Heart transplant

Why did the first human patient to receive a pig heart transplant die? | Science

Surgeon Bartley Griffith examines the pig’s heart before the transplant.
University of Maryland School of Medicine

Bartley Griffith is a heart surgeon at the University of Maryland, Baltimore, who says he’s probably performed more than a thousand heart transplants in a career that spans four decades. But on January 7 of this year, Griffith performed an operation like no other. He transplanted a pig’s heart into a human being for the first time.

When Griffith released the clamp on his 57-year-old patient’s new heart, blood rushed through David Bennett’s coronary arteries and turned the pale, lifeless pig organ into a vivacious scarlet pump. “Heart ignited,” Griffith said.

But 60 days later, Bennett died, and doctors could not pinpoint a specific cause of death. The answers are only beginning to emerge after Griffith’s team released their report on the landmark operation in The New England Journal of Medicine. Considering why Bennett may have died will help doctors prepare for future pig heart transplants.

“Heart xenotransplantation,” or the transfer of a heart between species, was first performed in 1964 with a human recipient: University of Mississippi surgeon James Hardy implanted a chimpanzee heart into Boyd Rush, 68 years old. At least eight other similar heart xenotransplantations took place over the next half-century, none of them truly successful.

With the gene-editing capabilities of CRISPR, this time was different. Biotech company Revivicor engineered pigs with ten genetic changes, removing four pig genes and adding six human genes, so their organs would be more compatible with humans. Bennett, who suffered from end-stage heart failure, was ineligible for a human heart due to his history of not following his doctors’ orders. So, on his deathbed and with no other options, Bennett obtained a heart from one of Revivicor’s pigs under Food and Drug Administration (FDA) “compassionate use” clearance, allowing for experimental treatments. for emergencies.

Currently, 17 people die every day on the transplant waiting list, and xenotransplantation, if fully realized, could end the national shortage of 100,000 organs with an almost unlimited supply of pigs. If these pig organ transplants are ever to replace human-to-human transplants, scientists will need to learn how to make xenotransplantation safe, accessible and truly life-extending.

As such, the focus naturally shifted from the novelty of Griffith’s operation to trying to figure out the cause of Bennett’s death. Griffith’s report clearly lays out the facts of the case. The capillaries around Bennett’s heart burst, causing fluid to leak and his heart to double in size. Because these burst capillaries supplied the heart with oxygen, heart muscle cells began to die in their absence. On Day 60, Griffith’s team withdrew life support because Bennett’s heart had been damaged beyond repair.

But why did it happen? “We still don’t really know,” admits Griffith. His paper considers three major possibilities, but a unifying fourth explanation also exists.

Surgeons transplant pig heart into human

Surgeons transplant a pig’s heart to David Bennett.

University of Maryland School of Medicine

Organ rejection may have occurred

One of the biggest concerns with any transplant is the risk of rejection where the body’s immune system sees the donor organ as foreign and destroys it. Unless the donor and recipient are identical twins, some rejection is inevitable, but doctors can usually limit organ rejection with drugs that suppress the patient’s immune system.

In Bennett’s xenotransplant, Revivicor’s genetic changes “humanized” his pig heart to evoke less of an immune response, and Griffith’s team gave him a cocktail of immunosuppressive drugs for added protection. As a result, Bennett tolerated her new organ fairly well in the first month, and biopsies never showed signs of acute rejection, according to Griffith.

But there is evidence the rejection actually happened, according to xenotransplantation pioneer David Cooper, whose early work helped launch the genetic engineering effort to make pig organs more humane. Griffith’s report states that damaged capillaries and a swollen heart are “not consistent with typical rejection,” but Cooper, who is also a principal investigator at Massachusetts General Hospital, says these findings are classic signs of organ rejection. of xenotransplantation experiences 30 years ago. Cooper believes that failure to maintain sufficiently high levels of immunosuppression over time, possibly due to medical professionals’ lack of experience with this new experience, may have contributed to organ rejection in Bennett’s case.

