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Targeted drug therapy prevents exercise-induced arrhythmias
Date:3/29/2009

de calcium-handling proteins, the ryanodine receptor and calsequestrin, cause the disorder.

In 2006, the group discovered how these mutations cause arrhythmias at the cellular level by allowing calcium to "leak" out of its storage containers inside heart cells. Knollmann's team developed a mouse model for CPVT (by eliminating the calsequestrin gene) and proposed using the model to study medications and interventions for the disorder.

They tried flecainide, a clinically available anti-arrhythmic that is used to treat atrial fibrillation. It worked.

In isolated heart cells, flecainide blocked the ryanodine receptor and the calcium "leak" (the underlying molecular defect in CPVT), and it completely prevented ventricular arrhythmias in the mouse model of CPVT.

"So we knew that this established drug specifically targets the disease mechanism in CPVT," Knollmann said.

With these encouraging results, the investigators teamed with Arthur Wilde, M.D., Ph.D., at the University of Amsterdam, to test flecainide in two patients with CPVT who continued to have arrhythmias while on conventional therapies the previously mentioned 12-year-old boy and a 36-year-old woman. The boy has a mutation in the calsequestrin gene, the same gene mutated in the mouse model; the woman has a mutation in the ryanodine receptor, which is more common among CPVT patients.

In both patients, flecainide (combined with a beta blocker in the boy) prevented exercise-induced ventricular arrhythmias. The patients have taken flecainide for more than six months now and are living normal lives.

The group is currently enrolling additional CPVT patients to clearly define the benefits and risks of flecainide and to compare how it works in patients who have varying ryanodine receptor and calsequestrin mutations.

Frank Fish, M.D., a pediatric cardiologist at Vanderbilt, has placed two patients with CPVT on flecainide therapy.

"We're hoping that
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Contact: Craig Boerner
craig.boerner@vanderbilt.edu
615-322-4747
Vanderbilt University Medical Center
Source:Eurekalert

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