Controversies in

Arrhythmia and
Electrophysiology
Management of Brugada Syndrome 2016:
Should All High Risk Patients Receive an ICD?

Alternatives to Implantable Cardiac Defibrillator Therapy

for Brugada Syndrome
Bernard Belhassen, MD

M ore than 20 years ago, the Brugada brothers reported 8

patients with recurrent episodes of aborted sudden death
and no demonstrable heart disease having a peculiar ECG pat-
tern of ST elevation in right precordial leads.1 The Brugada
syndrome (BrS), one of the most devastating causes of sudden
cardiac death (SCD) in relatively young patients with appar-
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type 2, and type 3),4 there has been a recent effort to estab-
lish a more simplified mode of classification, including only 2
ECG patterns6: pattern 1 identical to the classic type 1 of other
consensus (coved pattern) and pattern 2 that joins patterns 2
and 3 of previous consensus (saddle-back pattern). This is in
agreement with the classification presently adopted by most

ently normal heart, was born. In fact, it is likely that the first
case of BrS was reported a few years before by Martini et al.2
The syndrome was recognized although not fully characterized
even earlier in various southeastern Asian countries as respon-
sible for mysterious cases of unexpected nocturnal SCD.3
Over the following 2 decades, extensive research on the clini-
cal and ECG aspects, electrophysiological (EP) mechanism,
genetic background, and management of the syndrome has
been accomplished. Two consensus reports on the diagnostic
criteria, risk stratification, and management of BrS were pub-
lished in 20054 and 2013.5 Recent publication of several works
dealing with various modes of management of BrS has raised
questions about the optimal treatment that should be offered to
these patients. Hereunder, I review these updated results and
give my own viewpoint on the issue of management of BrS.
See Response by Sieira and Brugada
General Considerations
Importance of ECG Phenotype Ascertainment
Although there has been general initial consensus about the
ECG definition of Brugada ECG pattern into 3 types (type 1,
specialists that differentiates Brugada ECG type 1 versus non-
type 1 patterns.
However, to date, only the ECG type 1 pattern (J-point
elevation of ≥2 mm with a coved ST segment), spontaneously
evident or induced by a provocative drug challenge, should
be considered as the sine qua non-BrS diagnosis.4–6 The other
types are not considered diagnostic. In addition, it is of para-
mount importance to exclude various medical conditions, nor-
mal ECG variants, or ECG lead misplacement that can mimic
Brugada ECG patterns6–8 to avoid unnecessary implantable
cardiac defibrillator (ICD) implantations.8
We should recognize, however, that this is not always an
easy task even for experienced specialists in the field.9
Clinical Presentation
There are 3 main clinical presentations of BrS: (1) polymor-
phic ventricular tachycardia (VT)/ventricular fibrillation (VF)
associated with cardiac arrest (CA) or less frequently mono-
morphic VT10; (2) syncope; and (3) no symptoms.
If there is consensus in the definition of the first group of
patients, those adopted for the other 2 groups vary accord-
ing to the authors. Neurocardiogenic syncope is the most fre-
quent cause of syncope in the general population11 and also in

From the Department of Cardiology, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Israel.
Correspondence to Bernard Belhassen, MD, Department of Cardiology, Tel-Aviv Sourasky Medical Center, Weizman St 6, Tel-Aviv 64239, Israel.
E-mail bblhass@tasmc.health.gov.il
(Circ Arrhythm Electrophysiol. 2016;9:e004185. DOI: 10.1161/CIRCEP.116.004185.)
© 2016 American Heart Association, Inc.
Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org DOI: 10.1161/CIRCEP.116.004185

1
 2   Belhassen   Alternatives to ICD Therapy for Brugada Syndrome
the BrS population.12 Therefore, some workers included their
patients with neurocardiogenic syncope in the asymptom-
atic group.13 However, others14 included them in the syncope
group. In the FINGER registry (the France, Italy, Netherlands,
Germany Brugada syndrome registry),15 the word neurocar-
diogenic syncope did not appear in the article, but one might
understand from the given definition of syncope (only that
which has a probable arrhythmic origin) that neurocardiogenic
syncope was included in the asymptomatic group. Finally, in
PRELUDE (Programmed Electrical Stimulation Predictive
Value registry),16 the definition of the syncope group did not
clearly indicate that patients with neurocardiogenic syncope
were actually included in the asymptomatic group.
The issue of the classification of patients with neurocar-
diogenic syncope is far to be semantical for 4 reasons: (1)
increases in vagal tone may facilitate the onset of spontaneous
VF in some BrS patients17; (2) clinical symptoms suggesting
of vagal syncope may be observed in syncope of cardiac ori-
gin18; (3) an a priori inclusion of patients with neurocardio-
genic syncope in the asymptomatic group may increase the
threshold for not treating them; and (4) conversely an a priori
inclusion of these patients in the syncope group may increase
the threshold to treat them more aggressively (ICD, drugs,
ablation). Therefore, and notwithstanding the great difficulties
in establishing the actual cause of syncope in some patients, it
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is important and more scientifically correct that future studies
clearly separate the suspected arrhythmic syncope from the
neurocardiogenic type.19
Arrhythmic Risk Stratification
The arrhythmic risk stratification of BrS has been the subject
of many studies. The topic has been extensively reviewed by
Adler et al.20 An important pooled analysis of programmed
ventricular stimulation (PVS) for risk stratification has been
recently reported by Sroubek et al.21
• Clinical parameters: the risk of arrhythmic event
(AE) during follow-up is highest for patients present-
ing with CA, intermediate for patients with syncope,
and lowest for patients who are asymptomatic when
diagnosed.
• Age, sex, and genetics: although the prevalence of
gene carriers among males and females is similar
(BrS is an autosomal dominant genetic disorder with
incomplete penetrance), the majority of diagnosed
patients are male. First AEs usually occur between
35 and 55 years and very rarely in children or the
elderly. SCN5A mutations are found in ≈30% of BrS
patients. Large registries have not found an associa-
tion between the risk of VF and a family history of
SCD or mutations in the SCN5A gene.
• ECG parameters: A spontaneous type 1 Brugada
ECG is an independent predictor of VF. In the larg-
est multicenter study,15 annual incidences of AE in
asymptomatic patients with spontaneous and drug-
induced type 1 ECG were 0.8% and 0.4%, respec-
tively, during a mean follow-up period of 31 months.
In the largest single-center study,22 the figures were
1.2% and 0.3%, respectively, during a mean follow-
up period of 73 months. The presence of early repo-
larization in peripheral leads, fragmented QRS com-
plexes, late potentials, microscopic T wave alternans,
and wide or large S wave in lead I have also shown
promising results for predicting arrhythmic risk.20,23
• Value of PVS: Following the initial results of the
Brugada group showing high value of PVS in pre-
dicting arrhythmic risk in BrS patients,24 subse-
quent several large studies, including FINGER,15
PRELUDE,16 and 2 meta-analysis25,26 failed to con-
firm these results, leading to the abandon of PVS for
risk stratification by many cardiac electrophysiolo-
gists. It is only recently, after the latest meta-analysis
by Fauchier et al27 and mostly the publication of the
20-year experience of the Pedro Brugada group in
404 patients with various clinical presentations of
BrS,13 that the beneficial role of PVS in arrhyth-
mic risk stratification has been rehabilitated. In that
study, VF inducibility presented a hazard ratio for AE
of 8.3 (95% confidence interval 3.6–19.4), P<0.01.
More importantly, the analysis by Sroubek et al21
pooling the results of 8 studies (including FINGER15
and PRELUDE16 but not those of the Pedro Brugada
group) concluded on the positive role of PVS in pre-
dicting future arrhythmic risk in BrS patients with-
out a history of CA. This analysis showed that ar-
rhythmia induction during PVS was associated with
a 2.7-fold increased risk of AE over a median fol-
low-up of 38 months. The risk was greatest among
individuals who had their arrhythmias induced with
single or double extrastimuli.
Latest Consensus Statement
In addition to lifestyle changes (avoidance of drugs that may
induce or aggravate ST-segment elevation in right precordial
leads, avoidance of excessive alcohol intake, immediate treat-
ment of fever with antipyretic drugs), these guidelines recom-
mend the following5:
1. ICD implantation: as class I indication for BrS patients
who are CA survivors or have documented spontaneous
sustained VT with or without syncope. ICD therapy is
also considered useful in patients with a spontaneous
diagnostic type 1 ECG who have a history of syncope
judged to be likely caused by ventricular arrhythmias
(class IIa). ICD may be considered in patients with a di-
agnosis of BrS who develop VF during PVS (class IIb).
In contrast, ICD is not indicated in asymptomatic BrS
patients with a drug-induced type 1 ECG and on the ba-
sis of a family history of SCD alone.
2. Quinidine: this medication can be useful in patients with
a diagnosis of BrS and history of arrhythmic storms
defined as >2 episodes of VT/VF in 24 hours. This drug
can also be useful in patients with a diagnosis of BrS
who qualify for an ICD but present a contraindication
to the ICD or refuse it and have a history of documented
 3   Belhassen   Alternatives to ICD Therapy for Brugada Syndrome
supraventricular arrhythmias that require treatment
(class IIa). Finally, it may be considered in asymptom-
atic patients with a diagnosis of BrS with a spontaneous
type 1 ECG (class IIb)
3. Catheter ablation: this procedure may be considered in
patients with a diagnosis of BrS and history of arrhyth-
mic storms or repeated appropriate ICD shocks.
Presently Available Modalities of Treatment
There are presently 5 modalities of treatment of BrS patients:
(1) no treatment; (2) ICD implantation; (3) EP-guided class
1A antiarrhythmic therapy (mainly quinidine); (4) empirical
quinidine therapy; and (5) epicardial ablation. As stated ear-
lier, these modalities of treatment only concern the patients
with the Brugada ECG type 1 (spontaneous or drug-induced).
We will not deal here with the issue of the management of
arrhythmic storms.
No Treatment
Some investigators28 do not recommend any investigation (phar-
macological testing or EP testing) for arrhythmic risk stratification
in asymptomatic patients considered to be at low arrhythmic risk,
such as those with no spontaneous ECG type 1 Brugada. Such
decision may mainly affect female patients who have a lower inci-
dence of spontaneous type 1 ECG.29 However, in addition to the
fact that pharmacological tests are mandatory for BrS diagnosis
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in patients with no spontaneous type 1 ECG, such a policy should
take in account the following important points: (1) there is a strong
day-to-day variability in the ECG diagnosis of Brugada type 1, as
it was observed in a high-risk population with implanted ICD and
spontaneous type 1 ECG, with only every third ECG being diag-
nostic and every third normal30; (2) although the risk of AE is low
in patients with no spontaneous type 1 Brugada ECG as compared
with patients with spontaneous type 1, it is far from nil (annual
rates of 0.4% and 0.3% in FINGER15 and Sieira et al’s study,22
respectively); (3) although the proportion of female BrS patients
with aborted CA was relatively low in FINGER15 (11%) and in
our experience19(10%), higher figures have been reported by the
Pedro Brugada group (36%).31 In this regard, it is noteworthy that
women constituted 45% of the entire population of asymptomatic
patients in the Pedro Brugada experience,22 possibly because of
exhaustive familial screening program established in their institu-
tion. Such sex distribution is more consistent with the autosomal
mode of transmission of the disease. Moreover, in contrast to men,
most women with BrS and resuscitated SCD or appropriate ICD
shock do not have a spontaneous type 1 ECG pattern.32
The nontherapy option also has been recommended in
asymptomatic patients who underwent EP testing that yields
no inducible arrhythmias. Such option can rely on the rela-
tively low incidence rate of AE (3/289=1.04%, all patients
without a spontaneous type 1 Brugada ECG, ie, only drug-
induced) found in these cases by Sieira et al22 during a mean
follow-up of ≈6 years. The results of Sroubek et al21 over a
median follow-up of 38.3 months are less supportive of this
approach in patients with spontaneous type 1 ECG (Table 1).
However, comparison between these 2 studies should be
made with caution because of the marked higher proportion
of patients with spontaneous type 1 ECG in Sroubek et al’s
analysis (≈50% versus 8.7%).
In our experience, no AE occurred during long period
of follow-up (86.8±52 months) in any of our asymptomatic
patients with no inducible arrhythmias.19 This high negative
predictive value of EP testing was obtained using an aggres-
sive PVS protocol19 only used in our laboratory. However, we
should have in mind that BrS is a disease that may aggravate
over the time, thus, requiring long periods of follow-up before
the good long-term prognosis of patients with negative EP
testing could be ascertained.
ICD Therapy
For the last 2 decades, ICD therapy has been considered as
the cornerstone therapy of patients with documented ventricu-
lar tachyarrhythmias, as well as those assumed to be at high
arrhythmic risk. The goal of ICD is to detect and treat any
life-threatening tachyarrhythmias but not to prevent them.
The only randomized trial showing a benefit of ICD in BrS
has been DEBUT33 (Defibrillator Versus β-Blockers for Unex-
plained Death in Thailand). The large experience with ICD
accumulated during the last 20 years has been obtained with
transvenous ICDs that were introduced almost at the same
period of the princeps publication of the Brugada brothers.1
Most recent techniques presently under evaluation involve
subcutaneous electrode (S-ICD) and are expected to signifi-
cantly reduce the rate of complications related to traditional
transvenous ICD. Therefore, they might represent the most
reasonable choice in the future for BrS patients who usually
are young with an active lifestyle and long life expectancy.
