title: Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study.
abstract: BACKGROUND
  Hyperuricemia is common in chronic heart failure (CHF), and it is a strong independent marker of prognosis. Upregulated xanthine oxidase (XO) activity and impaired renal excretion have been shown to account for increased serum uric acid (UA) levels in CHF. Therapeutic interventions with allopurinol to reduce UA levels by XO inhibition have been shown to be beneficial. Discussions are ongoing whether UA itself is actively involved or it is a mere marker of upregulated XO activity within CHF pathophysiology. Therefore, the aim of this study was to test the effect of lowering UA by uricosuric treatment without XO inhibition on hemodynamic and metabolic characteristics of CHF. Impaired renal excretion of UA was taken into account.
  
  
  RESULTS
  Serum UA (SUA), urinary UA (uUA) excretion, and renal clearance test for UA (Cl(UA)) were measured in 82 patients with CHF. SUA was significantly increased compared with controls of similar age (control, 5.45+/-0.70 mg/dL; New York Heart Association I, 6.48+/-1.70 mg/dL; New York Heart Association II, 7.34+/-1.94 mg/dL; New York Heart Association III, 7.61+/-2.11 mg/dL; P<0.01). Patients with CHF showed lower uUA excretion and Cl(UA). On multivariate analysis, insulin, brain natriuretic peptide (P<0.01), and creatinine levels (P=0.05) showed independent correlation with SUA. The treatment effect of the uricosuric agent benzbromarone was tested in 14 patients with CHF with hyperuricemia in a double-blind, placebo-controlled, randomized crossover study design. Benzbromarone significantly decreased SUA (P<0.01). Brain natriuretic peptide, left ventricular ejection fraction, and dimensions in echocardiographic assessment did not change after benzbromarone therapy. In contrast, fasting insulin (placebo, 18.8+/-8.9 microU/mL; benzbromarone, 11.0+/-6.2 microU/mL; P<0.05), homeostasis model assessment of insulin resistance index (placebo, 5.4+/-2.6; benzbromarone, 3.0+/-1.7; P<0.05), and tumor necrosis factor-alpha (placebo, 2.59+/-0.63 pg/mL; benzbromarone, 2.14+/-0.51 pg/mL; P<0.05) improved after benzbromarone, and the changes in tumor necrosis factor-alpha levels were correlated with reduction of SUA (P<0.05).
  
  
  CONCLUSIONS
  These results show that UA lowering without XO inhibition may not have an effect on hemodynamic impairment in CHF pathophysiology. To the extent that these data are correct, this finding suggests that upregulated XO activity rather than UA itself is actively involved in hemodynamic impairment in CHF. Clinical Trial Registration- clinical trials.gov. Identifier: NCT00422318.
authors.affiliation: Center for Clinical Residency Program, Tottori University Hospital, Yonago, Japan. ko-36@umin.ac.jp
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Ogino
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kato
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Furuse
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kinugasa
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ishida
authors.forename: Shuichi
authors.initials: S
authors.lastname: Osaki
authors.forename: Toru
authors.initials: T
authors.lastname: Kinugawa
authors.forename: Osamu
authors.initials: O
authors.lastname: Igawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hisatome
authors.forename: Chiaki
authors.initials: C
authors.lastname: Shigemasa
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Anker
authors.forename: Wolfram
authors.initials: W
authors.lastname: Doehner
mesh_terms: D000368:Aged; D001553:Benzbromarone / Q000494:pharmacology / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000150:complications*; D006801:Humans; D033461:Hyperuricemia / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects*; D014527:Uric Acid / Q000097:blood; D014528:Uricosuric Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014969:Xanthine Oxidase / Q000187:drug effects
chemical_list: D014528:Uricosuric Agents; D014527:Uric Acid; D001553:Benzbromarone; D014969:Xanthine Oxidase