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Brugada Syndrome: A Heterogeneous Disease with a Common ECG Phenotype? BELINDA GRAY, M.B.B.S.,∗ ,†,‡ CHRISTOPHER SEMSARIAN, M.B.B.S., Ph.D.,∗ ,†,‡ and RAYMOND W. SY, M.B.B.S., Ph.D.∗ ,‡ From the ∗ Department of Cardiology, Royal Prince Alfred Hospital; †Agnes Ginges Centre for Molecular Cardiology, Centenary Institute; and ‡Sydney Medical School, University of Sydney, NSW, Australia
Brugada Syndrome. Our understanding of Brugada syndrome (BrS) has evolved since the syndrome was first described in 1992. BrS is considered to be a primary inherited channelopathy often involving the inward sodium current and the diagnosis has traditionally required the exclusion of overt structural heart disease. In view of recently published observations about BrS, we propose that the term BrS may actually encompass a heterogeneous group of disorders with a variety of genetic and clinical phenotypes. This disease has classically been described as a primary electrical disorder involving the sodium channel leading to the characteristic electrocardiogram (ECG) changes of BrS. We challenge the current understanding and propose that patients with structurally normal hearts, family history of sudden cardiac death, with associated genetic abnormalities only account for a subset of patients with the “Brugada pattern” ECG. There may also be some patients with a diagnosis of BrS who may also have features which overlap with arrhythmogenic right ventricular cardiomyopathy. In these patients there may be an underlying structural abnormality. In this context, it is possible that catheter ablation may abolish the “Brugada pattern” ECG changes as well as abolishing the risk of life threatening arrhythmias in these patients. Given the recent developments in the field, we propose a novel comprehensive multimodality model for risk stratification and assessment of patients with BrS. Identification of variations of diseases may facilitate more specific risk stratification models and management paradigms in patients with Brugada ECG pattern. (J Cardiovasc Electrophysiol, Vol. 25, pp. 450-456, April 2014) Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, heterogeneity, substrate, genetics, sodium channel Background Brugada syndrome (BrS) was first described in 1992, in which 8 patients with characteristic cove-shaped ST elevation in the right precordial leads on 12-lead ECG with associated sudden cardiac death (SCD) because of ventricular fibrillation (VF) were reported.1 The 2013 diagnostic criteria for BrS requires the patient to have spontaneous or drug-induced type I Brugada pattern ECG (ࣙ2 mm ST elevation with type 1 morphology in ࣙ1 right precordial lead V1 or V2 in either 2nd, 3rd, or 4th intercostal space).2 In patients with a type 2 or 3 Brugada ECG pattern, a diagnosis requires the provocation of a type I ECG pattern with sodium-channel blockade.2 The syndrome accounts for 4% of all SCDs and 20% of sudden deaths in patients with structurally normal hearts.3 A positive family history is found in 20–30% of patients.4 No disclosures. Address for correspondence: Raymond W. Sy, M.B.B.S., Ph.D., Department of Cardiology Royal Prince Alfred Hospital, Camperdown, NSW 2050 Australia. Fax: +612 9550 6262; E-mail: [email protected] Manuscript received 12 November 2013; Revised manuscript received 5 December 2013; Accepted for publication 31 December 2013. doi: 10.1111/jce.12366
BrS is considered to be a primary inherited channelopathy often involving the inward sodium current and the diagnosis has traditionally required the exclusion of overt structural heart disease. However, recent data have raised the possibility that “Brugada syndrome” as currently defined may represent a heterogeneous disease entity with a common electrocardiographic phenotype. Indeed, this has been a topic of recent debate among experts in the field, highlighting the potential complexity of the underlying pathophysiology in BrS.5,6 Moreover, such heterogeneity may explain current controversies in diagnostic and management paradigms in this disease. Heterogeneity in Cardiac Morphology There is increasing evidence that BrS may not be isolated to patients with a structurally normal heart, as was previously believed. Some patients with an apparent diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) have been shown to exhibit the characteristic right precordial ECG changes of BrS leading to some suggestions in the literature of an overlap syndrome. A series of autopsy findings from young patients with SCD in Italy was one of the earliest to suggest an overlap syndrome between BrS and ARVC.7 They found 14% of sudden death patients had a previously documented type I Brugada pattern ECG. All these patients
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Figure 1. Baseline ECG (A) from patient showing typical type I Brugada pattern. End-diastolic frames of RV (B) and LV (C) angiography from the same patient showing multiple small aneurysms of the inferior-apical wall (arrowheads) and a localized posterobasal LV microaneurysm (arrow). RV (D) and LV (E) endomyocardial biopsy sample from the same patient showing active lymphocytic myocarditis. D, Hematoxylin and eosin. E, Immunohistochemistry with mouse antihuman CD45RO antibody. Original magnification ×250. (Reproduced with permission from Frustaci et al., Circulation 2005).12
had ARVC except one with a structurally normal heart. Compared to the ARVC patients who did not have a Brugada type ECG, those with the ECG were more likely to have clinical characteristics that were shared with BrS.7 Even when diagnostic findings of ARVC are not present, more subtle morphologic changes have been reported by imaging studies. In a cohort of 20 patients with confirmed BrS, compared to normal controls, undergoing cardiac magnetic resonance imaging (cMRI), the patients with BrS were found to have a significantly larger right ventricular outflow tract (RVOT) area with a trend toward increased right ventricular (RV) volumes, and decreased RV ejection fraction (EF) with no difference in left ventricular parameters.8 There was also a 20% incidence of fatty infiltration of the RV in the BrS group.8 Similarly, in a study of 30 BrS patients compared to 30 age and sex matched controls, the BrS patients were found to have higher incidence of mild RV wall motion abnormalities, reduced RVOT EF and increased RV inflow tract diameter with no fatty infiltration seen in either group.9 However, these morphologic changes may be heterogeneous because the finding of structural abnormalities was not replicated in another cMRI study of 29 BrS patients compared with 20 normal controls.10
