Sourasky-Tel Aviv Medical Center,
Tel Aviv, Israel
To the Editor:
In the May 6, 1997, issue of Circulation, Kasanuki et
al1 reported a "new mechanism of idiopathic
ventricular fibrillation (VF)," ie, "increased vagal
activity," in patients who had VF in the absence of organic heart
disease and had the "Brugada sign" ("rSR' and ST elevation" in
the precordial leads).2 Before we accept
their proposed mechanism as "new" and their patient characteristics
as "different," a few observations are pertinent:
1. The patients described were (presumably) of Asian origin; almost all
(five of six) were males; and all the male patients had VF while
sleeping or resting (at an unspecified time of the day). Yet the
literature on the syndrome of nocturnal sudden death in southeast Asian
males3 4 5 was ignored by the authors and by the
reviewers of this article. It is important to point out this omission
in view of some evidence linking the "nocturnal sudden death
syndrome" and the "Brugada sign."6
2. Our own work7 was quoted to support the
authors' statement that in idiopathic VF, "ventricular
arrhythmias are exacerbated by psychological and physical
stress." In fact, we have stated that only a minority of patients
with idiopathic VF have symptomatic arrhythmias
during any form of stress.7 8
3. The authors' assertion that "vagal hyperactivity" is the
mechanism underlying the onset of spontaneous VF in their patients is
supported by scarce data: (1) the sinus rate preceding VF was not
reported, and (2) the "abrupt rise in high frequency (HF) values"
during heart rate variability assessment was seen before VF episodes in
only two patients (and the relevant figure in the article shows
convincing HF rises before only one of three VF episodes).
4. Further support for the "vagal hyperactivity" theory proposed by
the authors is interesting but inconclusive. The authors demonstrated
augmentation of the ST segment after intravenous
administration of parasympathomimetic or adrenergic-blocking drugs and
the opposite effects with parasympatholytic or adrenergic
stimulation.1 These results are in accordance
with the observations reported by Miyazaki et al9
in four patients with the Brugada syndrome. However, neither Kasanuki
et al1 nor Miyazaki et al9
controlled for heart rate with atrial pacing during performance
of these autonomic tests. Thus, the possibility that the changes in ST
segments observed are merely a function of heart rate cannot be
excluded. Moreover, the augmentation of ST segment observed with
autonomic manipulation may or may not be related to arrhythmogenesis.
Similarly, the "facilitation" and "exacerbation" of VF
induction after administration of edrophonium (two patients) or
propranolol (two patients) must be viewed with reservations
because of the small number of patients studied, the definition of
"exacerbation" used, and the limited reproducibility of programmed
ventricular stimulation reported by the
authors.1 Thus, more data are needed before we
can draw any conclusions regarding the role of increased vagal activity
in idiopathic VF.
References
1.
Kasanuki H, Ohnishi S, Ohtuka M, Matsuta N, Nirei T, Isogai
R, Shoda M, Toyoshima Y, Hosoda S. Idiopathic ventricular
fibrillation induced with vagal activity in patients without obvious
heart disease. Circulation. 1997;95:2277–2285.
2.
Brugada P, Brugada J. Right bundle branch block, persistent ST
segment elevation and sudden cardiac death: a distinct clinical and
electrocardiographic syndrome—a multicenter report. J Am
Coll Cardiol. 1992;20:1391–1396.[Abstract]
3.
Otto CM, Tauxe RV, Cobb LA, Greene HL, Gross BW, Werner JA,
Burroughs RW, Samson WE, Weaver WD, Trobaugh GB.
Ventricular fibrillation causes sudden death in Southeast
Asian immigrants. Ann Intern Med. 1984;101:45–47.
4.
Hayashi M, Murata M, Satoh M, Aizawa Y, Oda E, Oda Y, Watanabe
T, Shibata A. Sudden nocturnal death in young males from
ventricular flutter. Jpn Heart J. 1985;26:585–591.[Medline]
[Order article via Infotrieve]
5.
