Brugada Syndrome. Clinical, Genetic, Molecular, Cellular and Ionic Aspects

1. Clinical Characteristics and Diagnostic Criteria

The Brugada syndrome typically manifests in the third or fourth decade of life (average age of 41±15 years), although patients have been diagnosed with the syndrome at an age as young as 2 days and as old as 84 years. Prevalence of BrS ECG in the general population varies significantly among continents, countries and ethnic groups.^1–22 The prevalence of the disease is highest in Southeast Asia where the syndrome is endemic, estimated to be greater than 5 per 10,000 inhabitants.²³ In Japan, a Brugada syndrome ECG (Type 1) is observed in 12 per 10,000 inhabitants; Type 2 and 3 ECGs, which are not diagnostic of BrS, are much more prevalent, appearing in 58 per 10,000 inhabitants.²⁴ The true prevalence of the disease in the general population is difficult to estimate because the ECG pattern is often concealed.

Sudden unexplained nocturnal death syndrome (SUNDS also known as SUDS) and Brugada syndrome have been shown to be phenotypically, genetically and functionally the same disorder.²⁵ Most patients with a Brugada ECG are asymptomatic, usually diagnosed incidentally and they often remain asymptomatic for life. A small minority develop, nocturnal agonal breathing, syncope and/or palpitations, leading to ventricular tachycardia/fibrillation (VT/VF) or SCD. Approximately 20% of BrS patients also develop supraventricular arrhythmias, including atrial flutter, fibrillation, AV nodal reentry and pre-excitation syndromes such as WPW syndrome. Atrial fibrillation (AF) is reported in approximately 10–20% of cases. AV nodal reentrant tachycardia (AVNRT) and Wolf-Parkinson-White (WPW) syndrome have been described by Eckart et al. ²⁶ Prolonged sinus node recovery time and sino-atrial conduction time ²⁷ as well as slowed atrial conduction and atrial standstill have been reported in association with the syndrome. ²⁸ Ventricular inducibility is positively correlated with a history of atrial arrhythmias ²⁹. The incidence of atrial arrhythmias is 27% in Brugada syndrome patients with an indication for ICD vs 13% in patients without an indication for ICD, suggesting a more advanced disease process in patients with spontaneous atrial arrhythmias. ²⁹

The Brugada syndrome is characterized by an ST segment elevation in the right precordial leads. Three types of ST segment elevation are generally recognized ^30–32. Type 1 is characterized by a coved ST segment elevation ≥ 2 mm (0.2 mV) followed by a negative T wave (Figure 1). The initial guidelines also required one of the following for the definitive diagnosis of BrS: documented, polymorphic VT or VF, a family history of SCD (< 45 years old), coved type ECGs in family members, syncope or nocturnal agonal respiration. In the latest guidelines, clinical symptoms remain important in risk stratification, although they are no longer listed among the diagnostic criteria.³³ The diagnosis of BrS hinges exclusively on the presence of a Type 1 ST segment elevation in one or more right-precordial lead (V1–V3), ³⁴ spontaneously or in the presence of provocative agents, regardless of presence or absence of symptoms. This is a major departure from the original recommendation of the 2002 and 2005 Consensus Conferences.^{31, 32, 35} While this may serve to draw more attention to the syndrome, it disregards the fact that many subjects manifesting a Brugada pattern remain asymptomatic throughout life.

Patients with a Brugada Type 1 ECG have an approximate cardiac event-rate/year of 7.7% in patients with aborted SCD, 1.9% in patients with syncope, and 0.5% in asymptomatic patients.³⁶ Sodium channel blockers, including ajmaline, procainamide, flecainide, disopyramide, propafenone and pilsicainide are useful in the differential diagnosis when ST segment elevation is not diagnostic under baseline conditions.^37–41 However a negative I_Na-block test does not exclude a latent form of BrS (e.g. negative predictive value of flecainide-testing is 36%).^{40, 42} Ajmaline and pilsicainide seem to be more effective tools in unmasking BrS, compared to flecainide ^{43, 44} or procainamide³⁸. The electrocardiographic manifestations of the Brugada syndrome when concealed can be also be unmasked by bradycardia, febrile state or with vagotonic agents. ^{37, 45–50}

