Brugada syndrome is an inherited arrhythmogenic heart disease characterized by an increased risk of sudden cardiac death (SCD) due to ventricular tachycardia (VT)/ventricular fibrillation (VF). The syndrome accounts for approximately 4% of all SCD and up to 20% of sudden deaths in patients with structurally normal hearts.1 Several series have demonstrated a significant recurrence rate of malignant arrhythmic events in high-risk patients, suggesting that implantable cardioverter-defibrillator (ICD) implantation is beneficial.2–4 Risk stratification is thus a central step in assessment of patients with Brugada syndrome, allowing for the identification of individuals at higher risk of arrhythmic events who would benefit from an ICD. The problem is that there is still controversy as to how to stratify these patients and doubts as to which patients should receive a prophylactic ICD.

The most common variables associated with a higher risk of arrhythmic events in Brugada syndrome patients are aborted SCD, history of syncope and spontaneous type 1 electrocardiographic (ECG) pattern, but the role of the electrophysiological study (EPS) is not well established due to contradictory results in the published literature.4,5

There is consensus for the implantation of an ICD in cardiac arrest survivors, and there is general agreement that patients with a spontaneous ECG pattern and a history of syncope or documented VT that has not resulted in SCD should receive an ICD.6–8 At the other end of the spectrum, in low-risk patients (asymptomatic with type 1 ECG only after pharmacological provocation), clinical follow-up is also generally accepted.6–8 However, in patients with syncope and pharmacologically induced type 1 ECG or asymptomatic patients with spontaneous type 1 ECG, whether to implant a prophylactic ICD is currently a major dilemma.

In this study, the main objectives were to assess the long-term prognosis of Brugada syndrome patients with an ICD implanted for primary or secondary prevention of SCD and to identify independent predictors of appropriate shocks during follow-up.

Brugada syndrome is an arrhythmogenic disease associated with a high risk of SCD in young individuals with structurally normal hearts, and is classically characterized by an ECG phenotype of right bundle branch block and ST-segment elevation in the right precordial leads.1,9 The prevalence of the syndrome is difficult to estimate since ECG findings can be dynamic and/or concealed, and there are potentially endemic regions for the genetic alterations associated with this entity (mutations in the SCN5A sodium channel gene). Its prevalence is estimated at approximately 5/10 000 individuals, with a higher prevalence in Asia.10–13

Risk stratification of SCD is essential to the management of patients with Brugada syndrome. The objective is to identify patients at higher risk of SCD who may benefit from ICD implantation, the only measure with proven survival benefit in these patients.8 A substantial part of the evidence for the advantages of an ICD comes from the results of the DEBUT trial.14 No pharmacological therapy has shown to improve survival in Brugada syndrome patients, but class IA antiarrhythmic drugs, particularly quinidine, which inhibit the potassium transient outward current of the action potential, may be useful in refractory cases.15

In the present study, performed in patients with Brugada syndrome who received an ICD for primary or secondary prevention, the long-term (mean follow-up of 6.2 years) annual event rate of potentially life-threatening ventricular arrhythmias was 2.8%/year. The rate of appropriate ICD shocks was similar to results previously published by Rosso et al.16 and Sacher et al.,17 despite the longer follow-up in our analysis.

Several characteristics have been described as predictors of the occurrence of arrhythmic events in Brugada syndrome patients. Aborted SCD, history of syncope, spontaneous type 1 ECG pattern and positive EPS are associated with increased risk.2,18 However, distribution of these characteristics among different published studies is not homogeneous. In the FINGER registry,19 during a mean follow-up of 32 months, cardiac events (appropriate shocks or SCD) were recorded in 5% of Brugada patients. Independent predictors of the event were aborted SCD, syncope and spontaneous type 1 ECG. In fact, a history of syncope and aborted SCD are the most common clinical manifestations in Brugada syndrome patients, predominantly manifested in men during the third and fourth decades of life.15 Nevertheless, a significant number of patients with Brugada syndrome are asymptomatic at the time of diagnosis. These patients have a more favorable long-term prognosis compared with those with symptomatic presentation (e.g. aborted SCD, syncope or symptomatic VT).20

When analyzed in a multivariate model, aborted SCD and NSVT during follow-up were the only independent predictors of appropriate shocks in our analysis. Aborted SCD had moderate discriminatory power to predict this outcome. It is important to recall that an appropriate shock is not synonymous with SCD. Although a proven relation between aborted SCD and the risk of arrhythmic events in Brugada syndrome patients has been frequently reported, an independent association of NSVT with appropriate shocks during follow-up has also been described.21 However, it should be borne in mind that NSVT episodes saved in the ICD data log are dependent on the heart rate and duration in the device programming.

