People living with HIV infection (PLWH) on ART live longer today but the incidence and prevalence of chronic diseases is significantly higher that it is in those without HIV. As many as 50% of PLWH today have been reported to have left ventricular diastolic dysfunction (DD), which is associated with atrial fibrillation, exercise intolerance, and the progression to heart failure with preserved ejection fraction (HFpEF). The responsible mechanisms for DD and its progression in contemporary PLWH populations are poorly understood but our preliminary studies suggest that impaired cardiac energy metabolism may be a central factor linking previously reported risk factors to DD. ATP is absolutely required for the normal myocellular relaxation and considerable pre-clinical data and our pilot clinical studies using 31P magnetic resonance spectroscopy (MRS) suggest an “energetic myopathy” as a basis for the DD in PLWH. In addition, inflammation is increased despite combined ART and viral suppression in PLWH and is known to impair mitochondrial function. We propose here to examine cardiac high energy phosphate metabolism, its causes, and its relationship to left ventricular diastolic dysfunction (DD) and DD progression in PLWH. The central hypothesis is that cardiac mitochondrial energy metabolism is impaired even in well-treated PLWH, and promotes the development and progression of DD in PLWH as well as the consequences of DD including cardiac remodeling and HFpEF assessed with echocardiography, increased circulating heart failure biomarkers, heart failure symptoms and decreased exercise performance. The specific aims are 1) to define the scope and extent of myocardial energetic abnormalities at rest and exercise using 31P MRS/MRI in PLWH, 2) to probe the factors underlying cardiac muscle mitochondrial and energetic abnormalities in PLWH, including those unique to PLWH (ART history and cumulative viral history) and others more common in PLWH (increased inflammation, immune activation, insulin resistance, cardiac fibrosis, and/or higher cardiac muscle lipids by MRI), and 3) to determine the functional consequences of observed cardiac muscle energetic changes in PLWH, particularly the presence and progression of DD. The studies will leverage the expertise, resources, and established PLWH cohorts at Johns Hopkins and collect novel cardiac energetic, diastolic function, quantitative exercise tolerance and biomarker data. The results of these studies will deliver novel understandings of the type and extent of myocardial energetic-mitochondrial abnormalities in PLWH, the factors prevalent in PLWH that are most closely related to impaired cardiac mitochondrial-energetic metabolism, and the functional consequences, most importantly diastolic dysfunction. These studies, characterizing the presence and functional consequences of what appears to be a “mitochondriopathy” of cardiac and skeletal muscle in PLWH promise new avenues to better understand the pathophysiology...