Recovery from perioperative cardiac xenograft dysfunction and consequences of cardiac overgrowth in pig-to-baboon heterotopic thoracic cardiac xenotransplantation

Introduction: After the first xenotransplantation of a genetically modified pig heart in 2022, the clinical application is now more realistic than ever. However, it remains challenging to define the precise clinical setting: e.g., the back-up strategy in case of xenograft failure. In this regard, the heterotopic thoracic technique, a clinically accepted method initially introduced by Christiaan Barnard to overcome primary allograft failure, could be an alternative to the orthotopic procedure. We present new data of previous heterotopic thoracic pig-to-baboon experiments, now in the light of recent findings regarding perioperative cardiac xenograft dysfunction (PCXD) and xenograft overgrowth. Based on these analyses, we discuss the role of these phenomena as well as possible implications for future clinical applications. Method: We used n=17 genetically modified piglets as donors for heterotopic thoracic cardiac xenotransplantation in n=17 captive-bred baboons. In all animals, DSI pressure probes were implanted in the graft´s left ventricle and the recipient´s ascending aorta and recorded continuously. Results: Aortic pressures and heart rates of the recipients’ hearts were postoperatively stable and showed a similar course in all experiments. However, after reperfusion, 3 out of 17 grafts presented with low left ventricular pressure indicating PCXD (e.g., after 10 postoperative hours mean systolic graft pressure was 31 mmHg, while mean aortic pressure was 126 mmHg on average). These animals recovered from PCXD within 48 hours with the support of the normal working recipients´ hearts; there was no difference in survival compared to the remaining 14 experiments. After 48 hours, graft pressure increased from mean values around 110 mmHg to 200 mmHg in all 17 animals. This led to a progressive gradient between graft and ascending aortic pressure. With increasing gradients, the grafts stopped contributing to overall cardiac output. Grafts showed a marked weight increase from 84 g at implantation to 123 g at explantation. Conclusion: The heterotopic thoracic technique is a possible method to overcome PCXD in a clinical pilot study. In our pre-clinical model graft overgrowth limited cardiac output of the donor organ. We agree, that our pre-clinical model with a normal working recipient´s heart is different to the clinical situation after heterotopic allotransplantation. Nevertheless, we know from the clinical situation, that even a residual function of the remaining native heart is able to provide sufficient cardiac output for a certain time in cases of allograft failure. During that time, a new heart, either allo- or xenogeneic, will be found. In this situation the orthotopic procedure is preferred. German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) TRR 127. German Primate Center. Walter Brendel Centre of Experimental Medicine.