The association between syncope and the occurrence of appropriate shocks remains somewhat controversial.22,23 In our study, syncope was the major symptom at diagnosis, mainly of arrhythmic origin, but was not significantly associated with the occurrence of appropriate shocks at long-term follow-up. Similarly to our results, in a study by Sarkozy et al.,24 syncope was not a predictor of arrhythmic events after prophylactic ICD implantation. Unfortunately, sometimes it is not easy to differentiate the origin of syncope between benign (reflex) or potentially fatal (VT). This difficulty suggests that patients with benign syncope may have comprised a significant part of our syncopal population, which may have distorted the results. In another analysis of 203 patients with Brugada syndrome,25 the prevalence of syncope was 28% and in many cases a cardiac etiology was considered unlikely. The follow-up of these patients showed that long-term arrhythmic events occurred only in patients with syncope of cardiac origin. Similarly, in our study events occurred only in patients with possible arrhythmic syncope.

Type 1 ECG pattern and inducibility during EPS were not predictors of appropriate shocks. The role of EPS in risk stratification and management of Brugada syndrome patients is not well established, with published data revealing conflicting results. Brugada et al.5 suggest that VT/VF induction in asymptomatic patients is significantly correlated with an increased risk of SCD; on the other hand, Priori et al.4 suggest that EPS does not add significant value to risk stratification in either symptomatic or asymptomatic patients. These discrepancies may be explained by the differences in baseline characteristics of the study populations and the different stimulation protocols. In fact, it is known that programmed stimulation induces VF in 6–9% of apparently healthy individuals, representing false positives, particularly when more aggressive protocols are used.26,27 Paul et al.28 performed a meta-analysis to assess the role of programmed ventricular stimulation in patients with Brugada syndrome, and showed that EPS did not have a significant role in predicting arrhythmic events during follow-up.

In our study a family history of SCD in first-degree relatives was not associated with an increased risk of arrhythmic events during follow-up. This finding is in agreement with the results of several previously published studies.17,19,24 A positive provocative pharmacological test with flecainide also failed to identify patients with increased risk of appropriate shocks, as described in the PRELUDE Registry.18

Our results support both the importance of ICD implantation in SCD survivors and the current non-invasive strategy of close follow-up, without device implantation, in asymptomatic patients. In patients with syncope, discrepancies from previous results highlight the need for better discrimination of the nature of syncope (arrhythmic vs. reflex).

Only two patients had severe complications associated with ICD implantation (infection and lead fracture) requiring device replacement, while eight patients had inappropriate shocks during follow-up. Given the young age and active lifestyle of our patients, many engaging in regular sports, it is not surprising that the leading cause of inappropriate shocks was sinus tachycardia.17,19 The rate of ICD complications exceeding the rate of arrhythmic events during follow-up has been previously reported,21,29 highlighting the importance of an accurate risk stratification scheme. Inappropriate patient selection for ICD implantation may result in a considerable increase in healthcare costs and may expose asymptomatic individuals to ICD-related complications.17

The present study has some limitations. It is retrospective and the small number of patients and the low event rate during follow-up make it difficult to draw any definitive conclusions regarding predictors of long-term outcome. Some ventricular tachyarrhythmias may terminate spontaneously, depending on how the device is programmed.

Long-term prognostic analysis of patients with Brugada syndrome and an ICD implanted for primary or secondary prevention revealed an annual event rate of potentially life-threatening ventricular arrhythmias of 2.8%/year. Aborted SCD and NSVT during follow-up were independent predictors of the occurrence of appropriate shocks, whereas syncope, type 1 ECG pattern, EPS and family history of SCD were not associated with a higher rate of events in this population. The number of patients with inappropriate shocks was similar to the number of patients with appropriate shocks, and two patients had serious ICD-related complications. Risk stratification of patients with Brugada syndrome remains controversial and the risk/benefit ratio of this therapy should be taken into account.

The authors have no conflicts of interest to declare.