Duchenne muscular dystrophy (DMD) cardiomyopathy (DCM) is characterized by a hypokinetic, dilated phenotype progressively increasing with age. Regular cardiac care is crucial in DMD care. Early recognition and prophylactic use of angiotensin converting enzyme inhibitors (ACEi) are the main stay therapeutic strategy to delay incidence of DMD-DCM. Pharmacological treatment to improve symptoms and left ventricle (LV) systolic function, have been widely implemented in the past years. Because of lack of DMD specific drugs, actual indications for established DCM include current treatment for heart failure (HF). This review focuses on current HF strategies to identify, characterize, and treat DMD-DCM.  Dilated cardiomyopathy (DCM), arrhythmias, and congestive heart failure (HF) represent the most important life-limiting condition in Duchenne muscular dystrophy (DMD) ,2,3. Routinely cardiovascular evaluation including echocardiography is recommended in the current 2018 DMD Care consideration sponsored by Centers of disease control and prevention . MoreoveIn this review, we present the cardiologist perspective on current data regarding clinical management of DMD patients.DMD is an X-linked recessive disorder occurring in one in 3500 male births. It is caused by mutations in the dystrophin gene that result in marked reduction or absence of the sarcolemmal protein dystrophin. DMD belongs to the group of dystrophinopathies, characterized by different pathogenic conditions and variable degrees of skeletal and cardiac muscle impairment. Typically, DMD is the most severe form while Becker muscular dystrophy (BMD) is the more benign form along with the X-linked DCM (XL-DCM) ,7 and th2+ overload or oxidative stress. The activation of these damaging cellular pathways and Ca2+ signaling pathways lead to dystrophic DCM [Several patho-mechanisms are involved in the cellular damage initially caused by the lack of dystrophin, in both skeletal and cardiac muscles. Normally dystrophin provides structural support for the myocyte and sarcolemmal membrane by its linking of actin at the C amino-terminus with the dystrophin-associated protein complex and sarcolemma at the carboxyl-terminus and the extracellular matrix of muscle ,10. Dystphic DCM . As muscphic DCM .DMD-DCM is characterized by thinner left ventricle (LV) wall and progressive LV dilatation, reflecting the ongoing myocyte loss ,5. In paTypically, this devasting disease is characterized by progressive skeletal muscle waste, with loss of ambulatory capacity and decline of respiratory and cardiac functions. The onset of muscle weakness is at 7–12 years old and the patient become wheel chair bound at 13 years . The staCurrent 2018 DMD Care Considerations assessed that regular cardiac assessment is essential for DMD care . From thSeveral biomarkers are currently used in the diagnosis and monitoring of cardiac disease. Electrocardiogram and cardiac imaging are routinely used to detect the onset of DCM and its progression . These nIn addition, serum biomarkers provided to be very useful to characterize HF and are currently used to assess the functional status in adult and pediatric patients. In particular, serum levels of cardiac troponin I and T are known to be associated to the extension of myocardial damage, but there are conflicting results about their diagnostic and prognostic implications in the DMD DCM ,19,20. RElevation of left atrial pressure as result of left ventricular dysfunction and pulmonary hypertension caused by impairment of the respiratory muscles are considered to be involved in the mechanism of increased values of plasma natriuretic peptide in patients with DMD. A moderate or marked elevation in plasma alpha-ANP levels in patients with terminal DMD were found as a sign of a poor prognosis and may be a useful index for the management of the disease . Villa eEchocardiography plays the main role in identifying LV myocardial dysfunction and serial evaluation is necessary. Regional abnormalities of LV function may be revealed by early other imaging modalities such as speckle tracking echocardiography or cardiac magnetic resonance, before the overt LV dysfunction, assessed by echocardiography .By baseline echocardiography, a dilated LV has been defined in terms of standard deviations, assessed with Z-scores according to the wide variability in the age and body mass index in DMD patients. In particular, LV dysfunction is defined by a LVEF < 55% and a fractional shortening (FS) < 28% ,26. CorrRight ventricular (RV) function is often preserved in DMD patients, also in presence of LV dysfunction, probably because of the reduced afterload related to respiratory improvements . HoweverCardiac magnetic resonance is assuming an increasingly important role in DMD DCM, for the ability to identify myocardial fibrosis. Both 2D and 3D LV echocardiographic ejection fractions have a low correlation with CMR LVEF , and segCardiac magnetic resonance in DMD DCM is important not only to detect early myocardial changes in case of subtle LV dysfunction, but also to evaluate progression of fibrosis in DMD patients on medical treatment ,35. HoweUsually HF restricts the definition to the manifestation of clinical symptoms. Before clinical symptoms manifest, DCM progresses. Most of the DMD patients are asymptomatic for most of their life, so identifying precursors of the HF is crucial to manage this group. Demonstration of the ventricular dysfunction based on the assessment of ejection fraction help to guide therapy. DMD DCM really comprises a wide range of patients, from those with normal LVEF  to those with reduced LVEF. Patients with an LVEF in the range of 40–49% represent a “grey area,” considered as a mid-range of DCM. In the following section, we evaluate all cardiovascular drug therapies according to LVEF [This group includes all cases in which LVEF is normal or ≥50%. At this stage of the disease, the aim is to delay the onset of ventricular dysfunction. Because of lack of specific therapy for DMD DCM, 2018 DMD Care Considerations  recommenIn 2005, Duboc  for the Few studies have been addressed for DMD patients with mid-range systolic LV dysfunction.Current indication endorses the use of traditional HF treatment to treat the progression of the disease. In detail, for mid-range ventricular dysfunction, some studies have shown some beneficial effect to preserve ventricular function. Among ACE inhibitors, lisinopril and losartan have been used for comparative analysis in established DCM. Allen 2013  comparedCardioprotective effect of adding eplerenone to an ACE inhibitor or ARB was evaluated by MRI after 12 months in 42 DMD patients. This multicenter, randomized, placebo-controlled trial, Raman et al.  showed tRaman et al. showed that also spironolactone added to background therapy is noninferior to eplerenone in preserving contractile function. These findings support early mineralocorticoid receptor antagonist therapy as effective and safe in a genetic disease with high cardiomyopathy risk .Therefore, at the early stage of the disease, before any clinical overt DCM, the prophylactic use of perindopril for cardioprotection is entered widely in the clinical practice and endorsed by current indication although biological effects are still unclear. When the DCM is detectable even in case of mild reduction of ejection fraction (>45% LVEF), fosinopril or losartan with the combination of mineralocorticoid receptor antagonists  might improve ventricular function. p < 0.02), as well as the mean rate of pressure rise (dP/dt) during isovolumetric contraction  and the myocardial performance index  [In addition, beta blockers (BB) have been tested. Carvedilol was administered in 22 patients and was progressively uptitrated over 8 weeks. This therapy modestly improved cardiac MRI-derived measured ejection fraction  . While in recent years, many studies have focused on the early identification of myocardial damage and the early start of cardiac therapy capable of slowing cardiac remodeling has been emphasized in DMD, the therapeutic strategy for patients with established DCM has been studied less deeply ,16,54. CAlthough in adult HF, the use of betablockers is mandatory when ventricular function declines, the same evidence in children is lacking. In recent years, some retrospective and non-randomized prospective studies have demonstrated the beneficial effect of BB therapy in patients with DMD/DCM ,56,57,58Furthermore, in DMD DCM, this therapy is often indicated for the presence of autonomic dysfunction and the consequent predisposition to arrhythmias .In the current literature the drugs most frequently used are Carvedilol (0.01–0.02 mg/kg administered twice daily and slowly increased to a dose of 0.5–1 mg/kg) ,56,57,59In many studies the combination therapy with ACEi and BBs has been proved to be superior to ACEi alone in the improvement of LV function, ,56 in thIt was noted that in patients treated with BBs the improvement of LVEF was correlated with the reduction of mean heart rate (HR) .Our group has recently demonstrated the utility of the HR reduction (HRR) strategy obtained with BBs and Ivabradine (2.5 mg twice daily increasing until 15 mg daily every two weeks when HR was still above 70 bpm and LVEF < 40%) in the reduction of the long-term incidence of acute adverse events in DMD patients with advanced cardiac involvement . PreviouAccording to European and American Guidelines for the management of HF in adults, MRAs, spironolactone, and eplerenone, are recommended in all symptomatic patients (despite treatment with an ACEI and BB) with HF and LVEF ≤ 35%, to reduce mortality and HF hospitalization ,64.In the near future a new MRA called vamorolone, able to mirror the anti-inflammatory effect of glucocorticoids, probably could be a valid alternative to both “old MRAs” and “simple glucocorticoids” in the DMD therapy scenario . To dateSacubitril/valsartan, the first-in-class angiotensin receptor neprilysin inhibitor (ARNI) that in the past decade has changed the treatment of adult HF, has recently been approved by the Food and Drugs Administration (FDA) for the treatment of pediatric patients (aged 1 to 18 years) with symptomatic HF and systemic LV systolic dysfunction. This approval was based on the major reduction in the value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) that was observed in sacubitril/valsartan arm compared to enalapril one after 12 weeks of therapy from the ongoing 52-week PANORAMA-HF trial . Of noteFurosemide is the most common loop diuretic used to reduce systemic and pulmonary congestion and the correlated symptoms in the advanced stage of disease. For chronic use, 1 to 6 mg/kg of frusemide in partitioned doses are used. The addition of metolazone (0.1 mg/kg dose bis-in-die up to max 20 mg/day) may be useful in patients who are unresponsive to loop diuretic agents alone .It is important to remark that loop diuretics are symptomatic medications and there is no evidence of their effectiveness in improving long-term prognosis .Digoxin has been a pivotal drug in the treatment of HF in children and also reported as standard therapy for treatment of DCM DMD . Today iIn patients with severe LV dysfunction an antithrombotic therapy should be considered in the primary prevention of thromboembolic events, although not routinely recommended .A possible treatment for end-stage HF in these patients is the use of left ventricle assist device (LVAD) as a destination therapy (DT) ,72. ReceLVAD has been currently used in adult and pediatric population with end-stage HF as bridge to heart transplantation or as DT in selected adult patients with medically refractory HF who are not transplant candidates ,75,76,77LVADs have been recently considered as a therapeutic option as destination therapy in DMD with advanced HF ,87,88. TSelection of patients is crucial and several aspects should be considered . Analysis of costs  showed tActually, end-of-life management preferences in neuromuscular diseases, including DMD, are a challenging area. Ethical concerns remain open about which patient should be a candidate or excluded. Additionally, The Working Group acknowledged the value of a long-term patient/family/physician relationship before the urgent need for device placement . A multiArrhythmias occur frequently in cardiomyopathies. They may be also isolated manifestations, mostly in myotonic dystrophies and muscle channelopathies . PotentiArrhythmias are observed in a mouse model of DMD after acute β-adrenergic stimulation. In men, a case reported arrhythmic storm after abrupt withdrawal of beta-blocker therapy . Arrhyth2+) homeostasis and elevated reactive oxygen species. In an animal model of DMD, a susceptibility to pacing induced ventricular arrhythmias was demonstrated. Oxidated Ca2+/calmodulin-dependent protein kinase II, Ox-CaMKII, promotes aberrant sarcoplasmatic reticulum Ca2+ release through RyR2, which leads to delayed afterdepolarizations and triggered ventricular arrhythmias. Genetic inhibition of ox-CaMKII