|Year : 2018 | Volume
| Issue : 2 | Page : 41-48
Risk stratification in Brugada syndrome
Masahiko Takagi, Ichiro Shiojima
Department of Medicine II, Kansai Medical University, Moriguchi, Osaka, Japan
|Date of Web Publication||5-Feb-2019|
Dr. Masahiko Takagi
Division of Cardiac Arrhythmia, Department of Medicine II, Kansai Medical University, 10-15 Fumizono-Cho, Moriguchi 5708507, Osaka
Source of Support: None, Conflict of Interest: None
Brugada syndrome is an arrhythmogenic disease associated with sudden cardiac death due to ventricular arrhythmias. The risk stratification of patients without previous cardiac arrest remains the most controversial issue, especially for asymptomatic individuals, in Brugada syndrome. We review the recent data of several clinical, electrocardiographic, and electrophysiological parameters proposed for risk stratification. A history of documented fatal ventricular arrhythmias or aborted sudden cardiac death and/or arrhythmogenic syncope is a predictor of arrhythmic events, whereas the prognostic value of a familial history of sudden cardiac death and the presence of an SCN5A mutation are not well defined. On the electrocardiographic features, the spontaneous type 1 electrocardiogram (ECG) is associated with the risk for arrhythmic events in most of the studies, whereas early repolarization and fragmented QRS increases the risk in some studies. Late potentials using signal-averaged ECG and microscopic T-wave alternans indicate some available results in small studies that should be validated. The prognostic value of programmed electrical stimulation during electrophysiological study as a risk marker also remains controversial. A less aggressive protocol of programmed electrical stimulation may be preferable for risk stratification in the Brugada syndrome patients without previous cardiac arrest. Multiparametric approaches evaluating specific clinical factors and ECG may improve risk stratification.
Keywords: Brugada syndrome, noninvasive marker, programmed electrical stimulation, review, risk stratification
|How to cite this article:|
Takagi M, Shiojima I. Risk stratification in Brugada syndrome. Int J Heart Rhythm 2018;3:41-8
| Introduction|| |
Brugada syndrome (BrS) is an arrhythmogenic disease characterized by specific ST-segment elevation in the right precordial leads on the 12-lead electrocardiogram (ECG) without any structural heart disease and an increased risk of sudden cardiac death (SCD) due to fatal ventricular arrhythmia.,
Currently, little controversy exists on the highest risk of recurrence of ventricular fibrillation (VF) or SCD among patients with spontaneous type 1 ECG and documented VF or aborted SCD, who are strongly advised to implant an implantable cardioverter-defibrillator (ICD)., On the contrary, risk assessment in patients without previous documented VF or SCD, especially those for asymptomatic individuals, has not been fully established.
The current review aims to focus on the risk stratification in BrS patients based on available data mainly derived from registry studies.
| Diagnosis of Brugada Syndrome|| |
According to the 2015 guidelines for the management of patients with ventricular arrhythmia and prevention of SCD, and the J-wave syndromes expert consensus conference report, the diagnosis of BrS is based on the specific ECG characteristics: J-point elevation ≥2 mm followed by coved-type ST-segment elevation and negative T wave (type 1 ECG) in at least one of the right precordial leads positioned in the 2nd to 4th intercostal space occurring either spontaneously or after pharmacologic challenge with a Class I antiarrhythmic agent (ajmaline, procainamide, flecainide, or pilsicainide) which can convert type 2 or type 3 ECG to type 1 ECG [Figure 1]A,[Figure 1]B,[Figure 1]C. Type 2 ECG is characterized by a high take-off of ≥2 mm and a saddleback-type ST-segment configuration ≥1 mm [Figure 1]B. Type 3 ECG displays a J-point elevation ≥2 mm and either a saddleback-type or coved-type ST-segment elevation of <1 mm.
