Loss of Gonadal Hormones Has a Different Impact on Aging Female and Male Mice Submitted to a Heart Failure-Inducing Metabolic-Hypertensive Stress

Background: Aging and the female sex are considered risk factors for the development of heart failure with preserved ejection fraction (HFpEF). Unlike other risk factors, such as hypertension, obesity or diabetes, they do not represent therapeutic targets. Methods: In a recently developed two-hit murine HFpEF model (Angiotensin II + High-fat diet; MHS), we studied the relative contribution of the biological sex, aging and gonadal hormones to cardiac remodelling and function. We aimed to reproduce a fre-quent HFpEF phenotype in mice characterized by aging, hypertension, female sex, menopause and metabolic alterations. Using the MHS mouse model, we studied cardiac remodelling and function in C57Bl6/J mice of both sexes, young (12 weeks) and old (20 months), gonadectomized (Gx) or not. Results: We observed that aging was associated in mice with body weight gain, cardiac hypertrophy (CH), left ventricle (LV) concentric remodelling, left atrial (LA) enlargement and changes in echocardiography diastolic parameters (E and A wave velocities), but only in females. Submitting young and old mice to the MHS stress for 28 days induced the expected HFpEF phenotype consisting of CH, LV walls thickening, LA enlargement and diastolic dysfunction with preserved EF except for old males, which was signifi-cantly reduced. Young mice were Gx at five weeks, and old mice at six months (over a year before the MHS). Gx increased myocardial fibrosis in MHS females and helped preserve EF in males. Conclusion: Our results suggest that MHS has sex-specific effects in old mice, and loss of gonadal hormones significantly impacts the heart failure observed phenotype.