Cardiac channelopathies: The role of sodium channel mutations | Revista Portuguesa de Cardiologia (English edition)

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(A) O canal Nav1.5 integra um complexo macromolecular e interatua com diversas proteínas, entre as quais: subunidades β, caveolina‐3, MOG1, anquirina, sintrofina e citoesqueleto. Retirado e adaptado de Liu et al. (2014)<a class="elsevierStyleCrossRef" href="#bib0425">7</a> e de Amin et al. (2010).<a class="elsevierStyleCrossRef" href="#bib0500">22</a>(B) O ciclo de vida do Nav1.5 inicia‐se no núcleo, onde ocorre a transcrição do gene SCN5A e respetiva regulação por fatores de transcrição (FOXO1, NF‐KB e TBX5). Contudo, os microRNAs também regulam os níveis de mRNA. No retículo endoplasmático ocorre a tradução proteica e, após ocorrer folding apropriado e assembly de proteínas, essas são transportadas para a membrana celular (trafficking). Mutações ou variantes de splicing podem levar à formação de uma proteína Nav1.5 misfolded e pode ser ativada a via PERK com vista ao down regulation dos seus níveis de mRNA. A PKA, PKC, o stresse oxidativo (ERO) e os estados metabólicos (NADH e NAD+) podem modular o trafficking do canal. O NEDD4 regula a degradação mediada pela ubiquitina. Retirado e adaptado de Liu et al. (2014)<a class="elsevierStyleCrossRef" href="#bib0425">7</a>. CAV3: caveolina‐3; ERO: espécies reativas de oxigénio; FOXO1: forkhead box protein O1; MOG1: Ran guanine nucleotide release factor; NaChIP: Na+‐channel‐interacting protein; NEDD4: E3 ubiquitin‐protein ligase NEDD4; NF‐κB: factor nuclear NF‐κB; PERK: factor de iniciação da tradução eucariótica 2α‐cinase 3; PKA: proteína cínase dependente de AMPc (proteína cínase A); PKC: proteína cínase C; TBX5: fator de transcrição T‐box TBX5." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Diana João Fonseca, Manuel Joaquim Vaz da Silva" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Diana João" "apellidos" => "Fonseca" ] 1 => array:2 [ "nombre" => "Manuel Joaquim" "apellidos" => "Vaz da Silva" ] ] ] ] ] "idiomaDefecto" => "pt" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2174204918300114" "doi" => "10.1016/j.repce.2017.11.016" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => 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[ 0 => array:2 [ "paginaInicial" => "179" "paginaFinal" => "199" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Diana João Fonseca, Manuel Joaquim Vaz da Silva" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Diana João" "apellidos" => "Fonseca" "email" => array:1 [ 0 => "mimed11120@med.up.pt" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Manuel Joaquim" "apellidos" => "Vaz da Silva" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Faculdade de Medicina da Universidade do Porto, Porto, Portugal" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Canalopatias cardíacas: o papel das mutações nos canais de sódio" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ 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There are three patterns of electrocardiographic abnormalities in the right precordial leads (V1-V3). Type 1 is considered to be diagnostic, unlike types 2 and 3 (in presence of which provocation tests with SCB must be performed). Other electrocardiographic abnormalities that may be present in BrS are: prolongation of the PR interval and right branch block. A definitive diagnosis is made in presence of type 1 ST-segment elevation in at least one V1-V3 lead and when one of the clinical criteria presented in the figure is met. AMI: acute myocardial infarction; ANS: autonomic nervous system; C/ARVD: cardiomyopathy/arrhythmogenic right ventricular dysplasia; CCB: calcium channel blockers; CNS: central nervous system; ECG: electrocardiogram; LVH: left ventricular hypertrophy; PTE: pulmonary thromboembolism; RV: right ventricle; RVOT: right ventricular outflow tract; SCB: sodium channel blockers; SSRIs: selective serotonin reuptake inhibitors; VF: ventricular fibrillation; VT: ventricular tachycardia; β-blockers: beta blockers. *May unmask genetic susceptibility to BrS. Extracted and adapted from Berne and Brugada (2012).<a class="elsevierStyleCrossRef" href="#bib0645">51</a>" ] ] ] "textoCompleto" => "IntroductionCardiac channelopathies constitute a heterogeneous group of inherited cardiac diseases caused by mutations in genes that encode for the ion channels expressed in the heart (involved in Na+ [INa], K+ [IK] and Ca2+ [ICa] currents) and/or the proteins that regulate their function.<a class="elsevierStyleCrossRefs" href="#bib0395">1–3</a> These mutations result in different phenotypes according to the abnormalities induced in the sodium current and in other ion currents, leading to a greater likelihood of occurrence of syncope, seizures and arrhythmias, although most of the time there are no underlying structural heart defects.<a class="elsevierStyleCrossRef" href="#bib0410">4</a> This shows the importance of ion channels, namely sodium channels (NaC), in the genesis and propagation of the action potential (AP), and consequently in heart excitability.<a class="elsevierStyleCrossRefs" href="#bib0400">2,3,5–7</a>Induced arrhythmias are potentially fatal, and sudden cardiac death (SCD) frequently constitutes the first manifestation of these diseases.<a class="elsevierStyleCrossRefs" href="#bib0410">4,8</a> Sudden death (SD) is one of the most common causes of death due to cardiovascular pathologies and, in the adult Western population, cardiac channelopathies (1-2%) are one of the most frequently diagnosed predisposing pathologies together with cardiomyopathies (10-15%) and coronary disease (75%).<a class="elsevierStyleCrossRef" href="#bib0435">9</a> In reality, some studies show that cardiac channelopathies are responsible for approximately 1/3 of the SD cases in young people with a negative autopsy, and up to 50% of the cases of arrhythmic SCD.<a class="elsevierStyleCrossRefs" href="#bib0440">10,11</a>The main hereditary arrhythmias caused by ion channel dysfunctions are Brugada syndrome (BrS), long QT syndrome (LQTS), short QT syndrome (SQTS) and catecholaminergic polymorphic ventricular tachycardia (PVT).<a class="elsevierStyleCrossRefs" href="#bib0410">4,12</a> However, their prevalence in the general population is difficult to estimate.<a class="elsevierStyleCrossRefs" href="#bib0445">11,13–15</a> In addition to the pathologies mentioned above, pre-excitation syndrome, idiopathic ventricular fibrillation (VF) and rare cases of familial cardiomyopathies are also associated with ion channel mutations.<a class="elsevierStyleCrossRefs" href="#bib0410">4,12</a>In the last two decades, the knowledge about the genetic and molecular mechanisms underlying arrhythmias (especially those of hereditary nature – <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) has vastly increased, and various mutations and/or genetic variants have been described.<a class="elsevierStyleCrossRefs" href="#bib0470">16,17</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Although many mutations in different ion channels affect the heart's electrical currents, we only cover what concerns sodium currents in this literature review. In particular, we cover the structure of the NaC and their role in heart excitability, mutations in the NaC complex, the associated phenotypes and the implications of the relationship between genetic and clinical aspects at the level of diagnosis, risk stratification, prognosis and treatment, namely of LQTS and BrS.MethodsA narrative review of the literature covering the topic Cardiac channelopathies: the role of sodium channel mutations was conducted. The online Pubmed® database was used to search for articles published in this field, and the MeSH database was used to select the MeSH terms and to define the following query: “Mutation [Mesh] AND Sodium Channels [Mesh] AND Heart Diseases [Mesh]”.Applying the predefined inclusion criteria, only articles published in the last 15 years, written in English or in Portuguese, and referring to research in human beings were included. Additionally, the impact factor was taken into consideration.Other references were also included, some with a publication date prior to 2002, with the aim of widening the relevant content cited in the initially searched articles.Structure and function of sodium channelsThe NaC are transmembrane proteins consisting of an α subunit together with one or two β subunits (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>).<a class="elsevierStyleCrossRef" href="#bib0400">2</a> There are various types of α subunits, which are differentially expressed according to the type of tissue and are encoded by a family of 10 different genes (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<a class="elsevierStyleCrossRefs" href="#bib0480">18,19</a> The main α subunit expressed in the heart is called Nav1.5 (like the sodium channel it is part of) and is encoded by the SCN5A (sodium channel, voltage gated, type V alpha subunit) gene, which includes 28 exons and spans more than 100 kb in chromosome 3p22.<a class="elsevierStyleCrossRefs" href="#bib0480">18,20</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Regulation of transcription of the SCN5A gene is influenced by many factors, including: presence of three promoters, transcription factors and microRNAs with post-transcriptional activity. More than 10 isoforms resulting from splicing of this gene have been described, and the most abundant isoform in the human heart is SCN5A-003 (adult isoform).<a class="elsevierStyleCrossRefs" href="#bib0425">7,18,20</a>The α subunit has about 227 kDa and consists of a transmembrane protein with four homologous domains (DI-DIV) connected by cytoplasmic loops, each of them with six α-helix transmembrane segments (S1-6) connected by intra- and extracellular loops. It also has a C terminus (carboxy) and an N terminus (amino), both being cytoplasmic.<a class="elsevierStyleCrossRefs" href="#bib0415">5,6,21</a>The central pore is formed by the four S5 and S6 segments of subunit α, namely by the extracellular loops that connect them. It is selectively permeable to sodium, which travels through it according to the electrochemical gradient. Segments S1 to S4 act as voltage sensors. However, the latter has the peculiarity of having a positive charge.<a class="elsevierStyleCrossRefs" href="#bib0400">2,5,18,21</a>Like the other voltage-gated channels, the NaC show conformational changes during a process called gating that enables defining three functional states for the channel (open, inactive or closed), according to membrane potential. These alterations occur in the α subunit, which is the main one responsible for regulation of depolarization of excitable cells membranes.<a class="elsevierStyleCrossRefs" href="#bib0400">2,18,22</a>The subunits are proteins of approximately 30-40 kDa, with a single transmembrane segment, an intracellular C terminus and an extracellular N terminus.<a class="elsevierStyleCrossRef" href="#bib0415">5</a> These subunits associate with the α subunit of the NaC (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>), thus not only modulating their expression on the cell surface and the gating process, but also enabling connection with the cytoskeleton and other interaction proteins. In effect, the subunits are capable of increasing the channels traffic to the cell membrane, with subsequent increase in INa.<a class="elsevierStyleCrossRefs" href="#bib0415">5,18</a>There are four types of β subunits (β1, β2, β3 and β4), encoded by the SCN1B, SCN2B, SCN3B and SCN4B genes, respectively. These are preferentially associated with different α subunits according to the type of tissue where they are expressed.