pacing), RV pacing may be minimized using managed ventricular pacing or programming of standard devices. (See 'Pacing modes to limit RV pacing' above.) ACKNOWLEDGMENT The UpToDate editorial staff thank Michael Cao, MD, and Leslie A Saxon, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2022; 145:e895. 2. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021; 42:3599. 3. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74:e51. 4. Saxon LA, Stevenson WG, Middlekauff HR, Stevenson LW. Increased risk of progressive hemodynamic deterioration in advanced heart failure patients requiring permanent pacemakers. Am Heart J 1993; 125:1306. 5. Auricchio A, Salo RW. Acute hemodynamic improvement by pacing in patients with severe congestive heart failure. Pacing Clin Electrophysiol 1997; 20:313. https://www.uptodate.com/contents/overview-of-pacemakers-in-heart-failure/print 10/13 7/6/23, 10:57 AM Overview of pacemakers in heart failure - UpToDate 6. Hochleitner M, H rtnagl H, Ng CK, et al. Usefulness of physiologic dual-chamber pacing in drug-resistant idiopathic dilated cardiomyopathy. Am J Cardiol 1990; 66:198. 7. Hochleitner M, H rtnagl H, H rtnagl H, et al. Long-term efficacy of physiologic dual- chamber pacing in the treatment of end-stage idiopathic dilated cardiomyopathy. Am J Cardiol 1992; 70:1320. 8. Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 2002; 288:3115. 9. Sweeney MO, Prinzen FW. A new paradigm for physiologic ventricular pacing. J Am Coll Cardiol 2006; 47:282. 10. Hayes JJ, Sharma AD, Love JC, et al. Abnormal conduction increases risk of adverse outcomes from right ventricular pacing. J Am Coll Cardiol 2006; 48:1628. 11. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003; 107:2932. 12. Wilkoff BL, Kudenchuk PJ, Buxton AE, et al. The DAVID (Dual Chamber and VVI Implantable Defibrillator) II trial. J Am Coll Cardiol 2009; 53:872. 13. http://www.fac.org.ar/qcvc/llave/c121i/levinep.php (Accessed on December 08, 2014). 14. Goldenberg I, Moss AJ, Hall WJ, et al. Causes and consequences of heart failure after prophylactic implantation of a defibrillator in the multicenter automatic defibrillator implantation trial II. Circulation 2006; 113:2810. Topic 3493 Version 27.0 https://www.uptodate.com/contents/overview-of-pacemakers-in-heart-failure/print 11/13 7/6/23, 10:57 AM Overview of pacemakers in heart failure - UpToDate GRAPHICS Revised NBG code for pacing nomenclature I II III IV V Position Chamber(s) Chamber(s) Response to Rate Multisite Category paced sensed sensing modulation pacing O = None O = None O = None O = None O = None A = Atrium A = Atrium T = Triggered R = Rate modulation A = Atrium V = Ventricle V = Ventricle V = Ventricle I = Inhibited D = Dual D = Dual (A+V) (A+V) D = Dual (T+I) D = Dual (A+V) S = Single (A or V) S = Single (A or V) Manufacturer's designation only: Note: Positions I through III are used exclusively for antibradyarrythmia function. Adapted from Bernstein AD, Daubert JC, Fletcher RD, et al. Pacing Clin Electrophysiol 2002; 25:260. Graphic 68327 Version 3.0 https://www.uptodate.com/contents/overview-of-pacemakers-in-heart-failure/print 12/13 7/6/23, 10:57 AM Overview of pacemakers in heart failure - UpToDate Contributor Disclosures E Kevin Heist, MD, PhD Equity Ownership/Stock Options: Oracle Health [Device diagnostics]. Consultant/Advisory Boards: Biotronik [Cardiac resynchronization therapy and atrial fibrillation]; Boston Scientific [Cardiac resynchronization therapy and atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Frederick Masoudi, MD, MSPH, FACC, FAHA Consultant/Advisory Boards: Bristol Meyers Squibb [Hypertrophic cardiomyopathy]; Colorado Prevention Center [Diabetes trial steering committee, study sponsor, Better Therapeutics]; TurningPoint [Utilization policy review]. Other Financial Interest: American College of Cardiology [Cardiovascular disease]; Massachusetts Medical Society [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/overview-of-pacemakers-in-heart-failure/print 13/13

7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Pacing system malfunction: Evaluation and management : Mark S Link, MD : N A Mark Estes, III, MD : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 19, 2019. INTRODUCTION Periodic evaluations of an implanted pacemaker are required to maintain optimal programming and to identify any system problem that should be corrected. Common pacing system problems of single and dual chamber pacemakers and the methods of evaluation and therapy will be reviewed here. The malfunctions discussed will be limited to those that are manifest on an electrocardiogram (ECG) rhythm strip. Complications not related to pacing system malfunction Other complications not related to pacing are presented separately. These include infections, venous thrombosis and emboli, pacemaker syndrome, tricuspid regurgitation, and specific problems associated with dual- chamber pacemakers. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Cardiac implantable electronic devices: Long-term complications", section on 'Tricuspid regurgitation' and "Dual chamber pacing system malfunctions of timing, sensing, and capture: Evaluation and management".) PACING SYSTEM COMPONENTS The traditional pacing system is comprised of the pulse generator ( picture 1), also called the pacemaker, and the transvenous or epicardial lead or leads that connect the pulse generator to the heart. https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 1/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate The phrase "pacing system malfunction" includes problems that might arise from any of the components of the system. Inappropriately programmed pacemaker parameters, although they do not represent abnormal pacing system function, may be suboptimal for the patient. The normal characteristics and unique timing systems and algorithms of a given pacemaker are also an issue, as they may be interpreted as a malfunction by a clinician who is not familiar with the specific pulse generator. Recording system artifacts must always be considered in the differential diagnosis of a pacing system malfunction. INCIDENCE The incidence of pacing system malfunction is difficult to determine due to inconsistent definitions and the lack of any comprehensive reporting mechanism or registry [1,2]. Overall, device hardware is highly reliable [3]. In terms of comparative reliability, there is a higher incidence of complications of leads compared with pulse generators. In terms of lead malfunction, more complex implantable cardioverter-defibrillator leads have a higher incidence of failure than simpler pacemaker leads. As a result of a series of lead malfunctions, a policy was published by Heart Rhythm Society with lead performance guidelines [4]. PACING STIMULI PRESENT WITH LOSS OF CAPTURE One of the principal requirements of a pacing system is that it prevents a heart rate that is slower than a predefined rate. This is accomplished by the release of an output pulse or stimulus from the pacemaker that is delivered to the myocardium via the pacing lead, inducing a depolarization of either the atrium or ventricle, depending upon the location of the lead. The failure of that stimulus to produce electrical activation of the heart and a subsequent cardiac contraction is called noncapture or loss of capture. It is differentiated from capture by the absence of an evoked potential following the pacing stimulus. The diagnosis of loss of capture is based upon the presence of a stimulus, without a subsequent P wave or QRS complex, which occurs at a time when the myocardium is physiologically capable of being depolarized. One explanation for apparent loss of capture is failure to sense a native QRS complex followed by the release of the pacing stimulus at a time when the myocardium is physiologically refractory and incapable of being stimulated. While this may reflect a sensing malfunction, it is a normal phenomenon with regard to capture and should not be considered true capture malfunction. This is designated "functional failure to capture." https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 2/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate To establish true noncapture, it must be determined that a pacing stimulus was present on the ECG. Historically, on analog recording systems, unipolar stimuli were large and easily visible, and bipolar stimuli were diminutive and at times difficult to recognize. However, with current digital recording systems, this distinction is no longer reliable. If the output energy has been reduced, the stimulus may be virtually invisible on some ECG leads or may be eliminated entirely by high-frequency filters in the recording system. If no pacing stimuli are present in any of the available recording leads, then the problem is not loss of capture but a circuit interruption, which prevents delivery of the stimulus to the myocardium or oversensing. Causes of loss of capture The differential diagnosis of loss of capture is relatively limited, and the likelihood of a given problem is highly correlated with the time since implantation. Lead dislodgement or malposition The most common reason for loss of capture in the hours and days following implantation is either lead dislodgement or malposition. This is manifested as a change in the morphology of the pacemaker-evoked depolarization when capture is present. A change in the anatomic position of the lead on a chest radiograph may also be seen. Identifying these problems is dependent upon comparison with a baseline (ie, when normal capture was present) 12-lead ECG and chest radiograph. Failure to sense native complexes as well as atrial or ventricular ectopy may also be associated with an unstable electrode within one of the cardiac chambers. If identified, treatment may require operative intervention to reposition the lead. Lead dislodgement does not prevent pacemaker output. If a magnet is applied to the pulse generator when the lead is dislodged, even though it may not result in cardiac depolarization, output stimuli will still occur at the magnet rate of the pulse generator. Inflammation and fibrosis at the electrode/myocardial interface The inflammatory reaction and the resulting fibrous tissue that may occur after lead implantation may act as an insulating shield around the electrode, effectively raising the threshold for stimulation and attenuating the amplitude and slew rate of the endocardial signal being sensed. This is a process termed "lead maturation." Although improvements in electrode design and materials (eg, steroid elution) have essentially eliminated a reaction of such severity that a clinically issue is rarely encountered, loss of capture could result if the capture threshold exceeds the programmed output of the pacemaker. In the rare patient in whom this should occur, high thresholds associated with lead maturation may be diagnosed by a stable morphology of the evoked complex when capture is present and https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 3/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate there is a stable anatomic position on chest radiograph. The peak capture thresholds usually occur between several weeks to several months after implantation. Given sufficient time, the inflammatory reaction will subside, and the capture thresholds will improve. Management options include: Increasing the output of the pulse generator Lead repositioning Increase in capture threshold Loss of capture may occur months to years after implantation due to one or more of the following: A late rise in capture thresholds (ie, greater than four weeks post-implant) in the absence of dislodgment, thought to be secondary to excessive fibrosis at the lead/myocardial interface, also called exit block. This, too, is rarely seen given improvements in electrode design and materials (eg, steroid elution). A primary cardiomyopathic process. The addition of various medications or the occurrence of a metabolic abnormality, both of which can transiently elevate the pacemaker capture and sensing thresholds. Management is usually focused on correcting or eliminating the cause and, until this is accomplished, the output of the pacemaker is increased. When the etiology is a primary myocardial process, such as progressive fibrosis associated with a diffuse cardiomyopathy or a focal myocardial infarction, and the loss of capture cannot be managed by increasing the output of the pulse generator, an operative procedure will be required to place a new electrode. Sub-threshold pacemaker output programming Loss of capture may occur when the margin of safety for the programmed output with respect to the measured capture threshold is too low. While the capture threshold is a specific pulse amplitude at a given pulse duration, the measurement is made at only one point in time and usually with the patient in one position. Capture thresholds may change during the day; with body position; and in association with various physiologic stresses, such as exercise, eating, and infection. Programming the output too close to the measured capture threshold may not provide a sufficient margin of safety, resulting in intermittent loss of capture. In this setting, the pacemaker, leads, and patient are all functioning normally, but the pulse generator is programmed inappropriately for the patient. Increasing the output will correct this problem. Lead failure Intrinsic lead failure may result in loss of capture. This is usually a late occurrence (ie, many years after implantation). One or more of the following mechanisms may https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 4/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate be involved: Deterioration of the lead insulation may allow a current leak, resulting in loss of capture. Generation of nonphysiologic electrical transients, causing oversensing or attenuation of the intrinsic cardiac electrogram, can lead to undersensing. Extrinsic stresses on the lead, such as compression between the first rib and clavicle (ie, subclavian crush injury) may result in a conductor fracture or insulation breach due to a point of stress on the lead. These leads must be replaced to reestablish normal pacing system function. A primary lead problem can often be identified by the measurement of lead impedance. This information can be obtained by telemetry of measured data. The normal range for lead impedances typically varies from 300 to 1500 ohms. An insulation failure will result in very low impedances, often less than 250 ohms, while an open circuit associated with a conductor fracture is associated with very high impedances. Given the wide variability in impedance measurements between different lead models and even leads of the same model, trends or changes in serial measurements are often more important than a single isolated assessment. Chest radiograph may help diagnose a fracture of the conductor coil. The lead insulation is radiolucent and a defect in the insulation will generally not be visible radiographically. Compression or distortion of the conductor coil may identify a point of increased external stress on the lead. In a bipolar coaxial lead, capture may be restored in the presence of an internal insulation failure or a fracture of the outer conductor coil by programming to the unipolar (tip to case) output configuration. However, this should be considered a temporary measure. Battery depletion All pacemakers require a power source to function. They are powered by a battery, which is usually comprised of a lithium iodine power cell. The longevity of these systems is often six to eight years, but the longevity of any specific pulse generator depends upon the proportion of paced and sensed events, the programmed output and rate parameters, and the stimulation impedance. Each pacemaker incorporates one or more special features that will identify the recommended replacement time (RRT) or elective replacement indicator (ERI). When this occurs, one can expect the system to function properly for approximately three months, allowing sufficient time to electively replace the pulse generator. If these indicators are ignored or the patient is lost to follow-up, the battery may deplete to a point where the effective output falls below the capture threshold, resulting in loss of capture. https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 5/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate Battery depletion requires replacement of the pulse generator. If battery depletion occurs sooner than anticipated, based upon the programmed parameters of the pacemaker and the projections of the manufacturer, the integrity of the pacing lead should be carefully evaluated at the time of the replacement procedure. An insulation failure will result in a low-stimulation impedance that can accelerate battery depletion. Unless this is identified and the lead replaced, the new pulse generator will encounter a similar problem of rapid battery depletion. Recording system artifact Recording system artifacts may raise concerns about a system malfunction when they occur in a patient who has a pacemaker. Digital recording systems can either create a pacing stimulus in response to a high-frequency signal or initiate a blocking period in response to a very high-frequency signal to protect its own circuitry. This has the undesirable effect of either eliminating true pacing artifacts or creating a false artifact on the recording in response to a high-frequency transient of another etiology, mimicking either noncapture or undersensing. Another relatively common artifact occurs in systems that have special circuitry to protect the recorder from too large an incoming signal by blocking the circuit for a variable period of time. This may have the effect of showing the stimulus but eliminating the resultant evoked potential, leading to concerns about loss of capture. In this situation, there will be a visible T wave reflecting repolarization. Regardless of the cause, the likelihood of a recording system artifact is minimized by recording the rhythm in multiple simultaneous leads or sequentially in different leads. PACING STIMULUS PRESENT WITH FAILURE TO SENSE The second major functional capability of the modern pacemaker is the ability to sense or recognize intrinsic cardiac depolarizations. The pacemaker should be able to sense intrinsic atrial activity when the lead is located in the atrium, and intrinsic ventricular activity when the lead is located in the ventricle. Sensing is a complex phenomenon, being dependent upon the sense amplifier within the pacemaker and the size and characteristics of the signal inside the heart at the location of the pacing electrode. Although sensitivity is commonly reported as a function of the amplitude or size of the signal, it is a more complex process. Lack of sensing may occur with a QRS with very low amplitude. A signal with sufficient amplitude, but whose dominant frequencies fall outside the constraints imposed by the pacemaker's filters, will also not be sensed. Unless one is able to examine the intracardiac signal, which is what is actually sensed by the pacemaker (ie, the intrinsic deflection of the endocardial electrogram [EGM]), it is not feasible to ascertain from the surface recording of either the https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 6/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate isolated P wave or QRS complex why a specific signal is or is not sensed and where sensing occurs within the complex. To examine the intrinsic deflection as seen by the pacemaker, electrograms can either be recorded via the pacing lead at the time of implantation or be telemetered from the functioning pacemaker at any time postimplantation. The basic pacing interval associated with either single-chamber pacing or either channel of a dual-chamber system is divided into two subintervals. Immediately following a paced or sensed event, the sense amplifier is rendered refractory. The purpose of the refractory period is to prevent the pacemaker from sensing and responding to known but inappropriate electrical or physiologic signals, such as ringing on the sense amplifier from the output pulse, the T wave, or far-field signals, such as R waves detected on the atrial channel, which are known to occur in close proximity to the paced or sensed event. However, appropriate signals that would normally be sensed at other times will not be sensed if they coincide with the refractory period. This becomes more common during dual-chamber pacing, and is also more likely to occur if the refractory period is programmed to a long interval. If there is a failure to sense or recognize a signal that should otherwise be sensed because the signal coincided with the refractory period, this is not a true system malfunction and should be termed "functional undersensing." Both true and functional undersensing are commonly associated with functional noncapture because the timing intervals are not reset, allowing the pacing stimulus to be delivered at a time when the myocardium is physiologically refractory. The other portion of the single-channel timing cycle is the alert period. An event occurring during the alert period should be sensed to trigger or inhibit the output of the pacemaker, depending upon the design of the system. The failure to sense an event in the alert period is true "undersensing." Causes of undersensing The causes of true undersensing include: Inadequate signal A signal is inadequate when it does not fulfill the pacemaker's requirements for an appropriate signal; there is too low an amplitude, slew rate, or inappropriate frequency content. Pacemaker programmed to a value insufficient to sense intrinsic activity Undersensing occurs if the sensitivity parameter of the pacemaker is set inappropriately for the intrinsic signal characteristics. https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 7/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate Change in native signal A change in the native signal from the time of implant due to a primary myocardial process, such as an infarction, or transient changes as with drugs or metabolic abnormalities will cause undersensing. Ectopic beats Not uncommonly, ectopic beats that arise from a location different from that of the dominant intrinsic complex, whether atrial or ventricular, may not be sensed. Although a ventricular ectopic beat is frequently larger than the QRS on the surface ECG, the intrinsic deflection of the QRS on the intracardiac electrogram, what is actually sensed, may be of very low amplitude. Lead maturation Rarely, the inflammatory reaction associated with lead maturation may attenuate the amplitude and slew rate of the native complex by as much as 50 percent, so that if an original signal was only borderline in amplitude for appropriate sensing, undersensing may occur during this time. Lead failure Primary lead malfunctions, most typically an insulation failure, will effectively attenuate the signal coming into the sense amplifier, resulting in undersensing problems. Pulse generator failure There may be a true component malfunction involving the sense amplifier that results in undersensing. If this is the case, either the telemetered electrogram or the invasively recorded electrogram will be an appropriate signal for sensing, and other parameters of lead function will be normal. As a result, the pulse generator should be replaced and the leads reutilized. Although clinically important pulse generator failure is uncommon, if there is evidence of an unacceptable incidence of failures or potential failures, the US Food and Drug Administration (FDA) may issue a recall or advisory because of potentially harmful consequences resulting from device malfunction [5]. However, an advisory or a recall is not a guarantee that a problem will occur; rather these are usually issued when there is an increased incidence of a given problem about which the clinician should be made aware, at a minimum. The increased level of communication from the manufacturer to the clinical community facilitates the clinician's ability to care for the patient, although that same level of communication may increase the clinician's anxiety. Environmental electrical fields The pacemaker may detect and respond to strong electrical fields in the environment. There are very few sources of clinically significant electromagnetic interference found in the non-hospital environment. However, in the hospital a variety of diagnostic and therapeutic equipment, such as electrocautery, may interfere with normal pacing system function. (See 'Electromagnetic interference' below and "Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment".) https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 8/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate Magnet application During magnet application, a mechanism occurs within the pacemaker, whereby the sense amplifier is bypassed, inducing asynchronous function (eg, a pacemaker programmed to the DDD mode will function as DOO when the magnet is applied). Magnet application is essential to confirm the integrity of the output circuit when the pacemaker is otherwise being inhibited. A change in the magnet-induced behavior, usually rate but sometimes AV delay and mode, is also used by many manufacturers as an indicator of battery depletion. When the magnet behavior is unique and different from the programmed rates and intervals, it is relatively easy to identify the expected loss of sensing due to magnet application. If the magnet application results in rates and intervals that are identical to the programmed parameters of the pacemaker, even though in an asynchronous manner, and the individual interpreting the ECG is not informed that a magnet was placed over the pulse generator, there will probably be concern about loss of sensing as indicative of a true malfunction. Noise detection The noise mode response is another situation in which asynchronous behavior is consistent with normal system behavior. Electrical noise is defined by the pulse generator as a series of electrical signals occurring at a very rapid rate, frequently greater than 6 Hz or 360 cycles or signals per minute. This is above the physiologic range for heart rate, and if the pacemaker "sees" signals coming in this rapidly, it interprets these as not being true physiologic signals. Rather than inhibit the output in response to these signals, which leaves the patient at potential jeopardy from asystole, most systems are designed to function in an asynchronous manner as long as electrical noise is being detected. Noise detection typically occurs during the terminal portion of the refractory period. The beginning of the refractory period is the equivalent of the effective refractory period in the heart; at this time, there is absolutely no sensing. The last portion of the refractory period is the noise sampling period (NSP), which would be the equivalent of the functional refractory period. If an event is sensed during the NSP, another, and often shorter, refractory period is initiated. It is also comprised of an absolute refractory period and an NSP. If a signal is sensed in this next NSP, the refractory period is again reset. Assuming this continues to occur, the basic rate timing will complete and, since nothing that the pacemaker recognized as a true or appropriate signal occurred, a pacemaker pulse will be released. If the patient's native rhythm is asystole and the system is detecting electrical noise, pacing will be maintained and the patient will be protected. If, on the other hand, the patient has https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 9/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate an intrinsic rhythm, the noise mode response will result in asynchronous pacing, with potential competition between the pacemaker and native rhythm appearing as "undersensing" on the ECG. Management of undersensing The vast majority of contemporary pacemakers have the capability for electrogram telemetry with a broad band-pass filter, which provides an excellent means to evaluate the characteristics of the native signals to determine why they are not being sensed. Alternatively, management may involve programming the sensitivity of the device to a more sensitive value, which makes it responsive to progressively smaller amplitude signals. If the device was programmed to an overly sensitive value, it could result in inappropriate sensing of noncardiac signals, such as electrical potentials arising from either the skeletal muscle contiguous to the pulse generator or that associated with diaphragmatic contractions. ELECTROMAGNETIC INTERFERENCE Electrical noise from external sources in the hospital or non-hospital environment may result in a series of rapid and/or erratic electrical signals that, when sensed by the pacemaker, may result in a variety of responses. For example, if electromagnetic interference (EMI) is persistent, it could result in asynchronous pacing via noise reversion; if sensed on the ventricular lead, it could result in inhibition of the pacemaker; and if sensed on the atrial lead of a dual-chamber pacing, it could result in rapid ventricular tracking of the EMI. While some household- and work-based electrical equipment had the potential to inhibit early-generation pacemakers, improvements in circuit design and shielding have eliminated many causes of EMI. Strong electrical fields applied either in very close proximity or directly to the patient are usually required for there to be a major effect on the implanted pacing system. This most commonly occurs in the medical environment, when the implanted system is exposed to electrocautery at the time of surgery, internal or external cardioversion or defibrillation, and magnetic resonance imaging (MRI) ( table 1). (See "Perioperative management of patients with a pacemaker or implantable cardioverter-defibrillator".) Other non-medical causes of EMI are discussed separately. (See "Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment".) Therapeutic radiation Therapeutic radiation can have adverse effects on cardiac implantable electronic devices (CIEDs). Radiation equipment can temporarily or permanently alter CIED function in a variety of ways. (See 'Magnetic resonance imaging' below.) https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 10/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate Ionizing radiation may result in electrical reset of a device, reprogramming with errant behavior, or can permanently damage a pacemaker by causing defects in semiconductor insulation [6-10]. If there is permanent damage of components of the CIED, clinical manifestations may include sudden no-output of the pacemaker or runaway pacemaker. Manufacturers provide information regarding the amount of "scatter" radiation that is felt would be safe (ie, would not result in abnormalities of the implanted device). The acceptable dose of scatter radiation will not always be available, and the manufacturer would need to be contacted on a case by case basis. The following recommendations for the management of patients with pacemakers undergoing radiation therapy are adopted from published experience [11-14]: The patient's implantable device status should be evaluated by someone with pacemaker expertise prior to therapy. Before treatment, estimate and record the dose (from scatter) to be received by the CIED with the assistance of the radiation oncologist. Subsequent management is to be determined by patient characteristics, "beam type," beam energy and type of CIED. A professional society consensus document on the management of CIED patients when exposed to therapeutic radiation extensively details the steps to be taken in a patient with a CIED who will receive therapeutic radiation ( algorithm 1) [15]. External cardioversion/defibrillation and electrocautery The mechanism by which electrocautery, cardioversion, and defibrillation, all of which deliver a large amount of energy to the body, can damage the implanted pacing system is virtually identical. If a voltage surge is inadvertently delivered to the pulse generator, which can occur even when all appropriate clinical steps have been taken, there is potential to temporarily or permanently alter device function. Manufacturers have incorporated a variety of circuits designed to protect the complex electronics of the pacemaker from a large voltage surge. These circuits shunt the energy acquired by the housing of the pulse generator to the lead, which results in a large amount of energy being delivered to the heart via the electrode. Such a high level of energy concentrated at the electrode-myocardial interface can induce endocardial burns, causing an elevation of the capture and sensing threshold, which may be transient or permanent. https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 11/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate In addition, sustained electrical signals associated with electrocautery may induce ventricular fibrillation in the electrically unstable patient; this occurs in a manner analogous to the intentional induction of ventricular fibrillation for defibrillation threshold testing at the time of implantable cardioverter-defibrillator (ICD) insertion. Lower doses of electrical current that may not cause damage to the pacing system may nonetheless cause transient pacemaker malfunction. The pacemaker may sense the externally applied electrical field, causing inappropriate inhibition of pacing, or in a DDD pacemaker, the electrical field could be sensed on the atrial sensing circuit with "tracking" of the noise by the ventricular channel to result in inappropriately rapid ventricular pacing. When external cardioversion or defibrillation is performed, the paddles should be as far from the pulse generator as possible without compromising the efficacy of the procedure. Where feasible, the current path should be perpendicular to the plane of the pacing system; this would usually mean using anterior-posterior positioning. With appropriate positioning of the paddle or pads, cardioversion or defibrillation can be safely performed with minimal risk to the implanted device in most patients. This was illustrated in a series of 44 patients with implanted devices, including pacemakers and ICDs [16]. Patients were randomly assigned to either monophasic or biphasic shocks. Cardioversion paddles were placed in an anterior-posterior position, at least 8 cm from the device. Serial device interrogations demonstrated small changes in pacing impedances and ventricular sensing immediately after cardioversion that returned to baseline within one week. There were no differences between the effects of monophasic or biphasic shocks. When the patient undergoes surgery requiring electrocautery, the use of bipolar cautery will minimize the electrical field affecting the pacing system. At a minimum, every effort should be made to assure that the current path for the electrocautery will not encompass the pacing system. A full discussion regarding the perioperative management of patients with a permanent pacemaker, including optimal monitoring and pacemaker programming, is presented separately. (See "Perioperative management of patients with a pacemaker or implantable cardioverter-defibrillator".) Magnetic resonance imaging There has been significant debate about when patients with a CIED should be allowed to undergo an MRI study. The risks of scanning patients with permanent pacemakers or ICDs are related to programming changes, asynchronous pacing, activation of tachyarrhythmia therapies, inhibition of pacing output, and induced currents in lead wires leading to heating and/or cardiac stimulation. All aspects of MRI imaging in the CIED patient is https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 12/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate detailed in a professional society consensus document [15]. This subject is discussed in detail elsewhere. Computed tomography Although most patients with implanted cardiac devices can undergo computed tomography (CT) scans without any adverse consequences, direct exposure to high radiograph dose rates during CT examinations can potentially cause transient changes in pacemaker output pulse rate [17]. However, at this time, the evidence for device interference by CT is very limited and should rarely, if ever, limit device patients from undergoing standard CT imaging. Exceptions to this are detailed in a professional society consensus document [15]. Extracorporeal shock wave lithotripsy Extracorporeal shock wave lithotripsy is occasionally performed as a treatment for urinary tract calculi and cholelithiasis [18]. An older concern was that in patients with pacemakers or ICDs that incorporate a piezoelectric crystal for rate- adaptive pacing, the piezoelectric crystal can be shattered by the shock wave. Therefore, if such a sensor is incorporated in a device placed in the abdomen, extracorporeal shock wave lithotripsy is probably best avoided. However, there are now very few devices that incorporate a piezoelectric crystal. There have also been concerns that extracorporeal shock wave lithotripsy may cause significant mechanical forces that can shatter piezoelectric elements, circuitry, or lead connections but this is less well established. For patients who have any significant degree of pacemaker dependence, pacing mode should be reprogrammed to VOO or DOO because of the potential for inhibition of the ventricular pacing circuit due to interference from extracorporeal shock wave lithotripsy. However, in patients with an ICD, one study found that lithotripsy can be performed safely in those with tiered-therapy ICDs; however, it is recommended that antitachycardia therapies be turned "off" and the patient continuously monitored electrocardiographically during the procedure. Following the procedure the device should be interrogated, antitachycardia therapies turned back "on" and confirmation that final programming matches the programmed values prior to the procedure [19]. (See "Kidney stones in adults: Surgical management of kidney and ureteral stones".) PACING STIMULI ABSENT The absence of pacing stimuli is certainly appropriate when there is an intact native rhythm which inhibits pacemaker output. However, in the patient who has a pacemaker, one should usually not observe an absence of pacing stimuli with pauses in the rhythm that are longer than the programmed base rate of the pacemaker. If these pauses occur in the presence of pacing https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 13/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate stimuli that do not capture, this is a noncapture problem. If there are no visible pacing stimuli, then one of several possible system malfunctions have occurred: The malfunction may arise from oversensing by the pacemaker of an inappropriate signal that is not visible on the surface ECG. Failure to deliver a pacing stimuli at the appropriate time may result from an open circuit, which may be due to inadequate lead fixation to pacemaker generator at the time of implantation (loose set screw) or lead fracture. A component in the pulse generator may have failed. This is exceedingly rare, and other possibilities should be considered first. Hysteresis and ventricular pacing avoidance algorithms may result in intervals longer than the programmed base rate. Confusion may arise if it is not recognized that one of these features is programmed "on." Applying a magnet over the pacemaker will usually allow one to quickly differentiate an oversensing problem from an open circuit or pulse generator component malfunction: If pacing resumes with a stimulus being present, whether or not there is intact capture, the etiology of the absent pulses is likely oversensing. In unipolar pacing systems, particularly when programmed to a very sensitive setting, oversensing of myopotentials may be more likely to occur. If magnet application fails to eliminate the pauses, the problem is not one of oversensing, but is either a component failure within the pulse generator, an open circuit, or, in the setting of a bipolar coaxial lead, an internal insulation failure. Oversensing Historically, oversensing has been felt to be somewhat more common in the unipolar sensing configuration because the antenna for signal detection is much larger, extending from the housing of the pulse generator to the electrode located within the heart. Bipolar systems, in which both active electrodes are inside the heart, have a much smaller antenna effect and a better signal/noise ratio with respect to electrical noise originating from outside the heart. As a result, bipolar systems can often be programmed to very sensitive settings without encountering oversensing. Internal insulation failure in bipolar coaxial leads has produced repeated make-break contacts between the two conductor coils. Large nonphysiologic electrical transients result, which can be seen by the pacing system and inhibit it, but are not visible on the surface ECG. When this https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 14/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate occurs, reducing the sensitivity will probably not correct the system malfunction, and management will require replacement of the malfunctioning pacing lead. Management Oversensing can usually be corrected by reducing the pacemaker sensitivity (ie, programming the pacemaker to a higher sensitivity number that defines the smallest millivolt amplitude of the signal that the pacemaker can sense). Reducing the sensitivity predisposes to episodes of undersensing if the amplitude of the intrinsic signal is too small, a

performed with minimal risk to the implanted device in most patients. This was illustrated in a series of 44 patients with implanted devices, including pacemakers and ICDs [16]. Patients were randomly assigned to either monophasic or biphasic shocks. Cardioversion paddles were placed in an anterior-posterior position, at least 8 cm from the device. Serial device interrogations demonstrated small changes in pacing impedances and ventricular sensing immediately after cardioversion that returned to baseline within one week. There were no differences between the effects of monophasic or biphasic shocks. When the patient undergoes surgery requiring electrocautery, the use of bipolar cautery will minimize the electrical field affecting the pacing system. At a minimum, every effort should be made to assure that the current path for the electrocautery will not encompass the pacing system. A full discussion regarding the perioperative management of patients with a permanent pacemaker, including optimal monitoring and pacemaker programming, is presented separately. (See "Perioperative management of patients with a pacemaker or implantable cardioverter-defibrillator".) Magnetic resonance imaging There has been significant debate about when patients with a CIED should be allowed to undergo an MRI study. The risks of scanning patients with permanent pacemakers or ICDs are related to programming changes, asynchronous pacing, activation of tachyarrhythmia therapies, inhibition of pacing output, and induced currents in lead wires leading to heating and/or cardiac stimulation. All aspects of MRI imaging in the CIED patient is https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 12/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate detailed in a professional society consensus document [15]. This subject is discussed in detail elsewhere. Computed tomography Although most patients with implanted cardiac devices can undergo computed tomography (CT) scans without any adverse consequences, direct exposure to high radiograph dose rates during CT examinations can potentially cause transient changes in pacemaker output pulse rate [17]. However, at this time, the evidence for device interference by CT is very limited and should rarely, if ever, limit device patients from undergoing standard CT imaging. Exceptions to this are detailed in a professional society consensus document [15]. Extracorporeal shock wave lithotripsy Extracorporeal shock wave lithotripsy is occasionally performed as a treatment for urinary tract calculi and cholelithiasis [18]. An older concern was that in patients with pacemakers or ICDs that incorporate a piezoelectric crystal for rate- adaptive pacing, the piezoelectric crystal can be shattered by the shock wave. Therefore, if such a sensor is incorporated in a device placed in the abdomen, extracorporeal shock wave lithotripsy is probably best avoided. However, there are now very few devices that incorporate a piezoelectric crystal. There have also been concerns that extracorporeal shock wave lithotripsy may cause significant mechanical forces that can shatter piezoelectric elements, circuitry, or lead connections but this is less well established. For patients who have any significant degree of pacemaker dependence, pacing mode should be reprogrammed to VOO or DOO because of the potential for inhibition of the ventricular pacing circuit due to interference from extracorporeal shock wave lithotripsy. However, in patients with an ICD, one study found that lithotripsy can be performed safely in those with tiered-therapy ICDs; however, it is recommended that antitachycardia therapies be turned "off" and the patient continuously monitored electrocardiographically during the procedure. Following the procedure the device should be interrogated, antitachycardia therapies turned back "on" and confirmation that final programming matches the programmed values prior to the procedure [19]. (See "Kidney stones in adults: Surgical management of kidney and ureteral stones".) PACING STIMULI ABSENT The absence of pacing stimuli is certainly appropriate when there is an intact native rhythm which inhibits pacemaker output. However, in the patient who has a pacemaker, one should usually not observe an absence of pacing stimuli with pauses in the rhythm that are longer than the programmed base rate of the pacemaker. If these pauses occur in the presence of pacing https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 13/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate stimuli that do not capture, this is a noncapture problem. If there are no visible pacing stimuli, then one of several possible system malfunctions have occurred: The malfunction may arise from oversensing by the pacemaker of an inappropriate signal that is not visible on the surface ECG. Failure to deliver a pacing stimuli at the appropriate time may result from an open circuit, which may be due to inadequate lead fixation to pacemaker generator at the time of implantation (loose set screw) or lead fracture. A component in the pulse generator may have failed. This is exceedingly rare, and other possibilities should be considered first. Hysteresis and ventricular pacing avoidance algorithms may result in intervals longer than the programmed base rate. Confusion may arise if it is not recognized that one of these features is programmed "on." Applying a magnet over the pacemaker will usually allow one to quickly differentiate an oversensing problem from an open circuit or pulse generator component malfunction: If pacing resumes with a stimulus being present, whether or not there is intact capture, the etiology of the absent pulses is likely oversensing. In unipolar pacing systems, particularly when programmed to a very sensitive setting, oversensing of myopotentials may be more likely to occur. If magnet application fails to eliminate the pauses, the problem is not one of oversensing, but is either a component failure within the pulse generator, an open circuit, or, in the setting of a bipolar coaxial lead, an internal insulation failure. Oversensing Historically, oversensing has been felt to be somewhat more common in the unipolar sensing configuration because the antenna for signal detection is much larger, extending from the housing of the pulse generator to the electrode located within the heart. Bipolar systems, in which both active electrodes are inside the heart, have a much smaller antenna effect and a better signal/noise ratio with respect to electrical noise originating from outside the heart. As a result, bipolar systems can often be programmed to very sensitive settings without encountering oversensing. Internal insulation failure in bipolar coaxial leads has produced repeated make-break contacts between the two conductor coils. Large nonphysiologic electrical transients result, which can be seen by the pacing system and inhibit it, but are not visible on the surface ECG. When this https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 14/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate occurs, reducing the sensitivity will probably not correct the system malfunction, and management will require replacement of the malfunctioning pacing lead. Management Oversensing can usually be corrected by reducing the pacemaker sensitivity (ie, programming the pacemaker to a higher sensitivity number that defines the smallest millivolt amplitude of the signal that the pacemaker can sense). Reducing the sensitivity predisposes to episodes of undersensing if the amplitude of the intrinsic signal is too small, a problem that may be more common with atrial sensing. Careful programming will usually resolve sensing issues, but occasionally less commonly used triggered pacing mode could be considered in a pacemaker-dependent patient. Open circuit The most common cause of pauses due to an open circuit is a conductor fracture. This usually occurs at a point of stress, only becoming manifest months to years post implant. If pauses are recognized in the early post implant period, they are likely due to an inadequately tightened set screw that secures the lead to the pulse generator connector block. A chest radiograph may allow identification of either the location of the conductor fracture or a lead partially pulled out of the connector block, in which case the tip of the terminal pin does not extend through the set screw of the connector block. If either a loose set screw or a conductor fracture is identified, an operative procedure will be required to correct the problem by either replacing the lead or tightening the set screw. Short circuit due to loss of insulation integrity Another potential etiology for failure to output is a breach of the internal insulation in a bipolar coaxial lead. This occurs when both conductors are making intimate contact, allowing the current traveling down the distal conductor to short-circuit to the proximal conductor before it ever reaches the electrodes within the heart. Without any current or only minimal current reaching the heart, the effective output pulse will be subthreshold and may not be visible. Lead impedance measurements Lead impedance measurements, either invasively or via telemetry, will readily differentiate an open circuit, ie, conductor fracture or loose-set screw (very high impedances) from an insulation defect (very low impedances). Management In the case of a loss of insulation integrity, programming the output configuration to unipolar may restore capture. Part of the current flow down the distal conductor is shunted to the proximal conductor when it reaches the short circuit. If the insulation abnormality is in the outer portion of a bipolar lead, programming to a unipolar configuration excludes the abnormality and current flows between the inner electrode and the pulse generator "can." Restoration of capture may convert a potential emergency to a problem that can be managed electively. However, reestablishment of pacing using polarity https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 15/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate programmability of the pacemaker is not a permanent solution and the malfunctioning lead should be replaced when clinically appropriate. Hysteresis Hysteresis is a feature that can be misinterpreted as a pacing system problem when pacing stimuli are absent. In a pacemaker programmed with hysteresis, the escape interval of the pacemaker is significantly longer than the rate at which it will pace, and thus the escape pacing rate is slower than the automatic basic pacing interval. It is commonly reported as either a ratio of rates (ie, 70/50), which means that the basic rate is 70 bpm but the rate at which the pacemaker will escape to release the first pacing pulse is 50 bpm, or a millisecond addition to the basic pacing interval (ie, 300 msec), which means that the escape interval before the pacing will begin is 300 msec longer than the basic pacing interval. The original goal of hysteresis was to allow the patient who only intermittently and infrequently required pacing support to remain in a normal native rhythm at lower rates when pacing was not required. When AV block developed such that pacing was required, sustained pacing at a very slow rate would be hemodynamically compromising. At these times, hysteresis would allow for the faster paced ventricular rate required. The key to suspecting hysteresis is that the pacemaker is either still inhibited when native heart rates are lower than the programmed base rate, or when pauses occur, they only occur following a native sensed beat. Hysteresis is a programmable parameter in many pacemakers, and, if it is not desired, it can be turned off by programming. Hysteresis does not reflect a malfunction of either the pulse generator or the lead. Recording system artifact Recording system artifacts can also mimic no-output situations. Recording lead disconnections are a fairly common example of such an artifact. They will usually be characterized by an abrupt termination or initiation of a complex in the middle of another complex plus simultaneous failure of the native rhythm coincident with the paced rhythm. Thus, not only does the pacing system appear to fail, but the baseline becomes isoelectric and the patient's sinus mechanism or atrial fibrillation also disappears. Another recording system artifact is an isoelectric native complex, which, although appropriately sensed by the pacemaker causing inhibition, is not seen in the specific lead that is being monitored, resulting in the appearance of excessively long pauses. This occurs rarely and requires a high index of suspicion to recognize. Confirmation requires additional recordings using either different leads or multiple simultaneous leads. https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 16/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate RECORDING SYSTEM ARTIFACTS Many recording system artifacts have already been discussed in the preceding sections, but there are other recording system artifacts that are confusing in single-chamber systems and can render dual-chamber recordings virtually impossible to interpret. The amplitude of the pacing stimulus may provide a wealth of information, but only when recorded with an analog ECG machine. In a stable recording lead, changes in the amplitude of the pacing stimulus commonly reflect varying levels of delivered energy and polarity configuration. It must be stressed that this is only the case with analog recording systems and analog recording systems are now rarely used. The stimulus amplitude will decrease in a partially open circuit, which attenuates the current flow. An insulation defect in a unipolar lead will short-circuit the system, resulting in a decrease in the stimulus amplitude. An insulation defect developing between the proximal conductor and the tissue in a bipolar system will result in a larger stimulus, making it look more like a unipolar system. Beat-to-beat fluctuations in the stimulus raise concerns about a pacing system problem, with special attention directed to the lead. Contemporary ECG recording systems use digital technology, allowing for computer interpretations of the recorded rhythms and 12-lead ECGs. In these systems, the signals are digitized for data storage and processing. With the standard pacing pulse being only 0.4 to 0.6 msec in duration, the sampling rate of the standard digital ECG machine may miss the pulse entirely or detect a relatively large deflection associated with the primary pulse or a very small deflection of opposite polarity, which is the recharge pulse. A wide variety of complexes representing the pacing stimulus from a large deflection in one direction to a small deflection in the opposite direction and anything in between might be seen on the digital recording, all of which would be normal. The potential information that is available from an analog recording will be lost with most digital recordings, and the resulting variation in the pacing stimulus amplitude and polarity should not be misinterpreted as indicative of a malfunction. LEAD EXTRACTION https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 17/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate Pacemaker leads may need to be removed from time to time, most often for infection or mechanical lead failure. Lead extraction should be performed by someone trained in the technique. Although complications are lower when laser or electrocautery techniques are utilized, there are inherent potential complications and these should be discussed with the patient prior to the procedure. (See "Cardiac implantable electronic devices: Long-term complications", section on 'Lead extraction'.) SUMMARY Given the sophistication and complexity of contemporary pacemakers, appropriate evaluation may require a significant amount of time. It is imperative to perform a careful evaluation of the entire system with review of all stored data without presupposing that the superficial appearance of "normal" function truly reflects normal pacing system function. The pacemaker cannot unpredictably alter its manner of function unless there is a component malfunction. Given the overall reliability of the pulse generators, if a bizarre behavior is encountered, one should consider either some eccentricity of the specific pulse generator, a lead problem, or a recording artifact before entertaining the diagnosis of a pulse generator failure. ACKNOWLEDGMENT The UpToDate editorial staff thank Dr. David L. Hayes for his past contributions as an author to prior versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Maisel WH, Moynahan M, Zuckerman BD, et al. Pacemaker and ICD generator malfunctions: analysis of Food and Drug Administration annual reports. JAMA 2006; 295:1901. 2. Maisel WH. Pacemaker and ICD generator reliability: meta-analysis of device registries. JAMA 2006; 295:1929. 3. Hauser RG, Hayes DL, Kallinen LM, et al. Clinical experience with pacemaker pulse generators and transvenous leads: an 8-year prospective multicenter study. Heart Rhythm 2007; 4:154. 4. Maisel WH, Hauser RG, Hammill SC, et al. Recommendations from the Heart Rhythm Society Task Force on Lead Performance Policies and Guidelines: developed in collaboration with https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 18/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate the American College of Cardiology (ACC) and the American Heart Association (AHA). Heart Rhythm 2009; 6:869. 5. Maisel WH, Sweeney MO, Stevenson WG, et al. Recalls and safety alerts involving pacemakers and implantable cardioverter-defibrillator generators. JAMA 2001; 286:793. 6. Thomas D, Becker R, Katus HA, et al. Radiation therapy-induced electrical reset of an implantable cardioverter defibrillator device located outside the irradiation field. J Electrocardiol 2004; 37:73. 7. Kapa S, Fong L, Blackwell CR, et al. Effects of scatter radiation on ICD and CRT function. Pacing Clin Electrophysiol 2008; 31:727. 8. Nemec J. Runaway implantable defibrillator a rare complication of radiation therapy. Pacing Clin Electrophysiol 2007; 30:716. 9. Solan AN, Solan MJ, Bednarz G, Goodkin MB. Treatment of patients with cardiac pacemakers and implantable cardioverter-defibrillators during radiotherapy. Int J Radiat Oncol Biol Phys 2004; 59:897. 10. Gomez DR, Poenisch F, Pinnix CC, et al. Malfunctions of implantable cardiac devices in patients receiving proton beam therapy: incidence and predictors. Int J Radiat Oncol Biol Phys 2013; 87:570. 11. Marbach JR, Sontag MR, Van Dyk J, Wolbarst AB. Management of radiation oncology patients with implanted cardiac pacemakers: report of AAPM Task Group No. 34. American Association of Physicists in Medicine. Med Phys 1994; 21:85. 12. Hurkmans CW, Knegjens JL, Oei BS, et al. Management of radiation oncology patients with a pacemaker or ICD: a new comprehensive practical guideline in The Netherlands. Dutch Society of Radiotherapy and Oncology (NVRO). Radiat Oncol 2012; 7:198. 13. Makkar A, Prisciandaro J, Agarwal S, et al. Effect of radiation therapy on permanent pacemaker and implantable cardioverter-defibrillator function. Heart Rhythm 2012; 9:1964. 14. Zaremba T, Jakobsen AR, S gaard M, et al. Radiotherapy in patients with pacemakers and implantable cardioverter defibrillators: a literature review. Europace 2016; 18:479. 15. Indik JH, Gimbel JR, Abe H, et al. 2017 HRS expert consensus statement on magnetic resonance imaging and radiation exposure in patients with cardiovascular implantable electronic devices. Heart Rhythm 2017; 14:e97. 16. Manegold JC, Israel CW, Ehrlich JR, et al. External cardioversion of atrial fibrillation in patients with implanted pacemaker or cardioverter-defibrillator systems: a randomized comparison of monophasic and biphasic shock energy application. Eur Heart J 2007; 28:1731. https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 19/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate 17. http://www.fda.gov/medwatch/safety/2008/safety08.htm#ElectronicMedical (Accessed on Ju ne 12, 2012). 18. Platonov MA, Gillis AM, Kavanagh KM. Pacemakers, implantable cardioverter/defibrillators, and extracorporeal shockwave lithotripsy: evidence-based guidelines for the modern era. J Endourol 2008; 22:243. 19. Corzani A, Ziacchi M, Biffi M, et al. Clinical management of electromagnetic interferences in patients with pacemakers and implantable cardioverter-defibrillators: review of the literature and focus on magnetic resonance conditional devices. J Cardiovasc Med (Hagerstown) 2015; 16:704. Topic 1013 Version 32.0 https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 20/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate GRAPHICS Examples of cardiac pacemaker pulse generators Examples of cardiac pacemaker pulse generators commonly used in practice in 2015. Graphic 104720 Version 1.0 https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 21/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate Documented sources of electromagnetic interference (EMI) in patients with implanted cardiac devices Source Examples Electromagnetic fields Daily life* Faulty home appliances Metal detectors Anti-theft equipment Slot machines Cellular phones and accessories with strong magnets (eg, wireless charging, magnetic fasteners) [1] Work and industrial environment High voltage power lines Welding equipment Electronic motors while "on" Induction furnaces Degaussing coils Medical/hospital environment Magnetic resonance imaging Defibrillation or cardioversion Device-device interaction (eg, pacemaker and neural stimulator) Radiofrequency ablation Electrocautery Transcutaneous nerve stimulation Therapeutic diathermy Lithotripsy Radiation therapy There are many potential sources of single-beat inhibition. However, single-beat inhibition is not clinically significant and does not merit specific mention. If working at or near the level of the power line. There is no convincing evidence that being under the power lines at ground level will cause interference. Although all welding equipment is capable of causing interference, it most commonly occurs with equipment that operates at 150 amps. Radiation therapy may cause electromagnetic interference but may also result in direct damage to the pulse generator resulting in sudden no output or "runaway." https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 22/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate Reference: 1. Greenberg JC, Altawail MR, Singh G. Life saving therapy inhibition by phones containing magnets. Heart Rhythm; 2021. Reproduced with permission from: Pinski SL, Trohman RG. Interference in implanted cardiac devices, Part I. Pacing Clin Electrophysiol 2002; 25:1367. Copyright 2002 Blackwell Publishing. Graphic 51277 Version 8.0 https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 23/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate Algorithm for cardiac implantable electronic device management in patients undergoing radiation therapy CIED: cardiac implantable electronic device; LOE: level of evidence; EO: expert opinion; NR: nonrandomized. CIED relocation is not recommended for devices receiving a maximum cumulative incident dose of <5 Gy (Class III, LOE B-NR). Reproduced from: Indik JH, Gimbel JR, Abe H, et al. 2017 HRS expert consensus statement on magnetic resonance imaging and radiation exposure in patients with cardiovascular implantable electronic devices. Heart Rhythm 2017; 14:e97. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 116359 Version 2.0 https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 24/25 7/6/23, 11:01 AM Pacing system malfunction: Evaluation and management - UpToDate Contributor Disclosures Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/pacing-system-malfunction-evaluation-and-management/print 25/25

7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Permanent cardiac pacing: Overview of devices and indications : Mark S Link, MD : N A Mark Estes, III, MD : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 27, 2023. INTRODUCTION Cardiac pacemakers are effective treatments for a variety of bradyarrhythmias. By providing an appropriate heart rate and heart rate response, cardiac pacing can reestablish effective circulation and normalize hemodynamics that are compromised by a slow heart rate. This topic will present a broad review of the role of cardiac pacing in a variety of settings. The management of the specific disorders is discussed separately as is a description of the different types of pacemakers and pacing modes. (See "Sinus node dysfunction: Treatment" and "Third- degree (complete) atrioventricular block" and "Second-degree atrioventricular block: Mobitz type II" and "Modes of cardiac pacing: Nomenclature and selection".) GENERAL CONSIDERATIONS Despite the myriad of clinical situations in which permanent pacing is considered, most management decisions regarding permanent pacemaker implantation are driven by the following clinical factors: The association of symptoms with a bradyarrhythmia The location of the conduction abnormality The absence of a reversible cause https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 1/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate Symptoms Patients are often evaluated for permanent cardiac pacemaker placement because of symptoms that may be due to bradyarrhythmias (eg, dizziness, lightheadedness, syncope, fatigue, and poor exercise tolerance). These patients will often have evidence of persistent or intermittent sinus node dysfunction or atrioventricular (AV) conduction abnormalities. Establishing a direct correlation between symptoms and bradyarrhythmias, typically by taking a careful history and documenting the cardiac rhythm with either an electrocardiogram or ambulatory monitoring (external or insertable cardiac monitor [also sometimes referred to as an implantable cardiac monitor or an implantable loop recorder]), is essential for choosing the optimal candidates for pacemaker insertion [1,2]. A direct correlation between symptoms and bradyarrhythmias will increase the likelihood of pacemaker therapy resulting in clinical improvement. Conversely, failure to document such a correlation, or the presence of an alternative explanation for symptoms, decreases the likelihood of benefit from pacemaker insertion. Location of conduction abnormality The location of an AV conduction abnormality (ie, within the AV node or below the AV node in the His-Purkinje system) is an important determinant of both the probability and the likely pace of progression of conduction system disease ( figure 1). (See "Second-degree atrioventricular block: Mobitz type I (Wenckebach block)" and "Second-degree atrioventricular block: Mobitz type II".) Disease within the AV node is suggested by the following: First-degree AV block with significant PR prolongation (see "First-degree atrioventricular block") Second-degree AV block, Mobitz type I (Wenckebach) (see "Second-degree atrioventricular block: Mobitz type I (Wenckebach block)") Normal QRS complex Disease below the AV node, in the His-Purkinje system, is suggested by: Normal or minimally prolonged PR interval Second-degree AV block, Mobitz type II (see "Second-degree atrioventricular block: Mobitz type II") Third-degree (complete) AV block (see "Third-degree (complete) atrioventricular block") A wide QRS complex (bundle branch block and/or fascicular block) Disease in the His-Purkinje system is generally considered to be more concerning because it can progress quickly and lead to complete heart block. As a result, permanent pacemaker placement https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 2/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate is likely to be recommended, as it is more likely to provide significant clinical benefit in such patients. Reversible causes In addition to intrinsic conduction system disease, there are a number of extrinsic causes of bradyarrhythmias which are reversible. While patients who have a reversible bradyarrhythmia may require temporary pacemaker support, in most circumstances permanent cardiac pacing is not indicated or required. Some of the more common reversible causes of bradyarrhythmia include: Medications (eg, beta blockers, nondihydropyridine calcium channel blockers, antiarrhythmic medications [eg, sotalol, amiodarone]). (See "Etiology of atrioventricular block", section on 'Medications'.) Toxic, metabolic, and electrolyte disturbances (eg, hyperkalemia, digoxin toxicity). Acute myocardial ischemia or infarction. (See 'Post-myocardial infarction' below and "Conduction abnormalities after myocardial infarction", section on 'Management of patients with AV block'.) Cardiac trauma (eg, postoperative, blunt chest trauma, indwelling pulmonary artery catheters). Lyme disease. Cardiac surgery, especially valve disorder surgery. Transcatheter aortic valve implantation. Reversible causes of bradyarrhythmias and the management of reversible causes with temporary cardiac pacing are discussed in detail separately. (See "Temporary cardiac pacing", section on 'Reversible conditions'.) Concurrent ICD Some patients with an indication for a permanent pacemaker require an upgrade to an implantable cardioverter-defibrillator (ICD) or may require cardiac resynchronization therapy. ICDs (with the exception of the subcutaneous ICD) have antitachycardia and antibradycardia pacing therapeutic capabilities. In patients who have a permanent pacemaker and require an ICD or cardiac resynchronization therapy, the pacemaker should be upgraded to the appropriate device so that all functions can be served by one pulse generator. (See "Subcutaneous implantable cardioverter defibrillators".) TYPES OF PERMANENT PACEMAKER SYSTEMS https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 3/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate Cardiac pacemakers generally consist of two components: a pulse generator ( picture 1), which provides the electrical impulse for myocardial stimulation; and one or more electrodes (commonly referred to as leads), which deliver the electrical impulse from the pulse generator to the myocardium. A "leadless" pacemaker is now also available ( picture 2). Transvenous leads have potential long-term complications (eg, venous thrombosis, infection, lead malfunction, etc). Leadless cardiac pacing systems offer the promise of long-term pacing capability without lead- associated complications. Pulse generators Pulse generators are the "battery" component of the pacemaker ( picture 1), generating the electrical impulse which is transmitted to the myocardium, resulting in the heart beat. Pulse generators are currently implanted most commonly in the infraclavicular region of the anterior chest wall. The majority are placed in a pre-pectoral position, but in some cases a sub-pectoral position is advantageous. The pulse generator transmits the electrical impulse to the myocardium via transvenous leads. Epicardial systems are still available and may be necessary as a result of anatomical limitations to placing a transvenous lead(s). But these epicardial leads typically do not last as long. For the leadless systems, the pulse generator and the electrode are one self-contained unit, which is positioned via the femoral vein into the right ventricle (RV). (See 'Leadless systems' below.) Transvenous systems The vast majority of contemporary cardiac pacing systems utilize transvenous electrodes (leads) for transmission of the pacing impulses from the pulse generator to the myocardium. Transvenous leads, however, are associated with a nontrivial rate of long- term complications, including: Infection Venous thrombosis and resultant subclavian vein occlusion Lead malfunction Tricuspid valve injury (resulting in tricuspid regurgitation) The approach to the management of long-term transvenous lead complications is discussed separately. (See "Cardiac implantable electronic devices: Periprocedural complications" and "Cardiac implantable electronic devices: Long-term complications" and "Cardiac implantable electronic device lead removal".) His bundle pacing His bundle pacing has been developed to prevent the harmful effects of RV pacing. In this modality, the RV lead is actively fixed in the area of the His bundle with subsequent ventricular activation via the His-Purkinje system. Theoretically, this will reduce the https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 4/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate odds that dyssynchrony will occur. His bundle pacing may be beneficial in those with an anticipated high percent of RV pacing and possibly even those who have an indication for cardiac resynchronization therapy (CRT) such as a left bundle branch block. Clinical trials are ongoing [3,4]. While clinical trials are ongoing, registry data on His bundle pacing indicate a high rate of intervention for lead dislodgement. High capture thresholds result in more rapid battery depletion of the pacemaker pulse generator. This form of conduction system pacing is less commonly used than pacing in the region of the left bundle, as described below. (See 'Left bundle pacing' below.) Left bundle pacing Left bundle pacing has emerged as a competitor to His bundle pacing. While His bundle pacing typically occurs with the lead placed at the junction of the AV node and His bundle, left bundle pacing occurs with placement of the lead in the septum of the RV. Observational data show lower capture thresholds and dislodgement rates with left bundle area pacing compared with His bundle pacing. However, there are no large-scale randomized controlled trials. Epicardial systems Epicardial cardiac pacemaker systems utilize a pulse generator with leads that are surgically attached directly to the epicardial surface of the heart. These systems have largely been replaced by transvenous systems for patients requiring long-term cardiac pacing, although there is still a role for the occasional patient with vascular access problems (eg, venous thrombosis, congenital anatomical variations, prosthetic tricuspid valve). The major role for epicardial pacing systems in current practice is for temporary pacing following cardiac surgery; such systems, however, are designed as temporary systems that must be removed within the first days to weeks following cardiac surgery. Leadless systems In response to the limitations of both transvenous and epicardial pacing systems, efforts have been made to develop leadless cardiac pacing systems [5-12]. Leadless ventricular pacing Contemporary leadless systems include the pulse generator and the electrode within a single unit that is placed into the RV via a transvenous approach [13]. Multiple prospective, nonrandomized, multicenter trials with single-chamber RV leadless pacemakers followed for up to 12 months have demonstrated safety and efficacy [6,9,11,14-17]. In the SELECT-LV study, a prospective, nonrandomized study of safety and efficacy of leadless pacing for CRT among patients who "failed" conventional CRT, the leadless device was successfully implanted in 34 of 35 patients [12]. The primary efficacy endpoint (biventricular pacing on ECG at one month) was achieved in 33 of 34 patients; however, significant procedure https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 5/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate and device-related complication occurred in three patients (9 percent) at the time of implant and in eight patients (23 percent) within the first month postimplant. Leadless cardiac pacing systems have been approved for use in Europe since 2013, and, in April 2016, the first leadless cardiac pacing system was approved for use in the United States [18]. As of December 2016, two leadless pacemaker systems are approved by the US Food and Drug Administration (FDA) and commercially available, with slightly different sizes and implantation requirements [19]: Micra measures 2.6 x 0.7 cm, requires a 23-French introducer sheath, and was approved by the US FDA in 2016. Nanostim measures 4.2 x 0.6 cm and requires an 18-French sheath. However, the Nanostim was pulled from the market in 2017 because of early battery depletion issues. In 2022, the Aveir (a modification of the Nanostim device) was approved by the US FDA. In general, leadless pacemakers have been placed via the transfemoral approach, but in select patients the leadless pacemaker has been successfully implanted via a transjugular approach [20]. Following device approval and introduction into general clinical practice, patients have been prospectively enrolled in a registry to allow for postmarketing "real world" evaluation of safety and efficacy [6,7,9,21-29]. Among a cohort of 1817 patients from the postapproval registry, 1801 (99.1 percent) had successful implantation of the Micra leadless pacemaker at 179 centers [21]. A total of 41 major complications were reported at 30-day follow-up (2.3 percent), comparable to the major complication rate in the pre-approval investigational trial. Among 16 patients from three leadless pacemaker trials [6,7,9] who subsequently required device removal, the device was successfully extracted in 15 of 16 patients (94 percent), including all five patients in whom the device was in place for <6 weeks [22]. In a subsequent report on the extraction experience among 1423 worldwide recipients of the Nanostim device, among whom 73 patients underwent attempted device retrieval (implant duration ranging from one day to four years), 66 devices (90 percent) were successfully retrieved [23]. Of the 73 attempted retrievals, 53 were done in response to the clinical alert about potential battery malfunction, with the other 20 patients (1.4 percent) having another clinical indication for device retrieval. This rate of necessary revision is similar to the reported experience with the Micra device, in which an actuarial revision rate of 1.4 percent has also been reported [24]. https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 6/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate A report has been published describing the successful removal of the Nanostim device up to nearly three years postimplant [25]. Leadless pacemakers have been successfully implanted, with good short-term results, in patients at high risk of device infection, including hemodialysis patients (197 of 201 patients successfully implanted with no infections over mean 6.2 month follow-up) [26] and patients with a prior cardiac implantable electronic device (CIED) infection (105 patients implanted 30 days from prior infected CIED explant with no infections over mean 8.5 month follow-up) [27]. Among a small cohort of 43 patients who had the device implanted while on anticoagulant therapy, only one patient experienced a bleeding complication [28]. While implantation appears safe in patients treated with warfarin or another oral anticoagulant, additional data are required to guide the optimal approach to implantation in this setting. Leadless cardiac pacing holds promise as a long-term permanent cardiac pacing option for patients requiring single ventricle (RV only) pacing and appears both safe and efficacious in the short term. Leadless AV sequential pacing While initial leadless pacemakers could only sense and pace the RV, contemporary devices have the capacity to maintain AV synchrony: The US FDA-approved Micra AV uses an accelerometer-based algorithm to sense atrial activity and pace the ventricle and thus provide VDD pacing [30]. The device is used to treat patients with normal sinus function and complete AV block. The investigational leadless pacing system (Aveir DR) is composed of one device implanted in the right atrium and one device implanted in the RV. A prospective multicenter study of this system enrolled 190 patients with sinus node dysfunction and 100 with AV block [31]. The implantation procedure was successful in 98.3 percent of patients. The primary safety endpoint of freedom from complications at 90 days was met in 90.3 percent of patients. The first primary performance endpoint of adequate atrial capture threshold and sensing amplitude was met in 90.2 percent of patients. The second primary performance endpoint of at least 70 percent AV synchrony at three months while sitting was met in 97.3 percent of patients. COMMON INDICATIONS https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 7/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate Permanent pacemaker implantation is most commonly indicated for sinus node dysfunction or high-grade/symptomatic AV block. Guidelines for implantation of cardiac pacemakers have been published jointly by the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society (ACC/AHA/HRS) [1]. Although there are occasional cases that cannot be categorized according to these guidelines, they are, for the most part, comprehensive and have been widely endorsed. Similar guidelines have been established by the European Society of Cardiology [2]. Some indications for permanent pacing are relatively certain or unambiguous, while others require considerable expertise and judgment. It is helpful to divide the indications for pacemaker implantation into three specific categories, or classes, as defined by the ACC/AHA/HRS guidelines [1]: Class I Conditions in which permanent pacing is definitely beneficial, useful, and effective. In such conditions, implantation of a cardiac pacemaker is considered acceptable and necessary, provided that the condition is not due to a transient cause. Class II Conditions in which permanent pacing may be indicated but there is conflicting evidence and/or divergence of opinion; class IIA refers to conditions in which the weight of evidence/opinion is in favor of usefulness/efficacy, while class IIb refers to conditions in which the usefulness/efficacy is less well established by evidence/opinion. Class III Conditions in which permanent pacing is not useful/effective and in some cases may be harmful. Sinus node dysfunction The need for permanent pacing in patients with sinus node dysfunction is based largely upon the correlation of bradycardia with symptoms ( table 1) [1,2]. While patients with a heart rate of less than 40 beats per minute or pauses of greater than four seconds are more likely to develop symptoms, there is no definitive threshold for heart rate (or pause length) that determines the absolute need for a permanent pacemaker. This is especially true if the bradycardia occurs during sleep. Class I The following conditions are considered class I indications for pacemaker placement [1,2]: Sinus bradycardia in which symptoms are clearly related to the bradycardia (usually in patients with a heart rate below 40 beats per minute or frequent sinus pauses). Symptomatic chronotropic incompetence (an impaired heart rate response to exercise, generally defined as failure to achieve 85 percent of the age-predicted maximum heart rate during a formal or informal stress test or the inability to mount an age-appropriate heart https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 8/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate rate during activities of daily living, [ie, as documented by ambulatory monitoring]). (See "Prognostic features of stress testing in patients with known or suspected coronary disease", section on 'Heart rate response to exercise'.) Symptomatic sinus bradycardia due to the effects of clinically necessary evidence-based therapy (eg, antianginal or antiarrhythmic medications) with no effective alternative. Class II The following are considered to be class II indications for pacemaker placement in patients with sinus node dysfunction: Sinus bradycardia (heart rate <40 beats per minute) in a patient with symptoms suggestive of bradycardia, but without a clearly demonstrated association between bradycardia and symptoms. Sinus node dysfunction in a patient with unexplained syncope. Chronic heart rates <40 beats per minute while awake in a minimally symptomatic patient. Patients with sinus bradycardia of lesser severity (heart rate >40 beats per minute) who complain of dizziness or other symptoms that correlate with the slower rates are also potential candidates for pacemaker therapy. Acquired AV block Acquired AV block is the second most common indication for permanent pacemaker placement. Many disorders can cause acquired AV block, and these are discussed in detail separately. (See "Etiology of atrioventricular block" and "Third-degree (complete) atrioventricular block" and "Second-degree atrioventricular block: Mobitz type II" and "Second- degree atrioventricular block: Mobitz type I (Wenckebach block)".) Class I The following conditions represent severe conduction disease and are generally considered to be class I indications for pacing when not attributable to reversible causes: Complete (third-degree) AV block with or without symptoms Advanced second-degree AV block (block of two or more consecutive P waves) Second-degree AV block, Mobitz type II (with or without symptoms) Symptomatic second-degree AV block, Mobitz type I (Wenckebach) Exercise-induced second- or third-degree AV block (in the absence of myocardial ischemia) Some controversy exists concerning asymptomatic patients with congenital complete heart block (eg, complete heart block and a structurally normal heart). The ACC/AHA/HRS guidelines recommend permanent pacemaker implantation in patients with congenital complete heart block and any high-risk feature (symptoms attributed to bradycardia, wide QRS rhythm, mean https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 9/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate daytime heart rate <50 beats per minute, complex ventricular ectopy, or ventricular dysfunction), while noting that permanent pacing is reasonable in individuals with congenital complete heart block without these risk factors [1]. Similar recommendations are included in the European guidelines [2]. (See "Congenital third-degree (complete) atrioventricular block", section on 'Treatment'.) Class II Patients with varying degrees of acquired AV block may still benefit from pacemaker placement. In such patients, determinations are often based upon correlation of bradycardia with symptoms, exclusion of other causes of symptoms, and in rare instances based on results of electrophysiology (EP) testing. Conditions in which pacemaker placement can be considered include the following: First-degree AV block when there is hemodynamic compromise because of effective AV dissociation secondary to a very long PR interval. (See "First-degree atrioventricular block", section on 'Management'.) Bifascicular or trifascicular block associated with syncope that can be attributed to transient complete heart block, based upon the exclusion of other plausible causes of syncope ( table 2). Alternating bundle-branch block would also fulfill this criterion. (See "Chronic bifascicular blocks".) AV block in some patients may be due to the effects of medications (eg, antianginal or antiarrhythmic medications), a potentially reversible cause. However, if the pertinent medications cannot be discontinued (ie, alternative therapies are unavailable), permanent pacemaker insertion may be performed to allow for ongoing therapy with the drugs causing AV block [1,32]. Post-myocardial infarction The indications for permanent pacing, including those related to patients after an MI, are presented in detail separately. In general, our approach is in agreement with published professional society guidelines for implantation of a permanent cardiac pacemaker [1,33]. (See "Conduction abnormalities after myocardial infarction".) Neurally-mediated syncope Evaluation of the patient with syncope can be clinically challenging. Once a diagnosis of neurocardiogenic syncope is established or suspected, effective treatment can be similarly challenging. The use of pacemakers in this disorder is limited to very selected patients whose syncopal events are clearly associated with a marked cardioinhibitory or bradycardic event. Pacemaker treatment is effective only in patients with a marked isolated cardioinhibitory or bradycardic cause of syncope. However, since many patients have both bradycardic and vasodepressor https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 10/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate components, some patients with an indication for pacemaker placement may not have a significant improvement in symptoms with pacing. In fact, pacing is rarely necessary in neutrally- mediated syncope. (See "Reflex syncope in adults and adolescents: Treatment".) OTHER INDICATIONS Congenital complete heart block Congenital complete heart block has a variety of causes but most commonly is due to maternal neonatal lupus. Congenital complete heart block can present in utero, as a neonate, or later in childhood, with management directed by the time of presentation (ie, prenatal or postnatal) as well as the severity of symptoms. This topic is discussed separately. (See "Congenital third-degree (complete) atrioventricular block".) Neuromuscular diseases A number of neuromuscular diseases are associated with AV block, including myotonic muscular dystrophy, Kearns-Sayre syndrome, Erb dystrophy (limb-girdle), and peroneal muscular atrophy. Patients with these disorders have a class I indication for pacemaker placement once any evidence of second- or third-degree block develops. This is true even if the patient is asymptomatic, because there may be unpredictably rapid progression of AV conduction disease. (See "Inherited syndromes associated with cardiac disease".) Due to this potential for rapid progression, patients with these disorders are considered to have a class IIb indication for pacemaker placement even with first-degree AV block, regardless of symptoms [1,34]. Some of these patients may also require an implantable cardioverter- defibrillator or cardiac resynchronization therapy (CRT) [35]. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) Long QT syndrome High-risk patients with congenital long QT syndrome have been treated with pacemakers to prevent ventricular arrhythmias, generally with a dual chamber pacemaker. However, most of these patients are now treated with an implantable cardioverter-defibrillator, which has pacing capability as well. (See "Congenital long QT syndrome: Treatment".) Bradycardia-induced ventricular arrhythmias Bradycardia and/or prolonged pauses can precipitate ventricular arrhythmias. Although this phenomenon is most commonly associated with QT prolongation, it can occur in patients with a normal QT interval. Patients with pause- dependent ventricular arrhythmias, with or without QT prolongation, have an indication for pacemaker implantation. As noted above, however, many of these patients will be treated with an implantable cardioverter-defibrillator, which also has pacing capability. (See 'Long QT syndrome' above.) https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 11/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate Hypertrophic cardiomyopathy Pacing for medically refractory, symptomatic hypertrophic cardiomyopathy with significant resting or provoked left ventricular outflow obstruction is not generally recommended, particularly in patients who are candidates for septal reduction therapy [36]. The role of pacing in patients with HCM, along with the utilization of implantable cardioverter-defibrillators, is discussed in detail separately. (See "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction", section on 'Therapies of limited benefit'.) Heart failure Neither single-chamber RV pacing nor dual-chamber right heart pacing (RA and RV) are indicated for the treatment of heart failure symptoms in patients with heart failure. However, CRT, also referred to as biventricular pacing, is used to improve symptoms and survival in patients with medically refractory advanced heart failure, nonischemic or ischemic cardiomyopathy, and left bundle branch block. The use of CRT is discussed in detail separately, including the potential use of CRT in patients who have reduced left ventricular systolic function and an indication for permanent pacing in whom pacing will be frequent (ie, >40 percent cumulative pacing). (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) CLASS III: PACING NOT INDICATED These are conditions that do not reliably improve with cardiac pacing, or are considered to lack adequate evidence of benefit from permanent pacing. Most of these conditions are bradyarrhythmias that are asymptomatic or due to reversible causes. Syncope of undetermined etiology. This may require extensive investigation, including ambulatory monitoring, neurologic evaluation, electrophysiologic testing, and perhaps tilt- table testing. Cardiac pacing may be considered if no other etiology of syncope is uncovered, and the history strongly suggests a cardiogenic origin. In such cases, the patient must understand that permanent pacing may not alleviate the symptoms, since no correlation between symptoms and rhythm has been documented. In addition, if a pacemaker is implanted because of a strong clinical suspicion that the patient's symptoms are due to a bradyarrhythmia, in the absence of any objective evidence of conduction system disease, reimbursement may be disallowed. Sinus bradycardia without significant symptoms. Sinoatrial block or sinus arrest without significant symptoms. https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 12/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate Asymptomatic prolonged RR intervals with atrial fibrillation or other causes of transient ventricular pause. Asymptomatic bradycardia during sleep. Asymptomatic second-degree Mobitz I (Wenckebach) AV block. A hyperactive cardioinhibitory response to carotid sinus stimulation in the absence of symptoms or in the presence of vague symptoms such as dizziness, lightheadedness, or both. Right bundle branch block with left axis deviation without syncope or other symptoms compatible with intermittent AV block. Reversible AV block, such as those associated with electrolyte abnormalities, Lyme disease, sleep apnea, enhanced vagal tone, and some cases that occur postoperatively. AV block associated with drugs such as beta blockers, diltiazem, or verapamil is not always reversible and can be associated with underlying conduction system disease [32]. (See "Etiology of atrioventricular block", section on 'Medications'.) Long QT syndrome or torsades de pointes due to reversible causes. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 13/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Pacemakers (The Basics)" and "Patient education: Bradycardia (The Basics)") Beyond the Basics topic (see "Patient education: Pacemakers (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS General considerations Two general factors guide the vast majority of decisions regarding permanent pacemaker insertion: the association of symptoms with an arrhythmia and the potential for progression of the rhythm disturbance, which is largely dependent on the anatomical location of the conduction abnormality. (See 'General considerations' above.) Association of symptoms with arrhythmia Patients frequently present for consideration of pacemaker placement because of symptoms that may be due to bradyarrhythmias (eg, dizziness, lightheadedness, syncope, fatigue, and poor exercise tolerance). It is critical to attempt to establish a direct correlation between symptoms and bradyarrhythmias, which will increase the likelihood of recommending pacemaker placement. (See 'Symptoms' above.) Risk of progression The location of an atrioventricular (AV) conduction abnormality (ie, within the AV node or below the AV node in the His-Purkinje system) is an important determinant of both the probability and the likely pace of progression of conduction system disease. Disease below the AV node, in the His-Purkinje system, is generally considered to be less stable; as a result, permanent pacemaker placement is more likely to be recommended. (See 'Location of conduction abnormality' above.) Types of pacemaker systems Pacemakers ( picture 1) are most commonly placed in a thoracic pre-pectoral position and connected to one or two transvenous leads, which are positioned endocardially. Epicardial lead placement is still a viable option for patients with limited transvenous access. Leadless pacing systems are now available and hold significant promise for the future. (See 'Types of permanent pacemaker systems' above.) Indications for pacemaker implantation The most common indications for pacemaker implantation are sinus node dysfunction followed by AV block. All other indications are https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 14/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate much less common and include neurocardiogenic syncope and iatrogenic causes (eg, post- AV node ablation). While patients with a heart rate of less than 40 beats per minute, or pauses of greater than four seconds, are more likely to develop symptoms, there is no definitive threshold for heart rate (or pause length) which determines the absolute need for a permanent pacemaker. (See 'Common indications' above.) When to consider CRT or ICD With the advent of cardiac resynchronization therapy (CRT), it is important to also take into consideration the patient's left ventricular function at the time a pacemaker is considered. If the patient has left ventricular dysfunction and requires frequent pacing, it would be appropriate to consider CRT and/or an implantable cardioverter-defibrillator. Whether His bundle or left bundle pacing will provide benefits similar to CRT is yet to be determined. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Pacing not indicated Conditions with a lack of adequate evidence of benefit from permanent pacing, in which permanent pacing is generally non indicated, include, among others, syncope of undetermined etiology, asymptomatic sinus bradycardia, asymptomatic first-degree and second-degree Mobitz I (Wenckebach) AV block, reversible AV block, and long QT syndrome or torsades de pointes due to a reversible cause. (See 'Class III: Pacing not indicated' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges David L Hayes, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74:e51. 2. Glikson M, Nielsen JC, Kronborg MB, et al. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 2021; 42:3427. https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 15/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate 3. Upadhyay GA, Vijayaraman P, Nayak HM, et al. On-treatment comparison between corrective His bundle pacing and biventricular pacing for cardiac resynchronization: A secondary analysis of the His-SYNC Pilot Trial. Heart Rhythm 2019; 16:1797. 4. Upadhyay GA, Vijayaraman P, Nayak HM, et al. His Corrective Pacing or Biventricular Pacing for Cardiac Resynchronization in Heart Failure. J Am Coll Cardiol 2019; 74:157. 5. Auricchio A, Delnoy PP, Butter C, et al. Feasibility, safety, and short-term outcome of leadless ultrasound-based endocardial left ventricular resynchronization in heart failure patients: results of the wireless stimulation endocardially for CRT (WiSE-CRT) study. Europace 2014; 16:681. 6. Reddy VY, Knops RE, Sperzel J, et al. Permanent leadless cardiac pacing: results of the LEADLESS trial. Circulation 2014; 129:1466. 7. Knops RE, Tjong FV, Neuzil P, et al. Chronic performance of a leadless cardiac pacemaker: 1-

