title: Elevation of plasma cell-free hemoglobin in pulmonary arterial hypertension.
abstract: BACKGROUND
  Cell-free hemoglobin (CFH) is a potent nitric oxide scavenger associated with poor outcomes in several diseases. Pulmonary arterial hypertension (PAH) is characterized by reduced nitric oxide availability. We hypothesized that CFH would be elevated in PAH and would associate with hemodynamics and clinical outcomes.
  
  
  METHODS
  We measured CFH in 200 consecutively evaluated patients with PAH, 16 unaffected bone morphogenetic receptor protein type 2 (BMPR2) mutation carriers, 19 healthy subjects, and 29 patients with pulmonary venous hypertension (PVH). CFH values were tested for association with hemodynamics, time to hospitalization, and death.
  
  
  RESULTS
  CFH was elevated in patients with PAH and BMPR2 carriers compared with healthy subjects and patients with PVH (P ≤ .01 all comparisons). There were no differences in CFH across PAH subtypes. CFH modestly correlated with mean pulmonary artery pressure (ρ = 0.16, P = .03) and pulmonary vascular resistance (ρ = 0.21, P = .01) and inversely with cardiac index (ρ = -0.18, P = .02) in patients with PAH. CFH was not associated with hemodynamic response to nitric oxide or death. Patients with the highest CFH levels had increased risk of PAH-related hospitalization when adjusted for age, sex, and PAH cause (hazard ratio, 1.69; 95% CI ,1.08-2.66; P = .02).
  
  
  CONCLUSIONS
  CFH is elevated in patients with PAH and BMPR2 carriers compared with healthy subjects and patients with PVH. Elevated CFH levels are independently associated with an increased risk of hospitalization. Further study is required to understand the mechanism of CFH elevation and the potential pathologic contribution of CFH in PAH.
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University Medical School, Nashville, TN. Electronic address: evan.brittain@vanderbilt.edu.
authors.forename: Evan L
authors.initials: EL
authors.lastname: Brittain
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical School, Nashville, TN.
authors.forename: David R
authors.initials: DR
authors.lastname: Janz
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical School, Nashville, TN.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Austin
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical School, Nashville, TN.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Bastarache
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical School, Nashville, TN.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Wheeler
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical School, Nashville, TN.
authors.forename: Lorraine B
authors.initials: LB
authors.lastname: Ware
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical School, Nashville, TN.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Hemnes
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D006439:Hemodynamics / Q000502:physiology*; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood* / Q000503:physiopathology; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010950:Plasma Cells; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D014655:Vascular Resistance
chemical_list: D015415:Biomarkers; D006454:Hemoglobins; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II