Fatty acid metabolic defects and right ventricular lipotoxicity in human pulmonary arterial hypertension

EL Brittain, M Talati, JP Fessel, H Zhu, N Penner… - Circulation, 2016 - Am Heart Assoc
EL Brittain, M Talati, JP Fessel, H Zhu, N Penner, MW Calcutt, JD West, M Funke, GD Lewis
Circulation, 2016Am Heart Assoc
Background—The mechanisms of right ventricular (RV) failure in pulmonary arterial
hypertension (PAH) are poorly understood. Abnormalities in fatty acid (FA) metabolism have
been described in experimental models of PAH, but systemic and myocardial FA metabolism
has not been studied in human PAH. Methods and Results—We used human blood, RV
tissue, and noninvasive imaging to characterize multiple steps in the FA metabolic pathway
in PAH subjects and controls. Circulating free FAs and long-chain acylcarnitines were …
Background
The mechanisms of right ventricular (RV) failure in pulmonary arterial hypertension (PAH) are poorly understood. Abnormalities in fatty acid (FA) metabolism have been described in experimental models of PAH, but systemic and myocardial FA metabolism has not been studied in human PAH.
Methods and Results
We used human blood, RV tissue, and noninvasive imaging to characterize multiple steps in the FA metabolic pathway in PAH subjects and controls. Circulating free FAs and long-chain acylcarnitines were elevated in PAH patients versus controls. Human RV long-chain FAs were increased and long-chain acylcarnitines were markedly reduced in PAH versus controls. With the use of proton magnetic resonance spectroscopy, in vivo myocardial triglyceride content was elevated in human PAH versus controls (1.4±1.3% triglyceride versus 0.22±0.11% triglyceride, P=0.02). Ceramide, a mediator of lipotoxicity, was increased in PAH RVs versus controls. Using an animal model of heritable PAH, we demonstrated reduced FA oxidation via failure of palmitoylcarnitine to stimulate oxygen consumption in the PAH RV.
Conclusions
Abnormalities in FA metabolism can be detected in the blood and myocardium in human PAH and are associated with in vivo cardiac steatosis and lipotoxicity. Murine data suggest that lipotoxicity may arise from reduction in FA oxidation.
Am Heart Assoc