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A new concept of long-term donor heart preservation: nucleoside transport inhibition
W Flameng1, S Sukehiro, T Möllhoff
1Department of Cardiac Surgery, Katholieke Universiteit Leuven, Belgium.
Insights
Nucleoside transport inhibition (NTI) enhances cardiac preservation by preventing adenosine breakdown. This strategy improved donor heart function and survival after 24-hour storage, offering a promising approach for transplantation.
Area of Science:
- Cardiology
- Transplantation Medicine
- Biochemistry
Background:
- Myocardial ischemia causes adenosine triphosphate (ATP) breakdown, leading to adenosine and inosine accumulation.
- Adenosine is a cardioprotective agent, but its efficacy is limited by rapid endothelial transport and irreversible catabolism.
- Nucleoside transport inhibition (NTI) may enable endogenous adenosine accumulation at its production site, preventing breakdown and washout.
Purpose of the Study:
- To evaluate the efficacy of NTI drug administration for improving 24-hour preservation of donor hearts for transplantation.
- To assess the impact of NTI on cardiac function and ATP metabolism during cold storage and reperfusion.
Main Methods:
- Twelve dogs were divided into two groups for heart transplantation after 24-hour cold storage.
- Group 1 (control) received standard cold hyperkalemic cardioplegia.
- Group 2 received NTI in the cardioplegic solution and intravenously before reperfusion.
Main Results:
- Control hearts (Group 1) failed to wean from cardiopulmonary bypass, exhibiting irreversible cardiogenic shock within 1 hour.
- Hearts treated with NTI (Group 2) were successfully weaned and remained hemodynamically stable without support.
- Biopsies showed ATP catabolism in control hearts during storage and further decline upon reperfusion, with nucleoside washout.
Conclusions:
- NTI significantly improves the preservation of donor hearts during 24-hour storage for transplantation.
- This approach preserves cardiac ATP levels and prevents nucleoside washout, enhancing post-transplant cardiac function.
- NTI represents a promising strategy to improve outcomes in heart transplantation.
Abstract:
Myocardial ischemia results in a breakdown of adenosine triphosphate (ATP), which is associated with an accumulation of its catabolites adenosine and inosine. Adenosine is a potent but ineffective cardioprotective agent because it is rapidly transported to the endothelium and irreversibly catabolized. With the use of specific nucleoside transport inhibition (NTI), however, endogenous adenosine may accumulate at its site of production, and its further breakdown and washout on reperfusion is prevented. In this study we tested this concept and assessed the effect of NTI drug administration on 24 hours' preservation of donor hearts for transplantation. Twelve dogs were randomly allocated to two groups. In the first group (group 1, n = 6) the hearts were arrested with a cold hyperkalemic cardioplegic solution, excised and stored for 24 hours at 0.5 degrees C. After 24 hours the hearts were transplanted orthotopically. In group 2 (n = 6) the same procedure was followed, but a specific NTI agent was added to the cardioplegic solution (1 mg/L) and administered intravenously to the recipient dog before reperfusion of the transplanted heart (0.1 mg/kg). Despite maximal positive inotropic support, none of the control animals (group 1) could be weaned from cardiopulmonary bypass: within 1 hour irreversible cardiogenic shock occurred in all animals. In group 2 all hearts could be weaned from cardiopulmonary bypass and were hemodynamically stable without positive inotropic support. Serial transmural left ventricular biopsies revealed in group 1 moderate catabolism of ATP during cold storage. On reperfusion a further decline of the ATP content was seen, and the accumulated nucleosides were washed out.(ABSTRACT TRUNCATED AT 250 WORDS)