The BrS is a channelopathy transmitted as an autosomal dominant trait with incomplete penetrante and male predominance and an abnormal ECG pattern characterized by ST-segment elevation (= 2 mm) of the right precordial leads (V1-V3), with or without right bundle branch block in patients with structurally normal hearts (Brugada et al., 1992; Antzelevitch et al., 2005). Patients with BrS present a high incidence of syncope and primary VF often resulting in SCD, which can be the first clinical manifestation (Brugada 1992, 2002, 2003; Mizusawa et al., 2012).
The syndrome is manifested in adulthood, between 30 and 50 (mean 41) years of age, but can be diagnosed over the two days and 85 years of age (Antzelevitch et al., 2005). Indeed, the BrS is known as one of the causes for sudden infant death syndrome or SCD in young children (Probst et al., 2010).Furthermore, the BrS is for up to 12 % of all sudden deaths and 20 % of sudden deaths in patients with structurally normal hearts (Antzelevitch et al., 2005; Nielsen et al. 2013). Around 20-50% of patients have family history of SCD and almost 23% of them present presented a previous history of syncope. Asymptomatic elderly patients with BrS are thought to be at relatively low risk for future cardiac events. The annual incidence of arrhythmogenic events in asymptomatic patients is 0.5%, in patients with syncope is 0.6-1.9% and in those with FV of 7.7-10.2% (Probst et al., 2011).
The prevalence of BSr is estimated 1-5/10.000 inhabitants, but it can be much higher, since many patients are asymptomatic (Mizusawa and Wilde, 2012). The prevalence of BrS with a type 1 ECG in adults is higher in Asian countries, such as Japan (0.15–0.27%) and the Philippines (0.18%), and among Japanese-Americans in North America (0.15%) than in western countries, including Europe (0%–0.017%)and North America (0.005–0.1%) (Antzelevitch et al., 2016). In fact, in young men with normal hearts of some Southeast Asian countries the BrS is the second cause of death, surpassed only by car accidents (Veerakul and Nademanee, 2012). We don´t know how gender modulates the manifestation of the disease (Wilde et al., 2002; Antzelevitch et al., 2005). In pre-pubescent individuals, there are no significant gender differences in all 3 ST levels (ST-J, -M, and -E) in both leads V2 and V5, but levels increase significantly after puberty in males (Ezaki et al., 2010). Androgen-deprivation therapy significantly lowered all 3 ST levels in both V2 and V5 and closely resembled the ST levels in age-matched control females, suggesting that testosterone modulates the ion currents underlying the early phase of ventricular epicardial repolarization (AP notch). Furthermore, the effect of estrogens (they reduce Ito density and protein expression of the underlying Kv4.3 channels) and the differences in expression and density of the Ito current between both sexes (Ito density in the epicardium is higher in males than females) can also explain the predominance of BS phenotype among males)(Di Diego et al., 2002).
The BrS is attributed to mutations on different genes leading to a shortening of the cardiac AP due to a decrease in inward-depolarizing currents (INa and ICa) or an increase in repolarizing currents (Ito or IKATP) (Table). However, genetic heterogeneity of BrS is likely to be even geater as mutation screening on the known genes allows identifying a mutation in ~25-30% of clinically affected patients. As a consequence, the value of genetic testing for diagnostic purposes is limited and there is no evidence that results of genetic testing influence clinical management or risk stratification in BrS (Priori et al., 2012). Because of the low prevalence of non- SCN5A mutations, it has been suggested that it is reasonable to initially test most patients for SCN5A mutations alone, with further testing for the other minor BS genes only in special circumstances (Ackerman et al., 2011).
Loss-of-function mutations in SCN5A, the gene encoding a -subunit of the Na+ channel, has been identified in 15-25% of affected individuals with incomplete penetrance and variable expressivity (Chen et al., 1998; Kapplinger et al., 2010). They cause a decrease in INa through different mechanisms, including: decreased expression of Na v 1.5 proteins in the sarcolemma [because of either impaired protein trafficking to the cell membrane (with retention and degradation in the sarcoplasmic reticulum) or because they fail to interact with β subunits or other regulatory proteins that determine its location in the sarcolemma] (Valdivia et al., 2004; Baroudi et al., 2001), expression of nonfunctional channels (Kyndt et al., 2001), or altered gating properties [delayed activation (i.e., activation at more positive potentials), earlier inactivation (i.e., inactivation at more negative potentials) subsequent to channel opening, faster inactivation and/or delayed recovery from inactivation]](Cheng et al., 1998; Bezzina et al., 1999; Dumaine et al., 1999; Akai et al., 2000; Kapplinger et al., 2010; Grant et al., 2002; Schulze-Bahr et al., 2003; Wang et al., 2000; Amin et al., 2010; Smits et al., 2005). Delayed activation, earlier inactivation, and/or faster inactivation reduce INa by decreasing the probability of the channels to reside in the activated-open state. Enhanced slow inactivation requires relatively long recovery times during the phase 4 of th AP. At fast heart rates, phase 4 becomes too short so that channels do not recover completely from slow inactivation leading to an accumulation of the channels in the slow inactivation state, and INa reduction. This can explain why ECG changes in the BrS worsen during exercise. An increase in temperature may worsen the kinetics of INa and potentiate the effect of certain mutations, thus providing a potential explanation on the proarrhythmic role of fever in the BrS, particularly in younger patients.
The SCN5A mutation may affect the phenotype, so that mutations leading to premature truncation of the Nav1.5 protein or missense mutations with >90% peak INa reduction develop a more severe phenotype (syncope, longer PR interval at baseline, longer PR and QRS interval after a drug challenge test) than the missense mutations with =90% peak INa reduction (Meregalli et al., 2009). Loss-of-function mutations in SCN5A contribute to the development of both BrS and ERS, as well as to a variety of conduction diseases, Lenegre disease, and sick sinus syndrome. The presence of a prominent Ito determines whether loss-of-function mutations resulting in a reduction in INa will manifest as BrS/ERS or as conduction disease (Antzelevitch et al., 2016).
The important role of INa in the pathogenesis of BrS is supported by the fact that mutations in several other genes encoding several sodium-channel associated proteins implicated in the BrS decrease the INa (Table) (Weiss et al., 2002; London et al., 2007; Watanabe et al., 2008; Hu et al., 2009). SCN1B and SCN3B genes encode the β1 and β3 subunits of the Na+ channel. A missense mutation (p.Asp211Gly) in the sodium β2 subunit encoded by SCN2B reduced INa density (Riuro et al., 2013). Mutations in SCN3B-encoded Navβ3 subunit can lead to loss of transport and functional expression of the hNav1.5 protein, leading to reduction in sodium channel current and clinical manifestation of a Brugada phenotype (Hu et al., 2009). Similarly, INa was lower when Nav1.5 was coexpressed with mutant β1 or β1B subunits (Watanabe et al., 2008).
