Brugada Syndrome:
The Syndrome of
Right
Bundle Branch Block, ST segment Elevation in V1 to V3
and Sudden Death
Josep Brugada MD, Pedro Brugada MD*,
Ramon
Brugada MD.**
In 1992 a new syndrome consisting of syncopal episodes
and/or sudden death in patients with a structurally normal heart and a
characteristic electrocardiogram (ECG) with a pattern of right bundle
branch block with an ST segment elevation in leads V1 to V3 was
described 1 In
1998 the poor prognosis of patients with the syndrome not receiving an
implantable defibrillator was reported 2,3 In 1998 the genetic nature of
the disease and its assotiation to a mutation in the cardiac sodium
channel gene was described 4 . Because the diagnosis is easily made by means of the
ECG, an increasing number of patients with
the ECG pattern are being identified worldwide. In this article we will
review our present knowledge concerning patients with the classical ECG
pattern of the disease.
In the Brugada syndrome, the diagnosis is based on the history of
aborted sudden death with the typical electrocardiographic pattern of
ST segment elevation in leads V1-V3, with or without right bundle
branch block 1 (
Fig. 1). In some cases,
however, the diagnosis is different because some individuals present
with an abnormal electrocardiogram but are completely asymptomatic or
there is a history of sudden death in the family and the
electrocardiographic criteria are observed.
Fig. 1.
Typical ECG of the syndrome. Please note the pattern resembling a right
bundle
branch block in lead V1 and the ST segment elevation in leads V1 to V3.
Paper speed 25 mm/s.
Incidence of an abnormal ECG in the general population
A prospective study of an adult Japanese population
(22,027 subjects) showed an incidence of 0.05% of ECG’s compatible with
the syndrome (12 subjects)5.
A second study of adults in Awa (Japan) showed an incidence of 0.6 %
(66
cases out of 10,420) 6. However, a third study in children from Japan showed an
incidence of ECG’s compatible with the syndrome of only 0.0006% (1 case
in 163,110)7.
These
results suggest that the syndrome manifests primarily during adulthood,
which is in concordance with the mean age of sudden death victims (35
to 40 years).
The presence of concealed and intermittent forms,
however, makes the diagnosis difficult in some patients. The ECG can be
modulated by changes in autonomic balance and the administration of
antiarrhythmic drugs8. Beta-adrenergic stimulation normalises the ECG, while
IV ajmaline, flecainide or procainamide accentuate the ST segment
elevation and are capable of unmasking concealed and intermittent forms
of the disease. These data are very important when we deal with family
members of a patient with the syndrome. We know that
a normal ECG in the resting state is not sufficient to exclude that a
family member is affected with the syndrome. Some family members only
manifest
the typical ECG pattern after ajmaline or flecainide administration.
Recent data suggest that loss of the action potential
dome
in right ventricular epicardium but not endocardium underlies the ST
segment elevation seen in the Brugada syndrome 9,10. Also, electrical
heterogeneity within right ventricular epicardium leads to the
development of closely coupled extrasystoles via a phase 2 reentrant
mechanism, which then precipitate ventricular tachycardia-ventricular
fibrillation. Right ventricular epicardium is preferentially affected
because of the predominance of transient outward current in this
tissue.
Clinical manifestations
The complete syndrome is characterised by
episodes of rapid polymorphic VT in patients with an ECG pattern of
right bundle branch block and ST segment elevation in leads V1 to V3.
The manifestations of the syndrome are caused by episodes of
polymorphic VT/VF. When the episodes terminate spontaneously the
patient develops syncopal attacks. When the
episodes are sustained, cardiac arrest and eventually sudden death
occur.
There exist asymptomatic individuals in whom the
atypical ECG is detected during routine examination. This ECG cannot be
distinguished from that of symptomatic patients. In other patients, the
characteristic ECG is recorded during screening after the sudden death
of a family member with the disease.
On the other hand, there is the group of symptomatic
patients who have been diagnosed as suffering syncopal episodes of
unknown cause, or vaso-vagal origin, or have a diagnosis of idiopathic
ventricular fibrillation. Some of these patients are diagnosed at
follow-up, when
the ECG changes spontaneously from normal to the typical pattern of the
syndrome. This is also the case for those individuals in whom the
disease
is unmasked by the administration of an antiarrhythmic drug given for
other arrhythmias, for instance atrial fibrillation.
