European Heart Journal (2017) 38, 3029–3034 SPECIAL ARTICLE

doi:10.1093/eurheartj/ehx490 Arrhythmia/electrophysiology

The definition of the Brugada syndrome

Juan Sieira and Pedro Brugada*
Heart Rhythm Management Centre, Universitair Ziekenhuis Brussel, Postgraduate program in Cardiac Electrophysiology and Pacing, Vrije Universiteit Brussel, Brussels, Belgium

Received 14 April 2017; revised 22 July 2017; editorial decision 2 August 2017; accepted 7 August 2017; online publish-ahead-of-print 31 August 2017

Brugada syndrome (BS) is an inherited disease characterized by a coved-type ST-segment elevation in the right precordial leads and
increased risk of sudden cardiac death (SCD), in the absence of structural abnormalities. The cornerstone of BS diagnosis and definition, is
its characteristic ECG pattern that can be present spontaneously or unmasked by drugs. Brugada syndrome was first described 25 years
ago; paradoxically, in an era of great technological development, a new syndrome was described with a technology developed almost a
century before. Great scientific knowledge has been gathered since the description of the syndrome. The better understanding of its path-
ophysiology and genetic basis has led to several modifications in its definition. Despite these facts, the essential, the description of the spe-
cific ECG pattern has remained almost unchanged since the initial report. In this article, we present the definition of the BS, the rationale
behind it and our thoughts about its future.
...................................................................................................................................................................................................
Keywords Brugada syndrome • Definition • Sudden cardiac death

..
Brugada syndrome (BS) is as a channelopathy with a characteristic .. persistent ST elevation of at least 0.1 mV in the right precordial leads
electrocardiogram (ECG) (ST-segment elevation of >_2 mm with a .. (V1 to V2–V3) and repetitive resuscitated SCD (Figure 1). This was
..
coved-type morphology in >_1 right precordial lead) and an increased .. the first definition of BS, for several years known as the syndrome of
risk of sudden cardiac death (SCD), in the absence of gross structural .. ‘right bundle branch block, persistent ST segment elevation and sud-
..
heart disease. .. den death’. In 1996, several reports, mainly coming from Japan,
Brugada syndrome belongs to a group of diseases known as inher- .. started calling the syndrome Brugada syndrome.3
..
ited primary arrhythmia syndromes. These are heterogeneous .. This characteristic ECG pattern had occasionally appeared in
conditions, with differentiated aetiologies, but with the common .. previous literature but its association with SCD as a differentiated
..
denominators of a genetic basis and absence of structural heart .. syndrome had not been stablished. In 1953, an ECG displaying
anomalies. Interestingly some of these entities have been recently
.. the characteristic pattern was published4 and in 1989 it appeared
..
described, therefore their pathophysiology is not yet completely .. amongst others in a report of six cases of ventricular fibrillation in
understood and their definition is evolving.1
.. young patients.5 However, in contrast to the report in JACC, their
..
The scientific advances done in BS since the first cases were .. patients had structural heart disease with no evidence of a hereditary
reported and a better characterization of the patients has led to
.. disorder.
..
changes in its definition. Furthermore, we believe that the incorpora- .. After the publication of this initial report, a lively discussion
..
tion of new clinical and genetic data will lead to a better definition .. quickly developed. Concerns about its true nature and being an
and characterization of the syndrome in the future. .. independent entity were common. If even nowadays the patho-
..
.. physiology of the syndrome remains to be fully understood,6 at
.. that moment many suggested that the syndrome was related to
..
The initial definition .. myocarditis, right ventricular dysplasia, other forms of cardiomyo-
.. pathies, long QT or simply a normal variant. It was not until
..
Brugada syndrome was initially described in 1992 in an article pub- .. 1998, when the first genetic basis of the syndrome was stab-
lished in the Journal of the American College of Cardiology.2 It presented
.. lished,7 that the acceptance of an independent disease was
..
a series of eight patients who displayed a right bundle branch block, a . widely accepted (Table 1).

