title: Inhibition of xanthine oxidase improves myocardial contractility in patients with ischemic cardiomyopathy.
abstract: Reactive oxygen species, in particular superoxide, have been closely linked to the underlying pathophysiology of ischemic cardiomyopathy: superoxide not only mediates mechanoenergetic uncoupling of the myocyte but also adversely impacts on myocardial perfusion by depleting endothelial-derived nitric oxide bioavailability. Xanthine oxidase generates superoxide upon oxidation of hypoxanthine and xanthine and has been detected in cardiac myocytes and coronary endothelial cells of patients with ischemic heart disease. Here we investigated the effects of oxypurinol, a xanthine oxidase inhibitor, on myocardial contractility in patients with ischemic cardiomyopathy. Twenty patients (19 males, 66+/-8 years) with stable coronary disease, severely suppressed systolic function (left ventricular ejection fraction 22+/-2%), and nonelevated uric acid plasma levels received a single intravenous dose of oxypurinol (400 mg). Cardiac MRI studies, performed before and 5.2+/-0.9 h after oxypurinol administration, revealed a reduction in end-systolic volumes (-9.7+/-4.2%; p=0.03) and an increase in left ventricular ejection fraction (+17.5+/-5.2%; p=0.003), whereas 6 patients (6 males, 63+/-3.8 years, ejection fraction 26+/-5%) who received vehicle only did not show significant changes in any of the parameters studied. Oxypurinol improves left ventricular function in patients with ischemic cardiomyopathy. These results underscore the significance of reactive oxygen species as important pathophysiological mediators in ischemic heart failure and point toward xanthine oxidase as an important source of reactive species that serve to modulate the myocardial redox state in this disease.
authors.affiliation: Heart Center, Department of Cardiology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany. baldus@uke.uni-hamburg.de
authors.forename: Stephan
authors.initials: S
authors.lastname: Baldus
authors.forename: Kai
authors.initials: K
authors.lastname: Müllerleile
authors.forename: Phil
authors.initials: P
authors.lastname: Chumley
authors.forename: Daniel
authors.initials: D
authors.lastname: Steven
authors.forename: Volker
authors.initials: V
authors.lastname: Rudolph
authors.forename: Gunnar K
authors.initials: GK
authors.lastname: Lund
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Staude
authors.forename: Alexander
authors.initials: A
authors.lastname: Stork
authors.forename: Ralf
authors.initials: R
authors.lastname: Köster
authors.forename: Jan
authors.initials: J
authors.lastname: Kähler
authors.forename: Christian
authors.initials: C
authors.lastname: Weiss
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Thomas
authors.initials: T
authors.lastname: Meinertz
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
authors.forename: Thomas
authors.initials: T
authors.lastname: Heitzer
mesh_terms: D000368:Aged; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D019271:Hypoxanthine / Q000097:blood; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D010117:Oxypurinol / Q000097:blood / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014527:Uric Acid / Q000097:blood; D019820:Xanthine / Q000097:blood; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000097:blood
chemical_list: D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D019820:Xanthine; D014527:Uric Acid; D019271:Hypoxanthine; D014969:Xanthine Oxidase; D010117:Oxypurinol