Mineralocorticoid receptor blockade with finerenone improves heart function and exercise capacity in ovariectomized mice

Abstract

Aims In post-menopausal women, incidence of heart failure with preserved ejection fraction is higher than in men. Hormonal replacement therapies did not demonstrate benefits. We tested whether the non-steroidal mineralocorticoid receptor antagonist finerenone limits the progression of heart failure in ovariectomized (OVX) mice with metabolic disorders. Methods and results Ovariectomy was performed in 4-month-old mice, treated or not at 7 months old for 1 month with finerenone (Fine) 1 mg/kg/day. Left ventricular (LV) cardiac and coronary endothelial functions were assessed by echocardiography, catheterization, and myography. Blood pressure was measured by plethysmography. Insulin and glucose tolerance tests were performed. Exercise capacity and spontaneous activity were measured on treadmill and in combined indirect calorimetric cages equipped with voluntary running wheel. OVX mice presented LV diastolic dysfunction without modification of ejection fraction compared with controls (CTL), whereas finerenone improved LV filling pressure (LV end-diastolic pressure, mmHg: CTL 3.48 ± 0.41, OVX 6.17 ± 0.30**, OVX + Fine 3.65 ± 0.55 † , **P < 0.01 vs. CTL, † P < 0.05 vs. OVX) and compliance (LV end-diastolic pressure-volume relation, mmHg/RVU: CTL 1.65 ± 0.42, OVX 4.77 ± 0.37***, OVX + Fine 2.87 ± 0.26 † † , ***P < 0.001 vs. CTL, † † P < 0.01 vs. OVX). Acetylcholine-induced endothelial-dependent relaxation of coronary arteries was impaired in ovariectomized mice and improved by finerenone (relaxation, %: CTL 86 ± 8, OVX 38 ± 3**, OVX + Fine 83 ± 7 † † , **P < 0.01 vs. CTL, † † P < 0.01 vs. OVX). Finerenone improved decreased ATP production by subsarcolemmal mitochondria after ovariectomy. Weight gain, increased blood pressure, and decreased insulin and glucose tolerance in OVX mice were improved by finerenone. The exercise capacity at race was diminished in untreated OVX mice only. Spontaneous activity measurements in ovariectomized mice showed decreased horizontal movements, reduced time spent in a running wheel, and reduced VO 2 and VCO 2 , all parameters improved by finerenone. Conclusions Finerenone improved cardiovascular dysfunction and exercise capacity after ovariectomy-induced LV diastolic dysfunction with preserved ejection fraction.

Mineralocorticoid receptor in cardiovascular diseases -- clinical trials and mechanistic insights

“…Treatment with spironolactone also prevented diet-induced diastolic dysfunction and arterial stiffness in female mice (De Marco et al, 2015). Finerenone improved HFpEF by decreasing LV filling pressure, increasing LV compliance, and prevented coronary endothelial dysfunction in ovariectomized mice (Pieronne-Deperrois et al, 2021).…”

Mineralocorticoid receptor in cardiovascular diseases—Clinical trials and mechanistic insights

“…In transgenic mice with cardiac‐specific overexpression of Rac1 and increased left ventricular volumes, finerenone blocked left ventricular fibrosis and dilation (Lavall et al, 2019). Finally, finerenone improved heart failure with preserved ejection fraction by decreasing LV filling pressure, increasing LV compliance and prevented coronary endothelial dysfunction in ovariectomized mice (Pieronne‐Deperrois et al, 2021).…”

Cardiorenal benefits of finerenone: protecting kidney and heart

“…In ovariectomized mice with left ventricular diastolic dysfunction and preserved ejection fraction, finerenone improved left ventricular filling, coronary artery endothelium-dependent relaxation, mitochondrial ATP production, and exercise capacity [ 41 ]. Experimental studies of finerenone have also shown improvement in metabolic parameters, such as the average size of adipocytes, adipocyte differentiation, fat deposits, type of fat, and oxidative stress [ 42 , 43 ].…”