ABSTRACT Most patients with pulmonary arterial hypertension (PAH) die from right ventricular (RV) failure and all experience exercise limitation. No RV-specific therapies exist because the mechanisms underlying RV failure are poorly understood. The discovery of novel, potentially treatable causes of RV failure and exercise limitation would be an important advance in the treatment of PAH. RV steatosis may be a novel mechanism of RV failure in human PAH. We and others reported a high prevalence of insulin resistance in patients with PAH. We recently published that insulin resistance in PAH manifests primarily as abnormalities in lipid metabolism. Patients with PAH had elevated circulating free fatty acids and long-chain acylcarnitines and we found impaired mitochondrial fatty acid oxidation and RV lipid accumulation (steatosis) in a rodent model of PAH. We used proton magnetic resonance spectroscopy (MRS) to quantify RV lipid in vivo and showed that RV lipid content is over 10-fold higher in humans with PAH compared with matched controls and may be modifiable with metformin. In autopsy RV specimens, we found increased ceramide, a mediator of lipotoxicity, and identified candidate plasma surrogates for RV steatosis. Finally, we present new evidence of skeletal muscle steatosis in humans to demonstrate that insulin resistance is a systemic feature of PAH. The clinical relevance of RV steatosis in human PAH is unknown. RV steatosis is common in both heritable and idiopathic PAH and is not an end-stage phenomenon, which suggests potential for therapeutic intervention. We hypothesize that abnormal lipid metabolism in PAH leads to delivery of fatty acids in excess of RV oxidative capacity, resulting in steatosis and lipotoxicity. Our objectives are to: 1) Define the relationships between RV steatosis, RV function, and exercise capacity; 2) Identify mechanistic drivers of RV steatosis including BMPR2 expression and lipid metabolism; 3) Examine lipid metabolism in PAH skeletal muscle as a potential driver of reduced functional capacity; and 4) test the response of RV and skeletal muscle steatosis to metformin. In Aim 1 (clinical relevance) we will measure RV and LV lipid in participants with heritable, idiopathic, and scleroderma- associated PAH. Participants will undergo the 6-minute walk test, cardiopulmonary exercise testing, and will be followed for clinical events. A subgroup will undergo repeat MRS at four timepoints over three years to determine the natural history of steatosis. We will measure RV lipid in participants before and after metformin therapy in a separate on-going study. In Aim 2 (mechanism), we will perform metabolomic/lipidomic profiling of peripheral and coronary sinus plasma and measure BMPR2 expression to identify potential drivers of steatosis. In Aim 3 (specificity), we will perform MRS on skeletal muscle in Aim 1 participants and matched healthy controls to clarify the systemic effects of lipid metabolic defects in PAH. We will a...