The mutation did not affect Nav1.5 unitary channel conductance, but decreases Nav1.5 cell surface expression. The RAN guanine nucleotide release factor (RANGRF) gene encodes MOG1, which interacts with Nav1.5 channels through its intracellular loop between DII and DIII and is an important partner for the normal surface expression of Nav1.5 channels. Dominant-negative MOG1 mutations can impair Nav1.5 trafficking to the membrane, leading to INa reduction and clinical manifestation of BrS (Kattygnarath et al., 2011). The GPD1-L gene encodes the glycerol-3-phosphate-dehydrogenase 1-like protein that affect trafficking of the Nav1.5 subunit to the cell surface. Mutations in the GPD1L gene (A280V) reduced inward Na+ currents by approximately 50% and coexpression of mutant with wild-type channels reduced SCN5A cell surface expression by 30% (London et al., 2007). The sarcolemmal membrane-associated protein (SLMAP) is one of the components of T-tubules and sarcoplasmic reticulum located in T-tubules and in the sarcoplasmic reticulum. Two mutations in SLMAP (V269I, E710A ) impaired hNav1.5 trafficking and surface expression (Ishikawa et al., 2012). Cerrone et al. (2014) demonstrated that the loss of expression of desmosomal protein plakophilin-2 (PKP2) reduced Nav1.5 at the intercalated disks in BrS patients.
SCN10A, encodes the neuronal sodium channel Nav1.8, and modulates SCN5A expression and the electrical function of the heart. Hu et al (2014) described SCN10A mutations mainly localized to the transmembrane-spanning regions. Patients with BrS who had SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals compared with SCN10A-negative BrS probands. Heterologous coexpression of WT-SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current compared with WT-SCN5A alone, while coexpression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 80% reduction in sodium channel current, which is expected to reduce excitability and lead to development of the arrhythmogenic substrate. Other studies, reported a lower percentage of SCN10A mutation in the SCN5A mutation negative BrS in the Caucasian (3.8%) and Japanese BrS patients (2.5%) (Behr et al., 2015; Le Scouarnec et al., 2015; Fukuyama et al., 2015).
Moreover, mutations in the TRPM4 gene encoding the transient receptor potential melastatin protein number 4 (TRPM4) channel, a Ca2+-activated nonselective cation channel cation channel permeable to monovalent cations (Na+ and K+) resulted in BrS (Liu et al., 2013). In the BrS, both gain of function as well as loss of function of TRPM4 channel have been described, but it is unknown how the modifications can transform the physiological role of this channel which to participate to the BrS. Because of its effect on the resting membrane potential, reduction or increase of TRPM4 channel function may both reduce the availability of sodium channel and thus lead to BrS. (Liu et al., 2013).
Loss-of-function mutations in CACNA1C and CACNB2b genes, encoding for the α and β2b-subunits of the cardiac L-type Ca2+ calcium channel have been described in around 10% of patients with BrS. Some of these patients present a ‘mixed ECG phenotype’ combining the clinical features of short QT interval (QTc < 360 ms) and type I BrS (Antzelevitch et al., 2007¸ Burashnikov et al., 2010; Watanabe et al., 2008). These mutations have reduced penetrance and variable expressivity. CACNA2D1, encoding a-2/d subunit of the L-type calcium channel, regulates the current density and activation/inactivation kinetics of the Ca2+ channel and is associated with BrS (Burashnikov et al., 2010).A BrS family was reported to carry a mutation in the KCNE3 gene, encoding a β-subunit (MiRP2) that co-assembles to form the Kv4.3 channel that conducts the Ito (Delpón et al., 2008).
Gain-of-function mutations in genes encoding channels that conduct outward potassium currents (KCND3, KCNE3, KCNE5KCNE5, and KCNJ8) have also been reported in some BrS patients. Mutations in KCND3 genes, encoding a Kv4.3 channel lead to an increase of the Ito current in the right ventricle, and have been linked to BrS (Giudicessi et al., 2011). KCNE3 β-subunits (encoded by the KCNE3 gene) can interact with Kv4.3 channels, an interaction that decreases the current density. Mutations in KCNE3 (encoding MiRP2) reduces the inhibitory effect of KCNE3 on Kv4.3 channels, resulting in a significant increase in the magnitude and kinetics of Ito (Delpon et al., 2008). KCNE5 gene located on the X chromosome encodes an auxiliary β-subunit for voltage-gated K channels (potassium voltage-gated channel subfamily E regulatory subunit 5). Mutations in KCNE5 identified in Japanese patients with BrS and other idiopathic ventricular fibrillation (IVF). These variants upregulated reconstituted Ito compared with WT KCNE5 (Ohno et al. 2011). According to the hypothesis that the BrS occurs when there is an imbalance between outward and inward currents at the end of phase 1 of the epicardial ventricular AP, an increase in Ito is expected to trigger the ECG phenotype of BrS. Semaphorin 3A (SEMA3A) is a naturally occurring protein that selectively inhibits Kv4.3 and a possible BrS susceptibility gene (Boczek et al., 2014).
A missense mutation in the potassium inwardly rectifying channel, subfamily J, member 8 (KCNJ8) gene which encodes Kir6.1 (KCNJ8-S422L) was identified in patients with BrS and ERS leading to a gain-of-function in IKATP over the voltage range of 0 mV to 40 mV (Medeiros-Domingo et al., 2010). It was speculated that this mutation might accentuate epicardial KATP channel activity, thereby shortening the epicardial APD. The gene for ATP-binding cassette, subfamily C member 9 (ABCC9) encodes the sulfonylurea receptor subunit 2 A (SUR2A) (Hu et al., 2014). A missense gain-of-function mutation in KCNJ8, which encodes the pore-forming subunit (Kir6.1) of the cardiac KATP channel, causes activation of IK-ATP under normoxic conditions by reducing the sensitivity of the channel to intracellular levels of ATP (Barajas-Martinez et al., 2012). KCNH2 mutations exerted gain-of-function effects on IKr. R164C, W927G, and R1135H increased IKr density; T152I, R164C, and W927G, caused a negative shift in voltage-dependent activation curves and R1135H prolonged the deactivation time constants. (Wang et al., 2014). Mutations in the KCNH2 gene do not produce a BrS but they can modulate the manifestation of the syndrome (Verkerk et al., 2005).
