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Aims: Endothelial function is impaired in advanced chronic heart failure (ACHF) patients. We explored a possible association between endothelial function and subsequent mortality risk in ACHF. Methods and Results: We prospectively assessed brachial flow-mediated dilation (FMD) in 82 consecutive New York Heart Association class IV ischaemic ACHF patients with a mean left ventricular ejection fraction (LVEF) of 22 +/- 3%. Following overnight fasting and discontinuation of all medications for > or = 12 h, percent increase in FMD (%FMD) and nitroglycerin-mediated vasodilation were assessed using linear array ultrasound. All patients were followed for 14 +/- 2 months for adverse cardiovascular events, including death, hospitalization for CHF exacerbation, or myocardial infarction. Patients were divided into two groups: those with an FMD lesser than or equal to the median %FMD of 4.6% (n = 41) and those with an FMD above the median (n = 41). Both groups were comparable regarding cardiovascular risk factors, LVEF, and concomitant medications. During follow-up, 22 (53.6%) patients with FMD lesser than or equal to the median had composite adverse cardiovascular events compared with only eight patients (19.5%) with FMD above the median (P < 0.01). Furthermore, fiver deaths (12.1%) occurred in patients with FMD lesser than or equal to the median, compared with no deaths in patients with FMD above the median (P < 0.03). Cox regression analyses revealed that FMD was an independent predictor for these events. Conclusion: Flow-mediated dilation is associated with increased mortality risk in ischaemic ACHF patients. [ABSTRACT FROM AUTHOR]

Background: Heart failure with improved ejection fraction (HFimpEF) is a recently recognized entity presenting a diagnostic and therapeutic challenge. Our aim was to characterize the profile of HFimpEF patients and evaluate predictors for EF lack of improvement among heart failure with reduced ejection fraction (HFrEF) patients., Methods: We included ambulatory HFrEF patients (EF≤40%) between January 1, 2015, and September 1, 2022, with two consecutive echocardiography exams at least 6 months apart. HFimpEF was defined as improved EF from ≤40%->40% and by ≥10%., Results: A total of 567 HFrEF patients (72% male, 54.3 ± 14.4 years old) were analyzed. Patients without EF improvement were more likely to be male, had more comorbidities, ischemic cardiomyopathy (ICMP), markers of adverse cardiac remodeling (lower EF and higher left and right ventricular diameters) and presence of late gadolinium enhancement (LGE) in MRI ( P  < 0.05 for all). In a multivariate analysis, male sex, ICMP, lower EF, larger ventricular size and LGE remained independent predictors for lack of EF improvement. A prediction model for lack of EF improvement including LVEF, LV diameter, diastolic blood pressure and ischemic etiology exhibited an area under the ROC curve of 0.77 (95% CI 0.73-0.81; P  < 0.001). HFimpEF patients had better prognosis with lower hospitalizations and mortality rates. Guideline directed medical therapy (GDMT) were associated with improved outcomes in both groups regardless of EF improvement., Conclusions: Lack of improvement in EF among HFrEF patients may be predicted by HF etiology and imaging parameters of adverse cardiac remodeling, and is associated with worse prognosis. GDMT were associated with improved outcomes in both HFimpEF and HFrEF patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Segev, Avrahamy, Fardman, Matetzky, Freimark, Regev, Kuperstein and Grupper.)

