title: Plasma 12- and 15-hydroxyeicosanoids are predictors of survival in pulmonary arterial hypertension.
abstract: This study aimed to characterize alterations in select eicosanoids in experimental and human pulmonary arterial hypertension (PAH) and to assess their potential utility as predictors of outcome. Using liquid chromatography-mass spectrometry, we performed targeted lipidomic analyses of the lungs and right ventricles (RVs) of chronically hypoxic rats and plasma of consecutive PAH patients and healthy controls. In rat lungs, chronic hypoxia was associated with significantly decreased lung prostacyclin (PGI2)/thromboxane B2 (TXB2) ratio and elevated lung 8-hydroxyeicosanoid (HETE) acid concentrations. RV eicosanoids did not exhibit any changes with chronic hypoxia. PAH treatment-naïve patients had significantly increased plasma concentrations of TXB2 and 5-, 8-, 12-, and 15-HETE. The PGI2/TXB2 ratio was lower in PAH patients than in controls, especially in the treatment-naïve cohort (median: 2.1, 0.3, and 1.3 in controls, treatment-naïve, and treated patients, respectively, P = 0.001). Survival was significantly worse in PAH patients with 12-HETEhigh (≥57 pg/mL) and 15-HETEhigh (≥256 pg/mL) in unadjusted and adjusted analyses (hazard ratio [HR]: 2.8 [95% confidence interval (CI): 1.1-7.3], P = 0.04 and HR: 4.3 [95% CI: 1.6-11.8], P = 0.004, respectively; adjustment was performed with the REVEAL [Registry to Evaluate Early and Long-Term PAH Disease Management] risk score). We demonstrate significant alterations in eicosanoid pathways in experimental and human PAH. We found that 12- and 15-HETE were independent predictors of survival in human PAH, even after adjusting for the REVEAL score, suggesting their potential role as novel biomarkers.
authors.affiliation: Pulmonary, Critical Care and Sleep Division, Tufts University School of Medicine, Tufts Medical Center, Boston, Massachusetts, USA; Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Al-Naamani
authors.affiliation: Pulmonary, Critical Care and Sleep Division, Tufts University School of Medicine, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Kristen D
authors.initials: KD
authors.lastname: Sagliani
authors.affiliation: Mass Spectrometry Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Dolnikowski
authors.affiliation: Pulmonary, Critical Care and Sleep Division, Tufts University School of Medicine, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Rod R
authors.initials: RR
authors.lastname: Warburton
authors.affiliation: Pulmonary, Critical Care and Sleep Division, Tufts University School of Medicine, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Deniz
authors.initials: D
authors.lastname: Toksoz
authors.affiliation: Pulmonary, Critical Care and Sleep Division, Tufts University School of Medicine, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Usamah
authors.initials: U
authors.lastname: Kayyali
authors.affiliation: Pulmonary, Critical Care and Sleep Division, Tufts University School of Medicine, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Hill
authors.affiliation: Pulmonary, Critical Care and Sleep Division, Tufts University School of Medicine, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Barry L
authors.initials: BL
authors.lastname: Fanburg
authors.affiliation: Pulmonary, Critical Care and Sleep Division, Tufts University School of Medicine, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Kari E
authors.initials: KE
authors.lastname: Roberts
authors.affiliation: Pulmonary, Critical Care and Sleep Division, Tufts University School of Medicine, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Ioana R
authors.initials: IR
authors.lastname: Preston
keywords: eicosanoids; hydroxyeicosanoids; hypoxia-induced pulmonary hypertension; prognosis; prostaglandins; pulmonary arterial hypertension