Next Article in Journal
Systematic Review of Pharmacogenetics of Immunosuppressants in Heart Transplantation
Previous Article in Journal
Cardiac Involvement in Patients with MELAS-Related mtDNA 3243A>G Variant
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cardiogenetics
Volume 15
Issue 2
10.3390/cardiogenetics15020017
cardiogenetics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Brugada Syndrome: Channelopathy and/or Cardiomyopathy

by
Michele Ciabatti
1,*,
Pasquale Notarstefano
1,
Chiara Zocchi
2,
Giacomo Virgili
1,
Fulvio Bellocci
3,
Iacopo Olivotto
2,4 and
Maurizio Pieroni
2
1
Cardiovascular Department, San Donato Hospital, 52100 Arezzo, Italy
2
Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
3
Division of Cardiology, Catholic University of the Sacred Heart, 00168 Rome, Italy
4
Meyer Children’s Hospital IRCCS, Viale Pieraccini 24, 50134 Florence, Italy
*
Author to whom correspondence should be addressed.
Cardiogenetics 2025, 15(2), 17; https://doi.org/10.3390/cardiogenetics15020017
Submission received: 16 March 2025 / Revised: 3 June 2025 / Accepted: 9 June 2025 / Published: 13 June 2025
(This article belongs to the Section Rare Disease-Genetic Syndromes)
Browse Figures
Versions Notes

Abstract

Brugada syndrome (BrS) has been traditionally considered a pure electrical disorder without an underlying structural substrate. However, early ECG studies showed the presence of depolarization abnormalities in this condition, while many studies based on advanced imaging have suggested the presence of subtle structural alterations. On the other hand, electrophysiological study (EPS) and electroanatomic mapping (EAM) techniques have provided important data regarding right ventricular functional and structural arrhythmic substrate. More recently, histology and immunology shed light on the possible role of fibrotic and inflammatory substrates in BrS. Notably, a significant overlap between electro anatomical and structural features in BrS and arrhythmogenic cardiomyopathy has been proposed. In this review, we summarized the physio pathological pathways and substrate underlying BrS. A deeper knowledge of the structural abnormalities involved in the pathogenesis of this disease could improve our diagnostic and prognostic approach, while novel findings regarding the role of inflammation and immune activation could potentially lead to new therapeutic strategies for BrS.

1. Introduction

Brugada syndrome (BrS) is an inherited arrhythmic condition associated with a typical ECG pattern and increased sudden cardiac death (SCD) risk [1,2,3]. The type 1 ECG pattern is defined as an elevation of the J point with coved morphology in V1 and/or V2 lead in second, third or fourth intercostal spaces [1,2,3,4]. The pattern can be spontaneous or induced by drugs blocking the sodium channels. BrS has been traditionally considered a pure electrical disorder characterized by repolarization abnormalities without any underlying structural substrate [1,2,5,6]. The first genetic variant in the Sodium Voltage-Gated Channel Alpha Subunit 5 (SCN5A, OMIM * 600163) gene was discovered in 1998 [7]. Since then, hundreds of variants in the SCN5A gene have been discovered with an autosomal dominance inheritance pattern occurring in approximately 30% of cases [8]. However, the clinical significance of many SCN5A variants have been questioned following the criteria established by the American College of Medical Genetics [9]. Variants in other genes (CACNA1C, OMIM * 114205, GPD1L, OMIM * 611778, HEY2, OMIM * 604674, PKP2, OMIM * 602861, RANGRF, OMIM * 607954, SCN10A, OMIM * 604427, SCN1B, OMIM * 600235, SCN2B, OMIM * 601327, SCN3B, OMIM * 608214, SLMAP, OMIM * 602701, and TRPM4, OMIM * 606936) have been reported as potentially pathogenetic in the literature, but according to current diagnostic guidelines and recommendations, only pathogenic SCN5A variants should be considered causative of BrS [2]. Patients with pathogenetic variants in the SCN5A gene without arrhythmias or pathological findings at advanced imaging represent a gray area that should be appropriately addressed in future studies. Notably, genotype–phenotype correlation remains elusive in this population, and the prognostic role of these variants is still unclear.
Interestingly, both loss- and gain-of-function SCN5A variants have also been associated with dilated and arrhythmogenic cardiomyopathies (AC) [10,11]. Loss-of-function variants have been associated with BrS and sick sinus syndrome, while gain-of-function mutations can determine multifocal ectopic premature Purkinje-related complexes syndrome.
Electroanatomic mapping (EAM) studies, due to the high sensitivity in detecting subtle pathological alterations, have demonstrated the presence of pathological voltages in the right ventricular outflow tract (RVOT) in patients with BrS [2,12,13]. In addition, pathology studies showed the presence of fibrosis and inflammation in tissue samples obtained from RVOT by autopsy or endomyocardial biopsy (EMB) [14,15,16]. More recently, novel echocardiographic and cardiac magnetic resonance (CMR) tools demonstrated the presence of structural and functional RVOT abnormalities [17,18]. Notably, many similarities in terms of molecular and cellular phenotype have emerged between BrS and AC [19,20].
This review aims to provide a comprehensive overview of the evolving understanding of BrS pathophysiology, discussing the implications for diagnosis, risk stratification, and treatment. Potential future perspectives to improve the management of BrS patients are also explored.

2. Electrocardiography and Invasive Electrophysiology: A Complex Interaction of Repolarization and Depolarization Abnormalities

The diagnosis of BrS is based on the recognition of a spontaneous type 1 pattern (either on conventional or high right precordial leads) with high take-off ST segment elevation > 2 mm and coved morphology irrespective of the presence of symptoms [2,4,21]. Notably, many cardiac diseases (including myocarditis, pericarditis, infarction, pulmonary embolism, hyperkalemia, hypercalcemia, AC, and hypothermia) could potentially determine ECG abnormalities mimicking Brugada pattern [21]. Differential diagnosis could represent a significant challenge, since some of these disorders (such as AC) could share some pathophysiologic pathways with BrS.
The ECG pattern can be dynamic with variations during fever or alcohol consumption [2,22]. In case of patterns induced by sodium channel blockers (by ajmaline, flecainide, procainamide or pilsicainide infusion) type 1 pattern, additional ECG, family history, and clinical and genetic criteria are needed to diagnose BrS [2,23]. Early studies focused on the peculiar repolarization abnormalities leading to the postulation of the “repolarization” theory based on the imbalance between reduced Na+ currents and preserved transient outward potassium (Ito K) currents. This mismatch, due to the inhomogeneous distribution of the Ito between the epicardial and endocardial layers, could therefore determine a transmural voltage gradient leading to the diagnostic ECG pattern [24,25,26]. This phenomenon was also thought to be the basis for phase 2 re-entry mechanisms and ventricular arrhythmias.
Multiple works showed that the presence of spontaneous type 1 ECG pattern determines an increased arrhythmic risk [27,28]. The presence of early repolarization (ER), ST segment elevation, and even coved patterns in the inferolateral ECG leads can occur in BrS patients, and they could be associated with a more serious phenotype [29,30,31]. Kawata et al. showed that in some BrS patients with inferolateral ER pattern, VF onset was shortly preceded by multiple premature ventricular contractions originating from the left inferolateral wall [31]. These observations could suggest more extensive biventricular involvement rather than classical RVOT abnormalities.
The maximal interval between the T wave peak and end and its dispersion could potentially be associated with worse outcomes in BrS subjects [32]. Increased repolarization time dispersion and marked repolarization gradients (revealed by steep epicardial J waves) have been demonstrated in BrS during electrophysiological study (EPS) studies [33]. Moreover, T wave alternans during sodium channel blocker administration could be a marker of electrical instability and increased arrhythmic risk [34].
However, since the early 2000s, many studies have focused on the presence and significance of depolarization abnormalities in BrS patients. Ikeda et al. demonstrated a high prevalence of late potentials (LPs) with an association with worse outcomes by using signal-averaged ECG (SA-ECG) in BrS subjects [35]. Similarly, an increased QRS duration is independently associated with adverse arrhythmic events at follow-up [36,37]. Other authors demonstrated that the presence of fragmented QRS (f-QRS) at standard 12-leads and filtered high cut-off frequency ECG is associated with spontaneous ventricular fibrillation (VF) at follow-up (Figure 1) [38,39]. On the other hand, the presence of preserved HV intervals at EPS in many patients suggested the presence of a primary RV conduction delay [35]. Of note, Morita et al. were able to show in a canine RV tissue model of BrS that delayed epicardial activation reproduced similar f-QRS features along the myocardial layers, suggesting a possible pathogenetic mechanism [38]. Prominent R waves in aVR lead, an indirect marker of RV conduction delay, represent a negative prognostic marker in BrS patients [40]. The presence of deep S waves in leads I, II, and III, atrial fibrillation onset, and the Tzou criteria (V1R > 0.15 mV, V6S > 0.15 mV, and V6S: R > 0.2) have also been associated with ventricular arrhythmias at follow-up [41,42]. These ECG features provide additional evidence of delayed RVOT activation in BrS patients.
Cardiogenetics 15 00017 g001
Figure 1. (A): ECG of 50-year-old patient with spontaneous type 1 BrS and fragmented QRS complexes in inferior leads [27,28,38,39]. (B): During EPS, a rapid polymorphic VT was induced after a single extra stimulus, necessitating external defibrillation. The patient underwent transvenous ICD implantation [27,41,43]. (C,D): Abnormal voltages were detected at unipolar mapping (D), without significant pathological signals at bipolar map (C) [13,16,44]. BrS; Brugada syndrome; EPS; electrophysiological study; ICD, implanted cardioverter defibrillator.
Figure 1. (A): ECG of 50-year-old patient with spontaneous type 1 BrS and fragmented QRS complexes in inferior leads [27,28,38,39]. (B): During EPS, a rapid polymorphic VT was induced after a single extra stimulus, necessitating external defibrillation. The patient underwent transvenous ICD implantation [27,41,43]. (C,D): Abnormal voltages were detected at unipolar mapping (D), without significant pathological signals at bipolar map (C) [13,16,44]. BrS; Brugada syndrome; EPS; electrophysiological study; ICD, implanted cardioverter defibrillator.
Cardiogenetics 15 00017 g001
The presence of atrioventricular (AV) conduction disorders and increased HV interval in BrS patients (Figure 2) [45,46] have been respectively demonstrated in ECG and EPS studies. Moreover, atrioventricular and intraventricular conduction disorders (namely right bundle branch block and first-degree AV block) have been associated with malignant arrhythmias at follow-up, while RVOT depolarization abnormalities have been detected in many EPS studies, even by use of isochronal activation mapping [12,13,47,48,49]. More recently, Rossi et al. demonstrated that increased difference in the RV refractory period between RVOT and RV apex (expressed as ΔRPRVOT-apex > 60 ms) was independently related to adverse clinical events over conventional clinical risk factors and VT/VF inducibility at EPS [50].
Taken together, these studies suggest a prominent role of depolarization abnormalities mainly located in the RVOT of BrS patients.

