Combined high-fat, high sucrose diet and streptozotocin treatment induces cardiometabolic heart failure with preserved ejection fraction in mice

Diabetes is associated with an increased incidence of heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms are poorly understood. A shortage of mouse models reflecting the diverse HFpEF pathophysiology contributes to this inadequate understanding of disease mechanisms. We conducted a comprehensive analysis of a non-genetic, inducible T2DM mouse model with regard to its suitability as preclinical model of cardiometabolic, diabetes-induced HFpEF. T2DM was induced in C57Bl/6-mice by high-fat/high-sucrose diet and low-dose streptozotocin (DIO-STZ). Cardiac function was assessed in vivo by echocardiography and left ventricular catheterization, and in vitro using the isolated perfused heart. Structural, molecular and bioenergetic disturbances were analyzed by immunohistochemistry, RNA-seq, qPCR, westernblot, and extracellular flux analysis of myocardial tissue. Blood glucose, fatty acids and ketone body levels were elevated, and insulin level was reduced in DIO-STZ compared to chow. DIO-STZ mice showed a HFpEF-phenotype with reduced cardiac output, end-diastolic volume, and increased filling pressure. No differences in myocardial fibrosis nor in in vitro stiffness were detected between DIO-STZ and chow. RNA-Seq pointed towards disturbances in lipid and ketone metabolism. Extracellular flux analysis revealed increased fatty acid oxidation capacity without differences in glucose metabolism. No general mitochondrial dysfunction was observed, but a reduced capacity for β-hydroxybutyrate oxidation. The diabetic DIO-STZ mouse model showed a pronounced functional HFpEF phenotype with underlying mechanisms that remarkably differ from other HFpEF models making the DIO-STZ model a relevant extension of the range of HFpEF mouse models, especially for investigating molecular mechanisms or therapeutical interventions in diabetes associated HFpEF.