| Item type: | Article | ||||
|---|---|---|---|---|---|
| Journal or Publication Title: | ESC Heart Failure | ||||
| Publisher: | WILEY PERIODICALS, INC | ||||
| Place of Publication: | SAN FRANCISCO | ||||
| Volume: | 7 | ||||
| Number of Issue or Book Chapter: | 5 | ||||
| Page Range: | pp. 2992-3002 | ||||
| Date: | 2020 | ||||
| Institutions: | Medicine > Lehrstuhl für Innere Medizin II | ||||
| Identification Number: |
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| Keywords: | ANGIOTENSIN-NEPRILYSIN INHIBITION; LATE SODIUM CURRENT; PROTEIN-KINASE-II; NATRIURETIC PEPTIDE; CA2+ LEAK; SACUBITRIL/VALSARTAN; ARRHYTHMIAS; DYSFUNCTION; LCZ696; Heart failure; Entresto; Neprilysin inhibition; Ca cycling; SR Ca leak; Arrhythmia | ||||
| Dewey Decimal Classification: | 600 Technology > 610 Medical sciences Medicine | ||||
| Status: | Published | ||||
| Refereed: | Yes, this version has been refereed | ||||
| Created at the University of Regensburg: | Yes | ||||
| Item ID: | 49835 |
Web of ScienceAbstract
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 ...
Abstract
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 mu mol/L)/Val (13 mu mol/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 Ca2+-transient kinetics in freshly isolated murine ventricular CMs. The impact of Sac on myocardial contractility was evaluated usingin 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 Ca(2)leak in isolated murine ventricular CMs (nCMs/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 Ca2+-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 (ntrabeculae/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.
Metadata last modified: 11 Oct 2021 12:46
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