Risk Stratification and Therapeutic Approach in Brugada Syndrome

Login or register to view PDF.
Abstract

Brugada syndrome (BrS) is a clinical entity characterised by an incomplete right bundle branch block associated with an ST segment elevation in the right precordial leads and a risk of ventricular arrhythmia and sudden death in the absence of structural abnormalities. Patients with a personal history of sudden death have an annual arrhythmia risk of recurrence as high as 10 %. Similarly, the presence of syncope is consistently associated with an increased arrhythmic risk. This risk can be estimated at about 1.5 % per year. The risk is lower in asymptomatic patients. Regarding the relatively high rate of complication of Implantable cardioverter defibrillator (ICD) implantation, in most of the cases, asymptomatic patients with a Brugada syndrome revealed during ajmaline challenge do not need to be implanted. The situation is more complex in patients with a spontaneous type 1 aspect since the risk could be estimated to be around 0.8 % per year. For these patients, a careful evaluation of the arrhythmic risk using all the different tools available is mandatory.

Disclosure
The authors have no conflicts of interest to declare.
Correspondence
Vincent Probst, Service de cardiologie du CHU de Nantes, CHU de Nantes, Hôpital Nord, Bd Jacques Monod, 44093 Nantes Cedex, Fra nce. E: vincent.probst@chu-nantes.fr
Received date
02 July 2012
Accepted date
02 August 2012
Citation
Arrhythmia & Electrophysiology Review 2012; 1 :17–21
DOI
http://dx.doi.org/10.15420/aer.2012.1.17

Brugada syndrome (BrS) is a clinical entity identified in 1992 by Brugada brothers from a file of patients resuscitated from sudden cardiac death (SCD).1 Of these patients, some had a specific electrocardiogram (ECG) appearance characterised by an incomplete right bundle branch block associated with an ST segment elevation in the right precordial leads. It quickly became apparent that this disease was often familial with an autosomal dominant mode of inheritance. This ECG pattern is associated with an increased risk of sudden death resulting from polymorphic ventricular tachycardia (VT) and/or ventricular fibrillation (VF) in absence of structural abnormalities.

There is a strong male predominance (eight cases out of 10) and Brugada syndrome is usually found in patients older than forty years old.2–4 However, some cases have been described in very young children as well as in elderly people.5 BrS, initially considered as an extremely rare disease, is actually found in 4 % of patients with aborted SCD and represents 20 % of sudden deaths without underlying heart disease.3 The prevalence can be estimated around 5/10000. However, geographic disparities are observed with a higher frequency in Asia than in west Europe or North America.3,4

Diagnosis

The diagnostic criteria were well specified in two consensus conferences. Diagnosis of BrS can be performed only if a ≥2 mm ST-segment elevation in two consecutive leads is observed. It is also required a convex or triangular ST-elevation followed by a negative T wave in the same leads (see Figure 1).3,4

To perform BrS diagnosis, other possible causes of ST segment elevation, like ischemia or cardiomyopathies have to be eliminated.

Diagnosis of BrS can be established either on a basal electrocardiogram or after sodium channel blockers challenge. Several drugs can be used like flecainide, pilsicainide or ajmaline. When these tests are performed according to consensus conference recommendations, risk of accidents during the test is low.6–8 The aspects of type 2 or 3 of BrS, if not converted to type 1 aspect during sodium channel blocker challenge, are not related to an increase risk of SCD.

If making the diagnosis of BrS isn’t a real problem, evaluation of the prognosis is much more difficult. Over the last years, through the establishment of large databases, it became possible to have a relatively accurate idea of the risk associated with BrS at a population level.2,9–11 For this, clinical, electrocardiographic and eventually genetic data can be used.

However, it is important to keep in mind that these criteria are only valid at the population level and they have a limited value at the individual level. Therefore, one should be extremely cautious about the risk assessment that could be given to a single patient.

Clinical Parameters

Since the identification of BrS, several clinical parameters were found to be highly predictive of arrhythmia and sudden death occurrence.

