Genetic defect predicts cardiac risk

U. ROCHESTER (US) — Research into a rare genetic mutation may lead to new treatment for people with irregular heart rhythms that often lead to sudden death.

The new study, published in the journal Science Translational Medicine, shows that the function of specific genetic mutations—namely, the defects these mutations cause—are strong predictors of risk in patients with Long QT.

The finding is especially relevant for people who have the condition but don’t have particularly pronounced clinical risk factors, such as a very prolonged QT interval—the time it takes for the heart’s electrical system to recharge after each heartbeat and get ready for the next (hence, the name “Long QT” syndrome). When the QT interval is prolonged, the heart is more susceptible to arrhythmias.

These tricky, in-between patients, who make up about 70 percent of the Long QT syndrome population, often fall into a treatment gray area. In the future, physicians may be able to use mutation-specific information to better identify high-risk individuals in this group who should be followed more carefully and treated more aggressively.

“To our knowledge, this is the first time anyone’s linked the activity of specific mutations to actual risk in patients,” says Coeli Lopes, assistant professor of medicine at the University of Rochester. “We’re literally going from studying mutant proteins in cells in the lab to risk assessment in the clinic, which is an exciting and very promising concept.”

Teens with otherwise healthy hearts are affected most visibly by the condition, that may go unnoticed until a stressful event, like swimming, jumping into cold water, or hearing a particularly loud noise jolts the heart out of rhythm, leading to fainting, cardiac arrest, or death.

“Before we had such robust genetic information, we based risk solely on clinical measurements, such as the length of the QT interval and if patients had passed out in the past,” says Arthur Moss, professor of cardiology. “These results mean we can be much more specific in prescribing preventive therapy, which is terrific news for patients and their families.”

Current treatment options for patients with Long QT include beta blockers, which relieve stress on the heart by slowing the heart rate, and implantable cardioverter defibrillators or ICDs, which detect irregular and potentially fatal heartbeats and shock the heart back into a normal rhythm. Better knowledge of risk will help physicians decide if patients need treatment with a beta blocker, an ICD or both.

For the study, researchers looked at the most frequent mutations found in patients with Long QT syndrome type 1, one of the most common forms of the disease, and analyzed their influence on ion channels—small pores or holes on the surface of each heart muscle cell. These channels open and close to let electrically charged particles flow into and out of the cell, generating the signal the heart needs to stop contracting and relax after pumping blood throughout the body.

When results were compared with patient outcomes, it was discovered that mutations that cause ion channels to open more slowly than they should were strongly associated with increased risk for cardiac events. Patients with these slow activating channels were twice as likely as patients with other mutations to die before the age of 30 or experience serious symptoms.

Even for patients who lacked telltale clinical symptoms, the presence of mutations linked with slow-to-open ion channels was still associated with an increased risk of cardiac events.

“This study creates a paradigm that we not only have to take into account the presence of mutations, but the potential consequences of mutations as well,” notes Wojciech Zareba, professor of medicine. “Some mutations may be more benign and others less so and more research is needed to understand why this is the case.”

The team looked at the function of 17 common mutations found in approximately 390 patients drawn from the International Long QT Registry. In the lab, they recreated the mutant proteins and put them in cells to study their effect on ion channels. They used clinical follow-up data from the registry to relate mutant function to cardiac risk.

While this process of testing mutant function is a starting point, Lopes says that in the future new, emerging stem cell technologies may allow physicians to take cells (such as skin cells) directly from patients and turn them into heart cells to more precisely determine mutant function.

“Similar to genetic testing, a simple, standardized way to test mutation function on a large scale is needed in order for this method to be widely adopted in clinical practice.”

The study was funded by the National Institutes of Health.

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