Abstract 262: A Rat Model of Heart Failure With Preserved Ejection Fraction Induced by Pressure Overload

Abstract

The absence of animal models displaying clinical phenotypes of HFpEF represents a challenge to the pharmaceutical industry in the hope of identifying novel treatments that would benefit patients with this syndrome. We, at Merck, examined the supracoronary aortic banding (SAB) in rats as a potential model and set out to characterize its phenotypes. Juvenile Sprague-Dawley rats were used; a hemostatic clip with an opening of 0.7 mm was placed around the ascending aorta to elicit a pressure overload to the LV. Echocardiography was performed every 3 weeks and invasive hemodynamics was measured at week 9 to evaluate cardiac structural and functional effects; heart and lungs were harvested at the end for morphological and histological analysis. Nine weeks after SAB, LV hypertrophy and dysfunction were apparent, as manifested by increases in LVEDP, left atrial pressure, plasma BNP, LV and lung weights; LV relaxation time constant (Tau) and mitral early to late inflow ratio (E/A) were also increased; while EF and FS were preserved (see table, mean ± SEM). In addition, SAB rats had elevated mean pulmonary pressure (sham 14 ± 1.7 vs. SAB 37 ± 4.4 mm Hg, p<0.05) with an abnormal transpulmonary gradient (sham 12 ± 2.5 vs. SAB 23 ± 0.1 mm Hg, p<0.05), indicating comorbidity of pulmonary hypertension. Finally, piloerection, dyspnea and loss of muscle mass were evident and exercise tolerance measured by treadmill test was decreased in SAB rats. In summary, rats undergoing SAB exhibit many of the clinical phenotypes of HFpEF. Further work includes examining the effects of novel therapies in SAB rats on improving these clinical phenotypes of HFpEF and expanding the model to study morbidity and mortality.