Europace Advance Access originally published online on July 17, 2007
Europace 2007 9(10):951-956; doi:10.1093/europace/eum128
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MISCELLANEOUS
Comparison of conduction delay in the right ventricular outflow tract between Brugada syndrome and right ventricular cardiomyopathy: investigation of signal average ECG in the precordial leads
The First Department of Internal Medicine, Niigata University School of Medicine, 1-754 Asahi-machi-dori, Niigata, 951-8510, Japan
Manuscript submitted 2 May 2007. Accepted after revision 8 June 2007.
* Corresponding author. Tel: +81 25 227 2185; fax: +81 25 227 0774. E-mail address: chimiri{at}med.niigata-u.ac-jp
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Abstract |
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Background In both Brugada syndrome (BS) and arrhythmogenic right ventricular cardiomyopathy (ARVC), electrical abnormalities in the right ventricular outflow tract (RVOT) are important for arrhythmogenesis.
Objectives The aim of this study was to compare conduction delay in the right ventricular in BS with that in ARVC using the signal-averaged electrocardiogram.
Methods Twenty patients with BS (18 men and 2 women; 55 ± 12 years old; 9 symptomatic and 11 asymptomatic) and eight patients with ARVC (six men and two women; 53 ± 16 years old) were included. We assessed the presence of late potentials (LPs) and the filtered QRS duration (fQRSd) in V2 and V5 using a high-pass filter of 40 Hz (fQRSd:40) and 100 Hz (fQRSd:100).
Results In ARVC, there was no significant difference in fQRSd:40 between V2 and V5 (158 ± 19 vs. 145 ± 17 ms, respectively): however, in BS, fQRSd:40 in V2 was significantly longer than fQRSd:40 in V5 (147 ± 15 vs. 125 ± 10 ms, P < 0.001). In ARVC, there was no significant difference between fQRSd:40 and fQRSd:100 in V2 and V5 (158 ± 19 vs. 142 ± 23 ms and 145 ± 17 vs. 132 ± 9 ms, respectively). In contrast, in BS, fQRSd:100 was significantly shorter than fQRSd:40 in V2 (110 ± 8 ms vs. 147 ± 15, P < 0.001). The relative decrease in fQRSd:100 compared with fQRSd:40 in V2 was significantly greater in BS than in ARVC.
Conclusion The dominant prolongation of the fQRSd in the right precordial lead in BS was different from the characteristics of ARVC, which may be caused by the conduction delay due to fibro-fatty replacement in RV.
Key Words: Brugada syndrome, ARVC, Signal-averaged ECG, RV outflow tract, Delayed potential
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Introduction |
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Brugada syndrome (BS) is characterized by ST-segment elevation in the right precordial leads associated with ventricular fibrillation (VF). The pattern of the electrocardiogram (ECG) is augmented by sodium channel blockers.1
–3 It has been suggested that loss of the action potential dome in the subepicardial action potential in the right ventricular outflow tract (RVOT) results in phase 2 re-entry and polymorphic ventricular arrhythmias, and these have been demonstrated in an animal model.4–7
Ventricular fibrillation can often be induced by programmed electrical stimulation during an electrophysiological study (EPS),8,9 especially from the RVOT.10 Furthermore, the body surface map or the signal-averaged ECG (SAECG) has shown delayed activation of the RVOT in BS,11,12 which may play an important role in arrhythmogenesis. We also recently reported that the dominant prolongation of the filtered QRS duration (fQRSd) in the right precordial leads may be related to the risk of arrhythmic events in BS.13
Some investigators consider that BS is due in part to RV cardiomyopathy, because morphological and/or histological abnormalities are found in some patients with BS.14,15 However, structural anomalies are usually not detected by routine imaging and endomyocardial biopsy.16 Brugada syndrome may be a primary electrical disease, and this concept is strongly supported by the finding that 
30% of patients have a mutation in SCN5A gene. Arrhythmogenic right ventricular cardiomyopathy (ARVC) often shows a conduction delay in the right ventricle (RV), especially the right precordial leads in the surface ECG11,13 with epsilon waves in V1–3. The conduction delay in ARVC is associated with replacement of myocytes by fatty tissue and fibrosis in the RV. The aim of this study was to investigate differences in conduction delay in the RV between BS and ARVC using the SAECG.