Figure 1: Different Aspects of Brugada Syndrome – Only the Type 1 Aspect is Linked to an Arrhythmic Risk

Open in new tab

Figure 2: Electrogram of a Ventricular Fibrillation Successfully Treated by an Appropriated Shock in a Brugada Syndrome Patient

Open in new tab

Patients with a personal history of sudden death have an annual arrhythmia’s risk as high as 10 %.2,9–12 Similarly, the presence of syncope is consistently associated with an increased arrhythmic risk.2,9–11 This risk can be estimated at about 1.5 % per year. The difficulty for the assessment of arrhythmic risk associated with syncope is based on the ability to differentiate arrhythmic syncope from simple neurally mediated syncope. This is not so easy in clinical practice because patients affected by BrS are also frequently affected by neurally mediated syncope regardless clinical presentation of BrS.12,13 However, it has been recently demonstrated that only arrhythmic syncope are linked to an increase risk of ventricular fibrillation and SCD.13 In this situation, it is important to obtain all possible information to determine the actual cause of syncope. In case of arrhythmic origin syncope, given the risk of SCD, there is no doubt that an ICD is needed. However, when doubt remains about the nature of syncope, it may be useful to perform electrophysiological studies (EPS) to search for other abnormalities that could explain syncope, or even to implant implantable loop recorders to avoid too systematically implantation of ICD in patients who do not need.14 This is especially true regarding the high rate of complications in BrS patients implanted with an ICD.15

Other parameters like sex and age are clearly related to an increase risk of arrhythmia. There is a clear risk peak for cardiac arrhythmias occurrence and sudden death at the age of 40 years old. This criterion must be taken into account when assessing the patient’s risk. Indeed, BrS is mainly diagnosed in 40-year-old men. Thus, this population is over-represented in databases leading to an over-estimation of arrhythmic risk in populations that do not correspond to this category of patients (especially women and those aged over 60 years). Follow–up information for these categories of patients remains very limited.5,16

The presence of SCD in family is usually not considered as a risk factor for sudden death albeit some controversies exist.2,9–11,17 The assessment of familial SCD role is complex because usually in cases of sudden death, family screening is carried out more completely leading to the identification of patients whose risk is lower. This bias can lead to an underestimation of overall risk in families affected by sudden death.

Electrocardiographic Parameters

Since the identification of BrS, special attention was paid to electrocardiogram analysis in an attempt to determine arrhythmic risk.

Numerous parameters have been proposed. However, it should be noted that for most of these parameters, there was no prospective evaluation and no validation in a replication population that strongly limits the use of these parameters in daily clinical practice.

Presence of a spontaneous aspect of BrS is found consistently as an important risk of arrhythmias occurrence in different databases. This is true both in symptomatic and asymptomatic patients.2,9–11 It also appears that the presence of an intermittent type 1 aspect is associated with an increased risk of arrhythmias. It is also now clear that there is no difference in term of prognosis regarding the precordial leads where ST segment elevation is found. Presence of type 1 aspect at the third or fourth intercostal space is more a matter of morphology of the patient than a modification of the electrophysiological substrate.18

Type 1 burden could be seen as a marker of interest in risk classification. It should be noted that so far, likely due to technical difficulties to evaluate over a long period this parameter, there are few data supporting use of specific tools during a Holter ECG for assessment of type 1 burden.19

Presence of an increase of ST-segment elevation during recovery from exercise testing can be a predictor of poor prognosis, especially for patients with syncope alone and for asymptomatic patients.20 Prominent R wave in lead aVR may reflect more right ventricular conduction delay and subsequently more electrical heterogeneity, which in turn could be responsible for a higher risk of arrhythmia in BrS patients.21

Presence of fragmented QRS has long been recognised as a prognostic factor of interest. The evaluation of QRS fragmentation can be performed during an electrocardiogram with signal averaged ECG.22,23 Recently, presence of fragmentation on ascending limb of QRS defined as two or more spikes within the QRS complex in leads V1 to V3 has been shown to have prognostic value.9 QRS duration seems also to have some prognosis value.24

Early repolarisation is frequently identified in patients affected by BrS. However, this aspect does not change prognosis of these patients.25 T wave alternance has also been proposed as a marker of risk. However, up to now there is little clinical information and this parameter could not be used in clinical practice.26

