© 2005 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
Electrocardiographic predictors of Brugada type response during Na channel blockade challenge*
aAmiens-Picardie University Hospital Hôpital Sud, 80054 Amiens Cedex, France; bLariboisière University Hospital Paris, France
Manuscript submitted 28 November 2004. Revision received 25 July 2005. Accepted after revision 8 May 2005.
*Corresponding author. Tel.: +33 614 27 33 09; fax: +33 322 45 56 61. E-mail address: hermida.jean-sylvain{at}chu-amiens.fr (J.-S. Hermida).
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Abstract |
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AIM: To identify ECG predictors of Brugada type response during Na channel blockade challenge.
METHODS: We studied prospectively 103 patients (M=76, 45±13 years) in whom ECGs were collected during ajmaline challenge. ECG recordings included the high right precordial leads (–2V1 and –2V2). A positive response was defined by a >0.2 mV J point or ST segment elevation and a down-sloping pattern of the ST segment in at least one right precordial lead.
RESULTS: Ajmaline challenge was positive in 48 (47%) of the 103 cases. Baseline J wave elevation was greater in –2V1 (0.077±0.078 mV vs. 0.038±0.046 mV, P=0.003) and –2V2 (0.149±0.103 mV vs. 0.043±0.088 mV, P<0.001) in cases with a subsequent positive response. In contrast, ST segment elevation and T wave amplitudes were reduced in V1, V2 and V3. Logistic regression showed that J wave elevation in –2V2 and decreased T wave amplitude in V3 at baseline were independent predictors of a positive response. Baseline J wave elevation >0.16 mV in –2V2 had a specificity of 100%, a sensitivity of 40%, a positive predictive value of 100% and a negative predictive value of 28%.
CONCLUSION: J wave elevation >0.16 mV in –2V2 was the strongest predictor of a Brugada type response to Na channel blockade challenge when Brugada syndrome was suspected on a baseline ECG.
Key Words: antiarrhythmia agents, genetics, electrocardiography, ion channel, Brugada syndrome
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Introduction |
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The Brugada syndrome is a genetically determined cause of sudden cardiac death in patients without overt heart disease. Because no drug therapy is known to be effective and due to a high risk of recurrence, implantation of a cardiac defibrillator is recommended in symptomatic patients [1]
. ECG pattern of Brugada syndrome may fluctuate from typical coved or saddleback type to a simple non-specific ST segment elevation in right precordial leads or even to a normal ECG. Unfortunately, because a SCN5A mutation is only present in between 10 and 20% of the affected individuals [2–4], DNA sequencing of the SCN5A gene is not of great help to achieve the diagnosis of Brugada syndrome. In contrast, pharmacological challenge with a class I antiarrhythmic drug seems able to confirm the diagnosis of the disease with a high sensitivity and specificity in individuals with a suspicious but unconfirmed ECG [5–7]. Growing identification of asymptomatic patients with Brugada compatible ECG remains a key issue. ST segment elevation 
0.1 mV in V1, V2–V3 may be found in 0.58–6% of apparently normal individuals [8,9]. Identification of ECG predictors of a Brugada like response should be helpful to prioritise the realization of tests and of any further investigation. The aim of this study was to identify potential ECG predictors of Brugada like response during Na channel blockade challenge. |
Methods |
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Study population
Na channel blockade challenge was performed for diagnostic purposes in 103 patients (males=76, mean age=45±13 years). Patients were symptomatic in eight cases (syncope, n=6; resuscitated sudden death, n=2) and asymptomatic in 95 cases. Asymptomatic individuals were incidentally detected in the cardiology department (n=15), in families of patients with Brugada syndrome (n=35) or during systematic ECG screening of normal individuals followed in an occupational centre (n=52). Prevalence of Brugada syndrome in a population followed in an occupational centre was previously published [8]
. Baseline ECG showed a coved-type pattern in four patients, Brugada compatible pattern of ST segments in 82 patients and a normal ST segment (<0.1 mV ST segment elevation) in 17 relatives of patients with Brugada syndrome.
Definition of Brugada compatible ECG
Brugada compatible ECGs were defined by the presence of a 0.1 mV ST segment elevation in V1, V2–V3 in the first cases and in the population followed in the occupational centre. ST segment elevation 0.2 mV was used after 2002 according to the most recent recommendations (type 2 or 3 saddleback type ST segment elevation [10]).
