Asian Cardiovasc Thorac Ann 2005;13:241-246
© 2005 Asia Publishing EXchange Ltd
Clinical and Electrophysiologic Profile of Brugada Syndrome in Iranian Patients
Majid Haghjoo, MD,
Arash Arya, MD,
Zahra Emkanjoo, MD,
Mohammad Ali Sadr-Ameli, MD
Department of Pacemaker and Electrophysiology, Shahid Rajaie Cardiovascular Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
For reprint information contact: Majid Haghjoo, MD Tel: 98 21 2392 2931 Fax: 98 21 204 8174 Email: haghjoo{at}rhc.ac.ir, Department of Pacemaker and Electrophysiology, Shahid Rajaie Cardiovascular Center, Mellat Park, Vali-E-Asr Avenue, Tehran 1996911151, Iran.
 |
ABSTRACT
|
|---|
Clinical and electrophysiologic characteristics of 20 patients (15 males; mean age, 42 ± 9 years) with Brugada syndrome were studied. Electrocardiographic abnormalities (spontaneous in 6 and provoked in 14) were recognized in 5 symptomatic and 15 asymptomatic patients. Mean PR (188 ± 18 vs. 184 ± 24 ms) and QT (362 ± 34 vs. 382 ± 28 ms) intervals and ST-segment elevation (2.28 ± 0.42 vs. 2.70 ± 0.77 mm) were similar in both groups. The PR interval was slightly longer in males than females (191 ± 21 vs.168 ± 18 ms, p = 0.042), but ST-segment elevation (2.70 ± 0.78 vs. 2.24 ± 0.26 mm) was similar. The HV interval was longer in males than females (57 ± 4 vs. 50 ± 4 ms, p = 0.047). Ventricular arrhythmias were induced in 40% of asymptomatic patients. There was no significant difference in age, sex, PR interval, ST-segment elevation, or HV interval between inducible and non-inducible patients. A defibrillator was implanted in 8 patients. During 16 ± 2 months of follow-up, one symptomatic patient had appropriate device therapy. None of the asymptomatic and non-inducible patients experienced a cardiac event. Electrophysiologic data have no role in predicting inducibility in programmed stimulation.
|
INTRODUCTION
|
|---|
Brugada syndrome is characterized by ST-segment elevation in the right precordial leads, which is unrelated to ischemia, electrolyte disturbances, or obvious structural heart disease.1–2 This syndrome was initially described as a distinct clinical entity associated with a high risk of sudden cardiac death, by Brugada and Brugada in 1992.1 The syndrome is genetically inherited as an autosomal dominant trait with incomplete penetrance and an incidence ranging between 5 and 66 per 10,000.3–4 In regions of Southeast Asia where it is endemic, the clinical presentation of Brugada syndrome is distinguished by male predominance (male:female ratio of 8:1) and the appearance of arrhythmic events at an average age of 40 years (range, 1 to 77 years).5–6 The typical Brugada electrocardiogram (EKG) pattern includes ST-segment elevation in the right precordial leads (V1–V3) associated with right bundle branch block, normal QT duration, and mild conduction defects with prolonged PR and HV intervals.2 Although a number of candidate genes have been proposed for this syndrome, so far it has been linked only to mutations of SCN5A, the gene encoding for the 
-subunit of the cardiac sodium channel.7–10 Brugada syndrome is a newly recognized disease with many unknown aspects. Although several studies have been published, there has been no survey of these patients in our country.
|
PATIENTS AND METHODS
|
|---|
Between September 2001 and December 2003, 20 consecutive patients (15 males; mean age, 42 ± 9 years) with Brugada syndrome were investigated. All gave written informed consent for the procedure, and the local hospital ethical committee approved the study. Fourteen of the 20 subjects with a suspicious EKG were referred to our center for a Brugada syndrome diagnostic work-up. They underwent an antiarrhythmic challenge test with procainamide or flecainide. The other 6 patients had a typical baseline EKG. Among these 20 cases, 14 were probands and 6 (all asymptomatic) were detected during screening after diagnosis of Brugada syndrome in a family member. Structural heart disease was ruled out by noninvasive methods (echocardiography and exercise stress testing); one patient also underwent coronary arteriography. Serum electrolyte levels were normal. Risk stratification was performed by an electrophysiologic study.