Heterogeneity in Histopathology There have also been multiple studies assessing the histopathology from endomyocardial biopsies in BrS. Indeed, even in 1989, Martini et al. reported histological findings of fibrosis in their original description of patients with resuscitated VF arrest and apparent absence of heart disease, several of whom had ECG changes reminiscent of BrS.11 Subsequent studies have yielded mixed results, from lymphocytic infiltrates to severe fibrofatty infiltration suggestive of ARVC.12-14 In 2005, Coronel et al. published a provocative case report of a patient with clinical evidence of BrS who underwent heart transplantation for incessant ventricular fibrilllation.6 Following transplantation, the RVOT in the explanted heart was found to harbor significant intramyocardial fibrosis, hypertrophy and epicardial fatty infiltration. Frustaci et al. also examined 18 consecutive symptomatic BrS patients with endomyocardial biopsy of both ventricles, finding evidence of abnormalities in all patients.12 Histopathological assessment revealed lymphocytic right ventricular (RV myocarditis in 14 patients without SCN5A mutations, and viral genomes (for coxsackievirus B3, Epstein-Barr virus, and parvovirus B19) were detected in 4 of these patients
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Figure 2. Schematic representation of right ventricular epicardial action potential changes proposed to underlie the ECG changes of the Brugada syndrome. (Reproduced with permission from Antzelevitch, J Cardiovasc Electrophysiol 2001).18
(Fig. 1). In addition, 4 patients were found to be carriers of mutations in the SCN5A gene. Remarkably, cardiomyopathic changes were observed in 3 of these patients, and extensive fibrofatty replacement (diagnostic for arrhythmogenic RV cardiomyopathy) was seen in the other patient. Carriers of SCN5A mutations also showed more apoptosis. However, the histopathology of BrS is clearly heterogeneous as shown in a subsequent paper in 2009 whereby “nonspecific changes” were frequently observed on biopsy in 21 BrS patients (moderate myocardial hypertrophy in 11 patients, fatty replacement of the myocardium in 10, and moderate fibrosis in 5); however, there was no evidence of active myocarditis in any patient.13 The potential etiology of the histopathological changes observed in BrS is also intriguing. Although the presence of myocarditis and/or fibrosis may implicate an inflammatory or infective origin, SCN5A knockout mouse models have demonstrated that reduced SCN5A expression may itself cause myocardial structural abnormalities such as severe reactive fibrosis and altered gap junction protein expression, resulting in profound conduction abnormality.15,16 It is interesting to note that mutations in the SCN4A gene, the homologous skeletal muscle sodium channel gene, have also been associated with degenerative myopathy.17 Heterogenity in Electrophysiological Substrate The underlying arrhythmic substrate in BrS is currently believed to be because of a primary electrical disorder affecting the RVOT. This may be explained by abnormal repolarization or depolarization.15,16 In the “repolarization theory,” the characteristic BrS ECG changes result from an epicardial–endocardial transmural voltage gradient in the RVOT because of reduced inward Na+ current and unopposed outward K+ current, these changes being exaggerated
in the RVOT epicardium (Fig. 2).18 The alternative theory suggests abnormal RVOT depolarization or conduction delay. In this theory, there is delay in the action potential of the RVOT compared to the RV. The characteristic BrS ECG changes result from the directional changes in the current to and from the RVOT (Fig. 3).19 The mechanism is similar to the reentrant tachyarrhythmias seen in the border zones of ischemic myocardium.19 The presence of late potentials (LPs) on signal-averaged electrocardiogram (SAECG) has also been described in patients with BrS. Traditionally, LPs have been described and indeed been used as a predictor of arrhythmic risk in structural heart diseases such as myocardial infarction.20 In this context, LPs are because of the delayed activation of “islands” of myocardium within scar. The origin of LPs in BrS is intriguing. In an early study of 5 patients with BrS, when the RVOT was studied through cannulation of the RV conus branch, the patients were found to have delayed potentials (DPs) in the RVOT epicardium but not endocardium, these DPs correlating with LPs on SAECG.21 Ohkubo et al. also documented DPs with endocardial mapping from the RVOT in 60% of their BrS patients.22 Whether such epicardial and/or endocardial DPs are adequately explained by the existing theories of abnormal repolarization or depolarization is contentious. Questions surrounding the arrhythmic substrate have been further fueled by recent studies examining the role of ablation in BrS. Haissaguerre et al. described a case of a patient with severe BrS and recurrent implantable cardioverter defibrillators (ICD) shocks whereby ablation of the endocardial RVOT ectopic focus not only resulted in an apparent clinical cure but also the loss of the patient’s Brugada ECG pattern.23 Nademanee et al. has also recently described a substrate-based approach to ablation in patients with BrS and recurrent VF episodes.24 They found unique low
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Finally, returning to the original case report from Coronel et al., the explanted heart of a patient with BrS showed fibrosis and fatty infiltration in the RVOT.6 Electrophysiological evaluation of the explanted heart showed delayed activation in the RVOT endocardium without a transmural repolarization gradient. Patch clamp studies revealed that cells expressing the mutated sodium channels from the patient exhibited enhanced slow inactivation compared with wild-type channels. Further studies are required to explore the possibility of a “cause and effect” relationship between functional abnormalities in the sodium channel and pathological structural changes in patients with BrS. Heterogeneity in Genetic Basis
Figure 3. Qualitative model of the depolarization disorder hypothesis (Reproduced with permission from Meregalli et al., Cardiovascular Research 2005).20
voltage, prolonged, fractionated LPs clustering in anterior aspect of RVOT epicardium (Fig. 4). These electrograms were usually >80 milliseconds in duration, extending beyond the end of the QRS complex. In fact, some examples illustrated in their paper were >200 milliseconds in duration. These findings were also reminiscent of earlier reports of DPs in the epicardial RVOT.21 Moreover, such electrogram characteristics are usually observed in myocardial tissue where cell-to-cell coupling has been interrupted by fibrous or fatty replacement.2 The prototypical model is myocardial infarction although identical electrograms in the epicardial RV have also been described in patients with ARVC.25 Taken together, these observations would appear to support a disorder of depolarization, either functional or more likely structural, as the electrophysiological substrate in some patients with the Brugada ECG pattern. However, the possibility that heterogeneous repolarization and/or concealed phase 2 reentry may produce similar findings, though less likely, cannot be excluded.18 There may also be other avenues for exploring the arrhythmic substrate in patients with BrS. For example, unipolar endocardial voltage mapping has been used to identify epicardial substrate in patients with ARVC.11 This method obviates the need for epicardial access, reducing the risk of the diagnostic procedure. Perhaps a similar approach may be employed in the evaluation of patients with Brugada ECG pattern.