Na channel blockade protocol
Na channel blockade challenge was performed prospectively, after written informed consent was obtained, with the same protocol using 1 mg/kg intravenous ajmaline. ECGs were recorded continuously in an electrophysiology laboratory on a computerized electrophysiological system (EP MED systems, Mt Arlington, USA) and were stored on individual optical disks allowing unlimited re-analysis. ECG parameters were measured with computerized callipers at different speeds (50–200 mm/s). Additionally, V1 and V2 were recorded in the upper position (2nd intercostal space) in 91 of the 103 tests (–2V1, –2V2) [11,12]. A Brugada like response (positive response) was defined by the occurrence of both the following criteria in one right precordial lead (–2V1, –2V2, V1, V2, or V3):
- Elevation of the J point >0.2 mV or of the ST segment measured 20 ms (ST 20) after the end of the QRS complex [10].
- A down-sloping and coved aspect to the ST segment [13].
ST segment elevation 60 ms after the end of QRS (ST60) and T wave amplitude (from the isoelectric line to the apex) were also measured. Contraindications to Na channel blockade were the presence of left ventricular dysfunction on systematic echocardiography performed before the test, a conduction abnormality (left bundle branch block or atrioventricular block), a history of myocardial infarction, an electrolytic imbalance, pregnancy or breast feeding.
Statistics
Variables were expressed as mean±standard deviation. Comparisons between groups were performed with analysis of variance. Paired t-tests were used to evaluate ECG modifications during Na channel blockade.
A binary logistic regression model was used in order to estimate the ECG variables which could predict a positive response in patients with a Brugada compatible ECG. ECG variables which were significantly different between positive and negative responses in univariate analysis were included into the binary logistic regression. Due to the high number of measurements, data were included when the P value was 
0.001. A forward stepwise (Wald) procedure was used. All the statistical analyses were performed with the SPSS 11.0 software.
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Results |
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Baseline ECG variables
Na channel blockade challenge was positive in 48 (47%) of the 103 cases. Patients with positive or negative response were comparable regarding age (46±14 vs. 43±11 years) and proportion of normal (21% vs.13%) or suspicious (79% vs. 87%) ECGs. The sex ratio (M/F) was lower in patients with a positive response. There was a male predominance in the group with a negative response (M/F=5.8 vs. 1.5, P=0.01). SCN5A mutations were present in nine of the 23 patients (39%) with positive Na channel challenge who were genotyped.
Univariate analysis of baseline ECG intervals is shown in Table 1. Baseline J wave elevation in –2V1 and –2V2 was higher in cases with a positive response than in those with a negative response. In contrast, baseline ST20 and ST60 elevation was less pronounced in cases with positive outcome, especially in leads V1–V3 (Table 2). Lower T wave amplitudes were observed in V1, V2 and V3 in case of positive response (Table 3).
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Predictors of positive response to Na channel blockade challenge
J wave elevation in –2V2, ST20V3, ST60V1 and T wave amplitude in V3 were entered into a logistic regression model. J wave elevation in –2V2 (P=0.0001) and low T wave amplitude in V3 (P=0.0003) were found to be independent predictors of a positive response to Na channel blockade.
A baseline J wave elevation >0.16 mV in –2V2 had a specificity of 100%, a sensitivity of 40%, a positive predictive value of 100% and a negative predictive value of 28% for a positive response (Fig. 1). When the cut-off was set at >0.1 mV in –2V2, J wave elevation had a specificity of 89% and a sensitivity of 60%, and the relative risk for a positive challenge was 6 (P<0.001).
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A T wave amplitude <0.7 mV in V3 had a specificity of 63% and a sensitivity of 67%. The relative risk for a positive challenge was 1.8 (P=0.003).
Combining both a J wave >0.1 mV in –2V2 and a T wave amplitude <0.7 mV in V3 had a specificity of 96% but a sensitivity of only 29% for a positive response. The relative risk was increased by 9.5.
ECG changes during Na channel blockade
Figs. 2 and 3 show the changes in J wave elevation and those in T wave amplitude in leads –2V1, –2V2, V1–V3 during the Na channel blockade.
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A transient episode of asymptomatic runs of monomorphic ventricular tachycardia was observed in one case out of the 103 tests and isolated ventricular premature beats in three other cases.
