Off tempo  pg. 4

The rare syndromes have pointed to new components in cardiac physiology. And what's more, variations in the genes implicated by the rare syndromes have turned out to be more common than previously believed and to only sometimes cause disease, a phenomenon called “variable penetrance.”

“There’s a lot of commonality to these arrhythmia syndromes because the majority of them are caused by ion channel defects,” says Dawood Darbar, M.D., Ph.D., “but whether you get the congenital long QT syndrome or Brugada syndrome or atrial fibrillation, no one really knows why that is, and that’s something we’re trying to understand.”

Darbar, assistant professor of Medicine at Vanderbilt, focuses on atrial fibrillation, the most common arrhythmia observed in clinical practice. Atrial fibrillation carries a substantial risk of stroke and affects between two and three million people in the United States, a number that may climb up to eight million as the population ages. Symptoms range from nothing at one extreme to tremendous disability in terms of shortness of breath on exertion and heart failure on the other.

The fact that atrial fibrillation has a genetic basis has only been recently appreciated. “In the last five years there have been some fairly dramatic findings, and we now believe that up to a third of patients with atrial fibrillation probably have a genetic basis for their disease,” Darbar says.

Darbar and colleagues have conducted genetic screens in families with atrial fibrillation, identifying several DNA regions of interest. They also are building a database of clinical information and DNA samples for patients with atrial fibrillation, not just those who are part of large affected families. With more than 900 patients enrolled, this may be the largest such population in the country, he says.

“We’re trying to get to the point where we can do a genome-wide screen so that we can look beyond candidate genes to genes that intuitively don’t make any sense,” Darbar says.

Genotyped prescriptions

Understanding the genetic causes of arrhythmia disorders will ultimately improve treatments, the investigators argue.

Antiarrhythmic medications are not terribly effective, Roden says, and are famous for causing a wide range of side effects, including actually worsening the heart rhythm and even creating new abnormal rhythms. And antiarrhythmic drugs are not alone in having these “proarrhythmic” effects. A wide range of non-cardiovascular drugs including antihistamines, antibiotics, and antipsychotics also can create life-threatening abnormal heart rhythms.

It was one of these drug-induced arrhythmias—torsades de pointes—that first captivated Roden. What intrigued him, he recalls, was that the same unique pattern on the electrocardiogram occurred in a congenital syndrome (long QT) and a drug-induced arrhythmia. The connection suggested that the genome may hold clues for why drugs elicit this kind of adverse reaction in some individuals but not others.

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