Cardiac xenotransplantation: from concept to clinical reality.

Abstract

Advanced heart failure afflicts over 6 million adults in the United States alone, yet fewer than 4,000 donor hearts become available for transplantation each year. Mechanical circulatory support devices extend survival for many of these patients, but device-related complications, anatomic contraindications, and limited applicability to certain populations leave a substantial unmet need. For decades, xenotransplantation (XTx)-the transplantation of organs across species-has been proposed as a means of closing this gap. The discovery of CRISPR-Cas9 gene editing, improved immunosuppressive strategies, and refined preclinical models have accelerated the field at an unprecedented pace. Multi-gene-edited porcine donors now survive for more than 200 days in orthotopic non-human primate models, and two compassionate-use pig-to-human cardiac transplants at the University of Maryland (2022 and 2023) demonstrated the feasibility of clinical cardiac XTx for the first time. Parallel progress in kidney XTx has yielded the first FDA-cleared investigational new drug application and the initiation of a formal clinical trial in late 2025. In May 2026, the FDA granted clearance for the first-ever cardiac XTx clinical trial (EXPRESS), using a 10-gene-edited porcine heart. The 2026 International Society for Heart and Lung Transplantation Consensus Statement now provides a structured framework for recipient selection, immunologic assessment, and outcome benchmarking in cardiac XTx. Antibody-mediated rejection remains the dominant barrier, as both clinical cases ended in xenograft failure driven by antipig antibody responses despite aggressive immunosuppression. Porcine cytomegalovirus reactivation, coagulation dysregulation, and xenograft overgrowth represent additional obstacles that demand resolution before broader clinical application. The optimal immunosuppressive regimen for human recipients has yet to be defined, and long-term zoonotic surveillance protocols require further standardization. With the first cardiac XTx clinical trial now cleared by the FDA, the field continues to face not only the remaining immunologic and virologic hurdles but also the ethical, regulatory, and equity considerations that will shape how this therapy is introduced. This review synthesizes the historical, scientific, and clinical foundations of cardiac XTx, appraises the current evidence, and outlines the path toward responsible clinical translation.