* Corresponding author. Tel: þ32 476 3446, Fax: þ32 02 477 6851, Email: pedro@brugada.org
Published on behalf of the European Society of Cardiology. All rights reserved. V
C The Author 2017. For permissions, please email: journals.permissions@oup.com.
3030 J. Sieira and P. Brugada

The first consensus ..

..
..
In 2002, a consensus document for the diagnosis of BS was pub- ..
lished.8 It attempted to summarize the scientific knowledge gathered
..
..
since the initial description of the syndrome, 10 years before. ..
An operative definition of the syndrome was clearly stated. The
..
..
diagnostic ECG pattern was described as a prominent coved ST- ..
..
segment elevation displaying J wave amplitude or ST-segment ele- ..
vation >2 mm at its peak, followed by a negative T-wave, with little or ..
..
no isoelectric separation in right precordial leads (V1 to V3). ..
Three different ECG patterns were described at this moment ..
..
(Figure 2). Type 1 is the one described above and the only one that ..
establishes the diagnosis. Type 2 was defined as a high take-off of ST- ..
..
segment elevation, but J wave amplitude (2 mm) gives rise to a gradu- ..
ally descending ST-segment elevation (remaining 1 mm above the ..
..
baseline), followed by a positive or biphasic T-wave that results in a ..
saddle back configuration. Type 3 is a right precordial ST-segment ..
.. Figure 1 Original Brugada type 1 pattern described in the first
elevation of <1 mm of saddle back type, coved type, or both. .. report (modified from Brugada and Brugada2).
Even that this definition was formulated 15 years ago, the descrip- ..
..
tion of the type 1 ECG pattern remains unchanged nowadays. ..
Nevertheless, as will be discussed later, some aspects considered in ..
..
this consensus document are no longer up to date. At that moment, .. ventricular outflow tract.17 Use of higher intercostal leads increases
the V3 lead was considered as a useful lead for the diagnosis and
..
.. the sensitivity of the ECG to detect the type 1 pattern. The anatomi-
even, in selected patients, the recording of leads V3R and V4R was .. cal explanation for this has been recently described.18 Its importance
thought useful. We nowadays know that the ECG pattern should be
..
.. relies on the fact that prognosis of patients is irrespective of the posi-
interpreted only in V1 and V2 as the other leads offer no further ..
advanatge.9
.. tioning of the lead where the type 1 pattern is recognized.
..
The fact that the diagnostic type 1 ECG pattern can be present ..
..
intermittently is of great importance. Furthermore, the typical elec- ..
trocardiographic pattern might experience spontaneous variations, in .. Contemporary definition
..
both morphology and degree of elevation of the ST segment.10–12 In .. In 2013, a new expert consensus statement on the diagnosis and
addition to spontaneous fluctuations, many factors and drugs influ- .. management of patients with inherited primary arrhythmia syn-
..
ence the elevation.3,13 Some patients might only present the diagnos- .. dromes was published.19 More than 10 years had passed since the
tic ECG pattern under the effect of sodium channel blockers such as .. first one and great progress had been made since then (Figure 3). A
..
ajmaline, flecainide, or procainamide. .. better knowledge of the pathophysiology and risk stratification of BS
Use of sodium channel blockers to unmask the type 1 diagnostic .. was available at that moment. As a result, definition of BS had to be
..
pattern became generalized after 2000.14 Despite that current clinical .. updated. The BS definition established in this consensus is the one we
guidelines do not make specific statement of which should be chosen, .. use nowadays. This definition is also present in the 2015 European
..
probably ajmaline is the most efficient one. Initial reports suggested a .. Society of Cardiology guidelines for ventricular arrhythmias and the
similar effect of the different drugs in unmasking the Brugada type 1 .. prevention of SCD.20
..
pattern.14 Nevertheless, further ones demonstrated a superiority of .. Brugada syndrome is diagnosed in patients with ST-segment eleva-
ajmaline. Failure of flecainide in unmasking the Brugada pattern could ..
.. tion with type 1 morphology >_2 mm in >_1 lead in the right precordial
be up to 30%.15 The use of these drugs is directly linked to the patho- .. leads V1, V2, positioned in the 2nd, 3rd, or 4th intercostal space
physiology of the syndrome, the alteration of the sodium channels. It
..
.. occurring either spontaneously or after provocative drug test with
is of importance that while knowledge on BS has increased and more .. intravenous administration of class I antiarrhythmic drugs.
patients have been diagnosed, also the clinical presentation of
..
.. Two important aspects must be highlighted. First, only the type 1
patients with BS has changed. Nowadays most patients are diagnosed .. ECG pattern is diagnostic, either spontaneously or after a drug chal-
while still they are asymptomatic and many do not present the char-
..
.. lenge. A type 2 ECG pattern may raise the suspicion of BS but the
acteristic ECG pattern spontaneously, but after a pharmacologic chal- .. diagnosis can only be made when the type 1 pattern appears or is
lenge.16 This is the result of a greater clinical suspicion of the disease
..
.. induced by sodium channel blockers. This fact has also prognosis sig-
(for instance in patients with syncope or idiopathic atrial fibrillation) .. nificance as those patients that do not display the type 1 spontane-
..
and an intensive screening of family members of patients diagnosed .. ously have a better outcome, but arrhythmic events and SCD can still
with BS or who suffered SCD of unknown cause. .. occur.21 Interestingly, nowadays the type 3 ECG pattern is no longer
..
Interestingly, this consensus recognizes that the pattern could be .. considered in BS.22
recorded not only in the classical V1 and V2 lead positioning, in the .. Second, the presence of a type 1 ECG pattern in one single lead,
..
4th intercostal space, but also in higher intercostal spaces. We now .. V1 or V2, is enough for the diagnosis. Until now it was necessary to
know that ventricular arrhythmias in BS are originated in the right .. find the pattern in at least two leads and V3 was considered useful for
The definition of the Brugada syndrome 3031