|Figure 1: Representative Brugada-type ECGs. (A) Type 1 ECG in leads V1 and V2. (B) Type 2 ECG in lead V2. (C) Type 2 ECG in lead V2 before pilsicainide administration (a) and type 1 ECG in lead V2 after pilsicainide administration (b). ECG=Electrocardiogram|
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| Prevalence of Brugada Type Electrocardiogram (Types 1–3)|| |
The prevalence of Brugada type ECG (types 1–3) has been reported in several countries. However, it depends on regions and gender. According to some meta-analysis of the population-based studies,,, the mean worldwide prevalence was about 0.4%, with the highest in Asia (0.9%) and lowest in North America (0.2%). Pooled prevalence of types 1 and 2–3 ECG was 0.03%–0.05% and 0.42%–0.61%, respectively., The prevalence of type 1 ECG was higher in Asia (0.18%). The highest prevalence was found in Southeast Asia (0.37%), followed by the Middle Asia, East Asia, Europe, and North America. The prevalence of type 2 or 3 ECG was also higher in Asia (0.83%). The sex difference for the prevalence of Brugada type ECG was 0.9% in males, whereas 0.1% in females.
| Prognosis of Brugada Syndrome|| |
Definition of “arrhythmic events” in Brugada syndrome
In the majority of large-scale studies, appropriate ICD therapies or SCD was defined as the arrhythmic events, and most of them were appropriate ICD therapies rather than SCD., However, using “appropriate ICD therapies” as a surrogate for SCD tends to overestimate the actual risk of SCD among patients without ICD. This has been evaluated for BrS patients.
However, in this review, “arrhythmic events” represent appropriate ICD therapies or SCD because of evaluation based on data mainly from previous registry studies.
Prognosis of symptomatic patients with Brugada syndrome
Most of the studies consistently indicate that the risk of arrhythmic events is the highest for patients with previously documented VF or SCD, intermediate for those with arrhythmic syncope, and the lowest for asymptomatic individuals at enrollment. Therefore, the risk of recurrence of arrhythmic event is the highest for patients who previously experienced VF or SCD with an event rate of about 35% at 4 years,, 44% at 7 years, and 48% at 10 years. The risk of arrhythmic events for patients with syncope is 4 times higher than that of originally asymptomatic individuals but 4 times lower compared with that of patients with previously documented VF or SCD. Approximately 30% of BrS patients experience syncope., However, patients with syncope derived from most registries were divided into two groups: the arrhythmic syncope with bad prognosis and the nonarrhythmic syncope such as vagal syncope with good prognosis. A significant percentage of patients with nonarrhythmic syncope repeat some episodes of nonarrhythmic syncope and those with nonarrhythmic syncope are at a very low risk for SCD (0%–0.3% per year) compared with arrhythmic syncope (2.2% per year).
Prognosis of asymptomatic patients with Brugada syndrome
Although some initial studies showed a relatively high rate of fatal arrhythmic events in individuals without symptoms,,,, recent studies reported much lower rate of cardiac events (VF or SCD). In the France, Italy, Netherlands, and Germany (FINGER) registry, the largest series of BrS, the incidence of the arrhythmic events in individuals without symptoms was 0.5% per year. In a substudy of the FINGER registry with a 66-month follow-up period, 4.5% of the individuals without symptom had a newly arrhythmic event (0.8% per year). Similarly, in the PRogrammed Electrical stimUlation preDictive valuE (PRELUDE) registry, an annual rate of arrhythmic events in asymptomatic individuals with type 1 ECG was about 1%. Recently, we reported data on 267 asymptomatic BrS individuals with a mean follow-up of 50 ± 30 months and the annual rate of cardiac events was 0.3%. In a recent meta-analysis including 2743 individuals, the annual rate of cardiac event for individuals without symptom was 1%. Until now, similar results of the low incidence of arrhythmic events in asymptomatic individuals have been reported in some studies.,,,,,,,,
In about 50% of BrS patients, arrhythmic events will suddenly occur as VF without any premonition. It is difficult to predict the progression of the arrhythmic risk. Sacher et al. revealed that the rate of arrhythmic event is easily fixed over time in BrS patients with an ICD. The rate of appropriate therapy for 10 years after ICD implantation was 12% in asymptomatic individuals. Raju et al. have recently reported that most of SCD occur in previously asymptomatic individuals. These data reveal the necessity to establish a more precise risk marker for asymptomatic individuals.
