The combination of angiotensin II-Receptor-Neprilysin-Inhibitior (ARNi) has been approved for the treatment of chronic HFrEF and pointed towards beneficial effects in HFpEF patients in clinical trials. However, the potential underlying mechanisms remain a matter of debate.

In the present study, we investigated the effects of ARNi on cardiomyocyte and myocardial function in HFrEF but also HFpEF myocardium. Isolated cardiomyocytes and trabeculae from HFrEF hearts were acutely exposed to the combined Sacubitrilat (40µmol/L) and Valsartan (13µmol/L)).

Isometrically twitching trabeculae isolated from 4 human end-stage failing hearts did not change their systolic or diastolic contractile behaviour after exposure to ARNI during maximal stretch. However, in both human HFrEF and HFpEF cardiomyocytes, acute exposure to ARNi restored the hypo-phosphorylation of sarcomeric proteins including titin, myosin binding protein C (cMyBPC), troponin I (cTnI), and myosin light chain (MLC) to the level observed in control group (n=7-9/patients). The elevated passive stiffness (F_passive) in skinned cardiomyocytes isolated from HFrEF and HFpEF patients was significantly reduced upon ARNi treatment (n=5-6/patients and n=20-28 cardiomyocytes). The increased F_passive was accompanied by elevated kinase activity of protein kinase C (PKC), Calcium-calmodulin dependent proteinkinase II (CAMKII), and the extracellular signal–regulated kinase-2 (ERK 2). These changes in kinases activity were significantly corrected after ARNi administration except for unchanged ERK 2 activity in the ARNi treated HFrEF. Furthermore, oxidative stress and inflammation parameters were significantly elevated in HFrEF hearts compared to non-failing hearts and reversed after ARNi treatment. As known, oxidative stress and dysregulated phosphorylation of myofilament proteins strongly contribute to the altered Ca²⁺ sensitivity of force development. Indeed, we found altered maximum Ca²⁺-activated tension and Ca²⁺ sensitivity of force production of skinned single cardiomyocytes in HFrEF and HFpEF compared to non-failing hearts, which were corrected upon treatment with ARNi.

Here we provide evidence about the beneficial effect of ARNi on cardiomyocyte function characterised by reduced oxidative stress and improved signalling pathways in heart failure and thereby also highlight its potential use as a probable therapeutic approach for HFpEF.