Abstract 191 The effects of Angiotensin II-Receptor-Neprilysin-Inhibitor on cardiac contractility and myofilamental function in human HFrEF and HFpEF myocardium

Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02087-y
The effects of Angiotensin II-Receptor-Neprilysin-Inhibitor on cardiac contractility and myofilamental function in human HFrEF and HFpEF myocardium
M. Herwig¹, R. Hassoun¹, M. Sieme¹, M. Begovic¹, S. Zhazykbayeva¹, P. Tirilomis², A. Mügge³, S. T. Sossalla⁴, N. Hamdani¹, für die Studiengruppe: AG13
¹Molekulare und Experimentelle Kardiologie, Insitut für Forschung und Lehre (IFL), Ruhr-Universität Bochum, Bochum; ²Herzzentrum, Klinik für Kardiologie und Pneumologie, Universitätsmedizin Göttingen, Göttingen; ³Medizinische Klinik II, Kardiologie, Klinikum der Ruhr-Universität Bochum, Bochum; ⁴Klinik und Poliklinik für Innere Med. II, Kardiologie, Universitätsklinikum Regensburg, Regensburg;
Background: The combination of Angiotensin II-Receptor-Neprilysin inhibitor (ARNi) has been approved for the treatment of chronic HFrEF. Several clinical trials showed beneficial effects in HFrEF and HFpEF patients. However, the potential underlying mechanisms are not entirely clear yet. In the present study, we aimed to investigate 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)). Results: Isometrically twitching trabeculae isolated from 4 human end-stage failing hearts did not change their systolic or diastolic contractile behaviour after acute 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 Fpassive was accompanied by elevated kinase activity of Calcium-calmodulin dependent protein kinase II (CaMKII), protein kinase C (PKC) 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. In addition, the increased oxidation and auto-phosphorylation of CaMKII oxidation were significantly reduced after ARNi treatment in HFpEF and HFrEF. Furthermore, oxidative stress and inflammation parameters were significantly elevated in HFrEF and HFpEF 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. These findings were associated with reduced inflammasome, pro-inflammatory cytokines, and in addition to reduced oxidized cardiomyocytes and myeloperoxidase activity; a peroxidase enzyme abundantly present in neutrophil granulocytes. Finally, we found reduced neuropilin-1 (NPR-1) activity, a receptor found in the vasculature of the heart. Conclusions: Our study reveals beneficial effect of ARNi on cardiomyocyte function characterized by reduced oxidative stress and inflammation, and improved signalling pathways in heart failure and thereby also highlight its potential use as a probable therapeutic approach for HFpEF.
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