Baron RC, Thacker SB, Gorelkin L, Vernon AA, Taylor WR, Choi K.
Sudden death among Southeast Asian refugees: an unexplained nocturnal
phenomenon. JAMA. 1983;250:2947–2951.
6.
Nademanee K, Veerakul G, Nimmannit S, Chaowakul V, Bhuripanyo
K, Likittanasombat K, Tungsanga K, Kuasirikul S, Malasit P,
Tansupasawadikul S, Tatsanavivat P. Arrhythmogenic marker for the
sudden unexpected death syndrome in Thai men. Circulation. 1997;96:2595–2600.
7.
Viskin S, Belhassen B. Idiopathic ventricular
fibrillation. Am Heart J. 1990;120:661–671.[Medline]
[Order article via Infotrieve]
8.
Belhassen B, Viskin S. Idiopathic ventricular
tachycardia and fibrillation. J Cardiovasc
Electrophysiol. 1993;4:356–368.[Medline]
[Order article via Infotrieve]
9.
Miyazaki T, Mitamura H, Miyoshi S, Soejima K, Aizawa Y, Ogawa
S. Autonomic and antiarrhythmic drug modulation of ST segment elevation
in patients with Brugada syndrome. J Am Coll Cardiol. 1996;27:1061–1070.[Abstract]
Department of Cardiology,
The Heart Institute of Japan,
Tokyo, Japan
We thank Drs Viskin and Belhassen for their thoughtful comments
and welcome this opportunity to clarify some of the points made in our
article (Circulation. 1997;95:2277–2285) and to further
support our belief that in at least some cases of Brugada syndrome,
vagal activity may play a role in VF occurrence.
1. Drs Viskin and Belhassen were concerned that we ignored the
literature on the syndrome of nocturnal sudden death in southeast Asian
and Japanese males1 2 3 and the link between the
"nocturnal sudden death syndrome" and "Brugada
sign."4 In our article, we proposed a new
possible mechanism for VF occurrence involving vagal activity in a
subgroup of patients with Brugada syndrome. Regretfully, when we wrote
this paper, we were not aware of the abstract on sudden unexpected
death syndrome in young Thai men written by Nademanee et
al,4 and we thank Drs Viskin and Belhassen for
bringing this to our attention. Their data were of great interest to
us; in 9 of their 17 patients, they noted right bundle-branch block and
ST-segment elevation. Therefore, these Brugada cases, like ours, may
also possibly have a vagally influenced mechanism of induction. We
would be very interested in learning more about their cases. The VF
experienced by their remaining 8 patients, although not the Brugada
type, may also be induced by vagal activity; however, that remains to
be determined. Furthermore, in the article by Hayashi et
al3 describing the nocturnal sudden death
syndrome Pokkuri in Japanese males (by definition, Japanese are not
considered southeast Asian, yet this may suggest a racial tendency for
this nocturnal sudden death in Asians in general), although there were
no late r' waves and ST elevation during ECG monitoring, we cannot rule
out that their cases were of the Brugada type because as
Brugada5 and we pointed out, these ECG changes
may occur only transiently. Therefore, vagal activity may be involved
in the mechanism of one subgroup of patients with Pokkuri disease.
One of the points that we had hoped to have made in our article was
that we feel that idiopathic VF subjects should be classified according
to the mechanism of occurrence, particularly whether it is induced by
vagal hyperactivity or by sympathomimetic tone
(catecholamine induced). Perhaps in the future we will be
able to show that many of these southeast Asian and Japanese cases are
a common type and have a vagal hyperactivity–induced mechanism.
2. We apologize if we misinterpreted Drs Viskin's and
Belhassen's data and gave them the impression that they meant they
implied that there are a fair number of cases in idiopathic VF in which
the ventricular arrhythmias are exacerbated by
psychological and physical stress. In fact, we meant only to imply that
such cases have been described, and in the article by Belhassen et al
on idiopathic ventricular tachycardia and
VF,6 they do, as they said, state that "as a
rule, episodes of VF or syncope are not preceded by physical or
emotional stress." However, in their article on idiopathic
VF,7 they state concerning "the circumstances
preceding the occurrence of VF based on the data recorded from 40
patients ... Psychological stress preceded VF in nine (22%)
patients, while physical exertion was involved in six (15%)."
