Article

Current Controversies and Challenges in Brugada Syndrome

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Abstract

More than three decades since its initial description in 1993, Brugada syndrome remains engulfed in controversy. This review aims to shed light on the main challenges surrounding the diagnostic pathway and criteria, risk stratification of asymptomatic patients, pharmacological and interventional risk modification strategies as well as our current pathophysiological understanding of the disease.

Disclosure:The authors have no conflicts of interest to declare.

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Correspondence Details:Hariharan Raju, Suite 203, 2 Technology Place, Macquarie University, Sydney, NSW 2109, Australia. E: hari.raju@mqhealth.org.au

Open Access:

This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Brugada syndrome was first described in 1993 in a case series of eight patients with recurrent polymorphic ventricular tachycardia (VT) and stereotypical electrographic characteristics in the context of a structurally normal heart.1 Since then, the syndrome has been extensively studied and recognised worldwide as a major cause of sudden cardiac death (SCD) in otherwise healthy patients.2 Recent data support the premise that Brugada syndrome is the most common single underlying aetiology for sudden unexplained death with negative autopsy, representing 28% of cases in the UK.3

Yet more than 30 years since its recognition, there are many questions and uncertainties surrounding the pathophysiology, diagnosis, risk assessment and management of Brugada syndrome. This article aims to examine some of these issues with consideration of recently published data.

Diagnostic Process

Three distinct ECG patterns have been associated with Brugada syndrome (Figure 1); however, the type 2 and type 3 ECG patterns are less specific for the condition.2,4 The diagnosis of Brugada syndrome requires documentation of the type 1 ECG pattern (consisting of coved-type ST-segment elevation of ≥2mm followed by a negative T wave in the right precordial leads V1 and/or V2) either on a spontaneous ECG or following IV administration of a class I antiarrhythmic agent such as flecainide or ajmaline.2,5

The 2013 diagnostic criteria excluded the requirement for associated clinical features, with diagnosis based purely on the ECG phenotype.5 However, to avoid overdiagnosis of low-risk patients, a further consensus statement on J wave syndrome has proposed the reintroduction of additional clinical evidence to support the diagnosis in patients having type 1 ECG only in the context of sodium channel blockade.4 These clinical criteria include documented VF or polymorphic VT; syncope of probable arrhythmic cause; family history of SCD in a relative younger than 45 years; type 1 ECG in family members; nocturnal agonal respiration; and inducibility of VT/VF at programmed stimulation with one or two premature beats.

The J wave syndrome consensus group also proposed the novel Shanghai scoring system that takes into account various ECG, clinical history and family history, similar to the Schwartz score used for diagnosis of long QT syndrome (Table 1).5 However, this scoring system is controversial because it was based on expert opinion, rather than appropriate experimental data, and it has not yet been validated.

Past observations have shown that men more commonly present with spontaneous type 1 ECG pattern.1 Cranial displacement of the right precordial ECG leads from the fourth to the second or third intercoastal space – the high right precordial leads – has been shown to increase the sensitivity of the detection of the type 1 ECG pattern, possibly due to better anatomical correlation with the right ventricular outflow tract (RVOT), with no apparent change in prognostic value.2,6,7

In addition, a normal ECG does not rule out Brugada syndrome, as many patients with confirmed diagnosis only have intermittent Brugada ECG patterns.8,9 It has been suggested that prolonged 24-hour ambulatory monitoring using 12-lead ECG with high right precordial lead placement should be used for patients with a normal initial ECG with suspected Brugada syndrome. This may improve diagnostic yield without the risk associated with drug provocation.10,11

Other ECG findings that are non-diagnostic but are often associated with Brugada syndrome are shown in Table 2. In addition, Brugada syndrome remains a diagnosis of exclusion after considering other differential diagnoses that may chronically or acutely mimic the Brugada ECG pattern (Table 2).12 Normal cardiac structure and function on cardiac imaging is necessary to diagnose Brugada syndrome, since cardiomyopathies are recognised mimics. A reproducible type 1 ECG with sodium channel blockade is helpful to differentiate Brugada syndrome from phenocopies where there is uncertainty over diagnosis after an acute event.

