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Published on: May 22, 2018
Oligonucleotide-based Preconditioning of DCD Cardiac Donors and Its Impact on Cardiac Viability
Mark J Kearns1,2, Sally D Miller1, Hyejin J Kong1
1UBC Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada.
Insights
Preconditioning donor hearts with CpG oligonucleotides (CpG ODN) significantly improved cardiac viability and function in a rat model. This approach doubled the number of viable donation after circulatory death (DCD) hearts for transplantation.
Area of Science:
- Cardiology
- Immunology
- Transplantation Biology
Background:
- Donation after circulatory death (DCD) heart transplantation addresses donor organ shortages.
- Donor preconditioning strategies are unexplored for optimizing DCD heart viability.
- This study investigates CpG oligodeoxynucleotides (CpG ODN) for DCD heart preconditioning.
Purpose of the Study:
- To evaluate the impact of CpG ODN pretreatment on DCD rat hearts.
- To assess effects on cardiac function, injury markers, and gene expression.
- To determine the efficacy of CpG ODN in improving DCD heart viability.
Main Methods:
- Rats underwent a DCD protocol with warm acirculatory arrest.
- Donors were pretreated with CpG ODN or vehicle.
- Hearts were assessed using ex situ heart perfusion (ESHP), measuring LV function, histology, and biomarkers.
Main Results:
- CpG ODN pretreatment doubled the number of functional DCD hearts.
- Improved systolic and diastolic left ventricular (LV) function was observed.
- Reduced histological injury and cardiac troponin-I levels were noted.
Conclusions:
- CpG ODN pretreatment significantly enhances DCD heart viability by 100%.
- Reduced cardiac injury biomarkers were associated with CpG ODN treatment.
- This strategy shows promise for improving marginal DCD donor hearts.
Background:
While clinical donation after circulatory death (DCD) cardiac transplantation is being implemented with increasing frequency to address the supply/demand mismatch of donor grafts, no research to date has examined a strategy of donor preconditioning to optimize the viability of DCD hearts for transplantation. In our rat model of the DCD protocol, we investigate the impact of pretreating donors with phosphorothioate-linked cytosine and guanine rich oligodeoxynucleotides (CpG ODN) and their effects on cardiac function, injury, and a novel left ventricular (LV) mRNA biomarker panel.
Methods:
DCD rats were subjected to a withdrawal protocol, followed by 20 minutes of warm acirculatory standoff, representing a group of severely injured hearts as previously demonstrated. Beating heart controls and DCD rats were pretreated with vehicle or stimulatory CpG ODN (beating heart control and DCD stimulated with CpG ODN, BST and DST). Hearts were harvested for ex situ heart perfusion (ESHP), where LV function, histochemical injury, and differences in gene expression were characterized between groups.
Results:
Donor pretreatment with CpG ODN doubled the number of functional DCD hearts at ESHP. Pretreatment was associated with improved systolic and diastolic LV function, a reduction in histological injury, and markedly reduced elaboration of cardiac troponin-I in coronary effluent during ESHP. Pretreatment was also associated with a reduction in mRNA biomarkers associated with myocardial injury.
Conclusions:
A single dose of CpG ODN was associated with reduced biomarkers of cardiac injury and a 100% increase in cardiac viability in this rodent model of marginal DCD cardiac donation.
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