3. Electrophysiological Study: The Prognostic Role of Programmed Ventricular Stimulation

Over the years, many studies provided conflicting results regarding the prognostic significance of VT/VF inducibility after programmed ventricular stimulation (PVS) during EPS [27,43,51]. The use of EPS for risk stratification may be considered in BrS patients with low evidence levels according to current European Guidelines [4]. Heterogenous PVS protocols and selection biases in the cohorts could explain these differences. However, structural substrate inhomogeneity could potentially be another implicated factor. A recent large prospective study demonstrated that VF/VT inducibility during EPS was an independent predictor of major events in patients presenting spontaneous type 1 pattern monitoring [27]. Notably, the authors performed serial modified 12-lead Holter monitors to detect latent type 1 pattern in all subjects. In this way, they were able to identify a high-risk subgroup in this population.

4. Multimodality Imaging: Subtle Functional Abnormalities Revealed by Advanced Echocardiography and Cardiac Magnetic Resonance

BrS has been conventionally considered a pure channelopathy with normal biventricular function and structure. Conventional two-dimensional echocardiography did not demonstrate significant left or RV abnormalities in older BrS cohorts. Tissue Doppler and speckle tracking analysis can detect functional abnormalities in many cardiac disorders. Mitroi et al. demonstrated that higher RV index of myocardial performance (RIMP), reduced RVOT shortening, and higher RV mechanical dispersion were significantly associated with arrhythmic events in patients affected by BrS [17]. Interestingly, even impaired LV strain parameters (such as LV mechanical dispersion) have been associated with worse outcomes at follow-up [52]. Three-dimensional echocardiography demonstrated worsened mechanical contraction and reduced right ventricular ejection fraction (RVEF) after ajmaline infusion [53].
CMR, due to its high spatial resolution and the possibility to perform multiplanar sequences and tissue characterization, provided an incremental ability to detect subtle alterations in BrS patients. Early CMR studies showed increased biventricular volumes and reduced RVEF in BrS patients compared to controls, especially in genotype-positive subjects [54,55]. Dedicated CMR sequences demonstrated abnormal RVOT dimensions and contractions in BrS patients [56]. Bastiaenen et al. described the presence of late gadolinium enhancement (LGE) in 8% of BrS patients [57]. Moreover, an increasing prevalence of LGE over repeated CMRs has been described in the literature, suggesting a progressive increase in the substrate underlying BrS [58]. Novel CMR parameters (such as feature tracking analysis) could provide incremental sensitivity for RV dysfunction detection. Pappone et al. demonstrated that reduced RVOT feature tracking (RVOT-FT) was associated with increased pathological voltage mapping areas on the epicardial EAM [18]. Moreover, ajmaline infusion determined further RVOT-FT value reduction in this cohort.
The main ECG, imaging, and EPS features associated with adverse outcomes in BrS are summarized in Table 1.

5. Electroanatomic Mapping: Electrical and Structural Substrate Insights

EAM can provide detailed characterization of the myocardium in terms of reduced voltage areas and presence of fragmented signals and LPs. Due to its high sensitivity, it can detect abnormal underlying substrates even in patients without evident abnormalities at CMRs [61,62]. Letsas et al. demonstrated the presence of abnormal EAM voltages in patients with apparently normal CMRs [13]. Notably, more extensive pathological areas were detected at unipolar compared to bipolar mapping, suggesting a more pronounced epicardial substrate. Multiple groups reported higher VF inducibility during EPS in subjects presenting more diffuse pathological areas both at unipolar and bipolar mapping [13,44]. Transcatheter ablation has emerged as a possible therapy for recurrent ventricular arrhythmias in patients with BrS [12,63,64,65]. The presence of fragmented and delayed potentials and significant pathological voltages in the epicardial layer have been demonstrated in multiple works, with a further increase after sodium channel blocker infusion [63,64]. By targeting the abnormal substrate, a significant reduction in the ECG pattern and VT/VF inducibility at baseline and after ajmaline infusion has been described [12,63,64,65]. Interestingly, Pieroni et al. described high rates of fibrosis and inflammatory infiltrates (mainly activated T lymphocytes) in BrS with pathological unipolar and bipolar mapping [16]. Patients with edema and lymphocytic infiltrates presented higher rates of VF inducibility during EPS. It is notable that subjects with bipolar mapping abnormalities presented higher prevalence of inflammatory infiltrates, suggesting a strict relationship between transmural involvement and inflammatory activation. More recently, Pappone et al. described a significant worsening of RVEF and RVOT strain during ajmaline infusion [18]. Moreover, the authors reported a corresponding increase in altered unipolar mapping areas with a significant correlation with post-ajmaline RVEF.
Recently, the BRAVO registry provided important data regarding long-term outcomes after RVOT epicardial ablation in BrS [60]. BrS patients undergoing epicardial ablation experienced high event-free survival rates (up to 96% at the 5-year follow-up in the case of repeated procedures). The only variable independently associated with favorable outcomes at follow-up was the absence of Brugada ECG pattern at baseline or after sodium channel blockers after ablation at multivariate analysis. This element reinforces the importance of extensive substrate ablation in this setting. Interestingly, 29% of subjects presented an additional pathological substrate at EAM in the inferior RV epicardium, and three patients presented significant EAM abnormalities in the left posterolateral epicardium associated with the presence of early repolarization pattern.
In a recent study by Cheniti et al., the authors demonstrated the presence of LV EAM abnormalities in BrS patients undergoing epicardial mapping and ablation due to sustained ventricular arrhythmias [66]. Patients with LV substrates presented higher rates of conduction defects, more extensive RV EAM abnormalities, and frequent pathogenetic SCN5A variants.
Therefore, we could hypothesize that the presence of pathological EAM voltages in atypical RV and even LV segments could be the expression of subtle diffuse biventricular involvement in BrS.

