REVIEW ARTICLE

Prognosis, risk stratification and management of asymptomatic individuals with Brugada syndrome: a systematic review

Konstantinos P. Letsas1, MD, FEHRA, Dimitrios Asvestas1, MD, Adrian Baranchuk2, MD, PhD, Tong Liu3, MD, PhD, Stamatis Georgopoulos1, MD, Michael Efremidis1, MD, Panagiotis Korantzopoulos4, MD, PhD, George Bazoukis1, MD, Gary Tse5,6, MBBS, PhD, FESC, FACC, Antonios Sideris1, MD, Masahiko Takagi 7, MD, PhD, FHRS, Joachim R. Ehrlich8, MD, FESC, FHRS, FAHA.

1

Second Department of Cardiology, Laboratory of Cardiac Electrophysiology, Evangelismos General

Hospital of Athens, Greece; 2

Division of Cardiology, Queen's University, Kingston General Hospital, Kingston, Ontario, Canada;

3

Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical

University, People’s Republic of China; 4

Department of Cardiology, University Hospital of Ioannina, Greece;

5

Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, SAR, P.R.

China;

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/pace.13214.

This article is protected by copyright. All rights reserved.

6

Li Ka Shing Institute of Health Sciences, 30-32 Ngan Shing St, Chinese University of Hong Kong,

Hong Kong, SAR, P.R. China; 7

Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Osaka,

Japan; 8

Electrophysiology Section, St. Josefs-Hospital, Wiesbaden, Germany.

Running title: Risk stratification in Brugada syndrome.

Conflict of interest: None to declare

Corresponding author: Konstantinos P. Letsas, MD, FEHRA Laboratory of Cardiac Electrophysiology Evangelismos General Hospital of Athens, 10676, Athens, Greece Fax: +302132041344 e-mail: [email protected]

Abstract Brugada syndrome (BrS) is a primary electrical disease associated with increased risk of sudden cardiac death due to polymorphic ventricular arrhythmias. The prognosis, risk stratification and management of asymptomatic individuals remain the most controversial issues in BrS. Furthermore, the decision to manage asymptomatic patients with an implantable cardioverter defibrillator should be made after weighing the potential individual risk of future arrhythmic events against the risk of complications associated with the implant and follow-up of patients living with 2 This article is protected by copyright. All rights reserved.

such devices, and the accompanying impairment of the quality of life. Several clinical, electrocardiographic and electrophysiological markers have been proposed for risk stratification of subjects with BrS phenotype, but the majority have not yet been tested in a prospective manner in asymptomatic individuals. Recent data suggest that current risk factors are insufficient and cannot accurately predict sudden cardiac death events in this setting. This systematic review aims to discuss contemporary data regarding prognosis, risk stratification and management of asymptomatic individuals with diagnosis of Brugada ECG pattern and to delineate the therapeutic approach in such cases.

Key-words: Brugada syndrome; risk stratification; sudden cardiac death.

Introduction Brugada syndrome (BrS) is a primary electrical disease characterized by ST-segment elevation in the right precordial leads on the surface electrocardiogram (ECG), in the absence of any apparent structural heart disease, and increased risk of sudden cardiac death (SCD) due to polymorphic ventricular arrhythmias.1-5 The syndrome is considered responsible for 4-12% of all sudden deaths and at least 20% of deaths in patients with structurally normal hearts.3 The clinical phenotype is 8 to 10 times more prevalent in males than in females.3-5 BrS typically manifests with syncope or cardiac arrest, in the third or fourth decade of life, and usually at rest or during sleep.3-5 Currently, subjects with spontaneous type 1 ECG pattern and aborted SCD or syncope of arrhythmic origin are at the highest risk for future arrhythmic events and are advised to receive an implantable cardioverter defibrillator (ICD).6,7 On the contrary, the prognosis, risk stratification, and management of asymptomatic individuals and particularly those with spontaneous type-1 ECG pattern of BrS, still remain obscure. Several clinical, ECG and electrophysiological markers have been proposed for risk stratification of subjects with BrS phenotype, but most of them have not yet been tested in a prospective manner in asymptomatic individuals.3-5 There is some evidence which demonstrated low event rates in asymptomatic patients with BrS.8 However, emerging evidence clearly underscores our inability to stratify asymptomatic subjects with Brugada ECG pattern. In a study of 50 individuals with SCD, the majority of SCDs related to BrS occurred in asymptomatic 3 This article is protected by copyright. All rights reserved.

individuals (72%).9 Based on the Second Expert Consensus Conference on BrS, 68% of this population would have been categorized as low risk.3,10 These data suggest that current risk factors are insufficient or are not properly geared to predict SCD events in asymptomatic patients with BrS. The current review aims to focus on the prognosis, risk stratification and management of asymptomatic individuals with a diagnosis of Brugada ECG pattern based on available data mainly derived from registries. A critical reappraisal of the known clinical, ECG and electrophysiological tools used for risk stratification of these individuals will also be provided.

