Incidence, clinical implications and prognosis of atrial arrhythmias in brugada syndrome

Pierre Bordachar1, Sylvain Reuter1, Stephane Garrigue*, Xu Caï, Mélèze Hocini, Pierre Jaïs, Michel Haïssaguerre and Jacques Clementy

Cardiac Pacing and Clinical Electrophysiology Department, Hôpital Cardiologique du Haut-Leveque, University of Bordeaux, 19 avenue de Magellan, Pessac Cedex 33604, France

* Corresponding author. Tel.: +33-5-57-65-64-71; fax: +33-5-57-65-65-09
E-mail address: stephane.garrigue{at}chu-bordeaux.fr

Received 10 July 2003; revised 18 December 2003; accepted 13 January 2004

Abstract

Aims This single-centre prospective study was designed to determine the incidence, therapeutic implications and prognosis of atrial arrhythmias (AA) in patients with Brugada syndrome (BS).

Methods and results Fifty nine consecutive patients with BS and 31 age and gender-matched controls underwent an electrophysiological exploration and were followed-up during 34±13 months. The final AA incidence was 20% in BS patients vs 0% in controls (). Ventricular inducibility was significantly related to a history of AA (). The incidence of AA in patients with a spontaneous electrocardiogram of BS was 26% vs 10% in patients with a flecainide-induced electrocardiogram (). In patients with an indication of implantable cardioverter defibrillator (ICD), the incidence of AA reached 27% vs 13% in patients with BS but without ICD indication (). Inappropriate shocks due to AA episodes were observed in 14% of ICD patients vs 10.5% of appropriate shocks. Multivariate analysis identified the implantation of a single-chamber device as an independent predictive factor of inappropriate ICD discharges ().

Conclusion BS patients exhibit an abnormally high proportion of AA. Our data strongly suggest a more advanced disease process in BS patients with spontaneous AA. Careful programming of single-chamber ICD should be recommended to avoid inappropriate discharges.

Key Words: Brugada syndrome • Atrial arrhythmias • Clinical outcome • Implantable cardioverter defibrillator

Introduction

The Brugada syndrome (BS) is an inherited arrhythmogenic disease characterized by a specific electrocardiographic (ECG) pattern (appearance of right bundle branch block with ST-segment elevation in right precordial leads V1 to V3) and a high risk of sudden cardiac death.1–5 This syndrome displays an autosomal dominant mode of transmission with incomplete penetrance. Mutations in the SCN5A gene encoding for the cardiac sodium channel have been reported as the genetic basis of the disease.6–9 Since this sodium channel is not restricted to the ventricular tissue, the electrical abnormality might also affect the atria. Indeed, the association between supraventricular arrhythmias and BS has been previously reported.3,10,11 However, the incidence and clinical consequences of atrial arrhythmias in BS have not been clarified yet. Accordingly, we assessed the incidence, clinical implications and prognosis of supraventricular arrhythmias in BS patients with a long-term follow-up (see Fig. 1).



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Fig. 1 Panel A: Surface ECG of a BS-patient in sinus rhythm (V1 and V2 leads). Note the ECG pattern of right bundle-branch block with ST-segment elevation in leads V1 and V2. Panel B: The same patient during an atrial fibrillation episode.

 
Methods

This single-centre prospective study complied with the Declaration of Helsinki and was approved by our Institutional Ethics Committee. Two populations were included: a control group and a group of BS patients.

BS group
A total of 59 patients (mean age 43±9 years, 74% men) were referred to our centre between April 1998 and February 2001 with an ECG compatible with the BS. Structural heart disease was excluded in all patients by clinical history and extensive evaluation, including non-invasive and invasive procedures (echocardiography in all patients, nuclear magnetic resonance imaging (), coronary angiography (), left and right ventriculography (), and endomyocardial biopsy ()). All patients were unrelated except two brothers, two sisters and a brother and sister. Five patients (8%) were referred to our centre for aborted sudden death, 9 (15%) for sudden death in the family, and 9 (15%) for syncope. Thirty-six patients (62%) were strictly asymptomatic, with no family history of sudden death, and the diagnosis was made during routine screening. The mean left ventricular ejection fraction, assessed by Simpson's echocardiographic method, was 67±5%, the echocardiographic mean left atrial diameter was 35±4 mm, and the mean end-diastolic left ventricular diameter was 47±7 mm. At the onset of the study, all patients were in sinus rhythm and free of anti-arrhythmic drugs. SCN5A mutations (after written informed consent) were identified in five patients (8%).

