Abstract P2083: Heart Failure With Preserved Ejection Fraction Mouse Model Development With Aav-renin

Abstract

Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of heart failure patients, with limited approved evidence-based therapies. HFpEF is a complex multifactorial disease associated with comorbidities of hypertension, obesity, diabetes, and renal dysfunction. While the pathophysiology of HFpEF has yet to be fully understood, the development of therapies is hindered partially by limited choices of translationally relevant preclinical models that recapitulate human HFpEF clinical features. Here, we report the development of mouse models of HFpEF through a combination of metabolic and hypertensive stress mediated through activation of the renin-angiotensin-aldosterone system (RAAS) via AAV-Renin. These novel mouse models demonstrate clinically relevant features of human HFpEF, including preserved ejection fraction (EF), concentric cardiac hypertrophy, left atrial enlargement, diastolic dysfunction, elevated natriuretic peptides, inflammation, and exercise intolerance. We also demonstrate that approved HFpEF therapies valsartan/sacubitril (Entresto) and Empagliflozin effectively improve the cardiac phenotypes of HFpEF in this model. In summary, we have established two novel two-hit mouse HFpEF models by combing hypertension induced by AAV-Renin and metabolic stress caused by either HFD or a novel mouse strain with metabolic syndrome. These models faithfully represent the cardiometabolic HFpEF phenogroup and will provide new tools for HFpEF preclinical research and drug discovery.