6. Histology and Immunology: Exploring the Substrate and the Role of the Immune System in the Disease

Coronel et al. in 2005 described the presence of fibrofatty infiltration in the RVOT epicardium of the explanted heart of a BrS patient undergoing heart transplantation after multiple electrical storms [67]. Electrophysiological study of the explanted heart demonstrated conduction delays in the RVOT.
Tissue samples from autopsies and epicardial biopsies obtained during surgical RVOT ablations showed a high prevalence of fibrosis and reduced expression of gap junction protein connexin 43 (Cx43) in BrS patients compared to controls [15]. The authors detected similar histopathological findings from the left ventricular samples. Cx43 has a crucial function in determining correct cellular migration and RVOT zonation, and this evidence could explain the preferential RVOT involvement in BrS. Frustaci et al. performed biventricular angiography and EMBs in a cohort of BrS patients [14]. They detected the presence of microaneurysm and inflammatory infiltrates (activated T lymphocytes) in both ventricles with increased myocyte apoptosis and necrosis.
EAM can detect the presence of interstitial fibrosis at histology compared to CMR in right ventricular cardiomyopathies, as demonstrated by Santangeli et al. [68].
Pieroni et al. performed RVOT EMBs guided by EAM in BrS subjects [16]. Lymphomononuclear infiltrates were detected in 80% of cases together with necrosis, myofibrillar rarefactions, and cytoplasmic vacuolization.
A subsequent study described the presence of autoantibodies against alpha-cardiac actin, alpha-skeletal actin, keratin, and connexin-43 from sera of BrS patients [69]. Moreover, analysis of the tissue samples by autopsy or EMBs demonstrated abnormal a-cardiac actin, a-skeletal actin, keratin, and connexin-43 aggregates. The authors hypothesized that structural abnormalities in the sodium channels could determine inappropriate apoptotic processes leading to exposure of cryptic cardiac epitopes and the consequent activation of the immune system. Identification of circulating autoantibodies and related pathological protein aggregates in the myocardium could therefore potentially represent a possible pathological mechanism. We reviewed the main histopathological studies in Table 2.

7. Brugada Syndrome and Arrhythmogenic Cardiomyopathy: A Common Spectrum of Disease

AC is a genetic disorder caused by desmosomal and non-desmosomal genes characterized by biventricular fibrofatty replacement and high rates of ventricular arrhythmias [70,71,72]. Notably, RVOT structural abnormalities are common and have been included in the revised 2010 diagnostic criteria for RV AC [73,74]. Corrado et al. described a group of patients suffering sudden cardiac death with histological findings compatible with AC and presenting dynamic right anterior ST segment abnormalities diagnostic for BrS [75,76]. Similarly, the presence of epsilon waves has been described in BrS ECG [77]. Since then, growing evidence of structural and functional myocardial alterations in BrS has emerged. Multiple genetic studies described a wide spectrum of diseases caused by SCN5A variants, including BrS, long QT syndrome, sick sinus syndrome, AV block, atrial fibrillation, and dilated cardiomyopathy with pronounced arrhythmic burden [10,11,20,78].
The connexome and the intercalated disks provide correct intercellular adhesion and electromechanical coupling to the myocytes [19,20,79,80]. Desmosomes represent the main structure involved in electromechanical connections between cardiomyocytes. Heterozygous nonsense, frameshift, or splicing variants in the PKP-2 gene (expressing a protein of the armadillo family) have been associated with RV-dominant AC. PKP and junctional plakoglobin (encoded by JUP gene, OMIM * 173325) are strictly connected to desmoglein-2 (DSG-2 gene, OMIM * 125671) and desmocollin-2 (DSC-2 gene, OMIM * 125645) proteins in the extracellular space [79]. Interestingly, some authors described a homozygous DSC-2 deletion associated with AC onset [81]. The same group reported that hemi- and homozygous loss-of-function variants in DSG-2 determine an early onset form of AC [82]. Desmoplakin (DSP gene, OMIM * 125647), a protein of the plakin cytolinker family, ligates PKP and plakoglobin in the intracellular compartment, thereby creating a connection between desmosomes and intermediate filaments [79]. Variants in DSP genes have been associated with a form of AC with extensive fibrosis and inflammatory activity in both ventricles. Desmin (DES gene, OMIM * 125660) represents the main component of the intermediate filaments: mutations in this gene can cause heterogenous phenotypes, including AC, dilated, and restrictive cardiomyopathies [79].
Desmosome proteins, area composita, gap junctions (mostly composed of connexin-43), and ion channels (including voltage-gated sodium channels) are strictly interconnected to preserve the structural and functional stability of the connexome [19,20,80]. Ryanodine receptor-2 (encoded by RYR-2 gene, OMIM * 180902) regulates calcium release from the sarcoplasmic reticulum and is related to connexome function. Mutations in RYR-2 genes have been strongly associated with catecholaminergic polymorphic ventricular tachycardia syndrome. Pathogenetic variants of phospholamban (PLN gene, OMIM * 172405), a structural component of the sarcoplasmic reticulum, determine severe forms of AC [79].
Behr et al. hypothesized that BrS could be the expression of an impaired RVOT conduction reserve, determined by reduced sodium channel currents, structural alterations, and inflammatory processes [26].
This complex interplay at the level of the gap junctions and connexome could potentially explain the structural and functional similarities between BrS and AC.
Some echocardiographic and CMR studies described reduced RV strain rate abnormalities both in BrS and AC compared to controls [83,84]. These observations support the hypothesis that BrS and AC could represent different phenotypic manifestations of a common spectrum of disorders.
Recently, many works described the importance of inflammatory and potential autoimmune processes in AC [85,86,87]. This evidence led to the emergent concept of inflammatory “hot phases” over the natural history of patients affected by AC and could suggest a common pathological mechanism involved in the pathogenesis of both conditions.

8. Future Perspectives: Genetics and Immune Modulation

Inflammation, apoptosis, and immune dysregulation play a crucial role in the pathogenesis of genetic cardiomyopathies and could significantly influence the prognosis of the patients [85,86,87]. Over recent years, some authors have reported positive outcomes in patients with genetically determined arrhythmogenic cardiomyopathies undergoing immunosuppressive treatment [88,89,90,91]. A case of recurrent myocarditis requiring multiple immunosuppressive regimes in a patient with a truncating variant of the demosplakin gene has been described in the literature [89]. Peretto et al. demonstrated possible beneficial effects of immunosuppression in patients with genetic cardiomyopathies and histological evidence of inflammatory infiltrates [91]. Interestingly, other authors reported an episode of giant cell-related fulminant myocarditis in a patient with a previous diagnosis of BrS [90]. Li et al. reported some BrS patients with arrhythmic storms presenting pathological uptake at 18-fluorodeoxyglucose positron emission tomography [92]. Moreover, the authors reported transitory improvement of the arrhythmic burden after prednisolone and hydroxychloroquine therapy. As previously described, inflammation and dysregulated immune response might represent common pathogenetic pathways both in BrS and genetic cardiomyopathies. Further prospective studies should evaluate the role of inflammation in the pathogenesis of the disease.
Another critical issue in BrS is the relatively low diagnostic yield of genetic testing. Monogenic models could not appropriately catch the complex interplay between ion channel dysfunction, pathological substrate, and acquired alterations (such as inflammation) in BrS. Recently, a polygenic risk score has been associated with worse outcomes in this population [59]. Further prospective studies are needed to validate the widespread use of these models in clinical practice.

9. Conclusions

Over the last twenty years, our knowledge of the pathophysiological mechanisms involved in BrS has dramatically increased, although many aspects still present significant areas of uncertainty. The emergent role of depolarization abnormalities together with the evidence of pathological voltages at EAM have suggested the presence of structural substrates in this condition. Novel echocardiographic and CMR techniques demonstrated the presence of subtle functional alterations in BrS. Histopathological and immunological data derived from serum and tissue samples of patients affected by BrS provided important information regarding the underlying disease substrate in terms of fibrosis, inflammatory processes, and the potential role of autoimmunity in this disease. Moreover, growing evidence of structural and functional similarities between BrS and AC has highlighted the continuous spectrum of pathological processes affecting the connexome complex. A better understanding of the pathological mechanisms involved in BrS pathogenesis could therefore improve prognostic evaluation. Moreover, the growing evidence of the role of inflammation and autoimmunity in this condition could potentially offer novel therapeutic strategies in BrS.

Author Contributions

Conceptualization, M.C. and M.P.; methodology, M.C. and M.P.; writing—original draft preparation, M.C., P.N., C.Z. and M.P.; writing—review and editing, M.C., P.N., C.Z., G.V., F.B., I.O. and M.P. All authors have read and agreed to the published version of the manuscript.

Funding

We did not receive any funding for this work.

Conflicts of Interest

We have no conflicts of interest to declare.

