Editorial: Past, present, and future of Brugada syndrome: a comprehensive framework

The historical development of Brugada syndrome (BrS) in many respects parallels that of Wolff-Parkinson-White (WPW) syndrome. In WPW, the arrhythmogenic substrate-the accessory pathway-was anatomically identifiable. Early studies in asymptomatic individuals demonstrated that careful electrophysiological characterization of pathway properties could independently predict the risk of sudden cardiac death even in the absence of symptoms (1)(2)(3)(4)(5)(6). These findings influenced international guidelines and established a fundamental principle of clinical electrophysiology: a single electrical signal can reveal the mechanisms underlying life-threatening arrhythmias (1). It was during my training under the mentorship of John J. Gallagher and Fred Morady that I first learned to look beyond the surface electrocardiogram. They emphasized that subtle electrical signals often contain the roadmap to ventricular fibrillation (VF) and sudden cardiac death. This perspective later using high-density three-dimensional mapping guided investigations worldwide in understanding diagnosis, prognosis and therapy of BrS (7)(8)(9)(10)(11). For many years, however, BrS appeared fundamentally different from WPW. While WPW was defined by a clearly identifiable anatomical pathway on surface ECG, BrS seemed to be characterized solely by its electrocardiographic phenotype. The spontaneous type-1 ECG pattern became both the diagnostic hallmark of the disease and the principal marker of arrhythmic risk. Yet the absence of a clearly defined substrate made mechanistic interpretation difficult. Early observations described the type-1 ECG pattern primarily in patients resuscitated from VF or in small cohorts of predominantly symptomatic patients with implantable cardioverter-defibrillators. However, the prevalence and prognostic significance of this finding in asymptomatic individuals remained uncertain. Without knowledge of the underlying substrate, it was impossible to determine whether the ECG pattern represented a transient electrical phenomenon or the manifestation of a fixed arrhythmogenic substrate capable of sustaining ventricular fibrillation. As a consequence, risk stratification relied largely on clinical features and probabilistic combinations of variables, often leading to uncertainty and inconsistent recommendations.Over the past decade, this conceptual framework has begun to change (7)(8)(9)(10)(11)(12). Advances in highdensity epicardial mapping have revealed the presence of abnormal electrograms localized to the right ventricular outflow tract. These signals are characterized by low voltage, fractionation, and delayed activation, reflecting areas of slow and heterogeneous conduction capable of sustaining life-threatening ventricular arrhythmias and VF. Recognition of this arrhythmogenic substrate has profoundly reshaped our understanding of BrS. The disease is no longer viewed solely as an electrocardiographic phenotype but increasingly as a substrate-dependent arrhythmogenic disorder. Several observational and randomized studies involving large cohorts of highly symptomatic patients have demonstrated remarkable success with epicardial substrate ablation 10-12). In many cases, elimination of the abnormal substrate results not only in suppression of recurrent ventricular arrhythmias but also in normalization of the ECG pattern. These findings strongly support a causal relationship between substrate extent and the electrocardiographic phenotype. In this context, the type-1 ECG pattern may represent the surface manifestation of the underlying arrhythmogenic substrate rather than simply a diagnostic marker. Nevertheless, important challenges remain, particularly in asymptomatic individuals. Recent guideline revisions have attempted to incorporate some of these insights by refining diagnostic criteria and reducing the diagnostic weight of drug-induced ECG patterns in the absence of clinical manifestations (7). However, reliable strategies for risk stratification in asymptomatic patients remain limited. The contributions presented in this thematic series highlight the complexity of the field. Several reviews emphasize persistent diagnostic challenges, including the limited specificity of the ECG phenotype and the modest yield of genetic testing, with pathogenic variants in SCN5A identified in only a minority of patients. Other articles explore evolving strategies for risk stratification that integrate clinical, electrocardiographic, electrophysiological, and genetic variables. Yet the predictive performance of these models remains inconsistent. An additional layer of complexity arises from the temporal variability of the ECG pattern. In many patients, the type-1 ECG fluctuates in response to fever, medications, metabolic disturbances, or autonomic influences. In others, the pattern remains persistently present. This distinction may be clinically meaningful. Persistent ECG expression likely reflects a fixed and extensive arrhythmogenic substrate, whereas fluctuating patterns may indicate a more dynamic electrophysiological state. Understanding these temporal dynamics may therefore represent a crucial step toward distinguishing patients at true risk of malignant arrhythmias from those in whom the ECG pattern reflects a transient or less dangerous condition.The management of asymptomatic individuals remains one of the most challenging aspects of BrS. Many patients are diagnosed incidentally during family screening or routine clinical evaluation, yet reliable markers for predicting malignant arrhythmic events remain limited. This discrepancy between the strong association of the type-1 ECG pattern with VF and the relatively low incidence of events among asymptomatic individuals represents a persistent clinical paradox. The historical experience with WPW syndrome provides a useful analogy. In WPW, identification and characterization of the accessory pathway ultimately transformed both risk stratification and therapeutic strategies. A similar mechanistic approach is now emerging in BrS, integrating careful analysis of the ECG with characterization of the underlying arrhythmogenic substrate. Technological advances may further accelerate this transition. Electro-anatomical mapping, advanced imaging, and computational ECG analysis offer the possibility of linking surface electrical patterns with structural and functional properties of the substrate. These approaches move beyond descriptive ECG criteria toward a more mechanistic understanding of the disease. Large international registries integrating clinical, genetic, and electrophysiological data will be essential to validate emerging predictors and guide future therapeutic strategies. Another area of ongoing investigation concerns the potential role of autoantibodies in BrS. (13). Although mechanistically intriguing, this field remains largely experimental. Current clinical data do not demonstrate a clear relationship between autoantibody presence and the ECG phenotype. Importantly, these biomarkers do not capture the temporal stability or variability of the type-1 ECG pattern-features that may represent critical determinants of arrhythmic risk. Premature reliance on such markers could therefore increase false-positive diagnoses without improving risk prediction. Ultimately, the story of Brugada syndrome brings electrophysiology full circle. The same intellectual curiosity that guided early investigations in WPW-using a single electrical signal to understand sudden cardiac death-continues to illuminate the path forward. Today, growing evidence suggests that the type-1 ECG pattern is more than a diagnostic signature. It may represent the surface expression of an underlying arrhythmogenic substrate whose extent determines both the amplitude and the stability of the J-point elevation. In this perspective, the ECG becomes not merely a marker of disease but a window into its mechanism. Following this signal-from the surface ECG to the epicardial substrate-may ultimately allow clinicians to identify patients truly at risk for ventricular fibrillation while avoiding unnecessary interventions in those who are not. From WPW to Brugada syndrome, the surface 12-lead ECG continues to guide our understanding of ventricular arrhythmias. When interpreted in the context of the underlying substrate, a single electrical signal may once again transform uncertainty into mechanism-and mechanism into prevention.Scientific Director (2015-2025), Arrhythmology Department IRCCS Policlinico San Donato Milan, Italy Key words: Brugada syndrome, ventricular fibrillation, sudden cardiac death.