Familial BrS has traditionally been attributed to an autosomal dominant inheritance pattern. The most common abnormality is a loss of function mutation in the gene encoding the cardiac sodium channel, SCN5A. Mutations in other genes encoding the sodium channel (SCN1B, SCN3B), calcium channel (CACNA1C, CACNB2b), and potassium channels (KCNE3, KCNJ8) have also been implicated in BrS.26-31 However, a pathogenic mutation is identified in only 25– 30% of patients and there is marked heterogeneity in the genetic profile of patients with BrS.32-34 This stands in stark contrast to other “inherited arrhythmia syndromes” such as long-QT syndrome or catecholaminergic polymorphic ventricular tachycardia where the yield of genetic testing is much higher.35 Furthermore, BrS may not be a monogenic disease. The association between SCN5A mutation and Brugada ECG pattern is a complex one; in a recent study of BrS families with a known SCN5A mutation, there were several individuals with positive Brugada ECG pattern who were subsequently found to be mutation negative.36 These findings suggest that the genetic background may play an important role in the pathophysiology of BrS. For example, a genome-wide association study of 312 individuals with BrS suggested BrS may be a multigenic disorder, with cumulative effects from both causative mutations as well as common genetic variations.19 The study highlights the potential complexity of genetic causation and susceptibility in BrS patients. Implications and Future Directions The prospect of BrS being a heterogenous disease carries important implications to the evaluation and management of patients with BrS. Risk stratification in asymptomatic patients remains one of the most important and unresolved issues in BrS. Understanding the variations in disease patterns in BrS may fine tune how we may apply traditional markers such as syncope, spontaneous type I ECG pattern, and programmed electrical stimulation (PES), as well as novel markers such as LPs, ventricular refractory period, QRS-fragmentation, inferolateral early repolarization abnormalities, and temporal burden of ECG changes.33,37-47 For example, the utility of inferolateral ECG changes may be more important in patients without structural abnormalities, whereas PES may have a better predictive value in patients with structural abnormalities. This is of course purely speculative, but it highlights the need for a reexamination of BrS with a wider lens. A more comprehensive approach to patient evaluation
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Figure 4. Left lateral view of the RVOT displays the difference in ventricular electrograms between the endocardial (ENDO) and epicardial (EPI) site of the anterior RVOT of patient 4. The left and right insets display bipolar and unipolar electrograms recorded from the epicardium and endocardium from the same site of the RVOT, respectively. Bi-DIST indicates bipolar distal; Bi-PROX, bipolar proximal; Uni-DIST, unipolar distal; and Uni-PROX, unipolar proximal. (Reproduced with permission from Nademanee et al., Circulation 2011).24
including the routine use of multimodality assessment such as cMRI, SA-ECG, comprehensive EPS (including detailed RV electrogram characterization and voltage mapping) as well as multipanel gene testing (including screening for genes more often associated with ARVC) may reveal valuable insights into the pathophysiology of BrS. Such an approach may also provide the framework for the development of risk stratification models for asymptomatic patients with the Brugada ECG pattern. At present the management of BrS is limited to lifestyle modifications, avoidance of triggers and family screening in asymptomatic patients, with ICD being offered to symptomatic patients.2 Exploratory treatment options such as Quinidine and ablation have been recently proposed.24,48-50 Analogous to risk stratification, a better understanding of the heterogeneity in BrS may allow us to identify specific patient subsets that are most likely to benefit from these promising treatment strategies.
Summary Since the original description of a characteristic ECG pattern associated with SCD in 1992, we have gradually moved toward the currently accepted view of BrS as a primary inherited channelopathy often involving the inward sodium current occurring in the absence of structural heart disease. However, such a narrow definition of disease may be insufficient for explaining more recent observations such as: the presence of morphologic abnormalities in the right ventricle, pathological findings of inflammation or fibrosis in the RVOT, the presence of LPs on SAECG, the finding of low voltage, prolonged and fractionated potentials in the RV epicardium, and the potential for curative substrate ablation. Although one may be tempted to “bend” these observations to fit within our current paradigm, an alternative explanation may be that “Brugada syndrome” represents a heterogeneous clinical entity with a common ECG phenotype. Indeed, adopting such an open concept of BrS, embracing the possibilities of functional repolarization and/or depolarization abnormalities, as
well as localized structural pathology, may allow us to delineate novel patterns of disease. We have learned much about BrS over the past 2 decades but challenges remain as we move into the next phase of research into BrS, with the ultimate aim of improving the care of patients and families with BrS. 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. 2. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C: Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 2013;10:e85-108. 3. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A: Brugada syndrome: Report of the second consensus conference: Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005;111:659-670. 4. Vohra J: Diagnosis and management of Brugada syndrome. Heart, Lung Circ 2011;20:751-756. 5. Hoogendijk MG, Opthof T, Postema PG, Wilde AA, de Bakker JM, Coronel R: The Brugada ECG pattern: A marker of channelopathy, structural heart disease, or neither? Toward a unifying mechanism of the Brugada syndrome. Circ Arrhythm Electrophysiol 2010;3:283-290. 6. Brugada P: Commentary on the Brugada ECG pattern: A marker of channelopathy, structural heart disease, or neither? Toward a unifying mechanism of the Brugada syndrome. Circ Arrhythm Electrophysiol 2010;3:280-282. 7. 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. 8. Papavassiliu T, Wolpert C, Fluchter S, Schimpf R, Neff W, Haase KK, Duber C, Borggrefe M: Magnetic resonance imaging findings in patients with Brugada syndrome. J Cardiovasc Electrophysiol 2004;15:1133-1138. 9. Catalano O, Antonaci S, Moro G, Mussida M, Frascaroli M, Baldi M, Cobelli F, Baiardi P, Nastoli J, Bloise R, Monteforte N, Napolitano C, Priori SG: Magnetic resonance investigations in Brugada syndrome reveal unexpectedly high rate of structural abnormalities. Eur Heart J 2009;30:2241-2248.