A hyperactive cardioinhibitory response to carotid sinus stimulation in the absence of symptoms or in the presence of vague symptoms such as dizziness, lightheadedness, or both. Right bundle branch block with left axis deviation without syncope or other symptoms compatible with intermittent AV block. Reversible AV block, such as those associated with electrolyte abnormalities, Lyme disease, sleep apnea, enhanced vagal tone, and some cases that occur postoperatively. AV block associated with drugs such as beta blockers, diltiazem, or verapamil is not always reversible and can be associated with underlying conduction system disease [32]. (See "Etiology of atrioventricular block", section on 'Medications'.) Long QT syndrome or torsades de pointes due to reversible causes. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 13/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Pacemakers (The Basics)" and "Patient education: Bradycardia (The Basics)") Beyond the Basics topic (see "Patient education: Pacemakers (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS General considerations Two general factors guide the vast majority of decisions regarding permanent pacemaker insertion: the association of symptoms with an arrhythmia and the potential for progression of the rhythm disturbance, which is largely dependent on the anatomical location of the conduction abnormality. (See 'General considerations' above.) Association of symptoms with arrhythmia Patients frequently present for consideration of pacemaker placement because of symptoms that may be due to bradyarrhythmias (eg, dizziness, lightheadedness, syncope, fatigue, and poor exercise tolerance). It is critical to attempt to establish a direct correlation between symptoms and bradyarrhythmias, which will increase the likelihood of recommending pacemaker placement. (See 'Symptoms' above.) Risk of progression The location of an atrioventricular (AV) conduction abnormality (ie, within the AV node or below the AV node in the His-Purkinje system) is an important determinant of both the probability and the likely pace of progression of conduction system disease. Disease below the AV node, in the His-Purkinje system, is generally considered to be less stable; as a result, permanent pacemaker placement is more likely to be recommended. (See 'Location of conduction abnormality' above.) Types of pacemaker systems Pacemakers ( picture 1) are most commonly placed in a thoracic pre-pectoral position and connected to one or two transvenous leads, which are positioned endocardially. Epicardial lead placement is still a viable option for patients with limited transvenous access. Leadless pacing systems are now available and hold significant promise for the future. (See 'Types of permanent pacemaker systems' above.) Indications for pacemaker implantation The most common indications for pacemaker implantation are sinus node dysfunction followed by AV block. All other indications are https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 14/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate much less common and include neurocardiogenic syncope and iatrogenic causes (eg, post- AV node ablation). While patients with a heart rate of less than 40 beats per minute, or pauses of greater than four seconds, are more likely to develop symptoms, there is no definitive threshold for heart rate (or pause length) which determines the absolute need for a permanent pacemaker. (See 'Common indications' above.) When to consider CRT or ICD With the advent of cardiac resynchronization therapy (CRT), it is important to also take into consideration the patient's left ventricular function at the time a pacemaker is considered. If the patient has left ventricular dysfunction and requires frequent pacing, it would be appropriate to consider CRT and/or an implantable cardioverter-defibrillator. Whether His bundle or left bundle pacing will provide benefits similar to CRT is yet to be determined. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Pacing not indicated Conditions with a lack of adequate evidence of benefit from permanent pacing, in which permanent pacing is generally non indicated, include, among others, syncope of undetermined etiology, asymptomatic sinus bradycardia, asymptomatic first-degree and second-degree Mobitz I (Wenckebach) AV block, reversible AV block, and long QT syndrome or torsades de pointes due to a reversible cause. (See 'Class III: Pacing not indicated' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges David L Hayes, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74:e51. 2. Glikson M, Nielsen JC, Kronborg MB, et al. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 2021; 42:3427. https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 15/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate 3. Upadhyay GA, Vijayaraman P, Nayak HM, et al. On-treatment comparison between corrective His bundle pacing and biventricular pacing for cardiac resynchronization: A secondary analysis of the His-SYNC Pilot Trial. Heart Rhythm 2019; 16:1797. 4. Upadhyay GA, Vijayaraman P, Nayak HM, et al. His Corrective Pacing or Biventricular Pacing for Cardiac Resynchronization in Heart Failure. J Am Coll Cardiol 2019; 74:157. 5. Auricchio A, Delnoy PP, Butter C, et al. Feasibility, safety, and short-term outcome of leadless ultrasound-based endocardial left ventricular resynchronization in heart failure patients: results of the wireless stimulation endocardially for CRT (WiSE-CRT) study. Europace 2014; 16:681. 6. Reddy VY, Knops RE, Sperzel J, et al. Permanent leadless cardiac pacing: results of the LEADLESS trial. Circulation 2014; 129:1466. 7. Knops RE, Tjong FV, Neuzil P, et al. Chronic performance of a leadless cardiac pacemaker: 1- year follow-up of the LEADLESS trial. J Am Coll Cardiol 2015; 65:1497. 8. Ritter P, Duray GZ, Steinwender C, et al. Early performance of a miniaturized leadless cardiac pacemaker: the Micra Transcatheter Pacing Study. Eur Heart J 2015; 36:2510. 9. Reddy VY, Exner DV, Cantillon DJ, et al. Percutaneous Implantation of an Entirely Intracardiac Leadless Pacemaker. N Engl J Med 2015; 373:1125. 10. Miller MA, Neuzil P, Dukkipati SR, Reddy VY. Leadless Cardiac Pacemakers: Back to the Future. J Am Coll Cardiol 2015; 66:1179. 11. Reynolds D, Duray GZ, Omar R, et al. A Leadless Intracardiac Transcatheter Pacing System. N Engl J Med 2016; 374:533. 12. Reddy VY, Miller MA, Neuzil P, et al. Cardiac Resynchronization Therapy With Wireless Left Ventricular Endocardial Pacing: The SELECT-LV Study. J Am Coll Cardiol 2017; 69:2119. 13. Sperzel J, Burri H, Gras D, et al. State of the art of leadless pacing. Europace 2015; 17:1508. 14. Tjong FVY, Knops RE, Neuzil P, et al. Midterm Safety and Performance of a Leadless Cardiac Pacemaker: 3-Year Follow-up to the LEADLESS Trial (Nanostim Safety and Performance Trial for a Leadless Cardiac Pacemaker System). Circulation 2018; 137:633. 15. Sperzel J, Defaye P, Delnoy PP, et al. Primary safety results from the LEADLESS Observational Study. Europace 2018; 20:1491. 16. Piccini JP, Stromberg K, Jackson KP, et al. Long-term outcomes in leadless Micra transcatheter pacemakers with elevated thresholds at implantation: Results from the Micra Transcatheter Pacing System Global Clinical Trial. Heart Rhythm 2017; 14:685. 17. Duray GZ, Ritter P, El-Chami M, et al. Long-term performance of a transcatheter pacing system: 12-Month results from the Micra Transcatheter Pacing Study. Heart Rhythm 2017; https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 16/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate 14:702. 18. http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandCl earances/Recently-ApprovedDevices/ucm494390.htm (Accessed on April 08, 2016). 19. El-Chami MF, Merchant FM, Leon AR. Leadless Pacemakers. Am J Cardiol 2017; 119:145. 20. Saleem-Talib S, van Driel VJ, Chaldoupi SM, et al. Leadless pacing: Going for the jugular. Pacing Clin Electrophysiol 2019; 42:395. 21. El-Chami MF, Al-Samadi F, Clementy N, et al. Updated performance of the Micra transcatheter pacemaker in the real-world setting: A comparison to the investigational study and a transvenous historical control. Heart Rhythm 2018; 15:1800. 22. Reddy VY, Miller MA, Knops RE, et al. Retrieval of the Leadless Cardiac Pacemaker: A Multicenter Experience. Circ Arrhythm Electrophysiol 2016; 9. 23. Lakkireddy D, Knops R, Atwater B, et al. A worldwide experience of the management of battery failures and chronic device retrieval of the Nanostim leadless pacemaker. Heart Rhythm 2017; 14:1756. 24. Grubman E, Ritter P, Ellis CR, et al. To retrieve, or not to retrieve: System revisions with the Micra transcatheter pacemaker. Heart Rhythm 2017; 14:1801. 25. Gonz lez Villegas E, Al Razzo O, Silvestre Garc a J, Mesa Garc a J. Leadless pacemaker extraction from a single-center perspective. Pacing Clin Electrophysiol 2018; 41:101. 26. El-Chami MF, Clementy N, Garweg C, et al. Leadless Pacemaker Implantation in Hemodialysis Patients: Experience With the Micra Transcatheter Pacemaker. JACC Clin Electrophysiol 2019; 5:162. 27. El-Chami MF, Johansen JB, Zaidi A, et al. Leadless pacemaker implant in patients with pre- existing infections: Results from the Micra postapproval registry. J Cardiovasc Electrophysiol 2019; 30:569. 28. San Antonio R, Chipa-Ccasani F, Apolo J, et al. Management of anticoagulation in patients undergoing leadless pacemaker implantation. Heart Rhythm 2019; 16:1849. 29. Tachibana M, Banba K, Matsumoto K, Ohara M. The feasibility of leadless pacemaker implantation for superelderly patients. Pacing Clin Electrophysiol 2020; 43:374. 30. Steinwender C, Khelae SK, Garweg C, et al. Atrioventricular Synchronous Pacing Using a Leadless Ventricular Pacemaker: Results From the MARVEL 2 Study. JACC Clin Electrophysiol 2020; 6:94. 31. Knops RE, Reddy VY, Ip JE, et al. A Dual-Chamber Leadless Pacemaker. N Engl J Med 2023; 388:2360. https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 17/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate 32. Zeltser D, Justo D, Halkin A, et al. Drug-induced atrioventricular block: prognosis after discontinuation of the culprit drug. J Am Coll Cardiol 2004; 44:105. 33. American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, O'Gara PT, et al. 2013 ACCF/AHA guideline for the management of ST- elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61:e78. 34. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 35. Groh WJ. Arrhythmias in the muscular dystrophies. Heart Rhythm 2012; 9:1890. 36. Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2020; 142:e558. Topic 941 Version 43.0 https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 18/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate GRAPHICS Normal conduction system Schematic representation of the normal intraventricular conduction system (His- Purkinje system). The Bundle of His divides into the left bundle branch and right bundle branch. The left bundle branch divides into anterior, posterior, and, in some cases, median fascicles. AV: atrioventricular; RA: right atrium; LA: left atrium; RV: right ventricle; LV: left ventricle. Graphic 63340 Version 6.0 https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 19/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate Examples of cardiac pacemaker pulse generators Examples of cardiac pacemaker pulse generators commonly used in practice in 2015. Graphic 104720 Version 1.0 https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 20/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate A leadless pacing system: The Medtronic Micra This pacing system includes the pulse generator and the electrode within a single unit that is placed into the right ventricle via a transvenous approach. Reproduced with permission of Medtronic, Inc. Copyright 2021. Graphic 130297 Version 1.0 https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 21/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate Indications for pacing for sinus node dysfunction Pacemaker not Pacemaker necessary Pacemaker probably necessary necessary Symptomatic bradycardia Symptomatic patients with sinus node dysfunction with documented rates of <40 bpm without a clear-cut association between significant symptoms and the Asymptomatic sinus node dysfunction bradycardia Symptomatic sinus bradycardia due to long-term drug therapy of a type and dose for which there is no accepted alternative Graphic 70519 Version 2.0 https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 22/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate Indications for pacing in multifascicular block Pacemaker probably Pacemaker not Pacemaker necessary necessary necessary Symptomatic patients with fascicular Patients with syncope and Asymptomatic block and significantly prolonged H-V interval by electrophysiologic study bifascicular or trifascicular block with other etiologies of syncope excluded fascicular block without AV block Symptomatic patients with block distal to His at atrial paced rates of less than 100-120 bpm Pacing-induced block distal to His at atrial paced rates of less than 130 bpm Asymptomatic fascicular block and first degree AV block Symptomatic patients with bifascicular block and intermittent type II second Asymptomatic patients with fascicular block and intermittent degree AV block or third degree AV block type II second degree or third degree AV block Graphic 80379 Version 1.0 https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 23/24 7/6/23, 11:01 AM Permanent cardiac pacing: Overview of devices and indications - UpToDate Contributor Disclosures Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/permanent-cardiac-pacing-overview-of-devices-and-indications/print 24/24

7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Subcutaneous implantable cardioverter defibrillators : Bradley P Knight, MD, FACC : Samuel L vy, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Apr 20, 2021. INTRODUCTION Sudden cardiac death (SCD) resulting from cardiac arrhythmia is the world's leading cause of cardiovascular mortality, accounting for over 50 percent of cardiovascular deaths worldwide [1]. Implantable cardioverter defibrillators (ICDs) have been shown in numerous large clinical trials to reduce mortality from SCD in selected populations [2-6]. ICD systems consist of a pulse generator, typically placed in the pectoral region, and one or more leads which attach the pulse generator to the heart, most commonly to the endocardium via transvenous insertion (in rare circumstances epicardial leads can be used, but these require a thoracotomy and are typically only used if transvenous lead placement is no longer an option). However, conventional transvenous ICD (TV-ICD) systems come with the inherent drawbacks of transvenous leads, including: Risks at the time of insertion Cardiac perforation, pericardial effusion, cardiac tamponade, hemothorax, pneumothorax (see "Cardiac implantable electronic devices: Periprocedural complications") Delayed risks over the lifetime of the device Intravascular lead infection, lead failure (see "Cardiac implantable electronic devices: Long-term complications") Reports of complications at the time of TV-ICD range from 3 to 6 percent of implants. In addition, the delayed risks of transvenous leads include a risk of infection (incidence of 9 per 1000 device-years) and lead failure (ranging from 5 to 40 percent of leads at five years depending on the type of lead), both of which lead to repeat procedures and increased https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 1/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate morbidity for patients. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Epidemiology'.) Despite many well-documented benefits for appropriate patients, TV-ICDs possess a number of drawbacks, which are most notably related to the reliance on endovascular leads. The subcutaneous ICD (S-ICD) has been developed in an attempt to minimize some of the limitations of TV-ICD systems by avoiding endovascular access entirely ( figure 1 and image 1) [7]. The S-ICD system, including its indications, efficacy, complications, and our approach to choosing the proper candidates for the S-ICD, will be discussed in detail here. TV-ICD systems, including their potential complications, are discussed separately. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions".) S-ICD COMPONENTS AND CAPABILITIES The S-ICD, which is being implanted in many countries worldwide, was approved for use in the United States in September of 2012. Analysis of data from the NCDR ICD registry showed that adoption of the S-ICD progressed rapidly, with a ninefold increase in the number of S-ICDs implanted (from 0.2 to 1.9 percent of all ICD implants) over the initial 2.5 years of availability in the United States [8]. As with a standard TV-ICD, the S-ICD is comprised of a pulse generator and a shocking lead ( figure 1 and picture 1 and image 1) [9]: The pulse generator ( picture 1) is implanted in a subcutaneous pocket in the left lateral, midaxillary thoracic position between the anterior and midaxillary line ( image 2 and picture 2). The subcutaneous lead, which toward its terminal end contains an 8 cm shocking coil electrode, is tunneled from the pulse generator to a position along the left parasternal margin ( picture 3). There are proximal and distal sensing electrodes within the lead that flank the 8 cm shocking coil. The distal electrode sits just below the sternal notch, and the proximal electrode lies just above the xiphoid process. The cardiac rhythm is detected via a wide bipole between the two sensing electrodes or between one of the sensing electrodes and the pulse generator [10]. S-ICDs can deliver a maximum shock of 80 joules; however, in conversion testing, a successful conversion with 65 joules is considered to provide an adequate safety margin. Conversion https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 2/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate testing is generally performed with all newly implanted S-ICDs, while the need for defibrillation threshold (DFT) testing for TV-ICD is still debated and practice varies substantially [11]. The device delivers an 80-Joule shock for defibrillation of ventricular tachyarrhythmias including monomorphic ventricular tachycardia (VT), polymorphic VT, and ventricular fibrillation (VF). If VT or VF persists following the initial shock, the device will reverse polarity between the electrodes and deliver subsequent shocks. The S-ICD will deliver a maximum of five shocks for a single episode of a ventricular arrhythmia. If more than 3.5 seconds of asystole occurs following a shock, the S-ICD can deliver 30 seconds of demand pacing at a rate of 50 beats per minute. During an event, the S-ICD will store the electrocardiogram (ECG) tracing for subsequent review [10]. The S-ICD can be implanted without the use of fluoroscopy by using anatomic landmarks to guide proper positioning. The mean procedure time for implantation of an S-ICD among first- time operators is 67 33 minutes in one study, and 55 23 minutes among operators who have inserted at least three S-ICDs [10]. This is comparable to the procedure length for TV-ICD at a similar time in their development, but may be longer than contemporary TV-ICD implant times for experienced operators [12]. The results from a small, nonrandomized observational series of patients suggest that DFT testing may not be required for all patients receiving the S-ICD, although additional data are required to reproduce and validate this result [13]. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions", section on 'Defibrillation threshold testing'.) INDICATIONS, CONTRAINDICATIONS, AND AN APPROACH TO SELECTING THE S-ICD S-ICDs were designed to address the limitations of conventional TV-ICD systems, such as the need for vascular access. However, because of its unique capabilities and associated limitations, the S-ICD is not the best option for all patients requiring an ICD. The number of patients who might potentially benefit from the S-ICD rather than a standard TV- ICD is not known ( picture 4). In a retrospective single-center cohort study of 1345 patients who underwent ICD implantation for both primary and secondary indications, 463 patients (34 percent) received antitachycardia pacing as a therapy or developed an indication for ventricular pacing or cardiac resynchronization therapy which cannot be performed using the S-ICD [14]. However, at five years of follow-up, 55 percent of the cohort would have been eligible for the S- ICD. On the other hand, when patients are properly selected, very few require revision of their device to allow for anti-tachycardia pacing or bradycardia pacing. https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 3/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate When to consider the S-ICD Our approach to selecting an S-ICD for a particular patient is in general agreement with recommendations from the 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death [15]. S-ICDs are generally considered in the following situations: Younger patients (eg, age less than 45 years) with anticipated need for ICD therapy spanning decades (likely requiring multiple ICD systems over time). As examples, an S-ICD system might be an appropriate consideration in patients with hypertrophic cardiomyopathy, congenital cardiomyopathies, or inherited channelopathies. (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Recommendations for ICD therapy'.) Candidates for an ICD without a current or anticipated need for pacing [16]. Patients at high risk for bacteremia, such as patients on hemodialysis or with chronic indwelling endovascular catheters. Patients with challenging vascular access or prior complications with TV-ICDs [17,18]. The S-ICD may also be an appealing option in children and teenagers who require an ICD, though data in this population are limited [19,20]. When to avoid the S-ICD Aside from transient post-shock demand pacing, S-ICDs provide neither antitachycardia pacing as a therapy for ventricular arrhythmias nor continuous bradycardia pacing in the event of symptomatic bradyarrhythmias. Because of this, S-ICDs should not be implanted in patients who have VT that is known or anticipated to be responsive to antitachycardia pacing or patients with the need for bradycardia pacing. Also related to the inability to provide chronic pacemaker activity, S-ICDs are also not indicated in patients requiring biventricular pacing for cardiac resynchronization therapy [17,18]. The S-ICD can be expected to function normally within the presence of a permanent pacemaker functioning in a bipolar pacing mode, with one study reporting successful implantation and functioning of an S-ICD in three patients with a pre-existing single-chamber right ventricular pacemaker [21]. Unipolar pacing from a coexisting device is contraindicated. A preimplantation surface ECG manual screening tool has also been developed to minimize the number of patients at risk for inappropriate shock due to T-wave oversensing errors [9,22,23]. The tool identifies patients who have large and or late T-waves relative to the QRS using three vectors that mimic the device sensing vectors. ECG screening is available via automated software embedded on device programmers. Studies suggest that between 8 and 15 percent of patients https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 4/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate are ineligible for an S-ICD due to susceptibility to T-wave oversensing and thus high risk of inappropriate shocks [22,23]. Approach to S-ICD device selection While there are no defined guidelines for the selection of a S-ICD over a TV-ICD system, our experts generally considered several clinical factors in deciding between the S-ICD and TV-ICD ( algorithm 1): Does the patient have an indication for antitachycardia pacing or known to respond to antitachycardia pacing? Does the patient have an indication for standard transvenous pacing? Is the patient a candidate for biventricular pacing and cardiac resynchronization therapy? Is the patient relatively young with anticipated prolonged ICD therapy or multiple ICD systems in the course of one s lifetime? Does the patient have other indwelling venous catheters or leads? Is the patient at high risk for systemic infection? While there are no strict guidelines on the utilization of the S-ICD in place of a TV-ICD, the answers to the above questions can provide guidance to the clinician when discussing the situation with the patient. S-ICD EFFICACY One randomized trial, and several nonrandomized studies, have evaluated the feasibility of an entirely S-ICD system, which was approved for use in the United States by the FDA in 2013 [10,24-29]. Successful detection of ventricular arrhythmias ranges from 98 to 100 percent, and conversion of induced arrhythmias during defibrillation threshold (DFT) testing ranges from 95 to 100 percent ( table 1), with a mean time to therapy as low as 14 seconds (slightly longer than typically seen with TV-ICDs) [9,10,24-27,30-36]. In a 2017 systematic review of 5380 patients from 16 studies, the pooled rate of successfully terminating ventricular arrhythmias was 96 percent [35]. Nonrandomized studies have generally shown efficacy and safety of the S-ICD. In a prospective, nonrandomized, multicenter trial of patients with a standard indication for an ICD but no pacing requirement (mean age 52 years, 74 percent male, 79 percent primary prevention), 321 patients underwent S-ICD implantation and were followed for an average of 11 months [30]. Both primary endpoints were achieved, with a primary safety endpoint (180-day device and procedure-related complication free rate) of 92 percent and a primary efficacy endpoint (conversion of induced ventricular fibrillation at the time of https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 5/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate implantation) of 100 percent among patients who completed the DFT testing protocol. Even when a sensitivity analysis was performed that assumed that all 17 of the 321 patients who did not complete DFT testing at the time of implantation would have failed defibrillation testing, the predetermined primary efficacy endpoint was still met. Following implantation, 21 patients (7 percent) received a total of 38 appropriate ICD shocks, while 41 patients (13 percent) received at least one inappropriate ICD shock. Data from the EFFORTLESS S-ICD Registry, an observational study of 985 patients worldwide who have received the S-ICD (average follow-up 3.1 years), have shown complication-free rates of 96 and 92 percent at 30 and 360 days, respectively, with only 8 and 12 percent of patients having received an inappropriate shock at 1 year and 3.1 years, respectively [36]. Similar data have been reported from the S-ICD Post-Approval Study, a prospective registry involving 86 centers in the United States. Among 1637 patients who received the S-ICD, 1394 patients (99 percent) had successful termination of induced VT at the time of device insertion, with a 30-day complication-free rate of 96 percent [37]. Efficacy of S-ICD defibrillation can be maximized by optimal position of the device at the time of implantation [38,39]. A risk score (PRAETORIAN score) has been developed and validated based on the following determinants as identified on post-insertion posterior-anterior and lateral chest radiographs: subcoil fat, subgenerator fat, and anterior positioning of the S-ICD generator [38]. Higher amounts of fat between the coil and the sternum, higher amounts of fat between the generator and the rib cage, and more anterior generator position are associated with higher risk of failure to successfully defibrillate. A two incision implant technique with intermuscular placement (between anterior surface of serratus anterior and the posterior surface of latissimus dorsi) of the S-ICD generator has been generally adopted to achieve optimal posterior placement of the device and ideal cosmesis and patient comfort [40]. POTENTIAL COMPLICATIONS The S-ICD system obviates some of the mechanical complications associated with transvenous lead implantation (eg, cardiac perforation leading to pericardial effusion and cardiac tamponade, hemothorax, pneumothorax, endovascular lead infection). Additionally, the solid core design of the S-ICD lead and its lack of exposure to the repeated mechanical stresses of myocardial contraction may serve to improve lead durability when compared with TV-ICD leads [41]. However, the S-ICD system does have its own potential complications, including inappropriate shocks, pocket infection, and lead dislodgement or migration [42]. https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 6/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate Among various publications on the S-ICD, the complication rate requiring reintervention has ranged from 1.3 to 19 percent [9,10,24-27,29-33,35,41,43]. Inappropriate shocks Inappropriate shocks remain as one of the most common and concerning complications seen with S-ICDs, with most studies reporting an incidence ranging from 4 to 16 percent [10,25-27,30-35,44]. In a 2017 systematic review of 5380 patients from 16 studies, the pooled rate of inappropriate shocks was 4.3 percent [35]. Overall, the most common cause for inappropriate shocks from S-ICDs is oversensing of T- waves, which differs from TV-ICD systems, in which most of the inappropriate shocks are due to supraventricular arrhythmias or lead malfunction [31,35,45,46]. Inappropriate sensing of myopotentials from chest muscle activity may also be a source of inappropriate shocks. Inappropriate shocks are more likely to occur in younger, physically active patients, who are also those commonly selected for placement of an S-ICD system [24,31]. The programming of an arrhythmia discrimination zone can reduce the frequency of inappropriate S-ICD shocks due to supraventricular arrhythmias [30,47]. Discrimination zone programming reduced the incidence of inappropriate shocks caused by supraventricular arrhythmias by 70 percent (relative risk reduction) and those caused by T- wave oversensing by 56 percent [30]. In another study which compared 226 patients with dual-zone programming and 88 patients with single-zone programming, the two-year rates of freedom from inappropriate shock were 89.7 and 73.6 percent, respectively [47]. Pocket hematoma The development of pocket hematoma requiring evacuation, transfusion, or extended hospital stay following S-ICD implantation is relatively low (reported rates of 1 to 5 percent) and similar to rates seen with TV-ICDs [26,27,48]. In a retrospective study of 200 patients who received the S-ICD at one of two academic medical centers, 10 patients (5 percent) developed a hematoma, with significantly greater likelihood in patients in whom antithrombotic therapy was uninterrupted or bridged with heparin (6 of 30 patients [20 percent] compared with 0 of 26 patients in whom antithrombotic therapy was stopped) [48]. Given the relatively small number of patients and events in this study, the optimal approach to management of antithrombotic and antiplatelet therapy in patients undergoing S-ICD implantation remains to be determined. However, our authors feel that the general approach to management anticoagulation with S-ICD implantation should be similar to that with TV-ICD implantation, namely avoiding the use of bridging anticoagulation with the consideration of device implantation on uninterrupted oral anticoagulation for patients at highest risk of thromboembolic events. (See "Cardiac implantable electronic devices: Periprocedural complications", section on 'Bleeding'.) https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 7/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate Pocket infections While generally less concerning than infection involving TV-ICD systems, in which the indwelling venous leads pose a higher risk of systemic infection, pocket infections remain a concern with the S-ICD. Pocket infections have been noted in 1 to 10 percent of S-ICD recipients [10,25,26,30,31,35,43]. In a 2017 systematic review of 5380 patients from 16 studies, the pooled rate of pocket infection was 2.7 percent [35]. Complicated infections requiring device explantation are less frequent (1 to 4 percent of patients) [27,30,31]. Unlike the recommended course of therapy for an infected TV-ICD, S- ICD infections can be treated conservatively with a course of antibiotics and without removal of the S-ICD. Because the S-ICD device does not contain any endovascular leads, the risk of infection causing bacteremia/endocarditis is reduced, and in the event an S-ICD does require extraction, this procedure has less associated risk than transvenous lead extraction. Lead movement Lead dislodgement or migration had been noted to occur in 3 to 11 percent of patients in various studies [10,25,33]. Typically, lead dislodgement or migration is thought to result from vigorous physical activity occurring without adequate fixation of the parasternal lead and requires reoperation to reposition the lead [10,25]. In most patients, suture sleeves are now used to anchor the proximal segment of the parasternal lead, a technique was has essentially eliminated lead dislodgement and migration [25]. Other less common complications that may require reintervention may include skin erosion, premature battery depletion, or explantation due to need for antitachycardia/bradycardia pacing or a new indication for resynchronization therapy [25]. In a cohort of 55 patients with the S-ICD who were followed for a median of 5.8 years, 26 patients (47 percent) underwent device replacement, with 25 of 26 patients requiring replacement for battery depletion [49]. The median time to replacement was five years, with five patients requiring replacement due to premature battery depletion within 18 months after implantation. At five years, 71 percent of devices were still in service. Complication rates have been shown to improve as operators and centers gain experience with S-ICD implantation. In one study of 118 patients who underwent S-ICD implantation, adverse events were more frequent in the first 15 implantations per center compared with subsequent implantations (17 percent versus 10 percent with later implantations), suggesting significantly improved outcomes with center experience [25]. COMPARISON WITH TV-ICD https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 8/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate One randomized trial, and several nonrandomized studies, have directly compared the efficacy of the S-ICD with traditional TV-ICDs. The sole randomized trial comparing the S-ICD with TV-ICDs, the PRAETORIAN trial, was published in 2020 and suggested the S-ICD was noninferior to TV-ICDs for both complications and inappropriate shocks [50]. Among a total of 849 patients (81 percent primary prevention) randomized in a 1:1 ratio, followed for a median of 49 months, the primary composite endpoint of device-related complication and inappropriate shocks occurred in 15.1 percent of S-ICD recipients (versus 15.7 percent of TV-ICD recipients; hazard ratio [HR] 0.99, 95% CI 0.71-1.39). Device-related complications were more common with TV-ICDs, while inappropriate shocks were more common with S-ICDs. Appropriate shocks were more common in patients with the S-ICD (19.2 versus 11.5 percent); however, 12.9 percent of TV-ICD recipients were successfully treated with antitachycardia pacing, thereby reducing the frequency of shocks delivered. No S-ICD treatment failures were reported. In a retrospective cohort study of 1160 patients from two hospitals who received an ICD between 2005 and 2014 (including 148 who received an S-ICD between 2009 and 2014), propensity analysis was performed on 280 patients (140 S-ICD recipients and 140 matched TV-ICD recipients) [51]. The overall complication rate was not significantly different between the two groups (14 percent for S-ICD recipients versus 18 percent for TV-ICD recipients), with the S-ICD recipients experiencing significantly fewer lead-related complications (0.8 versus 11.5 percent) but significantly greater nonlead-related complications (9.9 versus 2.2 percent). While TV-ICD patients had significantly more ICD interventions (shocks plus antitachycardia pacing; HR 2.4), there was no significant difference in the frequency of shocks (both appropriate and inappropriate) between the two groups. In the START (Subcutaneous versus Transvenous Arrhythmia Recognition Testing) trial, which compared simulated sensing performance of the S-ICD with that of standard TV-ICDs in 64 patients, both S-ICD and TV-ICD devices were successful in detecting 100 percent of ventricular arrhythmias [52]. In this trial, the S-ICD also had greater success in discriminating supraventricular tachycardias from VTs (98 percent S-ICD versus 76.7 percent for single-chamber TV-ICD versus 68 percent for dual-chamber TV-ICD). SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 9/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Implantable cardioverter-defibrillators (The Basics)" and "Patient education: Sudden cardiac arrest (The Basics)") Beyond the Basics topic (see "Patient education: Implantable cardioverter-defibrillators (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Despite many well-documented benefits for appropriate patients, transvenous implantable cardioverter defibrillators (TV-ICDs) possess a number of drawbacks, which are most notably related to the reliance on endovascular leads. The subcutaneous ICD (S-ICD) has been developed in an attempt to minimize some of the limitations of TV-ICD systems by avoiding endovascular access entirely. (See 'Introduction' above.) The S-ICD is composed of a pulse generator and single shocking coil running along the left parasternal margin ( figure 1 and picture 3 and image 1). These are both implanted subcutaneously ( image 2 and picture 2) without endovascular access. Implantation https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 10/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate may be performed using anatomic landmarks, without the use of fluoroscopy. (See 'S-ICD components and capabilities' above.) Appropriate patient selection for the S-ICD is continuing to evolve. However, S-ICDs may be considered in certain subsets of patients (see 'Indications, contraindications, and an approach to selecting the S-ICD' above): Younger patients due to the expected longevity of the implanted leads and a desire to avoid chronic transvenous leads Candi ( figure 1) dates for an ICD without a current or anticipated need for pacing Patients at high risk for bacteremia, such as patients on hemodialysis or with chronic indwelling endovascular catheters Patients with challenging vascular access or prior TV-ICD complications S-ICDs do not have the capability of providing continuous pacing; therefore, S-ICDs should not be utilized for patients requiring pacing, antitachycardia pacing, or cardiac resynchronization therapy. (See 'When to avoid the S-ICD' above.) S-ICDs have proven to be very efficacious, with proper arrhythmia detection rates in >99 percent of patients and successful spontaneous arrhythmia conversion rates of 88 percent on first shock (100 percent with a maximum of five shocks), both of which are comparable to rates seen with traditional TV-ICDs. (See 'S-ICD efficacy' above.) The S-ICD system does have its own potential complications, including inappropriate shocks, pocket infection, and lead dislodgement or migration. Inappropriate shocks appear to be the most common and concerning complication, but their frequency may be minimized by appropriate patient screening prior to implantation and appropriate device programming following implantation. (See 'When to avoid the S-ICD' above and 'Potential complications' above.) While there are no defined guidelines for the selection of a S-ICD over a TV-ICD system, our approach in deciding between the S-ICD and TV-ICD is based on several clinical variables ( algorithm 1). (See 'Approach to S-ICD device selection' above.) ACKNOWLEDGMENT The UpToDate editorial staff thank Jeffrey Selan, MD, Arjun Majithia, MD, Jonathan Weinstock, MD, FACC, FHRS, and Leonard Ganz, MD, FHRS, FACC, who contributed to earlier versions of this topic review. https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 11/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Estes NA 3rd. Predicting and preventing sudden cardiac death. Circulation 2011; 124:651. 2. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352:225. 3. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996; 335:1933. 4. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002; 346:877. 5. Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 1997; 337:1576. 6. Moss AJ, Schuger C, Beck CA, et al. Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med 2012; 367:2275. 7. Al-Khatib SM, Friedman P, Ellenbogen KA. Defibrillators: Selecting the Right Device for the Right Patient. Circulation 2016; 134:1390. 8. Friedman DJ, Parzynski CS, Varosy PD, et al. Trends and In-Hospital Outcomes Associated With Adoption of the Subcutaneous Implantable Cardioverter Defibrillator in the United States. JAMA Cardiol 2016; 1:900. 9. McLeod CJ, Boersma L, Okamura H, Friedman PA. The subcutaneous implantable cardioverter defibrillator: state-of-the-art review. Eur Heart J 2017; 38:247. 10. Bardy GH, Smith WM, Hood MA, et al. An entirely subcutaneous implantable cardioverter- defibrillator. N Engl J Med 2010; 363:36. 11. Friedman DJ, Parzynski CS, Heist EK, et al. Ventricular Fibrillation Conversion Testing After Implantation of a Subcutaneous Implantable Cardioverter Defibrillator: Report From the National Cardiovascular Data Registry. Circulation 2018; 137:2463. 12. Anvari A, Stix G, Grabenw ger M, et al. Comparison of three cardioverter defibrillator implantation techniques: initial results with transvenous pectoral implantation. Pacing Clin Electrophysiol 1996; 19:1061. 13. Miller MA, Palaniswamy C, Dukkipati SR, et al. Subcutaneous Implantable Cardioverter- Defibrillator Implantation Without Defibrillation Testing. J Am Coll Cardiol 2017; 69:3118. https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 12/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate 14. de Bie MK, Thijssen J, van Rees JB, et al. Suitability for subcutaneous defibrillator implantation: results based on data from routine clinical practice. Heart 2013; 99:1018. 15. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 16. Huang J, Patton KK, Prutkin JM. Concomitant Use of the Subcutaneous Implantable Cardioverter Defibrillator and a Permanent Pacemaker. Pacing Clin Electrophysiol 2016; 39:1240. 17. Aziz S, Leon AR, El-Chami MF. The subcutaneous defibrillator: a review of the literature. J Am Coll Cardiol 2014; 63:1473. 18. Majithia A, Estes NA 3rd, Weinstock J. Advances in sudden death prevention: the emerging role of a fully subcutaneous defibrillator. Am J Med 2014; 127:188. 19. Pettit SJ, McLean A, Colquhoun I, et al. Clinical experience of subcutaneous and transvenous implantable cardioverter defibrillators in children and teenagers. Pacing Clin Electrophysiol 2013; 36:1532. 20. Bettin M, Larbig R, Rath B, et al. Long-Term Experience With the Subcutaneous Implantable Cardioverter-Defibrillator in Teenagers and Young Adults. JACC Clin Electrophysiol 2017; 3:1499. 21. Kuschyk J, Stach K, T l men E, et al. Subcutaneous implantable cardioverter-defibrillator: First single-center experience with other cardiac implantable electronic devices. Heart Rhythm 2015; 12:2230. 22. Groh CA, Sharma S, Pelchovitz DJ, et al. Use of an electrocardiographic screening tool to determine candidacy for a subcutaneous implantable cardioverter-defibrillator. Heart Rhythm 2014; 11:1361. 23. Randles DA, Hawkins NM, Shaw M, et al. How many patients fulfil the surface electrocardiogram criteria for subcutaneous implantable cardioverter-defibrillator implantation? Europace 2014; 16:1015. 24. Jarman JW, Lascelles K, Wong T, et al. Clinical experience of entirely subcutaneous implantable cardioverter-defibrillators in children and adults: cause for caution. Eur Heart J 2012; 33:1351. 25. Olde Nordkamp LR, Dabiri Abkenari L, Boersma LV, et al. The entirely subcutaneous implantable cardioverter-defibrillator: initial clinical experience in a large Dutch cohort. J Am Coll Cardiol 2012; 60:1933. https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 13/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate 26. K be J, Reinke F, Meyer C, et al. Implantation and follow-up of totally subcutaneous versus conventional implantable cardioverter-defibrillators: a multicenter case-control study. Heart Rhythm 2013; 10:29. 27. Lambiase PD, Barr C, Theuns DA, et al. Worldwide experience with a totally subcutaneous implantable defibrillator: early results from the EFFORTLESS S-ICD Registry. Eur Heart J 2014; 35:1657. 28. Moore JP, Mond sert B, Lloyd MS, et al. Clinical Experience With the Subcutaneous Implantable Cardioverter-Defibrillator in Adults With Congenital Heart Disease. Circ Arrhythm Electrophysiol 2016; 9. 29. Le n Salas B, Trujillo-Mart n MM, Garc a Garc a J, et al. Subcutaneous implantable cardioverter-defibrillator in primary and secondary prevention of sudden cardiac death: A meta-analysis. Pacing Clin Electrophysiol 2019; 42:1253. 30. Weiss R, Knight BP, Gold MR, et al. Safety and efficacy of a totally subcutaneous implantable- cardioverter defibrillator. Circulation 2013; 128:944. 31. Jarman JW, Todd DM. United Kingdom national experience of entirely subcutaneous implantable cardioverter-defibrillator technology: important lessons to learn. Europace 2013; 15:1158. 32. Aydin A, Hartel F, Schl ter M, et al. Shock efficacy of subcutaneous implantable cardioverter- defibrillator for prevention of sudden cardiac death: initial multicenter experience. Circ Arrhythm Electrophysiol 2012; 5:913. 33. Dabiri Abkenari L, Theuns DA, Valk SD, et al. Clinical experience with a novel subcutaneous implantable defibrillator system in a single center. Clin Res Cardiol 2011; 100:737. 34. Burke MC, Gold MR, Knight BP, et al. Safety and Efficacy of the Totally Subcutaneous Implantable Defibrillator: 2-Year Results From a Pooled Analysis of the IDE Study and EFFORTLESS Registry. J Am Coll Cardiol 2015; 65:1605. 35. Chue CD, Kwok CS, Wong CW, et al. Efficacy and safety of the subcutaneous implantable cardioverter defibrillator: a systematic review. Heart 2017; 103:1315. 36. Boersma L, Barr C, Knops R, et al. Implant and Midterm Outcomes of the Subcutaneous Implantable Cardioverter-Defibrillator Registry: The EFFORTLESS Study. J Am Coll Cardiol 2017; 70:830. 37. Gold MR, Aasbo JD, El-Chami MF, et al. Subcutaneous implantable cardioverter-defibrillator Post-Approval Study: Clinical characteristics and perioperative results. Heart Rhythm 2017; 14:1456. https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 14/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate 38. Quast ABE, Baalman SWE, Brouwer TF, et al. A novel tool to evaluate the implant position and predict defibrillation success of the subcutaneous implantable cardioverter- defibrillator: The PRAETORIAN score. Heart Rhythm 2019; 16:403. 39. Amin AK, Gold MR, Burke MC, et al. Factors Associated With High-Voltage Impedance and Subcutaneous Implantable Defibrillator Ventricular Fibrillation Conversion Success. Circ Arrhythm Electrophysiol 2019; 12:e006665. 40. Winter J, Siekiera M, Shin DI, et al. Intermuscular technique for implantation of the subcutaneous implantable cardioverter defibrillator: long-term performance and complications. Europace 2017; 19:2036. 41. Poole JE. Novel ICD therapy begets novel ICD detection: first look at the performance of the subcutaneous ICD discrimination algorithm. Heart Rhythm 2014; 11:1359. 42. Basu-Ray I, Liu J, Jia X, et al. Subcutaneous Versus Transvenous Implantable Defibrillator Therapy: A Meta-Analysis of Case-Control Studies. JACC Clin Electrophysiol 2017; 3:1475. 43. Brouwer TF, Driessen AHG, Olde Nordkamp LRA, et al. Surgical Management of Implantation-Related Complications of the Subcutaneous Implantable Cardioverter- Defibrillator. JACC Clin Electrophysiol 2016; 2:89. 44. Kooiman KM, Knops RE, Olde Nordkamp L, et al. Inappropriate subcutaneous implantable cardioverter-defibrillator shocks due to T-wave oversensing can be prevented: implications for management. Heart Rhythm 2014; 11:426. 45. Daubert JP, Zareba W, Cannom DS, et al. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II: frequency, mechanisms, predictors, and survival impact. J Am Coll Cardiol 2008; 51:1357. 46. Sharma D, Sharma PS, Miller MA, et al. Position and sensing vector-related triple counting and inappropriate shocks in the subcutaneous implantable cardioverter-defibrillator system. Heart Rhythm 2015; 12:2458. 47. Gold MR, Weiss R, Theuns DA, et al. Use of a discrimination algorithm to reduce

Implantation of a Subcutaneous Implantable Cardioverter Defibrillator: Report From the National Cardiovascular Data Registry. Circulation 2018; 137:2463. 12. Anvari A, Stix G, Grabenw ger M, et al. Comparison of three cardioverter defibrillator implantation techniques: initial results with transvenous pectoral implantation. Pacing Clin Electrophysiol 1996; 19:1061. 13. Miller MA, Palaniswamy C, Dukkipati SR, et al. Subcutaneous Implantable Cardioverter- Defibrillator Implantation Without Defibrillation Testing. J Am Coll Cardiol 2017; 69:3118. https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 12/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate 14. de Bie MK, Thijssen J, van Rees JB, et al. Suitability for subcutaneous defibrillator implantation: results based on data from routine clinical practice. Heart 2013; 99:1018. 15. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 16. Huang J, Patton KK, Prutkin JM. Concomitant Use of the Subcutaneous Implantable Cardioverter Defibrillator and a Permanent Pacemaker. Pacing Clin Electrophysiol 2016; 39:1240. 17. Aziz S, Leon AR, El-Chami MF. The subcutaneous defibrillator: a review of the literature. J Am Coll Cardiol 2014; 63:1473. 18. Majithia A, Estes NA 3rd, Weinstock J. Advances in sudden death prevention: the emerging role of a fully subcutaneous defibrillator. Am J Med 2014; 127:188. 19. Pettit SJ, McLean A, Colquhoun I, et al. Clinical experience of subcutaneous and transvenous implantable cardioverter defibrillators in children and teenagers. Pacing Clin Electrophysiol 2013; 36:1532. 20. Bettin M, Larbig R, Rath B, et al. Long-Term Experience With the Subcutaneous Implantable Cardioverter-Defibrillator in Teenagers and Young Adults. JACC Clin Electrophysiol 2017; 3:1499. 21. Kuschyk J, Stach K, T l men E, et al. Subcutaneous implantable cardioverter-defibrillator: First single-center experience with other cardiac implantable electronic devices. Heart Rhythm 2015; 12:2230. 22. Groh CA, Sharma S, Pelchovitz DJ, et al. Use of an electrocardiographic screening tool to determine candidacy for a subcutaneous implantable cardioverter-defibrillator. Heart Rhythm 2014; 11:1361. 23. Randles DA, Hawkins NM, Shaw M, et al. How many patients fulfil the surface electrocardiogram criteria for subcutaneous implantable cardioverter-defibrillator implantation? Europace 2014; 16:1015. 24. Jarman JW, Lascelles K, Wong T, et al. Clinical experience of entirely subcutaneous implantable cardioverter-defibrillators in children and adults: cause for caution. Eur Heart J 2012; 33:1351. 25. Olde Nordkamp LR, Dabiri Abkenari L, Boersma LV, et al. The entirely subcutaneous implantable cardioverter-defibrillator: initial clinical experience in a large Dutch cohort. J Am Coll Cardiol 2012; 60:1933. https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 13/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate 26. K be J, Reinke F, Meyer C, et al. Implantation and follow-up of totally subcutaneous versus conventional implantable cardioverter-defibrillators: a multicenter case-control study. Heart Rhythm 2013; 10:29. 27. Lambiase PD, Barr C, Theuns DA, et al. Worldwide experience with a totally subcutaneous implantable defibrillator: early results from the EFFORTLESS S-ICD Registry. Eur Heart J 2014; 35:1657. 28. Moore JP, Mond sert B, Lloyd MS, et al. Clinical Experience With the Subcutaneous Implantable Cardioverter-Defibrillator in Adults With Congenital Heart Disease. Circ Arrhythm Electrophysiol 2016; 9. 29. Le n Salas B, Trujillo-Mart n MM, Garc a Garc a J, et al. Subcutaneous implantable cardioverter-defibrillator in primary and secondary prevention of sudden cardiac death: A meta-analysis. Pacing Clin Electrophysiol 2019; 42:1253. 30. Weiss R, Knight BP, Gold MR, et al. Safety and efficacy of a totally subcutaneous implantable- cardioverter defibrillator. Circulation 2013; 128:944. 31. Jarman JW, Todd DM. United Kingdom national experience of entirely subcutaneous implantable cardioverter-defibrillator technology: important lessons to learn. Europace 2013; 15:1158. 32. Aydin A, Hartel F, Schl ter M, et al. Shock efficacy of subcutaneous implantable cardioverter- defibrillator for prevention of sudden cardiac death: initial multicenter experience. Circ Arrhythm Electrophysiol 2012; 5:913. 33. Dabiri Abkenari L, Theuns DA, Valk SD, et al. Clinical experience with a novel subcutaneous implantable defibrillator system in a single center. Clin Res Cardiol 2011; 100:737. 34. Burke MC, Gold MR, Knight BP, et al. Safety and Efficacy of the Totally Subcutaneous Implantable Defibrillator: 2-Year Results From a Pooled Analysis of the IDE Study and EFFORTLESS Registry. J Am Coll Cardiol 2015; 65:1605. 35. Chue CD, Kwok CS, Wong CW, et al. Efficacy and safety of the subcutaneous implantable cardioverter defibrillator: a systematic review. Heart 2017; 103:1315. 36. Boersma L, Barr C, Knops R, et al. Implant and Midterm Outcomes of the Subcutaneous Implantable Cardioverter-Defibrillator Registry: The EFFORTLESS Study. J Am Coll Cardiol 2017; 70:830. 37. Gold MR, Aasbo JD, El-Chami MF, et al. Subcutaneous implantable cardioverter-defibrillator Post-Approval Study: Clinical characteristics and perioperative results. Heart Rhythm 2017; 14:1456. https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 14/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate 38. Quast ABE, Baalman SWE, Brouwer TF, et al. A novel tool to evaluate the implant position and predict defibrillation success of the subcutaneous implantable cardioverter- defibrillator: The PRAETORIAN score. Heart Rhythm 2019; 16:403. 39. Amin AK, Gold MR, Burke MC, et al. Factors Associated With High-Voltage Impedance and Subcutaneous Implantable Defibrillator Ventricular Fibrillation Conversion Success. Circ Arrhythm Electrophysiol 2019; 12:e006665. 40. Winter J, Siekiera M, Shin DI, et al. Intermuscular technique for implantation of the subcutaneous implantable cardioverter defibrillator: long-term performance and complications. Europace 2017; 19:2036. 41. Poole JE. Novel ICD therapy begets novel ICD detection: first look at the performance of the subcutaneous ICD discrimination algorithm. Heart Rhythm 2014; 11:1359. 42. Basu-Ray I, Liu J, Jia X, et al. Subcutaneous Versus Transvenous Implantable Defibrillator Therapy: A Meta-Analysis of Case-Control Studies. JACC Clin Electrophysiol 2017; 3:1475. 43. Brouwer TF, Driessen AHG, Olde Nordkamp LRA, et al. Surgical Management of Implantation-Related Complications of the Subcutaneous Implantable Cardioverter- Defibrillator. JACC Clin Electrophysiol 2016; 2:89. 44. Kooiman KM, Knops RE, Olde Nordkamp L, et al. Inappropriate subcutaneous implantable cardioverter-defibrillator shocks due to T-wave oversensing can be prevented: implications for management. Heart Rhythm 2014; 11:426. 45. Daubert JP, Zareba W, Cannom DS, et al. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II: frequency, mechanisms, predictors, and survival impact. J Am Coll Cardiol 2008; 51:1357. 46. Sharma D, Sharma PS, Miller MA, et al. Position and sensing vector-related triple counting and inappropriate shocks in the subcutaneous implantable cardioverter-defibrillator system. Heart Rhythm 2015; 12:2458. 47. Gold MR, Weiss R, Theuns DA, et al. Use of a discrimination algorithm to reduce inappropriate shocks with a subcutaneous implantable cardioverter-defibrillator. Heart Rhythm 2014; 11:1352. 48. Sheldon SH, Cunnane R, Lavu M, et al. Perioperative hematoma with subcutaneous ICD implantation: Impact of anticoagulation and antiplatelet therapies. Pacing Clin Electrophysiol 2018; 41:799. 49. Theuns DA, Crozier IG, Barr CS, et al. Longevity of the Subcutaneous Implantable Defibrillator: Long-Term Follow-Up of the European Regulatory Trial Cohort. Circ Arrhythm Electrophysiol 2015; 8:1159. https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 15/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate 50. Knops RE, Olde Nordkamp LRA, Delnoy PHM, et al. Subcutaneous or Transvenous Defibrillator Therapy. N Engl J Med 2020; 383:526. 51. Brouwer TF, Yilmaz D, Lindeboom R, et al. Long-Term Clinical Outcomes of Subcutaneous Versus Transvenous Implantable Defibrillator Therapy. J Am Coll Cardiol 2016; 68:2047. 52. Gold MR, Theuns DA, Knight BP, et al. Head-to-head comparison of arrhythmia discrimination performance of subcutaneous and transvenous ICD arrhythmia detection algorithms: the START study. J Cardiovasc Electrophysiol 2012; 23:359. Topic 97158 Version 32.0 https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 16/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate GRAPHICS Subcutaneous implantable cardioverter-defibrillator (S- ICD) pulse generator and electrode Photograph showing the pulse generator (center) and electrode for a subcutaneous implantable cardioverter-defibrillator (S-ICD). Image provided courtesy of Boston Scienti c. Copyright 2014 Boston Scienti c Corporation or its a liates. All rights reserved. Graphic 97569 Version 1.0 https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 17/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate Posteroanterior (PA) and lateral chest radiographs of a subcutaneous implantable cardioverter-defibrillator (S-ICD) Posteroanterior (PA) and lateral chest radiographs of a subcutaneous implantable cardioverter-defibrillator (S-ICD) with the defibrillation lead visible adjacent to the sternum and the pulse generator in the axilla. Graphic 97372 Version 2.0 https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 18/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate Subcutaneous ICD pulse generator Example of subcutaneous implantable cardioverter-defibrillator pulse generator commonly used in practice in 2015. ICD: implantable cardioverter-defibrillator. Graphic 104722 Version 3.0 https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 19/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate S-ICD intramuscular insertion Subcutaneous implantable cardioverter defibrillator (S-ICD) implantation with the device placed in the intermuscular plane. Panel A shows the intermuscular space (*) between the latissimus dorsi muscle (arrow) and the serratus anterior muscle (double arrow) after dissection, but prior to placement of the subcutaneous ICD generator. Panel B shows the postoperative, lateral chest x-ray after subcutaneous ICD implantation with the device positioned posteriorly (dashed arrow). Graphic 129617 Version 1.0 https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 20/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate Lateral view of a patient with a subcutaneous implantable cardioverter-defibrillator (S-ICD) Lateral view of a patient with an S-ICD. S-ICD: subcutaneous implantable cardioverter-defibrillator. Reproduced with permission from: Magnusson P, Pergolizzi JV, LeQuang JA. The Subcutaneous Implantable Cardioverter-De brillator. In: Cardiac Pacing and Monitoring, Min M (Ed), IntechOpen, 2019. Copyright Peter Magnusson, MD, PhD. Graphic 131058 Version 2.0 https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 21/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate Subcutaneous implantable cardioverter-defibrillator Modi ed from: 1. Al-Khatib SM, Friedman P, Ellenbogen KA. De brillators: Selecting the Right Device for the Right Patient. Circulation 2016; 134:1390. 2. Mayo Clinic. Subcutaneous implantable cardioverter-de brillator (S-ICD). https://www.mayoclinic.org/diseases-conditions/ventricular-tachycardia/multimedia/img- 20303862 (Accessed on March 31, 2021). Graphic 130973 Version 1.0 https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 22/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate Comparison of transvenous and subcutaneous ICD pulse generators Comparison of four transvenous ICD pulse generators and one subcutaneous ICD pulse generator commonly used in practice in 2015. The term "subcutaneous" here refers to the ICD electrode positioning, which is subcutaneous rather than transvenous. Note the significantly larger size of the subcutaneous ICD pulse generator. ICD: implantable cardioverter-defibrillator. Graphic 104723 Version 2.0 https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 23/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate Algorithm for choosing subcutaneous ICD ICD: implantable cardioverter-defibrillator; CRT: cardiac resynchronization therapy; TV: transvenous; ATP: antitachycardia pacing; S-ICD: subcutaneous ICD. Graphic 97368 Version 4.0 https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 24/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate Summary of major clinical studies investigating the efficacy and safety of the subcutaneous implantable cardioverter-defibrillator (S-ICD) Successful M Number conversion Complications Appropriate Inappropriate fo Author of with requiring detection shock rate (year) patients defibrillator intervention rate (%) (%) dur (n) function (%) (mo testing (%) Lambiase 472 NR 7% 99.7% 6.4% et al [1] (2014) Weiss et al 314 99.8% 14% 100% 1.3% [2] (2013) K be et al 69 NR 4% 95.5% 4% [3] (2013) Jarman et 111 100% 15% 100% 16% al (2013) [4] Jarman et al (2012) [5] 16 100% 25% 100% 19% Aydin et al 40 NR 5% 97.5% 13% [6] (2012) Olde Nordkamp et al (2012) 118 NR 13% 100% 14% [7] Dabiri et al (2011) [8] 31 100% 16% 100% 10% Bardy et al (2010) 55 100% 9% 98% 11% [9] References: 1. Lambiase PD, Barr C, Theuns DAMJ, et al. Worldwide experience with a totally subcutaneous implantable de brillator: early results from the EFFORTLESS S-ICD Registry. Eur Heart J 2014; 35:1657. 2. Weiss R, Knight BP, Gold MR, et al. Safety and e cacy of a totally subcutaneous implantable-cardioverter de brillator. Circulation 2013; 128:944. 3. K be J, Reinke F, Meyer C, et al. Implantation and follow-up of totally subcutaneous versus conventional implantable cardioverter-de brillators: a multicenter case-control study. Heart Rhythm 2013; 10:29. https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 25/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate 4. Jarman JWE, Todd DM. United Kingdom national experience of entirely subcutaneous implantable cardioverter- de brillator technology: important lessons to learn. Europace 2013; 15:1158. 5. Jarman JWE, Lascelles K, Wong T, et al. Clinical experience of entirely subcutaneous implantable cardioverter- de brillators in children and adults: cause for caution. Eur Heart J 2012; 33:1351. 6. Aydin A, Hartel F, Schl ter M, et al. Shock e cacy of subcutaneous implantable cardioverter-de brillator for prevention of sudden cardiac death: initial multicenter experience. Circ Arrhythm Electrophysiol 2012; 5:913. 7. Olde Nordkamp LRA, Dabiri Abkenari L, Boersma LVA, et al. The entirely subcutaneous implantable cardioverter- de brillator: initial clinical experience in a large Dutch cohort. J Am Coll Cardiol 2012; 60:1933. 8. Dabiri Abkenari L, Theuns DAMJ, Valk SDA, et al. Clinical experience with a novel subcutaneous implantable de brillator system in a single center. Clin Res Cardiol 2011; 100:737. 9. Bardy GH, Smith WM, Hood MA, Crozier IG, Melton IC, Jordaens L, et al. An entirely subcutaneous implantable cardioverter-de brillator. N Engl J Med 2010; 363:36. Graphic 97342 Version 1.0 https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 26/27 7/6/23, 11:02 AM Subcutaneous implantable cardioverter defibrillators - UpToDate Contributor Disclosures Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/subcutaneous-implantable-cardioverter-defibrillators/print 27/27