Table 1 Genes identified in Brugada syndrome

Channel Gene Protein Proportion of BS attributed to

genetic variants (%)
....................................................................................................................................................................................................................
Calcium CACNA1C Voltage-dependent L-type calcium channel subunit alpha-1C 6.6
CACNB2B Voltage-dependent L-type calcium channel subunit beta-2 4.8
CACNA2D1 Voltage-dependent calcium channel subunit alpha-2/delta-1 1.8
TRPM4 Transient receptor potential cation channel subfamily M member 4 <1
Sodium SCN5A Sodium channel protein type 5 subunit alpha 11–28
SCN10A Neuronal sodium channel Nav1.8 5–16.7
GPD1-L Glycerol-3-phosphate dehydrogenase 1-like protein <1
SCN1B Sodium channel subunit beta-1 1.1
SCN2B Sodium channel subunit beta-2 <1
SCN3B Ran guanine nucleotide release factor <1
SLMAP Sarcolemmal membrane-associated protein <1
PKP2 Desmosomal protein plakophilin-2 <1
RANGRF Sodium channel subunit beta-3 <1
Potassium KCND3 Potassium voltage-gated channel subfamily D member 3 <1
KCNE3 Potassium voltage-gated channel subfamily E member 3 <1
KCNJ8 ATP-sensitive inward rectifier potassium channel 8 2
HCN4 Hyperpolarization-activated cyclic nucleotide-gated channel 4 <1
KCNE5 Potassium voltage-gated channel subfamily E member 1-like protein <1

