Identification of mechanisms underlying protective effects of neprilysin inhibitor sacubitrilat on cardiomyocyte calcium cycling and arrhythmic triggers

• Applicant: Privatdozent Dr. Thomas Fischer
• Subject Area: Cardiology, Angiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 507130856

With the drug Entresto (sacubitril/valsartan), an additional active substance has been available for some years for the treatment of patients with heart failure. It is a combination drug that, in addition to angiotensin receptor blockade, inhibits the degradation of natriuretic peptides by neprilysin (angiotensin receptor blocker/neprilysin inhibitor, ARNI). The PARADIGM-HF study demonstrated a mortality benefit compared to standard therapy. Further studies also showed an antiarrhythmic effect of ARNI therapy with a reduced number of ventricular arrhythmias and ICD shocks. However, the cellular mechanism of the antiarrhythmic effect of sacubitrilate remains unclear. In a previous study by our group, we were able to show that sacubitrilate/valsartan exerts direct antiarrhythmic effects on isolated murine and human cardiomyocytes by reducing arrhythmogenic diastolic leakage from the cellular calcium store (sarcoplasmic reticulum, SR) without affecting systolic calcium release and inotropy. This effect was similarly demonstrated by treatment with sacubitrilate alone. In addition, we were able to show that sacubitrilate leads to an increase in the cellular signalling molecule cGMP. The aim of the research project is to decipher the signalling pathways through which sacubitrilate positively influences calcium metabolism and cellular arrhythmias. Here, an auto-/paracrine effect of natriuretic peptides (ANP/BNP, CNP) via several NP receptors (GC-A, GC-B, NPR-C) may be postulated. To identify the underlying mechanism, we have KO mouse models (GC-A, GC-B) as well as specific inhibitors and activators at our disposal. In addition, possible direct effects on cGMP degradation through interaction with phosphodiesterases will be examined. Radioimmunoassays, confocal microscopy, epifluorescence microscopy and Western blots will be used to investigate in detail the effects of individual signalling cascades downstream of sacubitrilate treatment on intracellular cGMP levels, calcium metabolism and the phosphorylation of regulatory enzymes of excitation-contraction coupling. The identification of the cellular mechanism of the antiarrhythmic effect of sacubitrilate may be of great importance for the development of innovative antiarrhythmic therapies. This is of enormous importance from a clinical point of view, as currently only amiodarone is available for antiarrhythmic drug therapy in heart failure.

• DFG Programme: Research Grants