Exercise-induced cardiac adaptation in hypertrophic cardiomyopathy

点击翻译按钮获取中文摘要

PROJECT SUMMARY Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people and can lead to heart failure and sudden cardiac death. Mutations in genes encoding sarcomere proteins are responsible for a majority of HCM cases. These mutations induce a more disordered, energetically inefficient myosin conformation, which increases ATP utilization, leading to metabolic dysfunction and hypercontractility, and eventually, cardiac hypertrophy and dysfunction. Moderate endurance training improves cardiovascular function and metabolic health overall, reducing the risk for cardiovascular morbidity and mortality. However, current guidelines recommend that HCM patients limit exercise, leading to reduced levels of physical activity in this patient population. Contrary to this, recent evidence demonstrates that moderate and high-intensity endurance exercise training is safe and clinically beneficial for patients with HCM. However, the mechanisms behind exercise-induced cardiac adaptation in HCM are unknown. The hypothesis behind the proposed work is that systemic factors induced by repeated endurance exercise ameliorate the pathogenic phenotype in sarcomeric HCM by improving the energetically inefficient myosin structure and associated cardiomyocyte metabolic dysfunction. To address this hypothesis, the cardioprotective effects of exercise in HCM will be investigated in a well-established mouse model of HCM, in human HCM patients and in patient-specific iPSC-derived cardiomyocytes. In Aim 1, to determine if exercise training decelerates disease progression in HCM, deep metabolic and contractile phenotyping will be performed in cardiac tissue and isolated ventricular myocytes from trained and untrained mice. In Aim 2, the systemic effects of exercise are evaluated in response to a 30 min bout of exercise, where HCM patients are compared to healthy individuals. While long-term exercise training promotes health, this is driven by signalling events from individual exercise bouts. Serum from before and after exercise will be subjected to untargeted metabolomics, semi-targeted lipidomics and a multiplex cytokine assay analysis to identify potential mediators of the beneficial effects of exercise and determine the predictive power of metabolomics for cardiorespiratory fitness in HCM patients. Finally, Aim 3 will determine whether these exercise-induced systemic factors ameliorate the contractile and metabolic dysfunction of HCM; for this, iPSC-derived cardiomyocytes from HCM patients will be used as a model system. In addition, in vivo studies will be conducted in a mouse model of HCM. Altogether, exercise is an accessible intervention to improve health and overall quality of life, and through these innovative experiments I expect to delineate the mechanisms by which exercise improves health in HCM. By extension, I expect this work to reveal novel therapeutic targets for a disease where only symptom-alleviating drugs are available, and the results can be leveraged to encourage health-promoting exercise in this patient population.