In the 14 patients subjected to a pharmacologic challenge test, an intravenous class IA or IC antiarrhythmic drug was administered: flecainide in a dose of 2 mg·kg–1 (maximum, 150 mg) over a 10-min period in 4 patients; and procainamide 10 mg·kg–1 over a 10-min period in 10 patients. The ST segment was measured at the J points in leads V1, V2 and V3, and the difference between the ST heights before and after administration of flecainide or procainamide (ST-segment elevation) was calculated. Subjects were continuously monitored until 30 min after completion of drug administration, using a conventional bedside monitor (Zoll M series; Zoll Medical, Cologne, Germany) equipped with an external defibrillator. A simultaneous 12-lead EKG (Hellige EK501; Marquette Hellige, Freiburg, Germany) was recorded at a paper speed of 25 mm·s–1 and amplitude of 10 mm·mV–1 under basal conditions, twice (5th and 10th min) during infusion and 5 min after the completion of flecainide or procainamide infusion. The EKG was considered typical when it had a coved-type pattern: a terminal r’ wave with a J-point elevation of 
2 mm and a slowly descending ST segment in continuation with a flat or negative T wave in leads V1 to V3 (Figure 1
). A saddleback pattern was not considered typical.
View larger version (15K):
[in this window]
[in a new window]
|
Figure 1. (A) Resting electrocardiogram of a patient who presented with recurrent syncope. No significant abnormality was seen. (B) Marked ST-segment elevation in V1-V3 after procainamide administration.
|
|
An electrophysiologic study was carried out in 15 patients (10 asymptomatic and 5 with nonspecific symptoms such as chest pain, palpitation, fatigue, and dizziness), and induction of ventricular arrhythmia was attempted without the use of antiarrhythmic agents. The criterion for induction of ventricular arrhythmia was sustained polymorphic ventricular tachycardia (VT), monomorphic VT, or ventricular fibrillation (VF) induced by programmed electrical stimulation from the right ventricular apex (Figure 2). Our protocol included up to 3 extra stimuli (3 basic cycle lengths of 600, 500, 400 ms) and a minimum coupling interval of 200 ms, delivered only from the right ventricular apex. Symptomatic patients refer to those presenting with aborted sudden cardiac death or syncope, and asymptomatic to patients presenting with nonspecific symptoms or no symptom. Sudden cardiac death was defined as an unexpected death occurring within 1 hour after the onset of symptoms.
View larger version (67K):
[in this window]
[in a new window]
|
Figure 2. Electrophysiologic tracing of an asymptomatic Brugada patient. Polymorphic ventricular tachycardia was induced with S1-500, S2-290 ms from the right ventricular apex.
|
|
The data analysis was performed using SPSS 11.0 software (SPSS, Inc., Chicago, IL, USA). Quantitative values were expressed as mean ± standard deviation. Differences in characteristics between groups were assessed by unpaired t test for continuous variables and chi-squared statistics (or Fisher’s exact test if necessary) for discrete variables. A p value of < 0.05 was considered statistically significant.
|
RESULTS
|
|---|
In 5 (25%) symptomatic patients, the abnormal EKG pattern was first identified after an episode of aborted sudden cardiac death (n = 2) or syncope of unknown origin (n = 3). In the remaining 15 (75%) asymptomatic patients, the abnormal EKG was recognized during evaluation for nonspecific symptoms (n = 7), routine examinations (n = 2), or screening of other family members (n = 6; Table 1). None of the patients was taking any drug when the abnormal EKG was identified. A family history of sudden death was present in 4 (20%) patients (all asymptomatic). Physical examination was normal in all patients. During 16 ± 2 months of follow-up, none of the asymptomatic patients developed symptoms.
