Implantable cardioverter defibrillator and catheter ablation in Brugada syndrome

Pappone, Carlo; Santinelli, Vincenzo

Journal of Cardiovascular Medicine: January 2017 - Volume 18 - Issue - p e35–e39
doi: 10.2459/JCM.0000000000000449
SPECIAL ISSUE GUEST EDITORS: Francesco Prati, MD Mario Albertucci, MD

Arrhythmology Department, Policlinico San Donato, University of Milan, Milan, Italy

Correspondence to Carlo Pappone, MD, PhD, Policlinico San Donato, University of Milan, Department of Arrhythmology, Electrophysiology and Cardiac Pacing, Piazza E Malan, 20097 Milan, Italy Tel: +(39) 02 52774260; fax: +(39) 02 52774306; e-mail:

Received 22 July, 2016

Accepted 24 July, 2016

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The main clinical problem in Brugada syndrome (BrS) is the unpredictable and undetermined risk sudden cardiac death (SCD) because of malignant tachyarrhythmias characteristically and tragically occurring in young otherwise healthy study participants, as first described by the Brugada brothers in 1992.1 The prevalence of BrS appears to be higher in Asian and south-east Asian countries reaching 0.5–1 per 1000 and is 8–10 times more prevalent in men than in women.2 Inheritance of BrS occurs via an autosomal dominant mode of transmission and 12 responsible genes have been reported so far. At least 12 genes have been associated with BrS, but only two (SCN5A and CACN1Ac) individually account for 5% of positively genotyped patients.3 In all 12 genotypes, either a decrease in the inward sodium or calcium current or an increase in one of the outward potassium currents has been shown to be associated with the BrS phenotype. Symptoms associated with BrS include aborted SCD with rates peak in young healthy patients aged 40 years, syncope, palpitations, nocturnal agonal often occur during rest or sleep, during a febrile state, or with vagotonic conditions, but rarely during exercise. BrS is definitively diagnosed when a type I ST-segment elevation is observed either spontaneously or after intravenous administration of sodium channel blocking agents in at least one right precordial lead V1 and/or V2,4 which are placed in a standard or a superior position, up to the second intercostal space.4

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Implantable cardioverter defibrillator implantation in Brugada syndrome

Arrhythmic SCD is a significant cause of mortality, 5–15% of people with SCD have no structural abnormalities, and most of these events are because of underlying cardiac ion channelopathies.5,6 Although rates of cardiac ion channelopathies diagnosis are increasing, the optimal treatment for such people is poorly understood and current guidelines rely primarily on expert opinion.7,8 Unfortunately, a precise risk score cannot be formulated for patients with BrS. Currently, the only accepted strategy for secondary SCD prevention in BrS is an implantable cardioverter defibrillator (ICD) just to immediately terminate malignant tachyarrhythmias while for primary prevention available methods for risk stratification are lacking and then, the use of ICD is questionable.8,9 Indeed, patients who undergo ICD implantation may be exposed to several serious mechanical and psychological complications, which could have a negative impact on quality of life with considerable cost to healthcare systems. As a result, in BrS the physicians should decide whether or not to recommend ICD implantation and should justify their decision reassuring not the patients but also families, friends, and other healthcare providers that the risk of SCD warrants the potential adverse effects of ICD implantation or that the risk of SCD is lower than the disadvantages. Not only will the presumably low incidence of SCD influence the treatment's choice, but its severity is also important. This is challenging because now any risk of SCD is intolerable to some patients, and this may also explain why most BrS patients who receive ICD implantation for primary prevention never receive a life-saving intervention during long-term follow-up. In such a challenging rare disorder, risk stratification is indeed required to identify and select those patients at higher risk of malignant tachyarrhythmias as candidates for ICD implantation. However, identification of independent predictors in a patient population supposed to be at low risk of SCD requires a large number of untreated patients followed for many years. Unfortunately, no extensive published data are currently available on the epidemiology of BrS. In a recent meta-analysis, the incidence of arrhythmic events [sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) or appropriate ICD therapy or SCD] in patients with BrS was 13.5% per year in patients with a history of sudden cardiac arrest, 3.2% per year in patients with syncope, and 1% per year in asymptomatic patients.10 Programmed electrical stimulation (PES) has been used to evaluate the arrhythmic risk, but several investigators and laboratories have not found PES to be helpful in identifying BrS patients at risk for SCD.8,11 Despite the lack of uniform supporting evidence and the practice guideline recommendations, PES continues to be used for risk stratification of symptomatic and asymptomatic BrS patients and those with and without spontaneous ST-segment elevation. The original case series reported by the Brugada brothers depicted a few patients who all had coved ST-segment elevation in the right precordial leads, associated with a high risk of SCD and no apparent structural heart disease, but subsequently it became apparent that in BrS the spectrum of risk is wide, with the majority of patients classified as low risk.11 Despite intense research efforts, many controversies still exist over pathophysiology and risk stratification in BrS to prevent malignant tachyarrhytmias. Management continues to be challenging with a lack of drug therapy and high complication rates from ICDs. The 2015 European Society of Cardiology (ESC) guidelines recommend ICD implantation in BrS as class I indication (level of evidence C) for patients who are survivors of a cardiac arrest and/or have documented spontaneous sustained VT with or without syncope (secondary prevention); as class IIa indication for patients with a spontaneous diagnostic type I ECG who have a history of syncope judged to be likely caused by ventricular arrhythmias; and as class IIb indication for patients with a diagnosis of BrS who develop VF during PES with two or three extrastimuli at two sites.12 As a result, the current clinical scenario is that ICD implantation in patients with BrS at intermediate or low risk, who represent the majority of patients with BrS, remains questionable and not recommended by guidelines also in consideration that ICDs are not free from major complications and disadvantages, particularly in patients who are active young study participants who will need multiple device replacements during their lifetime.