In mammals, the hyperpolarized-activated cyclic nucleotide-gated channel (HCN) family is comprised of four distinct genes (HCN1-4). HCN4 is predominantly expressed in the central sino-atrial node and becomes permeable for K+ and Na+ in response to hyperpolarization, giving rise to slow diastolic depolarization resulting in automaticity (DiFancesco, 2013). Loss-of-function mutations in the HCN4 gene may unmask a BrS via a bradycardic effect (Ueda et al. 2004, 2009). Interestingly, the same mutation in the SCN5A gene can produce several phenotypes in the same family or in the same patient: BrS, SQT3, SSS and/or PICD (Bezzina et al., 1999; Shirai et al., 2002; Takehara et al., 2004; Makita et al., 2008).
Studies in Hey2-targeted mice provide strong support for the role of this gene in Brugada syndrome. HEY2 encodes the transcriptional repressor hairy/enhancer-of-split related with YRPW motif protein and plasy a role in the regulation of SCN5A expression and conduction velocity in the heart. One SNP, rs9388451 near the HEY2 gene was significantly associated with BrS through a genome-wide association study in 312 individuals with BrS (Bezzina et al., 2013).
Table. Genetic loci and identified genes and modifier genes associated with the Brugada syndrome (autosomal dominant)
BrS1 (15-25%) *
Nav1.5 α subunit
glycerol-3-phosphate-dehydrogenase 1-like protein
Cav1.2 α subunit
Cav1.2 β2 subunit
Nav1.5 β1 subunit
MIRP2 β subuniT
Nav1.5 β3 subunit
Cav1.2 αδ-1 subunit
Kv4.3 α subunit Kv4.3 α subunit
MOG1 protein: Nav1.5 cofactor
Sarcolemmal membrane-associated protein
Fibroblast growth factor homologus factor 12
Trasient receptor potential malastatin protein 4
MiRP4 β subunit
Peroxidasin homolog (Drosophila)-like
Cytoplasmic linker associated protein 2 (participates in the membrane localization of SCN5A)
Iroquois homebox 5
Dipeptidyl-peptidase-like protein 6
(+): Gain-of-function. (-): loss-of-function. *20-25% (Caucasian), 10-15% (Asian)
** Novel genes identified and not linked to any Brugada Syndrome subtype yet.FGF12: fibroblast growth factor homologous factor 12. IRX5: iroquois homeobox 5. NSCCa: calcium-activated non- selective cation channel function (mediates monovalent cations across membrane and contributes to the transient inward current Iti initiated by Ca2+ waves). RANGRF: RAN guanine nucleotide release factor. SLMAP: sarcolemmal membrane-associated protein SUR2A: cardiac specific sulfonyl urea receptor 2A subunit of the KATP potassium channel. TRMP4: transient receptor potential melastatin protein 4.
The electrophysiological background of arrhythmias in BrS is not fully understood. There is a debate on whether the BrS is a repolarization disorder [namely, transmural dispersion of right ventricular (RV) AP morphology, driven by the loss of the spike and dome action potential morphology at RV epicardium] or a depolarization disorder, namely RV conduction delay.
A current hypothesis is that the BrS phenotype occurs when there is an imbalance between outward and inward currents at the end of phase 1 of the epicardial ventricular AP (Di Diego et al., 2002). Epicardial cells display a characteristic spike-and-dome morphology due to large transient outward K+ current (Ito) and short APD resulting from a high density of IKs, while Ito density is less marked in the endocardial cells (Yan and Antzelevitch, 1999; Antzelevitch, 2005). Mutations reducing INa or I Ca amplitude in the presence of large repolarizing currents (Ito and IKs) may result in a rapid repolarization phase 1, disappearance of the dome and a marked shortening of the AP in the epicardial, but not in the endocadial cells. This creates a transmural voltage gradient that may be responsible the characteristic ST-segment elevation and a favorable substrate for ventricular arrhythmias due to a mechanism of phase 2 reentry. The RV outflow tract epicardium (RVOT) has a higher Ito density compared with the LV, which explains why only the right precordial leads present the coved-type ST-segment elevation. Reduced myocardial Na+ current (or Na+ channel blockers) will cause disproportionate shortening of epicardial AP because of unopposed Ito, lead to an exagerated transmural voltage gradient, increase ST segment elevation and unmask a concealed the type 1 ECG pattern. However, it is difficult to understand why mutations affect almost selectively the RV (not the entire heart) or why the type 1 ECG pattern is intermittently present. Thus, it is likely that the presence of a mutation is required but not sufficient to produce the electrical 'signature' of the disease. If so, the presence of structural abnormalities may play an important role (Frustaci et al., 2005; Yan et al., 1999).
The depolarization hypothesis suggests that slow conduction in the RVOT, secondary to fibrosis and reduced Cx43 leading to discontinuities in indeterminate conduction, plays a primary role in the development of the ECG and arrhythmic manifestations of the BrS (Nagase et al., 2002, Postema et al 2008; Wilde et al., 2010; Elizari et al., 2007). Conduction slowing is not necessarily limited to the RVOT area. It has been proposed that changes in ion channel current responsible for BrS (i. e., loss of function INa and ICa and gain of function of Ito) can alter AP morphology so as to reduce the safety of conduction at high resistance junctions, such as regions of extensive fibrosis (Hoogendijk et al. 2010). However, the typical behavior of patients with BrS to acceleration of rate is diminution of ST-segment elevation, opposite to that expected at a site of discontinuous conduction.
It has been demonstrated significant regional conduction delay, reduction in activation gradient and formation of lines of functional conduction block in the anterolateral free wall of the right ventricular outflow tract compared with the right ventricular body and apex of BS patients (Lambiase et al., 2009). Moreover, fractionated electrograms in the RV, possibly due to subtle structural abnormalities (hypertrophy, vacuolation and cardiomyocyte apoptosis, fibrofatty infiltration), have been also reported in patients with BS (Coronel et al., 2005; Postema et al., 2010). The delay in the AP of the RVOT causes an electrical gradient from the more positive RV to the RVOT, leading to ST-elevation in the right precordial leads and as the RVOT depolarizes later (during repolarization of the RV) this gradient is reversed and the net current flows towards the RV, resulting in a negative T-wave in the same right precordial leads (Meregalli et al., 2005). More recently, Nademanedee et al (2011) found in patients with a type 1 pattern BrS and episodes of VT/VF abnormal low voltage, prolonged duration, and fractionated late potentials clustering exclusively in the anterior aspect of the right ventricular outflow tract epicardium. These results confirm the presence of delayed depolarization at this site that would facilitate the development of epicardial reentry circuits and would be aggravated by the reduction of the INa. Under these circumstances, Na+ channel blockers create additional conduction delay between the other part of the ventricles and the RVOT (the depolarization theory) or induce the transmural gradient of AP by shortening AP more in the RVOT epicardium than endocardium (the repolarization theory), which, theoretically, both lead to the manifestation of coved-type ECG (Meregalli et al., 2005).