Aims: To describe the effect of subsequent pregnancies (SSP) on left ventricular (LV) function and outcomes in patients with peripartum cardiomyopathy (PPCM)., Methods: Among146 women with PPCM who were prospectively followed at two medical centres in Israel (2007-2019), 75 SSPs (in 50 women) were identified: 8 miscarriages, 8 terminations, and 59 life birth., Results: Forty-five patients with 59 full-term SSPs [mean age was 32.9 ± 4.1 years, LV ejection fraction (LVEF) 57.7 ± 5.1%] were analysed. Data on LVEF at 1-month post-delivery were available in 46 and at 6 months in 36 SSPs. There was a small decrease in the mean LVEF, mostly at third trimester (57.2 ± 5.6 vs. 54.4. ± 7.3, P < 0.001); and at 1-mont (57.9 ± 5.7% vs. 55.4 ± 6.1%, P = 0.001) and at 6-month post-delivery (57.4 ± 6.1 vs. 55.3 ± 7.9%, P = 0.03). In patients with pre-SSP LV LVEF ≥55%, a mild reduction in the mean group LVEF was seen at 1-month post-delivery (P = 0.009). One patient with pre-SSP LVEF ≥55% developed severe relapse. In patients with pre-SSP LVEF <55%, a mild reduction in LVEF was obtained mostly at third trimester (51.1 ± 5.6 vs 47.0 ± 7.4%, P < 0.001), which persisted at 6 months (P = 0.03). A relapse was observed in three (25%) women with LVEF <55%. There was no maternal mortality, 32 patients delivered by caesarean section, and there were no foetal complications., Conclusions: Our study indicates a favourable outcome and low likelihood of maternal mortality associated with SSP in women with a history of PPCM and recovered LV systolic function. SSP was associated with a slight reduction in LVEF mostly during the third trimester, which persisted up to 6 months after delivery., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: This is a sub-analysis of a randomized controlled trial on heart failure (HF) disease management (DM) in which patients with HF ( N = 1,360; 27.5% women) were assigned randomly to DM ( N = 682) or usual care (UC) ( N = 678). Study intervention did not significantly affect the rate of hospital admissions or mortality. This study evaluates sex-related differences in baseline characteristics, clinical manifestations, adherence to treatment and outcomes among the study cohort., Methods: Association between sex and hospital admissions and mortality was tested in multivariable models adjusted for the patients' baseline characteristics. The primary composite outcome of the study included time to first HF hospitalization or all-cause mortality. Secondary composite outcome included number of hospital admissions and days of hospitalization, for HF and all other causes., Results: Compared to males, females recruited in the study were on average 3 years older [median age 72 (62, 78) vs. 75 (65, 82), p = 0.001], with higher prevalence of preserved left ventricular function (LVEF ≥50%) and lower frequency of ischemic heart disease (IHD) ( p ≤ 0.001). Females had shorter 6-min walking distance and worse quality of life and depression scores at baseline ( p < 0.001). The proportion of patients receiving HF recommended medical treatment was similar among females and males. During a median follow-up of 2.7 years (range: 0-5), there were no significant differences between females and males with respect to the time elapsed until the study primary endpoint and its components in univariate analysis [557 (56.5%) males and 218 (58.3%) females were hospitalized for HF or died for any cause; p > 0.05]. Multivariable analysis showed that females were significantly less likely than males to experience the primary outcome [adjusted hazard ratio (HR) = 0.835, 95% CI: 0.699, 0.998] or to die from any cause [adjusted HR = 0.712; 95%CI: 0.560, 0.901]. The sex-related mortality differences were especially significant among patients with non-preserved EF, with IHD or with recent HF hospitalization. Females also had lower rates of all-cause hospital admissions [adjusted rate ratio = 0.798; 95%CI: 0.705, 0.904] and were more likely to adhere to HF medical therapy compared to males., Conclusion: Females with HF fare better than men. Sex related differences were not explained by baseline and morbidity-related characteristics or adherence to medical treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Grupper, Freimark, Murad, Olmer, Benderly, Ziv, Friedman, Kaufman, Silber and Kalter-Leibovici.)

Aims: To describe the phenotype, genetics, and events associated with the development of hypertrophic cardiomyopathy (HCM) with reduced ventricular function (HCMr). Heart failure in HCM is usually associated with preserved ejection fraction, yet some HCM patients develop impaired systolic function that is associated with worse outcomes., Methods and Results: Our registry included 1328 HCM patients from two centres in Spain and Israel. Patients with normal baseline ventricular function were matched, and a competing-risk analysis was performed to find factors associated with HCMr development. Patient records were reviewed to recognize clinically significant events that occurred closely before the development of HCMr. Genetic data were collected in patients with HCMr. A composite of all-cause mortality or ventricular assist device (VAD)/heart transplantation was assessed according to ventricular function. Median age was 56, and 34% were female patients. HCMr at evaluation was seen in 37 (2.8%) patients, and 46 (3.5%) developed HCMr during median follow up of 9 years. HCMr was associated with younger age of diagnosis, poor functional class, and ventricular arrhythmia. Atrial fibrillation, pacemaker implantation, and baseline left ventricular ejection fraction (LVEF) of ≤55% were significant predictors of future HCMr development, while LV obstruction predicted a lower risk. Genetic testing performed in 53 HCMr patients, identifying one or more pathogenic variant in 38 (72%): most commonly in myosin binding protein C (n = 20). Six of these patients had an additional pathogenic variant in one of the sarcomere genes. Patients with baseline HCMr had a higher risk (hazard ratio 6.4, 4.1-10.1) for the composite outcome and for the individual components. Patients who developed HCMr in the course of the study had similar mortality but a higher rate of VAD/heart transplantation compared with HCM with normal LVEF., Conclusions: Hypertrophic cardiomyopathy with reduced ejection fraction is associated with heart failure and poor outcome. Arrhythmia, cardiac surgery, and device implantation were commonly documented prior to HCMr development, suggesting they may be either a trigger or the result of adverse remodelling. Future studies should focus on prediction and prevention of HCMr., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Data about the prognostic interplay between mitral regurgitation MR and left ventricular (LV) function in the outcome of patients admitted with acute heart failure (AHF) are scarce. We evaluated the prognostic impact of MR severity and LV function on mortality and on recurrent heart failure hospitalization (re-HFH) in patients admitted with AHF. Methods and Results: In total, 6843 patients admitted with AHF were evaluated: 2521 patients with LV ejection fraction (LVEF) ≤ 40% (reduced LVEF), 1238 of them (51%) having ≥moderate MR; and 4322 with LVEF > 40% (preserved LVEF), 1175 of them (27%) having ≥moderate MR. One-year mortality and re-HFH rates were higher in patients with ≥moderate MR unrelated to the baseline LV function (p = 0.028 and p < 0.001, respectively). After multivariable analysis, only reduced LVEF, and not the severity of MR, predicted mortality risk (HR: 1.31 [95% CI: 1.12−1.53] for patients with reduced LV function and ≤mild MR; HR: 1.44 [95% CI: 1.25−1.67] for patients with reduced LV function and ≥moderate MR); p < 0.001 for both. There was an increased risk for re-HFH in each group (HR: 1.35 [95% CI: 1.17−1.52] for patients with preserved LV function and ≥moderate MR; HR: 1.31 [95% CI: 1.15−1.51] for patients with reduced LV function and mild MR; and HR: 1.65 [95% CI: 1.45−1.88] for patients with reduced LV function and ≥moderate MR); p < 0.001 for all. Conclusions: In patients admitted with AHF, the LV function is the main prognostic determinant for mortality after 1 year. Significant (≥moderate) MR is associated with an increased risk of recurrent hospitalization.