Two studies including large cohorts (n=37834 and n=17631)
of BrS patients implanted with transvenous ICDs with a follow-
up of ≤20 years have been reported. Most patients included in
these 2 studies had syncope (48%–60%), while only a minority
(8%–14%) were CA survivors. ICD was found to be extremely
effective in terminating arrhythmic episodes with only a single
lethal case of refractory VF at 18 years of age in the first patient
with BrS who presented to Pedro Brugada at 3 years of age.35
However, transvenous ICD therapy has been associated with a
significant rate of complications, including mainly (1) pocket/
leads infections because of multiple ICD replacements, device/
leads malfunction, or dislodgment; (2) inappropriate shocks
mainly because of T wave oversensing and less commonly to
noise related to myopotentials; and (3) psychological disor-
ders. Finally, a few cases of near fatal AE have been reported in
BrS patients wearing ICD, mainly in relation with arrhythmic
storms,36,37 and should question the appropriateness of therapy
using ICD alone in this group of patients.
EP-Guided Antiarrhythmic Therapy With Class 1A
Antiarrhythmic Drugs
In contrast to ICD, this mode of therapy aims to prevent the
arrhythmias rather than terminate them after they occur. Only
 4   Belhassen   Alternatives to ICD Therapy for Brugada Syndrome
Table.  Annual Incidence Rate of Arrhythmic Events
in Asymptomatic Patients Found to Have No Inducible
Arrhythmias, According to Brugada ECG Pattern and
Programmed Ventricular Stimulation Protocol21
Spontaneous Drug-Induced
Type 1 Type 1
Single/double extrastimuli 0.78% (0.36–1.47) 0.23% (0.05–0.68)
Single/double/triple
0.87% (0.35–1.79) 0.10% (0.01–0.58)
extrastimuli
The numbers in parentheses represent ranges.
few laboratories worldwide have gained extensive experience
with this mode of treatment.19,38 Among the class 1A drugs,
procainamide is contraindicated because of its effect to unmask
the BrS and induce arrhythmogenesis like class 1C drugs (fle-
cainide and ajmaline).39 We have recently reported our 33-year
experience in 96 patients with various clinical presentations of
BrS, including 3 patients studied before the initial publication
of the Brugada brothers.19 We found that quinidine (and diso-
pyramide in some patients) was highly and similarly effective
in preventing VF reinduction (≈90% efficacy) in CA survivors,
as well as in those presenting with syncope or were asymptom-
atic. This result was achieved despite the use of an aggressive
PVS protocol. No AE occurred during class 1A drug therapy in
any of the EP drug responders during long follow-up periods.
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None of our 10 CA survivors treated with quinidine (includ-
ing 9 EP–quinidine responders) experienced an AE during
146.4±90.9 months. This included our 3 patients who pre-
sented with arrhythmic storms and did not exhibit recurrent AE
on medication during ≥22 years of follow-up. The latter patient
even accepted not to have his ICD replaced on battery deple-
tion. AE occurred in only 2 of our study patients who were CA
survivors treated with ICD alone, but the arrhythmia did not
recur during quinidine therapy in any of them. In patients who
suffered recurrent syncope on quinidine, the mechanism of the
syncope was clearly attributed to a nonarrhythmic mechanism
(mainly vagal syncope). It is noteworthy that our 30 non-CA
patients with no inducible arrhythmias at baseline remained
arrhythmia-free on no therapy during long-term follow-up
(129.9±27 months and 86.8±52 months in the syncope and the
asymptomatic groups, respectively). Finally, our management
policy enabled us to implant ICD in only 21% of the study
patients, which is less than the implantation rate in other stud-
ies involving similar patient populations. In an earlier study,40
we showed that the long-term reproducibility of the EP effi-
cacy of quinidine in 5 patients with BrS was excellent, con-
firming that this therapeutic approach is a valuable long-term
alternative to ICD therapy.
However, this mode of therapy has 2 main adverse effects:
(1) it resulted in 38% incidence of clinical side effects that were
albeit transient but almost always required drug discontinua-
tion19; however, no instance of excessive QT prolongation has
been observed in any of our patients; (2) a non-negligible pro-
portion of patients who exhibited long-term poor compliance
to their medications refused an ICD at this time.19 In addi-
tion, quinidine was shown to be unavailable in many countries
around the world, which prevents its wide use.41
Empirical Quinidine Therapy
Based on the experience gained with empirical drug therapy
with β-blockers in the management of long QT syndrome
and the great efficacy of quinidine in the management of BrS
patients observed in our institution, Viskin et al42 initiated in
2009 a prospective registry of empirical quinidine for asymp-
tomatic BrS. Preliminary results in a small patient population
are encouraging.43 Such therapeutic approach, however, faces
3 main issues: (1) that of drug tolerance/compliance (as for
the EP-guided quinidine therapy approach)19; (2) it results in
unnecessary management of a substantial number of patients
at low to nil risk for AE; and (3) only long follow-up observa-
tion in a large patient cohort will be necessary before reaching
any conclusion about such therapeutic option.
Ablation
Endocardial Ablation
In 2003, Haïssaguerre et al44 were the first to report ablation of
ventricular ectopy originating from the right ventricular outflow
tract (RVOT) and the right ventricular anterior Purkinje system
in 3 patients. Nakagawa et al45 reported successful ablation of
ventricular focus initiating arrhythmic storms in the posterolat-
eral RVOT area. The RVOT location of most arrhythmias asso-
ciated with BrS was corroborated by Morita et al.46 In 4 patients
with VF storms, Sunsaneewitayakul et al47 from Thailand
reported that endocardial catheter ablation of the late activation
zone modified the Brugada ECG pattern in 3 and suppressed
VF storm in all their patients during 12 to 30 months follow-up.
Epicardial Ablation
In 2011, Nademanee et al48 from Thailand were the first to
report on epicardial ablation in 9 patients with type 1 Brugada
and a monthly median of 4 VT episodes requiring ICD shocks.
Combined endocardial and epicardial mapping of the right
ventricle revealed areas of abnormal low voltage with pro-
longed duration and fractionated electrograms localized to the
anterior aspect of the RVOT epicardium. Ablation of these sites
rendered VT/VF noninducible in 7/9 (78%) patients with no
clinical recurrence during a mean follow-up of 20 months. The
ECG pattern normalized after ablation in 8/9 (89%) patients.
This study supports the hypothesis that abnormal delayed
depolarization is the mechanism of VT/VF in BrS with an
arrhythmogenic substrate localized to the RVOT epicardial
region. Nademanee recently updated49 his group’s results in
>50 patients and reported complete elimination of Brugada
ECG pattern in all of them, with no recurrent VF during a
median follow-up of 3 years, despite persistent induction of
polymorphic ventricular tachycardia/VF in ≈40% of patients.
Similar results were recently published by Josep Brugada,
Carlo Pappone, and coworkers50 in a series of 14 patients
with symptomatic BrS (12 with ICD-documented ventricular
 5   Belhassen   Alternatives to ICD Therapy for Brugada Syndrome
arrhythmias). Interestingly, the arrhythmic substrate ablated
was delineated by a flecainide infusion. After epicardial abla-
tion, all patients became noninducible with PVS, and ECG
did not show any change, suggesting BrS ECG pattern after
flecainide infusion. After a median follow-up of 5 months, the
ECG remained normal in all patients, despite flecainide test-
ing, and ICD did not show any AE.
