Short- and long-term treatment with mineralocorticoid receptor antagonist improved heart failure with preserved ejection fraction in obese female mice with or without ovariectomy-induced post-menopausal condition

Obesity and metabolic syndrome are major risks for the development of heart failure with preserved ejection fraction (HFpEF), especially in women after menopause. Although mineralocorticoid receptor antagonists (MRAs) improve outcomes of HF with reduced EF, their beneficial effects on HFpEF remain to be established. We aimed to characterize the potential beneficial effects of an MRA treatment on HFpEF related to obesity in post-menopausal condition or not. After 12 weeks of a high fat diet (HFD), B6D2 female mice underwent an ovariectomy (OVX) followed by an MRA treatment (daily gavage) for a short- or long-term (1 or 12 weeks). The metabolic profile of the mice was analyzed by glucose and insulin tolerance tests. Echocardiography and hemodynamics measurements were performed to evaluate the left ventricular (LV) function. LV coronary perfusion and reserve were measured by MRI, and exercise capacity was evaluated on a treadmill. LV and adrenal gland remodeling were explored by histology and immunohistochemistry. After 12 weeks of HFD, the LV systolic fractional shortening, stroke volume and cardiac output in obese mice were not different to control mice. However, impairment of the LV diastolic compliance was significantly improved either by a short- or long-term MRA treatment (LV-End-Diastolic-Pressure-Volume-Relation, mmHG/RVU: CTL 1.00 ± 0.27, HFD 3.29 ± 0.56, HFD + OVX 7.33 ± 0.35; P < 0.01 vs. CTL; HFD + MRAshort 1.13 ± 0.35, HFD + OVX + MRAshort 0.95 ± 0.51; P < 0.01 vs. untreated). Furthermore, the long-term MRA treatment ameliorated glucose and insulin tolerance tests and reduced LV interstitial fibrosis (Fibrosis, %: CTL 7.03 ± 0.41, HFD 8.82 ± 0.36, HFD + OVX 9.80 ± 0.58; P < 0.01 vs. CTL; HFD + MRA 6.45 ± 0.51, HFD + OVX + MRA 8.26 ± 0.28; P < 0.01 vs. untreated). Moreover, in HFD + OVX mice, the long-term MRA treatment increased the coronary perfusion reserve as well as the running distance during the treadmill stress test. Obesity and post-menopausal condition affected adrenal gland organization with capsule thinning in all obese mice, spindles cortical extensions in the HFD group, cortical dysplasia and disorganized vascular network in the HFD + OVX group. Overall, our data demonstrate that both short- and long-term MRA treatment improved diastolic dysfunction in pre- and post-menopausal obese female mice with HFpEF.