Dimethyloxalylglycine treatment of brain-dead donor rats improves both donor and graft left ventricular function after heart transplantation

Péter Hegedus, Shiliang Li, Sevil Korkmaz-Icöz, T. Radovits, Tobias Mayer, Samer Al Said, Paige Brlecic, Matthias Karck, B. Merkely, G. Szabó

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Objective Hypoxia inducible factor (HIF)-1 pathway signalling has a protective effect against ischemia/reperfusion injury. The prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG) activates the HIF-1 pathway by stabilizing HIF-1α. In a rat model of brain death (BD)-associated donor heart dysfunction we tested the hypothesis that pre-treatment of brain-dead donors with DMOG would result in a better graft heart condition. Methods BD was induced in anesthetized Lewis rats by inflating a subdurally placed balloon catheter. Controls underwent sham operations. Then, rats were injected with an intravenous dose of DMOG (30 mg/kg) or an equal volume of physiologic saline. After 5 hours of BD or sham operation, hearts were perfused with a cold (4°C) preservation solution (Custodiol; Dr. Franz Köhler Chemie GmbH; Germany), explanted, stored at 4°C in Custodiol, and heterotopically transplanted. Graft function was evaluated 1.5 hours after transplantation. Results Compared with control, BD was associated with decreased left ventricular systolic and diastolic function. DMOG treatment after BD improved contractility (end-systolic pressure volume relationship E'max: 3.7 ± 0.6 vs 3.1 ± 0.5 mm Hg/μ1; p <0.05) and left ventricular stiffness (end-diastolic pressure volume relationship: 0.13 ± 0.03 vs 0.31 ± 0.06 mm Hg/μ1; p <0.05) 5 hours later compared with the brain-dead group. After heart transplantation, DMOG treatment of brain-dead donors significantly improved the altered systolic function and decreased inflammatory infiltration, cardiomyocyte necrosis, and DNA strand breakage. In addition, compared with the brain-dead group, DMOG treatment moderated the pro-apoptotic changes in the gene and protein expression. Conclusions In a rat model of potential brain-dead heart donors, pre-treatment with DMOG resulted in improved early recovery of graft function after transplantation. These results support the hypothesis that activation of the HIF-1 pathway has a protective role against BD-associated cardiac dysfunction.

Original languageEnglish
Pages (from-to)99-107
Number of pages9
JournalJournal of Heart and Lung Transplantation
Volume35
Issue number1
DOIs
Publication statusPublished - Jan 1 2016

Keywords

  • DMOG
  • graft function
  • heart transplantation
  • HIF-1
  • ischemia-reperfusion injury

ASJC Scopus subject areas

  • Transplantation
  • Cardiology and Cardiovascular Medicine
  • Pulmonary and Respiratory Medicine
  • Surgery

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