Overcoming perioperative inflammation as a hurdle for successful preclinical orthotopic cardiac xenogeneic transplantations – particular in regard of the mandatory use of heart‐lung machines

Abstract

Introduction:After orthotopic cardiac xenotransplantation, the combination of both the inflammatory responses to the exposure of a recipient to the xenogeneic organ and the use of cardiopulmonary bypass has been assumed to cause detrimental side effects.These have been described not only to affect the transplanted organ (heart) itself, but also the recipient's lungs. In this article, we summarize how these possible detrimental processes can be minimized or even avoided. Methods: Data from eight pig-to-baboon orthotopic cardiac xenotransplantation experiments were analyzed with a special focus on early (within the first week) postoperative organ dysfunction and systemic inflammatory responses. Non-ischemic heart preservation and the careful management of the heart-lung machine were deemed essential to guarantee not only the immediate function of the transplanted xenogeneic organ but also the prompt recovery of the recipient. Results: After weaning from cardiopulmonary bypass, very low catecholamine amounts were needed to ensure an adequate pump function and cardiac output. Central venous oxygen saturation and serum lactate levels remained within normal ranges. All animals were successfully weaned from ventilation within the first postoperative hours. Serum parameters of the transplants and native kidneys and livers were initially slightly elevated or always normal, as were hemoglobin, LDH, and platelet measurements. Markers of systemic inflammation, C-reactive protein, and IL-6 were slightly elevated, but the reactions caused no lasting damage. Conclusion: Consistent short-term and long-term results were achieved after orthotopic cardiac pig-to-baboon transplantation without detrimental inflammatory responses or signs of multiorgan failure. In comparison to allogeneic procedures, This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

The Endothelial Glycocalyx in Pig-to-Baboon Cardiac Xenotransplantation—First Insights

“…Cardiac xenotransplantation has seen remarkable success in recent years and is emerging as the most promising alternative to human cardiac allotransplantation [ 1 , 2 , 3 ]. This success was made possible by essential achievements and important findings in different in vivo and in vitro models [ 4 , 5 , 6 ]: the development of genetically modified donor pigs lacking surface sugar antigens as well as expressing different human genes [ 1 , 7 ], immunosuppression based on co-stimulation blockade of the CD40/CD40 ligand (CD40L) pathway [ 8 ], continuous cold non-ischemic heart preservation [ 9 , 10 ], the relevance of growth control [ 4 , 11 , 12 , 13 ], the absence of porcine cytomegalovirus (a porcine roseolovirus (PCMV/PRV)) [ 14 , 15 ] and other pathogens in the donor animals [ 1 , 16 ] and the relevant role of inflammatory responses and coagulation disorders following xenotransplantation [ 17 , 18 , 19 , 20 ]. Using these current strategies, consistent survival for up to nine months was achieved in life-supporting pig-to-baboon experiments [ 4 , 5 , 6 ] and the first pig-to-human cardiac xenotransplantations were performed as individual medical treatments in 2022 [ 21 , 22 ] and 2023 [ 23 ].…”