| Risk Stratification in Brugada Syndrome|| |
The majority of the clinical, electrocardiographic, and electrophysiological variables have been evaluated in symptomatic patients with syncope or aborted SCD.,, Most of these factors have not been evaluated in a prospective study. Therefore, their utility in risk stratification for asymptomatic individuals is still unknown.
Age and sex
Different registries have shown the male dominance of BrS., Male gender increases the 3-fold risk of a spontaneous type I ECG and of inducibility of ventricular tachycardia (VT)/VF by programmed electrical stimulation (PES). Moreover, male gender increases a 7-fold risk of arrhythmic events. In large registries, male gender was 64%, 89%, and up to 94% of patients with SCD. A recent pooled analysis from 24 clinical studies also showed that male gender is associated with a higher risk of arrhythmic events. In male patients, symptomatic patients have a higher risk of arrhythmic events compared to asymptomatic individuals, but not within the female patients. However, because most of the asymptomatic individuals are also male, gender is not an independent predictor of arrhythmic events., Recently, Sieira et al. have reported that female individuals tended to be asymptomatic and less displayed the type 1 ECG. The prognosis and clinical presentation in female are more benign with an annual rate of arrhythmic event (0.25% per year).
Although the genetic trait is present from birth, the mean age at the onset of cardiac arrest was 39–48 years in different large series.,, Most patients with arrhythmic events were between 20 and 65 years.,,, In a recent survey, the majority (94.2%) of the patients were 16–70 years at the time of arrhythmic event, whereas elderly (>70 years) and pediatric (<16 years) patients were 1.5% and 4.3%, respectively. Arrhythmic event most frequently occurred at 38–48 years (mean, 42 ± 15; range, 0.3–84 years).
Familial and genetic background
Physicians tend to pay attention to genetic tests and their values on risk assessment because BrS is classified as a genetic arrhythmic syndrome. However, results from some studies are still controversial. Kamakura et al. have shown that a family history of SCD occurring at <45 years old is an independent risk marker for poor prognosis. Delise et al. have demonstrated that family history of SCD may have prognostic value only in combination with other risk markers. On the contrary, in other studies including a meta-analysis, a family history of SCD was not confirmed to have predictive value for future arrhythmic events., Moreover, a family history of SCD was not associated with the increase of SCD in patients with family history of SCD in a first-degree relative, or in those with CD in a young (<35 years old) relative or multiple SCD in the same family.
In 19 genes, mutations have been identified in individuals with Brugada type ECG until now. Most of the mutation are SCN5A gene mutation encoding for the cardiac sodium channel. However, screening of gene abnormality identifies this mutation only in approximately 15%–20% of BrS patients.,,,,,,,,,,, Furthermore, risk stratification of other rare genes mutations associated with BrS is still lacking. Some large-scale registries had not found an association between the SCN5A gene mutations with the risk of cardiac events.,,, On the contrary, a recent multicenter registry demonstrated an association between the SCN5A gene mutations with the cardiac events. The individuals with SCN5A mutations in the pore region were associated with significantly poorer outcomes compared to those without the SCN5A mutation, among probands with prior syncope and probands without symptoms, as well as in the entire cohort. Multivariate analysis revealed that only BrS patients with SCN5A mutation showed more conduction delay and had a higher risk for future cardiac events. Moreover, a recent systemic review and meta-analysis from seven studies reported a significant association between SCN5A mutations and major arrhythmic events in the Asian population. Whether the detailed genetic analysis is a promising tool in risk assessment of BrS patients or not is needed to validate in future studies.
