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

Departments of 1 Cardiology, 2 Molecular Cell Biology and Genetics, 3 Clinical Genetics, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht and Maastricht University, Maastricht, The Netherlands; and 4 Cardiac 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 Ca 2+ 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 Address for reprint requests and other correspondence: P. G. A. Volders, Dept. of Cardiology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands (e-mail: p.volders{at}cardio.unimaas.nl )