Heart failure with preserved ejection fraction (HFpEF) has emerged as a public health burden with currently no effective medication. We assessed the treatment effects of the incretin hormone glucagon-like peptide-1 (GLP-1) on cardiac metabolism and function in a model of HFpEF. Following aortic banding, rats developed HFpEF characterized by diastolic dysfunction, pulmonary congestion, and poor survival (38%). A 4-week GLP-1 treatment via osmotic pumps significantly improved survival (70%) and reduced left ventricular stiffness, diastolic dysfunction, and pulmonary congestion. Isolated heart perfusion revealed preserved cardiac glucose oxidation (GO) and a shift in cardiac substrate utilization towards GO. While GLP-1 may boost insulin secretion and responsiveness, the protective effects were not related to cardiac insulin action. GLP-1 improves diastolic function and survival in rats with HFpEF, which was associated with a cardiac substrate switch towards GO. The therapeutic role of GLP-1 in HFpEF is new and warrants further investigation.

In heart failure, high‐fat diet (HFD) may exert beneficial effects on cardiac mitochondria and contractility. Skeletal muscle mitochondrial dysfunction in heart failure is associated with myopathy. However, it is not clear if HFD affects skeletal muscle mitochondria in heart failure as well. To induce heart failure, we used pressure overload (PO) in rats fed normal chow or HFD. Interfibrillar mitochondria (IFM) and subsarcolemmal mitochondria (SSM) from gastrocnemius were isolated and functionally characterized. With PO heart failure, maximal respiratory capacity was impaired in IFM but increased in SSM of gastrocnemius. Unexpectedly, HFD affected mitochondria comparably to PO. In combination, PO and HFD showed additive effects on mitochondrial subpopulations which were reflected by isolated complex activities. While PO impaired diastolic as well as systolic cardiac function and increased glucose tolerance, HFD did not affect cardiac function but decreased glucose tolerance. We conclude that HFD and PO heart failure have comparable effects leading to more severe impairment of IFM. Glucose tolerance seems not causally related to skeletal muscle mitochondrial dysfunction. The additive effects of HFD and PO may suggest accelerated skeletal muscle mitochondrial dysfunction when heart failure is accompanied with a diet containing high fat.

Introduction: Aerobic exercise capacity is inversely related to morbidity and mortality as well as to insulin resistance. However, exercising in patients has led to conflicting results, presumably because aerobic exercise capacity consists of intrinsic (genetically determined) and extrinsic (environmentally determined) parts. The contribution of both parts to insulin sensitivity is also not clear. We investigated sedentary and exercised (aerobic interval training) high (HCR) and low capacity runners (LCR) differing in their genetically determined aerobic exercise capacity to determine the contribution of both parts to insulin sensitivity. Methods and Results: LCR and HCR differed in their untrained exercise capacity and body weight. Sedentary LCR displayed a diabetic phenotype with higher random glucose, lower glucose infusion rate during hyperinsulinemic euglycemic clamping than HCR. Echocardiography showed equal morphological and functional parameters and no change with exercise. Four weeks of exercise caused significant improvements in aerobic exercise capacity, which was more pronounced in LCR. However, with respect to glucose use, exercise affected HCR only. In these animals, exercise increased 2-deoxyglucose uptake in gastrocnemius (+58.5 %, p= 0.1) and in epididymal fat (+106 %; p<0.05). Citrate synthase activity also increased in these tissues (gastrocnemius 69 % epididymal fat 63 %). Conclusion: In our model of HCR and LCR, genetic predisposition for low exercise capacity is associated with impaired insulin sensitivity and impedes exercise-induced improvements in insulin response. Our results suggest that genetic predisposition for low aerobic exercise capacity impairs insulin response, which may not be overcome by exercise.