Brugada ECG pattern and diagnosis According to the 2013 expert consensus statement on diagnosis and management on patients with inherited primary arrhythmia syndromes6, the 2015 guidelines for the management of patients with ventricular arrhythmia and prevention of sudden cardiac death7, and the J-Wave syndromes expert consensus conference report11, the diagnosis of BrS is based on specific ECG characteristics: J-point elevation ≥ 2mm followed by coved-type ST-segment elevation ≥ 2mm and negative T-wave (type-1 pattern) in at least one of the right precordial leads V1 and V2 positioned in the 2nd, 3rd or 4th intercostal space occurring either spontaneously or after pharmacological challenge (sodium channel blocking test) with a Class I antiarrhythmic agent (ajmaline, flecainide, procainamide or pilsicainide) which can convert type-2 or type-3 ECG patterns to type-1 (Figure 1a, b and c). Type-2 pattern displays a high take-off of ≥ 2mm and a saddleback ST-segment configuration ≥1 mm (Figure 1d). Type-3 is characterized by J-point elevation of less than 2mm and either a saddleback or coved-type ST-segment elevation of ≤ 1mm. 3,6,7,11 In contrast with previous reports where the term “Brugada Syndrome” referred only to symptomatic patients with type-1 ECG pattern,3 the diagnostic “Brugada ECG pattern”, according to the latest reports,6,7,11 is synonymous to the “Brugada Syndrome”. However, it is worthwhile to mention that the “Brugada ECG pattern” has been reported in various clinical settings. “Brugada phenocopies” have identical ECG patterns to true congenital BrS, but are elicited by different clinical circumstances.12 The recent J-Wave syndromes expert consensus conference report11 recommends that when a type-1 ECG pattern is unmasked after sodium channel blocking test, the diagnosis of BrS requires the presence one of the following: documented ventricular fibrillation (VF) or polymorphic ventricular tachycardia (VT), syncope of probable arrhythmic cause, a family history of SCD at 460 ms in lead V2 as well as an increased Tpeak-Tend interval, and Tpeak-Tend dispersion in precordial leads have been associated with life-threatening arrhythmic events in BrS.73 Similarly, Maury et al. reported that an increased Tpeak-Tend interval and dispersion was significantly higher in patients with sudden death 10 This article is protected by copyright. All rights reserved.

and appropriate ICD therapies confirming that the Tpeak-end interval is highly related to arrhythmic events of the BrS patients.74 The appearance of T-wave alternans after pilsicainide administration was predictive for spontaneous VF.75 The early repolarization (ER) pattern in inferior and/or lateral leads is commonly seen in BrS (12-15%).77-79 We initially failed to demonstrate any association between ER pattern and malignant arrhythmic events in BrS.76 Several other studies have shown that the ER pattern is predictive of future arrhythmic events.77-79 In particular, Takagi et al. have demonstrated that BrS patients with inferolateral J waves or horizontal ST-segment morphology after the J wave display a high incidence of cardiac events than those without.79 We have recently conducted a meta-analysis on the prognostic significance of ER pattern in BrS.80 Overall, BrS patients with ER pattern displayed an increased risk of arrhythmic events compared to patients without ER (OR 3.29). An inferolateral location (OR 4.87) conferred higher arrhythmic risk compared to inferior (OR 1.95) and lateral (OR 0.43) location.80 Based in these findings, the inferolateral ER pattern in BrS (global ER) appears to be highly arrhythmogenic. However, the presence of the global ER pattern warrants prospective evaluation as valid arrhythmogenic risk marker, particularly in the setting of