7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Temporary cardiac pacing : N A Mark Estes, III, MD : Bradley P Knight, MD, FACC : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Apr 14, 2022. INTRODUCTION Temporary cardiac pacing involves electrical cardiac stimulation to treat a bradyarrhythmia or tachyarrhythmia until it resolves or until long-term therapy can be initiated. The purpose of temporary pacing is to reestablish normal hemodynamics that are acutely compromised by a slow or fast heart rate. Temporary pacing can also be used prophylactically when the need for pacing is anticipated [1-7]. In some situations, temporary pacing can be lifesaving. This topic will review the indications, contraindications, techniques, and procedural aspects of temporary cardiac pacing. Issues related to permanent cardiac pacing are discussed separately. (See "Modes of cardiac pacing: Nomenclature and selection" and "Permanent cardiac pacing: Overview of devices and indications".) INDICATIONS Any symptomatic indication for permanent cardiac pacing is potentially an indication for temporary cardiac pacing. However, temporary cardiac pacing is most commonly used for patients with symptomatic bradyarrhythmias, most frequently due to atrioventricular (AV) nodal block. When it is evident that a permanent pacemaker is ultimately indicated, many implanting clinicians proceed directly with implantation of a permanent pacemaker. (See 'Temporary versus permanent cardiac pacing as the initial therapy' below and "Permanent cardiac pacing: Overview of devices and indications".) https://www.uptodate.com/contents/temporary-cardiac-pacing/print 1/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate In general, temporary cardiac pacing is indicated when a bradyarrhythmia causes symptoms and/or severe hemodynamic impairment and when permanent cardiac pacing is not immediately indicated, not available, or the risk of inserting a permanent pacemaker exceeds potential benefit. The main reason for temporary cardiac pacing is to treat severe symptoms and/or hemodynamic instability due to a bradycardia, or to prevent potential deterioration resulting in hemodynamic instability. Reversible conditions Temporary cardiac pacing is indicated for bradycardia that results from an acute and reversible cause that will likely not require permanent pacing. This includes: Acute myocardial infarction (MI). (See 'Acute MI' below.) Electrolyte disturbances, toxicities, and drug-induced causes for bradycardia including hyperkalemia, digoxin toxicity, beta blocker sensitivity or overdose, and calcium channel blocker sensitivity or overdose. (See "Causes and evaluation of hyperkalemia in adults" and "Cardiac arrhythmias due to digoxin toxicity" and "Major side effects of beta blockers" and "Major side effects and safety of calcium channel blockers".) Injury to the sinus or AV node or His-Purkinje system after heart surgery. Damage to the sinus or AV node from coronary bypass graft surgery usually improves over time [8,9]. In contrast, damage to the AV node or His-Purkinje system after valve surgery may not resolve, and a permanent pacemaker is often required. (See "Early cardiac complications of coronary artery bypass graft surgery", section on 'Bradyarrhythmias'.) Lyme disease. (See "Lyme carditis".) Chagas disease, found most commonly in Central and South America, is caused by Trypanosoma cruzi. It most commonly results in right bundle branch block, hemiblock (left anterior or left posterior fascicular block), or complete heart block and also leads to a cardiomyopathic state. (See "Chronic Chagas cardiomyopathy: Clinical manifestations and diagnosis", section on 'Arrhythmias'.) Heart transplantation, which may be associated with sinus node injury and dysfunction that usually recovers over time. (See "Heart transplantation in adults: Arrhythmias".) Cardiac trauma, as occurs after a motor vehicle accident with associated blunt chest trauma. (See "Initial evaluation and management of blunt thoracic trauma in adults", section on 'Cardiac injury'.) Subacute bacterial endocarditis with an aortic valve abscess damaging the His-Purkinje system and causing AV block, which may or may not improve following antimicrobial and https://www.uptodate.com/contents/temporary-cardiac-pacing/print 2/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate surgical treatment. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".) Catheter trauma to the right bundle branch in a patient with preexisting left bundle branch block, which may cause complete heart block. This may occur in a patient requiring hemodynamic monitoring with a pulmonary artery catheter placed into the right ventricle, when such a patient has a left bundle branch block or an intraventricular conduction delay. (See "Pulmonary artery catheterization: Indications, contraindications, and complications in adults".) Acute heart block may occur during transcatheter aortic valve implantation (TAVI) or alcohol septal ablation procedures and may require pacing support. Other acute pacing techniques related to the left ventricular wire already in place for the TAVI procedure have been successfully employed [1,2]. Repetitive monomorphic ventricular tachycardia requiring overdrive pacing, which can terminate the arrhythmia until proper drug or ablative therapy can be instituted. This can be accomplished by endocardial or epicardial pacing. One commonly used method is to "burst" pace at progressively more rapid rates. When using overdrive pacing for ventricular tachycardia termination, backup defibrillation must be available since ventricular fibrillation can be provoked. Myocarditis of an infectious etiology could result in conduction system abnormalities as a result of the related inflammatory process. There are multiple potential etiologies, but conduction system abnormalities that require temporary pacing are rare [1,2]. Acute MI Temporary cardiac pacing may be necessary in patients with an acute MI, even when permanent pacing is not ultimately required [1,2]. Revascularization strategies with thrombolysis and angioplasty have significantly reduced the need for temporary and permanent cardiac pacing since there is often less myocardial damage and a greater chance that bradycardia and conduction abnormalities will not occur. There may, however, be a need for temporary cardiac pacing. (See "Conduction abnormalities after myocardial infarction".) An important consideration in the setting of an acute MI is that a bradycardia, even if asymptomatic or transient, can cause decreased coronary blood flow and reduced myocardial perfusion. Guidelines from the American Heart Association and American College of Cardiology recommend temporary bradycardia pacing in patients with high-grade AV block and/or new bundle branch block (particularly left bundle branch block) or bifascicular block in patients with an anterior/lateral MI [1,2]. Clinical judgment should be used when applying the guidelines to an https://www.uptodate.com/contents/temporary-cardiac-pacing/print 3/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate individual patient's clinical situation and weighing the risk versus benefits of placing a temporary pacing lead. Weighing the benefits of temporary pacing A difficult issue is when, and if, a temporary pacemaker is needed for patients with intermittent conduction abnormalities. As an example, a patient admitted to the hospital because of presyncope who has a single, five-second pause documented on continuous monitoring might not need a temporary pacemaker wire, particularly since its insertion might actually cause complications that would offset any potential benefit. Similarly, a patient with complete heart block who has a stable escape rhythm can usually wait for a permanent pacemaker; a temporary pacemaker in such a patient might result in pacemaker-dependence with the risk of asystole if the lead dislodges. In such patients, it is best to place a temporary pacing wire only if there is the imminent risk of asystole before a permanent pacemaker can be placed. Permanent pacemaker system revisions Temporary cardiac pacing is required in patients who are pacemaker-dependent when a pacemaker generator change or lead revision/replacement is needed for either of the following: Pacemaker system (generator and/or lead) infection Ventricular lead malfunction or failure For the pacemaker-dependent patient whose pulse generator has reached elective replacement indicators, a temporary pacemaker would usually be placed at the onset of the permanent pulse generator replacement. In such situations, consideration must be given to a potential interaction between the permanent and temporary cardiac pacemakers. If, for example, the temporary cardiac pacemaker fails to capture but its output or pacing stimulus is sensed by the permanent cardiac pacemaker, the permanent cardiac pacemaker might be inhibited, resulting in a severe bradycardia or asystole. With a temporary pacemaker in place and programmed asynchronously, there would not be concern about interference from electrocautery, which would likely be used for dissection and/or to cauterize any bleeding within the pocket. With a functioning temporary pacemaker in place, there is no concern about maintaining an adequate heart rate when the permanent pulse generator is disconnected and a new one placed. There are some experienced implanters who prefer to do a very fast switch between the old and new pulse generator and avoid temporary pacemaker placement. However, this leaves the potential for asystole if there are any problems with the pulse generator switch, and placing a temporary pacemaker for dependent patients is the typical approach. Pacing to prevent tachyarrhythmias Rapid temporary cardiac pacing can be used in some situations to prevent a tachyarrhythmia from occurring. https://www.uptodate.com/contents/temporary-cardiac-pacing/print 4/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate Post-cardiac surgery Overdrive pacing has been used after cardiac surgery to prevent atrial fibrillation and atrial flutter, although beta blockers are usually the treatment of choice. The potential efficacy of overdrive pacing was illustrated in a randomized trial of 96 patients undergoing coronary artery bypass graft surgery who were in sinus rhythm without antiarrhythmic drugs on the second postoperative day [10]. Overdrive pacing for 24 hours significantly reduced the incidence of atrial fibrillation (10 versus 27 percent). (See "Atrial fibrillation and flutter after cardiac surgery".) Ventricular tachyarrhythmias Some ventricular tachycardias can be prevented by rapid pacing. An example is torsades de pointes (TdP), a polymorphic ventricular tachycardia associated with a long QT interval. Atrial or ventricular pacing at rates between 90 and 110 beats per minute can prevent initiation of TdP by shortening the QT interval and by preventing PVCs that might trigger the tachycardia. This approach is not commonly used but may be effective for some patients. (See "Congenital long QT syndrome: Treatment".) CONTRAINDICATIONS In patients with symptomatic bradyarrhythmias or other indications for temporary cardiac pacing, there are no absolute contraindications, particularly in patients who have life- threatening hemodynamic instability. However, temporary transvenous cardiac pacing should be avoided or used with caution in the following settings: In patients with intermittent, mild, or rare symptoms in whom the bradycardia is well tolerated. This includes symptomatic complete heart block with an adequate and "stable" escape rhythm or symptomatic sinus node dysfunction with only rare pauses. In patients with a prosthetic tricuspid valve, as the temporary cardiac pacemaker lead could damage the valve or become trapped in the prosthesis. In a patient with an MI who has received a thrombolytic agent and is being aggressively treated with anticoagulation or antiplatelet agents. Even insertion of the catheter by a cutdown, thus allowing direct visualization of the vessel and better control of bleeding, may be associated with significant bleeding in such patients. PACING TECHNIQUES https://www.uptodate.com/contents/temporary-cardiac-pacing/print 5/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate Temporary versus permanent cardiac pacing as the initial therapy The main reason for temporary cardiac pacing is to treat severe symptoms and/or hemodynamic instability due to a bradycardia, or to prevent potential deterioration resulting in hemodynamic instability. However, when it is evident that a permanent pacemaker is indicated, many electrophysiologists proceed directly with implantation of a permanent pacemaker to minimize the number of procedures performed and the associated complications related to temporary cardiac pacing. (See 'Indications' above and 'Complications' below.) Temporary cardiac pacing techniques Temporary cardiac pacing can be performed in a variety of ways: Internally using transvenous endocardial leads Externally via transthoracic patches Internally using atrial or ventricular epicardial leads placed at the time of surgery Internally via an esophageal electrode, which is primarily used for atrial pacing and recording Transvenous Temporary cardiac pacing via a transvenous approach is the preferred approach to temporary cardiac pacing for most patients [1-7]. Transvenous pacing requires expertise in both venous and cardiac anatomy in order to effectively access the vasculature and advance the electrode into the heart. (See 'Transvenous lead placement' below.) Transvenous pacing has the advantages of being more comfortable for the patient (compared with transcutaneous pacing) and more durable (compared with both transcutaneous and epicardial pacing) in patients in whom the anticipated duration of temporary cardiac pacing may be several days to weeks. Limitations to traditional transvenous pacing using a lead specifically designed for temporary pacing include limited patient mobility (most patients will be restricted to bed or chair and cannot ambulate). There are some situations when a longer duration of temporary pacing will be required. The most common scenario is removal of an infected system in a patient where bacteremia or endocarditis is present and prolonged antibiotics will be required to clear the systemic infection prior to implantation of a new pacing system. In such patients, essentially normal mobility can be restored if a permanent active fixation pacing lead (typically with a peel-away sheath) is placed in the right ventricle via internal jugular venous access and connected to a standard permanent pacemaker that is then secured to the patient. Centers that do a relatively high volume of pacemaker implants may have a device that cannot be permanently implanted because it is beyond its expiration date or it has been contaminated. There have been several published series using variations of this technique [11,12]. https://www.uptodate.com/contents/temporary-cardiac-pacing/print 6/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate More details regarding the placement of transvenous pacing electrodes are presented below. (See 'Procedural aspects of temporary transvenous pacing' below.) Transcutaneous In most situations where urgent temporary cardiac pacing is needed, transcutaneous pacing is the technique that can be initiated most rapidly [13,14]. Adhesive pads are placed directly on the patient's chest, typically in the anterior and left lateral positions or in the anterior and posterior positions ( figure 1). The pads are in addition to the standard adhesive electrodes for telemetry monitoring, which may need to be slightly repositioned to accommodate the transcutaneous pacing pads. In some patients with large amounts of body hair, the area will need to be shaved to allow for proper adhesive contact. Transcutaneous pacing is limited by two significant clinical issues, namely high capture thresholds and patient discomfort: Inability to achieve capture and successfully pace the heart Because of the impedance of the intervening chest wall structures (ie, skin, musculature, and bony and connective tissues) and the difficulty in knowing the exact location of the heart within the thorax, successful capture and pacing are not achieved in all patients. In addition, capture may be interrupted due to patient movement or inadequate adhesion of the pads to the chest wall (eg, in a diaphoretic patient). Another pitfall is difficulty assessing capture as the large stimulus artifact can make the monitor misleading, given the appearance of capture when this is not actually the case. Patient discomfort In order to overcome the higher impedance associated with intervening chest wall structures to successfully stimulate the myocardium, relatively higher energy levels are required when using transcutaneous pacing. This can result in non-myocardial muscle stimulation and discomfort that is not tolerated by the patient. Because of the limitations associated with transcutaneous pacing, this method should be considered only as a temporizing measure for unconscious patients or those in whom sedation can be administered, until either temporary transvenous pacing can be established or until a permanent cardiac pacemaker can be inserted. Epicardial Temporary cardiac pacing with epicardial pacing wires is used exclusively following cardiac surgery and can be used for temporary cardiac pacing if bradycardia occurs, or for overdrive pacing of postoperative tachyarrhythmias [15]. Leads may be attached to the atrium, ventricle, or both chambers at the time of the cardiac surgical procedure, with the wires tunneled and externalized [15]. https://www.uptodate.com/contents/temporary-cardiac-pacing/print 7/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate In most patients, temporary epicardial pacing is utilized only during the initial days following surgery. Temporary epicardial leads are generally only used for a limited period because of problems that can develop. One concern is that, when present for more than one week, the pacing threshold will often rise and there may not be adequate and reliable capture. Once the pacing threshold rises or consistent capture is not possible, the leads should be removed and an alternate means of temporary cardiac pacing, if needed, should be instituted if the clinical requirement persists. A variety of temporary epicardial leads are available, and the surgeon must be aware of the differences and various fixation mechanisms [15]. Transesophageal A transesophageal pacemaker lead can be used for atrial pacing and/or recording. It can be inserted through the mouth or the nose, depending upon the type of catheter used. However, the catheter is uncomfortable to place, pacing is unreliable, and pain is common because it requires high current and pulse width for adequate and continual capture. For these reasons, transesophageal pacing is not commonly used, although it may occasionally have a role for diagnostic purposes. It has also been of some use for pace termination of atrial tachycardia or atrial flutter and for establishing the presence of intrinsic sinus activity (P waves) if they are not obvious on the electrocardiogram. Permanent cardiac pacing techniques Permanent cardiac pacing is discussed in detail separately. (See "Permanent cardiac pacing: Overview of devices and indications" and "Modes of cardiac pacing: Nomenclature and selection".) PROCEDURAL ASPECTS OF TEMPORARY TRANSVENOUS PACING Prior to implantation of a temporary transvenous pacing system, knowledge about normal anatomy and endocardial structures and the ability to distinguish between normal electrograms and artifact are important to guide vascular access, proper lead positioning, and device programming [16]. Vascular access The preferred access sites for temporary transvenous pacing leads are the left subclavian vein and the right internal jugular vein; this relates primarily to the underlying venous anatomy, curvature of the pacing lead, and ease of advancing the lead into the heart. In addition, the subclavian approach permits more freedom of patient motion and might be useful in a patient who requires a long-term temporary pacemaker. A brachial vein approach is not recommended because of the risk of cardiac puncture and instability. While a femoral vein approach is fairly common, particularly among patients who receive a temporary pacemaker in the cardiac catheterization lab while undergoing percutaneous coronary intervention, this https://www.uptodate.com/contents/temporary-cardiac-pacing/print 8/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate approach is not recommended for longer-term temporary pacing because of the risks of deep vein thrombosis, infection, and right ventricular perforation. When temporary pacing is established via the femoral vein, patients should remain continuously supine with their leg straight. Ultimately, however, the best approach to minimize complications is the one with which the clinician has the most experience. If there is a high likelihood that a permanent pacemaker will be required, this should be taken into account at the time the venous access site for the temporary pacemaker is chosen. For example, if a patient is left-hand dominant and the permanent pacemaker would be placed in the right prepectoral region, then it would be desirable to use a site other than the right subclavian vein for the temporary lead. An extensive discussion of the preparation and techniques used for achieving central venous access is presented separately. (See "Central venous access in adults: General principles".) Transvenous lead placement Once central venous access has been secured and the introducer sheath is in place, the transvenous lead is inserted and advanced into the heart. The progress of the advancing lead can be monitored in several ways: Lead markings Leads designed as temporary transvenous leads have markings indicating the distance from the tip of the lead; these should be monitored to estimate the location of the lead tip within the vasculature or the heart. Continuous electrocardiographic monitoring Continuous electrocardiographic monitoring is recommended during the insertion of a transvenous pacing lead [16-18]. In nearly all patients, frequent PVCs or brief runs of nonsustained ventricular tachycardia will be seen when the tip of the transvenous pacing lead encounters the right ventricular myocardium. Fluoroscopy Fluoroscopy, either from a portable bedside unit or in a dedicated procedure room, is highly desirable and helpful when available as it allows for direct visualization of the transvenous pacing lead and optimal placement of the lead within the right ventricle. While not always necessary for lead placement via subclavian or internal jugular venous access, fluoroscopy is required for placement via femoral venous access in order to manipulate the catheter into the proper position. If fluoroscopy is not available, a preformed balloon-tipped catheter can be placed from the right internal jugular or left subclavian vein as it will tend to "float" toward the right ventricle. A balloon-tipped catheter cannot generally be placed during cardiac arrest due to inadequate blood flow. https://www.uptodate.com/contents/temporary-cardiac-pacing/print 9/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate Echocardiography Continuous echocardiographic monitoring has also been successfully used for placement of temporary pacing wires [19,20]. When the lead is placed in the right ventricular apex, there should be slight excess lead or "slack" (pressure at the tip, with a bend at the tricuspid ring) to ensure that the lead does not become dislodged. The lead should be tied down. If a technique has been used where the vein is visualized, then a "tie" is placed where the lead exits from the vein, and then another tie is placed between the patient's skin and a loop formed with the lead. The loop should be large enough to prevent tension on the lead, preventing it from becoming dislodged and the pacemaker losing capture. If the lead was placed in a percutaneous fashion, for example, then it is common to only place a tie between the patient's skin and a loop formed with the lead. When a patient is pacemaker-dependent, it is crucial that the lead be placed in a stable position, and fluoroscopy should be used whenever possible. Temporary dual-chamber pacing may rarely be useful for patients who require AV sequential pacing for hemodynamic benefit. Included in this group are patients with an acute MI, particularly when associated with right ventricular involvement, and after cardiac surgery, especially when diastolic dysfunction is present. Temporary BiV pacing with a transvenous pacing catheter placed in a coronary vein via the coronary sinus may provide short-term benefit to selected patients but is not a standard clinical technique at this time. It has been shown to be of value in cardiogenic shock and to improve coronary artery bypass graft flow following surgery [21,22]. (See "Prognosis and treatment of cardiogenic shock complicating acute myocardial infarction".) Types of transvenous leads Various types of transvenous leads are available. Transvenous pacing leads are typically stiffer than permanent pacing leads, making manipulation more difficult, but the leads are balloon-tipped for easier insertion. They come with various curves, including a preformed atrial "J" wire, and in 2, 5, 6, and 7 French sizes; they are generally bipolar or quadripolar. As noted, another option is to "exteriorize" permanent pacemaker leads if long- term temporary pacing (ie, weeks) is being considered. These leads can then be removed when temporary pacing is no longer needed. (See 'Transvenous' above.) Endocardial screw-in temporary leads can be used to help maintain stability. These leads, purposefully flimsy, are thin and deployed through a sheath that is then removed. These leads can maintain excellent pacing and sensing thresholds for many weeks. In general, atrial leads are not inserted when bradycardia alone is the indication for pacing. However, an atrial lead is inserted for the rare patient who has symptomatic sinus pauses or https://www.uptodate.com/contents/temporary-cardiac-pacing/print 10/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate sinus bradycardia but intact AV nodal conduction, or pace termination of atrial tachyarrhythmias, particularly atrial flutter, and rarely to provide AV synchrony for hemodynamic purposes [23-26]. The benefits of atrial pacing for conditions of sinus bradycardia or junctional rhythm are most prominent after cardiac surgery for patients with ischemia, ventricular hypertrophy, or heart failure. Connecting the lead and pulse generator The connector cable linking the transvenous pacing lead to the pacemaker generator is a simple aspect of the system, but it is important for these connectors to be screwed tightly and securely fastened. An improper connection or inadvertent disconnection can result in pacing malfunction or even asystole and possibly death in a patient who is pacemaker-dependent. Even if a patient is not initially pacemaker-dependent but is then paced, abrupt disconnection of the pacing or turning off of the pacemaker could lead to asystole due to newly acquired pacemaker-dependence as a result of overdrive pacing [27]. Several types of pulse generators are available that permit single- and dual-chamber pacing. For the vast majority of patients, single-chamber ventricular temporary pacing is most appropriate. For the patient with symptomatic sinus arrest and completely normal AV nodal conduction, atrial temporary pacing may be utilized. (See 'Pacemaker programming' below and "Modes of cardiac pacing: Nomenclature and selection".) Pacemaker programming The temporary pacing rate should be set to whatever rate optimizes the patient's hemodynamics. For a pediatric patient and often for postoperative patients, a faster heart rate (eg, 80 to 100 beats per minute) may be desired. For most other patients, a rate of 60 to 70 beats per minute will likely be adequate. If the patient is pacemaker- dependent, then the temporary pacer can be turned to the least sensitive value (ie, the temporary pacemaker will essentially function in an asynchronous mode). If the patient has an intermittent intrinsic ventricular rhythm, then the sensitivity should be adjusted to allow normal sensing of the intrinsic events. To ensure proper pacemaker sensing and capture, the pacemaker output should be set at least two to three times the pacing threshold (ie, the minimum output necessary for pacemaker capture). The pacing threshold, especially in the ventricle, should ideally be less than or equal to 1 milliamp, especially for the patient who is pacemaker-dependent. COMPLICATIONS Complications are not uncommon in patients treated with temporary cardiac pacing [5-7,27]. Complications may be related to venous access, the transvenous pacing lead, or external electromagnetic interference [5-7,27]. The complications associated with temporary cardiac https://www.uptodate.com/contents/temporary-cardiac-pacing/print 11/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate pacing, particularly temporary transvenous cardiac pacing, have led to many clinicians frequently proceeding directly with implantation of a permanent pacemaker (when the likelihood of conduction system recovery is minimal) or to utilizing a temporary transvenous system with a permanent endocardial screw-in lead. (See 'Temporary cardiac pacing techniques' above and 'Types of transvenous leads' above and "Central venous catheters: Overview of complications and prevention in adults".) Serious complications of temporary cardiac pacing are rare but are important to recognize and include: Lead dislodgement and disconnection, which could lead to asystole Bleeding Myocardial perforation, which could lead to cardiac tamponade Pulmonary embolism Catheter knotting Air embolism Various arrhythmias including ventricular tachycardia and ventricular fibrillation Pneumothorax Extracardiac stimulation Infection External temporary pacemakers are used mainly in intensive care units, and therefore the risk of electromagnetic interference is limited. External electromagnetic interference with cardiac devices is discussed in detail separately. (See "Cardiac implantable electronic device interactions with electromagnetic fields in the nonhospital environment".) POSTPROCEDURE MANAGEMENT Immediate postprocedural management Immediately following completion of transvenous lead placement, a chest radiograph should be obtained to establish the position of the lead. Additionally, an immediate postprocedure 12-lead electrocardiogram (ECG) should be recorded during pacing to determine the electrocardiographic appearance of the QRS complex. Although a standard transvenous ventricular lead is often positioned at or near the right ventricular apex, if a permanent endocardial lead is used for longer-term temporary pacing, the lead could be placed essentially anywhere in the right ventricle. With the lead positioned in the right ventricle, the QRS should generally have a left bundle branch block morphology and a superior axis (ie, an upright QRS complex in lead I and aVL). https://www.uptodate.com/contents/temporary-cardiac-pacing/print 12/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate A physical examination should be performed immediately following transvenous lead placement, with subsequent daily assessments, to evaluate for any of the following: Pericardial friction rub, which may be indicative of cardiac perforation Hypotension with muffled heart sounds and jugular venous distension, suggesting cardiac tamponade Asymmetrical or absent breath sounds, suggesting a pneumothorax Management for the duration of temporary pacing Continuous ECG monitoring is mandatory during the entire time the patient has a temporary cardiac pacemaker, and a separate intravenous access is recommended should there be a need for drug therapy. Daily chest radiographs are not mandatory, but a chest radiograph should be repeated if there is evidence of failure to capture or failure to sense, or if a ventricular tachyarrhythmia occurs, all of which suggest potential electrode dislodgement. Daily ECGs are also not needed. Patients with temporary pacemakers require a daily check of pacing thresholds to make certain that there is proper capture. The need to continue temporary cardiac pacing should be reevaluated daily, with device removal if the patient has recovered stable intrinsic electrical activity or consideration of permanent cardiac pacing if indicated. If there are any episodes of failure to sense a premature ventricular complex/contraction (PVC; also referred to a premature ventricular beats or premature ventricular depolarizations) or an intrinsic normally conducted QRS complex, the sensing of the temporary pacemaker should be reevaluated. In most institutions a special dressing may be applied that is felt to resist infection. Some of the occlusive and transparent dressings that are available can be left in place for up to seven days. Fever and/or local erythema or drainage at the venous access site would suggest an infection and should prompt appropriate evaluation and, if needed, removal of the temporary pacing system. All connections and pacemaker programmed settings should be checked routinely. If the patient has a permanent endocardial lead placed and attached to an externalized permanent pacemaker when it is assumed that longer duration temporary pacing will be necessary, the patient can have unrestricted movement other than limitation of arm/shoulder restriction on the ipsilateral side of the temporary pacemaker. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Cardiac implantable electronic devices".) https://www.uptodate.com/contents/temporary-cardiac-pacing/print 13/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate SUMMARY AND RECOMMENDATIONS Temporary cardiac pacing involves electrical cardiac stimulation to treat bradyarrhythmias and rarely a tachyarrhythmia, until it resolves or until long-term therapy can be initiated. The purpose of temporary pacing is to reestablish circulatory integrity and normal hemodynamics that are acutely compromised by a slow or fast heart rate. (See 'Introduction' above.) Temporary cardiac pacing is most commonly utilized for patients with symptomatic bradyarrhythmias, most frequently due to atrioventricular (AV) nodal block. Temporary cardiac pacing for bradycardia that results from an acute and reversible cause (eg, acute myocardial infarction, electrolyte disturbances, drug toxicities, Lyme disease, etc) will often not require permanent pacing. (See 'Indications' above.) Temporary cardiac pacing can be performed in a variety of ways, most commonly via transvenous endocardial leads designed for temporary pacing, transvenous endocardial leads designed for permanent cardiac pacing if longer-term temporary pacing will be required, or transcutaneous leads. Temporary transvenous pacing is the preferred approach for most patients, although transcutaneous pacing can be initiated more rapidly in an emergency. (See 'Pacing techniques' above.) The preferred access sites for temporary transvenous pacing leads are the left subclavian vein and the right internal jugular vein; this relates primarily to the curvature of the lead and ease of advancing the lead into the heart. A brachial vein approach is not recommended because of the risk of cardiac puncture and instability, while a femoral vein approach is not recommended because of the risks of deep vein thrombosis and infection and the need for the patient to remain continuously supine. (See 'Vascular access' above.) Once central venous access has been secured and the introducer sheath is in place, the transvenous lead is inserted and advanced into the heart. The progress of the advancing lead can be monitored using lead marking, continuous electrocardiographic monitoring, and/or fluoroscopy. (See 'Transvenous lead placement' above.) The temporary pacing rate should be set to whatever rate optimizes the patient's hemodynamics. For a pediatric patient and often for postoperative patients, a faster heart rate (eg, 80 to 100 beats per minute) may be desired. For most other patients, a rate of 60 to 70 beats per minute will likely be adequate. If the patient is pacemaker-dependent, then the temporary pacer can be turned to the least sensitive value (ie, the temporary pacemaker will essentially function in an asynchronous mode). If the patient has an https://www.uptodate.com/contents/temporary-cardiac-pacing/print 14/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate intermittent intrinsic ventricular rhythm, then the sensitivity should be adjusted to allow normal sensing of the intrinsic events. (See 'Pacemaker programming' above.) Immediately following completion of transvenous lead placement, a chest radiograph should be obtained to establish the position of the lead, an immediate postprocedure 12- lead ECG should be recorded during pacing to determine the electrocardiographic appearance of the QRS complex, and a physical examination should be performed to evaluate for any evidence of cardiac tamponade or pneumothorax. (See 'Immediate postprocedural management' above.) Continuous ECG monitoring is mandatory during the entire time the patient has a temporary cardiac pacemaker, and a separate intravenous access is recommended should there be a need for drug therapy. Daily chest radiographs and ECGs are not needed; however, patients with temporary pacemakers require a daily check of pacing thresholds to make certain that there is proper capture. (See 'Management for the duration of temporary pacing' above.) ACKNOWLEDGMENTS The UpToDate editorial staff acknowledges Brian Olshansky, MD, and David L Hayes, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. Circulation 2019; 140:e333. 2. Glikson M, Nielsen JC, Kronborg MB, et al. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 2021; 42:3427. 3. Tjong FVY, de Ruijter UW, Beurskens NEG, Knops RE. A comprehensive scoping review on

if a permanent endocardial lead is used for longer-term temporary pacing, the lead could be placed essentially anywhere in the right ventricle. With the lead positioned in the right ventricle, the QRS should generally have a left bundle branch block morphology and a superior axis (ie, an upright QRS complex in lead I and aVL). https://www.uptodate.com/contents/temporary-cardiac-pacing/print 12/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate A physical examination should be performed immediately following transvenous lead placement, with subsequent daily assessments, to evaluate for any of the following: Pericardial friction rub, which may be indicative of cardiac perforation Hypotension with muffled heart sounds and jugular venous distension, suggesting cardiac tamponade Asymmetrical or absent breath sounds, suggesting a pneumothorax Management for the duration of temporary pacing Continuous ECG monitoring is mandatory during the entire time the patient has a temporary cardiac pacemaker, and a separate intravenous access is recommended should there be a need for drug therapy. Daily chest radiographs are not mandatory, but a chest radiograph should be repeated if there is evidence of failure to capture or failure to sense, or if a ventricular tachyarrhythmia occurs, all of which suggest potential electrode dislodgement. Daily ECGs are also not needed. Patients with temporary pacemakers require a daily check of pacing thresholds to make certain that there is proper capture. The need to continue temporary cardiac pacing should be reevaluated daily, with device removal if the patient has recovered stable intrinsic electrical activity or consideration of permanent cardiac pacing if indicated. If there are any episodes of failure to sense a premature ventricular complex/contraction (PVC; also referred to a premature ventricular beats or premature ventricular depolarizations) or an intrinsic normally conducted QRS complex, the sensing of the temporary pacemaker should be reevaluated. In most institutions a special dressing may be applied that is felt to resist infection. Some of the occlusive and transparent dressings that are available can be left in place for up to seven days. Fever and/or local erythema or drainage at the venous access site would suggest an infection and should prompt appropriate evaluation and, if needed, removal of the temporary pacing system. All connections and pacemaker programmed settings should be checked routinely. If the patient has a permanent endocardial lead placed and attached to an externalized permanent pacemaker when it is assumed that longer duration temporary pacing will be necessary, the patient can have unrestricted movement other than limitation of arm/shoulder restriction on the ipsilateral side of the temporary pacemaker. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Cardiac implantable electronic devices".) https://www.uptodate.com/contents/temporary-cardiac-pacing/print 13/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate SUMMARY AND RECOMMENDATIONS Temporary cardiac pacing involves electrical cardiac stimulation to treat bradyarrhythmias and rarely a tachyarrhythmia, until it resolves or until long-term therapy can be initiated. The purpose of temporary pacing is to reestablish circulatory integrity and normal hemodynamics that are acutely compromised by a slow or fast heart rate. (See 'Introduction' above.) Temporary cardiac pacing is most commonly utilized for patients with symptomatic bradyarrhythmias, most frequently due to atrioventricular (AV) nodal block. Temporary cardiac pacing for bradycardia that results from an acute and reversible cause (eg, acute myocardial infarction, electrolyte disturbances, drug toxicities, Lyme disease, etc) will often not require permanent pacing. (See 'Indications' above.) Temporary cardiac pacing can be performed in a variety of ways, most commonly via transvenous endocardial leads designed for temporary pacing, transvenous endocardial leads designed for permanent cardiac pacing if longer-term temporary pacing will be required, or transcutaneous leads. Temporary transvenous pacing is the preferred approach for most patients, although transcutaneous pacing can be initiated more rapidly in an emergency. (See 'Pacing techniques' above.) The preferred access sites for temporary transvenous pacing leads are the left subclavian vein and the right internal jugular vein; this relates primarily to the curvature of the lead and ease of advancing the lead into the heart. A brachial vein approach is not recommended because of the risk of cardiac puncture and instability, while a femoral vein approach is not recommended because of the risks of deep vein thrombosis and infection and the need for the patient to remain continuously supine. (See 'Vascular access' above.) Once central venous access has been secured and the introducer sheath is in place, the transvenous lead is inserted and advanced into the heart. The progress of the advancing lead can be monitored using lead marking, continuous electrocardiographic monitoring, and/or fluoroscopy. (See 'Transvenous lead placement' above.) The temporary pacing rate should be set to whatever rate optimizes the patient's hemodynamics. For a pediatric patient and often for postoperative patients, a faster heart rate (eg, 80 to 100 beats per minute) may be desired. For most other patients, a rate of 60 to 70 beats per minute will likely be adequate. If the patient is pacemaker-dependent, then the temporary pacer can be turned to the least sensitive value (ie, the temporary pacemaker will essentially function in an asynchronous mode). If the patient has an https://www.uptodate.com/contents/temporary-cardiac-pacing/print 14/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate intermittent intrinsic ventricular rhythm, then the sensitivity should be adjusted to allow normal sensing of the intrinsic events. (See 'Pacemaker programming' above.) Immediately following completion of transvenous lead placement, a chest radiograph should be obtained to establish the position of the lead, an immediate postprocedure 12- lead ECG should be recorded during pacing to determine the electrocardiographic appearance of the QRS complex, and a physical examination should be performed to evaluate for any evidence of cardiac tamponade or pneumothorax. (See 'Immediate postprocedural management' above.) Continuous ECG monitoring is mandatory during the entire time the patient has a temporary cardiac pacemaker, and a separate intravenous access is recommended should there be a need for drug therapy. Daily chest radiographs and ECGs are not needed; however, patients with temporary pacemakers require a daily check of pacing thresholds to make certain that there is proper capture. (See 'Management for the duration of temporary pacing' above.) ACKNOWLEDGMENTS The UpToDate editorial staff acknowledges Brian Olshansky, MD, and David L Hayes, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. Circulation 2019; 140:e333. 2. Glikson M, Nielsen JC, Kronborg MB, et al. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 2021; 42:3427. 3. Tjong FVY, de Ruijter UW, Beurskens NEG, Knops RE. A comprehensive scoping review on transvenous temporary pacing therapy. Neth Heart J 2019; 27:462. 4. Sullivan BL, Bartels K, Hamilton N. Insertion and Management of Temporary Pacemakers. Semin Cardiothorac Vasc Anesth 2016; 20:52. https://www.uptodate.com/contents/temporary-cardiac-pacing/print 15/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate 5. Murphy JJ. Current practice and complications of temporary transvenous cardiac pacing. BMJ 1996; 312:1134. 6. Ng ACC, Lau JK, Chow V, et al. Outcomes of 4838 patients requiring temporary transvenous cardiac pacing: A statewide cohort study. Int J Cardiol 2018; 271:98. 7. Metkus TS, Schulman SP, Marine JE, Eid SM. Complications and Outcomes of Temporary Transvenous Pacing: An Analysis of > 360,000 Patients From the National Inpatient Sample. Chest 2019; 155:749. 8. Abd Elaziz ME, Allama AM. Temporary Epicardial Pacing After Valve Replacement: Incidence And Predictors. Heart Surg Forum 2018; 21:E049. 9. Reade MC. Temporary epicardial pacing after cardiac surgery: a practical review: part 1: general considerations in the management of epicardial pacing. Anaesthesia 2007; 62:264. 10. Blommaert D, Gonzalez M, Mucumbitsi J, et al. Effective prevention of atrial fibrillation by continuous atrial overdrive pacing after coronary artery bypass surgery. J Am Coll Cardiol 2000; 35:1411. 11. Kornberger A, Schmid E, Kalender G, et al. Bridge to recovery or permanent system implantation: an eight-year single-center experience in transvenous semipermanent pacing. Pacing Clin Electrophysiol 2013; 36:1096. 12. Kawata H, Pretorius V, Phan H, et al. Utility and safety of temporary pacing using active fixation leads and externalized re-usable permanent pacemakers after lead extraction. Europace 2013; 15:1287. 13. Bektas F, Soyuncu S. The efficacy of transcutaneous cardiac pacing in ED. Am J Emerg Med 2016; 34:2090. 14. Quast ABE, Beurskens NEG, Ebner A, et al. Feasibility of An Entirely Extracardiac, Minimally Invasive,Temporary Pacing System. Circ Arrhythm Electrophysiol 2019; 12:e007182. 15. Aser R, Orhan C, Niemann B, et al. Temporary epicardial pacemaker wires: significance of position and electrode type. Thorac Cardiovasc Surg 2014; 62:66. 16. Francis GS, Williams SV, Achord JL, et al. Clinical competence in insertion of a temporary transvenous ventricular pacemaker. A statement for physicians from the ACP/ACC/AHA Task Force on Clinical Privileges in Cardiology. Circulation 1994; 89:1913. 17. Ezeugwu CO, Oropello JM, Pasik AS, Benjamin E. Position of temporary transvenous pacemaker after insertion. J Cardiothorac Vasc Anesth 1994; 8:367. 18. Goldberger J, Kruse J, Ehlert FA, Kadish A. Temporary transvenous pacemaker placement: what criteria constitute an adequate pacing site? Am Heart J 1993; 126:488. https://www.uptodate.com/contents/temporary-cardiac-pacing/print 16/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate 19. Pinneri F, Frea S, Najd K, et al. Echocardiography-guided versus fluoroscopy-guided temporary pacing in the emergency setting: an observational study. J Cardiovasc Med (Hagerstown) 2013; 14:242. 20. Ferri LA, Farina A, Lenatti L, et al. Emergent transvenous cardiac pacing using ultrasound guidance: a prospective study versus the standard fluoroscopy-guided procedure. Eur Heart J Acute Cardiovasc Care 2016; 5:125. 21. Guo H, Hahn D, Olshansky B. Temporary biventricular pacing in a patient with subacute myocardial infarction, cardiogenic shock, and third-degree atrioventricular block. Heart Rhythm 2005; 2:112. 22. Madershahian N, Scherner M, Weber C, et al. Temporary biventricular pacing improves bypass graft flows in coronary artery bypass graft patients with permanent atrial fibrillation. Interact Cardiovasc Thorac Surg 2015; 21:435. 23. Baciewicz FA Jr, Leighton RF, Davis JT. Use of rapid atrial pacing to induce 2:1 atrioventricular block with marked improvement in hemodynamics. Int J Cardiol 1987; 17:327. 24. Scott WA, Lemler M, Farley L, Zehr R. Evaluation of temporary atrial pacing leads. Pacing Clin Electrophysiol 1993; 16:1789. 25. Takeda M, Furuse A, Kotsuka Y. Use of temporary atrial pacing in management of patients after cardiac surgery. Cardiovasc Surg 1996; 4:623. 26. Ohm OJ, Breivik K, Segadal L, Engedal H. New temporary atrial and ventricular pacing leads for patients after cardiac operations. J Thorac Cardiovasc Surg 1995; 110:1725. 27. Hildick-Smith DJ, Petch MC. Temporary pacing before permanent pacing should be avoided unless essential. BMJ 1998; 317:79. Topic 1005 Version 26.0 https://www.uptodate.com/contents/temporary-cardiac-pacing/print 17/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate GRAPHICS Options for hands-free pacemaker/defibrillator pad positioning Positioning options for hands-free pacemaker/defibrillator pads showing anterior/lateral positioning (left) and anterior/posterior positioning (right). Graphic 103268 Version 2.0 https://www.uptodate.com/contents/temporary-cardiac-pacing/print 18/19 7/6/23, 11:03 AM Temporary cardiac pacing - UpToDate Contributor Disclosures N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/temporary-cardiac-pacing/print 19/19

7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Unexpected rhythms with normally functioning dual- chamber pacing systems : Mark S Link, MD : N A Mark Estes, III, MD : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jul 22, 2022. INTRODUCTION A variety of electrocardiographic findings and rhythms may be encountered in which the pacing system is functioning normally. These include crosstalk, pacemaker-mediated or endless loop tachycardias, and repetitive nonreentrant ventriculoatrial synchronous rhythms. These might be considered functional system malfunctions since the resulting arrhythmia may be deleterious to the patient, although the device is functioning normally and in accord with its programmed specifications. A comprehensive discussion of the normal function and programming of permanent pacemakers is presented separately. (See "Permanent cardiac pacing: Overview of devices and indications" and "Modes of cardiac pacing: Nomenclature and selection".) CROSSTALK Basic concepts In a DDD pacemaker, a paced or sensed event in one channel initiates one or more timing circuits in the opposite channel. As a result, the release of an atrial output pulse will initiate an atrioventricular (AV) delay, which will permit a ventricular output pulse at the end of this interval if an R wave is not sensed. Concepts related to the AV interval are easiest to understand if the AV interval is not considered as a single interval but as having three distinct portions ( figure 1 and figure 2 and figure 3): https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 1/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate The portion that begins immediately with the atrial output pulse is the "postatrial ventricular blanking period" during which the ventricular sensing channel is disabled and anything occurring in this relatively short interval will not be seen. The second portion of the AV interval is called the "crosstalk sensing window" or "safety pacing window" and if an event is sensed during this portion of the AV interval, a foreshortened AV interval will occur if safety pacing is turned "on." The final or third portion of the AV interval is the "alert period" and if an event is sensed on the ventricular sensing channel during this period, ventricular pacing output will be inhibited. Current pacing systems, however, are incapable of recognizing morphologic characteristics of a complex. Any intrinsic complex, output decay, or artifact of electromagnetic interference of sufficient amplitude and frequency response that it is not filtered out by the sense amplifier is treated as a true signal. Although bipolar sensing configuration is believed to minimize far-field sensing, crosstalk can be seen with any sensing configuration. If any signal is interpreted as an R wave, and inhibits the ventricular output and resets the escape interval, the phenomenon is termed crosstalk-mediated ventricular output inhibition. When AV nodal conduction is otherwise intact, crosstalk is asymptomatic. If there is first degree AV block, the effective paced rate may be slower than the programmed base rate, because the conducted R wave will occur after completion of the ventricular refractory period initiated by the oversensing of the atrial stimulus. The conducted R wave will be sensed, thereby resetting the atrial escape interval yet again. A clinical catastrophe may occur in the presence of complete AV block combined with crosstalk (in the absence of safety-pacing), as the system will effectively pace the atrium, but the ventricular output may be repeatedly inhibited, leaving the patient asystolic. Predisposing factors Factors that predispose to crosstalk associated with the atrial output include a high atrial output (either pulse amplitude, pulse duration, or both), the ventricular sensing channel programmed to a very sensitive setting, and a short post-atrial ventricular blanking period. The post-atrial ventricular blanking period is a short interval of absolute refractoriness initiated in the ventricular sense amplifier upon completion of the atrial escape interval. It is designed to coincide with the atrial output pulse and initial decay of this output. The intent of the blanking period is to prevent sensing of the atrial stimulus and, hence, prevent crosstalk. Ventricular blanking periods are usually programmable. Lengthening the ventricular blanking period may avoid crosstalk. https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 2/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate Prevention An effective method to prevent crosstalk is to lengthen the post-atrial ventricular blanking period. However, a premature ventricular complex/contraction (PVC; also referred to as premature ventricular beats or premature ventricular depolarizations) that occurs within the ventricular blanking period may not be sensed if the intrinsic deflection of the PVC occurs during the blanking period. Events that are not sensed during the blanking period are a form of functional undersensing. This has the potential for inducing an adverse rhythm triggered by competition. Upon termination of the blanking period, the AV interval timer is allowed to complete, because nothing was sensed by the pacemaker, and a ventricular output pulse will be released. Depending upon the AV interval, this may place a ventricular stimulus on the apex of the T wave (ie, the vulnerable period) and may induce pathologic ventricular tachyarrhythmias in the electrically unstable patient. Thus, the extended blanking period could have an adverse effect, even though the pacing system is functioning in accord with its design and programmed parameters and the occurrence of crosstalk has been effectively prevented. Periods of forced inability to sense or inability to react to a sensed event (ie, refractory periods and blanking periods) should generally be kept as short as possible. Since the blanking periods for dealing with crosstalk may be associated with potential problems, a special detection or sensing window on the ventricular channel that immediately follows the blanking period has been incorporated into dual-chamber pacing systems. If an event is sensed during this crosstalk detection window, the logic incorporated in the pacemaker will treat this as if it were true crosstalk. The event sensed during this special detection window causes the ventricular circuit to trigger a ventricular output pulse at the end of an abbreviated AV interval (approximately 110 milliseconds) rather than inhibiting its output. This abbreviated AV interval will result in nonphysiologic AV sequential pacing, but will protect the patient from asystole in the presence of crosstalk combined with complete heart block. If the sensed event were a true R wave, particularly a PVC, the pacing stimulus occurring at a short AV interval would likely occur when the ventricular myocardium is physiologically refractory and would neither capture nor induce any dangerous arrhythmias. The overall phenomenon is generically called "safety pacing." In many pacing systems, this is a programmable parameter that can be enabled or disabled. INAPPROPRIATE MODE SWITCH Dual-chamber pacemakers capable of "tracking" the atrial rhythm recognize very rapid atrial rates and initiate mode switch to a nontracking mode when specific criteria are met. If the pacemaker senses nonphysiologic activity on the atrial channel (eg, noise) or inappropriately senses ventricular activity on the atrial sensing channel, (termed far field R wave [FFRW] sensing) https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 3/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate [1], the detected atrial rate may not represent a true atrial tachyarrhythmia. If this artificially detected atrial rate meets criteria for the mode switch algorithm, inappropriate mode switching will occur. PACEMAKER-INITIATED TACHYCARDIA Pacemaker-initiated tachycardia can occur when competition, due to undersensing, functional or otherwise, triggers a native tachycardia [2]. Once the tachycardia is initiated, the pacemaker becomes an innocent bystander, being inhibited by the native arrhythmia. PACEMAKER-MEDIATED TACHYCARDIA A pacemaker-mediated tachycardia (PMT) is a tachycardia that can only be sustained by the continued active participation of the pacemaker. Pacemaker-mediated tachycardia The classic form of pacemaker-mediated tachycardia requires retrograde conduction from the ventricle to the atrium via the AV node and sensing of the retrograde P waves during the atrial alert period. When all of these events occur in succession, the atrial sensing event triggers another ventricular pacing event, which perpetuates the cycle of "endless loop tachycardia" [3]. Most individuals with a normal heart are capable of demonstrating retrograde conduction in the appropriate circumstances. It does not occur during the normal synchronization between the atrium and ventricle, because atrial and AV nodal depolarization renders these tissues physiologically refractory. PMT is commonly initiated by premature ventricular complexes (PVCs) that occur prior to the anticipated P wave. PVCs that occur in this interval can cause retrograde conduction if the AV node and atrial tissue have recovered sufficiently to allow for conduction. Other events that may initiate PMT include atrial undersensing or oversensing and loss of atrial capture. There are two manifestations of PMT that are most commonly seen: The classic form, which results in ventricular pacing at the programmed maximum tracking rate. The sensed P wave is tracked, but the programmed AV interval is extended to delay release of the ventricular output pulse until the maximum tracking rate interval times out. This allows the atrial and AV nodal tissue to physiologically recover, enabling them to be depolarized by the next paced ventricular beat. https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 4/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate A "balanced" PMT. If retrograde conduction is sufficiently slow and the combination of the retrograde ventricular paced beat to P wave and anterograde intervals exceeds the maximum tracking rate, a PMT can result that is slower than the maximum tracking rate. Management of PMT Although there are a number of management options to prevent or terminate a PMT, the one way to prevent an PMT is to program the postventricular atrial refractory period (PVARP) sufficiently long to prevent the pacemaker from sensing and hence tracking the retrograde P wave. Extending the PVARP does not prevent retrograde conduction. A longer PVARP effectively lengthens the total atrial refractory period (TARP), thereby limiting the maximum atrial rate that can be sensed and tracked. If the reduction in the maximum paced atrial rate is not a clinical concern for the patient, increasing the length of the PVARP is often a definitive solution. However, many clinicians want the pacemaker to have a mean tracking rate that is higher than that allowed by programming a long PVARP. Since PMT is frequently initiated by PVCs, manufacturers have incorporated automatic PVARP extensions following a PVC. For a pacemaker, a PVC is defined as a sensed ventricular event (R wave) that is not preceded by any paced or sensed atrial activity. The various automatic PVARP extensions, while often effective, may simply postpone the PMT for one cycle or, result in sustained pacemaker inhibition when the P wave is able to conduct with a first-degree AV block. The P wave is not seen by the pacemaker because it coincides with the PVARP. The resultant native ventricular depolarization, which is due to anterograde conduction, is called a PVC by the pacing system, reinitiating the longer PVARP for that cycle and sustaining the pacemaker inhibition. However, since PVCs are not the only trigger for an PMT, this automatic post-PVC PVARP extension algorithm is usually only a partial solution. If permanently increasing the PVARP to a sufficient degree to prevent sensing of the retrograde P wave is not an option for prevention of PMT, a variety of tachycardia termination algorithms have been developed. As an example, when the device senses possible PMT, it can algorithmically inhibit ventricular pacing for a single beat, temporarily extend the PVARP, temporarily alter other timing intervals, or combine such maneuvers in an attempt to terminate PMT. REPETITIVE NONREENTRANT VENTRICULOATRIAL SYNCHRONOUS RHYTHMS (AV DESYNCHRONIZATION ARRHYTHMIA) Dual-chamber AV sequential pacing at relatively rapid rates, whether driven by the rate-adaptive sensor or associated with a relatively high programmed base rate, sets the stage for an AV https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 5/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate desynchronization arrhythmia, also called repetitive nonreentrant ventriculoatrial synchronous rhythms (RNRVAS), that may be hemodynamically deleterious and cause symptomatic palpitations [4]. The occurrence of this arrhythmia requires intact retrograde ventricular paced conduction [5]. The pacing system is functioning normally in accord with its programmed parameters. Mechanism At the onset of RNRVAS, an event occurs that triggers one cycle of AV dissociation, resulting in retrograde conduction. The retrograde P wave coincides with the postventricular atrial refractory period (PVARP), precluding it from being sensed. This is intentional and functional undersensing. Hence, a PMT does not occur. However, the atrial depolarization renders the atrial myocardium physiologically refractory. As a result, there may be failure to capture with the next atrial stimulus, which occurs at the end of a relatively short atrial escape interval since the pacing rate is high and in close proximity to the intrinsic atrial depolarization. This is functional atrial noncapture. The time from the atrial depolarization to the ensuing ventricular stimulus occurring at the end of the AV interval provides sufficient time for the atrial myocardium to recover, thereby allowing retrograde conduction to occur. This can result in a rhythm in which there is sustained retrograde conduction, followed each time by an ineffective atrial stimulus. The patient may experience palpitations from the retrograde conduction as the atrium contracts against a closed mitral and tricuspid valve, inducing cannon A waves. In addition, there may be hypotension and hemodynamic compromise due to the loss of optimal AV synchrony. This is, by definition, pacemaker syndrome. Prevention Prevention of an RNRVAS requires minimizing the duration of the refractory periods, allowing all native events to be sensed. If this results in a PMT, then a tachycardia termination algorithm should be used to terminate the PMT. If AV desynchronization arrhythmia is consistently enabled by a true premature ventricular complex (PVC), then a more specific post- PVC PVARP extension algorithm will prevent it. Most PVARP extensions lengthen the PVARP but do not alter the basic pacing interval that will simply sustain this problem because the atrial output pulse will still occur at a time when the atrial myocardium is physiologically refractory. A "+PVARP on PVC" algorithm lengthens the PVARP and adds an obligatory atrial alert period following the end of the extended PVARP. As a result, despite the programmed or sensor-driven AV pacing rate, the pacemaker is disabled in favor of an atrial escape interval defined by the "+PVARP on PVC" algorithm for this one cycle. When an atrial stimulus occurs at the end of this atrial escape interval, the atrial myocardium will have physiologically recovered, assuring atrial capture and preventing this arrhythmia. If a native P wave occurs during the atrial alert period, it https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 6/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate is sensed and tracked. Either a paced or sensed atrial event will terminate this algorithm and return the pacing system to its previous functional state. FUNCTIONAL SINGLE-CHAMBER ATRIAL PACING Many patients who require a pacemaker have AV conduction that is prolonged but intact. Such patients may pace their right ventricle a high percentage of the time. It is well recognized that unnecessary ventricular pacing may increase the incidence of both atrial fibrillation and congestive heart failure [6-10]. When AV nodal conduction is prolonged, but intact, and the QRS width is normal, programming the pacemaker to minimize ventricular pacing (ie, functional single-chamber atrial pacing) is recommended. A number of techniques are used to achieve this end, and these may produce unexpected rhythms. Long programmed AV delay One can achieve functional single-chamber atrial pacing by simply programming a very long AV delay (ie, the amount of time after an atrial beat that the pacemaker will wait to sense an intrinsically conducted QRS before pacing the RV). This is a simple approach that can be limited by the pacemaker sensing the intrinsic RV activation late in the QRS. Thus, even if the PR interval is only slightly prolonged, the RV lead may not sense the QRS until more than 300 msec after the P wave. In such cases, it may be difficult or impossible to program a long enough AV delay to avoid ventricular pacing. Many patients with mild or moderate PR prolongation would do well most of the time with native conduction, and markedly reduced frequency of RV pacing. Ventricular hysteresis With this feature, a basic AV delay is set, but periodically the system extends the AV delay by a programmed amount [11-13]. If a native QRS is sensed during this extended interval, the pacemaker will continue to function with this longer AV delay, allowing native conduction and minimizing ventricular pacing. If AV block worsens, and ventricular pacing is again required, the pacemaker will return to the original, shorter AV delay for a period of time, then it will repeat the test with the longer AV delay. AAI/DDD pacing AAI/DDD pacing is the most commonly used technique to minimize ventricular pacing. There are subtle differences among the algorithms available [14,15], but the basic design is similar. These devices will initially function as a single-chamber, AAI pacemaker, but with continuous ventricular sensing. The system will not attempt to pace the ventricle unless sustained AV block develops (ie, it will allow long PR intervals, the maximum length being programmable or defined by the algorithm, and even one or two nonconducted P waves https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 7/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate [dependent on algorithm]). If loss of AV conduction is sensed, the pacemaker will switch to DDD pacing for some period of time until the algorithm once again looks for intrinsic AV conduction. The rationale for this approach is that most patients will tolerate isolated pauses, and that it is more important to minimize ventricular pacing than it is to ensure that every P wave is followed by a sensed or paced QRS. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Modes to minimize ventricular pacing'.) An example of a ventricular pacing avoidance algorithm in the setting of AV block is shown based on recordings from a Holter monitor ( waveform 1). Intermittent AV block was present that was not associated with ventricular pacing, but this is consistent with the normal behavior of this algorithm. On the atrial paced beat following a cycle of AV block, ventricular pacing occurs at a foreshortened AV delay of 80 ms despite the programmed AV delay. Sustained AV block will result in a reversion to the DDD mode. As a result of the AV dissociation that may occur as the result of a ventricular pacing avoidance algorithm, pacemaker syndrome may occur [16]. Similarly, algorithms that promote atrial pacing by AV interval extension have also resulted in the occurrence of pacemaker-mediated tachycardia [12,17]. VENTRICULAR ARRHYTHMIAS Ventricular tachycardia (VT) and ventricular fibrillation (VF) are often preceded by abrupt changes in ventricular cycle lengths (ie, the interval between successive ventricular beats). These events are referred to as short-long-short (SLS) sequences. A common example of an SLS sequence involves premature ventricular complexes (PVCs). The "short" interval between a normal beat and a PVC is followed by a "long" interval before the next normal beat. A SLS sequence occurs if a second PVC occurs after this "long" interval. Such events produce changes in both the activation sequences and refractory periods of ventricular myocardium and the His- Purkinje system, and these alterations increase vulnerability to the onset of VT and VF. Normal single- and dual-chamber pacing can create SLS sequences that have the potential to trigger VT or VF [18,19]. Such events can occur in a variety of settings, usually due to the response of pacemaker algorithms to atrial and/or ventricular ectopy. The incidence of SLS induced VT or VF in pacemaker patients is unknown, but is rarely recognized clinically. In the cohort of implantable cardioverter-defibrillator (ICD) patients discussed below, pacemaker facilitated ventricular arrhythmias occurred in 1 to 4 percent of patients [19]. Because these patients were already known to be at high risk for such arrhythmias, the incidence in the general population of pacemaker patients is probably substantially lower. https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 8/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate Pacing algorithms that maximize native conduction and minimize ventricular pacing can allow relatively long ventricular pauses. Thus, it can be theorized that these pacing modalities may increase the risk of ventricular arrhythmias [20]. However, such an increased risk was not shown in a retrospective analysis of 1055 patients from two large ICD trials [19]. Among patients whose devices were programmed DDD, VVI, and managed ventricular pacing modes, VT and VF episodes associated with pacemaker-facilitated SLS sequences occurred in 5.2, 3.3, and 2.6 percent, respectively. (See 'Functional single-chamber atrial pacing' above and "Modes of cardiac pacing: Nomenclature and selection", section on 'Modes to minimize ventricular pacing'.) Because a ventricular pause is central to the SLS sequence, pacing strategies that minimize such pauses have been proposed as a method for reducing the risk of ventricular arrhythmias. However, such approaches have not proven successful [18,21]. This failure appears to be due to the relatively short pauses (eg, <1 second), and small changes in cycle length (eg, 40 to 200 msec) that are required to trigger ventricular arrhythmias [19,22]. SUMMARY AND RECOMMENDATIONS When an unexpected rhythm is observed in a patient with a dual-chamber pacing system, applying the following questions should provide a basis to understanding and managing unexpected rhythms: Is the pacing system functioning normally or not? Is the unexpected rhythm initiated by the pacemaker, mediated by the pacemaker, or a result of a specific pacing algorithm? To fully appreciate the variations that can occur as a result of company specific algorithms, is the provider aware of any algorithms that are programmed "on" and thoroughly understand how these algorithms function? Detailed discussion of identification and management of specific unexpected rhythms with dual-chamber pacing occurs in the body of the topic. Crosstalk. (See 'Crosstalk' above.) Inappropriate mode switch. (See 'Inappropriate mode switch' above.) Pacemaker-initiated tachycardia. (See 'Pacemaker-initiated tachycardia' above.) Pacemaker-mediated tachycardia (PMT). (See 'Pacemaker-mediated tachycardia' above.) https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 9/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate Repetitive nonreentrant ventriculoatrial synchronous rhythms (RNRVAS). (See 'Repetitive nonreentrant ventriculoatrial synchronous rhythms (AV desynchronization arrhythmia)' above.) Functional single-chamber atrial pacing. (See 'Functional single-chamber atrial pacing' above.) Ventricular arrhythmias. (See 'Ventricular arrhythmias' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges David L Hayes, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Stroobandt RX, Barold SS, Vandenbulcke FD, et al. A reappraisal of pacemaker timing cycles pertaining to automatic mode switching. J Interv Card Electrophysiol 2001; 5:417. 2. Luceri RM, Ramirez AV, Castellanos A, et al. Ventricular tachycardia produced by a normally functioning AV sequential demand (DVI) pacemaker with "committed" ventricular stimulation. J Am Coll Cardiol 1983; 1:1177. 3. Frumin H, Furman S. Endless loop tachycardia started by an atrial premature complex in a patient with a dual chamber pacemaker. J Am Coll Cardiol 1985; 5:707. 4. Barold SS, Levine PA. Pacemaker repetitive nonreentrant ventriculoatrial synchronous rhythm. A review. J Interv Card Electrophysiol 2001; 5:45. 5. Chien WW, Foster E, Phillips B, et al. Pacemaker syndrome in a patient with DDD pacemaker for long QT syndrome. Pacing Clin Electrophysiol 1991; 14:1209. 6. Nielsen JC, Kristensen L, Andersen HR, et al. A randomized comparison of atrial and dual- chamber pacing in 177 consecutive patients with sick sinus syndrome: echocardiographic and clinical outcome. J Am Coll Cardiol 2003; 42:614. 7. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003; 107:2932. https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 10/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate 8. Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 2002; 288:3115. 9. O'Keefe JH Jr, Abuissa H, Jones PG, et al. Effect of chronic right ventricular apical pacing on left ventricular function. Am J Cardiol 2005; 95:771. 10. Shukla HH, Hellkamp AS, James EA, et al. Heart failure hospitalization is more common in pacemaker patients with sinus node dysfunction and a prolonged paced QRS duration. Heart Rhythm 2005; 2:245. 11. Melzer C, Sowelam S, Sheldon TJ, et al. Reduction of right ventricular pacing in patients with sinus node dysfunction using an enhanced search AV algorithm. Pacing Clin Electrophysiol 2005; 28:521. 12. Dennis MJ, Sparks PB. Pacemaker mediated tachycardia as a complication of the autointrinsic conduction search function. Pacing Clin Electrophysiol 2004; 27:824. 13. Levine PA. First reported case where a PMT was repeatedly triggered by the AV. Pacing Clin Electrophysiol 2004; 27:1691. 14. Sweeney MO, Ellenbogen KA, Casavant D, et al. Multicenter, prospective, randomized safety and efficacy study of a new atrial-based managed ventricular pacing mode (MVP) in dual chamber ICDs. J Cardiovasc Electrophysiol 2005; 16:811. 15. Savour A, Fr hlig G, Galley D, et al. A new dual-chamber pacing mode to minimize ventricular pacing. Pacing Clin Electrophysiol 2005; 28 Suppl 1:S43. 16. Pascale P, Pruvot E, Graf D. Pacemaker syndrome during managed ventricular pacing mode: what is the mechanism? J Cardiovasc Electrophysiol 2009; 20:574. 17. Barold SS, Stroobandt RX. Pacemaker-mediated tachycardia initiated by an atrioventricular search algorithm to minimize right ventricular pacing. J Electrocardiol 2012; 45:336. 18. Himmrich E, Przibille O, Zellerhoff C, et al. Proarrhythmic effect of pacemaker stimulation in patients with implanted cardioverter-defibrillators. Circulation 2003; 108:192. 19. Sweeney MO, Ruetz LL, Belk P, et al. Bradycardia pacing-induced short-long-short sequences at the onset of ventricular tachyarrhythmias: a possible mechanism of proarrhythmia? J Am Coll Cardiol 2007; 50:614. 20. van Mechelen R, Schoonderwoerd R. Risk of managed ventricular pacing in a patient with heart block. Heart Rhythm 2006; 3:1384. 21. Friedman PA, Jalal S, Kaufman S, et al. Effects of a rate smoothing algorithm for prevention of ventricular arrhythmias: results of the Ventricular Arrhythmia Suppression Trial (VAST). Heart Rhythm 2006; 3:573. https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 11/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate 22. Viskin S, Fish R, Zeltser D, et al. Arrhythmias in the congenital long QT syndrome: how often is torsade de pointes pause dependent? Heart 2000; 83:661. Topic 1037 Version 26.0 https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 12/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate GRAPHICS Crosstalk A The AV interval should be considered as a single interval with two subportions. The entire AV interval corresponds to the programmed value, ie, the interval following a paced or sensed atrial beat allowed before ventricular pacing artifact is delivered. The initial portion of the AV interval is the blanking period. This interva is followed by the crosstalk sensing window. AV: atrioventricular From: Hayes DL, Wang PJ, Asirvatham SJ, Friedman PA. Timing cycles. In: Cardiac Pacing, De brillation and Resynchronization: A Clinica Approach, 3rd ed, Hayes DL, Asirvatham SJ, Friedman PA (Eds), Wiley-Blackwell, West Sussex 2013. Copyright 2013 Mayo Foundation Medical Education and Research. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned b Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 13/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate permissions department either via email: [email protected] or use the RightsLink service by clicking on the 'Request Permission' l accompanying this article on Wiley Online Library (https://onlinelibrary.wiley.com/). Graphic 121644 Version 1.0 https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 14/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate Crosstalk B If the ventricular sensing circuit senses activity during the crosstalk sensing window, a ventricular pacing artifact is delivered early, usually at 100-110 milliseconds after the atrial event. This has been referred to as "ventricular safety pacing," "110 millisecond phenomenon," and "nonphysiologic AV delay." AV: atrioventricular From: Hayes DL, Wang PJ, Asirvatham SJ, Friedman PA. Timing cycles. In: Cardiac Pacing, De brillation and Resynchronization: A Clinica Approach, 3rd ed, Hayes DL, Asirvatham SJ, Friedman PA (Eds), Wiley-Blackwell, West Sussex 2013. Copyright 2013 Mayo Foundation Medical Education and Research. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned b Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: [email protected] or use the RightsLink service by clicking on the 'Request Permission' l accompanying this article on Wiley Online Library (https://onlinelibrary.wiley.com/). https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 15/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate Graphic 121645 Version 1.0 https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 16/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate Crosstalk C The initial portion of the AVI in most dual-chamber pacemakers is designated as the blanking period. During this portion of the AVI, sensing is suspended. The primary purpose of this interval is to prevent ventricular sensing of the leading edge of the atrial pacing artifact. Any event that occurs during the blanking period, even if it is an intrinsic ventricular event, as shown in the figure, is not sensed. In this example, the ventricular premature beat that is not sensed is followed by a ventricular pacing artifact delivered at the programmed AV interval and occurring in the terminal portion of the T wave. AV: atrioventricular; AVI: atrioventricular interval; PVC: premature ventricular contraction From: Hayes DL, Wang PJ, Asirvatham SJ, Friedman PA. Timing cycles. In: Cardiac Pacing, De brillation and Resynchronization: A Clinical Approach, 3rd ed, Hayes DL, Asirvatham SJ, Friedman PA (Eds), Wiley-Blackwell, West Sussex 2013. Copyright 2013 Mayo Foundation for Medical Education and Research. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 17/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate shared or emailed. Please contact Wiley's permissions department either via email: [email protected] or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (https://onlinelibrary.wiley.com/). Graphic 121642 Version 1.0 https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 18/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate Electrocardiogram (ECG) showing managed ventricular pacing Managed ventricular pacing: a normal response for the algorithm when intrinsic ventricular conduction does not occur. Graphic 68792 Version 3.0 https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 19/20 7/6/23, 11:04 AM Unexpected rhythms with normally functioning dual-chamber pacing systems - UpToDate Contributor Disclosures Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/unexpected-rhythms-with-normally-functioning-dual-chamber-pacing-systems/print 20/20