Therefore, we feel safe in assuming that there actually are at least a
small number of cases in which psychological and physical stress are
assumed to exacerbate ventricular arrhythmias in
idiopathic VF.
3. Concerning their claim that our assertion that vagal hyperactivity
was a possible mechanism underlying the onset of spontaneous VF in our
patients was based on scarce data, in particular not reporting the
sinus rate just preceding the VF, and that the abrupt rise in the
high-frequency (HF) values seen before VF episodes was observed in only
two cases (with the figure in our article showing a convincing rise in
HF before only one of three VF episodes), we documented this in two of
our cases and agree with Drs Viskin and Belhassen that these two cases
are far too few. As you know, idiopathic VF itself is very rare, and it
is very difficult to be able to actually record the onset of the VF
episodes; therefore, there is very little that we can do to correct
that lack of data. However, we have added the ECG (Fig 1
Concerning this, there is one thing we would like to make clear that we
realize we did not do adequately in my article. That is, it is not only
the abrupt rise in vagal activity that is important for the occurrence
of this VF, but it is also a sudden decrease in sympathetic activity
after a period of elevated activity and/or fluctuation occurring in
combination with this sudden vagal rise that induces this VF, as shown
in Fig 3
4. Drs Viskin and Belhassen expressed that they feel our support for
the vagal hyperactivity theory is inconclusive. They went on to say
that because neither we nor Miyazaki et al8
controlled for heart rate with atrial pacing during autonomic testing,
we cannot exclude the possibility that the changes in ST segments we
observed were merely a function of heart rate. We agree with these
doctors; however, although we did not perform atrial pacing during drug
administration, we did perform atrial pacing when our subjects
exhibited late r' and ST elevation from a range of rates between 70 and
150 paces per minute. Throughout this range, only very minor changes in
the late r' and ST elevation were observed. Therefore, we believe that
heart rate had only a minor effect on the late r' and ST elevation.
They also stated that the augmentation of the ST segment observed with
autonomic manipulation may or may not be related to arrhythmogenesis.
This may be true; however, we believe that there is a possible
relationship between augmentation of the late r'/ST elevation and
arrhythmogenesis because this augmentation was always observed in our
cases just before the onset of VF induced by hyperventilation and just
before spontaneous VF episodes. Furthermore, we also observed
augmentation of late r'/ST elevation before VF episodes induced by
pacing after the administration of edrophonium. Therefore, although
further research is needed to confirm this, we believe a possible
relationship does exist, as we stated.
In regard to their statements concerning our observations that the
induction of VF was "facilitated" and "exacerbated" after the
administration of edrophonium (two patients) and
propranolol (two patients) (that they should be viewed with
reservations due to the small number of patients), our definition of
"exacerbation," and the limited reproducibility by programmed
ventricular stimulation, we partially agree. We agree that
the patient number was small; however, we feel our definition of
"exacerbation" was adequate. In two patients in the control study,
VF was not inducible even with triple extrastimuli from the right
ventricular outflow tract or right ventricular
apex. However, after the administration of edrophonium, VF was easily
induced with triple extrastimuli. Furthermore, in the control group, VF
was induced only by triple extrastimuli; however, after the
administration of propranolol, VF was easily induced by
single extrastimuli. Therefore, we concluded that edrophonium and
propranolol facilitated and exacerbated the induction of
VF. The reproducibility of this was very high on the days closest to
the day of spontaneous VF occurrence. It was possible to induce the VF
over and over again on those days. However, on days distant from the
day of spontaneous VF occurrence, VF could not be induced by any
method. Therefore, we feel our explanation of the "reproducibility"
in our article was not adequate and that the readers may have
misinterpreted it. In the article, we meant that the day-to-day
reproducibility was poor, but on days in which VF could be induced, the
reproducibility was high. We apologize for any confusion we may have
caused.
