Cardiac xenotransplantation: From imagination to achievable practice

Table 1 Key events in the development of clinical cardiac xenotransplantation

Year	Surgeon/team	Institution, country	Donor	Transplant type	Recipient profile	Survival/observation	Key outcome/Lesson	Ref.
1964	Hardy	University of Mississippi Medical Center, Jackson, United States	Chimpanzee	OHT	Moribund man with terminal heart failure	About 2 hours	Graft failure from donor-recipient size mismatch with early antibody-mediated injury; established the need for size matching and recognition of the preformed-antibody barrier	[7,8]
1968	Cooley	Texas Heart Institute, Houston, United States	Sheep	OHT	48-year-old man with terminal ischemic cardiomyopathy	Minutes	Hyperacute rejection in the operating room; demonstrated the preformed natural antibody/complement barrier against discordant species	[8]
1968	Ross	National Heart Hospital, London, United Kingdom	Pig	HHT	48-year-old man with terminal heart disease	Minutes (about 4 minutes)	Immediate hyperacute rejection; confirmed the hyperacute barrier for pig-to-human grafts and redirected the field toward concordant donors and, later, genetic engineering	[8]
1977	Barnard	Groote Schuur Hospital, University of Cape Town, South Africa	Baboon; chimpanzee	HHT (circulatory support)	Two patients with postcardiotomy shock unable to be weaned from cardiopulmonary bypass	< 1 day (baboon); 4 days (chimpanzee)	Heterotopic xenografts can provide temporary mechanical support, but rejection occurred before native-heart recovery, highlighting the need for effective immunosuppression	[9]
1984	Bailey	Loma Linda University Medical Center, Loma Linda, United States	Baboon	OHT	Neonate (“Baby Faye”) with hypoplastic left heart syndrome	21 days	Longest survival of the pre-genetic era under cyclosporine-based immunosuppression; death from humoral rejection across an ABO-incompatible barrier; catalyzed scientific and ethical debate	[10]
2022	Griffith/Mohiuddin	University of Maryland Medical Center, Baltimore, United States	10-gene-edited pig1	OHT	57-year-old man with end-stage heart failure, ineligible for allotransplantation or LVAD; FDA compassionate use (living recipient)2	60 days	Proof-of-concept xenograft function; late graft failure associated with PCMV/PRV reactivation, IVIG-associated anti-pig IgG, and progressive diastolic dysfunction; recipient died on POD 60	[14,15]
2022	Moazami	NYU Langone Health, New York, United States	10-gene-edited pig1	OHT	Two deceased (brain-dead) recipients on ventilatory support3	Observation period (66 hours)3	No hyperacute, cellular, or antibody-mediated rejection and no zoonotic transmission during observation; dysfunction in one graft attributed to donor-recipient size mismatch	[18]
2023	Griffith/Mohiuddin	University of Maryland Medical Center, Baltimore, United States	10-gene-edited pig1	OHT	58-year-old man with end-stage heart failure, ineligible for allotransplantation; FDA compassionate use (living recipient)2	About 40 days (died October 30, 2023)	Early biopsy evidence of antibody-mediated rejection by about 2 weeks despite a less compromised recipient, enhanced donor screening, and complement inhibition; graft failure led to withdrawal of support	[16,17]

¹The 10-gene-edited donor pigs carried knockouts of three carbohydrate xenoantigen genes (GGTA1, CMAH, B4GALNT2) and of the growth hormone receptor gene, together with human transgenes encoding complement-regulatory (CD46, CD55), coagulation-regulatory (thrombomodulin, endothelial protein C receptor), and immunomodulatory/anti-inflammatory proteins (CD47, heme oxygenase-1).

²Living compassionate-use recipients: Single-patient, United States Food and Drug Administration-authorized experimental procedures; outcomes represent patient survival.

³Deceased (brain-dead) recipient research model: The 66-hours figure denotes the protocol-defined observation period, not patient survival; this model provides short-term mechanistic evidence only.

OHT: Orthotopic heart transplantation; HHT: Heterotopic (auxiliary) heart transplantation; LVAD: Left ventricular assist device; FDA: United States Food and Drug Administration; POD: Postoperative day; PCMV/PRV: Porcine cytomegalovirus/porcine roseolovirus; IVIG: Intravenous immunoglobulin.

Table 2 Comparative summary of the human clinical evidence in cardiac xenotransplantation

Case	Evidence model	Donor genotype	Preservation strategy	Immunosuppression	Follow-up duration	Dominant complications	Key limitations	Ref.
University of Maryland, January 2022	Living compassionate-use recipient	10-gene-edited pig (GGTA1/CMAH/B4GALNT2 knockout, GHR knockout; hCD46, hCD55, hTBM, hEPCR, hCD47, hHMOX1 transgenes)	Not fully reported in the primary publication	Investigational anti-CD40 costimulation blockade combined with mycophenolate mofetil and corticosteroids	60 days (recipient died on POD 60)	Progressive diastolic dysfunction from POD 47; capillary injury with complement deposition; PCMV/PRV reactivation within the graft; IVIG-associated rise in anti-pig IgG	Single compassionate-use case; non-approved investigational agents; latent donor viral infection missed by conventional screening; mechanism of graft failure multifactorial and incompletely resolved	[14,15]
University of Maryland, September 2023	Living compassionate-use recipient	10-gene-edited pig (same editing platform)	Not fully reported	Costimulation blockade with intensified complement-directed therapy	Approximately 40 days (died October 30, 2023)	Early antibody-mediated rejection on biopsy at 2 weeks; subsequent anti-pig antibody surge with progressive graft injury and renal failure	Single compassionate-use case; antibody-mediated rejection emerged despite a healthier recipient, enhanced donor screening, and complement inhibition	[16,17]
NYU Langone, 2022 (two cases)	Deceased (brain-dead) recipient research model	10-gene-edited pig	Standard clinical procurement and preservation	Conventional allotransplant-style immunosuppression without investigational agents	Protocol-defined observation period of 66 hours (not patient survival)	Functional decline in one graft attributed to donor-recipient size mismatch; no rejection and no zoonotic transmission observed	Very short observation window; brain-death physiology does not model living recipients; cannot inform on long-term survival, chronic rejection, or infection risk	[18]

POD: Postoperative day; PCMV/PRV: Porcine cytomegalovirus/porcine roseolovirus; IVIG: Intravenous immunoglobulin; GHR: Growth hormone receptor; hTBM: Human thrombomodulin; hEPCR: Human endothelial protein C receptor; hHMOX1: Human heme oxygenase-1; NYU: New York University.