normalized intracellular Ca2+ and prevented ventricular arrhythmias in this model [DMD patients are prone to ventricular arrhythmias, which may be caused by abnormal calcium  but, in the absence of dedicated studies, the DMD Care Considerations Working Group suggests to apply the standard antiarrhythmic medications and device management recommendations. At present, also the indication for the ICD is based on the established adult HF guidelines  but shouCardiac resyncronization therapy (CRT) implantation improved symptoms and heart function in two DMD patients with HF and left bundle branch block. Mortality remains higher in similar DMD patients without CRT . Other aGlucocorticoid treatment has been the standard of care for patients with DMD. Prednisone and deflazacort are the most commonly recommended steroids. The introduction of steroid therapy has changed the natural history of the disease, prolonging the autonomous ambulation period, delaying the cardiorespiratory insufficiency occurrence, and increasing children life-expectancy ,108.The understanding of molecular basis and knowledge of DMD has led to the advent of several experimental therapeutic approaches. The therapeutic approaches for DMD have focused on restoring dystrophin expression or mitigating the processes downstream of dystrophin deficiency.The strategies that have been embraced for dystrophin protein restoration include (1) nonsense readthrough, (2) antisense oligonucleotides for exon skipping, and (3) gene therapy. To mitigate the dystrophic processes the approaches used are (1) inhibiting inflammation, (2) promoting muscle regeneration, (3) reducing fibrosis, and (4) facilitating mitochondrial function. This translational research has led to the approval of first treatments for DMD and several other agent are under clinical investigation. Ataluren  is the first approved drug for DMD in Europe. Ataluren is an oral molecule that binds ribosomal RNA subunits and enables ribosomal readthrough of mRNA containing a premature stop codon. It is indicated for the treatment of DMD resulting from a nonsense mutation in the dystrophin gene. More recently FDA conditionally approved AONs targeting exon 51 (eteplirsen) and 53 (golodirsen) for the treatment of DMD . DMD is an X-linked condition and it usually affects males, with the majority of females having mutation in a single allele being asymptomatic carriers. About one-third of all DMD cases are caused by de novo mutations, with the other two-thirds due to inheritance from the mother. This means that every mother of an isolated male DMD case has a two-thirds chance of being a carrier. Most females with a pathogenic DMD gene variant present as asymptomatic carriers because of the presence of a second normally functioning allele. However, some female carriers can present symptoms from mild to more severe clinical courses, as muscle weakness, abnormal gait, fatigue, and cardiac involvement . These pBesides cardiac manifestations, female DMD carriers can present with other systemic features: limb girdle weakness, gait disturbance, exercise intolerance, calf hypertrophy, and scoliosis have all been recognized as skeletal muscle manifestations in these patients. Elevated serum creatinine kinase (CK) is often found in patients with skeletal muscle presentations. Additionally, neurocognitive problems can present as learning disabilities or behavioral problems in this patient population ,113.


The pulmonary artery (PA) to ascending aorta diameter ratio (PA:A) has been evaluated in numerous studies analyzing cardiac magnetic resonance (CMR) and computed tomography (CT) data. Previously, no transthoracic echocardiography (TTE) cutoffs have been published. We sought to evaluate (1) the feasibility to image the pulmonary trunk in a prospective cohort, and (2) the ability of PA:A derived by TTE to predict pulmonary hypertension (PH).We performed a post-hoc analysis of a prospectively recruited consecutive cohort of patients referred to our tertiary center cardiology department due to suspicion for PH. Invasive hemodynamic assessment and quasi-simultaneous TTE was performed in all participants.A total of 84 patients were included in the analysis, median age was 70.5 years (IQR 58–75), 46 (55%) were female. The PA was significantly wider in the PH group  with a resulting median PA:A of 0.84 vs. 0.66 (p<0.001). Both PA diameter  and PA:A  significantly correlated with mPAP and with PVR, respectively. Area under the curve for the detection of PH was 0.853 .The PA can be visualized in almost all echocardiographic exams, especially when it is dilated. A view showing the pulmonary trunk should be included in every routine TTE. An increased PA:A should raise suspicion for PH and prompt further evaluation and follow-up examinations of these patients. Pulmonary hypertension (PH) is a disease with significant morbidity and mortality. The first imaging modality in the diagnostic work-up is transthoracic echocardiography (TTE). Despite significant technological advances in recent years and straight diagnostic algorithms, there are still patients with PH who are missed by TTE .The pulmonary artery to ascending aorta diameter ratio (PA:A) has been evaluated thoroughly in numerous studies analyzing cardiac magnetic resonance (CMR) and computed tomography (CT) data. The ratio was able to detect patients with PH –6, it coMeasurement of the diameter of the pulmonary trunk and/or the segmental pulmonary arteries is not included in the regular transthoracic echocardiography protocol in daily clinical practice. No prospective studies have so far evaluated how frequent exact visualization of the pulmonary trunk is possible in TTE.We sought to evaluate (1) the feasibility to image the pulmonary trunk in a prospective cohort, and (2) the ability of PA:A derived by TTE to predict PH.We performed a post-hoc analysis of a prospectively recruited consecutive cohort of patients referred to our tertiary center cardiology department due to suspicion for pulmonary hypertension.We included all adult patients with clinically indicated right heart catheterization (RHC) between July 2015 and July 2016. The study was conducted in accordance with the amended Declaration of Helsinki. The ethic committee of the Medical University of Vienna approved the conduct of the study (EK# 2012/2014). All patients gave written informed consent before enrollment. Exclusion criteria were patients <18 years of age.Standard transthoracic echocardiograms  were performed in all enrolled patients shortly before invasive hemodynamic assessment with echocardiography systems equipped with 3.5 MHz transducers  according to the recommendations and guidelines by the American Society of Echocardiography and the European Association of Cardiovascular Imaging –24.Maximal TR velocity was assessed from different angulations . PA diamInvasive hemodynamic assessment was performed in all study participants. Hemodynamic measurements were performed using a 7F Swan-Ganz catheter  via a femoral access. Pressures were documented as average of eight measurements over eight consecutive heart cycles using CathCorLX . In addition to mean pulmonary arterial wedge pressure (mPAWP), the systolic, diastolic, and mean (mPAP) pulmonary artery (PA) pressures were measured. In a subgroup of patients left ventricular end-diastolic pressure (LVEDP) was measured via left heart catheterization where clinically indicated . Left heart catheterization was performed directly after right heart catheterization.th World Symposium on Pulmonary HypertensionTask Force [Presence of PH was defined as a mPAP ≥25 mmHg as suggested by the current guidelines . Additiosk Force .Elevation of left ventricular filling pressures were defined as mPAWP > 12 mmHg if available, in the remaining patients if LVEDP > 16 mmHg.Pearson correlation coefficients were calculated to compare invasive with echo measurements. Area under the curve (AUC) and receiver operating characteristic curves (ROC) were performed to evaluate sensitivity and specificity. Differences between two groups were analyzed by T-test analysis. A p value ≤0.05 was considered statistically significant. SPSS Version 24  was used for all analyses.A total of 84 patients were included in the final analysis, median age was 70.5 years (IQR 58–75), 46 (55%) were female. Median NT-proBNP was 1,200pg/ml, creatinine 0.98mg/dl, and BUN 18mg/dl. Comorbidities were coronary artery disease in 24 (29%), arterial hypertension in 72 (86%), a history of smoking in 26 (31%), and diabetes mellitus in 16 (19%). Regarding comorbidities, there was no difference between the groups PH and non-PH .All had received quasi-simultaneous right heart catheterization (including LVEDP measurement in n = 62 (74%)) and comprehensive transthoracic echocardiography within a mean of 1 day (±2.8).Seventy (83%) had pulmonary hypertension, of these 22 (31%) had CTEPH, 30 (43%) had PH due to left heart disease, and 11 (16%) had pulmonary arterial hypertension .Median mPAP was 38.5mmHg and 20mmHg in the PH group and in the non-PH group. Median PVR was 5 WU and 1.7 WU, cardiac index 2.8 L/min and 2.5 L/min, mPAWP 10mmHg and 13 mmHg, and LVEDP 10.5mmHg and 13.5mmHg, respectively .There was no difference in TTE parameters of right ventricular function between the PH and the non-PH group. While there was also no difference in diameter of the ascending aorta, the PA was significantly wider in the PH group  with a resulting difference in median PA:A of 0.84 vs. 0.66 (p<0.001).Both PA diameter  and PA:A  significantly correlated with mPAP. Also, there was significant correlation with PVR for PA diameter  and for PA:A  .Area under the curve for the detection of PH (mPAP ≥25mmHg) was 0.853 . Youden index revealed a PA:A of 0.76 as a cutoff with a sensitivity of 68.6% and a specificity of 92.9% .Area under the curve for the detection of PH (mPAP ≥20mmHg and PVR ≥3WU) was 0.813 . For the cutoff 0.76, sensitivity was 70.8% and specificity was 75%.Two conclusions can be drawn from our data: (1) the pulmonary trunk can be visualized in most patients, especially when dilated due to the presence of pulmonary hypertension, and (2) an elevated PA:A is strongly predictive for the presence of pulmonary hypertension.With the 2015 guidelines, a straight forward diagnostic algorithm for how to stratify the probability for PH via TTE was proposed . As of nRecently, a new hemodynamic definition for presence of PH was suggested with mPAP ≥20mmHg in combination with a PVR ≥3WU . PulmonaThere have been numerous studies analyzing the diagnostic value of PA:A derived from CMR and CT calculations. They suggested a ratio of 0.83 to 1.1 for differentiation between those with and without PH and with and without dismal outcome , 20, 27.Interestingly, echocardiography seems to significantly underestimate PA diameter. In a cohort of never-smokers without known heart or lung disease, PA diameter measured by CT was 29mm in men and 27mm in women with a PA:A of 0.9 in both . AnotherMedian age of PH patients in this study was 72 years. In a previous study including PH patients with a mean age of 53 years, mean PA diameter measured by TTE was in the same range as in this study . Thus, tParameters including more than one variable have the limitation that a measurement mistake must be assumed in each of the assessed variables. This is the strength of solely considering a PA diameter of >25mm as cutoff to detect PH. We therefore suggest to consider the PA:A an additional indirect sign of PH and not a replacement of the assessment of PA diameter.Considering the increasing distribution of hand-held ultrasound machines where the examiner is limited to 2D imaging and color Doppler imaging without the possibility of CW Doppler measurements, additional 2D echocardiographic signs for hemodynamic assessment such as PA:A can be of great value and should be applied.The study population was small with only 84 patients. However, considering the complete hemodynamic and echocardiographic assessment, the number nevertheless allows for important insights regarding diagnostic accuracy.Size of the aorta increases with age. This will lead to a change of PA:A over time independent of changes in pulmonary pressures. As this study only considered one echocardiographic examination in each patient, and patients of different age were included, this could not be corrected for.Our data reflects the experience of a single tertiary care center. However, the potential advantages of a single-center approach are the enrolment of a homogenous patient population, the adherence to a consistent clinical routine, and a consistent quality of imaging procedures and right heart catheterization.The PA can be visualized in almost all echocardiographic exams, especially when it is dilated. A view showing the pulmonary trunk should be included in every routine TTE. An increased PA:A should raise suspicion for PH and prompt further evaluation and follow-up examinations of these patients.S1 Data(SAV)Click here for additional data file.