There is another explanation, i.e. the “developmental” hypothesis, in which abnormal expression of cardiac neural crest cells in the ROVT leads to abnormal connexin expression (Cx43) and combined depolarization–repolarization abnormalities favor¬ing arrhythmia (Elizari et al., 2007).
They are quite variable, from asymptomatic patients to those in which the first manifestation is a SCD (Antzelevitch et al., 2005). The most common clinical manifestations are syncope or seizures, agonal respiration or SCD caused by self-terminating VF episodes mostly occurring during sleep or at rest. Sinus function is normal, although supraventricular tachycardias, the most frequent atrial fibrillation (AF), are present in 20-30% of patients; indeed, AF can be the first manifestation of the BrS (Kusano et al., 2008). Atrioventricular block and intraventricular conduction delays (HV interval of 60-75 ms) are also part of the phenotype of BrS (Smits et al., 2002), and a high percentage of patients have inducible VT (or VF) during programmed ventricular stimulation. The intraventricular conduction delays explain the slight prolongation of the PR interval and the morphology of right bundle branch block and left anterior hemiblock in the ECG. Interestingly, hemodynamic studies are normal.
The ECG pattern ECG morphology is highly variable over time even in the same patient, so that in asymptomatic individuals the typical ECG syndrome can be found by chance during a routine examination or during a study because of a family history of SCD. Conversely, in some patients the diagnosis is reached because of unexplained or vasovagal syncope or idiopathic VF, or because they were challenged with class I antiarrhythmic drugs that unmask a concealed or non-diagnostic ECG pattern (Figure 1). T hree patterns have been described (Antzelevitch et al., 2005)(Figure 1).
Type 1: presents with ST elevation >2 mm with coved morphology in more than one right precordial lead (V1-V3) followed by a negative T wave in more than one right precordial ECG lead, associated with complete or incomplete block of the right branch followed by a negative T wave (Priori et al., 2013). This pattern allows the diagnosis of the BrS, but may be intermittent and not always detectable at baseline based on a single ECG recording. Right bundle branch block is not required for the diagnosis.
Type 2: characterized by ST segment elevation> 2 mm in right precordial leads followed by positive or isobiphasic T waves ("saddle back”).
Type 3: combined the two patterns with less than 2 mm J-point elevation and an STsegment elevation < 1 mm. Types 2 and 3 do not allow the diagnosis of BrS.
It is possible that the electrocardiographic patterns differ depending on the mutation and that the observed variations over time are related to changes in autonomic tone, body temperature or heart rate (Benito et al., 2008; Mizusawa et al., 2012). Adrenergic stimulation (isoproterenol), exercise and an increase in heart rate decrease the ST segment elevation; indeed, some patients with “VF storms” associated with BrS can be effectively treated with isoproterenol infusion (Tanaka et al., 2001).
Conversely, Brugada ECG is often concealed and can be unmasked with a wide variety of drugs and conditions, including vagotonic agents and maneuvers, a-adrenergic agonists, β-adrenergic blockers, Class IC antiarrhythmic drugs, tricyclic or tetracyclic antidepressants, hyperkalemia, hypokalemia, hypercalcemia, alcohol, cocaine toxicity, heavy meals (“full stomach test”), febrile state, bradycardia and certain drugs (Brugada et al., 2000; Veerakul and Nademanee, 2012). The mechanism of ST segment changes in the setting of fever is likely secondary to further compromise of INa due to accelerated inactivation of the channel with higher body temperature or reduced channel conductance (Dumaine et al., 1999). Preexcitation of RV can unmask the BrS phenotype in cases of RBBB (Chiale et al., 2012). An upto-date list of agents known to unmask the Brugada ECG that should be avoided by patients with BrS can be found at www. brugadadrugs.org.
A pharmacological test with Na+ channel blockers (ajmaline, flecainide, pilsicainide, procainamide) can unmask a concealed or non-diagnostic pattern into a coved Type 1 ECG diagnostic pattern (Wilde et al., 2002; Atzelevitch et al., 2016). These modulating and predisposing factors can affect the arrhythmia and the clinical outcomes by: modifying the VF substrate, affecting the gene expression of ion channel defects, triggering premature ventricular contractions (PVCs) and the initiating process of VF and influencing the sustaining process of the VF episodes (Veerakul and Nademanee, 2012).
Other factors, however, such as family history and SCN5A mutations are of little prognostic Importance (Probst et al., 2010).
According to the 2013 consensus statement on inherited cardiac arrhythmias (Priori et al., 2013) and the 2015 guidelines for the management of patients with ventricular arrhythmias and prevention of SCD (Priori et al., 2015): "BrS is diagnosed in patients with ST- segment elevation with type 1 morphology =2 mm in =1 lead among the right precordial leads V1, V2, positioned in the 2nd, 3rd or 4th intercostal space occurring either spontaneously or after provocative drug test with intravenous administration of Class I antiarrhythmic drugs. BrS is diagnosed in patients with type 2 or type 3 ST-segment elevation in =1 lead among the right precordial leads V1, V2 positioned in the 2nd, 3rd or 4th intercostal space when a provocative drug test with intravenous administration of Class I antiarrhythmic drugs induces a type I ECG morphology.” In any case, it is necessary to rule out other conditions producing a ST segment elevation of the ECG (ischemia, myocarditis, hyperkalemia, hypercalcemia, ventricular arrhythmogenic dysplasia or pulmonary embolism).
When the ECG is less characteristic and in patients with a normal ECG it is possible to unmask the characteristic ST-segment elevation in the right precordial leads following the intravenous administration of Class I antiarrhythmic drugs. These drugs cause an additional delay of conduction in the ROVT and induce a transmural gradient by shortening the AP more in the epicardial than in endocardial cells which contributes to the appearance of a type 1 pattern in the ECG (Maregalli et al., 2005). This is the reason why the intravenous administration of a Class I antiarrhythmic drug is recommended in all patients with unexplained syncope or idiopathic VF to exclude the presence of a BrS. The infusion of these drugs must end if the widening of the QRS complex is =130% as compared to baseline.
When Type 1 ECG is elicited through pharmacological challenge but is never spontaneously present, the arrhythmic risk is lower. Therefore, the challenge is to identify to further stratify the arrhythmic risk in this group, thus selecting who should receive an ICD. The value of programmed electrical stimulation is highly debated and no conclusive and prospective data are yet available (Brugada et al. 2002,2003; Probst et al., 2010); a family history for SCD and/or the presence of a genetic mutation does not influence the arrhythmic risk.
Proposed Shanghai Score System for diagnosis of Brugada syndrome (Taken from Antzelevitch et al., 2016)
I. ECG (12-Lead/Ambulatory)
A. Spontaneous type 1 Brugada ECG pattern at nominal or high leads
B. Fever-induced type 1 Brugada ECG pattern at nominal or high leads
C. Type 2 or 3 Brugada ECG pattern that converts with provocative drug challenge
*Only award points once for highest score within this category. One item from this category must apply.
