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Endothelial dysfunction after long-term cold storage in HTK organ preservation solutions: effects of iron chelators
Tamás Radovits1, Li-ni Lin, Julia Zotkina
1Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany. radovitstamas@yahoo.com
Insights
Supplementing histidine-tryptophan-ketoglutarate (HTK) solutions with cell-permeable iron chelators like LK-614 significantly improved endothelial function after 24-hour cold storage, preventing transplant complications.
Area of Science:
- Cardiovascular Surgery
- Organ Transplantation
- Vascular Biology
Background:
- Optimizing organ preservation is crucial for successful heart transplantation.
- Cold ischemic storage and reperfusion can cause endothelial injury, increasing complications.
- This study investigates iron chelators in histidine-tryptophan-ketoglutarate (HTK) solutions for preserving aortic endothelial function.
Purpose of the Study:
- To evaluate the efficacy of iron chelator-supplemented HTK solutions in preventing endothelial dysfunction.
- To assess the impact of chelator membrane permeability on endothelial protection during long-term cold storage.
Main Methods:
- Rat aortic rings were preserved for 24 hours in various HTK solutions with low (deferoxamine) and high (LK-614) permeability iron chelators.
- Vascular reactivity was measured, assessing phenylephrine-induced contraction and acetylcholine/sodium nitroprusside-induced vasorelaxation.
- Oxidant injury was induced during re-oxygenation to further evaluate endothelial function.
Main Results:
- Standard HTK (Custodiol) did not prevent endothelial dysfunction.
- Chloride-poor HTK solutions with N-alpha-acetyl-l-histidine, especially with LK-614, significantly improved endothelial function.
- Complete endothelial protection was achieved after 24-hour cold storage using specific HTK formulations.
- Endothelium-independent vascular smooth muscle function remained unaffected across all groups.
Conclusions:
- Iron-dependent oxidative injury plays a significant role in endothelial dysfunction post-cold storage.
- Cell-permeable iron chelators effectively prevent endothelial damage during organ preservation.
- Optimized HTK solutions with specific iron chelators offer a promising strategy for improving cardiac allograft survival.
Background:
To improve the rate of successful heart transplantations, organ preservation should be optimized in cardiac transplantation surgery. Iron-dependent oxidative damage and iron-independent, chloride-dependent injury of the endothelium have been described after cold ischemic storage and reperfusion, leading to an enhanced rate of complications and unfavorable outcomes. This screening study tested the effects of iron chelator supplementation in different histidine-tryptophan-ketoglutarate (HTK) organ preservation solutions on endothelial function in a long-term storage model of the isolated rat aorta.
Methods:
Isolated rat aortic rings underwent a 24-hour cold ischemic preservation in different HTK solutions supplemented with iron chelators of low (deferoxamine) and high (LK-614) membrane permeability. In vascular reactivity measurements we investigated the phenyleprine-induced contraction and both endothelium-dependent and -independent vasorelaxation by using cumulative concentrations of acetylcholine and sodium nitroprusside with and without an additional external oxidant injury during re-oxygenation.
Results:
Traditional HTK solution, Custodiol, failed to prevent endothelial dysfunction in our experiments. Use of chloride-poor HTK solutions containing N-alpha-acetyl-l-histidine with and without supplementation with LK-614, but not with deferoxamine, resulted in significant improvement of impaired endothelial function; moreover, complete protection of the endothelium was feasible after 24-hour cold storage. Endothelium-independent functions of vascular smooth muscle were not affected in any of the groups.
Conclusions:
Our results demonstrate the important pathophysiologic role of iron-dependent oxidative injury in the development of endothelial dysfunction after cold storage, which can be prevented by cell-permeable iron chelators.