Diagnosis.
The diagnosis of the syndrome is easily obtained by
electrocardiography as long as the patient presents the typical ECG
pattern and there is a
history of aborted sudden death or syncopes caused by a polymorphic VT.
The ST segment elevation in V1 to V3 with the right bundle branch block
pattern is characteristic. The ST changes are different from the ones
observed
in acute septal ischemia, pericarditis, ventricular aneurysm and in
some
normal variants like early repolarization. There are though, ECG’s
which
are not as characteristic, and they are only recognised by a physician
who is thinking of the syndrome. There are also many patients with a
normal
ECG in whom the syndrome can only be recognised a posteriori when the
typical
pattern appears in a follow-up ECG or after the administration of
ajmaline,
procainamide or flecainide.
It is possible that the electrocardiographic patterns are
different depending on the genetic abnormality. This is the case in
other genetic diseases like the long QT syndrome 11. The mutations that have
been discovered give proof of this fact in Brugada syndrome: their
ECG’s are similar, but not identical.
Even though the affected gene is the same, the exact mutation is
different.
It will be necessary to identify more mutations and make close
genotype-phenotype correlation to establish the links. However, we
cannot forget the great variability of the ECG in this syndrome,
something which will certainly not facilitate analysis.
Additional diagnostic problems are caused by the changes
in the ECG induced by the autonomous system and by antiarrhythmic
drugs.
The study by Myazaki et al 8 was the first one to show the variability of the ECG
pattern in the syndrome. Despite the fact that we described the
syndrome as a
persistent ECG pattern, we soon recognised that it is variable over
time,
depending on the autonomic interaction and the administration of
antiarrhythmic
drugs. Adrenergic stimulation decreases the ST segment elevation while
vagal stimulation worsens it. The administration of class Ia, Ic and
III
drugs increase the ST segment elevation. Patients with syncope of
unknown
cause must be challenged with antiarrhythmic drugs in order to exclude
the possibility of this syndrome as a cause of ventricular arrhythmias
and syncope.
Genetic characterisation.
In
the Brugada syndrome, as in the long QT syndrome, the best candidate
genes are those that are responsible for the formation of the cardiac
action
potential, namely the genes that encode for the cardiac ionic channels.
In animal studies, blockade of the calcium-independent
4-aminopyridine-sensitive
transient outward potassium current (Ito) results in surface
ECG findings of elevated, downsloping ST-segments due to greater
prolongation
in the epicardial action potential compared to the endocardium (which
lacks
a plateau phase). Loss of the action potential plateau (or dome) in the
epicardium but not endocardium would be expected to cause ST-segment
elevation. Because loss of the dome is caused by an outward shift in
the balance of currents active at the end of phase 1 of the action
potential (principally Ito and ICa), autonomic
neurotransmitters like acetylcholine facilitate loss of the action
potential dome by suppressing calcium current and augmenting potassium
current. b-adrenergic agonists (i.e. isoproterenol, dobutamine)
restore the dome by augmenting ICa. Sodium channel
blockers also facilitate loss of the canine right ventricular action
potential dome as a result of a negative shift in the voltage at which
phase 1 begins. Hence, Ito, ICa, and INa
would be good candidate genes to study. Since INa (SCN5A)
has been shown to cause VT/VF in humans (in the long QT syndrome) this
gene certainly is worthy of study.
Recently,
we reported the findings on six families and several sporadic cases of
Brugada syndrome 4.
The families were initially studied by linkage analysis
using markers to the known ARVD loci and linkage was excluded.
More
recently, seven other families have also excluded linkage to these
loci,
thus suggesting that the families recruited with the Brugada syndrome
to
date may indeed by an entity distinct from ARVD. Candidate gene
screening
using the mutation analysis approach of single strand conformation
polymorphism
(SSCP) analysis and DNA sequencing was performed and SCN5A was chosen
for
study. In three families, mutations in SCN5A were identified
including:
1.- a missense mutation (C-to-T base substitution) causing a
substitution
of a highly conserved threonine by methionine at codon 1620 (T1620M) in
the extracellular loop between transmembrane segments S3 and S4 of
domain IV
(DIVS3 - DIVS4), an area important for coupling of channel activation
to
fast inactivation; 2.- a two nucleotide insertion (AA) which disrupts
the splice-donor sequence of intron 7 of SCN5A; and 3.- a single
nucleotide
deletion (A) at codon 1397 which results in an in-frame stop codon that
eliminates DIIIS6, DIVS1 – DIVS6, and the carboxy-terminus of SCN5A.