Control group
The control population consisted of 31 asymptomatic age and sex-matched patients (mean age 42±7 years, 71% men) without structural heart disease who were referred to our centre because at least one of their family member presented an ECG compatible with BS. The family member presenting Brugada syndrome was not included in the study and was under the care of a different heart institution. Controls were referred to our centre because they live in the university hospital district. Controls did not present right bundle-branch block or ST-segment elevation in leads V1 through V3, either spontaneously or after flecainide infusion. These patients were considered to be free of BS.

We obtained written informed consent from all BS patients and controls.

Surface electrocardiogram
There were no significant differences between the two groups in terms of P-wave duration, morphology, and QRS duration. An electrocardiogram compatible with BS12 was observed spontaneously in 49 patients (82%), while intravenous administration of flecainide (2 mg/kg body weight/10 min) revealed the BS pattern in the remaining 10 patients.

Electrophysiological testing
Comprehensive electrophysiological testing was performed in all patients and controls, after obtaining written informed consent, in a fasting, drug-free and non-sedated state. The electrophysiological study included basal measurements of conduction intervals and assessment of the Wenckebach cycle length and corrected sinus node recovery time (three cycle lengths: 600, 500, and 400 ms). Atrial vulnerability was not studied. Programmed ventricular stimulation was performed at 2 ms and twice the threshold current from the right ventricular apex and the right ventricular outflow tract using two basic cycle lengths (600 and 400 ms) and a maximum of triple extra stimuli. The inducibility of ventricular arrhythmias was tested first at the apex using single and double extra stimuli at a minimal coupling interval of 200 ms. In the case of non inducibility, it was tested at the outflow tract using single and double extra stimuli. If ventricular arrhythmias were not induced using up to double extra stimuli, triple extra stimuli were introduced from the apex first and then from the outflow tract at a minimal coupling interval of 200 ms. A patient was considered inducible if sustained ventricular arrhythmia (ventricular fibrillation, polymorphic ventricular tachycardia, or monomorphic ventricular tachycardia lasting more than 30 s or requiring emergency intervention) was induced.

Management
Patients with a positive ECG and an episode of syncope or aborted sudden death received an implantable cardioverter-defibrillator (ICD). Asymptomatic individuals with a positive ECG and a family history of sudden cardiac death and/or inducible ventricular arrhythmias also received an ICD.

ICD programming was as follows:

(1) When a ventricular tachycardia (VT) episode was induced during programmed ventricular stimulation, two therapeutic windows were programmed,

(a) a VT window (from 10 beats per minute below the induced-VT rate to 210 beats per minute) with two phases of anti-tachycardia pacing and four shocks,

(b) a ventricular fibrillation (VF) window (rate over 210 beats per minute) with six shocks.

(2) When there was no inducible VT, a single window of VF was programmed (rate over 210 beats per minute) with six shocks.

Asymptomatic non-inducible patients with a positive BS ECG pattern and no family history of sudden death were not treated.

Controls were not treated and remained free of anti-arrhythmic drugs during the follow-up.

Follow-up
During follow-up, patients were considered to have a ventricular or a supraventricular arrhythmic event if the episode was documented on the surface ECG, 24-h Holter recording, or stored in the ICD memory. Patients without an ICD underwent a 24-h Holter ECG at 1, 3, and 6 months and thereafter every 6 months. In addition, a surface ECG was obtained in the closest medical centre and faxed to the core centre whenever a patient experienced symptoms compatible with an arrhythmic episode (syncope, palpitations, dyspnoea, chest pain and/or dizziness). In patients with ICDs, the device was interrogated 1, 3, and 6 months after implantation, and then every 6 months thereafter and after each clinical event as indicated above. ICD interventions (anti-tachycardia pacing or shock delivery) were classified as appropriate or inappropriate on the basis of stored electrocardiogram analysis. All ICD interventions were reviewed by two experienced investigators.

Statistical analysis

All data analyses were performed using the Statistica software (Statistica, Tucson, AZ, USA). Normally distributed, continuous data, unless otherwise stated, are expressed as mean values (±SD). Non-normally distributed continuous data are expressed as medians [25th and 75th percentile].

Cumulative univariate event rates were compared using tests and results were given with risk ratios and 95% confidence intervals. The mean clinical and electrophysiological values for patients with and without Brugada syndrome were compared by use of independent -tests, and median values were compared by the Mann–Whitney -test for quantitative variables and the Fisher exact test for qualitative variables. The Shapiro and Wilk's test was used to identify continuous, normally distributed variables.

To identify predictors of ventricular inducibility, Cox proportional hazards analysis was performed. Variables achieving on univariate analysis were then tested in a stepwise (forward) multiple Cox regression survival model to determine the independent predictors of ventricular inducibility. A was considered statistically significant (see Tables 1 and 2).


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Table 1 Patient characteristics

 

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Table 2 Multivariate Cox regression analysis for ventricular inducibility in Brugada syndrome patients

 
Results

Electrophysiological study
Electrophysiological parameters
Ten BS patients (17%) vs no control () demonstrated sinus node dysfunction (diurnal heart rate 55 bpm and a prolonged corrected sinus node recovery time 525 ms) (Table 1). The Wenckebach cycle length (500 ms) was abnormally prolonged in 8 BS patients vs no control (), but the mean Wenckebach cycle length was not significantly different (408±48 ms vs 399±37, ). There was no significant difference between the two groups in terms of AH interval (107±23 ms in BS patients, 105±14 ms in controls; ). The HV interval was significantly prolonged in BS patients (53±10 ms) compared to that of controls (45±7 ms; ). Twelve BS patients (21%) vs no control had an abnormally prolonged HV interval (55 ms; ).

Programmed ventricular stimulation
A ventricular arrhythmia was induced in 35% of BS patients (13 ventricular fibrillations, four polymorphic ventricular tachycardias, and three monomorphic ventricular tachycardias). All the controls were non-inducible ( compared with BS patients).

Therapeutic management
Twenty-nine BS patients (49%) received an ICD. Eight were implanted with a dual-chamber device because of sinus node dysfunction and 21 received a single-chamber ICD. Thirty asymptomatic and non-inducible patients (51%) without a family history of sudden death were not treated with drugs or devices.

Follow-up
The median follow-up was 32 [11–52] months
At the end of the follow-up, 20% of BS patients presented paroxysmal AAs vs no control () (Fig. 1). Ten patients presented paroxysmal atrial fibrillation, 1 atrial flutter, and 1 with both atrial flutter and fibrillation. None of them exhibited persistent atrial fibrillation. In ICD-BS patients, the incidence of atrial arrhythmias reached 27% vs 13% in non-ICD-BS patients (). Importantly, the incidence of atrial arrhythmias was significantly higher in patients with spontaneous appearance of BS (25%) than in patients with the typical tracing only after flecainide infusion (10%; ). Interestingly, we found that BS patients with an HV interval 55 ms had significantly more atrial arrhythmic events than BS patients with a normal HV interval (respectively 66% vs 8.5%; ). However, we are limited by the statistical power of our cohort since we have only 20% of BS patients with an HV interval 55 ms. Fifty-four out of the 59 patients (91.5%) were screened for SCN5A mutations. Five patients (8%) were identified as having this mutation, and only two of them had documented AF during follow-up. However, all patients who presented AAs had been screened for this specific gene.

Nine initiations of AA could be recorded on ambulatory Holter ECG, each time with a premature atrial contraction with P-on-T morphology triggering the episode.

Multivariate Cox regression analysis showed that ventricular inducibility during electrophysiological exploration was related to a history of sudden death or syncope (), an abnormally prolonged HV interval (55 ms, ), and the existence of atrial arrhythmic episodes () during follow-up (Table 2).

Throughout the entire follow-up, there were nine appropriate ICD interventions in 10.5% of ICD patients. Episodes of monomorphic tachycardia were observed in one patient and terminated with anti-tachycardia pacing. Episodes of ventricular fibrillation were documented in two patients appropriately treated by ICD shock. In these two patients, atrial arrhythmias were also documented during follow-up.

There were 11 inappropriate ICD interventions (two episodes of anti-tachycardia pacing and nine shocks) due to atrial arrhythmias with a rapid ventricular rate (170 bpm). Inappropriate shocks were observed in 14% of ICD patients, representing 52% of all the ICD therapies delivered during the follow-up period. These patients all had a single-chamber device. One patient with paroxysmal atrial flutter underwent successful radiofrequency ablation of the cavo-tricuspid isthmus. The implantation of an atrial lead performed in the three other patients suppressed inappropriate ICD shocks. In contrast, four patients with a dual-chamber ICD and atrial fibrillation during follow-up had no inappropriate shocks because the devices identified the episodes correctly. Multivariate statistical analysis identified the implantation of a single-chamber device as an independent predictive factor of inappropriate discharges ().

