**1. Introduction**

Since the original publication in 1992 [1], many researchers have tried to explain the mechanisms and substrate that causes an abnormal electrocardiographic (ECG) pattern and ventricular arrhythmias in Brugada syndrome (BrS) and few therapeutic options have been found. Initially three hypotheses were proposed for explain the mechanism and arrhythmias in BrS, the abnormal repolarization theory [2], the abnormal depolarization theory [3] and the abnormal expression of neural crest cells during cardiac development [4].

BrS is characterized by an elevated ST segment in the right precordial leads (V1–3) on the ECG and risk of sudden cardiac death (SCD) [1, 5]. The ECG 1 pattern is frequently intermittent and can be unmasked by the administration of a sodium channel blocker (**Figure 1**). The incidence of SCD in subjects with Brugada type 1 ECG pattern and no previous cardiac arrest is 2 per 1000 patients per year [6, 7].

At present, there are just two therapeutic strategies, which include implantable cardioverterdefibrillator (ICD) and/or chronic quinidine therapy [6, 7]. However, quinidine is not effective

**Figure 1.** Characteristic BrS ECG. A. In the N°3 patient the ECG at baseline show spontaneous and intermittent type 1 ECG BrS pattern. B. After flecainide test (400 mg, orally) [19].

in many patients and its use is frequently associated with intolerable adverse effects. ICD implantation may be effective in preventing SCD, and is currently recommended as a class I indication for symptomatic patients with type 1 Brugada ECG pattern. Unfortunately, ICD therapy in many patients is associated with inappropriate shocks (overall ICD complication rate is 9.1% and inappropriate shocks in BrS occur in 13.7%), lead fractures/failure, device infections and frequent ICD discharges by electric storms [6, 8, 9].

As an autosomal dominant disease with incomplete penetrance, BrS was initially linked to mutations in the SCN5A gene [9]. Currently, more than 450 pathogenic variants have been identified in 24 genes encoding sodium, potassium, and calcium channels or associated proteins [10, 11]. Known BrS-susceptibility genes can only partially explain the clinically diagnosed cases; therefore, many patients (65–70%) remain "genetically unresolved" [8, 9]. For many years, BrS has been considered a purely electric disease even if, more recently some authors have shown the presence of morphological and functional abnormalities (regional conduction slow in the endocardium and epicardium), predominantly located in the right ventricle outflow tract (RVOT) [12–14].

Radiofrequency ablation (RFA) has recently emerged as a therapeutic option in BrS patients of high risk. RFA in two previous reports was effective in preventing ventricular fibrillation (VF) in BrS [15, 16]. Two studies have recently shown fractionated systolic electrograms (EGMs) in epicardium of RVOT and RF normalized the ECG pattern and prevented ventricular fibrillation and ventricular tachycardia (VT/VF) occurrence in a short follow-up [17, 18].