<a class="elsevierStyleCrossRefs" href="#bib0415">5,18,20,23</a>In addition to the β subunits, there are other proteins with the ability to interfere and modulate Nav1.5 function (ankyrin-G, calmodulin, caveolin-3, syntrophin α1, plakophilin-2, Ran guanine nucleotide release factor [MOG1], glycerol-3-phosphate dehydrogenase 1-like [GPD1L], fibroblast growth factor homologous factor 1B [FHF-1B] and Nedd4-like ubiquitin ligases, among others) that integrate a macromolecular complex (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0415">5,6,18,20,21,24,25</a>The role of sodium channels in heart excitabilityThe heart AP is generated by depolarizing (INa; ICa) and re-polarizing (IK) ion currents.<a class="elsevierStyleCrossRef" href="#bib0500">22</a> NaC play an essential role in AP initiation through the generation of INa, and they are expressed in the membrane of atrial and ventricular cardiomyocytes and in specialized conduction tissue.<a class="elsevierStyleCrossRefs" href="#bib0495">21–23</a> However, although their expression is abundant in the bundle of His, bundle branches and Purkinje fibers, their expression is low or absent in the sinus and atrioventricular nodes.<a class="elsevierStyleCrossRefs" href="#bib0420">6,21</a>In the ventricular myocardium, during diastole, the transmembrane electrical potential (at rest) is approximately -85 mV, and the NaC are closed. When a stimulus depolarizes the membrane, the S4 segments of the four domains move simultaneously outside, the channel opens and there is Na+ movement to the intracellular medium, according to the electrochemical gradient.<a class="elsevierStyleCrossRefs" href="#bib0415">5,6,18,22</a> In addition, INa, the main agent responsible for the rapid AP depolarization phase (phase 0), is thus generated and then rapidly increases until it reaches its peak (INapeak) and decreases milliseconds later.<a class="elsevierStyleCrossRefs" href="#bib0480">18,23</a>In NaC inactivation, the loop between domains III and IV (inactivation gate) works as a “lid” and the channels gradually close in about 1 ms.<a class="elsevierStyleCrossRefs" href="#bib0480">18,26</a> It should be noted that the NaC undergo various conformational changes that translate into different inactivation states (rapid, intermediate and slow inactivation) which, in turn, have different recovery times.<a class="elsevierStyleCrossRefs" href="#bib0480">18,22</a> However, at the end of phase 0, the majority (≈99%) of the NaC are inactivated, precluding ion traffic. They remain like this until the cell membrane is repolarized, when they recover from inactivation and again become available to be activated during phase 4.<a class="elsevierStyleCrossRefs" href="#bib0415">5,18</a>Nevertheless, during AP phase 2, a small fraction of the NaC (<1% of the total NaC available) may maintain conductibility for Na+ and reopen, and thus a small INa called late current persists (INalate).<a class="elsevierStyleCrossRefs" href="#bib0415">5,18,27</a> Moreover, some channels may reactivate during the repolarization phase (phase 3), when inactivation is not yet completed but the AP enables their reactivation, generating a current called window current.<a class="elsevierStyleCrossRefs" href="#bib0480">18,22</a> This current corresponds to less than 1% of the sodium current peak.<a class="elsevierStyleCrossRef" href="#bib0500">22</a> An important role in the ventricular arrhythmogenesis present in certain cardiac pathologies, some of them covered in this review, has been attributed to these two currents.<a class="elsevierStyleCrossRefs" href="#bib0415">5,18,22,27</a>Under physiological conditions, the NaC activation and inactivation processes are strictly regulated in order to ensure normal cardiac electrical activity. Anomalies in the NaC cause significant abnormalities in heart electrophysiology and potentiate arrhythmogenesis, which may result from alterations in gating properties or in INa kinetics. These alterations change channel availability, the amplitude of the INapeak or prevent adequate channel inactivation, with maintenance of a persistent INa during the AP plateau. Therefore, the importance of the NaC in heart excitability is emphasized by the occurrence of potentially fatal arrhythmias (e.g., ventricular tachycardia and VF) in the presence of hereditary or acquired dysfunction in these channels.<a class="elsevierStyleCrossRefs" href="#bib0480">18,21,22</a>Mutations in sodium channelsMutations in subunit αIn the last few decades, the knowledge about the function of the SNC5A gene at the molecular and electrophysiological level has greatly increased, and various genetic studies show that mutations in this gene are associated with many heart diseases, namely hereditary cardiac arrhythmias.<a class="elsevierStyleCrossRefs" href="#bib0395">1,5,16,18,21,22,28</a> In most cases, the pathologies associated with NaC mutations are caused by mutations that alter channel permeability or the gating process.<a class="elsevierStyleCrossRefs" href="#bib0420">6,21</a>Mutations in the SCN5A gene leading to dysfunction of the Nav1.5 NaC may be due to gain of function, loss of function or both.<a class="elsevierStyleCrossRefs" href="#bib0425">7,18</a>The loss-of-function mutations result in decreased INa and are associated with BrS, sinus node disease (SND), atrial fibrillation (AF), Lev-Lenégre disease and dilated cardiomyopathy (DCM) (<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>).<a class="elsevierStyleCrossRefs" href="#bib0425">7,18</a> The mechanism most frequently involved is decreased INapeak (<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0425">7,18,23</a><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>Gain-of-function mutations result in increased INa and are associated with LQTS3 (<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>). There are also some gain-of-function mutations associated with AF and DCM.<a class="elsevierStyleCrossRefs" href="#bib0425">7,18</a> The most frequently involved mechanism consists of increased INalate.<a class="elsevierStyleCrossRefs" href="#bib0425">7,18,23</a> However, there are other mechanisms such as increased INa peak, decreased inactivation rate or increased window current (<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0480">18,22</a>Rarely, the mutations may simultaneously cause reduced INapeak and increased INalate, occurring with loss and gain of function, respectively.<a class="elsevierStyleCrossRefs" href="#bib0425">7,23</a>Mutations in β subunitsMutations in the β1 subunits were identified in patients with BrS, AF and cardiac conduction disease (CCD) (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). The mechanism involved in these phenotypes is believed to occur with a decrease in INa density (loss of function). However, given the limited number of patients with these mutations, the mechanism involved or the genotype-phenotype relationship cannot be completely determined.<a class="elsevierStyleCrossRefs" href="#bib0490">20,23,25</a><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>The prevalence of potentially pathogenic variants of the genes for the β subunits is similar to that of other minor genes involved in BrS.<a class="elsevierStyleCrossRefs" href="#bib0535">29,30</a> Indeed, even though in recent years the knowledge of the underlying mechanisms of BrS focuses mainly on the SCN5A gene, the screening of the four β subunits may lead to a potential increase in the genetic diagnosis of the syndrome, up to approximately 5.4%.<a class="elsevierStyleCrossRef" href="#bib0540">30</a>Mutations in the β1 and β2 subunits are associated with AF, and the mechanism consists of alterations in gating and decreased INa.<a class="elsevierStyleCrossRefs" href="#bib0420">6,31</a> In 2011, Olesen et al.<a class="elsevierStyleCrossRef" href="#bib0550">32</a> described mutations associated with AF, also in the β3 subunit. These mutations decrease INa, increasing the susceptibility for AF through one of two mechanisms: conduction delay or decrease in the refractory period (promoting the possibility of reentry circuits).<a class="elsevierStyleCrossRef" href="#bib0550">32</a> Moreover, mutations in SCN3B are also associated with BrS (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0430">8,23</a>Mutations in β4 subunit have already been described in LQTS10 and confer gain of function, whose most likely mechanism consists of increased INalate.<a class="elsevierStyleCrossRefs" href="#bib0505">23,25,30,33</a>Mutations in proteins associated with sodium channelsThe NaC are part of a macromolecular complex that includes various proteins that participate in cell adhesion, signal transduction pathways and the cytoskeleton (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0420">6,7,11</a> These proteins are directly or indirectly bound to the NaC and have the ability to modulate their expression, traffic and function.<a class="elsevierStyleCrossRefs" href="#bib0420">6,19,23</a> Therefore, their dysfunction contributes to the pathophysiology of the cardiac channelopathies.<a class="elsevierStyleCrossRefs" href="#bib0420">6,22,23,28</a>In fact, mutations in several of these proteins are associated with LQTS or BrS (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0415">5,22,34–36</a> Caveolin-3 (CAV3) is an important protein in membrane traffic and in the positioning of the ion channels in the sarcoplasmatic membrane, which regulates various ion currents in the heart such as INa. Syntrophin α1 (SNTA1) is a cytoskeleton protein that interacts with the NaC (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>). Gain-of-function mutations described in CAV3 are associated with LQTS9, whereas those described for SNTA1 are associated with a phenotype similar to LQTS3.<a class="elsevierStyleCrossRefs" href="#bib0420">6,15,22,28,37</a> On the other hand, mutations in ankyrin-B, whose function is to bind membrane proteins to cytoskeleton structures (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>), are associated with LQTS4 and AF, among others.<a class="elsevierStyleCrossRef" href="#bib0465">15</a>Mutations in the GPD1L gene, which encodes the glycerol-3-phosphate dehydrogenase 1-like protein, or in the MOG1 gene, which encodes a molecule that affects protein traffic, have already been described in BrS.<a class="elsevierStyleCrossRefs" href="#bib0420">6,15,23,25</a> In addition, mutations in plakophilin-2, a desmosomal protein, may decrease INa and therefore lead to a phenotype similar to BrS.<a class="elsevierStyleCrossRefs" href="#bib0465">15,38,39</a>“Cardiac” phenotypes associated with dysfunction in sodium channels and interacting proteinsThe numerous “cardiac” phenotypes associated with mutations in the genes encoding for the NaC and the proteins that make up its macromolecular complex are described in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>. The most prevalent cardiac channelopathies are LQTS (1:2500) and BrS (1:3300 to 1:10000), which are partially associated with NaC dysfunction.<a class="elsevierStyleCrossRef" href="#bib0450">12</a> Therefore, we will now cover only these two entities.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Brugada syndromeBrS was first described in 1992 as a syndrome characterized by a typical electrocardiographic pattern, absence of structural heart anomalies and family history of SD. Since then, progress has been made in understanding its pathophysiology and in identifying its genetic basis.<a class="elsevierStyleCrossRefs" href="#bib0395">1,40,41</a>BrS is a rare hereditary syndrome with an estimated prevalence of 1/3300 to 1/10000, and ethnic and geographic differences have already been described.