Brugada syndrome: clinical and genetic findings

Abstract

Review ARticleMore than 20 years ago, eight individuals were resuscitated from sudden cardiac death (SCD) caused by documented ventricular fibrillation (VF); all showed a characteristic ST segment elevation in the right precordial leads and a structurally normal heart. 1 In 1996, the term "Brugada syndrome" (BrS) was used to describe what was previously known as "right bundle branch block, persistent ST segment elevation, and sudden death syndrome. " 2 A year later, BrS was reported to be the same disease as sudden unexplained nocturnal death syndrome (SUNDS). In other countries, BrS has different names: Lai Tai (Thailand), Pokkuri (Japan), and Bangungut (Philippines). Currently, the prevalence of BrS is estimated at ~3-5 in 10,000 people, and it is higher in young men of Southeast Asian origin. It is the main cause of death among young healthy men in Southeast Asia. 3 Recent reports suggest that BrS could be responsible for 4% of all SCD and up to 12% of sudden death in patients with structurally normal hearts. The clinical phenotype manifests in adulthood, at a mean age of 41 years, and it is 8-to 10-times more frequent in males. Frequently, sudden death can be the first manifestation of the disease. 4 In 1998, the genetic basis of BrS was established when the sodium channel protein type V subunit α gene (SCN5A), which encodes the α-subunit of the voltage-gated Na v 1.5 cardiac sodium channel responsible for regulating rapid sodium current (I Na ), was associated with the disease. 5 Currently, BrS is recognized as a rare, inherited cardiac channelopathy caused by an alteration of ionic currents that leads to ventricular arrhythmias and SCD. It is clinically characterized by ST segment elevation in leads V1-V3 of the electrocardiogram, but incomplete penetrance and variable expressivity confound the diagnosis. 6 Despite the identification of 18 associated genes, 65-70% of clinically diagnosed cases remain without an identifiable genetic cause. 4 CLINICAL DIAGNOSIS Diagnostic criteriaThe clinical diagnosis of BrS requires the identification of the ST segment elevation in the right precordial leads at baseline or after the use of sodium blockers. Three different electrocardiographic (ECG) patterns can be often observed in families with BrS: type I, which consists of a coved-type ST segment elevation greater than 2 mm followed by a descending negative T wave in at least two right precordial leads (V1 to V3); type II ST elevation, saddleback-shaped patterns with a high initial increase followed by an ST elevation greater than 2 mm; and saddleback-shaped patterns with a high initial increase followed by an ST elevation less than 2 mm (Figure 1). The second Brugada Consensus Report proposed that only type I is diagnostic for BrS 7 and, in 2013, it was proposed that a definitive diagnosis of BrS considers both spontaneous type I pattern and a provoked type I pattern (with a baseline type II or III pattern) in at least one right precordial lead (V1 or V2). 8 The diagnosis of BrS is currently accepted in those patients ...

Cardiac ion channels

“…Conduction between adjacent cardiomyocytes involves gap junctions at the intercalated disc regions that express connexin proteins and high local concentrations of Nav1.5, and it is thought that local electrical fields may contribute to sodium channel activation in adjacent myocytes independent of gap junctional communication. 8 Human mutations in SCN5A have been linked to multiple perturbations in cardiac function: loss-of-function mutations are the cause of approximately 20% of Brugada syndrome cases 9 ; whereas gain-of-function mutations cause long QT Syndrome type 3. 10 SCN5A constitutive KO mice are embryonic lethal, with the SCN5AC/¡ heterozygotes displaying some of the conduction-related deficiencies seen in the human mutant population.…”

Negative Autopsy in Infant and Juvenile Population: Role of Cardiac Arrhythmias

“…After surviving a cardiac arrest or the occurrence of syncope, the only treatment having any proven efect on the prevention of sudden death is the implantable cardioverter-deibrillator (ICD) [36]. However, ICD implantation in symptomatic is not free from controversy, especially in children [37]. The irst genetic alteration was identiied in 1998 [38].…”

“…Nowadays, 24 genes have been associated to the dis- (Figure 1) but a comprehensive genetic analysis only identify the genetic alteration in a 35% of cases. Approximately 30% of patients with BrS carry a loss of function genetic alteration in SCN5A (BrS type 1) [37]. This gene is responsible for the phase 0 of the cardiac action potential, a key player in the cardiac electrical activity.…”

Updates in Brugada Syndrome

“…The BrS phenotype has been associated with 18 genotypes, 5,6 all showing a decrease in the inward sodium or calcium current or an increase in one of the outward potassium currents. Genetic testing is only recommended for family members of a successfully genotyped proband.…”