Although significant complications were not reported dur-
ing epicardial ablation of BrS in the 2 above mentioned stud-
ies, it is important to bear in mind that such a procedure may
result in rare but severe complications.51
Personal Viewpoint
Management of Cardiac Arrest Survivors
Although the guidelines recommend ICD therapy, our own
experience suggests that EP-guided therapy with quinidine
(or alternatively disopyramide) could be an excellent alterna-
tive to ICD if several conditions are fulfilled19: (1) sustained
polymorphic ventricular tachycardia/VF is induced during EP
testing; (2) the medication prevents arrhythmia reinduction
during EP testing; (3) the medication is well tolerated dur-
ing long term; and (4) patients are willing to accept the con-
straints of long-term antiarrhythmic medication and are aware
of the necessity to undergo periodic EP testing (ie, every 5–10
years) to confirm persistence of noninducibility of VF over
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time (Figure 1).
An important prerequisite for a wide application of such
a policy is the use of an aggressive PVS protocol19 that both
enables the achievement of highest sensitivity rates at baseline
and optimizes the confidence in the response to medication
when the arrhythmia is rendered no longer inducible. This
aggressive protocol is in fact a modified conventional proto-
col (≤3 extrastimuli, 2 right ventricular sites, 2 basic cycle
lengths) in which (1) pacing is performed using stimulus
Figure 1. Strategy of management of patients with Brugada
syndrome who are cardiac arrest survivors or have syncope
suspected to have an arrhythmic origin. CA indicates cardiac
arrest; EPS, electrophysiological study; ICD, implantable
cardioverter defibrillator; PVS, programmed ventricular
stimulation; QND, quinidine; and Tx, therapy. *See also text.
current of 2- to 5-fold the diastolic threshold and (2) double
and triple extrastimulation are repeated 10× and 5×, respec-
tively, at the shortest coupling intervals. It is noteworthy that
using this protocol, we induced VF in all our CA survivors
patients19 (100% inducibility rate). In comparison, in the same
patient population, an inducibility rate of 72% was achieved
with conventional PVS protocols,27 while an even lower rate
(23.5%) was obtained by the Pedro Brugada group13 with a
protocol that is the least aggressive in the EP assessment of
BrS (single right ventricular apical site, limitation of coupling
intervals to ≥200 ms, no repetition of extrastimulation).
Young patients and those who refuse the ICD therapy
option or desire to postpone it may represent the best candi-
dates. Decision on such policy should be taken after careful
assessment of the patient’s psychological profile, especially
regarding the future compliance to long-term drug therapy.
An important advantage of EP-guided quinidine
therapy over ICD therapy in CA survivors deals with the
40%19 to 56%31 of patients who remain arrhythmia-free
during long-term follow-up but are, nonetheless, commit-
ted to have their ICD replaced on battery depletion. In this
respect, 2 studies52,53 showed that the arrhythmic risk recur-
rence markedly decreased with age. I think that long-term
well-tolerated quinidine therapy (ie, 2–3 daily tablets of
300 mg hydroquinidine) would be better accepted by these
patients than multiple ICD replacements with their inherent
risk of complications. Successful long-term management
of arrhythmic storms with quinidine during ≤40 years have
been reported in 2 patients with idiopathic VF,54,55 including
1 of our patients55 who is presently enjoying his 37th year
without ICD.
Of course, an ICD is recommended for patients who have
persistent VF inducibility on quinidine or who develop drug
intolerance or become noncompliant with medications.
Management of Patients With Syncope Suspected
to Have an Arrhythmic Origin
This group of patients represents probably the one which needs
the most careful clinical assessment. Although there is con-
sensual agreement that most cases of syncope in BrS patients
have a nonarrhythmic mechanism,19,56 some may be related
to a paroxysmal malignant ventricular arrhythmia (Figure 1).
A systematic history taking looking mainly for presence/
absence of prodromes and specific triggers has been shown
to be useful in distinguishing arrhythmic from nonarrhythmic
syncope.12 Male sex and older age at time of first syncope also
have been shown to suggest an arrhythmic origin.12
For those BrS patients with syncope suspected to have an
arrhythmic origin, I think there are 2 therapeutic options: (1)
ICD therapy (as recommended by the guidelines); and (2) EP
testing using our aggressive PVS protocol as used for CA sur-
vivors (see above). The inability to induce VF at baseline will
allow recommending no therapy. EP-guided quinidine therapy
enables avoidance of an ICD in a non-negligible proportion
of patients.
 6   Belhassen   Alternatives to ICD Therapy for Brugada Syndrome
Figure 2. Strategy of management of patients with Brugada
syndrome who are asymptomatic or have neurocardiogenic
syncope. EPS indicates electrophysiological study; ICD,
implantable cardioverter defibrillator; PVS, programmed
ventricular stimulation; QND, quinidine; and Tx, therapy. *See
also text.
Management of Asymptomatic Patients (Including
Patients With Neurocardiogenic Syncope)
This group of patients represents the largest BrS patient
population encountered worldwide and certainly the one that
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is the most difficult to manage (Figure 2). Like Pedro Bru-
gada, I do recommend EP testing for arrhythmic stratifica-
tion in these patients. Nonetheless, I do not recommend using
our aggressive PVS protocol for this purpose because it has
shown an unacceptable high inducibility rate (61%) in this
patient group.19 Taking in account the fact that the PVS pro-
tocol used by the Pedro Brugada group13 achieved the high-
est positive predictive value (18.2%) and negative predictive
value (98.3%) ever reported in asymptomatic patients, I have
suggested using their PVS protocol57 with adjustment of the
stimulus current intensity to 2 to 5 the diastolic threshold
instead of their fixed 4 mA and inclusion of repetition of dou-
ble extrastimulation (n=10) and triple extrastimulation (n=5)
at the shortest coupling intervals (≥200 ms). The latter modi-
fications aim to further increase protocol sensitivity. Patients
with inducible VF will be invited to undergo EP-guided quin-
idine testing. ICD will be recommended in case of persistent
VF inducibility on medication, drug-induced side effects,
or poor patient compliance to medications. Patients with no
inducible arrhythmias will be followed on no therapy.
What Should Be the Place
of Epicardial Ablation?
For CA survivors with implanted ICD who have recurrent AE,
epicardial ablation certainly represents a promising therapeutic
option. It is noteworthy, however, that the promoters of this
mode of therapy are presently reluctant to leave their patients
without back-up ICD even if the ECG Brugada pattern and
the VF inducibility are abolished. The fact that Nademanee49
recently reported persistent VF inducibility in ≈40% of patients
after successful epicardial ablation casts a doubt about any
change of their policy in the future. Thus, it seems that epicar-
dial ablation will presently serve as an adjuvant rather than an
alternative to ICD therapy in patients with recurrent AE.
The question whether epicardial ablation should be pro-
posed to other groups of patients considered at increased
arrhythmic risk with the aim to avoid ICD or drug therapy will
deserve further studies. In the patient reported by Széplaki
et al58 (a 31-year-old male with syncope, spontaneous type
1 Brugada ECG and negative EP testing who refused the
implantation of an ICD), epicardial ablation was offered and
successfully performed. I assume that such a policy will gain
popularity in the future in centers that have great expertise in
the field of epicardial ablation.
Conclusions
From the experience accumulated to date, it seems that ICDs
no longer warrant the quote that they are the “only therapy
with proven efficacy for the management of patients with
BrS”. I think it would be more appropriate to state that there
are presently several possible modes of management of the
BrS, each of them presenting advantages and disadvantages.
A multicenter study performed in institutions where all modes
of therapy are available is certainly warranted, but I guess that
most research efforts will focus on comparison of ICD therapy
and epicardial ablation.49
Meanwhile, it is important to objectively inform the patient
about these various modalities of treatment. Patient’s final deci-
sion is likely to be affected by the cardiac electrophysiologist’s
experience and personal preference for each of these therapeutic
options, as well as the availability of pericardial interventions or
quinidine in the physician’s institution. At this stage, my impres-
sion is that epicardial ablation might play an increasing role in
the future because the number of cardiac electrophysiologists
gaining experience in epicardial ablation of ventricular tachyar-
rhythmias is growing. A major breakthrough will certainly be
achieved when the epicardial ablation option will render the need
for ICD implantation obsolete. It is likely that the Brugada broth-
ers, at the time they reported their malignant electric syndrome,
could not have believed that it will be managed <2 decades later
by epicardial ablation of the RVOT using a technique developed
by eminent Thai cardiac electrophysiologists.
Disclosures
None.
References
1. Brugada P, Brugada J. Right bundle branch block, persistent ST seg-
ment elevation and sudden cardiac death: a distinct clinical and elec-
trocardiographic syndrome. A multicenter report. J Am Coll Cardiol.
1992;20:1391–1396.
2. Martini B, Nava A, Thiene G, Buja GF, Canciani B, Scognamiglio R,
Daliento L, Dalla Volta S. Ventricular fibrillation without apparent heart
disease: description of six cases. Am Heart J. 1989;118:1203–1209.
3. Nademanee K, Veerakul G, Nimmannit S, Chaowakul V, Bhuripanyo K,
Likittanasombat K, Tunsanga K, Kuasirikul S, Malasit P, Tansupasawadikul
 7   Belhassen   Alternatives to ICD Therapy for Brugada Syndrome
S, Tatsanavivat P. Arrhythmogenic marker for the sudden unexplained
death syndrome in Thai men. Circulation. 1997;96:2595–2600.
4. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado
D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W,
Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the sec-
ond consensus conference: endorsed by the Heart Rhythm Society and the
European Heart Rhythm Association. Circulation. 2005;111:659–670.
5. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada
J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A,
Schwartz PJ, Shimizu W, Tomaselli G, Tracy C, Ackerman M, Belhassen B,
Estes NA 3rd, Fatkin D, Kalman J, Kaufman E, Kirchhof P, Schulze-Bahr
E, Wolpert C, Vohra J, Refaat M, Etheridge SP, Campbell RM, Martin ET,
Quek SC; Document Reviewers; Heart Rhythm Society; European Heart
Rhythm Association; Asia Pacific Heart Rhythm Society. Executive sum-
mary: HRS/EHRA/APHRS expert consensus statement on the diagnosis
and management of patients with inherited primary arrhythmia syndromes.
Europace. 2013;15:1389–1406. doi: 10.1093/europace/eut272.
6. Bayés de Luna A, Brugada J, Baranchuk A, Borggrefe M, Breithardt G,
Goldwasser D, Lambiase P, Riera AP, Garcia-Niebla J, Pastore C, Oreto
G, McKenna W, Zareba W, Brugada R, Brugada P. Current electrocardio-
graphic criteria for diagnosis of Brugada pattern: a consensus report. J
Electrocardiol. 2012;45:433–442.
7. Lehmann MH, Brugada R. Brugada syndrome: diagnostic pit-
falls. J Emerg Med. 2009;37:79–81; author reply 81. doi: 10.1016/j.
jemermed.2008.09.038.
8. Gallahue FE, Uzgiris R, Burke R, Abrahams W. Brugada syndrome pre-
senting as an “acute myocardial infarction”. J Emerg Med. 2009;37:15–
20. doi: 10.1016/j.jemermed.2007.09.038.
9. Gottschalk BH, Anselm DD, Brugada J, Brugada P, Wilde AA, Chiale PA,
Pérez-Riera AR, Elizari MV, De Luna AB, Krahn AD, Tan HL, Postema
PG, Baranchuk A. Expert cardiologists cannot distinguish between
Brugada phenocopy and Brugada syndrome electrocardiogram patterns.
Europace. 2016;18:1095–1100. doi: 10.1093/europace/euv278.
Downloaded from http://ahajournals.org by on June 13, 2023
10. Rodríguez-Mañero M, Sacher F, de Asmundis C, Maury P, Lambiase
PD, Sarkozy A, Probst V, Gandjbakhch E, Castro-Hevia J, Saenen J,
Fukushima Kusano K, Rollin A, Arbelo E, Valderrábano M, Arias MA,
Mosquera-Pérez I, Schilling R, Chierchia GB, García-Bolao I, García-
Seara J, Hernandez-Ojeda J, Kamakura T, Martínez-Sande L, González-
Juanatey JR, Haïssaguerre M, Brugada J, Brugada P. Monomorphic
ventricular tachycardia in patients with Brugada syndrome: a multicenter
retrospective study. Heart Rhythm. 2016;13:669–682. doi: 10.1016/j.
hrthm.2015.10.038.
11. Soteriades ES, Evans JC, Larson MG, Chen MH, Chen L, Benjamin
EJ, Levy D. Incidence and prognosis of syncope. N Engl J Med.
2002;347:878–885. doi: 10.1056/NEJMoa012407.
12. Olde Nordkamp LR, Vink AS, Wilde AA, de Lange FJ, de Jong JS,
Wieling W, van Dijk N, Tan HL. Syncope in Brugada syndrome: preva-
lence, clinical significance, and clues from history taking to distinguish
arrhythmic from nonarrhythmic causes. Heart Rhythm. 2015;12:367–375.
doi: 10.1016/j.hrthm.2014.10.014.
13. Sieira J, Conte G, Ciconte G, de Asmundis C, Chierchia GB, Baltogiannis
G, Di Giovanni G, Saitoh Y, Irfan G, Casado-Arroyo R, Juliá J, La Meir M,
Wellens F, Wauters K, Van Malderen S, Pappaert G, Brugada P. Prognostic
value of programmed electrical stimulation in Brugada syndrome: 20
years experience. Circ Arrhythm Electrophysiol. 2015;8:777–784. doi:
10.1161/CIRCEP.114.002647.
14. Delise P, Allocca G, Marras E, Giustetto C, Gaita F, Sciarra L, Calo L,
Proclemer A, Marziali M, Rebellato L, Berton G, Coro L, Sitta N. Risk
stratification in individuals with the Brugada type 1 ECG pattern without
previous cardiac arrest: usefulness of a combined clinical and electrophys-
iologic approach. Eur Heart J. 2011;32:169–176. doi: 10.1093/eurheartj/
ehq381.
15. Probst V, Veltmann C, Eckardt L, Meregalli PG, Gaita F, Tan HL, Babuty
D, Sacher F, Giustetto C, Schulze-Bahr E, Borggrefe M, Haissaguerre
M, Mabo P, Le Marec H, Wolpert C, Wilde AA. Long-term prognosis of
patients diagnosed with Brugada syndrome: results from the FINGER
Brugada Syndrome Registry. Circulation. 2010;121:635–643. doi:
10.1161/CIRCULATIONAHA.109.887026.
16. Priori SG, Gasparini M, Napolitano C, Della Bella P, Ottonelli AG,
Sassone B, Giordano U, Pappone C, Mascioli G, Rossetti G, De Nardis
R, Colombo M. Risk stratification in Brugada syndrome: results of the
PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) reg-
istry. J Am Coll Cardiol. 2012;59:37–45. doi: 10.1016/j.jacc.2011.08.064.
17. Mizumaki K, Fujiki A, Tsuneda T, Sakabe M, Nishida K, Sugao M, Inoue H.
Vagal activity modulates spontaneous augmentation of ST elevation in the
daily life of patients with Brugada syndrome. J Cardiovasc Electrophysiol.
2004;15:667–673. doi: 10.1046/j.1540-8167.2004.03601.x.
18. Alboni P, Brignole M, Menozzi C, Raviele A, Del Rosso A, Dinelli M,
Solano A, Bottoni N. Diagnostic value of history in patients with syncope
with or without heart disease. J Am Coll Cardiol. 2001;37:1921–1928.
19. Belhassen B, Rahkovich M, Michowitz Y, Glick A, Viskin S. Management
of Brugada syndrome: thirty-three-year experience using electrophysiolog-
ically guided therapy with class 1A antiarrhythmic drugs. Circ Arrhythm
Electrophysiol. 2015;8:1393–1402. doi: 10.1161/CIRCEP.115.003109.
20. Adler A, Rosso R, Chorin E, Havakuk O, Antzelevitch C, Viskin S. Risk
stratification in Brugada syndrome: clinical characteristics, electrocardio-
graphic parameters, and auxiliary testing. Heart Rhythm. 2016;13:299–
310. doi: 10.1016/j.hrthm.2015.08.038.
21. Sroubek J, Probst V, Mazzanti A, Delise P, Hevia JC, Ohkubo K, Zorzi
A, Champagne J, Kostopoulou A, Yin X, Napolitano C, Milan DJ,
Wilde A, Sacher F, Borggrefe M, Ellinor PT, Theodorakis G, Nault I,
Corrado D, Watanabe I, Antzelevitch C, Allocca G, Priori SG, Lubitz SA.
Programmed ventricular stimulation for risk stratification in the Brugada
syndrome: a pooled analysis. Circulation. 2016;133:622–630. doi:
10.1161/CIRCULATIONAHA.115.017885.
22. Sieira J, Ciconte G, Conte G, Chierchia GB, de Asmundis C, Baltogiannis
G, Di Giovanni G, Saitoh Y, Irfan G, Casado-Arroyo R, Julià J, La Meir M,
Wellens F, Wauters K, Pappaert G, Brugada P. Asymptomatic Brugada syn-
drome: clinical characterization and long-term prognosis. Circ Arrhythm
Electrophysiol. 2015;8:1144–1150. doi: 10.1161/CIRCEP.114.003044.
23. Calò L, Giustetto C, Martino A, Sciarra L, Cerrato N, Marziali M, Rauzino
J, Carlino G, de Ruvo E, Guerra F, Rebecchi M, Lanzillo C, Anselmino
M, Castro A, Turreni F, Penco M, Volpe M, Capucci A, Gaita F. A new
electrocardiographic marker of sudden death in Brugada syndrome: the
S-wave in lead I. J Am Coll Cardiol. 2016;67:1427–1440. doi: 10.1016/j.
jacc.2016.01.024.
24. 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;108:3092–3096. doi:
10.1161/01.CIR.0000104568.13957.4F.
25. Gehi AK, Duong TD, Metz LD, Gomes JA, Mehta D. Risk stratification
of individuals with the Brugada electrocardiogram: a meta-analysis. J
Cardiovasc Electrophysiol. 2006;17:577–583. doi: 10.1111/j.1540-8167.
2006.00455.x.
26. Paul M, Gerss J, Schulze-Bahr E, Wichter T, Vahlhaus C, Wilde AA,
Breithardt G, Eckardt L. Role of programmed ventricular stimulation in
patients with Brugada syndrome: a meta-analysis of worldwide published
data. Eur Heart J. 2007;28:2126–2133. doi: 10.1093/eurheartj/ehm116.
27. Fauchier L, Isorni MA, Clementy N, Pierre B, Simeon E, Babuty D.
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;168:3027–3029. doi:
10.1016/j.ijcard.2013.04.146.
28. Nishizaki M, Sakurada H, Yamawake N, Ueda-Tatsumoto A, Hiraoka
M. Low risk for arrhythmic events in asymptomatic patients with drug-
induced type 1 ECG. Do patients with drug-induced Brugada type ECG
have poor prognosis? (Con). Circ J. 2010;74:2464–2473.
29. Benito B, Sarkozy A, Mont L, Henkens S, Berruezo A, Tamborero D,
Arzamendi D, Berne P, Brugada R, Brugada P, Brugada J. Gender differ-
ences in clinical manifestations of Brugada syndrome. J Am Coll Cardiol.
2008;52:1567–1573. doi: 10.1016/j.jacc.2008.07.052.
30. Richter S, Sarkozy A, Veltmann C, Chierchia GB, Boussy T, Wolpert C,
Schimpf R, Brugada J, Brugada R, Borggrefe M, Brugada P. Variability
of the diagnostic ECG pattern in an ICD patient population with
Brugada syndrome. J Cardiovasc Electrophysiol. 2009;20:69–75. doi:
10.1111/j.1540-8167.2008.01282.x.
31. Conte G, Sieira J, Ciconte G, de Asmundis C, Chierchia GB, Baltogiannis
G, Di Giovanni G, La Meir M, Wellens F, Czapla J, Wauters K, Levinstein
M, Saitoh Y, Irfan G, Julià J, Pappaert G, Brugada P. Implantable car-
dioverter-defibrillator therapy in Brugada syndrome: a 20-year single-
center experience. J Am Coll Cardiol. 2015;65:879–888. doi: 10.1016/j.
jacc.2014.12.031.