<a class="elsevierStyleCrossRefs" href="#bib0450">12,14,42</a> It affects relatively young adults (<40 years old), more frequently males, with a family history of SD in 20-50% of the cases.<a class="elsevierStyleCrossRefs" href="#bib0495">21,43,44</a> Moreover, it is estimated that BrS is responsible for at least 4% of all SD cases and for at least 20% of all SD cases in individuals without structural heart abnormalities.<a class="elsevierStyleCrossRefs" href="#bib0430">8,45</a>The absence of structural heart anomalies was classically a characteristic of BrS.<a class="elsevierStyleCrossRef" href="#bib0595">41</a> However, mild structural anomalies in the right and left ventricles have been described in various studies.<a class="elsevierStyleCrossRef" href="#bib0620">46</a>Most individuals are asymptomatic at the time of diagnosis, which is made following a routine ECG in approximately 58% of cases or as a result of family screening in approximately 37% of cases.<a class="elsevierStyleCrossRef" href="#bib0610">44</a> However, SCD may be the first sign of the disease since these individuals are at increased risk for developing tachyarrhythmias, namely PVT and VF.<a class="elsevierStyleCrossRefs" href="#bib0500">22,47</a>It is estimated that the rate of arrhythmia events per year in symptomatic individuals is about 0.5%, occurring more frequently at rest and while sleeping, but also in the presence of fever or after a heavy meal.<a class="elsevierStyleCrossRefs" href="#bib0395">1,44,48</a> In fact, fever is one of the factors that may cause or exacerbate the electrocardiographic pattern of BrS, triggering potentially fatal arrhythmias in about 27% of cases.<a class="elsevierStyleCrossRefs" href="#bib0495">21,49</a>Diagnosis is made using clinical criteria, presence of a typical pattern of electrocardiographic abnormalities and exclusion of other etiologies that may mimic BrS, namely because they trigger ST-segment elevation (<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>).<a class="elsevierStyleCrossRefs" href="#bib0615">45,50,51</a> Provocation tests with NaC-blocking agents (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>) may be performed to provoke the electrocardiographic abnormalities seen in BrS (<a class="elsevierStyleCrossRef" href="#fig0025">Figure 5</a>), which enables diagnosing those individuals with transient electrocardiographic pattern.<a class="elsevierStyleCrossRefs" href="#bib0460">14,41,45,52</a> In these cases, Holter may also be used and, through prolonged monitoring, it may enable diagnosing intermittent abnormalities.<a class="elsevierStyleCrossRef" href="#bib0395">1</a><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia>Genetic tests (broad or specific for the SCN5A gene) may also be useful for diagnosis in any case where there is strong clinical suspicion of BrS according to the family and medical history and the ECG.<a class="elsevierStyleCrossRef" href="#bib0655">53</a> It should be noted that after identifying a pathogenic mutation in a BrS case index, specific genetic screening of family members is indicated.<a class="elsevierStyleCrossRefs" href="#bib0655">53,54</a>BrS presents high genetic complexity and there are various genes that may be mutated in this syndrome, although only a few are associated with abnormalities in INa (<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>).<a class="elsevierStyleCrossRefs" href="#bib0605">43,54,55</a> As of today, more than 300 mutations reducing INa amplitude through different mechanisms have been described.<a class="elsevierStyleCrossRefs" href="#bib0470">16,43,54,56</a> The mutations occur more frequently in the SCN5A gene, and usually occur in transmembrane segments S1-S4 and in the segments involved in pore formation (S5-S6).<a class="elsevierStyleCrossRefs" href="#bib0470">16,55</a> However, only a few (approximately 10-30%) of the total number of individuals diagnosed with BrS are positive for a mutation in this gene.<a class="elsevierStyleCrossRefs" href="#bib0495">21,43,56–58</a> Other genes (<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>) are involved in fewer than 5% of the cases.<a class="elsevierStyleCrossRef" href="#bib0665">55</a><elsevierMultimedia ident="tbl0030"></elsevierMultimedia>In fact, only 30-35% of the individuals with a clinical diagnosis have a genetic diagnosis as well (positive genotype).<a class="elsevierStyleCrossRef" href="#bib0430">8</a> Therefore, the majority of the individuals affected (approximately 65%) remains genetically undetermined (negative genotype) and for this reason identifying new susceptibility genes for BrS is necessary.<a class="elsevierStyleCrossRefs" href="#bib0470">16,56,59</a>Recently, the SCN10A gene was identified as a susceptibility gene for BrS, although its real prevalence has yet to be determined.<a class="elsevierStyleCrossRefs" href="#bib0670">56,60</a> The expression level and function of the Nav1.8 NaC in the heart are still controversial. However, a study published in 2014 shows that the variants of this gene influence the duration of the PR and QRS interval, heart rate (HR) and also the risk of arrhythmias.<a class="elsevierStyleCrossRef" href="#bib0670">56</a>A few recessive forms with homozygous or compound heterozygous mutations have been described, but most of the known pathogenic mutations in the SCN5A gene present an autosomal dominant transmission pattern with variable, and frequently incomplete, penetrance.<a class="elsevierStyleCrossRefs" href="#bib0480">18,43,45</a>The mechanism most frequently implicated is decreased INapeak due to mutations in the SCN5A gene (loss of function) and consequent slowing of cardiac conduction (<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0425">7,18,60,61</a> Nevertheless, there are many hypotheses for the pathophysiological mechanisms of BrS that involve depolarization and repolarization abnormalities; however, the latter are not covered in this article.<a class="elsevierStyleCrossRefs" href="#bib0590">40,51,54</a>The genotype of individuals with BrS does not currently carry relevant implications for prognosis or treatment (<a class="elsevierStyleCrossRef" href="#tbl0035">Table 7</a>).<a class="elsevierStyleCrossRef" href="#bib0435">9</a> Nonetheless, its influence in the risk of arrhythmia and in prognosis is still under debate.<a class="elsevierStyleCrossRef" href="#bib0660">54</a> In reality, genetic data may constitute a complementary tool for risk stratification.<a class="elsevierStyleCrossRefs" href="#bib0605">43,61</a> Nonsense mutations, which result in truncated proteins, have been associated with a poorer prognosis compared with other types of mutations with less marked repercussions in NaC function.<a class="elsevierStyleCrossRefs" href="#bib0590">40,43,59,61</a> A retrospective study published in 2009 shows that the phenotype is more severe in individuals with mutations associated with more significant INa reductions compared with individuals with mutations associated with lower reductions.<a class="elsevierStyleCrossRef" href="#bib0695">61</a> The same is seen when the mutation is located in a transmembrane region of the NaC.<a class="elsevierStyleCrossRef" href="#bib0695">61</a> Another study published in 2013 shows that different mutations in the SCN5A gene have a different impact on INa, emphasizing the role of mutation characterization in the risk assessment for nonaffected family members.<a class="elsevierStyleCrossRef" href="#bib0700">62</a> However, it is still not clear to what extent different mutations confer a risk for arrhythmia events or SCD, thus the risk is currently stratified only with clinical parameters.<a class="elsevierStyleCrossRefs" href="#bib0655">53,54</a><elsevierMultimedia ident="tbl0035"></elsevierMultimedia>The only treatment available proven capable of preventing SCD in patients with BrS was the implementation of an implantable cardioverter defibrillator (ICD).<a class="elsevierStyleCrossRefs" href="#bib0395">1,9,44,46</a> This procedure, however, results in a considerable risk of complications, which occur in approximately 9% of patients/year and, although rarely life-threatening, they are psychologically harmful.<a class="elsevierStyleCrossRefs" href="#bib0435">9,54</a> Therefore, a careful assessment of risks (namely the risk of arrhythmia) and benefits is a key process in this decision.<a class="elsevierStyleCrossRefs" href="#bib0610">44,54</a>A 2003 study that included 547 individuals diagnosed with BrS, showing a diagnostic electrocardiographic pattern but no prior “aborted” SCD, was conducted with the aim of assessing the prognostic value of clinical, electrocardiographic and electrophysiological variables. The authors observed that the group with lower risk (incidence of events: 0.5%) is characterized by absence of syncope episodes, an electrocardiographic pattern only triggered by antiarrhythmics and absence of arrhythmia during programmed ventricular stimulation (PVS). However, the group with higher risk (incidence of events: 27.2%) is characterized by prior history of syncope episodes, spontaneously abnormal ECG and presence of arrhythmias induced by PVS. Moreover, individuals with inducibility of arrhythmias in PVS have a six-fold higher risk of SCD or VF during the subsequent two years than those who do not have it.<a class="elsevierStyleCrossRef" href="#bib0705">63</a>Although some are controversial, there are many risk factors for arrhythmia events, and among them, symptoms are one of the most important.<a class="elsevierStyleCrossRefs" href="#bib0600">42,46,54,64</a> In fact, individuals diagnosed after an “aborted” SCD are at the highest risk, and in approximately 60% of these cases there is a new event 10 years after the diagnosis.<a class="elsevierStyleCrossRef" href="#bib0660">54</a> Individuals with syncope episodes have a rate of arrhythmia events of 1.9%/year, and the simultaneous presence of a type 1 electrocardiographic pattern is associated with a poor prognosis.<a class="elsevierStyleCrossRefs" href="#bib0620">46,54</a> Additionally there are other electrocardiographic parameters that are associated with a poorer prognosis, for example, presence of QRS-interval fragmentation in the ECG, identified in 30-40% of the patients.<a class="elsevierStyleCrossRef" href="#bib0660">54</a>Long QT syndromeCongenital LQTS is an arrhythmia syndrome with a genetic/hereditary etiology and incomplete penetrance, whose prevalence in Caucasians is approximately 1:2500, a value much higher than what was previously expected.<a class="elsevierStyleCrossRefs" href="#bib0450">12,13,65</a> It represents a heterogeneous group of diseases and, classically, it is divided into two variants: Romano-Ward syndrome and Jervell and Lange-Nielsen syndrome (<a class="elsevierStyleCrossRef" href="#tbl0040">Table 8</a>).<a class="elsevierStyleCrossRefs" href="#bib0395">1,43,65</a><elsevierMultimedia ident="tbl0040"></elsevierMultimedia>In 1995 and 1996, the three main genes conferring susceptibility to LQTS were identified: KCNQ1, KCNH2 and SCN5A.<a class="elsevierStyleCrossRefs" href="#bib0720">66–68</a> These genes constitute about 75% of the clinically defined LQTS and the remainder collectively represents only 5% of these cases.<a class="elsevierStyleCrossRefs" href="#bib0605">43,69</a> It should be noted that LQTS is associated with abnormalities in sodium currents only for types 3, 9, 10 and 12.<a class="elsevierStyleCrossRefs" href="#bib0500">22,69</a>LQTS is characterized by a delay in ventricular repolarization, which translates echocardiographically as QT interval prolongation (<a class="elsevierStyleCrossRef" href="#fig0030">Figure 6</a>).<a class="elsevierStyleCrossRefs" href="#bib0500">22,65</a> The duration of the QT interval depends on NaC inactivation, the alteration of which may trigger arrhythmias.