Background and Objectives: The goal was to evaluate the association of dynamic retinal vessel analysis (DVA) with echocardiographic parameters assessing systolic and diastolic function of the left ventricle in hypertension (HT) patients with preserved left ventricle ejection fraction. Materials and Methods: This observational retrospective study recruited 36 patients with HT and 28 healthy controls. Retinal vessel diameter and reactions to flicker light were examined. Each patient was examined with echocardiography to assess left ventricular systolic and diastolic function. Results: Multivariate analysis revealed that hypertension was an independent factor associated with lower flicker-induced arterial vasodilatation . In the HT group, there was a significant positive association between left ventricular ejection fraction and flicker-induced arterial vasodilation . Additionally, end-diastolic left ventricular diameter negatively correlated with both arterial  and venous  flicker responses. Additionally, the echocardiographic characteristics of the left atrium (LA) remodeling in the course of HT, including the area of the LA and its antero-posterior dimension, were both negatively correlated with the arterial flicker response . From tissue Doppler parameters, the left ventricular filling index E/e’ negatively correlated with AVR (arteriovenous ratio) values . Conclusions: We revealed that systolic and diastolic function of the left ventricle in hypertensive patients is associated with retinal microvascular function. Endothelial dysfunction is one of the well-recognized key pathomechanisms responsible for hypertension (HT). Previous studies have demonstrated that cardiovascular disorders (CVDs) are linked with similar neurohumoral factors and microvascular endothelial dysfunction is important for CVD progression. The endothelial dysfunction in the coronary vessels is, to a large extent, related to the severity and prognosis of CVD .The retinal microcirculation is an accessible vascular bed for the assessment of microvascular function ,3. RetinEndothelial dysfunction is an early pathophysiologic feature in the course of hypertension, and it is known that HT induces profound effects on both the structure and function of the microvasculature. Likewise, retinal microvessel changes, in particular generalized arterial narrowing and arteriolar-venous nicking, appeared not only to reflect current blood pressure levels but also blood pressure levels in the past ,8 MoreovHypertension potentially leads to myocardial diastolic dysfunction and long-lasting atrial remodeling from chronic pressure overload. To date, there is very little knowledge about impaired endothelial vasodilatation of retinal vessels under clinical and subclinical CVD-related pathophysiological conditions, particularly the myocardial dysfunction in the course of HT-associated target organ damage. Therefore, the aim of this study was to analyze the relationship between the functional retinal microcirculatory response and selected echocardiographic parameters evaluating the systolic and diastolic left ventricle function in a group of hypertensive patients compared to healthy controls. In this study scenario, we examine whether defective diastolic function of the left ventricle is associated with HT-induced endothelial dysfunction in the vascular system.The study group consisted of patients diagnosed with hypertension  treated at the Department of Cardiology, Pomeranian Medical University in Szczecin. The control group consisted of 28 age-matched apparently healthy volunteers , who were referred to hospital in order to receive routine healthcare with no history of cardiovascular diseases, with normal blood pressure values during longitudinal measurements at home and correct blood pressure measurements at the hospital during the whole study.Patients with coexisting ocular disease affecting the results of fundoscopy, i.e., glaucoma, advanced cataract, retinopathy, ocular inflammation and those treated with ocular surgery within 3 months prior to the study were excluded. We also excluded patients with systemic or chronic vascular diseases , Patients with valvar disease, previous myocardial infarction, or peripheral vascular disease were excluded from the study. Prior to the examination, informed written consent was obtained from all patients. The study protocol was approved by the Bioethics Committee of the Pomeranian Medical University in Szczecin and was compliant with the requirements of the Helsinki Declaration.2) and waist-hip ratio (WHR) (waist circumference/hip circumference (cm)).All patients were assessed for body mass index (BMI) (according to the formula: body weight (kg)/body height (m)Information on the disease, therapy, dyslipidemia and cigarette smoking (current and past) was obtained based on the patient’s interview, results of laboratory tests and analysis of medical records. Cigarette smoking was quantified in pack-years . All patients were also asked about their level of physical activity. Each patient declared the total number of hours he or she spent on physical activity and its frequency during the week.Before starting the blood pressure measurement, the patient rested for minimum 15 min. During the examination, blood pressure (BP) was measured by measuring blood pressure three times in five-minute intervals. The mean of three measurements was included in the study. From the obtained BP data, the systemic mean arterial pressure (MAP) was calculated as follows: MAP = diastolic BP + 1/3 (systolic BP−diastolic BP) mmHg.The concentration of creatinine in blood serum (glomerular filtration rate (GFR) was calculated based on the Cockcroft-Gault formula, with a normal level accepted as GFR > 60 mL/min) and fasting blood glucose  were measured in each examined subject.Ophthalmological examination of both eyes, including the measurement of intraocular pressure (IOP) and fundoscopy, was done in each patient. All measurements of the retinal vessels were taken after full pupil dilation induced by the application of 1% tropicamide. Retinal vessels were evaluated in the next stage of the study. The mean value measured for both eyes was used for further analysis.Static vessel analysis (SVA) was done with a FF450 fundus camera . The obtained retinal images were analyzed using VISUALIS (version 2.61) and VesselMap (version 3.10) software . Standard parameters included central retinal artery equivalent (CRAE), referring to the diameter of the central retinal artery, and central retinal vein equivalent (CRVE), referring to the diameter of the central retinal vein, as well as arteriovenous ratio (AVR), which is the quotient of CRAE/CRVE .In the subsequent stage, a dynamic retinal vessel analysis (DVA) was performed as previously described in detail by Machalinska et al. . The artEach patient had echocardiography performed by the same operator using a Vivid 7 Pro (GE Vingmed) apparatus connected to a 2.5–3.5 MHz phase probe. All measurements were averaged for 3 cardiac cycles. Left ventricular mass (LVM), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), posterior wall thickness (PWT), interventricular septal thickness (IVST) during diastole, the aortic bulb diameter and the size of the left atrium were measured in M-mode from the parasternal long-axis view according to the standards of the American Society of Echocardiography. Ejection fraction (EF) of the left ventricle was calculated based on left ventricular end-diastolic volume, and left ventricular end-systolic volume was measured from the apical two- and four-chamber view according to Simpson’s rule. LV mass as found on echocardiography was indexed (LVMI) using body surface area for each subject. Left atrial volume was calculated using the prolate ellipse method and indexed to body surface area . The left ventricular diastolic function was evaluated using the mitral flow velocity. We measured the peak early-diastolic velocity (E), the peak end-diastolic velocity (A), the E/A ratio (early-diastolic to end-diastolic velocity), isovolumic relaxation time (IVRT), Tei index  and mitral early flow propagation velocity. We used tissue Doppler echocardiography (TDE) to identify the s’ wave corresponding with the systolic myocardial tissue velocity of the left ventricle (LV), the e’ wave corresponding with the diastolic myocardial tissue velocity during the rapid filling phase of LV, the a’ wave corresponding to the diastolic myocardial tissue velocity during atrial contraction and the e’/a’ ratio at two points . We also calculated the ratio of the mitral flow velocity to mitral annular velocity at the early diastolic phase (E/e’).p < 0.05. The analysis was carried out separately for patients with and without diagnosed hypertension. The statistical power of the study was sufficient to detect with 80% probability associations between variables with an effect size corresponding to a correlation coefficient of ± 0.45 in the study group (36 patients) and ± 0.50 in the control group (28 subjects).Quantitative parameters measured in both eyes were averaged before further analysis. Since the distribution of the quantitative variables was, in most cases, significantly different from normal distribution, the nonparametric Mann-Whitney test was used to compare their values between groups and Spearman’s rank correlation coefficient was used to measure the strength of associations between them. Fisher’s exact test was used to compare qualitative variables between groups. Multivariate analysis of independent factors associated with retinal vessel parameters was performed with the general linear model (GLM). The statistical significance level was adopted at The clinical characteristics of the patients are presented in p = 0.005). Multivariate analysis of patients and controls adjusted for age, sex, LVMI, BMI and dyslipidemia revealed that hypertension was an independent factor associated with lower flicker-induced arterial vasodilatation , while no significant association was found for any of the covariates. No significant differences in venous response to flicker stimulation were identified between groups (p = 0.086). Similarly, the arterial-to-venous ratio (AVR) obtained by static vessel analysis did not differ between analyzed groups of eyes. The evaluated retinal vessel responses in hypertensive patients compared to healthy subjects are presented in p = 0.039), area (p = 0.014) and volume (p = 0.031) compared to those in controls . In hypertensive patients, end-diastolic left ventricular diameter (LVEDD) negatively correlated with both the arterial  and venous  responses to stimulation with flicker light. No such correlation was found in the control group. Isovolumic relaxation time was negatively correlated with flicker-induced venous vasodilatation  in patients with arterial hypertension, and there was no such correlation in the control group .Subsequent correlation analysis of the echocardiographic parameters with retinal vessel characteristics showed positive association between left ventricular ejection fraction values and flicker-induced arterial vasodilatation  and retinal veins . In the control group, the opposite correlation was observed . Likewise, the arterial response to stimulation with flicker light negatively correlated with the antero-posterior LA dimension  in patients with arterial hypertension. Interestingly, in the control group, the opposite correlation was observed . The volume of the left atrium (indexed to the body surface area) in the group with arterial hypertension was negatively correlated with the venous response to flicker stimulation , and no correlation was found in the control group.Next, we analyzed the echocardiographic markers of the left atrium remodeling in the course of HT, such as its size and geometry, I In hypertensive patients, the area of the left atrium (LA) negatively correlated with the flicker responses of the retinal arteries  in the hypertensive group, and no correlation was observed in the control group.The parameter of tissue Doppler imaging, such as the E/e’ ratio, significantly negatively correlated with AVR values  and tissue Doppler parameters . The terSome conditions predispose patients to myocardial diastolic dysfunction, including systemic hypertension, diabetes mellitus and myocardial ischemia. Endothelial dysfunction has been found to be related to impaired left ventricular diastolic reserve and subsequent diminished exercise capacity  VascularIn the past, several authors revealed the potential of DVA examination to specify the subjects with metabolic abnormalities, such as hypercholesterolemia  or hyperThe retina has been used as a surrogate to study general vascular changes. There is a growing interest in the identification of retinal microvascular changes as a safe, easily accessible, low cost and time-efficient approach to improve our understanding of the vascular complications associated with HT. There is evidence that microcirculation is coupled with macrocirculation not only in terms of structural but also functional parameters. For example, it was found that increased aortic stiffness occurring in hypertension was associated with microvascular remodeling. Central and brachial systolic, diastolic and mean BPs were significantly correlated with lumen diameter and the outer diameter of retinal arterioles  In additWe acknowledge that this study has several limitations, including the fact that the studied population was relatively small. Thus, this study should be treated as a small-population pilot study. Furthermore, this study included only Caucasian subjects and therefore our conclusions may not be generalizable to people of other races.Altogether, DVA might represent an adjunct and clinically relevant microvascular alternative outcome measure that can be used in a clinical approach for HT diagnosis and therapy. The guidelines of the European Society of Cardiology recommend examination of the fundus in people with hypertension of the second and third degree. However, due to the frequency of HT in general society, ophthalmologic examination should be considered in all hypertensive patients . StandarTo our knowledge, there have been no previously published reports on associations between echocardiographically measured parameters of the diastolic cardiac dysfunction and retinal vasodilatory response as a marker of microvascular endothelial dysfunction in hypertensive patients. On the basis of the obtained results, we propose that the DVA method might be useful for the detection of the early phases of myocardial diastolic dysfunction as a potential alternative microvascular outcome measure in patients with diagnosed HT undergoing longitudinal medical observation for this chronic disease. However, further studies in this area are necessary.


