Metabolic Profiling of Right Ventricular-Pulmonary Vascular Function Reveals Circulating Biomarkers of Pulmonary Hypertension.
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Abstract | BACKGROUND: Pulmonary hypertension and associated right ventricular (RV) dysfunction are important determinants of morbidity and mortality, which are optimally characterized by invasive hemodynamic measurements. OBJECTIVES: This study sought to determine whether metabolite profiling could identify plasma signatures of right ventricular-pulmonary vascular (RV-PV) dysfunction. METHODS: We measured plasma concentrations of 105 metabolites using targeted mass spectrometry in 71 individuals (discovery cohort) who underwent comprehensive physiological assessment with right-sided heart catheterization and radionuclide ventriculography at rest and during exercise. Our findings were validated in a second cohort undergoing invasive hemodynamic evaluations (n = 71), as well as in an independent cohort with or without known pulmonary arterial (PA) hypertension (n = 30). RESULTS: In the discovery cohort, 21 metabolites were associated with 2 or more hemodynamic indicators of RV-PV function (i.e., resting right atrial pressure, mean PA pressure, pulmonary vascular resistance [PVR], and PVR and PA pressure-flow response [ΔPQ] during exercise). We identified novel associations of RV-PV dysfunction with circulating indoleamine 2,3-dioxygenase (IDO)-dependent tryptophan metabolites (TMs), tricarboxylic acid intermediates, and purine metabolites and confirmed previously described associations with arginine-nitric oxide metabolic pathway constituents. IDO-TM levels were inversely related to RV ejection fraction and were particularly well correlated with exercise PVR and ΔPQ. Multisite sampling demonstrated transpulmonary release of IDO-TMs. IDO-TMs also identified RV-PV dysfunction in a validation cohort with known risk factors for pulmonary hypertension and in patients with established PA hypertension. CONCLUSIONS: Metabolic profiling identified reproducible signatures of RV-PV dysfunction, highlighting both new biomarkers and pathways for further functional characterization. |
Year of Publication | 2016
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Journal | J Am Coll Cardiol
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Volume | 67
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Issue | 2
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Pages | 174-89
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Date Published | 2016 Jan 19
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ISSN | 1558-3597
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DOI | 10.1016/j.jacc.2015.10.072
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PubMed ID | 26791065
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PubMed Central ID | PMC4962613
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Grant list | UL1 TR000445 / TR / NCATS NIH HHS / United States
R01 HL119154 / HL / NHLBI NIH HHS / United States
R01 HL131029 / HL / NHLBI NIH HHS / United States
R01 DK081572 / DK / NIDDK NIH HHS / United States
R01 HL098280 / HL / NHLBI NIH HHS / United States
K23 HL091106 / HL / NHLBI NIH HHS / United States
K01 GM103817 / GM / NIGMS NIH HHS / United States
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