Brugada and Short QT Syndromes

JOHN K. TRIEDMAN, M.D.

From the Children’s Hospital, Boston; and Harvard Medical School, Boston, Massachusetts

Brugada syndrome and short QT syndrome are among the rarer cardiac channelopathies that may
result in sudden cardiac arrest. The genetics and molecular mechanisms of these diseases provide insight
into the mechanisms of more common channelopathies, and may dictate special therapeutic approaches
with respect to drug therapy and risk stratification. (PACE 2009; 32:S58–S62)
electrophysiology-clinical, long QT, pediatrics

Brugada Syndrome action potential alterations is the creation of trans-

Brugada syndrome (BrS) is an autosomal dom-
inant familial syndrome of ST elevation in the
leads V 1 –V 3 , associated with ventricular arrhyth-
mia and sudden death in otherwise normal pa-
tients. It was first described in 1986 in a 3-year-
old Polish boy with recurrent syncope, whose
sister shared his unusual electrocardiographic pat-
tern and experienced sudden death despite pacing
therapy and antiarrhythmic drug therapy.1 The
syndrome has since been characterized with re-
spect to its molecular basis, electrophysiology,
epidemiology and clinical expression, and possi-
ble therapeutic approaches.
Molecular Basis of Brugada Syndrome
Chen et al. described a loss-of-function mu-
tation of the sodium channel SCN5A in a patient
with BrS in 1998.2 By 2006, over 160 mutations of
SCN5A had been identified, with ∼2/3 associated
with a clinical phenotype of BrS.3,4 Conversely,
though, only 15–30% of patients with the clini-
cal phenotype currently have a causative muta-
tion identified at the SCN5A locus. This reduces
the potential for genetic screening and mutation-
specific diagnosis and raises the question as to
whether other factors may play a role in disease
pathogenesis.
Electrophysiology of Brugada Syndrome
The abnormal electrocardiographic (ECG)
findings and propensity to ventricular arrhythmia
in BrS are due to differential alterations in the du-
ration and shape of the action potential in the
endocardium, midmyocardium, and epicardium
caused by changes in the inactivation of the
Na-channel. Although BrS has been viewed as
a “loss-of-function” mutation of the Na-channel
and contrasted to the related “gain of function” in
LQTS3, both syndromes appear to have a wider
spectrum of functional effects on cellular electro-
physiology. The result of regional dispersion of
There are no conflicts of interest or disclosures.
Address for reprints: John K. Triedman, M.D., 300 Long-
wood Ave., Boston, MA 02115. Fax: 617 566 5671; e-mail:
john.triedman@cardio.chboston.org
mural voltage gradients. In addition to typical elec-
trocardiographic findings, these permit the occur-
rence of Phase 2 reentry precipitating ventricular
arrhythmias.4,5
Patients with BrS are prone to inducibility of
ventricular arrhythmias by programmed stimula-
tion.6 A propensity to atrial arrhythmias, conduc-
tion defects, including mild prolongation of the
His-ventricular interval and an increased preva-
lence of prolonged Wenckebach cycle length are
also noted on electrophysiological study.7,8
In contrast to patients with long QT syn-
drome, some evidence would suggest that β-
blockade is detrimental to patients with BrS,9 and
catecholamines such as isoproterenol have been
used to suppress ST elevation and treat electri-
cal storm.10 Most notably, Belhassen et al. have
proposed the use of quinidine as a prophylactic
agent and demonstrated in a small prospective se-
ries its clinical utility.11 Presumably secondary to
its effects on the I to , quinidine is observed to sig-
nificantly normalize the ST-segment, as well as
resulting in a decrease in the inducibility of ven-
tricular arrhythmia on programmed stimulation.
In a clinical series of 25 patients treated with this
agent, approximately a third had medication side
effects, but all were alive with no incidence of ma-
jor recorded events on follow-up. Quinidine has
also been shown to be effective in the management
of electrical storm in this syndrome.12
Electrocardiology of Brugada Syndrome
The electrocardiogram is the sine qua non of
BrS (Figure 1). Of importance is the fact that the
specific morphology of the precordial QRST pat-
tern is critical for establishing the diagnosis of the
syndrome. Only the Type 1 ECG pattern—J-point
elevation of >2 mm with a coved (downward con-
vex) ST segment—is diagnostic of BrS, with Type 2
and Type 3 “saddleback” patterns being less spe-
cific. The presence of this Type 1 pattern is dy-
namic, and it is rare for patients to present with
uniformly diagnostic tracings.13 This implies the
need for serial ECGs for diagnostic evaluation in
high-risk patients. Use of more cephalad place-
ment of anterior precordial leads may increase the

C 2009, The Author. Journal compilation 

 C 2009 Wiley Periodicals, Inc.