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38. Priori SG, Napolitano C, Gasparini M, Pappone C, Della Bella P, Giordano U, Bloise R, Giustetto C, De Nardis R, Grillo M, Ronchetti E, Faggiano G, Nastoli J: Natural history of Brugada syndrome: Insights for risk stratification and management. Circulation 2002;105:13421347. 39. Wilde AA, Viskin S. EP testing does not predict cardiac events in Brugada syndrome. Heart Rhythm 2011;8:1598-1600. 40. Priori SG, Gasparini M, Napolitano C, Della Bella P, Ottonelli AG, Sassone B, Giordano U, Pappone C, Mascioli G, Rossetti G, De Nardis R, Colombo M: Risk stratification in Brugada syndrome: Results of the PRELUDE (programmed electrical stimulation predictive value) registry. J Am Coll Cardiol 2012;59:37-45. 41. Huang Z, Patel C, Li W, Xie Q, Wu R, Zhang L, Tang R, Wan X, Ma Y, Zhen W, Gao L, Yan GX: Role of signal-averaged electrocardiograms in arrhythmic risk stratification of patients with brugada syndrome: A prospective study. Heart Rhythm 2009;6:1156-1162. 42. Sarkozy A, Chierchia GB, Paparella G, Boussy T, De Asmundis C, Roos M, Henkens S, Kaufman L, Buyl R, Brugada R, Brugada J, Brugada P: Inferior and lateral electrocardiographic repolarization abnormalities in Brugada syndrome. Circ Arrhythm Electrophysiol 2009;2:154-161. 43. Kamakura S, Ohe T, Nakazawa K, Aizawa Y, Shimizu A, Horie M, Ogawa S, Okumura K, Tsuchihashi K, Sugi K, Makita N, Hagiwara N, Inoue H, Atarashi H, Aihara N, Shimizu W, Kurita T, Suyama K, Noda T, Satomi K, Okamura H, Tomoike H: Long-term prognosis of probands with Brugada-pattern ST-elevation in leads v1-v3. Circ Arrhythm Electrophysiol 2009;2:495-503. 44. Kawata H, Morita H, Yamada Y, Noda T, Satomi K, Aiba T, Isobe M, Nagase S, Nakamura K, Fukushima Kusano K, Ito H, Kamakura S,
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Shimizu W: 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. Rollin A, Sacher F, Gourraud JB, Pasquie JL, Raczka F, Duparc A, Mondoly P, Cardin C, Delay M, Chatel S, Derval N, Denis A, Sadron M, Davy JM, Hocini M, Jais P, Jesel L, Haissaguerre M, Probst V, Maury P: Prevalence, characteristics, and prognosis role of type 1 ST elevation in the peripheral ECG leads in patients with Brugada syndrome. Heart Rhythm 2013;10:1012-1018. Viskin S, Adler A, Rosso R: Brugada burden in Brugada syndrome: The way to go in risk stratification? Heart Rhythm 2013;10:10191020. Extramiana F, Maison-Blanche P, Badilini F, Messali A, Denjoy I, Leenhardt A: Type 1 electrocardiographic burden is increased in symptomatic patients with Brugada syndrome. J Electrocardiol 2010;43:408414. Hermida JS, Denjoy I, Clerc J, Extramiana F, Jarry G, Milliez P, Guicheney P, Di Fusco S, Rey JL, Cauchemez B, Leenhardt A: Hydroquinidine therapy in Brugada syndrome. J Am Coll Cardiol 2004;43:1853-1860. Viskin S, Wilde AA, Tan HL, Antzelevitch C, Shimizu W, Belhassen B: Empiric quinidine therapy for asymptomatic Brugada syndrome: Time for a prospective registry. Heart Rhythm 2009;6:401-404. Ohgo T, Okamura H, Noda T, Satomi K, Suyama K, Kurita T, Aihara N, Kamakura S, Ohe T, Shimizu W: Acute and chronic management in patients with Brugada syndrome associated with electrical storm of ventricular fibrillation. Heart Rhythm 2007;4:695700.
