*Purpose: 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 40-50% of life-supporting cardiac xenotransplantations. Non-ischemic cardiac preservation (NICP) between procurement and implantation to the recipient has been shown to prevent PCXD in GTKO.hCD46.hTBM models, albeit by an unknown mechanism. Here we investigate the role of NICP in overcoming PCXD in non-hTBM expressing models.

*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 (GTKO.hCD46.hTBM) or without hTBM (triple knock out-GTKO.B4KO.CMAHKO, 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) prior to implantation to the recipient. All animals were used in compliance with guidelines provided by the Institutional Animal Care and Use Committee (IACUC).

*Results: GTKO.hCD46.hTBM donors (n=4) without NICP prior to transplantation exhibited a 50% incidence of PCXD, consistent with prior literature. However, all NICP (n=2, one TKO donor and one TKO.hCD46.hDAF) avoided PCXD but overall survival was limited by intracardiac thrombus, likely related to lack of hTBM expression. These phenomena were not prevented by continuous heparin infusion. Histologic examination revealed no signs of immunologic rejection but non-hTBM expressing grafts exhibited both microscopic and macroscopic thrombotic phenomena.

*Conclusions: NICP prevents PCXD, however, by a mechanism that is not clear at this time. Further studies need to be conducted with hTBM-containing grafts for further elucidation of NICP on overall survival of pig cardiac xenografts.

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