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Methods |
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Patients
We studied 20 consecutive patients with BS, who met the diagnostic criteria of the second consensus conference of BS,17
including 9 symptomatic and 11 asymptomatic patients. Eighteen patients were men, and 2 patients were women (mean age: 55 ± 12 years; range: 33–74 years) (Table 1). No patient had a family history of sudden death. No patient from the same family and in six asymptomatic patients, a type-1 ECG was documented at least once, and in another five patients who had a type-2 ECG, pilsicainide (1 mg/kg in 5 min) provoked a type-1 ECG. Routine cardiac examinations, including echocardiography, left and right ventriculography, and coronary angiography were performed in all patients, and they showed no abnormality. In 3 of 20 patients, we obtained informed consent and investigated the mutation in SCN5A gene, and the results were negative (Table 1).
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We also studied eight patients (two women and six men) with ARVC. The mean age was 53 ± 16 years (range: 35–74 years). All patients fulfilled either two major or one major and two minor diagnostic criteria recommended by the Task Force of the European Society of Cardiology.18
All patients had RV dilatation and reduced-wall motion of the RV and ventricular tachycardia (VT) (left bundle branch block type), and three of eight patients had involvement of the left ventricle (LV). The mean ejection fraction of LV (LVEF) was 56 ± 9%. In all patients, T-wave inversion in the precordial leads was observed; however, no patient had a Brugada-type ECG (saddle back or coved type in V1–3) (Table 2).
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Signal-averaged electrocardiogram
Late potentials (LPs) were studied in a standard manner using an SAECG system (FDX-6521, Fukuda Denchi, Japan). Analysis of SAECGs was based on quantitative time-domain measurements of the filtered vector magnitude of the orthogonal leads, x, y, and z. The QRS complexes were amplified, digitized, averaged (200–300 beats/min), and high-pass filtered (40 Hz) with the low-pass cut-off frequency fixed at 250 Hz. Three parameters were obtained using a computer algorithm: the fQRSd (cutoff >114 ms), the root mean square voltage of the last 40 ms (RMS40) of the filtered QRS complex (cutoff <20 µV), and the duration of the low-amplitude signal <40 µV (LAS40) at the terminal portion of the QRS complex (cut-off >38 ms). The SAECG was considered positive for LPs when the two criteria (RMS40 <20 µV and LAS40>38 ms) were fulfilled. Recordings were acceptable when electrical noise was <0.3 µV. The standard precordial leads, V1–6, were amplified, digitized, averaged (200–300 beats/min), and the fQRSd was measured13
with a high-pass filter at 40 Hz (fQRSd:40) and 100 Hz (fQRSd:100). We compared the fQRSd:40 and fQRSd:100 in V2 and V5, which may preferentially reflect the electrical activity of the RVOT and the LV, respectively.
Electrophysiological Study
Electrophysiological study was performed in all patients to evaluate the inducibility of ventricular tachyarrhythmia after a written informed consent was obtained. No patient in either group received any antiarrhythmic drugs. Three quadripolar electrode catheters (6 F multipurpose catheters, USCI, Boston, MA, USA) were placed against the high right atrium, the apex of the right ventricle (RVA) or the RVOT, and the His bundle region through the right femoral vein. The His–ventricular (HV) interval was measured during constant right atrial pacing at a cycle length of 600 ms. Programmed ventricular stimulation was performed using two basic cycle lengths (400 and 600 ms) at the RVA and the RVOT with a 2-ms pulse width at twice the late diastolic threshold. The number of extra stimuli was limited to 3 and the shortest coupling interval of any extra stimulus was limited to 180 ms for safety. Rapid ventricular pacing up to 210 beats/min was performed at the RVA and the RVOT. Stimulation was attempted first at the RVA and then at the RVOT if ventricular arrhythmias were not induced by 1–2 extra stimuli; triple extra stimuli were introduced first from the RVOT, and then from the RVA. The endpoints of programmed ventricular stimulation were either induction of sustained VT/VF or the completion of the programmed stimulation protocol. When sustained monomorphic VT (SMVT) was induced, rapid ventricular pacing at a cycle length of 10–20 ms shorter than the cycle length of the tachycardia was applied in an attempt to entrain the tachycardia. The pacing was repeated after a decrement of the paced cycle length in steps of 10 ms until the SMVT was interrupted or acceleration of the tachycardia occurred.19
Statistical analysis
Quantitative values are expressed as the mean ± SD. Student's t-test for unpaired values was used to compare parameters between the two groups. A P-value of <0.05 was considered significant for all comparisons.
