Pig's heart took longer to generate a beat in transplant patient

Pig’s heart took longer to generate a beat in transplant patient

A genetically modified pig’s heart transplanted into a critically ill person took longer to generate a heartbeat than those from a typical pig or human heart, research has shown, another potential challenge for doctors to conduct clinical trials pig organ transplants.

Doctors took daily electrocardiograms of David Bennett, a 57-year-old handyman and father of two who received a genetically modified pig’s heart in an experimental surgery at the University of Maryland Medical Center in Baltimore in January. Mr Bennett died in March of heart failure, but doctors still don’t know why the pig’s heart thickened and lost its pumping ability.

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Doctors involved in the breakthrough surgery studied data from Mr. Bennett’s case, which is being closely watched in the wider transplant community. Researchers reported in May that a common swine virus has been detected in Mr. Bennett’s transplanted pig heart. They said there was no evidence the virus had infected Mr Bennett, but its presence in the pig’s heart could have caused inflammation which contributed to the cascade of events that led to his death by heart failure.

Researchers analyzed Mr. Bennett’s electrocardiogram data as part of efforts to understand his post-transplant decline, guide future research and determine a possible path to opening clinical trials. Widely used tests that measure the electrical signals that make the heart beat, electrocardiograms can help diagnose heart attacks, irregular heartbeats, and other possible abnormalities.

The researchers made unexpected discoveries about two aspects of Dr. Bennett’s EKG data: the time it takes for electricity to travel from the top to the lower chamber of the heart and through the lower chambers, which pumps the blood in the heart, and the time it takes for the lower chambers of the heart to go through a complete electrical cycle, which is associated with one heartbeat.

Why scientists are turning to pigs for organ transplants

Organs from human donors are rare for life-saving transplants. Pig organs have emerged as a potential alternative, in part because pigs are easy to raise and their organs are similar in size to humans. And scientists are now able to modify pig genes in ways that make organs more suitable for transplantation into humans.

The surface of pig cells contains a sugar molecule that triggers the human immune system to attack the organs. Scientists are using the gene-editing tool Crispr to overcome this obstacle.

Here is one approach:

…then insert the modified DNA into a pig egg from which the nucleus has been removed. The egg is then transferred to the uterus of a sow. The sow gives birth to pigs whose cells, including those of their organs, contain the altered genes.

Crispr acts like scissors cutting DNA at a specific location

scientists modify troublesome genes in pig DNA…

…and sometimes add human genes…

ORGAN OPTIONS

Researchers are trying various techniques that could allow genetically modified pig hearts, kidneys and livers to be transplanted into humans. Recent studies of pig organ transplantation in baboons and humans have focused primarily on hearts and kidneys.

HEART TO HEART

Pig and human hearts have similarities, but also differences.

Pigs can be bred to have hearts similar in size to humans.

Pig and human hearts each have four pumping chambers, two small ones called atria and two large ones called ventricles.

The tissue wall separating the ventricles is thicker in pig hearts than in human hearts.

Pig and human hearts are each attached to a large artery known as the aorta as well as a large vein known as the vena cava.

A pig’s inferior (inferior) vena cava joins the right atrium of a pig’s heart at an angle. The vein is longer in pigs than in humans.

FACILITATING ORGAN REJECTION

The surface of pig cells contains a sugar molecule that triggers the human immune system to attack the organs. Scientists are using the gene-editing tool Crispr to overcome this obstacle. Here is one approach:

Crispr acts like scissors cutting DNA at a specific location.

Scientists modify troublesome genes in pig DNA…

…and sometimes add human genes…

…then insert the modified DNA into a pig egg from which the nucleus has been removed. The egg is then transferred to the uterus of a sow. The sow gives birth to pigs whose cells, including those of their organs, contain the modified genes.

ORGAN OPTIONS

Researchers are trying various techniques that could allow genetically modified pig transplantation

hearts, kidneys and livers in humans. Recent studies of pig organ transplantation in baboons and humans have focused primarily on hearts and kidneys.

HEART TO HEART

Pig and human hearts have similarities, but also differences.

Pigs can be bred to have hearts similar in size to humans.

Pig and human hearts each have four pumping chambers, two small ones called atria and two large ones called ventricles.

