*Purpose: Cardiac xenotransplantation (CXTx) might be an alternative treatment for end-stage cardiac failure patients. The prolonged survival of a heterotopic genetically-engineered (GE) pig heart is well-established. In this study, we demonstrate the successful life-supporting orthotopic CXTx from GE donor pigs.

*Methods: Orthotopic cardiac xenotransplantation (OHTx) from GE donor pig was performed in a 3-4-year-old specific pathogen-free baboon (n=4). GE donor pigs were either GTKO (I.e. alpha 1-3 galactosidase knockout) along with overexpression of human complement inhibitory protein (CD46) & thrombomodulin (TBM) or Triple knockout which includes GTKO, CMAH gene and B4KO (i.e. beta-1,4- N-acetyl-galactosaminyltransferase 2 enzyme) with or without CD46 & DAF. Immunosuppression consisted of targeted T and B cell depletion along with costimulation blockade which is standardized or modified by us. Cardioplegia was performed using the combination of DelNido solution or steen solution and recipient blood. The total average ischemic time was around 120 minutes as the heart was re-perfused after left atrial and aortic anastomoses were completed. The animal was weaned from anesthesia and extubated either 14 hours or immediately post-operatively.

*Results: Life supporting OHTx were performed successfully and recipient with GE donor pig heart survived for 4, 5, 8 and 30 days. The use of heart preservation solution (either blood cardioplegia or Steen solution), minimal ischemic time and early extubation allowed rapid recovery of heart function in the recipient. The use of a larger baboon (>20Kg) eliminated the requirement of allogeneic blood during or immediately after cardiopulmonary bypass. In spite of the rapid recovery of the recipient with functioning xenoheart it was found that xenograft which doesn’t express TBM were failed early due to intracardiac thrombus whereas one of the recipients with TBM expressing xenograft survived for 30 days.

*Conclusions: These experiments demonstrate that OHTx can be achieved beyond the early perioperative period which has previously been reported a major hurdle in CXTx. Future studies will aim to prevent early xenograft dysfunction and achieve longer life-supporting cardiac xenotransplantation.

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