European Journal of Internal Medicine 44 (2017) 19–27

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European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Narrative Review

Brugada syndrome: A general cardiologist's perspective

Marija M. Polovina a,b, Milica Vukicevic b, Bojan Banko c, Gregory Y.H. Lip a,d, Tatjana S. Potpara a,b,⁎
a
School of Medicine, Belgrade University, Belgrade, Serbia
b
Cardiology Clinic, Clinical Centre of Serbia, Belgrade, Serbia
c
Centre for Radiology and MRI, Clinical Centre of Serbia, Belgrade, Serbia
d
University of Birmingham, Institute of Cardiovascular Science, City Hospital, Birmingham, United Kingdom

a r t i c l e i n f o a b s t r a c t

Article history: Brugada syndrome (BrS) is one of the commonest inherited primary arrhythmia syndromes typically presenting
Received 16 February 2017 with arrhythmic syncope or sudden cardiac death (SCD) due to polymorphic ventricular tachycardia and ventric-
Received in revised form 18 May 2017 ular fibrillation precipitated by vagotonia or fever in apparently healthy adults, less frequently in children. The
Accepted 16 June 2017
prevalence of the syndrome (0.01%–0.3%) varies among regions and ethnicities, being the highest in Southeast
Available online 20 June 2017
Asia.
Keywords:
BrS is diagnosed by the “coved type” ST-segment elevation ≥ 2 mm followed by a negative T-wave in ≥1 of the
Brugada syndrome right precordial leads V1–V2. The typical electrocardiogram in BrS is often concealed by fluctuations between nor-
Syncope mal, non-diagnostic and diagnostic ST-segment pattern in the same patient, thus hindering the diagnosis.
Sudden death Presently, the majority of BrS patients is incidentally diagnosed, and may remain asymptomatic for their lifetime.
Arrhythmia However, BrS is responsible for 4–12% of all SCDs and for ~ 20% of SCDs in patients with structurally normal
Fever hearts. Arrhythmic risk is the highest in SCD survivors and in patients with spontaneous BrS electrocardiogram
Sex-related differences and arrhythmic syncope, but risk stratification for SCD in asymptomatic subjects has not yet been fully defined.
Recent achievements have expanded our understanding of the genetics and electrophysiological mechanisms
underlying BrS, while radiofrequency catheter ablation may be an effective new approach to treat ventricular
tachyarrhythmias in BrS patients with arrhythmic storms.
The present review summarizes our contemporary understanding and recent advances in the inheritance, path-
ophysiology, clinical assessment and treatment of BrS patients.
© 2017 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.

1. Introduction
The Brugada syndrome (BrS) is a genetic disorder with autosomal-
dominant inheritance and variable phenotype, characterized by abnor-
malities in the surface electrocardiogram (ECG) – typically a pseudo-
right bundle branch block (RBBB) and persistent “coved type” ST-seg-
ment elevation in the leads V1–V2 (or, rarely, in the inferior leads) of
≥2 mm (≥0.2 mV) and increased risk of ventricular tachyarrhythmias
(VT) and sudden cardiac death (SCD) in apparently healthy individuals
[1].
The Brugada pattern (i.e., asymptomatic typical ECG abnormalities)
has been reported in 0.01–1.0% of adults in different populations, with
the highest prevalence in Asians [2–7]. The prevalence of “true” BrS (pa-
tients with typical ECG features who experienced sustained VT or SCD)
among individuals with the Brugada pattern is less well studied. A
meta-analysis of 30 studies revealed a 10% event-rate over a 2.5-year
follow-up in patients with the Brugada pattern [8]. Indeed, whilst
⁎ Corresponding author at: Cardiology Clinic, Clinical Centre of Serbia, School of
Medicine, University of Belgrade, Visegradska 26, 11000 Belgrade, Serbia.
E-mail address: tatjana.potpara@mfub.bg.ac.rs (T.S. Potpara).
most patients (64%) are incidentally diagnosed with the Brugada pat-
tern and remain asymptomatic for their lifetime [9], BrS is reportedly re-
sponsible for 4–12% of all SCDs and ~ 20% of SCDs in patients with
structurally normal hearts [10,11]. In the same patient, the ECG often
shows dynamic fluctuations between normal, non-diagnostic and diag-
nostic ST-segment patterns, thus hindering the diagnosis [12].
In this review, we summarize the contemporary knowledge on the
inheritance, pathophysiology, clinical assessment and treatment of pa-
tients with BrS. To illustrate the landmark features of BrS and diagnostic
challenges that might occur in clinical practice, we first present an illus-
trative case of our patient with malignant clinical presentation and elu-
sive ECG recordings ultimately diagnosed with BrS.
2. A patient presenting with recurrent syncope
A 48 year-old female was admitted to the Emergency Department
for recurrent syncope. The evening before admission, she complained
of nausea after a heavy meal. Subsequently, as witnessed by her hus-
band, she had several self-terminating episodes of disturbed breathing
during sleep. After awakening, she experienced two syncopal attacks
preceded by nausea, vomiting and palpitations.