We aimed to evaluate the efficacy of stentless strategy by drug-coated balloon (DCB) angioplasty following directional coronary atherectomy (DCA) for left main (LM) bifurcation lesions.  A total of 38 patients who underwent DCB angioplasty following DCA for LM bifurcation lesions were retrospectively enrolled. The primary endpoint was target vessel failure (TVF) at 12 months. Secondary endpoints included procedure-related major events during the hospitalization, major adverse cardiac events at 12 months, ischemia-driven target lesion revascularization (TLR) at 12 months, and bleeding complications defined as the Bleeding Academic Research Consortium criteria ≥2 at 12 months.  Among these 38 lesions, 31 lesions were de novo LM bifurcation lesions and 7 lesions were stent edge restenosis at the left anterior descending (LAD) ostium. The mean % plaque area (%PA) after DCA was 44.0 ± 7.4%. TVF at 12 months occurred in 1 lesion (3.2%) of de novo LM bifurcation lesion and in 3 lesions (42.9%) of stent edge restenosis at the LAD ostium. All events of TVF were ischemia-driven TLR by percutaneous coronary intervention. Among 4 TLR cases, %PA after DCA was high (55.9%) in the de novo LM bifurcation lesions; on the other hand, %PA after DCA was low  in stent edge restenosis at the LAD ostium. No procedure-related major events were observed during hospitalization. There was no cardiac death, no myocardial infarction, no coronary artery bypass grafting, and no bleeding complications at 12 months.  Stentless strategy by DCB angioplasty following DCA for de novo LM bifurcation lesions resulted in acceptable outcomes. On the other hand, its efficacy was limited for stent edge restenosis at the LAD ostium even after aggressive debulking by DCA. Clinical outcomes of percutaneous coronary intervention (PCI) have improved with the development of drug-eluting stents (DESs) and technical advancements. However, PCI for left main (LM) bifurcation lesions remains challenging due to concerns over future revascularization . PreviouThis was a retrospective observational study conducted at Saiseikai Yokohama-city Eastern Hospital. We retrospectively identified 78 patients with stable angina pectoris who underwent PCI using DCA from our database between April 2016 and October 2019. After the exclusion of 20 patients who underwent DCA for lesions other than LM bifurcation lesions, a total of 58 patients who underwent DCA for LM bifurcation lesion were identified. Our indications of DCA for LM bifurcation lesion were as follows: (1) stable angina pectoris with LM bifurcation lesion involving the distal LM trunk, ostium of left anterior descending (LAD), or left circumflex artery (LCX), (2) reference diameter in the main branch >2.5 mm by visual estimation, and (3) intravascular ultrasound (IVUS) findings were suitable for DCA . The exclusion criteria were as follows: (1) unstable angina pectoris and myocardial infarction, (2) poor general condition of the patient and renal insufficiency (Cr >1.5 mg/dl), (3) severe angled lesion, and (4) angiographical severe calcified lesion. This study was approved by the institutional review board of our hospital and complied with the Declaration of Helsinki.All the procedures were performed through the femoral artery using 8Fr sheath and 8Fr guiding catheter. A bolus injection of heparin (5000 U) was given after inserting the sheath and the activated coagulation time was maintained at >300 sec with an additional bolus of heparin. Lesion morphology was assessed by IVUS after crossing the lesion by a conventional guidewire. We carefully evaluated plaque distribution to be debulked and also assessed the existence of lipid rich plaque, thrombus, and superficial calcification. The ATHEROCUT®  was used for all the lesions and size selection was dependent on the reference diameter identified by IVUS. DCA was started with low balloon pressure (0 or 1 atm) and the IVUS evaluation was repeated after several sessions of DCA. Balloon pressure was gradually increased according to the IVUS findings and multiple cuts were repeated to obtain residual % plaque area (%PA) <60% if possible . ExperieQuantitative coronary angiography (QCA) analysis was performed using computer-based software  before the procedure, after the procedure, and at follow-up by an independent physician who was blinded to patient and procedural characteristics. Optimal views of the lesions were obtained at baseline, and the same projection angle was used at follow-up. The minimal lumen diameter (MLD), reference diameter (RD), lesion length, and percent diameter stenosis (%DS) were measured. The acute gain was defined as the increase in MLD after PCI; late lumen loss was defined as the difference between the postprocedural MLD and the MLD at follow-up. Binary restenosis was defined as %DS >50% at follow-up. All IVUS procedures were performed using commercially available IVUS catheters  with automatic pull-back at a rate of 0.5 mm/s. At the narrowest cross-section area, lumen diameter, lumen area, vessel area, and %PA were analyzed. The %PA was defined as (vessel area-lumen area) × 100/vessel area. The incidence of hematoma, intimal dissection, and medial dissection was recorded. The IVUS images were analyzed using computerized planimetry software . All images were independently assessed by physicians who were blinded to patient and clinical data.The primary endpoint was target vessel failure (TVF) at 12 months. TVF was defined as a composite of cardiac death, target vessel myocardial infarction (MI), and ischemia-driven target vessel revascularization (TVR) by PCI or coronary artery bypass grafting (CABG). Secondary endpoints included procedure-related major events during hospitalization, major adverse cardiac events (MACE) at 12 months, ischemia-driven target lesion revascularization (TLR) at 12 months, and bleeding complications which were defined as the Bleeding Academic Research Consortium criteria ≥2 at 12 months . MACE wet-test or Mann–Whitney U test. Two-sided P < 0.05 was considered statistically significant. All analyses were performed using SPSS software .Data were expressed as the mean ± standard deviation for continuous variables and categorical data were shown as numbers with percentages. Continuous variables were examined using the unpaired We performed DCA for LM bifurcation lesions for 58 patients during April 2016 to October 2019. We enrolled 38 patients who underwent stentless strategy by DCB angioplasty following DCA for LM bifurcation lesions after excluding 20 patients . Among 38 lesions, 31 lesions were de novo LM bifurcation lesions and 7 lesions were stent edge restenosis at the LAD ostium.L of the DCA catheter was the most frequently used (87%). The mean number of cuts was 27 ± 17 times and the maximum balloon pressure of the DCA catheter was 3.7 ± 1.3 atm. The DCB angioplasty was performed after DCA for all lesions and the diameter of the DCB was 3.3 ± 0.4 mm and balloon pressure was 8.4 ± 2.8 atm. In the QCA analysis, MLD and % DS improved significantly after the procedure  and %PA decreased significantly after DCA . Intimal dissection was observed in 5 lesions (13%); however, there was no medial dissection or hematoma formation. During the procedure, no complications including vessel perforation, slow flow phenomenon, and stuck of the DCA catheter occurred. There were no procedure-related major events including cardiac death, MI, any emergent revascularization, and access site problems during hospitalization  (Angiographic follow-up was performed for 35 patients (angiographic follow-up rate: 92.1%). At the follow-up coronary angiography, MLD and % DS were similar to that after the procedure  . Table 5L was performed and DCB angioplasty using 3.5 mm diameter by 15 mm was followed  The mean %PA after DCA for LM bifurcation lesions was 44.0% and the incidence of TVF at 12 months was low (3.1%) for de novo LM bifurcation lesions. On the other hand, the incidence of TVF was high (42.9%) for stent edge restenosis at the LAD ostium. All TVF resulted from ischemia-driven TLR. (2) There were no procedure-related major events during hospitalization, no cardiac death, no MI, and no bleeding events at 12 months. (3) The %PA of de novo LM bifurcation with TLR was higher (55.9%) compared to the mean %PA. On the other hand, for stent edge restenosis at the LAD ostium, TLR was required even with low %PA after DCA .The ABACAS study compared the incidence of TLR between balloon angioplasty after aggressive DCA and DCA alone, and there was no difference between the groups . The %PAStent thrombosis at LM bifurcation lesions is critical; therefore, it is important to decrease the risk of stent thrombosis as low as possible. In general, the incidence of stent thrombosis has decreased with the development of DES technology. However, it is difficult to nullify its incidence. Furthermore, optimal DAPT duration to avoid stent thrombosis and major bleeding events after stenting for LM bifurcation lesions remains unclear. We reckon that stentless strategy using DCB angioplasty following DCA is an acceptable option to resolve these issues. In particular, there were no procedure-related major events during hospitalization, no MACE except for ischemia-driven TLR at 12 months, and no bleeding events at 12 months in the current study. In addition, although we stopped DAPT at 3 months after the procedure, optimal DAPT duration after DCB angioplasty may shorten according to the future clinical studies. The DCA procedure requires a skilled operator. However, if stentless strategy for LM bifurcation lesions succeeds, it may be beneficial compared to stent implantation for LM bifurcation lesion.The current study demonstrated acceptable results of DCB angioplasty following DCA for de novo LM bifurcation lesions. However, the results of this strategy for stent edge restenosis at the LAD ostium were poor. Currently, data in relation to the efficacy of DCB angioplasty following DCA for stent edge restenosis is lacking. A previous study reported that there was a tendency towards higher TLR following DCB angioplasty compared to repeat implantations of DESs for stent edge restenosis . We reckThis study has several limitations. First, this was a retrospective analysis of a single center and sample volume, especially the number of patients with stent edge restenosis at the LAD ostium was small. Selection bias should be considered and other large-scale studies are needed to clarify the clinical impact of stentless strategy for LM bifurcation lesions. Second, we performed only IVUS after DCA to evaluate the lumen area and dissection formation. As such, we were unable to categorize the dissection severity. It is well known that optical coherence tomography (OCT) is superior to IVUS to evaluate detailed dissection morphology . TherefoThe early results of stentless strategy by DCB angioplasty following DCA for de novo LM bifurcation lesions are acceptable. On the other hand, this stentless strategy may not be effective for stent edge restenosis at the LAD ostium.


