A high-fat, high-sucrose diet combined with streptozotocin induces a functional HFpEF phenotype in mice driven by metabolic disturbances rather than myocardial fibrosis.
Does a combined high-fat, high-sucrose diet and streptozotocin treatment induce cardiometabolic HFpEF in mice?
The DIO-STZ mouse model successfully replicates a functional HFpEF phenotype with distinct metabolic disturbances, providing a valuable tool for studying diabetes-associated HFpEF.
Absolute Event Rate: 0% vs 0%
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.
Heinen et al. (Wed,) reported a other. A high-fat, high-sucrose diet combined with streptozotocin induces a functional HFpEF phenotype in mice driven by metabolic disturbances rather than myocardial fibrosis.