Repolarisation dispersion has also been involved in the occurrence of ventricular arrhythmia in BrS patients and is one of the major components of the pathophysiological hypothesis to explain BrS for both repolarisation and depolarisation hypothesis. One way to explore repolarisation dispersion is to analyse Tpeak-Tend dispersion on a surface ECG. This parameter has been related to positivity of electrophysiological study.27 Its value to determine the risk in BrS patients is more controversial.28

Role of the Electrophysiological Study

In the current literature, the predictive value of EPS is highly controversial. Indeed, while some authors report a high prognostic significance of EPS, others deny its usefulness.2,9–11,29–32 In 2005, the second consensus conference issued a Class IIa for use of EPS in patients with a spontaneous type 1 ECG and a Class IIb for EPS in patients without a spontaneous type 1 pattern.3 In 2006, the American Heart Association/ American College of Cardiology/ European Society of Cardiology guidelines for prevention of sudden death reflected the ongoing debate and did not provide stringent indication for EPS in BrS (Class IIb).33

Reasons why data is so controversial regarding the use of EPS in patients with BrS are probably multiple. These include a lack of homogeneity in protocols used for EPS, patient’s criteria selection, geographic and ethnic patient’s origin and the exhaustively of the follow-up after the EPS. Probably, the main cause of variation in EPS results remained the statistical methods used to evaluate usefulness of EPS. Indeed, the difficulty in analysing EPS value is that the results of EPS will change the management of patient. In most cases, when EPS is positive the patient is implanted with an ICD and then they will be carefully observed with frequent consultations and home monitoring. All the arrhythmic events will be recorded, even if the event is only a short run of polymorphic VT. Sometimes this can be totally asymptomatic and still be treated by the ICD with an appropriated shock.

On the contrary, in asymptomatic patients with a negative EPS, monitoring is not always performed in a tertiary center (since the information is given directly to the patient, they carry a low arrhythmic risk). In this case, complete follow-up is more difficult to obtain and probably not exhaustive in particular in patients who remained asymptomatic.

Recent results of Programmed electrical stimulation predictive value (PRELUDE) study demonstrate the prognosis value of EPS, seem to close the debate.9 Interestingly, in this study it was demonstrated that a short ventricular refractory period seems to be a strong prognosis parameter. This criterion has still to be demonstrated on an independent cohort of patients to be used in clinical practice.9

Use of Genetic to Evaluate the Risk of Arrhythmia

Twelve genes have been associated with Brugada syndrome. Involvement of SCN5A was the result of a candidate gene approach in 1998. Since, many mutations in this gene have been described in patients with BrS.

SCN5A-encoded cardiac sodium channel “loss-of-function” mutations provide pathogenic basis for an estimated 15-30 % of BrS, currently representing the most common BrS genotype.2,9,34,35 However, it must be recognised that nearly 2 % of healthy Caucasians and 5 % of non-whites also host rare mis-sense SCN5A mutations, leading to a potential conundrum in the interpretation of genetic test.35 In addition, it has recently been shown that if presence of mutations in SCN5A gene was strongly correlated with a presence of conduction disturbances, their relations with BrS were complex. Besides a low penetrance of these mutations there is a high frequency of phenocopies. These data are surprising in the context of a rare disease.36

Figure 3: Electrogram of an Oversensing of the T wave and Electrical Noise Leading to an Inappropriate Shock

Open in new tab

Regarding the genotype-phenotype relationships, ECG profiles of mutated and non-mutated patients can be distinguished by the longer conduction time in patients carrying a SCN5A mutation.37

A second locus was identified in 2002 by a family approach leading finally to identification of a GPD1L mutation.38 Recently, loss-of-function mutations in cardiac calcium channel (CACNA1C) and its regulatory subunit CACNB2b were detected in patients with Brugada syndrome sometimes associated with a QT interval shorter than normal.39 It is still early to state frequency of mutations in the L–type calcium channel, although authors suggested that it would be 4.9 % in BrS patients with a normal QT duration (> 370 ms).

