Abstract 13228: Finerenone Inhibits the Progression of Cardiac Hypertrophy in the HFpEF Mouse Model

Abstract

Background: The efficacy of mineralocorticoid receptor antagonists (MRA) for heart failure with preserved ejection fraction (HFpEF) has not been established, but there are some reports of MRA being effective for early HFpEF.Furthermore, the FIGARO-DKD trial has demonstrated that finerenone, a nonsteroidal MRA, improves cardiovascular outcomes in patients with type 2 diabetes mellitus.The pathogenesis of HFpEF has yet to be fully elucidated, and further investigation is required to validate the mechanistic role of MRAs based on the distinct pathogenesis of HFpEF. Methods: As an HFpEF mouse model, we used the 15 weeks combined stress model of obesity and hypertension. (Schiattarella et al., Nature 2019). High fat diet ingestion and 0.5 g / L of Nω-nitro-L-arginine methyl ester drinking were loaded. As a drug administration experiment, with combined stress for 10 weeks, placebo or 10 mg/kg/day finerenone was administered for the last two weeks. After loading, body weight, blood pressure, heart weight, myocardial cross-sectional area, and mitochondrial protein acetylation were evaluated. Results: Histological analysis revealed the enlargement of cardiomyocyte cross-sectional areas in the combined stress group. In addition, we found mitochondrial protein acetylation level, adjusted by ubiquinol-cytochrome c reductase, rieske iron-sulfur polypeptide 1 (UQCRFS1) was also enhanced in the combined stress model. Subsequently, finerenone administration did not show remarkable reduction of blood pressure compared to the placebo group. However, echocardiography showed that the finerenone group reduced left ventricular diastolic septal wall thickness. And histological analysis revealed reduction of cardiomyocyte CSAs in the finerenone group. Mitochondrial protein hyperacetylation tended to be reduced with the finerenone group, but the difference was not significant. Conclusion: In the HFpEF murine model, finerenone improved cardiac hypertrophy independent of blood pressure. In addition, mitochondrial protein hyperacetylation, which involves mitochondrial dysfunction, was also alleviated by finerenone administration. Our findings indicate that the cardioprotective effects of finerenone may also affect mitochondrial function.