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Results |
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Signal-averaged electrocardiogram
All patients with ARVC were LP positive (Table 2). On the other hand, only 13 of 20 patients (65%) in the Brugada group were LP positive (Table 1). The RMS40 was significantly lower in patients with ARVC than in patients with BS (4.6 ± 2.7 vs. 13.6 ± 8.7 µV, respectively; P < 0.01). The fQRSd:40 in V2 was 158 ± 19 ms in ARVC and was not significantly different from the fQRSd:40 in V2 in BS (147 ± 15 ms). In ARVC, there was no significant difference between fQRSd:40 in V2 and V5 (158 ± 19 vs. 145 ± 17 ms, respectively); however, in BS, fQRSd:40 in V2 was significantly longer than fQRSd:40 in V5 (147 ± 15 vs. 125 ± 10 ms, P < 0.001) (Table 3). In ARVC, there was no difference between fQRSd:40 and fQRSd:100 in V2 or V5 (158 ± 19 vs. 142 ± 23 ms and 145 ± 17 vs. 132 ± 9 ms, respectively). In contrast, in BS, fQRSd:100 was significantly shorter than fQRSd:40 in V2 (110 ± 8 vs. 147 ± 15 ms, P < 0.001) (Table 3). The relative decrease in fQRSd:100 in V2 compared with fQRSd:40 in V2 was significantly greater in BS than in ARVC (Fig. 1). Figures 2, 3, and 4 show typical recordings of the SAECG in the orthogonal leads and the fQRSd from a BS (Case 6 in Table 1) and an ARVC patient (Case 5 in Table 2). The relative decrease (per cent) in fQRSd:100 in V2 compared with fQRSd:40 in V2 was not significantly different between symptomatic (cardiac arrest and syncope) and asymptomatic BS patients (23 ± 7% vs. 24 ± 6%, respectively). Six of the 9 symptomatic BS patients (all the patients in the cardiac arrest group and two of the five patients in the syncope group) and 6 of the 11 asymptomatic BS patients had type-1 ECG at the time of investigation, 6 patients had type-2 ECG, and 2 patients had type-3 ECG. The relative decrease in fQRSd:100 in V2 compared with fQRSd:40 in V2 tended to be slightly, but not significantly, greater in patients with type-1 ECG than in patients with type-2 or -3 ECG, (26 ± 7% vs. 21 ± 6%, P = 0.128).
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Electrophysiological study
Brugada syndrome
The averaged HV interval for all patients was 50 ± 9 ms, and for six patients, the HV interval was
55 ms. In 19 of 20 patients (95%), VF was induced from the RVOT in nine patients, from the RVA with double extra stimuli in five patients, from the RVOT in three patients, and from the RVA with triple extra stimuli in two patients.
Arrhythmogenic right ventricular cardiomyopathy
The SMVTs, which were identical to the clinical VT, were induced in all patients, and the mean cycle length of VT was 296 ± 45 ms. Entrainment could be proved in 9 of 15 VTs, and the remaining 6 VTs could not be entrained because VT required DC shock for the haemodynamic shock. The averaged HV interval was 46 ± 6 ms, and there was no significant difference in HV interval between ARVC and BS.
Follow-up
Brugada syndrome
An implantable cardioverter defibrillator (ICD) was implanted in all patients and the patients were followed without antiarrhythmic drugs. During a follow-up period of 28 ± 16 months, all patients were alive and two (Case 1 and 15) had an episode of VF that was terminated by an ICD shock.
Arrhythmogenic right ventricular cardiomyopathy
All patients had ICD therapy and sotalol was prescribed in five of the eight patients because the drug was effective in suppressing inducible VT. During a follow-up period of 39 ± 15 months, all patients were alive and four patients had the delivery of an ICD shock because of SMVT, and anti-tachycardia pacing was effective in terminating VT.
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Discussion |
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Major findings of the present study
In this study, we found that the characteristics of the delayed potential in the right precordial lead were different between BS and ARVC. The fQRSd in the high-pass filter at 40 Hz was similar in both of them, but in the condition of cutting fQRSd at 100 Hz, fQRSd was much shorter in BS than in ARVC. Furthermore, in BS, the fQRSd in the right precordial leads was prolonged, as shown in previous reports, in comparison with that in ARVC.