Placement of the right precordial leads in a superior position (one or two intercostal space above normal) can increase the sensitivity of the ECG for detecting the Brugada phenotype in some patients, both in the presence or absence of a drug challenge. ^{51–53,54–56}

There are several conditions that produce a Brugada-like ECG-morphology, which should be distinguished from Brugada syndrome. They can be divided into two main categories: acute and persistent conditions. The most commonly observed acute conditions are acute coronary events, pericarditis, myocarditis, pulmonary embolism, metabolic disorders, impaired ion-balance, dissecting aorta aneurism, thiamine deficiency, electric shock and certain pharmacologic agents (see below)⁵⁷. These manifestations usually disappear with cessation of the provoking event. Most common permanent conditions producing right precordial ST-elevation are: left ventricular hypertrophy, athlete’s heart, right bundle branch block (RBBB), pectus excavatum, septal hypertrophy, arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), autonomic nervous system abnormalities, Duchenne-dystrophy, Friedreich’s ataxia, mediastinal tumor and Chagas disease^{31, 58–60}. Some investigators have labelled these “phenocopies” indicating that they mimic the phenotype without a genetic predisposition. We would prefer to avoid this term because data as to a genetic predisposition is lacking in almost all cases.

Additionally, inappropriate settings of the recording device can be misleading. In some circumstances, highly-set low cut filters can lead to “false” ST-elevation or altered shape.^{58, 61, 62}

Differentiating RBBB from BrS is not always easy, particularly because RBBB has been reported to mask BrS.^{63, 64} Pre-excitation of the right ventricle has been shown to be helpful in unmasking BrS under these circumstances. Criteria have been proposed to distinguish RBBB from BrS ECG pattern ^{58, 65, 66}. Thirty-eight consecutive patients with either Type 2 or Type 3 Brugada patterns that were referred for sodium block challenge were included in the study. Before administration of the provocative agent, α and β angles alone and in combination with QRS duration were measured from ECG leads V1 and/or V2 showing incomplete RBBB:

1. α angle was defined as the angle between a vertical line and the down slope of the r'-wave. Patients with BrS displayed wider α angles than patients with incomplete RBBB.

2. β angle was defined as the angle between the upslope of the S-wave and the down slope of the r'-wave. The mean β angle was significantly smaller in the 14 patients with incomplete RBBB than the 24 patients with BrS (positive response to sodium block) 36 ± 20° vs. 62 ± 20° (p < 0.01), respectively.

When the angles were combined with QRS duration, it improved discrimination. We must await further tests of the utility and validity of these diagnostic tools.

While most cases of BrS display prominent J waves, often appearing as ST segment elevation, limited to the right precordial leads, isolated cases of inferior lead ⁶⁷ or left precordial lead ⁶⁸ ST segment elevation have been reported in Brugada-like syndromes, in some cases associated with SCN5A mutations ⁶⁹. Coexistence of inferolateral early repolarization (ER) in BrS is not uncommon and is a recently identified risk factor for ventricular fibrillation.^{70,71, 72} However, in another interpretation, the presence of ER in inferior, lateral and anterior (right precordial) leads is referred to as global ER and designated as Type 3 early repolarization pattern (ERS3).⁷³

Minor prolongation of the QT-interval may accompany ST segment elevation in the Brugada syndrome .^{41, 74, 75} The QT-interval is prolonged more in the right vs. left precordial leads, probably due to a preferential prolongation of action potential duration (APD) in RV epicardium secondary to accentuation of the action potential notch. ^{76, 77} Depolarization abnormalities including prolongation of P wave duration, PR- and QRS-intervals are frequently observed, particularly in patients linked to SCN5A mutations.⁷⁸ PR prolongation likely reflects HV conduction delay. ⁷⁴

2. Genetic Basis

Inheritance of the Brugada syndrome is via an autosomal dominant mode of transmission. Mutations in 19 genes have been identified as associated with the Brugada phenotype (Table 1). These mutations cause either a decrease in inward sodium or calcium current or an increase in outward potassium currents resulting in an outward shift in the balance of current active during the early phases of the action potential.

3. Cellular and Ionic Basis

An outward shift in the balance of currents active during phases 1 and 2 of the epicardial action potential via either a reduction of inward current (I_Na or I_Ca ) or increase in outward current (I_Kr or I_K-ATP), allows the already prominent I_to to accentuate phase 1 repolarization (Figs. 2 and 3). When phase-1 is repolarized beyond the voltage range at which L-type Ca⁺² channels activate, the Ca⁺² channels fail to activate, resulting in loss of the action potential plateau, predominantly in the right ventricular subepicardial cells where I_to is most prominent .

Conduction of the AP dome from epicardial sites at which it is maintained to sites at which it is lost results in the development of phase 2 reentry, giving rise to a very closely coupled extrasystole.⁷⁷ Interestingly, these repolarization abnormalities give rise to low voltage fractionated electrogram activity (Figure 4) and high frequency late potentials when a bipolar electrogram is recorded in the region of the RVOT (Figure 5).¹⁶¹ The low voltage fractionated electrogram activity is due to dysynchrony in the appearance of the epicardial action potential dome secondary to accentuation of the action potential notch and the high frequency late potentials are due to concealed phase 2 reentry.

The ability of the right ventricular action potential to lose its dome, giving rise to phase 2 reentry and other characteristics of the Brugada syndrome were identified in the early 1990’s and evolved in parallel with the clinical syndrome. ^162–165

The development of prominent J waves, appearing as ST segment elevation, in the right precordial leads of BrS patients is believed to be due to accentuation of the right ventricular epicardial action potential notch secondary to the rebalancing of the currents active at the end of phase 1 (see ¹⁶⁶ for references). A spike and dome morphology due to a prominent transient outward current (I_to), or notch, in ventricular epicardium, but not endocardium, generates a transmural voltage gradient that inscribes the electrocardiographic J wave in larger mammals and in man. The ST segment is typically isoelectric because of the absence of transmural voltage gradients at the level of the action potential plateau. Under pathophysiologic conditions such as those associated with BrS, accentuation of the right ventricular action potential notch leads to exaggeration of transmural voltage gradients and thus to accentuation of the J wave, causing an apparent ST segment elevation. ¹⁶⁶ The repolarization waves take on a saddleback or coved appearance depending on the timing of repolarization of epicardium relative to endocardium. A delay in epicardial activation and repolarization time leads to progressive inversion of the T wave.

Accentuation of the action potential notch in the right ventricular outflow tract (RVOT) can give rise to the typical Brugada ECG without creating an arrhythmogenic substrate, as illustrated in Figure 2B. The arrhythmogenic substrate could then arise with a further shift in the balance of currents causing loss of the action potential dome at some epicardial sites but not others. Disappearance of the action potential dome in epicardium but not endocardium results in marked transmural dispersion of repolarization and refractoriness, which is responsible for the development of a vulnerable window, as illustrated in Figure 2C. Loss of the epicardial action potential dome is usually heterogeneous, leading to the development of epicardial dispersion of repolarization. Propagation of the action potential dome from RVOT sites at which it is maintained to sites at which it is lost can cause local re-excitation via a phase 2 reentry mechanism (P2R). The phase 2 reentrant extrasystole is often concealed because it is surrounded by refractory tissue. These concealed P2Rs are responsible for the appearance of high frequency late potentials (Figure 5) in epicardial electrograms recorded over these epicardial sites in patients with BrS.¹⁶¹ When the P2R succeeds in propgating out of its protected focus and capturing the vulnerable window, it can trigger a circus movement reentry, usually manifest as polymorphic VT/VF (Figure 2F). ^167–169 The phase 2 reentrant beat fuses with the negative T wave of the basic response. Support for these hypotheses derives in part from experiments involving arterially perfused right ventricular wedge preparations as well as from studies such as those of Kurita et al. who obtained monophasic action potential (MAP) recordings form the epicardial and endocardial surfaces of the right ventricular outflow tract (RVOT) of patients with the Brugada syndrome.^{164, 170} Figure 2E illustrates an example of programmed electrical stimulation-induced VT/VF under similar conditions.

