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(Circulation. 2002;105:e9081.)
© 2002 American Heart Association, Inc.

Cardiovascular News

Ruth SoRelle, MPH

Circulation Newswriter

Two Paradoxical Syndromes; One Mutation

Proving the axiom that answers are not always the solution, a mutation in the cardiac sodium (Na⁺) channel can cause both long-QT and Brugada syndromes. Although both lead to life-threatening cardiac arrhythmias, long-QT is associated with enhanced Na⁺ channel function and Brugada with reduced Na⁺ channel function.

In this week’s issue of Circulation, Colleen E. Clancy, PhD, and Yoram Rudy, PhD, of the Cardiac Bioelectricity Research and Training Center in the Departments of Biomedical Engineering and Physiology and Biophysics at Case Western University in Cleveland, Ohio, used a computational approach to determine how the same mutation could lead to such dissimilar results (Circulation. 2002;105:1208–1213). They posited that the mutation 1795insD in the C-terminus of the cardiac Na⁺ channel exerts its variable effects depending on the myocardial substrate.

Using a computer, the scientists developed models of the Na⁺ channel as it exists normally and as it is mutated and incorporated into virtual transgenic cells. The mutation, said the authors in their paper, "disrupts the Na⁺ current by enhancing channel inactivation states and stabilizing inactivation states, which reduces channel availability. The mutation also promotes channel bursting resulting in a persistent component of noninactivating current."

The authors point out that ion channel proteins exist haphazardly in the heart muscle, which results in "intrinsic electrophysiological heterogeneity." Through their computer analysis, the authors demonstrate that this heterogeneity is the reason that two seemingly opposite syndromes can result from a single mutation.

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