After the submission of our paper, Brugada and
Brugada5 reported that 2 of 11 patients receiving
pharmacological therapy, who were receiving ß-blockers, died
suddenly. In those cases, just as we proposed as a possibility for the
cases in our report, the ß-blocking effect of the drugs might have
exacerbated the VF, resulting in sudden death. Furthermore, Brugada and
Brugada5 went on to discuss the possible role of
M cells in this syndrome, and Yan and
Antzelevitch9 reported that J waves are caused by
the heterogeneous distribution of the action potentials in
the endocardium and epicardium. Litovsky and
Antzelevitch10 further reported that
acetylcholine facilitates the loss of the action potential dome by
suppressing ICa, resulting in ST elevation
and phase 2 reentry. These mechanisms may possibly explain the ST
elevation observed in our cases. Although previous reports have
stressed that the mechanism of the ST elevation is mainly abnormal
repolarization, the role of conduction delay in this mechanism has not
yet been elucidated. However, what we would like to stress is the
following: (1) when late r'/ST elevation was not present, late
potentials on the signal-averaged ECG were positive in some of our
cases; (2) when late r'/ST elevation was present, late potentials
were positive in all our cases, and the late potentials were
attenuated; (3) late r'/ST elevation was attenuated just before the
onset of spontaneous or induced VF and immediately after VF; and (4)
vagal hyperactivity and decreased sympathetic tone induced the
attenuation of the late r'/ST elevation.
In other words, although we feel that abnormal repolarization plays a
role in the mechanism of the ECG findings and VF occurrence in our
cases, we believe that it is abnormal depolarization that plays the
major role. Furthermore, on the basis of the findings of the body
surface map, the conduction delay is thought to be localized in the
right ventricular anterior wall and right
ventricular outflow tract. The mechanism of conduction
delay with ST elevation might be caused by the attenuation of cellular
uncoupling11 and anisotropic
conduction12 via gap junctions in abnormal cells
of the epicardium. Concerning the effect of the autonomic nervous
system on the gap junctions, the conductance of the gap junction might
be regulated by cAMP-dependent
phosphorylation.13 Furthermore,
one more possible mechanism is that there are partially depolarized
cells, the so-called "ICa-dependent
nodelike cells," in the epicardium, and acetylcholine suppresses the
conduction and shortens the action potential duration of these cells.
Therefore, in order to elucidate the exact mechanism responsible for
the ECG findings and VF occurrence in our study, further investigation
is required.
Once again we thank Drs Viskin and Belhassen for their thorough
critique of our article and hope that we may have clarified, at least
in part, some of their questions. We hope in the future we will have
the opportunity to discuss this topic further with them. We also thank
the editor for the opportunity to defend our article.
References
1.
Otto C, Tauxe R, Cobb L, Greene H, Gross B, Werner J,
Burroughs R, Samson WE, Weaver WD, Trobaugh GB. Ventricular
fibrillation causes sudden death in Southeast Asian immigrants.
Ann Intern Med. 1984;10:45–47.
2.
Baron R, Thacker S, Gorelkin L, Vernon A, Taylor W, Choi K.
Sudden death among Southeast Asian refugees: an unexplained nocturnal
phenomenon. JAMA. 1983;250:2947–2951.
3.
Hayashi M, Murata M, Satoh M, Aizawa Y, Oda E, Oda Y,
Watanabe T, Shibata A. Sudden nocturnal death in young males from
ventricular flutter. Jpn Heart J. 1985;26:585–591.
4.
Nademanee K, Veerakul G, Nimmanit S, Pungsanga K, Chaowakul
V, Malasit P, Tansupasawadikul S, Kungboonkrong V, Bhuripanyo K. Right
bundle branch block and ST-elevation, an arrhythmogenic marker for
sudden unexpected death syndrome in young Thai men.
