Marfan syndrome (MFS) is a heritable systemic connective tissue disease with important cardiovascular involvement, including aortic root dilatation and mitral valve prolapse. Life expectancy in patients with MFS is mainly determined by cardiovascular complications, among which aortic dissection or rupture are most dreaded. In recent years, heart failure and ventricular arrhythmia have drawn attention as extra-aortic cardiovascular manifestations and as additional reported causes of death. Imaging studies have provided data supporting a primary myocardial impairment in the absence of valvular disease or cardiovascular surgery, while studies using ambulatory ECG have demonstrated an increased susceptibility to ventricular arrhythmia. In this paper, current literature was reviewed in order to provide insights in characteristics, pathophysiology and evolution of myocardial function, heart failure and ventricular arrhythmia in MFS. Marfan syndrome (MFS) is a systemic connective tissue disease with autosomal dominant inheritance and a reported prevalence ranging from 1.5 to 17.2 per 100,000 individuals [FBN1 gene, encoding the extracellular matrix glycoprotein fibrillin-1, an important element in the assembly of microfibrils. Microfibrils may perform a structural role individually (in the extracellular matrix of elastic and non-elastic tissues), or unified as a supporting scaffold for elastin, thereby forming elastic fibers [In the majority of patients, a (likely) pathogenic variant is found in the c fibers . Elasticc fibers ,4,5.Life expectancy in patients with MFS is mainly determined by cardiovascular complications. Progressive dilatation of the proximal aorta is an important manifestation, rendering these patients at risk of aortic dissection or fatal rupture . AlthougIn recent years, heart failure and ventricular arrhythmia have drawn attention as additional cardiovascular manifestations of MFS . SeveralWe conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to evaluate the current literature on myocardial function and arrhythmia in MFS . Cohort The first mention of possible myocardial involvement in MFS can be found in a case-report by Fujiseki et al. in 1984 . Since tDiscrepancies between some of the previously mentioned studies led to further debate on myocardial involvement in MFS. A small number of studies reported no differences in LV diameters or systolic function compared to controls. Furthermore, some follow-up studies failed to detect changes in LV function or dimensions over time while others identified a small, yet significant, subgroup of patients presenting increased LV dimensions and reduced LV function ,22,23,25p = 0.009), an increased indexed end-systolic volume , and reduced peak systolic velocities. Furthermore, impaired diastolic function was observed in MFS [Additional insights in the LV function and volumes were provided in subsequent studies using tissue Doppler imaging (TDI), CMR and strain imaging. In 2006, De Backer et al. assessed diastolic filling in a small case-control study using TDI and systolic function using CMR in patients with MFS . Compared in MFS . Soon afd in MFS ,27.Three subsequent studies using CMR provided additional evidence for myocardial involvement, as demonstrated by the observation of a reduced LV EF in a subgroup of patients ,29,30. Ip < 0.005) [Most studies have focused on the LV, but right ventricular (RV) involvement in MFS has also been suggested ,35. In t< 0.005) . In both< 0.005) ,29. Although almost all of the aforementioned studies reported myocardial impairment in the absence of previous cardiac surgery or significant valvular disease, very few patients were diagnosed with clinical heart failure. In contrast, there are several reports on end-stage heart failure necessitating heart transplantation in patients with MFS . In addiOne of the cardiac stressors which may contribute in the development of heart failure is regurgitant valvular disease, which is frequently encountered in MFS and may induce volume overload ,51. By tAn association between prior aortic or valvular surgery and the development of heart failure as long-term complication in patients with MFS has also been suggested ,52,53,54A third potential cardiac stressor is decreased aortic distensibility, which may contribute to impairment of LV function by altering the hemodynamic load imposed on the LV . Aortic FBN1 gene variant has an influence on aortic outcome [FBN1 gene variants [FBN1 variant and the development of LV dilatation in MFS [p < 0.05) [FBN1 gene variants may also have a different effect on aortic elasticity [FBN1 gene variants was not evaluated [In addition to these hemodynamic factors, it is conceivable that intrinsic factors play a role, including gene-related factors. Several studies have already shown that the type of underlying  outcome ,64,65,66 outcome . In the variants ,68. Aalb < 0.05) . Differeasticity , therebyvaluated ,39. Futuvaluated .In the quest to unravel the pathophysiology underlying Marfan cardiomyopathy, mouse models have provided clues to possible underlying mechanisms and pathways ,69,70,71C1039G/+Fbn1 mouse model studied by Campens et al., impairment of cardiac function and structure remained mild and subclinical, resembling the myocardial phenotype observed in patients with MFS. Histologic examination of the myocardium revealed upregulation of TGF-β-related pathways and consistent abnormalities of the microfibrillar network, implicating a role for microfibrils in the mechanical properties of the myocardium [Fbn1mgR/mgR mouse model Cook et al. demonstrated that abnormal mechanosignaling by cardiomyocytes resulting from a deficient extracellular matrix caused dilated cardiomyopathy. The authors suggested that fibrillin-1 is implicated in the physiological adaptation of the myocardium to an increased workload and that dilated cardiomyopathy is a primary manifestation of MFS mice [In the ocardium . In the MFS mice .C1039G/+Fbn1 mouse model tested the hypothesis that either pressure or volume overload on an already susceptible heart could result in a more severe dilated cardiomyopathy [Two studies using the myopathy ,71. Valvmyopathy ,71. Takemyopathy ,71.FBN1 gene are thought to result in abnormal mechanosignaling of the microfibrils which may cause inadequate compensation of cardiac stressors such as volume- or pressure overload in a subgroup of patients with MFS. Whether impaired elastic fiber function and/or impaired biosignaling is reflected in increased TGF-β signaling remains to be elucidated [Fibrillin-1 and microfibrils can be found throughout the myocardium as components of the extracellular matrix. They are assumed to play a role in sustaining proper cardiac function by contributing to the diastolic and systolic properties of the myocardium ,74,75,76ucidated . It is pIn addition to aortic complications and cardiomyopathy, arrhythmia should be recognized as a relevant manifestation of the cardiac phenotype observed in MFS ,52,54. SThe mechanisms underlying severe ventricular arrhythmia are multifactorial. Ventricular tachycardia and ventricular fibrillation (VF) usually arise from an initiating trigger in the presence of a proarrhythmogenic substrate (as observed in genetic channelopathies and cardiomyopathies), which allows the perpetuation of severe ventricular arrhythmias . In patiPatients with mitral valve prolapse, mitral valve regurgitation and previous aortic surgery have been reported to have higher risk of ventricular arrhythmia in several studies ,54,77,78p = 0.0023). Furthermore, patients undergoing aortic surgery after 1980 demonstrated even longer life expectancy [Most of the improvement in life expectancy achieved throughout the years in patients with MFS was obtained by focusing on prophylactic treatment and prevention of aortic events . In 1995pectancy . Heart fpectancy ,88,89,90As shown in In their most recent study in 2009, Cameron et al. reported results after aortic root replacement in 373 patients with MFS in a time period of more than 30 years . In thesTaken together, the aforementioned studies confirm that ventricular dimensions as well as systolic and diastolic function are well within normal limits in the vast majority of patients with MFS. However, even in the absence of cardiac surgery or significant valvular disease, a mild biventricular dilatation with diastolic and systolic dysfunction in a subgroup of patients with MFS has been repeatedly reported ,26,28,35The relation between a reduced amount or quality of extracellular fibrillin in the myocardium, a primary impairment of myocardial function, increased likelihood of ventricular ectopy and possible alterations in the electrophysiological substrate remains unclear. It is possible that, due to the reduced amount or quality of fibrillin, mechanical forces imposed on the cardiomyocytes in patients with MFS may be less adequately compensated than in healthy individuals. Therefore, chronic or acute myocardial dilatation and associated stretch could perhaps induce (complex) ventricular ectopy more easily in these patients where subclinical myocardial impairment is noted. In addition, the impairment of myocardial function observed in some patients may also signify inherent abnormalities in the underlying electrophysiological substrate. The combination of (complex) ventricular ectopy together with the alterations in electrical and/or mechanical properties of the heart may be severe enough to induce SCD in some patients with MFS, as suggested in studies by Hoffmann et al.  and by YTo date, large multicentre studies reporting the overall incidence or prevalence of heart failure and severe arrhythmia in MFS are lacking. Therefore, identification of predisposing factors is limited. Additional studies are necessary to evaluate the clinical relevance of Marfan cardiomyopathy and ventricular ectopy, to elucidate the underlying mechanisms in MFS and to allow better risk stratification of patients with MFS. Information on these aspects could hold important implications for developing strategies to treat heart failure and ventricular arrhythmia in MFS.FBN1. Advancing insight in recent years shows us that caution is advised in grouping all these conditions.We should also take into account that—certainly in the case of older studies—some of the patients enrolled may have had some other form of Heritable Thoracic Aortic Disease, caused by pathogenic variants in genes other than Myocardial involvement in the absence of valvular disease can be observed in patients with MFS, usually presenting as mild, asymptomatic impairment of LV systolic and diastolic function. In addition, some patients with MFS present (complex) ventricular arrhythmia as well as alterations in repolarization. A subgroup of patients with MFS tends to develop heart failure, severe arrhythmia and SCD, in which the effects of cardiac stressors may play an important role. Reduced myocardial function, heart failure and ventricular arrhythmia should be considered an essential concern of medical care for patients with MFS. Careful assessment of these features should be added to the standard aortic evaluation.