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Discussion |
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The main finding of the present study is that J wave elevation >0.16 mV in –2V2 (high V2) at baseline is the strongest ECG predictor of a Brugada like response to Na channel blockade challenge. In contrast, no ECG parameter or ST segment morphological characteristic was helpful to predict negative Na challenge response.
Temporal and spatial characteristics of ST segment elevation
Based on in vitro observations [14], the J wave and ST segment elevation of the Brugada syndrome have been related to the over-expression of the transient outward potassium current (Ito) in the right ventricular epicardium but not in the endocardium, leading to a transmural voltage gradient. The predominance of Ito is supposed to be the consequence of the Na current abnormality. Accentuation of the gradient voltage induces further J wave elevation corresponding to the timing of Ito. The well defined sequence of ECG changes ranges from an initial saddle-type to a coved-type pattern and, in later stages, to inversion of T waves when the prolongation of epicardial repolarisation exceeds endocardial repolarisation [15]. The important role of the J wave observed in the present study is consistent with the electrophysiological mechanisms of the syndrome proposed by Antzelevitch. The J point appeared to be the most important part of the ST segment to analyse compared with ST20 or ST60. Indeed, J waves were higher in case of positive response whereas ST60 and ST20 were not different and sometimes lower compared with controls. In positive responses, the ECG showed a downward ST segment elevation with a J point higher than ST20. Conversely, in negative responses, the baseline ECG abnormality consisted of an upward ST segment elevation with a higher mean ST20 elevation compared with the mean J point elevation (Fig. 4). Reduced baseline T wave amplitude also seems to correspond to the proposed cellular mechanisms of the Brugada syndrome. Indeed, in major ECG forms of the Brugada syndrome, the T wave is negative in the right precordial leads.
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The preferential localization of the ECG abnormalities to the right precordial leads was recognized as early as 1992 [16]
. This could be the consequence of pronounced Ito-mediated phase one in the right ventricular epicardium [17] and of a marked dispersion of repolarisation in the right ventricular outflow tract (RVOT) [18]. Shimizu reported that the maximal increase of ST20 during Na channel blockade usually occurred in V2 [7] and sometimes in the high right precordial leads [11]. The value of V1, V2 and V3 recorded in the third or in the second intercostal spaces, even without drug testing, was discovered much more recently [12,19]. Clinical observations of frequent inducibility of ventricular fibrillation in the free-wall region of the RVOT [20,21] and the possibility of radiofrequency ablation of RVOT triggers [22] lead to the hypothesis of site-specific arrhythmogenesis [23,24]. Analysis of the activation sequence of ventricular arrhythmia in an experimental model revealed reentry between epicardium and endocardium or confined either to endocardium or to epicardium [25]. Consequently, the high precordial leads appear ideally localized to detect alterations of repolarisation in the RVOT free wall. Also, it is important that the baseline ECG markers, which were found to be associated with the ECG pattern of Brugada syndrome in the present study (J wave elevation and decreased T wave amplitude), also showed important changes during Na channel blockade (Figs. 2 and 3).
Study limitations
The control group is represented by the patients found with a negative response to the Na channel blockade. This group was comparable with the group of patients with a positive response to Na channel blockade for the main clinical variables except for the sex ratio. The sex ratio difference in the two groups may have influenced the results of the tests. The male predominance was more marked amongst the negative responders. The negative responses are considered to be normal variants or early repolarisation syndromes. To explain the difference of sex ratio between patients with positive response and subjects with negative response, we hypothesized that the male predominance is higher in the early repolarisation syndrome than in asymptomatic Brugada syndrome. Another hypothesis is that false positive responses may occur in the female gender.
Due to the fact that all the patients were not genotyped and because the presence of a SCN5A mutation is not constant in this syndrome, the diagnostic value of a Brugada type response in asymptomatic patients is not fully established. Also, long term follow-up of patients with drug induced Brugada type ECG is needed to clarify the clinical significance of such a finding.
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Conclusions |
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We found in this study that J wave elevation >0.16 mV in –2V2 was the strongest predictor of a Brugada type response to Na channel blockade challenge when Brugada syndrome was suspected on a baseline ECG. This indicator may be useful to select patients in whom Na channel challenge is more likely to result in a Brugada type response.
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Footnotes |
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*The study was supported by the Amiens-Picardie University Hospital.
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References |
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