<a class="elsevierStyleCrossRef" href="#bib0520">26</a>Mutations in the SCN5A gene associated with LQTS3 (gain of function) usually affect NaC inactivation, which is slower, unstable or incomplete.<a class="elsevierStyleCrossRefs" href="#bib0420">6,18,22,26</a> Consequently, there is an increase in INalate with prolongation of membrane depolarization and delay in repolarization.<a class="elsevierStyleCrossRefs" href="#bib0480">18,26,65,70</a> Other mechanisms potentially involved are: increased window current, slower inactivation and increased INapeak (<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0420">6,18,22</a>The first mutation associated with LQTS3 is found in the loop between domains III and IV, corresponding to the inactivation gate.<a class="elsevierStyleCrossRef" href="#bib0520">26</a> Since then, multiple mutations causing abnormalities in inactivation have been identified and functionally characterized. They may be located at different sites in the NaC structure, namely in the C terminus, to which a relevant function in this process has been attributed.<a class="elsevierStyleCrossRefs" href="#bib0500">22,26</a>Congenital LQTS occurs mainly in young, healthy individuals without concomitant structural heart abnormalities and is associated with an increased risk of syncope and potentially fatal heart arrhythmias such as Torsade de Pointes (TdP), which degenerates into VF and causes cardiac arrest.<a class="elsevierStyleCrossRefs" href="#bib0420">6,18,66</a> In LQTS3 (unlike LQTS1 and LQTS2 – <a class="elsevierStyleCrossRef" href="#fig0030">Figure 6</a>), arrhythmias usually occur at rest, particularly while sleeping (low HR).<a class="elsevierStyleCrossRefs" href="#bib0420">6,22,43,70</a> It should be noted that INalate is higher with slower stimulation frequencies, suggesting that the intensity of this current may be a strong factor in determining the occurrence of arrhythmias.<a class="elsevierStyleCrossRef" href="#bib0500">22</a>The first cardiac event (more frequently syncope) usually occurs in adolescents (16±10 years old in LQTS3) and earlier among males.<a class="elsevierStyleCrossRefs" href="#bib0435">9,71</a> However, in approximately 5-10% of cases, SCD is the initial event of the disease and, actually, LQTS is one of the main causes of SCD with negative autopsy.<a class="elsevierStyleCrossRefs" href="#bib0440">10,72</a>Diagnosis is mainly based on medical history and ECG (<a class="elsevierStyleCrossRefs" href="#fig0030">Figures 6 and 7</a>).<a class="elsevierStyleCrossRefs" href="#bib0715">65,70</a> In ECGs, the QT interval is the most relevant parameter (<a class="elsevierStyleCrossRef" href="#tbl0045">Table 9</a>), and is measured from the beginning of the QRS complex to the end of the T wave in the DII and V5 or V6 leads.<a class="elsevierStyleCrossRefs" href="#bib0715">65,73</a> The longest value is used, generally corrected for HR (QTc) with the Bazett formula (despite its limitations for particularly rapid or slow HR).<a class="elsevierStyleCrossRefs" href="#bib0395">1,46,65,73</a><elsevierMultimedia ident="fig0030"></elsevierMultimedia><elsevierMultimedia ident="fig0035"></elsevierMultimedia><elsevierMultimedia ident="tbl0045"></elsevierMultimedia>Additionally, secondary causes for QT interval prolongation (acquired LQTS) must be ruled out, for example: drugs, myocardial ischemia, cardiomyopathy, hypokalemia, hypomagnesemia and hypothermia, among others.<a class="elsevierStyleCrossRefs" href="#bib0620">46,65</a> Once ruled out, the presence of a repetition of a QTc value ≥500 ms (or 480-499 ms if conducted after an unexplained syncope episode) in an electrocardiogram is considered to be diagnostic.<a class="elsevierStyleCrossRefs" href="#bib0605">43,46</a> However, LQTS types 1, 2 and 3 may occur with normal QTc in the ECG at rest in 36%, 19% and 10% of cases, respectively.<a class="elsevierStyleCrossRef" href="#bib0735">69</a>A scoring system considering various clinical and electrocardiographic parameters was created for diagnosis and provides the likelihood for LQTS (<a class="elsevierStyleCrossRef" href="#fig0030">Figure 6</a>).<a class="elsevierStyleCrossRefs" href="#bib0605">43,46,70</a> In addition, Holter monitoring and the ECG obtained during an effort test or after adrenaline infusion may be useful in some particular cases.<a class="elsevierStyleCrossRefs" href="#bib0395">1,46,53,65,69</a>Once the diagnosis is made or given the occurrence of unexplained SD in a young individual, first-degree family members must be screened for LQTS.<a class="elsevierStyleCrossRefs" href="#bib0395">1,65,72</a> However, LQTS cannot be ruled out in family members with a normal ECG.<a class="elsevierStyleCrossRef" href="#bib0605">43</a> In fact, after identifying a pathogenic mutation in an index case, family members should undergo a genetic test specific for the mutation in question, with the aim of identifying individuals with a normal QT interval.<a class="elsevierStyleCrossRefs" href="#bib0605">43,53</a> This is important given the risk of arrhythmias, which is estimated to occur in 10% of asymptomatic carriers.<a class="elsevierStyleCrossRef" href="#bib0395">1</a>Moreover, genetic tests specific for LQTS (broad or specific for the three main genes) are recommended for any patient when there is a strong clinical suspicion of LQTS (based on the medical and family history and the ECG), or for any asymptomatic patient with QT interval prolongation in the absence of other clinical conditions that may prolong this interval.<a class="elsevierStyleCrossRef" href="#bib0655">53</a> In reality, genetic tests play an important role, not only in the diagnosis of LQTS (namely of asymptomatic carriers) and in ruling out disease for first-degree family members, but also in risk stratification, prognosis and treatment (according to the genotype – <a class="elsevierStyleCrossRef" href="#fig0035">Figure 7</a>).<a class="elsevierStyleCrossRefs" href="#bib0395">1,43,69,70,72</a>Risk stratification takes into account phenotype and genotype and is conducted for all patients with regular clinical assessments (<a class="elsevierStyleCrossRef" href="#fig0035">Figure 7</a>).<a class="elsevierStyleCrossRefs" href="#bib0620">46,65,70</a> Risk varies according to genotype and, additionally, in the most common genetic types, it is influenced by the specific type and location of the mutations, as well as by the degree of dysfunction that they cause.<a class="elsevierStyleCrossRefs" href="#bib0605">43,46</a>Priori et al. (2003)<a class="elsevierStyleCrossRef" href="#bib0745">71</a> followed up 647 individuals with mutations in the genes for LQTS types 1, 2 and 3, for an average period of 28 years. The authors found that 42% of the individuals with LQTS3 developed a first cardiac event (occurrence of syncope, cardiac arrest or SCD) before turning 40 years old and before starting treatment. The incidence of cardiac arrest or SCD in patients with LQTS3 was about 16%, and men presented with symptoms earlier than women. However, given the small study sample, no conclusions could be reached about this finding. Additionally, the authors found that the QTc interval of patients with cardiac events was significantly longer than that of asymptomatic patients (LQTS3 subgroup: 523±55 ms vs. 481±38 ms, p=0.003). They also concluded that only a QTc value higher than 498 ms is associated with a markedly increased likelihood of cardiac events. However, the percentage of individuals in the LQTS3 subgroup with a normal QT interval and carrying a silent mutation was 10%.<a class="elsevierStyleCrossRef" href="#bib0745">71</a>The result of the genetic tests is also important in the treatment and counseling of affected individuals and family members (<a class="elsevierStyleCrossRef" href="#fig0035">Figure 7</a>; <a class="elsevierStyleCrossRef" href="#tbl0050">Table 10</a>).<a class="elsevierStyleCrossRefs" href="#bib0435">9,43</a> It should be noted, for example, that LQTS1 involves higher risk during physical activity compared with LQTS2 and LQTS3.<a class="elsevierStyleCrossRefs" href="#bib0605">43,74,75</a><elsevierMultimedia ident="tbl0050"></elsevierMultimedia>Mexiletine, flecainide or ranolazine constitute “specific” therapeutic options for LQTS3 (<a class="elsevierStyleCrossRef" href="#tbl0050">Table 10</a>), for which β-blockers may not be so effective, since the adrenergic stress in this type is a trigger with less influence.<a class="elsevierStyleCrossRefs" href="#bib0395">1,43,70,76</a> Mexiletine may be used as an add-on to β-blockers.<a class="elsevierStyleCrossRefs" href="#bib0435">9,43,46,50</a> However, its effect depends on the type of mutation and may not be beneficial for all individuals with LQTS3.<a class="elsevierStyleCrossRefs" href="#bib0435">9,12,70</a>In fact, of the three main types of LQTS, type 3 is the one that involves a higher arrhythmia recurrence rate in individuals receiving treatment with β-blockers (10-15%).<a class="elsevierStyleCrossRef" href="#bib0740">70</a> This justifies the need for individuals with LQTS3 to undergo other invasive procedures, such as left cardiac sympathetic denervation and/or ICD implantation more frequently (<a class="elsevierStyleCrossRef" href="#tbl0050">Table 10</a>).<a class="elsevierStyleCrossRef" href="#bib0740">70</a>ConclusionsCardiac channelopathies are not common in clinical practice (although they are more common than once thought), but they have a significant impact on quality of life and survival.<a class="elsevierStyleCrossRefs" href="#bib0395">1,13</a> The clinical approach constitutes a challenge, owing to their high clinical and genetic heterogeneity.<a class="elsevierStyleCrossRefs" href="#bib0395">1,76</a>Although they were initially considered to be separate clinical entities with distinct phenotypes, these syndromes may have overlapping clinical and genetic presentations (<a class="elsevierStyleCrossRef" href="#fig0040">Figure 8</a>).<a class="elsevierStyleCrossRef" href="#bib0495">21</a> In fact, in addition to strictly loss- or gain-of-function mutations, there is a wide spectrum of mutations associated with various anomalies with different repercussions in NaC function.<a class="elsevierStyleCrossRef" href="#bib0515">25</a> In some cases, a single mutation in the SCN5A gene may result in multiple rhythm disorders, and various phenotypes may thus coexist in the same family.<a class="elsevierStyleCrossRefs" href="#bib0420">6,25</a><elsevierMultimedia ident="fig0040"></elsevierMultimedia>Moreover, some studies have recently reported structural heart anomalies secondary to mutations in this gene (namely DCM), although the underlying mechanism is unknown.<a class="elsevierStyleCrossRefs" href="#bib0420">6,18,22,77</a>The power of the genetic tests to identify mutations is currently 25% for BrS and 80% for LQTS (<a class="elsevierStyleCrossRef" href="#fig0045">Figure 9</a>).<a class="elsevierStyleCrossRefs" href="#bib0605">43,78</a> The impact of genetics in clinical approach varies considerably depending on the underlying channelopathies, and is more marked in LQTS, where influence at the level of diagnosis, prognosis and treatment is recognized.<a class="elsevierStyleCrossRefs" href="#bib0435">9,43,78</a><elsevierMultimedia ident="fig0045"></elsevierMultimedia>Great progress has been made in understanding the genotype-phenotype relationship and its implications.<a class="elsevierStyleCrossRef" href="#bib0605">43</a> However, despite increased scientific knowledge in this field, the genotype of a considerable number of affected individuals remains undetermined, some mechanisms still need to be clarified and the treatment options currently available are still limited.