Brugada Syndrome ECG Patterns

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Table 1: The Proposed Shanghai Score System for Diagnosis of Brugada Syndrome

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The benefit of using confirmatory diagnostic testing in all patients with non-diagnostic type 2 or 3 Brugada ECG pattern is questionable. Considering the low risk of asymptomatic patients without a spontaneous type 1 ECG, current consensus recommends testing with a class I antiarrhythmic agent to support the diagnosis only if the patient has at least one associated clinical feature.4,13

On the other hand, previous studies have reported worrying false-negative rates on pharmacological challenge testing of symptomatic and asymptomatic patients, with ajmaline being acknowledged as having greatest sensitivity.14,15 It has therefore been suggested that it is worthwhile to repeat a negative pharmacological test using a different agent in cases of high clinical suspicion.12 As with the case of non-pharmacological ECG recording, use of high right precordial lead position during ajmaline challenge testing has been shown to significantly increase the sensitivity of the test.16

Risk Stratification

Symptomatic presentation with previous aborted cardiac arrest or sustained ventricular arrhythmia carries the highest risk of recurrent arrhythmic event in the form of VT/VF, with a previously reported annual rate of about 8%, and secondary prevention with ICD implantation is recommended.5,17 Syncope is a common presentation, occurring in about 30% of patients, and arrhythmia-related syncope is also a well-established risk factor, with an annual event rate of about 2%.11,17 Therefore, it is recommended that a vasovagal cause of syncope is ruled out as these do not seem to carry any additional risk.12,18

Nevertheless, most patients diagnosed with Brugada syndrome are asymptomatic and present a greater challenge for risk stratification and management decisions.12,19 While the established risk of arrhythmic events is much lower for asymptomatic patients at about 1% annually overall, many cases of SCD still occur in this population.12,17,20 Yet despite multiple investigations into predictors of arrhythmic events in asymptomatic patients, no consensus is available for a risk stratification strategy in this population.12

A spontaneous type 1 Brugada ECG pattern is an important established risk factor for cardiac events, which has been reported to confer a three- to fourfold higher risk in asymptomatic patients.21,22 Despite this, only conservative surveillance and risk modification of lifestyle is universally recommended in asymptomatic patients.13 In contrast, a family history of SCD at any age is not an independent prognostic indicator for cardiac events in either symptomatic or asymptomatic patients.19,23

While a multitude of ECG parameters have been associated with increased risk of cardiac arrhythmias, two that have been consistently reported as independent risk factors are abnormal QRS fragmentation (defined as four spikes in one, or eight spikes in all of the leads V1, V2 and V3) and early repolarisation pattern in inferior and/or lateral leads.17,26–29 In addition, AF is more commonly seen in Brugada syndrome than in the general population and has been reported as a risk factor for ventricular arrhythmias in several studies.25,26,30,31

Electrophysiological Study for Risk Stratification

There is ongoing debate regarding the prognostic value of conducting electrophysiological study (EPS) with programmed electrical stimulation for risk stratification in patients without a history of cardiac arrest. Several investigations have demonstrated a positive association between the induction of VT/VF during EPS and the risk of future ventricular arrhythmias, while others have failed to do so.19,21,24,32,33

One important limitation (and potential source of bias) of studies in this area is that patients with a positive EPS are more likely to receive ICD implantation. Therefore, this population may have a higher frequency of recorded ventricular arrhythmias that may not result in cardiac arrest than in patients with negative EPS and no ICD.17,19 Another limitation is the lack of homogeneity between different EPS protocols in the literature.34 While aggressive stimulation protocols with ≥3 extrastimuli are more sensitive, they were found to be less specific than moderate protocols (≤2 extrastimuli).18,35

Despite previous reports describing a strong negative predictive value of EPS in patients without cardiac arrest, a recent systematic review concluded that a negative EPS does not reliably indicate low risk in asymptomatic patients in the presence of other high-risk features (such as spontaneous type 1 ECG, for example).18,34,36 Moreover, the negative predictive value is a function of the low event rate in this low risk population, further limiting the clinical value of EPS.