7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Wearable cardioverter-defibrillator : Mina K Chung, MD : Richard L Page, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 22, 2023. INTRODUCTION The implantable cardioverter-defibrillator (ICD) has been shown to improve survival from sudden cardiac arrest and to improve overall survival in several populations at high risk for sudden cardiac death (SCD). However, there remain situations in which implantation of an ICD is immediately not feasible (eg, patients with an active infection), may be of uncertain benefit, may not be covered by third-party payers (eg, early post-myocardial infarction, patients with limited life expectancy or new onset systolic heart failure), or when an ICD must be removed (eg, infection). In cases where ICD implantation must be deferred, a wearable cardioverter-defibrillator (WCD) offers an alternative approach for the prevention of SCD. The WCD (LifeVest [Zoll Medical Corporation] or Assure [Kestra Medical Technologies, Inc]) is an external device capable of automatic detection and defibrillation of ventricular tachycardia and ventricular fibrillation ( picture 1 and figure 1). While the WCD can be worn for years, typically the device is used for several months as temporary protection against SCD. The indications, efficacy, and limitations of the wearable cardioverter-defibrillator will be discussed here. Detailed discussions of the roles of the ICD are presented separately. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 1/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate DESCRIPTION AND FUNCTIONS OF THE WCD The WCD is an external device capable of automatic detection and defibrillation of ventricular tachycardia (VT) or ventricular fibrillation (VF) [1]. The approved devices do not have pacing capabilities and therefore are unable to provide therapy for bradycardic events or antitachycardic pacing. Wearing the WCD The WCD is composed of dry, nonadhesive monitoring electrodes, defibrillation electrodes incorporated into a chest strap or vest assembly, and a defibrillation battery and monitor unit ( picture 1). The Assure WCD garment has two styles designed for female and male body habitus and different sizes. The monitoring electrodes are positioned circumferentially around the chest and provide two to four surface electrocardiogram (ECG) leads. The defibrillation electrodes are positioned in a vest assembly for apex-posterior defibrillation. Proper fitting is required to achieve adequate skin contact to avoid noise and frequent alarms. Detection and delivery of shocks Arrhythmia detection by the WCD is programmed using ECG rate and morphology criteria. The system is programmed to define ventricular arrhythmias when the ventricular heart rate exceeds a preprogrammed rate threshold with an ECG morphology that does not match a baseline electrocardiographic template. Typical programming is reflected in default device settings: VT detection 150 beats per minute (LifeVest) or 170 beats per minute (Assure). Programmable ranges for LifeVest are 120 to 250 beats per minute, not to exceed the VF detection rate; for Assure they are, 130 to the programmed VF threshold minus 10 beats per minute. VF detection 200 beats per minute. Programmable ranges are 120 to 250 beats per minute (LifeVest) or 180 to 220 beats per minute (Assure). Treatment with 150 joules (LifeVest) or 170 joules (Assure) shocks for up to five shocks. For the Zoll LifeVest WCD, the tachycardia detection rate is programmable for VF between 120 and 250 beats per minute, and the VF shock delay can be programmed from 25 to 55 seconds. The VT detection rate is programmable between 120 bpm to the VF setting with a VT shock delay https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 2/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate of 60 to 180 seconds. VT signals can allow synchronized shock delivery on the R wave, but if the R wave cannot be identified, unsynchronized shocks will be delivered. For the Kestra Assure WCD, the tachycardia detection rate is programmable for VF between 180 and 220 beats per minute, and for VT detection programmable from 130 beats per minute up to the programmed VF rate: 10 beats per minute. Detection utilizes a segment-based analysis of 4.8-second segments that continuously overlap by 2.4 seconds. VF confirmation requires two out of two segments (approximately 5 seconds), and VT confirmation requires 15 out of 19 segments (approximately 45 seconds). The first and last segments must be in the programmed treatment zone. If an arrhythmia is detected, vibration and audible alarms are initiated. A flashing red light and shock icon are activated on the Assure monitor. Although shocks may be transmitted to bystanders in physical contact with the patient being shocked by a WCD, a voice cautions the patient and bystanders to the impending shock. Patients are trained to hold a pair of response buttons on the LifeVest device or press the alert button on the Assure device during these alarms to avoid receiving a shock while awake. A patient's response serves as a test of consciousness; if no response occurs and a shock is indicated, the device charges, extrudes gel from the defibrillation electrodes, and delivers up to five biphasic shocks at preprogrammed energy levels (ranging from 75 to 150 joules for the LifeVest device and 170 joules for the Assure device). The LifeVest device includes a default sleep time from 11 PM to 6 AM, programmable in one-hour increments, which allows additional time for deep sleepers, if they awaken, to abort shocks. Efficacy in terminating VT/VF Shock efficacy with the WCD appears to be similar to that reported with implantable cardioverter-defibrillators (ICDs). However, sudden cardiac death may still occur in those not wearing the device, those with improper positioning of the device, due to bystander interference, due to the inability of the WCD to detect the ECG signal, or due to bradyarrhythmias. These results highlight the importance of patient education and promotion of compliance while using the WCD. The efficacy of the WCD has been tested for induced ventricular tachyarrhythmias as well as for spontaneous events during clinical trials and postmarket studies. When worn properly, the WCD appears to be as effective as an ICD for the termination of VT and VF, with successful shocks occurring in up to 100 percent of cases [1-7]. In a study of induced VT/VF in the electrophysiology laboratory, the WCD successfully detected and terminated VT/VF with 100 percent first-shock success [2]. The following large registry studies of patients with WCDs showed high shock success rates: https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 3/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate In a US postmarket study of 8453 patients who wore a WCD after myocardial infarction, 146 VT/VF events occurred in 133 patients, and the overall shock success rate for terminating VT/VF was 82 percent, with 91 percent immediate survival [6]. In this study, shock success resulting in survival was 95 percent in revascularized and 84 percent in non-revascularized patients, suggesting that lower efficacy rates may be related to ischemic events. In the WEARIT-II registry of 2000 patients who wore a WCD for a median of 90 days, 120 episodes of sustained VT/VF were seen in 41 patients [7]. For 90 of the episodes, patients pressed the response buttons to abort shock delivery, with the majority of sustained VT episodes terminating spontaneously following use of the response button. All of the remaining 30 VT/VF episodes in 22 different patients were successfully terminated with a single shock. Among 6043 German patients who wore the device between April 2010 and October 2013, 94 patients were shocked for sustained VT/VF, with the WCD successfully terminating VT/VF in 88 patients (94 percent) [8]. The WCD appears equally efficacious among patients with and without myocardial ischemia immediately prior to VT/VF detection and shock (as defined by 0.1 mV ST-segment changes on ECG), with first shock termination rates of 96 percent in both groups [9]. Avoiding inappropriate shocks When electronic noise occurs, which may potentially be interpreted at VT or VF, the WCD emits a noise alarm. This electronic noise can often be minimized or eliminated by changing body position or tightening of the electrode belt, and shocks can be avoided by pushing the response buttons. While a dual-chamber ICD with an atrial lead would seemingly have greater ability to discriminate between supraventricular tachycardia (SVT) and VT, the incidence of inappropriate shocks due to atrial fibrillation, sinus tachycardia, or other supraventricular arrhythmias in clinical studies of WCDs has been low. The LifeVest WCD uses a two-channel proprietary vectorcardiogram morphology matching algorithm to prevent shocks during SVT if the QRS is unchanged, and inappropriate shocks can also be averted when the patient presses the response buttons. The Assure WCD uses a four-channel ECG with a single noise-free channel required for analysis and an algorithm that excludes noisy and low amplitude channels ( figure 2). (See 'Inappropriate shocks' below.) In a small study of the 60 patients with a permanent pacemaker, in which a variety of pacing modes (AAI, VVI, DDD) and configurations (unipolar, bipolar) were tested, unipolar DDD pacing triggered VT/VF detection in six patients (10 percent), while no other pacing modes or configurations triggered arrhythmia detection [10]. As such, patients whose pacemaker is https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 4/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate programmed to unipolar DDD pacing should be evaluated for pacemaker reprogramming to a bipolar mode prior to WCD usage. In a study of 130 patients with an ICD and fitted with an ASSURE WCD programmed for detection only and followed for 30 days, of 163 WCD-detected episodes, four were VT/VF and 159 were non-VT/VF with three false-positive shock alarm markers recorded, corresponding to a very low rate of inappropriate detection [11]. No ICD-recorded VT/VF episodes meeting WCD programmed criteria were missed. Median daily use was high at 23 hours. Bradycardia/asystole Neither of the approved WCDs deliver antibradycardic pacing, but they do record the ventricular rate when the heart rate decreases or asystole occurs: For the LifeVest device, asystole recordings are triggered when ventricular heart rates drop below 10 beats per minute or 16 seconds of asystole, and the device automatically records the event with 120 seconds preceding the onset. If using the secure website in conjunction with the WCD, alerts can be configured to prompt the healthcare provider that a patient is experiencing bradycardia or an asystole. For the Assure device, asystole is detected when there is no detected heart rate for >20 seconds (five of seven segments with heart rate 0 beats per minute or amplitude <100 uV); prolonged heart rates below 30 beats per minute may be detected as bradycardia. When asystole or bradycardia is detected, a loud alarm is triggered to attract bystanders and instruct them to call 911 and begin CPR if the patient is unconscious. The alert can be silenced by pressing the alert button or it resolves when a heart rate >30 bpm is detected for >30 seconds. Storage of ECGs and compliance data In addition to delivering therapeutic shocks for life- threatening ventricular arrhythmias, the WCD stores data regarding tachyarrhythmias, bradycardia/asystole (see 'Bradycardia/asystole' above), patient compliance with the device, and noise or interference with its proper functioning. Arrhythmia recordings from the WCD are available for clinician review once stored data are transmitted via a modem to the manufacturer's network. Treatments, patient compliance, ECG records, and system performance can be viewed using a secure website. The WCD stores ECGs from arrhythmia detections, usage, and compliance trends: For the LifeVest system: The system is programmed to define ventricular arrhythmias when the ventricular heart rate exceeds a preprogrammed rate threshold with an ECG morphology that does not match a baseline ECG template. The monitoring software captures 30 seconds of ECG https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 5/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate signal prior to the determination of VT or VF and continuously records until 15 seconds after the alarms stop. Patients can perform manual recordings by pressing response buttons for three seconds, which records the prior 30 seconds plus the next 15 seconds. Data on patient compliance, ECG signal quality, alarm history, and noise occurrence are recorded, including time/date stamps for device on/off switching, monitor connection to the electrodes, and electrode-to-skin contact. Compliance may be determined by assessing the time that the user had the device turned on, the belt connected, and at least one monitoring electrode contacting the skin. For the Assure system: Up to 120 seconds of data are recorded prior to arrhythmia onset detection, confirmation, and therapy are detected, and up to 60 seconds are detected after rate recovery or conversion. Patient activity is also stored, utilizing an accelerometer located in the hub component in the middle of the patient's back. Daily usage is recorded in one-minute increments when the sensors are in contact with the patient's skin. INDICATIONS The WCD is indicated as temporary therapy for patients with a high risk for sudden cardiac death (SCD) [1,12-16]. Our recommended approach is consistent with that of the 2016 science advisory from the American Heart Association (also endorsed by the Heart Rhythm Society) and the 2017 AHA/ACC/HRS guideline [16,17]. Examples of persons who may benefit from the temporary use of a WCD include: Patients with a permanent implantable cardioverter-defibrillator (ICD) that must be explanted, or those with a delay in implanting a newly indicated ICD (eg, due to systemic infection). (See 'Bridge to indicated or interrupted ICD therapy' below.) Patients with reduced left ventricular (LV) systolic function (LVEF 35 percent) who have had a myocardial infarction (MI) within the past 40 days. (See 'Early post-MI patients with LV dysfunction' below.) https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 6/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate Patients with reduced LV systolic function (LVEF 35 percent) who have undergone coronary revascularization with coronary artery bypass graft (CABG) surgery in the past three months. (See 'Patients with LV dysfunction early after coronary revascularization' below.) Patients with newly diagnosed nonischemic cardiomyopathy with severely reduced LV systolic function (LVEF 35 percent) that is potentially reversible. (See 'Newly diagnosed nonischemic cardiomyopathy' below.) Patients with severe heart failure who are awaiting heart transplantation. (See 'Bridge to heart transplant' below.) A 2019 systematic review and meta-analysis, which included 33,242 WCD users from 28 studies (the randomized VEST trial and 27 nonrandomized studies), assessed the likelihood of WCD therapy in a broad range of patient populations, including both primary/secondary prevention and ischemic/nonischemic cardiomyopathy patients. The incidence of appropriate shocks was 5 per 100 persons over three months (1.67 percent per month) with mortality while wearing the device noted to be 0.7 per 100 persons over three months [18]. Bridge to indicated or interrupted ICD therapy In some patients with an indication for ICD placement, implantation of the device may be delayed due to comorbid conditions, including [16,17]: Infection Recovery from surgery Lack of vascular access In addition, patients with a preexisting ICD who develop device infection or endocarditis usually require system extraction to effectively treat the infection. Unless the patient is pacemaker dependent, reimplantation in many patients is deferred until the infection is completely cleared after an appropriate course of antibiotics. The WCD may provide protection against ventricular tachyarrhythmias during these periods until an ICD can be implanted [4,5,16]. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis".) In a review of 8058 patients who were prescribed the WCD after ICD removal because of infection, median time to reimplantation was 50 days, and 334 (4 percent) experienced 406 ventricular tachycardia/ventricular fibrillation (VT/VF) events, with 348 events treated by the WCD and 54 treatments averted by conscious patients [19]. The one-year cumulative event rate was 10 percent. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 7/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate Early post-MI patients with LV dysfunction Among patients with LV ejection fraction (LVEF) 35 percent who are less than 40 days post-MI, there are conflicting data on the benefits of a WCD for primary prevention against SCD. Following discussion of the potential benefits and risks, use of the WCD within this 40-day window could be considered among motivated patients who have LVEF 35 percent and in New York Heart Association (NYHA) functional class II or III, or LVEF <30 percent and in NYHA class I, as these patients would be candidates for ICD implantation after 40 days [16,17]. Patients should be reminded of the importance of compliance with the WCD in order to optimize any potential benefits on prevention of arrhythmic death. Reevaluation of LVEF should occur one to three months after the MI. If LVEF remains 35 percent on follow-up assessment, while the patient is taking appropriate medical therapy, ICD implantation is indicated [16]. After ICD implantation, use of the WCD would be discontinued. Despite advances in the treatment of acute coronary syndromes with early revascularization and effective medical therapies that have reduced mortality, some residual risk of SCD remains in the early period following an MI, especially in the setting of severely reduced LVEF (2.3 percent/month for patients with LVEF 30 percent) [4,20]. However, there are conflicting data on the utility of an ICD in the early post-MI period. In an analysis of 712 patients with a history of MI who were enrolled in the SCD-HeFT trial, there was no evidence of differential mortality benefit with ICDs as a function of time after MI, indicating that the potential benefit of ICD therapy is not restricted only to remote MIs [21]. In the DINAMIT (674 patients) and IRIS (898 patients) trials, which randomized patients with LVEF 35 percent to either early ICD implantation 6 to 40 days after acute MI or medical therapy alone, there was no significant improvement in overall mortality [22,23]. Despite a reduction in arrhythmic deaths among patients with an ICD, there was a higher risk of nonarrhythmic deaths during this early period, resulting in similar overall mortality rates. Professional society guidelines do not recommend ICD implantation for primary prevention of SCD within 40 days of acute MI [16]. However, due to the risk of SCD in some patients early post- MI, the WCD has been studied in this patient population. In the VEST trial, 2302 patients with an acute MI and LVEF 35 percent were randomly assigned (within seven days of hospital discharge) in a 2:1 ratio to wear the WCD in addition to usual medical treatment (1524 patients) or to receive standard medical treatment alone (778 patients) [24]. Over an average follow-up of 84 days, patients in the https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 8/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate WCD group had no significant improvement in the primary outcome of arrhythmic death (25 patients [1.6 percent] versus 19 patients [2.4 percent] with medical therapy alone; relative risk [RR] 0.67; 95% CI 0.37-1.21). Compliance with medical therapy was excellent in both groups, likely contributing to fewer than expected events and the trial possibly being underpowered. However, compliance with WCD usage was markedly lower than expected (median and mean daily wear times of 18 and 14 hours, respectively), with over half of patients assigned to the WCD not wearing it by the end of the 90-day study. Among 48 total deaths in the WCD group, only 12 patients (25 percent) were wearing the WCD at the time of death. Asystolic events not treated by the WCD likely also contributed to the nonsignificant primary outcome results of the trial. A subsequent as-treated and per- protocol analysis of VEST (censoring participants at the time they stopped wearing the WCD) reported a significant reduction in total and arrhythmic mortality among participants wearing the WCD compared with control participants (total mortality hazard ratio 0.25; CI 0.13-0.43; arrhythmic death hazard ratio 0.09; CI 0.02-0.39) [25]. The VEST study also demonstrates the challenges in trying to improve mortality in the post- MI population. Not all patients will survive despite initial appropriate and successful shocks for VT or VF. Of nine patients wearing the WCD with arrhythmic death in the VEST trial, four had been initially successfully treated but subsequently died. Of six patients who had an appropriate shock from the WCD but died during the study, two developed post-VT/VF asystole. Similar WCD shock rates (between 1.5 and 2 percent within 90 days post-MI) have been reported in observational studies [3,5,6]. In registry data from two large registries (involving 3569 and 8453 patients, respectively), similar rates of WCD shocks have been seen (1.7 and 1.6 percent of patients, respectively) [5,6]. Patients with LV dysfunction early after coronary revascularization Among patients with LVEF 35 percent who have undergone coronary revascularization with coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI) in the past three months, we offer a WCD to highly motivated patients for primary prevention against SCD [16]. LVEF should be reassessed three months following CABG or PCI. If a sustained ventricular tachyarrhythmia has occurred, or if the LVEF remains 35 percent three months after CABG or PCI, implantation of an ICD is usually indicated [16]. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) While professional society guidelines do not specifically exclude ICD implantation for patients with LV dysfunction within three months of revascularization, reimbursement in some countries https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 9/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate may be denied. As an example, in the United States the national coverage decision for the Centers for Medicare & Medicaid Service (CMS) excludes coverage for primary prevention ICDs if patients have had CABG surgery or PCI within the past three months. This is based upon the clinical profile of subjects included in the major ICD trials for primary prevention of SCD in ischemic cardiomyopathy [12,13,26,27]. Despite this exclusion period, patients with LV dysfunction (eg, LVEF 30 percent) have been shown to have significantly higher rates of mortality early after PCI or CABG based on large National Cardiovascular Data Registry (NCDR) and Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database studies, respectively [28,29]. Patients with significant LV dysfunction have higher 30-day mortality rates after coronary artery bypass graft (CABG) surgery than patients with normal LV function. While these persons have an increased risk of SCD due to ventricular arrhythmias, they are also at risk for nonarrhythmic causes of death. There are limited data on the utility of an ICD in the early post-CABG period, as several ICD studies of primary prevention have excluded patients within one to three months after coronary revascularization [12-14]. However, the CABG Patch trial did not report a survival benefit from epicardial ICD implantation at the time of CABG in patients with LVEF 35 percent [27]. (See "Early cardiac complications of coronary artery bypass graft surgery" and "Early noncardiac complications of coronary artery bypass graft surgery".) Professional society guidelines do not recommend ICD implantation for primary prevention of SCD within three months of CABG [16]. However, due to the risk of SCD in some patients early post-CABG, the WCD has been studied in this patient population, in whom wearing the WCD may provide protection from SCD during healing and potential recovery of LV function [3,16,17]. The potential utility for a WCD in this setting is illustrated by the following studies: In a nonrandomized comparison of nearly 5000 patients with LVEF 35 percent from two separate cohorts who underwent revascularization with CABG or percutaneous coronary intervention (PCI) (809 patients discharged with a WCD from a national registry and 4149 patients discharged without WCD from Cleveland Clinic CABG and PCI registries), patients discharged with the WCD had significantly lower 90-day mortality rates (3 versus 7 percent) [30]. While patients using a WCD appear to have improved outcomes, only 1.3 percent of the WCD group received an appropriate therapy while wearing the device, thereby indicating that the majority of the mortality benefit was not attributable to life-saving therapies from the WCD. In a German cohort of 354 patients who wore the WCD, including approximately 90 patients in the early post-CABG period, 7 percent received a shock for a ventricular tachyarrhythmia during the three months of WCD use [4]. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 10/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate In a study of 3569 patients in the United States using the WCD, among which 9 percent of WCD use was early post-CABG, appropriate shocks for a ventricular tachyarrhythmia occurred in 0.8 percent of these patients over a mean follow-up of 47 days [5,31]. Newly diagnosed nonischemic cardiomyopathy In selected patients with newly diagnosed nonischemic cardiomyopathy with severely reduced LV systolic function that is potentially reversible, such as tachycardia- or myocarditis-associated cardiomyopathy, the WCD may be useful for the prevention of SCD due to ventricular arrhythmias while awaiting improvement in LV function [16,17]. While a benefit from ICD implantation has long been recognized in patients with significant LV systolic dysfunction related to underlying ischemic heart disease, an increase in SCD risk and potential benefit from an ICD has also been demonstrated in patients with a nonischemic cardiomyopathy in several studies [14,32]: In SCD-HeFT, which compared ICD implantation with amiodarone treatment alone or placebo for primary prevention of SCD in patients with ischemic or nonischemic heart failure and LVEF 35 percent, patients who received an ICD had significantly improved survival [14]. However, patients within three months of their initial heart failure diagnosis were excluded from this study. In DEFINITE, which compared ICD implantation with standard medical therapy to standard medical therapy alone for primary prevention of SCD in patients with a nonischemic cardiomyopathy, nonsustained VT, and LVEF 35 percent, there was a trend toward improved mortality in patients who received an ICD, regardless of duration since diagnosis [32]. Following DEFINITE, another study reported similar occurrences of lethal arrhythmias irrespective of diagnosis duration in patients with a nonischemic cardiomyopathy and LVEF 35 percent [33]. Major society guidelines recommend implantation of an ICD for nonischemic cardiomyopathy with LVEF 35 percent, provided that a reversible cause of transient LV dysfunction has been excluded and that response to optimal medical therapy has been assessed [16]. The guidelines do not specify a waiting period prior to reassessing LVEF. In the United States, however, the Center for Medicare Services (CMS) requires a three-month period of optimal medical therapy prior to reimbursement for ICD placement for primary prevention (if repeat LVEF assessment continues to show LVEF 35 percent). (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF", section on 'Nonischemic dilated cardiomyopathy'.) https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 11/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate In patients felt to be at high risk of SCD while undergoing a trial of optimal medical therapy, the WCD may provide protection against SCD while awaiting improvement in LV function, although the event rates in this population appear to be lower than patients with ischemic cardiomyopathy [16]. In a post-approval study of the WCD, 0.7 percent of patients prescribed a WCD for recently diagnosed nonischemic cardiomyopathy required shocks for a ventricular tachyarrhythmia over a mean follow-up period of 57 days [5,31]. Among a single-center cohort of 254 patients with newly diagnosed nonischemic cardiomyopathy treated with the WCD between 2004 and 2015 (median duration of treatment 61 days, total follow-up 56.7 patient-years) who were highly compliant with using the WCD (median wear time 22 hours per day), no patients received an appropriate shock, and only three patients (1.2 percent) received an inappropriate shock [34]. This was compared with 6 of 271 patients (2.2 percent) with newly diagnosed ischemic cardiomyopathy who received an appropriate shock; in this group, two (0.7 percent) received inappropriate shocks. Of interest, 39 percent of nonischemic and 32 percent of ischemic cardiomyopathy patients experienced improvement in LVEF to >35 percent, obviating the need for an ICD. In a prospective study of the WCD in advanced heart failure patients (SWIFT), 75 patients hospitalized with heart failure (66 percent nonischemic cardiomyopathy) were prescribed a WCD for three months. Among the nonischemic cardiomyopathy patients, one had recurrent supraventricular tachycardia and another had multiple ventricular premature beats detected, but no WCD therapies were delivered [35]. In the WEARIT II registry, which included 927 patients with nonischemic cardiomyopathy, over a median wear time of 90 days, the treated event rate was 1 percent, compared with 3 percent for the 805 patients with ischemic cardiomyopathy [7]. Special populations include those with alcoholic cardiomyopathy, postpartum cardiomyopathy, or myocarditis, all of which may or may not be associated with improvement in ventricular function with optimal medical therapy and reversal or treatment of causative factors. In a study of 127 patients with alcoholic cardiomyopathy wearing the WCD a median of 51 days, 5.5 percent had appropriate shocks for VT/VF [36]. Improved LVEF occurred in 33 percent, and 23.6 percent received an ICD. In the PROLONG study of 156 patients (111 with nonischemic cardiomyopathy) with newly diagnosed LVEF 35 percent wearing a WCD for an average of 101 days, WCD shocks for VT/VF were experienced by 7.2 percent, compared with 6.7 percent in the 45 patients with https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 12/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate ischemic cardiomyopathy [37]. The event rates were 21.1 percent in the 19 patients with postpartum cardiomyopathy, 0 percent in the six patients with myocarditis, and 4.7 percent in patients with other forms of nonischemic cardiomyopathy. In a separate study of 107 women with peripartum cardiomyopathy, who were matched to 159 nonpregnant women with nonischemic dilated cardiomyopathy, the event rate was 0 in the peripartum cardiomyopathy over an average WCD use of 124 days, compared with two shocks in one patient with nonperipartum nonischemic cardiomyopathy [38]. With such low event rates, the utility of the WCD for newly-diagnosed nonischemic cardiomyopathy has been debated. However, from the WEARIT II registry, the number of VT/VF events per 100 patient-years was 1.5 for treated events versus 12 for untreated events [7]. Presumably, some of the untreated events led to earlier ICD implantation and may represent a nontreatment yield from the WCD monitoring functions. As data remain limited for such patients, the decision on whether to use a WCD remains based on clinical judgment for patients assessed to have high-risk severe newly diagnosed nonischemic cardiomyopathy while undergoing optimization of medical therapy, awaiting improvement in LV function, ICD implantation, or if needed, cardiac transplantation. (See "Treatment and prognosis of myocarditis in adults", section on 'Therapy for arrhythmias'.) Bridge to heart transplant Patients with severe heart failure awaiting heart transplantation represent a group at particularly high risk for SCD [17]. ICD implantation is often recommended for such patients, particularly those discharged to home while awaiting transplantation. The WCD may be a reasonable noninvasive alternative approach, though data on its use in patients awaiting heart transplantation are limited: In one study of 91 cardiac transplant candidates discharged to home (UNOS Status 1B patients receiving home inotrope infusion), among whom 25 had an ICD and 13 used a WCD, two patients died suddenly at home, one who was not wearing his WCD and another who declined use of a WCD [39]. In the 13 patients wearing the WCD, three asymptomatic events occurred with one shock delivered for rapid atrial fibrillation. In a German study of 354 WCD patients, 6 percent wore the WCD while awaiting heart transplantation, with an incidence of ventricular arrhythmias of 11 percent [4]. In the WEARIT study of WCD use in 177 patients with NYHA functional class III or IV heart failure (not listed for heart transplant but with similar functional status to patients who might be listed for heart transplant), one patient received two successful defibrillations [3]. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 13/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate In a registry of 121 patients prescribed a WCD as a bridge to heart transplantation, seven patients (6 percent) received appropriate shocks over an average use of 127 days (median 39 days) [40]. The International Society for Heart and Lung Transplantation Guidelines state as a class I recommendation that an ICD or WCD should be provided for status 1B patients who are discharged home given that the wait for transplantation remains significant [41]. The WCD may also be appropriate in patients whose anticipated waiting time to transplant is short (ie, blood types A and B) if an ICD is not already present [41]. WCD in patients with VADs The role for ICD and WCD therapy remains unclear in patients with ventricular assist devices (VADs). With VADs, circulatory support is often adequate even in the event of a ventricular tachyarrhythmia. However, one study reported the presence of an ICD was associated with improved survival in patients undergoing VAD support [42]. Whether the WCD could impart similar survival benefits in patients awaiting transplantation with VAD support has yet to be studied. (See "Treatment of advanced heart failure with a durable mechanical circulatory support device".) WCD use in hemodialysis patients Patients with end-stage kidney disease on hemodialysis are at high risk for SCD, but they are also at higher risk for infection, bleeding, and other complications of implantable device therapies, which may lead to underutilization of ICDs. Although the arrhythmia event rates for patients on hemodialysis wearing a WCD are not published, a study of 75 hemodialysis patients who experienced sudden cardiac arrest events while wearing a WCD reported that 78.6 percent of events were due to VT/VF and 21.4 percent were due to asystole [43]. Survival was 71, 51, and 31 percent at 24 hours, 30 days, and one year, respectively, which was reported to be improved compared with historical controls. LIMITATIONS AND PRECAUTIONS In spite of its overall efficacy for terminating life-threatening ventricular arrhythmias, the WCD does have some limitations. The device must be fitted to each patient, and some patients may not have a good fit due to body habitus. Its external nature does not allow for pacemaker functionality and introduces a component of patient interaction and compliance as well as the potential for external noise leading to inappropriate shocks. The device must be removed for bathing, but no protection is afforded while the device is off. Therefore, it is advisable that caregivers or other persons be nearby during these periods when the WCD is not worn. Comfort may also be an issue for some patients due to the size and weight of the device. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 14/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate Patient size The WCD can only be fitted on patients with a chest circumference less than 57 inches (144 cm); therefore, it may not be an option for morbidly obese patients. However, among 574 patients from the WCD registry, which included normal weight (body mass index [BMI] between 18 and 24.9; n = 157), overweight (BMI between 25 and 29.9; n = 186), and obese (BMI 30; n = 231, including 55 with BMI 40) patients who experienced 623 ventricular tachycardia/ventricular fibrillation (VT/VF) events while wearing the WCD, the median daily wear time (21 hours), first shock success rate (93 to 94 percent), and 24-hour post-shock survival (92 to 94 percent) were similar across all BMI groups [44]. There are also limited data on WCD use in children, in whom the device may not fit properly if the child is small. (See 'Use of the WCD in children' below.) Lack of pacemaker functionality Because of its external nature, the WCD is not able to function as a pacemaker, which limits the possible therapies it can deliver in two ways: The WCD cannot deliver pacing therapies to treat bradycardia or asystole. In the German study, two patients developed asystole while wearing the WCD, and both patients died [4].

percent for the 805 patients with ischemic cardiomyopathy [7]. Special populations include those with alcoholic cardiomyopathy, postpartum cardiomyopathy, or myocarditis, all of which may or may not be associated with improvement in ventricular function with optimal medical therapy and reversal or treatment of causative factors. In a study of 127 patients with alcoholic cardiomyopathy wearing the WCD a median of 51 days, 5.5 percent had appropriate shocks for VT/VF [36]. Improved LVEF occurred in 33 percent, and 23.6 percent received an ICD. In the PROLONG study of 156 patients (111 with nonischemic cardiomyopathy) with newly diagnosed LVEF 35 percent wearing a WCD for an average of 101 days, WCD shocks for VT/VF were experienced by 7.2 percent, compared with 6.7 percent in the 45 patients with https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 12/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate ischemic cardiomyopathy [37]. The event rates were 21.1 percent in the 19 patients with postpartum cardiomyopathy, 0 percent in the six patients with myocarditis, and 4.7 percent in patients with other forms of nonischemic cardiomyopathy. In a separate study of 107 women with peripartum cardiomyopathy, who were matched to 159 nonpregnant women with nonischemic dilated cardiomyopathy, the event rate was 0 in the peripartum cardiomyopathy over an average WCD use of 124 days, compared with two shocks in one patient with nonperipartum nonischemic cardiomyopathy [38]. With such low event rates, the utility of the WCD for newly-diagnosed nonischemic cardiomyopathy has been debated. However, from the WEARIT II registry, the number of VT/VF events per 100 patient-years was 1.5 for treated events versus 12 for untreated events [7]. Presumably, some of the untreated events led to earlier ICD implantation and may represent a nontreatment yield from the WCD monitoring functions. As data remain limited for such patients, the decision on whether to use a WCD remains based on clinical judgment for patients assessed to have high-risk severe newly diagnosed nonischemic cardiomyopathy while undergoing optimization of medical therapy, awaiting improvement in LV function, ICD implantation, or if needed, cardiac transplantation. (See "Treatment and prognosis of myocarditis in adults", section on 'Therapy for arrhythmias'.) Bridge to heart transplant Patients with severe heart failure awaiting heart transplantation represent a group at particularly high risk for SCD [17]. ICD implantation is often recommended for such patients, particularly those discharged to home while awaiting transplantation. The WCD may be a reasonable noninvasive alternative approach, though data on its use in patients awaiting heart transplantation are limited: In one study of 91 cardiac transplant candidates discharged to home (UNOS Status 1B patients receiving home inotrope infusion), among whom 25 had an ICD and 13 used a WCD, two patients died suddenly at home, one who was not wearing his WCD and another who declined use of a WCD [39]. In the 13 patients wearing the WCD, three asymptomatic events occurred with one shock delivered for rapid atrial fibrillation. In a German study of 354 WCD patients, 6 percent wore the WCD while awaiting heart transplantation, with an incidence of ventricular arrhythmias of 11 percent [4]. In the WEARIT study of WCD use in 177 patients with NYHA functional class III or IV heart failure (not listed for heart transplant but with similar functional status to patients who might be listed for heart transplant), one patient received two successful defibrillations [3]. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 13/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate In a registry of 121 patients prescribed a WCD as a bridge to heart transplantation, seven patients (6 percent) received appropriate shocks over an average use of 127 days (median 39 days) [40]. The International Society for Heart and Lung Transplantation Guidelines state as a class I recommendation that an ICD or WCD should be provided for status 1B patients who are discharged home given that the wait for transplantation remains significant [41]. The WCD may also be appropriate in patients whose anticipated waiting time to transplant is short (ie, blood types A and B) if an ICD is not already present [41]. WCD in patients with VADs The role for ICD and WCD therapy remains unclear in patients with ventricular assist devices (VADs). With VADs, circulatory support is often adequate even in the event of a ventricular tachyarrhythmia. However, one study reported the presence of an ICD was associated with improved survival in patients undergoing VAD support [42]. Whether the WCD could impart similar survival benefits in patients awaiting transplantation with VAD support has yet to be studied. (See "Treatment of advanced heart failure with a durable mechanical circulatory support device".) WCD use in hemodialysis patients Patients with end-stage kidney disease on hemodialysis are at high risk for SCD, but they are also at higher risk for infection, bleeding, and other complications of implantable device therapies, which may lead to underutilization of ICDs. Although the arrhythmia event rates for patients on hemodialysis wearing a WCD are not published, a study of 75 hemodialysis patients who experienced sudden cardiac arrest events while wearing a WCD reported that 78.6 percent of events were due to VT/VF and 21.4 percent were due to asystole [43]. Survival was 71, 51, and 31 percent at 24 hours, 30 days, and one year, respectively, which was reported to be improved compared with historical controls. LIMITATIONS AND PRECAUTIONS In spite of its overall efficacy for terminating life-threatening ventricular arrhythmias, the WCD does have some limitations. The device must be fitted to each patient, and some patients may not have a good fit due to body habitus. Its external nature does not allow for pacemaker functionality and introduces a component of patient interaction and compliance as well as the potential for external noise leading to inappropriate shocks. The device must be removed for bathing, but no protection is afforded while the device is off. Therefore, it is advisable that caregivers or other persons be nearby during these periods when the WCD is not worn. Comfort may also be an issue for some patients due to the size and weight of the device. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 14/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate Patient size The WCD can only be fitted on patients with a chest circumference less than 57 inches (144 cm); therefore, it may not be an option for morbidly obese patients. However, among 574 patients from the WCD registry, which included normal weight (body mass index [BMI] between 18 and 24.9; n = 157), overweight (BMI between 25 and 29.9; n = 186), and obese (BMI 30; n = 231, including 55 with BMI 40) patients who experienced 623 ventricular tachycardia/ventricular fibrillation (VT/VF) events while wearing the WCD, the median daily wear time (21 hours), first shock success rate (93 to 94 percent), and 24-hour post-shock survival (92 to 94 percent) were similar across all BMI groups [44]. There are also limited data on WCD use in children, in whom the device may not fit properly if the child is small. (See 'Use of the WCD in children' below.) Lack of pacemaker functionality Because of its external nature, the WCD is not able to function as a pacemaker, which limits the possible therapies it can deliver in two ways: The WCD cannot deliver pacing therapies to treat bradycardia or asystole. In the German study, two patients developed asystole while wearing the WCD, and both patients died [4]. In the US post-approval registry study, 23 of 3569 patients (0.6 percent) experienced asystole, with an associated mortality of 74 percent [5]. In the post-myocardial infarction (MI) registry of 8453 patients, 34 died (0.4 percent) with bradycardia-asystole events [6]. In the WEARIT-II registry, 6 of 2000 patients (0.3 percent) had asystole, and all three of the deaths that occurred while wearing the WCD during the study (0.2 percent) occurred following an asystole event [7]. The WCD cannot provide antitachycardia pacing for VT, which can reduce patient shocks, when effective. When considering these limitations, an implantable cardioverter-defibrillator (ICD) would be preferred, if indicated, in a patient who is pacemaker-dependent or in whom antitachycardia pacing is desired as the initial therapy for VT. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions".) Use in patients with a preexisting permanent pacemaker With certain precautions, the WCD can be used in patients with a preexisting permanent pacemaker. The manufacturer recommends that the device not be worn if the pacemaker stimulus artifact exceeds 0.5 millivolts, as this may mask underlying ventricular fibrillation and prevent appropriate device therapy. Conversely, the VT threshold of the WCD should be set higher than the maximal pacing rate to avoid an inappropriate WCD shock due to oversensing paced beats. Following any WCD shock, the patient's pacemaker should be interrogated to ensure that there has been no damage to the pacemaker or any changes in the pacemaker setting. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 15/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate Inappropriate shocks Both the WCD and the ICD may inappropriately deliver shocks due to electronic noise, device malfunction, or detection of supraventricular tachycardia above the preprogrammed rate criteria. Studies of ICDs have reported an incidence of inappropriate shock of 0.2 to 2.3 percent of patients per month [32,45-51]. Comparable rates of inappropriate shocks have been reported among users of the WCD, with rates ranging from 0.5 to 1.4 percent per month [3-7]. In a systematic review and meta-analysis which included 33,242 patients from 28 studies (the randomized VEST trial and 27 nonrandomized studies), inappropriate shocks occurred at a rate of 2 per 100 persons over three months (0.67 percent per month) [18]. Inappropriate shocks with a WCD can be potentially reduced due to the ability to abort shocks while awake by pressing response buttons. (See 'Avoiding inappropriate shocks' above.) Patient compliance and complaints Patients may not comply with wearing the WCD for a variety of reasons, chief among them device size and weight, skin rash, itching, and problems sleeping. However, efficacy of the WCD in the prevention of sudden cardiac death is highly dependent on patient compliance and appropriate use of the device [3-5,7]. In the WEARIT/BIROAD study, 23 percent of the 289 subjects withdrew before reaching a study endpoint, with size and weight of the monitor being the most frequent reason for withdrawal [3]. Skin rash and/or itching were also reported by 6 percent of patients. In the US postmarket study, median and mean daily use were 21.7 hours and 19.9 hours, respectively [5]. Daily use was >90 percent (>21.6 hours) in 52 percent of patients and >80 percent (>19.2 hours) in 71 percent of patients. Longer duration of monitoring correlated with higher compliance rates. WCD use was stopped prematurely in 14 percent, primarily because of comfort issues related to the size and weight of the WCD. In the WEARIT-II registry, median daily use was 22.5 hours [7]. Similar to the US postmarket study, longer duration of monitoring (15 or more days) was associated with higher rates of compliance. In the nationwide German cohort, median daily use among 6043 patients was 23.1 hours for a median of 59 days [8]. Lower rates of compliance were reported in a study of 147 patients from two academic medical centers in Boston, in which median daily use was 21 hours for a median of 50 days [52]. In an international registry of 708 patients, appropriate WCD shock was documented in 2.2 percent, inappropriate shock in 0.5 percent, and mean wear time was 21.2 4.3 hours/day (and was lower in younger patients) [53]. https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 16/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate In the WEARIT-France cohort study of 1157 patients, median daily wear time was 23.4 hours, with younger age associated with lower compliance [54]. In the VEST randomized trial after MI, median and mean daily wear times were only 18 and 14 hours, respectively, with over half of patients assigned to the WCD not wearing it by the end of the 90-day study [24]. Among 48 total deaths in the WCD group, only 12 patients (25 percent) were wearing the WCD at the time of death. In the as-treated and per-protocol analysis of VEST [25], better WCD compliance was predicted by cardiac arrest during index MI, higher creatinine, diabetes, prior heart failure, ejection fraction 25 percent, Polish enrolling center, and number of WCD alarms. Worse compliance was associated with being divorced, Asian race, higher body mass index, prior PCI, or any WCD shock. In a study of 130 patients with an ICD and fitted with an ASSURE WCD programmed for detection only and followed for 30 days, median daily use was high at 23 hours [11]. Rates of WCD discontinuation appear similar to reported rates of compliance with other prescribed therapies. One study reported that 15 percent of patients stop using aspirin, ACE inhibitors and beta-blockers within 30 days of a MI [55]. Improved compliance and acceptance of the WCD may be seen with newer devices, which are 40 percent smaller in size and weight or which offer multiple sizes and gender-specific fitting. USE OF THE WCD IN CHILDREN In December 2015, the US Food and Drug Administration (FDA) approved the WCD for use in children, although the WCD was used off-label prior to FDA approval [56]. As such, there are relatively few peer-reviewed publications documenting experience with the WCD in children [57- 59]. In a retrospective review of all patients <18 years of age who were prescribed the WCD between 2009 and 2016 (n = 455 patients), median duration of use was 33 days and wear time 20.6 hours [59]. Eight patients received at least one shock (seven episodes of ventricular tachycardia/ventricular fibrillation [VT/VF] in six patients, two inappropriate shocks due to oversensing), with four of the seven episodes of VT/VF terminated with a single shock and all seven episodes successfully terminated by the WCD. There were seven deaths (1.5 percent); none were wearing the WCD at the time of death. Children require special attention to assure compliance and correct fitting for optimal use. A variety of device harness sizes are available, but the smallest option may still be too large for https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 17/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate smaller children. Additional data on clinical efficacy, compliance, and complications should be collected in children as WCD use increases. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) SUMMARY AND RECOMMENDATIONS Introduction The wearable cardioverter-defibrillator (WCD) is an external device capable of automatic detection and defibrillation of ventricular tachycardia (VT) or ventricular fibrillation (VF) ( picture 1). In cases where the need for an implantable cardioverter- defibrillator (ICD) is felt to be temporary or implantation of the ICD must be deferred, a WCD may be an acceptable alternative approach for the prevention of sudden cardiac death (SCD). (See 'Description and functions of the WCD' above.) Device functions In addition to delivering therapeutic shocks for life-threatening ventricular arrhythmias, the WCD stores data regarding arrhythmias, patient compliance with the device, and noise or interference with its proper functioning. Arrhythmia recordings from the WCD are available for clinician review once stored data are transmitted to the manufacturer's network. (See 'Storage of ECGs and compliance data' above.) Efficacy When worn properly, the WCD appears to be as effective as an ICD for the termination of VT and VF, with successful shocks occurring in nearly 100 percent of cases. In addition, inappropriate shock rates from the WCD appear to be comparable to and in some studies lower than those reported for ICDs. (See 'Efficacy in terminating VT/VF' above and 'Inappropriate shocks' above.) Indications The WCD is an option as temporary therapy for select patients with a high risk for SCD: Among patients with left ventricular ejection fraction (LVEF) 35 percent who are less than 40 days post-myocardial infarction (MI), we discuss the potential benefits and risks of WCD use and offer it to highly motivated patients with NYHA functional class II or III, or LVEF <30 percent and in NYHA class I, as these patients would be candidates for ICD https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 18/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate implantation after 40 days. Reevaluation of LVEF should occur one to three months after the MI. If LVEF remains 35 percent on follow-up assessment, despite appropriate medical therapy, ICD implantation is indicated and should be considered. (See 'Early post-MI patients with LV dysfunction' above and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) Among patients with LVEF 35 percent who have undergone coronary revascularization with coronary artery bypass graft (CABG) surgery in the past three months, we offer a WCD to highly motivated patients for primary prevention against SCD. LVEF should be reassessed three months following CABG. If a sustained ventricular tachyarrhythmia has occurred, or if the LVEF remains 35 percent three months after CABG, implantation of an ICD is usually indicated. (See 'Patients with LV dysfunction early after coronary revascularization' above and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) In selected patients with severe but potentially reversible cardiomyopathy, such as tachycardia- or myocarditis-associated cardiomyopathy, the WCD may be useful for the prevention of SCD due to ventricular arrhythmias while awaiting improvement in LV function, ICD implantation, or if needed, cardiac transplantation. (See 'Newly diagnosed nonischemic cardiomyopathy' above.) Patients with severe heart failure awaiting heart transplantation represent a group at particularly high risk for SCD in whom ICD implantation is often recommended. The WCD may be a reasonable noninvasive alternative approach, particularly for patients whose anticipated waiting time to transplant is short if an ICD is not already present. (See 'Bridge to heart transplant' above.) Some patients with an indication for an ICD may require a delay in ICD implantation due to comorbid conditions (ie, infection, recovery from surgery, lack of vascular access). Additionally, some patients who have an ICD need it removed due to infection. In such patients, the WCD may provide protection against ventricular tachyarrhythmias until an ICD can be implanted or reimplanted. (See 'Bridge to indicated or interrupted ICD therapy' above.) Device limitations Limitations of the WCD (compared with a traditional ICD) include the lack of pacemaker functionality, the requirement for patient interaction and compliance, and potential discomfort due to the size and weight of the device. (See 'Limitations and precautions' above.) https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 19/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Sharma PS, Bordachar P, Ellenbogen KA. Indications and use of the wearable cardiac defibrillator. Eur Heart J 2016. 2. Reek S, Geller JC, Meltendorf U, et al. Clinical efficacy of a wearable defibrillator in acutely terminating episodes of ventricular fibrillation using biphasic shocks. Pacing Clin Electrophysiol 2003; 26:2016. 3. Feldman AM, Klein H, Tchou P, et al. Use of a wearable defibrillator in terminating tachyarrhythmias in patients at high risk for sudden death: results of the WEARIT/BIROAD. Pacing Clin Electrophysiol 2004; 27:4. 4. Klein HU, Meltendorf U, Reek S, et al. Bridging a temporary high risk of sudden arrhythmic death. Experience with the wearable cardioverter defibrillator (WCD). Pacing Clin Electrophysiol 2010; 33:353. 5. Chung MK, Szymkiewicz SJ, Shao M, et al. Aggregate national experience with the wearable cardioverter-defibrillator: event rates, compliance, and survival. J Am Coll Cardiol 2010; 56:194. 6. Epstein AE, Abraham WT, Bianco NR, et al. Wearable cardioverter-defibrillator use in patients perceived to be at high risk early post-myocardial infarction. J Am Coll Cardiol 2013; 62:2000. 7. 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Prediction of long-term mortality after percutaneous coronary intervention in older adults: results from the National Cardiovascular Data Registry. Circulation 2012; 125:1501. 29. Shahian DM, O'Brien SM, Sheng S, et al. Predictors of long-term survival after coronary artery bypass grafting surgery: results from the Society of Thoracic Surgeons Adult Cardiac Surgery Database (the ASCERT study). Circulation 2012; 125:1491. 30. Zishiri ET, Williams S, Cronin EM, et al. Early risk of mortality after coronary artery revascularization in patients with left ventricular dysfunction and potential role of the wearable cardioverter defibrillator. Circ Arrhythm Electrophysiol 2013; 6:117. 31. Verdino RJ. The wearable cardioverter-defibrillator: lifesaving attire or "fashion faux pas?". J Am Coll Cardiol 2010; 56:204. 32. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004; 350:2151. 33. Makati KJ, Fish AE, England HH, et al. Equivalent arrhythmic risk in patients recently diagnosed with dilated cardiomyopathy compared with patients diagnosed for 9 months or more. Heart Rhythm 2006; 3:397. 34. Singh M, Wang NC, Jain S, et al. Utility of the Wearable Cardioverter-Defibrillator in Patients With Newly Diagnosed Cardiomyopathy: A Decade-Long Single-Center Experience. J Am Coll Cardiol 2015; 66:2607. 35. Barsheshet A, Kutyifa V, Vamvouris T, et al. Study of the wearable cardioverter defibrillator in advanced heart-failure patients (SWIFT). J Cardiovasc Electrophysiol 2017; 28:778. 36. Salehi N, Nasiri M, Bianco NR, et al. The Wearable Cardioverter Defibrillator in Nonischemic Cardiomyopathy: A US National Database Analysis. Can J Cardiol 2016; 32:1247.e1. 37. Duncker D, K nig T, Hohmann S, et al. Avoiding Untimely Implantable Cardioverter/Defibrillator Implantation by Intensified Heart Failure Therapy Optimization https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 22/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate Supported by the Wearable Cardioverter/Defibrillator-The PROLONG Study. J Am Heart Assoc 2017; 6. 38. Saltzberg MT, Szymkiewicz S, Bianco NR. Characteristics and outcomes of peripartum versus nonperipartum cardiomyopathy in women using a wearable cardiac defibrillator. J Card Fail 2012; 18:21. 39. Lang CC, Hankins S, Hauff H, et al. Morbidity and mortality of UNOS status 1B cardiac transplant candidates at home. J Heart Lung Transplant 2003; 22:419. 40. Opreanu M, Wan C, Singh V, et al. Wearable cardioverter-defibrillator as a bridge to cardiac transplantation: A national database analysis. J Heart Lung Transplant 2015; 34:1305. 41. Gronda E, Bourge RC, Costanzo MR, et al. Heart rhythm considerations in heart transplant candidates and considerations for ventricular assist devices: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates 2006. J Heart Lung Transplant 2006; 25:1043. 42. Cantillon DJ, Tarakji KG, Kumbhani DJ, et al. Improved survival among ventricular assist device recipients with a concomitant implantable cardioverter-defibrillator. Heart Rhythm 2010; 7:466. 43. Wan C, Herzog CA, Zareba W, Szymkiewicz SJ. Sudden cardiac arrest in hemodialysis patients with wearable cardioverter defibrillator. Ann Noninvasive Electrocardiol 2014; 19:247. 44. Wan C, Szymkiewicz SJ, Klein HU. The impact of body mass index on the wearable cardioverter defibrillator shock efficacy and patient wear time. Am Heart J 2017; 186:111. 45. Sweeney MO, Wathen MS, Volosin K, et al. Appropriate and inappropriate ventricular therapies, quality of life, and mortality among primary and secondary prevention implantable cardioverter defibrillator patients: results from the Pacing Fast VT REduces Shock ThErapies (PainFREE Rx II) trial. Circulation 2005; 111:2898. 46. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008; 359:1009. 47. Daubert JP, Zareba W, Cannom DS, et al. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II: frequency, mechanisms, predictors, and survival impact. J Am Coll Cardiol 2008; 51:1357. 48. Klein RC, Raitt MH, Wilkoff BL, et al. Analysis of implantable cardioverter defibrillator therapy in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. J Cardiovasc Electrophysiol 2003; 14:940. 49. Wilkoff BL, Ousdigian KT, Sterns LD, et al. A comparison of empiric to physician-tailored programming of implantable cardioverter-defibrillators: results from the prospective https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 23/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate randomized multicenter EMPIRIC trial. J Am Coll Cardiol 2006; 48:330. 50. Wilkoff BL, Williamson BD, Stern RS, et al. Strategic programming of detection and therapy parameters in implantable cardioverter-defibrillators reduces shocks in primary prevention patients: results from the PREPARE (Primary Prevention Parameters Evaluation) study. J Am Coll Cardiol 2008; 52:541. 51. Wilkoff BL, Hess M, Young J, Abraham WT. Differences in tachyarrhythmia detection and implantable cardioverter defibrillator therapy by primary or secondary prevention indication in cardiac resynchronization therapy patients. J Cardiovasc Electrophysiol 2004; 15:1002. 52. Leyton-Mange JS, Hucker WJ, Mihatov N, et al. Experience With Wearable Cardioverter- Defibrillators at 2 Academic Medical Centers. JACC Clin Electrophysiol 2018; 4:231. 53. El-Battrawy I, Kovacs B, Dreher TC, et al. Real life experience with the wearable cardioverter- defibrillator in an international multicenter Registry. Sci Rep 2022; 12:3203. 54. Garcia R, Combes N, Defaye P, et al. Wearable cardioverter-defibrillator in patients with a transient risk of sudden cardiac death: the WEARIT-France cohort study. Europace 2021; 23:73. 55. Ho PM, Spertus JA, Masoudi FA, et al. Impact of medication therapy discontinuation on mortality after myocardial infarction. Arch Intern Med 2006; 166:1842. 56. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm466852.htm (Access ed on December 21, 2015). 57. Everitt MD, Saarel EV. Use of the wearable external cardiac defibrillator in children. Pacing Clin Electrophysiol 2010; 33:742. 58. Collins KK, Silva JN, Rhee EK, Schaffer MS. Use of a wearable automated defibrillator in children compared to young adults. Pacing Clin Electrophysiol 2010; 33:1119. 59. Spar DS, Bianco NR, Knilans TK, et al. The US Experience of the Wearable Cardioverter- Defibrillator in Pediatric Patients. Circ Arrhythm Electrophysiol 2018; 11:e006163. Topic 15824 Version 35.0 https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 24/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate GRAPHICS Wearable cardioverter-defibrillator The wearable cardioverter-defibrillator consists of a vest incorporating two defibrillation electrodes and four sensing electrocardiographic electrodes connected to a waist unit containing the monitoring and defibrillation electronics. Reproduced with permission from: ZOLL Medical Corporation. Copyright 2012. All rights reserved. Graphic 60103 Version 3.0 https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 25/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate Electrocardiogram sensing (A) Five ECG electrodes are positioned circumferentially around the torso at the level of the subxiphoid process, labelled left front (LF), right front (RF), left back (LB), right back (RB), and right leg drive (RLD). Red dashed arrows represent the four differential ECG vectors derived using RLD as a ground reference. (B) Garment interior depicting five embedded, cushioned ECG electrodes and defibrillation pads (two posterior and one anterior). ECG: electrocardiogram. From: Poole JE, Gleva MJ, Birgersdotter-Green U, et al. A wearable cardioverter de brillator with a low false alarm rate. J Cardiovasc Electrophysiol 2022; 33:831. https://onlinelibrary.wiley.com/doi/10.1111/jce.15417. Copyright 2022 Wiley Periodicals, LLC. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: [email protected] or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (https://onlinelibrary.wiley.com/). Graphic 140856 Version 1.0 https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 26/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate ASSURE WCD System noise management The A WCD employs three levels of protection to achieve a low false alarm rate due to noise. Level 1 (blue) minimize noise. Level 2 (red) detect and remove noise that does occur. Level 3 (yellow) allow time for remaining noise to subside before alarming. A-WCD: ASSURE WCD System; VT: ventricular tachycardia; VF: ventricular fibrillation; ECG: electrocardiogram. From: Poole JE, Gleva MJ, Birgersdotter-Green U, et al. A wearable cardioverter de brillator with a low false alarm rate. J Cardiovasc Electrophysiol 2022; 33:831. https://onlinelibrary.wiley.com/doi/10.1111/jce.15417. Copyright 2022 Wiley Periodicals, LLC. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: [email protected] or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (https://onlinelibrary.wiley.com/). Graphic 140843 Version 1.0 https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 27/28 7/6/23, 11:04 AM Wearable cardioverter-defibrillator - UpToDate Contributor Disclosures Mina K Chung, MD No relevant financial relationship(s) with ineligible companies to disclose. Richard L Page, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/wearable-cardioverter-defibrillator/print 28/28

