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Circulation. 2017 Jan 31;135(5):460-475. doi: 10.1161/CIRCULATIONAHA.116.024602. Epub 2016 Nov 21.

Plasma Metabolomics Implicates Modified Transfer RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension.

Author information

1
From the Department of Medicine, Imperial College London, Hammersmith Campus, United Kingdom (C.J.R., P.G., J.W., K.C.R.-A., G.W., M.R.W.); Department of Medicine, University of Cambridge School of Clinical Medicine, United Kingdom (C.H., M.B., M.H., M.R.T., S.G., N.W.M.); Cardiology Department, Royal Free Hospital, London, United Kingdom (G.C.); Institute of Cellular Medicine, Newcastle University and the Newcastle Upon Tyne Hospitals NHS Foundation Trust, United Kingdom (P.A.C.); National Pulmonary Hypertension Service, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, United Kingdom (L.S.H., J.S.R.G.); National Heart and Lung Institute, Imperial College London, Hammersmith Campus, United Kingdom (L.S.H., J.S.R.G.); Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, United Kingdom (D.G.K.); Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, United Kingdom (D.G.K., A.L.); Scottish Pulmonary Vascular Unit, Golden Jubilee National Hospital, Glasgow, United Kingdom (A.J.P.); Pulmonary Vascular Disease Unit, Papworth Hospital, Cambridge, United Kingdom (J.P.Z., M.R.T.); Pulmonary Hypertension Service, Royal Brompton Hospital, London, United Kingdom (S.J.W.); and Department of Haematology, University of Cambridge, United Kingdom (S.G.).
2
From the Department of Medicine, Imperial College London, Hammersmith Campus, United Kingdom (C.J.R., P.G., J.W., K.C.R.-A., G.W., M.R.W.); Department of Medicine, University of Cambridge School of Clinical Medicine, United Kingdom (C.H., M.B., M.H., M.R.T., S.G., N.W.M.); Cardiology Department, Royal Free Hospital, London, United Kingdom (G.C.); Institute of Cellular Medicine, Newcastle University and the Newcastle Upon Tyne Hospitals NHS Foundation Trust, United Kingdom (P.A.C.); National Pulmonary Hypertension Service, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, United Kingdom (L.S.H., J.S.R.G.); National Heart and Lung Institute, Imperial College London, Hammersmith Campus, United Kingdom (L.S.H., J.S.R.G.); Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, United Kingdom (D.G.K.); Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, United Kingdom (D.G.K., A.L.); Scottish Pulmonary Vascular Unit, Golden Jubilee National Hospital, Glasgow, United Kingdom (A.J.P.); Pulmonary Vascular Disease Unit, Papworth Hospital, Cambridge, United Kingdom (J.P.Z., M.R.T.); Pulmonary Hypertension Service, Royal Brompton Hospital, London, United Kingdom (S.J.W.); and Department of Haematology, University of Cambridge, United Kingdom (S.G.). m.wilkins@imperial.ac.uk.

Abstract

BACKGROUND:

Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality.

METHODS:

We conducted a comprehensive study of plasma metabolites using ultraperformance liquid chromatography mass spectrometry to identify patients at high risk of early death, to identify patients who respond well to treatment, and to provide novel molecular insights into disease pathogenesis.

RESULTS:

Fifty-three circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy control subjects (n=121) after correction for multiple testing (P<7.3e-5) and confounding factors, including drug therapy, and renal and hepatic impairment. A subset of 20 of 53 metabolites also discriminated patients with PAH from disease control subjects (symptomatic patients without pulmonary hypertension, n=139). Sixty-two metabolites were prognostic in PAH, with 36 of 62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), tricarboxylic acid cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan, and polyamine metabolites and decreased levels of steroids, sphingomyelins, and phosphatidylcholines distinguished patients from control subjects. The largest differences correlated with increased risk of death, and correction of several metabolites over time was associated with a better outcome. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to those of healthy control subjects.

CONCLUSIONS:

Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterization of this disease. Our results support the investigation of targeted therapeutic strategies that seek to address the alterations in translational regulation and energy metabolism that characterize these patients.

KEYWORDS:

hypertension, pulmonary; metabolism; metabolome; metabolomics; pulmonary circulation

PMID:
27881557
PMCID:
PMC5287439
DOI:
10.1161/CIRCULATIONAHA.116.024602
[Indexed for MEDLINE]
Free PMC Article

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