Abbreviations

The following abbreviations are used in this manuscript:
BrSBrugada syndrome
EPSElectrophysiological study
EAMElectroanatomic mapping
LPLate potential
SA-ECGSignal-average ECG
f-QRSFragmented QRS
RVRight ventricle
LVLeft ventricle
RVOTRight ventricular outflow tract
AVAtrioventricular block
VTVentricular tachycardia
VFVentricular fibrillation
PVSProgrammed ventricular stimulation
RIMPRight ventricular index of myocardial performance
RVEFRight ventricular ejection fraction
CMRCardiac magnetic resonance
LGELate gadolinium enhancement
RVOT-FTRight ventricular outflow tract-feature tracking
EMBEndomyocardial biopsy

References

  1. Brugada, P.; Brugada, J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: A distinct clinical and electrocardiographic syndrome. A multicenter report. J. Am. Coll. Cardiol. 1992, 20, 1391–1396. [Google Scholar] [CrossRef] [PubMed]
  2. Brugada, J.; Campuzano, O.; Arbelo, E.; Sarquella-Brugada, G.; Brugada, R. Present Status of Brugada Syndrome: JACC State-of-the-Art Review. J. Am. Coll. Cardiol. 2018, 72, 1046–1059. [Google Scholar] [CrossRef] [PubMed]
  3. Nademanee, K.; Veerakul, G.; Nimmannit, S.; Chaowakul, V.; Bhuripanyo, K.; Likittanasombat, K.; Tunsanga, K.; Kuasirikul, S.; Malasit, P.; Tansupasawadikul, S.; et al. Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men. Circulation 1997, 96, 2595–2600. [Google Scholar] [CrossRef] [PubMed]
  4. Zeppenfeld, K.; Tfelt-Hansen, J.; de Riva, M.; Winkel, B.G.; Behr, E.R.; Blom, N.A.; Charron, P.; Corrado, D.; Dagres, N.; de Chillou, C.; et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur. Heart J. 2022, 43, 3997–4126. [Google Scholar] [CrossRef]
  5. Wilde, A.A.; Postema, P.G.; Di Diego, J.M.; Viskin, S.; Morita, H.; Fish, J.M.; Antzelevitch, C. The pathophysiological mechanism underlying Brugada syndrome. Depolarization versus repolarization. J. Mol. Cell. Cardiol. 2010, 49, 543–553. [Google Scholar] [CrossRef]
  6. Sieira, J.; Dendramis, G.; Brugada, P. Pathogenesis and management of Brugada syndrome. Nat. Rev. Cardiol. 2016, 13, 744–756. [Google Scholar] [CrossRef]
  7. Chen, Q.; Kirsch, G.E.; Zhang, D.; Brugada, R.; Brugada, J.; Brugada, P.; Potenza, D.; Moya, A.; Borggrefe, M.; Breithardt, G.; et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998, 392, 293–296. [Google Scholar] [CrossRef]
  8. Sarquella-Brugada, G.; Campuzano, O.; Arbelo, E.; Brugada, J.; Brugada, R. Brugada syndrome: Clinical and genetic findings. Genet. Med. 2016, 18, 3–12. [Google Scholar] [CrossRef]
  9. Richards, S.; Aziz, N.; Bale, S.; Bick, D.; Das, S.; Gastier-Foster, J.; Grody, W.W.; Hegde, M.; Lyon, E.; Spector, E.; et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 2015, 17, 405–424. [Google Scholar] [CrossRef]
  10. Jordan, E.; Peterson, L.; Ai, T.; Asatryan, B.; Bronicki, L.; Brown, E.; Celeghin, R.; Edwards, M.; Fan, J.; Ingles, J.; et al. Evidence-Based Assessment of Genes in Dilated Cardiomyopathy. Circulation 2021, 144, 7–19. [Google Scholar] [CrossRef]
  11. Peters, S.; Thompson, B.A.; Perrin, M.; James, P.; Zentner, D.; Kalman, J.M.; Vandenberg, J.I.; Fatkin, D. Arrhythmic Phenotypes Are a Defining Feature of Dilated Cardiomyopathy-Associated SCN5A Variants: A Systematic Review. Circ. Genomic Precis. Med. 2022, 15, E003432. [Google Scholar] [CrossRef] [PubMed]
  12. Nademanee, K.; Veerakul, G.; Chandanamattha, P.; Chaothawee, L.; Ariyachaipanich, A.; Jirasirirojanakorn, K.; Likittanasombat, K.; Bhuripanyo, K.; Ngarmukos, T. Prevention of ventricular fibrillation episodes in brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation 2011, 123, 1270–1279. [Google Scholar] [CrossRef]
  13. Letsas, K.P.; Efremidis, M.; Asvestas, D.; Vlachos, K.; Georgopoulos, S.; Tse, G.; Liu, T.; Bazoukis, G.; Sideris, A.; Baranchuk, A.; et al. Right Ventricular Outflow Tract Electroanatomical Abnormalities Predict Ventricular Fibrillation Inducibility in Brugada Syndrome. Circ. Arrhythm. Electrophysiol. 2018, 11, e005928. [Google Scholar] [CrossRef]
  14. Frustaci, A.; Priori, S.G.; Pieroni, M.; Chimenti, C.; Napolitano, C.; Rivolta, I.; Sanna, T.; Bellocci, F.; Russo, M.A. Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome. Circulation 2005, 112, 3680–3687. [Google Scholar] [CrossRef]
  15. Nademanee, K.; Raju, H.; De Noronha, S.V.; Papadakis, M.; Robinson, L.; Rothery, S.; Makita, N.; Kowase, S.; Boonmee, N.; Vitayakritsirikul, V.; et al. Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome. J. Am. Coll. Cardiol. 2015, 66, 1976–1986. [Google Scholar] [CrossRef]
  16. Pieroni, M.; Notarstefano, P.; Oliva, A.; Campuzano, O.; Santangeli, P.; Coll, M.; Nesti, M.; Carnevali, A.; Fraticelli, A.; Iglesias, A.; et al. Electroanatomic and Pathologic Right Ventricular Outflow Tract Abnormalities in Patients With Brugada Syndrome. J. Am. Coll. Cardiol. 2018, 72, 2747–2757. [Google Scholar] [CrossRef]
  17. Mitroi, C.; García-Izquierdo, E.; García-Lunar, I.; Castro-Urda, V.; Toquero-Ramos, J.; Moñivas-Palomero, V.; Mingo-Santos, S.; Cavero, M.A.; Brugada, J.; Fernández-Lozano, I. Right ventricular function and dyssynchrony in Brugada syndrome: Highlighting the importance of the mechanical substrate in the right ventricular outflow tract. Int. J. Cardiol. 2021, 333, 233–238. [Google Scholar] [CrossRef]
  18. Pappone, C.; Santinelli, V.; Mecarocci, V.; Tondi, L.; Ciconte, G.; Manguso, F.; Sturla, F.; Vicedomini, G.; Micaglio, E.; Anastasia, L.; et al. Brugada Syndrome: New Insights From Cardiac Magnetic Resonance and Electroanatomical Imaging. Circ. Arrhythm. Electrophysiol. 2021, 14, E010004. [Google Scholar] [CrossRef]
  19. Moncayo-Arlandi, J.; Brugada, R. Unmasking the molecular link between arrhythmogenic cardiomyopathy and Brugada syndrome. Nat. Rev. Cardiol. 2017, 14, 744–756. [Google Scholar] [CrossRef]
  20. Ben-Haim, Y.; Asimaki, A.; Behr, E.R. Brugada syndrome and arrhythmogenic cardiomyopathy: Overlapping disorders of the connexome? Europace 2021, 23, 653–664. [Google Scholar] [CrossRef]
  21. Priori, S.G.; Wilde, A.A.; Horie, M.; Cho, Y.; Behr, E.R.; Berul, C.; Blom, N.; Brugada, J.; Chiang, C.E.; Huikuri, H.; et al. HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes: Document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013, 10, 1932–1963. [Google Scholar] [CrossRef] [PubMed]
  22. Saura, D.; García-Alberola, A.; Carrillo, P.; Pascual, D.; Martínez-Sánchez, J.; Valdés, M. Brugada-like electrocardiographic pattern induced by fever. Pacing Clin. Electrophysiol. 2002, 25, 856–859. [Google Scholar] [CrossRef] [PubMed]
  23. Kawada, S.; Morita, H.; Antzelevitch, C.; Morimoto, Y.; Nakagawa, K.; Watanabe, A.; Nishii, N.; Nakamura, K.; Ito, H. Shanghai Score System for Diagnosis of Brugada Syndrome: Validation of the Score System and System and Reclassification of the Patients. JACC Clin. Electrophysiol. 2018, 4, 724–730. [Google Scholar] [CrossRef] [PubMed]
