UPDATED June 24, 2022 // It's a given that the case of David Bennett, Sr, and his transplanted, genetically modified porcine heart will have a lot to teach, and the peer-reviewed publication this week lends welcome authority to some of its earliest lessons.
Bennett lived for 2 months after receiving the heart in the pioneering surgery, and the new case report compiles many of the available clinical, anatomic, and histologic evidence and other potential clues to the underlying cause or causes of death.
It also describes a mystery that came to light at autopsy: a grossly enlarged heart due to pervasive interstitial edema, and at the cellular level, a peculiar pattern of myocardial damage that included microvascular destruction and — possibly as a result — myocyte necrosis, according to the new report.
The myocardium itself was described as "thickened and stiff," consistent with the "diastolic heart failure" that characterized Bennett's final 10 days and the likely convergence of several underlying processes. Missing, however, was any conventional sign of graft rejection as it is understood clinically or in animal models, the report states.
If a novel form of tissue rejection was the cause of graft failure, any cellular evidence might simply have been unrecognizable, given the unprecedented nature of the first pig-to-human heart transplantation, the donor animal's multiple anti-inflammatory gene deletions, and the partly investigational immunosuppression regimen, speculated Bartley P. Griffith, MD, University of Maryland School of Medicine, Baltimore.
"I'm betting against it being a fulminant rejection," he told theheart.org | Medscape Cardiology, "because we saw nothing like the [characteristic] platelet deposition or thrombosis of the capillaries."
Griffith, who performed the xenotransplant surgery and led Bennett's postoperative care, is lead author on the case report published June 22 in the New England Journal of Medicine. "Additional studies are under way to characterize the pathophysiologic mechanisms that resulted in this damage," the report states.
The report builds on recent meeting presentations on the case, which, as previously reported, gave cursory details regarding the organ damage and other clinical developments during and after the surgery, including evidence that the transplanted heart contained a porcine-specific virus.
Similar details appeared in a third-person account, based in part on personal communication with Griffith. The cardiac xenotransplantation (XTx) review that focused on the University of Maryland experience was published June 15 in JACC: Basic to Translational Science, with lead author Jacinthe Boulet, MD, CM, Brigham and Women’s Hospital, Boston.
"The question of how to move XTx forward remains uncertain, and appropriate selection of patients for experimental XTx will be one of the most important challenges to be addressed. The first issue we must contend with is whether we are ready to move to the next XTx in a human. We strongly believe this to be the case," the review states. "Once early experience is gained, with successive iterations of XTx, the bar for success can be raised with maturation of the technology."
Some of the likely challenges will be unique to xenotransplantation. In contrast to most other new technologies, xenotransplantation presents potential public health risks, observed transplant nephrologist and epidemiologist Peter P. Reese, MD, PhD, University of Pennsylvania, Philadelphia, who isn't connected with Bennett's case.
"No one knows how big those risks are, so it's important to do these transplants with a lot of transparency and deliberation," he told theheart.org | Medscape Cardiology. "I think the report is exciting, and that the team did a tremendous amount of work to advance the field and bring xenotransplantation to a place where it can benefit patients."
But, he added, "I think it would be better if future xenotransplants, while they remain in an experimental phase, are done as part of clinical trials. I think that's the way to go."
What Caused Graft Failure?
Immune rejection as the ultimate source of graft failure remains a possibility, nor has the evidence ruled out several other mechanisms that had been the focus of early speculations on the potential causes.
For example, the transplanted pig heart was infected with porcine cytomegalovirus (PCMV), as previously reported. And Bennett showed traces of DNA from PCMV in his circulation.
"Our work has consistently demonstrated that it was a hitchhiker virus in the heart that we transplanted, and that virus DNA was in the patient's blood — not the virus itself, just DNA — as was DNA from the porcine heart cells," Griffith said. "The heart was infected when we put it in, but that doesn't mean the virus could jump from the heart to the human liver, kidney, or spleen."
Still, PCMV remains a suspect, as does the patient's overall severely diminished condition even before the transplant surgery and his rocky postoperative clinical course.
For example, as noted previously, Bennett had suffered multiple arrests and resuscitations before the operation, and by then had been hospitalized for almost 2 months, 40 days on veno-arterial extracorporeal membrane oxygenation (ECMO).
Also, the transplantation procedure itself went as planned until removal of the aortic cross clamp, which led to a type-A aortic dissection that necessitated endovascular repair. Bennett also endured two laparotomies in the 10 days after the surgery related to signs of bowel inflammation and ischemia.
He also received intravenous immunoglobulin (IVIG) on two occasions, on postoperative day 43 to fight a nasty, protracted episode of sepsis, and again on day 50 for "presumed antibody-mediated rejection," the report states.
