A Novel Mouse Model of Cardiometabolic Heart Failure with Preserved Ejection Fraction

Abstract

Background Heart failure with preserved ejection fraction (HFpEF) is considered one of the greatest unmet clinical needs in cardiology that currently affects approximately 13 million people. With a lack of FDA-approved therapies, translational animal modeling is essential to identify beneficial HFpEF therapies with potential clinical impact. One recently reported murine HFpEF model involves C57/BL6N mice treated with high-fat diet (HFD) plus the eNOS inhibitor, L-NAME, on a continuous basis. The chronic administration of L-NAME fails to mimic human HFpEF and limits the study of therapies that modulate eNOS function and nitric oxide modulation. In the present study, we explored the combination of a Western high-fat (HFD) and the eNOS inhibitor, L-NAME administered continuously vs. HFD administration followed by withdrawal of L-NAME. Methods C57/BL6N mice at 10-12 weeks old (n = 4-8 per study group) were placed on a Western HFD (60% kCal from fat) and 0.5 g/L/d L-NAME via drinking water. At 20-22 weeks of age, 10 weeks into the protocol, L-NAME was withdrawn (WD) in one group while the HFD was maintained throughout the experimental protocol. We continued to assess the HFpEF phenotype in both study groups (HFD + L-NAME vs. HFD + L-NAME WD) as compared to age-matched control for an additional 5 weeks. Results Following L-NAME withdrawal (n=8) we observed that the cardiometabolic HFpEF phenotype was maintained in the C57/BL6N mice. (A). Diastolic functional measure E/E’ ratio remained pathologically elevated compared to untreated control animals (n=7) (B). Preservation of left ventricular ejection fraction (LVEF) was observed in the absence of L-NAME removal demonstrating continued preservation of ejection fraction. Conclusion These data clearly demonstrate that the severe cardiometabolic HFpEF phenotype is maintained in C57/BL6N mice following 10 weeks of exposure to Western diet and L-NAME despite withdrawal of the NO inhibitor. These data indicate that the deleterious effects of L-NAME induced during the initial 10 weeks of the protocol results in sustained cardiovascular dysfunction. This novel HFpEF model more faithfully reproduces HFpEF observed in patients and allows for the investigation of eNOS enzymatic function and nitric oxide modulation in this pre-clinical animal model.