Esaxerenone Attenuates Cardiac Hypertrophy in a Pressure Overload Model in Mice

Esaxerenone, a non-steroidal mineralocorticoid receptor (MR) blocker, exhibits high selectivity for MR. While clinically used as an anti-hypertensive drug, its impact on cardiac remodeling remains poorly understood. This study investigated the effect of esaxerenone on pressure overload-induced cardiac hypertrophy in mice. Eight-week-old C57BL/6 mice underwent either transverse aortic constriction (TAC) or sham surgery. Animals were divided into 2 groups: 0.003% (3.0 mg/kg) Esaxerenone-fed (EX) and normal-fed (CNT) groups (n = 64, Sham/CNT = 12, Sham/EX = 13, TAC/CNT = 18, TAC/EX = 21). Cardiac gene expressions were analyzed using quantitative real-time PCR. Food intake and body weight variations showed no significant differences between CNT and EX groups during the 2-week experimental period. The mortality rate from 24 hours after TAC surgery to the end of the experiment was 30.8% in the CNT group, however, all mice survived following TAC surgery in EX group. CNT group showed a remarkable increase in heart weight/tibial length ratio 2 weeks after TAC compared with the Sham group. The EX group demonstrated a significant decrease in HW/TL following TAC surgery (-23.4%, P = 0.041). Masson's trichrome staining revealed that the TAC/CNT group had a significantly higher proportion of fibrotic area than the Sham/CNT group. However, the TAC/EX group had a slightly lower proportion of fibrotic area than the TAC/CNT group. In cardiac gene expression analysis, ANP and Collagen 3a1 were upregulated in the TAC group but were significantly reduced following treatment with esaxerenone. Esaxerenone attenuates cardiac hypertrophy and hypertrophy-related gene expression, resulting in improved survival in a pressure overload model in mice.