Molecular Mechanisms

Transmembrane ionic fluxes generate an action potential (AP). In the ventricular myocyte, a rapid inward Na⁺ current, INa, depolarizes the cell membrane, produces phase 0 of the AP, and subsequently activates other ion currents. Activation of the transient outward K⁺ current, Ito, will overwhelm the late phase of the inward INa, initiating the repolarization phase, which will be followed by activation of L-type Ca²⁺ current, rapid and slow delayed rectifier K⁺ currents, IKr and IKs, and the inward rectifier K⁺ current, IK1, to finally reach the resting negative potential.

Brugada syndrome (BrS) is a channelopathy that induces an electrical dysfunction in channels that participate in generation of the cardiac AP. Experimental and clinical data have elucidated the cellular and molecular bases for the ECG morphology and arrhythmogenesis of BrS.⁴ Two mechanisms are believed to explain the ST segment elevation seen in the right precordial leads: First, a disequilibrium between INa and Ito that affects preferentially the right ventricular myocardium, generating transmural dispersion of repolarization and the substrate for arrhythmias. It has been suggested that the embryologic origin of the right ventricle (neural crest cells) differs from that of the left ventricle, and this fact predisposes the right ventricle to arrhythmias in adulthood.⁵ The cellular basis for this phenomenon is thought to be the result of a loss-of-function Na⁺ channel that differentially alters AP morphology in epicardial versus endocardial cells. The fast transient outward K⁺ current I_to is most prominent in epicardial cells of the right ventricle. This K⁺ current is quickly activated by membrane depolarization. It opposes and exceeds the depolarizing effect of Na⁺ inward flux during the early phase of the AP plateau, resulting in a pronounced AP notch and, in combination with depolarizing Ca²⁺ currents, in a “spike-and-dome” morphology. Consequently, Na⁺ current reduction leads to an outward shift of the net transmembrane current in epicardial cells, finally resulting in premature repolarization and significant AP shortening. In contrast, endocardial cells display a much smaller I_to, and consequently, Na⁺ current reduction would not significantly affect AP morphology and duration. The transmural homogeneity of the cellular membrane voltage finally causes ST segment elevation.⁶ The second mechanism that accounts for the ST segment elevation seen in the right precordial leads is conduction slowing in the right ventricular outflow tract (RVOT), leading to ST segment elevation in the right precordial leads.⁷

Genetics

Brugada syndrome (BrS) is a familial disease with an autosomal dominant pattern of inheritance. To date, more than 250 mutations in 13 genes have been published (Table 92-2). The first gene associated with BrS was SCN5A, which encodes the α-subunit of the cardiac sodium channel.⁸ The SCN5A gene is responsible for phase 0 of the cardiac action potential. Mutations in SCN5A result in loss-of-function of the sodium channel. In all, 20% to 25% of patients with BrS have a mutation in the SCN5A gene, classified as BrS type 1.⁹ Other mutations are seen in SCN1B (sodium channel β₁-subunit), which modifies Nav1.5, thus increasing I_Na,¹⁰ and in SCN3B (sodium channel β₃-subunit), which alters Nav1.5 trafficking, thereby decreasing I_Na.¹¹ Another gene reported as responsible for BrS is GPD1-L. Mutations in GPD1-L reduce both the surface membrane expression and the inward sodium current.¹² Kattygnarath et al. published a study supporting that RANGRF (MOG1 protein) can impair the trafficking of Nav1.5 to the membrane, leading to I_Na reduction and clinical manifestations of BrS.¹³

Apart from sodium channels, several potassium channels have also been related to BrS. The first one described was KCNE3, which codifies the MiRP2 protein (β-subunit that regulates the potassium channel I_to) and modulates some potassium currents in the heart.¹⁴ Another gene associated with BrS is KCNJ8, which was previously related to early repolarization syndrome (ERS).¹⁵ KCNJ8 was described as a novel J wave syndrome susceptibility gene and a marker of gain-of-function in the cardiac K_(ATP) Kir6.1 channel.¹⁶ In 2011, Giudicessi et al. provided the first molecular and functional evidence implicating novel KCND3 gain-of-function mutations (Kir4.3 protein) in the pathogenesis and phenotypic expression of BrS, with enhanced I_to current gradient within the right ventricle, where KCND3 gene expression is the highest.¹⁷ Also in 2011, novel variants of KCNE5 appeared to cause gain-of-function effects on I_to. The KCNE5 gene is located in the X chromosome and encodes an auxiliary β-subunit for K channels.¹⁸ BrS was also associated with HCN4, which codifies for the HCN4 channel or the If channel (hyperpolarization-activated cyclic nucleotide–gated potassium channel 4). Its mutations also predispose to inherited sick sinus syndrome (SSS) and to long QT syndrome (LQTS) associated with bradycardia.¹⁹ Calcium channels have also been associated with BrS. Mutations in the CACNA1C gene are responsible for a defective unit of the type L calcium channel. Mutation of the CACNB2B gene leads to a defect in the L-type calcium channel. Both induce loss of channel function.²⁰ In 2010 the CACNA2D1 gene was reported as responsible for BrS. The α₂/δ-subunit of voltage-dependent calcium channels regulates current density and activation/inactivation kinetics of the calcium channel.²¹