7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Acquired long QT syndrome: Clinical manifestations, diagnosis, and management : Charles I Berul, MD : Samuel Asirvatham, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 06, 2023. INTRODUCTION The long QT syndrome (LQTS) is a disorder of myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1). This syndrome is associated with a characteristic life-threatening form of polymorphic ventricular tachycardia known as torsades de pointes (TdP) ( waveform 2A-B). LQTS may be either congenital or acquired. Acquired LQTS usually results from drug therapy ( table 1), although other factors such as hypokalemia, hypomagnesemia, and bradycardia can increase the risk of drug-induced LQTS. The clinical manifestations, diagnosis, and management of acquired LQTS will be reviewed here. The pathophysiology and causes of acquired LQTS, as well as the clinical manifestations, diagnosis, and management of congenital LQTS, are discussed elsewhere. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) (See "Congenital long QT syndrome: Epidemiology and clinical manifestations".) (See "Congenital long QT syndrome: Diagnosis".) (See "Congenital long QT syndrome: Treatment".) CLINICAL PRESENTATION https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 1/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Overview Acquired LQTS should be suspected in patients who have an ECG that shows a prolonged QTc in the presence of a known QT-prolonging factor(s) such as a medication or electrolyte disturbance. The clinical presentation of acquired LQTS is variable; however, only a minority of patients experience symptoms. Symptoms The vast majority of patients are asymptomatic and identified solely by QT prolongation on the ECG. A small minority of patients with acquired LQTS experience an arrhythmia (usually torsades de pointes [TdP]). For these patients, the type and intensity of symptoms will vary depending upon the rate and duration of the TdP and the presence or absence of significant comorbid conditions. While TdP is frequently self-terminating, if the arrhythmia persists, patients may present with sudden cardiac arrest. The definition of TdP is provided separately. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Definitions'.) Patients with TdP related to acquired LQTS who notice symptoms typically present with one or more of the following: Presyncope Most commonly, symptomatic patients will be lightheaded or presyncopal and may or may not report palpitations. Palpitations These may or may not be related to TdP. These can occur alone or with one or more of the other symptoms. Syncope Patients presenting with syncope typically have faster and more sustained ventricular arrythmias that lead to hypotension and associated hemodynamic compromise. Patients with syncope do not always have accompanying palpitations. Cardiac arrest This results from fast and sustained ventricular arrhythmia and may be a more common presentation in patients with comorbid conditions such as underlying structural or functional heart disease. Unstable presentation Patients present with hemodynamic compromise such as hypotension, altered mental status, chest pain, or heart failure, but they generally remain awake with a discernible pulse. Differentiation between a hemodynamically unstable versus stable patient is detailed separately. (See "Wide QRS complex tachycardias: Approach to the diagnosis", section on 'Assessment of hemodynamic stability'.) EVALUATION https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 2/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate The evaluation of all patients with suspected acquired LQTS includes a 12-lead ECG and a thorough history, including medications and recent changes in medications, along with bloodwork (this usually includes serum electrolytes, particularly potassium and magnesium, as well as a toxicology screen). ECG findings All patients with suspected acquired LQTS should have a 12-lead ECG performed, with manual measurement of intervals. Normal QTc ranges and general ECG principles The sinus rhythm QT interval should be measured manually on all available ECGs (including old ECGs for comparison, when available) using multiple leads (preferably leads II and V5) and then corrected for heart rate. The 2011 American Heart Association/American College of Cardiology (AHA/ACC) scientific statement on prevention of torsades de pointes (TdP) in hospital settings recommended that a QTc over the 99th percentile should be considered abnormally prolonged [1]. The normal range for the rate-corrected QT interval (QTc) is similar in males and females from birth until the start of adolescence, while after puberty and in adults, females have slightly longer QT intervals than males. Before puberty, a QTc <450 ms is considered normal, between 450 and 459 ms is borderline, and 460 ms is prolonged. After puberty in males, a QTc between 460 and 469 ms is borderline and 470 ms is considered prolonged. In postpubertal females, 460 to 479 ms is borderline and 480 ms is considered prolonged. (See "Congenital long QT syndrome: Diagnosis", section on 'QT rate correction'.) The specific technique of measuring the QT interval, including consideration of U waves and intraventricular conduction delay, is discussed separately. (See "ECG tutorial: ST and T wave changes", section on 'Prolonged QT interval'.) ECG findings in TdP Typical features of TdP include an antecedent prolonged QT interval, particularly in the last heart beat preceding the onset of the arrhythmia. Additional typical features include a ventricular rate of 160 to 250 beats per minute, irregular RR intervals, and a cycling of the QRS axis through 180 degrees every 5 to 20 beats [2,3]. TdP is usually short-lived and typically terminates spontaneously. However, most patients experience multiple episodes of the arrhythmia. These episodes of TdP can recur in rapid succession, potentially degenerating to ventricular fibrillation and sudden cardiac death [2,3]. History A careful history is important in diagnosing acquired LQTS since the diagnosis depends on the presence of a QT-prolonging factor. We collect the following history factors in patients with suspected acquired LQTS: Symptoms (See 'Symptoms' above.) https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 3/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Medications This includes the starting date, dose, and duration of use. The medication history should include all drugs (ie, prescription medications [either taken as prescribed or misused], over-the-counter medications, or supplements [including herbal medications]). (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Specific drug regimen' and "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Drugs that prolong the QT interval'.) Causes of electrolyte abnormalities Specific factors underlying hypokalemia or hypomagnesemia should be obtained. Examples are recent gastroenteritis or the initiation of diuretic therapy. (See "Hypomagnesemia: Causes of hypomagnesemia" and "Causes of hypokalemia in adults".) Kidney or liver disease (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Metabolic factors' and "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Metabolic abnormalities'.) Thyroid disease The association with LQTS has been described but is not well established [4]. If abnormal thyroid function is found, a second electrolyte or rate-related phenomena (hysteresis) may underlie TdP. Hypothermia This includes accidental and iatrogenic hypothermia from targeted temperature management in patients who have had a postcardiac arrest. (See "Accidental hypothermia in adults", section on 'Electrocardiographic changes' and "Intensive care unit management of the intubated post-cardiac arrest adult patient", section on 'Adverse effects' and "Intensive care unit management of the intubated post-cardiac arrest adult patient", section on 'Electrocardiography and echocardiography'.) Bradycardia and bradyarrhythmia (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Bradyarrhythmias'.) Family history Taking a careful family and genetic history is important because congenital LQTS is important to distinguish from acquired LQTS given differing management strategies. In this regard, screening of family members is also important. (See 'Screening of family members' below.) History of eating disorders such as anorexia (See "Anorexia nervosa in adults and adolescents: Medical complications and their management", section on 'Functional changes'.) Laboratory tests Basic metabolic panel including serum electrolytes (eg, potassium and magnesium) with liver and kidney function tests should be obtained. If illicit drug or medication https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 4/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate misuse is suspected, toxicology testing can be obtained. DIAGNOSIS Diagnostic criteria The diagnosis of acquired LQTS can be made in a patient with sufficient QT prolongation on an ECG who is taking a medication or has another cause of QT prolongation (ie, hypokalemia, hypomagnesemia, ischemia, hypothermia). Ideally, the diagnosis is made following review of a full 12-lead ECG. Sometimes a single-lead rhythm strip is adequate if a full 12-lead ECG cannot be obtained. The acquired QT prolongation is typically reversed once the underlying etiology is removed or treated, such as discontinuation of an offending medication or correction of electrolyte derangements. Differential diagnosis The main differential diagnosis for acquired LQTS is congenital LQTS. Therefore, a careful family and genetic history is important. Acquired and congenital LQTS may be related since some patients who develop acquired LQTS have an inherited predisposition. Although these patients have abnormalities in repolarization, they do not have enough criteria to meet the definition of congenital LQTS. The diagnosis of congenital LQTS is discussed in detail separately. (See "Congenital long QT syndrome: Diagnosis".) INITIAL MANAGEMENT In all patients with acquired LQTS, we identify and treat any reversible underlying causes of long QT. The management of patients without torsades de pointes (TdP) differs from patients with TdP in terms of urgency of treatment. All patients The cornerstone of the management of patients with acquired LQTS is addressing the underlying cause of QT prolongation. This includes identifying and stopping a precipitating drug(s) and aggressive correction of any metabolic abnormalities, such as hypokalemia or hypomagnesemia [5]. Drugs that prolong the QT interval (see also www.crediblemeds.org/) should be avoided. These drugs typically inhibit IKr [6-19]. Therefore, in addition to stopping the QT-prolonging drug, correcting hypokalemia is important because a low serum potassium concentration enhances the degree of drug-induced inhibition of IKr, thereby increasing the QT interval [8]. For patients with multiple self-terminating episodes of TdP, the same therapies are utilized as for patients with a single episode (ie, intravenous [IV] magnesium, correction of metabolic/electrolyte derangements, and/or removal of any inciting medications), along with additional interventions to regularize the heart rate, which include overdrive atrial pacing and/or https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 5/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate IV isoproterenol infusion. Other antiarrhythmics are not commonly used for TdP. Specific therapies used are detailed below. Specific therapy for TdP (the ventricular arrhythmia typically seen in acquired LQTS) differs from congenital LQTS due to pathophysiologic differences between the two forms ( table 2). As an example, bradycardia is usually associated with TdP in acquired LQTS, whereas catecholamine surges trigger TdP in some types of congenital LQTS ( figure 1). (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Triggers of arrhythmia'.) Asymptomatic patients If the patient is on a medication that prolongs the QT interval, we make efforts to switch the patient to an alternative agent. If the patient has a strong medical requirement to be on the QT-prolonging medication, if they are truly asymptomatic (eg, no palpitations, presyncope, or syncope), and if they only have mild QT prolongation (QTc <500 ms and <60 ms increase from baseline, if available) without TdP, we may choose to monitor them in an outpatient setting. Specific protocols for such management have not been established, but we suggest intermittent monitoring with ECGs and Holter recordings, particularly at times of dose changes. Asymptomatic patients with long QT intervals should also have laboratory testing to evaluate for electrolyte abnormalities (eg, potassium, magnesium). Such abnormalities should be corrected as necessary. Patients with palpitations The cause of palpitations in a patient with LQTS should be quickly identified with careful history taking and Holter monitoring. If the patient is found to have TdP, management of this malignant arrythmia is discussed below. (See 'Patients with acute TdP' below.) Patients with presyncope or syncope Patients with prolonged QT with syncope (without documented TdP) or ECG signs of instability (ventricular ectopy, T wave alternans, atrioventricular block, or QRS widening) should be admitted for telemetry observation during withdrawal of the toxic agent (with immediate availability of an external defibrillator) and treatment of arrhythmias if indicated. In addition, admission and monitoring during drug withdrawal is suggested for patients with markedly prolonged QTc (>500 milliseconds) or an increase in QTc of at least 60 milliseconds compared with the predrug baseline value [1]. Patients with acute TdP Initial measures Patients with TdP should have an immediate assessment of the symptoms, vital signs, and level of consciousness to determine if they are hemodynamically stable or https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 6/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate unstable. While the assessment of hemodynamic status is being performed by a clinician, other members of the healthcare team should to the following: Attach the patient to a continuous cardiac monitor Establish IV access Obtain a 12-lead ECG Administer supplemental oxygen Send blood for appropriate initial studies Unstable patients In unstable patients, emergency management is required ( algorithm 1), and treatment should be promptly administered ( algorithm 2). In parallel, underlying etiology and treatment for precipitating factors should be determined. (See 'Unstable presentation' above.) Stable patients Patients with TdP who are initially stable may rapidly become unstable, particularly in the setting of extremely rapid heart rates (greater than 200 beats per minute) or significant underlying cardiac comorbidities. Emergency management should be anticipated in these patients in case it becomes necessary to rapidly deliver it. Such patients should remain in a monitored setting during evaluation and management. Magnesium therapy For all patients with TdP, IV magnesium sulfate is first-line therapy since it is highly effective for both the treatment and prevention of recurrence of long QT-related ventricular ectopic beats or TdP [2,3,20]. We usually administer this prior to cardioversion, but it can also be given afterwards. Evidence supporting the specific timing of magnesium is lacking. Treatment with magnesium is effective even without shortening of the QT interval and is beneficial even in patients with normal serum magnesium concentrations at baseline. The rate of magnesium infusion is slower when the patient has a pulse, as rapid magnesium infusion can cause hypotension and asystole. Adults with TdP and pulse The standard regimen for an adult is a 1 to 2 g IV bolus of magnesium sulfate (2 to 4 mL of 50% solution [500 mg/mL]) mixed with D5W to a total volume of 10 mL or more (eg, 50 to 100 mL over 15 minutes) [20,21]. If no response is seen or TdP recurs, the magnesium sulfate dose may be repeated immediately to a total of 4 grams in one hour. Use of continuous infusion (as an adjunct to bolus dosing) varies among clinicians. Some clinicians administer a continuous infusion of 0.5 to 1 g/hour (8 to 16 mg/min) if TdP persists after one or more bolus doses. Adults with TdP and no pulse Magnesium is administered in conjunction with electrical cardioversion/defibrillation. A dose of 1 to 2 g magnesium sulfate (2 to 4 mL of 50% solution [500 mg/mL]) is diluted in 10 mL D5W and administered as a bolus over one to two https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 7/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate minutes; the intraosseous route is used if IV is not available. If Tdp recurs or the QTc remains prolonged, some experts administer up to two additional 2 g bolus doses as needed (total maximum dose of 6 g). Children The bolus dose in children is 25 to 50 mg/kg; there are no published data on IV maintenance dosing in children. For patients with a single episode of TdP, treatment with IV magnesium along with correction of metabolic/electrolyte derangements and/or removal of any inciting medications may be sufficient. The patient should be carefully monitored until electrolytes are normalized and the QT interval nearly normalizes. Patients who do not respond to magnesium Pacing For patients with long QT related TdP who do not respond to IV magnesium, we use temporary transvenous overdrive pacing (atrial or ventricular) [2,3]. In patients with a pre-existing permanent pacemaker, we may reprogram the device to increase the pacing rate. In patients with a pre-existing implantable cardioverter-defibrillator (ICD), we may have the ICD reprogrammed to a prolonged detection time, thereby delaying ICD shock for episodes of TdP that may self-terminate. When the patient is stabilized with the temporary wire, we lower the pacing rate and watch for any return of TdP. Usually, the temporary wire will not be needed for longer than one to two days. If the patient requires temporary pacing in order to suppress TdP for longer than two days, this is usually an indication that the patient will need a permanent pacemaker. Only in rare circumstances, if transvenous pacing is not readily available, transcutaneous pacing may be performed as a temporizing measure. However, the patient must be fully sedated, as transcutaneous pacing is very painful in a patient who is awake. For children over age 5 and adults, pacing at rates of approximately 100 beats per minute will decrease the dispersion of refractoriness, decrease the development of early afterdepolarizations, and may shorten the surface QT interval, especially if there is an associated bradycardia. The efficacy of overdrive pacing was illustrated in a report of nine patients with life- threatening ventricular arrhythmias and drug-induced LQTS [22]. Acceleration of the heart rate produced immediate suppression of all arrhythmias, with a reduction in the QT interval from 0.65 to 0.50 seconds. Similar findings were noted in another small series [23]. Isoproterenol Although we favor placement of a temporary pacemaker in the treatment of most cases of TdP that do not respond to magnesium, isoproterenol can be used as a https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 8/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate temporizing measure prior to pacing. Isoproterenol increases the sinus rate and decreases the QT interval [2,3,24]. It should be noted that if ventricular tachycardia is misdiagnosed as TdP, isoproterenol will worsen the ventricular tachycardia by increasing the heart rate. The initial dose of isoproterenol is 0.05 to 0.1 mcg/kg/min in children and 2 mcg/min in adults, then titrated to achieve a heart rate of 100 beats per minute. Other therapy Alkalinization of the plasma via the administration of sodium bicarbonate is useful when TdP is due to quinidine [25]. (See "Major side effects of class I antiarrhythmic drugs", section on 'Cardiovascular toxicity' and "Enhanced elimination of poisons", section on 'Urinary alkalinization'.) Therapies with less evidence supporting their use Potassium In a single study, an IV infusion of potassium was shown to be beneficial even in patients with normal serum potassium. This was illustrated in a report of 20 normokalemic patients with QT prolongation due to quinidine or heart failure [26]. The administration of IV potassium (0.5 mEq/kg to a maximum of 40 mEq) raised the plasma potassium concentration by 0.7 mEq/L, reversed QT prolongation and QT morphologic changes (U waves and bifid T waves), and decreased QT dispersion. It is uncertain, however, if this therapy is effective for preventing or reversing TdP; therefore, we reserve using these medications for selected patients with clinically refractory TdP and would not give IV potassium if the serum level was in the normal range. Class IB antiarrhythmic drugs Medications such as lidocaine and phenytoin shorten the action potential duration and, based upon small case series, may be effective in the acute management of TdP and ventricular fibrillation [27-31]. They appear to be less predictably effective than pacing or isoproterenol [3,27]. Therefore, we reserve using these medications for selected patients with clinically refractory TdP. LONG-TERM MANAGEMENT Patients with acquired LQTS should be educated about the culprit drugs, other QT-prolonging drugs (including being provided with a list, available at www.crediblemeds.org/), and potential drug-drug interactions [1]. Additional information can also be found using the Lexicomp drug interactions tool. In some patients, drug-associated LQTS appears to represent a concealed form of congenital LQTS in which a pathogenic variant in one of the LQTS genes is clinically inapparent until the patient is exposed to a particular drug or other predisposing factor https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 9/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate (eg, hypokalemia or hypomagnesemia). If appropriate, the patient should be referred for genetic testing. (See "Congenital long QT syndrome: Pathophysiology and genetics".) A permanent pacemaker may be required in the occasional patient with a chronic bradyarrhythmia (due to sinus node dysfunction or atrioventricular block) who has bradycardia- or pause-dependent TdP ( table 3). (See "Permanent cardiac pacing: Overview of devices and indications".) PROGNOSIS OF TDP Among patients with TdP, the in-hospital and one-year mortality rates are relatively high. In a nested case control study from a genetics cohort of over 110,000 patients from an integrated health system, 56 patients with TdP were studied; their in-hospital and one-year mortality rates were 11 and 25 percent, respectively [32]. SCREENING OF FAMILY MEMBERS In addition to treating the underlying cause, thorough history and ECG screening of immediate family members are recommended because of the potential for unmasking an inherited form and, therefore, the potential for other family members to harbor mutations causing congenital LQTS. (See "Congenital long QT syndrome: Diagnosis" and "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Underlying pathogenic variant in a long QT syndrome gene'.) PRECAUTIONS FOR ANY PATIENT STARTING QT-PROLONGING DRUGS For any patient who is treated with drugs that have been associated with LQTS ( table 1) (see also www.crediblemeds.org/), the following recommendations have been made [33]: Risk factors Caution should be used when prescribing a drug that prolongs the QT interval in patients with one or more risk factors (eg, diuretic therapy, electrolyte abnormalities, kidney disease, etc). Decisions regarding use of a QT-prolonging drug should be based upon an individualized risk-benefit analysis. Alternative agents that do not prolong the QT interval should be considered. https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 10/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate The use of more than one QT-prolonging drug should be avoided whenever possible, as this is a common risk factor for drug-induced TdP. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Risk factors for drug-induced long QT syndrome'.) ECG monitoring A baseline ECG to detect prolongation of the QT interval should be obtained prior to the administration of the drug and during the course of treatment. The 2011 American Heart Association/American College of Cardiology (AHA/ACC) scientific statement on prevention of TdP suggests a strategy of documenting the QTc interval before and at least every 8 to 12 hours after the initiation, increased dose, or overdose of QT- prolonging drugs [1]. If QTc prolongation is observed, more frequent measurements are recommended. (See 'ECG findings' above.) The duration of QTc monitoring depends upon the duration of treatment with the QT- prolonging drug and the drug half-life. Once the patient is on a steady state of the drug, an ECG should be done to measure their QTc. Educating patients Patients who are taking QT-prolonging drugs should be instructed to promptly report any new symptoms including palpitations, syncope, or near-syncope. They should also report clinical changes that could lead to hypokalemia, such as gastroenteritis or the initiation of diuretic therapy. Any identified electrolyte abnormalities should be promptly corrected in order to minimize the risk of arrhythmias. TDP DECISION SUPPORT TOOL A study showed that a clinical decision support tool programmed to appear when prescribers attempt to order medications for patients with risk factors for TdP may help identify high-risk patients and lead to clinical responses that could potentially prevent TdP [34]. The decision support tool was embedded in the electronic medical record system of a large healthcare system in 30 hospitals. The tool included a risk advisory that was programmed to appear when prescribers attempted to order medications with a known risk of TdP in such patients with a modified Tisdale QT risk score 12 (The modified Tisdale is a validated TdP risk score based on patient demographic and clinical and ECG characteristics) [35]. The advisory presented the clinician with the patient's QT risk score, delineated factors contributing to the score, and then presented relevant single click management options. Over an eight-month period, 7794 advisories were issued. The study reported the following findings with respect to risk advisories issued: https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 11/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Antibiotics most frequently triggered the advisory (in 33 percent of advisories). More than one management action was taken for 35 percent of the advisories. The most common action was ordering an ECG (in 20 percent of all advisories). Medication orders were canceled in 10 percent of patients with an advisory. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Long QT syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Background Acquired long QT syndrome (LQTS) is a disorder of myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1). It usually results from drug therapy, hypokalemia, and/or hypomagnesemia ( table 1). (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Definitions'.) https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 12/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Clinical presentation The clinical presentation of acquired LQTS is variable; many patients are asymptomatic and identified solely by QT prolongation on the ECG, while a minority are symptomatic and present with presyncope, palpitations, syncope, and/or sudden cardiac arrest. (See 'Clinical presentation' above.) Evaluation The evaluation of all patients with suspected acquired LQTS includes a 12-lead ECG, a thorough history, and laboratory testing. (See 'Evaluation' above.) The history should include medications, recent medications changes, kidney or liver dysfunction symptoms, family history, and bloodwork (See 'History' above and 'Laboratory tests' above.) Diagnosis The diagnosis of acquired LQTS can be made in a patient with sufficient QT prolongation on the surface ECG in association with a medication or other clinical scenario (ie, hypokalemia or hypomagnesemia). In general, the cutpoints for abnormal QTc are the 99th percentile QTc values (470 ms in postpubertal males and 480 ms in postpubertal females). (See 'Diagnosis' above.) Precautions when starting a QT-prolonging medication It may be necessary to obtain a baseline and follow-up QT interval. We educate the patient on potential symptoms and ask them to report the symptoms should they arise. (See 'Precautions for any patient starting QT-prolonging drugs' above.) Management of patients without active torsades de pointes (TdP) Asymptomatic patients In such patients, we identify and treat any reversible underlying causes of long QT such as electrolyte disturbances and kidney or hepatic dysfunction. Any QT-prolonging medications should be stopped. (See 'Asymptomatic patients' above.) Palpitations In such patients, the cause of palpitations should be quickly identified with careful history taking and Holter monitoring. If the patient is found to have TdP, management of this malignant arrythmia is discussed elsewhere. (See 'Patients with palpitations' above.) Syncope If there is presyncope or syncope (without documented TdP) or ECG signs of instability (ventricular ectopy, T wave alternans, atrioventricular block, or QRS widening), the patient should be admitted for telemetry observation during withdrawal of the toxic agent (with immediate availability of an external defibrillator) and treatment of arrhythmias if indicated. (See 'Patients with presyncope or syncope' above.) https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 13/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Management of patients with acute TdP The initial management of patients with TdP varies depending on the hemodynamic stability of the patient. Emergency management is required in unstable patients ( algorithm 1), while additional time may be spent determining the etiology and treating any underlying precipitating factors in patients who are hemodynamically stable ( algorithm 2). (See 'Patients with acute TdP' above.) Hemodynamically unstable patients These patients are generally severely symptomatic or become pulseless. They require prompt emergency treatment ( algorithm 1). Initial treatment with antiarrhythmic medications, with the exception of intravenous (IV) magnesium, is not indicated for hemodynamically unstable or pulseless patients. Subsequent therapy is similar to that of hemodynamically stable patients with TdP. (See 'Unstable patients' above.) Hemodynamically stable patients These patients may become unstable rapidly and without warning. As such, therapy should be promptly provided to most patients. Initial therapy for patients with a single episode of TdP is IV magnesium along with correction of metabolic/electrolyte derangements and/or removal of any inciting medications. For patients with subsequent, multiple, self-terminating episodes of TdP, we use the same therapies as for patients with a single episode, along with additional interventions to slow the heart rate. These include overdrive atrial pacing and/or IV isoproterenol infusion. (See 'Initial measures' above and 'Patients who do not respond to magnesium' above.) Long-term management Patients with acquired LQTS should be educated about the culprit drugs, other QT-prolonging drugs (including being provided with a list, available at www.crediblemeds.org/), and potential drug-drug interactions. (See 'Long-term management' above.) ACKNOWLEDGMENT The editorial staff at UpToDate acknowledge Stephen Seslar MD, PhD, and the late Mark E. Josephson, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Drew BJ, Ackerman MJ, Funk M, et al. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 14/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Cardiology Foundation. Circulation 2010; 121:1047. 2. Passman R, Kadish A. Polymorphic ventricular tachycardia, long Q-T syndrome, and torsades de pointes. Med Clin North Am 2001; 85:321. 3. Khan IA. Long QT syndrome: diagnosis and management. Am Heart J 2002; 143:7. 4. Kannan L, Kotus-Bart J, Amanullah A. Prevalence of Cardiac Arrhythmias in Hypothyroid and Euthyroid Patients. Horm Metab Res 2017; 49:430. 5. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 6. Roden DM. Taking the "idio" out of "idiosyncratic": predicting torsades de pointes. Pacing Clin Electrophysiol 1998; 21:1029. 7. Kupershmidt S, Yang IC, Hayashi K, et al. The IKr drug response is modulated by KCR1 in transfected cardiac and noncardiac cell lines. FASEB J 2003; 17:2263. 8. Yang T, Roden DM. Extracellular potassium modulation of drug block of IKr. Implications for torsade de pointes and reverse use-dependence. Circulation 1996; 93:407. 9. Ridley JM, Milnes JT, Benest AV, et al. Characterisation of recombinant HERG K+ channel blockade by the Class Ia antiarrhythmic drug procainamide. Biochem Biophys Res Commun 2003; 306:388. 10. Jurkiewicz NK, Sanguinetti MC. Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide. Circ Res 1993; 72:75. 11. Yang T, Snyders DJ, Roden DM. Ibutilide, a methanesulfonanilide antiarrhythmic, is a potent blocker of the rapidly activating delayed rectifier K+ current (IKr) in AT-1 cells. Concentration-, time-, voltage-, and use-dependent effects. Circulation 1995; 91:1799. 12. Numaguchi H, Mullins FM, Johnson JP Jr, et al. Probing the interaction between inactivation gating and Dd-sotalol block of HERG. Circ Res 2000; 87:1012. 13. Kamiya K, Nishiyama A, Yasui K, et al. Short- and long-term effects of amiodarone on the two components of cardiac delayed rectifier K(+) current. Circulation 2001; 103:1317. 14. Daleau P, Lessard E, Groleau MF, Turgeon J. Erythromycin blocks the rapid component of the delayed rectifier potassium current and lengthens repolarization of guinea pig ventricular myocytes. Circulation 1995; 91:3010. https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 15/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate 15. Volberg WA, Koci BJ, Su W, et al. Blockade of human cardiac potassium channel human ether-a-go-go-related gene (HERG) by macrolide antibiotics. J Pharmacol Exp Ther 2002; 302:320. 16. Roy M, Dumaine R, Brown AM. HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine. Circulation 1996; 94:817. 17. Suessbrich H, Waldegger S, Lang F, Busch AE. Blockade of HERG channels expressed in

ECG, a thorough history, and laboratory testing. (See 'Evaluation' above.) The history should include medications, recent medications changes, kidney or liver dysfunction symptoms, family history, and bloodwork (See 'History' above and 'Laboratory tests' above.) Diagnosis The diagnosis of acquired LQTS can be made in a patient with sufficient QT prolongation on the surface ECG in association with a medication or other clinical scenario (ie, hypokalemia or hypomagnesemia). In general, the cutpoints for abnormal QTc are the 99th percentile QTc values (470 ms in postpubertal males and 480 ms in postpubertal females). (See 'Diagnosis' above.) Precautions when starting a QT-prolonging medication It may be necessary to obtain a baseline and follow-up QT interval. We educate the patient on potential symptoms and ask them to report the symptoms should they arise. (See 'Precautions for any patient starting QT-prolonging drugs' above.) Management of patients without active torsades de pointes (TdP) Asymptomatic patients In such patients, we identify and treat any reversible underlying causes of long QT such as electrolyte disturbances and kidney or hepatic dysfunction. Any QT-prolonging medications should be stopped. (See 'Asymptomatic patients' above.) Palpitations In such patients, the cause of palpitations should be quickly identified with careful history taking and Holter monitoring. If the patient is found to have TdP, management of this malignant arrythmia is discussed elsewhere. (See 'Patients with palpitations' above.) Syncope If there is presyncope or syncope (without documented TdP) or ECG signs of instability (ventricular ectopy, T wave alternans, atrioventricular block, or QRS widening), the patient should be admitted for telemetry observation during withdrawal of the toxic agent (with immediate availability of an external defibrillator) and treatment of arrhythmias if indicated. (See 'Patients with presyncope or syncope' above.) https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 13/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Management of patients with acute TdP The initial management of patients with TdP varies depending on the hemodynamic stability of the patient. Emergency management is required in unstable patients ( algorithm 1), while additional time may be spent determining the etiology and treating any underlying precipitating factors in patients who are hemodynamically stable ( algorithm 2). (See 'Patients with acute TdP' above.) Hemodynamically unstable patients These patients are generally severely symptomatic or become pulseless. They require prompt emergency treatment ( algorithm 1). Initial treatment with antiarrhythmic medications, with the exception of intravenous (IV) magnesium, is not indicated for hemodynamically unstable or pulseless patients. Subsequent therapy is similar to that of hemodynamically stable patients with TdP. (See 'Unstable patients' above.) Hemodynamically stable patients These patients may become unstable rapidly and without warning. As such, therapy should be promptly provided to most patients. Initial therapy for patients with a single episode of TdP is IV magnesium along with correction of metabolic/electrolyte derangements and/or removal of any inciting medications. For patients with subsequent, multiple, self-terminating episodes of TdP, we use the same therapies as for patients with a single episode, along with additional interventions to slow the heart rate. These include overdrive atrial pacing and/or IV isoproterenol infusion. (See 'Initial measures' above and 'Patients who do not respond to magnesium' above.) Long-term management Patients with acquired LQTS should be educated about the culprit drugs, other QT-prolonging drugs (including being provided with a list, available at www.crediblemeds.org/), and potential drug-drug interactions. (See 'Long-term management' above.) ACKNOWLEDGMENT The editorial staff at UpToDate acknowledge Stephen Seslar MD, PhD, and the late Mark E. Josephson, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Drew BJ, Ackerman MJ, Funk M, et al. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 14/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Cardiology Foundation. Circulation 2010; 121:1047. 2. Passman R, Kadish A. Polymorphic ventricular tachycardia, long Q-T syndrome, and torsades de pointes. Med Clin North Am 2001; 85:321. 3. Khan IA. Long QT syndrome: diagnosis and management. Am Heart J 2002; 143:7. 4. Kannan L, Kotus-Bart J, Amanullah A. Prevalence of Cardiac Arrhythmias in Hypothyroid and Euthyroid Patients. Horm Metab Res 2017; 49:430. 5. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 6. Roden DM. Taking the "idio" out of "idiosyncratic": predicting torsades de pointes. Pacing Clin Electrophysiol 1998; 21:1029. 7. Kupershmidt S, Yang IC, Hayashi K, et al. The IKr drug response is modulated by KCR1 in transfected cardiac and noncardiac cell lines. FASEB J 2003; 17:2263. 8. Yang T, Roden DM. Extracellular potassium modulation of drug block of IKr. Implications for torsade de pointes and reverse use-dependence. Circulation 1996; 93:407. 9. Ridley JM, Milnes JT, Benest AV, et al. Characterisation of recombinant HERG K+ channel blockade by the Class Ia antiarrhythmic drug procainamide. Biochem Biophys Res Commun 2003; 306:388. 10. Jurkiewicz NK, Sanguinetti MC. Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide. Circ Res 1993; 72:75. 11. Yang T, Snyders DJ, Roden DM. Ibutilide, a methanesulfonanilide antiarrhythmic, is a potent blocker of the rapidly activating delayed rectifier K+ current (IKr) in AT-1 cells. Concentration-, time-, voltage-, and use-dependent effects. Circulation 1995; 91:1799. 12. Numaguchi H, Mullins FM, Johnson JP Jr, et al. Probing the interaction between inactivation gating and Dd-sotalol block of HERG. Circ Res 2000; 87:1012. 13. Kamiya K, Nishiyama A, Yasui K, et al. Short- and long-term effects of amiodarone on the two components of cardiac delayed rectifier K(+) current. Circulation 2001; 103:1317. 14. Daleau P, Lessard E, Groleau MF, Turgeon J. Erythromycin blocks the rapid component of the delayed rectifier potassium current and lengthens repolarization of guinea pig ventricular myocytes. Circulation 1995; 91:3010. https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 15/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate 15. Volberg WA, Koci BJ, Su W, et al. Blockade of human cardiac potassium channel human ether-a-go-go-related gene (HERG) by macrolide antibiotics. J Pharmacol Exp Ther 2002; 302:320. 16. Roy M, Dumaine R, Brown AM. HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine. Circulation 1996; 94:817. 17. Suessbrich H, Waldegger S, Lang F, Busch AE. Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole. FEBS Lett 1996; 385:77. 18. Drolet B, Khalifa M, Daleau P, et al. Block of the rapid component of the delayed rectifier potassium current by the prokinetic agent cisapride underlies drug-related lengthening of the QT interval. Circulation 1998; 97:204. 19. Dumaine R, Roy ML, Brown AM. Blockade of HERG and Kv1.5 by ketoconazole. J Pharmacol Exp Ther 1998; 286:727. 20. Tzivoni D, Banai S, Schuger C, et al. Treatment of torsade de pointes with magnesium sulfate. Circulation 1988; 77:392. 21. Neumar RW, Otto CW, Link MS, et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122:S729. 22. DiSegni E, Klein HO, David D, et al. Overdrive pacing in quinidine syncope and other long QT-interval syndromes. Arch Intern Med 1980; 140:1036. 23. T tterman KJ, Turto H, Pellinen T. Overdrive pacing as treatment of sotalol-induced ventricular tachyarrhythmias (torsade de pointes). Acta Med Scand Suppl 1982; 668:28. 24. Keren A, Tzivoni D, Gavish D, et al. Etiology, warning signs and therapy of torsade de pointes. A study of 10 patients. Circulation 1981; 64:1167. 25. WASSERMAN F, BRODSKY L, KATHE JH, et al. The effect of molar sodium lactate in quinidine intoxication. Am J Cardiol 1959; 3:294. 26. Choy AM, Lang CC, Chomsky DM, et al. Normalization of acquired QT prolongation in humans by intravenous potassium. Circulation 1997; 96:2149. 27. Roden DM, Woosley RL, Primm RK. Incidence and clinical features of the quinidine- associated long QT syndrome: implications for patient care. Am Heart J 1986; 111:1088. 28. Assimes TL, Malcolm I. Torsade de pointes with sotalol overdose treated successfully with lidocaine. Can J Cardiol 1998; 14:753. 29. Takahashi N, Ito M, Inoue T, et al. Torsades de pointes associated with acquired long QT syndrome: observation of 7 cases. J Cardiol 1993; 23:99. https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 16/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate 30. Raehl CL, Patel AK, LeRoy M. Drug-induced torsade de pointes. Clin Pharm 1985; 4:675. 31. Vukmir RB, Stein KL. Torsades de pointes therapy with phenytoin. Ann Emerg Med 1991; 20:198. 32. Mantri N, Lu M, Zaroff JG, et al. Torsade de pointes: A nested case-control study in an integrated healthcare delivery system. Ann Noninvasive Electrocardiol 2022; 27:e12888. 33. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350:1013. 34. Gallo T, Heise CW, Woosley RL, et al. Clinician Responses to a Clinical Decision Support Advisory for High Risk of Torsades de Pointes. J Am Heart Assoc 2022; 11:e024338. 35. Tisdale JE, Jaynes HA, Kingery JR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes 2013; 6:479. Topic 116011 Version 26.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 17/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate GRAPHICS Single-lead electrocardiogram showing a prolonged QT interval The corrected QT interval (QTc) is calculated by dividing the QT interval (0.60 seconds) by the square root of the preceding RR interval (0.92 seconds). In this case, the QTc is 0.625 seconds (625 milliseconds). Graphic 77018 Version 7.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 18/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Single lead electrocardiogram (ECG) showing polymorphic ventricular tachycardia (VT) This is an atypical, rapid, and bizarre form of ventricular tachycardia that is characterized by a continuously changing axis of polymorphic QRS morphologies. Graphic 53891 Version 5.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 19/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Single lead electrocardiogram (ECG) showing torsades de pointes The electrocardiographic rhythm strip shows torsades de pointes, a polymorphic ventricular tachycardia associated with QT prolongation. There is a short, preinitiating RR interval due to a ventricular couplet, which is followed by a long, initiating cycle resulting from the compensatory pause after the couplet. Graphic 73827 Version 4.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 20/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial GnRH agonist/antagonist therapy ischemia or infarction, Hypomagnesemia Bilateral surgical orchiectomy Hypocalcemia Diuretic therapy via electrolyte disorders especially with Starvation particularly hypokalemia and hypomagnesemia prominent T-wave inversions Anorexia nervosa Herbs Liquid protein diets Cinchona (contains quinine), iboga (ibogaine), licorice extract in overuse via electrolyte disturbances Intracranial disease Hypothyroidism Bradyarrhythmias HIV infection Sinus node dysfunction Hypothermia Toxic exposure: Organophosphate insecticides AV block: Second or third degree Medications* High risk Adagrasib Cisaparide Lenvatinib Selpercatinib (restricted availability) Ajmaline Levoketoconazole Sertindole Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine Vandetanib Dofetilide (intracoronary) Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab ozogamacin Propafenone Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Carbetocin Erythromycin Ribociclib https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 21/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Certinib Escitalopram Levofloxacin Risperidone (systemic) Chloroquine Etelcalcetide Saquinavir Lofexidine Citalopram Fexinidazole Sevoflurane Meglumine Clarithromycin Flecainide Sparfloxacin antimoniate Clofazimine Floxuridine Sunitinib Midostaurin Clomipramine Fluconazole Tegafur Moxifloxacin Clozapine Fluorouracil Terbutaline Nilotinib (systemic) Crizotinib Thioridazine Olanzapine Flupentixol Dabrafenib Toremifene Ondansetrol (IV > Gabobenate dimeglumine Dasatinib Vemurafenib oral) Deslurane Voriconazole Osimertinib Gemifloxacin Domperidone Oxytocin Gilteritinib Doxepin Pazopanib Halofantrine Doxifluridine Pentamidine Haloperidol (oral) Pilsicainide Imipramine Pimozide Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole (systemic) Romidepsin Anagrelide Foscarnet Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- Glasdegib Mizolastine lumefantrine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine Nortriptyline Benperidol (rare reports) Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus Olodaterol (systemic) Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 22/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Leuprolide- Periciazine Tropisetron norethindrone Dexmedetomidine** Pimavanserin Vardenafil Levalbuterol Dolasetron Pipamperone Vilanterol Levomethadone Donepezil Pitolisant Vinflunine Lithium Efavirenz Ponesimod Voclosporin Loperamide overdose in Eliglustat Primaquine Vorinostat Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. [1,2] . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 23/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 24/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Treatment of torsades de pointes due to long QT syndrome Acquired LQTS Pharmacologic Magnesium sulfate Isoproterenol Lidocaine Phenytoin Sodium bicarbonate (for quinidine-related arrhythmia) Nonpharmacologic Temporary pacing (atrial or ventricular) Congenital LQTS Pharmacologic Beta blockers Mexiletine Nonpharmacologic Permanent dual chamber pacemaker Left cardiac sympathetic denervation (cardiothoracic sympathectomy) Implantable cardioverter-defibrillator Graphic 70083 Version 1.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 25/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Triggers for cardiac events in long QT syndrome are related to genotype In a study of 670 patients with long QT syndrome and known genotype, all symptomatic (syncope, aborted cardiac arrest, or sudden death), the occurrence of a lethal cardiac event (n = 110) provoked by a specific trigger (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced most of their events (90%) during exercise or emotion. These percentages were almost reversed among LQT2 and LQT3 patients who had most of their events during rest or sleep (63 and 80%, respectively); by contrast, they were at almost no risk of major events during exercise (arrows), which is explained by their having a normal I current. Ks ACA: aborted cardiac arrest; SCD: sudden cardiac death. Modi ed from: Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-speci c triggers for life-threatening arrhythmias. Circulation 2001; 103:89. Graphic 64239 Version 3.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 26/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Adult cardiac arrest algorithm https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 27/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 28/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Reprinted with permission. Highlights of the 2020 American Heart Association Guidelines for CPR and ECC. Copyright 2020 American Association, Inc. Graphic 129983 Version 9.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 29/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Acute management of torsades de pointes All patients with TdP should be treated with IV magnesium. TdP: torsades de pointes; IV: intravenous; ACLS: Advanced Cardiac Life Support; ECG: electrocardiogram. Refer to UpToDate content on ACLS in adults. Optimal timing of magnesium administration relative to cardioversion has not been determined. The rate o slower when the patient has a pulse, as rapid magnesium infusion can cause hypotension and asystole. https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 30/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Tests include basic metabolic panel (eg, serum electrolytes, potassium, and magnesium) with liver and kidn drug or medication misuse is suspected, toxicology testing can be obtained. Reduce the rate and watch for any recurrent TdP. Discontinue the pacing wire if there is no recurrent TdP (u Refer to UpToDate content for further information. The initial dose of isoproterenol in adults is 2 mcg/min and in children is 0.05 to 0.1 mcg/kg/min (maximum the dose is then titrated to achieve a heart rate of 100 beats per minute. Especially if TdP is secondary to quinidine. Graphic 140279 Version 2.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 31/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate ACC/AHA/HRS guideline summary: Indications for pacing to prevent tachycardia Class I - There is evidence and/or general agreement that pacing should be used to prevent tachycardia in the following setting: Sustained pause-dependent ventricular tachycardia (VT), with or without QT prolongation. (Level of Evidence: C) Class IIa - The weight of evidence or opinion is in favor of the usefulness of pacing to prevent tachycardia in the following setting: High-risk patients with congenital long QT syndrome. (Level of Evidence: C) Class IIb - The weight of evidence or opinion is less well established for the usefulness of pacing to prevent tachycardia in the following setting: Prevention of symptomatic, drug-refractory, recurrent atrial fibrillation in patients with coexisting sinus node dysfunction. (Level of Evidence: B) Class III - There is evidence and/or general agreement that pacing to prevent tachycardia is not useful in the following settings: Frequent or complex ventricular ectopic activity without sustained VT in the absence of the long QT syndrome. (Level of Evidence: C) Torsade de pointes VT due to reversible causes. (Level of Evidence: A) Adapted from Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation 2008; 117:e350. Graphic 80487 Version 2.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 32/33 7/6/23, 11:05 AM Acquired long QT syndrome: Clinical manifestations, diagnosis, and management - UpToDate Contributor Disclosures Charles I Berul, MD Patent Holder: PeriCor LLC [Pacemakers/defibrillators]. Grant/Research/Clinical Trial Support: Medtronic Inc [Pacemakers/defibrillators]. All of the relevant financial relationships listed have been mitigated. Samuel Asirvatham, MD Grant/Research/Clinical Trial Support: Medtronic [Defibrillators]; St Jude's [Sudden Cardiac Death]. Consultant/Advisory Boards: BioTronik [Defibrillators]; Boston Scientific [Sudden Cardiac Death]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/acquired-long-qt-syndrome-clinical-manifestations-diagnosis-and-management/print 33/33

7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Acquired long QT syndrome: Definitions, pathophysiology, and causes : Charles I Berul, MD : Samuel Asirvatham, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 21, 2022. INTRODUCTION Long QT syndrome (LQTS) is a disorder of myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1). This syndrome is associated with an increased risk of polymorphic ventricular tachycardia (VT) and a characteristic life-threatening cardiac arrhythmia also known as torsades de pointes (TdP) ( waveform 2A-B). LQTS may be either congenital or acquired. There is potential overlap between these two etiologies, as some people with acquired LQTS can have underlying pathogenic variants but do not meet all the clinical criteria for congenital LQTS. (See 'Underlying pathogenic variant in a long QT syndrome gene' below.) Acquired LQTS usually results from drug therapy, although a number of patient-specific and medication-related factors can enhance the risk of drug-induced LQTS. Other causes of acquired LQTS include electrolyte abnormalities, eating disorders, coronary artery disease, and bradyarrhythmias. In this topic, we review the definition, causes, and pathophysiology of acquired LQTS. The clinical manifestations, diagnosis, and management of congenital and acquired LQTS, as well as the genetics of congenital LQTS, are discussed elsewhere. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management" and "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Congenital long QT syndrome: Diagnosis" and "Congenital long QT syndrome: Treatment" and "Congenital long QT syndrome: Pathophysiology and genetics".) https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 1/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate DEFINITIONS Normal QT interval The normal range for the rate-corrected QT interval (QTc) is similar in males and females from birth until the start of adolescence, while after puberty and in adults, females have slightly longer QT intervals than males. Before puberty, a QTc <450 ms is considered normal, between 450 and 459 borderline, and 460 prolonged. After puberty in males, a QTc between 460 and 469 is borderline and 470 is considered prolonged. In post-pubertal females, 460 to 479 is borderline and 480 ms is considered prolonged. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'ECG findings'.) Polymorphic VT Polymorphic VT is defined as a ventricular rhythm faster than 100 beats per minute in adults with frequent variations of the QRS axis, morphology, or both [1,2]. Torsades de pointes Torsades de pointes (TdP) is a form of polymorphic VT that classically occurs in the setting of acquired or congenital QT interval prolongation and typically has a rate between 160 and 250 beats per minute [1,3]. In the specific case of TdP, these variations take the form of a progressive, sinusoidal, and cyclic alteration of the QRS axis ( waveform 2A-B). The peaks of the QRS complexes appear to "twist" around the isoelectric line of the recording, hence the name torsades de pointes or "twisting of the points." Typical features of TdP include an antecedent prolonged QT interval, particularly in the last beat preceding the onset of the arrhythmia. The stereotypical short-long-short sequence is an important trigger for initiation of TdP. Additional typical features include a ventricular rate of 160 to 250 beats per minute, irregular RR intervals, and a cycling of the QRS axis through 180 degrees every 5 to 20 beats [1,2]. TdP is usually short-lived and typically terminates spontaneously. However, most patients experience multiple episodes of the arrhythmia. These episodes of TdP can recur in rapid succession, potentially degenerating to ventricular fibrillation and sudden cardiac death (SCD) [1,2]. Potassium channels IK is the delayed rectifier cardiac potassium channel present in r cardiac myocytes. Many QT-prolonging drugs block the IK channel, which leads to r prolonged myocardial repolarization. Some medications can also impact the IKs channel and late sodium current, which may be important in the genesis of TdP. INCIDENCE https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 2/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate The incidence of acquired LQTS is uncertain because most available studies rely on selected cohorts rather than population-based studies. Additionally, the incidence of QT prolongation without torsades de pointes (TdP) is likely much higher than the incidence of TdP itself. Determining the absolute and comparative risk of the many drugs associated with QT prolongation is difficult, since most available data come from case reports or small observational series. Where available, drug-specific incidences are presented below. (See 'Drugs that prolong the QT interval' below.) Hospitalized patients In one retrospective review of over 41,649 hospital admissions over six months, 0.7 percent of patients had a QTc >500 milliseconds. Of these, less than 6 percent had severe QT prolongation, syncope, or a life-threatening arrhythmia [4]. In a separate study of patients in a tertiary-care hospital, the risk of TdP ranged from 0.1 to 0.3 percent per year; 46 percent of cases were from drug-induced TdP [5]. People with SCD Medication-related acquired LQTS may underlie a substantial proportion of SCD in the United States; SCD accounts for 5 to 15 percent of annual deaths in the United States. In a study of 525 autopsy-confirmed, non-traumatic sudden deaths from San Francisco County, over half of the individuals had been taking at least one QT-prolonging medication [6]. In this study, one-third of people who had experienced a drug overdose as a cause of SCD were taking a QT-prolonging medication. In contrast, a study from the Netherlands suggested a lower contribution of QT-prolonging medications in SCD cases. Among over 500,000 people, 775 cases of SCD were identified over a period of nine years. Among persons with SCD, 3.1 percent were using a QT- prolonging drug [7]. Current use of any noncardiac QT-prolonging drug was associated with a significantly increased risk of SCD (adjusted odds ratio [OR] 2.7), and the highest risk was associated with antipsychotic drugs (adjusted OR 5.0). Possible reasons for the differences between these two studies are population differences in causes of SCD, differences in accuracy of SCD definitions between the studies (the former had direct autopsy confirmation of SCD cases), and a 15-year difference between the studies, during which more QT-prolonging medications have been recognized. PATHOPHYSIOLOGY Acquired LQTS is most often due to drugs ( table 1). The proposed mechanism for drug- induced torsades de pointes (TdP) is the development of early afterdepolarizations and triggered activity resulting from prolonged repolarization [8]. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs", section on 'Triggered activity'.) https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 3/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate There are thought to be pathophysiologic differences between congenital and acquired LQTS, though these differences are not absolute. Pathophysiologic mechanisms of acquired LQTS and some differences with the congenital syndrome are discussed here. The pathophysiologies of both types of LQTS are described in more detail separately. (See "Congenital long QT syndrome: Pathophysiology and genetics", section on 'Pathophysiology'.) KCNH2 blockade Nearly all drugs that produce LQTS do so by blocking the IKr current, which is mediated by a potassium channel in myocardial cells. This potassium channel is encoded by the KCNH2 gene [9-28]. KCNH2 pathogenic genetic variants are common in both drug-induced LQTS and in some forms of congenital LQTS. (See "Congenital long QT syndrome: Pathophysiology and genetics".) The relationship between the degree of drug-induced KCNH2 blockade and the risk of ventricular arrhythmias and SCD was described in a study of over 280,000 cases of reported adverse drug reactions from the International Drug Monitoring Program of the World Health Organization [29]. For 54 medications associated with QT prolongation and TdP, the investigators studied the association between medication-specific degree of KCNH2 blockade and a composite endpoint of cardiac arrest, sudden death, TdP, VT, and ventricular fibrillation. The medications with the greatest chance of toxicity based on KCNH2 blockade were cisapride, sparfloxacin, quinidine, ibutilide, and thioridazine. There was a linear relationship between the measure of toxicity in this study and the reported incidence of a composite endpoint of cardiac arrest, sudden death, TdP, VT, and ventricular fibrillation. Reverse use dependence The association between bradycardia and antiarrhythmic drug- induced TdP is thought to be related to a property of some of these drugs called "reverse use dependence," which is defined as the inverse correlation between the heart rate and QT interval [30]. As a result, the QT interval decreases as the heart rate increases and lengthens as the heart rate slows. This explains why drug-induced TdP is more commonly seen with bradycardia or immediately following sinus pauses. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Whereas TdP in acquired LQTS is triggered by bradycardia and pauses, some forms of congenital LQTS can follow a sudden adrenergic surge (eg, exercise, emotional stress, or arousal). This can be a typical clinical presentation in congenital LQTS type 1 and, to a lesser degree, type 2 ( figure 1). (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Triggers of arrhythmia'.) https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 4/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Reverse use dependence may be mediated at least in part by changes in the extracellular potassium concentration. Virtually all of the drugs that produce LQTS act by blocking the outward IK current, which is mediated by the potassium channel encoded by r the KCNH2 gene [9-28]. Lower heart rates result in less potassium moving out of the cell during repolarization (before subsequent reuptake by the Na-K-ATPase pump), since there are fewer repolarizations. The associated reduction in extracellular potassium concentration enhances the degree of drug-induced inhibition of IK , increasing the QT interval [11]. (See r "Congenital long QT syndrome: Pathophysiology and genetics", section on 'Perturbations in ion channels'.) Pause dependence Polymorphic VT in acquired LQTS is commonly precipitated by short- long RR intervals (ie, a short RR interval followed by a long RR interval). The short-long interval is typically caused by a premature ventricular contraction followed by compensatory pause ( waveform 2B). Polymorphic VT also can occur in association with bradycardia or frequent pauses; this is sometimes referred to as "pause-dependent LQTS [31]. Patients with congenital LQTS can also have pause-dependent TdP. This was illustrated in an observational study of 15 patients with congenital LQTS in which pause-dependent TdP was noted in 14 of 15 patients [32]. RISK FACTORS FOR DRUG-INDUCED LONG QT SYNDROME Acquired LQTS usually results from drug therapy ( table 1), although a number of patient- specific demographic, regimen-related, and ECG-related factors can enhance the risk of drug- induced LQTS [9,33,34]. Demographic The most prevalent risk factor for drug-induced torsades de pointes (TdP) is female sex [35-38]. Between 55 and 70 percent of people with drug-induced TdP are female, regardless of whether TdP is caused by a cardiac or noncardiac medication [36,39,40]. Compared with males, females have a longer QTc, a lower repolarization reserve, and a higher risk of TdP with drugs that even mildly block IK [37]. Furthermore, sex steroids may affect ion channel r expression, leading to sex differences in the QT interval [41]. Estrogen potentiates bradycardia- induced QT prolongation and arrhythmia. By contrast, androgens shorten the QT interval and make it less susceptible to drug-induced prolongation [37]. Advanced age is another risk factor for prolonged QT [34]. Underlying pathogenic variant in a long QT syndrome gene In some patients, drug- associated LQTS appears to represent a concealed form of congenital LQTS in which a pathogenic https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 5/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate variant in one of the LQTS genes is clinically inapparent until the patient is exposed to a particular drug or other predisposing factor (eg, hypokalemia or hypomagnesemia) [42-45]. In these individuals, the alteration in repolarizing currents is insufficient to prolong the QT interval at rest. This may be due to a redundancy in repolarizing currents (called repolarization reserve) [9]. This topic is discussed in detail elsewhere. (See "Congenital long QT syndrome: Pathophysiology and genetics".) However, individuals with concealed congenital LQTS and their affected offspring might be at risk for TdP if they are exposed to drugs that can prolong the QT interval. Supporting evidence includes a case series of 92 patients with drug-induced TdP (77 percent of patients took antiarrhythmic drugs). Pathogenic variants in LQT1, LQT2, or LQT3 were identified in five patients (5.4 percent), and genetic variants that possibly contribute to risk were identified in up to 10 percent [45]. Furthermore, unaffected family members may carry clinically silent mutations in LQTS pathogenic variants with low penetrance [44,46-48]. This was illustrated in a study of nine families with sporadic cases of LQTS; 15 of 46 family members (33 percent) who were felt to be unaffected based upon clinical criteria were gene carriers [47]. Structural heart disease Heart failure, diastolic dysfunction, myocardial ischemia, and left ventricular hypertrophy are common risk factors for drug-induced TdP. In persons with structural heart disease, antiarrhythmic drugs and diuretic-induced hypokalemia and/or hypomagnesemia may contribute to proarrhythmia. Individuals with structural heart disease may have other non- medication-related factors that can lead to acquired LQTS, including a lower creatinine clearance [49,50]. Whether or not structural heart disease is an independent risk factor for TdP in the absence of the medications is not known. Specific drug regimen Rapid infusion This has been linked with TdP in animal models; however, equivalent studies in humans have not been performed [34,51]. It is likely that rapid infusion leads to supratherapeutic drug concentrations in cardiac tissues. High drug doses or concentration For example, thioridazine doses of 600 mg/day should generally be avoided [52]; however, doses <600 mg/day (less than 3 mg/kg/day in pediatric patients) may also be unsafe in the presence of other cardiac risks [53]. Some drugs, such as quinidine, can cause idiosyncratic QT prolongation and do not cause QT prolongation in a dose-dependent way; in such cases, QT prolongation is likely due to intracellular handling of the drug. https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 6/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Use of medications that inhibit hepatic cytochrome P450 (CYP45) enzymes Concurrent use of these medications can slow metabolism of other QT-prolonging drugs and/or directly cause QT prolongation ( table 2). Examples of CYP3A4 inhibitors are erythromycin (which both slows drug metabolism and directly causes QT prolongation) [17,18,22,54] and cimetidine [55]. Grapefruit juice also inhibits CYP3A4 and can increase the QT interval by two possible mechanisms: slowed metabolism of other drugs and direct inhibition of the IKr channel by flavonoids in grapefruit juice, thereby increasing parent drug concentrations [56]. Diuretics Diuretics can cause electrolyte abnormalities or can directly block the potassium current [34]. Diuretics are also commonly given for heart failure; these individuals are already predisposed to LQTS. (See 'Structural heart disease' above.) Medications to treat COVID-19 Several medications that prolong the QT interval have been suggested as treatment for severe COVID-19 infection. Hydroxychloroquine (and chloroquine), alone or given in combination with azithromycin for concomitant pneumonia treatment, were shown to compound the effect on I block, causing QT prolongation and Kr TdP [57-59]. (See "COVID-19: Arrhythmias and conduction system disease", section on 'Patients receiving therapies that prolong the QT interval'.) Electrocardiographic abnormalities Several ECG findings can enhance a person's risk of developing drug-induced LQTS. These include: Baseline QT prolongation (either sporadic or due to known genetic variants) In a 2016 study of patients with acquired LQTS and TdP, approximately one-third had pathogenic variants in one of the known LQTS genes [60]. (See 'Underlying pathogenic variant in a long QT syndrome gene' above.) Baseline T-wave lability Aperiodic repolarization lability can be quantified from ECGs, and T-wave lability can be quantified as a root-mean-square of the differences between corresponding signal values of subsequent beats. Repolarization lability may be provoked with exercise [61,62]. Development of specific ECG changes during drug therapy These include marked QT prolongation (eg >500 milliseconds), T-wave lability, or T-wave morphologic changes (such as LQT2-type repolarization [notching, long T peak-T end]). (See "Congenital long QT syndrome: Diagnosis", section on 'Other ECG features' and "Congenital long QT syndrome: Pathophysiology and genetics", section on 'Type 2 LQTS (LQT2)'.) https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 7/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Bradycardia Bradycardia may cause a fall in local extracellular potassium concentration, leading to enhanced drug-induced inhibition of IK [11]. Specific bradyarrhythmias that lead r to increased risk of TdP include sinus bradycardia, heart block, incomplete heart block with pauses, and premature complexes leading to short-long-short cycles. (See "Permanent cardiac pacing: Overview of devices and indications", section on 'Bradycardia-induced ventricular arrhythmias'.) Metabolic factors Electrolyte disturbances, especially hypokalemia and hypomagnesemia, and less often hypocalcemia, are risk factors for drug-induced LQTS. The risk for developing TdP in the presence of hypokalemia and/or hypomagnesemia is greatest in patients taking antiarrhythmic drugs [45,63-66]. In a series of 92 patients with drug-induced LQTS, 27 percent had hypokalemia or hypomagnesemia [45]. Virtually all of the drugs that produce LQTS act by blocking the IKr current mediated by the potassium channel encoded by the KCNH2 gene [9- 22,25]. The increase in risk with hypokalemia may be related to enhanced drug blockade of IK r [11]. Acidosis is another risk factor for drug-induced LQTS [67]. (See 'Metabolic abnormalities' below.) Patients with anorexia may be predisposed to an acquired long QTc because of catabolic metabolism, psychotropic medications, and electrolyte disturbances. This is discussed separately. (See "Anorexia nervosa in adults and adolescents: Medical complications and their management", section on 'Functional changes'.) Impaired hepatic and/or renal function are additional risk factors due to decreased metabolism leading to increased drug exposure [68,69]. Multiple risk factors Most patients who have drug-induced TdP have one or more risk factors, and having multiple risk factors confers a greater risk than having one risk factor [34]. In a review of 249 published cases of patients with TdP associated with noncardiac drugs, 97 percent had at least one, and 71 percent had at least two risk factors [39]. Risk factors included: Female sex 71 percent History of heart disease 41 percent Concurrent use of another QT-prolonging drug 39 percent Hypokalemia 28 percent High drug dose 19 percent Prior history of LQTS - 18 percent DRUGS THAT PROLONG THE QT INTERVAL https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 8/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Overview Drugs that can prolong the QT interval and cause torsades de pointes (TdP) include prescription medications (either taken as prescribed or misused) and over-the-counter medications or supplements (including herbal medications). A 2020 scientific statement from the American Heart Association details drugs associated with TdP [70]. Many medications are known to cause acquired LQTS, and more continue to be identified [44,71,72]. Several major classes of drugs prolong the QT interval. Medications along with their class and level of risk are detailed in a table ( table 1) [33,45,72-75]. Among drugs still commonly available, some of the best data on incidence of TdP come from studies of antiarrhythmic drugs, particularly class IA and III drugs, and from psychotropic medications. Data are not as readily available on the incidence of TdP with drugs other than antiarrhythmic medications, most of which are used for noncardiac reasons and in much less controlled settings than antiarrhythmic drugs Some drugs have been taken off the market in the United States and other countries, specifically because of concerns that they increase the risk of TdP (eg, cisapride, terfenadine, astemizole). The drugs that are most frequently implicated in prolonging the QT interval are discussed here. A more complete list of specific drugs that prolong the QT interval is available at www.crediblemeds.org/. Specific recommendations for the administration and monitoring of QT-prolonging drugs are discussed in UpToDate topics and Lexicomp monographs for individual drugs. Antiarrhythmic drugs Use of these medications may be the most common cause of drug- induced LQTS since many of these medications can induce arrhythmia (this is sometimes referred to as being "proarrhythmic"). In a review of 92 patients from the United States with drug-induced TdP, antiarrhythmic drugs were responsible in 77 percent of cases [45]. Among 761 cases of drug- induced TdP reported to the World Health Organization Drug Monitoring Centre between 1983 and 1999, the most common drug was sotalol (17 percent) [72]. In patients with atrial fibrillation on QT-prolonging antiarrhythmic drugs, there is a greater risk of QT prolongation and TdP shortly after cardioversion than before or some time after [76-78]. Sotalol Sotalol (class II and III) causes QT prolongation and TdP in approximately 4 percent of women and 2 percent of men in a dose-dependent relationship [35,79,80]. As a result, sotalol therapy is often initiated in a hospital with facilities for cardiac rhythm monitoring and assessment. The need to do this is controversial and is discussed separately. (See https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 9/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate "Clinical uses of sotalol", section on 'Initiation of therapy' and "Clinical uses of sotalol", section on 'Proarrhythmia'.) Intravenous sotalol is available for acute tachyarrhythmia conversion and/or for those patients who transiently cannot tolerate enteral sotalol administration (such as perioperatively). Dofetilide This is a class III agent associated with increased risk of TdP, generally within the first three days of therapy; this is when QT interval increase peaks [81,82]. Patients must be hospitalized for dofetilide initiation at a facility that can provide measurement of creatinine clearance, cardiac monitoring, and resuscitation. Patients who are on dofetilide and convert from atrial fibrillation to sinus rhythm have greater risks of QT prolongation and TdP than patients who are started on dofetilide when in sinus rhythm [78]. Dofetilide has a high risk of drug-drug interactions. (See "Clinical use of dofetilide" and "Clinical use of dofetilide", section on 'Safety'.) Ibutilide Proarrhythmia is the most common toxic reaction with intravenous ibutilide, a class III medication used for acute termination of atrial tachyarrhythmia. Sustained polymorphic VT occurs in 1.7 percent of patients [83,84]. When ibutilide is administered, it is done so in a carefully monitored setting with continuous telemetry to identify potential polymorphic VT. (See "Therapeutic use of ibutilide", section on 'Proarrhythmia'.) Amiodarone This class III antiarrhythmic medication can markedly prolong the QT interval. However, in contrast to the other class III antiarrhythmic drugs, amiodarone is rarely associated with TdP, except when used concomitantly with a class IA agent or when hypokalemia is present [85]. This is because amiodarone prolongs repolarization in a more homogeneous manner, with less transmural dispersion of refractoriness than other class III agents. Other factors contributing to the rare occurrence of TdP with amiodarone use are lack of reverse-use dependence, concurrent blockade of the L-type calcium channels, and less heterogeneity of ventricular repolarization (also called QT dispersion). The estimated incidence of TdP is less than 1 percent overall [86], and in a review of 738 patients in randomized trials of low-dose therapy ( 400 mg/day for at least one year), there were no cases of TdP [87]. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse cardiac effects'.) Quinidine This is a class IA ( table 3) sodium channel blocking agent with potassium channel blocking function at slow heart rates. It has historically been the most frequently implicated cause of drug-induced TdP; however, it is now less often prescribed when implantable defibrillators are a viable option [63]. Most cases occur within 48 hours of initiating drug therapy; associated factors are hypokalemia and excessive bradycardia. The https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 10/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate incidence may be reduced by correction of hypokalemia or hypomagnesemia before therapy and discontinuation of drug therapy if QT prolongation occurs [88]. Although quinidine-induced QT prolongation and TdP ("quinidine syncope") often are dose related, these abnormalities may represent an idiosyncratic reaction, occurring when drug dose and serum concentrations are low. (See "Major side effects of class I antiarrhythmic drugs", section on 'Proarrhythmia and ventricular arrhythmias'.) Disopyramide and procainamide Although TdP occurs with disopyramide and procainamide (also class IA), the reported incidence is lower than with quinidine [89,90]. With procainamide therapy, QT prolongation and TdP result from the major metabolite of the drug N-acetylprocainamide, which has class III potassium channel-blocking activity and thereby causes QT prolongation [91]. (See "Major side effects of class I antiarrhythmic drugs", section on 'Electrocardiographic and proarrhythmic effects' and "Major side effects of class I antiarrhythmic drugs", section on 'QT interval'.) Psychotropic medications Haloperidol This is an antipsychotic agent. The U S Food and Drug Administration (FDA) issued an alert for haloperidol in September of 2007 based upon the observation that QT prolongation and TdP have been observed in patients, especially when administered intravenously or in higher doses than recommended. Because of the potential confounding influence of other QT-prolonging factors, the magnitude of the risk associated with or attributable to haloperidol cannot be determined from the case reports upon which this advisory was based. However, a direct effect is likely since in vitro studies have shown that haloperidol is a high-potency blocker of the KCNH2 channel, which is blocked by virtually all drugs that cause LQTS [27]. (See 'Pathophysiology' above.) Particular caution should be exercised in treating patients with haloperidol who have any of the following characteristics: Electrolyte abnormalities (particularly hypokalemia or hypomagnesemia) Use of other drugs known to prolong the QT interval Congenital LQTS Underlying cardiac abnormalities Hypothyroidism Although typical antipsychotic drugs like haloperidol and thioridazine have received particular attention with regard to risk of arrhythmia and sudden death, there is evidence that several atypical antipsychotic medications can prolong the QT interval and cause TdP [92]. In addition, a large retrospective cohort study found that treatment with typical and https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 11/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate atypical antipsychotics was associated with similar increases in the risk of sudden death in patients with psychosis [93]. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects".) Antidepressants Antidepressants that can prolong the QTc and can cause drug-induced TdP include selective serotonin reuptake inhibitors, tricyclics, mirtazapine, and others ( table 1). This is discussed separately. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Cardiac' and "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Side effects' and "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects", section on 'Cardiac'.) Opioids Some synthetic opioids are increasingly recognized as a cause of QT prolongation, leading to TdP and sudden cardiac death [94]. Natural opioids have not been shown to prolong the QT interval. Opioid medications that prolong QTc and have been associated with TdP include methadone, levacetylmethadol, and loperamide. Methadone often increases the QTc interval and is a cause of TdP. Concern regarding the proarrhythmic potential of methadone prompted a clinician safety alert from the FDA in 2006, as well as a manufacturer's black-box warning. These issues, as well as safety recommendations for prescribing methadone, are discussed elsewhere [95]. (See "Medication for opioid use disorder", section on 'Prolonged QTc and cardiac arrhythmias'.) Gastrointestinal medications Cisapride, which is not easily available in the United States, was previously one of the most common causes of acquired TdP not due to antiarrhythmic drugs [72,96]. Among 761 cases of drug-induced TdP reported to the World Health Organization Drug Monitoring Centre between 1983 and 1999, the second most common drug was cisapride (13 percent), after sotalol [72]. This has become much less frequent since it was taken off the general market (ie, available only through a limited access program), along with awareness of the potential for QT prolongation, particularly when used concomitantly with other QT-prolonging drugs. The antiemetic agents droperidol and ondansetron have a moderate risk of prolonging the QTc and do so more commonly when given in an intravenous rather than oral formulation. (See "Arrhythmias during anesthesia", section on 'Medications that may prolong the QT interval'.) Antimicrobials QT-prolonging antimicrobial medications include macrolide and fluoroquinolone antibiotics and some antifungal and antiviral drugs. https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 12/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Macrolide antibiotics (eg, erythromycin, azithromycin, clarithromycin), fluoroquinolone antibiotics (eg, ciprofloxacin, gatifloxacin, levofloxacin, etc.), and antifungal drugs (eg, fluconazole, itraconazole, ketoconazole, etc.) can prolong the QT interval. Users of erythromycin in one report had a twofold increased risk of SCD over nonusers [54]. In addition, because erythromycin is metabolized by the CYP3A4 system, medications that inhibit CYP3A4 cause a further increase in risk when used with erythromycin ( table 2). (See "Azithromycin and clarithromycin", section on 'QT interval prolongation and cardiovascular events' and "Fluoroquinolones", section on 'QT interval prolongation'.) Arsenic Arsenic trioxide is used in the treatment of patients with acute promyelocytic leukemia and other advanced malignancies. It appears to be associated with a very high rate of QT prolongation but a lower rate of TdP [97-99]. The unusually high incidence of QT prolongation with arsenic trioxide may be a consequence of a unique effect on potassium flux. Most of the drugs that produce LQTS act by blocking the IKr current. However, arsenic trioxide blocks both IKr and IKs, an effect comparable to the combined effects of genetic LQT1 and LQT2 [100]. Tyrosine kinase inhibitors Tyrosine kinase inhibitors inhibit angiogenesis and are used to treat a variety of solid tumors. Potential toxicities of some tyrosine kinase inhibitors are QT prolongation and TdP. This is discussed in detail separately. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Prolongation of the QTc interval and cardiac arrhythmias'.) OTHER CAUSES Metabolic abnormalities Hypokalemia and hypomagnesemia can predispose to torsades de pointes (TdP) even in the absence of QT-prolonging drugs. As discussed above, electrolyte abnormalities can predispose to TdP. Multiple electrolyte abnormalities can coexist; hypomagnesemia directly causes hypokalemia. Hypocalcemia alone or induced by hypomagnesemia is a less common cause [101-103]. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Hypokalemia' and "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Calcium metabolism'.) The risk of hypokalemia itself may also be related to decreased IKr activity [104]. Further support for the importance of hypomagnesemia is the beneficial effect of magnesium administration in the acute therapy of TdP. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'Initial management'.) https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 13/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Impaired hepatic and/or renal function can also cause a prolonged QTc, independent of drug administration [68,69]. Patients with anorexia may be predisposed to a long QTc because of catabolic metabolism, electrolyte disturbances, psychotropic medications, or other physiologic changes. This is discussed separately. (See "Anorexia nervosa in adults and adolescents: Medical complications and their management", section on 'Functional changes'.) Ischemia QTc prolongation may be common during the early phase of ischemia. In a series of 74 patients undergoing serial ECGs during angioplasty, all patients developed QT prolongation during balloon inflation [105]. In addition, some patients with acute myocardial infarction (8 of 434 consecutive patients in one series) develop progressive QT interval prolongation that is maximal at days 3 to 11 during the healing phase of the infarct [106]. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features", section on 'Polymorphic VT'.) Bradyarrhythmias The likelihood of developing QT prolongation and TdP in patients taking antiarrhythmic drugs is increased by bradycardia due to reverse use dependency [11]. It is less clear whether bradycardia alone causes TdP [107,108]. This issue was addressed in a report of 14 patients with complete atrioventricular block, six of whom had a history of TdP [107]. The two groups did not differ with respect to the rate of the escape rhythm; however, the corrected QT interval was significantly longer in those who had experienced TdP (0.59 versus 0.48 seconds). After pacemaker placement, the corrected QT interval was also longer in patients who had TdP, with pacemaker set to 50 beats per minute (QTc 0.70 versus 0.53 seconds). (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'Long-term management'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 14/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Methadone often increases the QTc interval and is a cause of TdP. Concern regarding the proarrhythmic potential of methadone prompted a clinician safety alert from the FDA in 2006, as well as a manufacturer's black-box warning. These issues, as well as safety recommendations for prescribing methadone, are discussed elsewhere [95]. (See "Medication for opioid use disorder", section on 'Prolonged QTc and cardiac arrhythmias'.) Gastrointestinal medications Cisapride, which is not easily available in the United States, was previously one of the most common causes of acquired TdP not due to antiarrhythmic drugs [72,96]. Among 761 cases of drug-induced TdP reported to the World Health Organization Drug Monitoring Centre between 1983 and 1999, the second most common drug was cisapride (13 percent), after sotalol [72]. This has become much less frequent since it was taken off the general market (ie, available only through a limited access program), along with awareness of the potential for QT prolongation, particularly when used concomitantly with other QT-prolonging drugs. The antiemetic agents droperidol and ondansetron have a moderate risk of prolonging the QTc and do so more commonly when given in an intravenous rather than oral formulation. (See "Arrhythmias during anesthesia", section on 'Medications that may prolong the QT interval'.) Antimicrobials QT-prolonging antimicrobial medications include macrolide and fluoroquinolone antibiotics and some antifungal and antiviral drugs. https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 12/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Macrolide antibiotics (eg, erythromycin, azithromycin, clarithromycin), fluoroquinolone antibiotics (eg, ciprofloxacin, gatifloxacin, levofloxacin, etc.), and antifungal drugs (eg, fluconazole, itraconazole, ketoconazole, etc.) can prolong the QT interval. Users of erythromycin in one report had a twofold increased risk of SCD over nonusers [54]. In addition, because erythromycin is metabolized by the CYP3A4 system, medications that inhibit CYP3A4 cause a further increase in risk when used with erythromycin ( table 2). (See "Azithromycin and clarithromycin", section on 'QT interval prolongation and cardiovascular events' and "Fluoroquinolones", section on 'QT interval prolongation'.) Arsenic Arsenic trioxide is used in the treatment of patients with acute promyelocytic leukemia and other advanced malignancies. It appears to be associated with a very high rate of QT prolongation but a lower rate of TdP [97-99]. The unusually high incidence of QT prolongation with arsenic trioxide may be a consequence of a unique effect on potassium flux. Most of the drugs that produce LQTS act by blocking the IKr current. However, arsenic trioxide blocks both IKr and IKs, an effect comparable to the combined effects of genetic LQT1 and LQT2 [100]. Tyrosine kinase inhibitors Tyrosine kinase inhibitors inhibit angiogenesis and are used to treat a variety of solid tumors. Potential toxicities of some tyrosine kinase inhibitors are QT prolongation and TdP. This is discussed in detail separately. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Prolongation of the QTc interval and cardiac arrhythmias'.) OTHER CAUSES Metabolic abnormalities Hypokalemia and hypomagnesemia can predispose to torsades de pointes (TdP) even in the absence of QT-prolonging drugs. As discussed above, electrolyte abnormalities can predispose to TdP. Multiple electrolyte abnormalities can coexist; hypomagnesemia directly causes hypokalemia. Hypocalcemia alone or induced by hypomagnesemia is a less common cause [101-103]. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Hypokalemia' and "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Calcium metabolism'.) The risk of hypokalemia itself may also be related to decreased IKr activity [104]. Further support for the importance of hypomagnesemia is the beneficial effect of magnesium administration in the acute therapy of TdP. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'Initial management'.) https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 13/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Impaired hepatic and/or renal function can also cause a prolonged QTc, independent of drug administration [68,69]. Patients with anorexia may be predisposed to a long QTc because of catabolic metabolism, electrolyte disturbances, psychotropic medications, or other physiologic changes. This is discussed separately. (See "Anorexia nervosa in adults and adolescents: Medical complications and their management", section on 'Functional changes'.) Ischemia QTc prolongation may be common during the early phase of ischemia. In a series of 74 patients undergoing serial ECGs during angioplasty, all patients developed QT prolongation during balloon inflation [105]. In addition, some patients with acute myocardial infarction (8 of 434 consecutive patients in one series) develop progressive QT interval prolongation that is maximal at days 3 to 11 during the healing phase of the infarct [106]. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features", section on 'Polymorphic VT'.) Bradyarrhythmias The likelihood of developing QT prolongation and TdP in patients taking antiarrhythmic drugs is increased by bradycardia due to reverse use dependency [11]. It is less clear whether bradycardia alone causes TdP [107,108]. This issue was addressed in a report of 14 patients with complete atrioventricular block, six of whom had a history of TdP [107]. The two groups did not differ with respect to the rate of the escape rhythm; however, the corrected QT interval was significantly longer in those who had experienced TdP (0.59 versus 0.48 seconds). After pacemaker placement, the corrected QT interval was also longer in patients who had TdP, with pacemaker set to 50 beats per minute (QTc 0.70 versus 0.53 seconds). (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'Long-term management'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 14/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Long QT syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Background The long QT syndrome (LQTS) is a disorder of myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1). This syndrome is associated with an increased risk of polymorphic ventricular tachycardia and a characteristic life-threatening cardiac arrhythmia also known as torsades de pointes (TdP) ( waveform 2A-B). (See 'Definitions' above.) There is potential overlap between acquired and congenital LQTS, as some people with acquired LQTS can have underlying pathogenic genetic variants but do not meet all the clinical criteria for congenital LQTS. (See 'Underlying pathogenic variant in a long QT syndrome gene' above and "Congenital long QT syndrome: Pathophysiology and genetics".) Pathophysiology Nearly all drugs that produce LQTS do so by blocking the IKr current; this is mediated by a potassium channel in myocardial cells. This potassium channel is encoded by the KCNH2 gene. (See 'Pathophysiology' above.) Medication-induced LQTS Risk factors Several patient-specific and medication-related factors can enhance the risk of drug-induced LQTS. (See 'Risk factors for drug-induced long QT syndrome' above.) Drug-induced LQTS is more common in females, and the prevalence increases with age. Other risk factors include metabolic disturbances such as hypokalemia, hypomagnesemia, impaired hepatic and/or renal function, underlying heart disease, and recent conversion from atrial fibrillation https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 15/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Drug regimen associated risk factors for TdP (including rapid infusion high drug concentrations), concurrent use of other drugs that can prolong the QT interval or that slow drug metabolism due to inhibition of cytochrome P450 enzymes, or concurrent intake of grapefruit juice. Electrocardiogram (ECG)-related factors predisposing to drug-induced LQTS include baseline QT prolongation or T-wave lability, development of marked QT prolongation, or T-wave changes during therapy and bradycardia. Specific medications Acquired LQTS is usually secondary to drug therapy. (See 'Drugs that prolong the QT interval' above.) Common medications include antiarrhythmics (sotalol is the most common), psychotropic medications (antidepressants, antipsychotics), synthetic opioids (eg, methadone), gastrointestinal medications (cisapride and the antiemetics droperidol and ondansetron), and antimicrobials (including macrolide antibiotics and fluoroquinolones, antifungals and antivirals). Other causes Causes of acquired LQTS other than drugs include electrolyte abnormalities, structural and ischemic heart disease, and bradyarrhythmias. (See 'Other causes' above.) ACKNOWLEDGMENT The editorial staff at UpToDate acknowledge Stephen Seslar MD, PhD, and the late Mark E. Josephson, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Passman R, Kadish A. Polymorphic ventricular tachycardia, long Q-T syndrome, and torsades de pointes. Med Clin North Am 2001; 85:321. 2. Khan IA. 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Topic 1043 Version 50.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 23/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate GRAPHICS Single-lead electrocardiogram showing a prolonged QT interval The corrected QT interval (QTc) is calculated by dividing the QT interval (0.60 seconds) by the square root of the preceding RR interval (0.92 seconds). In this case, the QTc is 0.625 seconds (625 milliseconds). Graphic 77018 Version 7.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 24/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Single lead electrocardiogram (ECG) showing polymorphic ventricular tachycardia (VT) This is an atypical, rapid, and bizarre form of ventricular tachycardia that is characterized by a continuously changing axis of polymorphic QRS morphologies. Graphic 53891 Version 5.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 25/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Single lead electrocardiogram (ECG) showing torsades de pointes The electrocardiographic rhythm strip shows torsades de pointes, a polymorphic ventricular tachycardia associated with QT prolongation. There is a short, preinitiating RR interval due to a ventricular couplet, which is followed by a long, initiating cycle resulting from the compensatory pause after the couplet. Graphic 73827 Version 4.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 26/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial ischemia or GnRH agonist/antagonist therapy Hypomagnesemia Bilateral surgical orchiectomy infarction, Hypocalcemia Diuretic therapy via electrolyte disorders especially with prominent T-wave Starvation particularly hypokalemia and hypomagnesemia Anorexia nervosa Herbs inversions Liquid protein diets Cinchona (contains quinine), iboga Intracranial Hypothyroidism (ibogaine), licorice extract in overuse via electrolyte disturbances disease Bradyarrhythmias HIV infection Sinus node dysfunction Hypothermia Toxic exposure: Organophosphate AV block: Second or third degree insecticides Medications* High risk Adagrasib Cisaparide (restricted Lenvatinib Selpercatinib Ajmaline Levoketoconazole Sertindole availability) Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine Vandetanib Dofetilide (intracoronary) Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab Propafenone ozogamacin Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Levofloxacin Carbetocin Erythromycin Ribociclib (systemic) https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 27/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Certinib Escitalopram Lofexidine Risperidone Chloroquine Etelcalcetide Meglumine antimoniate Saquinavir Citalopram Fexinidazole Sevoflurane Midostaurin Clarithromycin Flecainide Sparfloxacin Moxifloxacin Clofazimine Floxuridine Sunitinib Nilotinib Clomipramine Fluconazole Tegafur Olanzapine Clozapine Fluorouracil (systemic) Terbutaline Ondansetrol (IV > Crizotinib Thioridazine oral) Flupentixol Dabrafenib Toremifene Osimertinib Gabobenate Dasatinib Vemurafenib dimeglumine Oxytocin Deslurane Voriconazole Gemifloxacin Pazopanib Domperidone Gilteritinib Pentamidine Doxepin Halofantrine Pilsicainide Doxifluridine Haloperidol (oral) Pimozide Imipramine Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole Romidepsin Anagrelide Foscarnet (systemic) Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- Glasdegib Mizolastine lumefantrine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine Nortriptyline Benperidol (rare reports) Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus (systemic) Olodaterol Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Periciazine Tropisetron https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 28/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Dexmedetomidine** Leuprolide- norethindrone Pimavanserin Vardenafil Dolasetron Pipamperone Vilanterol Levalbuterol Donepezil Pitolisant Vinflunine Levomethadone Efavirenz Ponesimod Voclosporin Lithium Eliglustat Primaquine Vorinostat Loperamide in Eribulin Promazine Zuclopenthixol overdose Ezogabine Radotinib Lopinavir Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM0 73161.pdf with additional data from CredibleMeds QT drugs list [1,2] . The use of other classification criteria may lead to some agents being classified differently by other sources. Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 29/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual

