Rhodes, C.J., Ghataorhe, P., Wharton, J. et al. (18 more authors) (2017) Plasma Metabolomics Implicate Modified Transfer RNAs and Altered Bioenergetics in the Outcome of Pulmonary Arterial Hypertension. Circulation, 135 (5). pp. 460-475. ISSN 0009-7322
Abstract
BACKGROUND: -Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality. METHODS: -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. CONCLUSIONS: -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 characterize these patients.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 American Heart Association. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. |
Keywords: | metabolism; metabolome; metabolomics; pulmonary circulation; pulmonary hypertension |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection, Immunity and Cardiovascular Disease The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 07 Dec 2016 16:51 |
Last Modified: | 29 Oct 2018 13:59 |
Published Version: | https://doi.org/10.1161/CIRCULATIONAHA.116.024602 |
Status: | Published |
Publisher: | American Heart Association |
Refereed: | Yes |
Identification Number: | 10.1161/CIRCULATIONAHA.116.024602 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:109115 |