Relationship between the filter setting and late potential
Late potentials in the SAECG would reflect the presence of slowed ventricular activation, and the presence of slowed ventricular conduction may provide a substrate for re-entry.20,21 This notion is supported by the finding that all patients with ARVC had re-entrant VT in this study. ARVC is characterized by the fibro-fatty replacement of the RV. This histological change is thought to interrupt the electrical continuity of the myocardial fibres, creating a slow pathway for re-entrant arrhythmias.22 Folino et al.23 analysed SAECGs using three different high-pass filters (20, 40, and 80 Hz). The results demonstrated that the prevalence of LPs increased as the high-pass cut-off frequency increased23 LPs at high frequency might reflect fibro-fatty replacement and fine anisotropic conductivity. On the other hand, in the patients with BS in the present study, the fQRSd was remarkably shortened at the 100-Hz filter setting compared with the 40-Hz filter setting. Although LPs can be detected frequently in BS, the mechanism of these LPs is not fully understood. It was proposed that BS is a primary electrical disease without structural abnormalities, and no abnormal electrograms (e.g. delayed potentials or fragmentation) have been reported in the endocardium of RV. Nagase et al.24 confirmed that the timing of a delayed potential in BS recorded from the epicardial surface of the anterior wall of the RV was identical to that of the LP recorded in the SAECG. However, the genesis of this potential remains unknown. Antzelevitch commented on Nagase's24 report that concealed occurrence of phase 2 re-entry may contribute to the generation of a delayed unipolar potential or LP in the SAECG.25 If so, the characteristics of the delayed potentials in BS might be different from those in ARVC. The shortening of fQRSd in the right precordial lead at 100 Hz in BS might be related to the delayed second upstroke of the epicardial action potential or local phase 2 re-entry. In the present study, the shortening of fQRSd at 100 Hz in V2 was not different between symptomatic and asymptomatic patients with BS or between patients with type-1 ECG and patients with type-2 or -3 ECG. This result suggested that the shortening of fQRSd in V2 in response to the change in the filter setting might be a characteristic not related to ECG type in BS. The clinical implication of a changing fQRSd in the right precordial leads at different filter settings is not clear and requires further investigation. To clarify whether or not the finding indicates a risk factor for cardiac events in BS, we will need to follow up the clinical outcome in a larger number of asymptomatic BS patients.
Comparison of fQRSd between the right and left precordial lead
Some previous reports have demonstrated that fQRSd was more often prolonged in V1 than in V5 in the patients with ARVC.26,27 This suggested that the prolongation of fQRSd is related to delayed conduction of the RV in ARVC and reflects on the 
-wave in the ECG. In the present study, fQRSd at 40 Hz tended to be longer in V2 than in V5, but the difference was not significant. This smaller difference in fQRSd between V2 and V5 compared with that in previous reports might have been caused by the degeneration of the inferior wall of the RV and/or the LV. Furthermore, the tendency for a longer fQRSd in V2 than V5 did not change at the low-pass filter setting of 100 Hz. In contrast, the fQRSd at 40 Hz in V2 was significantly longer than that in V5 in BS, and this difference disappeared at 100 Hz. This suggests the presence of abnormal delayed potentials predominantly in the RVOT, as we previously reported.13
Limitations
The major limitation of this study is the small number of the patients studied, especially in ARVC. However, to our knowledge, this is the first report of a comparison of the fQRSd in the SAECG between BS and ARVC and the first demonstration of a difference in the characteristics of a delayed potential in the RVOT in these two diseases. Even though there was no patient with a Brugada-type ECG in the ARVC group, our finding might help to resolve the problem of differentiation between BS and ARVC.
Conflict of interest: none declared.
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References |
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[1] Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden death: a distinct clinical and electrocardiographic syndrome. J Am Coll Cardiol (1992) 20:1391–6.[Abstract]
[2] Brugada J, Brugada R, Brugada P. Right bundle-branch block and ST-segment elevation in leads V1 through V3: a marker for sudden death in patients without demonstrable structural heart disease. Circulation (1998) 97:457–60.
[3] Brugada R, Brugada J, Antzelevitch C, Kirsch GE, Potenza D, Towbin JA, et al. Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. Circulation (2000) 101:510–5.
[4] Yan GX, Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation (1999) 100:1660–6.
[5] Gussak I, Antzelevitch C, Bjerregaard P, Towbin JA, Chaitman BR. The Brugada syndrome: clinical, electrophysiological and genetic aspects. J Am Coll Cardiol (1999) 33:5–15.
[6] Antzelevitch C, Brugada P, Brugada J, Brugada R, Nademanee K, Towbin J. The Brugada syndrome. In: Clinical Approaches to Tacharrhythmias (1999) Armonk, NY: Futura Publishing Co. 1–99.
[7] Antzelevitch C. The Brugada syndrome. J Cardiovasc Electrophysiol (2001) 12:268–72.[CrossRef][Web of Science][Medline]
[8] Takagi M, Aihara N, Kuribayashi S, Taguchi A, Shimizu W, Kurita T, et al. Localized right ventricular morphological abnormalities detected by electron-beam computed tomography represent arrhythmnogenic substrates in patients with the Brugada syndrome. Eur Heart J (2001) 22:1032–41.
