Abstract 4368244: The effect of LCZ696 on cardiac function and structure in a novel, shortened cardio-metabolic mouse model of heart failure with preserved ejection fraction

Background: Current preclinical murine models for heart failure with preserved ejection fraction (HFpEF) require prolonged modeling periods, pose significant challenges to fast screening in drug development. In response, our study sought to develop a novel, shortened, multifactorial HFpEF mouse model that coupled obesity, hyperglycemia, hypertension and cardiac hypertrophy to closely mirrors the cardio-metabolic phenotypes observed in human patients. Methods: Diet-induced obesity (DIO) male mice were administered with angiotensin II (Ang II) for 4 weeks via osmotic mini pumps. LCZ696 (60mpk), a novel FDA-approved medicine in heart failure patients, was administrated (P.O., QD) one day after angiotensin II infusion for 4 weeks. Results: The adult (27 week-old) DIO male mice developed overt overweight and hyperglycemia. After 4-weeks infusion by Ang II, DIO mice were conducted with echocardiography to identify the left ventricle structural and functional alterations. Typical phenotypes as observed in human HFpEF patients, were detected in Ang II-induced DIO mice, for example, unchanged LVEF, elevated IVRT and increased heart weight and LVPWTs/d, indicating that the diastolic dysfunction and cardiac hypertrophy happened in the model mice. Post-life analysis, heart tissue collection and histopathalogical stainings revealed an increased level of cardiac fibrosis with infiltration of inflammatory cells. Blood chemistry analysis also revealed an upregulation in cardiac biomarker NT-proBNP and inflammatory biomarker IL-6. Administration of LCZ696 significantly attenuated the cardiometabolic abnormalities with restored diastolic function, reduced cardiac hypertrophy and myocardial fibrosis. Conclusion: We have successfully developed a rapid mouse model that closely mimics human HFpEF, with modeling time around 4 weeks and a robust validation using LCZ696, offering a fast, valuable new platform for advancing therapeutic development of HFpEF treatment.