<a class="elsevierStyleCrossRefs" href="#bib0450">12,18,72</a> A better understanding of molecular principles may contribute not only to increasing knowledge of these aspects, but also to developing new specific treatment approaches for the gene or mutation.<a class="elsevierStyleCrossRefs" href="#bib0450">12,43</a>Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1005669" "titulo" => "Abstract" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec965455" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1005668" "titulo" => "Resumo" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0020" "titulo" => "Introdução e objetivos" ] 1 => array:2 [ "identificador" => "abst0025" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0030" "titulo" => "Conclusões" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec965456" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Structure and function of sodium channels" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "The role of sodium channels in heart excitability" ] ] ] 6 => array:3 [ "identificador" => "sec0025" "titulo" => "Mutations in sodium channels" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Mutations in subunit α" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Mutations in β subunits" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Mutations in proteins associated with sodium channels" ] 3 => array:2 [ "identificador" => "sec0045" "titulo" => "“Cardiac” phenotypes associated with dysfunction in sodium channels and interacting proteins" ] ] ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Brugada syndrome" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Long QT syndrome" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflicts of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec965455" "palabras" => array:5 [ 0 => "Mutations" 1 => "Sodium channels" 2 => "Heart diseases" 3 => "Heart arrhythmias" 4 => "Sudden cardiac death" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec965456" "palabras" => array:5 [ 0 => "Mutações" 1 => "Canais de Sódio" 2 => "Doenças cardíacas" 3 => "Arritmias cardíacas" 4 => "Morte súbita cardíaca" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Introduction and objectivesThe importance of sodium channels for the normal electrical activity of the heart is emphasized by the fact that mutations (inherited or de novo) in genes that encode for these channels or their associated proteins cause arrhythmogenic syndromes such as the Brugada syndrome and the long QT syndrome (LQTS). The aim of this study is to conduct a review of the literature on the mutations in the sodium channel complex responsible for heart disease and the implications of a close relationship between genetics and the clinical aspects of the main cardiac channelopathies, namely at the level of diagnosis, risk stratification, prognosis, screening of family members and treatment. MethodsThe online Pubmed® database was used to search for articles published in this field in indexed journals. The MeSH database was used to define the following query: “Mutation [Mesh] AND Sodium Channels [Mesh] AND Heart Diseases [Mesh]”, and articles published in the last 15 years, written in English or Portuguese and referring to research in human beings were included. ConclusionsIn the past few years, significant advances have been made to clarify the genetic and molecular basis of these syndromes. A greater understanding of the underlying pathophysiological mechanisms showed the importance of the relationship between genotype and phenotype and led to progress in the clinical approach to these patients. However, it is still necessary to improve diagnostic capacity, optimize risk stratification, and develop new specific treatments according to the genotype-phenotype binomial." "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Conclusions" ] ] ] "pt" => array:3 [ "titulo" => "Resumo" "resumen" => "Introdução e objetivosA importância dos canais de sódio para a normal atividade elétrica do coração é enfatizada pelo facto de as mutações (hereditárias ou de novo) nos genes que codificam esses canais ou as proteínas a esses associadas provocarem síndromes arritmogénicas como a síndrome de Brugada e a síndrome do QT longo. O objetivo deste trabalho é proceder a uma revisão bibliográfica sobre as mutações no complexo dos canais de sódio responsáveis por doença cardíaca e as implicações da relação estrita entre a genética e a clínica das principais canalopatias cardíacas, nomeadamente no nível do diagnóstico, da estratificação do risco, do prognóstico, do rastreio de parentes e terapêutica. MétodosFoi usada a base de dados online Pubmed® para pesquisar os artigos publicados nessa área, em revistas indexadas. Recorreu-se à MeSH Database para definir a seguinte query: “Mutation [Mesh] AND Sodium Channels [Mesh] AND Heart Diseases [Mesh]” e incluíram-se artigos publicados nos últimos 15 anos, escritos em inglês ou português e referentes à investigação em humanos. ConclusõesNos últimos anos, grandes avanços foram feitos no esclarecimento da base genética e molecular dessas síndromes. A maior compreensão dos mecanismos fisiopatológicos subjacentes demonstrou a importância da relação entre o genótipo e o fenótipo e permitiu efetuar progressos na abordagem clínica desses pacientes. Todavia, é ainda necessário melhorar a capacidade de diagnóstico, aprimorar a estratificação do risco e desenvolver novas terapêuticas específicas de acordo com o binómio genótipo-fenótipo." "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0020" "titulo" => "Introdução e objetivos" ] 1 => array:2 [ "identificador" => "abst0025" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0030" "titulo" => "Conclusões" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Fonseca DJNdO, Silva MJLVd. Canalopatias cardíacas: o papel das mutações nos canais de sódio. Rev Port Cardiol. 2018;37:179–199." ] ] "nomenclatura" => array:1 [ 0 => array:3 [ "identificador" => "nom0005" "titulo" => "List of abbreviations" "listaDefinicion" => array:1 [ 0 => array:1 [ "definicion" => array:35 [ 0 => array:2 [ "termino" => "AF" "descripcion" => "atrial fibrillation" ] 1 => array:2 [ "termino" => "AP" "descripcion" => "action potential" ] 2 => array:2 [ "termino" => "BrS" "descripcion" => "Brugada syndrome" ] 3 => array:2 [ "termino" => "Ca2+" "descripcion" => "calcium ion" ] 4 => array:2 [ "termino" => "CAV3" "descripcion" => "caveolin-3" ] 5 => array:2 [ "termino" => "CCD" "descripcion" => "cardiac conduction disease" ] 6 => array:2 [ "termino" => "CPVT" "descripcion" => "catecholaminergic polymorphic ventricular tachycardia" ] 7 => array:2 [ "termino" => "DCM" "descripcion" => "dilated cardiomyopathy" ] 8 => array:2 [ "termino" => "ECG" "descripcion" => "electrocardiogram" ] 9 => array:2 [ "termino" => "EPS" "descripcion" => "electrophysiological study" ] 10 => array:2 [ "termino" => "HR" "descripcion" => "heart rate" ] 11 => array:2 [ "termino" => "ICa" "descripcion" => "calcium current" ] 12 => array:2 [ "termino" => "IK" "descripcion" => "potassium current" ] 13 => array:2 [ "termino" => "INa" "descripcion" => "sodium current" ] 14 => array:2 [ "termino" => "INa late" "descripcion" => "late, persistent or sustained sodium current" ] 15 => array:2 [ "termino" => "INa peak" "descripcion" => "peak sodium current" ] 16 => array:2 [ "termino" => "K+" "descripcion" => "potassium ion" ] 17 => array:2 [ "termino" => "LQTS" "descripcion" => "long QT syndrome" ] 18 => array:2 [ "termino" => "LQTS1" "descripcion" => "long QT syndrome type 1" ] 19 => array:2 [ "termino" => "LQTS2" "descripcion" => "long QT syndrome type 2" ] 20 => array:2 [ "termino" => "LQTS3" "descripcion" => "long QT syndrome type 3" ] 21 => array:2 [ "termino" => "ms" "descripcion" => "milliseconds" ] 22 => array:2 [ "termino" => "Na+" "descripcion" => "sodium ion" ] 23 => array:2 [ "termino" => "NaC" "descripcion" => "sodium channels" ] 24 => array:2 [ "termino" => "PVS" "descripcion" => "programmed ventricular stimulation" ] 25 => array:2 [ "termino" => "PVT" "descripcion" => "polymorphic ventricular tachycardia" ] 26 => array:2 [ "termino" => "QTc" "descripcion" => "QT interval corrected for heart rate" ] 27 => array:2 [ "termino" => "SCD" "descripcion" => "sudden cardiac death" ] 28 => array:2 [ "termino" => "SD" "descripcion" => "sudden death" ] 29 => array:2 [ "termino" => "SNP" "descripcion" => "single nucleotide polymorphism" ] 30 => array:2 [ "termino" => "SNTA1" "descripcion" => "syntrophin" ] 31 => array:2 [ "termino" => "SQTS" "descripcion" => "short QT syndrome" ] 32 => array:2 [ "termino" => "TdP" "descripcion" => "Torsade de pointes" ] 33 => array:2 [ "termino" => "VF" "descripcion" => "ventricular fibrillation" ] 34 => array:2 [ "termino" => "VT" "descripcion" => "ventricular tachycardia" ] ] ] ] ] ] "multimedia" => array:19 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3493 "Ancho" => 3167 "Tamanyo" => 873830 ] ] "descripcion" => array:1 [ "en" => "Protein macromolecular complex, α subunits and life cycle of the Nav1.5 sodium channels. (A) The Nav1.5 channel is part of a macromolecular complex interacting with various proteins such as: β subunits, caveolin-3, MOG1, ankyrin, syntrophin and cytoskeleton. Extracted and adapted from Liu et al. (2014)<a class="elsevierStyleCrossRef" href="#bib0425">7</a> and Amin et al. (2010).<a class="elsevierStyleCrossRef" href="#bib0500">22</a>(B) The life cycle of Nav1.5 starts in the nucleus, where transcription of the SCN5A gene and the respective regulation by transcription factors (FOXO1, NF-KB and TBX5) occur. However, microRNAs also regulate mRNA levels. In the endoplasmic reticulum proteins are translated and, after appropriate protein folding and assembly, they are transported to the cell membrane (trafficking). Mutations or splicing variants may lead to a misfolded Nav1.5 protein, which may activate the PERK pathway for downregulation of their mRNA levels. PKA, PKC, oxidative stress (ROS) and metabolic states (NADH and NAD+) may modulate channel trafficking. NEDD4 regulates ubiquitin-mediated degradation. Extracted and adapted from Liu et al. (2014).<a class="elsevierStyleCrossRef" href="#bib0425">7</a> CAV3: caveolin-3; FOXO1: forkhead box protein O1; MOG1: Ran guanine nucleotide release factor; NaChIP: Na+-channel-interacting protein; NEDD4: E3 ubiquitin-protein ligase NEDD4; NF-κB: nuclear factor NF-κB; PERK: eukaryotic translation initiation factor 2α-kinase 3; PKA: AMPc-dependent protein kinase (protein kinase A); PKC: protein kinase C; ROS: reactive oxygen species; TBX5: T-box transcription factor TBX5." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1309 "Ancho" => 2333 "Tamanyo" => 179186 ] ] "descripcion" => array:1 [ "en" => "Clinical phenotypes associated with mutations in Nav1.5 sodium channels. Extracted and adapted from Liu et al. (2014).<a class="elsevierStyleCrossRef" href="#bib0425">7</a>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2147 "Ancho" => 3083 "Tamanyo" => 340233 ] ] "descripcion" => array:1 [ "en" => "Abnormalities in action potential and sodium currents associated with gain- and loss-of-function mutations in Nav1.5 channels. (1A) Gain-of-function mutations are associated with an increase in the duration of the action potential and may trigger arrhythmic events. (1B) Various mechanisms may be associated with gain of function in the sodium current. The most common mechanism is increased late sodium current (abnormally sustained increase of INa during the AP phase 2 with prolonged membrane depolarization and delayed repolarization), which may be due to incomplete or slowed inactivation. Other less common mechanisms are increased window current and increased INa peak (increase in influx of Na+ in AP phase 0). (1C) The mechanism of sodium current increase more frequently results from incomplete inactivation of the sodium channels (green circles). (1D) In the mechanism of window current increase (green circles), inactivation occurs in more positive AP states, “delaying” and broadening the amplitude of voltages during which NaC may be reactivated. (2A) In loss-of-function mutations, decreased peak sodium current decreases the upstroke speed of the AP phase 0, slowing down electrical conduction in the heart. Extracted and adapted from Amin et al. (2010).