Impact of intrinsic and acquired aerobic exercise capacity on pressure overload induced heart failure development

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Clinical studies demonstrate a strong relationship between aerobic exercise capacity and all cause morbidity and mortality. Low exercise capacity is a stronger predictor of cardiovascular mortality than all other accepted risk factors such as body mass index, diabetes, or hypertension. In addition, this relationship holds true for both healthy individuals and patients with heart failure. Importantly, exercise capacity is composed of intrinsic (genetically determined) and acquired (training induced) components. It is the current notion, that the larger fraction of this exercise capacity is genetically determined and the smaller part can be trained. However, due to the natural genetic heterogeneity in humans, it is impossible to clearly distinguish the two parts in patients. Fortunately, the rat model of high (HCR) and low (LCR) capacity runners, developed using selective breeding after testing for intrinsic exercise capacity, allows for this distinction. Recent evidence indicates that a major difference in the phenotype of these genetically different animals may be caused by differences in mitochondrial function, specifically in substrate oxidation and ATP production, ROS production and tolerance, and calcium handling. The same mitochondrial functions play an important role in the development of heart failure. We already demonstrated changes in the entire mitochondrial proteome in pressure overload heart failure and specifically identified reduced complex I activity and elevated ROS production. Preliminary experiments in HCR and LCR suggest higher complex I activity in HCR which further increases with exercise. We now aim to assess the role of the genetically determined and the acquired part of exercise capacity on the propensity for PO-HF development (Specific Aim 1) and how mitochondrial respiratory capacity (specifically complex I), ROS production and tolerance, and calcium handling is related to differences in PO-HF development in our genetic model with or without exercise training (Specific Aim 2). This investigation is possible because of our genetic model of HCR and LCR. We will transfer our established heart failure model and other established and new investigational techniques to this genetic model. We will assess cardiac contractile and mitochondrial function with or without pressure overload and with or without exercise training. The results will allow for the first time assessing the propensity to develop heart failure influenced by 1) genetic determination of exercise capacity and 2) the specific impact of endurance training. They will further provide insight into the underlying mitochondrial mechanisms.