Arrhythmia: Tapping the Power of the Pig

Studying the possible causes of inherited arrythmias is difficult using genetically altered mice or cultured human cells. But in a research breakthrough, doctors at NYU Langone Medical Center in Manhattan have come up with a genetically engineered pig. Since pig hearts function much like those of humans, that has made their work much more effective, says David S. Park, MD, PhD an assistant professor of cardiology at NYU Langone.

Inherited arrhythmic syndromes, caused by mutations in a cardiac ion channel or structural protein, can be lethal. Though in general arrhythmias can be caused by structural heart problems or heart disease, the inherited form of the syndrome is hard to spot because EKGs and the heart structure are usually normal. Then the patient dies.

If researchers could find out exactly what happens at the molecular level to trigger these lethal interruptions in normal heart rhythms they might find ways to prevent or treat them.

Doctors at NYU Langone Medical Center in Manhattan say they have a promising new ally in that quest—a genetically engineered pig.

No longer limited to studying inherited arrhythmia in mouse models or in cultured human cells, the NYU team, led by Glenn Fishman, MD director of the Leon Charney Division of Cardiology at NYU Langone, and David Park, MD, PhD, assistant professor at the division, worked with an Iowa biotech firm, Exemplar Genetics to develop a pig that has the same arrhythmia-causing mutation as humans.

There are many advantages to having a large animal to use to study the syndrome, Park said in a recent interview. Though scientists have been able to introduce the mutation in the mouse genome, actually studying the arrhythmias it can trigger has been difficult.

“The heart is a very complex 3-dimensional structure,” Park said, “If you show a mouse EKG to a cardiologist they wouldn’t even understand how to categorize the things that are happening—when does activation begin and end? or when repolarization starts—it’s all happening on top of each other in the mouse.”

But with a pig, it’s a different story, Park said.

It is a large animal with a heart that has been studied for decades in cardiac research.

“You have a pig EKG and any cardiologist can read it,” he said, “It looks like a human EKG and that is the power of the pig.”

The similarity means researchers can “challenge the pig” by putting it through situations likely to affect the heart, such as situations that trigger a vagal response. In theory that could include mimicking unhealthy habits of humans.

“We can give them large meals, we can get them drunk, we can exercise them,” he said. All are events known to be associated with arrhythmias in people with inherited arrhythmias. The researchers also can induce fever, known to cause some lethal events in this patient population.

Then the real work begins—looking at what has happened on the molecular level with a goal of finding ways to interrupt or reverse that process.

So far treatment for lethal arrythmia is limited to defibrillation, while there are many ways to treat other arrhythmias including drugs and ablation.

The researchers published their initial findings on channelopathies, disease-causing mutuations in cardiac ion channels, in the Journal of Clinical Investigation in Dec. 2014.

Park discusses the research in the videos below.