{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:53:28Z","timestamp":1791176008989,"version":"4.1.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Transplant."],"abstract":"<jats:p>Advanced heart failure affects over 6 million adults in the United States alone. Orthotopic heart transplantation remains the definitive treatment, with over 90% one-year survival and meaningful gains in functional status and quality of life. The therapy is, however, constrained by an intractable supply problem. For decades, xenotransplantation (XTx), the transplantation of organs across species, has been proposed as a means of closing this gap, though for most of that time it remained a theoretical aspiration. With the discovery of CRISPR-Cas9 gene editing, improved immunosuppressive strategies, and refined preclinical models, the field has accelerated at an unprecedented pace. Multi-gene-edited porcine donors have survived 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 some feasibility for clinical cardiac XTx for the first time. In May 2026, the FDA granted clearance under an investigational new drug application to allow the EXPRESS study, the first prospective clinical trial of a gene-edited porcine heart, to proceed. In this perspective, we discuss the ethical, regulatory, and equity considerations that remain as decisive barriers to clinical integration and may shape how this therapy is introduced along the remaining immunologic and virologic challenges. We outline what we regard as the near-term priorities: defining the antibody targets that drive xenograft rejection, standardizing virologic surveillance, candidate selection and outcome benchmarking, and building access patterns with embedded distributive justice from the outset of its implementation.<\/jats:p>","DOI":"10.3389\/frtra.2026.1971770","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:35:49Z","timestamp":1791174949000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Advancing cardiac xenotransplantation: overcoming challenges and ethical considerations for clinical integration"],"prefix":"10.3389","volume":"5","author":[{"given":"Ahmed A.","family":"Abdelrehim","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Alabama at Birmingham School of Medicine","place":["Birmingham, AL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Hurst","sequence":"additional","affiliation":[{"name":"Department of Medical Education & Scholarship, Rowan-Virtua School of Osteopathic Medicine","place":["Stratford, NJ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Hampton","family":"Gray","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Alabama at Birmingham School of Medicine","place":["Birmingham, AL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Sorabella","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Alabama at Birmingham School of Medicine","place":["Birmingham, AL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luz A.","family":"Padilla","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Alabama at Birmingham School of Medicine","place":["Birmingham, AL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1016\/j.ejheart.2007.04.003","article-title":"Advanced chronic heart failure: a position statement from the study group on advanced heart failure of the heart failure association of the European Society of Cardiology","volume":"9","author":"Metra","year":"2007","journal-title":"Eur J Heart Fail"},{"key":"B2","doi-asserted-by":"publisher","first-page":"S300","DOI":"10.1016\/j.ajt.2023.02.008","article-title":"OPTN\/SRTR 2021 annual data report: heart","volume":"23","author":"Colvin","year":"2023","journal-title":"Am J Transplant"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1001\/jama.1964.03060390034008","article-title":"Heart transplantation in man. 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