Ovarian Hormone Decline Aggravates Cardiometabolic Risk and Accelerates Heart Failure with Preserved Ejection Fraction in Female ZSF1 Rats

Heart failure with preserved ejection fraction (HFpEF) is more prevalent in women than men at higher ages, suggesting an impact of ovarian hormone decrease on disease development. However, the basis of this relationship is incompletely understood. Obese female ZSF1 rats, an established cardiometabolic HFpEF model, were ovariectomized at 5-6 weeks of age (Ov-ZSF1, n=11) or stayed intact (O-ZSF1, n=11). The manifestation of HFpEF was analyzed and compared to lean control rats (L-ZSF1, n=11) using echocardiography, invasive hemodynamics, vascular function and histology. At 20 weeks of age O-ZSF1 rats were obese and had metabolic syndrome and HFpEF. These characteristics were further pronounced in Ov-ZSF1: body weight +36%, heart weight +13%, systolic blood pressure +29%, peripheral blood glucose +19%, NT-proBNP +35%, left ventricular (LV)-end-diastolic pressure +26% and E/e’ ratio +10%. The rise of E/e’ ratio, a key HFpEF feature, was seen earliest in Ov-ZSF1, indicating accelerated diastolic dysfunction. Systolic function was generally unchanged but the diastolic function was increasingly affected according to L-ZSF1 10% increased cardiomyocyte diameter in septum and more macrophage infiltration into the heart, representing cardiac remodeling processes. Compared to L-ZSF1 the maximum contractibility of right carotid vessel specimen was increased in O-ZSF1 (+5%) and Ov-ZSF1 (+7%). Disturbed dilatation capacity (−29%) was observed in Ov-ZSF1 only. Concluding, a decrease of ovarian hormone accelerates cardiometabolic HFpEF progression in female ZSF1 rats through combined metabolic, hemodynamic, cardiac, and vascular abnormalities, without overt myocardial fibrosis in female ZSF1rats.