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Am J Physiol Heart Circ Physiol (September 23, 2005). doi:10.1152/ajpheart.00831.2005
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Submitted on August 4, 2005
Accepted on September 6, 2005

Xanthine Oxidase Inhibitors Improve Energetics and Function Following Infarction in the Failing Mouse Heart

Anna V Naumova1, Vadappuram P Chacko1, Ronald Ouwerkerk1, Linda Stull2, Eduardo Marban3, and Robert G Weiss4*

1 Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2 Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
3 Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
4 Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: rweiss{at}jhmi.edu.

Following myocardial infarction, ventricular geometry and function, as well as energy metabolism, change markedly. In non-ischemic heart failure inhibition of xanthine oxidase (XO) improves mechano-energetic coupling by improving contractile performance relative to a reduced energetic demand. However, the metabolic and contractile effects of XO inhibitors (XOI) have not been characterized in failing hearts following infarction. After undergoing permanent coronary ligation, mice received a XOI (allopurinol or oxypurinol) or matching placebo in the daily drinking water. Four weeks later 1H MRI and 31P MRS were used to quantify in vivo functional and metabolic changes in post-infarction remodeled mouse myocardium and the effects of XOIs on that process. End-systolic (ESV) and end-diastolic volumes (EDV) were increased by more than six-fold following infarction, left ventricle mass doubled (p<0.005), and the left ventricular ejection fraction (EF) decreased (14±9%), as compared with control hearts (59±8%, p<0.005) at one month. The myocardial PCr/ATP ratio was also significantly decreased in infarct remodeled hearts (1.4±0.6) as compared to control animals (2.1±0.5, p<0.02), in agreement with prior studies in larger animals. The XOIs allopurinol and oxypurinol did not change LV mass, but limited the increase in ESV and EDV of infarct hearts by 50%, increased EF (23±9%, p=0.01), and normalized cardiac PCr/ATP (2.0±0.5, p<0.04). We conclude that XOIs improve ventricular function following infarction and normalize high-energy phosphate ratio in heart failure. Thus XOI therapy offers a new and potentially complementary approach to limit the adverse contractile and metabolic consequences following infarction.




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