The SCN5A p.Phe2004Leu loss-of-function mutation decreased peak sodium current by 46%, leading to subepicardial phase 0 block and discontinuous transmural conduction that explains right precordial ST-segment elevation.
The study provides novel mechanistic insights showing that discontinuous transmural conduction and phase 0 block underlie Brugada syndrome ECG patterns in a specific SCN5A loss-of-function mutation.
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.
Bébarová et al. (Sun,) conducted a other in Brugada syndrome (n=9). SCN5A p.Phe2004Leu mutation vs. Wild-type SCN5A was evaluated. The SCN5A p.Phe2004Leu loss-of-function mutation decreased peak sodium current by 46%, leading to subepicardial phase 0 block and discontinuous transmural conduction that explains right precordial ST-segment elevation.