Clinical Review
Brugada Syndrome: A Heterogeneous Disease with a Common ECG Phenotype? BELINDA GRAY, M.B.B.S.,∗ ,†,‡ CHRISTOPHER SEMSARIAN, M.B.B.S., Ph.D.,∗ ,†,‡ and RAYMOND W. SY, M.B.B.S., Ph.D.∗ ,‡ From the ∗ Department of Cardiology, Royal Prince Alfred Hospital; †Agnes Ginges Centre for Molecular Cardiology, Centenary Institute; and ‡Sydney Medical School, University of Sydney, NSW, Australia
Brugada Syndrome. Our understanding of Brugada syndrome (BrS) has evolved since the syndrome was first described in 1992. BrS is considered to be a primary inherited channelopathy often involving the inward sodium current and the diagnosis has traditionally required the exclusion of overt structural heart disease. In view of recently published observations about BrS, we propose that the term BrS may actually encompass a heterogeneous group of disorders with a variety of genetic and clinical phenotypes. This disease has classically been described as a primary electrical disorder involving the sodium channel leading to the characteristic electrocardiogram (ECG) changes of BrS. We challenge the current understanding and propose that patients with structurally normal hearts, family history of sudden cardiac death, with associated genetic abnormalities only account for a subset of patients with the “Brugada pattern” ECG. There may also be some patients with a diagnosis of BrS who may also have features which overlap with arrhythmogenic right ventricular cardiomyopathy. In these patients there may be an underlying structural abnormality. In this context, it is possible that catheter ablation may abolish the “Brugada pattern” ECG changes as well as abolishing the risk of life threatening arrhythmias in these patients. Given the recent developments in the field, we propose a novel comprehensive multimodality model for risk stratification and assessment of patients with BrS. Identification of variations of diseases may facilitate more specific risk stratification models and management paradigms in patients with Brugada ECG pattern. (J Cardiovasc Electrophysiol, Vol. 25, pp. 450-456, April 2014) Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, heterogeneity, substrate, genetics, sodium channel Background Brugada syndrome (BrS) was first described in 1992, in which 8 patients with characteristic cove-shaped ST elevation in the right precordial leads on 12-lead ECG with associated sudden cardiac death (SCD) because of ventricular fibrillation (VF) were reported.1 The 2013 diagnostic criteria for BrS requires the patient to have spontaneous or drug-induced type I Brugada pattern ECG (ࣙ2 mm ST elevation with type 1 morphology in ࣙ1 right precordial lead V1 or V2 in either 2nd, 3rd, or 4th intercostal space).2 In patients with a type 2 or 3 Brugada ECG pattern, a diagnosis requires the provocation of a type I ECG pattern with sodium-channel blockade.2 The syndrome accounts for 4% of all SCDs and 20% of sudden deaths in patients with structurally normal hearts.3 A positive family history is found in 20–30% of patients.4 No disclosures. Address for correspondence: Raymond W. Sy, M.B.B.S., Ph.D., Department of Cardiology Royal Prince Alfred Hospital, Camperdown, NSW 2050 Australia. Fax: +612 9550 6262; E-mail: [email protected] Manuscript received 12 November 2013; Revised manuscript received 5 December 2013; Accepted for publication 31 December 2013. doi: 10.1111/jce.12366
BrS is considered to be a primary inherited channelopathy often involving the inward sodium current and the diagnosis has traditionally required the exclusion of overt structural heart disease. However, recent data have raised the possibility that “Brugada syndrome” as currently defined may represent a heterogeneous disease entity with a common electrocardiographic phenotype. Indeed, this has been a topic of recent debate among experts in the field, highlighting the potential complexity of the underlying pathophysiology in BrS.5,6 Moreover, such heterogeneity may explain current controversies in diagnostic and management paradigms in this disease. Heterogeneity in Cardiac Morphology There is increasing evidence that BrS may not be isolated to patients with a structurally normal heart, as was previously believed. Some patients with an apparent diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) have been shown to exhibit the characteristic right precordial ECG changes of BrS leading to some suggestions in the literature of an overlap syndrome. A series of autopsy findings from young patients with SCD in Italy was one of the earliest to suggest an overlap syndrome between BrS and ARVC.7 They found 14% of sudden death patients had a previously documented type I Brugada pattern ECG. All these patients
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Figure 1. Baseline ECG (A) from patient showing typical type I Brugada pattern. End-diastolic frames of RV (B) and LV (C) angiography from the same patient showing multiple small aneurysms of the inferior-apical wall (arrowheads) and a localized posterobasal LV microaneurysm (arrow). RV (D) and LV (E) endomyocardial biopsy sample from the same patient showing active lymphocytic myocarditis. D, Hematoxylin and eosin. E, Immunohistochemistry with mouse antihuman CD45RO antibody. Original magnification ×250. (Reproduced with permission from Frustaci et al., Circulation 2005).12
had ARVC except one with a structurally normal heart. Compared to the ARVC patients who did not have a Brugada type ECG, those with the ECG were more likely to have clinical characteristics that were shared with BrS.7 Even when diagnostic findings of ARVC are not present, more subtle morphologic changes have been reported by imaging studies. In a cohort of 20 patients with confirmed BrS, compared to normal controls, undergoing cardiac magnetic resonance imaging (cMRI), the patients with BrS were found to have a significantly larger right ventricular outflow tract (RVOT) area with a trend toward increased right ventricular (RV) volumes, and decreased RV ejection fraction (EF) with no difference in left ventricular parameters.8 There was also a 20% incidence of fatty infiltration of the RV in the BrS group.8 Similarly, in a study of 30 BrS patients compared to 30 age and sex matched controls, the BrS patients were found to have higher incidence of mild RV wall motion abnormalities, reduced RVOT EF and increased RV inflow tract diameter with no fatty infiltration seen in either group.9 However, these morphologic changes may be heterogeneous because the finding of structural abnormalities was not replicated in another cMRI study of 29 BrS patients compared with 20 normal controls.10
