PROJECT SUMMARY / ABSTRACT The candidate recently joined the staff at Massachusetts General Hospital (MGH) in the Cardiovascular Performance Program (CPP), a unique group whose goals include conducting top-caliber human health and performance research. A core mission of the CPP is to use longitudinal study design to examine cardiac adaptations to exercise. This proposal expands this model in a novel direction to evaluate cardiac metabolism using positron emission tomography (PET) through research collaboration with Brigham and Women's Hospital. This proposal focuses on left ventricular hypertrophy (LVH), which develops in numerous cardiac diseases, including hypertrophic cardiomyopathy (HCM), and has independent negative prognostic implications. In contrast to pathologic LVH, exercise-induced LVH (EI-LVH) is generally considered adaptive. Differentiating whether LVH is due to exercise or HCM is a clinical challenge with critical implications because HCM is the top cause of sudden death in young athletes. Though myocardial metabolism appears to be impaired in forms of pathologic LVH and is linked to the development of heart failure, comparatively little is known about myocardial metabolism in EI- LVH. The two major goals of this research proposal are to define if myocardial metabolic profiling will be capable of definitively differentiating EI-LVH from HCM AND, through this, to gain further mechanistic insight into how exercise capacity and myocardial function differ so widely in these two forms of LVH. Specifically, we hypothesize that characterization of myocardial metabolic efficiency (MME), substrate utilization, microvascular function, and circulating corollary plasma microRNAs (miRNA) will provide scientifically novel and clinically superior techniques for separating adaptive from pathologic LVH. To achieve these goals, the applicant proposes a longitudinal, repeated measures study in which athletes will be examined using cardiac PET, echocardiography, and circulating miRNA profiling before and after sport- specific exercise training. Cardiac PET assessment will include measurement of myocardial oxidative metabolism, metabolic efficiency, and substrate utilization, both at rest and with acute exercise provocation. The myocardial metabolic profiles of trained athletes with LVH will be compared to that of patients with mild HCM and healthy controls, who will be similarly studied in the absence of an exercise training intervention. The candidate's career development plan includes advanced training in exercise physiology, cardiac imaging, and research methodology, all under the mentorship of a unique multidisciplinary team. The science proposed in this grant will set the stage for future studies designed to manipulate myocardial metabolism across the spectrums of adaptive physiology and cardiovascular disease, which will form the basis of the candidate's future R01 proposals. Over the course of the K23 award, the candidate's goal is to devel...