Summary
Brugada syndrome is a rare inherited arrhythmia syndrome leading to an increased risk of sudden cardiac death, despite a structurally normal heart. Diagnosis is based on a specific electrocardiogram pattern, observed either spontaneously or during a sodium channel blocker test. Among affected patients, risk stratification remains a challenge, despite recent insights from large population cohorts. As implantable cardiac defibrillators – the main therapy in Brugada syndrome – are associated with a high rate of complications in this population, the main challenge is risk stratification of patients with Brugada syndrome. Aside from the two main predictors of arrhythmia (symptoms and spontaneous electrocardiogram pattern), many risk factors have been recently suggested for stratifying risk of sudden cardiac death in Brugada syndrome. We have reviewed these data and discuss current guidelines in light of recent progress in this complex field.
Résumé
Le syndrome de Brugada est une arythmie cardiaque héréditaire rare, responsable de mort subite. En l’absence de cardiopathie structurelle, le diagnostic repose sur l’ECG au repos ou lors d’un test de provocation pharmacologique. Comme le seul traitement ayant démontré sont efficacité est l’implantation d’un défibrillateur, mais qu’il s’accompagne d’un risque élevé de complication dans cette population, l’évaluation du risque rythmique est essentielle à la prise en charge de ces patients. Un aspect ECG spontané de syndrome de Brugada et la présence de symptômes restent les éléments les plus importants dans la stratification du risque mais de nombreux autres paramètres ont été récemment proposés pour stratifier le risque de mort subite. Nous discuterons l’analyse de l’ensemble de ces données au regard des dernières recommandations de prise en charge.
Background
Brugada syndrome (BrS) is a rare inherited arrhythmia disease predisposing to ventricular fibrillation (VF) and sudden cardiac death (SCD), without identifiable structural abnormalities . BrS mainly affects middle-aged patients (aged 45 years at diagnosis), with an eightfold higher diagnosis prevalence in men, despite an autosomal mode of inheritance .
Diagnosis is based solely on a specific but labile pattern on an electrocardiogram (ECG), defined as a ≥0.2 mV coved-type ST-segment elevation in the right precordial leads. However, the ECG can be silent, requiring sodium blockers to unmask the pathology. Identification of BrS patients is crucial to avoid sudden cardiac death (SCD), which is often the first symptom . Among the general population, the prevalence of BrS appears to be very low, affecting 5 in 10,000 people , and its real impact on SCD is uncertain. In the absence of proven efficient drug therapy, implantable cardiac defibrillators (ICD) – the main therapy in BrS – have been suggested for primary prevention in many BrS patients. However, the risk of SCD among asymptomatic patients remains relatively low (0.5–1.5% per year) and the rate of ICD-related complications is high in this young population . Consequently, the main challenge for the physician is the identification of patients at risk of arrhythmia who require specific treatment.
This review will focus on clinical aspects of the diagnosis of BrS, risk stratification and impact on management.
Clinical presentation and diagnosis
One-third of BrS patients are identified after symptoms (syncope or aborted SCD), most of which occur at rest with vagal symptoms or during the night . Syncope can be caused by either non-sustained VF or a vasovagal episode without a relevant characteristic to distinguish arrhythmic from non-arrhythmic aetiology . Fever, alcohol intake and medications can increase arrhythmia occurrence; these triggers can unmask a BrS ECG pattern in asymptomatic patients . The increased prevalence of atrial fibrillation in BrS can also suggest a need for BrS screening to the physician, particularly for young men .
Two-thirds of BrS patients are asymptomatic at diagnosis . Of these, more than one-third are identified during familial screening . Since the last guidelines were published, symptoms are not required for diagnosis that is based on a specific ECG pattern . This ECG pattern, previously known as a type 1 ECG, consists of a coved ST-segment elevation in one right precordial lead of >0.2 mV, ending with a negative T wave ( Fig. 1 ). Other ECG patterns are not sufficient for the diagnosis , but can suggest the need for a sodium channel blocker test to the physician, which can unmask a type 1 pattern. Ajmaline (1 mg/kg over 5–10 min), flecainide (2 mg/kg over 10 min) and procainamide can be used . The respective sensitivities and specificities of these drugs have been evaluated with a genetic gold standard, but remain a matter of debate because of the genetic heterogeneity of the syndrome . For now, it seems that flecainide and procainamide have a lower sensitivity than ajmaline . Besides ventricular arrhythmia and the appearance of a type 1 ECG pattern, the sodium channel blocker test is usually stopped if the QRS widens to 130% of the baseline. However, some data argue against this criterion, which does not seem to be associated with the occurrence of complications . Even if initial experiences reported a relatively high rate of complications during this test, more recent experiences have demonstrated that, under proper supervision, the risk is very low .