Significance: One key pathological characteristic of seronegative spondyloarthropathy (SpA) is inflammation at the insertion of tendons and ligaments into the bone (enthesitis).Aim: We explore the potential of the emerging photoacoustic (PA) imaging in diagnosis of SpA and review its feasibility in detecting SpA-associated Achilles tendon enthesitis.Approach: A light-emitting diode (LED)-based PA and ultrasound combined system was employed. The PA images, both along the long and the short axes of each Achilles tendon insertion region, were acquired at 850-nm wavelength, which is sensitive in depicting increased blood volume . To assess the hyperemia indicating enthesis inflammation, two parameters were quantified in the imaged tendons, including the average intensity and the density of the color pixels in the pseudo-color PA images. Ten SpA patients, all of which met Assessment of SpA International Society (ASAS) criteria for SpA and were found to have Achilles enthesitis by clinical exam according to a board-certified rheumatologist, were included in the study.Results: The PA and Doppler ultrasound imaging of Achilles enthesitis resulting from these 10 SpA patients were compared to those from 10 healthy volunteers, leading to statistically significant differences (Conclusions: This preliminary clinical study suggests that the LED-based PA imaging holds a promise for sensitive and objective assessment of SpA enthesitis in an outpatient setting of the rheumatology clinic. PsA affects about 30% of patients with psoriasis in the United States.–,,The physiological symptoms such as hyperemia and hypoxia in soft tissue are directly associated with the pathological condition of the joints, tendons, and entheses affected by inflammatory arthritis. By monitoring these features using the emerging photoacoustic (PA) imaging technology, joint inflammation has been detected and evaluated in previous studies.,Early symptoms of SpA are nonspecific and could be followed by a period of undifferentiated inflammatory arthritis that is difficult to distinguish from RA. Several distinct clinical features, such as hyperemia in tendons and entheses, distinguish SpA from other forms of inflammatory arthritis. In this initial clinical study on SpA patients, we, for the first time to the best of our knowledge, explored the feasibility of PA imaging in detecting inflammation in human Achilles entheses in patients who met the criteria for ASAS-defined SpA. In this study, a commercially available light-emitting diode (LED)-based PA imaging system was employed. A good performance of this system in detecting inflammation in arthritic joints has been reported.2,,,,The LED PA imaging system used in this study was built by Cyberdyne , as shown in ,In this study, conventional US Doppler imaging was used as the gold standard for confirming the hyperemia in the affected enthuses.All procedures for human subjects in this study were approved by the Institutional Review Board (IRB) of the University of Michigan Medical School. We performed the study in accordance with the approved protocol. Ten SpA patients, who are either men or women and are over 18 years old, were recruited through the University of Michigan Rheumatology clinics. Board-certified rheumatologists at the University of Michigan Medical School confirmed both the pathological condition of SpA, according to ASAS, and enthesitis. The normal control group includes 10 healthy volunteers who did not have symptoms or signs of enthesitis and no clinical record of any inflammatory arthritis. All participants provided written informed consent.3,t-test was conducted using the built-in functions of MATLAB® . The calculated p values were To evaluate the performance of PA imaging for detecting enthesis inflammation, the results from 10 SpA patients and 10 healthy volunteers were statistically compared. With the PA images acquired from each subject, two parameters that objectively reflect the severity of hyperemia were quantitatively analyzed, following the methods in previous publications.Statistical analysis was also conducted to compare the Doppler US images from the 10 SpA patients and the 10 healthy volunteers. The results in 4,Enthesitis is part of the ASAS criteria for SpA and can help distinguish this distinct pathological entity from RA;In this work, via an initial clinical study on SpA patients and healthy volunteers, the emerging PA imaging technique’s clinical potential for the detection of enthesis inflammation was explored. The PA images reflecting hyperemia were acquired using a PA and US combined system where the PA light source is based on two LED arrays. Due to its unique advantages over conventional laser-based PA imaging systems, such as portability, the LED-based system can be more beneficial as a point of care device for screening in a large population.The results from this initial clinical study demonstrated that the PA images acquired at an 850-nm wavelength shows high sensitivity to enthesis inflammation and can easily detect the spatially distributed hyperemia both along the long axis and the short axis of the affected entheses. Despite the low energy of the light pulse . Although acquiring 2D images by the handheld probe is convenient and fits into the current clinical protocol, 2D images along arbitrary imaging planes make the imaging results highly dependent on the operators and difficult for quantitative assessment. Hence, our plan includes developing a three-dimensional (3D) imaging of tendon insertion inflammation, which could present volumetric information for a more accurate evaluation of hyperemia. Another limitation of the current LED technology is that the PA imaging system used in this study has limited optical wavelength options. As a result, all the images were acquired at a single wavelength of 850 nm. Our plan includes PA imaging at two or more wavelengths, which could enable quantitative mapping of hypoxia  as another essential functional hallmark of tendon inflammation. This could be achieved by utilizing either dual-color LED arrays or other light sources working at multiple wavelengths. Despite these limitations, this initial clinical study has successfully demonstrated that PA imaging, as a safe and effective functional imaging modality, could offer an additional practical point of care tool for clinical diagnosis and treatment evaluation of SpA. This study extended the imaging ability for angiogenic microvessels to human tendon enthesitis. Encouraged by the promising results of the PA hyperemia imaging, we will move on to an advanced imaging system performing PA imaging together with US Doppler in a future study. Such a system that can obtain additional Doppler images simultaneously with PA imaging in tendon enthesitis will enable a more accurate comparison between the modalities.