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Catheter ablation in Brugada syndrome: a new approach to eliminate malignant arrhythmic substrates

It is well known that SCD in BrS is because of malignant tachyarrhythmias, including VT/VF, but arrhythmic substrates, physiopathology, and mechanisms have not been well defined. In the last 2 decades, catheter ablation has been considered as a well tolerated and effective strategy to definitively eliminate arrhythmic substrates also in patients with life-threateniing ventricular tachyarrhythmias. Recently, in highly symptomatic selected BrS patients with frequent repetitive ICD shocks endocardial or epicardial arrhythmic substrates have been identified and targeted for catheter ablation to prevent arrhythmia recurrences.13,14 Following the preliminary encouraging results on a potential benefit of endocardial/epicardial catheter ablation in selected BrS patients, the 2015 ESC guidelines have recommended radiofrequency catheter ablation (RFA) as class IIb indication for patients with a diagnosis of BrS and history of arrhythmic storms or repeated appropriate ICD shock to prevent frequent recurrences.12 More recently, Brugada et al.15 for the first time reported a systematic prospective follow-up study on anatomical location and how to define areas and extent of epicardial arrhythmogenic substrates in BrS patients to eliminate by RFA both typical BrS ECG pattern and malignant arrhythmias. These data for the first time suggest that the natural history of patients with BrS may be modified by early use of catheter ablation even in the vast majority of patients who initially are at indeterminate risk of SCD, for whom now there is no recommendation for ICD implantation at the time of diagnosis.12

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Natural history of Brugada syndrome

Primary prevention of SCD in BrS is essentially based on knowledge of the natural history of the disease, arrhythmic substrates, and predictors. There are few data on the natural history of BrS representing a limitation to define prognosis and preventive strategies based on assessment of the risk of death.9 In a more recent study, collecting a cohort of 200 BrS patients, Priori et al.11 reported that during the follow-up cardiac arrest occurred in 22 individuals between the ages of 2 months and 55 years, which clearly demonstrates that the risk of SCD in BrS is indeed underestimated. The information on the natural history of patients obtained from this study has provided a risk stratification scheme to quantify the risk for SCD and to target the use of ICD. From the proposed risk stratification ICD was indicated only for 10% of patients showing ST-segment elevation at least 2 mm and history of syncope. Among the patients with a spontaneous ST-segment elevation at least 2 mm without history of syncope representing 41% of the population, 14% had cardiac arrest, but were considered at intermediate risk and undetermined treatment. These data clearly indicate that the vast majority of patients with BrS are not recommended for ICD implantation remaining at indeterminate risk of SCD.