Background: Vaccines against SARS-COV2 have been crucial in efforts against COVID19, yet there have been reports of pericarditis following vaccination with mRNA-based vaccines., Methods: We questioned consecutive patients with a history of acute pericarditis (AP) evaluated in the pericardial disease clinic during 3-11/2020 in a single tertiary center. Patients with significant myocardial involvement or pericarditis secondary to another systemic disease were excluded., Results: We included 64 patients in the final analysis. Mean age was 53.1 (±18), and 26 (41%) were female. At least 1 recurrence of AP was documented in 47 (73%) cases, 32 (50%) had ≥ 3 recurrences prior to vaccination. AP was considered to be idiopathic\viral in 45 (70%) cases, 20 (31%) cases were post-injury. All patients received at least 2 doses of the vaccine, and 48 patients (75%) received a 3rd dose. Two cases of breakthrough COVID19 infections were documented. Overall, 12 patients (19%) reported any adverse events. Of which, 2 had recurrent pericarditis. There was a trend for a younger age in those patients who had adverse events (median age 45 [IQR 36-61] vs. 60 [38-71], p = 0.08). no other significant difference was seen., Conclusion: In patients with a history of acute\recurrent pericarditis, the use of BNT162b2 was mostly uneventful, but some mild disease recurrences did occur., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Objective: Investigate the safety and efficacy of preoperative levosimendan in patients undergoing left ventricular assist device (LVAD) implantation., Methods: Consecutive patients who received LVADs (HeartMate-2, 3, HVAD) in a single tertiary medical center (2012-2018). INTERMACS profile 1 patients were excluded. The primary outcome was post-LVAD right ventricular failure (RVF) and inhospital mortality rates. The secondary outcomes included other clinical, echocardiographic and hemodynamic parameters at follow-up., Results: Final cohort consisted of 62 patients (40[65%] in the levosimendan group and 22[35%] in the no-levosimendan group). Post-operative RVF rate and inotrope or ventilation support time were similar in the levosimendan and no-levosimendan groups (7.5% vs. 13.6%; P = 0.43, median of 51 vs. 72 h; P = 0.41 and 24 vs. 27 h; P = 0.19, respectively). Length of hospitalization, both total and in the intensive care unit, was not statistically significant (median days of 13 vs. 16; P = 0.34, and 3 vs. 4; P = 0.44, respectively). Post-operative laboratory and echocardiographic parameters and in-hospital complication rate did not differ between the groups, despite worse baseline clinical parameters in the Levosimendan group. There was no significant difference in the in-hospital and long term mortality rate (2.5% vs. 4.5%; P > 0.999 and 10% vs. 27.3% respectively; P = 0.64)., Conclusions: Levosimendan infusion prior to LVAD implantation was safe and associated with comparable results without significant improved post-operative outcomes, including RVF., (© 2022. The Author(s).)