Not
all the individuals had the typical electrocardiogram at baseline. The
diagnosis
for genetic purposes was based on the electrocardiographic changes
after
the administration of ajmaline iv. This test proved 100% sensitive and
specific,
as all the patients who developed the ST segment elevation had the
mutation
in the subsequent genetic analysis. Likewise, none of the individuals
without
the electrocardiographic abnormalities had the genetic abnormality.
Biophysical
analysis of the mutants in Xenopus oocytes demonstrated a
reduction in the number of functional sodium channels in both the
splicing mutation and one-nucleotide deletion mutation, which should
promote development
of reentrant arrhythmias. In the missense mutation, sodium channels
inactivated more rapidly than normal. In this case, the presence of
both normal and mutant channels in the same tissue would promote
heterogeneity of the refractory period, a well-established mechanism of
arrhythmogenesis. Inhibition of the sodium channel INa
current causes heterogeneous loss
of the action potential dome in the right ventricular epicardium,
leading
to a marked dispersion of depolarisation and refractoriness, an ideal
substrate for development of reentrant arrhythmias. Phase 2
reentry produced by the same substrate is believed to provide the
premature beat necessary for initiation of the VT and VF responsible
for symptoms in these patients.
Mutations
in the SCN5A gene were previously shown to be the cause of LQT3, a form
of Romano-Ward long QT syndrome. The differences in the clinical
findings between LQT3 and Brugada syndrome occur due to the different
biophysical results based on the position of the mutations within the
gene. Unlike
the Brugada syndrome, LQT3 occurs due to an augmentation of late INa
carried by SCN5A channels.
Prognosis and treatment.
Symptomatic
patients: Our recent data on 334 patients with the syndrome confirm
the generally accepted view that symptomatic patients with this
syndrome have an unacceptably high rate of arrhythmic events. Because
no effective antiarrhythmic drug or other therapies are available,
implantation of a cardioverter-defibrillator is mandatory in these
patients. Better understanding of the genetic basis and
electrophysiologic mechanisms of the disease may make other therapies
possible in the future. Recurrent arrhythmic events were
more frequent in patients with aborted sudden death as the presenting
symptom
as compared to patients with repetitive syncopal episodes. This could
suggest
a more severe disease in the former group with more frequent and
longer-lasting
arrhythmias. However, a word of caution is in order because the mean
follow-up
period of patients with aborted sudden death was significantly longer
than
the mean follow-up of patients with syncopal episodes. For both
categories
of symptomatic patients, the recurrence rates approximate a mean of 11%
per
mean follow-up year (8.8% per year in syncope patients and 13.7% per
year
in patients resuscitated from sudden cardiac death) and are
unacceptably high.
The gravity of the problem is amplified when one considers the mean age
of
the patients.
Asymptomatic individuals: The major concern at present is with
the group of individuals displaying an electrocardiogram compatible
with the diagnosis of Brugada syndrome but who are asymptomatic. The
initial diagnosis in these individuals was arrived at by different
means: In some individuals a spontaneously abnormal electrocardiogram
was recorded as part of a routine screening, for instance before
surgery. In other individuals, the abnormal electrocardiogram was
obtained because of a family history of sudden death. In some, the
abnormal electrocardiogram appeared only during treatment
with antiarrhythmic drugs given for the treatment of atrial
fibrillation
or other arrhythmias. Finally, in still others, the abnormal
electrocardiogram was obtained only after pharmacologic challenge
performed because of the suspicion or documentation of Brugada syndrome
in the family. The most recent data allow important conclusions in
terms of the management of these asymptomatic individuals.
First,
it is confirmed that a spontaneously abnormal electrocardiogram
is a marker of possible sudden arrhythmic death: 16 of 111 (14%)
asymptomatic individuals with a spontaneously abnormal
electrocardiogram developed
an arrhythmic event during a mean follow-up period of only 27±29
months. The arrhythmic event occurred within one year of diagnosis in 7
individuals, within 2 years in another 3 patients, but after more than
4 years in the remaining 6 individuals. The longest time interval
between
diagnosis and first arrhythmic event was 10 years. These data
demonstrate
that a mean follow-up time of slightly more than 2 years underestimates
the total number of events that can occur in this population.