  24. Yan, G.X.; Antzelevitch, C. Cellular basis for the electrocardiographic J wave. Circulation 1996, 93, 372–379. [Google Scholar] [CrossRef]
  25. Szél, T.; Antzelevitch, C. Abnormal repolarization as the basis for late potentials and fractionated electrograms recorded from epicardium in experimental models of brugada syndrome. J. Am. Coll. Cardiol. 2014, 63, 2037–2045. [Google Scholar] [CrossRef]
  26. Behr, E.R.; Ben-Haim, Y.; Ackerman, M.J.; Krahn, A.D.; Wilde, A.A.M. Brugada syndrome and reduced right ventricular outflow tract conduction reserve: A final common pathway? Eur. Heart J. 2021, 42, 1073–1081. [Google Scholar] [CrossRef]
  27. Gaita, F.; Cerrato, N.; Giustetto, C.; Martino, A.; Bergamasco, L.; Millesimo, M.; Barbonaglia, L.; Carvalho, P.; Caponi, D.; Saglietto, A.; et al. Asymptomatic Patients With Brugada ECG Pattern: Long-Term Prognosis From a Large Prospective Study. Circulation 2023, 148, 1543–1555. [Google Scholar] [CrossRef]
  28. Nakano, Y.; Shimizu, W.; Ogi, H.; Suenari, K.; Oda, N.; Makita, Y.; Kajihara, K.; Hirai, Y.; Sairaku, A.; Tokuyama, T.; et al. A spontaneous Type 1 electrocardiogram pattern in lead V2 is an independent predictor of ventricular fibrillation in Brugada syndrome. Europace 2010, 12, 410–416. [Google Scholar] [CrossRef]
  29. Sarkozy, A.; Chierchia, G.B.; Paparella, G.; Boussy, T.; De Asmundis, C.; Roos, M.; Henkens, S.; Kaufman, L.; Buyl, R.; Brugada, R.; et al. Inferior and lateral electrocardiographic repolarization abnormalities in brugada syndrome. Circ. Arrhythm. Electrophysiol. 2009, 2, 154–161. [Google Scholar] [CrossRef]
  30. Kamakura, S.; Ohe, T.; Nakazawa, K.; Aizawa, Y.; Shimizu, A.; Horie, M.; Ogawa, S.; Okumura, K.; Tsuchihashi, K.; Sugi, K.; et al. Long-term prognosis of probands with brugada-pattern ST-elevation in leads V 1-V 3. Circ. Arrhythm. Electrophysiol. 2009, 2, 495–503. [Google Scholar] [CrossRef]
  31. Kawata, H.; Morita, H.; Yamada, Y.; Noda, T.; Satomi, K.; Aiba, T.; Isobe, M.; Nagase, S.; Nakamura, K.; Kusano, K.F.; et al. Prognostic significance of early repolarization in inferolateral leads in Brugada patients with documented ventricular fibrillation: A novel risk factor for Brugada syndrome with ventricular fibrillation. Heart Rhythm 2013, 10, 1161–1168. [Google Scholar] [CrossRef] [PubMed]
  32. Castro Hevia, J.; Antzelevitch, C.; Tornés Bárzaga, F.; Dorantes Sánchez, M.; Dorticós Balea, F.; Zayas Molina, R.; Quiñones Pérez, M.A.; Fayad Rodríguez, Y. Tpeak-Tend and Tpeak-Tend Dispersion as Risk Factors for Ventricular Tachycardia/Ventricular Fibrillation in Patients With the Brugada Syndrome. J. Am. Coll. Cardiol. 2006, 47, 1828–1834. [Google Scholar] [CrossRef] [PubMed]
  33. Nagase, S.; Kataoka, N.; Morita, H.; Kamakura, T.; Ueoka, A.; Nakamura, T.; Oka, S.; Miyazaki, Y.; Wakamiya, A.; Nakajima, K.; et al. Demonstration of Arrhythmia Substrate-Associated Dispersion of Repolarization by Epicardial Unipolar Mapping in Brugada Syndrome. JACC Clin. Electrophysiol. 2024, 10, 1576–1588. [Google Scholar] [CrossRef]
  34. Tada, T.; Kusano, K.F.; Nagase, S.; Banba, K.; Miura, D.; Nishii, N.; Watanabe, A.; Nakamura, K.; Morita, H.; Ohe, T. Clinical significance of macroscopic T-wave alternans after sodium channel blocker administration in patients with Brugada syndrome. J. Cardiovasc. Electrophysiol. 2008, 19, 56–61. [Google Scholar] [CrossRef]
  35. Ikeda, T.; Sakurada, H.; Sakabe, K.; Sakata, T.; Takami, M.; Tezuka, N.; Nakae, T.; Noro, M.; Enjoji, Y.; Tejima, T.; et al. Assessment of Noninvasive Markers in Identifying Patients at Risk in the Brugada Syndrome: Insight Into Risk Stratification. J. Am. Coll. Cardiol. 2001, 37, 1628–1634. [Google Scholar] [CrossRef]
  36. Takagi, M.; Yokoyama, Y.; Aonuma, K.; Aihara, N.; Hiraoka, M. Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with Brugada syndrome: Multicenter study in Japan. J. Cardiovasc. Electrophysiol. 2007, 18, 1244–1251. [Google Scholar] [CrossRef]
  37. Junttila, M.J.; Brugada, P.; Hong, K.; Lizotte, E.; DEZutter, M.; Sarkozy, A.; Brugada, J.; Benito, B.; Perkiomaki, J.S.; Mäkikallio, T.H.; et al. Differences in 12-lead electrocardiogram between symptomatic and asymptomatic Brugada syndrome patients. J. Cardiovasc. Electrophysiol. 2008, 19, 380–383. [Google Scholar] [CrossRef]
  38. Morita, H.; Kusano, K.F.; Miura, D.; Nagase, S.; Nakamura, K.; Morita, S.T.; Ohe, T.; Zipes, D.P.; Wu, J. Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome. Circulation 2008, 118, 1697–1704. [Google Scholar] [CrossRef]
  39. Morita, H.; Watanabe, A.; Kawada, S.; Miyamoto, M.; Morimoto, Y.; Nakagawa, K.; Nishii, N.; Nakamura, K.; Ito, H. Identification of electrocardiographic risk markers for the initial and recurrent episodes of ventricular fibrillation in patients with Brugada syndrome. J. Cardiovasc. Electrophysiol. 2018, 29, 107–114. [Google Scholar] [CrossRef]
  40. Babai Bigi, M.A.; Aslani, A.; Shahrzad, S. aVR sign as a risk factor for life-threatening arrhythmic events in patients with Brugada syndrome. Heart Rhythm 2007, 4, 1009–1012. [Google Scholar] [CrossRef]
  41. Calò, L.; Giustetto, C.; Martino, A.; Sciarra, L.; Cerrato, N.; Marziali, M.; Rauzino, J.; Carlino, G.; de Ruvo, E.; Guerra, F.; et al. A New Electrocardiographic Marker of Sudden Death in Brugada Syndrome The S-Wave in Lead I. J. Am. Coll. Cardiol. 2016, 67, 1427–1440. [Google Scholar] [CrossRef] [PubMed]
  42. Ragab, A.A.Y.; Houck, C.A.; van der Does, L.J.M.E.; Lanters, E.A.H.; Muskens, A.J.Q.M.; de Groot, N.M.S. Prediction of ventricular tachyarrhythmia in Brugada syndrome by right ventricular outflow tract conduction delay signs. J. Cardiovasc. Electrophysiol. 2018, 29, 998–1003. [Google Scholar] [CrossRef] [PubMed]
  43. Sroubek, J.; Probst, V.; Mazzanti, A.; Delise, P.; Hevia, J.C.; Ohkubo, K.; Zorzi, A.; Champagne, J.; Kostopoulou, A.; Yin, X.; et al. Programmed ventricular stimulation for risk stratification in the Brugada syndrome: A pooled analysis. Circulation. 2016, 133, 622–630. [Google Scholar] [CrossRef]
  44. Pappone, C.; Ciconte, G.; Manguso, F.; Vicedomini, G.; Mecarocci, V.; Conti, M.; Giannelli, L.; Pozzi, P.; Borrelli, V.; Menicanti, L.; et al. Assessing the Malignant Ventricular Arrhythmic Substrate in Patients With Brugada Syndrome. J. Am. Coll. Cardiol. 2018, 71, 1631–1646. [Google Scholar] [CrossRef]
  45. Alings, M.; Wilde, A. “Brugada” syndrome: Clinical data and suggested pathophysiological mechanism. Circulation 1999, 99, 666–673. [Google Scholar] [CrossRef]