Aims: To assess the effect of angiotensin receptor blockers/neprilysin inhibitors (ARNI) on left ventricular (LV) ejection fraction (LVEF) and LV dimensions in a real-life cohort of heart failure and reduced ejection fraction (HFrEF) patients, while analysing patient characteristics that may predict reverse LV remodelling., Methods and Results: The ARNI-treated HFrEF patients followed at a single tertiary medical centre HF-outpatient clinic were included in the study. Clinical and echocardiographic parameters were evaluated prior to ARNI initiation, and while on ARNI therapy, assessing patient characteristics associated with reverse LV remodelling. The cohort included 91 patients (mean age 60.5 years, 90% male) and 47 (52%) patients exhibited ARNI responsiveness, defined as an increase in LVEF during therapy. Overall, LVEF increased by 19% post-ARNI (23.8 to 28.4%, P < 0.001). Subgroup analysis revealed several parameters associated with significant LVEF improvement, including baseline LVEF <30%, non-ischaemic HF aetiology, lack of cardiac resynchronization therapy (CRT), better initial functional class and ARNI initiation within 3 years from HF diagnosis (P ≤ 0.001 for all). Significant reduction in LV dimensions was noted in patients with lower initial LVEF, non-ischaemic HF and no CRT. Further combined subgrouping of the study population demonstrated that patients with both LVEF <30% and a non-ischaemic HF gained most benefit from ARNI with an average of 51% improvement in LVEF (19.9 to 30%, P < 0.001)., Conclusions: The ARNI treatment response is not uniform among HFrEF patient subgroups. More pronounce reverse LV remodelling is associated with early ARNI treatment initiation in the course of HFrEF, and in those with LVEF <30%, non-ischaemic HF and no CRT., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Dilated cardiomyopathy (DCM) associated with dystrophin gene (DMD) mutations in individuals with mild or absent skeletal myopathy is often indistinguishable from other DCM forms. We sought to describe the phenotype and prognosis of DMD associated DCM in DMD mutation carriers without severe skeletal myopathy., Methods and Results: At 26 European centres, we retrospectively collected clinical characteristics and outcomes of 223 DMD mutation carriers (83% male, 33 ± 15 years). A total of 112 individuals (52%) had DCM at first evaluation [n = 85; left ventricular ejection fraction (LVEF) 34 ± 11.2%] or developed DCM (n = 27; LVEF 41.3 ± 7.5%) after a median follow-up of 96 months (interquartile range 5-311 months). DCM penetrance was 45% in carriers older than 40 years. DCM appeared earlier in males and was independent of the type of mutation, presence of skeletal myopathy, or elevated serum creatine kinase levels. Major adverse cardiac events (MACE) occurred in 22% individuals with DCM, 18% developed end-stage heart failure and 9% sudden cardiac death or equivalent. Skeletal myopathy was not associated with survival free of MACE in patients with DCM. Decreased LVEF and increased left ventricular end-diastolic diameter at baseline were associated with MACE. Individuals without DCM had favourable prognosis without MACE or death during follow-up., Conclusions: DMD-associated DCM without severe skeletal myopathy is characterized by incomplete penetrance but high risk of MACE, including progression to end-stage heart failure and ventricular arrhythmias. DCM onset is the major determinant of prognosis with similar survival regardless of the presence of skeletal myopathy., (© 2021 European Society of Cardiology.)

Background: While single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is a well-established noninvasive procedure for the evaluation of patients with coronary artery disease (CAD), it is unable to detect the presence of, or underestimates the extent of CAD in certain patients. We aimed to show that a bio-impedance device can detect early post-stress changes in several hemodynamic parameters, thereby serving as a potential marker for the presence of significant ischemia., Methods: Prospectively enrolled patients, referred to our Medical Center for clinically-indicated MPI, underwent testing using a Non-Invasive Cardiac System (NICaS) before and immediately after exercise. The differences between rest and stress hemodynamic parameters were compared with the severity and extent of myocardial ischemia by MPI. The study included 198 patients; mean age was 62 years, 26% were women, 54% had hypertension, and 29% diabetes mellitus. Of them, 188 patients had ≤10%, and 10 had > 10% of myocardial ischemia., Results: In the first group, there was a significantly greater increase in post-exercise stroke index, stroke work index, cardiac index and cardiac power index (19.2, 29.1, 90.5 and 107%, respectively) compared with the second group (- 2.7, 3.8, 43.7 and 53.5%, respectively), as well as a significantly greater decrease in total peripheral resistance index (- 38.7% compared with - 16.3%), with corresponding p values of 0.015, 0.017, 0.040, 0.016, and < 0.001, respectively., Conclusions: Our data suggest that immediate post-stress changes in several hemodynamic parameters, detected by the NICaS, can be used as an important adjunct to SPECT MPI for the early detection of myocardial ischemia.

Background: While physical rehabilitation has been shown to be beneficial and safe for patients suffering from heart failure, data on rehabilitation for hypertrophic cardiomyopathy (HCM) patients are limited., Methods: Forty-five HCM patients participated in an exercise rehabilitation program. Exercise capacity was measured in metabolic equivalent of task (METs) units and functional status was defined according to the New York Heart Association (NYHA). Self-reported measurements addressed the quality of life and daily life function., Results: Of the 45 participants, 32 completed at least 3 months of rehabilitation and had data from two sequential exercise tests. A significant increase in exercise capacity (from mean 5.3 to 6.7 METs, p=0.01), was achieved at higher peak heart rates. Eighteen patients (56%) who showed improvement in exercise capacity did not differ in their NYHA class, clinical, electrocardiographic, or echo-Doppler parameters compared to those who did not improve. The benefit from training was associated with a lower exercise capacity at baseline and was most pronounced in those capable of less than 6.8 METs (p=0.008). No significant arrhythmias or adverse events were recorded in HCM patients during participation. In ∼40% of participants, training improved the subjective perception of functional capacity and quality of life; only 4 patients (9%) discontinued their participation due to discomfort during or following training. The improvement in exercise capacity was comparable between HCM and a reference group of dilated cardiomyopathy patients., Conclusions: Exercise rehabilitation appears to be applicable and safe in HCM. It mainly benefits patients suffering from significant functional limitation. Larger prospective studies are needed to validate these findings and better characterize patients expected to benefit from these programs., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Diabetes mellitus (DM) is a major cause of morbidity and mortality following heart transplantation (HT), with 21% and 35% of survivors being affected within 1 and 5 years following HT, respectively. Magnesium deficiency is common among HT patients treated with calcineurin inhibitors and is a known risk factor for DM in non-HT patients. We therefore investigated the association between serum Mg (s-Mg) levels and new-onset diabetes after transplantation (NODAT)., Methods: Between 2002 and 2017, 102 non-DM HT patients were assessed. In accordance with the mean value of all s-Mg levels recorded during the first year post-HT, patients were divided into high s-Mg (≥ 1.8 mg/dL) and low s-Mg (< 1.8 mg/dL) groups. The endpoint was NODAT, defined according to the diagnostic criteria of the American Diabetes Association., Results: Baseline clinical and demographic characteristics for the high (n = 45) and low s-Mg (n = 57) groups were similar. Kaplan-Meier survival analysis showed that 15-year freedom from NODAT was significantly higher among patients with high vs low s-Mg (85% vs 46% log-rank test, p < 0.001). Consistently, multivariate analysis adjusted for age, gender, immunosuppression therapies, BMI and mean creatinine values in the first year post-HT, showed that low s-Mg was independently associated with a significant > 8-fold increased risk for NODAT (95% CI 2.15-32.63, p = 0.003). Stroke rate was significantly higher in patients with low s-Mg levels vs high s-Mg (14% vs 0, p = 0.025), as well as long term mortality (HR 2.6, 95% CI 1.02-6.77, p = 0.05)., Conclusions: Low s-Mg level post-HT is an independent risk factor for NODAT in HT patients. The implications of interventions, focusing on preventing or correcting low s-Mg, for the risk of NODAT and for clinical outcomes should be evaluated.