<a class="elsevierStyleCrossRef" href="#bib0500">22</a>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 3519 "Ancho" => 3000 "Tamanyo" => 641314 ] ] "descripcion" => array:1 [ "en" => "Diagnostic algorithm for Brugada syndrome. There are three patterns of electrocardiographic abnormalities in the right precordial leads (V1-V3). Type 1 is considered to be diagnostic, unlike types 2 and 3 (in presence of which provocation tests with SCB must be performed). Other electrocardiographic abnormalities that may be present in BrS are: prolongation of the PR interval and right branch block. A definitive diagnosis is made in presence of type 1 ST-segment elevation in at least one V1-V3 lead and when one of the clinical criteria presented in the figure is met. AMI: acute myocardial infarction; ANS: autonomic nervous system; C/ARVD: cardiomyopathy/arrhythmogenic right ventricular dysplasia; CCB: calcium channel blockers; CNS: central nervous system; ECG: electrocardiogram; LVH: left ventricular hypertrophy; PTE: pulmonary thromboembolism; RV: right ventricle; RVOT: right ventricular outflow tract; SCB: sodium channel blockers; SSRIs: selective serotonin reuptake inhibitors; VF: ventricular fibrillation; VT: ventricular tachycardia; β-blockers: beta blockers. *May unmask genetic susceptibility to BrS. Extracted and adapted from Berne and Brugada (2012).<a class="elsevierStyleCrossRef" href="#bib0645">51</a>" ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 2859 "Ancho" => 2333 "Tamanyo" => 607751 ] ] "descripcion" => array:1 [ "en" => "Electrocardiographic patterns in BrS: spontaneous (1) and after provocation test with ajmaline (2)." ] ] 5 => array:7 [ "identificador" => "fig0030" "etiqueta" => "Figure 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 3472 "Ancho" => 3167 "Tamanyo" => 814266 ] ] "descripcion" => array:1 [ "en" => "Long QT syndrome – main characteristics and diagnostic criteria. (B) Scoring system used in the diagnosis of LQTS based on the findings in the electrocardiogram, medical history (symptoms) and family history. QTc is calculated using the Bazett formula. Scoring: ≤1 – low likelihood of LQTS; 1.5 to 3 – intermediate likelihood of LQTS; ≥3.5 – high likelihood of LQTS. LQTS is diagnosed in individuals with a score ≥3.5 in whom there are no secondary causes for QT interval prolongation. ♂: male individuals; ♀: female individuals; HR: heart rate. #Mutually exclusive. ¿Both cannot be accounted for in the same family. **HR at rest below the 2nd percentile for age. ***The low risk associated with exercise in LQTS2 and LQTS3 patients is explained by the fact that both have a normal IK current, stimulated by activation of the sympathetic nervous system, which in turn results in shortening of the ventricular repolarization whenever the heart rate increases, thus avoiding the likelihood of ventricular tachyarrhythmias during exercise. (A) Extracted and adapted from Furst and Aziz (2016)<a class="elsevierStyleCrossRef" href="#bib0765">75</a> and *Schwartz et al. (2001)<a class="elsevierStyleCrossRef" href="#bib0760">74</a>; (B) Extracted and adapted from Schwartz et al. (2013)<a class="elsevierStyleCrossRef" href="#bib0605">43</a>; (C) and (D) Extracted and adapted from Giudicessi and Ackerman (2013).<a class="elsevierStyleCrossRef" href="#bib0740">70</a>" ] ] 6 => array:7 [ "identificador" => "fig0035" "etiqueta" => "Figure 7" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr7.jpeg" "Alto" => 3738 "Ancho" => 2917 "Tamanyo" => 887120 ] ] "descripcion" => array:1 [ "en" => "Diagnostic approach, risk stratification and guidance for the treatment of long QT syndrome. USV: undetermined significance variant. Extracted and adapted from Giudessi and Ackerman (2013).<a class="elsevierStyleCrossRef" href="#bib0740">70</a>" ] ] 7 => array:7 [ "identificador" => "fig0040" "etiqueta" => "Figure 8" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr8.jpeg" "Alto" => 1690 "Ancho" => 2505 "Tamanyo" => 184098 ] ] "descripcion" => array:1 [ "en" => "Diagram illustrating the overlap between BrS, LQTS, SQTS, SND, ERS and ARVC. The sodium channel macromolecular complex genes are in bold. ARVC: arrhythmogenic right ventricular cardiomyopathy; ERS: early repolarization syndrome; LQTS: long QT syndrome; SND: sinus node disease; SQTS: short QT syndrome. Extracted and adapted from Sarquella-Brugada (2016)<a class="elsevierStyleCrossRef" href="#bib0430">8</a> and Fernandez-Falgueras (2017).<a class="elsevierStyleCrossRef" href="#bib0565">35</a>" ] ] 8 => array:7 [ "identificador" => "fig0045" "etiqueta" => "Figure 9" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr9.jpeg" "Alto" => 858 "Ancho" => 1413 "Tamanyo" => 48393 ] ] "descripcion" => array:1 [ "en" => "Cardiac channelopathies: positivity of the genetic tests in individuals clinically diagnosed with BrS and LQTS. Data presented in the charts from Schwartz and Dagradi (2016).<a class="elsevierStyleCrossRef" href="#bib0780">78</a>" ] ] 9 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Extracted and adapted from Mizusawa (2016).<a class="elsevierStyleCrossRef" href="#bib0435">9</a>, *Imbrici et al. (2016)<a class="elsevierStyleCrossRef" href="#bib0450">12</a> and Ackerman et al. (2011).<a class="elsevierStyleCrossRef" href="#bib0655">53</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Pathology \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genes (% of involvement) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Prevalence \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Hereditary arrhythmias in the absence of structural heart defects</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Brugada syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN5A (20-30%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1:3300 to 1:10000* \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Long QT syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KCNQ1 (30-35%), KCNH2 (25-30%), SCN5A (5-10%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1:2500* \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Catecholaminergic polymorphic ventricular tachycardia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RYR2 (60-65%), CASQ2 (<5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1:10000* \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cardiac conduction disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN5A (5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Short QT syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">None of the 3 known genes represents >5% of the disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Atrial fibrillation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">None of the known genes represents >5% of the disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Hereditary arrhythmias in the presence of structural heart defects</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Right ventricular arrhythmogenic cardiomyopathy/Right ventricular arrhythmogenic dysplasia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PKP2 (25-40%), DSG2 (5-10%), DSP (2-12%), DSC2 (2-7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dilated cardiomyopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TTN (≈25%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hypertrophic cardiomyopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MYBPC3 (30-40%), MYH7 (20-30%), TNNT2 (10%), TNNI3 (7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1702784.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Main genes associated with hereditary arrhythmias." ] ] 10 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "CNS: central nervous system; PNS: peripheral nervous system.Extracted and adapted from England and Groot (2009).<a class="elsevierStyleCrossRef" href="#bib0485">19</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Protein \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Tissue with major expression \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Gene \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Chromosome \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CNS and PNS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN1A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2q24 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CNS and PNS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN2A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2q23-24 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CNS and PNS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN3A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2q24 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Skeletal muscle \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN4A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17q23-25 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Heart \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN5A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3p21 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CNS and PNS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN8A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12q13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PNS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN9A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2q24 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PNS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN10A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3p21-24 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PNS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN11A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3p21-24 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav2.1 (Nax) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Glial cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN6/7A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2q21-23 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1702783.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Sodium channel α subunits." ] ] 11 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Ø: failure; (↑): increase; (↓): decrease; (+): depolarizing shift; (-): hyperpolarizing shift; AF: atrial fibrillation; BrS: Brugada syndrome; CCD: cardiac conduction disease; ISDS: infant sudden-death syndrome; LQTS: long QT syndrome; Rec.R: recovery rate; Ref.P: refractory period; RP.ST: ST segment in right precordial leads; SSI: steady state inactivation; VF: ventricular fibrillation.Extracted and adapted from Adsit et al. (2013).