From two families, mutations in the SCN1B gene were identified leading to a decrease of sodium current and inducing conduction disturbances and an aspect of BrS in some patients.40 More recently, a mutation in MOG1 gene, partner of Nav 1.5, was identified.41 Several gain of function mutations have been described in genes associated with Ito current (KCNE3, KCNE5 and KCND3) in sporadic cases of Brugada syndrome.42–44 Mutations were also identified in SCN3B, KCNJ8 and CACNA2D1.39,45,46

The low frequency of the detected mutations in the genes other than SCN5A prevents the possibility to evaluate a genotype-phenotype correlation.47

Even if more data are available for SCN5A mutation carriers, up to now, there is no relation between arrhythmic risk and presence of SCN5A mutation. A recent study showed that SCN5A mutation–positive patients present a significantly longer PQ interval, and that 39 % of BrS patients with a PQ interval ≥ 200 ms carry a SCN5A mutation.47

Currently and until further studies are available, genetic analysis could not be part of arrhythmic evaluation in BrS.

Therapeutic Consideration

Medical Treatment

Currently, no medical therapy has proven its efficacy in BrS. Several case reports and retrospective studies are in favour of a possible therapeutic effect of quinidine therapy.48,49 This drug could be used in symptomatic patients implanted with an ICD in whom frequently appropriate ICD shock occurred or in children.50 Data are missing concerning use of quinidine treatment in primary prevention in non–implanted patients. Some studies showed a beneficial effect to decrease the rate of positivity of EPS.51 However, regarding the low predictive value of EPS, potential pro-arrhythmic effect of the drug and low frequency of arrhythmic event in asymptomatic patients, use of quinidine in primary prevention in asymptomatic patients could not be encouraged. Many drugs such as antiarrhythmic or some antidepressant may increase ST segment elevation and for some of them increase risk of arrhythmic events. A list of these drugs should be provided to patients.52

Arrhythmic events frequently occurred during fever episode. For this reason, patients have to be informed to actively treated fever with anti pyretic treatment.

BrS is often a family disease. It is important to investigate presence of electrocardiographic abnormalities in first-degree relatives.

ICD implantation should be regarded as the perfect treatment for BrS patients. As the only risk is occurrence of VF, ICD is the perfect device to detect and treat VF. Unfortunately, because of a high rate of complications in patients implanted with an ICD, the situation is more complex. Inappropriate shocks occurred at an annual rate of 2.5 % per year and at five years 20 % of patients experienced lead failure.15

In symptomatic patients, there is no doubt about indication for ICD implantation. Patients should be interviewed carefully for atypical symptoms such accidental nocturnal enuresis or abnormal nocturnal breathing which may be considered as an equivalent of aborted sudden death.

The question of ICD implantation is much problematic in asymptomatic patients. In asymptomatic patients without a spontaneous type 1 aspect, arrhythmic risk is low (0.3 % per year in FINGER registry).2 In this situation, risks of ICD complications clearly outweigh risks of BrS and a careful annual follow-up should be proposed to the patient.

In asymptomatic patients with a spontaneous type 1 aspect of BrS, the arrhythmic risk is around 0.8 % per year. Therapeutic decision is much more complex here. All different parameters described before should be used in order to better determinate specific patient’s risk. However, as we do not have tools that can clearly distinguish patients who will experience sudden death and those who will remain asymptomatic all their life, special attention should be paid to patient’s wishes. This is particularly important for ICD implantation and it must be explain to the patient that on a statistical point of view, it is more likely that he will experience ICD complications rather than appropriate shock. Under these conditions, it is essential to obtain good patient adherence to treatment choice, to ensure a satisfactory quality of life.53

If finally an ICD is implanted, the choice of type of ICD will be preferentially VVI ICD with a monocoil active lead to facilitate future ICD lead extraction. To limit the risk of inappropriate shock, ICD program must be as simple as possible with a unique VF zone higher that 220 bpm (see Figure 2). During implantation special attention should be paid to obtain a good detection of R wave to reduce risk of T waves oversensing (see Figure 3).

In patients who frequently received electric shock, treatment with quinidine may be proposed. In case of recurrence of VF, it has been recently propose to perform ablation of the RVOT epicardium.54

Conclusion

Arrhythmic risk stratification and therefore treatment decisions remained complex in Brugada syndrome patients. In patients with an intermediate risk, it is essential to give clear information to patients, explaining that it remains many questions about the optimal management of this disease. In this situation, a careful evaluation of the arrhythmic risk using all the different tools available is mandatory.