Background: The donor's mode of brain death (BD), being associated with impairment of myocardial function and hemodynamic performance, impacts the prognosis of the heart transplantation (HTx) recipient., Methods: All patients who underwent HTx between 1996 and 2017 were categorized according to donor's BD mechanism: traumatic BD (TBD) versus non-traumatic BD (NTBD)., Results: The TBD group included 105 recipients, and the NTBD group, 85 recipients. Kaplan-Meier survival analysis showed that overall survival was significantly higher for recipients of TBD hearts (10-year survival 58.1 vs. 37.6%, p = 0.044). Consistently, multivariate analysis showed that TBD was independently associated with a significant 43% reduction in mortality [95% confidence interval (CI) 0.42-0.75, p = 0.033]. Rejection rate was lower in the TBD group (total rejection score 0.44 ± 0.32 vs. 0.51 ± 0.38, p = 0.04; any rejection score 0.38 ± 0.26 vs. 0.45 ± 0.31, p = 0.030), and freedom from cardiac allograft vasculopathy (CAV) was significantly higher in recipients of traumatic vs. non-traumatic donors (10 years: 82.9 vs. 62.4%, log-rank p-value = 0.024). Multivariate analysis showed a significant 42% reduction in CAV [hazard ratio (HR) = 0.58, 95% CI 0.51-0.85, p = 0.022)., Conclusion: Mode of brain death significantly impacts HTx outcomes, with TBD being associated with reduced mortality, rejections and CAV.

