AimsThe sarcoplasmic reticulum (SR) Ca 2+ leak is an important pathomechanism in heart failure (HF). It has been suggested that Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is only relevant for the induction of the SR Ca 2+ leak in non-ischaemic but not in ischaemic HF. Therefore, we investigated CaMKII and its targets as well as the functional effects of CaMKII inhibition in human ischaemic cardiomyopathy (ICM, n = 37) and dilated cardiomyopathy (DCM, n = 40 Methods and resultsWestern blots showed a significantly increased expression (by 54 ± 9%) and autophosphorylation at Thr286 (by 129 ± 29%, P < 0.05 each) of CaMKII in HF compared with healthy myocardium. However, no significant difference could be detected in ICM compared with DCM as to the expression and autophosphorylation of CaMKII nor the phosphorylation of the target sites ryanodine receptor 2 (RyR2)-S2809, RyR2-S2815, and phospholamban-Thr17. Isolated human cardiomyocytes (CMs) of patients with DCM and ICM showed a similar frequency of diastolic Ca 2+ sparks (confocal microscopy) as well as of major arrhythmic events (Ca 2+ waves, spontaneous Ca 2+ transients). Despite a slightly smaller size of Ca 2+ sparks in DCM (P < 0.01), the calculated SR Ca 2+ leak [Ca 2+ spark frequecy (CaSpF) × amplitude × width × duration] did not differ between CMs of ICM vs. DCM. Importantly, CaMKII inhibition by autocamide-2-related inhibitory peptide (AIP, 1 μmol/L) reduced the SR Ca 2+ leak by ∼80% in both aetiologies (P < 0.05 each) and effectively decreased the ratio of arrhythmic cells (P < 0.05).

This study is the first to functionally investigate the role of PP1/PP2A for Ca homeostasis in diseased human myocardium. Our data indicate that a modulation of phosphatase activity potently impacts Ca cycling properties. An activation of PP1 counteracts increased kinase activity in heart failure and successfully seals the arrhythmogenic SR Ca leak. It may thus represent a promising future antiarrhythmic therapeutic approach.

These data show that the SR Ca(2+) leak is lower in women than in men with comparable cardiac impairment. Since the SR Ca(2+) leak triggers delayed afterdepolarizations, our findings may explain why women are less prone to ventricular arrhythmias and confirm the rationale of therapeutic measures reducing the SR Ca(2+) leak.

Aim The wearable cardioverter‐defibrillator (WCD) is used for temporary protection from sudden cardiac death (SCD) in patients with newly diagnosed heart failure with reduced ejection fraction before considering an implantable cardioverter‐defibrillator (ICD). However, the prognostic significance of the WCD remains controversial due to conflicting evidence. The aim of the present study was to evaluate prognosis of patients receiving life‐saving WCD shocks. Methods and results All patients receiving a WCD at Hannover Medical School for heart failure with reduced ejection fraction between 2012 and 2017 were included. Data were acquired at baseline, at 3 months and at last available follow‐up (FU). Three hundred and fifty‐three patients were included (69% male; age 56 ± 15 years; left ventricular ejection fraction 25 ± 8%). FU after the WCD was 2.8 ± 1.5 years with a maximum of 6.8 years. Daily WCD wear time was 22 ± 4 h. Fourteen patients (4%) received appropriate WCD shocks. Two patients (0.6%) died during the WCD period. Thirty patients (9%) died during extended FU. Mean estimated survival after the WCD was similar between patients with and without WCD shocks. Patients without an ICD recommendation after WCD prescription did not experience SCD during FU. Conclusions Patients with WCD shocks showed a favourable survival. Patients without an ICD recommendation after WCD prescription had no SCD during FU. These findings support the practice of careful risk stratification before considering an ICD and the use of the WCD for temporary protection from SCD.

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Purpose The subcutaneous implantable cardioverter-defibrillator (S-ICD) could be a promising alternative to the conventional transvenous ICD in patients with LVAD due to its reduced risk of infection. However, surface ECG is altered following LVAD implantation and, since S-ICD detection is based on surface ECG, S-ICD could be potentially affected. The aim of the present study was to analyze S-ICD eligibility in patients with LVAD. Methods Seventy-five patients implanted with an LVAD were included in this prospective single-center study. The ECG-based screening test and the automated screening test were performed in all patients. Results Fifty-five (73.3%) patients had either a positive ECG-based or automated screening test. Out of these, 28 (37.3%) patients were found eligible for S-ICD implantation with both screening tests performed. ECG-based screening test was positive in 50 (66.6%) patients; automated screening test was positive in 33 (44.0%) patients. Three ECG-based screening tests could not be evaluated due to artifacts. With the automated screening test, in 9 (12.0%) patients, the test yielded no result. Conclusions Patients implanted with an LVAD showed lower S-ICD eligibility rates compared with patients without LVAD. With an S-ICD eligibility rate of maximal 73.3%, S-ICD therapy may be a feasible option in these patients. Nevertheless, S-ICD implantation should be carefully weighed against potential device-device interference. Prospective studies regarding S-ICD eligibility before and after LVAD implantation are required to further elucidate the role of S-ICD therapy in this population.