Gender-specific Risk

Brugada syndrome is about 7–10 times more prevalent in men, and male gender is associated with a higher incidence of ventricular arrhythmias and SCD at diagnosis and follow-up.17,37,38 However, despite the less favourable prognosis generally observed in men, gender alone may not be an independent prognostic indicator and the majority of men remain asymptomatic.17,19

Risk stratification in women with Brugada syndrome has been more challenging as most studies have mainly consisted of male participants. Available data suggest some classical risk factors, such as spontaneous type 1 ECG pattern, are not prognostic in women.38,39

A recent study including 494 women (31% of the total study population) has confirmed the prognostic value of symptomatic presentation with cardiac arrest or syncope in women.40 The only independent risk factors found in asymptomatic women – the majority of patients – were QRS fragmentation and duration >120 ms on ECG. Notably, asymptomatic women without QRS fragmentation had a very low event rate of only 0.1% per year. Previous smaller studies have described the presence of sinus node dysfunction and increased PR interval duration as the best independent markers of cardiac events in asymptomatic women.16,38

Of note is that these gender-specific observations are only relevant for adults (≥18 years), with no significant difference in phenotypic presentation in children.41,42

Genotype and Prognosis

The genetic characterisation of Brugada syndrome has proven to be challenging. The most common and well established Brugada syndrome genotype involve loss of function mutations in the SCN5A gene, representing between 15–30% of diagnosed patients.43 The SCN5A gene encodes for the cardiac voltage-gated sodium channel (Nav1.5) that is activated during the initial rapid depolarisation (phase 0) of the cardiac action potential cycle. About 300 mutations in the SCN5A gene have already been described, yet the role for genetic testing in the diagnosis of Brugada syndrome is limited due to the presence of ‘benign’ SCN5A variants in the general population.4,43

Commonly Associated ECG Findings and Differential Diagnoses

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It is clear that the genetic basis for Brugada syndrome is heterogenous and no pathogenic genotype can be currently identified in the majority of patients.12 Moreover, while numerous mutations in several other myocardial genes have also been suggested there is insufficient evidence to establish their unequivocal causality in the pathogenesis of Brugada syndrome.44

Results from several large registry studies have failed to establish an independent association between genotype status and prognosis in Brugada syndrome.12,13 However, recent data suggest that mutations specifically involving the pore region of the SCN5A gene carry a more severe phonotype and were found to be independently associated with the risk of adverse cardiac events in both symptomatic and asymptomatic patients.45

Risk Modification Treatments

The mainstay of treatment in high-risk patients remains ICD implantation.12 Important risk-reducing strategies for all patients include avoiding excessive alcohol intake, immediate treatment of fever with antipyretics as well as avoidance of potentially aggravating medications (Table 3).5

Quinidine Therapy

Treatment with quinidine can be considered as an adjunct to ICD in patients experiencing electrical storms or frequent appropriate shocks, or as an alternative to ICD in patients with contraindications to implantation. Quinidine reduces the Ito current during epicardial repolarisation and normalises the action potential and prevent re-entry and polymorphic VT formation in experimental models.47

List of Potential Aggravating Drugs

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The efficacy of quinidine monotherapy in long-term prevention of malignant ventricular arrhythmias after ICD implantation has been demonstrated in multiple studies.48 A retrospective study showed total elimination of appropriate ICD shocks in 66% (19 of 29) of patients with previous arrhythmic storm or frequent shocks over a mean period of 60 ± 41 months.49 The authors observed a significant and clinically relevant reduction in number of shocks experienced in the remaining patients.

Two main approaches have been previously reported for quinidine monotherapy as an alternative to ICD implantation. The first is guided by the effect of quinidine therapy on inducible VF during EPS. Three long-term prospective studies have reported high rates (76–90%) of prevention of inducible VT during programmed ventricular stimulation while on regular quinidine (600–900 mg daily) for both symptomatic and asymptomatic patients.50–52 No cardiac deaths or definite ventricular arrhythmias were reported while on appropriate quinidine therapy in all patient groups.

The second approach is the empirical use of quinidine for prevention of arrhythmic events without electrophysiological verification. This has so far been mainly evaluated by a randomised trial of quinidine versus placebo of 50 patients with previously implanted ICD.53 While treatment appeared to be effective with no associated arrhythmic events observed, no significant result could be obtained due to low event rate in the placebo group as well as high rates of treatment discontinuation.