http://dx.doi.org/10.1016/j.ejim.2017.06.019
0953-6205/© 2017 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
20 M.M. Polovina et al. / European Journal of Internal Medicine 44 (2017) 19–27
The patient reported no prior medical history, except for the typical
reflex syncope since the adolescence, usually triggered by venipuncture,
and a family history of SCD in her father and paternal grandfather, at age
of 36 and 43 years, respectively. Overall, our patient was ostensibly
healthy, apart from perimenopause symptoms. However, the last two
syncopal episodes, with palpitations and abrupt loss of consciousness
were suggestive of an arrhythmic cause.
The physical examination yielded completely normal findings; ECG
recorded with standard positioning of the leads V1–V2 (4th intercostal
space) showed sinus rhythm of 60 beats/min with the 1st degree atrio-
ventricular (AV) block (PR interval, 240 ms), corrected QT interval of
360 ms (normal), the non-specific “saddle-back” type ST-segment ele-
vation of 1 mm in the leads V1–V2 and shortly coupled ventricular pre-
mature beats (VPBs) of the left bundle branch block (LBBB) morphology
(Fig. 1A). Superior placement of the leads V1–V2 (2nd and 3rd intercos-
tal space) did not reveal typical BrS ECG.
Blood biochemistry was normal, including serum electrolytes, high-
sensitivity troponin T and thyroid hormones. However, in the next 48 h,
the patient experienced an electrical storm, with a total of 12 episodes
of polymorphic VT, usually heralded by frequent shortly coupled VPBs
of LBBB morphology, occurring at night or during daily rest and
progressing into ventricular fibrillation (VF), which were successfully
terminated by defibrillation (Fig. 1B). The electrical storm was unre-
sponsive to antiarrhythmic drug therapy (e.g. lidocaine, beta-blockers
and amiodarone) and spontaneously subsided after 48 h.
Diagnostic testing including echocardiography, cardiac magnetic
resonance imaging (MRI) and coronary angiography yielded normal
findings. After excluding underlying cardiac disease (e.g., acute coro-
nary syndrome, myo-pericarditis, or a structural heart disease) and po-
tential precipitating factors (e.g., drugs, alcohol, electrolyte
abnormalities, catecholaminergic excess, or sarcoidosis), further diag-
nostics was directed towards a primary arrhythmia syndrome, and BrS
was suspected based on ECG findings, vagotonia-mediated polymorphic
VT triggered by LBBB-type VPBs, and a family history of SCD. Since re-
peated ECG recordings showed either normal pattern or non-diagnostic
ST-segment elevation in the right precordial leads, without capturing
the typical type-1 ECG pattern, we performed a pharmacological chal-
lenge with a parenteral class I antiarrhythmic medication using
propafenone (the only readily available class I agent for intravenous
Fig. 1. (A) ECG at presentation displaying non-diagnostic minimal saddle-back type ST segment elevation in the leads V1–V2 and monomorphic ventricular premature beats. (B)
Polymorphic VT triggered by a shortly coupled ventricular premature beat.
use in Serbia) 2 mg/kg i.v. over 10 min, with continuous ECG monitor-
ing. The propafenone challenge evoked a borderline “coved-type” ST-
segment elevation of 2 mm in the leads V1–V2, best observed when
the leads V1–V2 were positioned in the 3rd intercostal space (Fig. 2A
and B).
Since the finding was suggestive of but insufficient for definite BrS
diagnosis, repeated challenge using a more sensitive class I agent (i.e.
ajmaline or flecainide) was intended, and genetic testing was consid-
ered, but not performed since it was not available in our country. How-
ever, our patient developed a fever of 38 °C, with a spontaneous
appearance of typical type-1 ECG, which was diagnostic of the BrS
(Fig. 2C and D). The patient was discharged following an implantation
of a cardioverter-defibrillator (ICD) for the secondary prevention of
SCD.
3. Genetics and pathophysiology of the Brugada syndrome
BrS is a considered a heritable disease, with a family history of SCD
reported in ~ 26% of patients [9]. To date, mutations in 23 genes have
been associated with BrS [13], but the list is not completed yet. In all ge-
notypes, mutations affect the sodium (Na+), potassium (K+) or calcium
(Ca2+) ion-channels in the cardiac cell membrane, causing either a de-
crease in the inward Na+ (INa) or Ca2+ currents, or an increase in the
outward K+ currents (i.e. transient outward current, Ito), resulting in a
pro-arrhythmic outward shift in the balance of transmembrane cur-
rents during the early phase of the action potential [14].
The first gene associated with BrS was SCN5A, encoding the α-sub-
unit of the principal cardiac Na+ channel protein [15,16]. Although
SCN5A represents the major BrS-susceptibility gene with N 300 muta-
tions, it accounts for only 20–30% of BrS probands [17,18]. ECG findings
predictive of SCN5A genotype include prolongation of the P-wave, PR
interval (due to increased HV interval) and the QRS [19]. Besides BrS,
SCN5A mutations have been associated with other inherited arrhythmia
syndromes (e.g., the long QT3 and early repolarization syndromes), and
a variety of conduction disorders (e.g., sick sinus syndrome), which
overlap in some patients [19,20]. Indeed, the prolonged PR interval in
our patient suggests a SCN5A genotype, but genotyping was not
performed.
 M.M. Polovina et al. / European Journal of Internal Medicine 44 (2017) 19–27
Fig. 2. ECG (precordial leads) before (A) and after pharmacological challenge with parenteral propafenone (B). ECG (precordial leads) without fever (C) and during fever of 38 °C (D).
Another common BrS-susceptibility gene, present in 16.7% of pro-
bands, is SCN10A, encoding the neuronal Na+ channel also expressed
