The primary clinical rationale for pursuing cardiac xenotransplantation lies in its capacity to address the critical shortage of donor hearts while simultaneously providing a potential alternative to established, yet often insufficient, palliative pathways. In the context of single-ventricle heart disease, where the potential role of a xenograft extends beyond mere organ availability, it could serve as a critical alternative to further staged palliation in select high-risk patients, or function as a vital bridge to allotransplantation when conventional strategies prove inadequate. This review synthesizes the current clinical and preclinical evidence, alongside the profound ethical considerations necessary for candidate selection, paying meticulous attention to the unique vulnerabilities of the pediatric population and the complexities of the single-ventricle pathway.

Preclinical investigations into orthotopic cardiac xenotransplantation have focused on pediatric-sized baboons, weighing between 4.5 and 9.5 kilograms. These studies have employed various donor genetic constructs, including GGTA1-knockout hearts modified with human transgenes such as hCD55 and hCD46/hTBM, as well as complex triple knockout backgrounds incorporating inactivated porcine endogenous retroviruses and multiple human transgenes like hCD46, hCD55, hTBM, hEPCR, and hCD47. The induction and maintenance of immunosuppression in these models are highly sophisticated, involving initial therapy with anti-thymocyte globulin, rituximab, methylprednisolone, and C1-esterase inhibition. Maintenance regimens have centered on costimulation blockade and rapamycin, with specific modifications, such as replacing anti-CD40 with anti-CD154, being implemented across the expanded series of 15 recipients. These rigorous protocols have yielded promising results, with the expanded series showing a median survival of 41 days, and crucially, the longest survivor exceeding 24 months, demonstrating the feasibility of prolonged xenograft support in a small animal model.

Despite these preclinical successes, the clinical translation of these findings to human infants requires addressing significant physiological and immunological challenges. One major concern is the potential for excessive xenograft growth, as observed in previous pig-to-baboon orthotopic transplants. While growth hormone receptor knockout has been used to reduce graft hypertrophy, the long-term question remains whether a growth-restricted porcine heart can maintain both appropriate size and function as an infant undergoes somatic growth. Furthermore, the intensity and long-term safety of the complex immunosuppressive regimens employed in nonhuman primates have not been established for infants. Adult clinical experience also suggests that even with extensive donor gene editing and costimulation blockade, endothelial and antibody-mediated graft injury can still occur, highlighting the need for further investigation into the durability of these interventions in a pediatric context.

Beyond whole-heart transplantation, partial-heart xenotransplantation presents a distinct and highly relevant application, specifically for pediatric valve replacement. In complex congenital anatomy, especially in neonates and infants, both conventional prosthetic and biologic valves present limitations, as they do not grow with the child, leading to issues of recurrence and the need for repeated interventions. Partial-heart allotransplantation addresses this growth limitation by utilizing viable valve tissue capable of adaptive growth. While this procedure currently relies on human donor tissue, a porcine source could provide size-matched living valves without the constraints of donor scarcity. Preclinical studies have explored implanting a gene-edited porcine right-ventricle-to-pulmonary-artery conduit in an infant baboon, successfully maintaining valve function without stenosis or regurgitation for five weeks. This suggests a potential strategy: using a living xenogeneic valve during early childhood and replacing it with a conventional prosthesis once somatic growth permits, thereby limiting the period of required immunosuppression.

The clinical utility of xenotransplantation is not monolithic; its rationale shifts depending on the specific stage of the single-ventricle palliation pathway. Before Stage I palliation, xenotransplantation could potentially offer a size-appropriate graft to high-risk neonates who are unlikely to survive Stage I or the allograft waitlist, thereby avoiding cumulative injury from further palliative operations. After Stage I, it could act as a rescue strategy for infants with a failing interstage course who cannot safely progress to Stage II palliation. After Stage II, before Fontan completion, it might provide replacement circulation for children with failing Glenn physiology. Finally, after Fontan completion, a xenograft could relieve complications such as protein-losing enteropathy or hepatic congestion, providing a physiologic basis for its consideration. In every scenario, the potential benefit is contingent upon the xenograft providing sustained function and the reversibility of any extracardiac disease.

Ethical considerations are paramount and must be addressed across all stages of clinical translation. The historical context, such as the 1984 case of Baby Fae, underscores the necessity of rigorous ethical debate regarding the evidence required before clinical application. Central to the ethical evaluation are parental permission, the child’s developing autonomy, and the necessity of lifelong infection surveillance. For living pediatric recipients, parental consent must reflect a clear understanding of the uncertain benefits, the risk of graft failure, immunosuppressive toxicity, and the potential for donor-derived infection. Furthermore, the concept of patient autonomy must evolve, with assent being required as the child develops and consent being sought upon reaching the legal age.

The implementation of pediatric cardiac xenotransplantation necessitates a comprehensive, multidisciplinary approach that extends far beyond the surgical procedure. Candidate selection must involve a detailed assessment of anatomy, organ function, neurological prognosis, and the feasibility of subsequent allotransplantation should the xenograft fail. Shared risks include rejection, thrombosis, immunosuppressive toxicity, and the risk of zoonotic infection, which requires lifelong monitoring. A robust contingency plan is essential to address xenograft deterioration before an allograft becomes available. This includes establishing a funded plan for lifelong surveillance and coordinating follow-up and transfer to adult services, ensuring that participation does not depend solely on a family’s resources. The ethical assessment of utilizing human decedent studies to gain knowledge must also be balanced against the emotional and practical burdens placed on bereaved families, requiring explicit authorization and defined limits on study duration.

In conclusion, while preclinical data strongly supports the continued investigation of porcine xenografts in pediatric cardiac surgery, the transition to clinical practice requires addressing numerous unresolved questions regarding graft growth, long-term immunosuppression safety, and the predictability of allograft availability. The potential for cardiac xenotransplantation to serve as a vital bridge to allotransplantation for selected children facing poor prognoses under current palliative or mechanical support is significant, but it remains a highly specialized and ethically complex frontier in pediatric cardiovascular medicine. Future clinical use must be strictly limited to highly selected patients for whom conventional palliation or mechanical support cannot provide an adequate bridge, and where a credible plan for subsequent treatment following xenograft failure is firmly established.

Subject of Research: The clinical and ethical considerations for pediatric cardiac xenotransplantation candidates.

Article Title: Clinical and ethical considerations for pediatric cardiac xenotransplantation candidates

Article References: Contorno, E., Takemoto, S., Javed, H., Sreenivasan, S., Kim, S., Schmitz, M., & Rajab, T. (2026). Clinical and ethical considerations for pediatric cardiac xenotransplantation candidates. Frontiers in Transplantation, 5, 1999444. https://doi.org/10.3389/frtra.2026.1999444

Image Credits: AI Generated

DOI: 10.3389/frtra.2026.1999444

Keywords: xenotransplantation, pediatric cardiology, congenital heart disease, single-ventricle physiology, gene editing, heart transplantation, medical ethics, Clinical, ethical, considerations, pediatric, cardiac