Address for correspondence:
Takeshi Tsuchiya, M.D., From Division of Cardiology, Hakuaikai
Hospital, Konya-ima machi 4-3, Kumamoto, 860-0092 Japan. E-mail: tsuchiya@s1.kcn-tv.ne.jp
Brugada syndrome is a unique form of
idiopathic ventricular fibrillation (VF), and is characterized by an
ECG pattern with right bundle branch block (J wave), ST-segment
elevation and terminal T-wave inversion in leads V1 through V3 1,2,3,4,5,6,7,8,9,10. It accounts for
approximately 20% of all cases of sudden cardiac death in patients with
structurally normal hearts and appears to be more frequent in Southeast
Asia than in other regions5.
To date, the only established therapy for preventing sudden cardiac
death due to VF in this disease is an implantation of an implantable
cardioverter defibrillator (ICD)1,2,3,4.
Although there is no room for discussion regarding the excellent and
uniform efficacy of ICDs for terminating VF, the effect is confined to
the termination of VF, and ICDs cannot contribute to the prevention of
VF. Therefore, there are some concerns regarding ICD
therapy. The first is electrical storm associated with VF or
polymorphic ventricular tachycardia, which is defined as frequent
appropriate ICD shock deliveries for ventricular tachyarrhythmias of >3
times over 24 hours. Chalvidan et al. 10,
reported a patient who suffered from incessant VF episodes (electrical
storm) and became near-fatal, but subsequently fully recovered.
The second is ICD related complications including lead dislodgment,
inappropriate shock delivery, infection requiring ICD removal and so on
11,12,13.
The third is the indication of ICDs for infant cases of Brugada
syndrome, in which the size of the ICD is too large for
implantation 11,12,13.
A new therapy other than ICD implantation to overcome these concerns
seems to be urgent.
Cellular mechanism
Brugada syndrome is suggested to
be a primary electrical disease, and two dozen mutations of the cardiac
sodium channel gene “SCN5A”, which lead to a loss of the channel
function, have been found in about 15-20 % of patients with Brugada
syndrome, and an autosomal mode of transmission has been
demonstrated 4,5,6,7,8.
The ionic and
cellular basis for the ST-segment elevation in Brugada syndrome is
hypothesized to be due to an outward shift in the balance of the
membrane ionic currents at the end of phase 1 and phase 2 of the action
potential, in which an outward current is mainly due to the activation
of the transient outward current (Ito), and the inward
current is mainly due to
the activation of an inward calcium current (ICa) and an
inactivating component of an inward sodium current (INa).
The net outward shift of this current balance leads to a loss of the
dome or phase 2 of the
action potential. Such changes may affect the right ventricular
epicardium more markedly than the endocardium and produce a marked
voltage gradient in the membrane potential between the end- and
epi-cardial sides of the
right ventricular muscle fibers during the phase 2 (a change
corresponding to the characteristic ST-segment elevation in V1 through
V3 in the ECGs of
Brugada Syndrome4,6,7,8.
The loss
of the action potential dome in the epicardium but not in the
endocardium results in the development of a marked transmural
dispersion of repolarization and refractoriness, responsible for the
development of a vulnerable window during which a premature impulse or
extrasystole can induce a reentrant arrhythmia. Because the loss
of the action potential dome in the epicardium
is usually heterogeneous, it leads to the development of epicardial
dispersion
of repolarization and refractoriness. Conduction of the action
potential
dome from sites at which it is maintained to sites at which it is lost
causes local re-excitation via a phase 2 reentry mechanism, leading to
the development of a very closely coupled extrasystole, which captures
the vulnerable window across the wall, thus triggering a circus
movement
reentry in the form of VT or VF 4,6,7,8.
In patients
with Brugada syndrome, an abnormal spike-and-dome configuration of the
epicardial monophasic action potentials (MAPs) obtained from the right
ventricular
outflow tract, may create a prominent J point elevation14. Furthermore, a MAP and repolarization
of longer duration in the epicardium than in the endocardium, resulting
from a delayed dome formation, suggests a reversal current flow during
phase 3 of the action potential. The longer duration of the
action potential in the epicardium may have created the typical
terminal T-wave inversion observed in Brugada syndrome 14.
Antelevitch et al., 4,7,8
suggested
that the arrhythmogenic substrate arises when a further shift in the
balance
of the current leads to a loss of the action potential dome at some
epicardial
sites but not others. Actually, Nagase et al.15,
reported that a delayed potential was observed in the epicardial
electrogram
of the right ventricular outflow tract but not others, which was
considered
to be the second upstroke of the epicardial action potential
(epicardial
echo beat) generated by local and concealed phase 2 reentry 16.