The risk of arrhythmic events in patients with syncope is intermediate. One of the reasons for this intermediate-risk prognosis is that the syncope population derived from most studies consists of patients with arrhythmic and nonarrhythmic syncope. One study showed that VF occurred in 22% of patients with presumably arrhythmic syncope but in none of the patients with nonarrhythmic syncope during follow-up. Similarly, in another study, 12% of patients with presumed arrhythmic syncope but none of those with nonarrhythmic syncope documented VF episodes during follow-up of 4.5 years. These data show that the discrimination of syncope is important by taking a detailed clinical history at the time of syncope. Some studies revealed prodromes with blurred vision suggests nonarrhythmic syncope and abnormal respiration is observed with arrhythmic syncope., Recently, some studies showed the presence of fragmented QRS and a spontaneous type 1 ECG correlate with a high arrhythmic risk in patients with arrhythmic syncope.,
Several ECG parameters have been proposed for the risk assessment in BrS patients [Table 1].
|Table 1: ECG parameters proposed for the risk stratification in Brugada syndrome|
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Spontaneous type 1 electrocardiogram
General consensus exists that patients with spontaneous type 1 ECG have a higher risk than those with drug-induced type 1 ECG for arrhythmic events.,,, A meta-analysis also demonstrated that individuals with spontaneous type 1 ECG had a threefold to 4-fold increased risk of arrhythmic events compared to those with a drug-induced type 1 ECG. This observation applies for asymptomatic individuals and for patients with syncope.,, In addition to place the recording electrodes on the standard fourth intercostal space, electrodes on the right precordial upper intercostal spaces increase the sensitivity for detecting the type 1 ECG., The value of spontaneous type 1 ECG for predicting VF was similar on ECG recorded on the right precordial upper intercostal spaces.,
Several studies indicated the fragmented QRS (f-QRS; multiple spikes in the QRS in leads V1 to V3) was associated with increased risk of arrhythmic events,,,, but another study did not support the result. Take et al. reported that, in patients with syncope, those with f-QRS had 2-fold risk of fatal ventricular arrhythmia compared to the risk in those without. A prospective study of patients without previous cardiac arrest revealed patients with f-QRS had 9-fold risk for fatal ventricular arrhythmia. Recent meta-analysis also showed an association between f-QRS and arrhythmic event in BrS. Rattanawong et al. reported that patients with baseline f-QRS had up to 3-fold arrhythmic events (VF, sustained VT, SCD, or sudden cardiac arrest). Moreover, a meta-analysis of f-QRS from eight studies showed f-QRS predicted future cardiac events in BrS. However, we need to pay attention to the definitions of f-QRS, which was different among studies, and ECG filter settings because it is still unclear how different filter settings would have an influence on f-QRS.
aVR sign and S wave in lead I
One study reported that the aVR sign defined R/q ≥0.75 or R wave ≥0.3 mV in lead aVR may be a risk factor for the development of fatal arrhythmic events. Recently, another study revealed the presence of a large and/or wide S-wave in lead I may be a predictive marker of ventricular tachyarrhythmias. These parameters have been speculated to be related to the conduction abnormality in the right ventricular outflow tract (RVOT)., However, this relationship with fatal ventricular tachyarrhythmias was not confirmed in a larger study.
Wide QRS width
A wide QRS duration in leads II, V2, and V6 has been proposed as a noninvasive risk factor of fatal VT/VF in BrS patients., Recent reports indicated that a wide QRS duration in lead V1 or V2 predicted ventricular tachyarrhythmias or syncope in BrS.,,,
Inferolateral early repolarization
The early repolarization (ER) pattern in inferior and/or lateral leads is seen in 12%–15% of BrS.,, Several studies have demonstrated that the ER pattern predicts future arrhythmic events.,, In particular, it have been shown that patients with inferolateral J waves and/or horizontal ST-segment morphology following the J wave [Figure 2] display a higher incidence of cardiac events than those without. The inferolateral ER is associated not only with VF episodes but with VF storms. A recent meta-analysis on the prognostic value of ER pattern in BrS revealed that patients with ER showed a higher risk of arrhythmic events compared to those without ER (odds ratio 3.29). Based on these findings, the inferolateral ER pattern in BrS appears to be highly arrhythmogenic.
