Myocardial substrate metabolism and regional ventricular wall deformation are altered in a diabetes associated HFpEF mouse model

Heart failure with preserved ejection fraction (HFpEF) represents a disease with high morbidity and mortality. Epidemiological data show that Diabetes mellitus is associated with an increased incidence of HFpEF, but the underlying pathophysiological mechanisms are poorly understood. Partly responsible for this inadequate understanding is a shortage of appropriate preclinical mouse models to investigate disease mechanisms.
We demonstrated that a combined treatment of male C57Bl/6J mice with high fat/high sucrose diet (DIO) and streptozotocin (STZ) causes a strong cardiometabolic HFpEF phenotype as seen by reduced cardiac output, unaltered ejection fraction, decreased end-diastolic volume and increased LV-filling pressure compared to chow-fed non-diabetic controls (con). A decrease in the reverse-peak of global longitudinal strain rate (rpGLS) further indicated a diastolic dysfunction. Blood glucose, fatty acids and ketone bodies were elevated, and insulin plasma level was reduced in DIO-STZ animals. No difference in arterial blood pressure was found. As indication of myocardial fibrosis, a 2-3 fold increase in expression of fibrosis-associated genes Postn, Acta2 and Col3a1, as well as an increase in WGA-staining was detected. Pathway analysis of RNASeq-Data strongly pointed towards alterations in energy metabolism, especially fatty acid oxidation. DIO-STZ mice showed an increased expression of PDK4 compared to healthy controls. Furthermore, genes associated with fat metabolism (e.g. CD36, CPT1b, or CPT2) were strongly upregulated, further supporting alterations in myocardial substrate metabolism. Extracellular flux analysis of intact ventricular tissue slices using glucose as well as palmitate as substrates revealed an increase in oxygen consumption rate (OCR) by 40% in DIO-STZ animals, whilst non-mitochondrial OCR was unchanged. In addition, pharmacological inhibition of CPT1 by etomoxir reduced maximal OCR to a larger extent in DIO-STZ myocardium indicating an improved capacity for long-chain fatty acid oxidation (61±5% vs 46±8%). In contrast, no difference in the capacity for glucose oxidation was observed. Furthermore, echocardiographic analysis of myocardial contraction cycle revealed abnormal ventricular geometry in DIO-STZ animals as seen by alterations in ventricular sphericity. Here, segmental strain analysis identified pronounced spatial differences, e.g. DIO-STZ hearts showed increased circumferential strain in the inferior wall segment and no change in the lateral wall, potentially contributing to the altered ventricular geometry.
In summary, the DIO-STZ mouse model, which presents the functional phenotype of HFpEF as well as a disturbed myocardial substrate metabolism, might be a promising tool to investigate pathophysiological mechanisms of cardiometabolic HFpEF.