Brugada Syndrome Editorial

Touch MEdical MEdia 23

AbstractA Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society (HRS/EHRA/APHRS) expert consensus

statement on the diagnosis and management of Brugada Syndrome was published in 2013. Since then new intriguing observations have

been made that are summarised in this editorial with a special focus on the underlying mechanism, genetics, provocative testing, risk

stratification and therapeutic options.

KeywordsBrugada syndrome, antiarrhythmic drugs, ICD implantation

Disclosure: Rajin Choudhury, Mattias Duytschaever, Sebastien Knecht, Yves Vandekerckhove and Rene Tavernier have no conflicts of interest to declare. No funding was received in the publication of this article.

Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.

Received: 19 June 2015 Published: 14 August 2015 Citation: European Journal of Arrhythmia & Electrophysiology, 2015;1(1):23–4

Correspondence: Rajin Choudhury, AZ Sint-Jan Bruges-Oostende, Department of Cardiology, Ruddershove 10, 8000 Bruges, Belgium. E: rajin_c@yahoo.com

Updates in Brugada Syndrome

Rajin Choudhury, Mattias Duytschaever, Sebastien Knecht, Yves Vandekerckhove and Rene Tavernier

Department of Cardiology, AZ Sint-Jan Brugge-Oostende AV, Belgium

Brugada syndrome (BrS), first described in 1992, is an autosomal

dominant, arrhythmogenic disease. There is a male predominance of

the syndrome and the prevalence is highest in Asian and Southeast

Asian countries, reaching 0.5–1 per 1,000.1 BrS is diagnosed in patients

with ST-segment elevation with type 1 morphology ≥2 mm in ≥1 lead in

the right precordial leads V1, V2, positioned in the second, third or fourth

intercostal space occurring either spontaneously or after intravenous

class I antiarrhythmic drugs.2 The majority of patients are asymptomatic

but they may also present with sudden cardiac death, aborted sudden

death, syncope, nocturnal agonal respiration, palpitations and chest

discomfort. Most events occur during rest, sleep, vagotonic conditions

or febrile state but rarely during exercise.1 A Heart Rhythm Society/

European Heart Rhythm Association/Asia Pacific Heart Rhythm Society

(HRS/EHRA/APHRS) expert consensus statement3 on the diagnosis

and management was published in 2013. Since then, new intriguing

observations have been made.

Underlying MechanismThere are two leading hypotheses for mechanisms underlying BrS

phenotype and arrhythmias: (1) the abnormal repolarisation hypothesis

(based on the canine wedge preparation) and (2) the abnormal

depolarisation hypothesis (based on whole heart studies in BrS patients).

Recently, panoramic electrophysiological mapping using non-invasive

electrocardiogram (ECG) imaging was performed in BrS patients. The

results indicate that the abnormal electrophysiological substrate is

localised exclusively in the right ventricular outflow tract that displays

delayed activation, prolonged repolarisation and steep repolarisation

gradients.4 The existence of both abnormal repolarisation and slow

discontinuous conduction in the BrS patient provide conditions that

promote sustained re-entry.

New Findings in GeneticsThe BrS phenotype has been associated with 18 genotypes,5,6 all showing

a decrease in the inward sodium or calcium current or an increase in one

of the outward potassium currents. Genetic testing is only recommended

for family members of a successfully genotyped proband.7

Cerrone et al.8,9 suggested that mutations in desmosomal genes (PKP2) can

also provide at least part of the molecular substrate of BrS. Consecutive

loss of desmosomal integrity could lead to reduced sodium current and

render in arrhythmogenic state through delayed depolarisation. Inclusion

of PKP2 as part of routine BrS screening however remains premature.

Provocative Testing with Class I Antiarrhythmic DrugsThe widespread use of ajmaline testing for diagnosing BrS is supported

by its excellent sensitivity.10 Hasdemir et al.11 performed an ajmaline

test in 96 patients undergoing radiofrequency ablation for typical

atrioventricular nodal re-entrant tachycardia (AVNRT) and 66 controls:

27 % of patients with AVNRT and 5 % of controls developed a type I

Brugada ECG in response to the ajmaline challenge. Based upon these

results the authors suggest a mechanistic link (genetic variants that

reduce sodium channel currents) between AVNRT and BrS. However, as

pointed out in an accompanying editorial these data could also suggest

that the specificity of the ajmaline test is not as high as we thought (i.e.

more false positives than expected) and “it is time to pause and think

before performing additional tests with sodium channel blockers.”12

Conte et al.13 repeated the ajmaline test on asymptomatic individuals

with first-degree relatives with Brugada syndrome and a negative

ajmaline test after they attained puberty (≥16 years of age with onset

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DOI: 10.17925/EJAE.2015.01.01.23

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Brugada Syndrome Editorial

EuropEan Journal of arrhythmia & ElEctrophysiology

of secondary sexual characteristics). In 23 % of these patients a type 1

ECG was unmasked.

Intriguing Observations on Risk StratifiersIn an observational retrospective study14 cohort of 246 BrS patients, the

presence of a fragmented QRS (f-QRS) as a risk indicator was confirmed

but also showed that BrS patients with the combination of f-QRS and

early repolarisation (ER) represented the highest risk group. Patients with

neither of the two patterns had an excellent prognosis.

The recommendation for programmed electrical stimulation (PES) for risk

stratification has dropped from a IIa indication to IIb in the 2013 Second

Brugada Syndrome Consensus document. A recent report of Sierra et al.15

however suggest a continued role for PES especially in the asymptomatic

patient: asymptomatic patients without PES inducibility had an event-free

survival of 100 % at 1 year, and 99.2 % at 5, 10 and 15 years.

New Treatment OptionsIn the 2013 Expert Consensus Recommends implantable cardioverter-

defibrillator (ICD) implantation is a class I treatment indication in survivors

of a cardiac arrest and or a documented spontaneous sustained

ventricular tachycardia (VT) with or without syncope. Kamakura et al.16

evaluated the necessity for ICD implantation in elderly patients. They

observed that in high-risk BrS patients the incidence of ventricular

fibrillation (VF) decreased with age, and VF did not recur in patients after

70 years of age without other underlying cardiac diseases. By contrast,

inappropriate shocks increased with age and reached a peak in patients

who were in sixties. They suggest that avoidance of ICD implantation or

replacement may be considered in elderly BrS patients who remain free

from VF until 70 years of age.

T-wave oversensing is a potential reason of inappropriate shocks in BrS

patients receiving ICDs. Recently, Rodríguez-Mañero et al.17 compared

the incidence of T-wave oversensing in patients with BrS with integrated

bipolar versus true/dedicated bipolar leads. Out of 480 patients, 5.8 %

had T-wave oversensing leading to inappropriate shocks in 3.8  %. All

these events occurred in patients with true bipolar ICD leads.

Nademanee et al.18 showed that electrical epicardial substrate ablation

at the RVOT prevents VF inducibility in a high-risk population. However,

randomised data on the effect of catheter ablation on spontaneous

arrhythmic events are lacking. n

1. Antzelevitch C, Brugada P, Borggrefe M, et al., Brugada syndrome: report of the second consensus conference, Heart Rhythm, 2005;2:429–40.

2. Obeyesekere MN, Klein GJ, Modi S, et al., How to perform and interpret provocative testing for the diagnosis of Brugada syndrome, long-QT syndrome, and catecholaminergic polymorphic ventricular tachycardia, Circulation, 2011;4:958–64

3. Priori SG, Wilde AA, Shimizu W, et al.; Document Reviewers, Ackerman M, Belhassen B,.ÉQuek SC. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes, Europace, 2013;15:1389–406.

4. Zhang J, Sacher F, Hocini M, et al., Cardiac electrophysiological substrate underlying the ECG phenotype and electrogram abnormalities in brugada syndrome patients, Circ, 2015;131:1950–9.

5. Sarquella-Brugada G, Campuzano O, et al., Brugada syndrome: clinical and genetic findings, Genet Med, 2015 [Epub ahead of print].

6. Mizusawa Y, Wilde AA, Brugada syndrome, Circ Arrhythm Electrophysiol, 2012;5:606–16.

7. Ackerman MJ, Priori SG, Willems S, et al., HRS/EHRA expert consensus statement on the state of genetic testing for

the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA), Heart Rhythm, 2011;8:1308–39.

8. Cerrone M, Lin X, Zhang M,É., Napolitano C, Priori SG, Delmar M. Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype, Circulation, 2014;129:1092–1103.

9. Cerrone M, Delmar M, Desmosomes and the sodium channel complex: Implications for arrhythmogenic cardiomyopathy and Brugada syndrome, Trends Cardiovasc Med, 2014;24:184–90.

10. Brugada R, Brugada J, Antzelevitch C, et al., Sodium channel blockers identify?risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts, Circulation, 2000;101:510–5.

11. Hasdemir C, Payzin S, Kocabas U, et al., High prevalence of concealed Brugada syndrome among patients with atrioventricular nodal reentrant tachycardia, Heart Rhythm, 2015, 2015;12:1284–94.

12. Viskin S, Rosso R, Friedensohn L, et al., Everybody has Brugada syndrome until proven otherwise? Heart Rhythm, 2015;12:1595–8.

13. Conte G, de Asmundis C, Ciconte G, et al., Follow-up from childhood to adulthood of individuals with family history of Brugada syndrome and normal electrocardiograms, JAMA, 2014;19;312:2039–1.

14. Nademanee K, Veerakul G. Overlapping risks of early repolarization and Brugada syndrome, J Am Coll Cardiol, 2014;63:2139–40.

15. Sieira J, Conte G, Ciconte G, et al., Prognostic value of programmed electrical stimulation in brugada syndrome: 20 years experience, Circ Arrhythm Electrophysiol, 2015 [Epub ahead of print].

16. Kamakura T, Wada M, Nakajima I, et al., Evaluation of the necessity for cardioverter-defibrillator implantation in elderly patients with brugada syndrome, Circ Arrhythm Electrophysiol, 2015 [Epub ahead of print].

17. Rodríguez-Mañero M, de Asmundis C, et al., T-wave oversensing in patients with brugada syndrome - true bipolar versus integrated bipolar ICD leads: A multicenter retrospective study, Circ Arrhythm Electrophysiol, 2015 [Epub ahead of print].

18. 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.

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