|Figure 2: Inferolateral ER in patients with Brugada syndrome. (a) Horizontal ST segment in the leads deploying notching type of J wave (J waves are marked with solid arrows). Dotted arrow indicates slurring type of J wave. (b) Rapidly ascending (dotted arrow) ST segment in the leads deploying notching type of J wave (solid arrows). ER=Early repolarization|
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Type 1 electrocardiogram in peripheral leads
One study reported that 10% of patients with a positive ajmaline challenge test developed type 1 ECG not only in the right precordial leads but in peripheral leads. In another study, 9% of the patients showed type 1 ECG in at least one peripheral lead either spontaneously or after ajmaline challenge test. In this study, spontaneous VF was documented in 8 of the 30 patients with peripheral type 1 ECG but in 18 of 293 patients who showed type 1 ECG only in the right precordial leads. Furthermore, in the series of 234 initially asymptomatic individuals, it has been reported that 13% of those with right precordial and peripheral type 1 ECG but 3% with only right precordial type 1 ECG developed spontaneous VF within 4 years.
Intervals between T peak and T end (T p-e) and T p-e dispersion
A QTc interval >460 ms in lead V2 as well as an increased T peak-T end interval (T p-e), and T p-e dispersion in the precordial leads have been reported to be associated with fatal arrhythmic events in BrS. Another study also showed that the T p-e and T p-e dispersion significantly increased in patients with SCD and appropriate ICD therapies and that the T p-e is associated with arrhythmic events in BrS. Recent meta-analysis demonstrated that increased T p-e was related to up to 5.7-fold risk of VT/VF and/or SCD in BrS patients.
A prospective study evaluating signal-averaged ECG reported that positive late potentials may have good predictive value for fatal ventricular arrhythmias in BrS. In another study, the positive predictive value, the predictive accuracy, and the negative predictive value of the late potentials were 92.0%, 86.4%, and 78.9%, respectively. We reported that daily fluctuations in specific 12-lead ECG and signal-averaged ECG characteristics were useful for distinguishing high-risk and low-risk patients in BrS, and that patients with previously VF episodes more frequently have late potentials after a pilsicainide challenge test. The limitation of late potentials for clinical use is the high prevalence in both symptomatic and asymptomatic cases. The late potentials might be helpful for risk assessment in the setting of multiparametric approach.
Whether T-wave alternans (TWA) is a predictor for fatal arrhythmic event in BrS is still controversial., In our recent study, a higher level of TWA was more frequently observed at night in BrS patients with prior VF. Moreover, the increased nocturnal TWA was one of the independent predictors of cardiac events during the follow-up. Furthermore, in another study, we reported the prognostic significance of the seasonal variations of TWA in BrS. The patients with prior VF episodes showed the greatest max-TWA value in lead V2 at the third intercostal space during morning and had higher the max-TWA value in summer than in the other seasons.
