Cardiac Allograft Immunoprotection in Combined Heart-Liver Transplantation: Mechanisms and Clinical Translation for the Sensitized Candidate

Highly sensitized heart transplant candidates face substantially restricted access to transplantation and adverse waitlist outcomes, and no pharmacological desensitization strategy has consistently mitigated posttransplant rejection risk. A growing number of these candidates carry an independent indication for liver transplantation. For this population, combined heart-liver transplantation addresses both organ failures, and evidence demonstrates that the liver allograft confers immunological protection to the cardiac allograft through multiple convergent mechanisms. Clinical data confirm that this protection is powerful but selective, abolishing de novo class I donor-specific antibody (DSA) formation and dramatically reducing T cell-mediated rejection, while not preventing de novo class II alloimmunity. Cardiac allograft vasculopathy is also attenuated through a rejection-mediated pathway. The heart-after-liver transplantation protocol operationalizes this immunological protection by sequencing the liver implant before the cardiac allograft, permitting real-time DSA clearance in highly sensitized recipients. This principle has evolved with the heart-after-liver transplantation with domino approach to patients without independent hepatic indication, with early outcomes demonstrating successful immunoprotection and domino donation of the native liver partially offsetting the ethical concern of dual organ utilization. For highly sensitized candidates who independently meet the threshold for liver transplantation (fibrosis ≥F3), combined heart-liver transplantation with liver-first surgical sequencing represents a feasible approach; however, incomplete class II protection necessitates particular attention to persistent or de novo class II antibodies on routine posttransplant DSA surveillance, and mitigation of perioperative ischemic exposure, rather than immunological failure, represents the principal remaining challenge.