<a class="elsevierStyleCrossRef" href="#bib0505">23</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Gene \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Protein \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Normal effect on INa \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mutations \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mutation effect \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Phenotype \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="5" align="left" valign="top">SCN1B</td><td class="td" title="table-entry " rowspan="5" align="left" valign="top">β1</td><td class="td" title="table-entry " align="left" valign="top">(↓) INa late \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Trp179X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(Ø-) Activation, (Ø-) SSI, (Ø↑) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BrS, CCD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↑) Rec.R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">E87Q \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(Ø-) Activation, (Ø↑) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BrS, CCD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↑) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">R85H \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) Activation, SSI, (Ø↑) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Familial AF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">D153N \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(Ø↑) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Familial AF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">R214Q \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(Ø↑) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BrS, Familial AF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">SCN2B</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">β2</td><td class="td" title="table-entry " align="left" valign="top">State of sialylation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">R28Q \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) Activation, (↓) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Familial AF (↑) PR, (↑) RP.ST \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↑) Late current \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">R28W \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) SSI, (+) Activation, (↓) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Familial AF (↑) PR, (↑) RP.ST \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top">SCN3B</td><td class="td" title="table-entry " rowspan="4" align="left" valign="top">β3</td><td class="td" title="table-entry " align="left" valign="top">(↑) INa, (↑) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">R6K, L10P and M161T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mixed, (↓) INa peak, (-) SSI, (↓) Rec.R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Familial AF BrS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rec.R, (+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">A130V \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(↓) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Familial AF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SSI, (↑) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">V54G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(↓) INa peak (↓) Trafficking \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Idiopathic VF, ISDS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ref.P \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">V36M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(↓) INa peak (↑) INa late \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ISDS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">SCN4B</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">β4</td><td class="td" title="table-entry " align="left" valign="top">(↑) Speed of AP upstroke \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">S206L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(↑) INa late \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ISDS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(+) SSI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">L179F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(↑) Window current \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LQTS10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">CAV3</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Caveolin 3</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Scaffolding, (↓) INa late</td><td class="td" title="table-entry " align="left" valign="top">F97C, S141R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(↑) INa late \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LQTS9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">V14L, T78M and L79R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(↑) INa late \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ISDS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">GPD1L</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">GPD1L</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">(↑) INa by phosphorylation</td><td class="td" title="table-entry " align="left" valign="top">A280V \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(↓) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BrS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">E83K, I124V, R273C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(↓) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ISDS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">RANGRF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MOG1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(↑) Surface density, (↑) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">E83D \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(↓) INa peak (↓) Trafficking \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BrS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">SNTA1</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Syntrophin α1</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Scaffolding</td><td class="td" title="table-entry " align="left" valign="top">A390V \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(↑) INa peak, (↑) INa late \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LQTS12 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">S287R, T372M, G460S \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(↑) INa peak, (↑) INa late, (+) SSI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ISDS \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1702789.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Mutations in proteins of the sodium channel macromolecular complex." ] ] 12 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AF: atrial fibrillation; AV: atrioventricular; BrS: Brugada syndrome; CCD: cardiac conduction disease; DCM: dilated cardiomyopathy; ISDS: infant sudden death syndrome; LQTS: long QT syndrome; SND: sinus node disease.Extracted and adapted from Wilde and Brugada (2011),<a class="elsevierStyleCrossRef" href="#bib0415">5</a> Remme (2013),<a class="elsevierStyleCrossRef" href="#bib0420">6</a> Abriel (2010)<a class="elsevierStyleCrossRef" href="#bib0465">15</a> and Adsit et al. (2013).<a class="elsevierStyleCrossRef" href="#bib0505">23</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Gene \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Protein \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Abnormalities in INa \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">“Cardiac” phenotype \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top">Sodium channel</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="11" align="left" valign="middle">SCN5A</td><td class="td" title="table-entry " rowspan="11" align="left" valign="middle">Nav1.5</td><td class="td" title="table-entry " align="left" valign="top">(↓) INa by different mechanisms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Type 1 BrS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↑) INa late \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Type 3 LQTS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↓) INa by different mechanisms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CCD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↓) INa by different mechanisms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lev-Lenégre disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↓) INa by different mechanisms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Congenital AV block \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↓) INa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↓) INa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Atrial standstill \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Different and mismatched molecular phenotypes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Different and mismatched molecular phenotypes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DCM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↑) INa late/(↓) INa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ISDS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Combination of molecular phenotypes present in other clinical entities \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Overlap Syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top">Proteins of sodium channel macromolecular complex</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">SCN1B</td><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Subunit β1</td><td class="td" title="table-entry " align="left" valign="top">(↓) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Type 5 BrS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↓) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CCD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↓) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SCN2B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Subunit β2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(↓) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="5" align="left" valign="top">SCN3B</td><td class="td" title="table-entry " rowspan="5" align="left" valign="top">Subunit β3</td><td class="td" title="table-entry " align="left" valign="top">(↓) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Type 7 BrS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↓) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↓) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CCD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↓) INa peak/(↑) INa late \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ISDS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↓) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Idiopathic VF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">SCN4B</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Subunit β4</td><td class="td" title="table-entry " align="left" valign="top">(↑) INa late \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Type 10 LQTS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↑) INa late \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ISDS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">SNTA</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Syntrophin α1</td><td class="td" title="table-entry " align="left" valign="top">(↑) INa late/(↑) INapeak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Type 12 LQTS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↑) INa late/(↑) INapeak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ISDS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">RANGRF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MOG1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(↓) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Type 8 BrS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">CAV3</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Caveolin-3</td><td class="td" title="table-entry " align="left" valign="top">(↑) INa late \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Type 9 LQTS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↑) INa late \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ISDS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">GPD1L</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Glycerol-3-phosphate dehydrogenase 1-like</td><td class="td" title="table-entry " align="left" valign="top">(↓) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Type 2 