title: Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study.
abstract: BACKGROUND
  The mechanism of ECG changes and arrhythmogenesis in Brugada syndrome (BS) patients is unknown.
  
  
  RESULTS
  A BS patient without clinically detected cardiac structural abnormalities underwent cardiac transplantation for intolerable numbers of implantable cardioverter/defibrillator discharges. The patient's explanted heart was studied electrophysiologically and histopathologically. Whole-cell currents were measured in HEK293 cells expressing wild-type or mutated sodium channels from the patient. The right ventricular outflow tract (RVOT) endocardium showed activation slowing and was the origin of ventricular fibrillation without a transmural repolarization gradient. Conduction restitution was abnormal in the RVOT but normal in the left ventricle. Right ventricular hypertrophy and fibrosis with epicardial fatty infiltration were present. HEK293 cells expressing a G1935S mutation in the gene encoding the cardiac sodium channel exhibited enhanced slow inactivation compared with wild-type channels. Computer simulations demonstrated that conduction slowing in the RVOT might have been the cause of the ECG changes.
  
  
  CONCLUSIONS
  In this patient with BS, conduction slowing based on interstitial fibrosis, but not transmural repolarization differences, caused the ECG signs and was the origin of ventricular fibrillation.
authors.affiliation: Experimental and Molecular Cardiology Group, Academic Medical Center, Amsterdam, The Netherlands. r.coronel@amc.nl
authors.forename: Ruben
authors.initials: R
authors.lastname: Coronel
authors.forename: Simona
authors.initials: S
authors.lastname: Casini
authors.forename: Tamara T
authors.initials: TT
authors.lastname: Koopmann
authors.forename: Francien J G
authors.initials: FJ
authors.lastname: Wilms-Schopman
authors.forename: Arie O
authors.initials: AO
authors.lastname: Verkerk
authors.forename: Joris R
authors.initials: JR
authors.lastname: de Groot
authors.forename: Zahurul
authors.initials: Z
authors.lastname: Bhuiyan
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.forename: Marieke W
authors.initials: MW
authors.lastname: Veldkamp
authors.forename: André C
authors.initials: AC
authors.lastname: Linnenbank
authors.forename: Allard C
authors.initials: AC
authors.lastname: van der Wal
authors.forename: Hanno L
authors.initials: HL
authors.lastname: Tan
authors.forename: Pedro
authors.initials: P
authors.lastname: Brugada
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Jacques M T
authors.initials: JM
authors.lastname: de Bakker
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D002460:Cell Line; D004558:Electric Stimulation; D006801:Humans; D007668:Kidney; D008297:Male; D012016:Reference Values; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology; D013577:Syndrome; D014693:Ventricular Fibrillation / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*
chemical_list: D015222:Sodium Channels