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

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...

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Published in:	ESC Heart Failure Vol. 8; no. 3; pp. 1933 - 1943
Main Authors:	Pieronne‐Deperrois, Marie, Guéret, Alexandre, Djerada, Zoubir, Crochemore, Clément, Harouki, Najah, Henry, Jean‐Paul, Dumesnil, Anaïs, Larchevêque, Marine, Rego, Jean‐Claude, Rego, Jean‐Luc, Nicol, Lionel, Richard, Vincent, Jaisser, Frédéric, Kolkhof, Peter, Mulder, Paul, Monteil, Christelle, Ouvrard‐Pascaud, Antoine
Format:	Journal Article
Language:	English
Published:	England John Wiley & Sons, Inc 01-06-2021 Wiley John Wiley and Sons Inc
Subjects:	Aldosterone Androgens Animals Diabetes Diastolic dysfunction Exercise Exercise Tolerance Female Heart failure Hypertension Kidney diseases Laboratory animals Life Sciences Menopause Metabolic syndrome Mice Mineralocorticoid receptor Mineralocorticoid Receptor Antagonists Mortality Naphthyridines Normal distribution Obesity Oophorectomy Original Original s Ovariectomy Receptors, Mineralocorticoid Ultrasonic imaging Womens health France Georgia Russia United States > US Exercise Ovariectomy Mineralocorticoid receptor Menopause Diastolic dysfunction Aldosterone Metabolic syndrome
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Summary:	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 VO2 and VCO2, all parameters improved by finerenone. Conclusions Finerenone improved cardiovascular dysfunction and exercise capacity after ovariectomy‐induced LV diastolic dysfunction with preserved ejection fraction.
Bibliography:	These authors have equally contributed to this work. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC8120350
ISSN:	2055-5822 2055-5822
DOI:	10.1002/ehf2.13219