Allopurinol attenuates left ventricular remodeling and dysfunction after experimental myocardial infarction. A new action for an old drug?

• Published in: Circulation (New York, N.Y.) Vol. 110; no. 15; pp. 2175 - 2179
• Main Authors: ENGBERDING, Niels, SPIEKERMANN, Stephan, LANDMESSER, Ulf, SCHAEFER, Arnd, HEINEKE, André, WIENCKE, Antje, MÜLLER, Maja, FUCHS, Martin, HILFIKER-KLEINER, Denise, HORNIG, Burkhard, DREXLER, Helmut
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 12.10.2004
• Subjects: Allopurinol - therapeutic use; Animals; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular system; Coronary heart disease; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Drug Evaluation, Preclinical; Fibrosis; Heart; Ligation; Male; Medical sciences; Mice; Mice, Inbred C57BL; Miscellaneous; Myocardial Infarction - complications; Myocardial Infarction - drug therapy; Myocardial Infarction - pathology; Oxidative Stress; Pharmacology. Drug treatments; Random Allocation; Reactive Oxygen Species; Superoxides - metabolism; Ventricular Dysfunction, Left - etiology; Ventricular Dysfunction, Left - prevention & control; Ventricular Remodeling - drug effects; Xanthine Oxidase - antagonists & inhibitors; Xanthine Oxidase - metabolism; Heart; Myocardial infarction; heart failure; free radicals; remodeling; Hypouricemic agent; Enzyme; Allopurinol; Enzyme inhibitor; Cardiovascular disease; Heart ventricle; Left ventricular failure; Myocardial disease; Heart disease; Xanthine oxidase; Circulatory system; Oxidoreductases; Left ventricle performance
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000144303.24894.1C

Accumulating evidence suggests a critical role for increased reactive oxygen species (ROS) production in left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). Increased expression of xanthine oxidase (XO), a major source of ROS, has recently been demonstrated in experimental and clinical heart failure; however, a potential role for LV remodeling processes remains unclear. We therefore studied the effect of long-term treatment with allopurinol, a potent XO inhibitor, on myocardial ROS production and LV remodeling and dysfunction after MI. Mice with extensive anterior MI (n=105) were randomized to treatment with either vehicle or allopurinol (20 mg x kg(-1) x d(-1) by gavage) for 4 weeks starting on day 1 after surgery. Infarct size was similar among the groups. XO expression and activity were markedly increased in the remote myocardium of mice after MI, as determined by electron spin resonance spectroscopy. Myocardial ROS production was increased after MI but markedly reduced after allopurinol treatment. Importantly, allopurinol treatment substantially attenuated LV cavity dilatation and dysfunction after MI, as assessed by echocardiography, and markedly reduced myocardial hypertrophy and interstitial fibrosis. The present study reveals a novel beneficial effect of treatment with allopurinol, ie, a marked attenuation of LV remodeling processes and dysfunction after experimental MI. Allopurinol treatment therefore represents a potential novel strategy to prevent LV remodeling and dysfunction after MI.