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Room: E-Poster Hall

P-21.05 Comparison of minimally ischemic cardiac preservation techniques to overcome Perioperative Cardiac Xenograft Dysfunction (pcxd) in life-supporting cardiac xenotransplantation model

Corbin Goerlich, United States

Cardiac Xenotransplantation Program
University of Maryland

Abstract

The use of minimally ischemic cardiac preservation techniques to overcome Perioperative Cardiac Xenograft Dysfunction (pcxd) in life-supporting cardiac xenotransplantation model

Corbin Goerlich1, Avneesh Singh1, David Kaczorowski1, Mohamed Abdullah1, Billeta Lewis1, Ivan Tatarov1, Alena Hershfeld1, Tianshu Zhang1, Erik Strauss1, Patrick Odonkor1, Brittney Williams1, David Ayares2, Bartley Griffith1, Muhammad Mohiuddin1.

1Surgery, University of Maryland School of Medicine, Baltimore, MD, United States; 2Revivicor, Inc., Blacksburg, VA, United States

Introduction: Transplantation of organs from animals to humans (xenotransplantation) has been proposed to address the critical shortage of organs for transplantation. The use of genetically engineered organ xenografts, including knock-out (KO) of alpha 1-3 galactosyltransferase (GTKO) along with insertion of a human complement regulator genes (hCD46-human CD46, hDAF-human decay accelerating factor, hTBM-human thrombomodulin) and other cell surface carbohydrate KOs, has been helpful in circumventing acute rejection. However, perioperative cardiac xenograft dysfunction (PCXD) still occurs in 40-60% of life-supporting xenotransplantations. Non-ischemic cardiac preservation (NICP) between procurement and implantation to the recipient has been shown to prevent PCXD in GTKO.hCD46.hTBM models, however, using preservation solution with several principle components of unknown significance. Here we investigate the role of minimally ischemic static preservation (MISP) versus NICP technique in overcoming PCXD. 
Methods: Specific pathogen-free baboons of either sex weighing 15-30 kg (2-3 years of age) were used as recipients. 6 to 8-week-old genetically modified pigs with hTBM or triple knock out-GTKO.B4KO.CMAHKO pigs with or without hCD46 and hDAF) were used as donors. Expression of transgenes were consistent and high level across all pigs. NICP was performed using an XVIVO perfusion system for 2-4 hours and continuously perfused with Steen solution at 8°C with pressure maintained at 20mmHg at a physiological pH (7.2-7.6). Static preservation with MICP was performed with 30cc/kg of blood cardioplegia using 25% concentration of fresh oxygenated donor blood. All animals were used in compliance with guidelines provided by the Institutional Animal Care and Use Committee (IACUC). 
Results: GTKO.hCD46.hTBM donors (n=3) with MICP prior to transplantation exhibited a 33% incidence of PCXD, an incidence that is lower than reported in the literature, compared to 100% incidence of PCXD in donors with traditional cardioplegia and static preservation (n=3). However, all NICP (n=3) avoided PCXD. Overall survival in the NICP group was limited by lack of expression of hTBM, with average survival of 7 days. The GTKO.hCD46.hTBM donor receiving NICP has well surpassed this survival, with survival still ongoing at the time of this abstract submission. Histologic examination revealed no signs of immunologic rejection but non-hTBM expressing grafts exhibited both microscopic and macroscopic thrombotic phenomena, likely related to accelerated antibody mediated rejection. 
Conclusion: Both MICP and NICP reduce the incidence of PCXD. At the time of this abstract survival is still ongoing from GTKO.hCD46.hTBM donors that utilized a NICP approach, suggesting it may be superior. However, MICP may also have some utility in overcoming PCXD in this model. Further studies should be done to better characterized myocardial protection conferred between NICP and MICP in this model.

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