BACKGROUND: The mechanism of ECG changes and arrhythmogenesis in Brugada syndrome (BS) patients is unknown. METHODS AND 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.
BACKGROUND: The mechanism of ECG changes and arrhythmogenesis in Brugada syndrome (BS) patients is unknown. METHODS AND 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: Markéta Bébarová; Tom O'Hara; Jan L M C Geelen; Roselie J Jongbloed; Carl Timmermans; Yvonne H Arens; Luz-Maria Rodriguez; Yoram Rudy; Paul G A Volders Journal: Am J Physiol Heart Circ Physiol Date: 2008-05-02 Impact factor: 4.733
Authors: Prince J Kannankeril; Brett M Mitchell; Sanjeewa A Goonasekera; Mihail G Chelu; Wei Zhang; Subeena Sood; Debra L Kearney; Cristina I Danila; Mariella De Biasi; Xander H T Wehrens; Robia G Pautler; Dan M Roden; George E Taffet; Robert T Dirksen; Mark E Anderson; Susan L Hamilton Journal: Proc Natl Acad Sci U S A Date: 2006-07-27 Impact factor: 11.205
Authors: Hiroshi Watanabe; Tao Yang; Dina Myers Stroud; John S Lowe; Louise Harris; Thomas C Atack; Dao W Wang; Susan B Hipkens; Brenda Leake; Lynn Hall; Sabina Kupershmidt; Nagesh Chopra; Mark A Magnuson; Naohito Tanabe; Björn C Knollmann; Alfred L George; Dan M Roden Journal: Circulation Date: 2011-08-08 Impact factor: 29.690