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.
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.
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.
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.
1 UBC Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada.
2 Division of Cardiovascular Surgery, St. Paul’s Hospital, Vancouver, BC, Canada.
3 Department of Critical Care Medicine, University of British Columbia, Vancouver, BC, Canada.
4 Department of Pathology, University of British Columbia, Vancouver, BC, Canada.
Received 22 April 2019. Revision received 29 May 2019.
Accepted 7 June 2019.
M.J.K. assisted in design, conduct, and analysis of all content presented in this article and writing and editing of draft and final versions of this article. S.D.M. assisted in the conduct of all experiments and some data analysis. H.J.K. assisted in the conduct of some experiments. D.S. assisted in designing and planning of the experiments in this article and reviewing and editing of multiple drafts of this article. A.C. and J.B. assisted in co-supervisory roles, designing and planning of the experiments in this article, and reviewing and editing of multiple drafts of this article. M.A.S. is responsible for blind evaluation of histology and assignment of injury scores to cardiac specimens and assisted in reviewing and editing of drafts of this article. J.H.B. is a primary supervisor and assisted in design of experiments, formatting data for presentation, and review and editing of multiple drafts of this article.
The authors declare no conflicts of interest.
This work was supported by a Canadian Institutes of Health Research 5-year project grant, a Transplant Research Foundation of British Columbia Venture Grant, and a Vancouver Coastal Health Research Institute Translational Research Award.
Correspondence: Mark J. Kearns, MD, UBC Centre for Heart & Lung Innovation and Division of Cardiovascular Surgery, St. Paul’s Hospital, Attn: Julia Kong, Rm. 166 – 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada. (firstname.lastname@example.org).