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Inducible Ventricular Fibrillation in the Brugada Syndrome:
Diagnostic and Prognostic Implications
SAMI VISKIN, M.D.
From the Department of Cardiology, Tel Aviv-Sourasky Medical Center, Sackler-School of Medicine, Tel Aviv University, Israel
Editorial Comment
Two leading groups of investigators are reporting differing
conclusions regarding the value of electrophysiologic studies (EPS) in the Brugada syndrome. First, Brugada et al.1
reported that EPS has excellent accuracy for predicting outcome in the Brugada syndrome. Soon thereafter, however,
Priori et al.2 concluded quite the opposite. Based on a study
of 86 patients with Brugada syndrome who underwent EPS,
Priori et al.2 found that the test was not useful in identifying
patients at risk for arrhythmic events. Finally, in this issue of
the Journal, Brugada et al.3 reinforce their previous findings1
by reporting on more patients and a longer follow-up period, thus reaffirming that EPS effectively predicts outcome.
When authorities of this scale reach opposing conclusions,
statements such as “the discrepancies observed are due to
differences in patient selection and EPS protocols” usually
apply. Nevertheless, the clinician is left with so much uncertainty that a critical look at the evidence is warranted.
Is Inducible Ventricular Fibrillation of Diagnostic
Value in the Brugada Syndrome?
The first question is whether the induction of ventricular
fibrillation (VF) increases the odds that the disease “Brugada
syndrome” is present in, for example, a patient with syncope,
or a patient without symptoms, who has a Brugada-type ECG.
As opposed to the induction of sustained monomorphic
ventricular tachycardia (VT), which is always viewed as a
true-positive result of EPS, the induction of polymorphic VT
and VF has generally been viewed with reservation. This
reservation originates from animal studies showing that VF
can be provoked with appropriately timed electrical stimuli
in the normal heart.4 Furthermore, studies performed in the
1980s showed that VF could be induced (by double or triple
ventricular extrastimulation) in 6% to 9% of patients who did
not have either heart disease or ventricular arrhythmias.5-7
It should be noted that induction of nonsustained polymorphic VT, which occurred in 40% of 46% of patients, led to
premature discontinuation of EPS in two of these studies.5,7
In addition, in these studies only the right ventricular apex
was stimulated. One must conclude, therefore, that the falsepositive rate of VF induction at EPS is likely to be higher
than 9% if a complete pacing protocol, including pacing at
two ventricular sites, three ventricular extrastimuli, and short
coupling intervals, is used. On the other hand, it should be
noted that these studies included only 16 to 32 patients.5-7
Despite this small number of patients, these studies led to
J Cardiovasc Electrophysiol, Vol. 14, pp. 458-460, May 2003.
Address for correspondence: Sami Viskin, M.D., Department of Cardiology,
Tel Aviv Sourasky Medical Center, Weizman 6, Tel Aviv 64239, Israel. Fax:
972-3-6974418; E-mail: [email protected]
the designation of VF as “a nonspecific response to aggressive extrastimulation that has no diagnostic value in patients
with no heart disease and no documented arrhythmias,”8 a
designation that is still in vogue 2 decades later.9 Furthermore, because the induction of these nonspecific polymorphic
arrhythmias occurred mainly with short-coupled extrastimuli,10 physicians performing EPS with the aim of inducing
monomorphic VT (the only arrhythmia perceived as “clinical
arrhythmia”) avoid using extrastimuli with coupling intervals
shorter than 200 msec.11 In fact, VF is the clinical arrhythmia
in the Brugada syndrome, and spontaneous initiations of arrhythmias in idiopathic VF and Brugada syndrome invariably
follow extrasystoles with very short coupling intervals.12,13
Consequently, to learn about the sensitivity of EPS in the Brugada syndrome, one must focus on studies using “aggressive
extrastimulation” limited by the ventricular refractory period
rather than the “nominal” 200-msec interval.14
The present study by Brugada et al.3 includes data on 80
patients with definite Brugada syndrome (cardiac arrest survivors with Brugada-type ECG); 81% of these patients had
inducible VF. Smaller series reporting EPS with aggressive
stimulation also report VF inducibility in 61%,15 85%,14 and
93%16 of patients with “definite Brugada syndrome.” This
high inducibility rate and the reproducibility of EPS results17
suggest that electric vulnerability of the myocardium is a
distinctive feature of the Brugada syndrome. Finally, the observed “dose-response curve” (the fact that VF is induced in
81% of Brugada patients with cardiac arrest and in 61% of
those with syncope but in only 35% of patients with Brugadatype ECG but no symptoms)3 suggests that inducible VF is a
marker of this electric instability. Even the lower inducibility
rate reported by Priori et al.2 (67% for patients with definite Brugada syndrome) using nonuniform EPS protocols is
higher than the false-positive rate of “nonspecific” VF induction that one would expect based on the limited data mentioned earlier. One must conclude that inducible VF is of
diagnostic value in the Brugada syndrome. Nevertheless, for
the individual patient, one must remember that there is at
least a 10% chance of “accidentally” inducing VF as a nonspecific response to aggressive extrastimulation. Therefore,
one should recommend EPS only to those patients in whom
the clinical history or the ECG changes are serious enough
to accept VF induction as “positive response” if this occurs.
