Lipid Deposition in the Right Ventricle in Pulmonary Arterial Hypertension

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DESCRIPTION (provided by applicant): Right ventricular failure is the primary cause of mortality in patients with pulmonary arterial hypertension and there currently are no therapies to reverse right ventricular dysfunction. Other's work and our own preliminary data have suggested altered metabolism including decreased fatty acid oxidation and lipid deposition may contribute to right ventricular failure in both human pulmonary arterial hypertension and in rodent models of RV dysfunction associated with pulmonary arterial hypertension. We have identified both fatty acid oxidation and increased lipid transport into cardiomyocytes as mechanisms that promote right ventricular lipid accumulation. Moreover, in preliminary data we have used MR spectroscopy to measure lipid deposition in the right ventricle of a patient with pulmonary arterial hypertension and found 10 fold higher percent triglyceride compared with controls. Based on these preliminary data, we now hypothesize that cardiomyocyte lipid deposition promotes RV failure in pulmonary arterial hypertension. Multiple mechanisms may result in right ventricular myocyte lipid deposition including Western diet resulting in increased lipid import or genetic mutations associated with impaired fatty acid oxidation with resultant accumulation of fatty acid metabolites and we propose two specific aims to study the mechanisms leading to lipid accumulation and the effect of deposition on right ventricular dysfunction. Our third specifi aim will translate these findings to humans in a trial of metabolic therapy for right ventricular failure with metformin and test the effect of this fatty acid oxidation enhancer on right ventriculr lipid measured by cardiac magnetic resonance spectroscopy. We will use cell culture, rodent model and human studies to study the mechanisms by which lipid deposition occurs, the functional consequences of lipid accumulation and if metabolic interventions to decrease lipid accumulation will improve right ventricular function in both rodent models and human disease. The long-term goal of these studies is to develop effective metabolic therapy for right heart failure in pulmonary arterial hypertension.