Abstract Wed092: Embracing the complex pathophysiology of heart failure with preserved ejection fraction by developing rodent models to feature different patients’ phenogroups.

Heart failure with preserved ejection fraction (HFpEF) is complex clinical phenotype associated with multiple comorbidities; type2 diabetes, obesity, metabolic syndrome, Metabolic Dysfunction associated Steatohepatitis (MASH). No animal model captures all HFpEF variables. Thus, it is important to develop different models each replicating some features to optimize bench-to-bed translation. We developed 3 models each representing specific phenogroup of patients. Empagliflozin (EMPA), clinically proven SGLT-2i was used for validation. Methods: MASH related HFpEF was induced in male Golden Syrian hamsters fed free choice diet (free access to control chow/water or high fat/high cholesterol diet+10% fructose water). HFpEF associated with metabolic disorders was induced in C57Bl6N mice fed high-fat diet (60% kcal from fat) and water with L-NAME (0.5 g/L) for 5 weeks. Spontaneously Diabetic Torii (SDT) fatty rat was characterized as a model of diabetes/obesity-related HFpEF. EMPA or vehicle was administered orally at 10mg/kg for at least 3 weeks before evaluation of cardiac function by echocardiography and invasive hemodynamics. Results: While the systolic function was preserved in all models, different stages of diastolic dysfunction were observed. In HFD+L-NAME model, mild diastolic dysfunction characterized by pseudo-normal profiles was observed (E/A=1.2±0.04 E/E’= 16.2±0.9 in HFD/L-NAME vs E/A=1.4 ± 0.02 E/E’= 14.4±0.4 in control). Restrictive pattern (i.e. grade 3 diastolic dysfunction) was predominant in MASH hamster model (E/A= 2.16±0.09 E/E’=20.50±1.05 vs E/A 1.44±0.02 E/E’=14.23±0.9 in control) and in 12-week old SDT ( E/A=1.5±0.1 E/E’=19.5± 0.9 vs E/A= 1.2±0.04 E/E’=12.1±0.1 in control). EMPA alleviated partially the diastolic dysfunction and had positive outcome on cardiac remodeling in terms of left ventricle hypertrophy and enlargement (p<0.05). Conclusion: These results suggest that each of these models help features a specific phenogroup of HFpEF patients. One model does not fil all, thus it is probable that new therapies have to be tested in several models, each replicating some features of the disease to increase the success rate in clinical trials.