in the heart; SCN10A mutation produces a significant decrease in INa
[17]. Other rare BrS-susceptibility genes have been collectively docu-
mented in ~16% of probands.
BrS is regarded as an autosomal dominant disorder with variable
penetrance and expressivity [11], but recent evidence suggests a more
complex polygenic mode of inheritance including multiple common
and rare genetic variants acting in concert though different mechanisms
to produce BrS phenotype [13,15,21]. Further research is needed to ex-
plore the extent to which genetic variants alone or in combination de-
termine the phenotype and prognosis [22–24]. The phenotype is also
modulated by non-hereditary factors, such as hormones [25], medica-
tions or, possibly, concomitant disorders (e.g. autonomic dysfunction;
interstitial fibrosis) [26,27].
4. Mechanisms of arrhythmogenesis
Two major hypotheses have been proposed to explain
arrhythmogenesis in BrS [28]. The repolarization hypothesis stipulates
that the “coved-type” ST-segment elevation represents an accentuated
J-wave inscribed by transmural voltage gradient created by genetically
mediated imbalance in ionic currents that is particularly prominent in
the right ventricular outflow tract (RVOT) epicardium [29,30]. Further
accentuation of repolarization abnormalities produces closely coupled
VPBs, shown to trigger polymorphic VT, resembling torsades de pointes,
or VF [29]. Occasionally, monomorphic VT may also be triggered [29].
21
The depolarization hypothesis proposes that BrS results as a consequence
of increased fibrosis and reduced density of the gap junction protein
connexin-43 and Na+ channels, resulting in a slowed and dispersed
conduction manifested as fractionated electrograms and late potentials
in the RVOT region [26,31]. Indeed, catheter ablation of RVOT sites with
fractionated electrograms and late potentials can abolish arrhythmias
and normalize ST-segment appearance in BrS [32,33]. Importantly, nei-
ther hypothesis has been ascertained as a single underlying mechanism,
nor these two hypotheses should be regarded as mutually exclusive.
5. Prevalence and clinical presentation
The true prevalence of BrS is difficult to estimate since the syndrome
is often concealed. A higher prevalence (15–27 per 10,000 individuals)
has been observed in Southeast Asia [6,34,35], compared to predomi-
nantly Caucasian populations (1–7 per 10,000 inhabitants) in Europe
and North America [2–5]. The observed regional heterogeneity in BrS
prevalence could be attributed to a genetic polymorphism in SCN5A
promoter region, commonly observed in Asians [36]. Symptoms usually
appear in the adulthood, with SCD occurring at the mean age of 41 ±
15 years, however the syndrome may manifest at any age, from new-
borns to octogenarians [37].
Despite equal genetic transmission, BrS is more prevalent and more
severe in men [8,38]. Of note, the striking male predominance (~70% of
adults with BrS are males) has led to the custom among men in the
Southeast Asia to dress in women's bedclothes at night to fool the
“evil spirits” searching for young men in their sleep [39]. Possible
22 M.M. Polovina et al. / European Journal of Internal Medicine 44 (2017) 19–27
mechanisms behind sex-related disparities in BrS phenotype include
subtle sex-related differences in cardiac electrophysiology [39], or tes-
tosterone-promoted arrhythmogenesis [40,41] consistent with the ob-
servation that in children no sex-related difference in BrS prevalence
has been described [42], whereas in adults symptoms usually appear
between the 3rd and 5th decade of life coincident with peak testoster-
one levels [43]. Indeed, population studies showed that spontaneous
type-1 ECG is more commonly observed in males, with a 3.4-fold higher
risk of VT/VF relative to females [8,38]. Females with BrS are less likely
to have spontaneous type-1 ECG, but more often have conduction ab-
normalities and QT interval prolongation [38].
Owing to increasing awareness of BrS, most patients are now asymp-
tomatic at diagnosis and may never develop symptoms (the annual
event-rate in asymptomatic subjects in the largest BrS registry was
0.5%) [9]. Unfortunately, the first presentation may be (aborted) SCD,
as in our patient. In successfully resuscitated patients, the precipitating
arrhythmia is usually a polymorphic VT, or VF, often triggered by a
VPB [15]. Other symptoms of BrS include syncope, nocturnal agonal res-
piration (presumably caused by self-terminating VT/VF), palpitations or
chest discomfort [11].
Symptoms tend to occur with increased vagal tone, usually at rest,
during sleep and after large meals [14,44], triggered by vagotonia-medi-
ated aggravation of the putative electrophysiological abnormalities [15].
In our patient, the occurrence of malignant arrhythmias coincided with
nausea and vomiting after a large meal, and VT/VF reoccurred during
sleep and at rest, exemplifying a true electrical storm triggered by
vagotonia.
Fever has been also reported to unmask type-1 ECG and may trigger
VT/VF [45]. Fever could accelerate inactivation of the mutant Na+ chan-
nels [46], or cause other alterations in cardiac electrophysiology [47,48],
thus temporarily increasing the arrhythmic propensity in BrS [42,49].
Syncope is common in BrS, occurring in 30% of patients [9]. Both ar-
rhythmic and non-arrhythmic (reflex) syncope are observed with dif-
ferent prognostic implications. While arrhythmic syncope is an
ominous sign, precipitated by runs of self-terminating VT with in-
creased risk of SCD, reflex syncope with distinct clinical presentation
(e.g. typical prodromes and triggers) does not impart an adverse prog-
nosis [9,50,51]. Our patient suffered from typical reflex syncope, but
subsequently presented with arrhythmic syncope, thus stressing the
necessity of careful history taking for differential diagnosis between
the two prognostically divergent presentations of syncope in BrS [51].
6. Diagnosis
The diagnosis of BrS requires the following [52]:
• Documentation of the type-1 ECG, characterized by the “coved-type”
ST-segment elevation of ≥2 mm in the leads V1 and/or V2, positioned
in the 2nd, 3rd or 4th intercostal space, occurring either spontaneous-
ly or after intravenous administration of Class I antiarrhythmic drugs
(Table 1A). Superior positioning of the leads V1–V2 up to the 2nd in-
tercostal space increases the sensitivity for the detection of type-1
ECG [53].
• In patients with non-diagnostic type-2 or type-3 ECG (Table 1A) the
diagnosis of BrS can be made only if type-1 ECG is documented either
spontaneously or with pharmacological-challenge.
Several caveats need consideration regarding the diagnosis of BrS.
First, persistent type-1 ECG is extremely rare even in genetically proven
BrS patients; more commonly, normal ECG recording alternates with in-
termittent appearances of non-diagnostic ST-segment morphologies
and the diagnostic type-1 ECG [12,43]. As illustrated by our case, docu-
mentation of type-1 ECG may be difficult in clinical practice. Hence, re-
peated ECGs should be recorded on separate occasions with leads V1–V2
positioned in standard and superior intercostal spaces whenever BrS is
suspected. The 24-hour 12-lead ambulatory ECG monitoring is also use-
ful for BrS diagnosis, since spontaneous “coved-type” ECG pattern may
be elicited by nocturnal bradycardia or large meals [28,54], and the di-
agnostic yield could be increased with the attachment of precordial
electrodes in the 3rd intercostal space [55]. Since fever may also unmask
type-1 ECG, referral for an ECG during a febrile episode could confirm
the diagnosis, as in our patient.
Other ECG findings, supportive but non-diagnostic of BrS, are pre-
sented in Table 1B. In our patient, we documented the 1st degree AV
block and shortly coupled LBBB-type VPBs occurring with increased fre-
quency during the electrical storm. In the absence of typical ST-segment
changes, these ECG abnormalities only raised suspicion of BrS, requiring
confirmation by pharmacological testing or spontaneous appearance of
type-1 ECG.
Another important caveat concerns the risk of BrS “over-diagnosis”
in asymptomatic subjects with drug-induced type-1 ECG [28]. The re-
ported arrhythmic risk in such subjects is very low [50], while the risk
of false-positive pharmacological test [56] and the psychological burden
of the diagnosis should not be underestimated. Similar to previous BrS
consensus documents [37,57], the 2016 Expert Consensus document
on J-wave syndromes, including the BrS and early repolarization syn-
drome, proposes that in patients with the type-1 ECG unmasked by
Class I antiarrhythmic medications, the diagnosis of the “true” BrS
should be supported by at least one of the following clinical characteris-
tics: polymorphic VT/VF, syncope, a family history of SCD in a subject
aged b 45 years, type-1 ECG in family members, or nocturnal agonal res-
piration [28].
The Brugada “phenocopies”, representing conditions that transiently
or permanently present with Brugada-like ECGs without known under-
lying genetic predisposition, should be considered in the differential di-
agnosis of BrS (Table 2C). Whether any of the Brugada “phenocopies”
confers an increased arrhythmic risk remains to be determined.
BrS is considered a “channelopathy” occurring in structurally normal
hearts, with the RVOT epicardium representing a major arrhythmogenic
region [11]. Imaging techniques such as echocardiography, coronary an-
giography, and cardiac MR play a role in differential diagnosis and
should be performed in diagnostic assessment of patients suspected of
BrS [52].
6.1. The pharmacological challenge
Pharmacological testing using intravenous Class IA (e.g., ajmaline,
procainamide) or Class IC (e.g., flecainide, pilsicainide, propafenone) an-
tiarrhythmic drugs (Table 2) is indicated in patients with strong clinical
suspicion of BrS in the absence of spontaneous type-1 ECG on serial re-
cordings. Since the challenge does not contribute to risk-stratification
for SCD, it should not be performed in subjects with a spontaneous
type-1 ECG [37]. The test is considered safe to perform at bedside pro-
vided that cardioversion facilities are available, using continuous 12-
lead ECG monitoring with standard and superior placement of the
leads V1–V2 [11,58].
The test is positive if the type-1 ST-segment elevation is unmasked
[11], and should be terminated if frequent VPBs or other arrhythmias
occur, or if the QRS widens N130% of the baseline [28].
The ability of Class I agents to unmask the type-1 ECG in BrS depends
on the inhibition of already genetically impaired INa. Accordingly, pre-
caution is warranted when performing and interpreting the pharmaco-
logical challenge. Firstly, the pharmacological challenge may trigger
polymorphic VT/VF in 0.5% of BrS patients [59]. Second, depending on
the balance between INa and Ito blockade, class I agents exhibit a variable
potency to evoke the type-1 ECG. For example, ajmaline and flecainide
are the two most frequently used medications in Europe for BrS chal-
lenge. Ajmaline combines the advantages of higher sensitivity and a
shorter half-life compared to flecainide [60,61], and is the preferred
agent for pharmacological testing. The higher sensitivity of ajmaline is
attributable to its weaker Ito blocking properties compared to flecainide,
 M.M. Polovina et al. / European Journal of Internal Medicine 44 (2017) 19–27 23

Table 1
(A) Diagnosis of Brugada syndrome. (B) ECG findings common in Brugada syndrome patients. (C) Conditions mimicking Brugada ECG pattern.

(A) Diagnosis of Brugada syndrome Class of Level of Reference

recommendationa evidencea

Definitive diagnosis
Type-1 ECG: coved-type ST-segment elevation of ≥2 mm followed by a negative T wave in the right precordial leads V1 and/or I C [11,28]
V2, positioned in the 2nd, 3rd or 4th intercostal space, occurring either spontaneously or after challenge with Class I [52]
antiarrhythmic drugs
Suspected Brugada syndrome - pharmacological challenge indicated to confirm the diagnosis
Type-2 ECG: ST-segment elevation ≥0.5 mm in ≥1 right precordial leads V1-V3 positioned in the 2nd, 3rd or 4th intercostal I C [11] [28]
space - generally a convex ST elevation of ≥2 mm in V2 with a high takeoff and a trough of ≥1 mm ST elevation, followed by [52]
either a positive or biphasic T wave.
Type-3 ECG: ST-segment elevation ≤ 1 mm in ≥1 right precordial leads V1–V3 with either saddleback or coved-type
morphology in the 2nd, 3rd or 4th intercostal space

(B) ECG findings commonly associated with Brugada syndrome Reference

Decrease in ST-segment elevation during tachycardia at maximal stress-exercise test and reappearance in the recovery phase [92,93]
1st degree AV block and left-axis deviation of the QRS [94]
Right bundle branch block [94]
Minor QT prolongation [95]
Late potentials in the signal-averaged ECG [74]
Fragmented QRS in leads V1–V3 [77]
VPBs with left-bundle branch block morphology originating from the RVOT [96]
Atrial fibrillation [70,71]
Early repolarization in the inferior or infero-lateral leads [97]

(C) Differential diagnosis - conditions mimicking Brugada syndrome ECG (modified from the ref. [28])

Transient ECG patterns mimicking Brugada syndrome Permanent ECG patterns mimicking Brugada syndrome
Acute ischemia/infarction, particularly of the RVOT region Atypical right bundle branch block
Prinzmetal angina Left ventricular hypertrophy
Myocarditis/pericarditis Pulmonary arterial hypertension
Pulmonary embolism Mechanical compression of the RVOT:
Pectus excavatum
Mediastinal tumor
Dissecting aortic aneurysm Myotonic dystrophy
Electrolyte abnormalities: Duchenne muscular dystrophy
Hyperkalemia
Hypokalemia
Hypercalcemia
Hyponatremia
Hyperthermia (fever)/hypothermia Fridreich's ataxia
Post-defibrillation/post-electrocution ECG Athlete's heart
Autonomic nervous system disturbances Chagas disease
a
Class of recommendation and level of evidence are provided according to the European Society of Cardiology Guidelines on the management of ventricular arrhythmias and the prevention
of sudden cardiac death, ref. [52], ECG: electrocardiogram; AV: atrioventricular; RVOT: right ventricular outflow tract.

