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Primary Arrhythmogenic Cardiomyopathies. Channelopathies  

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).

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1. Prevalence

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).

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2. Genetic basis

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)

Syndrome

Locus

Gene

Gene product

Current

Function

BrS1 (15-25%) *

3p21

SCN5A

Nav1.5 α subunit

INa

(-)

BrS2

3p24

GPD1-L

glycerol-3-phosphate-dehydrogenase 1-like protein

INa

(-)

BrS3 (6.6%)

12p13.3

CACNA1C

Cav1.2 α subunit

ICa,L

(-)

BrS4 (4.8%)

10p12.33

CACNB2b

Cav1.2 β2 subunit

ICa,L

(-)

BrS5 (1-2%)

19q13.1

SCN1B

Nav1.5 β1 subunit

INa

(-)

BrS6

11q13-14

KCNE3

MIRP2 β subuniT

Ito/IkS

(+)

BrS7

11q23.3

SCN3B

Nav1.5 β3 subunit

INa

(-)

BrS8 (2%)

12p11.23

KCNJ8

Kir6.1

IKATP

(+)

BrS9

7q21-22

CACNA2D1

Cav1.2 αδ-1 subunit

ICa,L

(-)

BrS10

1p13.2

KCND3
KCND2

Kv4.3 α subunit
Kv4.3 α subunit

Ito
Ito

(+)
(+)

BRS11

17p13.1

RANGRF

MOG1 protein: Nav1.5 cofactor

INa

(-)

BrS12

3p21.2-p14.3

SLMAP

Sarcolemmal membrane-associated protein

INa

(-)

BrS13 (4-5%) 12p12.1

ABCC9

SUR2A IKATP (+)
BrS14 11q23 SCN2B Navβ2 subunit INa (-)
BrS15 12p11.21 PKP2 Plakophilin-2 INa (-)
BrS16 3q28 FGF12 Fibroblast growth factor homologus factor 12 INa/ICa,L (-)
BrS17 3p22.2 SCN10A Nav1.8 INa (-)
BrS18 6q22 HEY2 Nav1.5 INa (-)
** 19q13.33 TRPM4 Trasient receptor potential malastatin protein 4 NSCCa (-)
  15q24.1 HCN4 α subunit If (-)
  7q35 KCNH2 kV11.1 IKar (-)
  Xq22.3 KCNE5 MiRP4 β subunit Ito/IKs (+)
** 8q11.3 PXDNL Peroxidasin homolog (Drosophila)-like    
  3p22.3 CLASP2 Cytoplasmic linker associated protein 2 (participates in the membrane localization of SCN5A)    
  16q12.2 IRX5 Iroquois homebox 5 KCND3 (+)
  7q36.2 DPPX Dipeptidyl-peptidase-like protein 6    
  7q21.11 SEMA3A Semaphorin 3A Ito (+)

(+): 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.

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3. Electrophysiological basis

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).

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4. Clinical manifestations

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).

Table. Drug-induce Brugada syndrome (see www.brugadadrugs)

    • Antiarrhythmic drugs: class IA and IC (ajmaline, amiodarone, cibenzoline, disopyramide, flecainide, lidocaine, pilsicainide, procainamide), diltiazem, verapamil, beta-blockers, vernakalant
    • Antianginal drugs: calcium antagonists, nitrates
    • Psychotropic drugs: bupropion, carbamazepine, clothiapine, cyamemazine, dosulepine, doxepin, fluoxetine, fluvoxamine, imipramine, lamotrigine, maprotiline, paroxetine, perphenazine, phenytoin, thioridazine
    • Analgesics/anesthetics: ketamine, tramadol
    • Other: acetylcholine, first-generation antihistamines (dimenhydrinate, diphenhydramine), edrophonium, indapamide, metoclopramide, terfenadine/fexofenadine

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5. Diagnosis

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)

 

Features

Points

I. ECG (12-Lead/Ambulatory)

A. Spontaneous type 1 Brugada ECG pattern at nominal or high leads

3.5

B. Fever-induced type 1 Brugada ECG pattern at nominal or high leads

3

C. Type 2 or 3 Brugada ECG pattern that converts with provocative drug challenge

2

*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

3

B. Nocturnal agonal respirations

2

C. Suspected arrhythmic syncope

2

D. Syncope of unclear mechanism/unclear etiology

1

E. Atrial flutter/fibrillation in patients o30 years without alternative etiology

0.5

*Only award points once for highest score within this category.

III. Family history 

 

A. First- or second-degree relative with definite BrS

2

B. Suspicious SCD (fever, nocturnal, Brugada aggravating drugs) in a first- or second-degree relative

1

C. Unexplained SCD o45 years in first- or second- degree relative with negative autopsy

0.5

*Only award points once for highest score within this category.

IV. Genetic Test Result

 

A. Probable pathogenic mutation in BrS susceptibility gene

0.5

Score (requires at least 1 ECG finding)

3.5 points: Probable/definite BrS
3 points: Possible BrS
2 points: Nondiagnostic

ER: early repolarization; ERS: early repolarization syndrome; PVC: premature ventricular contraction; VF: ventricular fibrillation; VT: ventricular tachycardia.

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7. Treatment

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).

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