Nonsteroidal mineralocorticoid receptor antagonist finerenone ameliorates cardiac hypertrophy with increasing glucocorticoid signaling sensitivity.

Abstract

BACKGROUND: Nonsteroidal mineralocorticoid receptor antagonists (MRAs) have emerged as promising therapies for cardiovascular disease. Finerenone, a highly selective nonsteroidal MRA, has shown efficacy in slowing the progression of heart failure with mildly reduced or preserved ejection fraction, as demonstrated in the FINEARTS-HF trial. However, its mechanisms of action, particularly in heart failure with preserved ejection fraction (HFpEF), remain poorly understood. METHODS: We established a murine model of HFpEF characterized by obesity, metabolic dysfunction-associated fatty liver disease, type 2 diabetes, and hypertension-induced cardiac hypertrophy. This was induced through long-term administration of a high-fat, high-fructose diet combined with NG-nitro-l-arginine methyl ester (l-NAME). Finerenone was administered during the early stage of myocardial remodeling, coinciding with the first histological evidence of cardiac hypertrophy. Cardiac function and structure were evaluated using transthoracic echocardiography, 24-h ambulatory blood pressure monitoring, and histological analysis. To investigate cardiomyocyte-specific transcriptional changes, we performed RNA sequencing on isolated cardiomyocyte nuclei. RESULTS: Fifteen weeks of combined metabolic and hypertensive stress resulted in obesity, glucose intolerance, hypertension, reduced exercise capacity, and myocardial hypertrophy. Finerenone, administered during the final two weeks, significantly attenuated myocardial hypertrophy without affecting systemic blood pressure. Cardiomyocyte-specific transcriptomic analysis revealed downregulation of hypertrophic gene expression and upregulation of glucocorticoid receptor (GR)-responsive genes. CONCLUSIONS: Finerenone alleviates early-stage cardiac hypertrophy in a murine HFpEF model driven by metabolic and hemodynamic stress. Its cardioprotective effects appear to be independent of systemic blood pressure reduction and may involve modulation of GR signaling pathways in cardiomyocytes.