Overlapping causes likely contributed to man’s death after first pig heart xenotransplant
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Key takeaways:
- Researchers identified what likely led to heart failure in the world’s first successful transplant of a genetically modified pig heart.
- The data may help inform testing protocols for future xenotransplants.
A combination of complex causes likely contributed to the death of the man who received the world’s first genetically modified pig heart transplant in 2022, including the presence of a latent porcine virus, researchers reported.
In a case report published in The Lancet, the researchers noted that the first successful cardiac xenograft from a 10-gene modified pig in a human “sustained life despite the recipient’s preexisting conditions” and multiple surgical and nonsurgical complications, until the patient died from graft failure 2 months after the procedure.
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As Healio previously reported, David Bennett, aged 57 years, died March 8, 2022, 2 months after receiving a procedure that was hailed as a milestone for xenotransplantation. Bennett had terminal heart disease and was deemed ineligible for a conventional heart transplant; the FDA authorized the procedure under its compassionate use provision. According to officials from the University of Maryland, where the xenotransplant was performed, Bennett’s condition began deteriorating several days before he died. When it became clear he would not recover, he received palliative care.
“We were determined to shed light on what led to the heart transplant dysfunction in Mr. Bennett, who performed a heroic act by volunteering to be the first in the world,” Bartley Griffith, MD, professor of surgery and the Thomas E. and Alice Marie Hales Distinguished Professor in Transplantation at University of Maryland School of Medicine, said in a press release. “We want out next patient to not only survive longer with a xenotransplant but to return to normal life and thrive for months or even years.”
The researchers investigated the possible cause or causes of the xenograft dysfunction by conducting extensive immunological and histopathological studies, including electron microscopy and quantification of porcine cytomegalovirus or porcine roseolovirus (PCMV/PRV) in the xenograft, recipient cells, and tissue by DNA polymerase chain reaction and RNA transcription. Researchers also performed IV immunoglobulin (IVIg) binding to donor cells and single-cell RNA sequencing of peripheral blood mononuclear cells.
After successful xenotransplantation, the graft functioned well on echocardiography and sustained CV and other organ systems functions until postoperative day 47, when diastolic HF occurred.
At postoperative day 50, the endomyocardial biopsy revealed damaged capillaries with interstitial edema, red cell extravasation, rare thrombotic microangiopathy and complement deposition, according to the researchers. Additionally, the researchers noted there were increased anti-pig xenoantibodies, mainly IgG, detected after IVIg administration for hypogammaglobulinemia and during the first plasma exchange.
Endomyocardial biopsy on postoperative day 56 also showed fibrotic changes consistent with progressive myocardial stiffness. Microbial cell-free DNA testing indicated increasing titers of PCMV/PRV cell-free DNA.
Postmortem single-cell RNA sequencing showed overlapping causes, the researchers wrote.
“We conclude that, except for a few unexpected complications, the genetically engineered pig heart and anti-CD40-based regimen could sustain a patient’s life for 60 days,” the researchers wrote. “More genetically engineered pig-to-human transplantations could improve our understanding of the mechanism of xenograft failure in humans and help us better manage clinical xenotransplantation.”
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