which exerts stronger Ito inhibition that could offset its INa blocking ef-
fect in unmasking the type-1 ECG [60]. If ajmaline is not available,
other agents can be used for the test but physicians should be aware
of the possibility of a false-negative test due to a lower sensitivity of
the applied agent. For example, the sensitivity of flecainide in genetical-
ly proven BrS patients is 77% (specificity 80%) [56], while propafenone
has sensitivity of 41% compared to ajmaline (specificity 81%) [62]. In
our case, only propafenone was available and the elicited ECG changes
were borderline (and insufficient for the diagnosis), which is a known
limitation of propafenone challenge compared to more potent Class I
drugs [63].
In the USA, the most commonly used agent for BrS challenge is pro-
cainamide, which displays rapid dissolution from the Na+ channel
resulting in a weaker use-dependent INa inhibition. Consequently, pro-
cainamide might exhibit lesser potency than ajmaline or flecainide to
Table 2
Pharmacological challenge - recommended medications and administration protocols.
Medications Administration protocol
Ajmaline 1 mg/kg i.v. administered over 10 min
Flecainide 2 mg/kg i.v. administered over 10 min
Procainamide 10 mg/kg i.v. administered over 10 min
Pilsicainide 1 mg/kg i.v. administered over 10 min
Modified from the references [37,59,61].
unmask the typical Brugada ECG, but contrary to ajmaline or flecainide,
procainamide exerts no Ito blocking effect [60]. In Japan, pilsicainide, a
pure Na+ channel blocker, is commonly used for BrS testing. Data are
lacking on the comparative discriminative characteristics of procain-
amide and pilsicainide for BrS diagnosis.
As exemplified by our case, a negative pharmacological challenge
does not exclude BrS, particularly when the test was performed using
a less sensitive agent. Repeated challenge with a more sensitive medica-
tion could be diagnostic [63]. However, a false-positive test is difficult to
define, since a gold standard is lacking [28]. Therefore, recent consensus
document on the J-wave syndromes proposes a probabilistic rather
than binary interpretation of the pharmacological challenge, consider-
ing other relevant factors such as clinical presentation and family histo-
ry [28].
Siblings of BrS patients should undergo repeated ECG assessment for
diagnostic and prognostic purposes. Whether asymptomatic individuals
without spontaneous type-1 ECG, who have a family history of BrS or
SCD, should undergo pharmacological challenge is a sensitive issue.
Those individuals should be informed of the availability of pharmaco-
logical testing and the attendant risks [28]. Before the test, they should
be informed that no therapeutic measures might be recommended in
case of a positive test considering favorable long-term prognosis of
asymptomatic individuals and weak prognostic implication of a family
history alone [9]. Also, a positive test might be regarded as valuable in-
formation to avoid prescription of potentially harmful antiarrhythmic
24 M.M. Polovina et al. / European Journal of Internal Medicine 44 (2017) 19–27
medications in case of future arrhythmias. The patients should be
warned about potential psychological burden of having a positive test
without definitive therapy and final decision to proceed with the test
should be left to the well-informed patient [28].
6.2. Genetic testing
Since contemporary evidence does not support genetic testing for
diagnostic, prognostic or therapy-related purposes [9,24], genotyping
should not be routinely offered to subjects suspected of having BrS or
to the patients with the confirmed diagnosis [52]. Presently, the utility
of genetic testing could be regarded in the context of advancing re-
search on genotype-phenotype relations, with a notion to improve
risk-assessment and therapeutic decisions in the future.
7. Risk-assessment
A history of VT/VF is the strongest predictor of mortality in BrS pa-
tients [9,50,64]. Considering the reported 7.7% annual event-rate of re-
current VF [9], ICD implantation is strongly recommended in SCD
survivors.
Current evidence indicates that patients without VT/VF, who repre-
sent the majority of BrS population in clinical practice, are at a signifi-
cantly lower risk of SCD, particularly if they are asymptomatic [9,50].
Lack of robust risk-stratification metric for patients without VT/VF im-
poses a challenge when deciding on the indication for ICD in primary
prevention, and consideration of a single electrocardiographic, clinical
or electrophysiological risk factor may not be sufficient to adequately
assess the risk of adverse events [65]. Hence, evaluation of several risk
factors in a multifactorial approach has been proposed to improve dis-
crimination of patients at risk of SCD from the truly low-risk subjects.
For example, spontaneous type-1 ECG imparts an intermediate risk of
SCD with the annual event-rate of 2.6% [65]. However, several studies
have confirmed that when a spontaneous type-1 ECG was combined
with a history of syncope, the risk of SCD greatly increased, independent
of other clinical characteristics, identifying those patients as a high-risk
group [9,50,66]. Similarly, discrimination of arrhythmic risk could be