Although the genetic mutations are equally distributed between the sexes, the clinical phenotype is 8 to 10 times more prevalent in males than in females. The basis for this sex-related distinction was shown to be due to a more prominent I_to-mediated action potential notch in the right ventricular (RV) epicardium of males vs. females.¹⁷¹ The more prominent I_to causes the end of phase 1 of the RV epicardial action potential to repolarize to more negative potentials in tissue and arterially perfused wedge preparations from males, facilitating loss of the action potential dome and the development of phase 2 reentry and polymorphic VT. The gender distinction is not seen in all families; some authors described families without a male predominance of the Brugada phenotype.¹⁷²

Available data support the hypothesis that the Brugada syndrome is the result of amplification of heterogeneities intrinsic to the early phases of the action potential among the different transmural cell types. This is due to a rebalancing of currents active during phases 1 and 2 of the acion potential secondary to a decrease in I_Na or I_Ca or augmentation of outward currents including IKr, I_Ks, I_Cl(Ca) or I_to (Figure 3). The accentuation of the action potential notch leads to elevation of the ST segment, eventually leading to loss of the action potential dome in right ventricular epicardium, where I_to is most prominent. Loss of the dome causes a transmural as well as epicardial dispersion of repolarization. The transmural dispersion contributes to development of ST segment elevation and the generation of a vulnerable window across the ventricular wall, whereas the epicardial dispersion leads to development of phase 2 reentry, thus providing a closely coupled extrasystole that captures the vulnerable window and precipitates VT/VF. The polymorphic VT generated resembles a rapid form of Torsade de Pointes (Figures 2F and 3).

The cellular mechanisms underlying Brugada syndrome have long been a matter of debate ^{173, 174}. Two principal hypotheses have been advanced: 1) The repolarization hypothesis maintains that an outward shift in the balance of currents in right ventricular epicardium leads to repolarization abnormalities resulting in the development of phase 2 reentry, which generates closely-coupled premature beats capable of precipitating VT/VF; 2) The depolarization hypothesis maintains that slow conduction in the right ventricular outflow tract plays a primary role in the development of the electrocardiographic and arrhythmic manifestations of the syndrome. Although these theories are not mutually exclusive and may indeed be synergistic, from the standpoint of appropriate therapy, correct assessment of the cellular pathophysiology is important.

To date, the most compelling evidence in support of the depolarization hypothesis was the demonstration by Nademanee et al.⁸³ of late potentials and fractionated electrogram (EGs) recorded from the right ventricular outflow tract (RVOT) of BrS using bipolar electrograms. They further demonstrated that radiofrequency (RF) ablation these epicardial sites significantly reduced the arrhythmia-vulnerability and ECG-manifestation of the disease. These authors concluded that the high frequency late potential (LP) and low voltage fractionated electrogram activity are due to conduction delays within the RVOT and elimination of the sites of slow conduction is the basis for the ameliorative effect of ablation therapy⁸³. In a direct test of this hypothesis, our group recently suggested an alternative cellular electrophysiological mechanism as the basis for late potentials and fractionated electrogram activity in the setting of BrS.¹⁶¹ Using the coronary-perfused wedge model of BrS, Szel et al. ¹⁶¹ demonstrated that the high frequency late potentials are due to concealed phase 2 reentry and that the low-voltage fractionated electrogram activity recorded from the RV epicardium is due to different timing of the second upstroke of the action potential secondary to accentuation of the epicardial action potential notch (Figures 4 and 5).

If late potentials and fractionated electrogram activity recorded from the RVOT do not reflect depolarization and conduction abnormalities, what is the basis for the ameliorative effect of RVOT ablation? As we will discuss below, our preliminary data strongly support the hypothesis that ablation destroys the cells with the most prominent action potential notch, thus eliminating the cells responsible for the repolarization abnormalities that give rise to phase 2 reentry and VT/VF (Figure 6).

5. Approach to Therapy

Table 3 lists device and pharmacologic therapies suggested on the basis of clinical experience or experimental stduies.