Aims: Diabetes mellitus (DM) aggravates the clinical features of ischaemic and hypertensive heart diseases and worsens the prognosis of heart failure patients. Hypertrophic cardiomyopathy (HCM) and diabetes coexist fairly frequently in elderly patients but the impact of DM on the clinical phenotype of HCM is yet unknown. We sought to describe if predominant features of heart failure in DM patients exist independently in HCM., Methods and Results: We reviewed clinical characteristics of 937 patients, age ≥40, diagnosed with HCM, from two tertiary medical centres in Spain and Israel. A propensity score matched cohort of 294 patients was also analysed. Our cohort comprised 102 HCM patients with diabetes (8.7%). Patients with DM were older at diagnosis {median 56 [interquartile range (IQR) 47-67] vs. 53 (IQR 43-63), P = 0.02} and had a higher prevalence of comorbidities. Hypertrophic cardiomyopathy patients with DM had a higher prevalence of diastolic dysfunction, pulmonary hypertension, significant mitral regurgitation, and pacemaker implantation. Hypertrophic cardiomyopathy patients with DM had a higher New York Heart Association (NYHA) class (P < 0.001) and lower exercise capacity [7.0 METS (IQR 5.0-10.0) vs. 9.0 METS (IQR 6.6-11.0), P = 0.002]. These findings were independent of age, gender, country of origin, hypertension, and coronary artery disease. Patients with diabetes had a significantly higher 15-year mortality (22% vs. 15%, P = 0.03), with no differences in sudden cardiac death, appropriate implanted cardioverter-defibrillator therapy, or heart transplantation., Conclusion: Hypertrophic cardiomyopathy patients with diabetes are older and have a higher cardiovascular risk profile. They have a lower functional capacity and more heart failure symptoms due to diastolic dysfunction., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle degenerative disease, caused by mutations in the dystrophin gene and resulting in death because of respiratory or cardiac failure. To investigate the cardiac cellular manifestation of DMD, we generated induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (iPSC-CMs) from two DMD patients: a male and female manifesting heterozygous carrier. Dystrophin mRNA and protein expression were analysed by qRT-PCR, RNAseq, Western blot and immunofluorescence staining. For comprehensive electrophysiological analysis, current and voltage clamp were used to record transmembrane action potentials and ion currents, respectively. Microelectrode array was used to record extracellular electrograms. X-inactive specific transcript (XIST) and dystrophin expression analyses revealed that female iPSCs underwent X chromosome reactivation (XCR) or erosion of X chromosome inactivation, which was maintained in female iPSC-CMs displaying mixed X chromosome expression of wild type (WT) and mutated alleles. Both DMD female and male iPSC-CMs presented low spontaneous firing rate, arrhythmias and prolonged action potential duration. DMD female iPSC-CMs displayed increased beat rate variability (BRV). DMD male iPSC-CMs manifested decreased I f density, and DMD female and male iPSC-CMs showed increased I Ca,L density. Our findings demonstrate cellular mechanisms underlying electrophysiological abnormalities and cardiac arrhythmias in DMD., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: Ethnicity may affect graft longevity and recipient mortality after heart transplantation (HTx). We hypothesized that differences in ethnic origin between Arabs and Jews undergoing HTx in Israel may contribute to differences in long-term outcomes., Methods: The study population comprised all 254 patients who underwent HTx between 1991 and 2017 in a tertiary medical center located in the center of Israel. Patients were categorized as either Jews (226 patients, 89%) or Arabs (28 patients, 11%). The primary end point was cardiac allograft vasculopathy (CAV), secondary end points were cardiovascular (CV) mortality and the combined end point of CAV/CV mortality., Results: In comparison with Jews, Arab patients were significantly younger (ave. age 42 vs. 50) and had shorter in-hospital stay (45 vs. 80 days). However, Kaplan-Meier survival analysis showed that at 10 years of follow-up CAV rates were significantly higher among Arabs (58%) compared with Jews (23%; log-rank P = 0.01) for the overall difference during follow-up. Similar results were shown for the separate end point of CV mortality and the combined end point of CAV/CV mortality. Multivariate analysis, which controlled for age, gender, statin treatment, and other potential confounders, showed that Arab recipient ethnic origin was associated with a significant > 2.5-fold (p = 0.01) increase in the risk for CAV; a > 4-fold increase in the risk for CV mortality (p = 0.001); and approximately 4-fold increase in the risk for the combined end point (p = 0.001). These findings were validated by propensity score analysis., Conclusions: Our data suggest that Arab ethnic origin is associated with a significantly increased risk for CAV and mortality following HTx. Suggested explanations contributing to ethnic disparities in Israel include socioeconomic, environmental and genetic factors. Further studies are required to evaluate whether more aggressive risk factor management in the Israeli Arab population following HTx would reduce CAV and CV mortality in this high-risk population. Increased awareness and early intervention of the Israeli healthcare system and cooperation with the Arab community is of paramount importance.

Aims: Dilated cardiomyopathy (DCM), a myocardial disorder that can result in progressive heart failure and arrhythmias, is defined by ventricular chamber enlargement and dilatation, and systolic dysfunction. Despite extensive research, the pathological mechanisms of DCM are unclear mainly due to numerous mutations in different gene families resulting in the same outcome-decreased ventricular function. Titin (TTN)-a giant protein, expressed in cardiac and skeletal muscles, is an important part of the sarcomere, and thus TTN mutations are the most common cause of adult DCM. To decipher the basis for the cardiac pathology in titin-mutated patients, we investigated the hypothesis that induced Pluripotent Stem Cell (iPSC)-derived cardiomyocytes (iPSC-CM) generated from patients, recapitulate the disease phenotype. The hypothesis was tested by 3 Aims: (1) Investigate key features of the excitation-contraction-coupling machinery; (2) Investigate the responsiveness to positive inotropic interventions; (3) Investigate the proteome profile of the AuP cardiomyocytes using mass-spectrometry (MS)., Methods and Results: iPSC were generated from the patients' skin fibroblasts. The major findings were: (1) Sarcomeric organization analysis in mutated iPSC-CM showed defects in assembly and maintenance of sarcomeric structure. (2) Mutated iPSC-CM exhibited diminished inotropic and lusitropic responses to β-adrenergic stimulation with isoproterenol, increased [Ca2+]out and angiotensin-II. Additionally, mutated iPSC-CM displayed prolonged recovery in response to caffeine. These findings may result from defective or lack of interactions of the sarcomeric components with titin through its kinase domain which is absent in the mutated cells., Conclusions: These findings show that the mutated cardiomyocytes from DCM patients recapitulate abnormalities of the inherited cardiomyopathies, expressed as blunted inotropic response., Competing Interests: The authors have declared that no competing interests exist.