The tissue wall separating the ventricles is thicker in pig hearts than in human hearts.

Pig and human hearts are each attached to a large artery known as the aorta as well as a large vein known as the vena cava.

A pig’s inferior (inferior) vena cava joins the right atrium of a pig’s heart at an angle. The vein is longer in pigs than in humans.

FACILITATING ORGAN REJECTION

The surface of pig cells contains a sugar molecule that triggers the human immune system to attack the organs. Scientists are using the gene-editing tool Crispr to overcome this obstacle. Here is one approach:

Crispr acts like scissors cutting DNA at a specific location.

Scientists modify troublesome genes in pig DNA…

…and sometimes add human genes…

…then insert the modified DNA into a pig egg from which the nucleus has been removed. The egg is then transferred to the uterus of a sow. The sow gives birth to pigs whose cells, including those of their organs, contain the modified genes.

ORGAN OPTIONS

Researchers are trying various techniques that could allow genetically modified pig transplantation

hearts, kidneys and livers in humans. Recent studies of pig organ transplantation in baboons and humans have focused primarily on hearts and kidneys.

HEART TO HEART

Pig and human hearts have similarities, but also differences.

Pigs can be bred to have hearts similar in size to humans.

Pig and human hearts each have four pumping chambers, two small ones called atria and two large ones called ventricles.

The tissue wall separating the ventricles is thicker in pig hearts than in human hearts.

Pig and human hearts are each attached to a large artery known as the aorta as well as a large vein known as the vena cava.

A pig’s inferior (inferior) vena cava joins the right atrium of a pig’s heart at an angle. The vein is longer in pigs than in humans.

The time intervals are generally shorter in pig hearts than in pigs. But they took longer in genetically modified pig heart inside a human. The time it took for electricity to travel through the heart’s electrical system and generate a heartbeat also took longer than is typical for human hearts, said Timm Dickfeld, professor of medicine and director of electrophysiology research. at the University of Maryland Medical Center, which was the EKG study leader.

What this might mean in the future for doctors caring for patients who have undergone genetically modified porcine heart transplants is uncertain, said Paul Wang, director of Stanford’s Cardiac Arrhythmia Service and professor of medicine and bioengineering at Stanford University, which reviewed the data but wasn’t involved in the study.

“It was only done once,” Dr. Wang said. “It needs to be done multiple times for us to understand what these differences mean.”

Two brain-dead individuals whose bodies were donated to science have received genetically modified pig heart transplants, as scientists aim to launch clinical trials of animal-to-human organ transplants. Photo: Joe Carrotta for NYU Langone Health

The ECG data has not been published or subjected to an external verification process. They are presented by the Maryland team at an annual meeting of the American Heart Association starting Nov. 5. The Maryland team said they are investigating the significance of the findings and hope to collect more data in future studies.

The fact that the electrical signals passed through Mr Bennett’s heart more slowly than expected “does not appear to be associated with a pathological outcome”, said Bartley Griffith, co-director of the cardiac xenotransplantation program at the University’s medical school. of Maryland, who performed Mr. Bennett’s surgical transplant.

Dr Griffith added that if Mr Bennett had survived longer and the time intervals had gotten even slower, eventually a pacemaker would have been needed.

Researchers have been trying for decades to develop organ transplantation between different species, or xenotransplantation, to cope with a chronic shortage of organs. More than 3,500 people are on the waiting list in the United States for heart transplants, according to a 2022 update from the American Heart Association.

Megan Sykes, director of the Columbia Center for Translational Immunology in New York, said that although pigs are similar to humans in terms of organ size and physiology, EKG data shows there are differences that don’t. may appear only after performing transplants in humans.

“We’ve reached the point where we need human studies as well as animal studies,” Dr Sykes said.

The Maryland team and other groups recently met with the Food and Drug Administration to discuss how to start small clinical trials of genetically modified pig organs. The FDA has requested additional data from the Maryland baboon team, said Muhammad Mohiuddin, director of the cardiac xenotransplantation science program at the University of Maryland School of Medicine. Dr Mohiuddin said they plan to collect additional ECG data as part of the research.

Write to Amy Dockser Marcus at amy.marcus@wsj.com

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