multiparametric models with other arrhythmogenic markers in BrS. Other investigators showed the prognostic significance of the combination of repolarization and depolarization disorders. A recent study demonstrated that the combination of ER pattern and QRS-fragmentation is an independent predictor of arrhythmic events.81 ST-segment augmentation at the early recovery after exercise has been significantly associated with a higher cardiac event rate, notably for patients with previous episode of syncope or for asymptomatic patients.47 Amin et al. found that exercise in BrS affect the ECG phenotype inducing changes which are known to increase the risk of cardiac arrest. The QRS interval becomes wider during exercise in BrS with SCN5A+ probably associated at more Ina reduction. Similarly, an augmentation of peak J-point elevation has been observed with the maximum amplitude at the early phase of recovery time.82 Another important ECG parameter in BrS is the ST-segment elevation in peripheral leads. Rollin et al. demonstrated that ST-segment elevation in these leads is present in approximately 10% of BrS and associated with more severe phenotype and higher risk of arrhythmogenic events.83 An additional predictive factor of cardiac arrhythmic events is the presence of conduction abnormalities. First degree atrioventricular block has been independently associated with SCD or appropriate ICD therapies.84 Miyamoto et al. revealed that a prolonged PQ≥170ms in lead V1 wan an 11 This article is protected by copyright. All rights reserved.

independent risk factor of arrhythmic events associated with poor prognosis.85 Atrial arrhythmias and mainly atrial fibrillation, are commonly observed in subjects with BrS.86 Spontaneous AF has been associated with a high incidence of syncopal episodes and documented VF.87,88 Sieira et al. have recently reported that asymptomatic BrS subjects with a history of sinus node dysfunction display an 8-fold increased risk for future arrhythmic events.89 A recent report has shown that interatrial block can be associated to BrS patients that develop AF. This opens a possibility of studying the effects of sodium channel blockers on atrial electrophysiology, as a way to identify patients prone to develop AF. 90

Electrophysiological Study Conflicting evidence exists on the prognostic value of EPS in asymptomatic BS subjects.8,36,48,50-52,91 Previous studies have demonstrated an excellent negative predictive value. Brugada et al. have initially reported that EPS exhibits a high negative predictive value (99%) as a tool for risk stratification.91 Delise et al. showed that the positive predictive value of EPS was 14% and the negative predictive value was 100%.48 However, in the PRELUDE registry, a negative EPS was not associated with a low risk of arrhythmic events.36 There is also disagreement on the positive predictive value of EPS. Data from the Brugada series have shown that VT/VF inducibility is predictive for future events.41,42,91 Sieira at al. from P. Brugada’s group have recently reported their 20-year experience on 273 asymptomatic patients with BrS who underwent EPS.89 The positive and negative predictive values of VF induction in this series were 18% and 98%, respectively. In the largest registry on BrS, results of EPS were available in 369 asymptomatic individuals.8 In univariate analysis, patients with positive EPS (37%) had a shorter time to first arrhythmic event compared with those with a negative EPS (63%; event rate per year, 1.1% vs. 0.4%; HR: 5.2). 8 The multivariable analysis, restricted to the asymptomatic patients, showed no independent predictive value of EPS (p: 0.09). However, based on the Finger registry, there is a trend towards statistical significance for the prognostic value of EPS in BrS.8 In our series of BrS patients, programmed right ventricular stimulation induced VT/VF in 56.3% of asymptomatic subjects. None of them suffered from syncope or ventricular arrhythmic event during the follow-up, and the positive and negative predictive values of EPS were 0% and 100%, respectively.56 However, the small number of patients included in this study is a major limitation. Similarly, Bouzeman et al. have recently reported that the 12 This article is protected by copyright. All rights reserved.