The electrocardiographic rhythm strip shows torsades de pointes, a polymorphic ventricular tachycardia associated with QT prolongation. There is a short, preinitiating RR interval due to a ventricular couplet, which is followed by a long, initiating cycle resulting from the compensatory pause after the couplet. Graphic 73827 Version 4.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 26/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial ischemia or GnRH agonist/antagonist therapy Hypomagnesemia Bilateral surgical orchiectomy infarction, Hypocalcemia Diuretic therapy via electrolyte disorders especially with prominent T-wave Starvation particularly hypokalemia and hypomagnesemia Anorexia nervosa Herbs inversions Liquid protein diets Cinchona (contains quinine), iboga Intracranial Hypothyroidism (ibogaine), licorice extract in overuse via electrolyte disturbances disease Bradyarrhythmias HIV infection Sinus node dysfunction Hypothermia Toxic exposure: Organophosphate AV block: Second or third degree insecticides Medications* High risk Adagrasib Cisaparide (restricted Lenvatinib Selpercatinib Ajmaline Levoketoconazole Sertindole availability) Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine Vandetanib Dofetilide (intracoronary) Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab Propafenone ozogamacin Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Levofloxacin Carbetocin Erythromycin Ribociclib (systemic) https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 27/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Certinib Escitalopram Lofexidine Risperidone Chloroquine Etelcalcetide Meglumine antimoniate Saquinavir Citalopram Fexinidazole Sevoflurane Midostaurin Clarithromycin Flecainide Sparfloxacin Moxifloxacin Clofazimine Floxuridine Sunitinib Nilotinib Clomipramine Fluconazole Tegafur Olanzapine Clozapine Fluorouracil (systemic) Terbutaline Ondansetrol (IV > Crizotinib Thioridazine oral) Flupentixol Dabrafenib Toremifene Osimertinib Gabobenate Dasatinib Vemurafenib dimeglumine Oxytocin Deslurane Voriconazole Gemifloxacin Pazopanib Domperidone Gilteritinib Pentamidine Doxepin Halofantrine Pilsicainide Doxifluridine Haloperidol (oral) Pimozide Imipramine Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole Romidepsin Anagrelide Foscarnet (systemic) Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- Glasdegib Mizolastine lumefantrine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine Nortriptyline Benperidol (rare reports) Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus (systemic) Olodaterol Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Periciazine Tropisetron https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 28/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Dexmedetomidine** Leuprolide- norethindrone Pimavanserin Vardenafil Dolasetron Pipamperone Vilanterol Levalbuterol Donepezil Pitolisant Vinflunine Levomethadone Efavirenz Ponesimod Voclosporin Lithium Eliglustat Primaquine Vorinostat Loperamide in Eribulin Promazine Zuclopenthixol overdose Ezogabine Radotinib Lopinavir Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM0 73161.pdf with additional data from CredibleMeds QT drugs list [1,2] . The use of other classification criteria may lead to some agents being classified differently by other sources. Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 29/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 30/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Triggers for cardiac events in long QT syndrome are related to genotype In a study of 670 patients with long QT syndrome and known genotype, all symptomatic (syncope, aborted cardiac arrest, or sudden death), the occurrence of a lethal cardiac event (n = 110) provoked by a specific trigger (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced most of their events (90%) during exercise or emotion. These percentages were almost reversed among LQT2 and LQT3 patients who had most of their events during rest or sleep (63 and 80%, respectively); by contrast, they were at almost no risk of major events during exercise (arrows), which is explained by their having a normal I current. Ks ACA: aborted cardiac arrest; SCD: sudden cardiac death. Modi ed from: Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-speci c triggers for life-threatening arrhythmias. Circulation 2001; 103:89. Graphic 64239 Version 3.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 31/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Cytochrome P450 3A (including 3A4) inhibitors and inducers Strong inhibitors Moderate inhibitors Strong inducers Moderate inducers Adagrasib Amiodarone Apalutamide Bexarotene Atazanavir Aprepitant Carbamazepine Bosentan Ceritinib Berotralstat Enzalutamide Cenobamate Clarithromycin Cimetidine Fosphenytoin Dabrafenib Cobicistat and Conivaptan Lumacaftor Dexamethasone cobicistat- containing Crizotinib Lumacaftor- Dipyrone ivacaftor Cyclosporine Efavirenz coformulations Mitotane Diltiazem Elagolix, estradiol, Darunavir Phenobarbital and norethindrone Duvelisib Idelalisib therapy pack Phenytoin Dronedarone Indinavir Eslicarbazepine Primidone Erythromycin Itraconazole Etravirine Rifampin (rifampicin) Fedratinib Ketoconazole Lorlatinib Fluconazole Levoketoconazole Mitapivat Fosamprenavir Lonafarnib Modafinil Fosaprepitant Lopinavir Nafcillin Fosnetupitant- Mifepristone* Pexidartinib palonosetron Nefazodone Rifabutin Grapefruit juice Nelfinavir Rifapentine Imatinib Nirmatrelvir- Sotorasib Isavuconazole ritonavir (isavuconazonium sulfate) St. John's wort Ombitasvir- paritaprevir- ritonavir Lefamulin Letermovir Ombitasvir- Netupitant paritaprevir- Nilotinib ritonavir plus dasabuvir Ribociclib Schisandra Posaconazole Verapamil Ritonavir and ritonavir-containing coformulations Saquinavir Telithromycin Tucatinib Voriconazole https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 32/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or activation. [1,2] These classifications are based upon US Food and Drug Administration (FDA) guidance. sources may use a different classification system resulting in some agents being classified Other differently. Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration. Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a drug interaction program such as the Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 33/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 34/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 35/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Contributor Disclosures Charles I Berul, MD Patent Holder: PeriCor LLC [Pacemakers/defibrillators]. Grant/Research/Clinical Trial Support: Medtronic Inc [Pacemakers/defibrillators]. All of the relevant financial relationships listed have been mitigated. Samuel Asirvatham, MD Grant/Research/Clinical Trial Support: Medtronic [Defibrillators]; St Jude's [Sudden Cardiac Death]. Consultant/Advisory Boards: BioTronik [Defibrillators]; Boston Scientific [Sudden Cardiac Death]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 36/36

7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Congenital long QT syndrome: Diagnosis : Peter J Schwartz, MD, Michael J Ackerman, MD, PhD : John K Triedman, MD, Samuel Asirvatham, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 13, 2019. INTRODUCTION Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death (SCD) [1]. The primary symptoms in patients with LQTS include syncope, seizures, cardiac arrest, and SCD. LQTS is associated with an increased risk of a characteristic life-threatening cardiac arrhythmia known as torsades de pointes or "twisting of the points" ( waveform 2) [2]. LQTS may be congenital or acquired [1,3-7]. Pathogenic variants in up to 17 genes have been identified thus far in patients with congenital LQTS; the three major genetic subtypes are designated LQT1 through LQT3 while the minor LQTS-susceptibility genes are designated by their genetic substrate (eg, CALM1-LQTS) ( table 1) [7]. Acquired LQTS usually results from undesired QT prolongation and potential for QT-triggered arrhythmias by either QT-prolonging disease states, QT-prolonging medications ( www.crediblemeds.org), or QT-prolonging electrolyte disturbances ( table 2). (See "Congenital long QT syndrome: Pathophysiology and genetics".) The ECG features and diagnostic approach to persons with suspected congenital LQTS will be reviewed here [1]. The epidemiology, clinical features, and management of congenital LQTS in children and adults and the acquired LQTS are discussed separately. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Congenital long QT syndrome: Treatment" and "Acquired long QT syndrome: Definitions, pathophysiology, and causes" and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 1/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate DIAGNOSTIC EVALUATION Our approach Our approach to evaluating the patient with suspected congenital LQTS involves multiple steps [1]: For all patients, the initial evaluation of suspected congenital LQTS should include obtaining a comprehensive personal and family history, performance of a physical examination, and review of an ECG (examination of serial ECGs is extremely helpful). The ECGs are examined to determine both the length of repolarization (the QTc) and the look of repolarization (T wave morphology). When available, ECGs are also obtained from immediate family members to determine if any first-degree relatives (parents, siblings, and/or children) exhibit QT prolongation or other associated abnormalities. Secondary causes of QT prolongation and the acquired LQTS should be excluded ( table 2). Besides the resting ECG, 24-hour ambulatory ECG monitoring (full 12-lead monitoring, if available) is performed as well, looking for arrhythmias as well as any dynamic T wave changes including (rarely) macroscopic T wave alternans, especially at nighttime. If the patient is old enough and able to perform a bicycle or treadmill stress test, we perform an exercise stress test looking for exercise-associated arrhythmias, changes in T wave morphology, and the presence of a maladaptive QT response during the recovery phase. A QTc >470 milliseconds at two through five minutes of recovery is highly suggestive of LQT1. (See 'Exercise testing' below.) Calculation of the LQTS diagnostic score, also known as the "Schwartz Score." (See 'Diagnosis' below.) Clinical and family history Obtaining a detailed personal medical history and a multi- generation family history is crucial in determining the pretest likelihood of congenital LQTS. The personal clinical history should focus on signs and symptoms suggestive of tachyarrhythmia, particularly ventricular tachyarrhythmias, as many LQTS families have pre-sudden death warning signs including: Syncope suggestive of cardiac/arrhythmic origin (ie, not vasovagal syncope) Syncope followed by generalized seizures Resuscitated sudden cardiac arrest https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 2/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Additionally, obtaining a multi-generation family history, and utilizing a genetic counsellor when available, is also crucial to establishing the clinical likelihood of congenital LQTS. Key family history items that increase the likelihood of congenital LQTS include: Premature sudden deaths (<40 years of age and autopsy negative) Unexplained motor vehicle accidents Unexplained drownings Generalized seizures (frequently, patients with LQTS have been misdiagnosed with, and treated for, epilepsy) After obtaining the clinical and family history and reviewing the results of the resting, ambulatory, and stress ECGs, the LQTS diagnostic score can be calculated. (See '12-lead ECG' below and 'Ambulatory ECG monitoring' below and 'Diagnosis' below.) 12-lead ECG All patients being evaluated for congenital LQTS should have multiple 12-lead ECGs performed. The QT interval should be measured manually on serial ECGs using multiple leads (preferably leads II and V5) and then corrected for heart rate. Once consistent QTc prolongation has been shown on two ECGs (on occasion even one ECG is sufficient), serial ECG testing may be discontinued altogether or at least the interval of surveillance lengthened. The point at which serial ECG testing can be discontinued is highly variable, depending upon the patient s age, growth patterns, and the significance of previous ECG findings. Even after the diagnosis of LQTS is established, most pediatric patients with LQTS will have a 12-lead ECG and 12-lead ambulatory ECG monitoring performed every one to two years. In Europe there is a preference for yearly (rather than every two years) follow-up, including an exercise stress test. If low-risk and asymptomatic, most adults with LQTS will continue to have periodic cardiac re- evaluations every one to five years. Sometimes, the ECG itself is used to monitor satisfaction with the LQTS-directed treatment program such as when mexiletine is used to attenuate the QTc. If so, a follow-up ECG may be obtained even more frequently than annually. While yearly ECGs in general are most appropriate, obtaining an ECG more frequently (eg, every one to two months) is usually unnecessary and unacceptable. In addition, beat-to-beat variability and respiratory sinus arrhythmia affect formulas used to correct for heart rate. As a result, several successive beats may on occasion need to be measured and averaged for each ECG. (See 'QT rate correction' below and 'Special circumstances' below.) Prolongation of the QTc is an essential component of the diagnosis of LQTS. However, the QTc varies in response to a number of factors, such as autonomic state, electrolyte imbalance, drugs, and diurnal changes [8,9]. https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 3/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Other ECG features, such as T wave morphology and bradycardia, may be useful in the evaluation of the patient with suspected LQTS, but the QTc appears to be the most useful diagnostic and prognostic parameter [10]. General ECG principles The QT interval reflects the time required for both depolarization (the QRS complex) and repolarization (the T wave) of the ventricles. Repolarization is a larger component of the entire QT interval, and QT prolongation is generally considered to reflect abnormalities of repolarization. The QT interval varies inversely with the heart rate; therefore, the QT measurement is adjusted for the heart rate, resulting in the corrected QT interval, or QTc. (See 'QT rate correction' below.) Measuring the QT interval The computer-derived QTc should always be confirmed or corrected manually. The QT interval is measured from the onset of the QRS complex to the point at which the T wave ends ( waveform 1). Accurate measurements can be technically challenging, largely due to difficulties in determining the precise termination of the T wave. The QT interval should be measured in different beats and in several leads. The technique of measuring the QT interval is discussed separately. (See "ECG tutorial: ST and T wave changes", section on 'Prolonged QT interval'.) Impact of U waves Identifying the termination of the T wave can be particularly difficult when a U wave is present. The U wave should not be included if it is distinct from and smaller than the T wave (generally excluded if the T wave has returned completely to the isoelectric line and then a U wave that is <one-half the amplitude of the preceding T wave is inscribed). Erroneous inclusion of the U wave in the QT interval measurement can lead to overdiagnosis of LQTS [11]. Which lead should be used? QT intervals vary significantly among leads [12]. Most normal reference ranges are based upon measurements from lead II, and lead V5 is often favored because of the clarity of T wave termination [13,14]. Additionally, some experts find leads V2 and V3 to be very useful, since QT measurements are typically the longest in these leads [12,14]. Other experts, however, avoid measuring the QT interval in leads V2 and V3, particularly in adolescents and children in whom a U wave is frequently present, making it more difficult to precisely determine the point of T wave termination. QT rate correction Under normal circumstances, the duration of repolarization depends upon the heart rate. The QT interval is longer at slower rates and shorter at faster rates. For this reason, formulas have been developed to "correct" the QT interval for heart rate (or the duration of the RR interval), although none is ideal (calculator 1) [8,15-17]. The most commonly used rate correction formula was developed by Bazett [18]: https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 4/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate QTc = QT interval RR interval (in sec) Although this approach is simple and generally accurate, it is less accurate at heart rate extremes and results in overcorrecting at high heart rates and undercorrecting at low heart rates [8]. Normative values are available for newborns and older children, which are standardized by age [19-21]. Normal QTc ranges Overall, the average QTc in healthy persons after puberty is 420 20 milliseconds, while during infancy the average QTc is 400 20 milliseconds. By contrast, the average QTc among patients with genetically confirmed LQTS is approximately 470 milliseconds, although patients with confirmed LQTS can exhibit a wide range of QTc values (360 to >800 milliseconds in our experts practices). In general, the 99th percentile QTc values are 460 milliseconds (prepuberty), 470 milliseconds in postpubertal males, and 480 milliseconds in postpubertal females. Asymptomatic patients who incidentally exceed these values on serial ECGs, and do not have any acquired QT-prolonging factors, should be evaluated further for the possibility of congenital LQTS as they now have a 10 percent chance of having LQTS (rather than the 1 in 2000 chance that they had prior to getting an ECG). Further, for asymptomatic children with an otherwise idiopathic QTc >480 milliseconds and asymptomatic adults with an otherwise idiopathic QTc >500 milliseconds, LQTS genetic testing is recommended since at these thresholds, LQTS is now more likely for that patient than merely being an extreme QTc outlier. Further, patients with a QTc >500 milliseconds are at increased risk of SCD. (See 'Genetic testing' below.) Special circumstances In addition to the methodologic and technical challenges discussed above, QT measurement and interpretation is complicated in the following situations: Atrial fibrillation (AF) Due to the irregular changes in the RR interval, the QT interval can vary on a beat-to-beat basis during AF. To accommodate this variability, some clinicians recommend averaging the measurements over 10 beats. Others advise measuring the QT intervals that follow the longest and shortest RR intervals in the ECG, then dividing each by the square root of the preceding RR interval [15]. The average of these two values is then used as the corrected QT interval. Still others find the measurement of QT and QTc in AF to be completely unreliable and instead focus on the look of repolarization (T wave morphology characteristics) rather than trying to measure the length of repolarization in AF. https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 5/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Sinus arrhythmia Similarly, in cases with marked RR variability, the QT rate correction formulas may not be as accurate, and taking an average of multiple beats can reduce the variation due to respiratory sinus arrhythmia. Another approach in such patients is to attempt to identify beats which are further away from any longer pauses and measure the QT in those beats. QRS prolongation QT prolongation usually reflects abnormal repolarization, but when depolarization (the QRS complex) is abnormal and prolonged, the significance of mild QT prolongation is uncertain. It has been suggested that measurement of the JT interval (defined as the QT interval minus the QRS duration) may be a more appropriate way to identify abnormalities in repolarization in such patients [22]. The normal JTc is less than 360 milliseconds in children without LQTS and is typically greater than 360 milliseconds in children with LQTS [22]. However, the validity of using the JT interval in this manner has been questioned. An alternative approach is to adjust the QT interval as a linear function to account for QRS duration and heart rate in the setting of ventricular conduction delay [23]. Another approach is to use a threshold of 500 milliseconds for a prolonged QTc in the setting of a wide QRS complex [15]. However, this threshold will result in an overdiagnosis of LQTS. Importantly, patients with congenital LQTS almost never have concomitantly prolonged QRS values. Recalling JT interval norms is also problematic. Instead, a simple wide QRS adjustment formula can be used: Wide QRS adjusted QTc = QTc [QRS 100] Other ECG features The T waves of patients with congenital LQTS are frequently abnormal with a biphasic contour or a prominent notched component (particularly in LQT2). However, this finding is fairly insensitive, and the absence of an abnormal T wave morphology does not exclude patients from having congenital LQTS. In one report, notched or biphasic T waves were present in 62 percent of patients with LQTS compared with 15 percent of control subjects [24]. A variety of other atypical T wave shapes have also been described in LQTS [25]. In experienced hands, T wave morphology, when coupled with knowledge about arrhythmia triggers, may suggest a particular genotype (such as notched T waves plus auditory triggers during the postpartum period equating with LQT2), but the presence or absence of T wave abnormalities does not alter the diagnostic evaluation in any notable way. Exercise testing In nearly all patients (ie, those who are old enough to cooperate and are capable of performing an exercise protocol) with known or suspected congenital LQTS, we perform an exercise (treadmill or bicycle) ECG stress test as part of the initial diagnostic evaluation. Additionally, for patients diagnosed with congenital LQTS, we repeat an exercise ECG https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 6/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate stress test every one to five years (annually for previously symptomatic patients, less frequently for asymptomatic, low-risk adults) as part of the ongoing follow-up. The response to ECG testing in patients with suspected congenital LQTS is frequently subtle and complex, requiring a high degree of aptitude to correctly interpret and diagnose the findings. If doubt exists surrounding the interpretation or implication of ECG findings post-exercise, the patient should be referred to a clinician with specific expertise and experience with congenital LQTS. ECG stress testing in patients with suspected congenital LQTS is performed to assess for exercise-associated arrhythmias, changes in T wave morphology, and the presence of a maladaptive QT response during the recovery phase. Physiologically, the QT interval shortens with exercise and with increased heart rate. By contrast, in individuals with LQT1, the QT interval may fail to shorten or may lengthen with exertion and at higher heart rates, and may be prolonged during the recovery phase after exercise. At least part of the variability in the response to exercise in LQTS patients results from different responses among the major types of congenital LQTS: Patients with LQT1 have diminished shortening of the QT interval and a reduced chronotropic response during exercise followed by exaggerated lengthening of the QT interval as the heart rate declines during early and late (eg, one and four minutes) recovery after exercise [26-28]. This is due to the fact that their pathogenic variants impair the function of the Kv7.1 outward-rectifying potassium channels, which contributes to shortening the action potential during activation of the sympathetic nervous system. Many patients with LQT2 have marked QT interval shortening and a normal chronotropic response during exercise, although there are exceptions [26,29]. There is exaggerated lengthening of the QT interval as the heart rate declines during late recovery (eg, > four minutes) after exercise [26,28]. These characteristics may explain the observation that many cardiac events occur during exercise in LQT1 ( figure 1) [30]. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Triggers of arrhythmia'.) Accentuated heart rate recovery following standard exercise testing, a marker of vagal activity, appears to be a marker of increased risk of cardiac events (syncope or aborted SCD) in patients with LQT1. Among 169 patients identified as LQT1 genotype positive who underwent standard exercise testing and achieved similar maximal heart rate and workloads, those with prior cardiac events had a significantly greater heart rate recovery during the first minute following exercise compared with those without prior events (19 versus 13 beats per minute in a 47 patient South African cohort; 27 versus 20 beats per minute in a 122 patient Italian cohort) [31]. Greater heart https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 7/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate rate reductions immediately following exercise in persons positive for the LQT1 genotype appear to risk stratify them at a higher risk of arrhythmic events. The response of QTc during exercise recovery may be helpful in identifying LQTS in asymptomatic relatives of individuals with LQTS as well as in identifying probands [28]. Supine QTc at rest: If 470 milliseconds in males or 480 milliseconds in females with personal or family history suspicious for LQTS, then the patient has high probability LQTS (estimated at >90 percent likelihood). However, if the patient exceeds these QTc thresholds but is <500 milliseconds AND has no personal or family history to suggest LQTS, then although the patient is graded as intermediate probability LQTS by the Schwartz score, this should not be viewed as definite LQTS. Instead, the patient has a small but definite chance (5 to 20 percent) of having congenital LQTS. If normal or borderline normal Check the QTc during the recovery phase of the stress test. Recovery QTc at two, three, or four minutes into recovery after peak exercise: If QTc 470 milliseconds, then there is an estimated 70 percent positive predictive value (PPV) for unmasking LQT1 [32]. If the QTc at five minutes of recovery is 470 milliseconds and is 40 to 50 milliseconds greater than the QTc at one minute of recovery (ie, QTc latency), then LQT2 is possible (approximately 70 percent PPV). The QTc values shorten during exercise and in recovery in patients with LQT3, and therefore stress testing is not helpful in LQT3. However, if the patient exhibits QT prolongation at rest and then the QTc shortens at peak exercise and in recovery, then LQT3 emerges as the possible underlying genotype. In addition, the stress test is often used to assess the adequacy of beta blockade by noting a measurable reduction in maximum heart rate. However, there is no particular threshold of peak heart rate reduction (ie, 20, 25, 30 percent, etc) that guarantees protection from ventricular arrhythmias and SCD. Instead, this assessment at least confirms that reasonable levels of beta blocker have been achieved in the patient. Ambulatory ECG monitoring In patients with known or suspected congenital LQTS, we perform ambulatory ECG monitoring to help establish the diagnosis of LQTS and to add https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 8/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate corroborative information in borderline cases [33-36]. The QT interval and other ECG features of LQTS may vary with activity and time of day. Holter monitoring can detect intermittent QT prolongation, bradyarrhythmia, macroscopic T wave alternans, and T wave notching [33,35,36]. A 12-lead ambulatory ECG monitor can be helpful to detect abnormal changes in T wave morphology, especially at night. The results of ambulatory monitoring should be interpreted with caution, however, since patients without congenital LQTS can have QT intervals over the normal limits at times, reducing the specificity of Holter monitor QTc results [37]. However, this usually happens with rapid heart rate increases, and the expert observer is not misled. Discrepancies in measurements may occur when Holter recordings are compared with standard ECGs. Given the limitations of Holter monitoring for establishing the diagnosis of LQTS, we do not recommend making the diagnosis of LQTS based solely on the QTc measurement during ambulatory recordings. The results of such testing should be used only as ancillary information. Provocative testing In some patients, the diagnosis of congenital LQTS may be uncertain after application of the diagnostic criteria outlined above. Additional testing, including serial cardiologic testing of the index case and appropriate relatives and provocative electrocardiographic testing with catecholamines (the epinephrine QT stress test), facial immersion, abrupt supine-to-standing ECG, or mental stress test [38], may be helpful in such patients. However, these tests must be interpreted with great caution as the positive predictive values are generally 70 percent or less. Genetic testing Our recommendations for genetic testing in the evaluation of suspected congenital LQTS are generally in accord with those of professional societies [39-41]. We proceed with genetic testing in the following instances: Patients with a high clinical suspicion of congenital LQTS based on history, family history, ECG findings, and results of any additional testing, such as a high Schwartz score 3.5 (Class I recommendation). Patients with an intermediate clinical suspicion of congenital LQTS based on history, family history, ECG findings, and results of any additional testing, such as an intermediate Schwartz score of 1.5 to 3 (Class II recommendation). Asymptomatic patients without a family history of congenital LQTS but who have serial ECGs with QTc 480 milliseconds before puberty or 500 milliseconds post-puberty (Class I recommendation). https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 9/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Asymptomatic patients without a family history of congenital LQTS but who have serial ECGs with QTc 460 milliseconds before puberty or 480 milliseconds post-puberty (Class II recommendation). Cascade/variant-specific testing of all appropriate relatives when the disease-causative variant has been identified in the proband (Class I recommendation). This generally proceeds in concentric circles of relatedness. For example, if the LQTS- causative variant was inherited paternally, then the paternal aunts and uncles are tested first rather than testing them and the cousins at the same time. If an aunt, for example, tests negative, then there is generally no need to perform cascade testing on that aunt's children. Among families with genetically proven/confirmed LQTS, it is unacceptable to tell family members/relatives that they do or do not have LQTS based solely on their ECG. Only a negative variant-specific genetic test result and a normal ECG in that relative can prompt the conclusion that the relative does not have LQTS and can be dismissed from follow-up. Genetic testing will identify a specific LQTS-causative variant in approximately 80 percent of patients with a high probability LQTS diagnosis (ie, Schwartz score >3.5). It may establish the diagnosis when it is uncertain, allow for efficient identification of affected family members, and have prognostic and therapeutic utility by determining which gene is involved. (See "Congenital long QT syndrome: Pathophysiology and genetics".) Genetic testing to identify the patient's LQTS-causative variant is now more readily available for clinical use [4,7,42-44]. As a result, genotyping has become more frequently utilized as part of the diagnostic and prognostic evaluation of patients with congenital LQTS. However, congenital LQTS is a complex and genetically heterogeneous condition, so a negative test does not exclude disease. Nevertheless, when a negative genetic test is obtained (which by itself rules out approximately 80 percent of congenital LQTS), it is very reasonable to reassess the veracity of the clinical diagnosis of congenital LQTS. If the diagnosis is robust, then the patient belongs to the 20 percent subset of genotype negative congenital LQTS patients, and the patient and their family should be connected to research laboratories to search for their genetic cause of LQTS. On the other hand, if the strength of the evidence was weak/inconclusive in the first place, then a negative genetic test can help begin the subsequent reevaluation efforts to move away from and rescind the previously rendered diagnosis of congenital LQTS, which can involve the removal of previously implanted defibrillators as well [45,46]. This is yet another reason why consideration for referral to LQTS specialty centers should be given. In one dedicated LQTS clinic, 40 percent of the patients who came with the diagnosis of LQTS were dismissed without the diagnosis of LQTS, with the vast majority of those being reclassified as otherwise healthy without any evidence of important heart disease [45]. https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 10/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Genetic testing in LQTS is discussed in detail separately. (See "Congenital long QT syndrome: Pathophysiology and genetics".) DIAGNOSIS For all patients in whom congenital LQTS is suspected following the initial evaluation, we calculate the Schwartz score to better estimate the clinical likelihood of a congenital LQTS diagnosis and proceed directly to phenotype-directed genetic testing (ie, the genetic test panel that comprises the established LQTS-susceptibility genes) ( table 3). A weighted, non-genetic scoring system for the diagnosis of congenital LQTS, also called the "Schwartz score," incorporates the measured QTc and other clinical and historical factors; the score was developed in 1985 [47] and revised in 1993 [48], 2006 [49], and 2011 [50]. An algorithm was developed in which diagnostic criteria were assigned points as follows ( table 3): ECG findings (in the absence of medications or disorders known to affect these features): QTc (= QT/ RR, interpret with caution with tachycardia since QTc overcorrects at fast heart rates) - - 480 milliseconds: 3 points 460 to 479 milliseconds: 2 points 450 to 459 milliseconds (in males): 1 point QTc at fourth minute of recovery from exercise stress test 480 milliseconds: 1 point [50] (see 'Exercise testing' above) Torsades de pointes* (in the absence of drugs known to prolong QT): 2 points T wave alternans: 1 point Notched T wave in three leads: 1 point Resting heart rate below second percentile for age (restricted to children): 0.5 point Clinical findings: Syncope* (*Points for documented torsade and syncope are mutually exclusive) - With stress: 2 points Without stress: 1 point https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 11/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Family history (the same family member cannot be counted in both of these criteria): Family members with LQTS: 1 point Unexplained SCD in immediate family members <30 years of age: 0.5 point The points are added to calculate the LQTS diagnostic score ("Schwartz Score"). The 2006 and 2011 versions rate the probability of having LQTS according to the number of accrued points [49,50]: Low 1 point Intermediate 1.5 to 3 points High 3.5 points When a patient satisfies a high probability Schwartz score (ie, 3.5 points), the likelihood of a positive LQTS genetic test is approximately 80 percent. While an intermediate probability Schwartz score warrants further pursuit of the possibility of congenital LQTS (ie, genetic testing of the patient and ECG testing of his/her relatives), it does not equal a diagnosis of congenital LQTS. In this setting, the likelihood of LQTS is approximately a 5 to 20 percent chance, far higher than the 1 in 2000 background rate for this disease. In such a patient, when genetic testing is pursued, and if it comes back negative (thereby ruling out 80 percent of LQTS by itself), such a patient with an "intermediate probability" Schwartz score could be dismissed as normal eventually with insufficient evidence to merit the diagnosis of LQTS. Importantly, if the Schwartz score is low (<1 point), genetic testing should not be pursued. Do not label such individuals as borderline LQTS or possible LQTS. Instead, in most circumstances, these patients should be reclassified quickly as normal and dismissed from follow-up. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 12/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Long QT syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1), ventricular arrhythmias, and an increased risk of sudden cardiac death (SCD) caused by torsades de pointes or "twisting of the points" ( waveform 2). (See 'Introduction' above.) LQTS may be congenital or acquired. Pathogenic variants in up to 17 genes have been identified thus far in patients with genetic LQTS; the major and most important genetic subtypes are designated LQT1 through LQT3, while the minor LQTS-susceptibility genes are designated by their genetic substrate such as CALM1-LQTS, for example ( table 1). (See 'Introduction' above.) The initial diagnostic strategy includes evaluation of the presenting event (eg, syncope, seizures, sudden cardiac arrest, or SCD), obtaining a careful family history, careful evaluation of the QTc, exclusion of secondary causes of QT prolongation, ambulatory ECG monitoring (with 12-lead ECG if at all possible), exercise testing, and calculation of the LQTS diagnostic score (the "Schwartz score"). (See 'Our approach' above.) Obtaining a detailed personal medical history and multi-generation family history is crucial in determining the pretest likelihood of congenital LQTS. The personal clinical history should focus on signs and symptoms suggestive of tachyarrhythmia, particularly ventricular tachyarrhythmias, as many LQTS families have pre-sudden death warning signs including syncope suggestive of cardiac etiology, syncope followed by generalized seizures, or resuscitated sudden cardiac arrest. (See 'Clinical and family history' above.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 13/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate All patients being evaluated for congenital LQTS should have a 12-lead ECG performed. The QT interval should be measured manually on serial ECGs using multiple leads (preferably leads II and V5), and then corrected for heart rate. The heart rate corrected QT interval (QTc) is the most useful diagnostic and prognostic parameter for LQTS. The computer- derived QTc should always be confirmed or corrected manually. Since the QTc varies in response to physiologic factors and drugs, the sensitivity of a QTc from a single ECG is less than 100 percent, and serial ECG testing is required frequently. (See '12-lead ECG' above.) The average QTc values in healthy adults are 420 20 milliseconds with 99th percentile values being 460 milliseconds (prepuberty), 470 milliseconds (postpubertal males), and 480 milliseconds (postpubertal females). (See 'Normal QTc ranges' above.) Other ECG features of LQTS include abnormal T wave morphology, T wave alternans, and increased QT dispersion. (See 'Other ECG features' above.) In nearly all patients (ie, those who are old enough to cooperate and are capable of performing an exercise protocol) with known or suspected congenital LQTS, we perform an exercise (treadmill or bicycle) ECG stress test as part of the initial diagnostic evaluation to assess for exercise-associated arrhythmias, changes in T wave morphology, and the presence of maladaptive QT response during the recovery phase. (See 'Exercise testing' above.) In patients with known or suspected congenital LQTS, we perform ambulatory ECG monitoring (with 12-lead ECG if available) to help establish the diagnosis of LQTS and to add corroborative information in borderline cases. (See 'Ambulatory ECG monitoring' above.) The LQTS diagnostic score ("Schwartz score") may be helpful in evaluating individuals with suspected LQTS but is not adequate for screening of family members of affected individuals. (See 'Diagnosis' above.) Genetic testing will identify a specific LQTS-causative variant in approximately 80 percent of patients with a definite diagnosis of LQTS. Genetic testing should be viewed as standard of care in the diagnostic and prognostic evaluation of LQTS on par with the ECG itself. It may establish the diagnosis when it is uncertain, allow for efficient identification of affected family members, and have prognostic and therapeutic utility by determining which gene is involved. By all major cardiac societies throughout the world, genetic testing is indicated clinically for any patient in whom the diagnosis of LQTS is being considered or for whom the diagnosis of LQTS has been established already. (See 'Genetic testing' above.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 14/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Among families with genetically proven/confirmed LQTS, it is unacceptable to tell family members/relatives that they do or do not have LQTS based solely on their ECG. Only a negative variant-specific genetic test result and a normal ECG in that relative can prompt the conclusion that the relative does not have LQTS and can be dismissed from follow-up. (See 'Genetic testing' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013; 34:3109. 2. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350:1013. 3. Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med 2002; 112:58. 4. Wehrens XH, Vos MA, Doevendans PA, Wellens HJ. Novel insights in the congenital long QT syndrome. Ann Intern Med 2002; 137:981. 5. Camm AJ, Janse MJ, Roden DM, et al. Congenital and acquired long QT syndrome. Eur Heart J 2000; 21:1232. 6. Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol 2000; 36:1. 7. Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AAM. Impact of genetics on the clinical management of channelopathies. J Am Coll Cardiol 2013; 62:169. 8. Funck-Brentano C, Jaillon P. Rate-corrected QT interval: techniques and limitations. Am J Cardiol 1993; 72:17B. 9. Malik M. Problems of heart rate correction in assessment of drug-induced QT interval prolongation. J Cardiovasc Electrophysiol 2001; 12:411. 10. M nnig G, Eckardt L, Wedekind H, et al. Electrocardiographic risk stratification in families with congenital long QT syndrome. Eur Heart J 2006; 27:2074. 11. Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation 2007; 115:2613. 12. Cowan JC, Yusoff K, Moore M, et al. Importance of lead selection in QT interval measurement. Am J Cardiol 1988; 61:83. 13. Goldman MJ. Principles of Clinical Electrocardiography, 8th ed, Lange Medical Pub, Los Altos 1973.

th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 12/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Long QT syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1), ventricular arrhythmias, and an increased risk of sudden cardiac death (SCD) caused by torsades de pointes or "twisting of the points" ( waveform 2). (See 'Introduction' above.) LQTS may be congenital or acquired. Pathogenic variants in up to 17 genes have been identified thus far in patients with genetic LQTS; the major and most important genetic subtypes are designated LQT1 through LQT3, while the minor LQTS-susceptibility genes are designated by their genetic substrate such as CALM1-LQTS, for example ( table 1). (See 'Introduction' above.) The initial diagnostic strategy includes evaluation of the presenting event (eg, syncope, seizures, sudden cardiac arrest, or SCD), obtaining a careful family history, careful evaluation of the QTc, exclusion of secondary causes of QT prolongation, ambulatory ECG monitoring (with 12-lead ECG if at all possible), exercise testing, and calculation of the LQTS diagnostic score (the "Schwartz score"). (See 'Our approach' above.) Obtaining a detailed personal medical history and multi-generation family history is crucial in determining the pretest likelihood of congenital LQTS. The personal clinical history should focus on signs and symptoms suggestive of tachyarrhythmia, particularly ventricular tachyarrhythmias, as many LQTS families have pre-sudden death warning signs including syncope suggestive of cardiac etiology, syncope followed by generalized seizures, or resuscitated sudden cardiac arrest. (See 'Clinical and family history' above.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 13/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate All patients being evaluated for congenital LQTS should have a 12-lead ECG performed. The QT interval should be measured manually on serial ECGs using multiple leads (preferably leads II and V5), and then corrected for heart rate. The heart rate corrected QT interval (QTc) is the most useful diagnostic and prognostic parameter for LQTS. The computer- derived QTc should always be confirmed or corrected manually. Since the QTc varies in response to physiologic factors and drugs, the sensitivity of a QTc from a single ECG is less than 100 percent, and serial ECG testing is required frequently. (See '12-lead ECG' above.) The average QTc values in healthy adults are 420 20 milliseconds with 99th percentile values being 460 milliseconds (prepuberty), 470 milliseconds (postpubertal males), and 480 milliseconds (postpubertal females). (See 'Normal QTc ranges' above.) Other ECG features of LQTS include abnormal T wave morphology, T wave alternans, and increased QT dispersion. (See 'Other ECG features' above.) In nearly all patients (ie, those who are old enough to cooperate and are capable of performing an exercise protocol) with known or suspected congenital LQTS, we perform an exercise (treadmill or bicycle) ECG stress test as part of the initial diagnostic evaluation to assess for exercise-associated arrhythmias, changes in T wave morphology, and the presence of maladaptive QT response during the recovery phase. (See 'Exercise testing' above.) In patients with known or suspected congenital LQTS, we perform ambulatory ECG monitoring (with 12-lead ECG if available) to help establish the diagnosis of LQTS and to add corroborative information in borderline cases. (See 'Ambulatory ECG monitoring' above.) The LQTS diagnostic score ("Schwartz score") may be helpful in evaluating individuals with suspected LQTS but is not adequate for screening of family members of affected individuals. (See 'Diagnosis' above.) Genetic testing will identify a specific LQTS-causative variant in approximately 80 percent of patients with a definite diagnosis of LQTS. Genetic testing should be viewed as standard of care in the diagnostic and prognostic evaluation of LQTS on par with the ECG itself. It may establish the diagnosis when it is uncertain, allow for efficient identification of affected family members, and have prognostic and therapeutic utility by determining which gene is involved. By all major cardiac societies throughout the world, genetic testing is indicated clinically for any patient in whom the diagnosis of LQTS is being considered or for whom the diagnosis of LQTS has been established already. (See 'Genetic testing' above.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 14/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Among families with genetically proven/confirmed LQTS, it is unacceptable to tell family members/relatives that they do or do not have LQTS based solely on their ECG. Only a negative variant-specific genetic test result and a normal ECG in that relative can prompt the conclusion that the relative does not have LQTS and can be dismissed from follow-up. (See 'Genetic testing' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013; 34:3109. 2. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350:1013. 3. Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med 2002; 112:58. 4. Wehrens XH, Vos MA, Doevendans PA, Wellens HJ. Novel insights in the congenital long QT syndrome. Ann Intern Med 2002; 137:981. 5. Camm AJ, Janse MJ, Roden DM, et al. Congenital and acquired long QT syndrome. Eur Heart J 2000; 21:1232. 6. Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol 2000; 36:1. 7. Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AAM. Impact of genetics on the clinical management of channelopathies. J Am Coll Cardiol 2013; 62:169. 8. Funck-Brentano C, Jaillon P. Rate-corrected QT interval: techniques and limitations. Am J Cardiol 1993; 72:17B. 9. Malik M. Problems of heart rate correction in assessment of drug-induced QT interval prolongation. J Cardiovasc Electrophysiol 2001; 12:411. 10. M nnig G, Eckardt L, Wedekind H, et al. Electrocardiographic risk stratification in families with congenital long QT syndrome. Eur Heart J 2006; 27:2074. 11. Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation 2007; 115:2613. 12. Cowan JC, Yusoff K, Moore M, et al. Importance of lead selection in QT interval measurement. Am J Cardiol 1988; 61:83. 13. Goldman MJ. Principles of Clinical Electrocardiography, 8th ed, Lange Medical Pub, Los Altos 1973. https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 15/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate 14. LEPESCHKIN E, SURAWICZ B. The measurement of the Q-T interval of the electrocardiogram. Circulation 1952; 6:378. 15. Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA 2003; 289:2120. 16. Toivonen L. More light on QT interval measurement. Heart 2002; 87:193. 17. Hnatkova K, Malik M. "Optimum" formulae for heart rate correction of the QT interval. Pacing Clin Electrophysiol 1999; 22:1683. 18. Bazett, HC . An analysis of the time-relations of electrocardiograms. Heart 1920; 7:353. 19. Schwartz PJ, Garson A Jr, Paul T, et al. Guidelines for the interpretation of the neonatal electrocardiogram. A task force of the European Society of Cardiology. Eur Heart J 2002; 23:1329. 20. Vink AS, Neumann B, Lieve KVV, et al. Determination and Interpretation of the QT Interval. Circulation 2018; 138:2345. 21. Stramba-Badiale M, Karnad DR, Goulene KM, et al. For neonatal ECG screening there is no reason to relinquish old Bazett's correction. Eur Heart J 2018; 39:2888. 22. Berul CI, Sweeten TL, Dubin AM, et al. Use of the rate-corrected JT interval for prediction of repolarization abnormalities in children. Am J Cardiol 1994; 74:1254. 23. Rautaharju PM, Zhang ZM, Prineas R, Heiss G. Assessment of prolonged QT and JT intervals in ventricular conduction defects. Am J Cardiol 2004; 93:1017. 24. Malfatto G, Beria G, Sala S, et al. Quantitative analysis of T wave abnormalities and their prognostic implications in the idiopathic long QT syndrome. J Am Coll Cardiol 1994; 23:296. 25. Zhang L, Timothy KW, Vincent GM, et al. Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes. Circulation 2000; 102:2849. 26. Swan H, Viitasalo M, Piippo K, et al. Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects. J Am Coll Cardiol 1999; 34:823. 27. Takenaka K, Ai T, Shimizu W, et al. Exercise stress test amplifies genotype-phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome. Circulation 2003; 107:838. 28. Sy RW, van der Werf C, Chattha IS, et al. Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands. Circulation 2011; 124:2187. 29. Schwartz PJ, Priori SG, Locati EH, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 16/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate increases in heart rate. Implications for gene-specific therapy. Circulation 1995; 92:3381. 30. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001; 103:89. 31. Crotti L, Spazzolini C, Porretta AP, et al. Vagal reflexes following an exercise stress test: a simple clinical tool for gene-specific risk stratification in the long QT syndrome. J Am Coll Cardiol 2012; 60:2515. 32. Horner JM, Horner MM, Ackerman MJ. The diagnostic utility of recovery phase QTc during treadmill exercise stress testing in the evaluation of long QT syndrome. Heart Rhythm 2011; 8:1698. 33. Eggeling T, Hoeher M, Osterhues HH, et al. Significance of noninvasive diagnostic techniques in patients with long QT syndrome. Am J Cardiol 1992; 70:1421. 34. Garson A Jr, Dick M 2nd, Fournier A, et al. The long QT syndrome in children. An international study of 287 patients. Circulation 1993; 87:1866. 35. Eggeling T, Osterhues HH, Hoeher M, et al. Value of Holter monitoring in patients with the long QT syndrome. Cardiology 1992; 81:107. 36. Lupoglazoff JM, Denjoy I, Berthet M, et al. Notched T waves on Holter recordings enhance detection of patients with LQt2 (HERG) mutations. Circulation 2001; 103:1095. 37. Mauriello DA, Johnson JN, Ackerman MJ. Holter monitoring in the evaluation of congenital long QT syndrome. Pacing Clin Electrophysiol 2011; 34:1100. 38. Etienne P, Huchet F, Gaborit N, et al. Mental stress test: a rapid, simple, and efficient test to unmask long QT syndrome. Europace 2018; 20:2014. 39. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013; 10:1932. 40. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm 2011; 8:1308. 41. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation 2018; 138:e272. https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 17/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate 42. Priori SG, Barhanin J, Hauer RN, et al. Genetic and molecular basis of cardiac arrhythmias: impact on clinical management parts I and II. Circulation 1999; 99:518. 43. Priori SG, Barhanin J, Hauer RN, et al. Genetic and molecular basis of cardiac arrhythmias: impact on clinical management part III. Circulation 1999; 99:674. 44. Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000; 102:1178. 45. Taggart NW, Haglund CM, Ackerman MJ. Diagnostic miscues in congenital long QT syndrome. Heart Rhythm 2006; 3:S67. 46. Gaba P, Bos JM, Cannon BC, et al. Implantable cardioverter-defibrillator explantation for overdiagnosed or overtreated congenital long QT syndrome. Heart Rhythm 2016; 13:879. 47. Schwartz PJ. Idiopathic long QT syndrome: progress and questions. Am Heart J 1985; 109:399. 48. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation 1993; 88:782. 49. Schwartz PJ. The congenital long QT syndromes from genotype to phenotype: clinical implications. J Intern Med 2006; 259:39. 50. Schwartz PJ, Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation 2011; 124:2181. Topic 1053 Version 31.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 18/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate GRAPHICS Single-lead electrocardiogram showing a prolonged QT interval The corrected QT interval (QTc) is calculated by dividing the QT interval (0.60 seconds) by the square root of the preceding RR interval (0.92 seconds). In this case, the QTc is 0.625 seconds (625 milliseconds). Graphic 77018 Version 7.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 19/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Single lead electrocardiogram (ECG) showing torsades de pointes The electrocardiographic rhythm strip shows torsades de pointes, a polymorphic ventricular tachycardia associated with QT prolongation. There is a short, preinitiating RR interval due to a ventricular couplet, which is followed by a long, initiating cycle resulting from the compensatory pause after the couplet. Graphic 73827 Version 4.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 20/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Summary of heritable arrhythmia syndrome susceptibility genes: Long QT syndrome (LQTS) Gene Locus Protein Major LQTS genes KCNQ1 (LQT1) 11p15.5 I Ks Kv7.1) potassium channel alpha subunit (KVLQT1, KCNH2 (LQT2) 7q35-36 I Kr Kv11.1) potassium channel alpha subunit (HERG, SCN5A (LQT3) 3p21-p24 Cardiac sodium channel alpha subunit (NaV1.5) Minor LQTS genes AKAP9 7q21-q22 Yotiao CACNA1C 12p13.3 Voltage gated L-type calcium channel (CaV1.2) CALM1 14q32.11 Calmodulin 1 CALM2 2p21 Calmodulin 2 CALM3 19q13.2-q13.3 Calmodulin 3 CAV3 3p25 Caveolin-3 KCNE1 21q22.1 Potassium channel beta subunit (MinK) KCNE2 21q22.1 Potassium channel beta subunit (MiRP1) KCNJ5 11q24.3 Kir3.4 subunit of I channel KACH SCN4B 11q23.3 Sodium channel beta 4 subunit SNTA1 20q11.2 Syntrophin-alpha 1 TRDN 6q22.31 Triadin Adapted from: Tester DJ, Ackerman MJ. Genetics of cardiac arrhythmias. In: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 10th ed, Mann DL, Zipes DP, Libby P, et al (Eds), Elsevier, Philadelphia 2015. Graphic 114927 Version 2.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 21/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial ischemia or infarction, GnRH agonist/antagonist therapy Hypomagnesemia Bilateral surgical orchiectomy Hypocalcemia Diuretic therapy via electrolyte disorders particularly hypokalemia and hypomagnesemia especially with prominent T-wave inversions Starvation Anorexia nervosa Herbs Liquid protein diets Cinchona (contains quinine), iboga (ibogaine), licorice extract in overuse via electrolyte disturbances Intracranial disease Hypothyroidism Bradyarrhythmias HIV infection Sinus node dysfunction Hypothermia Toxic exposure: Organophosphate AV block: Second or third degree insecticides Medications* High risk Adagrasib Cisaparide (restricted availability) Lenvatinib Selpercatinib Ajmaline Levoketoconazole Sertindole Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine (intracoronary) Vandetanib Dofetilide Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab Propafenone ozogamacin Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Carbetocin Erythromycin Ribociclib https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 22/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Certinib Escitalopram Levofloxacin (systemic) Risperidone Chloroquine Etelcalcetide Saquinavir Lofexidine Citalopram Fexinidazole Sevoflurane Meglumine antimoniate Clarithromycin Flecainide Sparfloxacin Clofazimine Floxuridine Sunitinib Midostaurin Clomipramine Fluconazole Tegafur Moxifloxacin Clozapine Fluorouracil (systemic) Terbutaline Nilotinib Crizotinib Thioridazine Olanzapine Flupentixol Dabrafenib Toremifene Ondansetrol (IV > oral) Gabobenate dimeglumine Dasatinib Vemurafenib Deslurane Voriconazole Osimertinib Gemifloxacin Domperidone Oxytocin Gilteritinib Doxepin Pazopanib Halofantrine Doxifluridine Pentamidine Haloperidol (oral) Pilsicainide Imipramine Pimozide Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole Romidepsin Anagrelide Foscarnet (systemic) Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- Glasdegib Mizolastine lumefantrine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine Nortriptyline Benperidol (rare reports) Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus Olodaterol (systemic) Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 23/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Leuprolide- norethindrone Periciazine Tropisetron Dexmedetomidine** Pimavanserin Vardenafil Levalbuterol Dolasetron Pipamperone Vilanterol Levomethadone Donepezil Pitolisant Vinflunine Lithium Efavirenz Ponesimod Voclosporin Loperamide in Eliglustat Primaquine Vorinostat overdose Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM [1,2] 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 24/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 25/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Triggers for cardiac events in long QT syndrome are related to genotype In a study of 670 patients with long QT syndrome and known genotype, all symptomatic (syncope, aborted cardiac arrest, or sudden death), the occurrence of a lethal cardiac event (n = 110) provoked by a specific trigger (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced most of their events (90%) during exercise or emotion. These percentages were almost reversed among LQT2 and LQT3 patients who had most of their events during rest or sleep (63 and 80%, respectively); by contrast, they were at almost no risk of major events during exercise (arrows), which is explained by their having a normal I current. Ks ACA: aborted cardiac arrest; SCD: sudden cardiac death. Modi ed from: Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-speci c triggers for life-threatening arrhythmias. Circulation 2001; 103:89. Graphic 64239 Version 3.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 26/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Schwartz score diagnostic criteria for long QT syndrome (LQTS) Points Electrocardiographic findings* A. QTc 3 480 ms 2 460 to 479 ms 1 450 to 459 ms (in males) 1 B. QTc fourth minute of recovery from exercise stress test 480 ms 2 C. Torsades de pointes 1 D. T wave alternans 1 E. Notched T wave in 3 leads 0.5 F. Low heart rate for age Clinical history A. Syncope 2 With stress 1 Without stress 0.5 B. Congenital deafness Family history 1 A. Family members with definite LQTS 0.5 B. Unexplained sudden cardiac death below age 30 among immediate family members SCORE: 1 point = low probability of long QT syndrome (LQTS). 1.5 to 3 points = intermediate probability of LQTS. 3.5 points = high probability of LQTS. In the absence of medications or disorders known to affect these electrocardiographic features. QTc calculated by Bazett's formula where QTc = QT/ RR. Mutually exclusive. Resting heart rate below the second percentile for age. https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 27/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate The same family member cannot be counted in A and B. From: Schwartz PJ, Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation 2011; 124:2181. DOI: 10.1161/CIRCULATIONAHA.111.062182. Copyright 2011 American Heart Association. Reproduced with permission from Lippincott Williams & Wilkins. Unauthorized reproduction of this material is prohibited. Graphic 113828 Version 4.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 28/29 7/6/23, 11:06 AM Congenital long QT syndrome: Diagnosis - UpToDate Contributor Disclosures Peter J Schwartz, MD No relevant financial relationship(s) with ineligible companies to disclose. Michael J Ackerman, MD, PhD Consultant/Advisory Boards: Abbott [Education around ICD/device therapy for genetic heart diseases including LQTS]; ARMGO Pharma [Novel therapies for genetic heart diseases, CPVT in particular]; Boston Scientific [Education around ICD/device therapy for genetic heart diseases including LQTS]; Daiichi Sankyo [Drug-induced QT prolongation for one of their drugs]; Invitae [Genetic testing for genetic heart diseases]; LQT Therapeutics [Development of a novel QT-shortening medication]; Medtronic [Education around ICD/device therapy for genetic heart diseases including LQTS]; UpToDate [Genetic heart diseases, especially LQTS]. Other Financial Interest: AliveCor [QTc analytics for smartphone-enabled mobile ECG]; Anumana [Artificial intelligence ECG for early detection of hypertrophic cardiomyopathy]; Pfizer [Gene therapy for genetic heart diseases including LQTS]. All of the relevant financial relationships listed have been mitigated. John K Triedman, MD Consultant/Advisory Boards: Biosense Webster and Sentiar [Supraventricular and ventricular topics]. All of the relevant financial relationships listed have been mitigated. Samuel Asirvatham, MD Grant/Research/Clinical Trial Support: Medtronic [Defibrillators]; St Jude's [Sudden Cardiac Death]. Consultant/Advisory Boards: BioTronik [Defibrillators]; Boston Scientific [Sudden Cardiac Death]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/print 29/29