Discussion

Incidence and mechanism of atrial arrhythmias in Brugada syndrome
Our data not only confirmed that BS patients exhibit a high prevalence of atrial arrhythmias,3,10,11 but also highlighted the high incidence of AAs in a 3-year follow-up. Our patients presented with a normal P wave (duration and morphology) on the surface ECG and a normal echocardiographic atrial size. These findings argue against a structural form of atrial disease, but suggest a pure electrical aetiology of AAs as an extension of the arrhythmogenic substrate to the atrial level. Atrial vulnerability was not tested since we voluntarily studied the clinical incidence of spontaneous AA episodes and their therapeutic consequences. However, it has already been shown that this parameter could be pathological in a high proportion of BS patients.11 Concerning the trigger of these arrhythmias, recording of atrial arrhythmic episodes on Holter ambulatory ECG demonstrated a premature atrial contraction triggering these episodes. We could not record 12-lead ECGs of these premature atrial contractions, which appeared to be rare. However, the prematurity and P-on-T morphology of these beats suggest a pulmonary vein origin.

Prognostic value of atrial arrhythmias in Brugada syndrome
The highly significant relationship between a history of atrial arrhythmias and the inducibility of ventricular arrhythmias during electrophysiological study is an important step in the risk stratification of BS patients. Despite conflicting evidence on the prognostic value of programmed ventricular stimulation,9,12–16 it has been suggested that ventricular inducibility is likely to be a good predictor of outcome in terms of the incidence of ventricular arrhythmias.2,17 Patients who presented a BS-type ECG only after administration of flecainide have been suggested to have a better prognosis.9,13,18 In our study, these patients presented less atrial arrhythmic events than those with a spontaneous BS ECG pattern. Accordingly, we suggest that BS patients with paroxysmal atrial arrhythmias may present with a more advanced level in the disease process. Furthermore, during follow-up, the incidence of atrial arrhythmias was significantly much higher in BS patients with an ICD (27%) than in BS patients without (13%). Since BS patients with an ICD are supposed to be the population with the highest risk of sudden death (i.e., the most severe patients), it was not surprising to observe the highest proportion of patients with atrial arrhythmias in the ICD group. This observation might indicate a more severe disease process in the group with both a BS-ECG pattern and atrial arrhythmias.

The low incidence of ventricular arrhythmias in the follow-up (10.5% of our patients) did not allow evaluation of the close relationship between ventricular and atrial arrhythmias during follow-up.

Therapeutic implications
Our study showed a higher proportion of inappropriate ICD discharges than appropriate ones. Even though some BS patients presented with conduction disturbances, the mean Wenckebach cycle did not differ between BS patients and controls and we recorded a fast ventricular rate during atrial arrhythmia episodes. At the onset of the study, the presence of atrial arrhythmias was not an indication for dual-chamber ICD implantation unless we diagnosed sinus node dysfunction. Multivariate statistical analysis revealed that single-chamber device implantation and the presence of atrial arrhythmic episodes were the two independent predictive factors of inappropriate ICD interventions. This finding has two important implications. First, in BS patients with already documented atrial arrhythmias, a dual-chamber ICD appears more appropriate. Second, in BS patients without a history of atrial arrhythmia, meticulous programming of a single-chamber ICD is required. However, in the present study inappropriate shocks occurred despite careful programming of the single-chamber ICD. The latter finding indicates that larger studies are needed to determine if a dual-chamber ICD should be recommended in BS patients to prevent inappropriate shocks for atrial arrhythmias.

Study limitations
The number of AAs might have been underestimated due to the eventual presence of asymptomatic episodes. The ventricular inducibility rate was lower than has been observed in previous studies. However, Eckard et al.14 have reported that 65% of their cohort of BS patients were only inducible with coupling intervals of less than 200 ms. The fact that our stimulation protocol stopped at 200 ms could explain these differences. Our PES protocol consisted in 3 (S2–S3–S4) ventricular extra stimuli with 2 cycle lengths (600 and 400 ms) at 2 right ventricular sites (apex and pulmonary outflow tract). It may be that our patients were less severely affected than others in recent published studies. In addition, the particularly low proportion of BS patients with an increased HV interval might also partially explain the relatively low percentage of ventricular inducibility.

Finally, controls were matched by sex and age criteria because the results provided by electrophysiological exploration are known to be influenced by such variables. The aim of the control group was to compare the electrophysiological variables between Brugada syndrome patients and healthy subjects. Only 31 healthy subjects gave us their written consent to undergo this electrophysiological exploration.

Footnotes

1 The first two authors contributed equally to this work. Back

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