A new study published today in The Lancet has revealed the most extensive analysis to date on what led to the eventual heart failure in the world's first successful transplant of a genetically-modified pig heart into a human patient. This groundbreaking procedure was conducted by University of Maryland School of Medicine (UMSOM) physician-scientists back in January 2022 and marked an important milestone for medical science.
The patient, 57-year-old David Bennett, Sr., was treated at the University of Maryland Medical Center. He experienced strong cardiac function with no obvious signs of acute rejection for nearly seven weeks after the surgery. A sudden onset of heart failure led to his death two months after the transplant. Since then, the transplant team has been conducting extensive studies into the physiologic processes that led to the heart failure to identify factors that can be prevented in future transplants to improve the odds of longer-term success. Poultry Medicine
“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 in end-stage heart failure and nearing the end of his life, did not qualify for a traditional heart transplant. The procedure was authorized by the U.S. Food and Drug Administration under its expanded 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.”
To better understand the processes that led to dysfunction of the pig heart transplant, the research team performed extensive testing on the limited available tissues in the patient. They carefully mapped out the sequence of events that led to the heart failure demonstrating that the heart functioned well on imaging tests like echocardiography until day 47 after surgery.
The new study confirms that no signs of acute rejection occurred during the first several weeks after the transplant. Likely, several overlapping factors led to heart failure in Mr. Bennett, including his poor state of health prior to the transplant that led him to become severely immunocompromised. This limited the use of an effective anti-rejection regimen used in preclinical studies for xenotransplantation. As a result, the researchers found, the patient was likely more vulnerable to rejection of the organ from antibodies made by the immune system. The researchers found indirect evidence of antibody-mediated rejection based on histology, immuno-histochemical staining and single cell RNA analysis.
The use of an intravenous immunoglobulin, IVIG, a drug that contains antibodies, may also have contributed to damage to the heart muscle cells. It was given to the patient twice during the second month after the transplant to help prevent infection, likely also triggering an anti-pig immune response. The research team found evidence of immunoglobulin antibodies targeting the pig vascular endothelium layer of the heart.
Lastly, the new study investigated the presence of a latent virus, called porcine cytomegalovirus (PCMV), in the pig heart, which may have contributed to the dysfunction of the transplant. Activation of the virus may have occurred after the patient’s anti-viral treatment regimen was reduced to address other health issues. This may have initiated an inflammatory response causing cell damage. However, there is no evidence that the virus infected the patient or spread to organs beyond the heart. Improved PCMV testing protocols have been developed for sensitive detection and exclusion of latent viruses for future xenotransplants.
Other UMSOM faculty co-authors of this study include: Avneesh K Singh, PhD, Alison Grazioli, MD, Kapil Saharia, MD, Tianshu Zhang, MD, and Christine Lau, MD.
“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.”
Disclosures: Members of Program in Cardiac Xenotransplantation at UMSOM received research funding from United Therapeutics, Inc. Revivicor, Inc provided the pigs, and Kiniksa Pharmaceuticals provided anti-CD40 antibodies. The University of Maryland School of Medicine and the University of Maryland Medical Center supported the remaining costs.
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Deborah Kotz Senior Director of Media Relations Office of Public Affairs & Communications University of Maryland School of Medicine Email: DKotz@som.umaryland.edu o: 410-706-4255 c: 410-804-0054 t: @debkotz2
University of Maryland School of Medicine (UMSOM) Department of Surgery Chair Christine Lau, MD, MBA, along with UMSOM Dean Mark T. Gladwin, MD, announced today the appointment of Bartley P. Griffith, MD, as the Department of Surgery’s first Vice Chair for Innovation. In this role, Dr. Griffith will nurture a culture of innovation, entrepreneurship, and collaboration in the Department, and expand the integration of related sciences into surgical practice. The appointment is effective on February 1.
It is with great sadness that we announce the passing of Lawrence Faucette, the 58-year-old patient with terminal heart disease who received the world’s second genetically-modified pig heart transplant. Mr. Faucette received the transplant on September 20 and lived for nearly six weeks following the surgery.
A 58-year-old patient with terminal heart disease became the second patient in the world to receive a historic transplant of a genetically-modified pig heart on September 20. He is recovering and communicating with his loved ones. This is only the second time in the world that a genetically modified pig heart has been transplanted into a living patient. Both historic surgeries were performed by University of Maryland School of Medicine (UMSOM) faculty at the University of Maryland Medical Center (UMMC).
The world-renowned journal Nature, named Muhammad Mohiuddin, MD, DSc, Program and Scientific Director of the Cardiac Xenotransplantation Program at the University of Maryland School of Medicine (UMSOM), on its annual list of 10 people who helped shaped science in 2022. His pivotal work over the past three decades transplanting genetically-modified pig hearts into non-human primates led to the historic xenotransplant of a pig heart into a human patient this past January. The surgery was led by Bartley Griffith, MD, the Thomas E. and Alice Marie Hales Distinguished Professor of Transplant Surgery and Clinical Director of the Cardiac Xenotransplantation Program, who was also recognized by Nature for his ground-breaking efforts to move the field of transplantation into a new era.
Ten months after transplanting the first genetically-modified pig heart into a human patient, University of Maryland School of Medicine (UMSOM) researchers continue to report on new findings from the landmark transplant. Their latest study demonstrates for the first time that unexpected electrical changes occurred in the pig heart transplanted into the patient David Bennett. The findings were presented at the American Heart Association (AHA) meeting this past weekend.
Six months ago, University of Maryland School of Medicine surgeon-scientists successfully implanted a genetically modified pig heart into a 57 year-old patient with terminal heart disease in a first-of-its-kind surgery. It was considered an early success because the patient lived for two months with a strong functioning heart showing no obvious signs of rejection, according to a new paper published today in the New England Journal of Medicine.
David Bennett, the 57 year old patient with terminal heart disease who made history as the first person to receive a genetically modified pig’s heart, passed away yesterday on March 8. Mr. Bennett received the transplant on January 7 and lived for two months following the surgery. His condition began deteriorating several days ago. After it became clear that he would not recover, he was given compassionate palliative care. He was able to communicate with his family during his final hours.
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