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Several lines of inquiry remain for why the recipient of the world's first pig-to-human heart xenotransplantation died 2 months later.

The transplant surgeon Bartley Griffith, MD, of University of Maryland School of Medicine in Baltimore, and colleagues revealed that David Bennett, age 57, had severe cardiac failure, and was denied a traditional human heart transplant from several programs when he ultimately agreed to the experimental xenotransplant.

Following FDA emergency use authorization, Bennett received a heart from a pig carrying 10 different gene edits designed to prevent graft rejection by his immune system and to stop the porcine heart from growing bigger after placement.

The patient underwent heavy immunosuppression and endomyocardial biopsy showed no evidence of rejection at day 34 after the surgery. However, he was found to have developed sudden diastolic thickening and antibody-mediated failure of the xenograft by day 49. Despite treatment, the injury to the xenograft was deemed irreversible, the patient's condition worsened, and life support was withdrawn on day 60, Griffith's group reported in the (NEJM).

"The pronounced sudden diastolic failure and global pathologic myocardial thickening without systolic dysfunction remains unexplained. These findings, in combination with focal capillary injury in the virtual absence of complement deposition, are not normally seen in human allotransplantation," the group wrote.

"On autopsy, the xenograft was found to be edematous, having nearly doubled in weight. Histologic examination revealed scattered myocyte necrosis, interstitial edema, and red-cell extravasation, without evidence of microvascular thrombosis -- findings that were not consistent with typical rejection. Studies are under way to identify the mechanisms responsible for these changes," the authors noted.

One potential mechanism is zoonosis: Bennett unexpectedly tested positive for porcine cytomegalovirus (pCMV) starting on day 20 despite testing of the donor animal before organ transplantation and use of antiviral prophylaxis. Postmortem samples showed no signs of pCMV infection to his thoracic and abdominal regions, however.

Bennett's xenotransplantation nevertheless remains a despite the patient's death. Widely hailed as a landmark surgery, it marked a new era for heart failure patients.

"The normal function of a pig heart in a human and the avoidance of graft rejection for more than a month is an achievement supported by decades of research in immunity, embryology, genetics, and animal husbandry," wrote NEJM deputy editor Elizabeth Phimister, PhD, in an accompanying

If methods are improved, pig-to-human donation may open the door to shorter wait lists while human donor hearts stay in short supply.

"Reduction in the number and extent of genetic modifications of pigs could benefit the long term function of xenotransplants, since the untoward insertion of genetic sequences has been associated with myocardial aging," suggested Jeffrey Platt, MD, and Marilia Cascalho, MD, PhD, both of University of Michigan, Ann Arbor, in another.

Future developments in the transplant world do not have to be limited to xenotransplantation, either.

Platt and Cascalho noted that "techniques like those used to engineer pigs could be applied to generating human tissues and organs for implantation into patients with organ failure. Pluripotent stem cells and cells of other types are increasingly explored for generation of autologous organs through organogenesis or three-dimensional tissue engineering. Use of autologous organs, modified to resist underlying disease, presumably would avert the need for -- and toxic effects of -- lifelong immunosuppression."

In this case, xenografts may offer temporary support while an autologous implant is generated for a patient, they suggested.

Phimister predicted that technological developments in heart transplantation are likely.

"In the meantime, we can be grateful for the patient's willingness to volunteer for this extraordinary test of xenotransplantation and humbly acknowledge the contribution of animal models and animal donors to biomedical research," she stated.