In 1984, Leonard Bailey transplanted a baboon heart into Baby Fae, a newborn with hypoplastic left heart syndrome. The xenograft supported her circulation for 20 days before failing due to rejection. Four decades later, Cleveland et al. revisit that concept but redefined its purpose: rather than serving as permanent cardiac replacement, the animal heart would provide temporary circulatory support until a human donor heart becomes available.
End-stage heart failure in infants represents one of the most challenging scenarios in pediatric cardiology and cardiac surgery. Heart transplantation may offer a definitive solution, but the waiting time is not always compatible with the patient’s clinical course. Mechanical circulatory support has transformed outcomes in many children, although its greatest limitations persist precisely among the smallest patients, those with certain congenital heart defects, and those with single-ventricle physiologies.
It is within this therapeutic gap—between a human heart that does not arrive and mechanical support that cannot always be provided—that Cleveland et al. place their proposal: the temporary use of a genetically modified pig heart to keep an infant alive until a human donor becomes available. The concept itself is not new. What has changed is how close it has moved toward clinical reality.
Cleveland et al. developed an orthotopic pig-to-baboon cardiac xenotransplantation model specifically designed to investigate its potential use as a bridge to pediatric allotransplantation. Unlike heterotopic transplantation, in which the native heart continues to support the circulation, the orthotopic model requires the xenograft to assume the entire cardiac workload. Thus, the model does more than assess the immunological survival of an organ: it evaluates whether that organ can sustain the recipient’s life.
The study included 15 pediatric-sized baboons receiving hearts from young genetically modified pigs. Rather than relying on a single uniform donor configuration, the program incorporated different combinations of genetic modifications as it evolved. This progressive development enabled the removal of porcine antigens targeted by naturally occurring primate antibodies, together with the expression of human proteins intended to regulate complement activation, coagulation, inflammation, and the immune response.
The latest experiments used miniature Yucatan pigs, whose adult size is smaller than that of conventional pig breeds. This choice addressed a particularly important issue in pediatric recipients: disproportionate xenograft growth within a small thoracic cavity. Some donors also carried growth hormone receptor inactivation, providing an additional strategy to limit excessive graft growth.
Immunosuppression was based on blockade of the CD40/CD154 costimulatory pathway, combined with rapamycin and other agents. This pathway has become one of the foundations of experimental xenotransplantation because it helps control an immune response that would be difficult to suppress using conventional allotransplantation regimens alone.
The group also introduced a technical decision with important translational implications. Instead of using the continuous nonischemic perfusion preservation systems adopted in other orthotopic xenotransplantation models, they employed static preservation and del Nido cardioplegia. The aim was to bring the procedure closer to a reproducible surgical approach that would be less dependent on highly specialized infrastructure.
Fourteen of the 15 recipients were successfully weaned from cardiopulmonary bypass, although three died within the first 24 hours. Eight animals, representing 53%, survived for more than one month with a functioning xenograft, and six survived beyond three months. Median survival for the entire series was 41 days; among animals surviving the first month, median survival increased to 193 days.
The most striking result was the survival of one recipient for slightly more than 24 months. This case demonstrates that a genetically modified pig heart can provide prolonged circulatory support in a pediatric-sized primate. Nevertheless, this individual record should not obscure the overall variability: almost half of the animals did not survive the first month, and the most favorable outcomes were concentrated in the later phases of the program.
This chronological evolution is important. The study combines experiments performed with different donor generations, immunosuppressive protocols, and technical strategies. It should therefore not be interpreted as a homogeneous series capable of providing a stable estimate of success, but rather as the progressive development of an experimental platform. The improvement observed in the most recent cases is encouraging, although it still requires confirmation using a standardized protocol applied reproducibly in consecutive recipients.
The mechanisms of failure were also heterogeneous. The study reported perioperative, infectious, immunological, and arrhythmic complications. Antibody-mediated rejection and the systemic inflammatory response associated with the xenograft remained relevant threats. The investigators also observed progressive T-cell recovery after initial depletion, highlighting the need to balance two opposing risks: insufficient immunosuppression, which may expose the graft to rejection, and excessive immunosuppression, which increases susceptibility to infection.
The distinctive contribution of this work lies not only in the duration of support. After more than four months of xenograft function, three recipients were selected for conversion to allogeneic heart transplantation. The investigators therefore sought to address a question that had previously remained largely theoretical: can prolonged exposure to a pig heart still permit subsequent conventional transplantation?
The most illustrative example was recipient 10. After 133 days of xenograft support, the pig heart was electively explanted and replaced with a baboon heart. The animal survived for a further 105 days after allotransplantation. Examination of the explanted pig heart showed globally preserved myocardium, indicating that replacement was not prompted by terminal xenograft failure but was instead performed as a planned component of the bridging strategy.
The analyses did not identify significant sensitization against either xenoantigens or alloantigens during the support period. This finding is particularly relevant because one of the central objections to the bridging concept is that exposure to a pig organ could induce antibodies that might subsequently reduce the likelihood of identifying a compatible human donor.
The study therefore demonstrates more than prolonged xenograft survival: it provides experimental evidence that subsequent transition to allotransplantation is feasible. However, the very small number of transitions and the limited follow-up prevent the complete bridging strategy from being considered validated. This is a proof-of-concept study, not an approach ready for incorporation into clinical practice.