Heterogeneity in Histopathology There have also been multiple studies assessing the histopathology from endomyocardial biopsies in BrS. Indeed, even in 1989, Martini et al. reported histological findings of fibrosis in their original description of patients with resuscitated VF arrest and apparent absence of heart disease, several of whom had ECG changes reminiscent of BrS.11 Subsequent studies have yielded mixed results, from lymphocytic infiltrates to severe fibrofatty infiltration suggestive of ARVC.12-14 In 2005, Coronel et al. published a provocative case report of a patient with clinical evidence of BrS who underwent heart transplantation for incessant ventricular fibrilllation.6 Following transplantation, the RVOT in the explanted heart was found to harbor significant intramyocardial fibrosis, hypertrophy and epicardial fatty infiltration. Frustaci et al. also examined 18 consecutive symptomatic BrS patients with endomyocardial biopsy of both ventricles, finding evidence of abnormalities in all patients.12 Histopathological assessment revealed lymphocytic right ventricular (RV myocarditis in 14 patients without SCN5A mutations, and viral genomes (for coxsackievirus B3, Epstein-Barr virus, and parvovirus B19) were detected in 4 of these patients
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Figure 2. Schematic representation of right ventricular epicardial action potential changes proposed to underlie the ECG changes of the Brugada syndrome. (Reproduced with permission from Antzelevitch, J Cardiovasc Electrophysiol 2001).18
(Fig. 1). In addition, 4 patients were found to be carriers of mutations in the SCN5A gene. Remarkably, cardiomyopathic changes were observed in 3 of these patients, and extensive fibrofatty replacement (diagnostic for arrhythmogenic RV cardiomyopathy) was seen in the other patient. Carriers of SCN5A mutations also showed more apoptosis. However, the histopathology of BrS is clearly heterogeneous as shown in a subsequent paper in 2009 whereby “nonspecific changes” were frequently observed on biopsy in 21 BrS patients (moderate myocardial hypertrophy in 11 patients, fatty replacement of the myocardium in 10, and moderate fibrosis in 5); however, there was no evidence of active myocarditis in any patient.13 The potential etiology of the histopathological changes observed in BrS is also intriguing. Although the presence of myocarditis and/or fibrosis may implicate an inflammatory or infective origin, SCN5A knockout mouse models have demonstrated that reduced SCN5A expression may itself cause myocardial structural abnormalities such as severe reactive fibrosis and altered gap junction protein expression, resulting in profound conduction abnormality.15,16 It is interesting to note that mutations in the SCN4A gene, the homologous skeletal muscle sodium channel gene, have also been associated with degenerative myopathy.17 Heterogenity in Electrophysiological Substrate The underlying arrhythmic substrate in BrS is currently believed to be because of a primary electrical disorder affecting the RVOT. This may be explained by abnormal repolarization or depolarization.15,16 In the “repolarization theory,” the characteristic BrS ECG changes result from an epicardial–endocardial transmural voltage gradient in the RVOT because of reduced inward Na+ current and unopposed outward K+ current, these changes being exaggerated
in the RVOT epicardium (Fig. 2).18 The alternative theory suggests abnormal RVOT depolarization or conduction delay. In this theory, there is delay in the action potential of the RVOT compared to the RV. The characteristic BrS ECG changes result from the directional changes in the current to and from the RVOT (Fig. 3).19 The mechanism is similar to the reentrant tachyarrhythmias seen in the border zones of ischemic myocardium.19 The presence of late potentials (LPs) on signal-averaged electrocardiogram (SAECG) has also been described in patients with BrS. Traditionally, LPs have been described and indeed been used as a predictor of arrhythmic risk in structural heart diseases such as myocardial infarction.20 In this context, LPs are because of the delayed activation of “islands” of myocardium within scar. The origin of LPs in BrS is intriguing. In an early study of 5 patients with BrS, when the RVOT was studied through cannulation of the RV conus branch, the patients were found to have delayed potentials (DPs) in the RVOT epicardium but not endocardium, these DPs correlating with LPs on SAECG.21 Ohkubo et al. also documented DPs with endocardial mapping from the RVOT in 60% of their BrS patients.22 Whether such epicardial and/or endocardial DPs are adequately explained by the existing theories of abnormal repolarization or depolarization is contentious. Questions surrounding the arrhythmic substrate have been further fueled by recent studies examining the role of ablation in BrS. Haissaguerre et al. described a case of a patient with severe BrS and recurrent implantable cardioverter defibrillators (ICD) shocks whereby ablation of the endocardial RVOT ectopic focus not only resulted in an apparent clinical cure but also the loss of the patient’s Brugada ECG pattern.23 Nademanee et al. has also recently described a substrate-based approach to ablation in patients with BrS and recurrent VF episodes.24 They found unique low
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Finally, returning to the original case report from Coronel et al., the explanted heart of a patient with BrS showed fibrosis and fatty infiltration in the RVOT.6 Electrophysiological evaluation of the explanted heart showed delayed activation in the RVOT endocardium without a transmural repolarization gradient. Patch clamp studies revealed that cells expressing the mutated sodium channels from the patient exhibited enhanced slow inactivation compared with wild-type channels. Further studies are required to explore the possibility of a “cause and effect” relationship between functional abnormalities in the sodium channel and pathological structural changes in patients with BrS. Heterogeneity in Genetic Basis
Figure 3. Qualitative model of the depolarization disorder hypothesis (Reproduced with permission from Meregalli et al., Cardiovascular Research 2005).20
voltage, prolonged, fractionated LPs clustering in anterior aspect of RVOT epicardium (Fig. 4). These electrograms were usually >80 milliseconds in duration, extending beyond the end of the QRS complex. In fact, some examples illustrated in their paper were >200 milliseconds in duration. These findings were also reminiscent of earlier reports of DPs in the epicardial RVOT.21 Moreover, such electrogram characteristics are usually observed in myocardial tissue where cell-to-cell coupling has been interrupted by fibrous or fatty replacement.2 The prototypical model is myocardial infarction although identical electrograms in the epicardial RV have also been described in patients with ARVC.25 Taken together, these observations would appear to support a disorder of depolarization, either functional or more likely structural, as the electrophysiological substrate in some patients with the Brugada ECG pattern. However, the possibility that heterogeneous repolarization and/or concealed phase 2 reentry may produce similar findings, though less likely, cannot be excluded.18 There may also be other avenues for exploring the arrhythmic substrate in patients with BrS. For example, unipolar endocardial voltage mapping has been used to identify epicardial substrate in patients with ARVC.11 This method obviates the need for epicardial access, reducing the risk of the diagnostic procedure. Perhaps a similar approach may be employed in the evaluation of patients with Brugada ECG pattern.