[9] Aizawa Y, Naitoh N, Washizuka T, Takahashi K, Uchiyama H, Shiba M, et al. Electrophysiological findings in idiopathic recurrent ventricular fibrillation: special reference to mode of induction, drug testing, and long-term outcomes. Pacing Clin Electrophysiol (1996) 19:929–39.[CrossRef][Medline]
[10] Morita H, Kusano KF, Nagase S, Morita ST, Nishi N, Kakishita M, et al. Site-specific arrhythmogenesis in patients with Brugada syndrome. J Cardiovasc Electrophysiol (2003) 14:373–9.[CrossRef][Web of Science][Medline]
[11] Kasanuki H, Ohnishi S, Ohtuka M, Matsuda N, Nirei T, Isogai R, et al. Idiopathic ventricular fibrillation induced with vagal activity in patients without obvious heart disease. Circulation (1997) 95:2277–85.
[12] Ikeda Y, Sakurada H, Sakabe K, Sakata T, Takami M, Tezuka N, et al. Assessment of noninvasive markers in identifying patients at risk in the Brugada syndrome: insight into risk stratification. J Am Coll Cardiol (2001) 37:1628–34.
[13] Furushima H, Chinushi M, Hirono T, Sugiura H, Watanabe H, Komura S, et al. Relationship between dominant prolongation of the filtered QRS duration in the right precordial leads and clinical characteristics in Bruagada syndrome. J Cardiovasc Electrophysiol (2005) 16:1311–7.[Web of Science][Medline]
[14] Corrado D, Nava A, Buja G, et al. Familial cardiomyopathy underlies syndrome of right bundle branch block, ST-segment elevation and sudden death. J Am Coll Cardiol (1996) 27:443–8.[Abstract]
[15] Corrado D, Basso C, Buja G, Nava A, Rossi L, Thiene G. Right bundle branch block, right precordial ST-segment elevation, and sudden death in young people. Circulation (2001) 103:710–7.
[16] Remme CA, Wever EF, Wilde AA, Derksen R, Hauer RN. Diagnosis and long-term follow-up of the Brugada syndrome in patients with idiopathic ventricular fibrillation. Eur Heart J (2001) 22:400–9.
[17] Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome. Report of the second consensus conference. Endrosed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation (2002) 111:659–70.
[18] McKenna WJ, Thiene G, Nava A, et al. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology. Br Heart J (1994) 71:215–8.
[19] Aizawa Y, Niwano S, Chinushi M, et al. Incidence and mechanism of interruption of reentrant ventricular tachycardia with rapid pacing. Circulation (1992) 85:585–589.
[20] Briethardt G, Borggrefe M. Pathophysiological mechanisms and clinical significance of ventricular late potentials. Eur Heart J (1986) 7:364–85.
[21] Briethardt G, Borggrefe M, Kabenn U, et al. Prevalence of late potentials in patients with and without ventricular tachycardia: correlations with angiographic findings. Am J Cardiol (1982) 48:1932–7.[CrossRef]
[22] Daliento L, Turrini P, Nava A, et al. Arrhythmogenic right ventricular cardiomyopathy in young versus adult patients: similarities and differences. J Am Coll Cardiol (1995) 25:655–64.[Abstract]
[23] Folino A, Corso LD, Oselladore L, et al. Signal-averaged electrocardiogram. In: Nava A, Rossi L, Thiene G, eds. Arrhythmogenic Right Ventricular Cardiomyopathy/Dyspasia. New York: Elsevier, pp. (1997) 210–23.
[24] Nagase S, Kusano KF, Morita H, Fujimoto Y, Kakishita M, Nakamura K, et al. Epicardial electrogram of the right ventricular outflow tract in patients with the Brugada syndrome: using the epicardial lead. J Am Coll Cardiol (2002) 39:1992–5.
[25] Antzelevitch C. Late potential and the Brugada syndrome. J Am Coll Cardiol (2002) 39:1996–9.
[26] Blomström-Lundqvist C, Hirch I, Olsson B, Edvardsson N. Quantitative analysis of the signal-averaged QRS in patients with arrhythmogenic right ventricular dysplasia. Eur Heart J (1988) 9:301–12.
[27] Ohe T, Konoe A, Shimizu A, Daikoku S, Kamakura S, Matsuhisa M, et al. Differentiation between late potentials of right ventricular and of left ventricular origin. Am J Cardiol (1989) 64:37–41.[CrossRef][Web of Science][Medline]
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