low rate of arrhythmic events among asymptomatic BrS patients with positive EPS is maintained over time, while residual inducibility under hydroquinidine treatment is of limited value to predict events during the follow-up.92 Fauchier et al. have performed a meta-analysis of 13 studies evaluating the prognostic role of EPS in BrS patients according to clinical presentation.45 In the whole population of BrS patients, VT/VF inducibility was associated with a non-significant higher risk of arrhythmic event during follow-up. However, induction of sustained VT/VF was significantly and homogeneously associated with an increased risk of arrhythmic events during follow-up in patients with syncope (odds ratio of 3.30). Similarly, the asymptomatic patients with inducible sustained VT/VF had an increased risk of arrhythmic events during follow-up (odds ratio of 4.62) with homogeneous results across the different studies. Our meta-analysis, which enrolled 1,104 asymptomatic subjects with BrS, demonstrated that inducible sustained ventricular arrhythmias at EPS were definitely predictive of future arrhythmic events (odds ratio of 3.51).93 Likewise, Sroubek et al. published a recent meta-analysis analysing the value of EPS in 1,312 asymptomatic individuals with BrS and confirming that arrhythmia induction with programmed ventricular stimulation is associated with a 2- to 3-fold increased risk of SCD particularly in less aggressive stimulation protocols.94 These data contradict the findings from the two initial meta-analyses on the same topic.61,95 This might be related to the fact that the authors did not distinguish the prognostic role of EPS according to the initial clinical presentation in these two meta-analyses. There are several possible reasons for the heterogeneity regarding the utility of EPS in risk stratification of BrS. First, methodological differences in the stimulation protocols, including the number of extrastimuli, the minimum coupling interval used (up to 200 ms or refractoriness), the site of stimulation (right ventricular apex and/or right ventricular outflow tract), and the amplitude of the electrical impulse during stimulation have a clear impact on EPS results. The stimulation protocol displays a major impact on VF inducibility rate in BrS.96 Of note, positive and negative predictive values of VF inducibility with up to 2 extrastimuli (36% and 87%, respectively) were better than those with VF inducibility with up to 3 extrastimuli (23% and 81%, respectively).97 Second, a small number of asymptomatic BrS patients suffers malignant arrhythmic events during follow-up, and therefore, the statistical analysis used for the evaluation of the prognostic significance of several parameters including the role of EPS becomes challenging. Third, the predictive value of EPS is difficult to assess because its positive result will most frequently lead to ICD implantation. This possibly explains why the positive predictive value of EPS was found only at univariate analysis in the FINGER registry,8 and was not confirmed by multivariable analysis, whereas the presence of an ICD 13 This article is protected by copyright. All rights reserved.

was found to be predictive of the occurrence of arrhythmic events. Forth, the inducibility rate may be related to the BrS ECG type the day of EPS. The VF inducibility rate has been shown to be higher in patients with spontaneous type-1 ECG pattern compared to those with other ECG types (42.5% vs. 13.3%).89

Finally, the PRELUDE registry added a ventricular effective refractory period of less than 200 ms as an additional prognostic EPS marker.36 However, Makimoto et al. failed to show such an association.97 Based on the above-mentioned data, and particularly on the three recent meta-analyses on the prognostic significance of EPS in BrS,45,93,94 programmed ventricular stimulation may be considered in risk stratification of asymptomatic individuals with spontaneous type-1 ECG pattern.

Μultiparametric risk scores Μultiparametric scores including the aforementioned markers may improve risk stratification of BrS subjects. Brugada et al. have shown that patients with a spontaneously abnormal ECG, a previous history of syncope, and an inducible sustained ventricular arrhythmia had a probability of 27.2% to suffer with arrhythmic events during follow-up.62 Similarly, Priori et al. have demonstrated the combined presence of a spontaneous ST-segment elevation in leads V1 through V3 and the history of syncope identifies subjects at risk of cardiac arrest.50 Likewise, Delise et al. have recently exhibited that subjects with spontaneous type-1 ECG pattern and at least two additional risk factors (syncope, family history of SCD, or positive EPS) are at higher risk.48 Okamura et al. have shown that syncope, spontaneous type 1 ECG pattern and inducible ventricular arrhythmias at EPS are important risk factors and the combination of these well stratify the risk for later arrhythmic events. When dividing patients according to the number of these 3 risk factors present, patients with 2 or 3 risk factors experienced more frequently arrhythmic events than those with no or 1 risk factor.98 Additionally, two studies demonstrated that the combination of fragmented QRS and early repolarization pattern is an independent predictor of further arrhythmic events.82,99 More recently, Kawazoe et al. established a new prediction method for risk stratification of VF in BrS based on previously reported non-invasive clinical and ECG risk factors for arrhythmic events. Specifically, the 14 This article is protected by copyright. All rights reserved.

combination of history of syncope, r-J interval in V1, QRS duration in V6 and Tpeak-Tend dispersion was useful to identify BrS patients with high risk of VF.100 A new risk model has recently been proposed by Sieira et al. in order to improve the stratification and management of BrS patients. The combination of specific risk factors such as spontaneous type-1 ECG, early familial SCD, inducible EPS, syncope, sinus node dysfunction and aborted SCD predicts more accurately risk of arrhythmic events in BrS patients.101 Although multiparametric scores appear promising in risk stratification of BrS subjects,

and particularly of asymptomatic ones, they have to validated prospectively in large number of patients. Furthermore, the majority of them underscore the presence of syncope, and therefore the clinical utility of these models in asymptomatic ones remains controversial. Multiparametric scores validated only in asymptomatic patients may be more useful.