Anti-pig antibodies may have attacked the heart

On day 43 after surgery, Bennett was given something called intravenous immunoglobulin (IVIg) in order to treat a potential infection. Prepared from donated blood from thousands of people, IVIG is a highly concentrated antibody therapy that is given to boost a patient’s weakened immune system.

Transplant surgery is about balancing the double risk of organ rejection and infection: if the immune system is too strong, it will destroy the organ, but if it is too weak, the patient will die of infection. In this case, Griffith’s team may have initially overdone the immunosuppression, so they had to give IVIG to boost Bennett’s immune system and help him fight his infections.

The problem is that, among a diverse collection of antibodies, IVIGs naturally contain anti-pig antibodies that could have attacked Bennett’s heart. Griffith is quick to point out that in Revivicor’s tests, IVIG did not appear to kill pig cells. But he also acknowledges that, in real life, IVIG’s anti-pig antibodies could nonetheless have targeted and destroyed the pig’s heart, killing Bennett in the process.

A pig virus may have blown the heart

One of the most dangerous infections Bennett contracted was porcine cytomegalovirus (pCMV). The virus is only found in pigs and generally does not affect their health beyond sneezing and runny nose. But if pCMV makes it to humans, it could theoretically cause a deadly pandemic. Revivicor therefore takes great care in raising pigs for xenotransplantation, such as housing them in biosecure facilities and testing them for pathogens with regular nasal swabs.

But that virus test may not have been rigorous enough. Mike Curtis, CEO of xenotransplantation company eGenesis, said nasal swabs cannot detect dormant infections in adult pigs. So he was surprised why Revivicor used them. Instead, actual blood tests should have been done to make sure the donor pig didn’t have any type of pCMV, Curtis says.

Griffith thinks the pig’s heart may have been infected with an inactivated form of pCMV which, once inside Bennett’s immunocompromised body, “woke up, burst some capillaries and killed the heart” , he said.

Bennett may have been too ill to benefit from the organ

“Which of these things was the cause?” asks Curtis, referring to the three possibilities considered in the report. “Maybe it wasn’t just one thing, but it was a combination of everything.”

Cooper thinks there is a simpler explanation. “They chose a patient who was too weak to undergo this procedure,” he says.

Bennett had been confined to his hospital bed for two months before his operation, with his condition so bad he needed ECMO (extracorporeal membrane oxygenation) to replace his heart and lung function. Although ECMO is a life-saving technology, over long periods of use it causes progressive deterioration of organs. Bleeding in his digestive tract and a bacterial infection in his blood also likely weakened Bennett before the operation. “The odds were stacked against them from the start,” Cooper says of Griffith’s team. “You have to choose a patient who has a realistic chance of doing well.”

Griffith also acknowledges that “David was almost too sick to benefit from it”, but he presents this xenotransplantation as a learning opportunity. With further testing expected to provide more clarity on Bennett’s death, Griffith is confident that whether it’s from rejection, IVIG, infection, or all of the above, they’ll learn to deal with it. remedy.

What happens afterwards?

Bennett’s postoperative course was filled with numerous attempts to save his life. He needed continuous dialysis because his kidneys were failing. He needed emergency abdominal surgery because he had unexplained stomach pain. He needed to restart ECMO when his heart started to deteriorate. “This patient’s two months must have been a nightmare for him and for the medical team,” says Cooper. He doesn’t think there’s much value in giving another patient with a similar disease a pig heart transplant. Instead, Cooper thinks surgeons should go straight to clinical trials with patients “who are reasonably fit and have a realistic chance of doing well.”

Griffith estimates it will be at least a year and a half before the FDA approves a clinical trial for xenotransplantation, but rather than wait that long, he intends to continue these one-off surgeries in the meantime. Because the best way to learn is by doing, Griffith believes that each additional xenograft over the next 18 months will allow him to better optimize patient survival in the ultimate trial. Of course, the only way to gain more experience at this point is to operate on “compassionate use” patients who, like Bennett, have no other options left.

“Patients are a remarkable source of courage; they make us doctors brave because they’re ready to move on, even if they might not have the chance to snowball,” says Griffith. “They’re going anyway because it’s better than certain death.”