Finerenone improves HFpEF in obese female mice and slows down its acceleration after a postmenopausal transition

Abstract

Introduction

Metabolic syndrome (MetS) and its related comorbidities significantly elevate the risk of heart failure with preserved ejection fraction (HFpEF), especially after menopause.

Objective

In obese mice with MetS and HFpEF, after 12 weeks on a high-fat-sucrose (HFS) diet, we studied the effects of ovariectomy (Ovx) to induce a post-menopausal state. Ten days after surgery, we began finerenone treatment (1.5 mg/kg/day, gavage) for either 4 days (short-term) or 11 weeks (long-term), ending after 14 or 25 weeks of the HFS diet, respectively.

Method

The functional study of the left ventricle (LV) was carried out using ultrasound, MRI for coronary flow reserve measurements, and invasive hemodynamic. Exercise capacity was assessed by treadmill. LV remodeling was assessed by weighing and the measurement of mean cross-sectional area for hypertrophy, and Sirius red staining for fibrosis.

Results

After 14 weeks on HFS diet, obese mice developed MetS and HFpEF, with LV compliance worsening rapidly after just two weeks of Ovx. Despite no LV hypertrophy at this stage, short-term Fine treatment allowed rapid recovery of compliance (LVEDPVR, mmHg/RVU: Ctrl 1.00 ± 0.27, HFS 3.29 ± 0.56*, HFS + Ovx 7.33 ± 0.35*†, HFS + fine 1.13 ± 0.35$, HFS + Ovx + fine 0.95 ± 0.51$; * vs. Ctrl, † vs. non-OVX, $ vs. untreated). After 25 weeks on HFS diet, obese female mice still had HFpEF, with impaired LV filling pressure and compliance, along with LV hypertrophy and fibrosis. Long-term Fine treatment improved diastolic parameters (LVEDPVR: Ctrl 1.51 ± 0.15, HFS 6.90 ± 0.79*, HFS + Ovx 6.82 ± 0.95*, HFS + fine 2.38 ± 0.26$, HFS + Ovx + fine 3.12 ± 0.33$). MRI showed improved coronary flow reserve in Fine-treated post-menopausal obese mice (CFR, mL/min/g: HFS + Ovx 3.53 ± 0.52, HFS + Ovx + fine 6.21 ± 0.91$), but exercise capacity improved only in non-Ovx obese mice with finerenone. Finerenone more effectively reduced LV fibrosis in Ovx obese mice than in non-Ovx obese mice (collagen, %: Ctrl 7.0 ± 0.4, HFS 9.3 ± 0.3*, HFS + Ovx 9.8 ± 0.6*, HFS + fine 6.45 ± 0.5$, HFS + Ovx + fine 8.26 ± 0.3#; # vs. non-OVX treated). Finally, larger cardiomyocyte size was observed in Ovx obese mice compared to non-Ovx obese mice, persisting after treatment despite finerenone's efficacy in reducing LV hypertrophy.

Conclusion

Our findings show that finerenone treatment ameliorates diastolic dysfunction in obese female mice with HFpEF and MetS and helps limit the consequences of a more rapid progression of HFpEF after a post-menopausal transition.