August 12, 2005

‘Big science’ key to new discoveries: Roden

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Dan Roden, M.D.

‘Big science’ key to new discoveries: Roden

For more than 25 years, Dan Roden, M.D., has tried to figure out what causes arrhythmias — abnormal heart rhythms — and why drug treatment doesn't work in every patient.

Today he and his colleagues at Vanderbilt University Medical Center are closer than ever to cracking these mysteries, thanks in part to their involvement in “big science” projects at the national and international levels.

“Big genetics; big databases; big statistics: I deeply believe that really important biological insights will flow from that,” said Roden, director of the John A. Oates Institute for Experimental Therapeutics.

Roden and Denis Escande, M.D., Ph.D., of the National Institute of Health and Medical Research in Nantes, France, have been named co-coordinators of a five-year, $6 million multi-center grant from the Paris-based Leducq Foundation to identify genetic risk factors for sudden cardiac death.

Half a million Americans die suddenly every year when the lower chambers of their hearts, the ventricles, “fibrillate,” or flutter, and stop pumping blood.

“Some of those deaths occur in people who are readily recognizable — (they have) advanced heart disease — but about half of those sudden deaths occur in an otherwise healthy person,” said Roden, also William Stokes Professor of Experimental Therapeutics. “Our long-term goal has to be to identify markers of sudden death risk before somebody has heart disease.”

In addition to Roden and Escande, the network includes Eduardo Marban, M.D., Ph.D., chief of Cardiology at Johns Hopkins University; Robert Myerburg, M.D., director of Cardiology at the University of Miami; and Arthur Wilde, M.D., of the Academic Medical Center in Amsterdam.

Escande and Wilde have collaborated with Vanderbilt researchers for several years. Each of the five groups has an extensive database of patients — including clinical data, family histories and genetic information — that can aid the search for genetic variations which may increase risk for ventricular fibrillation and sudden cardiac death.

The Leducq Foundation grant — awarded earlier this year — will be split five ways, with about $200,000 coming annually to Vanderbilt. “It's a huge springboard,” Roden said.

For the past four years, Roden's group also has participated in the Pharmacogenetics Research Network, a national effort to understand the genetics of drug responses supported by the National Institute of General Medical Sciences.

Roden's grant — entitled the “Pharmacogenomics of Arrhythmia Therapy” — has just been renewed for another five years.

“The fundamental questions I've been interested in my entire career are what makes people have abnormal rhythms, and what makes people respond variably to anti-arrhythmic drugs, and generally, to all drugs,” Roden said.

“I think those two questions are intimately linked,” he said. “Until we understand the fundamental molecular, cellular and genetic bases of diseases like atrial fibrillation, it's not a big surprise that drugs don't work very well.

“We're very, very interested in understanding fundamental mechanisms, not only to direct new therapy but also to direct the appropriate choice of (current) therapy.”

Five million Americans each year suffer heart palpitations and breathlessness due to atrial fibrillation, abnormal beating of their upper heart chambers, the atria. Atrial fibrillation does not cause sudden cardiac death but its symptoms can be disabling, and a significant percentage of patients don't respond to the drugs used to treat it.

Roden and his colleagues have made major contributions to understanding the genetic variations that affect response to these drugs. Earlier this month, they reported finding a variation, called a polymorphism, in a potassium channel gene that prevented two drugs commonly used to treat atrial fibrillation from binding to and blocking the channel.

The potassium channel variant functioned normally in cell studies, but was significantly less sensitive to the antiarrhythmic drugs, the researchers reported in the current issue of The Journal of Clinical Investigation.

Roden's coauthors were postdoctoral fellows Benoit Drolet, Ph.D., and Chantale Simard, Ph.D., now at Laval University in Quebec, and Laura Mizoue, Ph.D., research assistant professor of Biochemistry and assistant director of the Vanderbilt Center for Structural Biology.

Channels are pores in the cell membranes that allow the inward and outward flow of electrically charged atoms called ions, and thus the electrical spark for heart muscle contraction.

It is thought that genetic variations affecting channel structure or function may lead to abnormal heart rhythms, and that one way antiarrhythmic drugs work is blocking these channels.

The Vanderbilt study showed that the variant potassium channel has a structure different enough from the usual to account for differences in drug sensitivity.

Large clinical studies will be required to determine whether patients with atrial fibrillation who have this genetic variant — including 2 percent of African-Americans — are resistant to standard antiarrhythmic therapy. If so, researchers may be able to develop new drugs specifically for these patients.

This is the promise of individualized medicine, Roden said. “The tools are in hand,” he said. “We're on the precipice of a really new era.”