  46. Smits, J.P.; Eckardt, L.; Probst, V.; Bezzina, C.R.; Schott, J.J.; Remme, C.A.; Haverkamp, W.; Breithardt, G.; Escande, D.; Schulze-Bahr, E.; et al. Genotype-phenotype relationship in Brugada syndrome: Electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. J. Am. Coll. Cardiol. 2002, 40, 350–356. [Google Scholar] [CrossRef]
  47. Lambiase, P.D.; Ahmed, A.K.; Ciaccio, E.J.; Brugada, R.; Lizotte, E.; Chaubey, S.; Ben-Simon, R.; Chow, A.W.; Lowe, M.D.; McKenna, W.J. High-density substrate mapping in brugada syndrome: Combined role of conduction and repolarization heterogeneities in arrhythmogenesis. Circulation 2009, 120, 106–117. [Google Scholar] [CrossRef]
  48. Maury, P.; Rollin, A.; Sacher, F.; Gourraud, J.B.; Raczka, F.; Pasquié, J.L.; Duparc, A.; Mondoly, P.; Cardin, C.; Delay, M.; et al. Prevalence and prognostic role of various conduction disturbances in patients with the brugada syndrome. Am. J. Cardiol. 2013, 112, 1384–1389. [Google Scholar] [CrossRef]
  49. Migliore, F.; Testolina, M.; Zorzi, A.; Bertaglia, E.; Silvano, M.; Leoni, L.; Bellin, A.; Basso, C.; Thiene, G.; Allocca, G.; et al. First-degree atrioventricular block on basal electrocardiogram predicts future arrhythmic events in patients with Brugada syndrome: A long-term follow-up study from the Veneto region of Northeastern Italy. Europace 2019, 21, 322–331. [Google Scholar] [CrossRef]
  50. Rossi, A.; Giannoni, A.; Nesti, M.; Notarstefano, P.; Castiglione, V.; Solarino, G.; Teresi, L.; Mirizzi, G.; Russo, V.; Panchetti, L.; et al. Prognostic value of right ventricular refractory period heterogeneity in Type-1 Brugada electrocardiographic pattern. Europace 2023, 25, 651–659. [Google Scholar] [CrossRef]
  51. Priori, S.G.; Gasparini, M.; Napolitano, C.; Della Bella, P.; Ottonelli, A.G.; Sassone, B.; Giordano, U.; Pappone, C.; Mascioli, G.; Rossetti, G.; et al. Risk stratification in brugada syndrome: Results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) registry. J. Am. Coll. Cardiol. 2012, 59, 37–45. [Google Scholar] [CrossRef] [PubMed]
  52. Scheirlynck, E.; Van Malderen, S.; Motoc, A.; Lie, Ø.H.; de Asmundis, C.; Sieira, J.; Chierchia, G.B.; Brugada, P.; Cosyns, B.; Droogmans, S. Contraction alterations in Brugada syndrome; association with life-threatening ventricular arrhythmias. Int. J. Cardiol. 2020, 299, 147–152. [Google Scholar] [CrossRef] [PubMed]
  53. Pappone, C.; Mecarocci, V.; Manguso, F.; Ciconte, G.; Vicedomini, G.; Sturla, F.; Votta, E.; Mazza, B.; Pozzi, P.; Borrelli, V.; et al. New electromechanical substrate abnormalities in high-risk patients with Brugada syndrome. Heart Rhythm 2020, 17, 637–645. [Google Scholar] [CrossRef] [PubMed]
  54. Catalano, O.; Antonaci, S.; Moro, G.; Mussida, M.; Frascaroli, M.; Baldi, M.; Cobelli, F.; Baiardi, P.; Nastoli, J.; Bloise, R.; et al. Magnetic resonance investigations in Brugada syndrome reveal unexpectedly high rate of structural abnormalities. Eur. Heart J. 2009, 30, 2241–2248. [Google Scholar] [CrossRef]
  55. Van Hoorn, F.; Campian, M.E.; Spijkerboer, A.; Blom, M.T.; Planken, R.N.; van Rossum, A.C.; de Bakker, J.M.; Wilde, A.A.; Groenink, M.; Tan, H.L. Scn5a mutations in brugada syndrome are associated with increased cardiac dimensions and reduced contractility. PLoS ONE 2012, 7, e42037. [Google Scholar] [CrossRef]
  56. Gray, B.; Gnanappa, G.K.; Bagnall, R.D.; Femia, G.; Yeates, L.; Ingles, J.; Burns, C.; Puranik, R.; Grieve, S.M.; Semsarian, C.; et al. Relations between right ventricular morphology and clinical, electrical and genetic parameters in Brugada Syndrome. PLoS ONE 2018, 13, e0195594. [Google Scholar] [CrossRef]
  57. Bastiaenen, R.; Cox, A.T.; Castelletti, S.; Wijeyeratne, Y.D.; Colbeck, N.; Pakroo, N.; Ahmed, H.; Bunce, N.; Anderson, L.; Moon, J.C.; et al. Late gadolinium enhancement in Brugada syndrome: A marker for subtle underlying cardiomyopathy? Heart Rhythm 2017, 14, 583–589. [Google Scholar] [CrossRef]
  58. Isbister, J.C.; Gray, B.; Offen, S.; Yeates, L.; Naoum, C.; Medi, C.; Raju, H.; Semsarian, C.; Puranik, R.; Sy, R.W. Longitudinal assessment of structural phenotype in Brugada syndrome using cardiac magnetic resonance imaging. Heart Rhythm O2 2023, 4, 34–41. [Google Scholar] [CrossRef]
  59. Kukavica, D.; Trancuccio, A.; Mazzanti, A.; Napolitano, C.; Morini, M.; Pili, G.; Memmi, M.; Gambelli, P.; Bloise, R.; Nastoli, J.; et al. Nonmodifiable Risk Factors Predict Outcomes in Brugada Syndrome. J. Am. Coll. Cardiol. 2024, 84, 2087–2098. [Google Scholar] [CrossRef]
  60. Nademanee, K.; Chung, F.P.; Sacher, F.; Nogami, A.; Nakagawa, H.; Jiang, C.; Hocini, M.; Behr, E.; Veerakul, G.; Jan Smit, J.; et al. Long-Term Outcomes of Brugada Substrate Ablation: A Report from BRAVO (Brugada Ablation of VF Substrate Ongoing Multicenter Registry). Circulation 2023, 147, 1568–1578. [Google Scholar] [CrossRef]
  61. Marra, M.P.; Leoni, L.; Bauce, B.; Corbetti, F.; Zorzi, A.; Migliore, F.; Silvano, M.; Rigato, I.; Tona, F.; Tarantini, G.; et al. Imaging study of ventricular scar in arrhythmogenic right ventricular cardiomyopathy comparison of 3d standard electroanatomical voltage mapping and contrast-enhanced cardiac magnetic resonance. Circ. Arrhythm. Electrophysiol. 2012, 5, 91–100. [Google Scholar] [CrossRef] [PubMed]
  62. Casella, M.; Dello Russo, A.; Bergonti, M.; Catto, V.; Conte, E.; Sommariva, E.; Gasperetti, A.; Vettor, G.; Tundo, F.; Sicuso, R.; et al. Diagnostic Yield of Electroanatomic Voltage Mapping in Guiding Endomyocardial Biopsies. Circulation 2020, 142, 1249–1260. [Google Scholar] [CrossRef] [PubMed]
  63. Brugada, J.; Pappone, C.; Berruezo, A.; Vicedomini, G.; Manguso, F.; Ciconte, G.; Giannelli, L.; Santinelli, V. Brugada Syndrome Phenotype Elimination by Epicardial Substrate Ablation. Circ. Arrhythm. Electrophysiol. 2015, 8, 1373–1381. [Google Scholar] [CrossRef]
  64. Pappone, C.; Brugada, J.; Vicedomini, G.; Ciconte, G.; Manguso, F.; Saviano, M.; Vitale, R.; Cuko, A.; Giannelli, L.; Calovic, Z.; et al. Electrical Substrate Elimination in 135 Consecutive Patients with Brugada Syndrome. Circ. Arrhythm. Electrophysiol. 2017, 10, e005053. [Google Scholar] [CrossRef]
  65. Talib, A.K.; Takagi, M.; Shimane, A.; Nakano, M.; Hayashi, T.; Okajima, K.; Kentaro, M.; Fukada, K.; Kowase, S.; Kurosaki, K.; et al. Efficacy of Endocardial Ablation of Drug-Resistant Ventricular Fibrillation in Brugada Syndrome. Circ. Arrhythm. Electrophysiol. 2018, 11, e005631. [Google Scholar] [CrossRef]
  66. Cheniti, G.; Haissaguerre, M.; Dina, C.; Kamakura, T.; Duchateau, J.; Sacher, F.; Racine, H.P.; Surget, E.; Simonet, F.; Gourraud, J.B.; et al. Left Ventricular Abnormal Substrate in Brugada Syndrome. JACC Clin. Electrophysiol. 2023, 9, 2041–2051. [Google Scholar] [CrossRef]