II. Clinical history
A. Unexplained cardiac arrest or documented VF/polymorphic VT
B. Nocturnal agonal respirations
C. Suspected arrhythmic syncope
D. Syncope of unclear mechanism/unclear etiology
E. Atrial flutter/fibrillation in patients o30 years without alternative etiology
*Only award points once for highest score within this category.
III. Family history
A. First- or second-degree relative with definite BrS
B. Suspicious SCD (fever, nocturnal, Brugada aggravating drugs) in a first- or second-degree relative
C. Unexplained SCD o45 years in first- or second- degree relative with negative autopsy
*Only award points once for highest score within this category.
IV. Genetic Test Result
A. Probable pathogenic mutation in BrS susceptibility gene
Education and lifestyle changes for the prevention of arrhythmias are critical in BrS. All patients with a Brugada ECG should be taught to treat aggressively any episodes of fever and to avoid drugs known to exacerbate the condition (http://www.brugadadrugs.org).
Implantable cardioverter-defibrillator. At the present time there is no medical treatment (amiodarone, β-blockers) effective in preventing arrhythmias and sudden death in BrS and the only proven effective therapeutic strategy for the prevention of SCD in high-risk BrS is an ICD (Priori et al., 2013). ICDs, however, may present several disadvantages, especially in young active individuals, including low rates of appropriate shocks (8–15%, median follow-up 45 months; annual appropriate discharge rate=2.6%) and high rate of inappropriate shocks (20–36% at 21–47 months follow-up)(Berne and Brugada, 2012; Conte et al., 2015; Sacher et al., 2013).
The HRS/EHRA/APHRS expert consensus states that implantation of an ICD is first-line therapy for BrS patients presenting with aborted SCD or documented VT/VF with or without syncope (Class I recommendation) (Brugada et al., 1999; 2000). ICDs can be useful (Class IIa) in symptomatic BrS patients with type 1 pattern, in whom syncope was likely caused by VT/VF. However, the implantation should be considered on a case-by-case basis by an electrophysiologist experienced in BrS, taking into consideration age, gender, clinical presentation, ECG characteristics (QRS fragmentation, Jp amplitude), and patient preference. ICD may be considered (Class IIb) in asymptomatic patients with inducible VF during programmed electrical stimulation (PES) (Priori et al., 2013). If VT/VF is inducible, an ICD should be considered (Priori et al., 2013). An ICD is not indicated in asymptomatic patients without any of these characteristics.
Other patients that should also receive an ICD are: a) asymptomatic patients with a family history of SCD, especially if VT/VF can be induced in an electrophysiology study (EPS) and have present a prolongation of the HV interval, and b) asymptomatic patients with no family history MSC, when the BrS is inducible during EPS. However, although Brugada et al (2005) proposed that arrhythmia inducibility during an EPS is a marker of risk for VT/VF regardless of whether or not the type 1 pattern is present and whether or not they are symptomatic, other studies have not found a correlation between inducibility and arrhythmic events, raising serious doubts whether an EPS should be performed in asymptomatic patients (Wilde and Viskin, 2011). Asymptomatic patients in whom the SBr is discovered only after a challenge with class I antiarrhythmic drugs have no events at 25 months. Therefore, and because of the relatively high complication rate in BrS patients with ICDs, one has to be extremely cautious about using ICDs in asymptomatic BrS patients.
Cardiac pacing. Because arrhythmic events and SCD in BrS generally occur during sleep or at rest and are associated with slow heart rates there is a potential therapeutic role for cardiac pacing (van den Berg et al., 2001). Some studies suggest that the predictive value of EP studies may be improved by limiting the PES protocol to 2 extrastimuli (Sroubeck et al., 2016), but that observation is not supported by others (Priori et al., 2012).
Radiofrequency ablation (RFA). Nademanee et al. (2011) showed that RFA of abnormal low voltage, prolonged duration, and fractionated late potentials clustering exclusively in the anterior aspect of the right ventricular outflow tract (RVOT) epicardium reduced arrhythmia vulnerability and the ECG manifestations. Ablation at these sites results in normalization of the Brugada ECG pattern and prevents VT/VF, both during electrophysiological studies as well as spontaneous recurrent VT/VF episodes in patients with BrS results in normalization of the Brugada ECG pattern and prevents VT/VF, both during electrophysiological studies as well as spontaneous recurrent VT/VF episodes in patients with BrS (Nademanee et al., 2011). Additional evidence in support of the effectiveness of epicardial substrate ablation was provided (Sacher et al., 2014; Shah et al., 2011). Recently, Brugada et al (2015) used flecainide to identify the full extent of low-voltage electrogram activity in the anterior RV and RVOT and targeted this region for RFA. RFA eliminated abnormal bipolar electrograms, normalized ST-segment elevation on right precordial leads of ECG, and VT/VF was no longer inducible. Thus, RFA may be considered (Class IIb recommendation) in BrS patients with frequent appropriate ICD shocks due to recurrent electrical storms (Priori et al., 2013).
Pharmacologic approach to the BrS. Antiarrhythmic agents such as amiodarone and beta-blockers are ineffective (Brugada et al., 1998) and class IC (e.g., flecainide, propafenone) and Class IA antiarrhythmic drugs (e.g., procainamide) are contraindicated because they can unmask the BrS. Disopyramide normalizes ST-segment elevation in some Brugada patients, while unmasks the syndrome in others (Chinushi et al., 1997). Because of the key role of Ito;the therapeutic objective will be a selective blocker. The only agent with significant selective Ito-blocking properties is quinidine. In experimental models and clinical trials, quinidine is effective in restoring the epicardial AP dome, normalizes the ST segment and prevents phase 2 reentry and polymorphic VT (Antzelevitch et al., 2016). Hermida et al (2004) reported that hydroquinidine prevents VT/VF inducibility in 76% of asymptomatic patients with BrS and inducible arrhythmia, as well as VT/VF recurrence in all BrS patients with multiple ICD shocks and Belhassen et al (2015) that quinidine, disopyramide or both showed a 90% efficacy in preventing VF induction despite the use of very aggressive protocols of extrastimulation. Furthermore, no arrhythmic events occurred among BrS patients treated with quinidine during a mean follow-up period of 10 years. In asymptomatic BrS patients with inducible VT/VF, 77% were no longer inducible while treated with 600 mg/day hydroquinidine for 6.2–3 years (Bouzeman et al., 2014). The HRS/EHRA/APHRS expert consensus recommends quinidine in BrS patients presenting with electrical storms and in patients implanted with an ICD who are experiencing repeated appropriate shocks (Class IIb indication) and can also be useful in asymptomatic BrS patients displaying a spontaneous type I ECG, if they qualify for an ICD and the device is refused or is contraindicated (Class IIa recommendation) (Priori et al., 2013). Doses between 600 and 900 mg were recommended, if tolerated (Viskin et al., 2009). However, chronic quinidine treatment is poorly tolerated, due to the high incidence adverse effects (gastrointestinal, thrombocytopenia). Interestingly, cholestyramine can control the diarrhea induced by quinidine.