Analysis of ST-segment morphology, QT interval, and PR interval was performed in all patients. A spontaneous characteristic pattern was present in at least one recorded EKG of 6 (30%) patients. In the remaining 14 (70%), the typical Brugada EKG pattern was unmasked by intravenous infusion of class IA or IC drugs (Table 1
). The morphology of ST-segment elevation (coved vs. saddleback pattern) was similarly distributed between aborted sudden cardiac death or syncope victims and other patients ( p = 0.35). The mean ST-segment elevation was 2.28 ± 0.42 mm in symptomatic and 2.70 ± 0.77 mm in asymptomatic patients ( p = 0.26). The mean ST-segment elevation was similar in both sexes (2.70 ± 0.78 mm in men, 2.24 ± 0.26 mm in women; p = 0.15). The QT interval was normal in all patients and no difference was found between the 2 groups (362 ± 34 vs. 382 ± 28 ms; p = 0.18). The mean PR interval was 188 ± 18 ms in symptomatic and 184 ± 24 ms in asymptomatic patients ( p = 0.75). The mean PR interval was longer in men (191 ± 21 ms) than women (168 ± 18 ms; p = 0.042).
Programmed electrical stimulation was carried out in 15 (75%) asymptomatic patients who provided informed consent. In 6 of the 15 patients (40%), VF or sustained polymorphic VT was induced (5 males) with 1 extra stimulus (n = 1), 2 extra stimuli (n = 2), and 3 extra stimuli (n = 3), as shown in Table 1. The mean ages were similar in inducible and non-inducible patients (Table 2). There was no difference in inducibility between males and females. The HV intervals were mildly prolonged for the entire study population (46–60 ms; mean, 55.5 ± 5 ms). The mean HV interval was 57 ± 4 ms in men and 50 ± 4 ms in women ( p = 0.047), but it was comparable between inducible and non-inducible individuals (Table 2).
View this table:
[in this window]
[in a new window]
|
Table 2. Correlation of Demographic and Electrophysiologic Findings with Inducibility in Programmed Electrical Stimulation
|
|
No echocardiographic evidence of structural heart disease was found in any of the 20 patients. Ischemia was excluded in 7 patients with atypical chest pain, by exercise stress testing in 6 and by coronary arteriography in one. An implantable cardioverter defibrillator (ICD) was recommended in 11 high-risk patients (5 symptomatic and 6 inducible patients on an electrophysiologic study) and implanted in 8 (7 males and 1 female, p = 0.63). The other 3 candidates rejected this recommendation. The remaining low-risk patients (asymptomatic and non-inducible) were followed-up clinically. In the ICD group, 2 patients had inappropriate therapy for sinus tachycardia, and one with appropriate discharge for fast VT. One patient in the ICD group developed thrombophlebitis in the left arm, which was managed successfully by intravenous and oral anticoagulants. In this patient, a near normal EKG on admission converted to the typical coved-type EKG following a rise of body temperature to 39°C. This patient had no ventricular arrhythmia during the febrile state. In the non-ICD group, no patient had any event during a mean follow-up of 16 ± 2 months.
|
DISCUSSION
|
|---|
In agreement with previous studies, the EKG diagnosis of Brugada syndrome was predominantly seen among males (75%), and 80% of major events (syncope and sudden cardiac arrest) occurred in males after the 3rd decade of life.1,5,7 In most patients, the EKG diagnosis was made during assessments of nonspecific complaints, routine evaluations, or screening of family members; only 25% of patients were detected after a major event. A family history of sudden death was reported by 20% of patients, who were all asymptomatic. This may be due to the fact that a substantial proportion of asymptomatic patients were detected during family screening. A number of patients were diagnosed after atypical chest pain; no acceptable explanation has been found for this presentation.