Clinical and electrophysiological characteristics of asymptomatic subjects who suffered an arrhythmic event in major studies We systematically searched PubMed and EMBASE databases for studies published up to September 2016 using the following terms: “Brugada”, “syndrome”, “asymptomatic”, “arrhythmias”, “death”, “prognosis”, “risk”. The clinical and electrophysiological characteristics of asymptomatic subjects who suffered an arrhythmic event during follow-up are depicted in Table 1. The number of asymptomatic subjects who suffered an arrhythmic event during follow-up in major studies is very small. As shown in Table 1, incomplete data regarding the clinical, ECG and electrophysiological characteristics can be retrieved from nine studies including a total of 54 previously asymptomatic subjects who suffered an arrhythmic event during follow-up.36,38,43,44,51-53,102,103 Studies with possible overlap of cases were excluded from the analysis. With respect to gender, as anticipated, 20/22 (91%) of the subjects were males. A spontaneous type-1 ECG pattern of BrS was present in the majority of cases (33/48, 69%). VT/VF was induced in 38/52 patients (73%) at EPS. The total number of the groups “gender”, “spontaneous type 1 ECG pattern” and “inducible arrhythmias at EPS” are different due to the missing data in the analysed studies. However, the results of these data are indicative of a potential high risk profile of asymptomatic subjects including the following characteristics: males with spontaneous type 1 ECG and inducible arrhythmias at EPS (Figure 3).

15 This article is protected by copyright. All rights reserved.

Management of asymptomatic individuals with Brugada ECG pattern

Life style modification According to the current ESC guidelines, lifestyle changes are mandatory in all patients with BrS. Specifically, BrS patients should not drink excessive alcohol, consume heavy meals and use drugs (not only antiarrhythmic but also psychotropic drugs, anaesthetics/analgesics and other substances) that may induce ST-segment elevation in right precordial leads.3,7,11 A list of drugs that are avoided is available on the website www.brugadadrugs.org. Additionally, fever should be quickly treated with antipyretic drugs. 3,7,11

ICD implantation There is a clear indication for ICD in symptomatic BrS patients presenting with aborted SCD or sustained VT (class I, LOE C) and for patients with spontaneous type-1 ECG and a history of syncope (class IIa, LOE C). On the other hand, for the primary prevention of SCD, the induction of VF at EPS in asymptomatic patients is not a clear indication for ICD implantation (class IIb, LOE C).7 The decision to implant an ICD in asymptomatic patients should be made weighing the potential individual risk for future arrhythmic events against the risk of complications and expected quality of life.52 Sacher et al. have demonstrated a high rate of complications (36%) during long-term follow-up in BrS patients implanted with an ICD including more commonly inappropriate shocks and lead failures, and less commonly ICD-related infection.38 Six years after ICD implantation, BrS patients displayed twice the rate of inappropriate shock (24%) compared with appropriate shock (12%). The major reason for this complication is the high risk of lead failure. Sacher et al.38 reported a 16% lead failure during a mean follow-up of 77±42 months, and Sarkozy et al.43 reported a 13% during a median follow-up of 47.5 months. In addition, a high incidence of T-wave oversensing is seen in BrS patients leading to inappropriate shocks in 3.8% of patients during a mean follow-up of 74.9±51.7 months. All these events occurred in patients with true bipolar ICD leads and can be solved by changing the configuration from a dedicated to an integrated bipolar sensing configuration.104 The subcutaneous ICD (S-ICD) is one of the modern therapeutic alternatives in patients with ICD indication who do not need pacing and antitachycardia therapy, particularly younger patients. S16 This article is protected by copyright. All rights reserved.

ICD offers a lot of benefits reducing major complications such as pneumothorax, infections, lead malfunctions and inappropriate therapies.105 With respect to BrS, these patients present the highest rate of screening failure and a lower number of appropriate S-ICD vectors as compared to patients with other channelopathies (18% vs. 5%). Ajmaline unmasks screening failure in up to 15% of druginduced BrS patients previously considered suitable for S-ICD implantation.106 Due to these limitations, inappropriate S-ICD therapy mainly due to T-wave oversensing remains one of the main clinical problems of S-ICDs in BrS patients.107 Furthermore, S-ICD lead damage has been described as a cause of device malfunction.