The presented case by Johnsrude et al.6 highlights the potential pitfalls of automated algorithms in systems with known or potential lead issues.Automatic threshold management algorithms in modern cardiac implantable electronic devices (CIEDs) have helped to extend device battery life..The case describes periods of asystole due to the temporary substitution of right ventricular (RV)-only pacing for biventricular pacing during automatic atrial threshold testing in a patient with a cardiac resynchronization therapy pacemaker  with epicardial RV lead failure. Automatic atrial threshold algorithms are available in CIEDs of all of the major device companies with the exception of those from Microport CRM . Notably, the possible inclusion of RV-only pacing in place of biventricular pacing during automatic atrial threshold testing is not limited to Medtronic devices. Rather, this peculiarity applies to most devices with automatic atrial threshold algorithms apart from devices from Abbott Laboratories  and some selected Biotronik  and Medtronic models. Automatic atrial threshold algorithms are nominally “on” at the time of implant in devices from the latter two companies with the capability. Although devices from Boston Scientific  and Abbott Laboratories are nominally set to “monitor” only at implant, atrial threshold testing is still performed  without adjustment to atrial pacing outputs In the clinical scenario described by the authors, even if was possible to program left ventricular (LV)-only pacing or to maintain biventricular pacing during atrial threshold testing, a functioning RV lead is still required in the vast majority of devices, as LV pacing timing is still dependent on RV sensed events. Hence, lead noise from a failing RV lead could lead to unpredictable LV pacing during atrial threshold testing.As the authors have discovered, these issues are not widely recognized. In preparing this editorial, our informal survey of device company representatives, cardiac physiologists, and implanting physicians at high-volume cardiac device implant centers in New Zealand found variable awareness existed regarding these issues. When connecting a pacemaker generator to epicardial leads, the decision to alter the nominal programming of these algorithms varies across implant centers in New Zealand. Some implant centers are guided by advice from device company representatives or evaluate each implant on a case-by-case basis, while others choose to turn off all automated threshold algorithms in epicardial systems at implant due to concerns regarding early lead failure. However, once an RV lead has been identified to be failing, it is considered a best practice to turn off all automatic threshold algorithms due to concerns regarding the reliability of those algorithms in that setting. With the recent interest in His-bundle pacing and the complexity of such systems, the clinical impact of automatic atrial threshold algorithms must be carefully considered when used in combination with nonstandard device systems.10 At the time of the last surgery in the present case, the patient’s RV lead was a 10-year old unipolar epicardial lead. This case highlights the difficult decisions faced during device revision—does one use suboptimal existing leads and risk future lead failure or attempt the implantation of a new lead with all the attendant morbidity of the extra lead implant procedure? These questions are never easy and, sometimes, the answer is only known in retrospect. We commend the authors of this case in bringing this issue to the attention of the device community.Epicardial leads have a higher rate of lead failure, which can be difficult to predict.md (shawnfoo@icloud.com)1 and Martin K. Stiles, mbchb, phd, fracp, fcsanz, fhrs2Fang Shawn Foo, 1Department of Cardiology, North Shore Hospital, Auckland, New Zealand2Department of Cardiology, Waikato Hospital, Hamilton, New ZealandThe authors report no conflicts of interest for the published content.1.ChenRChenKWangFHuaWZhangSImpact of automatic threshold capture on pulse generator longevity.Chin Med J (Engl).200611911925929[PubMed]167807722.GelvanDCrystalEDokumaciBGoldshmidYOvsyshcherIEEffect of modern pacing algorithms on generator longevity: a predictive analysis.Pacing Clin Electrophysiol.200326917961802[CrossRef][PubMed]129304923.SperzelJMilasinovicGSmithTWAutomatic measurement of atrial pacing thresholds in dual-chamber pacemakers: Clinical experience with atrial capture management.Heart Rhythm.200521112031210[CrossRef][PubMed]162539104.CohenMBuckKTanelRECapture management efficacy in children and young adults with endocardial and unipolar epicardial systems.Europace.200463248255[CrossRef][PubMed]151210795.HiippalaASerwerGAClaussonEDavenportLBrandTHapponenJMAutomatic atrial threshold measurement and adjustment in pediatric patients.Pacing Clin Electrophysiol.2010333309313[CrossRef][PubMed]199545056.JohnsrudeCLLauKCA cautionary tale on atrial capture management, biventricular pacing, and recurrent asystole.J Innov Cardiac Rhythm Manage.201910103848385210.19102/icrm.2019.1010017.CohenMIBushDMVetterVLPermanent epicardial pacing in pediatric patients: seventeen years of experience and 1200 outpatient visits.Circulation.20011032125852590[CrossRef][PubMed]113827288.MurayamaHMaedaMSakuraiHUsuiAUedaYPredictors affecting durability of epicardial pacemaker leads in pediatric patients.J Thorac Cardiovasc Surg.20081352361366[CrossRef][PubMed]182422699.PostMCBudtsWVan de BruaeneAFailure of epicardial pacing leads in congenital heart disease: not uncommon and difficult to predict.Neth Heart J.2011197–8331335[CrossRef][PubMed]2156721710.FortescueEBBerulCICecchinFWalshEPTriedmanJKAlexanderMEPatient, procedural, and hardware factors associated with pacemaker lead failures in pediatrics and congenital heart disease.Heart Rhythm.200412150159[CrossRef][PubMed]158511461 and still refer to the simpler 1987 code.2 Those trained in cardiac electrophysiology are even more familiar with the nuances of “ventricular safety pacing” and other, more obscure algorithms that have enhanced device functionality and safety. However, very few physicians understand the specifics of device algorithms such as the “capture management” algorithm described in the report by Johnsrude et al.3 As suggested in the case report, this lack of knowledge can have potentially devastating consequences.One could argue that the quote “life is really simple, but we insist on making it complicated,” attributed to Confucius in 500 B.C., is applicable to device algorithms in modern CIEDs. The first implanted cardiac pacemakers were incapable of sensing and had no ability for interrogation or programming. At that point, the addition of functionality despite its associated complexity was beneficial for patients. Collaborations between engineers and physicians have led to the introduction of devices with incredible capabilities but required convolution. Physicians trained in cardiology are familiar with the North American Society of Pacing and Electrophysiology Mode Code Committee/British Pacing and Electrophysiology Group pacemaker code, although most have shunned the 2002 revisionIn the last 30 years, there has been a proliferation of these algorithms in the industry. They have developed in a manner akin to an “arms race” by manufacturers trying to create “a better mouse-trap.” Unfortunately, the various algorithms that exist are for the most part proprietary and there is no agreed-upon “international standard” at this time. This adds additional complexity for practitioners attempting to decipher different formulas from different manufacturers or even on different platforms from the same manufacturer that are designed to deal with the same concern. On most devices, these algorithms are nominally programmed to an “on” status. From the inception of our device clinic, our practice has been to turn off all algorithms at the time of implant unless we feel that the patient will benefit from them. We can then turn them on as indicated by the evolution of the patient’s specific situation. As demonstrated in the aforementioned case report, even an algorithm as seemingly innocuous as “capture management” can have significant consequences. The level of complexity is further illustrated by the fact that the patient’s asystole was the result of atrial and not ventricular capture management.As illustrated in the case, many of these monitoring algorithms are programmed to function in the early morning hours, presumably so as not to disturb the patient. In my experience, the effects are often discovered when patients are admitted to the hospital on “full-disclosure” monitoring or when ambulatory electrocardiography is performed. Unfortunately, the use of ambulatory electrocardiography in patients with CIEDs has become quite uncommon, as many clinicians have been lulled into a sense of security by the availability of internal device monitoring capabilities.Deleterious effects of CIED algorithms could be mitigated using a few simple steps. First, unless there is a proven benefit of an algorithm in a large population outweighing the deleterious effects, manufacturers should nominally program all algorithms to “off.” Second, all algorithms should be able to be tested in a clinic setting, similar to the performance of a sensing or capture threshold test, while the patient is being monitored so that the clinician can observe the effects. Third, clinicians should turn off all algorithms that they do not think are offering specific benefits to the patient and strongly consider incorporating ambulatory monitoring after the initial implantation of a device or after activating an algorithm. As further changes in devices will likely be a long-time coming (if ever), this third step will be the most important now.5 Presenting definitive proof that the inclusion of redundant pacing is life-saving is somewhat challenging, but a report published by Ceresnak et al.6 in 2015 suggested a reduction of cardiovascular events in pediatric patients with redundant leads when a lead failed.The life of the man described in this case report may well have been saved by the presence of a redundant ventricular lead. He was at risk for a fatal event during the two-year period between reprogramming of the RV lead output to minimal settings and the discovery of the capture management issue. He may remain at risk, as the replacement of a new redundant lead was not described in the report. After witnessing the sudden death of a pacemaker-dependent patient from lead fracture during my fellowship training, I have always considered including a redundant lead for “back-up” pacing in my patients who are pacemaker-dependent. Prior to the development of biventricular pacemakers, this meant the placement of two pacemakers, but, with the relatively high failure rate of pacing leads in pediatric patients, it didn’t take long to see patients in whom this approach was either life-saving or at least avoided a significant symptomatic event. Sudden death in device-dependent patients may be related to continued asystole or to ventricular fibrillation following a period of asystole.7Even though it will likely require an open-chest procedure, placement of a redundant ventricular lead, in my opinion, would be advisable for the man in the presented case report as well as for most pacemaker-dependent patients in the pediatric age range and those with epicardial leads due to the high lead failure rate in these groups. Further, it should really be considered in all pacemaker-dependent patients of any age and any lead type, and the approach should at least be mentioned in guidelines for bradycardia pacing (which has never before occurred).md (timothy.knilans@cchmc.org)1,2Timothy K. Knilans, 1Department of Pediatrics, Division of Cardiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA2University of Cincinnati College of Medicine, Cincinnati, OH, USAThe author reports no conflicts of interest for the published content.1.BernsteinADDaubertJCFletcherRDThe Revised NASPE/BPEG generic code for antibradycardia, adaptive-rate and multisite pacing.Pacing Clin Electrophysiol.2002252260264[CrossRef][PubMed]119160022.BernsteinADCammAJFletcherRDThe NASPE/BPEG generic pacemaker code for antibradyarrhythmia and adaptive-rate pacing and antitachyarrhythmia devices.Pacing Clin Electrophysiol.1987104 Pt 1794799[CrossRef][PubMed]24413633.JohnsrudeCLLauKCA cautionary tale on atrial capture management, biventricular pacing, and recurrent asystole.J Innov Cardiac Rhythm Manage.201910103848385210.19102/icrm.2019.1010014.UndaviaMFischerAMehtaDFatal outcome in a pacemaker-dependent patient.Pacing Clin Electrophysiol.200932455055310.1111/j.1540-8159.2009.02320.x193358695.YesilMBayataSPostaciNPacemaker inhibition and asystole in a pacemaker dependent patient.Pacing Clin Electrophysiol.199518101963196410.1111/j.1540-8159.1995.tb03846.x85391666.CeresnakSRPereraJLMotonagaKSVentricular lead redundancy to prevent cardiovascular events and sudden death from lead fracture in pacemaker-dependent children.Heart Rhythm.2015121111116[CrossRef][PubMed]252779887.KusomotoFMSchoenfeldMHBarrettC2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay.Heart Rhythm.2018 Nov 6[CrossRef][PubMed]pii: S1547-5271(18)31127-5. 