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Circulation. 2016 May 17;133(20):1936-44. doi: 10.1161/CIRCULATIONAHA.115.019351. Epub 2016 Mar 22.

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

Author information

1
From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.). evan.brittain@vanderbilt.edu.
2
From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.).

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.

KEYWORDS:

fatty acids; heart ventricles; hypertension, pulmonary; lipid metabolism; lipids; magnetic resonance spectroscopy; pulmonary circulation

PMID:
27006481
PMCID:
PMC4870107
DOI:
10.1161/CIRCULATIONAHA.115.019351
[Indexed for MEDLINE]
Free PMC Article

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