108

Although, BrS patients are young and do not usually require

pacing, a small percentage might have sinus node dysfunction and will need an atrial and a ventricular lead104,109 Additionally, a minority of BrS patients (~4%) may experience monomorphic ventricular tachycardia which can effectively respond in antitachycardia pacing.110 As a result, careful assessment of all of these factors should be considered in order to make the right decision on choosing S-ICD or transvenous ICD implantation. S-ICDs should be used after a meticulous screening test in candidates with BrS.

Antiarrhythmic drugs Quinidine may be considered as an alternative therapy only in patients who deny an ICD implantation or in case of ICD contraindication.52,111,112 In Belhassen’s reports,111,112 daily doses of 1500 mg for quinidine bisulfate and 900 mg for hydroquinidine were used in order to achieve therapeutic serum levels. Quinidine has been additionally shown to prevent reinduction of sustained VF during programmed ventricular stimulation in 89.6% of patients tested.112 Quinidine bisulfate at a mean dose of 1406±242 mg (mean serum level 2.49±0.8 mg/L) was effective in 89% of patients, whereas hydroquinidine at a mean dose of 900 mg (mean serum level 1.18±0.44 mg/L) was effective in 92.3% of patients. None of the responders displayed an arrhythmic event during long-term followup. In this study, quinidine therapy resulted in side effects in 38% patients.112 The QUIDAM study, the first prospective randomized double-blind study, failed to provide the efficacy of the quinidine since frequent side effects and few arrhythmic events were the cause to premature termination of this study.113 The mean hydroquinidine daily dose was 738±174 mg, with a mean hydroquinidine serum level of 3.14±0.63 μmol/L. The investigators concluded that despite the favourable effects of quinidine in preventing ventricular arrhythmias, it could not be a safe and alternative solution from ICD Implantation.113 Lower doses of quinidine (≤ 600 mg/d) that are better tolerated has been shown 17 This article is protected by copyright. All rights reserved.

to be effective in preventing the VF recurrence, including arrhythmic storm, in subjects with BrS with an ICD.114 Isoprenaline infusion is effective in suppressing VF, ICD and arrhythmic storms.115 Cilostazol and milrinone that boost calcium channel current and quinidine together with bepridil and the Chinese herb extract Wenxin Keli that inhibit the transient outward current may be used to suppress the triggers for VF in BrS.13

Follow-up of asymptomatic patients Implantable loop recorders (ILRs) provide a very close follow-up and might be helpful in further risk stratification of asymptomatic individuals with potential risk factors. The use of ILR has been already tested in high risk subjects with Brugada ECG pattern and atypical symptoms.116 For asymptomatic individuals with drug-induced ECG pattern, a close follow-up with twelve-lead ECG Holter recordings that concomitantly records data form the 4th, 3rd and 2nd intercostal space in order to reveal a spontaneous diagnostic ECG pattern should be considered.117 This strategy may have important implications in risk stratification of these patients.117

Conclusions Risk stratification of asymptomatic individuals with BrS represents a great challenge for the treating physician. Despite limited evidence for this population, it is of utmost importance to provide optimal risk stratification using every available tool and modality that has demonstrated some prognostic significance. As individual risk markers and factors display limited prognostic value,

multiparametric risk scores evaluating specific ECG and clinical factors may improve risk stratification. Prospective studies on risk stratification including a large number of previously asymptomatic subjects will be the focus of interest within the next decade.

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18 This article is protected by copyright. All rights reserved.

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Legends Figure 1. a. Type-1 ECG pattern of Brugada syndrome (coved-type) in right precordial leads; b. QRS fragmentation (arrows) in lead V2 in a patient with Brugada syndrome recorded before (b1) and after ajmaline challenge (b2); c. Epsilon-like waves (arrows) in lead V2 in a patient with type-1 ECG pattern of Brugada syndrome; d. Epsilon-like waves (arrows) in lead V2 in a patient with type-2 ECG pattern of Brugada syndrome.

31 This article is protected by copyright. All rights reserved.

Figure 2. Incidence of arrhythmic events (syncope, sustained VT/VF, SCD) in previously asymptomatic subjects with spontaneous type-1 Brugada ECG pattern. VT: ventricular tachycardia; VF: ventricular fibrillation; SCD: sudden cardiac death.