 8   Belhassen   Alternatives to ICD Therapy for Brugada Syndrome
32. Sacher F, Meregalli P, Veltmann C, Field ME, Solnon A, Bru P, Abbey
S, Jaïs P, Tan HL, Wolpert C, Lande G, Bertault V, Derval N, Babuty
D, Lacroix D, Boveda S, Maury P, Hocini M, Clémenty J, Mabo P,
Lemarec H, Mansourati J, Borggrefe M, Wilde A, Haïssaguerre M, Probst
V. Are women with severely symptomatic Brugada syndrome differ-
ent from men? J Cardiovasc Electrophysiol. 2008;19:1181–1185. doi:
10.1111/j.1540-8167.2008.01223.x.
33. Nademanee K, Veerakul G, Mower M, Likittanasombat K, Krittayapong
R, Bhuripanyo K, Sitthisook S, Chaothawee L, Lai MY, Azen SP.
Defibrillator versus beta-blockers for unexplained death in Thailand
(DEBUT): a randomized clinical trial. Circulation. 2003;107:2221–2226.
doi: 10.1161/01.CIR.0000066319.56234.C8.
34. Sacher F, Probst V, Maury P, Babuty D, Mansourati J, Komatsu Y,
Marquie C, Rosa A, Diallo A, Cassagneau R, Loizeau C, Martins
R, Field ME, Derval N, Miyazaki S, Denis A, Nogami A, Ritter P,
Gourraud JB, Ploux S, Rollin A, Zemmoura A, Lamaison D, Bordachar
P, Pierre B, Jaïs P, Pasquié JL, Hocini M, Legal F, Defaye P, Boveda
S, Iesaka Y, Mabo P, Haïssaguerre M. Outcome after implantation of
a cardioverter-defibrillator in patients with Brugada syndrome: a mul-
ticenter study-part 2. Circulation. 2013;128:1739–1747. doi: 10.1161/
CIRCULATIONAHA.113.001941.
35. Brugada P, Brugada J, Brugada R. When our best is not enough: the
death of a teenager with Brugada syndrome. J Cardiovasc Electrophysiol.
2009;20:108–109. doi: 10.1111/j.1540-8167.2008.01247.x.
36. Chalvidan T, Deharo JC, Dieuzaide P, Defaye P, Djiane P. Near fa-
tal electrical storm in a patient equipped with an implantable cardio-
verter defibrillator for Brugada syndrome. Pacing Clin Electrophysiol.
2000;23:410–412.
37. Belhassen B, Viskin S. Near fatal ventricular fibrillation in Brugada
syndrome despite presence of an implanted implantable cardioverter
defibrillator. Can J Cardiol. 2014;30:1460.e3–1460.e5. doi: 10.1016/j.
cjca.2014.06.015.
38. Bouzeman A, Traulle S, Messali A, Extramiana F, Denjoy I, Narayanan K,
Downloaded from http://ahajournals.org by on June 13, 2023
Marijon E, Hermida JS, Leenhardt A. Long-term follow-up of asymptom-
atic Brugada patients with inducible ventricular fibrillation under hydro-
quinidine. Europace. 2014;16:572–577. doi: 10.1093/europace/eut279.
39. Antzelevitch C, Yan GX. J-wave syndromes: Brugada and early repolar-
ization syndromes. Heart Rhythm. 2015;12:1852–1866. doi: 10.1016/j.
hrthm.2015.04.014.
40. Belhassen B, Glick A, Viskin S. Excellent long-term reproducibility of the
electrophysiologic efficacy of quinidine in patients with idiopathic ven-
tricular fibrillation and Brugada syndrome. Pacing Clin Electrophysiol.
2009;32:294–301. doi: 10.1111/j.1540-8159.2008.02235.x.
41. Viskin S, Wilde AA, Guevara-Valdivia ME, Daoulah A, Krahn AD,
Zipes DP, Halkin A, Shivkumar K, Boyle NG, Adler A, Belhassen B,
Schapachnik E, Asrar F, Rosso R. Quinidine, a life-saving medication for
Brugada syndrome, is inaccessible in many countries. J Am Coll Cardiol.
2013;61:2383–2387. doi: 10.1016/j.jacc.2013.02.077.
42. Viskin S, Wilde AA, Tan HL, Antzelevitch C, Shimizu W, Belhassen B.
Empiric quinidine therapy for asymptomatic Brugada syndrome: time for
a prospective registry. Heart Rhythm. 2009;6:401–404. doi: 10.1016/j.
hrthm.2008.11.030.
43. Adler A, Olde Nordkamp L, Crotti L, Schwartz P, Castelletti S, Veltmann
C, Shimizu W, Antzelevitch C, Belhassen B, Tan H, Wilde A, Viskin S.
Empiric quinidine for asymptomatic Brugada syndrome—preliminary re-
sults of an international registry. Heart Rhythm. 2012;9:1918–1919. doi:
10.1016/j.hrthm.2012.09.116.
44. Haïssaguerre M, Extramiana F, Hocini M, Cauchemez B, Jaïs P,
Cabrera JA, Farré J, Farre G, Leenhardt A, Sanders P, Scavée C, Hsu
LF, Weerasooriya R, Shah DC, Frank R, Maury P, Delay M, Garrigue S,
Clémenty J. Mapping and ablation of ventricular fibrillation associated
with long-QT and Brugada syndromes. Circulation. 2003;108:925–928.
doi: 10.1161/01.CIR.0000088781.99943.95.
45. Nakagawa E, Takagi M, Tatsumi H, Yoshiyama M. Successful radiofre-
quency catheter ablation for electrical storm of ventricular fibrillation in a
patient with Brugada syndrome. Circ J. 2008;72:1025–1029.
46. Morita H, Fukushima-Kusano K, Nagase S, Takenaka-Morita S, Nishii N,
Kakishita M, Nakamura K, Emori T, Matsubara H, Ohe T. Site-specific
arrhythmogenesis in patients with Brugada syndrome. J Cardiovasc
Electrophysiol. 2003;14:373–379.
47. Sunsaneewitayakul B, Yao Y, Thamaree S, Zhang S. Endocardial mapping
and catheter ablation for ventricular fibrillation prevention in Brugada
syndrome. J Cardiovasc Electrophysiol. 2012;23(suppl 1):S10–S16. doi:
10.1111/j.1540-8167.2012.02433.x.
48. Nademanee K, Veerakul G, Chandanamattha P, Chaothawee L,
Ariyachaipanich A, Jirasirirojanakorn K, Likittanasombat K, Bhuripanyo
K, Ngarmukos T. Prevention of ventricular fibrillation episodes in Brugada
syndrome by catheter ablation over the anterior right ventricular out-
flow tract epicardium. Circulation. 2011;123:1270–1279. doi: 10.1161/
CIRCULATIONAHA.110.972612.
49. Wilde AA, Nademanee K. Epicardial Substrate Ablation in Brugada
Syndrome: Time for a Randomized Trial! Circ Arrhythm Electrophysiol.
2015;8:1306–1308. doi: 10.1161/CIRCEP.115.003500.
