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Editorial
Brugada Syndrome
Why Are There Multiple Answers to a Simple Question?
Ramon Brugada, MD; Robert Roberts, MD
I
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n 1986, two young brothers who survived documented
cardiac arrests exhibited a specific electrocardiographic
pattern providing a link to sudden death. Similar observations in other individuals led to the original description in
1992 of the syndrome consisting of right bundle branch
block, ST-segment elevation in leads V1 to V3, and sudden
death with structurally normal heart—ie, the Brugada syndrome.1 This syndrome has stimulated research in many
centers. What before was an electrocardiographic pattern
resembling early repolarization has now become a marker for
increased risk of sudden death. Fortunately, this observation
coincided with an outpouring of molecular research in cardiology and with the success already encountered in identifying
the genetic basis of other arrhythmic diseases. Brugada
syndrome likely will continue to benefit from the application
of genomics. In just 10 years, the disease has become widely
recognized, and researchers in multiple disciplines in basic
and clinical research have come together to decipher its
pathogenesis.
suspected since the original description, also has been
confirmed.5
Insight from cellular electrophysiology suggests that STsegment elevation is caused by a shift in the ionic current
balance and the creation of a voltage gradient, with predominance of the transient outward current (Ito) in the epicardium
over the endocardium.6 A difference in the pattern of expression of this current in the right ventricle versus the left
ventricle accounts for the presence of the electrocardiographic pattern solely in the right precordial leads.6 Without
a doubt, however, genetics afforded the basis to integrate the
clinical phenotype with the cellular electrophysiology by
identifying responsible mutations in the gene that encodes for
the cardiac sodium channel, SCN5A.7 This genetic basis has
proven that the disease is a channelopathy and primarily an
electrical disease. Electrophysiological analysis shows that
mutated channels inactivate faster or are nonfunctional.7
These nonfunctional channels, which act in phase 0 of the
action potential, leave Ito currents unopposed in phase 1,
creating a transmural voltage gradient and a substrate for
reentrant arrhythmias. Electrophysiological analysis has also
indicated worsening of function at higher temperatures in
some mutations.8 This may explain why some patients
present with ventricular fibrillation during febrile episodes.
Diagnosis and risk stratification were not to remain as
simple as they seemed. The typical clinical presentation of the
middle-aged patient with a classic ECG and aborted sudden
death has now been confounded with the identification of
asymptomatic individuals, family members, and transient
normalization of the ECG in some patients.9 Everyone agrees
that there is a high risk of recurrence of cardiac arrest;
therefore, symptomatic individuals require some form of
protection.2 Some investigators advocate guinidine, although
others prefer an implantable cardioverter-defibrillator.2
Asymptomatic individuals present a greater dilemma. One
must expect events to occur in these individuals because
symptomatic patients usually have been asymptomatic for
many years. The question is, who? And when? It seems from
the latest follow-up that programmed electrical stimulation
(PES) will help to predict who is at risk.10
The degree and type of ST-segment elevation (coved
versus saddle-back) and transient normalization are issues
that are presently being investigated to assess whether they
afford better risk stratification. The normalization of the ECG
represents an important diagnostic challenge. Fortunately,
investigators have described the induction of electrocardiographic alterations with autonomic factors or the use of
antiarrhythmics.11 The latter, in the form of class I agents,
have since become an important diagnostic tool. The diagnostic specificity and sensitivity of the antiarrhythmic drug
See p 3081
The most common presentation is a middle-aged man, with
the electrocardiographic blueprint, no structural heart disease,
and a documented history of ventricular fibrillation.2 In 1997,
Nademanee et al3 linked Brugada syndrome to sudden unexpected death syndrome (SUDS) in Southeast Asia. SUDS has
been recognized since the 1980s, when the Centers for
Disease Control reported a higher than usual incidence of
sudden death in individuals from that geographic area.4 The
individuals usually die during their sleep from ventricular
tachyarrhythmias. In some countries, SUDS is an important
cause of death in young males, second only to car accidents.
The electrocardiographic pattern is the same as that seen in
Brugada syndrome, indicating that SUDS and Brugada syndrome are similar diseases, if not the same.3 A sex difference
in Brugada syndrome is obvious in Southeast Asia, where
only males are symptomatic. In Europe, the sex difference is
not as distinct. The association between Brugada syndrome
and sudden infant death syndrome (SIDS), which had been
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the Section of Cardiology, Baylor College of Medicine, Houston, Tex.
Correspondence to Robert Roberts, MD, Don W. Chapman Professor
of Medicine, Professor of Medicine and Cell Biology, Department of
Medicine, Section of Cardiology, Baylor College of Medicine, 6550
Fannin, MS SM677, Houston, TX 77030. E-mail [email protected]
(Circulation 2001;104:3017-3019.)
© 2001 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
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Circulation
December 18/25, 2001
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challenge was assessed in individuals who carried SCN5A
mutations and in patients with transient normalization of the
ECG. The infusion of ajmaline was shown to be highly
accurate in identifying affected individuals.12 Reports of
false-negative studies, however, have challenged its specificity.13 The diagnostic challenge is further complicated by the
fact different drugs are approved for use in different countries, and each physician is obliged to use what is available.
It is accepted, though, that ajmaline is the most potent
antiarrhythmic, followed by flecainide, with procainamide
the least likely to uncover the electrocardiographic
abnormality.
