Nonischemic and normothermic beating cardiac xenotransplantation

Cardiac xenotransplantation—the transplantation of a heart from one species to another- offers a clinically viable solution to the organ shortage problem. Despite significant advances in genetic engineering technologies and new immunosuppressive medications such as co-stimulatory blockade, bringing cardiac xenotransplantation to the clinic still has several challenges. Perioperative cardiac xenograft dysfunction is a major limitation to long-term xenograft survival and is attributed to the ischemia-reperfusion damage associated with the procurement and transplant of the porcine heart. This dysfunction can be reduced by utilizing commercial ex vivo perfusion devices which limit the cold ischemia time. Unfortunately, these devices still require an obligatory ischemic period during the initial arrest with cardioplegia and subsequent explanting of the organ, and then again during the implantation of the heart. These commercial devices also do not support smaller pediatric sized hearts, reducing the pool of recipients eligible for xenografts. We sought to establish a novel method of explanting and orthotopically implanting beating donor hearts from genetically modified pigs without any ischemia, while maintaining normothermic perfusion in a pig-to-nonhuman primate model. Eliminating cold and warm ischemia has never previously been achieved in cardiac xenotransplantation and has important implications for bringing it to the clinic, as well as broader translatability in allotransplantation. We performed a proof-of-concept experiment utilizing our novel technique in a non-survival model and then performed a successful experiment with nearly 8 weeks of survival of a single GGTA1 knockout pig heart. Our initial data suggest that utilization of a normothermic coronary perfusion circuit in cardiac xenotransplantation is feasible and safe and may be a plausible method towards achieving survival.