  67. Coronel, R.; Casini, S.; Koopmann, T.T.; Wilms-Schopman, F.J.; Verkerk, A.O.; de Groot, J.R.; Bhuiyan, Z.; Bezzina, C.R.; Veldkamp, M.W.; Linnenbank, A.C.; et al. Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: A combined electrophysiological, genetic, histopathologic, and computational study. Circulation 2005, 112, 2769–2777. [Google Scholar] [CrossRef]
  68. Santangeli, P.; Hamilton-Craig, C.; Dello Russo, A.; Pieroni, M.; Casella, M.; Pelargonio, G.; Di Biase, L.; Smaldone, C.; Bartoletti, S.; Narducci, M.L.; et al. Imaging of scar in patients with ventricular arrhythmias of right ventricular origin: Cardiac magnetic resonance versus electroanatomic mapping. J. Cardiovasc. Electrophysiol. 2011, 22, 1359–1366. [Google Scholar] [CrossRef]
  69. Chatterjee, D.; Pieroni, M.; Fatah, M.; Charpentier, F.; Cunningham, K.S.; Spears, D.A.; Chatterjee, D.; Suna, G.; Bos, J.M.; Ackerman, M.J.; et al. An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins. Eur. Heart J. 2020, 41, 2878–2890. [Google Scholar] [CrossRef]
  70. Corrado, D.; van Tintelen, P.J.; McKenna, W.J.; Hauer, R.N.W.; Anastastakis, A.; Asimaki, A.; Basso, C.; Bauce, B.; Brunckhorst, C.; Bucciarelli-Ducci, C.; et al. Arrhythmogenic right ventricular cardiomyopathy: Evaluation of the current diagnostic criteria differential diagnosis. Eur. Heart J. 2020, 41, 1414–1427. [Google Scholar] [CrossRef]
  71. Del Franco, A.; Ruggieri, R.; Pieroni, M.; Ciabatti, M.; Zocchi, C.; Biagioni, G.; Tavanti, V.; Del Pace, S.; Leone, O.; Favale, S.; et al. Atlas of Regional Left Ventricular Scar in Nonischemic Cardiomyopathies: Substrates and Etiologies. JACC Adv. 2024, 3, 101214. [Google Scholar] [CrossRef] [PubMed]
  72. Santangeli, P.; Dello Russo, A.; Pieroni, M.; Casella, M.; Di Biase, L.; Burkhardt, J.D.; Sanchez, J.; Lakkireddy, D.; Carbucicchio, C.; Zucchetti, M.; et al. Fragmented and delayed electrograms within fibrofatty scar predict arrhythmic events in arrhythmogenic right ventricular cardiomyopathy: Results from a prospective risk stratification study. Heart Rhythm 2012, 9, 1200–1206. [Google Scholar] [CrossRef] [PubMed]
  73. Marcus, F.I.; McKenna, W.J.; Sherrill, D.; Basso, C.; Bauce, B.; Bluemke, D.A.; Calkins, H.; Corrado, D.; Cox, M.G.; Daubert, J.P.; et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/Dysplasia: Proposed modification of the task force criteria. Circulation 2010, 121, 1533–1541. [Google Scholar] [CrossRef]
  74. Santangeli, P.; Pieroni, M.; Dello Russo, A.; Casella, M.; Pelargonio, G.; Macchione, A.; Camporeale, A.; Smaldone, C.; Bartoletti, S.; Di Biase, L.; et al. Noninvasive diagnosis of electroanatomic abnormalities in arrhythmogenic right ventricular cardiomyopathy. Circ. Arrhythm. Electrophysiol. 2010, 3, 632–638. [Google Scholar] [CrossRef] [PubMed]
  75. Corrado, D.; Nava, A.; Buja, G.; Martini, B.; Fasoli, G.; Oselladore, L.; Turrini, P.; Thiene, G. Familial cardiomyopathy underlies syndrome of right bundle branch block, ST segment elevation and sudden death. J. Am. Coll. Cardiol. 1996, 27, 443–448. [Google Scholar] [CrossRef]
  76. Corrado, D.; Basso, C.; Buja, G.; Nava, A.; Rossi, L.; Thiene, G. Right bundle branch block, right precordial st-segment elevation, and sudden death in young people. Circulation 2001, 103, 710–717. [Google Scholar] [CrossRef]
  77. Letsas, K.P.; Efremidis, M.; Weber, R.; Korantzopoulos, P.; Protonotarios, N.; Prappa, E.; Kounas, S.P.; Evagelidou, E.N.; Xydonas, S.; Kalusche, D.; et al. Epsilon-like waves and ventricular conduction abnormalities in subjects with type 1 ECG pattern of Brugada syndrome. Heart Rhythm 2011, 8, 874–878. [Google Scholar] [CrossRef]
  78. Wilde, A.A.M.; Amin, A.S. Clinical Spectrum of SCN5A Mutations: Long QT Syndrome, Brugada Syndrome, and Cardiomyopathy. JACC Clin. Electrophysiol. 2018, 4, 569–579. [Google Scholar] [CrossRef]
  79. Gerull, B.; Brodehl, A. Insights Into Genetics and Pathophysiology of Arrhythmogenic Cardiomyopathy. Curr. Heart Fail. Rep. 2021, 18, 378–390. [Google Scholar] [CrossRef]
  80. Agullo-Pascual, E.; Cerrone, M.; Delmar, M. Arrhythmogenic cardiomyopathy and Brugada syndrome: Diseases of the connexome. FEBS Lett. 2014, 588, 1322–1330. [Google Scholar] [CrossRef]
  81. Brodehl, A.; Weiss, J.; Debus, J.D.; Stanasiuk, C.; Klauke, B.; Deutsch, M.A.; Fox, H.; Bax, J.; Ebbinghaus, H.; Gärtner, A.; et al. A homozygous DSC2 deletion associated with arrhythmogenic cardiomyopathy is caused by uniparental isodisomy. J. Mol. Cell. Cardiol. 2020, 141, 17–29. [Google Scholar] [CrossRef] [PubMed]
  82. Brodehl, A.; Meshkov, A.; Myasnikov, R.; Kiseleva, A.; Kulikova, O.; Klauke, B.; Sotnikova, E.; Stanasiuk, C.; Divashuk, M.; Pohl, G.M.; et al. Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset. Int. J. Mol. Sci. 2021, 22, 3786. [Google Scholar] [CrossRef]
  83. Iacoviello, M.; Forleo, C.; Puzzovivo, A.; Nalin, I.; Guida, P.; Anaclerio, M.; Marangelli, V.; Sorrentino, S.; Monitillo, F.; Ciccone, M.M.; et al. Altered two-dimensional strain measures of the right ventricle in patients with Brugada syndrome and arrhythmogenic right ventricular dysplasia/cardiomyopathy. Eur. J. Echocardiogr. 2011, 12, 773–781. [Google Scholar] [CrossRef]
  84. Heermann, P.; Fritsch, H.; Koopmann, M.; Sporns, P.; Paul, M.; Heindel, W.; Schulze-Bahr, E.; Schülke, C. Biventricular myocardial strain analysis using cardiac magnetic resonance feature tracking (CMR-FT) in patients with distinct types of right ventricular diseases comparing arrhythmogenic right ventricular cardiomyopathy (ARVC), right ventricular outflow-tract tachycardia (RVOT-VT), and Brugada syndrome (BrS). Clinical Research in Cardiology. Clin. Res. Cardiol. 2019, 108, 1147–1162. [Google Scholar] [CrossRef]
  85. Bariani, R.; Cipriani, A.; Rizzo, S.; Celeghin, R.; Bueno Marinas, M.; Giorgi, B.; De Gaspari, M.; Rigato, I.; Leoni, L.; Zorzi, A.; et al. “Hot phase” clinical presentation in arrhythmogenic cardiomyopathy. Europace 2021, 23, 907–917. [Google Scholar] [CrossRef]
  86. Peretto, G.; Casella, M.; Merlo, M.; Benedetti, S.; Rizzo, S.; Cappelletto, C.; Di Resta, C.; Compagnucci, P.; De Gaspari, M.; Dello Russo, A.; et al. Inflammation on Endomyocardial Biopsy Predicts Risk of MACE in Undefined Left Ventricular Arrhythmogenic Cardiomyopathy. JACC Clin. Electrophysiol. 2023, 9, 951–961. [Google Scholar] [CrossRef]
  87. Caforio, A.L.P.; Re, F.; Avella, A.; Marcolongo, R.; Baratta, P.; Seguso, M.; Gallo, N.; Plebani, M.; Izquierdo-Bajo, A.; Cheng, C.Y.; et al. Evidence from Family Studies for Autoimmunity in Arrhythmogenic Right Ventricular Cardiomyopathy: Associations of Circulating Anti-Heart and Anti-Intercalated Disk Autoantibodies with Disease Severity and Family History. Circulation 2020, 141, 1238–1248. [Google Scholar] [CrossRef]
  88. Bassetto, G.; Angriman, F.; Gava, C.P.L.D.; Paldino, A.; Perotto, M.; Bordignon, L.; Gigli, M.; Ferro, M.D.; Massa, L.; Altinier, A.; et al. Hot Phases Cardiomyopathy: Pathophysiology, Diagnostic Challenges, and Emerging Therapies. Curr. Cardiol. Rep. 2025, 27, 11. [Google Scholar] [CrossRef]
