Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies.
Brugada syndrome (BrS), is a primary electrical disorder predisposing affected individuals to sudden cardiac death via the development of ventricular tachycardia and fibrillation (VT/VF). Originally, BrS was linked to mutations in theSCN5A, which encodes for the cardiac Na+channel. To date, variants in 19 genes have been implicated in this condition, with 11, 5, 3, and 1 genes affecting the Na+, K+, Ca2+, and funny currents, respectively. Diagnosis of BrS is based on ECG criteria of coved- or saddle-shaped ST segment elevation and/or T-wave inversion with or without drug challenge. Three hypotheses based on abnormal depolarization, abnormal repolarization, and current-load-mismatch have been put forward to explain the electrophysiological mechanisms responsible for BrS. Evidence from computational modeling, pre-clinical, and clinical studies illustrates that molecular abnormalities found in BrS lead to alterations in excitation wavelength (λ), which ultimately elevates arrhythmic risk. A major challenge for clinicians in managing this condition is the difficulty in predicting the subset of patients who will suffer from life-threatening VT/VF. Several repolarization risk markers have been used thus far, but these neglect the contributions of conduction abnormalities in the form of slowing and dispersion. Indices incorporating both repolarization and conduction and based on the concept of λ have recently been proposed. These may have better predictive values than the existing markers.
Department of Medicine and Therapeutics, Chinese University of Hong KongHong Kong, Hong Kong; Li Ka Shing Institute of Health Sciences, Chinese University of Hong KongHong Kong, Hong Kong.
Gary
G
Tse
Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University Tianjin, China.
Tong
T
Liu
Faculty of Medicine, Newcastle University Newcastle, UK.
Ka H C
KH
Li
Intensive Care Department, Royal Brompton and Harefield NHS Trust London, UK.
Victoria
V
Laxton
School of Biological Sciences, University of Cambridge Cambridge, UK.
Yin W F
YW
Chan
Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, The University of Hong Kong Pokfulam, Hong Kong.
Wendy
W
Keung
Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet Solna, Sweden.
Ronald A
RA
Li
Department of Medicine and Therapeutics, Chinese University of Hong KongHong Kong, Hong Kong; Department of Epidemiology and Preventive Medicine, Monash UniversityMelbourne, VIC, Australia.
Bryan P
BP
Yan
Brugada syndrome; arrhythmia; depolarization; repolarization; risk stratification; sodium channel