Abstract 4139791: A short version of HFD/L-NAME mouse model enabling time-effective proof of concept studies to evaluate drugs targeting the cardiometabolic and mild hypertension associated HFpEF phenotype
Abstract
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…
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