A perspective on the potential detrimental role of inflammation in pig orthotopic heart xenotransplantation

Abstract

There is a critical shortage of deceased human donor organs for transplantation. The need is perhaps most acute in neonates and infants with life‐threatening congenital heart disease, in whom mechanical support devices are largely unsuccessful. If orthotopic (life‐supporting) heart transplantation (OHTx) were consistently successful in the genetically engineered pig‐to‐nonhuman primate (NHP) model, a clinical trial of bridging with a pig heart in such patients might be justified. However, the results of pig OHTx in NHPs have been mixed and largely poor. We hypothesise that a factor is the detrimental effects of the inflammatory response that is known to develop (a) during any surgical procedure that requires cardiopulmonary bypass, and (b) immediately after an NHP recipient is exposed to a pig xenograft. We suggest that the combination of these two inflammatory responses has a direct detrimental effect on pig heart graft function, but also, and possibly of more importance, on recipient baboon pulmonary function, which further impacts survival of the pig heart graft. In addition, the inflammatory response almost certainly adversely impacts the immune response to the graft. If our hypothesis is correct, the potential steps that could be taken to reduce the inflammatory response or its effects (with varying degrees of efficacy) include (a) white blood cell filtration, (b) complement depletion or inactivation, (c) immunosuppressive therapy, (d) high‐dose corticosteroid therapy, (e) cytokine/chemokine‐targeted therapy, (f) ultrafiltration or CytoSorb hemoperfusion, (g) reduction in the levels of endogenous catecholamines, (h) triiodothyronine therapy and (i) genetic engineering of the organ‐source pig. Prevention of the inflammatory response, or attenuation of its effects, by judicious anti‐inflammatory therapy may contribute not only to early survival of the recipient of a genetically engineered pig OHTx, but also to improved long‐term pig heart graft survival. This would open the possibility of initiating a clinical trial of genetically engineered pig OHTx as a bridge to allotransplantation.

Clinical cardiac xenotransplantation first in the clinical arena

“…Remarkably, serum IL‐6 levels did not return to baseline within the first postoperative week, which was probably caused by the treatment with the anti‐IL‐6 receptor antibody tocilizumab 19 . In contrast to Thompson and colleagues, 1 however, we did not observe any signs of severe organ dysfunction despite these elevated levels of IL‐6, and the slightly abnormal changes disappeared within the first postoperative week; creatinine levels stayed normal throughout the full observation time.…”

“…Although this brief summary of possible detrimental reactions triggered by the use of a heart‐lung machine might indeed sound frightening to a noncardiac surgeon (as is the description of Thompson and colleagues 1 ), it is a fact that most sick patients, some of them in end‐stage heart disease, survive the operations and improve after a relatively short course of post‐operative care.…”

“…In the July/August 2021 issue of this journal, Thompson et al 1 . discussed the “potential detrimental role of inflammation in pig orthotopic heart xenotransplantation.” After dealing with common reactions to porcine tissues, the authors focused on severe pathological responses due to the cardiopulmonary bypass that is necessary to keep the baboon recipients alive during heart replacement, emphasizing the susceptibility of the lungs to injury in this setting.…”

“…So, why are the results after orthotopic porcine heart‐xenotransplantation “mixed and largely poor” as Thompson and colleagues 1 write? Theoretically, one would expect rather the opposite.…”

Don't pig(!) the wrong heart!

“…Basic problems of immune response have not been fully answered. [22][23][24] Patient selection is completely unclear and it appears, that there is no distinct patient population that could even remotely and temporarily benefit from cardiac xenotransplantation. 25,26 Fundamental ethical questions have been addressed, but only within the xenotransplant community.…”