Prevalence and prognostic value of conduction disturbances in patients with the Brugada syndrome (BrS) remains poorly known. Electrocardiograms (ECGs) from 325 patients with BrS (47 ± 13 years, 258 men) with spontaneous (n = 143) or drug-induced (n = 182) type 1 ECG were retrospectively reviewed. Two hundred twenty-six patients (70%) were asymptomatic, 73 patients (22%) presented with unexplained syncope, and 26 patients (8%) presented with sudden death or implantable cardioverter-defibrillator appropriated therapies at diagnosis or during a mean follow-up of 48 ± 34 months. P-wave duration of ≥120 ms was present in 129 patients (40%), first degree atrioventricular block (AVB) in 113 (35%), right bundle branch block (BBB) in 90 (28%), and fascicular block in 52 (16%). Increased P-wave duration, first degree AVB, and right BBB were more often present in patients after drug challenge than in patients with spontaneous type 1 ST elevation. Left BBB was present in 3 patients. SCN5A mutation carriers had longer P-wave duration and longer PR and HV intervals. In multivariate analysis, first degree AVB was independently associated with sudden death or implantable cardioverter-defibrillator appropriated therapies (odds ratio 2.41, 95% confidence interval 1.01 to 5.73, p = 0.046) together with the presence of syncope and spontaneous type 1 ST elevation. In conclusion, conduction disturbances are frequent and sometimes diffuse in patients with BrS. First degree AVB is independently linked to outcome and may be proposed to be used for individual risk stratification.
The Brugada syndrome (BrS) has been initially described on an electrocardiogram (ECG) by the association of a right bundle branch block (RBBB) and persistent ST elevation in the right precordial leads. However, the first item of this initial definition—the RBBB—seems to have been forgotten since these initial reports, as only ST elevation was present in the definition given in both consensus reports from 2002 to 2005.
Paucity of true RBBB in patients with BrS was noted early on. However, many patients with BrS have prolonged PR and HV intervals, and late potentials can be found in most patients on signal-averaged ECG. Delayed activation at the right ventricular outflow tract was observed in explanted heart, on endocardial and epicardial mapping and on body surface maps when r’ wave was present in lead V 1 . ST elevation has been proposed to be the result of a delayed activation at the right ventricular outflow tract. Thus, diverse conduction disturbances at various levels seem to be present in BrS, prevalence of which is however poorly known. Furthermore, conduction abnormalities may contribute to the occurrence of malignant ventricular arrhythmias in BrS by providing or worsening a proarrhythmic substrate.
The aim of this work was to study the prevalence of various conduction disturbances in a large series of patients with BrS and their correlations with usual clinical and electrophysiologic parameters and with outcome.
Methods
We performed a retrospective multicentric study including consecutive patients with BrS recruited at 4 French University Hospitals. BrS diagnosis was made according to the currently accepted criteria in patients with either spontaneous type 1 ST elevation or type 1 ST elevation occurring after drug challenge (ajmaline 1 mg/kg over 5 minutes or flecainide 2 mg/kg over 10 minutes). For each patient, the 12-lead surface ECG with the highest type 1 ST elevation was used for analysis, either spontaneous or after provocative test (paper speed 25 mm/s, amplification 1 cm/mV).
Durations of the P wave, PR interval, and QRS complex were measured in lead II. Presence of intraventricular conduction disturbances was defined according to slightly modified criteria drawn from the current guidelines for electrocardiographic interpretation :
- 1.
RBBB was defined by a QRS duration of >0.12 second (complete RBBB) or >0.11 second (incomplete RBBB) together with an S wave >40 ms in lead I. We added a minimal amplitude of 0.1 mV for this S wave to be significant to exclude some inconsistent negative terminal waves. QRS patterns in leads V 1 and V 2 were not used for defining RBBB because these indexes are very difficult or even impossible to characterize in case of prominent J wave or ST elevation in the right precordial leads.
- 2.
Left anterior fascicular block (LAFB) was defined by a QRS axis between −45° and −90° together with a Q wave and R peak time >40 ms in lead aVL.
- 3.
Left posterior fascicular block (LPFB) was defined by a QRS axis between +90° and 180° together with a Q wave in leads III and aVF and rS pattern in leads I and aVL.
- 4.
Left bundle branch block (LBBB) was defined by a QRS duration >0.12 second (complete LBBB) or >0.11 second (incomplete LBBB) together with a broad notched or slurred R wave in leads I and VL and lack of Q wave in lead I. QRS patterns in leads V 1 and V 2 were not used because of the presence of J wave interfering with the morphology of the QRS complex.
Furthermore, we analyzed aVR lead, looking for the “aVR sign” and the presence of fragmented QRS in leads V 1 to V 3 .
Electrocardiographic analysis and measurements were performed by a single observer blinded to the symptoms (PM) and further independently performed by a second observer (AR) in a randomly selected subgroup of ECGs (1 of 3 patients) to define the interobserver correlations.
