The potential of cardiac xenotransplantation for management of infants with complex congenital heart disease

Gene editing of the porcine genome has enabled the production of pigs that do not express the three known carbohydrate antigens that are associated with hyperacute rejection of a pig organ xenotransplant. In addition, it is now possible to insert a variety of human transgenes to protect against the human immune response, e.g., to protect from complement and coagulation activation. As a result, cardiac xenotransplantation of the gene-edited porcine heart is progressing towards clinical application. Many hope that it will definitively address the disparity between organ supply and demand. The role of cardiac xenotransplantation in pediatric care remains controversial but we believe there is an infant patient population with complex congenital heart disease (CHD) (not optimally managed by conventional surgical approaches) that is ideally suited to initial clinical application of this new technology. The most efficacious start would be to initiate clinical use as a short-term bridge to allotransplantation, particularly in infants with single ventricle pathology and significant risk factors for first stage Norwood palliation. Infants with end-stage heart failure after first stage palliation would represent a second target population. Infants experience unacceptably high mortality and morbidity when placed on mechanical circulatory support as a bridge to allotransplant. Effectively bridging these vulnerable populations could promote acceptance of cardiac xenotransplantation, allowing indications and use to expand, e.g., by (I) bridging patients with failed second and third stage single ventricle disease, or (II) with complex biventricular CHD, or (III) those with a restrictive or dilated cardiomyopathy. Finally, there is a reasonable expectation that the immunologic privilege of infants will allow porcine heart xenotransplantation to be destination therapy for some patients. In summary, heart allotransplantation in infants offers superior outcomes when compared to three-stage single ventricle palliation, but there is a continual shortage of deceased human donor organs. We should pursue research towards the application of xenotransplantation in patients with single ventricle pathology, in whom the results of staged palliation are likely to be suboptimal. There are many remaining issues to be resolved before cardiac xenotransplantation enters regular pediatric clinical use, but experience in this field is progressing rapidly.