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Relationship between ST-segment elevation and malignant arrhythmias in Brugada syndrome

Although a potential relationship between ST-segment elevation and VF development in BrS appears to be closely related, the precise mechanisms remain unknown. Prior reports have suggested that repolarization heterogeneity within the right ventricular outflow tract (RVOT) epicardium (repolarization abnormality) triggers premature ventricular contractions, facilitates polymorphic ventricular tachycardia contributing to VF development in BrS patients.16–20 Recent clinical and experimental observations have supported the presence of arrhythmogenic epicardial substrate abnormalities with fragmented potentials in high-risk BrS suggesting a depolarization disorder rather than a repolarization disorder.14–23

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Location and extent of arrhythmogenic epicardial substrate in Brugada syndrome

Initially, in BrS the arrhythmogenic substrate as target for ablation was localized and mapped on the RVOT endocardial wall and endocardial radiofrequency ablation was proposed in 2003 by Haïssaguerre et al.13 as an investigational procedure just to avoid frequent ICD shocks in three BrS patients with recurrent VF and premature ventricular complexes triggering VT/VF. Subsequently, the results of the study by Nademanee et al.14 focused attention on the mapping and ablation of epicardial arrhythmogenic substrates. In that study, among a series of nine BrS patients who had been suffering from frequent ICD discharges because of VF episodes, radiofrequency ablation of epicardial sites exclusively localized in the anterior aspect of the RVOT was able to prevent VT/VF inducibility in seven of the nine patients with normalization of the Br ECG pattern in only five of the nine patients.14 More recently, the methodology, results, and complication rates of epicardial mapping using flecainide testing (2 mg/kg/10 min) have been reported in a systematic prospective follow-up study among a series of 14 consecutive patients (median age, 39 years) with BrS and ICD implantation.15 Epicardial contact mapping and ablation were performed after endocardial mapping to have a good delimitation of the right venticle boundaries when mapping the epicardium. Abnormal electrograms were defined as those with amplitude less than 1.5 mV and/or associated wide duration (>80 ms), multiple (>3), or delayed components extending beyond the end of the QRS complex. Once epicardial low-voltage areas were identified and quantified after flecainide, all abnormal electrograms inside these areas were ablated with an irrigated 3.5-mm tip mapping/ablation catheter. Each radiofrequency application lasted 30–60 s, depending on complete elimination of the targeted electrograms. A remap was obtained to confirm the complete elimination of abnormal electrograms. Flecainide test was repeated at the end of the RFA procedure. Programmed radiofrequency stimulation was used for VT/VF induction. Our experience confirms and extends prior reports13,14 providing new insights on the relationship and pathophysiology of typical BrS ECG pattern and the epicardial arrhythmogenic substrate in BrS. The results demonstrate that the extent and distribution of arrhythmogenic epicardial substrate are variable potentially extending beyond the RVOT after flecainide testing and are correlated with the extent of BrS ECG pattern. It is likely that in the absence of provocative testing lower success rates and delayed effects of epicardial ablation on the Br S ECG pattern, as reported by Nademanee et al.14 were because of incomplete or limited epicardial substrate identification/elimination. In our experience, after flecainide testing (Fig. 1), baseline low-voltage epicardial areas may expand about two times and the duration of abnormal electrograms may increase more than two times (Fig. 2), whereas the total procedure time can be similar to or even shorter than that reported by Nademanee et al.14 Transient diffuse ST-segment elevation in the absence of pericardial effusion may rarely occur after epicardial ablation spontaneously normalizing within a few days after the procedure. In our series, during the follow-up, no arrhythmic events occurred after ablation whereas the ECG pattern remains normal even after flecainide rechallenge (Fig. 3).

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Our findings are clinically important leading to a potentially definitive treatment of the phenotypic manifestations of BrS in a larger symptomatic BrS patient population not only to prevent inappropriate ICD shocks, but also to prevent malignant arrhythmias and SCD. Further larger randomized studies with longer follow-up periods are required to define the role of epicardial catheter ablation in improving the natural history of BrS.

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Brugada syndrome; catheter ablation; implantable cardioverter defibrillator; mapping; sudden cardiac death

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