The document represents several years of incredibly hard work on the part of the first author and leader of the document, Karen Stout, as well as of her coauthors. I am proud to be one of these coauthors. As the study group points out, the prevalence of adult CHD is increasing, primarily due to the incredible successes that have occurred in pediatric cardiology and pediatric cardiothoracic surgery that have allowed patients with even the most severe congenital heart defects to reach adulthood. Pediatric cardiologists and cardiac surgeons alike can be justly proud of what they have accomplished in the care of infants with critical CHD. Most of us feel very attached to our teenaged and young adult CHD survivors, and we are now placing a high priority on promoting an effective transition for them to adult congenital care.Recently, new guidelines for the management of adults with congenital heart disease (CHD) were released by the American Heart Association and the American College of Cardiology.The management of these patients truly represents a new specialty in the field of cardiology, as these individuals often exhibit novel clinical problems that are certainly not limited to the cardiovascular system. Often, science advances when clinicians are confronted by new patient populations with novel medical problems and so, we are at a particularly exciting juncture in the field of cardiology. In addition to having the opportunity to ensure that these patients live as long and as productive lives as possible, there are tremendous scientific and academic opportunities available to cardiologists working in this field.As electrophysiologists, we have always known that the repair of these defects, even when completely successful from a hemodynamic standpoint, often leads to downstream electrical issues. Indeed, for many patients who reach adulthood with repaired CHD, their most significant and troubling issues are in the area of postoperative arrhythmias.3 This extensive document covered all aspects of arrhythmias in all forms of CHD in adults and had more than 500 references. Thus, the more recent AHA/ACC document did not attempt to redo that work but rather instead sought to focus on some of the most important issues facing adults with CHD with respect to arrhythmias.The Pediatric and Congenital Electrophysiology Society (PACES), in partnership with the Heart Rhythm Society (HRS), recently published a comprehensive expert consensus statement on the management of arrhythmias in adults with repaired CHD.First and foremost, comprehensive adult CHD programs need electrophysiology expertise. Just as the field of adult CHD is distinct from and requires different expertise versus both the fields of pediatric cardiology and adult cardiology, so too is adult congenital electrophysiology developing as its own separate field. The expertise in adult congenital electrophysiology may come from either pediatric or adult electrophysiology programs, or ideally from both in partnership. While an understanding of the congenital and surgical anatomy of these patients is important in addressing their arrhythmias, particularly in the ablation suite and for device implantation, the effects of aging are equally if not more important and the significance of atrial fibrillation in this patient population cannot be overstated. With respect to available facilities, the electrophysiology laboratory should be equipped with three-dimensional mapping and other advanced mapping technologies as well as the necessary professional expertise.Many might find it reassuring that the role of electrocardiography was confirmed in this document. While it may seem obvious, obtaining electrocardiograms at the time of routine clinic visits is quite important, as occult arrhythmias are fairly common in this patient population—including, for example, slow intra-atrial reentry tachycardia (IART)—and, as they may not always be symptomatic, detecting them during routine follow-up is important. Similarly, sinus node dysfunction and junctional rhythm are often seen and have important implications. Most cardiologists are aware of the importance of the QRS duration as a risk factor for ventricular tachycardia and sudden death in patients following the repair of tetralogy of Fallot as an easily obtained index of right ventricular dilation. Finally, it is important not to forget Wolff-Parkinson-White syndrome, which is often seen in patients with Ebstein’s anomaly and can occasionally be acquired following specific forms of heart surgery.Similarly, ambulatory electrocardiography (Holter monitoring) as well as the deployment of various approaches to event monitoring are important in this patient population, as atrial and ventricular arrhythmias can develop with time and with changes in patients’ hemodynamic status.Two forms of repaired CHD were highlighted with respect to the risk of arrhythmias. First, patients with dextro-transposition of the great arteries who have previously undergone an atrial switch procedure  are known to have a high incidence of IART, and the document highlights the importance of understanding a patient’s congenital anatomy in order to perform effective catheter ablation for this arrhythmia, which usually originates from structures on the pulmonary venous side of the interatrial baffle. Second, there is a large focus on tetralogy of Fallot and related anatomies, including the problem of risk stratification for the possibility of sudden cardiac death in these patients. The importance of cardiac magnetic resonance imaging is highlighted, as is the utility of programmed ventricular stimulation to seek inducible sustained monomorphic ventricular tachycardia. In fact, the latter is perhaps one of the only remaining indications for diagnostic ventricular programmed stimulation! The document comments on the use of implantable cardioverter-defibrillator (ICD) placement as primary prevention in tetralogy of Fallot patients with multiple risk factors for sudden cardiac death, which is considered a class IIa indication. Finally, the document discusses the importance of protecting the right ventricle as a way of preventing the development of the substrate for ventricular tachycardia and sudden death through appropriate timing of pulmonary valve replacement, either surgically or by transcatheter techniques.The spectrum of adults with CHDs is broad and encompasses patients with well-repaired defects with little need for frequent cardiology follow-up at one end to those patients who are most severely affected, such as postoperative Fontan patients who require very close follow-up in specialized adult congenital centers, at the other. Helpfully, the document categorizes the various forms of repaired CHD into a number of categories based on severity and provides helpful tables indicating both the ideal frequency of adult CHD clinic follow-up as well as the specific testing methods, including arrhythmia monitoring and other procedures, to be included as part of routine follow-up. While much of the information in this document will primarily be helpful to specialists in the adult CHD field, there is plenty here for pediatric cardiologists, adult cardiologists, and electrophysiologists who are confronted from time to time with adults with CHD.


Myocardial hemorrhage is a common complication following reperfusion of ST-segment-elevation acute myocardial infarction (MI). Although its presence is clearly related to infarct size, at present it is unknown whether post-reperfusion hemorrhage affects left ventricular (LV) remodeling. Magnetic resonance imaging (MRI) can be used to identify myocardial infarction, myocardial hemorrhage and microvascular obstruction (MVO), as well as measure LV volumes, function and mass.Ninety-eight patients  with MI reperfused with percutaneous coronary intervention (PCI) were studied in the first week and at 4 months after the event. T2-weighted MRI was used to differentiate between hemorrhagic  and non-hemorrhagic infarcts . MVO and infarct size were determined on contrast-enhanced MRI, while cine MRI was used to quantify LV volumes, mass and function. Twenty-four patients (25%) presented with a hemorrhagic MI. In the acute phase, presence of myocardial hemorrhage was related to larger LV end-diastolic and end-systolic volumes and infarct transmurality, lower LV ejection fraction as well as lower systolic wall thickening in the infarcted myocardium . Infarct size, size of area at risk and size of MVO were significantly larger in patients with hermorrhagic MI. At 4 months, a significant improvement in LV ejection fraction in patients with non-hemorrhagic MI was seen . LV ejection fraction did, however, not improve in patients with hemorrhagic MI . Multivariate analysis showed myocardial hemorrhage to be an independent predictor of adverse LV remodeling at 4 months (defined as an increase in LV end-systolic volume). This pattern was independent of initial infarct size (See Table Myocardial hemorrhage, the presence of which can easily be detected with T2-weighted MRI, is a frequent complication after successful myocardial reperfusion, and an independent predictor of adverse LV remodeling regardless of initial infarct size.


