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1 Anesthesiology and Critical Care, Johns Hopkins University, Baltimore, MD, USA
2 Pediatrics, Johns Hopkins University, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: murphy{at}jhmi.edu.
Background: Heart failure is a clinical syndrome associated with elevated levels of oxygen-derived free radicals. Xanthine oxidase activity is believed to be one source of reactive oxygen species in the failing heart. Interventions designed to reduce oxidative stress are believed to have significant therapeutic potential in heart failure. This study tested the hypothesis that xanthine oxidase activity would be elevated in a mouse model of dilated cardiomyopathy and evaluated the effect of chronic oral allopurinol, an inhibitor of xanthine oxidase, on contractility and progressive ventricular dilation in these mice. Methods and Results: Non-transgenic and transgenic mice containing a troponin I truncation were treated with oral allopurinol from 2-4 months of age. Myocardial xanthine oxidase activity was three-fold higher in untreated transgenic mice compared to non-transgenic mice. Analyses of myofilament proteins for modification of carbonyl groups demonstrated myofibrillar protein damage in untreated transgenic mice. Treatment with allopurinol for two months suppressed xanthine oxidase activity and myofibrillar protein oxidation. Allopurinol treatment also alleviated ventricular dilation and preserved fractional shortening in the transgenic animals. Additionally, cardiac muscle twitch tension was preserved to 70% of non-transgenic levels in allopurinol-treated transgenic mice, a significant improvement over untreated transgenic mice. Conclusions: These findings indicate that chronic inhibition of xanthine oxidase can markedly alter the progression of heart failure in dilated cardiomyopathy.
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