The value of the pharmacological challenge test is its ability to establish the diagnosis in individuals with a suspicious EKG. Two EKG patterns were noted in our study: coved-type (Figure 3) and saddleback (Figure 4). Brugada syndrome cannot be diagnosed in an individual with a saddleback EKG without inducing a coved-type pattern with the pharmacological challenge test. All symptomatic and asymptomatic individuals included in this study had spontaneous or drug-induced coved-type EKG morphology. The accentuation of ST elevation by class IA or IC antiarrhythmic drugs is a characteristic of Brugada syndrome.11 These drugs were used to unmask the concealed or intermittent forms of Brugada syndrome, as ST elevation of a symptomatic patient fluctuates periodically.12 Krishnan and Antzelevitch13–14 reported that strong sodium channel current inhibition in the epicardium led to loss of the action potential dome in the epicardium but not in the endocardium, inducing dispersion of repolarization accompanied by a prominent conduction delay, which resulted in local reexcitation (phase 2 reentry). The arrhythmia in Brugada syndrome has been ascribed to this mechanism. While all patients with a saddleback EKG in this study showed accentuation of ST-segment elevation with procainamide or flecainide, there was no correlation between the degree of increase in ST-segment elevation and inducibility in programmed electrical stimulation (Table 2). Thus, pharmacological challenge probably has no role in predicting polymorphic VT/VF induction in asymptomatic patients with Brugada syndrome.
View larger version (23K):
[in this window]
[in a new window]
|
Figure 3. Resting electrocardiogram of an asymptomatic patient, showing the typical Brugada pattern of incomplete right bundle branch block and coved-type ST-segment elevation in V1–V3.
|
|
View larger version (14K):
[in this window]
[in a new window]
|
Figure 4. Resting electrocardiogram of a patient with aborted sudden cardiac death, showing incomplete right bundle branch block and saddleback ST-segment elevation.
|
|
Brugada and colleagues5 reported a high incidence of polymorphic VT or VF induction during programmed electrical stimulation in symptomatic patients (78%), and also a very high rate of inducibility in asymptomatic patients (85%). We did not find such a high inducibility rate in our asymptomatic patients (40%) despite a family history of sudden death in 27% of this group. Our results are more compatible with the findings of Morita and colleagues15 (VF induced in 33% of asymptomatic patients). This difference in inducibility of asymptomatic patients can be explained by the use of different programmed electrical stimulation protocols. As in other studies, polymorphic VT or VF induction required 2 or 3 extra stimuli (in 5/6 patients) in our series.5,15 We did not find any correlation between demographic, clinical, electrocardiographic data, or HV interval and inducibility in programmed electrical stimulation, whereas Brugada and colleagues16 found males were more frequently inducible than females. They also found that inducible individuals had a longer HV interval than non-inducible patients. These differences may relate to our smaller sample size or to differences between study populations. We also found that the HV interval was longer in males than females, which may be related to the ionic and cellular differences of male and female patients with Brugada syndrome.
Eleven patients were candidates for ICD implantation on the basis of history of aborted sudden death, syncope, or polymorphic VT/VF induction in an electrophysiologic study.2,17 An important finding was the unmasking of a typical Brugada-type EKG in one patient in a febrile state due to left arm thrombophlebitis. This feature of Brugada syndrome has been reported in several recent case studies.18–19 The underlying mechanism of this phenomenon is the temperature-dependency of the sodium channel responsible for Brugada syndrome.8 We found that asymptomatic and non-inducible patients remained as such after a mean follow-up of 16 months, but we cannot exclude the possibility that these patients might have cardiac events later in life. In the 3 patients who rejected ICD implantation, we recommended quinidine, on the basis of recent studies.20
Our follow-up data confirmed the relatively benign course of asymptomatic and non-inducible Brugada syndrome patients (even those with a positive family history), and the recurrence of arrhythmic events in symptomatic patients. Thus, ICD implantation is not justified in the former group. It was also concluded that electrophysiologic data have no role in predicting inducibility in programmed electrical stimulation.
