Key result
Sacubitrilat cuts pro-arrhythmogenic sarcoplasmic reticulum Ca2+ leak ~74% in human end-stage heart failure cardiomyocytes.
Why the study?
Sacubitril/valsartan reduces mortality in heart failure, but the direct effects of sacubitrilat on myocardial Ca2+ cycling remain elusive.
Does direct neprilysin inhibition with sacubitrilat reduce pro-arrhythmogenic sarcoplasmic reticulum Ca2+ leak without impairing systolic Ca2+ release or contractility in murine and human end-stage heart failure ventricular myocardium?
Does direct neprilysin inhibition with sacubitrilat reduce pro-arrhythmogenic sarcoplasmic reticulum Ca2+ leak without impairing systolic Ca2+ release or contractility in murine and human end-stage heart failure ventricular myocardium?
Answers are grounded in this paper and cite their sources.
This study provides the first cellular evidence that sacubitrilat directly reduces pro-arrhythmogenic sarcoplasmic reticulum Ca2+ leak in human end-stage heart failure cardiomyocytes without impairing inotropy, offering a mechanistic explanation for reduced ventricular arrhythmias and sudden cardiac death with sacubitril/valsartan.
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 Ca2+ cycling remain elusive. Methods and results Confocal microscopy (Fluo-4 AM) was used to investigate pro-arrhythmogenic sarcoplasmic reticulum (SR) Ca2+ 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 Ca2+ release, SR Ca2+ load, and Ca2+-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 Ca2+-spark frequency (CaSpF) nor pro-arrhythmogenic SR Ca2 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 Ca2+ 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 Ca2+ leak by 76 ± 5%; n = 101/4 vs. 108/4, P < 0.01 each), whereas sole Val treatment did not. Systolic Ca2+ release, SR Ca2+ load, and Ca2+-transient kinetics including SERCA activity (kSERCA) 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 Ca2+ 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 Ca2+ homeostasis in human end-stage HF by reducing pro-arrhythmogenic SR Ca2+ leak without acutely affecting systolic Ca2+ release and inotropy. These effects might contribute to the mortality benefits observed in the PARADIGM-HF trial.
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Eiringhaus et al. (2020) studied End-stage heart failure (NYHA class IV) (n=11). Sacubitrilat (LBQ657) alone or in combination with valsartan vs. Untreated control or sole valsartan (13 μmol/L) or sole isoproterenol (30 nmol/L) was evaluated on Diastolic sarcoplasmic reticulum (SR) Ca2+ leak and Ca2+-spark frequency (CaSpF) in human end-stage heart failure left ventricular cardiomyocytes (74 ± 7% reduction in SR Ca2+ leak, p=<0.001). Sacubitrilat reduced pro-arrhythmogenic sarcoplasmic reticulum Ca2+ leak by 74 ± 7% (P < 0.001) in human ventricular cardiomyocytes from patients with end-stage heart failure without compromising contractility.
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