7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Congenital long QT syndrome: Epidemiology and clinical manifestations : Peter J Schwartz, MD, Michael J Ackerman, MD, PhD : John K Triedman, MD, Samuel Asirvatham, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 20, 2023. INTRODUCTION Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death (SCD) [1,2]. The primary symptoms in patients with LQTS include arrhythmic syncope, arrhythmic syncope followed by generalized seizures, and sudden cardiac arrest (SCA). These LQTS-triggered symptoms stem from a characteristic life-threatening cardiac arrhythmia known as torsades de pointes or "twisting of the points" ( waveform 2A-B) [3,4]. LQTS may be congenital or acquired [1,5]. Likely pathogenic or pathogenic variants in at least 17 genes have been identified thus far in patients with congenital LQTS ( table 1) [5]. However, pathogenic variants in the three canonical genes, KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3), account for approximately 80 to 90 percent of all congenital LQTS cases, with pathogenic variants in the minor LQTS-susceptibility genes contributing approximately 5 percent. An estimated 10 percent of patients satisfying a robust clinical diagnosis of LQTS will have a negative LQTS genetic test. Acquired LQTS usually results from undesired QT prolongation and potential for QT-triggered arrhythmias by either QT-prolonging disease states, QT-prolonging medications ( www.crediblemeds.org), or QT-prolonging electrolyte disturbances ( table 2) [6]. (See "Congenital long QT syndrome: Pathophysiology and genetics".) https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 1/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate While disease-causative variants in numerous genes have been identified in patients with congenital LQTS, two clinical phenotypes have been described that differ in the type of inheritance and the presence or absence of sensorineural hearing loss: The more common autosomal dominant form, originally named the Romano-Ward syndrome, has a purely cardiac phenotype of QT prolongation and QT-triggered cardiac events. (See "Congenital long QT syndrome: Pathophysiology and genetics".) The autosomal recessive form, originally named the Jervell and Lange-Nielsen syndrome, is associated with LQTS and sensorineural deafness, and a more malignant clinical course [7]. (See 'Congenital sensorineural deafness' below.) The epidemiology, clinical features, and conditions that are associated with congenital LQTS will be reviewed here. The diagnosis and management of congenital LQTS in children and adults and the clinical features of acquired LQTS are discussed separately. (See "Congenital long QT syndrome: Diagnosis" and "Congenital long QT syndrome: Treatment" and "Acquired long QT syndrome: Definitions, pathophysiology, and causes" and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) EPIDEMIOLOGY In contrast with other channelopathies that are less common, the prevalence of congenital LQTS is at least 1 in 2000 live births. This prevalence, derived from a prospective study in over 44,000 infants with the combination of ECG and genetic testing, refers to the infants who have an LQTS- causing genetic variant plus manifest a prolonged QT interval [8]. The prevalence of LQTS including genotype positive/phenotype negative individuals is obviously higher, but difficult to quantify, and is probably close to 1 in 1000 persons overall. The frequency of LQTS-causative variants may be much greater since some pathogenic variants result in only subtle clinical abnormalities and do not come to medical attention. Penetrance is variable and can be as low as 10 to 25 percent [9]. (See "Congenital long QT syndrome: Pathophysiology and genetics".) LQTS is highly penetrant early in life among patients with the Jervell and Lange-Nielsen syndrome, multiple LQTS-causative variants but without deafness, and in the much rarer infantile/toddler forms of malignant LQTS stemming from autosomal dominant or sporadic variants in the CALM-encoded calmodulin proteins (ie, the Calmodulinopathies) [10] and homozygous/compound heterozygous mutations in TRDN-encoded triadin (ie, the Triadin Knockout Syndrome) [11]. (See 'Congenital sensorineural deafness' below.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 2/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate CLINICAL MANIFESTATIONS The clinical manifestations of congenital LQTS are highly variable. The majority of individuals with LQTS are asymptomatic at diagnosis and remain so their entire life. Symptomatic patients present most commonly with LQTS-triggered syncope or syncope followed by generalized seizures. In fact, many patients with LQTS continue to be misdiagnosed as having epilepsy and treated incorrectly with anti-epileptic medications. Uncommonly, the sentinel event can be SCD [1]. Patients without symptoms typically come to medical attention because they have an affected family member and either their surveillance ECG and/or their family-specific genetic variant test has identified them as having LQTS (either phenotypically or genotypically). In addition, asymptomatic individuals with LQTS are being discovered increasingly by a prolonged QTc (QT interval corrected for heart rate) that was detected by an ECG obtained for some other reason including pre-sports participation screening tests. The clinical manifestations of LQTS have been described in several large cohorts, with the following three being the most prominent [12,13]: The largest cohort of patients with LQTS, from the International Long QT Syndrome Registry, included 3343 individuals (all with QTc >440 milliseconds) from 328 families [13]. The proband (or index case) was considered the first affected family member who was identified independently of relatives. A cohort of 287 patients younger than 21 years of age from the registry of the Pediatric Electrophysiology Society included patients who met one of the following criteria [12]: QTc >440 milliseconds OR Both a family history of LQTS and one of the following: unexplained syncope, seizures, or cardiac arrest preceded by exercise or emotion The largest single-center cohort of patients with LQTS in the United States comprising 606 patients with LQTS of which 27 percent experienced at least one LQTS-triggered cardiac event [14]. Patient characteristics Age at diagnosis Patients with congenital LQTS generally come to medical attention within the first three decades of life, although the exact time of presentation is highly variable depending on the severity of symptoms and associated QTc prolongation. https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 3/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Among the previously symptomatic patients seen at Mayo Clinic s LQTS clinic, the average age at first symptom was 12 years [14]. Among patients from the Pediatric Electrophysiology Society registry (which only included patients younger than 21 years of age), the mean age at presentation was 6.8 years [12]. Notably, 20 percent presented at less than one month of age, and 36 percent presented between the ages of 9 and 15 years. Among patients from the International Long QT Syndrome Registry, probands were diagnosed at an average age of 21 years, significantly later in life than the average patient from the Pediatric Electrophysiology Society cohort [13]. Affected family members were identified at an average age of 34 years. Frequency of symptoms By definition, most probands (ie, index cases) diagnosed with congenital LQTS will be symptomatic at presentation. However, in populations where ECG screening is performed frequently (eg, competitive athletes and school-based screening programs), a good number of index cases are identified while asymptomatic. Subsequently, the majority of affected family members (usually identified by screening following the proband diagnosis) will be asymptomatic at the time of diagnosis. Among the 606 patients (probands and affected family members combined) from the Mayo Clinic LQTS clinic, 166 patients (27 percent) were symptomatic, with the sentinel event being syncope/seizures in 80 percent, fetal arrhythmia in 12 percent, and cardiac arrest in 8 percent [14]. Among patients from the Pediatric Electrophysiology Society registry, 175 patients (61 percent) were symptomatic at presentation [12]. The presenting symptoms were syncope, seizures, and cardiac arrest in 26, 10, and 9 percent of patients, respectively. Other symptoms included presyncope and palpitations. Among patients from the International Long QT Syndrome Registry, 80 percent of probands were symptomatic with syncope or cardiac arrest at the time of diagnosis [13]. Among the 647 patients with a confirmed mutation causing LQT1, LQT2, or LQT3, there were 87 SCDs (13 percent) prior to initiation of therapy [15]. Influence of puberty, pregnancy and menopause In females with LQTS, cardiac events are most prevalent during puberty compared with other life stages [16]. This was shown in the Rochester registry of 767 females with LQTS; the adjusted yearly cardiac event rate was 8 events per 100 patient years versus 2, 4, and 2 in childhood, young adulthood, and menopause, respectively. https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 4/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Pregnancy is accompanied by a variety of changes that can provoke new, or exacerbate previously occurring, arrhythmias. Although there is no increased risk of LQTS-triggered arrhythmias, there is a higher risk of cardiac events in the first six to nine months postpartum in patients with LQTS, particularly for women with LQT2. The effect of pregnancy in patients with congenital LQTS and the possible influence of genotype is discussed separately. Beta blockers are protective [17]. (See "Ventricular arrhythmias during pregnancy", section on 'Long QT syndrome'.) An increased risk of recurrent syncope has also been observed after the onset of menopause among women with LQT2 (hazard ratio [HR] 3.38 during the transition to menopause and 8.10 during the postmenopausal period) [18]. By contrast, the onset of menopause was associated with a reduction in risk of recurrent syncope among women with LQT1 (HR 0.19). Symptoms Patients with LQTS-triggered arrhythmias may present with one or more of the following: Arrhythmic syncope Arrhythmic syncope followed by generalized seizures SCA SCD Patients may present with syncope or SCA if the arrhythmia is sustained or results in hemodynamic collapse, with SCD occurring as the initial manifestation in approximately 13 percent of index cases [15]. A screening ECG should be performed in all patients following a first afebrile, generalized seizure (especially if the "seizure" occurred during exertion or emotional excitement/distress) or unexplained syncope. Even if the syncopal episode has been deemed consistent with neurocardiogenic (vasovagal) syncope, an ECG is still reasonable. However, importantly, the QTc can be prolonged transiently if the ECG was obtained in near proximity to the vasovagal episode and patients have been overdiagnosed with LQTS because of this timing issue [19]. Those with borderline or prolonged QT intervals should be referred to a cardiologist for further evaluation. (See "Congenital long QT syndrome: Diagnosis".) Patients with LQTS who present with arrhythmic syncope or syncope of uncertain origin (and which is not clearly vasovagal in nature) and/or an apparent seizure due to an arrhythmia typically have polymorphic ventricular tachycardia (VT). Syncopal episodes associated with ventricular arrhythmias due to LQTS may have tonic-clonic movements and may be misdiagnosed as a primary seizure disorder, often with tragic consequences [13,20-22]. Distinguishing between a primary seizure disorder and generalized seizures secondary to LQTS may be challenging, and the entities may overlap. In addition, patients with epilepsy and a https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 5/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate recent seizure (within the preceding two years) as well as patients who are taking anti-epileptic medications with sodium channel blocker properties (eg, phenytoin, carbamazepine, gabapentin, etc) appear to have an increased risk of SCD [23]. As an example of the challenge in establishing the correct diagnosis in patients who present with apparent seizures, one report details eight patients who were treated for a seizure disorder for up to five years until arrhythmia was identified as the underlying cause [21]. Of the five patients who had LQTS, QT prolongation on baseline ECG was significant in only one patient and borderline in two other patients, with the diagnosis being established in four patients by the appearance of exercise-induced polymorphic VT with Holter monitoring. Minor abnormalities detected on electroencephalography may have contributed to the delay of the diagnosis of LQTS in four patients. Types of arrhythmias The majority of arrhythmias in patients with congenital LQTS are ventricular tachyarrhythmias, although bradycardia, atrioventricular (AV) block, and atrial arrhythmias are present in a small minority of patients. The range of arrhythmias that can occur in LQTS was illustrated in the Pediatric Electrophysiology Society registry of 287 children, 61 percent of whom were symptomatic at presentation [12]. Ventricular arrhythmias were present in 16 percent, with polymorphic VT (also called torsades de pointes) being most common (6 percent at rest and 9 percent during an exercise test), followed by multiform ventricular premature beats (5 percent), uniform ventricular premature beats (4 percent), and monomorphic VT (1 percent). In addition, bradycardia was present in 20 percent and AV block in 5 percent. Polymorphic VT/torsades de pointes The classic arrhythmia associated with congenital LQTS is a form of polymorphic VT called torsades de pointes. Torsades de pointes is a common presentation in patients with congenital LQTS, as noted among probands from the International Registry, of whom 80 percent presented with syncope or resuscitated cardiac arrest [13]. In fact, if a patient with LQTS is having a true LQTS-attributable symptom it is because they developed torsades de pointes. Polymorphic VT is defined as a ventricular rhythm faster than 100 beats per minute with frequent variations of the QRS axis, morphology, or both [4,24]. In the specific case of torsades de pointes, these variations take the form of a progressive, sinusoidal, cyclic alteration of the QRS axis ( waveform 2A-B). The peaks of the QRS complexes appear to "twist" around the isoelectric line of the recording, hence the name "torsades de pointes" or "twisting of the points." https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 6/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Typical features of torsades de pointes include a markedly prolonged QT interval in the last sinus beat preceding the onset of the arrhythmia, a ventricular rate of 160 to 250 beats per minute, irregular RR intervals, and a cycling of the QRS axis through 180 degrees every 5 to 20 beats [4,24]. Notably, macroscopic T wave alternans (TWA), when identified, is a marker of high cardiac electrical instability and is considered an important warning for imminent torsades de pointes. However, macroscopic TWA is an insensitive risk factor as most patients with symptomatic LQTS have not exhibited TWA on their annual ECGs, stress tests, or Holters. Torsades de pointes episodes usually are short-lived and terminate spontaneously. However, patients may experience multiple episodes of the arrhythmia, and episodes can recur in rapid succession and may induce syncope or progress to ventricular fibrillation ( waveform 3) [4,24]. AV block When AV block is present in patients with congenital LQTS, particularly among neonates, there is a significant increase in the likelihood of cardiac arrhythmias and an associated poor prognosis [25]. While AV block has been noted in 5 percent of patients in the Pediatric Electrophysiology Society cohort, high-grade AV block necessitating permanent pacemaker placement is rare [12]. One mechanism of 2:1 AV block is prolonged ventricular refractoriness, which inhibits alternate depolarizations. True AV conduction abnormalities account for the remaining cases. Bradycardia While sinus bradycardia itself is generally not considered an arrhythmia, the presence of bradycardia (a resting heart rate less than 60 beats per minute) is a common finding in patients with LQTS, occurring in 20 percent of patients in the Pediatric Electrophysiology Society registry and in 31 percent of probands from the International Long QT Syndrome Registry [12,13]. Bradycardia appears to be more common in children during the first three years of life [26]. Bradycardia has also been reported in fetuses and neonates with LQTS [27-29]. Patients with fetal bradycardia (fetal heart rate 110 beats per minute or third percentile or lower for gestational age) should be evaluated for LQTS in the neonatal period with an ECG. (See "Congenital long QT syndrome: Diagnosis".) Atrial arrhythmias Atrial arrhythmias (eg, atrial fibrillation, supraventricular tachycardia, etc) are uncommon in patients with congenital LQTS but appear at a significantly higher frequency than in patients in the general population without LQTS [30,31]. Triggers of arrhythmia Arrhythmias in patients with congenital LQTS are triggered frequently by external events (eg, noise, exercise, stress, etc) and are often pause-dependent (the beat triggering torsades de pointes is preceded by an ectopic beat and a subsequent https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 7/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate pause). In addition, factors that contribute to the development of acquired LQTS, such as medications known to prolong the QT interval and electrolyte disturbances, can provoke arrhythmias in patients with congenital LQTS that is "mild" or previously unknown to the patient. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Pause dependence The duration of repolarization, which is defined by the duration of the T wave and the QRS interval, varies in relation to the preceding RR interval. At higher heart rates, with shorter RR intervals, repolarization accelerates and the QT interval shortens. The opposite occurs during slower heart rates with longer RR intervals. (See "Congenital long QT syndrome: Diagnosis", section on '12-lead ECG'.) Pause dependence refers to the phenomenon in which torsades de pointes is initiated by a "long-short" or "short-long-short" sequence ( waveform 2B). This beat-to-beat variation is usually caused by ectopic beats, which can be either ventricular or supraventricular in origin. Following an ectopic beat, there is a slight pause in which the RR interval lengthens for one beat (the "long" RR in the sequence). This pause causes the following QT interval to prolong. If, during this lengthened QT interval, a second ectopic beat occurs early (a "short" RR interval), during the vulnerable period of repolarization (so-called R-on-T phenomenon), torsades de pointes can develop. Pause-dependent torsades de pointes is common among patients with LQT2 but rare in patients with LQT1 [32]. In a series of 50 patients with congenital LQTS who had the onset of torsades de pointes captured on an ECG, a pause preceded the onset of torsades de pointes in 68 percent of patients with LQT2, compared with none of the patients with LQT1. Other genotypes were not adequately represented in this series to assess the frequency of pause-dependent torsades de pointes. (See 'Influence of genotype on triggers' below.) External triggers Ventricular arrhythmia in patients with congenital LQTS, most often the torsades de pointes type of polymorphic VT, is often initiated by an external trigger, most commonly exercise, particularly swimming and diving, and particularly in patients with LQT1 [12,13,33,34]. In addition to exercise, most of the other common triggers are associated with acute arousal (eg, noise, emotion, sudden wakening from sleep by an alarm clock, telephone, thunder, etc), particularly in LQT2. In addition, the postpartum period represents a transient six- month window of increased risk for LQTS-triggered events for women with LQTS, predominantly LQT2 [35,36]. Emotional stress or physical exertion preceding syncope or seizure is highly suggestive of LQTS- associated arrhythmia [21,37]. Among 175 symptomatic patients in the Pediatric Electrophysiology Society study, symptoms were related to exercise in 67 percent, exercise and https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 8/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate emotion in 18 percent, emotion alone in 7 percent, loud noise and exercise in 3 percent, and anesthesia in 2 percent [12]. Influence of genotype on triggers While numerous genotypes have been described, the great majority of cases of LQTS are accounted for by three genotypes: LQT1 (35 percent), LQT2 (25 to 35 percent), and LQT3 (5 to 10 percent) ( table 1) [33,38]. (See "Congenital long QT syndrome: Pathophysiology and genetics".) There is an association between the triggers that initiate arrhythmic events and the specific genotype of LQTS ( figure 1) [33,39]: Exercise Arrhythmic events in patients with LQT1 are most often related to exercise. In a review of 371 patients with LQT1, exercise accounted for 62 percent of events [33]. The sensitivity of patients with LQT1 to exercise may be related to exaggerated prolongation of the QT interval during exercise [40]. Events related to swimming (occurring either immediately after diving into water or during recreational or competitive swimming activities) may be specific for LQT1 [33,41,42]. However, swimming-related events may also occur with other disorders such as catecholaminergic polymorphic VT [43]. (See "Congenital long QT syndrome: Pathophysiology and genetics" and "Catecholaminergic polymorphic ventricular tachycardia".) Acute arousal Acute arousal events (such as exercise, emotion, or noise) are much more likely triggers in LQT1 and LQT2 than in LQT3 [33,44]. Events triggered by auditory stimuli, such as an alarm clock or telephone ringing, are most typically seen in LQT2 [33,34,41]. Rest/sleep Patients with LQT2 and LQT3 are at highest risk of events when at rest or asleep (68 percent of events), compared with LQT1 in which only 3 percent of events occurred at rest or when asleep [33]. Postpartum period Women with LQTS are at increased risk of LQTS-triggered events in the six to nine months postpartum compared with the 40 weeks of pregnancy and the 40 weeks prior to conception, and this risk is seen almost exclusively in women with LQT2 [35,36]. Medications and electrolyte abnormalities Causes of acquired LQTS, such as certain medications, certain non-cardiac disease states, and certain electrolyte disturbances such as hypokalemia and hypomagnesemia ( table 2), can also precipitate ventricular arrhythmia in patients with congenital LQTS. Patients with phenotypically manifest LQTS may certainly have an increased risk of cardiac events when electrolyte disturbances are present or medications known to lengthen the QT interval are prescribed. In addition, due to incomplete penetrance in many https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 9/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate patients, those without prior phenotypic manifestations of LQTS may develop ventricular arrhythmias only after such an added trigger, the so-called "second hit" hypothesis [45]. There are also an increasing number of reports of "forme fruste" (ie, incompletely manifest) mutations or polymorphisms in LQTS genes in patients with no family history and apparent drug-induced LQTS. The largest study in patients with drug-induced LQTS has shown that 28 percent of 188 patients were carriers of LQTS-causing mutations [46]. As such, when a seemingly sentinel event of drug-induced QT prolongation with or without torsades de pointes is documented, it is important to inquire about past symptoms of potential concern and about their family history. If concerns are raised or if the QTc does not fully normalize after discontinuation of the offending medication, the possibility of congenital LQTS should be evaluated further. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) ASSOCIATED CONDITIONS A number of specific clinical conditions in children are associated with LQTS. These warrant ECG screening and, occasionally, further evaluation for LQTS. Although the majority of LQTS cases occur without associated noncardiac syndromic features, recognition of these non-cardiac features may allow presymptomatic identification of patients with LQTS-plus, (ie, multi-system LQTS) thereby, prompting early treatment to prevent potentially life-threatening arrhythmias. Congenital sensorineural deafness The Jervell and Lange-Nielsen syndrome refers to the autosomal recessive phenotype of congenital LQTS that is associated with profound sensorineural hearing loss and a higher risk for sudden death when compared with autosomal dominant LQTS. We recommend that a 12-lead ECG be performed to screen for LQTS in all children with congenital sensorineural deafness. However, the statistical comparison of a single screening ECG versus serial ECGs for diagnostic accuracy in Jervell and Lange-Nielsen syndrome has not been assessed. (See "Congenital long QT syndrome: Diagnosis".) The Jervell and Lange-Nielsen syndrome has only been identified in patients with either homozygous or compound heterozygous pathogenic variants in KCNQ1 (LQT1) or KCNE1 (LQT5); these genes encode the alpha and beta subunits of the slowly acting component of the outward- rectifying potassium current (IKs, Kv7.1) that is involved in ventricular repolarization ( table 1) [47-49]. Homozygous mutations in KCNQ1 (exact same mutation), compound heterozygous variants in KCNQ1 (two different mutations on the same gene, one on the paternal allele and a different one on the maternal allele), and compound heterozygous variants involving one KCNQ1 pathogenic variant and one KCNE1 pathogenic variant have been identified, the latter being associated to a lower risk [7]. These mutations also disrupt production of endolymph in the stria https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 10/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate vascularis in the cochlea, resulting in the observed deafness [50]. (See "Hearing loss in children: Etiology", section on 'Sensorineural hearing loss'.) LQTS is highly penetrant early in life among patients with the Jervell and Lange-Nielsen syndrome. In a series of 186 patients with the Jervell and Lange-Nielsen syndrome, the QTc was markedly prolonged (mean 557 milliseconds), and clinical manifestations were present early in life, with event rates of 15, 50, and 90 percent by ages 1, 3, and 18, respectively [7]. Cardiac events occurred in 86 percent of the cohort, with 95 percent of events triggered by emotional or physical stress, and SCD rates exceeded 25 percent. High rates of symptoms and sudden cardiac death persisted in spite of beta-blocker therapy. Referral bias may have contributed to these very high event rates, but the young age at onset of symptoms and the poor response to medical therapy suggest the need to consider aggressive therapy in these patients. (See "Congenital long QT syndrome: Treatment".) Sudden infant death syndrome Approximately 5 to 10 percent of cases of sudden infant death syndrome (SIDS), as well as some cases of unexplained intrauterine fetal death, may be caused by LQTS, although the low incidence of SIDS makes it difficult to establish the exact impact on congenital LQTS as a potential etiology [51-58]. Although not endorsed by professional societies thus far, the UpToDate authors advocate for universal ECG screening of all infants at around two to four weeks of age for the early identification of this highly treatable condition of LQTS. (See "Sudden infant death syndrome: Risk factors and risk reduction strategies".) The frequency with which this might occur has been evaluated in large studies of screening ECGs of newborns and in genetic analyses of series of SIDS cases [51,54,55]. In a prospective cohort study, ECGs were recorded on the third or fourth day after birth in 34,442 newborns who were then followed for one year, during which 34 deaths occurred, 24 of which were classified as SIDS [51]. The QTc was significantly longer in the infants who died from SIDS compared with the survivors and those who died from other causes (435 versus 400 and 393 milliseconds, respectively). In fact, 12 of the 24 SIDS infants (50 percent) had a day 3 or day 4 of life ECG with a th QTc >440 milliseconds which was the 97.5 percentile value among the living infants. The odds ratio for SIDS in infants with a QTc 440 milliseconds was 41.3 (95% CI 17.3-98.4). Andersen-Tawil syndrome Andersen-Tawil syndrome, or hypokalemic periodic paralysis with cardiac arrhythmia, is a rare autosomal dominant disorder characterized by episodes of paralysis, ventricular arrhythmias, and dysmorphic features [59]. Subsequent genetic studies identified disease-causative variants in KCNJ2-encoded Kir2.1 as the root cause for some cases of Andersen-Tawil syndrome which subsequently prompted the designation of KCNJ2-mediated https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 11/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate disease as LQT7. However, ATS1, stemming from such KCNJ2 mutations, is preferred over LQT7 since these patients virtually never exhibit true QT prolongation but instead display QTU prolongation [60]. Patients affected with Andersen-Tawil syndrome usually present in childhood with spontaneous attacks of paralysis, which may be associated with low, normal, or elevated potassium levels. The characteristic skeletal and facial phenotype of Andersen-Tawil syndrome includes short stature, hypertelorism, a broad nose, low-set ears, and a hypoplastic mandible [61]. (See "Hypokalemic periodic paralysis", section on 'Andersen syndrome'.) Patients with hypokalemic periodic paralysis and other typical phenotypic features are diagnosed with Andersen-Tawil syndrome following a 12-lead ECG that reveals QTU prolongation. Characteristic T-U wave morphologies have also been identified in patients with Andersen-Tawil syndrome ( waveform 4) [62]. The ECG features were initially characterized in a series of 39 patients with genetically confirmed ATS1 and then validated in a series of 147 individuals (57 with ATS1, 61 unaffected family members, and 29 with phenotypic features of Andersen-Tawil syndrome, but negative for ATS1). The following abnormalities were identified by visual inspection: Prolonged terminal T wave downslope Biphasic U waves in limb leads Wide T-U junction, in contrast to bifid T waves in LQT2 Enlarged U waves occurring with a distinct isoelectric segment after the end of the T wave Treatment of Andersen-Tawil syndrome is complicated because of the opposing effects of potassium replacement on the QT interval and on skeletal muscle weakness. Elevation of the serum potassium concentration shortens the QT interval and suppresses ventricular arrhythmias, but it may accentuate skeletal muscle weakness. (See "Hypokalemic periodic paralysis", section on 'Andersen syndrome'.) Timothy syndrome There are rare reports of infants with severe QT prolongation and syndactyly involving both fingers and toes, frequently with associated patent ductus arteriosus and other cardiac abnormalities [63,64]. The constellation of QT prolongation (usually marked), syndactyly, and often developmental delays is called Timothy syndrome. The lack of a family history of LQTS suggested that the disorder resulted from spontaneous de novo variants. Although Timothy syndrome is extremely rare, it may be reasonable to obtain a screening ECG to assess the QT interval in children with complex syndactyly [65,66]. SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 12/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Long QT syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Background Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval (a prolonged QTc, QT interval corrected for heart rate) on the electrocardiogram (ECG) ( waveform 1) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death. LQTS may be congenital or acquired. (See 'Introduction' above and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Clinical presentations The clinical manifestations of congenital LQTS are highly variable. The majority of patients will never have a symptom, while symptomatic patients (before diagnosis and initiation of effective therapies) can present with arrhythmic syncope with or without generalized seizures, or cardiac arrest. Patients without symptoms typically come to medical attention because they have an affected family member or a prolonged QTc is identified on an ECG obtained for some other reason. (See 'Clinical manifestations' above.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 13/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Arrythmia presentation Patients with LQTS-triggered arrhythmias may present with syncope, seizures, or sudden cardiac arrest. Most times, the arrhythmias are transient or self-terminating. (See 'Symptoms' above.) Polymorphic ventricular tachycardia The classic arrhythmia associated with congenital LQTS is a form of polymorphic ventricular tachycardia (VT) called torsades de pointes. Polymorphic VT is defined as a ventricular rhythm faster than 100 beats per minute with frequent variations of the QRS axis, morphology, or both. In the specific case of torsades de pointes, these variations take the form of a progressive, sinusoidal, cyclic alteration of the QRS axis ( waveform 2A-B). The peaks of the QRS complexes appear to "twist" around the isoelectric line of the recording, hence the name torsades de pointes or "twisting of the points." (See 'Polymorphic VT/torsades de pointes' above.) Triggers of arrythmias Arrhythmias in patients with LQTS are frequently triggered by external events (eg, noise, exercise, stress, etc) and are often pause-dependent (the beat triggering the arrhythmia is preceded by an ectopic beat and a subsequent pause). In addition, factors that contribute to the development of acquired LQTS, such as medications known to prolong the QT interval and electrolyte disturbances, can provoke arrhythmias in patients with congenital LQTS that is "mild" or previously unknown to the patient. (See 'Triggers of arrhythmia' above.) Congenital syndromes The autosomal recessive form of congenital LQTS, the Jervell and Lange-Nielsen syndrome, is associated with sensorineural deafness and a more malignant clinical course. We recommend that a 12-lead ECG be performed to screen for LQTS in all children with congenital, bilateral sensorineural deafness. (See 'Congenital sensorineural deafness' above.) Some cases of sudden infant death syndrome and intrauterine fetal demise may be caused by LQTS. (See 'Sudden infant death syndrome' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013; 34:3109. 2. Moss AJ. Long QT Syndrome. JAMA 2003; 289:2041. 3. El-Sherif N, Turitto G. Torsade de pointes. Curr Opin Cardiol 2003; 18:6. https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 14/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate 4. Passman R, Kadish A. Polymorphic ventricular tachycardia, long Q-T syndrome, and

prolongation [60]. Patients affected with Andersen-Tawil syndrome usually present in childhood with spontaneous attacks of paralysis, which may be associated with low, normal, or elevated potassium levels. The characteristic skeletal and facial phenotype of Andersen-Tawil syndrome includes short stature, hypertelorism, a broad nose, low-set ears, and a hypoplastic mandible [61]. (See "Hypokalemic periodic paralysis", section on 'Andersen syndrome'.) Patients with hypokalemic periodic paralysis and other typical phenotypic features are diagnosed with Andersen-Tawil syndrome following a 12-lead ECG that reveals QTU prolongation. Characteristic T-U wave morphologies have also been identified in patients with Andersen-Tawil syndrome ( waveform 4) [62]. The ECG features were initially characterized in a series of 39 patients with genetically confirmed ATS1 and then validated in a series of 147 individuals (57 with ATS1, 61 unaffected family members, and 29 with phenotypic features of Andersen-Tawil syndrome, but negative for ATS1). The following abnormalities were identified by visual inspection: Prolonged terminal T wave downslope Biphasic U waves in limb leads Wide T-U junction, in contrast to bifid T waves in LQT2 Enlarged U waves occurring with a distinct isoelectric segment after the end of the T wave Treatment of Andersen-Tawil syndrome is complicated because of the opposing effects of potassium replacement on the QT interval and on skeletal muscle weakness. Elevation of the serum potassium concentration shortens the QT interval and suppresses ventricular arrhythmias, but it may accentuate skeletal muscle weakness. (See "Hypokalemic periodic paralysis", section on 'Andersen syndrome'.) Timothy syndrome There are rare reports of infants with severe QT prolongation and syndactyly involving both fingers and toes, frequently with associated patent ductus arteriosus and other cardiac abnormalities [63,64]. The constellation of QT prolongation (usually marked), syndactyly, and often developmental delays is called Timothy syndrome. The lack of a family history of LQTS suggested that the disorder resulted from spontaneous de novo variants. Although Timothy syndrome is extremely rare, it may be reasonable to obtain a screening ECG to assess the QT interval in children with complex syndactyly [65,66]. SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 12/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Long QT syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Background Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval (a prolonged QTc, QT interval corrected for heart rate) on the electrocardiogram (ECG) ( waveform 1) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death. LQTS may be congenital or acquired. (See 'Introduction' above and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Clinical presentations The clinical manifestations of congenital LQTS are highly variable. The majority of patients will never have a symptom, while symptomatic patients (before diagnosis and initiation of effective therapies) can present with arrhythmic syncope with or without generalized seizures, or cardiac arrest. Patients without symptoms typically come to medical attention because they have an affected family member or a prolonged QTc is identified on an ECG obtained for some other reason. (See 'Clinical manifestations' above.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 13/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Arrythmia presentation Patients with LQTS-triggered arrhythmias may present with syncope, seizures, or sudden cardiac arrest. Most times, the arrhythmias are transient or self-terminating. (See 'Symptoms' above.) Polymorphic ventricular tachycardia The classic arrhythmia associated with congenital LQTS is a form of polymorphic ventricular tachycardia (VT) called torsades de pointes. Polymorphic VT is defined as a ventricular rhythm faster than 100 beats per minute with frequent variations of the QRS axis, morphology, or both. In the specific case of torsades de pointes, these variations take the form of a progressive, sinusoidal, cyclic alteration of the QRS axis ( waveform 2A-B). The peaks of the QRS complexes appear to "twist" around the isoelectric line of the recording, hence the name torsades de pointes or "twisting of the points." (See 'Polymorphic VT/torsades de pointes' above.) Triggers of arrythmias Arrhythmias in patients with LQTS are frequently triggered by external events (eg, noise, exercise, stress, etc) and are often pause-dependent (the beat triggering the arrhythmia is preceded by an ectopic beat and a subsequent pause). In addition, factors that contribute to the development of acquired LQTS, such as medications known to prolong the QT interval and electrolyte disturbances, can provoke arrhythmias in patients with congenital LQTS that is "mild" or previously unknown to the patient. (See 'Triggers of arrhythmia' above.) Congenital syndromes The autosomal recessive form of congenital LQTS, the Jervell and Lange-Nielsen syndrome, is associated with sensorineural deafness and a more malignant clinical course. We recommend that a 12-lead ECG be performed to screen for LQTS in all children with congenital, bilateral sensorineural deafness. (See 'Congenital sensorineural deafness' above.) Some cases of sudden infant death syndrome and intrauterine fetal demise may be caused by LQTS. (See 'Sudden infant death syndrome' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013; 34:3109. 2. Moss AJ. Long QT Syndrome. JAMA 2003; 289:2041. 3. El-Sherif N, Turitto G. Torsade de pointes. Curr Opin Cardiol 2003; 18:6. https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 14/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate 4. Passman R, Kadish A. Polymorphic ventricular tachycardia, long Q-T syndrome, and torsades de pointes. Med Clin North Am 2001; 85:321. 5. Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AAM. Impact of genetics on the clinical management of channelopathies. J Am Coll Cardiol 2013; 62:169. 6. Schwartz PJ, Woosley RL. Predicting the Unpredictable: Drug-Induced QT Prolongation and Torsades de Pointes. J Am Coll Cardiol 2016; 67:1639. 7. Schwartz PJ, Spazzolini C, Crotti L, et al. The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome. Circulation 2006; 113:783. 8. Schwartz PJ, Stramba-Badiale M, Crotti L, et al. Prevalence of the congenital long-QT syndrome. Circulation 2009; 120:1761. 9. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999; 99:529. 10. Crotti L, Spazzolini C, Tester DJ, et al. Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry. Eur Heart J 2019; 40:2964. 11. Clemens DJ, Tester DJ, Giudicessi JR, et al. International Triadin Knockout Syndrome Registry. Circ Genom Precis Med 2019; 12:e002419. 12. Garson A Jr, Dick M 2nd, Fournier A, et al. The long QT syndrome in children. An international study of 287 patients. Circulation 1993; 87:1866. 13. Moss AJ, Schwartz PJ, Crampton RS, et al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation 1991; 84:1136. 14. Rohatgi RK, Sugrue A, Bos JM, et al. Contemporary Outcomes in Patients With Long QT Syndrome. J Am Coll Cardiol 2017; 70:453. 15. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003; 348:1866. 16. Younis A, Zareba W, Goldenberg I, et al. Biological Life-Stage and the Burden of Cardiac Events in Women With Congenital Long QT Syndrome. Circ Arrhythm Electrophysiol 2022; 15:e011247. 17. Rashba EJ, Zareba W, Moss AJ, et al. Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome. LQTS Investigators. Circulation 1998; 97:451. 18. Buber J, Mathew J, Moss AJ, et al. Risk of recurrent cardiac events after onset of menopause in women with congenital long-QT syndrome types 1 and 2. Circulation 2011; 123:2784. 19. Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation 2007; 115:2613. https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 15/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate 20. Pacia SV, Devinsky O, Luciano DJ, Vazquez B. The prolonged QT syndrome presenting as epilepsy: a report of two cases and literature review. Neurology 1994; 44:1408. 21. Pfammatter JP, Donati F, D rig P, et al. Cardiac arrhythmias mimicking primary neurological disorders: a difficult diagnostic situation. Acta Paediatr 1995; 84:569. 22. Anderson JH, Bos JM, Cascino GD, Ackerman MJ. Prevalence and spectrum of electroencephalogram-identified epileptiform activity among patients with long QT syndrome. Heart Rhythm 2014; 11:53. 23. Bardai A, Blom MT, van Noord C, et al. Sudden cardiac death is associated both with epilepsy and with use of antiepileptic medications. Heart 2015; 101:17. 24. Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med 2002; 112:58. 25. Gorgels AP, Al Fadley F, Zaman L, et al. The long QT syndrome with impaired atrioventricular conduction: a malignant variant in infants. J Cardiovasc Electrophysiol 1998; 9:1225. 26. Vincent GM. The heart rate of Romano-Ward syndrome patients. Am Heart J 1986; 112:61. 27. Beinder E, Grancay T, Men ndez T, et al. Fetal sinus bradycardia and the long QT syndrome. Am J Obstet Gynecol 2001; 185:743. 28. Lupoglazoff JM, Denjoy I, Villain E, et al. Long QT syndrome in neonates: conduction disorders associated with HERG mutations and sinus bradycardia with KCNQ1 mutations. J Am Coll Cardiol 2004; 43:826. 29. Mitchell JL, Cuneo BF, Etheridge SP, et al. Fetal heart rate predictors of long QT syndrome. Circulation 2012; 126:2688. 30. Kirchhof P, Eckardt L, Franz MR, et al. Prolonged atrial action potential durations and polymorphic atrial tachyarrhythmias in patients with long QT syndrome. J Cardiovasc Electrophysiol 2003; 14:1027. 31. Johnson JN, Tester DJ, Perry J, et al. Prevalence of early-onset atrial fibrillation in congenital long QT syndrome. Heart Rhythm 2008; 5:704. 32. Tan HL, Bardai A, Shimizu W, et al. Genotype-specific onset of arrhythmias in congenital long-QT syndrome: possible therapy implications. Circulation 2006; 114:2096. 33. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001; 103:89. 34. Wilde AA, Jongbloed RJ, Doevendans PA, et al. Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). J Am Coll Cardiol 1999; 33:327. https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 16/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate 35. Khositseth A, Tester DJ, Will ML, et al. Identification of a common genetic substrate underlying postpartum cardiac events in congenital long QT syndrome. Heart Rhythm 2004; 1:60. 36. Seth R, Moss AJ, McNitt S, et al. Long QT syndrome and pregnancy. J Am Coll Cardiol 2007; 49:1092. 37. Davis AM, Wilkinson JL. The long QT syndrome and seizures in childhood. J Paediatr Child Health 1998; 34:410. 38. Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000; 102:1178. 39. Wehrens XH, Vos MA, Doevendans PA, Wellens HJ. Novel insights in the congenital long QT syndrome. Ann Intern Med 2002; 137:981. 40. Takenaka K, Ai T, Shimizu W, et al. Exercise stress test amplifies genotype-phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome. Circulation 2003; 107:838. 41. Moss AJ, Robinson JL, Gessman L, et al. Comparison of clinical and genetic variables of cardiac events associated with loud noise versus swimming among subjects with the long QT syndrome. Am J Cardiol 1999; 84:876. 42. Ackerman MJ, Tester DJ, Porter CJ. Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. Mayo Clin Proc 1999; 74:1088. 43. Choi G, Kopplin LJ, Tester DJ, et al. Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. Circulation 2004; 110:2119. 44. Ali RH, Zareba W, Moss AJ, et al. Clinical and genetic variables associated with acute arousal and nonarousal-related cardiac events among subjects with long QT syndrome. Am J Cardiol 2000; 85:457. 45. Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. N Engl J Med 1992; 327:846. 46. Itoh H, Crotti L, Aiba T, et al. The genetics underlying acquired long QT syndrome: impact for genetic screening. Eur Heart J 2016; 37:1456. 47. Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol 2000; 36:1. 48. Duggal P, Vesely MR, Wattanasirichaigoon D, et al. Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of Long-QT syndrome. Circulation 1998; 97:142. 49. Huang L, Bitner-Glindzicz M, Tranebjaerg L, Tinker A. A spectrum of functional effects for disease causing mutations in the Jervell and Lange-Nielsen syndrome. Cardiovasc Res 2001; https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 17/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate 51:670. 50. Tranebjaerg L, Bathen J, Tyson J, Bitner-Glindzicz M. Jervell and Lange-Nielsen syndrome: a Norwegian perspective. Am J Med Genet 1999; 89:137. 51. Schwartz PJ, Stramba-Badiale M, Segantini A, et al. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med 1998; 338:1709. 52. Schwartz PJ, Priori SG, Dumaine R, et al. A molecular link between the sudden infant death syndrome and the long-QT syndrome. N Engl J Med 2000; 343:262. 53. Wedekind H, Smits JP, Schulze-Bahr E, et al. De novo mutation in the SCN5A gene associated with early onset of sudden infant death. Circulation 2001; 104:1158. 54. Ackerman MJ, Siu BL, Sturner WQ, et al. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA 2001; 286:2264. 55. Arnestad M, Crotti L, Rognum TO, et al. Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation 2007; 115:361. 56. Wang DW, Desai RR, Crotti L, et al. Cardiac sodium channel dysfunction in sudden infant death syndrome. Circulation 2007; 115:368. 57. Crotti L, Tester DJ, White WM, et al. Long QT syndrome-associated mutations in intrauterine fetal death. JAMA 2013; 309:1473. 58. Tester DJ, Wong LCH, Chanana P, et al. Cardiac Genetic Predisposition in Sudden Infant Death Syndrome. J Am Coll Cardiol 2018; 71:1217. 59. Andersen ED, Krasilnikoff PA, Overvad H. Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. A new syndrome? Acta Paediatr Scand 1971; 60:559. 60. Tristani-Firouzi M, Jensen JL, Donaldson MR, et al. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest 2002; 110:381. 61. Sansone V, Griggs RC, Meola G, et al. Andersen's syndrome: a distinct periodic paralysis. Ann Neurol 1997; 42:305. 62. Zhang L, Benson DW, Tristani-Firouzi M, et al. Electrocardiographic features in Andersen- Tawil syndrome patients with KCNJ2 mutations: characteristic T-U-wave patterns predict the KCNJ2 genotype. Circulation 2005; 111:2720. 63. Marks ML, Whisler SL, Clericuzio C, Keating M. A new form of long QT syndrome associated with syndactyly. J Am Coll Cardiol 1995; 25:59. 64. Marks ML, Trippel DL, Keating MT. Long QT syndrome associated with syndactyly identified in females. Am J Cardiol 1995; 76:744. 65. Krause U, Gravenhorst V, Kriebel T, et al. A rare association of long QT syndrome and syndactyly: Timothy syndrome (LQT 8). Clin Res Cardiol 2011; 100:1123. https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 18/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate 66. Splawski I, Timothy KW, Sharpe LM, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004; 119:19. Topic 1036 Version 34.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 19/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate GRAPHICS Single-lead electrocardiogram showing a prolonged QT interval The corrected QT interval (QTc) is calculated by dividing the QT interval (0.60 seconds) by the square root of the preceding RR interval (0.92 seconds). In this case, the QTc is 0.625 seconds (625 milliseconds). Graphic 77018 Version 7.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 20/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Single lead electrocardiogram (ECG) showing polymorphic ventricular tachycardia (VT) This is an atypical, rapid, and bizarre form of ventricular tachycardia that is characterized by a continuously changing axis of polymorphic QRS morphologies. Graphic 53891 Version 5.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 21/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Single lead electrocardiogram (ECG) showing torsades de pointes The electrocardiographic rhythm strip shows torsades de pointes, a polymorphic ventricular tachycardia associated with QT prolongation. There is a short, preinitiating RR interval due to a ventricular couplet, which is followed by a long, initiating cycle resulting from the compensatory pause after the couplet. Graphic 73827 Version 4.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 22/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Summary of heritable arrhythmia syndrome susceptibility genes: Long QT syndrome (LQTS) Gene Locus Protein Major LQTS genes KCNQ1 (LQT1) 11p15.5 I potassium channel alpha subunit (KVLQT1, Ks Kv7.1) KCNH2 (LQT2) 7q35-36 I potassium channel alpha subunit (HERG, Kr Kv11.1) SCN5A (LQT3) 3p21-p24 Cardiac sodium channel alpha subunit (NaV1.5) Minor LQTS genes AKAP9 7q21-q22 Yotiao CACNA1C 12p13.3 Voltage gated L-type calcium channel (CaV1.2) CALM1 14q32.11 Calmodulin 1 CALM2 2p21 Calmodulin 2 CALM3 19q13.2-q13.3 Calmodulin 3 CAV3 3p25 Caveolin-3 KCNE1 21q22.1 Potassium channel beta subunit (MinK) KCNE2 21q22.1 Potassium channel beta subunit (MiRP1) KCNJ5 11q24.3 Kir3.4 subunit of I channel KACH SCN4B 11q23.3 Sodium channel beta 4 subunit SNTA1 20q11.2 Syntrophin-alpha 1 TRDN 6q22.31 Triadin Adapted from: Tester DJ, Ackerman MJ. Genetics of cardiac arrhythmias. In: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 10th ed, Mann DL, Zipes DP, Libby P, et al (Eds), Elsevier, Philadelphia 2015. Graphic 114927 Version 2.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 23/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial GnRH agonist/antagonist therapy ischemia or infarction, Hypomagnesemia Bilateral surgical orchiectomy Hypocalcemia Diuretic therapy via electrolyte disorders especially with Starvation particularly hypokalemia and hypomagnesemia prominent T-wave inversions Anorexia nervosa Herbs Liquid protein diets Cinchona (contains quinine), iboga (ibogaine), licorice extract in overuse via electrolyte disturbances Intracranial disease Hypothyroidism Bradyarrhythmias HIV infection Sinus node dysfunction Hypothermia Toxic exposure: Organophosphate insecticides AV block: Second or third degree Medications* High risk Adagrasib Cisaparide Lenvatinib Selpercatinib (restricted availability) Ajmaline Levoketoconazole Sertindole Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine Vandetanib Dofetilide (intracoronary) Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab ozogamacin Propafenone Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Carbetocin Erythromycin Ribociclib https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 24/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Certinib Escitalopram Levofloxacin Risperidone (systemic) Chloroquine Etelcalcetide Saquinavir Lofexidine Citalopram Fexinidazole Sevoflurane Meglumine Clarithromycin Flecainide Sparfloxacin antimoniate Clofazimine Floxuridine Sunitinib Midostaurin Clomipramine Fluconazole Tegafur Moxifloxacin Clozapine Fluorouracil Terbutaline Nilotinib (systemic) Crizotinib Thioridazine Olanzapine Flupentixol Dabrafenib Toremifene Ondansetrol (IV > Gabobenate dimeglumine Dasatinib Vemurafenib oral) Deslurane Voriconazole Osimertinib Gemifloxacin Domperidone Oxytocin Gilteritinib Doxepin Pazopanib Halofantrine Doxifluridine Pentamidine Haloperidol (oral) Pilsicainide Imipramine Pimozide Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole (systemic) Romidepsin Anagrelide Foscarnet Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- Glasdegib Mizolastine lumefantrine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine Nortriptyline Benperidol (rare reports) Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus Olodaterol (systemic) Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 25/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Leuprolide- Periciazine Tropisetron norethindrone Dexmedetomidine** Pimavanserin Vardenafil Levalbuterol Dolasetron Pipamperone Vilanterol Levomethadone Donepezil Pitolisant Vinflunine Lithium Efavirenz Ponesimod Voclosporin Loperamide overdose in Eliglustat Primaquine Vorinostat Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. [1,2] . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 26/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 27/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate ECG macroscopic T wave alternans Example of T wave alternans from a 3-year-old patient with long QT syndrome with multiple episodes of cardiac arrest. Tracings are from a 24-hour Holter recording. ECG: electrocardiogram. Reproduced from: Schwartz PJ, Crotti L. Long QT and short QT syndromes. In: Cardiac Electrophysiology: From Cell to Bedside, 6th ed, Zipes DP, Jalife J (Eds), Saunders, Philadelphia 2014. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 115857 Version 1.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 28/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Triggers for cardiac events in long QT syndrome are related to genotype In a study of 670 patients with long QT syndrome and known genotype, all symptomatic (syncope, aborted cardiac arrest, or sudden death), the occurrence of a lethal cardiac event (n = 110) provoked by a specific trigger (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced most of their events (90%) during exercise or emotion. These percentages were almost reversed among LQT2 and LQT3 patients who had most of their events during rest or sleep (63 and 80%, respectively); by contrast, they were at almost no risk of major events during exercise (arrows), which is explained by their having a normal I current. Ks ACA: aborted cardiac arrest; SCD: sudden cardiac death. Modi ed from: Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-speci c triggers for life-threatening arrhythmias. Circulation 2001; 103:89. Graphic 64239 Version 3.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 29/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate 12-lead electrocardiogram (ECG) in Andersen-Tawil syndrome 12-lead electrocardiogram (ECG) in a patient with Andersen-Tawil syndrome showing QTU prolongation with biphasic U waves Biphasic U wave. Arrows indicate U wave. Graphic 98517 Version 3.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 30/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Contributor Disclosures Peter J Schwartz, MD No relevant financial relationship(s) with ineligible companies to disclose. Michael J Ackerman, MD, PhD Consultant/Advisory Boards: Abbott [Education around ICD/device therapy for genetic heart diseases including LQTS]; ARMGO Pharma [Novel therapies for genetic heart diseases, CPVT in particular]; Boston Scientific [Education around ICD/device therapy for genetic heart diseases including LQTS]; Daiichi Sankyo [Drug-induced QT prolongation for one of their drugs]; Invitae [Genetic testing for genetic heart diseases]; LQT Therapeutics [Development of a novel QT-shortening medication]; Medtronic [Education around ICD/device therapy for genetic heart diseases including LQTS]; UpToDate [Genetic heart diseases, especially LQTS]. Other Financial Interest: AliveCor [QTc analytics for smartphone-enabled mobile ECG]; Anumana [Artificial intelligence ECG for early detection of hypertrophic cardiomyopathy]; Pfizer [Gene therapy for genetic heart diseases including LQTS]. All of the relevant financial relationships listed have been mitigated. John K Triedman, MD Consultant/Advisory Boards: Biosense Webster and Sentiar [Supraventricular and ventricular topics]. All of the relevant financial relationships listed have been mitigated. Samuel Asirvatham, MD Grant/Research/Clinical Trial Support: Medtronic [Defibrillators]; St Jude's [Sudden Cardiac Death]. Consultant/Advisory Boards: BioTronik [Defibrillators]; Boston Scientific [Sudden Cardiac Death]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 31/31

7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Congenital long QT syndrome: Pathophysiology and genetics : Michael J Ackerman, MD, PhD, Peter J Schwartz, MD : John K Triedman, MD, Samuel Asirvatham, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 03, 2022. INTRODUCTION Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death (SCD) [1,2]. The primary symptoms in patients with LQTS include syncope, seizures, aborted cardiac arrest, and SCD. LQTS is associated with an increased risk of a characteristic life-threatening cardiac arrhythmia known as torsades de pointes (TdP) or "twisting of the points" ( waveform 2A-B) [3,4]. LQTS may be congenital or acquired [1,5]. Pathogenic variants in at least 17 LQTS-susceptibility genes have been identified thus far ( table 1 and figure 1) [5]. However, pathogenic variants in the three canonical genes, KCNQ1 (previously called KVLQT1, LQT1), KCNH2 (previously called HERG, LQT2), and SCN5A (LQT3), account for at least 75 to 80 percent of all LQTS, with disease- causative variants in the minor LQTS-susceptibility genes contributing only another 5 percent. Less than 15 to 20 percent of patients satisfying a robust clinical diagnosis of LQTS will have a negative, contemporary LQTS genetic test. Acquired LQTS usually results from undesired QT prolongation and potential for QT-triggered arrhythmias by either QT-prolonging disease states, QT-prolonging medications ( www.crediblemeds.org), or QT-prolonging electrolyte disturbances ( table 2) [6]. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 1/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate The pathophysiology and genetics of congenital LQTS will be reviewed here. Other aspects of LQTS are discussed separately: Congenital LQTS Clinical features (See "Congenital long QT syndrome: Epidemiology and clinical manifestations".) Diagnosis (See "Congenital long QT syndrome: Diagnosis".) Treatment (See "Congenital long QT syndrome: Treatment".) LQTS genes (See "Gene test interpretation: Congenital long QT syndrome genes (KCNQ1, KCNH2, SCN5A)".) Acquired LQTS Causes (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Diagnosis and management (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) PATHOPHYSIOLOGY Although the relatively simple clinical definition of LQTS applies to both acquired and the variety of congenital forms, the pathophysiology of the disorder is complex, incompletely understood, and probably varies among patients. Two leading pathophysiologic hypotheses have emerged to explain commonly observed features of LQTS: Extensive and growing clinical and genetic evidence supports the importance of perturbations in cardiac ion channels, resulting in prolongation of the action potential ( figure 1). Based on these data, congenital LQTS is considered a disease of ion channels and is the most common "cardiac channelopathy." The observation that the immediate trigger for torsades de pointes (TdP) in the inherited form is often a sudden surge in sympathetic tone (a feature not seen in the acquired form) led to the hypothesis that the congenital LQTS may be caused by an imbalance in the sympathetic innervation of the heart. Perturbations in ion channels The established pathogenic basis for the vast majority of congenital LQTS involves perturbations in three critical ion channels of the heart. Loss-of- function mutations in the KCNQ1-encoded Kv7.1 potassium channel (phase 3 I ) and KCNH2- Ks encoded Kv11.1 potassium channels (phase 3 I ) cause prolongation in the action potential Kr duration at the cellular level and hence QT prolongation for at least two-thirds of all patients https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 2/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate with LQTS. Gain-of-function mutations in the SCN5A-encoded Nav1.5 sodium channel account for approximately 5 to 10 percent of LQTS; they prolong the action potential duration by accentuating the sodium channel's late current or its window current. This action potential prolongation at the ventricular cardiac cell level sets up the increased vulnerability for early afterdepolarizations (EADs) and triggered activity via re-entrant mechanisms, which then produces torsadogenic syncope, seizure, or worse. (See 'Prolonged repolarization and early afterdepolarizations' below.) The normal action potential An understanding of normal cardiac cell electrophysiology is required in order to fully appreciate the known perturbations in ion channels and their associated ion currents, and the electrophysiologic mechanisms that cause congenital LQTS. The normal action potential is composed of the following five phases, beginning with phase 4 ( figure 2 and movie 1). (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Phase 4 (resting membrane potential) Phase 4 represents the normal diastolic resting membrane potential of myocardial cells. The resting membrane potential of myocardial ventricular cell membranes during diastole is approximately -85 to -90 mV, which largely represents the equilibrium membrane potential for potassium in healthy states. This occurs because of the inwardly rectifying potassium channel Kir2.1 (I current) that is K1 encoded by KCNJ2. Phase 0 (depolarization) Phase 0 occurs when the membrane potential reaches approximately -70 mV. A rapid inward flow of sodium ions (I ) through the fast Nav1.5 Na sodium channels (encoded by SCN5A) ensues and depolarizes the cell membrane. Inward current during phase 0 is also sustained by activation of L- and T-type calcium channels (I Ca- and I ). L Ca-T Phase 1 (initial repolarization) Phase 1 represents an initial repolarization after the overshoot of phase 0 and is caused by a transient outward potassium current (I ) from to1 the KCND3-encoded Kv4.3 potassium channels. Phase 2 (plateau phase) Phase 2 is called the plateau phase, because it represents an equilibrium between the inward calcium (I /Cav1.2 encoded by CACNA1C and I ) and Ca-L Ca-T late sodium (I ) currents and the outward potassium currents coming from the Kv7.1/I Na Ks (KCNQ1) and the Kv11.1/I (KCNH2) potassium channels. Kr Phase 3 (rapid repolarization) Phase 3 represents the rapid repolarization that occurs when the outward potassium currents dominate over the decaying inward calcium current. Repolarization is predominantly mediated by the aforementioned outward potassium https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 3/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate currents (I and I ). These channels open in response to depolarization and allow Ks Kr potassium to flow out of cells and repolarize the membrane potential toward its resting level, until activated KCNJ2-encoded Kir2.1 potassium channels (I ) drive and hold the K1 membrane potential around -90 mV. The QT interval on the surface ECG is determined by the activity of these channels. Prolonged repolarization and early afterdepolarizations Prolongation of the QT interval increases the probability for EADs. EADs are single or multiple oscillations of the membrane potential that can occur during phase 2 or 3 of the action potential ( figure 2). EADs occur in association with prolongation of the repolarization phase of the action potential. If occurring in phase 2 of the action potential, EADs are thought to be caused by increased inward current through L-type calcium channels [7] or through the sodium-calcium exchanger [8]. Depolarizing currents occurring late in phase 3 are thought to be due to inward currents through T-type calcium channels or sodium channels [9]. Pathologic prolongation of repolarization results most often from a decrease in the outward currents (LQT1 and LQT2) or increases in the sodium current (LQT3). (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs", section on 'Triggered activity'.) Triggered activity Triggered responses or triggered activity are EADs that reach threshold potential, depolarize cell membranes, and result in additional action potentials. Propagation of these triggered responses produce ventricular premature depolarizations that may initiate LQTS' pathognomonic polymorphic ventricular tachycardia (VT), known as TdP, in susceptible individuals. EADs and triggered responses are particularly easy to induce in Purkinje fibers and M cells, a group of cells in the left ventricular free wall that have been identified as the site of EAD-induced triggered activity after exposure to drugs such as quinidine, sotalol, and erythromycin [10,11]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Common precipitants of early afterdepolarizations and triggered activity The development of EADs is potentiated by bradycardia, hypokalemia, hypomagnesemia, and a long list of medications. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Bradycardia Slow heart rates are associated with increased inactivation of the outward repolarizing potassium current and a reduction in the Na-K-ATPase pump outward current (3 Na out/2 K in = net outward positive current). Slow heart rates also enhance the activity of certain antiarrhythmic drugs on repolarization (ie, repolarization and the QT interval are more prolonged). This property is called reverse use dependence and can lead to ion fluxes that facilitate EADs and TdP. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 4/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Hypokalemia Low potassium levels lead to a decreased outward repolarizing current via reductions in electrogenic Na-K-ATPase pump activity and outward potassium channel activity. Role of sympathetic activity Evidence supporting the significance of sympathetic activity in LQTS includes observations on the impact of the stellate ganglia. The left cardiac sympathetic nerves (left stellate ganglion and first four thoracic ganglia) are quantitatively dominant in terms of release of norepinephrine in the heart compared with the right-sided sympathetic nerves. In addition, the left-sided cardiac sympathetic nerves innervate primarily the posterior and left part of the ventricles [12,13]. In addition, sympathetic stimulation can also facilitate the onset of ventricular arrhythmias, including triggered activity and early after depolarizations. Experimental studies have demonstrated that right stellectomy or stimulation of the left stellate ganglion both prolong the QT interval and alter T wave morphology in a manner that mimics the surface ECG found in patients with LQTS, including the induction of T wave alternans [14]. Antiadrenergic therapies, including beta blockers and left cardiac sympathetic denervation (LCSD), substantially reduce the risk of TdP in patients with LQTS. Whereas beta blockers have a modest effect on the QT interval, LCSD shortens it significantly in most patients [15]. (See "Congenital long QT syndrome: Treatment".) Dispersion of repolarization and re-entry Both the dispersion of repolarization and re-entry may be other potential mechanisms for the development of TdP. Dispersion of repolarization refers to an inhomogeneity in repolarization or recovery of excitability in a region of myocardium. A specific population of cells in the myocardium, called M cells, demonstrate marked prolongation of action potential duration in response to drugs such as quinidine, sotalol, and erythromycin [10,11]. Dispersion of repolarization could therefore occur in response to these drugs if the action potential is prolonged in M cells but not in the surrounding myocardium. The result is a functional block in the M cell region, providing the necessary milieu for the development of a reentrant arrhythmia [10]. Initiation and maintenance of torsades de pointes EADs and triggered activity are thought to be the most common initiating mechanism for the ventricular ectopy and TdP associated with long QT intervals [16,17]. Alterations in sympathetic activity and dispersion of repolarization probably contribute to the electrophysiologic milieu that facilitates malignant arrhythmias, at least in certain cases. TYPES OF CONGENITAL LQTS https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 5/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Pathogenic variants in at least 17 genes have been identified thus far in patients with congenital LQTS ( table 1 and figure 1) [5]. However, as clinical genetic testing evolves and the available data become more robust, some previously associated LQTS-susceptibility genes have been reclassified as having limited evidence or disputed evidence as LQTS-causative genes in terms of the strength of their disease-gene association [18]. Additionally, the classifications and nomenclature are evolving, with the historical naming convention (LQT followed by the next number in sequence) being replaced by more descriptive names [19,20]. LQTS-causative variants in the three canonical genes, KCNQ1 (LQT1; 35 to 40 percent), KCNH2 (LQT2; 25 to 30 percent), and SCN5A (LQT3; 5 to 10 percent), account for at least 75 to 80 percent of all LQTS, with pathogenic variants in the minor LQTS-susceptibility genes contributing another 5 percent. (See "Gene test interpretation: Congenital long QT syndrome genes (KCNQ1, KCNH2, SCN5A)".) The remaining 15 to 20 percent of patients with an established clinical diagnosis of congenital LQTS will not have an identifiable genetic cause following clinically indicated contemporary genetic testing, and they are referred to as having either genetically elusive LQTS or genotype negative LQTS. Canonical LQTS-causative genes Type 1 LQTS (LQT1) The first association between a chromosomal marker and congenital LQTS was identified by analysis of a Utah family with a high prevalence of this disorder [21]. Linkage was found between the LQTS phenotype and a marker on the short arm of chromosome 11. Investigators using positional cloning techniques identified the involved gene KvLQT1, which is now called KCNQ1 [22]. LQT1 accounts for up to 45 percent of cases of LQTS (35 to 40 percent in most countries and most cohorts) [23]. Most patients with LQT1 show paradoxical prolongation of the QT interval during an exercise stress test, especially during the recovery phase of the stress test, which can be used to unmask patients with electrocardiographically concealed LQT1 [24,25]. The protein product of KCNQ1 (Kv7.1 alpha-subunit), when coexpressed with the cardiac protein minK (IsK or beta-subunit, which is encoded by KCNE1), forms the slowly acting component of the outward-rectifying potassium current (I ) [26-28]. Suppression of I by loss-of-function Ks Ks variants in the KCNQ1 gene in the absence or presence of minK can be correlated with and likely underlie prolongation of human ventricular action potentials [29]. Pathogenic variants in the KCNE1-encoded minK (LQT5) produces a similar defect in I ( figure 3). Gain-of-function Ks variants in KCNQ1 have been associated with familial atrial fibrillation [30] and with the congenital short QT syndrome, designated as type 2 short QT syndrome or SQT2 [31]. (See https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 6/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Genetic factors' and "Short QT syndrome".) Many missense variants and some other types of loss-of-function variants have been identified in KCNQ1. The severity of the clinical features of LQT1 vary with the specific LQT1-causative variant [32]. In particular, disease-causative variants localizing to the transmembrane region are associated with more frequent cardiac events (syncope, aborted cardiac arrest, or sudden cardiac death) than those variants that reside in the C-terminal region (55 versus 21 percent) [33]. Variants close to A341V carry a higher risk for arrhythmic events [32]. For example, one particular LQT1 variant (KCNQ1 A341V) is associated with high clinical severity independent of ethnic origin [34]. In a study comparing 244 patients with A341V with 205 patients with non-A341V LQT1 variants at a median follow-up of approximately 30 years, patients with LQT1-A341V were significantly more likely to have cardiac events (75 versus 24 percent), were younger at first event (6 versus 11 years), and had a longer QTc (485 43 versus 465 38 ms). Also, other LQT1-causative variants in proximity to A341V have been associated with a higher risk of arrhythmic events [32]. Homozygous loss-of-function variants in KCNQ1 can cause the Jervell and Lange-Nielsen syndrome [35,36]. Hearing loss can also be induced by the loss of functional minK protein, which seems to disrupt the production of endolymph. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Congenital sensorineural deafness'.) Type 2 LQTS (LQT2) LQT2, which accounts for 25 to 40 percent of cases of congenital LQTS [23,37,38], is caused by loss-of-function variants in a different potassium channel gene, localized to chromosome 7 [39-41]. The disease-causative gene is called KCNH2 (formerly HERG), which encodes the Kv11.1 potassium channel that underlies the rapidly acting component of the outward-rectifying potassium current (I ) ( figure 3) [42-45]. This current is largely responsible Kr for repolarization and thus the QT interval duration. The KCNH2-encoded Kv11.1 channels have unique electrophysiologic features that may normally protect against early afterdepolarizations (EADs) [44]. Most of the drugs that cause acquired/drug-induced QT prolongation block these Kv11.1 channels. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) LQT2-causative variants span the entirety of the Kv11.1 channel [41,46]. In a study of 201 patients, those with pathogenic variants localizing to the pore region had a significantly greater risk of a cardiac event (74 percent, versus 35 percent with variants in the non-pore region) and sudden cardiac death (SCD) or aborted cardiac arrest (15 versus 6 percent); these manifestations occurred at an earlier age in the patients with pore-localizing variants [41]. Patients with a LQT2- causative variant in Kv11.1's pore had a significantly greater risk of a cardiac event at a QTc of https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 7/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 500 ms (hazard ratio 11); each 10 ms change in the QTc above or below 500 ms increased or decreased the risk by 16 percent. In some reports, non-pore variants are more likely to be associated with torsades de pointes (TdP) in the presence of hypokalemia [46]. However, a malignant phenotype has been described in a family with a novel variant in the nonpore region [47]. In contrast to LQT2-associated loss-of-function variants in KCNH2, there are gain-of-function variants in KCNH2 that result in accentuated I activity. Patients with KCNH2 gain-of-function Kr variants are classified as SQT1. (See "Short QT syndrome".) Type 3 LQTS (LQT3) LQT3, which accounts for 5 to 10 percent of cases [23,37,38], is caused by pathogenic variants in the sodium channel gene (SCN5A) located on chromosome 3; many variants have been associated with LQT3 [48,49]. The LQT3-causative variants result in gain-of- function by either increasing the late sodium current (like one of the originally discovered in- frame deletions, DeltaKPQ), increasing the window current through biophysical alterations of the kinetics of activation or inactivation, or through both mechanisms. One of the most interesting variants in SCN5A is the missense mutation, E1784K, which demonstrates most clearly the phenomenon of host-dependent disease expressivity, as E1784K is not only the most common LQT3-associated variant published to date but also the single most common SCN5A variant associated with a completely different genetic arrhythmia syndrome known as Brugada syndrome [50,51]. (See "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) Similar to LQT1 and LQT2, sporadic (de novo) SCN5A variants have also been described in which neither parent had either the variant or a prolonged QT interval. In contrast to the heritable variants, one of these de novo variants resulted in a prolonged opening and early reopening of the sodium channel, and therefore a threefold prolongation of sodium current decay [52]. Pathogenic variants in SCN5A have been associated with sudden infant death syndrome, at least some of which are sporadic [53-55]. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Sudden infant death syndrome'.) Other disease-causative variants in SCN5A Different genetic variants in SCN5A can also cause a variety of other cardiac abnormalities, including Brugada syndrome, a related disorder, the sudden unexpected nocturnal death syndrome, an isolated familial atrioventricular conduction defect, congenital sinus node dysfunction, and familial dilated cardiomyopathy with conduction defects and susceptibility to atrial fibrillation. In addition, some pathogenic variants are associated with both LQT3 and the Brugada syndrome, with or without a conduction block [56,57]. (See "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 8/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate The differences in clinical manifestations are probably due to differences in the electrophysiologic abnormalities induced by the specific variants [58,59]. (See "Brugada syndrome: Epidemiology and pathogenesis", section on 'Genetics' and "Etiology of atrioventricular block", section on 'Familial disease' and "Genetics of dilated cardiomyopathy" and "Sinus node dysfunction: Epidemiology, etiology, and natural history", section on 'Childhood and familial disease' and "Approach to sudden cardiac arrest in the absence of apparent structural heart disease", section on 'Brugada syndrome'.) Compound/multiple variant-mediated LQTS In different large series, 4.5 and 7.9 percent of unrelated individuals who were each the first in their families to be diagnosed with LQTS (probands) had two disease-causing variants [60,61]. This unexpectedly high incidence of compound variants could be a reflection of selection bias, since such individuals would be more likely to develop clinical disease. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Epidemiology'.) Consistent with this hypothesis is the observation that patients with multiple variants, compared with those with only one variant, have significantly longer QT intervals and are more likely to experience a life-threatening cardiac arrhythmia [61,62]. The presence of >1 pathogenic variant can also affect the success of genetic testing. (See 'Genetic testing' below.) Minor LQTS-susceptibility genes Since the discovery of the three canonical LQTS-causative genes in the 1980s and 1990s, up to 14 additional, albeit minor, LQTS-susceptibility genes have been discovered by either hypothesis-driven candidate gene research or genomic triangulation strategies using whole exome sequencing [19]. The LQTS genotypes stemming from these minor genes ( table 1) have been annotated in the past as LQT4-17. However, these subtypes are best described by their gene, such as CACNA1C-LQTS (instead of LQT8) and TRDN-LQTS (instead of LQT17). Some of these minor genetic subtypes converge upon the final common pathway of one of the canonical subtypes. For example, LQT5 (preferred name: KCNE1-LQTS) mimics LQT1, while CAV3-LQTS results in accentuation of the late sodium current akin to primary variants in SCN5A (LQT3). The most common of the minor LQTS-susceptibility genes is probably CACNA1C-mediated LQTS (previously called LQT8) [63]. Gain-of-function variants in CACNA1C-encoded Cav1.2 were first discovered in a complex multisystem disorder called Timothy syndrome, which included marked QT prolongation [64]. More recently, however, other CACNA1C variants have been associated with cardiac-only, autosomal dominant LQTS. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 9/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Among all of the minor LQTS-susceptibility genes, the most penetrant ones have involved either autosomal dominant or sporadic de novo variants in one of the three CALM genes that encode the 100 percent identical 103 amino-acid-containing calmodulin proteins or homozygous/compound heterozygous, autosomal recessive inherited variants in TRDN-encoded triadin [65,66]. The CALM1-3-LQTS subtypes are referred to collectively as the calmodulinopathies, since the phenotype overlaps with not only LQTS but also catecholaminergic polymorphic ventricular tachycardia [67]. These are listed in an International Calmodulinopathy Registry [68]. Similarly, patients with autosomal recessive loss-of-function variants in TRDN are referred to as having Triadin Knockout Syndrome (TKOS) because of phenotypic overlap; there is an International TKOS Registry to enroll patients with this severe channelopathy [68]. Children with these severe forms of disease (calmodulinopathies and TKOS) continue to experience breakthrough cardiac events despite receiving optimal guideline-directed LQTS therapies. GENETIC TESTING Clinical genetic testing is standard of care to identify LQTS-causative variants in any patient for which a clinical diagnosis of LQTS is being contemplated [69-72]. However, such testing is subject to limitations given the complexity and heterogeneity of the disorder. It has been estimated that a specific LQTS-causative variant in one of the three canonical genes (KCNQ1, KCNH2, and SCN5A) will be identified in at least 75 to 80 percent of patients who express a robust phenotype consistent with the diagnosis of LQTS [23]. Approximately 4 percent of controls have a rare variant of uncertain significance (in KCNQ1, KCNH2, or SCN5A), which represents a lower point estimate for the potential false positive rate for genetic testing [73,74]. In a series of 541 unrelated patients from the Mayo Clinic, the overall yield of genetic testing was approximately 50 percent and correlated with clinical measures of disease severity [75]: The likelihood of identifying a pathogenic variant increased progressively with increasing QTc, ranging from 0 to 62 percent as the QTc increased from the lowest (<400 ms) to the highest (>480 ms) category. A clinical LQTS diagnostic tool that predicts the likelihood of LQTS, the Schwartz LQTS score, is derived from the QTc, symptoms, and family history [76]. Patients with a Schwartz LQTS score 4, suggesting a strong probability of LQTS, had a disease- causative variant identified more frequently than those with a score <4 (72 versus 44 percent). (See "Congenital long QT syndrome: Diagnosis", section on 'Diagnosis'.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 10/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Additional information on the approach to a genetic test result is presented separately. (See "Gene test interpretation: Congenital long QT syndrome genes (KCNQ1, KCNH2, SCN5A)".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Long QT syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Genetic variants At least 17 congenital long QR syndrome (LQTS)-susceptibility genes have been identified ( table 1). (See 'Types of congenital LQTS' above.) LQT1, LQT2, and LQT3 account for approximately 75 to 80 percent of cases of congenital LQTS. The minor LQTS-susceptibility genes account for <5 percent of LQTS. Some are associated with distinct clinical syndromes (eg, CALM1-3-mediated LQTS is called calmodulinopathy; TRDN-mediated LQTS is triadin knockout syndrome [TKOS]). https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 11/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate LQT1 This accounts for up to 45 percent of cases of the LQTS and is caused by loss-of- function variants in the KCNQ1-encoded Kv7.1 potassium channel. Most patients show paradoxical prolongation of the QT interval during the recovery phase after treadmill stress testing, which can be used to unmask patients with otherwise electrocardiographically (ECG) concealed LQT1. Events triggered by exercise, particularly swimming, are characteristic of (but not specific for) LQT1. (See 'Type 1 LQTS (LQT1)' above.) LQT2 This accounts for 25 to 40 percent of cases of congenital LQTS and is caused by a variety of loss-of-function variants in the KCNH2-encoded Kv11.1 potassium channels. Intragenic risk stratification is possible; as an example, patients with LQT2-causative variants localizing to Kv11.1's pore have worse clinical outcomes than those with pathogenic variants localizing the channel's C-terminal region. LQT3 This accounts for 5 to 10 percent of cases and is caused by gain-of-function variants in the SCN5A-encoded Nav1.5 sodium channel. Events occurring at rest or during sleep are characteristic of (but not specific for) LQT3. (See 'Type 3 LQTS (LQT3)' above.) LQTS genetic testing This has been available clinically/commercially since 2004 in the United States, and LQTS genetic testing is a class I recommendation for any patient being considered to have LQTS to enable genotype-guided risk stratification and genotype- guided tailoring of therapy and to permit cascade variant-specific testing of the appropriate relatives. (See 'Genetic testing' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013; 34:3109. 2. Moss AJ. Long QT Syndrome. JAMA 2003; 289:2041. 3. El-Sherif N, Turitto G. Torsade de pointes. Curr Opin Cardiol 2003; 18:6. 4. Passman R, Kadish A. Polymorphic ventricular tachycardia, long Q-T syndrome, and torsades de pointes. Med Clin North Am 2001; 85:321. 5. Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AAM. Impact of genetics on the clinical management of channelopathies. J Am Coll Cardiol 2013; 62:169. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 12/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 6. Schwartz PJ, Woosley RL. Predicting the Unpredictable: Drug-Induced QT Prolongation and Torsades de Pointes. J Am Coll Cardiol 2016; 67:1639. 7. January CT, Riddle JM. Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current. Circ Res 1989; 64:977. 8. Szabo B, Sweidan R, Rajagopalan CV, Lazzara R. Role of Na+:Ca2+ exchange current in Cs(+)- induced early afterdepolarizations in Purkinje fibers. J Cardiovasc Electrophysiol 1994; 5:933. 9. Roden DM, Lazzara R, Rosen M, et al. Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS. Circulation 1996; 94:1996. 10. Antzelevitch C, Sicouri S. Clinical relevance of cardiac arrhythmias generated by afterdepolarizations. Role of M cells in the generation of U waves, triggered activity and torsade de pointes. J Am Coll Cardiol 1994; 23:259. 11. Antzelevitch C, Sun ZQ, Zhang ZQ, Yan GX. Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes. J Am Coll Cardiol 1996; 28:1836. 12. Ben-David J, Zipes DP. Torsades de pointes and proarrhythmia. Lancet 1993; 341:1578. 13. Schwartz P, Locati E, Priori E, Zaza A. Cardiac Electrophysiology: From Cell to Bedside. In: Car diac Electrophysiology: From Cell to Bedside, Zipes D, Jalife J (Eds), WB Saunders, Philadelphi a 1990. p.589. 14. Schwartz PJ, Malliani A. Electrical alternation of the T-wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long Q-T syndrome. Am Heart J 1975; 89:45. 15. Dusi V, Pugliese L, De Ferrari GM, et al. Left Cardiac Sympathetic Denervation for Long QT Syndrome: 50 Years' Experience Provides Guidance for Management. JACC Clin Electrophysiol 2022; 8:281. 16. Tan HL, Hou CJ, Lauer MR, Sung RJ. Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes. Ann Intern Med 1995; 122:701. 17. Yan GX, Wu Y, Liu T, et al. Phase 2 early afterdepolarization as a trigger of polymorphic ventricular tachycardia in acquired long-QT syndrome : direct evidence from intracellular recordings in the intact left ventricular wall. Circulation 2001; 103:2851. 18. Hosseini SM, Kim R, Udupa S, et al. Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome. Circulation 2018; 138:1195. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 13/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 19. Giudicessi JR, Wilde AAM, Ackerman MJ. The genetic architecture of long QT syndrome: A critical reappraisal. Trends Cardiovasc Med 2018; 28:453. 20. Giudicessi JR, Roden DM, Wilde AAM, Ackerman MJ. Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing. Circulation 2018; 137:619. 21. Jackman WM, Friday KJ, Anderson JL, et al. The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis 1988; 31:115. 22. Wang Q, Curran ME, Splawski I, et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 1996; 12:17. 23. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm 2011; 8:1308. 24. Ackerman MJ, Khositseth A, Tester DJ, et al. Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome. Mayo Clin Proc 2002; 77:413. 25. Shimizu W, Noda T, Takaki H, et al. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome. J Am Coll Cardiol 2003; 41:633. 26. Barhanin J, Lesage F, Guillemare E, et al. K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature 1996; 384:78. 27. Sanguinetti MC, Curran ME, Zou A, et al. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 1996; 384:80. 28. Splawski I, Tristani-Firouzi M, Lehmann MH, et al. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet 1997; 17:338. 29. Shalaby FY, Levesque PC, Yang WP, et al. Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome. Circulation 1997; 96:1733. 30. Chen YH, Xu SJ, Bendahhou S, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science 2003; 299:251. 31. Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 2004; 109:2394. 32. Schwartz PJ, Moreno C, Kotta MC, et al. Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region. Eur Heart J 2021; 42:4743. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 14/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 33. Shimizu W, Horie M, Ohno S, et al. Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: multicenter study in Japan. J Am Coll Cardiol 2004; 44:117. 34. Crotti L, Spazzolini C, Schwartz PJ, et al. The common long-QT syndrome mutation KCNQ1/A341V causes unusually severe clinical manifestations in patients with different ethnic backgrounds: toward a mutation-specific risk stratification. Circulation 2007; 116:2366. 35. JERVELL A, LANGE-NIELSEN F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J 1957; 54:59. 36. Schwartz PJ, Spazzolini C, Crotti L, et al. The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome. Circulation 2006; 113:783. 37. Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000; 102:1178.