Circulation. 1995;92(suppl I):I-335. Abstract.
5.
Brugada J, Brugada P. Further characterization of the
syndrome of right bundle branch block, ST segment elevation, and sudden
cardiac death. J Cardiovasc Electrophysiol. 1997;8:325–331.[Medline]
[Order article via Infotrieve]
6.
Belhassen B, Shapiral I, Shoshani D, Paredes A, Miller H,
Laniado S. Idiopathic ventricular fibrillation:
inducibility and beneficial effects of class I antiarrhythmic agents.
Circulation. 1987;75:809–816.
7.
Belhassen B, Viskin S. Idiopathic ventricular
tachycardia and fibrillation. J Cardiovasc
Electrophysiol. 1993;4:356–368.
8.
Miyazaki T, Mitamura H, Miyoshi S, Soejima K, Aizawa Y,
Ogawa S. Autonomic and antiarrhythmic drug modulation of ST segment
elevation in patients with Brugada syndrome. J Am Coll
Cardiol. 1996;27:1061–1070.
9.
Yan GX, Antzelevitch C. Cellular basis for the
electrocardiographic J wave. Circulation. 1996;93:372–379.
10.
Litovsky SH, Antzelevitch C. Differences in the
electrophysiological response of canine
ventricular subendocardium and subepicardium to
acetylcholine and isoproterenol: a direct effect of acetylcholine in
ventricular myocardium. Circ Res. 1990;67:615–627.
11.
Tan RC, Osaka T, Joyner RW. Experimental model of
effects on normal tissue of injury current from ischemic
region. Circ Res. 1991;69:965–974.
12.
Spach MS, Dolber PC. Abnormalities in depolarization mediating
arrhythmogenic mechanisms: focus on anisotropy and reentry: In: Singh
BN, Wellens HJJ, Hiraoka M, eds. Electropharmacological Control
of Cardiac Arrhythmias: To Delay Conduction or to Prolong
Refractoriness. Mount Kisco, NY: Futura Publishing Co Inc;
1994:83–99.
13.
Spray DC, Burt JM. Structure-activity relations of the cardiac
gap junction channel. Am J Physiol. 1990;258(Cell
Physiol 27):C195–C205.
© 1998 American Heart Association, Inc.
Correspondence
Increased Vagal Activity in Idiopathic VF
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Figure 1.
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Figure 2.
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Figure 3.
Response
)
below showing the heart rate decreasing just before the third VF
episode in case one and a Figure (Fig 2)
showing the heart rate at every 30 seconds during the last 2 minutes
just before all VF episodes. We hope this will further support our
observation that vagal hyperactivity does indeed appear to be the
mechanism involved in this VF, as evidenced in part by the slowing of
the heart rate just before the VF episode. Furthermore, we would like
to emphasize, as we stated in our article, that other than there being
an abrupt rise in the HF before only one (first episode) of three VF
episodes in subject 1, there were similar findings for another two VF
episodes in subject one and the three VF episodes in subject 4. We have
added Fig 3
to show the change in the HF and low frequency/HF every 2 minutes
during the last 20 minutes just before the onset of the second and
third VF episodes in subject 1 and the first and second VF episodes in
subject four. . It is this combination of interplay between the vagal and
sympathetic activity that we would like to stress to you. Since we
began writing the article, my patient population has grown to 12
patients. However, unfortunately, we were unable to capture any further
VF episodes on Holter ECG recordings. Perhaps if the editor
will allow it, in the future we can publish our new autonomic testing
data on this larger group of patients, which will further support our
present paper.
This article has been cited by other articles:
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  G.-X. Yan and C. Antzelevitch Cellular Basis for the Brugada Syndrome and Other Mechanisms of Arrhythmogenesis Associated With ST-Segment Elevation Circulation, October 12, 1999; 100(15): 1660 - 1666. [Abstract] [Full Text] [PDF]
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