title: Endothelin antagonism and uric acid levels in pulmonary arterial hypertension: clinical associations.
abstract: BACKGROUND
  Elevated serum uric acid is detected in pulmonary arterial hypertension (PAH) and is associated with poor patient outcomes. High serum uric acid is an independent risk factor for cardiovascular disease and renal impairment. We analyzed the effects of endothelin receptor antagonism on serum uric acid in PAH patients participating in the Sitaxentan to Relieve Impaired Exercise (STRIDE)-2/2X trial, and the impact of uric acid on 6-minute walk distance (6MWD), time to clinical worsening (TtCW) and survival.
  
  
  METHODS
  In the 18-week, double-blind, placebo-controlled STRIDE-2 trial, 246 PAH patients were randomized and received matched placebo, sitaxentan 50 or 100 mg orally once daily, or open-label bosentan 125 mg twice daily. STRIDE-2X was a 1-year, open-label extension of STRIDE-2.
  
  
  RESULTS
  Baseline serum uric acid was similar between groups. Increased serum uric acid was a significant risk factor for 1-year mortality and TtCW. Compared with placebo, sitaxentan 50 and 100 mg and bosentan all reduced serum uric acid (p < 0.05). Reduced serum uric acid correlated with increased 6MWD (p = 0.0037).
  
  
  CONCLUSIONS
  Endothelin receptor antagonism reduces serum uric acid in PAH patients, and this reduction is associated with improved survival and longer TtCW. Further prospective studies are needed to investigate the pathogenic role of serum uric acid in PAH and its prognostic potential.
authors.affiliation: Clinical Pharmacology Unit, University of Edinburgh, The Queen׳s Medical Research Institute, Edinburgh, UK. Electronic address: bean.dhaun@ed.ac.uk.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Dhaun
authors.affiliation: Pulmonary Hypertension and Heart Failure Clinic, Cliniques Universitaires de Bruxelles - Erasme Hospital, Brussels, Belgium.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Vachiery
authors.affiliation: Cardiovascular Research, Allegheny General Hospital, Pittsburgh, Pennsylvania.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Benza
authors.affiliation: Pulmonary Hypertension and Heart Failure Clinic, Cliniques Universitaires de Bruxelles - Erasme Hospital, Brussels, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Naeije
authors.affiliation: Pfizer Inc New York, New York.
authors.forename: Lie-Ju
authors.initials: LJ
authors.lastname: Hwang
authors.affiliation: Quintiles, Durham, North Carolina.
authors.forename: Xuexuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Pfizer Ltd Tadworth, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Teal
authors.affiliation: Clinical Pharmacology Unit, University of Edinburgh, The Queen׳s Medical Research Institute, Edinburgh, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000077300:Bosentan; D002648:Child; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists / Q000008:administration & dosage*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D007555:Isoxazoles / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013449:Sulfonamides / Q000008:administration & dosage; D015996:Survival Rate / Q000639:trends; D013876:Thiophenes / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology; D014527:Uric Acid / Q000097:blood*; D055815:Young Adult
chemical_list: D065128:Endothelin Receptor Antagonists; D007555:Isoxazoles; D013449:Sulfonamides; D013876:Thiophenes; D014527:Uric Acid; C106276:sitaxsentan; D000077300:Bosentan
keywords: 6-minute walk distance; bosentan; hyperuricemia; pulmonary arterial hypertension; sitaxentan; uric acid