The world’s first successful transplant of a genetically modified pig heart into a human patient led to eventual heart failure, a new study published in The Lancet is the most extensive analysis to date. Performed by medical scientists at the University of Maryland School of Medicine (UMSOM) in January 2022, the groundbreaking procedure marks a major milestone in medical science.
The 57-year-old patient, David Bennett Sr., was treated at the University of Maryland Medical Center. Nearly seven weeks after surgery, his heart was functioning robustly and there were no obvious signs of acute rejection. However, two months after the transplant, a sudden onset of heart failure resulted in his death. Since then, the transplant team has conducted extensive research to understand the physiological processes that lead to heart failure to identify factors that could be prevented in future transplants to improve the odds of long-term success.
Dr. Muhammad M. Mohiuddin, lead author of the study, professor of surgery at the University of Maryland School of Medicine, and scientific/programme director of the cardiac xenotransplantation program, said: “Our goal is to continue to advance the field as we prepare for clinical trials involving xenotransplantation of pig organs.”
Muhammad M. Mohiuddin
To better understand the processes that lead to dysfunction in pig heart transplants, the research team performed extensive tests on the limited amount of tissue available in patients. They carefully mapped the sequence of events leading to heart failure, demonstrating that the heart was functioning well by imaging tests such as echocardiography up to 47 days after surgery.
The new study confirmed that there were no signs of acute rejection during the first few weeks after transplantation. The cause of Mr Bennett’s heart failure is likely the result of several overlapping factors, including his poor health prior to the transplant which left him with a severely compromised immune system. This limits the application of effective anti-rejection regimens used in preclinical studies of xenotransplantation. As a result, the patient’s organs may be more susceptible to rejection by antibodies produced by the immune system, the researchers found. The researchers found indirect evidence of antibody-mediated rejection based on histology, immunohistochemical staining, and single-cell RNA analysis.
The use of intravenous immune globulin (IVIG), a drug that contains antibodies, may also cause damage to heart muscle cells. In the second month after transplantation, the patient received two injections to help prevent infection and possibly trigger an anti-pig immune response. The team found evidence of immunoglobulin antibodies targeting the endothelial lining of pig heart vessels.
Finally, the new study investigated the presence of a latent virus called porcine cytomegalovirus (PCMV) in pig hearts, which could lead to graft dysfunction. The virus may be reactivated after patients reduce their antiviral regimen to address other health concerns. This may trigger an inflammatory response that leads to cell damage. However, there was no evidence that the virus infected patients or spread to organs other than the heart. An improved PCMV test protocol has been developed for sensitive detection and exclusion of potential viruses in future xenografts.
“We can learn from this groundbreaking procedure and from Mr. Valuable lessons learned to better guide future xenotransplantation.”
“In the future, our team of surgeon scientists will utilize newly designed immune cell assays to more precisely monitor patients in the days, weeks and months following xenotransplantation. This will allow for more rigorous monitoring of the earliest signs of early rejection.” control, and bring the prospect of innovation that truly saves lives.”