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. Probst V, et al. Long-term prognosis of patients diagnosed with Brugada syndrome: Results from the FINGER Brugada Syndrome Registry. Circulation 2010;121:635–43.
    Crossref | PubMed
  3. Antzelevitch C, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005;111:659–70.
    Crossref | PubMed
  4. Wilde AAM, et al. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation 2002;106:2514–9.
    Crossref | PubMed
  5. Probst V, et al. Clinical aspects and prognosis of Brugada syndrome in children. Circulation 2007;115:2042–8.
    Crossref | PubMed
  6. Hong K, et al. Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations. Circulation 2004;110:3023–7.
    Crossref | PubMed
  7. Veltmann C, et al. Response to intravenous ajmaline: a retrospective analysis of 677 ajmaline challenges. Europace 2009;11:1345–52.
    Crossref | PubMed
  8. Brugada J, Brugada P, Brugada R. The ajmaline challenge in Brugada syndrome: a useful tool or misleading information? Eur Heart J 2003;24:1085–6.
    Crossref | PubMed
  9. Priori SG, 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
  10. Priori SG, et al. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation 2002;105:1342–7.
    Crossref | PubMed
  11. Brugada J, et al. Long-term follow-up of individuals with the electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V1 to V3. Circulation 2002;105:73–8.
    Crossref | PubMed
  12. Brugada P, Brugada J, Brugada R. The yet unresolved dilemma of syncope in Brugada syndrome. Europace 3, 2001;157–8.
    Crossref | PubMed
  13. Sacher F, et al. Syncope in Brugada syndrome patients: Prevalence, characteristics, and outcome. Heart Rhythm 2012;9(8):1272–9.
    Crossref | PubMed
  14. Kubala M, Aïssou L, Traullé S, et al. Use of implantable loop recorders in patients with Brugada syndrome and suspected risk of ventricular arrhythmia. Europace 2012:14:898–902.
    Crossref | PubMed
  15. Sacher F, et al. Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study. Circulation 2006;114:2317–24.
    Crossref | PubMed
  16. Sacher F, et al. Are women with severely symptomatic Brugada syndrome different from men? J Cardiovasc Electrophysiol 2008;19:1181–5.
    Crossref | PubMed
  17. Sarkozy A, 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
  18. Miyamoto 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
  19. Extramiana F, et al. Quantitative assessment of ST segment elevation in Brugada patients. Heart Rhythm 2006;3:1175–81.
    Crossref | PubMed
  20. Makimoto H, et al. Augmented ST-segment elevation during recovery from exercise predicts cardiac events in patients with Brugada syndrome. J Am Coll Cardiol 2010;56:1576–84.
    Crossref | PubMed
  21. Babai Bigi MA, Aslani A, Shahrzad S. aVR sign as a risk factor for life-threatening arrhythmic events in patients with Brugada syndrome. Heart Rhythm 2007;4:1009–12.
    Crossref | PubMed
  22. Morita H, 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
  23. Das MK, et al. Fragmented QRS on a 12-lead ECG: a predictor of mortality and cardiac events in patients with coronary artery disease. Heart Rhythm 2007;4:1385–92.
    Crossref | PubMed
  24. Takagi A, Nakazawa K, Sakurai T, et al. Prolongation of LAS40 (duration of the low amplitude electric potential component (<40 microV) of the terminal portion of the QRS) induced by isoproterenol in 11 patients with Brugada syndrome. Circ J 2002;66:1101–4.
    Crossref | PubMed
  25. Letsas KP, et al. Prevalence of early repolarization pattern in inferolateral leads in patients with Brugada syndrome. Heart Rhythm 2008;5:1685–9.
    Crossref | PubMed
  26. Fish JM, Antzelevitch C. Cellular and ionic basis for the sex-related difference in the manifestation of the Brugada syndrome and progressive conduction disease phenotypes. J Electrocardiol 2003;3:(6 Suppl.):173–9.
    Crossref | PubMed
  27. Letsas KP, Weber R, Astheimer K, et al. Tpeak-Tend interval and Tpeak-Tend/QT ratio as markers of ventricular tachycardia inducibility in subjects with Brugada ECG phenotype. Europace 2010;12:271–4.
    Crossref | PubMed