Ventricular remodeling is a compensatory process that is little understood in the right ventricle (RV). We have previously reported an association between abnormalities in RV shape and function in patients with dilated RVs. In these studies we used the piecewise smooth subdivision surface (PSSS) reconstruction method because it provides accurate representation of the 3D shape of the RV. However the complexity of RV shape mandates manual tracing of RV borders from many images.2).We tested the error in RV volume, ejection fraction (EF), and shape accrued by reducing the number of borders traced from MRI studies of 18 patients with congenital heart disease and 2 normal subjects. The true volume and shape were defined by tracing RV borders from 17 to 33 (mean 23 ± 4) images recorded in short axis (SAX), long axis (LAX), oblique, and inflow-outflow track (IOT) views. LAX views could be radially oriented about the left ventricular LAX or parallel to the 4-chamber view, but always visualized the entire free wall from its inferior to superior aspect. Reduced data sets were created containing 10, 12, 14, or 16 image planes distributed between SAX, LAX, and IOT views. Because pilot studies suggested that 12 might suffice, 3 subsets of 12 views were created that emphasized SAX views (12s), LAX views (12l), or the combination (12c). The RV was reconstructed at end diastole and end systole from full border sets and from each subset of borders using the PSSS method. Volume was computed directly from the 3D surface and used to calculate EF. Shape was measured at 20 cross sections from apex to tricuspid valve as eccentricity (= 4 piArea/PerimeterRV volume at end systole was overestimated by 1.5 ± 3.0% (p < 0.05) using 10 and 12c subsets. RV EF was underestimated by 2–3% (p < 0.05) using 10, 12l, and 12c subsets. RV volume and EF did not differ significantly from true when measured using 12s, 14, or 16 view subsets. RV shape at end diastole but not at end systole was slightly but significantly more rounded in the two most apical slices when measured using 14 views. There was also small but significant underestimation at end diastole, although not at end systole, of other RV shape metrics: the ratio of septal area to total surface area, RV LAX length, and extent of bulging at the base. When reconstructed using 16 views, the only shape metric to show a significant difference from true was eccentricity at one slice.Accurate measurement of RV volume and EF can be obtained from the PSSS method after tracing 14 views comprising 6 SAX slices mainly concentrated at the base, 6 LAX views distributed evenly from inferior to superior aspects of the free wall, and 2 IOT views. For the detailed 3D shape analysis that PSSS reconstruction enables, a minimum of 16 views is recommended.


A 79-year-old female presented with acute left-sided chest pain with shortness of breath; she was afebrile and vitally stable. She had a mildly elevated troponin (0.11 ng/mL). Her N terminal pro B-type natriuretic peptide (NT-proBNP) was 7053 pg/mL and electrocardiography (ECG) showed nonspecific ST, T wave changes. Transthoracic echocardiogram (TTE) revealed an ejection fraction (EF) of 65-70%. She was diagnosed with a non-ST elevation myocardial infarction (NSTEMI) and underwent a nuclear stress test, which was negative for ischemia with no left ventricular motion abnormality and an EF of 73%. The patient developed acute respiratory failure following the Lexiscan  and had to be intubated. A chest X-ray showed pulmonary edema, and transesophageal echocardiography (TEE) revealed a severely reduced EF of 25% with a new anterior wall motion abnormality. Left heart catheterization showed no significant coronary artery disease. Ventriculogram revealed a significantly reduced EF of 30% with apical akinesia. These findings were compatible with myocardial infarction with non-obstructive coronary arteries (MINOCA), likely secondary to regadenoson, which presented like takotsubo cardiomyopathy (TCM). Her condition gradually improved and the follow-up echo revealed baseline EF without symptoms of heart failure. In conclusion, takotsubo cardiomyopathy can be a potential complication from Lexiscan and can present as new-onset heart failure after the stress test. Takotsubo cardiomyopathy (TCM) is a cardiac syndrome that involves a transitory decrease in the ejection fraction (EF) in the absence of significant coronary artery disease and reversible left ventricular or mid ventricular apical akinesis . The terA 79-year-old female presented with acute, spontaneous, left-sided chest pain associated with shortness of breath and lightheadedness for the past four hours. The pain was continuous, non-radiating, and 4/10 in intensity, and it had started when she had been getting ready for bed. She was nauseated but denied emesis, diaphoresis, or palpitations. She denied any history of angina or having similar pain in the past. In the emergency department, she was afebrile and vitally stable but had elevated blood pressures of 163/75 mm Hg. Her medical history was significant for end-stage renal disease requiring hemodialysis, atrial fibrillation, hypertension, and sarcoidosis. Additionally, initial laboratory investigations revealed a mildly elevated troponin (0.11 ng/mL), N terminal pro B-type natriuretic peptide (NT-proBNP) at 7053 pg/mL, and nonspecific ST, T wave changes on ECG. Transthoracic echocardiogram (TTE) revealed an EF of 65-70%, severe dilatation of left atrium, with mitral annular calcification. These findings were consistent with her last echo 10 months back. She was diagnosed with a non-ST elevation myocardial infarction (NSTEMI) and scheduled for a nuclear stress test. She was given 0.4 mg regadenoson  tetrofosmin intravenously, and the test was negative for ischemia with no left ventricular motion abnormality and an EF of 73%. The patient experienced severe shortness of breath after the regadenoson injection and was given intravenous theophylline, which led to a transient improvement of her symptoms. However, her shortness of breath eventually worsened and she became tachycardic (141/min) and hypotensive (86/59 mm Hg); her oxygen saturation was not detectable on the pulse oximetry, and she was placed on Bilevel Positive Airway Pressure (BiPAP). She did not show any improvement and was subsequently intubated.On exam, while she was intubated, she was awake but lethargic with a Glasgow Coma Scale (GCS) of 5T. She had bilateral diffuse coarse crackles, and a cardiovascular exam revealed S1, S2, S4, and 1+ pitting pedal edema. Chest X-ray showed pulmonary edema secondary to acute systolic heart failure; she had a troponin level of 2.260 ng/mL and NT-proBNP up to 41,182. Her EKG revealed prolonged PR interval, early repolarization changes in V3-V6, and ST elevations in leads V2, V3, and V4, consistent with acute anterior MI  thought to be secondary to takotsubo cardiomyopathy. She was continued on aspirin, statin, beta-blocker, and started on angiotensin-converting enzyme (ACE) inhibitor subsequently for her MI/heart failure (HF). Her condition gradually improved. She was extubated, her troponin trended down, and her EKG changes resolved. At the eight-week follow-up, she was asymptomatic, and a repeat echo revealed recovered EF of 60-65%.TCM, also known as stress cardiomyopathy, is a rare but well-known entity and is estimated to account for up to 0.02% of all in-patient admissions . It has The etiology of the condition is not completely understood but the most commonly accepted hypothesis is the endogenous catecholamine-induced myocardial stunning in the background of severe emotional or physiological stress . It has Regadenoson is known to induce myocardial ischemia; however, TCM’s association with regadenoson is exceedingly rare. There is only one previously reported case of such association with a similar presentation of new-onset heart failure; this was reported in a middle-aged female following Lexiscan, with a clean left heart catheterization and spontaneous resolution of the heart failure . RegadenIn conclusion, takotsubo cardiomyopathy can be a potential complication of the Lexiscan stress test. It is important to consider this and recognize the association between new-onset heart failure and recent Lexiscan stress test. Patients can present with delayed symptoms of new-onset heart failure after the stress test. Hence, even an uncomplicated Lexiscan still carries a risk.