Isoproterenol infusion, which increases the L-type Ca2+ current (ICa), has been used successfully to control arrhythmic storms and to suppress induction of VT/VF on programmed stimulation, particularly in children (Tanaka et al., 2001; Shimizu et al., 2001; Mok et al., 2004; Maury et al., 2005; Watanaba et al., 2006; Antzelevitch and Fish, 2006; Ohgo et al., 2007; Pellegrino et al., 2013). Spontaneous VF in patients with BrS is often related to increases in vagal tone and responds to treatment by an increase of sympathetic tone via isoproterenol administration. Administration of isoproterenol is a Class IIa recommendation for BrS patients presenting with electrical storms (Priori et al., 2013).
Another approaches include the administration of the phosphodiesterase III inhibitor cilostazol, which normalizes the ST segment, most likely by inscreasing the ICa as well as by reducing Ito secondary to an increase in cAMP and heart rate (Ohgo et al., 2007; Tsuchiya et al., 2002). Bepridil suppresses VT/VF in several studies of patients with BrS via the inhibition of Ito, augmentation of INa via up-regulation of the sodium channels and prolongation of QT interval at slow rates thus increasing the QT/RR slope. (Ohgo et al., 2007; Aizawa et al., 2013; Murukami et al., 2010; Antzelevitch et al., 2016).
Because malignant ventricular arrhythmias are infrequent in asymptomatic patients with BrS (Probst et al., 2010) and usually unrelated to physical activity, the presence of these patterns does not contraindicate participation in sports, although, as previously discussed, insufficient data are currently available to make definitive recommendations (Antzelevitch et al., 2016).
Ackerman M, Priori S, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm 2011; 8: 1308-1339.
Aizawa Y, Yamakawa H, Takatsuki S, et al. Efficacy and safety of bepridil for prevention of ICD shocks in patients with Brugada syndrome and idiopathic ventricular fibrillation. Int J Cardiol 2013;168:5083–5.
Akai J, Makita N, Sakurada H, Set al. A novel SCN5A mutation associated with idiopathic ventricular fibrillation without typical ECG findings of Brugada syndrome. FEBS Lett. 2000;479:29-34.
Amin A, Asghari A, Tan HL. Cardiac sodium channelopathies. Pflugers arch 2010;460:223-237.
Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, et al. Brugada syndrome: Report of the Second Consensus Conference: Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation. 2005;111:659-670.
Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 2007; 115:442-449.
Antzelevitch C, Fish JM. Therapy for the Brugada syndrome. Handb Exp Pharmacol 2006; 171:305-330.
Antzelevitch C, Yan GX, Ackerman MJ, et al. J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge. J Arrhythm 2016;32:315-339.
Antzelevitch C., Nof E. Brugada syndrome: recent advances and controversies. Curr Cardiol Rep. 2008;10:376–383.
Antzelevitch C. Role of transmural dispersion of repolarization in the genesis of drug-induced torsades de pointes. Heart Rhythm. 2005;2(2 Suppl):S9–S15.
Barajas-Martinez H, Hu D, Ferrer T. Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8. Heart Rhythm. 2012;9:548–555.
Baroudi G, Pouliot V, Denjoy I, et al. Novel mechanism for Brugada syndrome: defective surface localization of an SCN5A mutant (R1432G). Circ Res 2001;88:E78-83.
Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation. 2004;110:1731-1737.
Belhassen B, Rahkovich M, Michowitz Y, et al. Management of Brugada syndrome: a 33-year experience using electrophysiologically-guided therapy with Class1A antiarrhythmic drugs. Circ Arrhythm Electro- physiol 2015;6:1393–402.
Bouzeman A, Traulle S, Messali A, et al. Long-term follow-up of asymptomatic Brugada patients with inducible ventricular fibrillation under hydro-quinidine. Europace 2014;16:572–7.
Behr ER, Savio-Galimberti E, Barc J, et al. Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study. Cardiovasc Res 2015;106:520–9.
Berne P, Brugada J. Brugada syndrome 2012. Circ J 2012;76:1563-1571.
Benito B, Sarkozy A, Mont L, Henkens S, Berruezo A, Tamborero D, et al. Gender differences in clinical manifestations of Brugada syndrome. J Am Coll Cardiol. 2008;52:1567-73
Bennett PB, Yazawa K, Makita N, et al. Molecular mechanism for an inherited cardiac arrhythmia. Nature 1995;376:683 - 685
Bezzina C, Veldkamp MW, van den Berg MP, et al. A single Na+ channel mutation causing both long-QT and Brugada syndromes. Circ Res. 1999;85:1206-1213.
Bezzina C.R., Barc J., Mizusawa Y. Common variants at SCN5A-SCN10Aand HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nat Genet. 2013;45:1044–1049.
Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol. 1992;20:1391-1396.
Brugada J, Brugada R, Brugada P. Pharmacological and device approach to therapy of inherited cardiac diseases associated with cardiac arrhythmias and sudden death. J Electrocardiol. 2000;33(Suppl):41–47.
Brugada J, Brugada R, Antzelevitch C, et al. Long-term follow-up of individuals with the electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V1 to V3. Circulation. 2002;105:73-78.
Brugada J, Brugada R, Brugada P. Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest. Circulation. 2003;108:3092-3096.
Brugada J, Pappone C, Berruezo A. Brugada syndrome phenotype elimination by epicardial substrate ablation. Circ Arrhythm Electrophysiol. 2015;8:1373–1381.
Burashnikov E, Pfeiffer R, Barajas-Martinez H, et al. Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm. 2010;7:1872-1882.
Cerrone M, Lin X, Zhang M, et al. Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype. Circulation 2014;129:1092–103.
Chen Q, Kirsch GE, Zhang D, et al. Natural history of Brugada syndrome: the prognostic value of programmed electrical stimulation of the heart. J Cardiovasc Electrophysiol 2003; 14:455-457.
Chen Q, Kirsch GE, Zhang D, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998; 392:293-296
Cerrone M, Priori S. Genetics of sudden death: focus on inherited channelopathies. Eur Heart J 2011; 32:2109-2120
Coronel R, Casini S, Koopmann TT, et al. Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: A combined electrophysiological, genetic, histopathologic, and computational study. Circulation 2005; 112: 2769-2777.