improved with a multifactorial approach, including the type-1 ECG
and the presence of ≥2 additional risk factors (syncope, family history
of SCD, and/or inducible VF), [65]. The highest event-rate (30% over a
median of 40 months) was observed in patients with spontaneous
type-1 ECG and ≥ 2 risk factors, albeit none of the risk factors alone
was able to identify subjects at risk. Conversely, in subjects with drug-
induced type-1 ECG, the event-rate was low (b 2%) and was confined
to subjects with 2 risk factors [65]. Recently, a 6-item score, including
spontaneous type-1 ECG (1-point), early familial SCD (1-point), induc-
ible VF (2-points), syncope (2-points), sinus node dysfunction (3-
points), and aborted SCD (4-points) was derived in a population of
BrS patients with a long follow-up (N80 months) [67]. The overall pre-
dictive performance of the score was excellent (0.82), and a score N 2 in-
dicated a 5-year event probability of 9.2%; therefore, the score holds a
promise for clinical risk-assessment after further validation.
Asymptomatic patients have the lowest annual arrhythmic event-
rate of 0.5–0.8% [9,65], translating into favorable long-term prognosis
[68]. The risk is particularly low among asymptomatic subjects with
drug-elicited type-1 ECG [50,69].
Additional risk factor may include atrial fibrillation (AF), which has
been documented with a higher prevalence in BrS patients compared
to the general population (6–38% vs. 1–2%) [70,71], and several studies
have reported higher incidence of VT/VF in patients with concurrent AF
[38,72]. A number of ECG markers have been associated with arrhyth-
mic propensity in BrS, including features of abnormal depolarization
(e.g. QRS width ≥ 120 ms; fragmented QRS) and/or repolarization (e.g.
late potentials; prolonged QT interval; early repolarization) [73,74],
sinus node dysfunction [67], prominent S-wave in the lead I [75], T-
wave alternans etc. [76]. Among those markers, fragmented QRS (i.e.
abnormal fragmentation within the QRS complex defined as 4 spikes
in one, or 8 spikes in all of the leads V1, V2, and V3) [50,77,78], and
early repolarization [73,78] have been consistently reported to predict
independent risk of VT/VF, and therefore deserve consideration in the
context of risk-assessment.
Currently, there is no consensus concerning the validity of electro-
physiological study (EPS) with programmed ventricular stimulation
for risk-stratification of BrS patients, since research data are ambiguous
regarding the value of EPS for predicting spontaneous arrhythmic
events. While some studies have demonstrated independent prognostic
value of EPS for arrhythmia occurrence in BrS [69,79,80], the other stud-
ies have not (including the PRELUDE [PRogrammed ELectrical stimuLa-
tion preDictive value] and large FINGER [France, Italy, Netherlands,
GERmany] registries) [50,66,68]. The observed discrepancies possibly
reflect differences in the applied EPS protocols [9]. Hence, prognostic
value of EPS could be regarded in a multifactorial approach, where a
positive EPS denotes an additional risk factor for SCD in intermediate-
risk patients (e.g. patients with spontaneous type-1 ECG) [65,69],
whereas a negative EPS helps to identify low-risk subjects, with a high
negative predictive value [65,80].
BrS genotype has not been consistently demonstrated to provide in-
dependent prognostic information concerning the risk of SCD, although
some studies have documented an increased arrhythmic risk in carriers
of particular mutations in SCN5A gene [22,81]. Currently, genetic testing
is not recommended for SCD risk-assessment in BrS [11,52].
8. Therapy
Table 3 summarizes treatment options for BrS patients, as recom-
mended by the latest European Society of Cardiology Guidelines, includ-
ing the strength of recommendation and level of evidence, which is
always “C”, indicating that recommendations have been based on con-
sensus of expert opinion, small studies and registries [52].
8.1. Implantable cardioverter-defibrillator
The mainstay of SCD prevention in patients with BrS is ICD implan-
tation and indications for ICD are presented in Table 3. Conventional,
transvenous ICD (TV-ICD) implantation might be challenging in pediat-
ric patients, and in young and active adults due to an increased risk of
inappropriate shocks secondary to lead failure/dislodgement, cardiac
signal oversensing, or supraventricular tachyarrhythmias (SVT) [82],
and a requirement for multiple device replacements during the lifetime
[11]. Subcutaneous ICD (S-ICD), which has no transvenous leads, elimi-
nates the risk of periprocedural and long-term lead-associated compli-
cations. Also, S-ICD sensing algorithm offers improved SVT/AF
discrimination and carries lower risk of inappropriate discharges due
to SVT/AF compared to TV-ICD [83,84]. Hence, S-ICD has been proposed
as an effective alternative to TV-ICD in patients who do not require pac-
ing therapy [52], and it might be particularly advantageous for young
and active subjects with long life expectancy and a proclivity to SVT/
AF, such as BrS patients, although issues concerning S-ICD eligibility
and appropriate device programing deserve further research in BrS pa-
tients [85,86]. Long-term efficacy and safety of S-ICD in BrS patients is
