Published online before print October 21, 2004, doi: 10.1161/01.RES.0000148635.73331.c5
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© 2004 American Heart Association, Inc.
Cellular Biology |
Chronic Treatment With Allopurinol Boosts Survival and Cardiac Contractility in Murine Postischemic Cardiomyopathy
From the Institute of Molecular Cardiobiology (L.B.S., M.K.L., W.D.G., E.M.), Johns Hopkins University School of Medicine, Baltimore, Md; and Department of Biophysics (L.S.), Case Western Reserve University, Cleveland, Ohio.
Correspondence to Eduardo Marbán, MD, PhD, Division of Cardiology, 844 Ross Bldg, 720 Rutland Ave, Baltimore, MD 21205. E-mail marban{at}jhmi.edu
Oxidative stress is a hallmark of systemic illnesses, including heart failure. Nevertheless, the overall importance of radical production in the heart remains conjectural; is it merely a marker of illness, or can intervention alter the progression of disease? This question was addressed by blocking xanthine oxidase (XO), a superoxide-generating enzyme that is upregulated in animal models of heart failure. In a randomized prospective trial design, we administered the XO inhibitor allopurinol orally to mice that had undergone massive myocardial infarction (MI). Cardiac XO activity was elevated in untreated mice after MI; allopurinol suppressed the XO activity to levels comparable to those in sham-operated mice. Eighty-one percent of untreated mice died of advanced heart failure over 2 to 4 weeks of follow-up. Survival doubled in the allopurinol-treated mice, whereas cardiac contractile function (both in vivo and in isolated muscle) was markedly improved. Response to isoproterenol was restored to near-normal levels in the allopurinol group but was attenuated in untreated mice. Oxidative modifications to proteins were prevented in the allopurinol-treated mice. Our findings indicate that targeted blockade of just one source of oxidants, XO, impacts dramatically on the progression of postischemic cardiomyopathy in mice and prevents oxidative protein modifications.
Key Words: heart failure • mice • myocardial contraction • oxygen
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