Heart of the matter: Silva studying genetic mutations

In the last 20 years, researchers have discovered a genetic mutation behind the second-leading cause of death in Southeast Asian males under age 40: Brugada Syndrome, which leads to sudden death from abnormal heart rhythm, or arrhythmia.

Jonathan Silva

Jonathan Silva, in the School of Engineering & Applied Science at Washington University in St. Louis, will take a close look at the changes at the molecular level in the heart that are behind this syndrome with a two-year, $154,000 grant from the American Heart Association.

"Researchers have some understanding of how the whole heart and its cells are altered by these mutations, but the lack of basic molecular information is a major impediment to developing therapies that would correct the consequences of this mutation," said Silva, assistant professor of biomedical engineering.

Silva's lab has been working on this problem for several years and has developed new methods to study the heart sodium channel, which starts the electrical signal that tells the heart to contract. Mutations in sodium channels often expose patients to arrhythmia.

"What we're trying to understand is how altering the movements of the sodium channel causes arrhythmia," he said. "We are trying to go all the way from the molecular level where the mutations are having an effect to the whole heart level, and it is very challenging."

The challenge comes from the size of the area where the mutation is, Silva said.

"A human is 2 meters big, but the mutant channels that we look at are about 10 nanometers across," he said. In comparison, a human hair measures about 50,000 to 100,000 nanometers in diameter.

To meet that challenge, Silva's lab put fluorescent markers on the mutant sodium channel, and when it moves, they see a fluorescent signal. From those signals, they will learn how the channel is altered at the molecular level. They will then try to connect this molecular understanding to the heart-level function.

But that connection isn't always a straight line, he said.

"These systems have hundreds of moving parts, so they are non-linear" he said. "It's hard to predict how changing one movement of one part is going to affect the whole system, and a lot of times you get things you don't expect. That's a real challenge for therapy, because therapies are designed to move one thing, but they may be affecting something somewhere else."

Computer models are able to handle these types of systems, Silva said. To complete the connection, they will make a computational model that connects the molecular movements to the chaos theory of whole heart arrhythmias.

Ultimately, the improved understanding from this work could aid in discovering new drug targets to halt the life-threatening arrhythmia linked to Brugada Syndrome, Silva said.

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