Allopurinol acutely increases adenosine triphospate energy delivery in failing human hearts

Research output: Contribution to journalArticle

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 31P 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)

Original languageEnglish (US)
Pages (from-to)802-808
Number of pages7
JournalJournal of the American College of Cardiology
Volume59
Issue number9
DOIs
StatePublished - Feb 28 2012

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Allopurinol
Adenosine
Creatine Kinase
Adenosine Triphosphate
Xanthine Oxidase
Heart Failure
Phosphates
MB Form Creatine Kinase
Phosphocreatine
Adenine Nucleotides
Cardiomyopathies
Intravenous Administration
Adenosine Diphosphate
Energy Metabolism
Reactive Oxygen Species
Hydrolysis
Magnetic Resonance Spectroscopy
Animal Models
Placebos
Enzymes

Keywords

  • creatine kinase
  • energy metabolism
  • heart failure
  • magnetic resonance spectroscopy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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title = "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 31P 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)",
keywords = "creatine kinase, energy metabolism, heart failure, magnetic resonance spectroscopy",
author = "Hirsch, {Glenn A.} and Bottomley, {Paul A} and Gary Gerstenblith and Weiss, {Robert George}",
year = "2012",
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day = "28",
doi = "10.1016/j.jacc.2011.10.895",
language = "English (US)",
volume = "59",
pages = "802--808",
journal = "Journal of the American College of Cardiology",
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TY - JOUR

T1 - Allopurinol acutely increases adenosine triphospate energy delivery in failing human hearts

AU - Hirsch, Glenn A.

AU - Bottomley, Paul A

AU - Gerstenblith, Gary

AU - Weiss, Robert George

PY - 2012/2/28

Y1 - 2012/2/28

N2 - 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 ∼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)

AB - 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 ∼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)

KW - creatine kinase

KW - energy metabolism

KW - heart failure

KW - magnetic resonance spectroscopy

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