Grant Abstract: Genomic and Circulating Predictors of PAH response

Grant Number: 3R01HL142720-02
PI Name: Hemnes
Project Title: Genomic and Circulating Predictors of PAH response

Abstract: Nearly half of patients with pulmonary arterial hypertension (PAH) die within five years of diagnosis. The primary cause of death is right ventricular (RV) failure, yet RV failure remains poorly understood and without specific therapies. We have previously found that a key feature of RV failure altered lipid metabolism in RV myoctyes with decreased fatty acid oxidation. Carnitine links to acyl groups and shuttles fatty acids across the mitochondrial membrane to undergo fatty acid oxidation and is widely available as a dietary supplement. Some inborn errors of metabolism can be corrected with supplemental carnitine, thus dosing in humans is well defined and the supplement is well tolerated. We have demonstrated a relative carnitine deficiency in the PAH RV using human tissue and indirect evidence for inadequate carnitine delivery through the plasma in PAH patients. We have found in preliminary data that carnitine supplementation in a rodent model of RV failure improves RV function and enhances fatty acid oxidation. We now aim to translate this early rodent finding to humans. Carnitine supplementation is widely used as an over the counter supplement that is well tolerated by the general population, but the frequency of use is unknown in PAH. This administrative supplement aims to 1) define carnitine intake in patients with pulmonary arterial hypertension through food diaries, 2) define plasma carnitine levels in patients with pulmonary arterial hypertension and 3) perform a pilot study of carnitine supplementation in patients with pulmonary arterial hypertension to determine if carnitine levels can be changed in the plasma and carnitine supplementation is tolerable. The studies proposed herein will provide key mechanistic preliminary data that will enable us to propose a mechanistic clinical trial of carnitine supplementation in PAH. The long-term goal is to develop effective metabolic therapy for right heart failure in human pulmonary arterial hypertension.

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