Résumé
Metabolic syndrome (MetS) and its related comorbidities significantly elevate the risk of heart failure with preserved ejection fraction (HFpEF), especially after menopause.
In obese mice with MetS and HFpEF, after 12weeks 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 (1.5mg/kg/day, gavage) for either 4days (short-term) or 11weeks (long-term), ending after 14 or 25weeks of the HFS diet, respectively.
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.
After 14weeks 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 25weeks 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.
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.