Programmed electrical stimulation
The prognostic role of PES during electrophysiologic study remains to be debated because of conflicting evidence in BrS., Some studies suggest that inducibility of VT/VF during electrophysiologic testing predicts the future arrhythmic events,,, whereas large recent studies show the opposite result.,,
The prognostic value of PES for patients without previous cardiac arrest is limited and not enough for risk stratification and clinical decision-making. The recent large-scale studies,,,, including approximately 500 patients with syncope and studies with 3–5 years' follow-up, show the occurrence of arrhythmic events tends to be higher in patients with inducible VT/VF, but the risk for noninducible patients is also high. As mentioned earlier, the discrimination of syncope as arrhythmic or nonarrhythmic based on clinical history, is more important than the results of PES for risk stratification. For asymptomatic individuals at presentation, several meta-analysis of previous studies evaluating the prognostic significance of PES has been reported and the results remain controversial. The initial two meta-analysis demonstrated VT/VF inducibility was not associated with fatal arrhythmic events,, whereas recent other meta-analysis showed that inducibility of VT/VF at PES definitely predicted the future arrhythmic events.,,
There are several possible reasons for the conflicting evidence regarding the prognostic value of PES in BrS. First, the differences in the stimulation protocols, including basic cycle lengths, the number of extrastimuli, the minimum coupling intervals used (up to 200 ms or refractoriness), and the pacing site (right ventricular apex [RVA] and/or RVOT), impact on the results of the inducibility at PES. Second, a few number of asymptomatic individuals experience fatal ventricular arrhythmias during follow-up. Therefore, the statistical analysis for the prognostic significance of several parameters including the value of PES becomes challenging. The stimulation protocol differs in each study. The PRELUDE registry used a fixed stimulation protocol. RV was stimulated from RVA and RVOT. Basic cycle lengths were 600 and 400 ms, and minimal coupling intervals were effective refractory period ≥200 ms by up to 2 extrastimuli or effective refractory period by 3 extrastimuli. The order of pacing sites and the number of extrastimuli at both basic cycle lengths were up to 3 extrastimuli at one site then moved to another site. In this registry, inducibility of VT/VF was not confirmed to be a significant risk factor in all patients as well as those induced by up to 2 ventricular extrastimuli. On the other hand, Brugada group stimulated RV only from RVA. Basic cycle lengths were 600, 500, and 430 ms, and minimal coupling intervals were effective refractory period ≥200 ms by up to 3 extrastimuli. Using the same protocol, Sieira et al. indicated inducibility of VT/VF is only significant risk factor in 363 asymptomatic individuals at multivariate analysis. Recent two Japanese studies reported a utility of a uniform less aggressive protocol of PES for risk stratification in patients without previous cardiac arrest., In these studies, RV was stimulated from RVA and RVOT. The order of pacing sites and the number of extrastimuli were single and double stimulus from RVA, single and double from RVOT, triple from RVA, and then triple stimuli from RVOT. These studies revealed the PES inducibility by up to 2 extrastimuli had significant predictive value for future cardiac events. A less aggressive stimulation protocol at PES for VT/VF induction is preferable for risk assessment in patients without previous cardiac arrest.
Combinations of risk factors
Several studies showed the presence of several independent risk markers may improve risk stratification of patients without previous cardiac arrest.,,,,,, Most of them have shown the combination of spontaneous type 1 ECG and at least one other proposed risk marker is useful to identify high-risk patients for cardiac events.,, Two studies reported that combination of spontaneous type 1 ECG, syncope and inducible VT/VF at PES was predictive of later arrhythmic events., Delise et al. recently demonstrated that patients with spontaneous type 1 ECG and at least two other proposed risk factors (family history of SCD, syncope, or inducibility of VT/VF) are at higher risk of cardiac events. Furthermore, other studies exhibited that the combination of ER pattern and f-QRS is an independent risk marker of further arrhythmic events., Kawazoe et al. reported the combination of syncope, r-J interval in lead V1, QRS duration in lead V6 and T p-e dispersion was a useful marker to identify high-risk patients for cardiac events. Moreover, Sieira et al. revealed the combination of specific risk markers such as aborted SCD, syncope, spontaneous type 1 ECG, familial SCD at young age, inducible VT/VF, and sinus node dysfunction predicts more precisely risk of future arrhythmic events.
Although multiparametric approaches appear to be promising in risk stratification in BrS, the approaches should be validated in prospective studies including a larger number of patients, particularly for asymptomatic individuals.
| Conclusions|| |
Risk stratification in BrS patients is still a big challenge for physicians. Despite limited and conflicting evidence for risk assessment, especially in individuals without previous cardiac arrest, multiparametric approaches evaluating specific clinical, electrocardiographic, and electrophysiologic parameters may improve risk stratification, as individual risk factors show limited prognostic values. Prospective large-scale multicenter studies on risk stratification with longer follow-up more than 10 years will be needed to clarify this unsolved issue within the next decade.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]