Cardio-Metabolic Traits of a Heart Failure with Preserved Ejection Fraction Mouse Model

Introduction: Heart failure with preserved ejection fraction (HFpEF, EF>50%) syndrome is often associated with hypertension, hyperlipidemia, obesity, and diabetes. Morbidity and mortality in patients with HFpEF are similar to those with heart failure with reduced ejection fraction, however therapies are scarce. Mouse models used to understand sarcomere dysfunction in HFpEF and to identify new targets are needed. In this study we challenged young mice with volume overload and metabolic perturbations induced by high fat diet (HFD) to harbor the conditions of HFpEF. Methods: C57BL/6N 16-weeks old female and male mice were treated with subcutaneous pellets of controlled released DOCA (Deoxycorticosterone Acetate, 0.71 mg/d), drinking water with 1% saline and HFD for a period of 3 weeks to induce obesity and mild hypertension. Cardiac function was evaluated at baseline (before treatment) and 2 and 3 weeks after treatment. Body weight, % fat mass, %lean mass, glucose tolerance test, and lipid profile were also evaluated at baseline and 3 weeks after treatment. Results (Table): Treatment induced diastolic dysfunction measurable by echocardiography at 3 weeks with slower peak myocardial relaxation velocity (e’), increased peak blood inflow velocity at early diastolic filling E/e’ ratio, increased E/A ratio, and increased isovolumetric relaxation time (IVRT). Meanwhile ejection fraction is preserved. As expected HFD feeding elicited body weight increase with increased fat mass accumulation associated with decreased lean mass, glucose intolerance and hypercholesterolemia. Conclusions: This study describes a mouse model of HFpEF that only requires 3 weeks of treatment with DOCA, 1% saline drinking water and HFD. This model reproduces the most common comorbidities of HFpEF such as diastolic dysfunction, obesity, glucose intolerance, and hypercholesterolemia, and may be used to understand the molecular pathophysiology of HFpEF.