Chinushi M, Aizawa Y, Ogawa Y, et al. Discrepant drug action of disopyramide on ECG abnormalities and induction of ventricular arrhythmias in a patient with Brugada syndrome. J Electrocardiol. 1997;30:133–136.
Conte G, Sieira J, Ciconte G, et al. Implantable cardioverter-defibrillator therapy in Brugada syndrome: a 20-year single-center experience. J Am Coll Cardiol 2015;65:879–88.
Delpon E, Cordeiro JM, Nunez L, Thomsen PEB, Guerchicoff A, Pollevick GD, et al. Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome. Circ Arrhythm Electrophysiol. 2008;1:209-18
Di Diego JM, Cordeiro JM, et al. Ionic and cellular basis for the predominance of the Brugada syndrome phenotype in males. Circulation 2002; 106:2004-2011.
DiFrancesco D. Funny channel gene mutations associated with arrhythmias. J Physiol. 2013;591:4117–4124.
Dumaine R, Towbin JA, Brugada P, et al. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res. 1999;85:803-809.
Ezaki K, Nakagawa M, Taniguchi Y, et al. Gender differences in the ST segment: Effect of androgendeprivation therapy and possible role of testosterone. Circ J 2010; 74: 2448-2454.
Fukuyama M, Ohno S, Makiyama T, et al. Novel SCN10A variants associated with Brugada syndrome. Europace 2015;18:905–11.
Grant, A.O., et al. 2002. Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation. J. Clin. Invest. 110:1201-1209.
Hermida JS, Denjoy I, Clerc J, et al. Hydroquinidine therapy in Brugada syndrome. J Am Coll Cardiol 2004; 43:1853-1860.
Hoogendijk MG, Opthof T, Postema PG, etal. The Brugada ECG pattern: a marker of channelopathy, structural heart disease, or neither?. Toward a unifying mechanism of the Brugada syndrome. Circ Arrhythm Electrophysiol 2010;3:283–90.
Hu D, Barajas-Martínez H, Medeiros-Domingo A, et al. A novel rare variant in SCN1Bb linked to Brugada syndrome and SIDS by combined modulation of Na(v)1.5 and K(v)4.3 channel currents. Heart Rhythm. 2012;9:760-766.
Hu D, Barajas-Martinez H, Burashnikov E, et al. A mutation in the beta 3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype. Circ Cardiovasc Genet. 2009;2:270-278.
Huang J-M, Horie M. Genetics of Brugada syndrome. J Arrhythmia. 2016; 32: 418–425.
Kattygnarath D, Maugenre S, Neyroud N, et al. MOG1: a new susceptibility gene for Brugada syndrome. Circ Cardiovasc Genet. 2011;4:261-268.
Kusano KF, Taniyama M, Nakamura K, et al. Atrial fibrillation in patients with Brugada syndrome relationships of gene mutation, electrophysiology, and clinical backgrounds. J Am Coll Cardiol. 2008;51:1169-75.
Kyndt F, Probst V, Potet F, et al. Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family. Circulation. 2001;104:3081-3086.
Lambiase PD, Ahmed AK, Ciaccio EJ, Brugada R, Lizotte E, Chaubey S, Ben-Simon R, Chow AW, Lowe MD, McKenna WJ. High-density substrate mapping in Brugada syndrome: combined role of conduction and repolarization heterogeneities in arrhythmogenesis. Circulation 2009; 120:106-117, 101-104.
Le Scouarnec S, Karakachoff M, Gourraud JB, et al. Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome. Hum Mol Genet 2015; 24:2757–63.
Liu H, Chatel S, Simard C, et al. Molecular genetics and functional anomalies in a series of 248 Brugada cases with 11 mutations in the TRPM4 channel. PLoS One 2013;8:e54131.
London B, Michale M, Mehdi H, et al. Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPDL-1) decreases cardiac Na-current and causes inherited arrhthmias. Circulation. 2007;116:2260-2268.
Makita N, Behr E, Shimizu W, et al. The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. J Clin Invest. 2008;118:2219-2229.
Maury P, Hocini M, Haissaguerre M. Electrical storms in Brugada syndrome: review of pharmacologic and ablative therapeutic options. Indian Pacing Electrophysiol J. 2005;5:25-34.
Medeiros-Domingo A, Tan BH, Crotti L, et al. Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes. Heart Rhythm. 2010;7:1466-1471.
Meregalli PG, Wilde AA, Tan HL. Pathophysiological mechanisms of Brugada syndrome: depolarisation disorder, repolarisation disorder or more? Cardiovasc Res. 2005;67:367-378.
Meregalli PG, Tan HL, Probst V, et al. Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. Heart Rhythm 2009;6:341-348.
Mizusawa Y, Sakurada H, Nishizaki M, et al. Effects of low-dose quinidine on ventricular tachyarrhythmias in patients with Brugada syndrome: low-dose quinidine therapy as an adjunctive treatment. J Cardiovasc Pharmacol. 2006;47:359-364.
Mizasuwa Y, Wilde AA. Brugada syndrome. Circ Arrhythm Electrophysiol 2012;5:606-616.
Mok NS, Chan NY, Chi-Suen CA. Successful use of quinidine in treatmentof electrical storm in Brugada syndrome. Pacing Clin Electrophysiol 2004;27: 821–823.
Murakami M, Nakamura K, Kusano KF, et al. Efficacy oflow-dose bepridil for preventionofventricular fibrillation in patients with Brugada syndrome with and without SCN5A mutation. J Cardiovasc Pharmacol 2010;56:389–95.
Nademanee K, Veerakul G, Chandanamattha P, et al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation. 2011;123:1270-1279.
Nagase S, Kusano KF, Morita H, et al. Epicardial electrogram of the right ventricular outflow tract in patients with the Brugada syndrome: using the epicardial lead. J Am Coll Cardiol 2002; 39: 1992 - 1995.
Nielsen MW, Holst AG, Olesen SP, et al. The genetic component of Brugada syndrome. Front Physiol. 2013;4:179.
Ohgo T, Okamura H, Noda T, et al. Acute and chronic management in patients with Brugada syndrome associated with electrical storm of ventricular fibrillation. Heart Rhythm 2007; 4: 695-700.
Ohno S, Zankov DP, Ding WG, et al. KCNE5 (KCNE1L) variants are novel modulators of Brugada syndrome and idiopathic ventricular fibrillation. Circ Arrhythm Electrophysiol. 2011;4:352-361.
Pellegrino PL, Di BM, Brunetti ND. Quinidine for the management of electrical storm in an old patient with Brugada syndrome and syncope. Acta Cardiol 2013;68:201–3.
