Abstract 98a: A Novel Rodent Model of HFpEF: a Potential Platform for Understanding Disease Mechanisms and Evaluating New Therapies

Abstract

Heart failure with preserved ejection fraction (HFpEF) occurs in over 50% of total HF population today and is growing with no approved therapies today. A major challenge to the field is that truly representative experimental models of HFpEF do not exist and therefore, the advancement of the science and treatment is minimal. We have set out to develop a reliable and reproducible HFpEF rodent model to provide a platform for preclinical investigation of potential therapies. Diagnostic criteria to validate the model included (a) LVEDP > 15 mmHg, (b) left ventricular (LV) stiffness and impaired LV relaxation, (c) preserved ejection fraction (EF ≥ 55%), and (d) LV concentric hypertrophy. Adult SHR were given isoproterenol by subcutaneous mini pump infusion for 4-weeks. After first week of isoproterenol treatment initiated, L-NAME was added for 8-weeks to accelerate transition from concentric hypertrophy to HFpEF. Echocardiography and invasive hemodynamics were used to evaluate cardiac structure and function at baseline, immediately after stopping L-NAME and at 4 and 8 weeks. Treated SHR had significantly increased LVEDP, Tau and left ventricular hypertrophy with preserved EF. A follow-up study confirmed these initial data and demonstrated this HFpEF phenotype remained for at least 8-week after end of L-NAME/Iso treatment (see table). This rodent model mimics many characteristics of HFpEF patients, such as concentric cardiac hypertrophy, slow LV relaxation, and increased LV stiffness with a chronic hypertensive background and may provide a valuable platform for understanding the pathophysiology of HFpEF, as well as facilitating preclinical investigation of potential therapies.