One substantial problem with quinidine therapy used as an alternative to ICD implantation is the issue of poor adherence and treatment discontinuation or interruption due to associated adverse effects, most commonly gastrointestinal.48 While treatment with low-dose quinidine (<600 mg daily) is associated with greater tolerability, it has only been investigated in a small number of patients.54,55 Another important, but less common, adverse effect of quinidine is QT interval prolongation that can result in the paradoxical initiation of ventricular arrhythmias.56 These concerns have limited the use of quinidine as a risk modification agent in low-risk asymptomatic people with Brugada syndrome, although an ongoing international registry study hopes to provide evidence to support this (NCT00789165).

Role of Radiofrequency Ablation in Brugada Syndrome

Radiofrequency ablation (RFA) of arrhythmogenic zones in the right ventricular epicardium has emerged over the past decade as a possible future curative treatment option for Brugada syndrome. However, only a small number of studies with limited follow-up periods have reported successful results with RFA in symptomatic Brugada patients.

The first to describe a successful RFA procedure in Brugada were Nademanee et al. using a selected cohort of nine high-risk patients with frequent ICD shocks for ventricular arrhythmias.57 All patients were found to have a unique arrhythmogenic focus at the anterior RVOT on epicardial mapping as well as typical type 1 ECG and inducible VT/VF at baseline. Following ablation, the ECG had normalised in 89% and VT/VF was no longer inducible in 78% of the cohort. Only one of the nine patients had a single subsequent arrhythmic event during the follow-up period (20 ± 6 months).

More recently, Brugada et al. and Pappone et al. described an improved technique for successful elimination of the Brugada syndrome phenotype with epicardial RFA.58,59 The mapping was performed before and after administration of flecainide/ajmaline which resulted in identification of more extensive arrhythmogenic segments in the RV epicardium beyond the RVOT. In the larger and more recent study, the described RFA procedure showed normalisation of ECG and nondeducibility of VT/VF in all of the 135 patients with symptomatic Brugada syndrome and previous ICD.59 Additionally, a type 1 ECG could not be provoked with ajmaline following RFA in the vast majority. During a median follow-up period of 10 months only two patients required a repeat procedure due to recurrent VF.

The only adverse effect reported for all the above studies was mild uncomplicated pericarditis after ablation.58,59 RFA treatment is therefore recommended for symptomatic patients with recurrent ICD shocks or as an alternative to ICD implantation when contraindicated.13,60 Whether this is a suitable alternative to ICD for people with high risk, or even an option for low risk people as a potential ‘cure’ remains to be determined.

Is Brugada Syndrome a Channelopathy or Cardiomyopathy?

Two main pathophysiogical mechanisms have been described for the formation of ventricular tachyarrhythmias leading to SCD in Brugada syndrome. Historically, Brugada syndrome was perceived as a repolarisation disorder, caused by the unequal expression of transient outward potassium current (mediated by a reduction in early sodium inflow) between the epicardium and inner myocardial layers. This results in abbreviation of the epicardial action potential and susceptibility to the formation of re-entry polymorphic ventricular tachycardia triggered by a premature ventricular complex (PVC), due to the epicardial-to-endocardial transmembrane ionic imbalance.61 The evidence for this theory is mainly derived from transmembrane action potential recording in canine right ventricular wedge preparations and is consistent with the clinical effects seen with quinidine, which reduces outward potassium current.62,63

The depolarisation theory is modelled around action potential conduction delay in the RVOT relative to the surrounding myocardium. Under such circumstances, ventricular tachyarrhythmias can be triggered by the resulting unequal membrane potential around the RVOT border, similar to the formation of ventricular tachyarrhythmia seen in circumstances of regional myocardial ischaemia.64 This theory is supported by several clinical studies demonstrating relative conduction delay in the RVOT.65–67

Brugada syndrome was originally described as a disease of cardiac ion channel dysfunction leading to sudden death in otherwise healthy people without the presence of associated structural heart disease.2 However, evidence demonstrating normalisation of the pathognomonic ECG pattern and elimination of the arrhythmic disposition in most patients following radiofrequency ablation of the RVOT epicardium supports the theory that structural abnormalities play an important role in the pathophysiology of Brugada syndrome.68

