Mineralocorticoid receptor antagonists and heart failure with preserved ejection fraction: current understanding and future prospects.

The mineralocorticoid receptor (MR), part of the steroid hormone receptor subfamily within nuclear hormone receptors, is found in the kidney and various non-epithelial tissues, including the heart and blood vessels. When improperly activated, it can contribute to heart failure processes such as cardiac hypertrophy, fibrosis, stiffening of arteries, inflammation, and oxidative stress. MR antagonists (MRAs) have shown clear clinical benefits in patients with heart failure with reduced ejection fraction (HFrEF). However, in cases of heart failure with preserved ejection fraction (HFpEF), there is considerable diversity due to its complex underlying mechanisms, resulting in conflicting findings regarding the effectiveness of MRAs in relevant studies. The concept of phenomapping presents an encouraging avenue for investigating different intervention targets and novel therapies for HFpEF. Post hoc analysis of the TOPCAT trial identified certain HFpEF phenotypes that responded favorably to spironolactone. Growing clinical and preclinical evidence suggests that non-steroidal MRAs, which exhibit greater receptor selectivity, stronger anti-fibrotic and anti-inflammatory properties, and fewer hormone-related side effects, may emerge as another promising treatment option for HFpEF alongside sodium-glucose co-transporter 2 (SGLT2) inhibitors. This review aims to outline the structural and functional characteristics of MR, discuss the physiological effects of its activation and inhibition, and delve into the potential for personalized MRA therapy based on the concept of HFpEF phenotype.