The diagnosis of a type 1 ECG pattern is usually performed in V1–V3 leads at baseline or during the sodium channel blocker test. Diagnosis can also be performed by elevating V1–V2 leads in the third and the second intercostal space, as this increases sensitivity without modifying prognosis . Based on a single tertiary-centre study, the latest consensus report also proposed acceptance of the diagnosis of BrS even in patients with only one lead showing the typical aspect . Many conditions and diseases, including myocardial ischaemia, acute pericarditis, pulmonary embolism, right ventricular compression and metabolic disorder (hyper/hypokalaemia, hypercalcaemia), can exhibit a Brugada-like type 1 ECG pattern . These BrS phenocopies cannot be differentiated from true BrS because of their identical ECG patterns, and argue for a systematic diagnostic approach to avoid misdiagnosis .
True congenital BrS has been shown to follow an autosomal mode of inheritance in families, and mutation identification has been suggested for diagnosis. Over 20 genes have been associated with BrS , and SCN5A has the majority of mutations. However, studies have shown that some previously associated variants are actually present in the general population, and are probably non-causal . Furthermore, except for the SCN5A gene, the other BrS-associated genes present as many rare variants in cases as in controls, suggesting a minor role for these genes . Interestingly, the concept of a more complex inheritance has emerged from the observation of incomplete penetrance among mutation carriers and of phenocopies among families , and has been recently illustrated by the discovery of frequent genetic variants (>10% in the general population) with an unexpectedly high impact on BrS susceptibility . Thus, the indication for SCN5A screening in clinical diagnostics may be restricted to the identification of patients at risk in a family .
Risk stratification
Once the diagnosis of BrS has been made, the main challenge is to stratify the risk of VF. Numerous variables have been suggested , but other than previous symptoms (syncope and aborted SCD) and spontaneous ECG pattern, all remain a matter of debate ( Table 1 ).
| Variables | Definition | Effect on SCD | Main publications |
|---|---|---|---|
| Aborted SCD | – | Increased risk a | |
| Syncope | Cause by arrhythmia | Increased risk a | |
| Spontaneous ECG pattern | Type 1 ECG | Increased risk | |
| Old age | Aged > 60 years | Decreased risk, but needs to be confirmed b | |
| Sex | Female sex | Decreases risk b | |
| EPS | VF occurrence | Increased risk, with conflicting data, particularly with three extra stimuli b | |
| Sinus dysfunction | In females | Increased risk, but needs to be confirmed b | |
| S wave in D1 | S wave > 0.1 mV and/or > 40 ms | Increased risk, but needs to be confirmed b | |
| QRS fragmentation | At least four spikes in one or at least eight spikes in all of the precordial leads | Increased risk, but needs to be confirmed b | |
| Inferior type 1 | Type 1 ECG in inferior or lateral leads | Increased risk, but needs to be confirmed b | |
| Tpeak–Tend interval | Maximum Tpeak–Tend interval > 100 ms in precordial lead | Increased risk, but needs to be confirmed b | |
| Early repolarization | J wave > 0.1 mV in two inferolateral leads | Increased risk, with conflicting data b | |
| Post-exercise ST-segment elevation | ≥0.05 mV in V1–V3 post exercise | Increased risk, but needs to be confirmed b | |
| Type 1 ECG burden | 24-h Holter monitoring | Increased risk, but needs to be confirmed b | |
| Young age | Aged < 18 years | Conflicting data c | |
| Family history of SCD | SCD in first-degree relatives | Conflicting data c | |
| Genetic | SCN5A mutations | Conflicting data c | |
| Atrial fibrillation | – | Conflicting data c | |
| PR duration | PR > 200 ms | Conflicting data c | |
| QRS duration | QRS > 120 ms | Conflicting data c | |
| Late potentials | Two of three positive criteria | Conflicting data c | |
| aVr sign | R wave ≥ 0.3 mV or R/q ≥ 0.75 in aVr | Conflicting data c |
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