  89. McColl, H.; Cordina, R.; Lal, S.; Parker, M.; Hunyor, I.; Medi, C.; Gray, B. Recurrent immunosuppressive-responsive myocarditis in a patient with desmoplakin cardiomyopathy: A case report. Eur. Heart J. Case Rep. 2024, 8, ytae129. [Google Scholar] [CrossRef]
  90. Kuroki, K.; Yamamoto, M.; Sato, A. Successful treatment of life-threatening giant cell myocarditis in a patient with Brugada syndrome, controlled through dual ablation procedures and immunosuppressive therapy. Eur. Heart J. Cardiovasc. Imaging 2024, 25, E97. [Google Scholar] [CrossRef]
  91. Peretto, G.; De Luca, G.; Villatore, A.; Di Resta, C.; Sala, S.; Palmisano, A.; Vignale, D.; Campochiaro, C.; Lazzeroni, D.; De Gaspari, M.; et al. Multimodal Detection and Targeting of Biopsy-Proven Myocardial Inflammation in Genetic Cardiomyopathies: A Pilot Report. JACC Basic Transl. Sci. 2023, 8, 755–765. [Google Scholar] [CrossRef] [PubMed]
  92. Li, A.; Tung, R.; Shivkumar, K.; Bradfield, J.S. Brugada syndrome—Malignant phenotype associated with acute cardiac inflammation? HeartRhythm Case Rep. 2017, 3, 384–388. [Google Scholar] [CrossRef] [PubMed]
Cardiogenetics 15 00017 g002
Figure 2. (A): ECG of 30-year-old male presenting spontaneous type 1 BrS pattern, first degree AV block, and rightward axis deviation [27,28,48,49]. (B): Unipolar electroanatomic mapping demonstrated the presence of pathological voltages in the anterior RVOT. (C): Presence of abnormal voltages in bipolar mapping [13,16,44]. BrS, Brugada syndrome; AV, atrioventricular; RVOT, right ventricular outflow tract.
Figure 2. (A): ECG of 30-year-old male presenting spontaneous type 1 BrS pattern, first degree AV block, and rightward axis deviation [27,28,48,49]. (B): Unipolar electroanatomic mapping demonstrated the presence of pathological voltages in the anterior RVOT. (C): Presence of abnormal voltages in bipolar mapping [13,16,44]. BrS, Brugada syndrome; AV, atrioventricular; RVOT, right ventricular outflow tract.
Cardiogenetics 15 00017 g002
Table 1. Clinical, genetic, ECG, and imaging characteristics associated with adverse outcomes.
Table 1. Clinical, genetic, ECG, and imaging characteristics associated with adverse outcomes.
Clinical and Genetic VariablesECGImagingEPS
Elevates Shanghai score values [23]
Family history of SCD [30,41]
Unexplained syncope [43,48,49,51,59]
Missense SCN5A mutations in BrS-enriched domains [59]
Polygenic risk score for BrS [59]		Spontaneous type 1 Brugada pattern [27,28,43,48,49,51,59]
LPs on SAE-ECG [35,36]
Increased QRS duration [37,38]
Fragmented QRS [39,40,43]
Tpeak to Tend [33,40]
Early repolarization pattern in inferolateral leads [30,31,39]
Tall R wave in aVR [40]
S-wave duration in lead I ≥ 40 ms [41]
Atrial fibrillation [41]
Deep S waves in lead I [42]
S in lead II > S in lead III [42]
Positive Tzou criteria [42]
Atrioventricular block [48,49]
TWA during sodium channels blocker infusion [34]		Increased RV index of myocardial performance [17]
Reduced RVOT values on STE [17]
Increased RVMD on STE [17]
Increased LVMD on STE [52]
RV dysfunction on three-dimensional echocardiography [53]		VT/VF inducibility during EPS [27,41,43]
Reduced RV refractory period [51]
Heterogenous RV refractory period [50]
Persistence of BrS pattern after RVOT ablation [60]
SCD, sudden cardiac death; BrS, Brugada syndrome; LP, late potential; SAE-ECG, signal-averaged ECG; TWA, T wave alternans; RV, right ventricle; RVOT, right ventricular outflow tract; RVMD, right ventricular mechanical dispersion; LVMD, left ventricular mechanical dispersion; STE, speckle tracking echocardiography; VT, ventricular tachycardia; VF, ventricular fibrillation; EPS, electrophysiological study.
Table 2. Histopathological studies in patients with Brugada syndrome.
Table 2. Histopathological studies in patients with Brugada syndrome.
StudyPopulation DesignPathological FindingsNotes
Coronel et al. [67]1 BrS patient undergoing heart transplantation due to refractory electrical storm.Histopathological and electrophysiological evaluation of the explanted heart.Presence of fibrous and fatty infiltrations in RV and RVOT. Presence of conduction delay in RVOT at electrophysiological study.
Frustaci et al. [14]18 BrS patients suffering arrhythmic events. Biventricular angiography and EMBs. Activated T lymphocytes and necrosis in 14/18 patients. Myocyte vacuolization and fibrofatty replacement in 3/18 subjects. Presence of viral genome in 28% of subjects.
Evidence of microaneurysm in the RV and LV (7 and 4 subjects, respectively) at angiography.
Nademanee et al. [15]6 BrS patients suffering SCD and 6 BrS subjects undergoing surgical epicardial RVOT ablation. Histopathological evaluation of the explanted heart. RVOT mapping and biopsies in patients undergoing surgical ablation. Increased fibrosis and collagen in the RVOT. Reduced Cx43 expression in BrS patients. Presence of delayed, prolonged and fragmented QRS on RVOT epicardial electrocardiogram in patients undergoing ablation.
Pieroni et al. [16]30 BrS patients (37% of them symptomatic). 30 BrS patients underwent EPS and endocardial RV EAM.
20/30 subjects underwent EAM-guided EMB.		Activated T lymphocytes infiltrate in 12/20 subjects and myocyte necrosis in 3 of them. Interstitial fibrosis and replacement necrosis in 15/20 patients. Patients with inflammation at EMB presented higher rates of VF inducibility and more extensive bipolar abnormalities at EAM.
BrS, Brugada syndrome; RV, right ventricle; RVOT, right ventricular outflow tract; EMB, endomyocardial biopsy; LV, left ventricle: SCD, sudden cardiac death; Cx43, connexin-43; EPS, electrophysiological study; VF, ventricular fibrillation; EAM, electroanatomic mapping.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Ciabatti, M.; Notarstefano, P.; Zocchi, C.; Virgili, G.; Bellocci, F.; Olivotto, I.; Pieroni, M. Brugada Syndrome: Channelopathy and/or Cardiomyopathy. Cardiogenetics 2025, 15, 17. https://doi.org/10.3390/cardiogenetics15020017

AMA Style

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. https://doi.org/10.3390/cardiogenetics15020017

Chicago/Turabian Style

Ciabatti, Michele, Pasquale Notarstefano, Chiara Zocchi, Giacomo Virgili, Fulvio Bellocci, Iacopo Olivotto, and Maurizio Pieroni. 2025. "Brugada Syndrome: Channelopathy and/or Cardiomyopathy" Cardiogenetics 15, no. 2: 17. https://doi.org/10.3390/cardiogenetics15020017

APA Style

Ciabatti, M., Notarstefano, P., Zocchi, C., Virgili, G., Bellocci, F., Olivotto, I., & Pieroni, M. (2025). Brugada Syndrome: Channelopathy and/or Cardiomyopathy. Cardiogenetics, 15(2), 17. https://doi.org/10.3390/cardiogenetics15020017

Article Metrics

Back to TopTop