Allopurinol Acutely Increases Adenosine Triphospate Energy Delivery in Failing Human Hearts

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• 作者：Glenn A. Hirsch ; MD ; MHS^?/sup> ; Paul A. Bottomley ; PhD^&dagger ; ; Gary Gerstenblith ; MD^?/sup> ; Robert G. Weiss ; MD^?/sup> ; ^{rweiss@jhmi.edu}
• 关键词：creatine kinase ; energy metabolism ; heart failure ; magnetic resonance spectroscopy
• 刊名：Journal of the American College of Cardiology
• 出版年：2012
• 出版时间：28 February, 2012
• 年：2012
• 卷：59
• 期：9
• 页码：802-808
• 全文大小：676 K

文摘

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Objectives

This study tested the hypothesis that acute administration of the xanthine oxidase (XO) inhibitor allopurinol improves cardiac high-energy phosphate concentrations in human heart failure (HF) and increases the rate of adenosine triphosphate (ATP) synthesis through creatine kinase (CK), the primary myocardial energy reserve.

Background

Studies of patients and animal models implicate impaired myocardial high-energy phosphate availability in HF. The XO reaction is a critical terminal step in ATP and purine degradation and an important source of reactive oxygen species. Thus, XO inhibition is a potentially attractive means to improve energy metabolism in the failing human heart.

Methods

We randomized 16 patients with nonischemic cardiomyopathy in a double-blind fashion to allopurinol (300 mg intravenously) or placebo infusion, 4-to-1, the latter for purposes of blinding only. The myocardial concentrations of ATP and creatine phosphate (PCr) and the rate of ATP synthesis through CK (CK flux) were determined by ³¹P magnetic resonance spectroscopy.

Results

Allopurinol infusion increased mean cardiac PCr/ATP and PCr concentration by ?1 % (p < 0.02), and mean CK flux by 39 % (2.07 ¡À 1.27 ¦Ìmol/g/s to 2.87 ¡À 1.82 ¦Ìmol/g/s, p < 0.007). Calculated cytosolic adenosine diphosphate concentration decreased, whereas the free energy of ATP hydrolysis (¦¤G_¡«ATP) increased with allopurinol. The increased CK flux was disproportionate to substrate changes, indicating increased CK enzyme activity.

Conclusions

Intravenous administration of the XO inhibitor allopurinol acutely improves the relative and absolute concentrations of myocardial high-energy phosphates and ATP flux through CK in the failing human heart, offering direct evidence that myofibrillar CK energy delivery can be pharmaceutically augmented in the failing human heart. (Intravenous Allopurinol in Heart Failure; )