title: Metabolic Profiling of Right Ventricular-Pulmonary Vascular Function Reveals Circulating Biomarkers of Pulmonary Hypertension.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Electronic address: glewis@partners.org.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Lewis
authors.affiliation: Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Debby
authors.initials: D
authors.lastname: Ngo
authors.affiliation: Vanderbilt University Pulmonary Unit, Nashville, Tennessee.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Hemnes
authors.affiliation: Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Laurie
authors.initials: L
authors.lastname: Farrell
authors.affiliation: Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Carly
authors.initials: C
authors.lastname: Domos
authors.affiliation: Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Pappagianopoulos
authors.affiliation: Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Bishnu P
authors.initials: BP
authors.lastname: Dhakal
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Amanda
authors.initials: A
authors.lastname: Souza
authors.affiliation: Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Xu
authors.initials: X
authors.lastname: Shi
authors.affiliation: Vanderbilt University Pulmonary Unit, Nashville, Tennessee.
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Pugh
authors.affiliation: Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Arkadi
authors.initials: A
authors.lastname: Beloiartsev
authors.affiliation: Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sumita
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: rgerszten@partners.org.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D062186:Arterial Pressure / Q000502:physiology; D015415:Biomarkers / Q000097:blood; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D011652:Pulmonary Circulation / Q000502:physiology; D011687:Purines / Q000378:metabolism*; D015203:Reproducibility of Results; D013223:Statistics as Topic; D014233:Tricarboxylic Acids / Q000378:metabolism*; D014655:Vascular Resistance / Q000502:physiology; D018497:Ventricular Dysfunction, Right / Q000175:diagnosis / Q000378:metabolism
chemical_list: D015415:Biomarkers; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011687:Purines; D014233:Tricarboxylic Acids; D009569:Nitric Oxide; D001120:Arginine
keywords: exercise; hemodynamics; metabolism; pulmonary circulation