Pharmacological therapy
based on the cellular mechanism
A variety of pathophysiologic
conditions and pharmacologic interventions, which either increase the
membrane outward currents or reduce the inward currents should produce
a loss of the action potential dome
in the right ventricular epicardium and facilitate the occurrence of
VF. Phase 2 of the action potential could be abolished by
reducing the INa as predicted by the ST-segment elevation
after the application of Class
IC agents and restored by increasing the inward current, e.g., by
enhancing the ICa or by decreasing the outward Ito
current, e.g., by the application of quinidine as reported 4,7,8.
There are many pharmacologic therapies that have been clinically
examined. Class IC agents are clearly contraindicated because theses
drugs reduce the INa as mentioned above 17.
Class IA agents, including procainamide and disopyramide, are
contraindicated since these drugs strongly depress the INa
but only mildly affect Ito, and are well known to exacerbate
the ST elevation and occurrence of VF4,7,8,9. Class IB agents, which lack an Ito
blocking effect and display little use-dependence owing to a rapid
dissociation from the sodium channel, are not at all effective in the
normalization
of the ST-segment elevation 13.
Both
amiodarone and beta-blockers are also shown to be ineffective4,7,8,9.
Because the
presence of a prominent Ito is at the heart of the
mechanism underlying Brugada syndrome, any agent that blocks this
current in the heart is likely to be protective 4,6,7,8.
At the time of writing this review, there was no drug developed that
could cardio-selectively block the Ito. An isolated
case report showed that DDD-pacing at a relatively high rate is
effective in decreasing the Ito (and hence suppressing
VF), possibly because
the repriming time of the Ito channels is reported to be
fairly long 18. There is, however,
no systematic study to examine the effect of relatively high rate
pacing on the prevention of VF. Quinidine, another class IA
agent, has been shown to directly inhibit Ito in addition to
a secondary inhibition due to an
increase in the heart rate by a vagolytic action4,7,8.
Experimental studies have shown quinidine to be effective in restoring
the epicardial action potential dome, thus normalizing the ST-segment
and preventing phase 2 reentry and polymorphic VT in experimental
models of Brugada syndrome 7,8.
Belhassen et
al. 11, reported very important and
provocative observations regarding the effect of quinidine on the
prevention of VF in 34 consecutive patents with idiopathic VF, 5 of
whom met the diagnostic criterion of Brugada syndrome. In the
study, electrophysiologic study (EP)-guided therapy with class IA
agents (mainly quinidine) was performed. These agents effectively
prevented the induction of sustained polymorphic ventricular
tachycardia (SPVT) and/or VF in 26 of 27 patients (96%), in all of whom
SPVT or VF was induced in the baseline EP studies. Of the
23 patients treated with these medications, no patients died or had a
sustained
ventricular arrhythmia during a mean follow-up period of 9.1+5.6
years.
They concluded that EP-guided therapy with class IA agents (mainly
quinidine)
was a reasonable, safe and effective approach for the long-term
management
of patients with idiopathic VF including Brugada syndrome.
Although
there have been no randomized placebo-controlled prospective studies of
EP-guided
quinidine therapy, I think that quinidine is a promising antiarrhythmic
agent.
The experimental antiarrhythmic agent, tedisamil, with its potent Ito,
among other outward current, blocking action, has been suggested as a
therapeutic
candidate8.
This drug may be more potent than quinidine because it lacks the
relatively strong inward current blocking actions of quinidine.
There are,
however, some limitations in using quinidine for the prevention of VF
in patients with Brugada syndrome. There are some risks with
antiarrhythmic agents with regard to the potential for a loss of
efficacy or proarrhythmic effects under a number of conditions
including hypokalemia, hypomagnesemia, bradycardia, therapy with other
agents that alter repolarization, metabolic inhibitors, and changes in
myocardial substrates. Furthermore, quinidine is known to have
other non-cardiac side effects including abdominal cramping, diarrhea,
cinchonism, which consists of decreased hearing, tinnitus, and blurred
vision, thrombocytopenia, lupus syndrome, and anticholinergic
side effects including a dry mouth, urinary retention and so
on. These side effects may affect the compliance with
the drug 11.
The anticholinergic action on the heart might contribute to the anti-VF
effect of the drug by increasing the heart rate 13.
Another
approach for the prevention of VF in patients with Brugada syndrome is
to increase the ICa by promoting an intracellular level of
cyclic-AMP. Intravenous isoproterenol administration is
especially known to be effective in suppressing ST elevation in leads
V1 through V3 in Brugada syndrome
patients, and to restore the action potential dome in models of this
syndrome 4,7,8
and
patients with Brugada syndrome 9,19,
because it markedly increases the ICa secondary to an
elevation in the intracellular level of cyclic-AMP.
