Detrimental Effects of Aging, Ovariectomy and Weight Gain on Left Ventricular Structure and Function: A Potential Preclinical Model of Early Stage HFpEF

Abstract

The incidence of heart failure with preserved ejection fraction (HFpEF) continues to increase and little is known about its pathophysiology. Two‐thirds of HFpEF patients are senile women and risk factors include hypertension and metabolic syndrome. Currently, no drugs are effective for HFpEF treatment and the development of animal models would assist in novel therapy evaluation. We implemented a rodent female animal model of aging, estrogen depletion and weight gain to evaluate the role of these factors in altering cardiac structure/function. Female, 18 month old, Fischer F344 rats were allocated into an aging (A) group, aging + ovariectomy (O) and aging + ovariectomy and 10% fructose (OF) in drinking water (n=8–13/group). For comparison purposes a young (3 month old, n=8) cohort of female rats was included. Left ventricular (LV) structure/function was monitored monthly by echocardiography. At 22 months of age, animals were anesthetized and LV function evaluated using a Millar conductance catheter. Histological measures of chamber morphometry, inflammation and collagen density (fibrosis) were also obtained. OF animals significantly increased body weight vs. A and O. While echocardiography did not detect major alterations in cardiac endpoints, intraventricular pressure‐volume loop analysis evidenced significant (p<0.05) decreases in stroke volume (19% O and 27% for OF vs. A), stroke work (27 O and 31% OF vs. A), cardiac output (43 O and 44% OF vs. A) and increases in Tau (30–35% in A, O and OF vs. young) and LV end‐diastolic pressure volume relationship slope (i.e. stiffness) with ovariectomy in the presence of preserved ejection fraction for all groups. Histomorphometry did not detect changes in chamber dimensions. However, histological analysis indicated progressively increasing levels of inflammatory infiltration, perivascular and interstitial fibrosis with ovariectomy and with fructose supplementation in particular, in the subendocardium (see figure). In conclusion, in the setting of aging, ovariectomy (which depletes estrogens), further deteriorates myocardial microstructure which may facilitate the loss of diastolic and global functional indices in the apparent presence of preserved ejection fraction. This model may serve to understand the role that estrogen depletion and weight gain may have in the development of HFpEF.Support or Funding InformationDoD 150090 to FVThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.