Fatty Acid Metabolic Defects and Right Ventricular Lipotoxicity in Human Pulmonary Arterial Hypertension.

Circulation
Authors
Keywords
Abstract

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.

Year of Publication
2016
Journal
Circulation
Volume
133
Issue
20
Pages
1936-44
Date Published
2016 May 17
ISSN
1524-4539
URL
DOI
10.1161/CIRCULATIONAHA.115.019351
PubMed ID
27006481
PubMed Central ID
PMC4870107
Links
Grant list
R01 HL095797 / HL / NHLBI NIH HHS / United States
K08 HL121174 / HL / NHLBI NIH HHS / United States
K08 HL093363 / HL / NHLBI NIH HHS / United States
UL1 RR024975 / RR / NCRR NIH HHS / United States
P01 HL108800 / HL / NHLBI NIH HHS / United States
R01 HL122417 / HL / NHLBI NIH HHS / United States
L30 HL129281 / HL / NHLBI NIH HHS / United States
K23 HL098743 / HL / NHLBI NIH HHS / United States