Shulou(Shulou.com)11/24 Report--

This article comes from the official account of Wechat: ID:fanpu2019, author: Guo Xiaoqiang

The first and second patients who received a pig heart transplant died shortly after the operation, which is depressing news. However, it must be noted that porcine heart transplantation is a highly experimental operation, and the two patients bravely chose this cutting-edge exploratory operation without a better medical plan, and also used their own cases. it adds a spark to the journey to save patients with end-stage heart disease.

Lawrence Faucette, 58, died on October 30th, the second human patient to have a pig heart transplant.

Previously, he was a patient with advanced heart disease who was hospitalized after showing symptoms of heart failure and was not suitable for traditional heart transplant because of serious complications. As a result, the University of Maryland Medical Center performed a genetically modified pig heart transplant on September 20. In the first month after operation, the transplanted heart was functioning normally in Fawcett, but recently there were signs of rejection until the tragedy.

In January last year, the world's first genetically modified pig heart transplant was also performed by the University of Maryland Medical Center, and the patient survived for about two months.

The final results of both operations are not good, so is it life-saving or risky to transplant pig hearts to humans? What other difficulties do you face in this operation? Will it be the ultimate solution for human heart transplantation?

The same kind of heart transplantation is facing a thorny bottleneck. Let's start with the beginning of organ transplantation technology.

The scientific logic of organ transplantation is simple and clear. If the human body is compared to a car, when the parts are damaged, the fundamental solution is replacement, and the solution to organ damage is transplantation.

The idea of replacing sick or damaged body organs has been around for a long time, and many pioneers have made bold attempts. In 600 BC, people envisioned using autologous skin flaps to replace the missing nose, and plastic surgeons realized this idea in the 16th century. Skin transplantation is another success story.

However, early successful transplantation was mainly on the body surface, and although there were some successful reports of organ transplantation in vivo, it was difficult to tell whether it was true or false. considering the limitations of technology at that time, some reports of so-called "success" were mostly doubtful and exaggerated.

At the end of the 19th century, with the emergence of anesthesia, aseptic surgery, blood transfusion and other technologies, the development of surgery entered the fast lane, and the development of microsurgery further cleared the operational obstacles for organ transplantation, so the real sense of organ transplantation research officially began. But unfortunately, the application has not made a breakthrough for a long time.

On December 23, 1954, the first kidney transplant in human history was successfully performed by Joseph Edward Murray. The donor and recipient were identical twins. The younger brother who received the transplant survived for eight years and eventually died of heart failure rather than renal function problems. This success has made many researchers regain their confidence and see the dawn of victory again. Later, with the understanding and understanding of the mechanism of immune rejection and the use of immunosuppressants, the effect of organ transplantation became more and more ideal, including kidney, lung, liver and heart. Murray also shared the 1990 Nobel Prize in Physiology or Medicine.

Success stories in other organ transplants have inspired the forerunners' ambition to operate on the heart.

As we all know, the heart is one of the most important organs of the human body, and its abnormal function has a great impact on health. Heart failure is a common heart disease in which blood cannot be effectively pumped to the whole body because of impaired heart function. In 2022, there were about 64 million patients with heart failure. For most patients, it can be effectively controlled by drugs, but 5% of Murray's 10% progress to the end stage, when the only treatment is a heart transplant.

Christiaan Barnard, a South African heart surgeon, was the one who set the record. He performed the first human heart transplant for a 54-year-old man, Louis Washkansky, on December 3, 1967. The donor was Davor (Denise Darvall), a young woman who died of a brain death in a traffic accident, and the operation lasted five hours. After the operation, Vashkansky woke up and was lucky to survive. Unfortunately, he died of pneumonia 18 days later.

But this is still a far-reaching success, it brings great confidence to many clinicians, but also promotes the rapid development of the field. On January 2, 1968, Barnard completed his second heart allograft and the patient survived for 19 months. From December 1967 to November 1974, Barnard performed 10 allogeneic heart transplants. Four patients survived more than 18 months, two of them more than 13 years and 24 years respectively.

In 1968, doctors around the world performed about 100 heart transplants, but only 1/3 patients lived more than three months, causing many medical centers to stop heart transplants.

With the development of new immunosuppressant drugs and the promotion and application in the field of organ transplantation, the effect of heart transplantation is gradually improved, and the postoperative survival time of transplant patients is greatly prolonged, thus the demand for heart transplantation is significantly increased. The shortage of donor heart has become the main bottleneck of clinical limitation. On the one hand, a person has only one heart, so the donor can only be a brain-dead individual; on the other hand, not everyone agrees to donate.

The shortage of the human heart has led researchers to turn their attention to other species with relatively abundant supplies.

The attempt of xenotransplantation gradually locked the pig heart. In fact, the completion of xenotransplantation was earlier than that of allogeneic heart transplant (mainly because of organ shortage), and people first turned their attention to other species of primates.

On January 23, 1964, surgeon James Hardy performed his first xenotransplantation at the University of Mississippi Medical Center to transplant an orangutan heart into a dying patient, Boyd Rush, but the heart beat only for more than an hour in the patient's chest, and the patient died before he regained consciousness. The failure sparked public discontent and hindered the Hardy team's incentive to try further.

