Brugada Syndrome and Sudden Cardiac Death Mechanisms

Brugada syndrome is an inherited cardiac channelopathy characterised by a distinctive right precordial ECG pattern and a high risk of ventricular fibrillation leading to sudden cardiac death. The syndrome arises principally from loss-of-function variants in genes encoding cardiac ion channels, most notably SCN5A, which encodes the Nav1.5 sodium channel. Electrophysiological disturbances in the right ventricular outflow tract, often compounded by subtle structural abnormalities and fibrotic changes, create a substrate for re-entrant arrhythmias. Modulating factors such as fever, autonomic tone and inflammatory mediators can unmask or exacerbate the ECG phenotype by altering channel kinetics or cellular signalling pathways. Risk stratification relies on clinical history, ECG markers, provocative drug testing and increasingly on genetic and polygenic risk profiling. Therapeutic approaches range from lifestyle modification and antiarrhythmic drugs to implantable cardioverter-defibrillators and targeted ablation of arrhythmogenic substrates. Global efforts now focus on refining genotype–phenotype correlations, improving non-invasive diagnostics and developing tailored interventions to prevent sudden death in affected individuals.

Research from Nature Portfolio

A comprehensive stratified scoring system has been developed to categorise the pathogenicity of rare genetic variants across cardiac channelopathies. By integrating in silico predictions, population allele frequencies, family segregation data and functional assay results, this framework refines the classification of SCN5A and other ion-channel gene variants. The approach enhances clinical interpretation, supports personalised risk assessment and guides decision-making in patients with suspected Brugada syndrome and related arrhythmogenic disorders.

Brugada Syndrome and Sudden Cardiac Death Mechanisms publication trend

The graph below shows the total number of articles in brugada syndrome and sudden cardiac death mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

SCN5A gene: Gene encoding the Nav1.5 cardiac sodium channel, loss-of-function variants of which underlie most Brugada syndrome cases.

Human-induced pluripotent stem cell (hiPSC): Somatic cells reprogrammed to a pluripotent state, capable of differentiating into cardiomyocytes for disease modelling.

Protein Kinase A (PKA): A cAMP-dependent kinase that modulates ion-channel phosphorylation and cellular excitability.

Autophagy: A lysosome-mediated degradation pathway that influences cellular homeostasis and may alter ion-channel turnover.

Atrial P-wave: The portion of the ECG representing atrial depolarisation, whose morphology can reflect subtle conduction abnormalities.

Quinidine: A Class Ia antiarrhythmic that blocks sodium channels and reduces phase-1 repolarisation currents to stabilise cardiac conduction.

References

1. Novel insights in the pathomechanism of Brugada syndrome and fever‐related type 1 ECG changes in a preclinical study using human‐induced pluripotent stem cell‐derived cardiomyocytes. Clinical and Translational Medicine (2023).
2. Quinidine for ventricular arrhythmias: A comprehensive review. Trends in Cardiovascular Medicine (2024).
3. Identification of Brugada syndrome based on P-wave features: an artificial intelligence-based approach. EP Europace (2023).
4. Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome. Journal of the American College of Cardiology (2015).
5. Brugada syndrome genetics is associated with phenotype severity. European Heart Journal (2020).
6. Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores. European Heart Journal (2019).
7. Determining the Pathogenicity of Genetic Variants Associated with Cardiac Channelopathies. Scientific Reports (2015).