Allopurinol acutely increases adenosine triphospate energy delivery in failing human hearts

Abstract

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 (31)P magnetic resonance spectroscopy.

Results: Allopurinol infusion increased mean cardiac PCr/ATP and PCr concentration by ∼11% (p < 0.02), and mean CK flux by 39% (2.07 ± 1.27 μmol/g/s to 2.87 ± 1.82 μmol/g/s, p < 0.007). Calculated cytosolic adenosine diphosphate concentration decreased, whereas the free energy of ATP hydrolysis (ΔG(∼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; NCT00181155).

Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. MR Spectroscopy Study with Corresponding Spectra

Annotated scout MRI (a) showing four locations (#1–4) of 31P spectra acquired from the chest wall (#1) and anterior myocardium (#2–4) of a 45 year-old male with dilated cardiomyopathy and NYHA Class II-III HF (b-d). The spectra in (b) were acquired in Step 3 of the MRS protocol without chemical selective irradiation for quantification of metabolite concentrations. Part (c) spectra were acquired in Step 2 with chemical selective irradiation applied to the □-ATP resonance (orange arrow), and at the control location (green arrow). The change in height in PCr (red line) is a measure of the forward CK flux. Part (d) is from Step 6 of the MRS protocol following, in this case, allopurinol infusion. An increase in CK flux from 0.7 to 1.7 μmol/g/s is evidenced, in part, by a greater decline in the PCr signal (blue line). All spectra are scaled identically.

Figure 2. Effect of Allopurinol on ATP Synthesis via Creatine Kinase

Abbreviations are the same in Figure 1. The rate of ATP synthesis through cardiac CK (μmol/g/s) under baseline (right) and allopurinol (left) conditions (summary bars represent mean ± SD).