Abstract Body (Do not enter title and authors here): Intro: Drug Development for Heart failure with Preserved Ejection Fraction (HFpEF) is a major challenge facing cardiovascular research due to its complex pathophysiology and existence of comorbidities, leading to recognize distinct HFpEF phenogroups. Animal model development should consider this heterogeneity and each model capturing features of specific phenogroups.

Hypothesis: We established a 2-hit model consistent with one of the leading phenogroups, the cardiometabolic and mild hypertension associated HFpEF, by combining a high fat diet to trigger obesity/metabolic syndrome and L-NAME to induce mild hypertension (HFD/L-NAME). We evaluated the presence of HFpEF hallmark and corroborated our data with literature. Empagliflozin (EMPA), the clinical benchmark, was used to confirm the relevance of the model.

Methods: To induce obesity/metabolic syndrome, mild and HFpEF, C57BL6N mice were fed HFD (60% Kcal from fat) and water with L-NAME (0.5g/l) for 8 weeks. Control mice (Ctrl) were fed normal chow and water. At 5weeks, mice were randomized based on E/A ratio and ejection fraction and were treated QD for 3weeks with vehicle or EMPA (10mg/kg). Then, treadmill exercise tolerance test was performed, cardiac geometry, systolic and diastolic function were evaluated by echocardiography and heart and lungs were harvested. Longitudinal blood pressure was evaluated by tail cuff.

Results: Compared with Ctrl, HFD/L-NAME mice showed cardiac remodeling, preserved systolic function and moderate diastolic dysfunction characterized by inverted or pseudonormal profiles and higher filling pressure (E/A=1.2±0.04 E’/A’=1.1±0.02 E/E’=16.4±0.6 in HFD/L-NAME vs E/A=1.4 ± 0.02 E’/A’=1.3±0.01 E/E’=14.4±0.4 in Ctrl). HFD/L-NAME mice showed altered exercise capacity (p<0.05 for running distance and time vs. Ctrl). Cardiac hypertrophy was confirmed by increased heart weight (p<0.01 vs. Ctrl). Consistent with elevated filling pressure, lung weight was increased in HFD/L-NAME mice (p<0.01 vs. Ctrl), indicative of pulmonary congestion. Mean blood pressure was consistently increased in HFD/L-NAME mice (p<0.05 vs. Ctrl). EMPA had positive outcome on cardiac remodeling in terms of left ventricle hypertrophy and enlargement (p<0.05 vs. Ctrl) and alleviated diastolic dysfunction.

Conclusion: The 8-week HFD diet/L-NAME captures several aspects of patients suffering from moderate HFpEF associated to obesity/metabolic syndrome and mild hypertension allowing cost and time effective POC studies.