Hyperuricemia (HU) is a marker for heart failure. There are relatively few data in the Asian population regarding the effects of hyperuricemia and gouty disorders on cardiac remodeling and diastolic dysfunction (DD), an intermediate stage in the development of heart failure. We consecutively recruited asymptomatic Asian individuals to undergo cardiovascular surveys. We categorized them into Non-HU, HU, and Gout groups. We measured cardiac structure and indices for diastolic function, including tissue Doppler (TDI)-derived LV e’ and E/e’. Among 5525 participants, 1568 had HU and 347 had gout. The presence of gout and higher uric acid levels (SUA)  were associated with greater LV wall thickness, greater LV mass/volumes, larger LA volume, lower LV e’ and higher E/e’. Higher SUA was associated with greater LV mass index (adjusted coefficient: 0.37), greater mass/volume ratio (adjusted coefficient: 0.01) and larger LA volume index . Both HU and Gout groups were associated with lower LV e’ , higher E/e’ , larger LA volume, and higher DD risk . SUA set at 7.0 mg/dL provided the optimal cut-off for identifying DD, with markedly lower e’  and higher LV E/e’ in HU/Gout women than in men . Hyperuricemia, even at a relatively low clinical cut-off, was associated with unfavorable remodeling and was tightly linked to diastolic dysfunction. The presence of gout likely aggravated these conditions. Women with hyperuricemia or gout had worse diastolic indices than men despite similar degrees of LV remodeling. Circulating serum uric acid (SUA) is the final product of purine metabolism and is closely associated with a variety of metabolic abnormalities and coronary artery disease , 2. Seveper se was proposed to be more directly linked to DD [Left ventricular remodeling and hypertrophy are thought to be adverse cardiac adaptations in response to stress, pressure-, or volume-overload conditions . Unfavored to DD . NeverthWe studied consecutive patients undergoing annual cardiovascular surveys and health evaluations (from June 2009 to March 2012) at MacKay Memorial Hospital, Taipei, a tertiary medical center in Northern Taiwan. All study participants underwent comprehensive physical exams, chest radiography, 12-lead ECG, biochemical analysis and transthoracic echocardiography with tissue Doppler imaging (TDI). Baseline clinical characteristics and all biochemical data, including uric acid level, and echocardiography were examined on the same day. Structured questionnaires were administered to obtain information on subjective symptoms, lifestyles and detailed past medical histories. All the participants provided written informed consent. We excluded subjects with significant valvular heart disease, pulmonary hypertension , histories of prior cardiac surgery, congenital heart disease, permanent pacemaker implantation, LV ventricular ejection fraction (LVEF) <50% or clinical diagnosis of clinical heart failure (HF), and those receiving regular hemodialysis. The investigation conformed to the principles outlined in the Declaration of Helsinki and the local ethics committee  approved the study (number: 14MMHIS202). The descriptions of our study settings were further detailed in a previous publication [We further categorized our study cohort into three groups based on circulating SUA levels and medical history of gout: 1) Non-hyperuricemic Group (Non-HU): serum uric acid (SUA) level ≤6 mg/dL in women and ≤7 mg/dL in men without any known prior gout history; 2) Hyperuricemic Group (HU): SUA >6 mg/dL in women and >7 mg/dL in men without known gout history; and 3) Gout: individuals with known gouty arthritis or current medication use for gouty disorder. The clinical diagnosis of gout was based on ACR guidelines: at least one episode of peripheral joint or bursal swelling, pain, or tenderness with either presence of tophus or monosodium urate monohydrate crystals in symptomatic joint/bursa or a threshold score ≥8 in different domains in the new American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) gout classification criteria .2) and indexed LA volume (LAVi) were defined as the ratio of LV mass and LAV to body surface area, respectively. LV hypertrophy was defined as LVMi >95 mg/m2 in women and >115 mg/m2 in men.All echocardiographic studies were acquired using commercially available ultrasound Hewlett-Packard instruments  or GE systems (Vivid i) equipped with 2–4-MHz transducers (3S-RS) during the recruitment period by a single experienced technician blinded to clinical information. All echocardiographic measures were obtained through consecutive three heart cycles. Cardiac chamber dimensions, LV and left atrial (LA) volumes (LAV), LVEF as well as LV mass (LVM) were measured according to current guidelines of the American Society of Echocardiography . RelativWe further classified the participants into normal, concentric remodeling, and left ventricular hypertrophy groups based on RWT and LV mass index. Normal group: RWT ≤0.42 and no LVH; Concentric remodeling: RWT >0.42 and no LVH; LV hypertrophy: individuals with LVH. Diastolic functional evaluation included pulsed wave Doppler sampling positioned at the mitral leaflet tip area  with early (E), and the late diastolic (A) filling velocities ratio (E/A ratio). Tissue Doppler imaging (TDI)-based mitral annular relaxation velocity (e’) of ventricular septal and lateral segments were also obtained. Grading of diastolic dysfunction was then determined according to European Association of Echocardiography/American Society of Echocardiography (EAE/ASE) recommendations. We further graded diastolic function as follows: Normal: septal e’ ≥8 cm/s and lateral e’ ≥10 cm/s and E/e’ ≤8; mild diastolic dysfunction: septal e’ <8 cm/s or lateral e’ <10 cm/s and deceleration time (DT) >200 ms and E/e’ ≤8; moderate-to-severe diastolic dysfunction: septal e’<8 cm/s or lateral e’<10 cm/s and DT ≤200 ms and E/e’ >8 .Data were expressed as mean ± SDs for continuous variables and percentage (%) for categorical variables. The clinical characteristics across Non-HU, HU and Gout categories  and echop <0.05 were considered statistically significant.Statistical analyses were performed using STATA statistical software . Two-sided values of There were 5525 asymptomatic participants . The baseline characteristics of these three groups are displayed in 2) in both sexes , greater LV mass (with and without index), greater wall thickness, greater RWT, larger LA size (both LAV and LAVi)/LV volumes, lower E/A ratio, and reduced mitral annular relaxation e’ (9.48 vs 8.61 vs 7.46 cm/s) and higher LV E/e’   were botth sexes . Subjectctively) .While women tended to have lower SUA and had lesser degrees of cardiac remodeling, they demonstrated significantly lower mitral annular relaxation velocity e’  and markedly higher LV E/e’  in both HU and Gout groups; there were no differences on LV e’ by gender in the Non-HU group . There wOur study is the largest to date to demonstrate the relationships among SUA levels, diastolic function, and LV remodeling in an asymptomatic ethnic Asian population. There were three main findings: (1) Both hyperuricemia and gout groups had greater LV mass indexes, more concentric remodeling, and worse LV diastolic function that was more pronounced in the gout group; (2) Elevated SUA levels were related to concentric LV, ventricular hypertrophy, and worse diastolic function; and (3) In individuals with hyperuricemia, women demonstrated greater degrees of concentric LV remodeling and worse diastolic function than did men.Increased production of uric acid promotes LV hypertrophy and cardiac fibrosis by stimulating inflammation and oxidative stress, thereby leading to diastolic dysfunction . Uric acIncreased XO pathway activity produces free superoxide radicals and consequent heart failure. Inhibition of XO activity causes left ventricular regression and LV contractile functional improvement by way of SUA reduction , 24. IntWomen with hyperuricemia appeared to be more susceptible to the development of diastolic dysfunction than did men, even after adjustment for diuretics use . To dateThe link between hyperuricemia and clinical diastolic dysfunction (DD)  may start at a relatively low clinical cut-off point (7.0 mg/dL), demonstrating independent associations with impaired myocardial relaxation e’ and ventricular filling E/e'.While men and women showed similar degree of cardiac remodeling, women in general presented with worse diastolic parameters than did men.The major limitation of our research is its single center, observational, and retrospective nature; our results may not be representative of the general population. As a cross-sectional study design, our current findings failed to explain the causal relationship. Second, there was a relatively small sample size to determine associations between SUA levels and LV diastolic function; nevertheless, we provided detailed data regarding the relationship between diastolic function and LV remodeling in a large asymptomatic ethnic Asian cohort. Third, the number of females was relatively small in the hyperuricemia and gout groups; therefore the findings regarding sex differences should be interpreted carefully.In a large Asian population, hyperuricemia was both tightly linked to unfavorable LV remodeling and was independently associated with impaired diastolic dysfunction, even at relatively low values. These structural and functional alterations were more pronounced in subjects with known gout history. Women in general experienced less pronounced cardiac remodeling with hyperuricemia or gout, despite the fact that they a demonstrated greater degree of diastolic functional impairment than did men, with underlying comparable diastolic function in non-hyperuricemia status. Our data suggest that SUA may serve as a marker for unfavorable cardiac remodeling or pre-clinical heart failure marker at very early stages, especially for women.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 Fig(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.