Second,
the data allowed recognition of groups of asymptomatic individuals with
a good prognosis. The group of asymptomatic individuals in whom the
abnormal electrocardiogram was recognized only after pharmacologic
challenge had no events during follow-up. This observation has
important implications for the management of individuals who are
members of a family with Brugada syndrome. When the individual is
asymptomatic and the electrocardiogram is normal, the unmasking of the
abnormal electrocardiogram with a drug identifies a carrier of the
disease. However, because no events occurred in this group, it is not
justified to recommend further investigations in terms of management.
Conclusions.
The syndrome of right bundle branch block, ST segment
elevation from V1 to V3 and sudden death is a new entity. This disease
is genetically determined and it is different from the long QT syndrome
and right ventricular dysplasia. The incidence of sudden death in this
syndrome is very high
and, at present, sudden death can only be prevented by implanting a
cardioverter-defibrillator.
References.
1.
Brugada
P, Brugada J. Right bundle branch block, persistent ST segment
elevation and sudden cardiac death: A distinct clinical and
electrocardiographic
syndrome. J Am Coll Cardiol 1992;20:1391-1396.
Medline
2.
Brugada
J, Brugada R, Brugada P. Right bundle branch block and ST segment
elevation in leads V1-V3: A marker for sudden death in patients with no
demonstrable structural heart disease. Circulation 1998;97:457-460.
Medline
3.
Nademanee
K, Veerakul G, Nimmannit S, et al. Arrhythmogenic marker for the sudden
unexplained death syndrome in Thai men. Circulation 1997;96:2595-2600.
Medline
4.
Chen
Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, et al. Genetic
basis and molecular mechanisms for idiopathic ventricular fibrillation.
Nature; 1998;392:293-296. Medline
5.
Tohyou
Y, Nakazawa K Ozawa A, et al. A survey in the incidence of right bundle
branch block with ST segment elevation among normal population. Jpn J Electrocardiol 1995;15:223-226. (No Abstract
Available)
6.
Namiki
T, Ogura T, Kuwabara Y, et al. Five-year
mortality and clinical characteristics of adult subjects with right
bundle branch block and ST elevation. Circulation 1995;93:334. Medline
7.
Hata
Y, Chiba N, Hotta K, et al. Incidence and clinical significance of
right bundle branch block and ST segment elevation in V1-V3 in 6-to
18-year-old school children in Japan. Circulation 1997;20:2310.
(No Abstract
Available)
8.
Miyazaki
T, Mitamura H, Miyoshi S, Soejima K, Aizawa Y, Ogawa S. Autonomic and
antiarrhythmic modulation of ST segment elevation in patients with
Brugada syndrome. J
Am Coll Cardiol 1996;27:1061-1070. Medline
9.
Antzelevitch
C: The Brugada syndrome. J Cardiovasc Electrophysiol 1998;9:513-516. (No Abstract Available)
10.
Gussak
I, Antzelevitch C, Bjerregaard P, Towbin JA, Chaitman BR. The Brugada
syndrome. Clinical, electrophysiologic and genetic aspects. J Am Coll
Cardiol 1999;33:5-15. Medline
11.
Priori
SG, Diehl L, Schwartz PJ. Torsade de pointes. In: Podrid PJ, Kowey PR, eds. Cardiac Arrhythmia.
Williams
and Wilkins, Baltimore 1995, p 951-963.
This article has been cited by other articles:
|
 Home
|
Johnson Francis, C.G. Sajeev, K. Venugopal
Brugada Syndrome: The Enigma
Calicut Medical Journal 2003;1(1):e3 [Full
Text]
|
|
|
|
Home
|
Khan IA, Nair CK
Brugada and Long QT-3 Syndromes: Two Phenotypes of the
Sodium Channel Disease.
Annals of Noninvasive Electrocardiology 2004; 9 (3), 280-289 [Medline]
|
|
|
|
|
Home
|
Johnson Francis and Charles Antzelevitch
Brugada Syndrome.
International Journal of Cardiology [In
Press]
|
|
|