Is Inducible Ventricular Fibrillation of Prognostic
Value in the Brugada Syndrome?
The second question is whether the induction of VF in a
patient with Brugada syndrome increases the odds that VF
eventually will occur spontaneously. Because the risk for future arrhythmias is so high (≥45%)3,15 in patients who already experienced cardiac arrest (or syncope of arrhythmic
origin), the consensus is that all such patients should undergo
Viskin
placement of an implantable cardioverter defibrillator
(ICD).18 Thus, there is no reason to perform EPS in symptomatic patients with Brugada syndrome unless one is willing
to try EPS-guided quinidine therapy.19,20
The remaining and most controversial question is related
to the value of EPS in predicting outcome in asymptomatic
patients. This is not a trivial question. Increased awareness of
the ECG of this disorder is leading to more frequent referral
of asymptomatic patients: 59%3 and 72%2 of the patients in
the latest series had no previous symptoms.
Positive predictive value
Brugada et al.3 report the outcome of 263 asymptomatic
patients who underwent EPS because they had a Brugadatype ECG: 91 (35%) of the asymptomatic patients had inducible VF and 11 (12%) of them eventually had spontaneous VF. On the other hand, a very large number of patients
(172 asymptomatic patients) had negative EPS and only 2
(1%) subsequently developed arrhythmias.3 The relatively
low 12% positive predictive value is not surprising given that
the patients are otherwise healthy. Although most physicians
and patients probably would be willing to intervene with ICD
placement18 (or quinidine)20 to prevent a 12% risk of cardiac
arrest in a young patient, one should attempt to identify those
patients at higher risk to reduce the number of unnecessary
ICD implantations. One would assume that the asymptomatic
patients who also have a history of familial sudden death are
at greater risk. Priori et al.2 reported a 33% incidence of
spontaneous VF among asymptomatic patients with a positive family history and inducible VF. Whether the presence
of “high-risk” ECG criteria21,22 will increase the predictive
value of EPS remains to be established. Other authors have
reported lower positive predictive values (range 0%14,17 to
8%2 ) for EPS in asymptomatic patients. It should be noted
that the number of patients included in all of those studies
combined is considerably smaller than the number of patients
reported by Brugada et al.3
Negative predictive value
Priori et al.2 reported that 7% of asymptomatic patients
with a negative family history and negative EPS eventually
had a cardiac arrest, but this figure was derived from a single calamity out of 14 cases. The fact that only 2 (1%) of the
172 asymptomatic patients with negative EPS in the report by
Brugada et al.3 developed VF represents the “best news.” The
follow-up period of noninducible patients was shorter than
that of inducible patients (29 vs 36 months), and it is possible
that the negative predictive value of EPS will diminish (as
more patients develop VF) with longer follow-up periods. In
fact, a close look at the survival curve provided by Brugada
et al.3 (their Fig. 1) suggests that this might be the case. Although the survival curves of inducible versus noninducible
patients continued to diverge after 10 years (meaning that
the excellent prognostic value of EPS persisted), the negative predictive value of EPS became unacceptable in the long
term as almost 30% of asymptomatic patients with negative
EPS still followed by 100 months developed cardiac arrest.
These survival curves should be viewed with caution because
the number of patients followed for >70 months was small.
Nevertheless, we are reminded that the Brugada syndrome
is a newly described entity and, therefore, follow-up periods
are still short. Although the Brugada syndrome is a genetic
Editorial Comment
459
disorder (present since birth), the majority of patients who actually develop symptoms do so only in adulthood. Therefore,
one should be careful about concluding anything about the
value of EPS for predicting a first event in asymptomatic patients when the mean follow-up is less than 3 years (34 ±
44 months2 and 31 ± 41 months3 ), especially when the
asymptomatic patients included are younger than those with
symptoms. In a recent series reporting a low predictive value
for EPS,14 the age of the asymptomatic patients—even at the
end of the follow-up period—was still younger than the age
recorded for symptomatic patients at the onset of the study.
Time will tell the real prognostic role of EPS in the Brugada
syndrome, but in view of the lethality of this disorder, patients (and physicians) should be willing to intervene based
on a certain degree of uncertainty.
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