Chagas disease (CD) will account for 200,000 cardiovascular deaths worldwide over the next 5 years. Early detection of chronic Chagas cardiomyopathy (CCC) is a challenge. We aimed to test if speckle-tracking echocardiography (STE) can detect incipient myocardial damage in CD. METHODS: Among 325 individuals with positive serological tests, 25 (age 55±12yrs) were selected to compose the group with indeterminate form of Chagas disease (IFCD), based on stringent criteria of being asymptomatic and with normal EKG/X-ray studies. This group was compared with a group of 20 patients with CCC (55±11yrs) and a group of 20 non-infected matched control (NC) subjects (48±10yrs). CD patients and NC were submitted to STE and CD patients were submitted to cardiac magnetic resonance (CMR) with late gadolinium administration to detect cardiac fibrosis by the late enhancement technique. Global longitudinal strain (GLS), circumferential (GCS) and radial strain (GRS) were defined as the average of segments measured from three apical view (GLS) and short axis views (GRS and GCS). Regional left ventricular (LV) longitudinal strain (Reg LS) was measured from each of the 17 segments. Twist was measured as systolic peak difference between basal and apical rotation and indexed to LV length to express torsion. RESULTS: STE global indices  were reduced in CCC vs NC , but showed no differences in IFCD vs NC. RegLS was reduced in IFCD vs NC in four LV segments: basal-inferior , basal inferoseptal , mid-inferoseptal  and mid-inferolateral . These abnormalities in RegLS occurred in the absence of myocardial fibrosis detectable with CMR in nearly 92% of subjects with IFCD, while myocardial fibrosis was present in 65% with CCC. CONCLUSION: RegLS detects early regional impairment of myocardial strain that is independent from fibrosis in IFCD subjects. Regional longitudinal strain is reduced in IFCD before significant fibrosis. As CD progresses to CF, global STE measurements of left ventricle  and GLS of right ventricle are reduced.Early abnormal strain pattern of CD comprises inferior, septoinferior and inferolateral segments of LV. Recognizing the regional strain pattern of Chagas cardiomyopathy may help identifying the disease even at early stages. Trypanosoma cruzi protozoan, is still a major public health problem in Latin America [More than one century after its discovery in 1909 [ America  and, due America –5.T. cruzi remain throughout life with the indeterminate form of CD (IFCD) i.e. they do not show any clinical signs of organic involvement. Although the concept of the IFCD has been occasionally challenged [An estimated 50–60% of subjects chronically infected with the allenged , 8. Thisallenged , 9–11.Two main issues regarding the IFCD remain unsolved. The first is related to which genetic or acquired factors determine, in a specific patient, the installation of the cardiomyopathy , 13. TheT. cruzi infection, showing reduced parasite load and cardiac damage [The second issue is particularly relevant when it is known that no etiological treatment has been proven to benefit patients already with the CCC , whereasc damage . In thisTwo-dimensional speckle-tracking echocardiography (STE), a method to quantitate global and regional myocardial deformation , 18 has Preliminary studies in IFCD individuals using STE described mixed results, failing to show reduction of LV global strain but reported lower values of radial strain in the mid-inferior segment in individuals with the IFCD as compared with NC subjects . In anotWe hypothesized that RegLS or global STE can identify early myocardial dysfunction in IFCD. Thus, the aims of this study were (1) to compare LV systolic global , radial (GRS) or circumferential (GCS)) and RegLS values between individuals with IFCD, age matched NC and patients with the CCC; and (2) to observe if LV strain abnormality correlates with presence and the extent of myocardial fibrosis measured by cardiac magnetic resonance imaging (CMR).This cross-sectional study was designed to compare ventricular strain values between Chagas subjects (IFCD and CCC) and an age matched NC individuals. Sample size calculation was based on a presumed difference of 15% on LV global longitudinal strain values among the three groups and resulted in an estimation of 23 individuals in each study group .≥ 85 years old; presence of any other cardiovascular disease, motor disability limiting cardiac tests; arterial hypertension; significant psychiatric diseases, renal failure or hepatic cirrhosis. Patients who already had the diagnosis of CCC were enrolled consecutively from the outpatient clinics of the University Hospital of the Medical School of Ribeirão Preto, University of São Paulo Brazil. Healthy volunteers who were age and gender matched to the IFCD individuals were invited to participate and had serological tests for CD that yielded negative results in all cases. All recruited subjects underwent standard 12-lead EKG, upright chest X-rays and rest transthoracic echocardiography. Subjects with CD underwent CMR at the same day of echocardiography. NC volunteers were submitted to the same exams except for CMR. All EKG abnormalities such as complete right bundle branch block (RBBB), complete left bundle branch block (LBBB) and left anterior fascicular block (LAFB) were defined following previous published guidelines (20). Any kind of atrio-ventricular block was classified simply as an "AV block".To compose the IFCD group, individuals with positive serology for CD and no symptoms of cardiac disease, normal EKG and normal chest X-ray were recruited searching hospital medical records during the years 2015–2016. Inclusion criteria were: two positive serology tests for CD, age ≥18 years old. Exclusion criteria were: age 17096/2015), which was conducted in accordance with the Helsinki Declaration. Written informed consent was obtained from all participants.The institutional research ethics committee approved the study protocol , who was trained to acquire complete conventional echocardiography and image sequences dedicated to speckle tracking analysis including left ventricular (LV) twist and torsion. Images were acquired with Vivid E9 or S6 , with a phased-array transducer of 1.4–4.6 MHz. Image acquisition strictly followed previous published guidelines , 28. BriImages were archived as GE dedicated raw data and analyzed by another researcher (MMDR), blinded to the subject study group, with EchoPac software (GE Vingmed Ultrasound AS) version 112.Conventional echocardiographic left (LV) and right (RV) ventricular dimensions and function were collected as follows: LV linear transversal dimension at diastole and systole , longitudinal dimension measured as an average of longitudinal linear dimensions in two-chamber view and four-chamber views, end-diastolic volume (LV EDV), end-systolic volume (LV ESV) and ejection fraction (LVEF) derived from Simpson’s modified rule ; RV lineA single experienced physician (MMDR) performed all two-dimensional strain analyses using the three LV apical views, a 4-chamber dedicated RV view and short LV axis view at basal, mid papillary and apical levels. The second of the three acquired cardiac cycles was chosen for analysis whenever possible. All strain measurements were collected as "full thickness” (or meso) myocardium and end-systolic strain values (ESS) were measured, avoiding post-systolic strain measurements. Reference time point was manually set to the beginning of the QRS. End-systole  was defiLongitudinal strain (LV and RV) was measured as end-systolic strain (ESS) from full thickness myocardial, which is named mid-layer in GE EchoPac software as a default. Global longitudinal strain (GLS) was measured automatically by the system as an average of 17 segmental strain values from three projections of LV in apical view. LV segmental strain from each of 17 LV segments was similarly collected. Circumferential and radial strain were also measured as ESS. Global circumferential (GCS) and radial strain (GRS) were calculated as an average of each segmental value from a 18- segmentation model, derived from short axis views at basal (6 segments), mid (6 segments) and apical (6 segments) LV levels. All strain values were expressed as % changes. LV twist value was collected from the derived curve of apex-basal rotation. The end-systolic peak of the derived subtraction curve was manually measured using the aortic valve closure time mark as the time reference point into the software. Twist value was expressed in degrees and was divided by LV longitudinal dimension to construct the torsion value, the former being expressed in degrees/cm .Cardiac magnetic resonance images were acquired from all Chagas subjects (IFCD and CCC groups) the same day as the echocardiography recording. Cine loops were acquired using a steady-state free precession pulse sequence gated by EKG, obtained with a 1.5 Tesla scanner Achieva , with a predefined protocol as follows: repetition time of 3.8 msec, echo time of 6 msec, flip angle of 45°, 30 acquisition phases, 256x160 matrix and 360–400 mm field of view. LV and RV were analysed in short axis slices . For myocardial tissue evaluation and fibrosis detection, subjects received 0.2 mmol/Kg gadolinium-based contrast  by intravenous infusion. T1-weighted inversion recovery fast gradient echo pulse sequence was applied 10 min after the contrast injection. LV slices with 10mm of thickness and no gap were accessed to identify gadolinium enhancement. Exams were recorded in the DICOM pattern in HCRP-Brazil. Images were transferred to a dedicating reading software (Duke precession Saas) following HIPPA privacy guidelines and de-identified for blind analysis. Two experienced physicians were responsible for reading CMR images , blinded to both echocardiography data and subject group. Simpson’s disk summation technique was used to determine ventricular volumes and ejection fraction from short axis slices. RV outflow tract was not included into RV volumes. Endocardial borders were manually delineated excluding papillary muscles and trabeculae. To detect myocardial scar, hyper-enhancement signal was visually scored by using a 17-segmentation model with a five point scale for each segment, in which 0 = no hyper-enhancement, 1 = 1–25%, 2 = 26–50%, 3 = 51–75% and 4 = 76–100%. We calculated total size of LV scarring (% of myocardium) by summing the regional scores and dividing by the total numbers of segments analyzed (n = 17). The percentages of any amount of scar (> 0%) in any wall (%LV) for both IFCD and CCC Chagas groups were recorded.Echocardiography strain parameters GLS, GCS, GRS and RegLS were tested for reproducibility in a subset of 15 subjects randomly selected proportionally to the three studied groups . For intra-observer variability, a re-reading (MMDR) was performed at least one month after the first reading, blinded to the previous one. For inter-observer variability a second experienced echocardiographer physician (FA) performed analyses using the same technique previously described, also blinded to both first reader analysis and individual study group. Comparisons of results were done with intra-class correlation coefficient (ICC) to assess absolute agreement and a coefficient of variation (CV) determined by the standard deviation divided by the mean and expressed as percentage.Sample size calculation was done using standard methods . Data weFig 1). We reviewed the hospital records of all 325 