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.
- Copyright © 1998 by American Heart Association
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.
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.
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.
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 malesR1 R2 R3 and the link between the “nocturnal sudden death syndrome” and “Brugada sign.”R4 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,R4 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 alR3 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 BrugadaR5 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,R6 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,R7 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⇑) 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.
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⇑. 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.
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 alR8 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 BrugadaR5 reported that 2 of 11 patients receiving pharmacological therapy, who were receiving β-blockers, died suddenly. In those cases, just as we proposed as a possibility for the cases in our report, the β-blocking effect of the drugs might have exacerbated the VF, resulting in sudden death. Furthermore, Brugada and BrugadaR5 went on to discuss the possible role of M cells in this syndrome, and Yan and AntzelevitchR9 reported that J waves are caused by the heterogeneous distribution of the action potentials in the endocardium and epicardium. Litovsky and AntzelevitchR10 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 uncouplingR11 and anisotropic conductionR12 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.R13 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.
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