Plasma metabolomics implicate modified transfer RNAs and altered bioenergetics in the outcome of pulmonary arterial hypertension

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Title: Plasma metabolomics implicate modified transfer RNAs and altered bioenergetics in the outcome of pulmonary arterial hypertension
Authors: Rhodes, CJ
Ghataorhe, P
Wharton, J
Rue-Albrecht, K
Hadinnapola, C
Watson, G
Bleda, M
Haimel, M
Coghlan, G
Corris, P
Howard, LS
Kiely, DG
Peacock, AJ
Pepke-Zaba, J
Toshner, MR
Wort, SJ
Gibbs, JSR
Lawrie, A
Graf, S
Morrell, NW
Wilkins, MR
Item Type: Journal Article
Abstract: Background: Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality. Method: We conducted a comprehensive study of plasma metabolites using ultra-performance liquid chromatography mass-spectrometry to (1) identify patients at high risk of early death, (2) identify patients who respond well to treatment and (3) provide novel molecular insights into disease pathogenesis. Results: 53 circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy controls (n=121) following correction for multiple testing (p<7.3e-5) and confounding factors, including drug therapy, renal and hepatic impairment. A subset of 20/53 metabolites also discriminated PAH patients from disease controls (symptomatic patients without pulmonary hypertension, n=139). 62 metabolites were prognostic in PAH, with 36/62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), TCA cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan and polyamine metabolites and decreased levels of steroids, sphingomyelins and phosphatidylcholines distinguished patients from controls. 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 healthy controls. Conclusion: Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterisation 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 characterise these patients.
Issue Date: 21-Nov-2016
Date of Acceptance: 9-Nov-2016
ISSN: 0009-7322
Publisher: American Heart Association
Start Page: 460
End Page: 475
Journal / Book Title: Circulation
Volume: 135
Copyright Statement: © 2016 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Sponsor/Funder: British Heart Foundation
National Institute for Health Research
British Heart Foundation
Medical Research Council (MRC)
Wellcome Trust
British Heart Foundation
Funder's Grant Number: RG/10/16/28575
RG68204 13/EE/0203 A092860
Keywords: hypertension, pulmonary
pulmonary circulation
Cardiovascular System & Hematology
1103 Clinical Sciences
1102 Cardiovascular Medicine And Haematology
1117 Public Health And Health Services
Publication Status: Published
Appears in Collections:National Heart and Lung Institute
Department of Medicine
Faculty of Medicine

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