title: Mechanism of right precordial ST-segment elevation in structural heart disease: excitation failure by current-to-load mismatch.
abstract: BACKGROUND
  The Brugada sign has been associated with mutations in SCN5A and with right ventricular structural abnormalities. Their role in the Brugada sign and the associated ventricular arrhythmias is unknown.
  
  
  OBJECTIVE
  The purpose of this study was to delineate the role of structural abnormalities and sodium channel dysfunction in the Brugada sign.
  
  
  METHODS
  Activation and repolarization characteristics of the explanted heart of a patient with a loss-of-function mutation in SCN5A (G752R) and dilated cardiomyopathy were determined after induction of right-sided ST-segment elevation by ajmaline. In addition, right ventricular structural discontinuities and sodium channel dysfunction were simulated in a computer model encompassing the heart and thorax.
  
  
  RESULTS
  In the explanted heart, disappearance of local activation in unipolar electrograms at the basal right ventricular epicardium was followed by monophasic ST-segment elevation. The local origin of this phenomenon was confirmed by coaxial electrograms. Neither early repolarization nor late activation correlated with ST-segment elevation. At sites of local ST-segment elevation, the subepicardium was interspersed with adipose tissue and contained more fibrous tissue than either the left ventricle or control hearts. In computer simulations entailing right ventricular structural discontinuities, reduction of sodium channel conductance or size of the gaps between introduced barriers resulted in subepicardial excitation failure or delayed activation by current-to-load mismatch and in the Brugada sign on the ECG.
  
  
  CONCLUSIONS
  Right ventricular excitation failure and activation delay by current-to-load mismatch in the subepicardium can cause the Brugada sign. Therefore, current-to-load mismatch may underlie the ventricular arrhythmias in patients with the Brugada sign.
authors.affiliation: Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. m.g.hoogendijk@amc.uva.nl
authors.forename: Mark G
authors.initials: MG
authors.lastname: Hoogendijk
authors.forename: Mark
authors.initials: M
authors.lastname: Potse
authors.forename: André C
authors.initials: AC
authors.lastname: Linnenbank
authors.forename: Arie O
authors.initials: AO
authors.lastname: Verkerk
authors.forename: Hester M
authors.initials: HM
authors.lastname: den Ruijter
authors.forename: Shirley C M
authors.initials: SC
authors.lastname: van Amersfoorth
authors.forename: Eva C
authors.initials: EC
authors.lastname: Klaver
authors.forename: Leander
authors.initials: L
authors.lastname: Beekman
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.forename: Pieter G
authors.initials: PG
authors.lastname: Postema
authors.forename: Hanno L
authors.initials: HL
authors.lastname: Tan
authors.forename: Annette G
authors.initials: AG
authors.lastname: Reimer
authors.forename: Allard C
authors.initials: AC
authors.lastname: van der Wal
authors.forename: Arend D J
authors.initials: AD
authors.lastname: Ten Harkel
authors.forename: Michiel
authors.initials: M
authors.lastname: Dalinghaus
authors.forename: Alain
authors.initials: A
authors.lastname: Vinet
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Jacques M T
authors.initials: JM
authors.lastname: de Bakker
authors.forename: Ruben
authors.initials: R
authors.lastname: Coronel
mesh_terms: D000293:Adolescent; D000404:Ajmaline; D000889:Anti-Arrhythmia Agents; D053840:Brugada Syndrome / Q000235:genetics / Q000503:physiopathology; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000503:physiopathology*; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D020022:Genetic Predisposition to Disease; D016027:Heart Transplantation; D006801:Humans; D066298:In Vitro Techniques; D034904:Lamin Type A / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics; D018497:Ventricular Dysfunction, Right / Q000235:genetics / Q000503:physiopathology*
chemical_list: D000889:Anti-Arrhythmia Agents; C494847:LMNA protein, human; D034904:Lamin Type A; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D000404:Ajmaline