Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study.
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.
Coronel
Ruben
R
Experimental and Molecular Cardiology Group, Academic Medical Center, Amsterdam, The Netherlands. r.coronel@amc.nl
Casini
Simona
S
Koopmann
Tamara T
TT
Wilms-Schopman
Francien J G
FJ
Verkerk
Arie O
AO
de Groot
Joris R
JR
Bhuiyan
Zahurul
Z
Bezzina
Connie R
CR
Veldkamp
Marieke W
MW
Linnenbank
André C
AC
van der Wal
Allard C
AC
Tan
Hanno L
HL
Brugada
Pedro
P
Wilde
Arthur A M
AA
de Bakker
Jacques M T
JM
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*
D015222:Sodium Channels