  28. Wang J, et al. [Tpeak-Tend interval and risk of cardiac events in patients with Brugada syndrome], Zhonghua Xin Xue Guan Bing Za Zhi 2007;35:629–32.
    PubMed
  29. Gehi AK, Duong TD, Metz LD, et al. Risk stratification of individuals with the Brugada electrocardiogram: a metaanalysis. J Cardiovasc Electrophysiol 2006;17:577–83.
    Crossref | PubMed
  30. Delise P, 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
  31. Brugada P, Geelen P, Brugada R, et al. Prognostic value of electrophysiologic investigations in Brugada syndrome. J Cardiovasc Electrophysiol 2001;12:1004–7.
    Crossref | PubMed
  32. Brugada J, Brugada R, Brugada P. Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest. Circulation 2003;108:3092–6.
    Crossref | PubMed
  33. Zipes DP, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e385–484.
    Crossref | PubMed
  34. Schulze-Bahr E, et al. Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: different incidences in familial and sporadic disease. Hum Mutat 2003;21:651–2.
    Crossref | PubMed
  35. Kapplinger JD, 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
  36. Probst V, et al. SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome. Circ Cardiovasc Genet 2009;2:552–7.
    Crossref | PubMed
  37. Smits JPP, et al. Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5Arelated patients. J Am Coll Cardiol 2002;40:350–6.
    Crossref | PubMed
  38. London B, et al. Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias. Circulation 2007;116:2260–8.
    Crossref | PubMed
  39. Antzelevitch C, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 2007;115:442–9.
    Crossref | PubMed
  40. Watanabe H, et al. Sodium channel beta1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. J Clin Invest 2008;118:2260–8.
    Crossref | PubMed
  41. Kattygnarath D, et al. MOG1: A new susceptibility gene for Brugada syndrome. Circ Cardiovasc Genet 2011;4(3):261–8.
    Crossref | PubMed
  42. Delpón E, et al. Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome. Circ Arrhythm Electrophysiol 2008;1:209–18.
    Crossref | PubMed
  43. Ohno S, et al. KCNE5 (KCNE1L) variants are novel modulators of Brugada syndrome and idiopathic ventricular fibrillation. Circ Arrhythm Electrophysiol 2011;4:352–61.
    Crossref | PubMed
  44. Giudicessi JR, et al. Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome. Heart Rhythm 2011;8:1024–32.
    Crossref | PubMed
  45. Hu D, et al. A mutation in the beta 3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype, Circ Cardiovasc Genet 2009;2:270–8.
    Crossref | PubMed
  46. Medeiros-Domingo A, et al. Gain-of-function mutation, S422L, in the KCNJ8-encoded cardiac K ATP channel Kir6.1 as a pathogenic substrate for J Wave syndromes. Heart Rhythm 2010;7(10):1466–71.
    Crossref | PubMed
  47. Crotti L, et al. Spectrum and prevalence of mutations involving BrS1- through BrS12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome Genetic Testing: Implications for Genetic Testing. J Am Coll Cardiol 2012; [Epub ahead of print].
  48. Hermida JS, et al. Hydroquinidine therapy in Brugada syndrome. J Am Coll Cardiol 2004;43:1853–60.
    Crossref | PubMed
  49. Probst V, et al. Monomorphic ventricular tachycardia due to Brugada syndrome successfully treated by hydroquinidine therapy in a 3-year-old child. J Cardiovasc Electrophysiol 2006;17:97–100.
    Crossref | PubMed
  50. Baruteau AE, Mabo P, Probst V. Quinidine therapy in children affected by Brugada syndrome: are we far from a safe alternative? Cardiol Young 2009;19:652–4.
    Crossref | PubMed
  51. Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation 2004;110:1731–7.
    Crossref | PubMed
  52. Postema PG, et al. Drugs and Brugada syndrome patients: review of the literature, recommendations, and an up-todate website (www.brugadadrugs.org). Heart Rhythm 2009;6:1335–41.
    Crossref | PubMed
  53. Probst V, et al. The psychological impact of implantable cardioverter defibrillator implantation on Brugada syndrome patients. Europace 2011;13(7):1034–9.
    Crossref | PubMed
  54. Nademanee K, 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