Figure 2 The three different electrocardiogram (ECG) patterns described in the first consensus (modified from Wilde et al.8).
3032
Figure 3 Number of publications related to Brugada syndrome (BS) per year.
..
diagnosis. These changes are based in a study from our group demon- ..
strating a similar prognosis of patients irrespective of the number of ..
..
ECG leads displaying the Brugada pattern and the fact that V3 did not ..
yield additional diagnostic or prognostic information in BS99. ..
..
The scientific progress achieved during these years led to the ..
appearance of ‘overlapping syndromes’. Brugada syndrome and right ..
..
ventricular dysplasia present some overlapping characteristics. Mild ..
fibrosis in the RVOT and even fibro-fatty infiltration has been ..
..
reported in BS but its presence is not universal.23 Recently, mutations ..
in the PKP-2 gene, related to desmosomes have been identified in ..
..
BS.24,25 Desmosomal mutations are known to cause arrhythmogenic ..
cardiomyopathy and, interestingly, also sodium channel dysfunction. ..
..
Though the two syndromes are separate identifiable clinical entities, ..
they might represent in certain cases ‘bookends’ of a spectrum of
..
..
clinical manifestations that vary depending on the effect that a partic- ..
ular mutation has on the connexome as a whole.26
..
..
Furthermore, we know that sodium channel interacting partners are ..
proteins that can interact and modulate the expression and/or function
..
..
of sodium channels. They might be involved in some case of BS.
Amongst them Plakophilin-2 and Connexin-43 might be relevant.27,28
The concept of Brugada phenocopies has recently aroused. They
are clinical entities that present identical ECG patterns to BS but are
elicited by other circumstances. They form a group of heterogeneous
conditions that are sometimes difficult to differentiate from true BS.
Entities that might induce a Brugada phenocopy include metabolic con-
ditions, mechanical compression, myocardial ischaemia, pulmonary
embolism, and myocardial and pericardial disease amongst others.29
Differential diagnosis with some clinical entities can be challeng-
ing. Doubts can arise when dealing with patients with right bundle
branch block, athletes and, as mentioned before, with arrhytmo-
genic ventricular dysplasia. A careful study of the ECG might help.
Specifically, in right bundle branch block, the ST segment is not
elevated in the right precordial leads, the terminal wave is syn-
chronous with the broad S wave observed in leads I and V6, and
J. Sieira and P. Brugada
the QRS is wider than in BS. As opposed to athletes’ ECG, BS
Type 1 ECG pattern depicts an ST segment clearly elevated and
down-sloping, usually with no visible r0 . In arrhytmogenic right
ventricular dysplasia, atypical right bundle branch block morphol-
ogies have been shown, with a ‘plateau’ in the R wave in lead V1.
The ST segment is at times elevated but does not usually mimic
type 2 Brugada pattern. Moreover, T waves are more frequently
negative in many precordial leads (V1 to V3–V5) and ECG pattern
is fixed with no spontaneous changes in morphology or ST eleva-
tion.22 Interestingly, vectocardiography might have a role in the
diagnosis of BS.30 It can help in the differential diagnosis of BS with
early repolarization syndromes or right bundle branch block.31,32
The future of Brugada syndrome
Twenty-five years ago, when BS was first described, great contro-
versy surrounded the syndrome, we lacked knowledge about it and
.. still today many aspects of the syndrome have not been fully eluci-
..
.. dated. The scepticism has largely, though not entirely, abated as BS
.. has become an everyday cardiological problem to be considered in
..
... patients and families with ventricular arrhythmias, syncope, and a
.. structurally normal heart, but also in patients with isolated atrial fibril-
.. lation, that may be the first manifestation of BS.33
..
.. Especially during the first years, the absence of a clear pathophysio-
.. logic mechanism, raised doubts regarding its consideration as an inde-
..
.. pendent entity. It was in 1998, when the first genetic evidence of the
.. syndrome was described when most concerns were cleared.
..
.. Numerous pathogenic mutations in several genes have been found
.. that encode for subunits of cardiac sodium, potassium, and calcium
..
.. channels, as well as genes involved in the regulation of these chan-
.. nels.34–36 However, many of these identified gene mutations are
..
.. probably not directly responsible for the disease or at least not
.. alone.
The definition of the Brugada syndrome 3033

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..
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..
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