Postema PG, van Dessel PF, de Bakker JM, Dekker LR, Linnenbank AC, Hoogendijk MG, Coronel R, Tijssen JG, Wilde AA, Tan HL. Slow and discontinuous conduction conspire in Brugada syndrome: a right ventricular mapping and stimulation study. Circ Arrhythm Electrophysiol 2008;1:379-386.
Postema PG, van Dessel PF, Kors JA, Linnenbank AC, van Herpen G, Ritsema van Eck HJ, van Geloven N, de Bakker JM, Wilde AA, Tan HL. Local depolarization abnormalities are the dominant pathophysiologic mechanism for type 1 electrocardiogram in brugada syndrome a study of electrocardiograms, vectorcardiograms, and body surface potential maps during ajmaline provocation. J Am Coll Cardiol 2010;55:789-797.
Priori SG, Napolitano C, Gasparini M, et al. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation 2002; 105:1342-1347.
Priori SG, Gasparini M, Napolitano C, et al. Risk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) registry. J Am Coll Cardiol 2012;59:37-45.
Priori S.G., Wilde A.A., Horie M. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10:1932–1963.
Priori S.G., Blomstrom-Lundqvist C., Mazzanti A, et al. 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J. 2015;36:2757–2759.
Probst V, Veltmann C, Eckardt L, et al. Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry. Circulation 2010; 121:635-643.
Probst V, Denjoy I, Meregalli PG, et al. Clinical aspects and prognosis of Brugada syndrome in children. Circulation. 2007;115:2042-2048. ç
Probst V, Veltmann C, Eckardt L,etal. Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry. Circulation 2010;121:635–43.
Sacher F, Probst V, Maury P. Outcome after implantation of cardioverter- defibrillator in patients with Brugada syndrome: a multicenter study—part 2. Circulation. 2013;128:1739–1747.
Sacher F, Jesel L, Jais P, et al. Insight into the mechanism of Brugada syndrome: epicardial substrate and modification during ajmaline testing. Heart Rhythm. 2014;11:732–734.
Schulze-Bahr E, Eckardt L, Breithardt G, et al. 2003. Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: different incidences in familial and sporadic disease. Hum. Mutat. 21:651-652.
Shah AJ, Hocini M, Lamaison D. Regional substrate ablation abolishes Brugada syndrome. J Cardiovasc Electrophysiol. 2011;22:1290–1291
Shimizu W, Kamakura S .Catecholamines in children with congenital long QT syndrome and Brugada syndrome. J Electrocardiol 2001;34:173–5.
Shirai N, Makita N, Sasaki K, et al. A mutant cardiac sodium channel with multiple biophysical defects associated with overlapping clinical features of Brugada syndrome and cardiac conduction disease. Cardiovasc Res. 2002;53:348-354.
Smits JP, Eckardt L, Probst V, et al. Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. J Am Coll Cardiol 2002; 40:350-356.
Smits JP, Koopmann TT, Wilders R, et al. A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families. J Mol Cell Cardiol 2005;38:969 - 981.
Sroubek J, Probst V, Mazzanti A. Programmed Ventricular Stimulation for Risk Stratification in the Brugada Syndrome: A Pooled Analysis. Circulation. 2016;133:622-30.
Ueda K, Nakamura K, Hayashi T, et al. Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. J Biol Chem 2004; 279: 27194-27198.
Ueda K, Hirano Y, Higashiuesato Y, et al. Role of HCN4 channel in preventing ventricular arrhythmia. J Hum Genet. 2009;54:115-121.
Takehara N, Makita N, Kawabe J, et al. A cardiac sodium channel mutation identified in Brugada syndrome associated with atrial standstill. J Intern Med. 2004;255:137-142.
Tanaka H, Kinoshita O, Uchikawa S, et al. Successful prevention of recurrent ventricular fibrillation by intravenous isoproterenol in a patient with Brugada syndrome. Pacing Clin Electrophysiol 2001;1293-1294.
Tanaka H, Kinoshita O, Uchikawa S, et al. Successful prevention of recurrent ventricular fibrillation by intravenous isoproterenol in a patient with Brugada syndrome. Pacing Clin Electrophysiol 2001;24:1293–4.
Tsuchiya T, Ashikaga K, Honda T, et al. Prevention of ventricular fibrillation by cilostazol, an oral phosphodiesterase inhibitor, in a patient with Brugada syndrome. J Cardiovasc Electrophysiol 2002;13:698–701.
Valdivia CR, Tester DJ, Rok BA, et al. A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs. Cardiovasc Res. 2004;62:53-62.
van Den Berg MP, Wilde AA, Viersma TJW. Possible bradycardic mode of death and successful pacemaker treatment in a large family with features of long QT syndrome type 3 and Brugada syndrome. J Cardiovasc Electrophysiol. 2001;12:630–636.
Veerakul G, Nademanee K. Brugada syndrome: two decades of progress. Circ J 2012;76:2713-2722.
Verkerk AO, Wilders R, Schulze-Bahr E, et al. Role of sequence variations in the human ether-ago-go -related gene (HERG, KCNH2) in the Brugada syndrome 1. Cardiovasc Res 2005; 68: 441-453.
Viskin S, Wilde AA, Tan HL, et al. Empiric quinidine therapy for asymptomatic Brugada syndrome: time for a prospective registry. Heart Rhythm 2009;6:401–4.
Wang DW, Makita N, Kitabatake A., et al. Enhanced Na+ channel intermediate inactivation in Brugada syndrome. Circ. Re 2000; 87:E37-E43.
Wang Q, Ohno S, Ding WG. Gain-of-function KCNH2 mutations in patients with Brugada syndrome. J Cardiovasc Electrophysiol. 2014;25(5):522–530.
Watanabe H, Koopmann TT, Le Scouarnec S, et al. Sodium channel beta1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. J. Clin. Invest 2008; 118: 2260-2268.
Watanabe A, Fukushima KK, Morita H, et al. Low-dose isoproterenol for repetitive ventricular arrhythmia in patients with Brugada syndrome. Eur Heart J 2006;27:1579–83.
Weiss R, Barmada MM, Nguyen T, et al. Clinical and molecular heterogeneity in the Brugada syndrome: a novel gene locus on chromosome 3. Circulation. 2002;105:707–713.
Wilde AA, Antzelevitch C, Borggrefe M, et al. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation 2002; 106:2514-2519.
Wilde AA, Viskin S. EP testing does not predict cardiac events in Brugada syndrome. Heart Rhythm 2011; 8: 1598-1600.
Wilde AA, Postema PG, Di Diego JM, et al. The pathophysiological mechanism underlying Brugada syndrome: depolarization versus repolarization. J Mol Cell Cardiol. 2010;49:543–553.
Yan GX, Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation. 1999;100:1660-1666.