The mineralocorticoid receptor antagonist finerenone enhances cardiovascular recovery upon food intake normalization in obese mice.

BACKGROUND: Patients with obesity exhibit high prevalence of heart failure with preserved or mildly reduced ejection fraction (HFpEF or HFmrEF). Recently, the mineralocorticoid receptor antagonist finerenone demonstrated benefits in this population. Glucagon-like peptide-1 analog aided weight loss also showed benefits. We hypothesized that finerenone would improve cardiovascular parameters when combined with weight loss in previously obese mice. METHODS: Mice were fed a high-fat diet (HFD) for 24 weeks, and were compared to mice fed a HFD for 16 weeks before returning to a standard diet for a further 8 weeks (rSD), with or without finerenone treatment 1 mg.kg(-1).day(-1) (rSD + F). Glycaemia and insulin tolerance were assessed, cardiac left ventricle (LV) function was evaluated by ultrasound and invasive hemodynamics, myocardial perfusion reserve (MPR) was measured by MRI, and exercise capacity was evaluated on a treadmill. RESULTS: After 16 weeks of HFD, compared to controls, obese mice had hyperglycaemia and insulin resistance, no difference in LV fractional shortening but increased LV filling pressure, impaired LV compliance, and reduced exercise capacity. After 24 weeks, this obesity phenotype was worsened by a reduction in MPR, LV fractional shortening, and cardiac output. After returning to standard diet, compared to the HFD group, body weight decreased in both the rSD and rSD + F groups, with improvements in glycaemia, insulin resistance, LV stroke volume, and LV compliance. In the rSD + F group, compared to rSD group, finerenone further improved LV compliance (34% improvement) (LVEDPVR: Ctl 1.19 ± 0.25, HFD 4.75 ± 0.31(***), rSD 3.44 ± 0.39(†), rSD + F 2.27 ± 0.23(†††,§); (***)P < 0.001 vs C, (†, †††)P < 0.05 and < 0.001 vs H, (§)P < 0.05 vs HS), as well as LV interstitial collagen fibrosis (-47%), and was necessary to improve LV fractional shortening, cardiac output, LV filling pressure (-30%) (LVEDP: Ctl 2.73 ± 0.17, HFD 4.73 ± 0.34(***), rSD 4.53 ± 0.33, rSD + F 3.18 ± 0.26(††,§); (*) vs C,(†) vs H,(§) vs rSD), MPR (+ 28%), and exercise capacity (+ 43%). Benefits of finenerone were likely due, in part, to reduced LV mRNA and protein expression (-49%) of the protein tyrosine-phosphatase PTP-1B, a downstream negative regulator of the insulin receptor, associated with increased phosphorylation level (+ 82%) of AKT kinase. CONCLUSION: In the mouse model of HFD-induced obesity and heart failure, finerenone improves weight loss-induced recovery of cardiac function.