l-Carnitine therapy improves right heart dysfunction through Cpt1-dependent fatty acid oxidation

Pulmonary arterial hypertension (PAH) is a fatal vasculopathy that ultimately leads to elevated pulmonary pressure and death by right ventricular (RV) failure, which occurs in part due to decreased fatty acid oxidation and cytotoxic lipid accumulation. In this study, we tested the hypothesis that decreased fatty acid oxidation and increased lipid accumulation in the failing RV is driven, in part, by a relative carnitine deficiency. We then tested whether supplementation of l-carnitine can reverse lipotoxic RV failure through augmentation of fatty acid oxidation. In vivo in transgenic mice harboring a human BMPR2 mutation, l-carnitine supplementation reversed RV failure by increasing RV cardiac output, improving RV ejection fraction, and decreasing RV lipid accumulation through increased PPARγ expression and augmented fatty acid oxidation of long chain fatty acids. These findings were confirmed in a second model of pulmonary artery banding-induced RV dysfunction. In vitro, l-carnitine supplementation selectively increased fatty acid oxidation in mitochondria and decreased lipid accumulation through a Cpt1-dependent pathway. l-Carnitine supplementation improves right ventricular contractility in the stressed RV through augmentation of fatty acid oxidation and decreases lipid accumulation. Correction of carnitine deficiency through l-carnitine supplementation in PAH may reverse RV failure.