S58 July 2009, Supplement 2 PACE, Vol. 32

 BRUGADA AND SHORT QT SYNDROMES
Figure 1. Electrocardiographic appearance of Type 1
Brugada syndrome in anterior precordium.
sensitivity of ECG to the presence of a Type 1 Bru-
gada pattern.14
The Type 1 ECG pattern can be elicited by
stress, fever, various autonomic stimuli includ-
ing gastric distension, and particularly by admin-
istration of Na-channel blocking agents. This ef-
fect is most prominent with Type 1C agents, such
as flecainide, and not seen with Type 1B agents
with rapid kinetics. The reliability with which fle-
cainide and the IV agent ajmaline elicit the Type
1 ECG pattern has led to their use as a provocative
diagnostic test for the syndrome, with sensitivity
and specificity of flecainide testing recently esti-
mated at 77 and 80%, respectively.15 Structured
investigation of the effect of gastric distension on
expression of the Brugada pattern has led to its
proposed use as a diagnostic tool as well.16
Clinical Epidemiology and Risk Stratification
Estimates of the prevalence of BrS vary from
5 to 66/10,000,2 with increased prevalence in
Asian population where the disease was originally
termed sudden unexplained nocturnal death syn-
drome (SUNDS). Although the disease is autoso-
mal dominant in its inheritance, there is a marked
male predominance in its phenotype, with men
outnumbering women ∼8:1. Average age at pre-
sentation is 40 years, but cases have been diag-
nosed in infancy and in patients in their late 1970s.
Similarly to its genetic relative LQTS3, cardiac ar-
rhythmia and death in BrS seem to occur largely
in the early morning hours during sleep and in the
setting of bradycardia.17
PACE, Vol. 32 July 2009, Supplement 2
In patients with BrS and a history of syn-
cope or resuscitated cardiac arrest, the risk of
subsequent major arrhythmic event is high. Early
reports showed the risk of recurrent event after
aborted sudden death to be >15% per year, and
among those with syncope and a spontaneously
demonstrated Type 1 ECG, 8.8% per year.18 The
initial assessments of mortality risk in asymp-
tomatic BrS was also sobering. In their first re-
port of asymptomatic patients in 1998, Brugada
et al. found that 10% per year experienced mor-
tality or VF.19 However, this estimate has been
progressively revised downward, with a report in
2002 showing 3.5% per year mortality18 and a
2005 report showing a 1.7% per year event rate
in these patients.20 A recent series of 212 patients
followed for 40 months published by Eckardt et al.
further reduced estimated mortality risks in BrS,
with patients having an episode of aborted sudden
death having an annual mortality of 5.0% per year,
those presenting with syncope 1.8% per year, and
asymptomatic patients having an event rate of only
one in 123 patients.21 It is clear that quantification
of the specific lethality of this syndrome remains
a moving target.
The utility of response to programmed stim-
ulation as a predictor of risk has been debated
and is unresolved. Brugada et al. have found pro-
grammed stimulation to be a useful discriminator
of risk,22 while other investigators with compara-
ble groups in terms of size and follow-up have not
found it to be predictive.20,21 It has been specu-
lated that one reason for these discrepancies may
be subtle difference in the diagnostic criteria ap-
plied to kindreds entered into these respective
groupings.
A meta-analysis of studies enrolling approxi-
mately 1,500 patients with BrS was published re-
cently by Gehi et al.23 This report noted that the
overall event rate among patients diagnosed with
BrS was 10% over 32 months, or ∼3.8% per year.
Specific predictors of events included: history of
syncope or aborted sudden death, odds ratio (OR)
3.24 [2.13–4.93]; male gender, OR 3.47 [1.58–7.63];
and spontaneous occurrence of diagnostic, Type 1
ECG, OR 4.65 [2.25–9.58]. Not associated with ar-
rhythmic events on follow-up were: positive fam-
ily history for sudden cardiac death, the result of
programmed stimulation, and the identification of
an SCN5A genotype.
There is general consensus among authors
that patients with a history of aborted sudden
death or syncope and a diagnostic ECG for BrS,
whether or not elicited by drug challenge, have
a Class I indication for implantable cardioverter
defibrillator (ICD) implantation. Because of the
evolving assessment of the lethality in asymp-
tomatic patients and uncertainties regarding risk
S59
 TRIEDMAN

