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Plasma Metabolomics Implicates Modified Transfer RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension.
Rhodes, Christopher J; Ghataorhe, Pavandeep; Wharton, John; Rue-Albrecht, Kevin C; Hadinnapola, Charaka; Watson, Geoffrey; Bleda, Marta; Haimel, Matthias; Coghlan, Gerry; Corris, Paul A; Howard, Luke S; Kiely, David G; Peacock, Andrew J; Pepke-Zaba, Joanna; Toshner, Mark R; Wort, S John; Gibbs, J Simon R; Lawrie, Allan; Gräf, Stefan; Morrell, Nicholas W; Wilkins, Martin R.
Afiliación
  • Rhodes CJ; 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, Roy
  • Ghataorhe P; 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, Roy
  • Wharton J; 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, Roy
  • Rue-Albrecht KC; 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, Roy
  • Hadinnapola C; 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, Roy
  • Watson G; 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, Roy
  • Bleda M; 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, Roy
  • Haimel M; 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, Roy
  • Coghlan G; 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, Roy
  • Corris PA; 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, Roy
  • Howard LS; 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, Roy
  • Kiely DG; 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, Roy
  • Peacock AJ; 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, Roy
  • Pepke-Zaba J; 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, Roy
  • Toshner MR; 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, Roy
  • Wort SJ; 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, Roy
  • Gibbs JS; 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, Roy
  • Lawrie A; 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, Roy
  • Gräf S; 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, Roy
  • Morrell NW; 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, Roy
  • Wilkins MR; 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, Roy
Circulation ; 135(5): 460-475, 2017 01 31.
Article en En | MEDLINE | ID: mdl-27881557
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.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: ARN de Transferencia / Metabolómica / Hipertensión Pulmonar Tipo de estudio: Prognostic_studies Idioma: En Revista: Circulation Año: 2017 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: ARN de Transferencia / Metabolómica / Hipertensión Pulmonar Tipo de estudio: Prognostic_studies Idioma: En Revista: Circulation Año: 2017 Tipo del documento: Article