Familial BrS has traditionally been attributed to an autosomal dominant inheritance pattern. The most common abnormality is a loss of function mutation in the gene encoding the cardiac sodium channel, SCN5A. Mutations in other genes encoding the sodium channel (SCN1B, SCN3B), calcium channel (CACNA1C, CACNB2b), and potassium channels (KCNE3, KCNJ8) have also been implicated in BrS.26-31 However, a pathogenic mutation is identified in only 25– 30% of patients and there is marked heterogeneity in the genetic profile of patients with BrS.32-34 This stands in stark contrast to other “inherited arrhythmia syndromes” such as long-QT syndrome or catecholaminergic polymorphic ventricular tachycardia where the yield of genetic testing is much higher.35 Furthermore, BrS may not be a monogenic disease. The association between SCN5A mutation and Brugada ECG pattern is a complex one; in a recent study of BrS families with a known SCN5A mutation, there were several individuals with positive Brugada ECG pattern who were subsequently found to be mutation negative.36 These findings suggest that the genetic background may play an important role in the pathophysiology of BrS. For example, a genome-wide association study of 312 individuals with BrS suggested BrS may be a multigenic disorder, with cumulative effects from both causative mutations as well as common genetic variations.19 The study highlights the potential complexity of genetic causation and susceptibility in BrS patients. Implications and Future Directions The prospect of BrS being a heterogenous disease carries important implications to the evaluation and management of patients with BrS. Risk stratification in asymptomatic patients remains one of the most important and unresolved issues in BrS. Understanding the variations in disease patterns in BrS may fine tune how we may apply traditional markers such as syncope, spontaneous type I ECG pattern, and programmed electrical stimulation (PES), as well as novel markers such as LPs, ventricular refractory period, QRS-fragmentation, inferolateral early repolarization abnormalities, and temporal burden of ECG changes.33,37-47 For example, the utility of inferolateral ECG changes may be more important in patients without structural abnormalities, whereas PES may have a better predictive value in patients with structural abnormalities. This is of course purely speculative, but it highlights the need for a reexamination of BrS with a wider lens. A more comprehensive approach to patient evaluation
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Figure 4. Left lateral view of the RVOT displays the difference in ventricular electrograms between the endocardial (ENDO) and epicardial (EPI) site of the anterior RVOT of patient 4. The left and right insets display bipolar and unipolar electrograms recorded from the epicardium and endocardium from the same site of the RVOT, respectively. Bi-DIST indicates bipolar distal; Bi-PROX, bipolar proximal; Uni-DIST, unipolar distal; and Uni-PROX, unipolar proximal. (Reproduced with permission from Nademanee et al., Circulation 2011).24
including the routine use of multimodality assessment such as cMRI, SA-ECG, comprehensive EPS (including detailed RV electrogram characterization and voltage mapping) as well as multipanel gene testing (including screening for genes more often associated with ARVC) may reveal valuable insights into the pathophysiology of BrS. Such an approach may also provide the framework for the development of risk stratification models for asymptomatic patients with the Brugada ECG pattern. At present the management of BrS is limited to lifestyle modifications, avoidance of triggers and family screening in asymptomatic patients, with ICD being offered to symptomatic patients.2 Exploratory treatment options such as Quinidine and ablation have been recently proposed.24,48-50 Analogous to risk stratification, a better understanding of the heterogeneity in BrS may allow us to identify specific patient subsets that are most likely to benefit from these promising treatment strategies.
Summary Since the original description of a characteristic ECG pattern associated with SCD in 1992, we have gradually moved toward the currently accepted view of BrS as a primary inherited channelopathy often involving the inward sodium current occurring in the absence of structural heart disease. However, such a narrow definition of disease may be insufficient for explaining more recent observations such as: the presence of morphologic abnormalities in the right ventricle, pathological findings of inflammation or fibrosis in the RVOT, the presence of LPs on SAECG, the finding of low voltage, prolonged and fractionated potentials in the RV epicardium, and the potential for curative substrate ablation. Although one may be tempted to “bend” these observations to fit within our current paradigm, an alternative explanation may be that “Brugada syndrome” represents a heterogeneous clinical entity with a common ECG phenotype. Indeed, adopting such an open concept of BrS, embracing the possibilities of functional repolarization and/or depolarization abnormalities, as
well as localized structural pathology, may allow us to delineate novel patterns of disease. We have learned much about BrS over the past 2 decades but challenges remain as we move into the next phase of research into BrS, with the ultimate aim of improving the care of patients and families with BrS. 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. 2. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C: Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 2013;10:e85-108. 3. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A: Brugada syndrome: Report of the second consensus conference: Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005;111:659-670. 4. Vohra J: Diagnosis and management of Brugada syndrome. Heart, Lung Circ 2011;20:751-756. 5. Hoogendijk MG, Opthof T, Postema PG, Wilde AA, de Bakker JM, Coronel R: The Brugada ECG pattern: A marker of channelopathy, structural heart disease, or neither? Toward a unifying mechanism of the Brugada syndrome. Circ Arrhythm Electrophysiol 2010;3:283-290. 6. Brugada P: Commentary on the Brugada ECG pattern: A marker of channelopathy, structural heart disease, or neither? Toward a unifying mechanism of the Brugada syndrome. Circ Arrhythm Electrophysiol 2010;3:280-282. 7. 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. 8. Papavassiliu T, Wolpert C, Fluchter S, Schimpf R, Neff W, Haase KK, Duber C, Borggrefe M: Magnetic resonance imaging findings in patients with Brugada syndrome. J Cardiovasc Electrophysiol 2004;15:1133-1138. 9. Catalano O, Antonaci S, Moro G, Mussida M, Frascaroli M, Baldi M, Cobelli F, Baiardi P, Nastoli J, Bloise R, Monteforte N, Napolitano C, Priori SG: Magnetic resonance investigations in Brugada syndrome reveal unexpectedly high rate of structural abnormalities. Eur Heart J 2009;30:2241-2248.
