*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 40-60% 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 a cardioplegia solution with several unknown principle components. 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) without 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=2) avoided PCXD but overall survival was limited by intracardiac thrombus, likely related to lack of hTBM. Histologic examination revealed no signs of immunologic rejection but non-hTBM expressing grafts exhibited both microscopic and macroscopic thrombotic phenomena.

*Conclusions: Both MICP and NICP reduce the incidence of PCXD. 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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