Indeed, recent results suggest that microanatomical changes such as increased collagen, fibrosis and reduced gap junction expression, which may be mediated by underlying pan-myocardial inflammation, are responsible for the characteristic electrographic pattern and arrhythmic susceptibility.68,69

As a result of these findings, Brugada syndrome and arrhythmogenic cardiomyopathy have been proposed to be part of the same disease spectrum.70 Although these two conditions have distinct macropathological appearance, known genetic predisposition and clinical features, several overlapping manifestations can be seen.2 The Brugada ECG pattern is seen in some patients with arrhythmogenic cardiomyopathy and sudden death can occur in the initial phase of the condition in the absence of its characteristic structural changes.71 Experimental data suggest that the arrhythmogenic process in both conditions is mediated by dysfunction of a complex protein network in the myocardial intercalated disc microarchitecture called the connexome.71 Nevertheless, while dysfunction of the connexome process may represent a common aetiology for Brugada syndrome and arrhythmogenic cardiomyopathy, the phenotypic presentation in Brugada syndrome appears to be restricted to microanatomical changes and sodium channel dysfunction in the RVOT region.

It therefore appears that the pathophysiology of disease generation and progression is more complex than initially described and greater understanding of these underlying processes is likely to improve the diagnosis and management of Brugada syndrome.

Conclusion

Brugada syndrome has been clouded in controversy since its first description more than three decades ago. While expert consensus has been reached on many aspects of the disease, a significant number of core issues such as the underlying pathophysiology of the disease, diagnostic criteria and risk stratification of asymptomatic patients remain unresolved. The unravelling of its underlying pathological mechanisms coupled with improved techniques and protocols for invasive mapping and ablation procedures shine an optimistic light on the possibility of a future cure for the syndrome.