Patients were divided into 3 groups depending of their symptoms and/or documented spontaneous ventricular arrhythmias at the time of diagnosis or during follow-up as asymptomatic, unexplained syncope (supposed to be caused by malignant ventricular arrhythmia after exclusion of other causes such as neurocardiogenic syncope), and malignant ventricular arrhythmias: sudden cardiac death (SD) or implantable cardioverter-defibrillator therapies (ICDth).
Continuous data are expressed as mean ± standard deviation, or as median and range in case of variable with non-Gaussian distribution. Continuous variables were compared using unpaired t test or Mann-Whitney nonparametric test as suitable, and categorical variables were compared using chi-square test. Correlations between numerical values were tested using Spearman rank correlation test. For evaluating interobserver correlations, intraclass correlations and κ statistics were used when appropriate. Logistic regression was used to investigate the association between variables and arrhythmic events and to determine odds ratio and 95% confidence intervals for univariate and multivariate analyses. Multivariate analysis was performed with the variables significantly associated in univariate analysis (with a p value <0.1). Because a very few events happened during the follow-up, and for a more simple presentation of the results, cardiac events both at initial presentation and during follow-up were combined for statistical analysis. Analysis and calculations were performed using STATVIEW program (Abacus Concepatients Inc., Berkeley, California; 1992 to 1996, version 5.0). A p value <0.05 was considered statistically significant for each analysis.
Results
Three hundred twenty-five patients with BrS were included (mean age 47 ± 13 years, 258 men [79%]). Most patients were index cases (only 35 related cases from 14 families). BrS diagnosis was made in 143 (44%) patients because of spontaneous type 1 ST elevation and in 182 (56%) after drug challenge.
Electrophysiologic investigation had been performed in 219 patients (67%) and a sustained ventricular arrhythmia was inducible in 93 (42%) of 219. Mean HV interval was 52 ± 10 ms, with 30% and 3.5% displaying a prolonged HV interval of ≥55 and ≥70 ms, respectively.
Atrial fibrillation was documented in 26 patients (8%). There was a familial history of SD in 94 (29%) of 324 patients. Result of genetic testing was available in 189 patients (58%), with presence of SCN5A mutation in 42 (22%) of 189 patients. An implantable cardioverter-defibrillator was implanted in 135 patients (42%). The indication for implantable cardioverter-defibrillator implantation was a resuscitated SD in 10 patients, an unexplained syncope in 55, an inducible arrhythmia in 56, a history of familial death in 11, and unspecified in the remaining 3 patients.
The intraclass correlations were 0.88 for the QRS width and 0.81 for the P-wave duration, whereas κ value was 0.95 for the presence of RBBB and 1 for the presence of fascicular block (FB).
PR interval and/or P-wave durations could not be measured in a few patients because of atrial fibrillation (2 patients), junctional escape rhythm (1 patient), or unreliable P-wave analysis (3 patients).
Mean P-wave duration was 107 ± 23 ms. A P-wave duration of ≥120 ms was present in 129 patients (40%), more often after drug challenge than in patients with spontaneous type 1 ST elevation (45% vs 27%, p = 0.001).
Mean PR interval was 182 ± 36 ms. First degree atrioventricular block (AVB; PR of ≥200 ms) was present in 113 patients (35%), more often during pharmacologic challenge than in patients with spontaneous type 1 ECG (43% vs 23%, p = 0.0003). No patient presented with second or third degree AVB on baseline ECG.
Mean QRS duration was 109 ± 19 ms. RBBB was present in 90 patients (28%; complete in 75 and incomplete in 15; Figure 1 ). Because of the only 10 ms difference between complete and incomplete RBBB (see Methods), only RBBB (whether complete or incomplete) was used for further analysis. RBBB was more often present in patients during pharmacologic challenge than in patients with baseline type 1 ST elevation (33% vs 20%, p = 0.01).
LAFB was present in 35 patients (11%) and LPFB in 17 patients (5%) leading to a total of FB in 52 patients (16%; Figure 2 ). FB was not more often observed in patients after drug challenge than in patients with spontaneous type 1 ECG (17% vs 14%, p = 0.3). Twenty patients (6%) presented with bi-FB (13 LAFB + RBBB and 7 LPFB + RBBB).
LBBB was present in 3 patients (complete in 2; <1%). Seventy-nine patients (24%) have undetermined intraventricular conduction disturbances (QRS of ≥110 ms without RBBB or LBBB pattern).
Only 69 (21%) patients with BrS presented without any conduction disturbance on ECG.
Significant correlations between conduction disturbances and clinical or electrophysiologic parameters are listed in Table 1 . In addition, PR duration was positively correlated to P-wave (p <0.0001), QRS (p = 0.02), and HV interval durations (p = 0.002).
| Parameters | p | ||
|---|---|---|---|
| P Wave of ≥120 ms (%) | P Wave of <120 ms (%) | ||
| Age (yrs) | 49 ± 14 | 45 ± 12 | 0.007 |
| First degree AVB | 66/123 (53) | 46/196 (23) | <0.0001 |
| RBBB | 43/123 (34) | 86/196 (23) | 0.026 |
| FB | 28/123 (24) | 21/196 (11) | 0.004 |
| PR interval (ms) | 198 ± 38 | 173 ± 31 | <0.0001 |
| Heart rate (beats/min) | 65 ± 23 | 71 ± 20 | 0.003 |
| First degree AVB | No AVB | ||
| HV interval (ms) | 55 ± 12 | 50 ± 9 | 0.004 |
| Heart rate (beats/min) | 72 ± 21 | 63 ± 16 | 0.0001 |
| P wave of ≥120 ms | 66/112 (59) | 57/207 (28) | <0.0001 |
| RBBB | 38/113 (34) | 52/209 (25) | 0.09 |
| FB | 29/113 (26) | 20/209 (10) | 0.0001 |
| P-wave duration (ms) | 120 ± 24 | 99 ± 19 | 0.0001 |
| RBBB | No RBBB | ||
| PR interval (ms) | 190 ± 39 | 180 ± 34 | 0.02 |
| QRS width (ms) | 125 ± 15 | 103 ± 17 | <0.0001 |
| P wave of ≥120 ms | 43/89 (48) | 80/230 (35) | 0.026 |
| First degree AVB | 38/90 (42) | 75/232 (32) | 0.09 |
| FB | 20/90 (22) | 32/235 (14) | 0.05 |
| P-wave duration (ms) | 112 ± 24 | 105 ± 23 | 0.01 |
| FB | No FB | ||
| PR interval (ms) | 200 ± 38 | 180 ± 35 | 0.0003 |
| P-wave duration (ms) | 117 ± 22 | 105 ± 23 | 0.0002 |
| QRS duration (ms) | 114 ± 22 | 108 ± 18 | 0.03 |
| Age (yrs) | 50 ± 13 | 46 ± 13 | 0.03 |
| HV interval (ms) | 59 ± 14 | 51 ± 9 | 0.002 |
| AFib | 9/52 (17) | 17/273 (6) | 0.007 |
| First degree AVB | 29/49 (59) | 84/273 (31) | 0.0001 |
| RBBB | 20/52 (38) | 70/273 (26) | 0.05 |
| P wave of ≥120 ms | 28/49 (57) | 95/270 (35) | 0.004 |
The “aVR sign” was present in 118 patients (36%) and was independently associated to the presence of both RBBB (56% in case of “aVR sign” vs 29%, p <0.0001) and FB (65% vs 31%, p <0.0001). Fragmented QRS was noted in 8 patients (2.5%) and was not correlated to any other electrocardiographic or electrophysiologic finding.
Characteristics of conduction parameters in patients with and without SCN5A mutation are listed in Table 2 . There was no significant difference in the proportion of spontaneous type 1 ST elevation between patients with or without SCN5A gene mutation (55% vs 44%, p = 0.2).
| Variable | SCN5A + , n = 42 (%) | SCN5A − , n = 147 (%) | p |
|---|---|---|---|
| P-wave duration (ms) | 115 ± 26 | 108 ± 22 | 0.09 |
| PR interval (ms) | 204 ± 33 | 185 ± 35 | 0.0017 |
| QRS duration (ms) | 114 ± 22 | 109 ± 20 | 0.19 |
| HV interval (ms) | 59 ± 14 | 51 ± 8 | 0.001 |
| Heart rate (beats/min) | 69 ± 25 | 60 ± 17 | 0.019 |
| P wave of >120 ms | 21/42 (51) | 62/144 (43) | 0.35 |
| First degree AVB | 27/42 (64) | 48/145 (33) | 0.0003 |
| Fascicular block | 11/42 (26) | 20/147 (14) | 0.05 |
| RBBB | 15/42 (36) | 39/147 (27) | 0.24 |
| Unspecified intraventricular conduction disturbances ∗ | 7/42 (17) | 37/147 (25) | 0.25 |
Combining cardiac events both at initial presentation and during follow-up (48 ± 34 months), 226 patients (70%) remained asymptomatic, unexplained syncope occurred in 73 patients (22%), and 26 (8%) presented with malignant ventricular arrhythmias (12 patients with SD and 14 with ICDth).
Correlations of usual clinical and electrophysiologic parameters and of various conduction disturbances with the occurrence of malignant ventricular arrhythmias (SD and/or ICDth) in univariate and multivariate analyses are listed in Table 3 . The presence of first degree AVB was independently associated with SD and/or ICDth (odds ratio 2.41, 95% confidence interval 1.01 to 5.73, p = 0.046) together with the presence of syncope and of spontaneous type 1 ST elevation. The presence of a first degree AVB had 54% sensitivity, 67% specificity, 12% positive, and 94% negative predictive values for the occurrence of malignant ventricular arrhythmia (accuracy 66%). We observed a proportion of events of 12.4% in patients with AVB and 5.7% in those without AVB. A population size of 903 patients would provide an 80% power to significantly assess such a difference between groups (with a 1% type 1 error rate).
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