PROJECT SUMMARY/ABSTRACT There is a critical need for novel cardiac support techniques in infants with complex cardiac disease. A recent analysis of UNOS database from 1987 to 2016 documented only 55% of infants placed on cardiac transplant wait list survived to transplantation. The results of mechanical circulatory support (MCS) in infants is suboptimal. Actuarial six month survival of infants placed on MCS is reported by PEDIMACS to be 50% and most have adverse events. These results establish a pressing need for a new treatment paradigm in this age group. The potential of a completely implantable biologic support for infants on the cardiac transplant list would be transformative. Our preliminary data strongly suggest that anti-pig antibodies will not be a barrier to GEPH transplantation in infants if hearts are taken from `triple-knockout' (TKO) pigs. These pigs lack the 3 enzymes 1,3-galactosyltransferase (produces galactose-1,3galactose [GaL], cytidine monophosphate-N-acetylneuraminic acid hydroxylase (produces Neu5Gc), and 1,4-acetylgalactosaminyltrnsferase (adds Sda). (Table 1). These pigs are referred to as triple knockouts (TKO). We documented a lack of pre-formed antibodies to red blood cells (RBCs) of TKO pigs even after complex cardiac procedures. Binding of anti-pig IgM and IgG is greatly reduced compared with that to wild-type (i.e., unmodified [WT] pigs). This R33 application will allow us to target enabling technology to address a major translational clinical deficiency in the management of infants with critical cardiac disease. If successful, it establishes a transformative platform for the management of heart failure in the infant population. To our knowledge, we are the only research group focused on the potential application of this rapidly developing technology in this patient population. Access to the most advanced GEPHs available (hearts that would be suitable for transplantation in human infants) indicates the potential for data developed in this study to provide support for clinical application within five years.