While identification of the genetic defects in SCN5A has
clarified the molecular basis of Brugada syndrome, the field
of genetics was casting shadows in other directions. The
sodium channel determines the upstroke or phase 0 of the
action potential in atrial and ventricular cells. This rapid
inward sodium current predominates in cardiac depolarization. Therefore, it perhaps was expected that different mutations in the gene that encodes for SCN5A would be linked to
multiple arrhythmic diseases. Mutations in SCN5A were
shown to induce Brugada syndrome, idiopathic ventricular
fibrillation, isolated cardiac conduction defect (ICCD),14 and
long-QT syndrome (LQT3).15 Our hope was that genetics
actually would help to distinguish among the different diseases. So it seemed at the beginning, when analysis of the
mutations indicated that in some way LQT3 and Brugada
syndrome could be considered mirror images, with faster
inactivation or a nonfunctional channel in Brugada syndrome7 and delayed inactivation with persistent current in
LQT3.15 Then, a family was described that had the same
mutation and 2 different phenotypes: some members had
LQT3, and others, Brugada syndrome.16
The study by Kyndt et al17 in the present issue of
Circulation is an illustrative example of the same mutation
inducing either Brugada syndrome or a conduction defect,
which emphasizes the complexity of a single-gene disease.
Despite the fact that the 13 individuals in this study have the
same mutation in SCN5A, 4 have a phenotype of Brugada
syndrome; 8, ICCD; and 1, a completely normal ECG. The
loss of function caused by the mutation leaves the gene
carriers with half the normal amount of sodium current. This
indicates that despite the fact that these are monogenic
diseases and originate from the same mutation, the specific
phenotype depends not only on the site of involvement of the
sodium channel, but probably also on the balance between the
different ionic currents. The alteration in overall current
balance may be caused by the expression of minor differences
in the genes responsible for these currents. It is well recognized that the phenotype of single-gene disorders may be
modified by slight differences in other genes and by environmental stimuli. These minor genetic differences, referred to
as polymorphisms, comprise an area of active research in
identifying modifier genes and understanding polygenic disorders.18 It seems, therefore, that it is the level of alteration of
the ionic balance that determines the risk of sudden death in
these SCN5A mutations. This is a hypothesis that has been
advocated in recent years, and it is in accordance with certain
clinical observations. Individuals who require sodium chan-
nel blockers to induce the electrocardiographic pattern seem
to have the least level of alteration in the ionic balance and,
so far, have a better prognosis than do individuals with
abnormal ECG at baseline.19
The sex difference in the long-QT and Brugada syndromes
has been puzzling. The study by Kyndt et al17 rekindles this
important debate. It appears that among gene carriers, males
have a Brugada phenotype or a higher degree of impaired
conduction than do females. Do estrogen, progesterone, or
other hormones affect the expression of cardiac ionic channels? Do women require a higher level of alteration of the
ionic balance to develop the disease? It seems so, and
although fascinating, it is also a testable hypothesis. There is
always the challenging exception, however—for example,
individual III-13, male, who carries the mutation but has a
normal ECG.
Lastly, but probably most important to the clinician, this
family raises ethical, diagnostic, and therapeutic issues. The
field of genetics is emerging as the gold standard in the
diagnosis of monogenic diseases. There is now proof in this
family that several individuals carry a mutation that has been
linked to malignant arrhythmias and probably to sudden death
in some of its members. Is patient III-13 entitled to know that
he is a carrier of the mutation? Just as importantly, who at this
point needs protection? Not all clinicians would come to the
same conclusion. Some advocate the use of class I antiarrhythmics to unmask the syndrome; they attach prognostic
value to PES and thus believe that ICCD patients have a
better prognosis because of the negative flecainide test and
negative PES.10 Other investigators think flecainide and PES
are not so reliable.13 Therefore, can one assume that individuals with ICCD, negative flecainide test, and negative PES
are at lower risk? We must accept that the specific phenotype
does not depend solely on the predominant mutation, but one
thing is true: All are carriers of a potentially malignant
mutation.
Unfortunately, only time, events, and further clinical and
basic research will be able to answer these questions. We
must not downplay the progress provided by genetic findings.
This disease is caused in part by defects in the gene for the
SCN5A channel, and thus we must avoid antiarrhythmics that
inhibit the sodium channel. Second, we now have a specific
molecular target to aid in the development of more precise
and appropriate therapy. Third, a genetic diagnosis, though
presently available only in highly specialized centers, with
improved technology can be expected to be a routine test in
the future. Thus, at this time, it remains for the physician to
determine the ultimate treatment on the basis of the available
diagnostic tools for risk stratification.
What started as a simple clinical description has become
the fodder of thorough investigations that use the tools of the
clinician, molecular biologist, and electrophysiologist. In 10
years we have achieved a certain level of knowledge and
comfort in the basic aspects of this disease. There remain,
however, many controversial issues and many more questions
that defy our ability to understand, diagnose, and treat this
complex biological process. There is nothing better than
unanswered questions to stimulate much-needed research,
Brugada and Roberts
with the hope that this soon will provide an accurate diagnosis and more effective treatment.
References
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KEY WORDS: Editorials
䡲 fibrillation
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bundle-branch block
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arrhythmia
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genetics
Brugada Syndrome: Why Are There Multiple Answers to a Simple Question?
Ramon Brugada and Robert Roberts
Circulation. 2001;104:3017-3019
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