consecutive asymptomatic subjects with positive serological Chagas tests evaluated at our institution from 01 of January of 2015 to 31 of December of 2016. After the exclusion criteria as shown in Fig 1, the IFCD group was composed of 25 individuals. Another subset of 20 consecutive screened patients with Chagas disease and clinical signs of heart involvement constituted the CCC group.Population screening of IFCD individuals is described in flowchart  are described in Table 2. When comparing the NC and the IFCD groups, echocardiography conventional variables did not differ statistically, except for a slightly increased LV end-systolic diameter of 3.0 ±0.5 vs 2.8±0.4 (p = 0.023).Conventional echocardiographic and deformation parameters analyzed in the 3 groups are shown in Global strain parameters GLS and GCS from both LV and RV were also similar between individuals in the IFCD and NC groups. GRS was lower in IFCD group versus the NC group  and there was a trend for being lower in the CCC group as compared to the NC group . Individuals with CCC had reduced GLS and GCS, twist and torsion in comparison with the NC group. These patients with CCC had also lower values of RV GLS from both the four-chamber view and from RV free wall. (Table 3). Reduction of RegLS was even more marked in patients with CCC for all segments, except for the 2 , 6  and 8 , 4 , 9  and 11 (Table 4). Fibrosis was more prevalent in the mid infero-lateral, basal infero-lateral and apex segments.Myocardial fibrosis was quantified in 36 out of 45 individuals with CD (IFCD+CCC). Fibrosis was detected in 12 of them  of IFCD, and in 10 patients (65%) of CCC group). Among CD individuals there were no significant differences in demographic characteristics between individuals with or without fibrosis. In comparison with those without fibrosis, individuals with fibrosis had significantly higher LV diameters  and lower left ventricle systolic function . Patients without fibrosis had significantly higher values of GLS  versus those with detected fibrosis. However GCS, GRS, twist and torsion did not differ between them . From the graphic, no significant fibrosis is detected even when GLS is below normal levels (dotted line) for this software, and only marked reductions in GLS identify patients with a significant extent of fibrosis .Although there was a statistically significant correlation  between GLS and fibrosis in the whole set of patients with CD (IFCD and CCC), it was not linear  as follows: 0.99, 0.90, 0.86 and 0.97. ICC for inter-observer variability of GLS, GCS, GRS and twist were 0.99, 0.89, 0.86 and 0.98. Inter-observer variability of RegLS varied from 0.43  to 0.91 (mid inferior segment).The fundamental hypothesis of the study, that STE can identify early global or regional myocardial impairment in individuals at early stages of CD, was confirmed by the finding that RegLS is indeed reduced in four segments of LV  in the group of IFCD, despite the absence of any other evidence of LV dysfunction , or fibrosis as detected by CMR. To the best of our knowledge this is the first investigation to show an abnormal strain pattern of early myocardial involvement in IFCD individuals who do not have detectable fibrosis. Global indexes of myocardial deformation analysis were not impaired in IFCD. However, in patients with the CCC, almost all LV segments showed markedly reduced RegLS, and the impairment of myocardial strain is correlated with the presence of regional fibrosis.Comparison of our findings with those of previous preliminary studies using STE in the context of CD is hampered by dissimilarities in sample populations and technical approaches. For example, the findings of RegLS reduction in early stages of CD presented here are in part concordant with those reported by Barbosa et al, of reduction in RegLS in two LV segments , as compared to NC . The conIt is important to emphasize that the results of our study, reinforcing previous data which showed that LV global myocardium deformation strain indexes GLS and GCS are still preserved in presumably early phases of CD , 24, 25,STE measurements in our study were strictly controlled. This is the first study using STE in patients with CD which strictly followed the recently published standardization document to measure myocardial strain . Strain Measurement of GRS has yielded more controversial data in studies of patients with diverse forms of CD . ResultsThis study also shows that LV twist and torsion values are reduced only in advanced forms of CD, while previous data reported in a small subset of 9 patients with IFCD by García-Álvarez et al found reduction in twist values compared to controls . In contMyocardial fibrosis detected by CMR has been shown to have prognostic value in patients with CCC , 40. HowAn important consideration about our results is that fewer individuals (8%) with IFCD had myocardial fibrosis in comparison with previously reported data from other IFCD series (12%-27% of subjects) . SeveralRecognizing an abnormal regional strain pattern in CD can guide the detection of cardiac involvement even in early stages of the disease. It can be helpful to identify this entity in the group of patients with suspected non-ischemic cardiomyopathies who still present a diagnostic challenge , mainly Early detection of regional myocardial damage can help design strategies for follow-up and management of this group of CD patients. Since regional myocardial impairment has been prognostic in this population, treatment strategies could be driven, in the future, by assessment of RegLS.We recognize sample size is a limitation. However, we based sample size on the underlying hypothesis of the study and followed prospectively devised strict criteria to screen 325 subjects and to select a group of 25 individuals of IFCD.There was a significant but random loss of CMR data for analysis of fibrosis. Although all CD subjects were prospectively studied with CMR at the same day of echocardiography, which is an important and costly aspect of the study, still a proportion of 38% in the CCC group and 23.3% in the IFCD group could not undergo fibrosis assessment because of technical problems with acquired images. Also, this study did not provide evaluation of oedema and inflammation by CMR images to test the hypothesis of early impairment of strain indexes being related to those pathological changes, rather than to fibrosis.Finally, the cross-sectional design of the study does not allow conclusions about the prognostic importance of the abnormal RegLS pattern in early stages of CD. Further studies with specific design should be performed to address this question. The results of an on-going such study should soon become available .RegLS is reduced in the infero-septal, inferior and inferior-lateral LV segments in subjects with IFCD in absence of impairment of global indexes of myocardial deformation and of detectable myocardial fibrosis. Patients with CCC presented a markedly abnormal strain pattern, associated to reduction of LV GLS, GCS, twist and torsion and also of RV GLS.Chronic cardiomyopathy caused by Chagas disease is the most prevalent of nonischemic cardiomyopathies in endemic countries of Latin America and because of migration movements during the last decades its prevalence is augmenting also in North America and Europe. RegLS is reduced in subjects with the IFCD even before myocardium fibrosis or any other signs of cardiac involvement. In the CCC group of patients there is impairment of global strain indexes from LV as GLS and GCS, twist and torsion and also RV GLS.


Segment length in cine (SLICE) strain analysis on standard cardiovascular magnetic resonance (CMR) cine images was recently validated against gold standard myocardial tagging. The present study aims to explore predictive value of SLICE for cardiac resynchronization therapy (CRT) response.sep), systolic stretch index (SSIsep-lat), and internal stretch factor (ISFsep-lat) all correlated significantly with LVESV change . Of all strain parameters, end-systolic septal strain (ESSsep) showed strongest correlation with LVESV change (R − 0.63). Multivariable analysis showed ESSsep to be independently related to LVESV change together with age and QRSAREA.Fifty-seven patients with heart failure and left bundle branch block (LBBB) were prospectively enrolled in this multi-center study and underwent CMR examination before CRT implantation. Circumferential strains of the septal and lateral wall were measured by SLICE on short-axis cine images. In addition, timing and strain pattern parameters were assessed. After twelve months, CRT response was quantified by the echocardiographic change in left ventricular (LV) end-systolic volume (LVESV). In contrast to timing parameters, strain pattern parameters being systolic rebound stretch of the septum (SRSsep) demonstrates the strongest correlation with reverse remodeling after CRT. This parameter may be of special interest in patients with non-strict LBBB morphology for whom CRT benefit is doubted.The practicable SLICE strain technique may help the clinician to estimate potential benefit from CRT by analyzing standard CMR cine images without the need for commercial software. Of all strain parameters, end-systolic septal strain (ESS Cardiac resynchronization therapy (CRT) is an established therapy for patients with chronic heart failure, reduced left ventricular (LV) ejection fraction and left bundle branch block (LBBB). Patient selection is primarily guided by the electrocardiogram (ECG), but this results in approximately one-third of patients not benefitting from the therapy , 2. AddiThis study was part of the Markers And Response to CRT (MARC) study, a non-randomized, multi-center study that investigated the role of various clinical-, ECG-, echocardiographic-, and biomarker parameters to predict LV reverse remodeling after CRT . The MARDevice programming was DDD mode in all patients with a sensed atrioventricular (AV) delay of 90 ms, paced AV-delay of 130 ms and interventricular (VV) delay 0 ms. Echocardiographic assessment of LV volumes was performed before, and twelve months after CRT implantation. LV end-systolic volume (LVESV) was measured using the biplane Simpson’s method by two experienced observers. Patients with ≥ 15% reduction in LVESV were classified as CRT responders .Patients underwent CMR examination using a 1.5 T system . Standard CMR cine images were acquired using a retrospectively ECG-gated balanced steady-state free-precession (bSSFP) sequence with standard short-axis and long-axis orientations to measure LV volumes and calculate LV ejection fraction (LVEF). Typically, temporal resolution was < 50 ms and the number of reconstructed temporal phases within the cardiac cycle was set between 20 and 30. Typical image acquisition parameters were: slice thickness/slice gap: 5/5 mm, 8/0 mm or 6/4 mm; echo time (TE)/repetition time (TR): 1.6 ms/3.2 ms; in-plane spatial resolution: 1.5 by 2.1 mm; flip angle: 45 to 75 degrees. Cine imaging of the LV in the three-chamber view was performed to assess aortic valve closure (AVC). Myocardial scar territory was assessed by late gadolinium enhancement (LGE) imaging, and infarct size was measured using the full width at half maximum method . All CMRImageJ to measure segment length measurements between the marks over the myocardium midline in each phase using the segmented line tool, see Fig. A detailed description of the SLICE analysis post-processing steps