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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 295/1/H48    most recent 91495.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Bébarová, M. Articles by Volders, P. G. A. PubMed PubMed Citation Articles by Bébarová, M. Articles by Volders, P. G. A.

Subepicardial phase 0 block and discontinuous transmural conduction underlie right precordial ST-segment elevation by a SCN5A loss-of-function mutation

Departments of ¹Cardiology, ²Molecular Cell Biology and Genetics, ³Clinical Genetics, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht and Maastricht University, Maastricht, The Netherlands; and ⁴Cardiac Bioelectricity and Arrhythmia Center, Washington University in St. Louis, St. Louis, Missouri

Submitted 19 December 2007 ; accepted in final form 28 April 2008

Two mechanisms are generally proposed to explain right precordial ST-segment elevation in Brugada syndrome: 1) right ventricular (RV) subepicardial action potential shortening and/or loss of dome causing transmural dispersion of repolarization; and 2) RV conduction delay. Here we report novel mechanistic insights into ST-segment elevation associated with a Na⁺ current (I_Na) loss-of-function mutation from studies in a Dutch kindred with the COOH-terminal SCN5A variant p.Phe2004Leu. The proband, a man, experienced syncope at age 22 yr and had coved-type ST-segment elevations in ECG leads V1 and V2 and negative T waves in V2. Peak and persistent mutant I_Na were significantly decreased. I_Na closed-state inactivation was increased, slow inactivation accelerated, and recovery from inactivation delayed. Computer-simulated I_Na-dependent excitation was decremental from endo- to epicardium at cycle length 1,000 ms, not at cycle length 300 ms. Propagation was discontinuous across the midmyocardial to epicardial transition region, exhibiting a long local delay due to phase 0 block. Beyond this region, axial excitatory current was provided by phase 2 (dome) of the M-cell action potentials and depended on L-type Ca²⁺ current ("phase 2 conduction"). These results explain right precordial ST-segment elevation on the basis of RV transmural gradients of membrane potentials during early repolarization caused by discontinuous conduction. The late slow-upstroke action potentials at the subepicardium produce T-wave inversion in the computed ECG waveform, in line with the clinical ECG.

arrhythmia (mechanisms); computer modeling; conduction (block); electrocardiogram; sodium channel