stratification strategies, there is no similar consen-

sus regarding use of programmed stimulation and
recommendations for ICD placement in asymp-
tomatic patients. A recent study of ICD utiliza-
tion in 220 patients with BrS, nearly 50% symp-
tomatic, showed an appropriate shock rate of 2.6%
per year, associated with inappropriate shocks in
20% of patients and an overall complication rate of
8.9% per year.24 It is possible that in patients who
are deemed at significant risk and who demon-
strate a plausible therapeutic response to and tol-
erance of quinidine therapy (i.e., ECG normaliza-
tion and noninducibility of ventricular arrhythmia
on programmed stimulation) that this may consti-
tute an acceptable alternative therapeutic strategy
to early ICD implant.
Brugada Syndrome and Arrhythmogenic Right
Ventricular Cardiomyopathy (ARVC)
Soon after the description of this syndrome,
a pathophysiological association between BrS and
ARVC was proposed. Similarities between BrS and
ARVC were noted with respect to familial trans-
mission, propensity for sudden cardiac death and
ventricular arrhythmia, and occurrence of right
bundle branch block and precordial ST elevation.
Additionally, pathological specimens drawn from
a BrS population suggested that at least some over-
lap might exist between the two syndromes.25–27
However, further characterization of both syn-
dromes with respect to molecular genetics has pri-
marily illustrated the difference between these two
syndromes, with the genetic basis of BrS almost
fully attributable to mutations of the SCN5A gene,
and ARVC being a more heterogeneous disease
with mutations drawn from at least ten genetic
loci (none of them SCN5A) underlying the cardiac
phenotype.
Pediatric Issues
Although the mean age of presentation for BrS
is around 40, the heritable nature of the disease
and its occasionally remarkable presentation has
yielded a number of interesting anecdotal obser-
vations of the arrhythmia and its therapy options
down to the newborn age.28–30 It is clear from
family pedigrees that at least some episodes of
sudden infant death syndrome (SIDS) can be at-
tributed to BrS.31 Of particular interest to pediatric
electrophysiologists is the apparent temperature-
sensitive relation between some sodium channel
variants and phenotypic expression, possibly ex-
plaining the clinical observation that fever may
be arrhythmogenic in BrS. In a study of 30 chil-
dren affected by BrS by Probst et al., fever was the
most frequently observed precipitating factor for
arrhythmic events, occurring in five patients.32 In
this report, more than half of these patients were
Figure 2. Electrocardiographic appearance of short QT
syndrome in anterior precordium.
asymptomatic and identified by family screening
after relatives were identified with BrS. As in
adults with the syndrome, the risk of arrhythmia
was increased in the setting of previous symptoms
and spontaneously occurring type I ECG.
Of specific relevance to diagnosis of BrS in
childhood is the study recently published by
Beaufort-Krol et al., exploring the developmental
aspects of ECG expression of SCN5A mutations
in BrS and LQTS Type 3. This review of a large
number of carriers of a single SCN5A mutation in
childhood revealed age-dependent penetrance of
some of the phenotypic characteristics of LQTS
and BrS, with QT prolongation and conduction
disease evident at birth but ST-segment elevation
appearing only after 5 years of age.33
Short QT Syndrome
The clinical phenotype of short QT syndrome
was proposed by Gussak et al. in 2000,34 and in
a brief period the molecular basis and genotype–
phenotype correlation of this arrhythmia syn-
drome has been remarkably well elaborated. Short
QT syndrome is a familial syndrome of sudden
death, syncope, and atrial arrhythmia caused by
several gain of function mutations of the potas-
sium rectifier currents resulting in dramatic short-
ening of the corrected QT interval on baseline
ECG (Fig. 2). In comparison to the normal pop-
ulation, among whom less than 1:10,000 patients
will show a QTc interval <340 ms,35 patients with
short QT syndrome typically have QTc intervals of
<300 ms.

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 BRUGADA AND SHORT QT SYNDROMES
Three genetic variants of SQTS are currently
described. Type 1 involves an N588K mutation
of HERG I Kr (KCNH1) channel, affecting the S5-
P loop of the membrane protein. The fact that
this specific mutation has been identified in more
than one kindred suggests that it is a “hotspot”
for SQTS mutation.36,37 Type 2 involves a muta-
tion of the KvLQT1 I Ks (KCNQ1) channel,38 and
most recently Type 3 has been shown caused by
a mutation of the Kir2.1 I K1 (KCNJ2) channel.39
Multiple patients have not had a specific mutation
identified, and in sum these findings indicate that
similar to long QT syndrome, this is a genetically
heterogeneous group.
The electrocardiographic signatures of SQTS
are the occurrence of tall, narrow, and peaked T-
waves with almost complete absence of an ST seg-
ment (variant T-wave findings may be noted for
SQTS Type 3). QT interval in this syndrome does
not accommodate normally to heart rate, and cau-
tion in interpreting ECGs at rapid rates must be
employed due to the possibility of pseudonormal-
ization of the QT interval. Clinically, SQTS ap-
pears to be impressively lethal, as indicated by
several kindreds demonstrating both an autosomal
dominant pattern and a high frequency of sud-
den cardiac death in the familial phenotypes.40
Although the mean age of diagnosis is in adult-
hood, there are three well-documented cases pre-
senting with cardiac arrest and/or syncope dur-
ing infancy, as well as two undiagnosed cases of
sudden infant death in kindreds known to have
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