Genetic and Environmental Modulators

In recent years, several genetic and environmental modulators of the phenotype have been described. It is well known that environment may play a role in the predisposition to arrhythmias in patients with Brugada syndrome. The identification of several triggering factors of the Brugada ECG pattern and that of sudden cardiac death (SCD)—fever, cocaine, electrolyte disturbances, class I antiarrhythmic medications, and several other noncardiac medications,²² some of them with a genetic predisposition—has resulted in the need to adopt preventive measures in patients with the diagnostic ECG pattern.²³ In addition, incomplete penetrance of the disease, as well as its variable expressivity, has brought into question the role of additional genetic factors in the final phenotype. Single-nucleotide polymorphisms (SNPs) became one of the first players to be studied in defining this variability. The SCN5A polymorphism H558R is present in 20% of the population. This polymorphism has been shown to partially restore the sodium current impaired by other simultaneous BrS-causing mutations in SCN5A.²⁴ Thus, this common variant is a genetic modulator of BrS among carriers of an SCN5A mutation, in whom the presence of the less common allele makes BrS less severe.²⁵ Genetics variants in the SCN5A promoter region may also play a pathophysiological role in BrS. A haplotype of six polymorphisms in the SCN5A promoter has been identified and has been functionally linked to reduced expression of the sodium current in the Japanese population.²⁶ Other studies have shown the role of double mutants in causing a more severe phenotype.^27,28 The role of the genetic mutation in risk stratification has yet to be clearly defined. Recent data suggest that the type of genetic mutation can serve as a tool for risk stratification in BrS. In this study, patients and relatives with a truncated protein had a more severe phenotype and more severe conduction disorders. Although this provides proof of the concept that some mutations appear to confer a worse prognosis, use of these data in the clinical setting is not yet sufficient to alter clinical decisions.²⁹

Early Repolarization Syndrome

The early repolarization syndrome (ERS) is a common electrocardiographic variant characterized by J point elevation, ST segment elevation with upper concavity, and prominent T waves in at least two contiguous leads.³⁰ Despite the overlap degree between ERS and BrS remains undetermined, ERS and BrS share cellular, ionic, and ECG similarities (appearance of J waves), representing parts of a phenotypic spectrum called J wave syndromes.³¹ In the last 5 years, it has been published patients with BrS and ERS.³² ERS has been linked to mutations in CACNA1C, CACNB2, CACNA2D1, and KCNJ8.³³

Lev-Lenègre Syndrome

Lev-Lenègre syndrome (also called progressive cardiac conduction disease [PCCD]) is a rare entity characterized by disruption of the conduction system through the His-Purkinje system, associated with syncope and even SCD. The presence of PCCD among BrS families is not uncommon, as both conditions result from a reduction in the sodium current, which has been described as a different expression of the same genetic phenotype. The first mutations associated with PCCD were described with the SCN5A gene34,35 and its β₁-subunit.¹⁰

Sick Sinus Syndrome

Sick sinus syndrome (SSS) is characterized by persistent inappropriate sinus bradycardia, sinus arrest, atrial standstill, and tachycardia–bradycardia syndrome, all of which are associated with dysfunction of the sinoatrial node (SAN). Patients may exhibit varied symptoms including syncope and even SCD. The course of SSS can be intermittent and unpredictable, according to the severity of the underlying heart disease.³⁶ So far, both autosomal recessive and dominant forms have been described. In 2003 the association between SCN5A mutations and congenital SSS was reported.³⁷ In 2005 a novel SCN5A mutation was identified in patients presenting with both SSS and BrS,³⁸ showing that in the same family, both diseases may be related to the expression of a loss-of-function mutation in I_Na.

Atrial Fibrillation

Atrial fibrillation (AF) is the most common atrial arrhythmia found in BrS.³⁹ It is of extreme clinical importance to realize that atrial fibrillation can be the first manifestation of Brugada syndrome. Administration of antiarrhythmic drugs in these cases can lead to ventricular fibrillation and sudden death. Brugada syndrome should be excluded by drug challenge in young individuals with atrial flutter or fibrillation and a normal heart and a normal ECG. Approximately 15% to 20% of patients with BrS develop supraventricular arrhythmias.⁴⁰ Some studies have reported prolongation of atria His and the His ventricular (HV) interval; these changes occur principally in patients with SCN5A mutations⁴¹ and are consistent with decreased excitability in the conduction system secondary to loss-of-function of sodium channel activity.⁴²

Long QT Syndrome Type 3

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