Antifibrotic Effect of (−)‐Epicatechin in a Rodent Model of Early Stage HFpEF

Background The prevalence of heart failure with preserved ejection fraction (HFpEF) continues to increase and no effective therapies have been identified. Two‐thirds of HFpEF patients are post‐menopausal women with hypertension and/or metabolic syndrome, key factors of cardiac fibrosis. The goals of this study were: 1) to develop a rat model that displays cardiac features of HFpEF in humans evaluated using a comprehensive panel of physiological endpoints and, 2) to characterize the antifibrotic potential of the cacao flavanol (−)‐epicatechin (Epi) which we have demonstrated to exert such activity in an animal model of muscular dystrophy. Methods using a model integrating the roles of aging, estrogen depletion and metabolic syndrome on promoting diastolic dysfunction and myocardial fibrosis. Female, 18‐month‐old, Fischer 344 rats were allocated into an ovariectomy (OVX), ovariectomy+epi (OVE), ovariectomy+fructose (OVF) and ovariectomy+fructose+epi (OFE) (n=8–11/group). Left ventricular (LV) function was monitored monthly by echocardiography. At 22 months of age, in vivo studies included LV hemodynamics using pressure‐volume (PV) loops obtained with a conductance catheter, as well as ex‐vivo passive LV PV curves and epicardial strains in diastole arrested hearts. Histological measures and collagen area fraction were obtained. Subgroups of animals received vehicle (water) or Epi (1 mg/kg/day) by gavage for 1 month (from 21 to 22 months of age). Results all aged groups exhibited high systolic blood pressure while OVF animals showed increased body weight. Echocardiographic assessment was not able to detect mayor morphometric changes between groups with treatment and their vehicle counterpart, but there is evidence of time‐dependent changes in cardiac morphometry. The intraventricular analysis showed increased Tau, decreased Stroke Volume index, and changes in aortic pressures at both diastole and systole. (−)‐Epi treatment revealed differences pressure and heart rate, fructose animals showed changes on systolic function and aortic pressures (p<0.05 vs OVF). Intraventricular measures did not change between treated and vehicle groups maintaining a normal ejection fraction (EF) (>50%). Passive PV curves showed no differences between treated and vehicle groups. Regional strain analysis revealed no differences for circumferential strain (E 11 ), but showed differences in longitudinal strain (E 22 ) for OVE vs OVX (p<0.05). Histological analysis indicated increasing levels of perivascular and interstitial fibrosis at both endo‐ and epicardium (p<0.05). Differences were present between OVF and OFE groups in base and septum sections (p<0.05) for collagen content. Conclusion This aging female rat model appears to mimic many of the features in female HFpEF patients. OVX appears to compromise cardiac output while not affecting EF. Although preliminary, results suggest that Epi, which has been tested in humans with other conditions, may deserve consideration as an antifibrotic agent in the setting of diseases such as HFpEF. Support or Funding Information Department of Defense PR150090 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .