Brugada syndrome (BrS) is a genetic arrhythmic disorder characterized by a distinct electrocardiographic pattern and an increased risk of sudden cardiac death. The first disease-associated variant in the sodium voltage-gated channel alpha subunit 5 (SCN5A) gene was discovered in 1988. However, the clinical significance of SCN5A variants remains uncertain. Currently, diagnostic criteria and recommendations identify only pathogenic SCN5A mutations as definitive contributors to BrS. Notably, both gain-of-function and loss-of-function variants of SCN5A have been related to a variety of arrhythmogenic disorders. Loss-of-function variants are linked to sick sinus syndrome and BrS. While gain-of-function variants are linked with multifocal ectopic Purkinje-related premature complex syndrome. These mutations have also been identified in arrhythmogenic cardiomyopathy and dilated cardiomyopathy. It reflects a broad phenotypic spectrum linked to abnormalities in the sodium channel functioning.
A comprehensive review published in Cardiogenetics provides an updated overview of the evolving understanding of BrS pathogenesis, including diagnosis implications, risk assessment, and treatment strategies. This review also explores emerging options for improving the management of BrS patients.
BrS is a primary arrhythmogenic condition of the right ventricular outflow tract (RVOT) that causes abrupt arrhythmic death in young individuals with structurally normal hearts. The hallmark of diagnosis is a type 1 electrocardiogram (ECG) pattern, which has covered ST-segment elevations > 2 mm in the right precordial leads (V1-V2). BrS is affected by a variety of conditions, like myocarditis, pericarditis, hypercalcemia, and medications that affect sodium channels. The ECG pattern IN BrS is dynamic and may change in response to triggers such as fever, alcohol, and sodium channel-blocking medicines.
Historically, BrS pathogenesis has been attributed to abnormalities in repolarization currents, specifically decreased inward sodium current (INa) and increased transient outward potassium current (Ito), which leads to a transmural voltage gradient and a substrate for arrhythmias by phase 2 re-entry. However, this emerging evidence suggests an additional role of depolarization variations and conduction delay, specifically in the RVOT. Abnormalities such as intraventricular conduction abnormalities, first-degree atrioventricular block, and prominent S waves in lateral leads indicate a conduction defect primarily affecting the RVOT.
Some cases show arrhythmogenic changes extend to the left ventricular epicardium, suggesting a more diffuse pathological substrate. Non-invasive imaging techniques like echocardiography and cardiac magnetic resonance imaging (MRI) provide further insight into BrS-related structural abnormalities. Electro-anatomical mapping further enables detailed visualization of arrhythmogenic regions, primarily within the RVOT. Catheter ablation of these abnormal substrates has become a powerful therapeutic tool.
The investigation into the overlap between BrS and arrhythmogenic cardiomyopathy (AC) has revealed a shared set of underlying disorders involving both desmosomal and non-desmosomal genes. The RVOT or right ventricle of the heart is distinguished by fibrotic changes and reduced expression of the gap junction protein connexin 43 (Cx43), which is essential for proper cellular migration and RVOT zonation. Autoantibodies to alpha-cardiac actin, alpha-skeletal actin, keratin, and connexin-43 have been found in BrS patients, as well as aberrant a-cardiac actin, a-skeletal actin, keratin, and connexin-43 aggregates.
The connexome, a structural-functional complex within intercalated discs, coordinates electromechanical coupling between cardiomyocytes through the integration of desmosomes, gap junctions, ion channels, and associated proteins. Ryanodine receptor-2 (RYR2), which regulates calcium release from the sarcoplasmic reticulum and is involved in connexome function. Mutations in the RYR-2 genes have been strongly linked to catecholaminergic polymorphic ventricular tachycardia.
Inflammation, apoptosis, and immune dysregulation are key factors in the development of genetic cardiomyopathies, impacting patient prognosis. Immunosuppressive treatment has shown positive outcomes in patients with genetically determined arrhythmogenic cardiomyopathies. However, the diagnostic yield of genetic testing in BrS is low, and monogenic models struggle to accurately capture the complex interplay between ion channel dysfunction, pathological substrate, and acquired alterations, necessitating further prospective studies to validate their widespread use in clinical practice.
Over the past two decades, the pathophysiology of BrS includes evidence of structural substrates, functional abnormalities, and histological and immunological findings. The overlap with arrhythmogenic cardiomyopathy highlights a diverse range of pathogenic mechanisms involving the connexome. Understanding these pathways may improve patient outcomes and provide new therapy options for BrS.
Reference: Ciabatti M, Notarstefano P, Zocchi C, Virgili G, Bellocci F, Olivotto I, Pieroni M. Brugada Syndrome: Channelopathy and/or Cardiomyopathy. Cardiogenetics. 2025; 15(2):17. doi:10.3390/cardiogenetics15020017