In 1983, surgeon Leonard Bailey performed another xenograft, transplanting a baboon heart into a baby girl. The procedure was successful, but the patient died 20 days later due to strong rejection.

In addition to the above unsuccessful cases, there are many defects in using non-human primates as donors. The first is the price factor, because of its small number and low fecundity, even the ultimate success will become a sky-high price; the second is the ethical factor, these primates are relatively intellectually high, and it is too cruel to kill them to get the heart; and finally, there are safety factors. because of their close relationship with humans, viruses tend to cross species boundaries and cause disease.

On the basis of comprehensive consideration, the researchers turned their attention to pigs. This is because pigs have natural advantages in all three aspects, and the size and structure of their organs are similar to those of humans, making them the best candidates. However, the disadvantage of pigs is also quite obvious, that is, they are more closely related to humans, so the immune rejection is greater.

In order to make pigs meet the requirements of clinical transplantation as soon as possible, in the late 1980s, scientists began to explore the mechanism and solutions of transplant rejection. When a pig heart is transplanted into a non-human primate, there will be hyperacute rejection that leads to failure. It was later found that this was caused by a gene unique to pigs. Therefore, after gene knockout, the hyperacute rejection can be greatly reduced, so that the pig heart can survive in baboons for 2-6 months, which is the first step to success.

In 2012, the emergence of efficient gene editing technology ushered in a new opportunity for the transformation of pigs. It can destroy multiple genes that affect immune rejection at the same time, and further increase the success rate of transplantation. In addition, gene editing technology is also used to knock out porcine endogenous retrovirus (PERV) perfectly, thus greatly eliminating the risk of disease transmission and genome integration and increasing security.

After decades of development, a series of significant progress has been made in the study of porcine-non-human primate heart transplantation, which can be summarized as follows: first, to understand the pathological process of heart changes after transplantation and develop improved methods; second, the genetic modification of pigs to reduce immune rejection as much as possible; third, the application of low-toxic and efficient immunosuppressants to further reduce rejection; and finally, the refinement of the transplantation process to improve surgical accuracy.

After improvement, pig heart transplantation into baboons usually survives for 6 to 9 months or even longer, providing solid data support for practical clinical applications.

On January 7, 2022, the University of Maryland Medical Center performed the first human pig heart transplant for David Bennett, a 57-year-old heart failure patient. The whole operation is more successful, at first, the pig heart can play a normal role in the body, the overall condition of the patient is also ideal, everything is developing in a good direction.

However, with the passage of time, various problems began to appear, such as drowsiness, hypotension, lung infection and so on. Bennett finally died on March 9, the whole process lasted more than 2 months.

On September 20, 2023, the University of Maryland Medical Center performed the world's second pig heart transplant for a 58-year-old heart failure patient named Fawcett. At first, the overall condition was relatively good, the heart function was basically normal, and the immune rejection and infection were all under control. Unfortunately, the follow-up progress failed again, and the patient finally died on October 30, which lasted only six weeks, no longer than the survival time of the first patient.

The implementation of two pig-to-human heart transplants preliminarily shows that the scheme is feasible, at least the initial cardiac function can be maintained, but it also shows that it is complex and uncontrollable, which does not reach the duration of animal experiments. there is also a lack of predictability for the development of patients after transplantation, which needs further study.

The effect does not meet the expectations may be due to many reasons, not only related to the technology itself, but also closely related to individual differences, as a whole can be summarized into the following aspects.

The first is adaptability. Although the hearts of humans and pigs are similar in morphology and anatomy, after all, there are differences between humans and pigs (far greater than the gap between humans). Therefore, after the pig heart is transplanted into the human body, there must be a problem of inconsistent pace in its operation, just like machine parts. parts of different standards assembled together, easy to wear over time, there are many problems.

The second is immune rejection. Although genetic modification can minimize the rejection of pig heart by human immune system, there is a huge gap in evolutionary relationship, and unsuccessful human-to-human matching will lead to greater rejection, not to mention such a huge gap between pigs and humans. Even with the use of immunosuppressants, too much repulsion will eventually lead to drug failure.

Finally there is the problem of infection. The use of immunosuppressants to reduce immune rejection weakens the body's defense against foreign pathogens, thereby increasing the risk of infection. Therefore, there is a need to strike a balance between the use of immunosuppressants and infection, which is also a huge challenge.

From the perspective of the history of organ transplantation, xenotransplantation is by no means the ultimate measure, but it is an expedient measure, mainly to solve the current serious imbalance between demand and supply. From this point of view, pig-to-human heart transplantation needs to be carried out in depth. It not only needs a breakthrough in basic research, but also needs the improvement of clinical operation process, in order to maximize the normal function of organs and prolong the survival time of patients. Thus become an important supplement to the same kind of organ transplantation.

It should be noted that the fundamental way to solve the problem of patients with end-stage heart disease is still organ transplantation, and the shortage of donors is the main contradiction. While improving the pig-to-human heart transplantation program, we also need to expand our thinking and actively explore other solutions, including in vitro tissue engineering (such as organ-like organs), in vivo chimerism (such as the use of in situ culture of human organs in animals) and other strategies to effectively alleviate the current bottleneck of heart transplantation and provide as many safe and high-quality heart donors as possible.

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