Throughout history, people have experimented with transplantation and transfusion. Until the discovery of Human Leukocyte Antigen, blood groups, and tissue typing – donors commonly consisted of animals. My favorite one was using lamb blood because of religious aspects (Lamb of God), although it did not work as often. Expected, right? However, today with genetic modification and the possibility to work in extremely sterile environments we are going back to animal donors.
One of the most interesting (and real) stories I have, is of a 57-year-old man with biventricular heart failure, who agreed to receive a heart from a genetically engineered pig. This first-of-its-kind transplant was performed at the University of Maryland Medical Center. More than being extremely experimentative, the patient tried the pig’s heart because he was rejected from four different transplantation programs. Before agreeing to the transplantation, three institutional and one external independent psychiatric professional performed patient evaluation to confirm the patient’s mental capacity for consent. Afterwards, the patient gave his written informed consent.
A couple years back, a baboon transplanted with a pig’s heart survived for about six months post-transplant, which was a huge step forward in the field and a huge hope for the pig-to-human heart transplant.
Let’s remind ourselves about the different transplantation procedures:
1) Autotransplantation -> when the recipient and donor are the same biological unit
2) Allotransplantation -> when the recipient and donor are of the same species
3) Xenotransplantation -> when the recipient and donor are of different species
Where did the heart come from?
It came from a pig, clonally derived from fibroblasts that had 10 gene edits. Amongst others, some gene edits included immunodominant xenoantigen knockouts to make the graft more compatible with the human recipient. The animal was 100 kg in weight and deemed appropriate for the 85kg. The genetic edits could reduce the growth of the xenotransplanted heart. The pig was tested for pathogens that can affect both pigs and humans (PERV-A, B, C, pCMV, pLHV), every three months. After transplantation, the patient was tested for said pathogens at certain time points.
Let’s take you through his post-surgery journey:
Day 2
The patient had clear lungs and a heartbeat of 70-90 beats per minute. Left ventricular wall thickness was 1.2 – 1.4 cm and right 1.0-1.1 cm.
Day 12
Patient reported abdominal pain. He faced thickening of the small bowel and presence of free fluid, along with Escherichia coli and Candida tropicalis infection. His platelet count dropped to 21,000 plt/microliter but slightly rose over the next 5 weeks (40,000 – 60,000). The patient started tube feeding and had dropped in weight from 85 to 62 kg.
Day 21
The patient suffered from severe neutropenia, his white blood cell count was 200/microliter and his neutrophil count was 100/microliter. He will be receiving granulocyte colony-stimulating factor for the next 5 days.
Day 34
Xenograft functioned normally and there was no evidence of rejection. The patient did not need cardiovascular support.
Day 43
The patient became heavy-eyed. Doctors intubated the patient’s trachea. Worsening soft infiltrates were present in both lungs. Ulcers in airways suggested viral or fungal infection that alongside hypogammaglobulinemia was a sign to start antimicrobial therapy with immune globulin. There was an increase in pCMV (porcine Citomegalovirus) but no viral inclusion or cytopathic effect. Donor’s spleen was pCMV positive which points to a latent infection of the source animal.
Day 47
The patient’s trachea was extubated, and in-room rehabilitation continued.
Day 48
As reported, “the patient sat alone in a chair and waved to caregivers, he was free from bed for the first time in 109 days.”
Day 49
The patient’s serum lactate levels rose (pointing to lower tissue oxygenation) and experienced hypotension. His trachea was intubated again. Low cardiac output was reported for the first time since transplantation. However, the exploratory laparoscopy showed no abnormalities. Left ventricular wall thickened to 1.7 cm and the right one to 1.4 cm. Left ventricular chamber space was reduced. After consulting with the family, venoarterial ECMO (extracorporeal membrane oxygenation) was started again.
Day 50
Endomyocardial biopsy showed no antibody-mediated or acute cellular rejection. Focal capillary damage with extravasated red blood cells and oedema was present. IgG and IgM levels grew but no complement C3d or C4d were present. There was one ischemic myocyte and no cellular infiltrates. Troponin I (when present suggests heart muscle damage) levels rose. Xenograft donor cell-free DNA and xenograft-specific IgG levels grew so treatment for antibody-mediated rejection was started.
Day 56
Endomyocardial biopsy showed a grade I pathologic antibody-mediated rejection of ISHLT (International Society for Heart and Lung Transplantation). Although IgG and IgM were still at lower levels, but C4d was present now as well. Interstitial red blood cell extravasation and oedema decreased. However, there was 40% of myocyte necrosis. There wasn’t any cellular rejection, but focal capillary damage was seen. Biventricular wall thickening slightly decreased but left ventricular chamber size continued being decreased. ECMO was continued.
Day 60
With consent from the family, the patient was taken off life support.
Post-mortem examination:
The transplanted heart grew from 328 to 600 g. Cardiac myocyte necrosis was scattered with myocytes being widely spaced, having central nuclei and separated by a thin layer of fibrosis. Endothelial changes ranged from prominent nuclei, cell swelling and areas of complete vascular dissolution. Red blood cells were in between myocytes in a pattern consistent with vascular extravasation. Findings are not consistent with typical xenograft rejection.
This study is extremely interesting because it is the modern world’s first “reported” pig-to-human heart transplantation. Unfortunately, the patient did not survive past day 60 post-surgery, which would make this experimental procedure unsuccessful. But was this a complete failure? Was the issue a graft rejection or maybe a microbial pathogen that caused this misfortune? We must certainly follow up with the future information that comes from this study. However, if pig-to-human heart becomes the trend in future, there is a moral part that must not be overlooked. Will there be mass cultivation of pigs for organ harvesting? How would you feel about that? What do you think could have been done differently to the pig or the person to ensure a healthy recovery? Which issue/portion of post-surgical recovery would you pick up for a detailed study? Add your views in the comment section!
Sources:
- Griffith BP, Goerlich CE, Singh AK, Rothblatt M, Lau CL, Shah A, Lorber M, Grazioli A, Saharia KK, Hong SN, Joseph SM, Ayares D, Mohiuddin MM. Genetically Modified Porcine-to-Human Cardiac Xenotransplantation. N Engl J Med. 2022 Jul 7;387(1):35-44. doi: 10.1056/NEJMoa2201422.
- Kotz, D., 2022. University of Maryland School of Medicine Faculty Scientists and Clinicians Perform Historic First Successful Transplant of Porcine Heart into Adult Human with End-Stage Heart Disease. 2022.
- Sara Reardon. First pig-to-human heart transplant: what can scientists learn? Nature 601, 305-306 (2022). doi: https://doi.org/10.1038/d41586-022-00111-9
Article author: Ines Poljak. Ines is a MSc graduate from University of Copenhangen who worked on multiple myeloma bone disease. She worked in several clinical laboratories before committing herself completely to research.
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