COMMENTARY:
The main potential value of pediatric xenotransplantation becomes apparent when considered in the context of the real-world limitations of mechanical circulatory support. In an infant with cardiomyopathy and biventricular anatomy, a paracorporeal ventricular assist device may provide an effective bridge. The comparison becomes less favorable in very-low-weight patients, those requiring biventricular support, and children with specific congenital heart defects involving venous return, intracardiac anatomy, or physiologies that impair adequate cannula filling and drainage.
An orthotopic xenograft replaces both ventricles and maintains pulsatile circulation. This may be attractive when the underlying anatomy limits the effectiveness of mechanical support, although it introduces a different set of problems: rejection, immunosuppression, and infection. It does not eliminate risk; it shifts it elsewhere.
The anticoagulation, bleeding, and thrombosis associated with mechanical circulatory support are replaced by other concerns: xenogeneic rejection, intensive immunosuppression, opportunistic infections, surveillance for porcine microorganisms, and potentially unpredictable graft dysfunction. Whereas failure of a mechanical support device may, in selected configurations, be managed through device exchange or escalation of support, acute dysfunction of an orthotopic pig heart would require an immediate rescue strategy involving ECMO, ventricular assist support, or urgent transplantation.
The comparator for xenotransplantation should therefore not simply be death on the waiting list. It should be the best available alternative for each individual patient. Only when mechanical support is unfeasible, disproportionately hazardous, or unable to provide a reasonable bridge could the balance potentially favor an experimental strategy of this kind.
Demonstrating that a xenograft can sustain circulation for months is an extraordinary achievement, but it is insufficient to validate it as temporary support until allotransplantation. Merely prolonging the waiting period is not enough: the xenograft must preserve the patient’s candidacy for transplantation.
The goal is not simply to survive xenotransplantation. The recipient must reach human heart transplantation without uncontrolled infection, multiorgan failure, or sensitization that reduces the likelihood of compatibility. The patient must then undergo repeat sternotomy, explantation of the pig heart, a second period of ischemia and cardiopulmonary bypass, and a new phase of immunosuppression.
The work by Cleveland et al. directly addresses this transition and demonstrates that it can be accomplished. This is probably its most original finding. Nevertheless, it also shows the extent to which the second operation is itself part of the challenge. Residual porcine tissue must be avoided, inflammation triggered by graft replacement must be minimized, and an immunosuppressive regimen initially designed to control two distinct immunological barriers must be readjusted.
It also remains uncertain whether exposure to the xenograft modifies the immune response to the subsequent human heart. The absence of significant sensitization in this model is reassuring but not definitive. Baboons and humans do not recognize certain porcine antigens in the same way, particularly after specific carbohydrate antigens have been removed through genetic engineering. Compatibility observed in the preclinical model cannot therefore be extrapolated automatically to infants.
The candidate population should not be defined solely by disease severity. The initial candidate should not simply be the most critically ill patient, but rather one for whom the xenograft offers a meaningful advantage over the available support options and who retains a reasonable likelihood of subsequently completing allotransplantation.
The most appropriate candidates might include neonates or small infants with complex congenital heart disease, failure or infeasibility of mechanical circulatory support, and a realistic expectation of later receiving a human heart. Patients with single-ventricle physiology represent a population of particular interest, but also one of the most challenging: the same anatomical features that complicate mechanical support may also make xenograft implantation and subsequent allotransplantation more difficult.
High HLA sensitization should not, by itself, be regarded as an indication favoring xenotransplantation. Although a pig organ could extend the duration of support, these patients would continue to face difficulties in finding a compatible allograft. The value of the strategy would therefore depend not only on keeping the recipient alive, but also on preserving a realistic possibility of subsequently receiving a human heart.
There is also a particular ethical dimension. The decision would affect more than the recipient alone. Surveillance for potential zoonotic infections could require long-term monitoring of the child, the family, and healthcare professionals. The consent process would need to explain not only the uncertainty surrounding the xenograft, but also the possibility that the strategy might fail before a human heart became available or might compromise subsequent transplantation.
Cleveland et al. have brought pediatric cardiac xenotransplantation closer to a recognizable clinical question. Their contribution is not limited to showing that a pig heart can continue beating for more than two years in a primate. They developed a pediatric-sized model, simplified certain aspects of the procedure, and deliberately initiated the transition from xenograft support to allotransplantation.
The findings do not yet support the conclusion that xenotransplantation represents a clinical alternative to ventricular assist support. The heterogeneity of donor configurations and protocols, early mortality, the limited number of transitions, and the immunological differences between baboons and humans all require caution. Before a clinical trial can be considered, the results must be reproduced using a standardized genetic configuration and immunosuppressive protocol, rescue criteria must be clearly defined, and success must be shown not to depend on exceptional individual cases.
However, the threshold of the discussion has changed. The question is no longer merely whether a pig heart can support the circulation of a pediatric recipient, but rather which patients might benefit, for how long, and under what conditions the xenograft could carry them to a human heart. This study demonstrates that the transition from a pig heart to an allograft is possible in the laboratory. The decisive question remains whether it can be reproduced with sufficient safety and whether, in a specific infant, it could prove preferable to the available mechanical circulatory support options.
REFERENCE:
Cleveland JD, Mitchell CB, Swicord W, Neal SJ, Vo C, Bakshi K, et al. Gene-edited pig cardiac xenotransplantation as a bridge to allotransplantation in infants: Progress in a pig-to-baboon model. Am J Transplant. 2026 May;26(5):980-991. doi: 10.1016/j.ajt.2025.12.017. Epub 2025 Dec 24. PMID: 41453738; PMCID: PMC12935157.
