Circulation. 2002;105:1208-1213
Published online before print February 18, 2002, doi: 10.1161/hc1002.105183
Published online before print February 18, 2002, doi: 10.1161/hc1002.105183
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(Circulation. 2002;105:1208.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Na+ Channel Mutation That Causes Both Brugada and Long-QT Syndrome Phenotypes
A Simulation Study of Mechanism
From the Cardiac Bioelectricity Research and Training Center, Department of Biomedical Engineering and Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio.
Correspondence to Yoram Rudy, PhD, Director, Cardiac Bioelectricity Research and Training Center, 509 Wickenden Bldg, Case Western Reserve University, Cleveland, OH 44106-7207. E-mail yxr{at}po.cwru.edu
Background— Complex physiological interactions determine the functional consequences of gene abnormalities and make mechanistic interpretation of phenotypes extremely difficult. A recent example is a single mutation in the C terminus of the cardiac Na+ channel, 1795insD. The mutation causes two distinct clinical syndromes, long QT (LQT) and Brugada, leading to life-threatening cardiac arrhythmias. Coexistence of these syndromes is seemingly paradoxical; LQT is associated with enhanced Na+ channel function, and Brugada with reduced function.
Methods and Results— Using a computational approach, we demonstrate that the 1795insD mutation exerts variable effects depending on the myocardial substrate. We develop Markov models of the wild-type and 1795insD cardiac Na+ channels. By incorporating the models into a virtual transgenic cell, we elucidate the mechanism by which 1795insD differentially disrupts cellular electrical behavior in epicardial and midmyocardial cell types. We provide a cellular mechanistic basis for the ECG abnormalities observed in patients carrying the 1795insD gene mutation.
Conclusions— We demonstrate that the 1795insD mutation can cause both LQT and Brugada syndromes through interaction with the heterogeneous myocardium in a rate-dependent manner. The results highlight the complexity and multiplicity of genotype-phenotype relationships, and the usefulness of computational approaches in establishing a mechanistic link between genetic defects and functional abnormalities.
Key Words: arrhythmia • genes • long-QT syndrome • Brugada syndrome • sodium
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