Aims Inhibition of neprilysin and angiotensin II receptor by sacubitril/valsartan (Val) (LCZ696) reduces mortality in heart failure (HF) patients compared with sole inhibition of renin-angiotensin system. Beneficial effects of increased natriuretic peptide levels upon neprilysin inhibition have been proposed, whereas direct effects of sacubitrilat (Sac) (LBQ657) on myocardial Ca 2+ cycling remain elusive. Methods and results Confocal microscopy (Fluo-4 AM) was used to investigate pro-arrhythmogenic sarcoplasmic reticulum (SR) Ca 2+ leak in freshly isolated murine and human ventricular cardiomyocytes (CMs) upon Sac (40 μmol/L)/Val (13 μmol/L) treatment. The concentrations of Sac and Val equalled plasma concentrations of LCZ696 treatment used in PARADIGM-HF trial. Epifluorescence microscopy measurements (Fura-2 AM) were performed to investigate effects on systolic Ca 2+ release, SR Ca 2+ load, and Ca 2+-transient kinetics in freshly isolated murine ventricular CMs. The impact of Sac on myocardial contractility was evaluated using in toto-isolated, isometrically twitching ventricular trabeculae from human hearts with end-stage HF. Under basal conditions, the combination of Sac/Val did not influence diastolic Ca 2+-spark frequency (CaSpF) nor pro-arrhythmogenic SR Ca 2 leak in isolated murine ventricular CMs (n CMs/hearts = 80/7 vs. 100/7, P = 0.91/0.99). In contrast, Sac/Val treatment reduced CaSpF by 35 ± 9% and SR Ca 2+ leak by 45 ± 9% in CMs put under catecholaminergic stress (isoproterenol 30 nmol/L, n = 81/7 vs. 62/7, P < 0.001 each). This could be attributed to Sac, as sole Sac treatment also reduced both parameters by similar degrees (reduction of CaSpF by 57 ± 7% and SR Ca 2+ leak by 76 ± 5%; n = 101/4 vs. 108/4, P < 0.01 each), whereas sole Val treatment did not. Systolic Ca 2+ release, SR Ca 2+ load, and Ca 2+-transient kinetics including SERCA activity (k SERCA) were not compromised by Sac in isolated murine CMs (n = 41/6 vs. 39/6). Importantly, the combination of Sac/Val and Sac alone also reduced diastolic CaSpF and SR Ca 2+ leak (reduction by 74 ± 7%) in human left ventricular CMs from patients with end-stage HF (n = 71/8 vs. 78/8, P < 0.05 each). Myocardial contractility of human ventricular trabeculae was not acutely affected by Sac treatment as the developed force remained unchanged over a time course of 30 min (n trabeculae/hearts = 3/3 vs. 4/3). Conclusion This study demonstrates that neprilysin inhibitor Sac directly improves Ca 2+ homeostasis in human end-stage HF by reducing pro-arrhythmogenic SR Ca 2+ leak without acutely affecting systolic Ca 2+ release and inotropy. These effects might contribute to the mortality benefits observed in the PARADIGM-HF trial.

Introduction: In patients with a left ventricular assist device (LVAD), the subcutaneous implantable cardioverter-defibrillator (S-ICD) can be an alternative to transvenous ICD systems due to reduced risk of systemic infection, which could lead to extraction of the ICD as well as the LVAD. S-ICD eligibility is lower in patients with LVAD than in patients with end-stage heart failure without LVAD. Several reports have shown inappropriate S-ICD therapy in the coexistence of LVAD and S-ICD. The aim of the present study was to evaluate S-ICD eligibility in patients with LVAD using the established electrocardiogram (ECG)-based screening test as well as a novel device-based screening test to identify potentially inappropriate S-ICD sensing in this specific patient cohort. Methods and Results: The present study included 115 patients implanted with an LVAD. The standard ECG-based screening test and a novel device-based screening test were performed in all patients. Eighty patients (70%) were eligible for S-ICD therapy with the standard ECG-based screening test. Performance of the novel device-based screening test identified device-device interference in 14 of these 80 patients (12%). Conclusion: Using a novel extended device-based S-ICD screening method, a small number of patients with LVAD deemed eligible for S-ICD with the standard ECG-based screening test exhibit device-device interference. Careful S-ICD screening should be performed in patients with LVAD, who are candidates for S-ICD therapy, to prevent inappropriate sensing or ICD therapy.