50. Brugada J, Pappone C, Berruezo A, Vicedomini G, Manguso F, Ciconte
G, Giannelli L, Santinelli V. Brugada syndrome phenotype elimination by
epicardial substrate ablation. Circ Arrhythm Electrophysiol. 2015;8:1373–
1381. doi: 10.1161/CIRCEP.115.003220.
51. Tung R, Michowitz Y, Yu R, Mathuria N, Vaseghi M, Buch E, Bradfield
J, Fujimura O, Gima J, Discepolo W, Mandapati R, Shivkumar K.
Epicardial ablation of ventricular tachycardia: an institutional experience
of safety and efficacy. Heart Rhythm. 2013;10:490–498. doi: 10.1016/j.
hrthm.2012.12.013.
52. Conte G, DE Asmundis C, Sieira J, Levinstein M, Chierchia GB, DI
Giovanni G, Baltogiannis G, Ciconte G, Saitoh Y, Casado-Arroyo
R, Pappaert G, Brugada P. Clinical characteristics, management, and
prognosis of elderly patients with Brugada syndrome. J Cardiovasc
Electrophysiol. 2014;25:514–519. doi: 10.1111/jce.12359.
53. Kamakura T, Wada M, Nakajima I, Ishibashi K, Miyamoto K, Okamura
H, Noda T, Aiba T, Takaki H, Yasuda S, Ogawa H, Shimizu W, Makiyama
T, Kimura T, Kamakura S, Kusano K. Evaluation of the necessity for
cardioverter-defibrillator implantation in elderly patients with Brugada
syndrome. Circ Arrhythm Electrophysiol. 2015;8:785–791. doi: 10.1161/
CIRCEP.114.002705.
54. Kontny F, Dale J. Self-terminating idiopathic ventricular fibrilla-
tion presenting as syncope: a 40-year follow-up report. J Intern Med.
1990;227:211–213.
55. Belhassen B. A 25-year control of idiopathic ventricular fibrillation with
electrophysiologic-guided antiarrhythmic drug therapy. Heart Rhythm.
2004;1:352–354. doi: 10.1016/j.hrthm.2004.04.006.
56. Sacher F, Arsac F, Wilton SB, Derval N, Denis A, de Guillebon M, Ramoul
K, Bordachar P, Ritter P, Hocini M, Clémenty J, Jaïs P, Haïssaguerre
M. Syncope in Brugada syndrome patients: prevalence, characteris-
tics, and outcome. Heart Rhythm. 2012;9:1272–1279. doi: 10.1016/j.
hrthm.2012.04.013.
57. Belhassen B, Michowitz Y. Arrhythmic risk stratification by pro-
grammed ventricular stimulation in Brugada syndrome: the end of the
debate? Circ Arrhythm Electrophysiol. 2015;8:757–759. doi: 10.1161/
CIRCEP.115.003138.
58. Széplaki G, Özcan EE, Osztheimer I, Tahin T, Merkely B, Gellér L.
Ablation of the epicardial substrate in the right ventricular outflow tract
in a patient with Brugada syndrome refusing implantable cardioverter
defibrillator therapy. Can J Cardiol. 2014;30:1249.e9–1249.e11. doi:
10.1016/j.cjca.2014.05.019.
Key Words: ablation ◼ Brugada syndrome ◼ drug therapy ◼ electric
stimulation ◼ electrophysiology test ◼ quinidine
 9   Belhassen   Alternatives to ICD Therapy for Brugada Syndrome

Response to Bernard Belhassen, MD

Juan Sieira, MD, and Pedro Brugada, MD, PhD

Dr Belhassen presents an electrophysiological-guided approach for the management of Brugada syndrome patients. This is a
very valuable strategy that might reduce the number of implantable cardioverter defibrillator implantations and, what is even
more interesting, the number of arrhythmic events in this population. Nevertheless, we have several concerns.
We have presented our doubts about the long-term efficacy of quinidine in preventing arrhythmic events, especially in
real-life settings. We believe that the drug, as opposed to implantable cardioverter defibrillator implantation, cannot guaran-
tee complete protection of all patients. Pathophysiological mechanisms underlying Brugada syndrome are diverse, and the
drug might not act on all of them.1 Furthermore, secondary effects of the drug are relevant and limit its use.2
Electrophysiological-guided therapy for high-risk patients, survivors of a sudden cardiac death or even those with syn-
cope, have excellent outcomes in highly experienced hands.2 Generalization and adoption by less experienced physicians
might jeopardize the patients’ prognosis. As Dr Belhassen points out, several requisites have to be fulfilled to adopt this
strategy, which include a careful selection of patients and their awareness of the necessity of high therapeutic compliance.
Drug compliance in other fields of cardiology is far from perfect,3 and in Brugada syndrome, its lack might mean the death
of the patient. Compliance of asymptomatic patients taking a drug with a prophylactic intention that has multiple side effects
has to be carefully assessed before recommending its generalization.
Asymptomatic patients, especially those with a nonspontaneous drug-induced ECG type 1 pattern, merit special con-
sideration. They are probably the most numerous group, and their management is challenging and even controversial.4 We
have always supported the value of electrophysiological study in the risk stratification of these patients. A mild stimulation
protocol achieves a very high negative predictive value, but arrhythmic events can still happen. We believe that other char-
acteristics have also to be considered (such as spontaneous type 1 pattern, familial antecedents, ECG characteristics, etc).
The electrophysiological-based strategy proposed by Dr Belhassen, with a mild stimulation protocol, has undoubtedly great
advantages, but it needs the support of further evidence.
Downloaded from http://ahajournals.org by on June 13, 2023

Up to this time, we believe that implantable cardioverter defibrillator placement is the only strategy that fully protects
Brugada syndrome patients. Its protection is reproducible and not limited by the physician’s experience or patients’ behavior.
We believe that risk stratification is of utmost importance to adequately identify those patients who will benefit from it. A
drug-based strategy that effectively eliminates arrhythmic events, that is well tolerated, and that achieves high compliance is
desirable. Quinidine does not meet these goals. However, we believe that the protocol presented by Dr Belhassen is highly
valuable, with excellent outcomes, and could constitute an alternative to an implantable cardioverter defibrillator in selected
patients.
References
1. Meregalli PG, Wilde AA, Tan HL. Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more?
Cardiovasc Res. 2005;67:367–378.
2. Belhassen B, Rahkovich M, Michowitz Y, Glick A, Viskin S. Management of Brugada syndrome: thirty-three-year experience using electrophysiologi-
cally guided therapy with class 1A antiarrhythmic drugs. Circ Arrhythm Electrophysiol. 2015;8:1393–1402.
3. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D,
Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med.
2009;361:1139–1151.
4. Sieira J, Ciconte G, Conte G, Chierchia GB, de Asmundis C, Baltogiannis G, Di Giovanni G, Saitoh Y, Irfan G, Casado-Arroyo R, Julià J, La Meir M,
Wellens F, Wauters K, Pappaert G, Brugada P. Asymptomatic Brugada syndrome: clinical characterization and long-term prognosis. Circ Arrhythm
Electrophysiol. 2015;8:1144–1150.