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Lookup NU author(s): Emeritus Professor Nick Europe-Finner
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Rhodes CJ, Ghataorhe P, Wharton J, Rue-Albrecht KC, Hadinnapola C, Watson G, Bleda M, Haimel M, Coghlan G, Corris PA, Howard LS, Kiely DG, Peacock AJ, Pepke-Zaba J, Toshner MR, Wort SJ, Gibbs JSR, Lawrie A, Graf S, Morrell NW, Wilkins MR
Publication type: Article
Publication status: Published
Journal: Circulation
Year: 2017
Volume: 135
Issue: 5
Pages: 460-475
Print publication date: 31/01/2017
Online publication date: 21/11/2016
Acceptance date: 09/11/2016
Date deposited: 13/04/2017
ISSN (print): 0009-7322
ISSN (electronic): 1524-4539
Publisher: Lippincott Williams & Wilkins
URL: https://doi.org/10.1161/CIRCULATIONAHA.116.024602
DOI: 10.1161/CIRCULATIONAHA.116.024602
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