currently under evaluation (NCT02344277).
8.2. Pharmacological therapy
Medications that could restore the balance of ionic currents in the RV
epicardium could be effective in BrS [29] (Table 3). Most evidence is
available for isoproterenol [87] and quinidine [88–90], which have
been successful in termination of electrical storms, while quinidine
may be considered as an alternative to ICD when the device is refused
or contraindicated, and for the treatment of AF/SVT [52].
 M.M. Polovina et al. / European Journal of Internal Medicine 44 (2017) 19–27
Table 3
Management of the Brugada syndrome.
Brugada syndrome therapy Class of Level of
recommendationa evidencea
ICD implantation
ICD is recommended in patients who: I C
a) are survivors of an aborted cardiac arrest
and/or
b) Have spontaneous sustained VT.
ICD should be considered in patients with IIa
spontaneous type-1 ECG a history of syncope
S-ICD should be considered as an alternative to IIa
transvenous ICD in patients with an indication
for ICD when antibradycardia and/or
antitachycardia pacing, or cardiac
resynchronization therapy is not needed.
S-ICD may be considered as an alternative to IIa
transvenous ICD when venous access is
difficult, after the removal of a transvenous
ICD for infections or in young patients with a
long-term need for ICD therapy.
ICD may be considered in patients who develop IIb
VF during programmed ventricular pacing
with two or three extrastimuli at two sites.
Pharmacological therapy
Quinidine or isoproterenol should be considered IIa
to treat electrical storms.
Quinidine should be considered in patients with IIa
an indication for ICD when the device is
unavailable or contraindicated, and for the
management of supraventricular arrhythmias.
Catheter ablation
Catheter ablation may be considered in patients IIa
with a history of electrical storms or repeated
appropriate ICD shocks.
a
Class of recommendation and level of evidence are provided according to the Euro-
pean Society of Cardiology Guidelines on the management of ventricular arrhythmias and
the prevention of sudden cardiac death, ref. [52]; ICD: implantable cardioverter-defibrilla-
tor; VT: ventricular tachycardia; ECG: electrocardiogram; S-ICD: subcutaneous implant-
able cardioverter-defibrillator; VF: ventricular fibrillation.
8.3. Catheter ablation
Catheter ablation has been introduced as a viable treatment of BrS
patients following successful endocardial ablation of VPBs originating
from the RV, considered responsible for triggering VF [91]. The role of
catheter ablation in BrS has been confirmed when epicardial ablation
of the RV sites demonstrating late potentials and fractionated electro-
grams has been shown to restore normal ECG features, and prevent re-
currence of VT/VF [33]. Hence, ablation may be considered in BrS
patients with a history of arrhythmic storms or recurrent appropriate
ICD discharges (Table 3) [52].
9. Life-style changes
Patients with BrS should receive advice on drugs and life-style
choices pertaining to arrhythmic risk. These recommendations include
the following (Class of recommendation I, Level C) [52]:
• Complete avoidance of medications with an established pro-arrhyth-
mic effect, including:
- Class I antiarrhythmic drugs (except quinidine),
- Psychotropic drugs (e.g. amitriptyline, clomipramine, lithium etc.),
- Anesthetics (e.g. bupivacaine, procaine, propofol etc.).
• Preferable avoidance or cautious use of medications with a potential
pro-arrhythmic effect, including common antiarrhythmic agents:
- Amiodarone, lidocaine, propranolol and verapamil.
25
• Avoidance of large meals, alcoholic beverages, cannabis or cocaine.
• Prompt treatment of fever with antipyretics (e.g. aspirin;
paracetamol).
A detailed list of medications that should be avoided, or used under
strict control in BrS patients is available at the www.BrugadaDrugs.org.
C
10. Conclusions
C
BrS is a rare primary arrhythmia syndrome that should be consid-
ered in patients presenting with syncope of presumed arrhythmic ori-
gin or in SCD survivors. The typical type-1 ECG is often concealed and
C
occasionally the diagnosis may be challenging.
BrS usually presents in adults with a male predominance, while the
affected females are less likely to display spontaneous type-1 ECG. Clin-
ical presentation with a history of malignant ventricular arrhythmias,
syncope and spontaneous type-1 ECG is the strongest predictor of ar-
C
rhythmic risk in BrS patients. Nevertheless, most BrS patients are
asymptomatic and contemporary evidence suggests a low arrhythmic
risk in such patients. Further research is needed to optimize the risk-as-
C sessment in asymptomatic individuals with type-1 ECG and define bet-
ter the role of genetics, electrophysiology and specific clinical features in
C diagnosis and prognosis of BrS patients.
Conflict of interests
The authors report no conflict of interests pertinent to this work.
C
Author contribution
M.P. drafted the manuscript, M.V. and B.B. reviewed and edited the
manuscript, G.Y.H.L critically revised the manuscript for important in-
tellectual content, T.P. conceived the manuscript content, reviewed
and critically revised the manuscript for important intellectual content.
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