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;20:1391–6.
    Crossref | PubMed
  2. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference. Circulation 2005;111:659–70.
    Crossref | PubMed
  3. Papadakis M, Papatheodorou E, Mellor G, et al. The diagnostic yield of Brugada syndrome after sudden death with normal autopsy. J Am Coll Cardiol 2018;71:1204–14.
    Crossref | PubMed
  4. Antzelevitch C, Yan G-X, Ackerman MJ, et al. J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge. Europace.2017;19:665–94.
    Crossref | PubMed
  5. Priori SG, Wilde AA, Horie M, et al. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Europace. 2013;15:1389–406.
    Crossref | PubMed
  6. Nagase S, Hiramatsu S, Morita H, et al. Electroanatomical correlation of repolarization abnormalities in Brugada syndrome: detection of type 1 electrocardiogram in the right ventricular outflow tract. J Am Coll Cardiol. 2010;56:2143–5.
    Crossref | PubMed
  7. Miyamoto K, Yokokawa M, Tanaka K, et al. Diagnostic and prognostic value of a type 1 Brugada electrocardiogram at higher (third or second) V1 to V2 recording in men with Brugada syndrome. Am J Cardiol 2007;99:53–7.
    Crossref | PubMed
  8. Veltmann C, Schimpf R, Echternach C, et al. A prospective study on spontaneous fluctuations between diagnostic and non-diagnostic ECGs in Brugada syndrome: implications for correct phenotyping and risk stratification. Eur Heart J 2006;27:2544–52.
    Crossref | PubMed
  9. Richter S, Sarkozy A, Veltmann C, et al. Variability of the diagnostic ECG pattern in an ICD patient population with Brugada syndrome. J Cardiovasc Electrophysiol 2009;20:69–75.
    Crossref | PubMed
  10. Shimeno K, Takagi M, Maeda K, et al. Usefulness of multichannel holter ECG Recording in the third intercostal space for detecting type 1 Brugada ECG: comparison with repeated 12-lead ECGs. J Cardiovasc Electrophysiol 2009;20:1026–31.
    Crossref | PubMed
  11. Polovina MM, Vukicevic M, Banko B, et al. Brugada syndrome: a general cardiologist’s perspective. Eur J Int Med 2017;44:19–27.
    Crossref | PubMed
  12. Brugada J, Campuzano O, Arbelo E, et al. Present status of Brugada syndrome: JACC state-of-the-art review. J Am Coll Cardiol 2018;72:1046–59.
    Crossref | PubMed
  13. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2018;15:e190–252.
    Crossref | PubMed
  14. Priori Silvia G, Napolitano C, Gasparini M, et al. Clinical and genetic heterogeneity of right bundle branch block and ST-segment elevation syndrome. Circulation 2000;102:2509–15.
    Crossref | PubMed
  15. Wolpert C, Echternach C, Veltmann C, et al. Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome. Heart Rhythm 2005;2:254–60.
    Crossref | PubMed
  16. Govindan M, Batchvarov VN, Raju H, et al. Utility of high and standard right precordial leads during ajmaline testing for the diagnosis of Brugada syndrome. Heart 2010;96:1904–8.
    Crossref | PubMed
  17. Letsas KP, Asvestas D, Baranchuk A, et al. Prognosis, risk stratification, and management of asymptomatic individuals with Brugada syndrome: a systematic review. Pacing Clin Electrophysiol 2017;40:133–245.
    Crossref | PubMed
  18. Sroubek J, Probst V, Mazzanti A, et al. Programmed ventricular stimulation for risk stratification in the Brugada syndrome. Circulation 2016;133:622–30.
    Crossref | PubMed
  19. Probst V, Veltmann C, Eckardt L, et al. Long-term prognosis of patients diagnosed with Brugada syndrome. Circulation 2010;121:635–43.
    Crossref | PubMed
  20. Raju H, Papadakis M, Govindan M, et al. Low prevalence of risk markers in cases of sudden death due to Brugada syndrome: relevance to risk stratification in Brugada syndrome. J Am Coll Cardiol 2011;57:2340–5.
    Crossref | PubMed
  21. Letsas KP, Liu T, Shao Q, et al. Meta-analysis on risk stratification of asymptomatic individuals with the Brugada phenotype. Am J Cardiol 2015;116:98–103.
    Crossref | PubMed
  22. Gehi AK, Duong TD, Metz LD, et al. Risk stratification of individuals with the Brugada electrocardiogram: A meta-analysis. J Cardiovasc Electrophysiol 2006;17:577–83.
    Crossref | PubMed
  23. Sarkozy A, Sorgente A, Boussy T, et al. The value of a family history of sudden death in patients with diagnostic type I Brugada ECG pattern. Eur Heart J 2011;32:2153–60.
    Crossref | PubMed
  24. Priori SG, Gasparini M, Napolitano C, 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.
