title: Subepicardial phase 0 block and discontinuous transmural conduction underlie right precordial ST-segment elevation by a SCN5A loss-of-function mutation.
abstract: 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.
authors.affiliation: Dept. of Cardiology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht, 6202 AZ, Maastricht, The Netherlands.
authors.forename: Markéta
authors.initials: M
authors.lastname: Bébarová
authors.forename: Tom
authors.initials: T
authors.lastname: O'Hara
authors.forename: Jan L M C
authors.initials: JL
authors.lastname: Geelen
authors.forename: Roselie J
authors.initials: RJ
authors.lastname: Jongbloed
authors.forename: Carl
authors.initials: C
authors.lastname: Timmermans
authors.forename: Yvonne H
authors.initials: YH
authors.lastname: Arens
authors.forename: Luz-Maria
authors.initials: LM
authors.lastname: Rodriguez
authors.forename: Yoram
authors.initials: Y
authors.lastname: Rudy
authors.forename: Paul G A
authors.initials: PG
authors.lastname: Volders
mesh_terms: D000200:Action Potentials; D000328:Adult; D000818:Animals; D053840:Brugada Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D004562:Electrocardiography; D020022:Genetic Predisposition to Disease; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D008297:Male; D008955:Models, Cardiovascular; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010496:Pericardium / Q000378:metabolism* / Q000503:physiopathology; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
chemical_list: D020746:Calcium Channels, L-Type; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D012964:Sodium; D002118:Calcium