Lessons from First Pig to Human Heart Transplant

A new study published in The Lancet provides the most comprehensive examination to date of what caused the eventual heart failure in the world’s first successful heart transplant of a genetically modified pig heart into a human patient. In January 2022, physician-scientists from the University of Maryland School of Medicine (UMSOM) performed a ground-breaking treatment that marked an important milestone in medical science.

David Bennett, Sr., 57, received treatment at the University of Maryland Medical Center. For over seven weeks following the surgery, he had good heart function with no visible evidence of acute rejection. He died two months after the heart transplant due to a sudden onset of heart failure. Since then, the transplant team has been undertaking significant research into the physiologic mechanisms that led to the heart failure in order to uncover aspects that can be avoided in future transplants in order to improve the chances of long-term success.

“Our paper provides crucial insight into how a multitude of factors likely played a role in the functional decline of the transplanted heart,” said study lead author Muhammad M. Mohiuddin, MD, Professor of Surgery and Scientific/Program Director of the Cardiac Xenotransplantation Program at UMSOM. “Our goal is to continue moving this field forward as we prepare for clinical trials of xenotransplants involving pig organs.”

Mr. Bennett, who was nearing the end of his life and in end-stage cardiac failure, did not qualify for a standard heart transplant. The procedure was approved by the United States Food and Drug Administration under the extended access (compassionate use) provision.

“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,” said study co-author Bartley Griffith, MD, Professor of Surgery and The Thomas E. and Alice Marie Hales Distinguished Professor in Transplantation at UMSOM. “We want our next patient to not only survive longer with a xenotransplant but to return to normal life and thrive for months or even years.”

The research team conducted comprehensive testing on the patient’s limited available tissues to better understand the processes that contributed to the pig heart transplant’s malfunction. They meticulously traced the events that led to cardiac failure, demonstrating that the heart functioned normally on imaging tests such as echocardiogram until day 47 after surgery.

The latest study reveals that there were no evidence of acute rejection during the first few weeks after the transplant. Mr. Bennett’s heart failure was most likely caused by a combination of events, including his poor health previous to the transplant, which caused him to become highly immunocompromised. This hampered the utilization of a successful anti-rejection regimen utilized in preclinical xenotransplantation experiments. As a result, the researchers discovered, the patient was more likely to be rejected by antibodies produced by the immune system. Based on histology, immunohistochemical labeling, and single cell RNA analysis, the researchers discovered indirect evidence of antibody-mediated rejection.

The use of an intravenous immunoglobulin, IVIG, a medication containing antibodies, may also have contributed to heart muscle cell injury. It was administered to the patient twice during the second month following the transplant to assist avoid infection, and it most likely triggered an anti-pig immune response. The researchers discovered IgG antibodies targeting the pig heart’s vascular endothelium layer.

Finally, the new study looked into the existence of a dormant virus called porcine cytomegalovirus (PCMV) in the pig heart, which could have contributed to the transplant’s failure. The virus may have been activated when the patient’s anti-viral therapy regimen was decreased to address other health concerns. This could have triggered an inflammatory reaction, resulting in cell damage. There is no evidence, however, that the virus infected the patient or spread to organs other than the heart. PCMV testing techniques have been improved to allow for the sensitive detection and exclusion of latent viruses in future xenotransplants.

“Valuable lessons can be learned from this groundbreaking surgery and the courageous first patient, Mr. Bennett, that will better inform us for future xenotransplants,” said UMSOM Dean Mark T. Gladwin, MD, Vice President for Medical Affairs, University of Maryland, Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor. “In the future, our team of surgeon-scientists will utilize newly designed immune cell assays to monitor the patient more precisely in the days, weeks, and months following the xenotransplant. This will provide stricter control of the earliest signs of rejection and the promise of a truly lifesaving innovation.”

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