1 highlights the unique complexities of cardiac rhythm management in pediatric and congenital heart disease patients and the importance of understanding these unique events to improve overall device programming and safety for all patients. Here, potentially dangerous asystolic events due to a “perfect storm” of underlying conduction disease (complete heart block), device type , device functionality (failed/”turned off” RV lead), and device programming  resulted in failed ventricular capture. It was serendipitous that the patient was placed on inpatient telemetry for a neurology evaluation, as the malfunction attributed to the algorithm in question only manifested during sleep, which is when the device normally runs said algorithm. The identification of this issue raises a few clear practical considerations that the authors highlight regarding device programming, monitoring, and device setup.The case reported by Johnsrude et al.The identification of device programming problems that may arise requires a thorough understanding of the “bells and whistles” that newer device models have. The outcome of this device programming issue might have been avoided with this knowledge. Alternatively, the outcome could be prevented using a relatively simple software solution. There are certainly many alerts during the course of implantable device programming that communicate potentially dangerous situations to the health care provider who is programming and monitoring the device. One potential solution is for an alert to occur when the Atrial Capture Management™ algorithm is enabled that would remind the clinician that RV lead-only pacing would occur while the capture threshold test is being performed. Alternatively, when the Atrial Capture Management™ algorithm is engaged, there could be a programming hard-stop to prevent the RV lead from being “turned off”/ programmed subthreshold. In hindsight, the use of the Atrial Capture Management™ algorithm in this patient with only 13% atrial pacing was unlikely to provide a substantial benefit in extending battery longevity, and turning on this optional feature resulted in unintended consequences. In addition, placing the more recently implanted and better-performing LV lead in the RV port of the CRT-P device could have averted the problem that was encountered. As is common with congenital heart disease patients, the port and lead functionality should dictate pairing rather than lead location and port label.1 a simple 24-hour Holter monitor would be sufficient. Unfortunately, if the abnormality occurs less frequently, more detailed and longer-term monitoring would be necessary. There are no published data to help support practice guidelines regarding ambulatory cardiac monitoring after device implantation. This is likely a consequence of the many safety features/alerts that cardiac rhythm devices currently have. However, as devices become even more complex, there will always remain the potential for these “perfect storms” that result in rare pacemaker “malfunctions” that may only be identified by ambulatory cardiac monitoring. Therefore, it is critical to make every effort to understand existing device algorithms.The assessment of device performance generally has relied on device interrogation rather than the use of ambulatory electrocardiographic monitoring unless prompted by clinical concerns or device interrogation abnormalities. At the time of implantation of cardiac rhythm devices in the setting of pediatric or congenital heart disease, patients are often observed using telemetry/cardiac rhythm monitoring postimplantation, which can provide short-term information regarding device functionality. However, features such as capture management are generally turned on automatically or in-person after the acute implant phase (after the first one to three months), which, as demonstrated in this patient, does not allow for the identification of the observed consequence with routine device follow-up. At our institution, we do not necessarily perform routine ambulatory cardiac rhythm monitoring in all cardiac rhythm management device patients. Additional monitoring is prompted by signs or symptoms concerning for bradycardia or pacemaker failure, signs or symptoms suggestive of arrhythmias not recorded by the device, a need for further rhythm/arrhythmia discrimination, or concerns about device malfunction/lead failure. The most difficult question remains not if but when and for how long monitoring should be performed. For malfunctions that occur every night, like in the case described by Johnsrude et al.,1 is not surprising. Patients with multiple re-do sternotomies have extensive epicardial scar that makes placing epicardial leads a challenge. Sites for implantation may be limited and capture thresholds may be high. Exit block is not unusual, and delayed conduction through diseased myocardium may make pacing from some sites suboptimal with regard to timing.4 In young children, the size of the heart often results in far-field oversensing of adjacent chambers. Finally, young patients are generally more active and sustain injuries or perform repetitive motions that can result in lead insulation breakage or lead fracture. For all of these reasons, pacing systems may be less durable and result in shorter battery longevity than is desired in these young individuals who are anticipated to have many years of pacemaker dependence ahead of them. Therefore, health care providers must often craft innovative and alternative, “off-label” uses of hardware. Here, the authors used a CRT-P device to provide a redundant ventricular lead in the setting of pacemaker dependence for complete atrioventricular block with an unreliable escape. This concept of a back-up pacing option is also performed using two devices , a dual-chamber device with a second ventricular lead placed in the atrial port, or a CRT-P device as discussed here. However, when using devices in nontraditional ways, we must recognize these limitations, pay vigilant attention, and disseminate recognized shortcomings and possible untoward effects from these practices.Device placement in patients with complex congenital heart disease can be limited and challenging due to the anatomy or multiple surgical procedures during childhood. The case described by Johnsrude et al.6 Beaufort-Krol et al. found that steroid-eluting epicardial leads had the same longevity as conventional endocardial leads. Further, the pacing and sensing thresholds were similar and did not change during follow-up. Therefore, steroid-eluting epicardial pacing leads were deemed to be a good alternative in small children and children with congenital heart disease.Finally, transvenous systems are often regarded as superior to epicardial systems but may not be a realistic option for young patients or patients with complex congenital heart disease. More importantly, these cohorts of patients are not immune to similar problems, as noted by the authors. Although a head-to-head comparison of the longevity and survival of epicardial and endocardial leads in pediatric and congenital heart disease patients has not been performed in some time, the conventional understanding that epicardial leads fail at a higher rate is not necessarily always true.Ultimately, the case report of Johnsrude et al. is a sobering lesson to remind us that some off-label practices in the most complex patients may have unintended deleterious effects. A careful understanding of the tools that we use must be taken into consideration, especially when some of the possible risks have not been previously experienced or reported.md1,2 and Ronn E. Tanel, md (ronn.tanel@ucsf.edu)1,2Akash R. Patel, 1Department of Pediatrics, UCSF School of Medicine, San Francisco, CA, USA2Pediatric and Congenital Arrhythmia Service, UCSF Benioff Children’s Hospital, San Francisco, CA, USAThe authors report no conflicts of interest for the published content.1.JohnsrudeCLLauKCA cautionary tale on atrial capture management, biventricular pacing, and recurrent asystole.J Innov Cardiac Rhythm Manage.201910103848385210.19102/icrm.2019.1010012.CohenMIBushDMVetterVLPermanent epicardial pacing in pediatric patients: seventeen years of experience and 1200 outpatient visits.Circulation.20011032125852590[CrossRef][PubMed]113827283.MurayamaHMaedaMSakuraiHUsuiAUedaYPredictors affecting durability of epicardial pacemaker leads in pediatric patients.J Thorac Cardiovasc Surg.20081352361366[CrossRef][PubMed]182422694.FortescueEBBerulCICecchinFWalshEPTriedmanJKAlexanderMEPatient, procedural, and hardware factors associated with pacemaker lead failures in pediatrics and congenital heart disease.Heart Rhythm.200412150159[CrossRef][PubMed]158511465.Beaufort-KrolGCMulderHNaqelkerkeDWaterbolkTWBink-BoelkensMTComparison of longevity, pacing, and sensing characteristics of steroid-eluting epicardial versus conventional endocardial pacing leads in children.J Thorac Cardiovasc Surg.19991173523528[CrossRef][PubMed]100476566.OdimJSuckowBSaediBLaksHShannonKEquivalent performance of epicardial versus endocardial permanent pacing in children: a single institution and manufacturer experience.Ann Thorac Surg.200885414121416[CrossRef][PubMed]18355537


In patients with end-stage heart failure, advanced therapies such as heart transplantation and long-term mechanical circulatory support (MCS) with a left ventricular assist device (LVAD) have to be considered. LVADs can be implanted as a bridge to transplantation or as an alternative to heart transplantation: destination therapy. In the Netherlands, long-term LVAD therapy is gaining importance as a result of increased prevalence of heart failure together with a low number of heart transplantations due to shortage of donor hearts. As a result, the difference between bridge to transplantation and destination therapy is becoming more artificial since, at present, most patients initially implanted as bridge to transplantation end up receiving extended LVAD therapy. Following LVAD implantation, survival after 1, 2 and 3 years is 83%, 76% and 70%, respectively. Quality of life improves substantially despite important adverse events such as device-related infection, stroke, major bleeding and right heart failure. Early referral of potential candidates for long-term MCS is of utmost importance and positively influences outcome. In this review, an overview of the indications, contraindications, patient selection, clinical outcome and optimal time of referral for long-term MCS is given. Since the introduction of continuous-flow LVADs in the Netherlands in 2006, the number of implantations has increased substantially, outnumbering heart transplantation as treatment for advanced heart failure.The results after LVAD implantation justify the use as an alternative to heart transplantation.Currently, the four implanting centres  have sufficient capacity for the LVAD implantations needed.Early referral to an LVAD-implanting centre is mandatory for optimal timing and outcome of LVAD implantation.Patients suffering from advanced heart failure despite individualised optimal medical treatment, with or without cardiac resynchronisation therapy, should be considered for heart transplantation or long-term mechanical circulatory support (MCS) . CurrentLVADs can be used as bridge to transplantation, or as an alternative to heart transplantation, which is known as destination therapy and in some patients as a bridge to decision in case of temporary contraindications. The present situation in the Netherlands is that most patients with an LVAD as bridge to transplantation will have to wait several years before a donor heart becomes available and many patients will never be transplanted at all. In that way the difference between bridge to transplantation and destination therapy is becoming more and more artificial.Currently, the HeartWare Ventricular Assist Device (HVAD)  and the Heartmate 3  are the most frequently used devices for long-term MCS Fig. . The HM3Advanced heart failure with a low left ventricular ejection fraction <30% despite optimal therapy consisting of maximally tolerable medication with or without resynchronisation therapy and other interventions to optimise the cardiac condition, as indicated by the current heart failure guideline ;2 <12 ml/min/kg (<14 ml/kg/min if intolerant to beta blocker) or <50% of the predicted value for age and sex in ambulatory patients: strong intrinsic motivation and Inter-agency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 2–6  despite an intra-aortic balloon pump, temporary MCS and/or inotropic support are not eligible for long-term MCS. In addition, a life expectancy of less than 2 years, based on extracardiac disease, is a contraindication for long-term MCS. Furthermore, severe comorbidities may be temporary or persistent contraindications  are generally not candidates for long-term MCS directly, but require stabilisation on temporary MCS first, to see if organ function recovers. Primary LVAD implantation in these patients has a proven worse outcome in comparison with patients in INTERMACS profile 2–4 , 11.Besides INTERMACS classification, the evaluation of right ventricular function is very important as there are no reliable options for long-term right ventricular support and right heart failure (RHF) is one of the main complications after LVAD implantation. It is thought to occur in 20–30% of patients, especially early postoperatively after LVAD implantation and is the primary cause