32 This article is protected by copyright. All rights reserved.

Figure 3. The chart indicates the clinical, ECG and electrophysiological characteristics of asymptomatic patients with BrS who suffered an arrhythmic event during follow-up in major clinical studies. Males with spontaneous type-1 ECG and inducible arrhythmias at EPS appears to be at high risk.

Table 1. Major prospective studies reporting data on clinical, ECG and EPS characteristics associated with worse outcome of asymptomatic individuals with BS.

Authors (year)

Total number of individuals with BS ECG pattern

Number of asymptomatic individuals

Follow-up period

Arrhythmic events

(months)

among asymptomatic

Clinical, ECG and EPS characteristics associated with worse outcome in asymptomatic individuals

individuals Brugada et al. (2002)

334

190 (57%)

27±29

16 (8.4%)

 spontaneous type 1 ECG pattern  inducibility of VT/VF at EPS  female sex showed a trend toward a better outcome but without reaching statistical significance  a family history of SCD was not predictive of arrhythmia occurrence

33 This article is protected by copyright. All rights reserved.

 spontaneous type 1 ECG pattern and inducible VT/VF at EPS (HR:14.0; CI:8.1-23.0)  spontaneous type 1 ECG pattern and non-inducible ventricular arrhythmias at EPS (HR: 1.8; CI: 0.6-5.1)  in these non-familial asymptomatic individuals, the best predictor of spontaneous VF was the inducibility of sustained arrhythmias at EPS

Brugada et al. (2003)

547

423 (77%)

24±32

NR

Brugada et al. (2005)

547

167 cases

28±42

11 (6.5%)

Eckardt et al. (2005)

210

123 (59%)

33.7±52.2

1 (0.8%)

Sacher et al. (2006)

220

114 (54%)

38±27

5 (4.4%)

Sarkozy et al. (2007)

47

21 (45%)

47.5

4 (19%)

Huang et al. (2009)

43

19 (44%)

35.9±9.1

2 (11%)

Giustetto et al. (2009)

166

103 (62%)

30+21

1 (1%)

 male gender  spontaneous type 1 ECG pattern

Kamakura et al. (2009)

330

207 (63%)

48.7

3 (1.4%)

 spontaneous type 1 EGC pattern (3/3, 100%)  inducible VT/VF at EPS (1/3, 33%)

Delise et al. (2010)

328

223 (66%)

40

6 (2.7%)

 the negative predictive value of EPS was 100% indicating that 6 asymptomatic subjects who suffered arrhythmic events displayed a positive EPS  in subjects with spontaneous type 1 ECG pattern, no single clinical risk factor, nor EPS alone, was able to identify subjects at highest risk  the combination of spontaneous type 1 ECG pattern, family history of

without family history of SCD or BS

 male gender  spontaneous type 1 ECG pattern  spontaneous type 1 ECG pattern (4/5, 80%)  inducible VT/VF at EPS (5/5, 100%)  male gender (4/4, 100%)  spontaneous type 1 ECG pattern (4/4, 100%)  inducible VT/VF at EPS (4/4, 100%)  presence of LP on SAECG

34 This article is protected by copyright. All rights reserved.

Probst et al. (2010)

1029

654 (64%)

31

10 (1.5%)

Makimoto et al. (2010)

93

36 (39%)

76±38

3 (8.3%)

Priori et al. (2012)

308

243 (79%)

34 (36±8)

7 (2.8%)

Sacher et al. (2013)

378

166 (44%)

77±42

12 (7.2%)

Sieira et al. (2015)

363

363 (100%)

73.2±58.9

9 out of 303 (3%)

SCD and inducible ventricular arrhythmias at EPS indicates a high risk population [C-statistics 0.81 (0.75–0.85)]  in univariate analysis, patients with inducible VT/VF at EPS had a shorter time to first arrhythmic event compared with those with a negative EPS (event rate per year, 1.1% versus 0.4%; p: 0.05). However, in multivariable analysis, EPS failed to show an independent predictive value  neither spontaneous type 1 ECG pattern (event rate per year, 0.8% versus 0.4%; p: 0.26) nor male gender (0.7% versus 0.2%; p: 0.35) was predictive of a shorter time to the first arrhythmic event during follow-up  augmentation of STsegment elevation during the recovery phase of the exercise stress test  male gender (7/7, 100%)  spontaneous type 1 EGC pattern (7/7,100%)  VRP