    Crossref | PubMed
  25. Morita H, Kusano KF, Miura D, et al. Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome. Circulation 2008;118:1697–704.
    Crossref | PubMed
  26. de Asmundis C, Mugnai G, Chierchia G-B, et al. Long-term follow-up of probands with Brugada syndrome. Am J Cardiol 2017;119:1392–400.
    Crossref | PubMed
  27. Tokioka K, Kusano KF, Morita H, et al. Electrocardiographic parameters and fatal arrhythmic events in patients with Brugada syndrome: combination of depolarization and repolarization abnormalities. J Am Coll Cardiol 2014;63:2131–8.
    Crossref | PubMed
  28. Takagi M, Aonuma K, Sekiguchi Y, et al. The prognostic value of early repolarization (J wave) and ST-segment morphology after J wave in Brugada syndrome: multicenter study in Japan. Heart Rhythm 2013;10:533–9.
    Crossref | PubMed
  29. Kawata H, Morita H, Yamada Y, 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;10:1161–8.
    Crossref | PubMed
  30. Francis J, Antzelevitch C. Atrial fibrillation and Brugada syndrome. J Am Coll Cardiol 2008;51:1149–53.
    Crossref | PubMed
  31. Morita H, Kusano-Fukushima K, Nagase S, et al. Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome. J Am Coll Cardiol 2002;40:1437–44.
    Crossref | PubMed
  32. Brugada P, Brugada R, Mont L, et al. Natural history of Brugada syndrome. J Cardiovasc Electrophysiol 2003;14:455–7.
    Crossref | PubMed
  33. Fauchier L, Isorni MA, Clementy N, et al. Prognostic value of programmed ventricular stimulation in Brugada syndrome according to clinical presentation: An updated meta-analysis of worldwide published data. Int J Cardiol 2013;168:3027–9.
    Crossref | PubMed
  34. Delise P, Allocca G, Marras E, et al. Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach. Eur Heart J 2011;32:169–76.
    Crossref | PubMed
  35. Makimoto H, Kamakura S, Aihara N, et al. Clinical impact of the number of extrastimuli in programmed electrical stimulation in patients with Brugada type 1 electrocardiogram. Heart Rhythm 2012;9:242–8.
    Crossref | PubMed
  36. Sieira J, Conte G, Ciconte G, et al. Prognostic value of programmed electrical stimulation in Brugada syndrome. CircArrhythm Electrophysiol 2015;8:777–84.
    Crossref | PubMed
  37. Yuan M, Tian C, Li X, et al. gender differences in prognosis and risk stratification of Brugada syndrome: a pooled analysis of 4,140 patients from 24 clinical trials. Front Physiol 2018;9:1127.
    Crossref | PubMed
  38. Benito B, Sarkozy A, Mont L, et al. Gender differences in clinical manifestations of Brugada syndrome. J Am Coll Cardiol 2008;52:1567–73.
    Crossref | PubMed
  39. Sieira J, Conte G, Ciconte G, et al. Clinical characterisation and long-term prognosis of women with Brugada syndrome. Heart 2016;102:452.
    Crossref | PubMed
  40. Berthome P, Tixier R, Briand J, et al. Clinical presentation and follow-up of women affected by Brugada syndrome. Heart Rhythm 2019;16:260–7.
    Crossref | PubMed
  41. Probst V, Denjoy I, Meregalli PG, et al. Clinical aspects and prognosis of Brugada syndrome in children. Circulation 2007;115:2042–8.
    Crossref | PubMed
  42. Michowitz Y, Milman A, Andorin A, et al. Characterization and management of arrhythmic events in young patients with Brugada syndrome. J Am Coll Cardiol 2019;73:1756.
    Crossref | PubMed
  43. Kapplinger JD, Tester DJ, Alders M, et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm 2010;7:33–46.
    Crossref | PubMed
  44. Hosseini SM, Kim R, Udupa S, et al. Reappraisal of reported genes for sudden arrhythmic death. Circulation 2018;138:1195–205.
    Crossref | PubMed
  45. Yamagata K, Horie M, Aiba T, et al. Genotype-phenotype correlation of scn5a mutation for the clinical and electrocardiographic characteristics of probands with Brugada syndrome. Circulation 2017;135:2255–70.
    Crossref | PubMed
  46. BrugadaDrugs.org Advisory Board. Drugs to be avoided by Brugada syndrome patients. Available at: https://www.brugadadrugs.org/avoid/ (accessed 10 August 2019).
  47. Argenziano M, Antzelevitch C. Recent advances in the treatment of Brugada syndrome. Exp Rev Cardiovasc Therap 2018;16:387–40.
    Crossref | PubMed
  48. Brodie OT, Michowitz Y, Belhassen B. Pharmacological therapy in Brugada syndrome. Arrhythm Electrophysiol Rev 2018;7:135–42.
    Crossref | PubMed