|
REFERENCES
|
|---|
- 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;20:1391–6.[Abstract]
- Alings M, Wilde A. "Brugada syndrome": clinical data and suggested pathophysiological mechanism. Circulation 1999;99:666–73.[Free Full Text]
- Brugada J, Brugada P, Brugada R. The syndrome of right bundle branch block, ST segment elevation in V1 to V3 and sudden death. Cardiovas Drugs Ther 2002;16:25–27.[Medline]
- Namiki T, Ogura T, Kuwabara Y. Five-year mortality and clinical characteristics of adult subjects with right bundle branch block and ST elevation. Circulation 1995;92(Supp1):334[Abstract/Free Full Text]
- Brugada J, Brugada R, Brugada P. Right bundle branch block and ST-segment elevation in leads V1 to V3: a marker for sudden death in patients without demonstrable structural heart disease. Circulation 1998;97:457–60.[Abstract/Free Full Text]
- Atarashi H, Ogawa S, Harumi K, Hayakawa H, Sugimoto T, Okada R, et al. Characteristics of patients with right bundle branch block and ST-segment elevation in right precordial leads. Idiopathic Ventricular Fibrillation Investigators. Am J Cardiol 1996;78:581–3.[Medline]
- Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, et al. Genetic basis and molecular mechanisms for idiopathic ventricular fibrillation. Nature 1998;392:393–6.
- Dumaine R, Towbin JA, Brugada P, Vatta M, Nesterenko DV, Nesterenko VV, et al. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res 1999;85:803–9.[Abstract/Free Full Text]
- Priori SG, Napolitano C, Grillo M. Concealed arrhythmogenic syndromes: the hidden substrate of idiopathic ventricular fibrillation? Cardiovasc Res 2001;50:218–23.[Abstract/Free Full Text]
- Weiss R, Barmada MM, Nguyen T, Seibel JS, Cavlovich D, Kornblit CA, et al. Clinical and molecular heterogeneity in the Brugada syndrome: a novel gene locus on chromosome 3. Circulation 2002;105:707–13.[Abstract/Free Full Text]
- 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;27:1061–70.[Abstract]
- Brugada R. Use of intravenous antiarrhythmics to identify concealed Brugada syndrome. Curr Control Trial Cardiovasc Med 2000;1:45–7.
- Krishnan SC, Antzelevitch C. Flecainide-induced arrhythmia in canine ventricular epicardium. Phase 2 reentry? Circulation 1993;87:562–72.[Abstract/Free Full Text]
- Krishnan SC, Antzelevitch C. Sodium channel block produces opposite electrophysiological effects in canine ventricular epicardium and endocardium. Circ Res 1991;69:277–91.[Abstract/Free Full Text]
- Morita H, Fukushima-Kusano K, Nagase S, Takenaka-Morita S, Nishii N, Kakishita M, et al. Site-specific arrhythmogenesis in patients with Brugada syndrome. J Cardiovasc Electrophysiol 2003;14:373–9.[Medline]
- Brugada P, Brugada R, Mont L, Rivero M, Geelen P, Brugada J. Natural history of Brugada syndrome. J Cardiovasc Electrophysiol 2003;14:455–70.[Medline]
- Brugada P, Brugada J, Brugada R. The Brugada syndrome. Card Electrophysiol Rev 2002;6:45–8.[Medline]
- Mok NS, Priori SG, Napolitano C, Chan NY, Chahine M, Baroudi G. A newly characterized SCN5A mutation underlying Brugada syndrome unmasked by hyperthermia. J Cardiovasc Electrophysiol 2003;14:407–11.[Medline]
- Antzelevitch C, Brugada R. Fever and the Brugada syndrome. Pacing Clin Electrophysiol 2002;25:1537–9.[Medline]
- Belhassen B, Viskin S, Antzelevitch C. The Brugada syndrome: is an implantable cardioverter defibrillator the only therapeutic option? Pacing Clin Electrophysiol 2002;25:1634–40.[Medline]
This article has been cited by other articles:
|
|
|
|
 
M. Schnoor, T. Schafer, D. Luhmann, and H. H. Sievers
Bicaval versus standard technique in orthotopic heart transplantation: a systematic review and meta-analysis.
J. Thorac. Cardiovasc. Surg.,
November 1, 2007;
134(5):
1322 - 1331.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Paul, J. Gerss, E. Schulze-Bahr, T. Wichter, C. Vahlhaus, A. A.M. Wilde, G. Breithardt, and L. Eckardt
Role of programmed ventricular stimulation in patients with Brugada syndrome: a meta-analysis of worldwide published data
Eur. Heart J.,
September 1, 2007;
28(17):
2126 - 2133.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
ABSTRACT
INTRODUCTION