has been published previously . In briesep); the systolic stretch index (SSIsep-lat); and the internal stretch index (ISFsep-lat). Lastly, septal strain patterns were visually classified to the following pre-specified patterns: double peaked systolic shortening (LBBB-1); early pre-ejection shortening followed by prominent systolic stretch (LBBB-2); and pseudonormal shortening with a late-systolic shortening peak and less pronounced end-systolic stretch (LBBB-3).Four subsets of strain parameters were evaluated. First, basic strain values were quantified by the septal and lateral peak negative strain (peak strain); and end-systolic strain (ESS) at the time of AVC (determined by cine imaging of the LV in the three-chamber view). Secondly, timing differences were measured by the septal-to-lateral delay in onset of shortening (onset-delay); and the septal-to-lateral time difference in peak contraction (peak-delay); Thirdly, strain pattern parameters included systolic rebound stretch of the septum  score was calculated as previously described in the MARC main study [A detailed description of the ECG- and echocardiographic analysis has been published previously . In briethe apex . In addiin study .p-value of < 0.05 was considered statistically significant.Statistical analysis was performed in the study core lab  by a specialized team led by a bioinformatician (BG) using the R software . Continuous variables are expressed as mean ± standard deviation or in absence of a normal distribution as median and interquartile range. Categorical variables are presented as numbers and percentages. Strain parameters were compared between CRT responder and non-responder groups by an independent student t-test, or a non-parametric test when appropriate. Correlations between strain parameters and echocardiographic CRT response were assessed using the Pearson’s correlation coefficient or when normal distribution was absent, the Spearman’s Rho correlation coefficient. Receiver operating characteristics (ROC) curve analysis was used to find optimal cut-off values and determine predictive value of strain parameters. Univariable linear regression analysis was performed to assess the association of other  parameters with echocardiographic CRT response. To test the additional value of SLICE strain analysis on top of conventional determinants of CRT response, multivariable linear regression analysis was performed by entering the best performing strain parameter (based on R) to a model with standard CMR parameters (model 1), clinical parameters (model 2) and the CAVIAR score parameters (model 3). Multiple testing was corrected for when appropriate. A After screening 63 patients, three patients were excluded from the analysis due to incomplete- or insufficient CMR image quality. Of the remaining 60 patients, 57 patients completed the 1-year follow up. One patient was lost to follow-up because of non-cardiac death (lung carcinoma), one withdrew informed consent, and one lacked sufficient image-quality during echocardiographic examination. Patient characteristics of the remaining 57 patients are presented in Table sep) showed the highest correlation coefficient of all parameters  with good predictive value for CRT response  patients  compared with LBBB patients . Timing parameters onset-delay and peak-delay were unrelated to LVESV change and yielded no predictive value for CRT response . As demonstrated in Fig. Strain values for the total patient group, and both responder and non-responder subgroups are presented in Additional file sep, to standard CMR parameters in a multivariable model (model 1) showed ESSsep to be independently related to LVESV change whereas other CMR parameters were not, although there was a trend towards significance for scar size. Clinical parameters that were associated with CRT response included age, gender, etiology, QRS duration and QRS morphology. In a multivariable model with clinical determinants (model 2), ESSsep showed to be independently related to LVESV change together with age. The CAVIAR score parameters age, QRSAREA, IVMD, and apical rocking, were all significantly associated with CRT response. Addition of ESSsep to CAVIAR (model 3), showed ESSsep to be independently related to LVESV change together with age and QRSAREA.CRT responders were younger, had relatively less often ischemic etiology and wider QRS duration compared to non-responders Table . LV leadAREA) parameters in estimating potential benefit from CRT.This study is the first to demonstrate predictive value of the novel SLICE strain technique for functional LV recovery after CRT implantation. Various SLICE strain parameters showed to be closely related with CRT response after 1 year. When comparing different types of strain parameters, strain pattern- rather than timing variables correlated with CRT response. Of all strain parameters, end-systolic septal strain demonstrated the strongest correlation with LV reverse remodeling after 1 year. Moreover, multivariable regression analysis showed end-systolic septal strain to be additive to clinical (age) and electrical  all correlated with reverse remodeling after CRT and accurately predicted response to CRT [In patients with LBBB, slow cell-to-cell LV conduction results in a time-difference of electrical activation between the septal and lateral wall. Although SLICE analysis revealed mechanical contraction always to be delayed in the lateral wall relative to the septal wall, absolute time delays between the septal and lateral wall  were unrelated to the amount of echocardiographic response after CRT. These findings are in agreement with those of the predictors of response to cardiac resynchronization therapy (PROSPECT) trial, showing disappointing results of timing (i.e. dyssynchrony) parameters . More ree to CRT , 4, 6.sep) to be strongest related with reverse remodeling after CRT as illustrated in Fig. sep to be the best performing strain parameter in the prediction of CRT outcome irrespective of imaging technique [sep reflects net septum length change throughout systole and varied widely between patients ranging between − 15.5% (shortening) and 17.1% (stretching). These large differences in strain can be easily detected by SLICE and require septal analysis in only two (end-diastolic and end-systolic) frames  with excellent intra-observer reproducibility (ICC: 0.94) and good inter-observer reproducibility (ICC: 0.86) [sep was higher compared to other strain parameters, presumably because of the wide spread in strain values. ROC curve analysis in the present study revealed an optimal cut-off value to predict CRT response around zero (0.3) percent. Patients with septal stretching rather than shortening during systole (positive numbers indicate stretching) are highly inefficient at baseline and leave more room for improvement in contractile function after CRT. These patients showed a three-fold larger reduction in LVESV compared to patients with preserved septal contraction. Alternatively, septal behavior can be evaluated in a subjective manner by the visual classification of septal strain curves to a pre-described pattern. Patients with a typical LBBB (i.e. LBBB-1 or LBBB-2) pattern demonstrated larger reductions in LVESV compared to patients with a pseudo-normal (i.e. LBBB-3) which is in line with previous studies [During LBBB, systolic stretching is most profound in early-activated  segments whereas contractile function is increased in late-activated  regions, resulting in an imbalanced septal-to-lateral work load ratio –17. CRT echnique . The prey ICC: 0.4 and gooy ICC: 0.6 [sep wa studies . Howeversep to be the only parameter independently related to LVESV change, although there was a trend towards significance for scar size. Scar size and septal discoordination were interrelated  as they possibly share mutual information on LV contractility [sep with lower values indicating poor CRT outcome.In clinical practice, the role of CMR is of interest as it offers accurate LVEF measurement combined with LGE imaging to guide LV lead placement in CRT candidates –26. Leyvactility . Informasep parameter may add to the decision for CRT, especially in patients with IVCD in whom benefit from CRT is doubted. It can be appreciated in Fig. sep to provide predictive value over QRS morphology (model 2). Moreover, predictive performance of ESSsep was stronger within IVCD patients than LBBB patients. The potential value of ESSsep in IVCD patients is illustrated by two examples in Fig. Furthermore, the role of SLICE in relation to clinical parameters was explored. Clinical predictors of CRT response included age, gender, etiology, QRS width and QRS morphology see Fig. , all conAREA derived by vector-loop ECG analysis and two echocardiographic parameters being IVMD and detection of apical rocking [sep to CAVIAR in multivariable analysis showed ESSsep to be an independent predictor of response together with age and QRSAREA, whereas echocardiographic parameters  were expelled from the model. These findings indicate that response to CRT is multifactorial [AREA) and mechanical information (SLICE-ESSsep) may improve patient selection for CRT. As QRSAREA can be measured from a standard 12-lead ECG and SLICE-ESSsep from standard CMR cine images, the work-up of CRT candidates is feasible in clinical practice.Lastly, the value of SLICE was evaluated with respect to a specially designed prediction model in the MARC main study (model 3). The CAVIAR response score incorporates age, QRS rocking . Additioactorial , and thasep should be evaluated in a validation cohort which is part of future work. Secondly, 18% of patients had their LV lead implanted in a region with myocardial scarring. Targeting LV lead placement outside scar regions could potentially improve response to CRT and may impact predictive value of ESSsep albeit not being investigated in the present study. Thirdly, CMR feature tracking (CMR-FT) post-processing software is now commercially available and offers automated strain analysis on standard CMR cine images. Nevertheless, CMR-FT has several downsides as it requires the purchase of commercial software and the user is not able to track and trace the analysis steps. SLICE, on the other hand, can be performed without the use of specialized software tools. Fourthly, strain parameters that require SLICE analysis of the entire strain curve may take a long processing time (up to 60 min). Measuring the specific ESSsep parameter, however, requires only two SLICE measurements and can be performed in around twelve minutes. Furthermore, the SLICE analysis could be standardized by implementing radial taglines to standard cine imaging  demonstrated the strongest correlation with reverse remodeling after CRT. This parameter can be measured in around 12 min and may be of special interest in patients with non-strict LBBB morphology in whom CRT benefit is doubted. New clinical trials are needed to determine whether detection of septal discoordination yields additive value to traditional CRT parameters in clinical practice.The practicable SLICE strain technique helps the clinician to estimate potential benefit from CRT by analyzing standard CMR cine images without the need for commercial software. Of all strain parameters, end-systolic septal strain . Table S3. Septal strain patterns and CRT response. Figure S1. Localization of the anatomical landmarks. Figure S2. Modification of the SLICE technique by implementing radial taglines.


