Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies

Abstract

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 the SCN5A, 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.

Tpeak‐Tend, Tpeak‐Tend/QT ratio and Tpeak‐Tend dispersion for risk stratification in Brugada Syndrome: A systematic review and meta‐analysis

“…These heterogeneities can occur locally or across the myocardial wall, potentially causing arrhythmias by inducing unidirectional conduction block and therefore circus‐type or spiral wave re‐entry . Moreover, a greater epicardial‐endocardial repolarization time difference may increase the propensity of phase 2 re‐entry, which is hypothesized to generate extrasystolic activity in Brugada syndrome . This occurs when sites with an action potential dome to sites which a dome morphology, leading to direct depolarization of the downstream sites .…”

“…28,29 Moreover, a greater epicardial-endocardial repolarization time difference may increase the propensity of phase 2 re-entry, which is hypothesized to generate extrasystolic activity in Brugada syndrome. 30 This occurs when sites with an action potential dome to sites which a dome morphology, leading to direct depolarization of the downstream sites. 31 Once an extrasystole is generated, together with a favorable re-entrant substrate, ventricular tachycardia and fibrillation can result.…”

The Emergence of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs) as a Platform to Model Arrhythmogenic Diseases

“…Mutations in other ion channels involved in early repolarization have also been associated with BrS [68,69]. To date, 19 genes encoding either Na, K, or Ca channels have been associated with BrS [70].…”

Identification of transmembrane protein 168 mutation in familial Brugada syndrome

“…The only effective treatment at present is the implantation of an implantable cardioverter‐defibrillator (ICD) . Despite intensive study of BrS, many controversies remain regarding the risk stratification of patients, correct treatments, arrhythmogenic mechanisms, and the morphological substrate in the heart …”