Gray et al. Brugada Syndrome 10. Tessa C, Del Meglio J, Ghidini Ottonelli A, Diciotti S, Salvatori L, Magnacca M, Chioccioli M, Lera J, Vignali C, Casolo G: Evaluation of Brugada syndrome by cardiac magnetic resonance. Int J Cardiovasc Imaging 2012;28:1961-1970. 11. Martini B, Nava A, Thiene G, Buja GF, Canciani B, Scognamiglio R, Daliento L, Dalla Volta S: Ventricular fibrillation without apparent heart disease: Description of six cases. Am Heart J 1989;118:1203-1209. 12. Frustaci A, Priori SG, Pieroni M, Chimenti C, Napolitano C, Rivolta I, Sanna T, Bellocci F, Russo MA: Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome. Circulation 2005;112:3680-3687. 13. Zumhagen S, Spieker T, Rolinck J, Baba HA, Breithardt G, Bocker W, Eckardt L, Paul M, Wichter T, Schulze-Bahr E: Absence of pathognomonic or inflammatory patterns in cardiac biopsies from patients with Brugada syndrome. Circ Arrhythm Electrophysiol 2009;2:16-23. 14. Ohkubo K, Watanabe I, Okumura Y, Takagi Y, Ashino S, Kofune M, Sugimura H, Nakai T, Kasamaki Y, Hirayama A, Morimoto S: Right ventricular histological substrate and conduction delay in patients with Brugada syndrome. Int Heart J 2010;51:17-23. 15. van Veen TA, Stein M, Royer A, Le Quang K, Charpentier F, Colledge WH, Huang CL, Wilders R, Grace AA, Escande D, de Bakker JM, van Rijen HV: Impaired impulse propagation in scn5a-knockout mice: Combined contribution of excitability, connexin expression, and tissue architecture in relation to aging. Circulation 2005;112:1927-1935. 16. Royer A, van Veen TA, Le Bouter S, Marionneau C, Griol-Charhbili V, Leoni AL, Steenman M, van Rijen HV, Demolombe S, Goddard CA, Richer C, Escoubet B, Jarry-Guichard T, Colledge WH, Gros D, de Bakker JM, Grace AA, Escande D, Charpentier F: Mouse model of scn5a-linked hereditary Lenegre’s disease: Age-related conduction slowing and myocardial fibrosis. Circulation 2005;111:17381746. 17. Plassart E, Reboul J, Rime CS, Recan D, Millasseau P, Eymard B, Pelletier J, Thomas C, Chapon F, Desnuelle C: Mutations in the muscle sodium channel gene (scn4a) in 13 French families with hyperkalemic periodic paralysis and paramyotonia congenita: Phenotype to genotype correlations and demonstration of the predominance of two mutations. Eur J Hum Genet 1994;2:110-124. 18. Antzelevitch C: The Brugada syndrome: Ionic basis and arrhythmia mechanisms. J Cardiovasc Electrophysiol 2001;12:268-272. 19. Bezzina CR, Barc J, Mizusawa Y, Remme CA, Gourraud JB, Simonet F, Verkerk AO, Schwartz PJ, Crotti L, Dagradi F, Guicheney P, Fressart V, Leenhardt A, Antzelevitch C, Bartkowiak S, Schulze-Bahr E, Zumhagen S, Behr ER, Bastiaenen R, Tfelt-Hansen J, Olesen MS, Kaab S, Beckmann BM, Weeke P, Watanabe H, Endo N, Minamino T, Horie M, Ohno S, Hasegawa K, Makita N, Nogami A, Shimizu W, Aiba T, Froguel P, Balkau B, Lantieri O, Torchio M, Wiese C, Weber D, Wolswinkel R, Coronel R, Boukens BJ, Bezieau S, Charpentier E, Chatel S, Despres A, Gros F, Kyndt F, Lecointe S, Lindenbaum P, Portero V, Violleau J, Gessler M, Tan HL, Roden DM, Christoffels VM, Le Marec H, Wilde AA, Probst V, Schott JJ, Dina C, Redon R: Common variants at scn5a-scn10a and hey2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nat Genet 2013;45:1044-1049. 20. Meregalli PG, Wilde AA, Tan HL: Pathophysiological mechanisms of Brugada syndrome: Depolarization disorder, repolarization disorder, or more? Cardiovasc Res 2005;67:367-378. 21. Nagase S, Kusano KF, Morita H, Fujimoto Y, Kakishita M, Nakamura K, Emori T, Matsubara H, Ohe T: Epicardial electrogram of the right ventricular outflow tract in patients with the Brugada syndrome: Using the epicardial lead. J Am Coll Cardiol 2002;39:1992-1995. 22. Ohkubo K, Watanabe I, Takagi Y, Okumura Y, Ashino S, Kofune M, Kofune T, Shindo A, Sugimura H, Nakai T, Kunimoto S, Kasamaki Y, Saito S, Hirayama A: Endocardial electrograms from the right ventricular outflow tract after induced ventricular fibrillation in patients with Brugada syndrome. Circ J 2007;71:1258-1262. 23. Shah AJ, Hocini M, Lamaison D, Sacher F, Derval N, Haissaguerre M: Regional substrate ablation abolishes Brugada syndrome. J Cardiovasc Electrophysiol 2011;22:1290-1291. 24. 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. 25. Garcia FC, Bazan V, Zado ES, Ren JF, Marchlinski FE: Epicardial substrate and outcome with epicardial ablation of ventricular tachy-
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![[Brugada ECG].](/assets/img/hold.png)