Cilostazol, a
new oral phosphodiesterase type-III inhibitor is primarily used as a
strong antiplatelet agent, but has been shown to increase the ICa
and modestly increase the heart rate as well as contractile function.
All these effects are secondary to an increased level of the cyclic-AMP
caused by an inhibition of phosphodiesterase type-III activity, in
guinea-pig ventricular myocytes and papillary muscles 20. From these findings, it is reasonable
to expect that this drug has an antiarrhythmic efficacy for preventing
the VF often observed in patients with Brugada
syndrome, because it increases the ICa due to inhibition of
the phosphodiesterase activity in the ventricular myocytes and
decreases the Ito due to an increased heart rate which again
is secondary to an increased ICa in the sinus node. I
recently presented a case of a 67-year-old man with Brugada syndrome,
in whom daily episodes of ventricular fibrillation occurred early in
the morning for 4 days straight and the VF was completely prevented by
an oral administration of cilostazol 21.
This effect was confirmed by the on-and-off challenge test, in which
the discontinuation of this drug resulted in recurrence of VF, and the
resumption of this drug again prevented the VF.
This effect may be related to the suppression of the Ito
secondary
to an increase in the heart rate and/or increase in the ICa
due
to an elevation in the intracellular cyclic-AMP concentration via
inhibition of phosphodiesterase activity. I performed a long-term
follow-up with cilostazol in three patients (the follow-up periods were
12, 26 and 32 months, respectively), and in all an ICD was implanted
for the termination of spontaneous VF. In all the patients
several VF episodes were observed over a one year period prior to the
cilostazol, no VF was recorded by the ICD memory and the patients were
free from symptoms under 100-200 mg/day of cilostazol. Further
study is needed to examine the effectiveness of the drug.
Practical way to use
anti-VF drugs
In patients who undergo aborted
sudden cardiac death or syncope of unknown origin (symptomatic Brugada
syndrome), no one argues that the implantation of an ICD is the
first-line therapy regardless of the findings of the EP study.
For those patients, drug therapy plays not a contradictory but a
complimentary role to the ICD by reducing the number
of ICD shock deliveries. Prevention of VF contributes to the
improvement
in the quality of life of the patients by avoiding uncomfortable ICD
shock
deliveries.
As mentioned
above, Belhassen et al. 11, performed
EP-guided medical therapy in 34 patients with idiopathic VF, in 5 of
whom the criterion of Brugada syndrome were fulfilled, and reported
excellent long-term results. Although medical therapy requires markers
that can accurately predict the preventive effect of VF over a
long-term period, there, however, seems to be no reliable marker.
An EP study is usually used to examine the
preventive effects of antiarrhythmic agents on sustained ventricular
tachycardia
in patients with structural heart disease, whereas the prognostic value
of
the EP study in predicting life-threatening events in Brugada syndrome
is
still controversial. Brugada et al., 3
suggested that
among the asymptomatic patients, the inducibility of VT during the EP
study
might be a prognostic marker of risk. Studies by Priori et al., 22 and Kanda et al., 23
failed to find an association between the inducibility and recurrence
of VT/VF in patients with Brugada syndrome regardless of whether it was
symptomatic or asymptomatic. As Belhassen suggested 13, the difference might be due to the VF
induction protocol in the EP study, in which Belhassen et al., used a
stimulus current intensity of five times the diastolic threshold along
with the use of repetition of double and triple extrastimulation at the
shortest coupling intervals that resulted in ventricular capture.
Further appropriate clinical trials are needed to clarify this issue.
In patients
with asymptomatic Brugada syndrome who are family members of
symptomatic Brugada syndrome patients, the same strategy as that for
the symptomatic Brugada syndrome patients should be considered 2,3,4. In
another asymptomatic-patient group in whom an ECG that discloses the
Brugada sign is performed for routine reasons such as a workup prior to
surgery or sport license or screening for insurance, risk
stratification to find the patients at high risk is needed because in
most cases these patients have a benign prognosis3,22,23. Antzelevitch et
al. 4,
recommended that all asymptomatic patients with the Brugada sign should
undergo an EP study for risk stratification, and, if inducible, an ICD
should be implanted since Brugada et al.3,
reported that an overall 8% life-threatening event rate was found in
initially asymptomatic patients. Belhassen et al.,13
suggested that EP study-guided quinidine therapy might become an
alternative to ICD therapy for prophylaxis of arrhythmic events in
these patients. Further appropriate clinical trials are needed.
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