of death in 10% , 10, 11.The final decision on LVAD implantation is made by the MCS team  weighing indication, contraindications, right ventricular function, age, previous operations and the ability and willingness of the patient to comply to a complex medical regime against a prospect of potential improvement after LVAD implantation.With respect to contraindications, potential reversibility has to be analysed, especially with regard to renal insufficiency and hepatic failure –15. Age EUROMACS data, including 2113 patients, demonstrated a survival of 69% (CI 66–71%), 55% (CI 52–58%) and 44% (CI 40–47%) at 1, 2 and 3 years after continuous-flow LVAD implantation, respectively . In the Device-related infections might be limited to the exit site of the driveline but may also extend to other parts of the system. Incidence rates are highest in the first 3 months postoperatively, namely 0.25 events per patient-year. Thereafter, incidence is 0.17 events per patient-year . PatientRHF is defined by INTERMACS as increased central venous pressure (>15 mm Hg) with echocardiographic  and clinical signs of venous congestion . This maDevice malfunction, including pump thrombosis and driveline-related problems, were most often seen in the HM-II resulting in the need for LVAD replacement. Technical improvement led to almost elimination of pump thrombosis in HM3, as shown in the MOMENTUM 3 trial . HoweverMajor bleeding is defined as a suspected internal or external bleeding, resulting in death, rethoracotomy, hospitalisation and/or transfusion of red blood cells  .Bleeding is related to the use of anticoagulation and antiplatelet therapy in combination with acquired Von Willebrand syndrome after LVAD implantation as a result of decreased pulsatility –28. Thisp = 0.09, respectively) in both devices during short-term follow-up (31–180 days postoperatively), but beyond this period strokes were 3.3 times less frequently seen with HM3 [Patients on MCS may suffer from ischaemic and/or haemorrhagic stroke. In the MOMENTUM 3 trial strokes occurred equally , both in the early postoperative phase and later in the course of the disease . VentricSeverely symptomatic: NYHA III+ to IV despite optimal heart failure treatment;Relatively young patients with symptomatic heart failure;Genetic cardiomyopathies with a likelihood of rapid progression of disease (e.g. PLN mutation);Recurrent admissions for heart failure;Inotrope dependency;Difficulties in titration of heart failure medication ;The need for high-dose diuretics (arbitrary >4 mg bumetanide/>160 mg furosemide).Given the fact that the optimal timing of LVAD implantation is crucial and that the outcome after LVAD implantation in patients with rapidly progressive heart failure (INTERMACS I) is far inferior to outcome in patients with less severe heart failure, early referral to a transplant and MCS centre is mandatory. Several characteristics suggesting referral are:The mnemonic ‘I Need Help’, is a helpful tool for timely referral (Tab. All patients with advanced heart failure that proves refractory to optimal conventional therapy have to be considered for heart transplantation and/or long-term MCS. Early consultation and referral to a tertiary centre for evaluation of treatment options and the correct timing of advanced therapies is mandatory. In this analysis, many factors have to be weighed, including prognosis without heart transplantation/MCS, outcome after heart transplantation/MCS with regard to mortality and morbidity as well as an idea on potential improvement after heart transplantation/MCS implantation.Currently, survival after LVAD therapy in the Netherlands approximates 83%, 76% and 70% after 1, 2 and 3 years, respectively. However, this therapy is still associated with substantial morbidity. The intensive management of LVAD patients is restricted to implanting centres, but in case of adverse events, these patients may present to other hospitals. Therefore, all cardiologists need to be aware of the management of adverse events in MCS patients . Outcome


Patients with advanced heart failure (HF) symptoms constitute stage D heart failure with high mortality and less response to conventional guideline directed medical therapies. These patients are subjected to receive non-medical therapies including heart transplant or mechanical circulatory support for increasing survival. Considering the low availability and serious complications of these strategies,effective medical therapies for this group of patients would be pivotal for decreasing mortality and morbidity of them. Angiotensin receptor neprilysin inhibitor (ARNI) is a class of drugs approved for ambulatory heart failure patients. ARNI use like other groups of heart failure drugs has not been fully evaluated in end-stage heart failure patients. Herein, we describe four inotrope-dependent heart failure patients. Initiation of ARNI in these patients, lead to discontinuation of inotrope and reducing the need for inotrope in the follow-up period. ARNI initiation leads to inotrope discontinuation.The main study population of heart failure (HF) clinical trials is the group with mild to moderate symptoms. Patients with advanced symptoms constitute low percentage in these studies and the evidence for the use of guideline directed medical therapy in this group of patients are less robust than other patients, besides these patients are at increased risk of HF medical treatment complications. Patients with advanced HFrEF (Heart Failure Reduced Ejection Fraction) are subjected to receive non-medical therapies such as heart transplantation, mechanical circulatory support and palliative care.He is a 56-year-old man with non-ischemic Dilated Cardiomyopathy (DCM) since 6 years ago and on guideline directed medical therapy (GDMT). Due to symptomatic heart failure (NYHA FC III) despite tolerated dose of GDMT and wide QRS (LBBB pattern), cardiac resynchronization therapy with defibrillator (CRT-D) was implanted according to Heart failure guidelines. Two years later, he was admitted with palpitation. atrioventricular (AV) node ablation and CRT-D mode changing to VVI (Ventricular pacing and sensing) mode was done due to supraventricular tachycardia episodes. There were another three admissions in six months later due to ventricular fibrillation (VF) episodes and implantable cardioverter defibrillation (ICD) shocks. Mexiletine was initiated. Two years ago, he had 9 admissions during ten months with dyspnea and decompensated heart failure despite optimal target dose of GDMT. Furosemide and milrinone were administered in each episode. Meanwhile, Sacubitril/valsartan (LCZ696) 24/26 mg twice daily was initiated with close follow-up regarding drug side effects. Due to acceptable the drug tolerance of patient without side effects like hypotension or worsening renal function, the drug was up-titrated to maximum tolerated dose. There is not any hospitalization due to de-compensation in recent fifteen months.The patient is a 30-year-old man with DCM diagnosis since 4 years ago. ICD-VR (ICD single chamber) was implanted through the disease course. While he was on tolerated doses of HF medical therapies, the patient had three admissions with nausea, vomiting, epigastric pain and diarrhea. Upper GI endoscopy revealed, erythematous gastritis and erosive duodenitis. During these hospitalizations, inotrope was administered, due to hypotension and cardiogenic shock. Two weeks after the last hospitalization, he came with heart failure symptoms and in Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) 3 state Profile. Decreased urine output was the prominent feature. Norepinephrine was initiated. Several trials for inotrope discontinuation were unsuccessful. Finally, we decided to initiate ARNI sacubitril/valsartan (S/V) 24/26 mg twice daily, at this time the patient systolic blood pressure was about 100 mm Hg. Interestingly, we could taper and off norepinephrine infusion. The patient did not show any adverse side effects of the drug and up-titration was done at follow-up visits. There was not any admission thereafter during 18 months.He is a 35-year-old man with DCM diagnosis and on heart failure treatment since 3 years ago. ICD-VR was also implanted. There were three hospitalizations due to heart failure de-compensation during the second year of diagnosis despite administration of optimal tolerable dose of GDMT. In third admission, Norepinephrine was administered, due to hypotension and cardiogenic shock. Few days later, blood pressure increased to acceptable range, and we could withdraw norepinephrine. Elevated bilirubin level and reduced urine output developed after norepinephrine discontinuation. At that time, he was in INTERMACS 3 state. Milrinone was initiated, and he was doing well while on this inotrope but with reduction of it, there were the same signs of organ hypo-perfusion. We initiated S/V 24/26 mg twice daily when the patient systolic pressure was in acceptable range (~100 mm Hg). Few days later we could discontinue milrinone without organ damage signs and the patient discharged in good condition without any side effects of S/V. There was not any admission for heart failure during 1 year follow-up except one admission only two weeks after initiation of ARNI.The patient is a-24-year old male with DCM diagnosis from one year ago. At his first admission with de-compensation symptoms while he was on optimal tolerable dose of GDMT two inotropes including norepinephrine and milrinone were administered. Inotropes could not be discontinued due to deterioration of congestive symptoms and low output state. S/V (24/26 mg twice daily) was initiated for patient after achievement of systolic blood pressure to the range of approximately 100 mm Hg. Few days later, besides improvement of patient condition without S/V side effects, inotropes discontinued and patient discharged in good condition. In about one year after that time, the patient was in acceptable function without any hospitalization for heart failure.4Beneficial effects of S/V has been shown in various disorders including, chronic HFrEF, acute HFrEF, HF with preserved ejection fraction, acute coronary syndrome, left ventricular remodeling, functional mitral regurgitation, hypertension, chronic kidney disease, pulmonary hypertension, cognitive function, obstructive sleep apnea, right ventricle dysfunction and reverse myocardial remodeling even in early stages of treatment. Extensive effects of S/V is probably due to diverse properties of natriuretic peptides including vasodilation, natriuresis, antiproliferative effects, modulation of renin-angiotensin-aldosterone system and vascular remodeling.6The safety and efficacy of S/V in the setting of acute heart failure were evaluated in the multicenter, double-blind PIONEER trial. The higher time-average change from baseline to weeks 4 and 8 in plasma levels of NT-proBNP in the S/V group vs enalapril group was in favor of higher efficacy of S/V. Similar rates of worsening renal function or hyperkalemia between two groups were indicative of acceptable safety outcome of S/V. In this trial only NT-proBNP was used as a surrogate of S/V efficacy and cardiovascular outcomes were not evaluated.Our patients had acceptable renal function before initiation of S/V and we did not encounter significant complications of S/V including hypotension or worsening renal function after initiation of the drug and during the follow-up period.7In a recent report, S/V was initiated for five inotrope-dependent heart failure patients while they had inactive status on heart transplant waiting list due to significant pre-capillary pulmonary hypertension. Improvement in filling pressures, PA systolic pressure and pulmonary vascular resistance were observed following initiation of S/V leading to reactivation of them on heart transplant waiting list. The mechanism of this observation is proposed to be other than a simple vasodilatation. Right ventricular-PA (Pulmonary Artery) coupling improvement as the result of increased pulsatility index and decreased Pulmonary Vascular resistance (PVR) besides increase in cardiac index are the suggested mechanisms for this observation.8Martyn et al in their study showed that patients with reduced cardiac output could be safely bridged from intravenous vasoactive therapy to S/V with maintenance of hemodynamic improvement including Pulmonary Artery Pulsatility index (PAPi) obtained from vasoactive drugs.Unfortunately we could not perform hemodynamic assessment immediately before and after initiation of S/V in our patients but it seems the same findings of the two mentioned studies have been occurred in our patients leading to clinically improvement in condition of the patients.Although these recent studies and our report have been done on small sample sizes, but it might be an indicator of this drug potential for use in stage D and inotrope dependent HF patients.Limited available treatments for stage D HF patients necessitate new treatment strategies in this group. Promising reported results of ARNI use in stage D heart failure patients could represent this class of drugs as a potential treatment in end stage HF patients.The authors declare that there is no conflict of interest.This study was approved by the ethics committee of Rajaie Cardiovascular, Medical and Research Center. Written informed consent was obtained from patients.