variants localizing to Kv11.1's pore have worse clinical outcomes than those with pathogenic variants localizing the channel's C-terminal region. LQT3 This accounts for 5 to 10 percent of cases and is caused by gain-of-function variants in the SCN5A-encoded Nav1.5 sodium channel. Events occurring at rest or during sleep are characteristic of (but not specific for) LQT3. (See 'Type 3 LQTS (LQT3)' above.) LQTS genetic testing This has been available clinically/commercially since 2004 in the United States, and LQTS genetic testing is a class I recommendation for any patient being considered to have LQTS to enable genotype-guided risk stratification and genotype- guided tailoring of therapy and to permit cascade variant-specific testing of the appropriate relatives. (See 'Genetic testing' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013; 34:3109. 2. Moss AJ. Long QT Syndrome. JAMA 2003; 289:2041. 3. El-Sherif N, Turitto G. Torsade de pointes. Curr Opin Cardiol 2003; 18:6. 4. Passman R, Kadish A. Polymorphic ventricular tachycardia, long Q-T syndrome, and torsades de pointes. Med Clin North Am 2001; 85:321. 5. Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AAM. Impact of genetics on the clinical management of channelopathies. J Am Coll Cardiol 2013; 62:169. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 12/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 6. Schwartz PJ, Woosley RL. Predicting the Unpredictable: Drug-Induced QT Prolongation and Torsades de Pointes. J Am Coll Cardiol 2016; 67:1639. 7. January CT, Riddle JM. Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current. Circ Res 1989; 64:977. 8. Szabo B, Sweidan R, Rajagopalan CV, Lazzara R. Role of Na+:Ca2+ exchange current in Cs(+)- induced early afterdepolarizations in Purkinje fibers. J Cardiovasc Electrophysiol 1994; 5:933. 9. Roden DM, Lazzara R, Rosen M, et al. Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS. Circulation 1996; 94:1996. 10. Antzelevitch C, Sicouri S. Clinical relevance of cardiac arrhythmias generated by afterdepolarizations. Role of M cells in the generation of U waves, triggered activity and torsade de pointes. J Am Coll Cardiol 1994; 23:259. 11. Antzelevitch C, Sun ZQ, Zhang ZQ, Yan GX. Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes. J Am Coll Cardiol 1996; 28:1836. 12. Ben-David J, Zipes DP. Torsades de pointes and proarrhythmia. Lancet 1993; 341:1578. 13. Schwartz P, Locati E, Priori E, Zaza A. Cardiac Electrophysiology: From Cell to Bedside. In: Car diac Electrophysiology: From Cell to Bedside, Zipes D, Jalife J (Eds), WB Saunders, Philadelphi a 1990. p.589. 14. Schwartz PJ, Malliani A. Electrical alternation of the T-wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long Q-T syndrome. Am Heart J 1975; 89:45. 15. Dusi V, Pugliese L, De Ferrari GM, et al. Left Cardiac Sympathetic Denervation for Long QT Syndrome: 50 Years' Experience Provides Guidance for Management. JACC Clin Electrophysiol 2022; 8:281. 16. Tan HL, Hou CJ, Lauer MR, Sung RJ. Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes. Ann Intern Med 1995; 122:701. 17. Yan GX, Wu Y, Liu T, et al. Phase 2 early afterdepolarization as a trigger of polymorphic ventricular tachycardia in acquired long-QT syndrome : direct evidence from intracellular recordings in the intact left ventricular wall. Circulation 2001; 103:2851. 18. Hosseini SM, Kim R, Udupa S, et al. Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome. Circulation 2018; 138:1195. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 13/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 19. Giudicessi JR, Wilde AAM, Ackerman MJ. The genetic architecture of long QT syndrome: A critical reappraisal. Trends Cardiovasc Med 2018; 28:453. 20. Giudicessi JR, Roden DM, Wilde AAM, Ackerman MJ. Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing. Circulation 2018; 137:619. 21. Jackman WM, Friday KJ, Anderson JL, et al. The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis 1988; 31:115. 22. Wang Q, Curran ME, Splawski I, et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 1996; 12:17. 23. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm 2011; 8:1308. 24. Ackerman MJ, Khositseth A, Tester DJ, et al. Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome. Mayo Clin Proc 2002; 77:413. 25. Shimizu W, Noda T, Takaki H, et al. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome. J Am Coll Cardiol 2003; 41:633. 26. Barhanin J, Lesage F, Guillemare E, et al. K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature 1996; 384:78. 27. Sanguinetti MC, Curran ME, Zou A, et al. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 1996; 384:80. 28. Splawski I, Tristani-Firouzi M, Lehmann MH, et al. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet 1997; 17:338. 29. Shalaby FY, Levesque PC, Yang WP, et al. Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome. Circulation 1997; 96:1733. 30. Chen YH, Xu SJ, Bendahhou S, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science 2003; 299:251. 31. Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 2004; 109:2394. 32. Schwartz PJ, Moreno C, Kotta MC, et al. Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region. Eur Heart J 2021; 42:4743. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 14/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 33. Shimizu W, Horie M, Ohno S, et al. Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: multicenter study in Japan. J Am Coll Cardiol 2004; 44:117. 34. Crotti L, Spazzolini C, Schwartz PJ, et al. The common long-QT syndrome mutation KCNQ1/A341V causes unusually severe clinical manifestations in patients with different ethnic backgrounds: toward a mutation-specific risk stratification. Circulation 2007; 116:2366. 35. JERVELL A, LANGE-NIELSEN F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J 1957; 54:59. 36. Schwartz PJ, Spazzolini C, Crotti L, et al. The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome. Circulation 2006; 113:783. 37. Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000; 102:1178. 38. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001; 103:89. 39. Jiang C, Atkinson D, Towbin JA, et al. Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity. Nat Genet 1994; 8:141. 40. Furutani M, Trudeau MC, Hagiwara N, et al. Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel. Circulation 1999; 99:2290. 41. Moss AJ, Zareba W, Kaufman ES, et al. Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel. Circulation 2002; 105:794. 42. Curran ME, Splawski I, Timothy KW, et al. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995; 80:795. 43. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 1995; 81:299. 44. Miller C. The inconstancy of the human heart. Nature 1996; 379:767. 45. Tseng GN. I(Kr): the hERG channel. J Mol Cell Cardiol 2001; 33:835. 46. Berthet M, Denjoy I, Donger C, et al. C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence. Circulation 1999; 99:1464. 47. Rossenbacker T, Mubagwa K, Jongbloed RJ, et al. Novel mutation in the Per-Arnt-Sim domain of KCNH2 causes a malignant form of long-QT syndrome. Circulation 2005; 111:961. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 15/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 48. Wang Q, Shen J, Splawski I, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995; 80:805. 49. Wei J, Wang DW, Alings M, et al. Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel. Circulation 1999; 99:3165. 50. Kapplinger JD, Tester DJ, Salisbury BA, et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm 2009; 6:1297. 51. Kapplinger JD, Tester DJ, Alders M, et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm 2010; 7:33. 52. Kambouris NG, Nuss HB, Johns DC, et al. Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel. Circulation 1998; 97:640. 53. Schwartz PJ, Priori SG, Dumaine R, et al. A molecular link between the sudden infant death syndrome and the long-QT syndrome. N Engl J Med 2000; 343:262. 54. Wedekind H, Smits JP, Schulze-Bahr E, et al. De novo mutation in the SCN5A gene associated with early onset of sudden infant death. Circulation 2001; 104:1158. 55. Ackerman MJ, Siu BL, Sturner WQ, et al. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA 2001; 286:2264. 56. Grant AO, Carboni MP, Neplioueva V, et al. Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation. J Clin Invest 2002; 110:1201. 57. Clancy CE, Rudy Y. Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism. Circulation 2002; 105:1208. 58. Desch nes I, Baroudi G, Berthet M, et al. Electrophysiological characterization of SCN5A mutations causing long QT (E1784K) and Brugada (R1512W and R1432G) syndromes. Cardiovasc Res 2000; 46:55. 59. Clancy CE, Kass RS. Defective cardiac ion channels: from mutations to clinical syndromes. J Clin Invest 2002; 110:1075. 60. Napolitano C, Priori SG, Schwartz PJ, et al. Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA 2005; 294:2975. 61. Westenskow P, Splawski I, Timothy KW, et al. Compound mutations: a common cause of severe long-QT syndrome. Circulation 2004; 109:1834. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 16/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 62. Mullally J, Goldenberg I, Moss AJ, et al. Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations. Heart Rhythm 2013; 10:378. 63. Boczek NJ, Best JM, Tester DJ, et al. Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome. Circ Cardiovasc Genet 2013; 6:279. 64. Splawski I, Timothy KW, Tateyama M, et al. Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science 2002; 297:1333. 65. Reed GJ, Boczek NJ, Etheridge SP, Ackerman MJ. CALM3 mutation associated with long QT syndrome. Heart Rhythm 2015; 12:419. 66. Altmann HM, Tester DJ, Will ML, et al. Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest: Elucidation of the Triadin Knockout Syndrome. Circulation 2015; 131:2051. 67. Boczek NJ, Gomez-Hurtado N, Ye D, et al. Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G. Circ Cardiovasc Genet 2016; 9:136. 68. Clemens DJ, Tester DJ, Giudicessi JR, et al. International Triadin Knockout Syndrome Registry. Circ Genom Precis Med 2019; 12:e002419. 69. Wehrens XH, Vos MA, Doevendans PA, Wellens HJ. Novel insights in the congenital long QT syndrome. Ann Intern Med 2002; 137:981. 70. Priori SG, Barhanin J, Hauer RN, et al. Genetic and molecular basis of cardiac arrhythmias: impact on clinical management parts I and II. Circulation 1999; 99:518. 71. Li H, Fuentes-Garcia J, Towbin JA. Current concepts in long QT syndrome. Pediatr Cardiol 2000; 21:542. 72. Priori SG, Barhanin J, Hauer RN, et al. Genetic and molecular basis of cardiac arrhythmias: impact on clinical management part III. Circulation 1999; 99:674. 73. Ackerman MJ, Tester DJ, Jones GS, et al. Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome. Mayo Clin Proc 2003; 78:1479. 74. Ackerman MJ, Splawski I, Makielski JC, et al. Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing. Heart Rhythm 2004; 1:600. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 17/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 75. Tester DJ, Will ML, Haglund CM, Ackerman MJ. Effect of clinical phenotype on yield of long QT syndrome genetic testing. J Am Coll Cardiol 2006; 47:764. 76. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation 1993; 88:782. Topic 1009 Version 34.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 18/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate GRAPHICS Single-lead electrocardiogram showing a prolonged QT interval The corrected QT interval (QTc) is calculated by dividing the QT interval (0.60 seconds) by the square root of the preceding RR interval (0.92 seconds). In this case, the QTc is 0.625 seconds (625 milliseconds). Graphic 77018 Version 7.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 19/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Single lead electrocardiogram (ECG) showing polymorphic ventricular tachycardia (VT) This is an atypical, rapid, and bizarre form of ventricular tachycardia that is characterized by a continuously changing axis of polymorphic QRS morphologies. Graphic 53891 Version 5.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 20/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Single lead electrocardiogram (ECG) showing torsades de pointes The electrocardiographic rhythm strip shows torsades de pointes, a polymorphic ventricular tachycardia associated with QT prolongation. There is a short, preinitiating RR interval due to a ventricular couplet, which is followed by a long, initiating cycle resulting from the compensatory pause after the couplet. Graphic 73827 Version 4.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 21/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Summary of heritable arrhythmia syndrome susceptibility genes: Long QT syndrome (LQTS) Gene Locus Protein Major LQTS genes KCNQ1 (LQT1) 11p15.5 I potassium channel alpha subunit (KVLQT1, Ks Kv7.1) KCNH2 (LQT2) 7q35-36 I potassium channel alpha subunit (HERG, Kr Kv11.1) SCN5A (LQT3) 3p21-p24 Cardiac sodium channel alpha subunit (NaV1.5) Minor LQTS genes AKAP9 7q21-q22 Yotiao CACNA1C 12p13.3 Voltage gated L-type calcium channel (CaV1.2) CALM1 14q32.11 Calmodulin 1 CALM2 2p21 Calmodulin 2 CALM3 19q13.2-q13.3 Calmodulin 3 CAV3 3p25 Caveolin-3 KCNE1 21q22.1 Potassium channel beta subunit (MinK) KCNE2 21q22.1 Potassium channel beta subunit (MiRP1) KCNJ5 11q24.3 Kir3.4 subunit of I channel KACH SCN4B 11q23.3 Sodium channel beta 4 subunit SNTA1 20q11.2 Syntrophin-alpha 1 TRDN 6q22.31 Triadin Adapted from: Tester DJ, Ackerman MJ. Genetics of cardiac arrhythmias. In: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 10th ed, Mann DL, Zipes DP, Libby P, et al (Eds), Elsevier, Philadelphia 2015. Graphic 114927 Version 2.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 22/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate [1] Current-centric classification of long-QT syndrome susceptibility genes The clinical phenotypes resulting from the abnormal ventricular cardiac action potential depolarization or repolarization are grouped according to the specific current perturbed by an underlying genetic defect (refer to graphic s key, above). The graphic shows both mutations that confer a loss of function to the specified current and mutations that confer a gain of function (refer to graphic s key, above). Solid lines indicate those disorders that are autosomal dominant, whereas dashed lines indicate those disorders that are autosomal recessive. Thin outlines indicate nonsyndromic genotypes and thick outlines represent multisystem genotypes. COTS: cardiac-only Timothy syndrome; LQTS: long-QT syndrome; ABS: ankyrin-B syndrome; JLNS: Jervell : cardiac and Lange-Neilson syndrome; I : L-type calcium current; TKO: triadin knockout syndrome; I Ca,L Na sodium current; I the delayed rectifier potassium current; I : slow-component of the delayed rectifier potassium current; I : rapid component of KS Kr : G-protein-coupled inwardly rectifying potassium current; KAch I : inwardly rectifying potassium current. K1 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 23/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Reference: 1. Giudicessi JR, Ackerman MJ. Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes. Transl Res 2013; 161:1. Original gure modi ed for this publication. Illustration used with the permission of Elsevier Inc. All rights reserved. From: Giudicessi JR, Ackerman MJ. Calcium revisited: New insights into the molecular basis of long-QT syndrome. Circ Arrhythm Electrophysiol 2016; 9:1. DOI: 10.1161/CIRCEP.116.002480. Copyright 2016 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 120655 Version 2.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 24/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial GnRH agonist/antagonist therapy ischemia or infarction, Hypomagnesemia Bilateral surgical orchiectomy Hypocalcemia Diuretic therapy via electrolyte disorders especially with Starvation particularly hypokalemia and hypomagnesemia prominent T-wave inversions Anorexia nervosa Herbs Liquid protein diets Cinchona (contains quinine), iboga (ibogaine), licorice extract in overuse via electrolyte disturbances Intracranial disease Hypothyroidism Bradyarrhythmias HIV infection Sinus node dysfunction Hypothermia Toxic exposure: Organophosphate insecticides AV block: Second or third degree Medications* High risk Adagrasib Cisaparide Lenvatinib Selpercatinib (restricted availability) Ajmaline Levoketoconazole Sertindole Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine Vandetanib Dofetilide (intracoronary) Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab ozogamacin Propafenone Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Carbetocin Erythromycin Ribociclib https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 25/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Certinib Escitalopram Levofloxacin Risperidone (systemic) Chloroquine Etelcalcetide Saquinavir Lofexidine Citalopram Fexinidazole Sevoflurane Meglumine Clarithromycin Flecainide Sparfloxacin antimoniate Clofazimine Floxuridine Sunitinib Midostaurin Clomipramine Fluconazole Tegafur Moxifloxacin Clozapine Fluorouracil Terbutaline Nilotinib (systemic) Crizotinib Thioridazine Olanzapine Flupentixol Dabrafenib Toremifene Ondansetrol (IV > Gabobenate dimeglumine Dasatinib Vemurafenib oral) Deslurane Voriconazole Osimertinib Gemifloxacin Domperidone Oxytocin Gilteritinib Doxepin Pazopanib Halofantrine Doxifluridine Pentamidine Haloperidol (oral) Pilsicainide Imipramine Pimozide Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole (systemic) Romidepsin Anagrelide Foscarnet Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- Glasdegib Mizolastine lumefantrine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine Nortriptyline Benperidol (rare reports) Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus Olodaterol (systemic) Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 26/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Leuprolide- Periciazine Tropisetron norethindrone Dexmedetomidine** Pimavanserin Vardenafil Levalbuterol Dolasetron Pipamperone Vilanterol Levomethadone Donepezil Pitolisant Vinflunine Lithium Efavirenz Ponesimod Voclosporin Loperamide overdose in Eliglustat Primaquine Vorinostat Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. [1,2] . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 27/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 28/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Myocardial action potential Representation of a ventricular action potential. There are 5 phases of the action potential beginning with phase 0, rapid depolarization by sodium influx. Phase 1 is a rapid repolarization via potassium efflux followed by phase 2 or the plateau phase. The plateau phase results from entry of calcium into the cell and potassium efflux. Phase 3 repolarization is dominated by potassium currents which polarize the cell and potassium inward rectifier maintains the resting potential or phase 4. See text for full description. Graphic 71390 Version 4.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 29/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Action potential currents Major cardiac ion currents and channels responsible for a ventricular action potential are shown with their common name, abbreviation, and the gene and protein for the alpha subunit that forms the pore or transporter. The diagram on the left shows the time course of amplitude of each current during the action potential, but does not accurately reflect amplitudes relative to each of the other currents. This summary represents a ventricular myocyte, and lists only the major ion channels. The currents and their molecular nature vary within regions of the ventricles, and in atria, and other specialized cells such as nodal and Purkinje. Ion channels exist as part of multi-molecular complexes including beta subunits and other associated regulatory proteins which are also not shown. Courtesy of Jonathan C Makielski, MD, FACC. Graphic 70771 Version 4.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 30/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Contributor Disclosures Michael J Ackerman, MD, PhD Consultant/Advisory Boards: Abbott [Education around ICD/device therapy for genetic heart diseases including LQTS]; ARMGO Pharma [Novel therapies for genetic heart diseases, CPVT in particular]; Boston Scientific [Education around ICD/device therapy for genetic heart diseases including LQTS]; Daiichi Sankyo [Drug-induced QT prolongation for one of their drugs]; Invitae [Genetic testing for genetic heart diseases]; LQT Therapeutics [Development of a novel QT-shortening medication]; Medtronic [Education around ICD/device therapy for genetic heart diseases including LQTS]; UpToDate [Genetic heart diseases, especially LQTS]. Other Financial Interest: AliveCor [QTc analytics for smartphone- enabled mobile ECG]; Anumana [Artificial intelligence ECG for early detection of hypertrophic cardiomyopathy]; Pfizer [Gene therapy for genetic heart diseases including LQTS]. All of the relevant financial relationships listed have been mitigated. Peter J Schwartz, MD No relevant financial relationship(s) with ineligible companies to disclose. John K Triedman, MD Consultant/Advisory Boards: Biosense Webster and Sentiar [Supraventricular and ventricular topics]. All of the relevant financial relationships listed have been mitigated. Samuel Asirvatham, MD Grant/Research/Clinical Trial Support: Medtronic [Defibrillators]; St Jude's [Sudden Cardiac Death]. Consultant/Advisory Boards: BioTronik [Defibrillators]; Boston Scientific [Sudden Cardiac Death]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 31/31

7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Congenital long QT syndrome: Treatment : Peter J Schwartz, MD, Michael J Ackerman, MD, PhD : John K Triedman, MD, Samuel Asirvatham, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 02, 2022. INTRODUCTION Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death (SCD) [1]. The primary symptoms in patients with LQTS include syncope, seizures, sudden cardiac arrest (SCA), and SCD. This syndrome is associated with an increased risk of a characteristic life- threatening cardiac arrhythmia known as torsades de pointes or "twisting of the points" ( waveform 2) [2]. LQTS may be congenital or acquired [1,3-7]. Pathogenic variants in at least 17 genes have been identified thus far in patients with congenital LQTS. An estimated 75 to 80 percent of all congenital LQTS is accounted for by LQTS-causative variants in either KCNQ1-encoded Kv7.1 (LQT1), KCNH2-encoded Kv11.1 (LQT2), or SCN5A-encoded Nav1.5 (LQT3). The minor LQTS genotypes account for at most 5 percent of LQTS and are best referred to by their genetic cause rather than their numerical subtype (eg, CACNA1C-LQTS rather than LQT8) ( table 1) [7]. Acquired LQTS usually results from undesired QT prolongation and potential for QT-triggered arrhythmias by either QT-prolonging disease states, QT-prolonging medications ( www.crediblemeds.org), or QT-prolonging electrolyte disturbances ( table 2). The treatment of congenital LQTS will be reviewed here. The epidemiology, clinical manifestations, diagnosis, and genetics of congenital LQTS, as well as issues related to the management of acquired LQTS, are discussed separately. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Congenital long QT syndrome: Diagnosis" and https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 1/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate "Congenital long QT syndrome: Pathophysiology and genetics" and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) TREATMENT Regardless of genotype, age, and previous symptomatic/asymptomatic status, all patients with congenital LQTS should be advised of simple QT preventive measures and implement them whenever possible. These include avoidance of medications with QT-prolonging potential ( www.crediblemeds.org); replacing electrolytes during vomiting and diarrheal illnesses, as both hypokalemia and hypomagnesemia can be QT aggravating; and lowering fever. Like the 2015 Heart Rhythm Society (HRS) guidelines, the 2017 American Heart Association/American College of Cardiology (AHA/ACC) guidelines continue to recommend universal beta-blocker therapy for all patients with congenital LQTS, whether asymptomatic or symptomatic, in the absence of a contraindication [8]. In the setting of breakthrough cardiac events while on beta-blocker therapy or in the setting of beta-blocker intolerance, patient- specific tailoring of therapy is appropriate, based on the assessed risk from the disease and the potential comorbidities of the various treatments under consideration with the patients and their families also involved in the shared decision making. Recommended options for treatment intensification may include one or more of the following: Other medications (such as mexiletine) Left cardiac sympathetic denervation (LCSD) Placement of a pacemaker to enable intentional atrial pacing Placement of an implantable cardioverter-defibrillator (ICD) The treatment of patients with congenital and acquired LQTS differs greatly because of pathophysiologic differences between the two forms. As an example, bradycardia is usually associated with torsades de pointes (TdP) in acquired LQTS, whereas catecholamine surges trigger TdP in congenital LQTS. The following discussion is limited to the treatment of congenital LQTS. The management of acquired LQTS is presented separately; it involves acute therapy of arrhythmia, discontinuation of any precipitating drug, and correction of any metabolic abnormalities such as hypokalemia or hypomagnesemia. The acute management of TdP is also discussed in detail elsewhere. (See "Overview of the acute management of tachyarrhythmias", section on 'Polymorphic ventricular tachycardia' and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 2/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Our approach to symptomatic patients Because of the appreciable risk of symptoms and SCD without treatment, all previously symptomatic patients with congenital LQTS should be treated [9,10]. Our general approach is as follows: All patients with congenital LQTS should adhere to standard general preventive measures, such as the avoidance of medications known to prolong the QT interval ( www.crediblemeds.org) and the aggressive treatment of electrolyte imbalances (eg, hypokalemia in the setting of vomiting, diarrhea, or diuretic use). (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'Initial management'.) Athletes with LQTS who desire to remain athletes should be evaluated by an LQTS specialist to enable shared decision making to occur successfully. Importantly, there are laws in some countries that supersede professional society guidelines regarding return-to-play issues. For all patients with congenital LQTS and a history of syncope or seizures, we recommend treatment with a beta blocker. We prefer propranolol or nadolol, given their superior efficacy in this patient population. All patients with congenital LQTS who present with resuscitated SCA should be treated with a beta blocker, preferably propranolol or nadolol, given their superior efficacy in this patient population. Additionally, for most patients with congenital LQTS who present with resuscitated SCA while previously undiagnosed and therefore untreated, the treatment program should also include an ICD as secondary prevention. Potential exceptions to this include patients with previously undiagnosed and therefore untreated LQT1. For patients with recurrent arrhythmic events in spite of maximally tolerated doses of a beta blocker, or for patients who discontinue beta blockers due to intolerable side effects, treatment intensification with either concomitant drug therapy, LCSD, and/or an ICD is recommended depending on the nature of the arrhythmic event, the genotype, and the patient's degree of QT prolongation at rest (ie, their resting QTc). The risks and benefits of each treatment intensification option need to be reviewed with the patient and shared decision making should be utilized to decide upon and implement the chosen therapeutic strategy. Physical activity and LQTS Before tailoring any LQTS-specific therapies or recommending activity modification, it is vital to confirm the diagnosis of LQTS. Athletes are often flagged for the possibility of LQTS based on their pre-sports participation ECG screen. While a subsequent evaluation is necessary and appropriate, studies show that exercise can elicit a maladaptive remodeling in the repolarization reserve, yielding an acquired, reversible form of QT https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 3/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate prolongation rather than congenital LQTS itself [11]. If such an athlete's genetic test is negative and if their QT normalizes after detraining, they should not be classified as having LQTS or restricted from activity [11]. After establishing the correct diagnosis of LQTS and implementing the initial treatment program, patients with LQTS can continue to be recreationally active, especially those with LQT2 and LQT3. In general, children and adolescents can resume participation in physical education classes and adults should be encouraged to stay aerobically active in accordance with national/international recommendations on active living. Athletes with LQTS who desire to remain competitive athletes should be evaluated by an LQTS specialist to enable shared decision making to occur successfully. Importantly, there are laws in some countries that supersede professional society guidelines regarding return-to-play issues. There is a divergence of opinions on competitive athletics for individuals with congenital LQTS [12-15]. The 2015 AHA/ACC Scientific Statement on Eligibility and Disqualification Recommendations for Competitive Athletes discusses participation in competitive events and training sessions as allowable and dependent on the existence of an emergency action plan with an automated external defibrillator (AED) immediately available on site. However, a different approach is dictated by the previous European guidelines, which advise precautionary restriction from competitive sports in these instances. The differences in the American and European approaches are outlined as follows: The following approach is proposed in the 2015 AHA/ACC Scientific Statement [12,13]: Asymptomatic persons who are genotype positive/phenotype negative (ie, with normal QTc at rest) can reasonably participate in all competitive sports with appropriate safety precautions, including avoidance of drugs known to exacerbate LQTS; avoidance and/or treatment of fever, hyperthermia, or heat exhaustion/heat stroke; electrolyte repletion; avoidance of dehydration; and establishment of an emergency action plan with an AED immediately available. Symptomatic (or previously symptomatic) patients, or patients with LQTS (QTc >470 milliseconds in males or >480 milliseconds in females), may consider participation in competitive athletics (with the exception of swimming in patients with LQT1 genotype) if they remain asymptomatic after three months of treatment and with appropriate cautionary measures, including an emergency action plan with an AED immediately available. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 4/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate For patients with LQTS and an ICD who have had three or more months without ICD therapy, participation in class IA sports ( figure 1) may be reasonable. Experts disagree on participation in higher levels of sport for patients with an ICD in place. Some experts feel that participation in sports with higher levels of exertion might be considered following counselling of the patient of the potential risks and appropriate cautionary measures, including an emergency action plan to implement should arrhythmias arise. However, other experts disagree and feel it is unwise to expose patients to the risk of ventricular arrhythmias and multiple shocks just to perform a competitive sport. A different approach was stated in the previous European guidelines, which advise precautionary restriction from essentially all competitive sports, based in part on the considerations that the safety measures recommended by the 2015 AHA/ACC guidelines (ie, training and competing in places where an AED is available) are not always feasible in the real world [14]. In a single-center retrospective cohort study of nearly 500 patients with LQTS who were managed with a return-to-play protocol and shared decision-making, the rates of breakthrough cardiac events (ie, seizures, syncope, cardiac arrest) among patients who returned to competitive sport were low [16]. In 494 self-identified athletes who returned to play (mean age 14.8 10.8 years), during follow-up for 4.2 4.8 years, there were no sports-related deaths; 29 patients (5.9 percent) had nonlethal LQTS-associated breakthrough cardiac events, only three (0.6 percent) of which occurred during exercise. Gene-specific management There is an association between genotype and triggers of arrhythmia ( figure 2) [17-20]. In particular: Patients with LQT1 primarily have exercise-related arrhythmic events; in a review that included 371 patients with LQT1, exercise was the trigger in 62 percent of arrhythmic events [17]. In addition, events related to swimming (occurring either immediately after diving into water or during recreational or competitive swimming activities) may be specific for LQT1 [19,21,22]. The sensitivity of patients with LQT1 to exercise may be related to exaggerated prolongation of the QT interval during exercise [23]. Events triggered by auditory stimuli, such as an alarm clock or telephone ringing, are most typically seen in LQT2 [18,19]. Acute arousal events (such as exercise, emotion, or noise) are much more likely triggers in LQT1 and LQT2 than LQT3 (85 and 67 versus 33 percent in one report) [17,20]. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 5/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Patients with LQT3 are at highest risk of events when at rest or asleep, while the risk is low during sleep in LQT1, accounting for only 3 percent of events [17]. Patients with LQT3 may have fewer events with exercise or stress because they significantly shorten their QTc with tachycardia [24] and therefore become less susceptible to catecholamine-induced arrhythmias. (See 'Beta blockers' below.) Initial therapy Beta blockers For all patients with congenital LQTS and a history of syncope, seizures, or resuscitated SCA, we recommend treatment with a beta blocker [8]. In general, we suggest propranolol or nadolol, given their superior efficacy in this patient population. The use of atenolol and metoprolol has been associated with an increased rate of recurrences [25]. In addition, if the symptom was resuscitated SCA, then an ICD as secondary prevention is indicated as well in most circumstances. (See 'Implantable cardioverter-defibrillator' below.) Beta blockers are a mainstay of therapy in both asymptomatic and symptomatic patients with congenital LQTS since they reduce both syncope and SCD [8]. Because of extensive observational data and expert consensus on the efficacy of beta blockers in this population, it is widely felt to be unethical to randomize patients to placebo, such that a randomized controlled trial in this population is unlikely. The overall benefit of beta-blocker therapy in congenital LQTS has been demonstrated in a number of observational studies, with many of the patients recruited from the International LQTS Registry [17,26-30]. In a series of 869 registry patients treated with a beta blocker, in whom clinical event rates for the five-year periods before and after beta-blocker therapy were compared, treatment with beta blockers reduced the rate of cardiac events (eg, syncope, aborted cardiac arrest, or SCD) in probands (0.31 events per patient per year on therapy versus 0.97 events per patient per year off therapy) and in affected family members [27]. Despite this benefit, 32 percent of patients with syncope or aborted SCA before beta-blocker therapy had another cardiac event during the five-year period while on a beta blocker (hazard ratio 5.8 compared with asymptomatic patients before therapy, 95% CI 3.7-9.1). Nearly one-half of these events occurred within the first six months of therapy ( figure 3). The importance of compliance with beta-blocker therapy in LQT1 was highlighted in a retrospective study of 216 genotyped patients followed for a median time of 10 years [31]. Among the 12 patients who suffered SCA or SCD after beta blockers were prescribed, 11 were either noncompliant with beta-blocker therapy and/or on a potentially contraindicated QT- prolonging drug. The only death in a beta-blocker-compliant patient not on a QT-prolonging drug occurred in a patient with Jervell and Lange-Nielsen syndrome, which is a more malignant form of LQT1. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Congenital sensorineural deafness'.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 6/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Differences among various beta blockers Propranolol (either given three times per day or extended-release formulations for improved compliance) and/or nadolol are the preferred beta blockers for therapy of LQTS, particularly for patients with LQT1 or LQT2. Because various beta blockers differ in their pharmacologic properties (eg, beta-1 selectivity, lipophilicity, half-life, etc), there appear to be differences in the efficacy of beta blockers on QT shortening and clinical outcomes. In a retrospective cohort study of 382 patients (56 percent female, median age 14 years) with LQT1 or LQT2 who were treated with propranolol (134 patients), metoprolol (147 patients), or nadolol (101 patients) and followed for up to eight years, the following findings were noted [25]: Patients receiving propranolol had more significant QTc shortening (27 versus 14 versus 12 milliseconds with metoprolol and nadolol, respectively). Patients receiving metoprolol had significantly more breakthrough clinical events (eg, syncope, aborted cardiac arrest, ICD shock, or SCD) compared with those receiving propranolol or nadolol (29 versus 8 versus 7 percent, respectively; odds ratio 3.9, 95% CI 1.2-13.1 for metoprolol versus any other beta blocker). Effect of genotype Patients with LQT1 derive the greatest benefit, but beta-blocker therapy is also very effective for both LQT2 and LQT3 patients [32]. The three genotypes (LQT1, LQT2, and LQT3) account for over 90 percent of known mutations in congenital LQTS [33]. The clinical efficacy of beta blockers in relation to these genotype has been examined in several observational studies. [17,27,28] LQT1 Beta blockers have relatively increased efficacy in LQT1 versus LQT3. This is probably related to the sympathetic sensitivity in this disorder. Most humans with LQT1 show paradoxical prolongation of the QT interval after an infusion of catecholamine, such as epinephrine or isoproterenol. The epinephrine QT stress test was used in the past to unmask patients with concealed LQT1 [34,35]. However, the test is subject to a large amount of interpretation error. Thus, genetic testing for LQTS has largely replaced the epinephrine QT stress test. LQT3 There is reduced efficacy of beta blockers in LQT3 compared with LQT1. Unlike patients with LQT1, patients with LQT3 shorten their QT interval with tachycardia [24], making them less susceptible to catecholamine-induced arrhythmias. This could explain the comparatively reduced efficacy of beta blockers in LQT3 versus LQT1 and the lower rate of events triggered by exercise or stress in patients with the LQT3 subtype ( figure 2) [17,27]. (See "Congenital long QT syndrome: Pathophysiology and genetics", section on 'Type 1 LQTS (LQT1)'.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 7/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate There is some evidence that females with LQT3 may have greater benefit from beta blockers compared with men, although current data are insufficient to draw definite conclusions. In a multicenter registry study, 391 LQT3 patients (aged 1 to 41 years) were followed for development of a first cardiac events or CE (syncope, aborted cardiac arrest, or long-QT- syndrome-related sudden death). Of these, 118 (77 females) patients experienced at least 1 CE, and 24 patients had LQT3-related aborted cardiac arrest/sudden death. Time-dependent beta-blocker therapy was associated with an 83 percent reduction in CEs in females but not in males (who had many fewer events). Efficacy in males could not be determined conclusively because of the low number of events. Oral contraceptive pills in females One observational study of 1600 females suggested that use of progestin-only oral contraceptive pills (OCPs) was associated with increased cardiac events in women not taking beta-blockers [36]. Use of progestin-only OCPs was associated with the highest burden of cardiac events per 100 patient-years: 14.1 for progestin only, 6.2 in estrogen-only, 7.5 for combined, and 7 events in the no-OCP group. In contrast, in women who were treated with beta blockers, progestin-only OCP use was associated with fewer cardiac events (4.5 events per 100 patient years). Possible misclassification of OCP type and non-randomized design limit our ability to draw firm conclusions from this analysis. Subsequent therapies For patients with recurrent arrhythmic events in spite of maximally tolerated doses of a beta blocker or in the setting of unacceptable beta-blocker-associated side effects, treatment intensification is pursued with either concomitant drug therapy, LCSD, and/or an ICD depending on the nature of the arrhythmic event, the genotype, and the patient's degree of QT prolongation at rest (ie, their resting QTc). Treatment intensification for patients with recurrent arrhythmic events should ideally take place in a center with expertise in the management of congenital LQTS, or for patients without access to an expert center, in consultation with a specialist with expertise in congenital LQTS. Other pharmacologic therapies There is a role for select other pharmacologic therapies targeted to specific subsets of congenital LQTS patients. Potassium and/or spironolactone Routine potassium supplementation/replacement and/or use of potassium-retaining medications like spironolactone is not generally indicated. However, for patients with malignant LQTS who continue to receive appropriate ICD shocks or who have a high-risk phenotype but prefer to avoid an ICD, potassium retention strategies are implemented, regardless of the underlying LQTS genotype. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 8/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Mexiletine For patients with LQT3, mexiletine pharmacotherapy is not only QT- attenuating but also confers a significant protective effect. Increasingly, combination therapy with propranolol and mexiletine is utilized in patients with LQT3. Targeted dosing for mexiletine is generally 4 to 6 mg/kg/dose administered approximately every eight hours. Mexiletine trough levels can be obtained. Both mexiletine and propranolol are metabolized via cytochrome P4502D6 (CYP2D6) and approximately 10 percent of the White populations are either poor metabolizers of 2D6 substrates like mexiletine or are ultra-rapid metabolizers. CYP2D6 genotype status can be obtained to help guide dosing strategy. Although blocking the LQT3-associated accentuation of the late sodium current with mexiletine makes sense, in our authors experience, a significant QTc attenuation effect has also been seen in patients with other LQTS genotypes, particularly LQT2. As such, for patients with higher-risk LQT2, combination drug therapy with a beta blocker and mexiletine can be considered as well [37]. Left cardiac sympathetic denervation LCSD is an effective therapy in patients with congenital LQTS and persistent arrhythmias on beta blockers as well as in those who cannot tolerate beta blockers [8,38-41]. While LCSD produces significant reductions in the number of subsequent cardiac events per patient overall, postdenervation recurrences can occur especially when the predenervation expressivity was malignant and extreme [42]. However, in most patients, LCSD offers an additional risk reduction prior to considering an ICD, although it does not preclude ICD placement in appropriate high-risk patients. LCSD interrupts the major source of norepinephrine released in the heart via preganglionic denervation [43]. Since denervation is preganglionic, there is no reinnervation. The procedure does not completely eliminate catecholamines in the ventricles, and it does not lead to post- denervation supersensitivity to catecholamines [44]. LCSD is similarly effective across genotypes, when infants with events in the first year of life are not considered [45-47]. LCSD is similarly effective in LQT1 and LQT2 patients [41]. Implantable cardioverter-defibrillator ICDs are an important component of therapy for patients with congenital LQTS, particularly among patients who present with resuscitated SCA or those who have recurrent major events [48-51]. However, complications, including infection, lead fracture and dislodgement, inappropriate discharges, and psychiatric sequelae, are not uncommon with ICDs (25 percent within five years) [52]. For these reasons, it is not appropriate to consider ICDs in all patients with congenital LQTS. In fact, most patients with LQTS (90 percent or more in LQTS expert centers) do not need and should not receive an ICD just because they have been diagnosed with LQTS in general or even LQT3 in particular (where highest ICD implant https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 9/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate rates have been noted). Instead, our approach to the utilization of ICDs in this population is as follows [8]: We recommend an ICD in most patients whose initial presentation was SCA and in whom a reversible cause is not identified. We recommend an ICD in patients with LQTS-associated SCA while compliant with beta- blocker therapy. If an ICD was chosen instead of additional medications or LCSD following this on-therapy SCA, then LCSD therapy is often kept as a subsequent treatment option if an appropriate ICD shock occurs. Although we generally recommend an ICD for patients with resuscitated SCA occurring prior to diagnosis of and treatment for their LQTS, it may be possible to assemble a non- ICD treatment program for some of these patients. However, this should be considered only in LQTS specialty centers because guidelines essentially recommend an ICD for any LQTS patient (diagnosed or previously undiagnosed) who experiences SCA [8,12,13]. For example, one potential exception to this in our practices are patients with a sentinel event of SCA with previously undiagnosed and therefore untreated LQT1 substrate. For such LQT1 patients who are trying to avoid an ICD if at all possible, we have configured beta- blocker therapy plus LCSD as part of their initial treatment program. We suggest an ICD for patients with recurrent cardiac syncope in spite of beta blockers and LCSD, or for patients with recurrent cardiac syncope while taking beta blockers in whom LCSD is not an option. Importantly, an ICD is never indicated based solely on the family history. A family history of LQTS-associated SCD is not a personal risk factor for the patient with LQTS. Overall, most patients with LQTS do not need and should not receive an ICD. The vast majority of LQTS patients can be treated effectively without an ICD. Combined, among all of the patients with LQTS that are evaluated, risk stratified, and treated at expert LQTS centers, approximately 3 to 10 percent of them have an ICD [47]. Cardiac pacing Cardiac pacing is seldom utilized in isolation when treating patients with LQTS. For the patient with an indication for an ICD, a single-lead system is generally advised. If the patient then goes on to experience an appropriate ventricular fibrillation (VF)-terminating ICD shock where a bradycardia or long-short-long pause mechanism is documented, an upgrade to the device to include atrial pacing is sometimes performed. In our experience, the therapeutic role of atrial pacing, with an intentional lower rate limit of 80 beats per minute, may be best realized in women with LQT2 [53]. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 10/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Our approach to asymptomatic patients Asymptomatic patients with congenital LQTS have different levels of risk for experiencing an LQTS-associated sentinel event, and it can be difficult to identify patients who will become symptomatic. Our general approach to asymptomatic patients with congenital LQTS is as follows: As with symptomatic patients, asymptomatic patients with congenital LQTS should adhere to standard general preventive measures, such as the avoidance of medications known to prolong the QT interval and the aggressive treatment of electrolyte imbalances (eg, hypokalemia in the setting of vomiting, diarrhea, or diuretic use). As with symptomatic patients, the 2015 AHA/ACC Scientific Statement supports continuation of competitive sports in asymptomatic patients with LQTS with appropriate cautionary measures, including an AED safety plan, while the European guidelines remain more restrictive. Some disagreement among experts persists, however. (See 'Physical activity and LQTS' above.) For most asymptomatic patients with congenital LQTS, we suggest treatment with a beta blocker [1]. In general, we prefer propranolol or nadolol. However, for asymptomatic patients with a QTc <470 milliseconds, beta-blocker therapy may not always be required. Accordingly, there may be times when the risk-benefit calculus clearly favors intentional non-therapy with implementation of only the aforementioned preventative measures. As one example, beta-blocker therapy may not be necessary in the asymptomatic 55-year-old male with LQT1 and a resting QTc <440 milliseconds. For asymptomatic patients who wish to follow preventative measures only and intentionally forego beta-blocker therapy, an evaluation with an LQTS specialist may be beneficial to best assess the potential for a sentinel event and the comfort/confidence with intentional non-therapy [54]. (See 'Beta blockers' above.) In asymptomatic patients with either LQT2 or LQT3 whose resting QTc is >550 milliseconds or postpubertal women with LQT2, a prophylactic LCSD at a lower QTc threshold (QTc >500 milliseconds) is reasonable. These profiles in asymptomatic patients may warrant more aggressive surgical or device-related interventions. However, if the addition of QT-shortening therapies like mexiletine produced a now-on- therapy baseline QTc <500 ms, we continue with pharmacotherapy alone, or add additional anti-fibrillatory protection with LCSD (rather than adding a prophylactic ICD) [37,45,55]. Patients with high-risk genetic mutations such as those in the KCNQ1 S6 region require closer and more aggressive therapy to prevent SCA/SCD [56]. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 11/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Long QT syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Background Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the ECG ( waveform 1). LQTS can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death (SCD). (See 'Introduction' above.) Symptomatic patients Our general approach to treatment of symptomatic (or previously symptomatic) patients with congenital LQTS is as follows: General measures All patients with congenital LQTS should adhere to standard general preventive measures, such as the avoidance of medications known to prolong the QT interval ( www.crediblemeds.org) and the aggressive treatment of electrolyte https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 12/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate imbalances (eg, hypokalemia in the setting of vomiting, diarrhea, or diuretic use). (See 'Our approach to symptomatic patients' above.) Activity After establishing the correct diagnosis of LQTS and implementing the initial treatment program, patients with LQTS can continue to be recreationally active, especially those with LQT2 and LQT3. Athletes with LQTS who desire to remain athletes should be evaluated by an LQTS specialist to enable shared decision making to occur successfully. Importantly, there are laws in some countries that supersede professional society guidelines regarding return-to-play issues. (See 'Physical activity and LQTS' above.) Asymptomatic persons who are genotype positive/phenotype negative (ie, with normal QTc at rest) can reasonably participate in all competitive sports with appropriate safety precautions. Symptomatic (or previously symptomatic) patients, or patients with LQTS (QTc >470 milliseconds in males or >480 milliseconds in females) may consider participation in competitive athletics (with the possible exception of swimming in patients with LQT1 genotype) if they remain asymptomatic after three months of treatment and with appropriate cautionary measures, including an emergency action plan with an automated external defibrillator immediately available. Local laws and regulations may apply. Experts disagree on participation in higher levels of sport for patients with an implantable cardioverter-defibrillator (ICD) in place, with some experts allowing participation following counselling of the patient of potential risks and appropriate cautionary measures, while other experts feel it is unwise to expose patients to the risk of ventricular arrhythmias and multiple shocks just to perform a competitive sport. Beta blockers For all patients with congenital LQTS and a history of syncope or seizures, we recommend treatment with a beta blocker (Grade 1B). We suggest propranolol or nadolol, given their superior efficacy in this patient population (Grade 2C). (See 'Beta blockers' above.) Implantable cardiac defibrillator Patients with LQTS-associated sudden cardiac arrest (SCA), while compliant with beta-blocker therapy, should generally receive an ICD. Importantly, self-limiting syncope/seizures, even if assessed to be LQTS-triggered (ie, secondary to TdP) are not equivalent to SCA. (See 'Implantable cardioverter-defibrillator' https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 13/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate above and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Treatment intensification For patients with recurrent, LQTS-triggered arrhythmic events in spite of maximally tolerated doses of a beta blocker, or for patients who discontinue beta blockers due to intolerable side effects, treatment intensification is pursued with either concomitant drug therapy, left cardiac sympathetic denervation, and/or an ICD depending on the nature of the arrhythmic event, the genotype, and the patient's degree of QT prolongation at rest (ie, their resting QTc). Treatment intensification for patients with recurrent arrhythmic events should ideally take place in a center with expertise in the management of congenital LQTS, or for patients without access to an expert center, in consultation with a specialist with expertise in congenital LQTS. (See 'Subsequent therapies' above.) Asymptomatic patients Our general approach to treatment of asymptomatic patients with congenital LQTS is as follows (see 'Our approach to asymptomatic patients' above): For most asymptomatic patients with congenital LQTS, we suggest a beta blocker (Grade 2C). In general, the choice of a beta blocker is the same as in symptomatic patients (ie, propranolol or nadolol). However, for asymptomatic patients with a QTc <470 milliseconds, beta-blocker therapy may not be required. If an asymptomatic patient with either LQT2 or LQT3 maintains a QTc >550 ms while on pharmacotherapy, we suggest either a prophylactic left cardiac sympathetic denervation (LCSD) or a prophylactic ICD (Grade 2C). For postpubertal women with LQT2, either prophylactic LCSD or a prophylactic ICD at a lower QTc threshold (QTc >500 milliseconds) is reasonable again if pharmacotherapy (namely mexiletine) has not attenuated the QTc to <500 ms. Importantly, an ICD is never indicated based solely on a family history of LQTS-associated SCD, as family history is not a personal risk factor for the patient. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013; 34:3109. 2. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350:1013. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 14/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate 3. Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med 2002; 112:58. 4. Wehrens XH, Vos MA, Doevendans PA, Wellens HJ. Novel insights in the congenital long QT syndrome. Ann Intern Med 2002; 137:981. 5. Camm AJ, Janse MJ, Roden DM, et al. Congenital and acquired long QT syndrome. Eur Heart J 2000; 21:1232. 6. Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol 2000; 36:1. 7. Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AAM. Impact of genetics on the clinical management of channelopathies. J Am Coll Cardiol 2013; 62:169. 8. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 9. Locati EH, Zareba W, Moss AJ, et al. Age- and sex-related differences in clinical

th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Long QT syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Background Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the ECG ( waveform 1). LQTS can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death (SCD). (See 'Introduction' above.) Symptomatic patients Our general approach to treatment of symptomatic (or previously symptomatic) patients with congenital LQTS is as follows: General measures All patients with congenital LQTS should adhere to standard general preventive measures, such as the avoidance of medications known to prolong the QT interval ( www.crediblemeds.org) and the aggressive treatment of electrolyte https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 12/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate imbalances (eg, hypokalemia in the setting of vomiting, diarrhea, or diuretic use). (See 'Our approach to symptomatic patients' above.) Activity After establishing the correct diagnosis of LQTS and implementing the initial treatment program, patients with LQTS can continue to be recreationally active, especially those with LQT2 and LQT3. Athletes with LQTS who desire to remain athletes should be evaluated by an LQTS specialist to enable shared decision making to occur successfully. Importantly, there are laws in some countries that supersede professional society guidelines regarding return-to-play issues. (See 'Physical activity and LQTS' above.) Asymptomatic persons who are genotype positive/phenotype negative (ie, with normal QTc at rest) can reasonably participate in all competitive sports with appropriate safety precautions. Symptomatic (or previously symptomatic) patients, or patients with LQTS (QTc >470 milliseconds in males or >480 milliseconds in females) may consider participation in competitive athletics (with the possible exception of swimming in patients with LQT1 genotype) if they remain asymptomatic after three months of treatment and with appropriate cautionary measures, including an emergency action plan with an automated external defibrillator immediately available. Local laws and regulations may apply. Experts disagree on participation in higher levels of sport for patients with an implantable cardioverter-defibrillator (ICD) in place, with some experts allowing participation following counselling of the patient of potential risks and appropriate cautionary measures, while other experts feel it is unwise to expose patients to the risk of ventricular arrhythmias and multiple shocks just to perform a competitive sport. Beta blockers For all patients with congenital LQTS and a history of syncope or seizures, we recommend treatment with a beta blocker (Grade 1B). We suggest propranolol or nadolol, given their superior efficacy in this patient population (Grade 2C). (See 'Beta blockers' above.) Implantable cardiac defibrillator Patients with LQTS-associated sudden cardiac arrest (SCA), while compliant with beta-blocker therapy, should generally receive an ICD. Importantly, self-limiting syncope/seizures, even if assessed to be LQTS-triggered (ie, secondary to TdP) are not equivalent to SCA. (See 'Implantable cardioverter-defibrillator' https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 13/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate above and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Treatment intensification For patients with recurrent, LQTS-triggered arrhythmic events in spite of maximally tolerated doses of a beta blocker, or for patients who discontinue beta blockers due to intolerable side effects, treatment intensification is pursued with either concomitant drug therapy, left cardiac sympathetic denervation, and/or an ICD depending on the nature of the arrhythmic event, the genotype, and the patient's degree of QT prolongation at rest (ie, their resting QTc). Treatment intensification for patients with recurrent arrhythmic events should ideally take place in a center with expertise in the management of congenital LQTS, or for patients without access to an expert center, in consultation with a specialist with expertise in congenital LQTS. (See 'Subsequent therapies' above.) Asymptomatic patients Our general approach to treatment of asymptomatic patients with congenital LQTS is as follows (see 'Our approach to asymptomatic patients' above): For most asymptomatic patients with congenital LQTS, we suggest a beta blocker (Grade 2C). In general, the choice of a beta blocker is the same as in symptomatic patients (ie, propranolol or nadolol). However, for asymptomatic patients with a QTc <470 milliseconds, beta-blocker therapy may not be required. If an asymptomatic patient with either LQT2 or LQT3 maintains a QTc >550 ms while on pharmacotherapy, we suggest either a prophylactic left cardiac sympathetic denervation (LCSD) or a prophylactic ICD (Grade 2C). For postpubertal women with LQT2, either prophylactic LCSD or a prophylactic ICD at a lower QTc threshold (QTc >500 milliseconds) is reasonable again if pharmacotherapy (namely mexiletine) has not attenuated the QTc to <500 ms. Importantly, an ICD is never indicated based solely on a family history of LQTS-associated SCD, as family history is not a personal risk factor for the patient. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013; 34:3109. 2. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350:1013. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 14/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate 3. Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med 2002; 112:58. 4. Wehrens XH, Vos MA, Doevendans PA, Wellens HJ. Novel insights in the congenital long QT syndrome. Ann Intern Med 2002; 137:981. 5. Camm AJ, Janse MJ, Roden DM, et al. Congenital and acquired long QT syndrome. Eur Heart J 2000; 21:1232. 6. Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol 2000; 36:1. 7. Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AAM. Impact of genetics on the clinical management of channelopathies. J Am Coll Cardiol 2013; 62:169. 8. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 9. Locati EH, Zareba W, Moss AJ, et al. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation 1998; 97:2237. 10. Zareba W, Moss AJ, Schwartz PJ, et al. Influence of the genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med 1998; 339:960. 11. Dagradi F, Spazzolini C, Castelletti S, et al. Exercise Training-Induced Repolarization Abnormalities Masquerading as Congenital Long QT Syndrome. Circulation 2020; 142:2405. 12. Ackerman MJ, Zipes DP, Kovacs RJ, Maron BJ. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 10: The Cardiac Channelopathies: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2424. 13. Zipes DP, Link MS, Ackerman MJ, et al. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 9: Arrhythmias and Conduction Defects: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2412. 14. Pelliccia A, Fagard R, Bj rnstad HH, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 15/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005; 26:1422. 15. Turkowski KL, Bos JM, Ackerman NC, et al. Return-to-Play for Athletes With Genetic Heart Diseases. Circulation 2018; 137:1086. 16. Tobert KE, Bos JM, Garmany R, Ackerman MJ. Return-to-Play for Athletes With Long QT Syndrome or Genetic Heart Diseases Predisposing to Sudden Death. J Am Coll Cardiol 2021; 78:594. 17. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001; 103:89. 18. Wilde AA, Jongbloed RJ, Doevendans PA, et al. Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). J Am Coll Cardiol 1999; 33:327. 19. Moss AJ, Robinson JL, Gessman L, et al. Comparison of clinical and genetic variables of cardiac events associated with loud noise versus swimming among subjects with the long QT syndrome. Am J Cardiol 1999; 84:876. 20. Ali RH, Zareba W, Moss AJ, et al. Clinical and genetic variables associated with acute arousal and nonarousal-related cardiac events among subjects with long QT syndrome. Am J Cardiol 2000; 85:457. 21. Ackerman MJ, Tester DJ, Porter CJ. Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. Mayo Clin Proc 1999; 74:1088. 22. Batra AS, Silka MJ. Mechanism of sudden cardiac arrest while swimming in a child with the prolonged QT syndrome. J Pediatr 2002; 141:283. 23. Takenaka K, Ai T, Shimizu W, et al. Exercise stress test amplifies genotype-phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome. Circulation 2003; 107:838. 24. Schwartz PJ, Priori SG, Locati EH, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. Circulation 1995; 92:3381. 25. Chockalingam P, Crotti L, Girardengo G, et al. Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol. J Am Coll Cardiol 2012; 60:2092. 26. Sauer AJ, Moss AJ, McNitt S, et al. Long QT syndrome in adults. J Am Coll Cardiol 2007; 49:329. 27. Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation 2000; 101:616. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 16/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate 28. Priori SG, Napolitano C, Schwartz PJ, et al. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA 2004; 292:1341. 29. Hobbs JB, Peterson DR, Moss AJ, et al. Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome. JAMA 2006; 296:1249. 30. Goldenberg I, Moss AJ, Peterson DR, et al. Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome. Circulation 2008; 117:2184. 31. Vincent GM, Schwartz PJ, Denjoy I, et al. High efficacy of beta-blockers in long-QT syndrome type 1: contribution of noncompliance and QT-prolonging drugs to the occurrence of beta- blocker treatment "failures". Circulation 2009; 119:215. 32. Wilde AA, Moss AJ, Kaufman ES, et al. Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study. Circulation 2016; 134:872. 33. Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000; 102:1178. 34. Ackerman MJ, Khositseth A, Tester DJ, et al. Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome. Mayo Clin Proc 2002; 77:413. 35. Shimizu W, Noda T, Takaki H, et al. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome. J Am Coll Cardiol 2003; 41:633. 36. Goldenberg I, Younis A, Huang DT, et al. Use of oral contraceptives in women with congenital long QT syndrome. Heart Rhythm 2022; 19:41. 37. Bos JM, Crotti L, Rohatgi RK, et al. Mexiletine Shortens the QT Interval in Patients With Potassium Channel-Mediated Type 2 Long QT Syndrome. Circ Arrhythm Electrophysiol 2019; 12:e007280. 38. Schwartz PJ, Priori SG, Cerrone M, et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation 2004; 109:1826. 39. Collura CA, Johnson JN, Moir C, Ackerman MJ. Left cardiac sympathetic denervation for the treatment of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia using video-assisted thoracic surgery. Heart Rhythm 2009; 6:752. 40. Schwartz PJ. 1970-2020: 50 years of research on the long QT syndrome-from almost zero knowledge to precision medicine. Eur Heart J 2021; 42:1063. 41. Dusi V, Pugliese L, De Ferrari GM, et al. Left Cardiac Sympathetic Denervation for the Long QT Syndrome. 50 Years experience provides guidance for management. JACC Clin https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 17/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Electrophysiol 2021. 42. Bos JM, Bos KM, Johnson JN, et al. Left cardiac sympathetic denervation in long QT syndrome: analysis of therapeutic nonresponders. Circ Arrhythm Electrophysiol 2013; 6:705. 43. Schwartz PJ. The rationale and the role of left stellectomy for the prevention of malignant arrhythmias. Ann N Y Acad Sci 1984; 427:199. 44. Schwartz PJ, Stone HL. Left stellectomy and denervation supersensitivity in conscious dogs. Am J Cardiol 1982; 49:1185. 45. Dusi V, Pugliese L, De Ferrari GM, et al. Left Cardiac Sympathetic Denervation for Long QT Syndrome: 50 Years' Experience Provides Guidance for Management. JACC Clin Electrophysiol 2022; 8:281. 46. Schwartz PJ, Snebold NG, Brown AM. Effects of unilateral cardiac sympathetic denervation on the ventricular fibrillation threshold. Am J Cardiol 1976; 37:1034. 47. Schwartz PJ, Ackerman MJ. Cardiac sympathetic denervation in the prevention of genetically mediated life-threatening ventricular arrhythmias. Eur Heart J 2022; 43:2096. 48. Wedekind H, Burde D, Zumhagen S, et al. QT interval prolongation and risk for cardiac events in genotyped LQTS-index children. Eur J Pediatr 2009; 168:1107. 49. Zareba W, Moss AJ, Daubert JP, et al. Implantable cardioverter defibrillator in high-risk long QT syndrome patients. J Cardiovasc Electrophysiol 2003; 14:337. 50. Etheridge SP, Sanatani S, Cohen MI, et al. Long QT syndrome in children in the era of implantable defibrillators. J Am Coll Cardiol 2007; 50:1335. 51. Proclemer A, Ghidina M, Facchin D, et al. Use of implantable cardioverter-defibrillator in inherited arrhythmogenic diseases: data from Italian ICD Registry for the years 2001-6. Pacing Clin Electrophysiol 2009; 32:434. 52. Schwartz PJ, Spazzolini C, Priori SG, et al. Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: data from the European Long-QT Syndrome Implantable Cardioverter-Defibrillator (LQTS ICD) Registry. Circulation 2010; 122:1272. 53. Kowlgi GN, Giudicessi JR, Barake W, et al. Efficacy of intentional permanent atrial pacing in the long-term management of congenital long QT syndrome. J Cardiovasc Electrophysiol 2021; 32:782. 54. MacIntyre CJ, Rohatgi RK, Sugrue AM, et al. Intentional nontherapy in long QT syndrome. Heart Rhythm 2020; 17:1147. 55. Mazzanti A, Maragna R, Faragli A, et al. Gene-Specific Therapy With Mexiletine Reduces Arrhythmic Events in Patients With Long QT Syndrome Type 3. J Am Coll Cardiol 2016; https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 18/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate 67:1053. 56. Schwartz PJ, Moreno C, Kotta MC, et al. Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region. Eur Heart J 2021; 42:4743. Topic 988 Version 32.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 19/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate GRAPHICS Single-lead electrocardiogram showing a prolonged QT interval The corrected QT interval (QTc) is calculated by dividing the QT interval (0.60 seconds) by the square root of the preceding RR interval (0.92 seconds). In this case, the QTc is 0.625 seconds (625 milliseconds). Graphic 77018 Version 7.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 20/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Single lead electrocardiogram (ECG) showing torsades de pointes The electrocardiographic rhythm strip shows torsades de pointes, a polymorphic ventricular tachycardia associated with QT prolongation. There is a short, preinitiating RR interval due to a ventricular couplet, which is followed by a long, initiating cycle resulting from the compensatory pause after the couplet. Graphic 73827 Version 4.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 21/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Summary of heritable arrhythmia syndrome susceptibility genes: Long QT syndrome (LQTS) Gene Locus Protein Major LQTS genes KCNQ1 (LQT1) 11p15.5 I Ks Kv7.1) potassium channel alpha subunit (KVLQT1, KCNH2 (LQT2) 7q35-36 I Kr Kv11.1) potassium channel alpha subunit (HERG, SCN5A (LQT3) 3p21-p24 Cardiac sodium channel alpha subunit (NaV1.5) Minor LQTS genes AKAP9 7q21-q22 Yotiao CACNA1C 12p13.3 Voltage gated L-type calcium channel (CaV1.2) CALM1 14q32.11 Calmodulin 1 CALM2 2p21 Calmodulin 2 CALM3 19q13.2-q13.3 Calmodulin 3 CAV3 3p25 Caveolin-3 KCNE1 21q22.1 Potassium channel beta subunit (MinK) KCNE2 21q22.1 Potassium channel beta subunit (MiRP1) KCNJ5 11q24.3 Kir3.4 subunit of I channel KACH SCN4B 11q23.3 Sodium channel beta 4 subunit SNTA1 20q11.2 Syntrophin-alpha 1 TRDN 6q22.31 Triadin Adapted from: Tester DJ, Ackerman MJ. Genetics of cardiac arrhythmias. In: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 10th ed, Mann DL, Zipes DP, Libby P, et al (Eds), Elsevier, Philadelphia 2015. Graphic 114927 Version 2.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 22/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial ischemia or infarction, GnRH agonist/antagonist therapy Hypomagnesemia Bilateral surgical orchiectomy Hypocalcemia Diuretic therapy via electrolyte disorders especially with prominent T-wave Starvation particularly hypokalemia and hypomagnesemia Anorexia nervosa Herbs inversions Liquid protein diets Cinchona (contains quinine), iboga Intracranial Hypothyroidism (ibogaine), licorice extract in overuse via electrolyte disturbances disease Bradyarrhythmias HIV infection Sinus node dysfunction Hypothermia Toxic exposure: Organophosphate AV block: Second or third degree insecticides Medications* High risk Adagrasib Cisaparide Lenvatinib Selpercatinib (restricted availability) Ajmaline Levoketoconazole Sertindole Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine (intracoronary) Vandetanib Dofetilide Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab ozogamacin Propafenone Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Carbetocin Erythromycin Ribociclib https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 23/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Certinib Escitalopram Levofloxacin Risperidone (systemic) Chloroquine Etelcalcetide Saquinavir Lofexidine Citalopram Fexinidazole Sevoflurane Meglumine antimoniate Clarithromycin Flecainide Sparfloxacin Clofazimine Floxuridine Sunitinib Midostaurin Clomipramine Fluconazole Tegafur Moxifloxacin Clozapine Fluorouracil (systemic) Terbutaline Nilotinib Crizotinib Thioridazine Olanzapine Flupentixol Dabrafenib Toremifene Ondansetrol (IV > Gabobenate Dasatinib Vemurafenib oral) dimeglumine Deslurane Voriconazole Osimertinib Gemifloxacin Domperidone Oxytocin Gilteritinib Doxepin Pazopanib Halofantrine Doxifluridine Pentamidine Haloperidol (oral) Pilsicainide Imipramine Pimozide Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole Romidepsin Anagrelide Foscarnet (systemic) Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- Glasdegib Mizolastine lumefantrine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine (rare reports) Nortriptyline Benperidol Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus Olodaterol (systemic) Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 24/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Leuprolide- Periciazine Tropisetron norethindrone Dexmedetomidine** Pimavanserin Vardenafil Levalbuterol Dolasetron Pipamperone Vilanterol Levomethadone Donepezil Pitolisant Vinflunine Lithium Efavirenz Ponesimod Voclosporin Loperamide in Eliglustat Primaquine Vorinostat overdose Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM [1,2] 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 25/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 26/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Classification of sports based on peak static and dynamic components during competition This classification is based on peak static and dynamic components achieved during competition; however, higher values may be reached during training. The increasing dynamic component is defined in terms of the estimated percentage of maximal oxygen uptake (VO max) achieved and results in an increasing cardiac output. The increasing static component is related to the estimated percentage of maximal 2 voluntary contraction reached and results in an increasing blood pressure load. The lowest total cardiovascular demands (cardiac output and blood pressure) are shown in the palest color, with increasing dynamic load depicted by increasing blue intensity and increasing static load by increasing red intensity. Note the graded transition between categories, which should be individualized on the basis of player position and style of play. Danger of bodily collision (refer to UpToDate content regarding sports according to risk of impact and educational background). https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 27/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Increased risk if syncope occurs. Reproduced from: Levine BD, Baggish AL, Kovacs RJ. Eligibility and disquali cation recommendations for competitive athletes with cardiovascular abnormalities: Task force 1: Classi cation of sports: Dynamic, static, and impact: A scienti c statement from the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015; 66:2350. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 105651 Version 9.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 28/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Triggers for cardiac events in long QT syndrome are related to genotype In a study of 670 patients with long QT syndrome and known genotype, all symptomatic (syncope, aborted cardiac arrest, or sudden death), the occurrence of a lethal cardiac event (n = 110) provoked by a specific trigger (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced most of their events (90%) during exercise or emotion. These percentages were almost reversed among LQT2 and LQT3 patients who had most of their events during rest or sleep (63 and 80%, respectively); by contrast, they were at almost no risk of major events during exercise (arrows), which is explained by their having a normal I current. Ks ACA: aborted cardiac arrest; SCD: sudden cardiac death. Modi ed from: Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-speci c triggers for life-threatening arrhythmias. Circulation 2001; 103:89. Graphic 64239 Version 3.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 29/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Outcome with beta blocker in the long QT syndrome is good in asymptomatic patients During a five-year follow-up of 869 patients with a long QT syndrome, the estimated cumulative probability of experiencing aborted cardiac arrest or death on beta blocker therapy was significantly reduced in those who were asymptomatic (0.97 versus 0.31 events per year on therapy in probands and 0.26 versus 0.15 events per year in affected family members). Recurrent events despite beta blocker therapy were significantly higher in those with a history of syncope (hazard ratio 3.1) or aborted sudden death (hazard ratio 12.9). Data from Moss AJ, Zareba W, Hall WJ, et al, Circulation 2000; 101:616. Graphic 78184 Version 2.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 30/31 7/6/23, 11:08 AM Congenital long QT syndrome: Treatment - UpToDate Contributor Disclosures Peter J Schwartz, MD No relevant financial relationship(s) with ineligible companies to disclose. Michael J Ackerman, MD, PhD Consultant/Advisory Boards: Abbott [Education around ICD/device therapy for genetic heart diseases including LQTS]; ARMGO Pharma [Novel therapies for genetic heart diseases, CPVT in particular]; Boston Scientific [Education around ICD/device therapy for genetic heart diseases including LQTS]; Daiichi Sankyo [Drug-induced QT prolongation for one of their drugs]; Invitae [Genetic testing for genetic heart diseases]; LQT Therapeutics [Development of a novel QT-shortening medication]; Medtronic [Education around ICD/device therapy for genetic heart diseases including LQTS]; UpToDate [Genetic heart diseases, especially LQTS]. Other Financial Interest: AliveCor [QTc analytics for smartphone-enabled mobile ECG]; Anumana [Artificial intelligence ECG for early detection of hypertrophic cardiomyopathy]; Pfizer [Gene therapy for genetic heart diseases including LQTS]. All of the relevant financial relationships listed have been mitigated. John K Triedman, MD Consultant/Advisory Boards: Biosense Webster and Sentiar [Supraventricular and ventricular topics]. All of the relevant financial relationships listed have been mitigated. Samuel Asirvatham, MD Grant/Research/Clinical Trial Support: Medtronic [Defibrillators]; St Jude's [Sudden Cardiac Death]. Consultant/Advisory Boards: BioTronik [Defibrillators]; Boston Scientific [Sudden Cardiac Death]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 31/31