  49. Anguera I, García-Alberola A, Dallaglio P, et al. Shock reduction with long-term quinidine in patients with Brugada syndrome and malignant ventricular arrhythmia episodes. J Am Coll Cardiol 2016;67:1653–4.
    Crossref | PubMed
  50. Belhassen B, Rahkovich M, Michowitz Y, et al. Management of Brugada syndrome: thirty-three-year experience using electrophysiologically guided therapy with class 1A antiarrhythmic drugs. Circ Arrhythm Electrophysiol 2015;8:1393–402.
    Crossref | PubMed
  51. Bouzeman A, Traulle S, Messali A, et al. Long-term follow-up of asymptomatic Brugada patients with inducible ventricular fibrillation under hydroquinidine. Europace 2014;16:572–7.
    Crossref | PubMed
  52. Hermida JS, Denjoy I, Clerc J, et al. Hydroquinidine therapy in Brugada syndrome. J Am Coll Cardiol2004 May 19;43:1853–60.
    Crossref | PubMed
  53. Andorin A, Gourraud JB, Mansourati J, et al. The QUIDAM study: hydroquinidine therapy for the management of Brugada syndrome patients at high arrhythmic risk. Heart Rhythm 2017;14:1147–54.
    Crossref | PubMed
  54. Márquez MF, Bonny A, Hernández-Castillo E, et al. Long-term efficacy of low doses of quinidine on malignant arrhythmias in Brugada syndrome with an implantable cardioverter-defibrillator: a case series and literature review. Heart Rhythm 2012;9:1995–2000.
    Crossref | PubMed
  55. Hasegawa K, Ashihara T, Kimura H, et al. Long-term pharmacological therapy of Brugada syndrome: is J-wave attenuation a marker of drug efficacy? Int Med 2014;53:1523–6.
    Crossref | PubMed
  56. Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation 2004;110:1731–7.
    Crossref | PubMed
  57. Nademanee K, Veerakul G, Chandanamattha P, et al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation 2011;123:1270–9.
    Crossref | PubMed
  58. Brugada J, Pappone C, Berruezo A, et al. Brugada syndrome phenotype elimination by epicardial substrate ablation. Circ Arrhythm Electrophysiol 2015;8:1373–81.
    Crossref | PubMed
  59. Pappone C, Brugada J, Vicedomini G, et al. Electrical substrate elimination in 135 consecutive patients with Brugada syndrome. Circ Arrhythm Electrophysiol 2017;10:e005053.
    Crossref | PubMed
  60. Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J 2015;36:2793–867.
    Crossref | PubMed
  61. Antzelevitch C. The Brugada syndrome: ionic basis and arrhythmia mechanisms. J Cardiovasc Electrophysiol 2001;12:268–72.
    Crossref | PubMed
  62. Yan GX, Antzelevitch C. Cellular basis for the Brugada Syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation 1999;100:1660–6.
    Crossref | PubMed
  63. Antzelevitch C, Yan GX, Shimizu W. Transmural dispersion of repolarization and arrhythmogenicity: the Brugada syndrome versus the long QT syndrome. J Electrocardiol 1999;32(Suppl 1):158–65.
    Crossref | PubMed
  64. Meregalli PG, Wilde AAM, Tan HL. Pathophysiological mechanisms of Brugada syndrome: Depolarization disorder, repolarization disorder, or more? Cardiovasc Res 2005;67:367–78.
    Crossref | PubMed
  65. Tukkie R, Sogaard P, Vleugels J, et al. Delay in right ventricular activation contributes to Brugada syndrome. Circulation 2004;109:1272–7.
    Crossref | PubMed
  66. Nagase S, Kusano KF, Morita H, et al. Epicardial electrogram of the right ventricular outflow tract in patients with the Brugada syndrome: Using the epicardial lead. J Am Coll Cardiol 2002;39:1992–5.
    Crossref | PubMed
  67. Izumida N, Asano Y, Doi S, et al. Changes in body surface potential distributions induced by isoproterenol and Na channel blockers in patients with the Brugada syndrome. Int J Cardiol 2004;95:261–8.
    Crossref | PubMed
  68. Pieroni M, Notarstefano P, Oliva A, et al. Electroanatomic and pathologic right ventricular outflow tract abnormalities in patients with Brugada syndrome. J Am Coll Cardiol 2018;72:2747–57.
    Crossref | PubMed
  69. Nademanee K, Raju H, de Noronha SV, et al. Fibrosis, connexin-43, and conduction abnormalities in the Brugada syndrome. J Am Coll Cardiol 2015;66:1976–86.
    Crossref | PubMed
  70. Moncayo-Arlandi J, Brugada R. Unmasking the molecular link between arrhythmogenic cardiomyopathy and Brugada syndrome. Nat Rev Cardiol 2017;14:744.
    Crossref | PubMed
  71. Agullo-Pascual E, Cerrone M, Delmar M. Arrhythmogenic cardiomyopathy and Brugada syndrome: diseases of the connexome. FEBS Lett 2014;588:1322–30.
    Crossref | PubMed