Delayed depolarization and histologic abnormalities underlie the Brugada syndrome

Abstract

Brugada syndrome (BrS) is a controversial disease whose pathophysiology is still far from being fully understood. Unlike other cardiological disorders, a definite etiology has not yet been established so that it could be summarized under two main chapters: “functional” or “organic”, “repolarization” or “depolarization” disorder. Despite initial descriptions leaned towards the organic substrate and delayed depolarization features, functional and repolarization theories have attracted most of the Cardiological attention for many years. Data from electrocardiography, endocavitary tracings, electroanatomic mapping and histopathology, however, demonstrated that BrS is mainly characterized by structural myocardial changes mostly at the right ventricular outflow tract (RVOT), but also at the right ventricle (RV) and by delayed conduction at the same sites. Conduction disorders at different levels may also be present and identify patients at high risk for major arrhythmic events. The aim of the present review is to provide the current state of art of the pathophysiology of BrS, focusing on electro‐vectorcardiography and electrophysiological features, histopathology, echocardiography, and cardiac magnetic resonance imaging (CMRI).

Brugada Syndrome: More than a Monogenic Channelopathy

“…This is because many patients follow a non-Mendelian inheritance and present rare variants in non-coding regions or unknown genes, or even CNVs [ 85 ]. Thus, it is highly likely that disease manifestation, variability and severity can result from a number and interplay of rare and common variants occurring at the genotype level [ 32 ] and from more than one pathophysiological mechanism [ 2 , 101 , 113 , 114 ]. Despite most BrS cases resulting from variants in SCN5A , the emerging picture is that the molecular mechanisms underlying BrS may be far more complex than expected by the sole electrophysiological Nav1.5 defect [ 115 ].…”

“…The spectrum of severity of the ECG and clinical manifestations of BrS correlate with the existence of various underlying genetic and cellular abnormalities of the right ventricular outflow tract (RVOT) and surrounding structures. One could speculate that BrS is a heterogeneous disease with a common clinical phenotype (ECG abnormalities) potentially explained by more than one pathophysiological mechanism [ 2 , 101 ].…”

“…Alternatively, the depolarization hypothesis claims that the loss of INa, by impairing phase 0 of the AP, likely slows the electrical conduction in the RVOT, thus being primarily responsible for conduction delay and AP re-entry leading consequently to abnormal heart rhythm [ 101 ]. Evidence-based studies sustained this latter pathogenetic mechanism over time.…”

“…Regardless of their origin, structural abnormalities can induce conduction block and promote re-entrant arrhythmias. Catheter ablation of the surviving myocardium between fibrotic tissue can eliminate this arrhythmogenic substrate, thus restoring the Brugada ECG pattern and reducing arrhythmic risk in symptomatic patients with recurrent VF events [ 101 , 107 ].…”