Tacrolimus, the major immunosuppressant after heart transplant (HTx) therapy, is a narrow therapeutic index drug. Hence, achieving stable therapeutic steady state plasma concentrations is essential to ensure efficacy while avoiding toxicity. Whether high variability in steady state concentrations is associated with poor outcomes is unknown. We investigated the association between tacrolimus trough level variability during the first year post-HTx and outcomes during and beyond the first postoperative year. Overall, 72 patients were analyzed for mortality, of whom 65 and 61 were available for rejection analysis during and beyond the first year post-HTx, respectively. Patients were divided into high (median >28.8%) and low tacrolimus level variability (<28.8%) groups. Mean tacrolimus levels did not differ between the groups (12.7 ± 3.4 ng/mL vs 12.8 ± 2.4 ng/mL, P = .930). Patients in the high variability group exhibited higher long-term rejection rate (median total rejection score: 0.33 vs 0, P = .04) with no difference in rejection scores within the first year post-HTx. Multivariate analysis showed that high tacrolimus trough level variability was associated with >8-fold increased risk for any rejection beyond the first year post-HTx (P = .011). Mortality was associated only with cardiovascular complications (P = .018), with no effect of tacrolimus through level variability., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Heart transplantation (HT) is the treatment of choice for patients with end-stage heart failure. The HT unit at the Sheba Medical Center is the largest of its kind in Israel., Objectives: To evaluate the experience of HT at a single center, assess trends over 3 decades, and correlate with worldwide data., Methods: Between 1990 and 2017, we reviewed all 285  adult HT patients. Patients were grouped by year of HT: 1990-1999 (decade 1), 2000-2009 (decade 2), and 2010-2017 (decade 3)., Results: The percentage of women undergoing HT has increased and etiology has shifted from ischemic to non-ischemic cardiomyopathy (10% vs. 25%, P = 0.033; 70% vs. 40% ischemic, for decades 1 vs. 3, respectively). Implantation of left ventricular assist device as a bridge to HT has increased. Metabolic profile has improved over the years with lower low-density lipoprotein, diabetes, and hypertension after HT (101 mg/dl, 27%, and 41% at decade 3, respectively). There has been a prominent change in immunosuppressive treatments, currently more than 90% are treated with tacrolimus, compared with 2.7% and 30.9% in decades 1 and 2, respectively (P < 0.001). Cardiac allograft vasculopathy (CAV) rates have declined significantly (47% vs. 17.5% for decades 1 and 2, P < 0.001) as have the combined endpoint of CAV/death. Similarly, the current incidence of acute rejections is significantly lower., Conclusions: Our analysis of over 25 years of a single-center experience with HT shows encouraging improved results, which are in line with worldwide standards and experience.

Background: Cardiac damage caused by oncological therapy may manifest early or many years after the exposure., Objectives: To determine the differences between sub-acute and late-onset cardiotoxicity in left ventricular ejection fraction (LVEF) recovery as well as long-term prognosis., Methods: We studied 91 patients diagnosed with impaired systolic function and previous exposure to oncological therapy. The study population was divided according to sub-acute (from 2 weeks to ≤ 1 year) and late-onset (> 1 year) presentation cardiotoxicity. Recovery of LVEF of at least 50% was defined as the primary end point and total mortality was the secondary end point., Results: Fifty-three (58%) patients were classified as sub-acute, while 38 (42%) were defined as late-onset cardiotoxicity. Baseline clinical characteristics were similar in the two groups. The mean LVEF at presentation was significantly lower among patients in the late-onset vs. sub-acute group (28% vs. 37%, respectively, P < 0.001). Independent predictors of LVEF recovery were trastuzumab therapy and a higher baseline LVEF. Although long-term mortality rates were similar in the groups with sub-acute and late-onset cardiotoxicity, improvement of LVEF was independently associated with reduced mortality., Conclusions: Our findings suggest that early detection and treatment of oncological cardiotoxicity play an important role in LVEF recovery and long-term prognosis.

Background: The efficacy of disease management programs in improving the outcome of heart failure patients remains uncertain and may vary across health systems. This study explores whether a countrywide disease management program is superior to usual care in reducing adverse health outcomes and improving well-being among community-dwelling adult patients with moderate-to-severe chronic heart failure who have universal access to advanced health-care services and technologies., Methods: In this multicenter open-label trial, 1,360 patients recruited after hospitalization for heart failure exacerbation (38%) or from the community (62%) were randomly assigned to either disease management or usual care. Disease management, delivered by multi-disciplinary teams, included coordination of care, patient education, monitoring disease symptoms and patient adherence to medication regimen, titration of drug therapy, and home tele-monitoring of body weight, blood pressure and heart rate. Patients assigned to usual care were treated by primary care practitioners and consultant cardiologists. The primary composite endpoint was the time elapsed till first hospital admission for heart failure exacerbation or death from any cause. Secondary endpoints included the number of all hospital admissions, health-related quality of life and depression during follow-up. Intention-to-treat comparisons between treatments were adjusted for baseline patient data and study center., Results: During the follow-up, 388 (56.9%) patients assigned to disease management and 387 (57.1%) assigned to usual care had a primary endpoint event. The median (range) time elapsed until the primary endpoint event or end of study was 2.0 (0-5.0) years among patients assigned to disease management, and 1.8 (0-5.0) years among patients assigned to usual care (adjusted hazard ratio, 0.908; 95% confidence interval, 0.788 to 1.047). Hospital admissions were mostly (70%) unrelated to heart failure. Patients assigned to disease management had a better health-related quality of life and a lower depression score during follow-up., Conclusions: This comprehensive disease management intervention was not superior to usual care with respect to the primary composite endpoint, but it improved health-related quality of life and depression. A disease-centered approach may not suffice to make a significant impact on hospital admissions and mortality in patients with chronic heart failure who have universal access to health care., Clinical Trial Registration: Clinicaltrials.gov identifier: NCT00533013 . Trial registration date: 9 August 2007. Initial protocol release date: 20 September 2007.