Patients may have signs of hypovolemia, but fluid administration is not always beneficial. We are in need of bedside devices and techniques, which can predict fluid responsiveness effectively and safely. This study is aiming to compare the effectiveness and reliability of the pleth variability index (PVI) and IVC distensibility index (dIVC) as predictors of fluid responsiveness by simultaneous recordings in all sedated mechanically ventilated patients in the surgical intensive care unit (ICU). We used the passive leg raising test (PLR) as a harmless reversible technique for fluid challenge, and patients were considered responders if the cardiac index (CI) measured by transthoracic echocardiography (TTE) increased ≥ 15% after passive leg raising test (PLR).P < .0001), with an area under the curve (AUC) of 0.886 (0.801–0.944), while PVI at a threshold value of > 14% provided 93.75% sensitivity and 87.5% specificity and was statistically significant (P < .0001), with an AUC of 0.969 (0.889–0.988).This observational cross-sectional study was performed randomly on 88 intubated ventilated sedated patients. Compared with CI measured by transthoracic echocardiography, the dIVC provided 79.17% sensitivity and 80% specificity at a threshold value of > 19.42% for fluid responsiveness prediction and was statistically significant (PVI and dIVC are effective non-invasive bedside methods for the assessment of fluid responsiveness in ICU for intubated ventilated sedated patients with sinus rhythm, but PVI has the advantage of being continuous, operator-independent, and more reliable than dIVC. Perioperative prediction of fluid responsiveness has been a challenge for many years. It is known as the ability of the circulation to increase cardiac output (CO) in response to volume expansion. Accommodation of the large volume of venous return (VR) is done by stretching ventricles, which is known as cardiac preload. Since preload is related to CO, increased negativity of intrathoracic pressure (ITP) during inspiration subsequently increases VR and subsequently CO, and the reverse occurs during expiration  fluid administration is very important to correct any fluid deficits created by fasting, blood loss, and urinary excretion, or in septic and other critically ill patients to improve oxygen delivery and overall hemodynamic function. However, it may be ineffective or harmful to patients if no suitable monitoring methods are used. Interstitial fluid accumulation by more volume expansion may worsen oxygen diffusion to the tissues and decrease myocardial compliance. Therefore, it became essential to develop an approach for the evaluation of patients who are likely to get benefit from fluid administration , but due to its complications and the same limitations as central venous pressure (CVP)  is a dynamic variable, which has recently gained a lot of interest. By using the amplitude of the pulse oximeter waveform, it measures the respiratory variation continuously and automatically. Therefore, it became an effective dynamic fluid response predictor in sedated mechanically ventilated patients with sinus rhythm by providing simple numeric value on the monitor screen  in mechanically ventilated patients has been reported as a widely available and non-invasive measure for prediction of fluid responsiveness in multiple patient settings  or postoperative, and sedated on controlled mechanical ventilation with arterial and central venous catheters. The included patients were in need of IV fluid challenge for resuscitation based on the clinical characteristics  < 90 mmHg, or mean arterial pressure (MAP) < 65 mmHg, or a fall of > 20 mmHg from the baseline of MAP, or with signs of hypoperfusion as oliguria less than 0.5 ml/kg/h and arterial lactate > 2.5 mmol/L).The exclusion criteria are spontaneous breathing, poor cardiac echogenicity, cardiac arrhythmia, severe valvular heart disease or intracardiac shunt, impaired left ventricular function (ejection fraction < 40%), ascites, pregnancy, and any contraindication to fluid resuscitation, such as congestive heart failure, evidence of fluid overload, and renal dysfunction.All patients were fully assessed with general physical examination, and their baseline characteristics, including age, gender, height, weight, body mass index, body surface area, and Acute Physiology and Chronic Health Evaluation score (APACHE) II score , MAP, CVP with a zero referenced to the middle axillary line, PVI, dIVC, and cardiac index (CI). At first, every patient was positioned semi-recumbent with an angle of 45° between the trunk and the bed plane to record the initial measurements. Then, in the passive leg raising (PLR) position, other measurements were recorded after 1 min from leg elevation to 45° with the horizontal plane of the trunk. Positioning was done by an automatic bed mechanism controlled by a remote controller.CO was measured by the same operator using transthoracic echocardiography (TTE) , as the product of stroke volume (SV) and heart rate (HR). SV is equal to the product of the aortic cross-sectional area, and the distance of a column of blood travels through it with each stroke, which is known as the velocity time integral (VTI)  of the annulus using the parasternal long-axis view of the left ventricle. From this view, D is the maximal distance between the hinge points of the anterior and posterior aortic cusps in early systole, and the cross-sectional area is equal to the product of square D by 3.14 divided by 4  view, then tilting the ultrasound beams anteriorly to get the apical five-chamber (A5C) view, where the proximal ascending aorta, aortic valve, and left ventricular outflow tract (LVOT) come in the view  placed on the finger and wrapped with a black protector for minimizing light interference and then connected to a Masimo Radical-7 monitor .The dIVC is the percentage of variation in the IVC diameter during inspiration vs expiration. Which we measured by another single operator simultaneously, using the convex probe of ultrasound  by the subcostal view approach using M-mode during the same respiratory cycle, then we calculated dIVC percentage by the following formula:Data were collected, revised, coded, and entered to the MedCalc software , and the Statistical Package for Social Sciences, version 25.0 . The quantitative data were presented as mean, standard deviations, and ranges. Also, qualitative variables were presented as number and percentages.t test was used to compare between hemodynamic data before and after PLR. Independent sample t test was used to compare between responders and non-responders for normally distributed parametric variables, while for the non-parametric data, we used the Mann-Whitney test.The paired Student The receiver operating characteristic (ROC) curves and area under the curve  of PVI, dIVC, and CVP were calculated and compared for the assessment of the ability of these methods to predict fluid responsiveness.P value < 0.05 was considered significant, a P value < 0.001 was considered as highly significant, and a P value > 0.05 was considered insignificant.The confidence interval was set to 95%, and the margin of error accepted was set to 5%. So, a The PASS program is used, setting alpha error at 5% and power at 80%. The result from the previous study by Pişkin and Öz , the study was conducted on 88 patients; we divided them into two groups (48 responders and 40 non-responders). There were no significant differences in patient demographics between the groups as shown in Table P < 0.5), while only HR showed a significant difference after PLR in the non-responders group. The baseline MAP, CVP, and CI of the responders were significantly lower than the non-responders (P < .05); the baseline PVI and dIVC were significantly higher than responders (P < 0.5), while HR readings showed no significant difference (P > .05) between the baselines of the two groups.Hemodynamic data presented in Table P = 0.0648). dIVC had 79.17% sensitivity and 80% specificity at a threshold value of > 19.42% with AUC = 0.886 (0.801–0.944) and was highly significant (P < 0.0001).The difference between CVP, PVI, and dIVC regarding performance is presented in Table P < 0.0001). Figure PVI had a 93.75 sensitivity and an 87.50 specificity at a threshold value of > 14% with AUC = 0.955 (0.889–0.988) and was highly significant .The best way to test the sensitivity of the heart to preload changes is to detect the change in CO after a fluid bolus  for the ROC curve of 0.955 (0.889–0.988).In a recent meta-analysis done by Liu et al. which was including 25 studies, they concluded that PVI has a good bedside reliability in ICU especially with 79% sensitivity, 88% specificity, and AUC of 0.89 (0.86–0.92) also its limited ability in the prediction of fluid responsiveness in general  with 38% sensitivity and 61% specificity (Charbonneau et al., Many factors can affect dIVC measurements and cause this difference between studies as respiratory compliance (Lakhal et al., The results of our study showed that assessment of PVI and dIVC non-invasively were good predictors for fluid management and responsiveness prediction using PLR technique in the surgical ICU mechanically ventilated patients.Our observational study has many limitations. The first one was in the accuracy of measuring CO by VTI using TTE. It necessitates good echogenicity of the patients, so we excluded 18 patients not fulfilling these criteria before data analysis.The second limitation was in the comparison between PVI and dIVC; it is difficult to equalize blood volume added to circulation to all patients after PLR. However, the reversible PLR technique was proven trustworthy for preload responder identification (Monnet et al., The third limitation was intra-abdominal pressure, as we did not measure it in our patients. However, we excluded all patients with any expected cause of increased intra-abdominal pressure like ascites, pregnancy, abdominal malignancy, distension, and acute abdomen.PVI and dIVC can be used in the assessment of fluid responsiveness of the intubated ventilated sedated patients with sinus rhythm in ICU, and both methods are non-invasive and can be performed at the bedside, but PVI has the advantage of being continuous, operator-independent, and more reliable than dIVC.