A reaction to the IVIG, which was derived from pooled donor antibodies, can be added to the list of potential causes of the unusual myocardial damage observed, Griffith said.
"I think it's become clear from the report that the patient was very sick and developed a lot of complications, probably from how sick he was when he went into the transplant," Reese said. "I'd like to know more about what plans would have been set up to support this patient if he had survived to discharge from the hospital."
Among likely postdischarge issues for future patients, he proposed, would be the form of prior consent to long-term surveillance that would be required. For example, "if it becomes a concern that a patient has an infection acquired from a pig, then months or years later they and their families and close contacts might be expected to give blood samples or to quarantine. Those are issues you would want the family and the patient to enter into well-informed and with open eyes."
Rapid Turn for the Worse
Bennett's condition worsened dramatically on postoperative day 50, when echocardiography showed a striking degree of myocardial wall thickening and heart enlargement, which, it would be determined, was caused by interstitial edema. "The heart got amazingly stiff, but maintained a systolic function that wasn't too terrible, even to the very end. But his heart seemed as though it had swollen overnight," Griffith said. "We had never seen that type of process, the suddenness of this swelling, in our nonhuman primate studies."
Endomyocardial biopsy demonstrated not antibody-mediated or acute cellular rejection, the report says, but "focal capillary damage with extravasated erythrocytes and edema."
"We began to lose myocardial cells to necrosis," but "not a typical rejection-type of necrosis," Griffith said." By his group's interpretation, the cells were dying from ischemia that resulted from the rapid microvascular destruction.
"These findings, in combination with focal capillary injury in the virtual absence of complement deposition, are not normally seen in human allotransplantation," the report states. "The pronounced sudden diastolic failure and global pathologic myocardial thickening without systolic dysfunction remain unexplained."
The pathologic findings might represent a novel form of rejection with an unfamiliar cellular mechanism, which could have potentially led to graft failure, Griffith said, given that much of Bennett's clinical journey was in unexplored territory. Especially, he noted, "the immunosuppressant regimen was unique and "it was the first time we ever used a genetically engineered pig in a human."
The myocardial damage appeared irreversible, the report notes, so the decision was made to withdraw life support 60 days after the transplant surgery.
Among the apparent lessons for future cardiac xenotransplantation learned from this experience, Griffith said, might be to select patients who are in more robust condition than Bennett was, and who are perhaps ambulatory, not sarcopenic, and not recently on prolonged mechanical circulatory support.
"We're going to try to pick a patient who, on the front end, is less critically ill but who is just as likely not to benefit from continued medical therapy," he said, and who isn't a candidate for conventional heart transplantation.
Also, Griffith proposed, the preoperative anti-B-cell and anti-T-cell induction therapy Bennett had received — with rituximab and antithymocyte globulin, respectively — would probably be eliminated or scaled back in future efforts.
Reese observed that the xenotransplantation relied on aggressive immunosuppressant therapy that included the investigational anti-CD40 antibody KPL-404 (Kiniksa Pharmaceuticals), which raises further questions. "There appears to have been a need for unapproved medical therapies." How would the patient obtain such medications in the future, should hospitalization again be needed? "Who would take responsibility for that?" he asked.
"The field has learned a lot, but I think the story of this xenotransplantation isn't really finished, that more will be reported. There seems to be a fair amount of suspicion that this heart was rejected," Reese said. "That's obviously very important to sort out, because it may tell us that the immunosuppression regimen was not sufficient."
Effect on Donor Organs?
Because of universal efforts to manage conditions like diabetes, hypertension, and vascular disease in the population, and "because these conditions cause many of the cases of organ failure and fuel demand for transplantation, one might wonder whether the advances reported by Griffith and colleagues presage a decreasing demand for organ transplantation," speculates an accompanying editorial from Jeffrey L. Platt, MD, and Marilia Cascalho, MD, PhD, University of Michigan, Ann Arbor.
"We think the answer is no. Since aging is associated with progressive decline in the function of the heart, kidneys, and other organs, advances that extend life expectancy will ultimately increase the prevalence of organ failure and potentially the demand for transplantation."
The donor pig was developed and provided by Revivicor, and the investigational KPL-404 antibody drug used in the experience was provided by Kiniksa. Other disclosures for the case report and editorial from Platt and Cascalho are available at NEJM.com. Boulet reports no relevant relationships; disclosures for the other authors are in their report. Reese has disclosed consulting for Collaborative Healthcare Research & Data Analytics; receiving research funding from CVS Caremark, National Institutes of Health, AbbVie, Gilead Sciences, and Merck; contracting for eGenesis; receiving honoraria from academic centers or academic consortia for speaking; and serving as scientific advisor to or holding membership with the American Journal of Kidney Diseases and the United Network for Organ Sharing.
J Am Coll Cardiol Basic Trans Science. Published online June 15, 2022. Full text
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