Aims: There are limited data on the effect of low-dose, intermittent inotropic therapy in an outpatient setting on the quality of life (QOL) in patients with advanced refractory heart failure (HF) symptoms. We aimed to analyse the effect of this treatment modality on QOL and subsequent survival., Methods and Results: The study population comprised 287 consecutive patients with advanced refractory HF symptoms who were treated with low-dose, intravenous intermittent inotropic therapy in the HF Day Care Service at Sheba Medical Centre between September 2000 and September 2012. All patients completed a baseline Minnesota Living with Heart Failure Questionnaire (MLWHFQ), and 137 (48%) completed a 1 year follow-up questionnaire. MLWHFQ scores' means ranged from 0 (better QOL) to 5 (worse QOL). Mean age was 68 ± 12, 86% were men, 77% had ischaemic cardiomyopathy, and the mean left ventricle ejection fraction (LVEF) was 26% ± 13. The mean baseline MLWHFQ score was 3.1 (±1), while the mean at 1 year of treatment was of 2.7 (±1.1), indicating an overall improvement in QOL associated with intermittent low-dose inotrope therapy ( p  < 0.01). Multivariate analysis showed that younger age, non-ischaemic cardiomyopathy, and worse renal function were independently associated with improvement in QOL at 1 year. Improvement in QOL was not associated with a significant survival benefit during subsequent follow-up., Conclusions: In patients with advanced refractory HF symptoms, treatment with low-dose, intermittent intravenous inotropes in an outpatient setting is associated with significant improvement in QOL. However, improvement in QOL in this population does not appear to affect subsequent long-term survival.

Aims: The role of donor/recipient gender matching on the long-term rejection process and clinical outcomes following heart transplantation (HT) outcomes is still controversial. We aim to investigate the impact of gender matching on early and long-term outcome HT., Methods and Results: The study population comprised 166 patients who underwent HT between 1991 and 2013 and were prospectively followed up in a tertiary referral centre. Early and late outcomes were assessed by the type of donor-recipient gender match (primary analysis: female donor-male recipient [FD-MR, n  = 36] vs. male donor-male recipient [MD-MR, n  = 109]). Early mortality, need for inotropic support, length of hospital stay, and major perioperative adverse events did not differ between the FD-MR and MD-MR groups. However, the FD-MR group experienced significantly higher rates of early major rejections per patient as compared with the MD-MR group (1.2 ± 1.6 vs. 0.4 ± 0.8; P  = 0.001), higher rates of overall major rejections (16 vs. 5.5 per 100 person years; P  < 0.05), and higher rate of cardiac allograft vasculopathy (43% vs. 20%; P  = 0.01). Kaplan-Meier survival analysis showed that the cumulative probabilities of survival free of rejections and major adverse events were significantly higher in MD-MR group ( P  = 0.002 and 0.001, respectively). Multivariate analysis showed that FD-MR status was associated with >2.5-fold ( P  = 0.03) increase in the risk for rejections and with a >3-fold ( P  = 0.01) increase in the risk for major adverse events during follow-up., Conclusions: Donor-recipient gender mismatch is a powerful independent predictor of early and late rejections and long-term major adverse events following HT.

Background: Functional mitral regurgitation (MR) is a common finding in dilated cardiomyopathy. Left ventricular (LV) reverse remodeling with LV size reduction and improvement in LV function is a well recognized phenomenon. We aimed to evaluate the impact of LV remodeling on the mechanism leading to functional MR., Methods: Among 188 patients with non-ischemic dilated cardiomyopathy, 10 patients significantly improved their LV function, reduced LV size and MR severity during follow-up (RRMR). A comparison was made between their baseline and follow-up echocardiographic examinations and to a matched-control group of patients who did not improve (no RRMR). LV and left atrium (LA) dimensions and volumes, LV mass (LVM), LV ejection fraction (LVEF) (Simpsons), sphericity index (SI), mitral valve tenting area (TA) coaptation distance (CD), effective regurgitant orifice (ERO), and regurgitant volume were calculated. Multivariable analysis was performed in order to evaluate which echocardiographic parameters related to MR improvement in reverse remodeling., Results: LV and LA dimensions and volumes, LVM, SI, TA, CD, ERO and right ventricle, in the RRMR group significantly decreased at follow-up (p < 0.04 for all). When compared to no RRMR, despite a similar ERO (0.2 ± 0.05 vs. 0.2 ± 0.08, p = 0.13) and a larger regurgitant volume (38 ± 9 vs. 29 ± 8 mL, p = 0.05) and despite similar clinical characteristics and medical treatment we found significantly higher LVEF, smaller LV dimensions and volumes, smaller LVM and SI in the RRMR group (p < 0.05 for all). On multivariable analysis the SI was the sole predictor of RRMR (p = 0.04, OR = 0.76, CI 0.58-0.99)., Conclusions: Reverse remodeling characterized by improvement in LV function, reduction in LV size and an associated reduction in MR severity is related to LV SI at baseline.