Key Points
Disease summary:
Brugada syndrome (BrS) was described in 1992. It is characterized by the presence of a typical electrocardiographic (ECG) pattern (right bundle branch block and persistent ST-segment elevation in right precordial leads) and it is associated with sudden cardiac death (SCD). To date, it is supposed to be responsible for 4% to 12% of total SCD cases, and 20% of SCD in patients with structurally normal hearts. The prevalence of the disease is difficult to estimate because the pattern is not always recognized or because it may transiently normalize. Nevertheless it is believed to be in the range of 1 to 5 in 10,000, being higher in Southeast Asia where the disease occurs endemically. The average age of diagnosis is usually around age 40, however, there has been description of affected individuals from age 1 to 84, and is more common in males than in females (8:1). BrS has also been described as responsible for sudden infant death syndrome (SIDS).
Hereditary basis:
The BrS is a familial disease inherited with an autosomal dominant pattern of transmission and variable penetrance. In up to 60% of patients the disease can be sporadic, that is, absent in parents and other relatives. The BrS was classified as genetically determined with the identification in 1998 of the first mutations in SCN5A. Since then, more than 200 BrS-associated mutations have been described in SCN5A. Conversely, though, only 15% to 30% of patients with the clinical phenotype currently have a causative mutation identified at the SCN5A locus. Other 15 genes have been associated to BrS but with minor incidence: GPD1L, SCN1B, SCN2B, SCN3B, RANGRF, SLMAP, KCNE3, KCNj8, HCN4, KCNE5, KCND3, CACNA1C, CACNB2B, CACNA2D1, and TRPM4.
Differential diagnosis:
The ECG pattern is the sine qua non of BrS diagnosis. Of importance is the fact that the specific morphology of the precordial QRST pattern is critical for establishing the diagnosis of the syndrome. Only the type 1 ECG pattern—J-point elevation of greater than 2 mm with a coved (downward convex) ST segment—is diagnostic of BrS, with type 2 and type 3 “saddleback” patterns being less specific.
Diagnostic Criteria and Clinical Characteristics
Sometimes, the diagnosis of BrS is difficult because of incomplete penetrance and dynamic ECG manifestations. Three repolarization patterns have been described: (a) type-1 ECG pattern, in which a coved ST-segment elevation greater than or equal to 2 mm is followed by a negative T wave, with little or no isoelectric separation, being this feature present in greater than one right precordial lead (from V1-V3); (b) type-2 ECG pattern, also characterized by a ST-segment elevation but followed by a positive or biphasic T wave that results in a saddle back configuration; (c) type-3 ECG pattern, a right precordial ST-segment elevation less than or equal to 1 mm either with a coved-type or a saddle-back morphology. Only the ECG type 1 would be considered as diagnostic of BrS. This ECG pattern type 1 may be spontaneously evident or it may be induced by a provocative drug challenge test using intravenous application of class 1A or 1C antiarrhythmic drugs (eg, ajmaline, flecainide), which block the cardiac sodium channel.
Cardiac events typically occur at rest, during sleep. The occurrence of arrhythmias during sleep may be due to an increased vagal activity and/or decreased sympathetic activity. This has been suggested in BrS patients by right precordial ST-segment elevation following intracoronary injection of acetylcholine, and decreased levels of norepinephrine in the synaptic cleft on positron emission tomography (PET). Some episodes of syncope or SCD may be triggered by hyperpyrexia, large meals (even leading to the suggestion of a full stomach test as a diagnostic test in the BrS), cocaine, and excessive alcohol consumption and sodium blockers. In some of these induced cases a genetic predisposition has been identified, indicating that some of these are acquired BrS, genetically predisposed.
Risk stratification in BrS is a matter of continuous controversy in these last years. In the medical and research community it is well accepted that symptoms (syncope or SCD) and male gender are associated with a higher risk or events. In these instances all agree that these patients should be protected with an implantable cardioverter-defibrillator (ICD). The controversy is most important in the approach to the asymptomatic patient, the individual who presents with a typical ECG pattern and who has no history of previous syncopal episodes. In this instance some experts will advocate for a close follow-up while others will propose the use of the electrophysiologic study as a risk stratifier to predict prognosis and to decide on the implantation of the ICD.
Patients with BrS may remain asymptomatic although syncope or cardiac arrest has been described in 17% to 42% of diagnosed individuals. The age of symptom occurrence is consistently around the fourth decade of life in all the series (especially cardiac arrest), with no definite explanation for this observation thus far. Previous syncope may be present in up to 23% of patients who present with cardiac arrest. Up to 20% of patients with BrS may present supraventricular arrhythmias, and thus complain of palpitations and/or dizziness. An increased atrial vulnerability to both spontaneous and induced AF has been reported in patients with BrS. The electrophysiologic basis could be an abnormal atrial conduction. Whether atrial vulnerability is correlated to an increased susceptibility for ventricular arrhythmias is thus far unknown. Moreover, the typical ECG changes and arrhythmias in BrS may also be triggered by fever. Although the mechanism is not fully understood, some SCN5A mutations have been shown to alter the gating properties of cardiac sodium channels in a temperature-dependent manner, for example, more slow inactivation at higher temperatures. It has also been reported worst BrS ECG changes during exercise. This may be partially attributed to an enhanced slow inactivation in mutant channels, leading to an accumulation of the mutant channels in the slow inactivation state at fast heart rates. Other symptoms, such as neurally mediated syncope have been also recently associated to the BrS, but their implications for prognosis have not yet been established. As in the case of other Na+ channel–related disorders as type-3 long QT syndrome (LQTS), ventricular arrhythmias in the BrS typically occur at rest, especially during sleep, suggesting that vagal activity may play an important role in the arrhythmogenesis of BrS. In fact, published data on cardiac autonomic nervous system assessed by PET confirm that BrS patients display a certain degree of sympathetic autonomic dysfunction.
In a comparison between the ECG morphology of SCN5A mutation carriers versus patients where mutations in SCN5A had been excluded with the mutation-screening techniques currently available, it was described that SCN5A mutation carriers had significantly longer PQ intervals on the ECG and prolonged His-to-ventricle time during electrical programmed stimulation. Additionally, no significant differences have been described in QT time, QRS duration, and the magnitude of ST elevation. No significant difference with respect to prognosis has been published between SCN5A
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