BrS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(↓) INa peak \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ISDS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PTPH1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Tyrosine phosphatase H1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">NEDD4L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nedd4-2/Nedd4-like \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CALM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Calmodulin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CAMK2D \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Calcium/Calmodulin-dependent protein kinase II delta \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SAP97 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SAP97 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">YWHAH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14-3-3-a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FGF13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FGF13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ANK3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ankyrin-G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ACTN2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Actinin α2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PKP2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Plakophilin-2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Arrhythmogenic cardiomyopathy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">DSG2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Desmoglein-2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Arrhythmogenic cardiomyopathy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TCAP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Telethonin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ZASP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Z band \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1702780.png" ] ] ] ] "descripcion" => array:1 [ "en" => "“Cardiac” phenotypes associated with dysfunction of sodium channels and related proteins." ] ] 13 => array:8 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at5" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "IV: intravenous; PO: per os.Extracted and adapted from Antzelevitch et al. (2005).<a class="elsevierStyleCrossRef" href="#bib0615">45</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dose and duration \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Route of administration \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ajmaline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 mg/kg for 5 minutes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IV \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Flecainide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 mg/kg for 10 minutes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IV \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">400 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PO \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pilsicainide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 mg/kg for 10 minutes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IV \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Procainamide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 mg/kg for 10 minutes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IV \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1702786.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Drugs used in provocation tests to “unmask” Brugada syndrome." ] ] 14 => array:8 [ "identificador" => "tbl0030" "etiqueta" => "Table 6" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at6" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "AD: autosomal dominant." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Phenotype \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Gene \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Locus \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Protein \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Effect on function \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Inheritance \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">Sodium channels and associated proteins</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN5A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3p21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nav1.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11-28% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN10A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3p22.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nav1.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.0-16.7% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN1B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19q13.12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Subunit β1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN2B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11q23.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Subunit β2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN3B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11q24.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Subunit β3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">GPD1L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3p22.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Glycerol-3-phosphate dehydrogenase 1-like \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RANGRF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17p13.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MOG1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SLMAP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3p14.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Protein associated with sarcolemma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PKP2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12p11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Plakophilin 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">INa deficit<a class="elsevierStyleCrossRef" href="#tblfn0010">#</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HEY2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6q22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nav1.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">Calcium channels</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CACNA1C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12p13.33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">α1c subunit of voltage-gated L-type calcium channel (Cav1.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.6% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CACNB2B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10p12.33-p12.31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">β2 subunit of voltage-gated L-type calcium channel (Cav β2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.8% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CACNA2D1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7q21.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">α2/δ1 subunits of voltage-gated calcium channel (Cavα2δ1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.8% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TRPM4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19q13.33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">“Transient receptor potential cation channel subfamily M member 4” \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">Potassium channels</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KCND3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1p13.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Voltage-gated potassium channel subfamily D member 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KCNE3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11q13.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Voltage-gated potassium channel subfamily E member 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KCNJ8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12p12.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inward rectifier potassium channel 8 sensitive to ATP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HCN4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15q24.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">“Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4” \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KCNE5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Xq22.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Voltage-gated potassium channel subfamily E “regulatory β” subunit 5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">X-linked \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KCNH2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7q35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Kv11.1, IKr \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1-2% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BrS21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ABCC9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12p12.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SUR2A (subunit 2A of the sulfonylurea receptor), IK-ATP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4-5% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1702787.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "#" "nota" => "Plakophilin causes INa deficit. Extracted and adapted from Sarquella-Brugada-et al. (2016),<a class="elsevierStyleCrossRef" href="#bib0430">8</a> Sieira et al. (2016)<a class="elsevierStyleCrossRef" href="#bib0660">54</a> and Juang and Horie (2016).<a class="elsevierStyleCrossRef" href="#bib0690">60</a>" ] ] ] "descripcion" => array:1 [ "en" => "Mutated genes in Brugada syndrome." ] ] 15 => array:8 [ "identificador" => "tbl0035" "etiqueta" => "Table 7" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at7" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "BrS: Brugada syndrome; ICD: implantable cardioverter defibrillator; RF: radiofrequency; RPCld: right precordial leads; SCD: sudden cardiac death; VF: ventricular fibrillation; VT: ventricular tachycardia." "tablatextoimagen" => array:2 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">General measures for lifestyle alterations</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Avoid drugs that may induce or worsen ST segment elevation in RPCld \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(Class I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Avoid excessive alcohol consumption \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(Class I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">In presence of fever, promptly medicate with antipyretic drug \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(Class Ia) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1702781.png" ] ] 1 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Risk stratification and specific treatment</th></tr><tr title="table-row"><th class="td" title="table-head " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Symptomatic individuals<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a></th><th class="td" title="table-head " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Asymptomatic individuals</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">“aborted” SCD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ICD (Class I) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Spontaneous type 1 electrocardiogram (ECG) pattern \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Quinidine (Class IIb) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Documented spontaneous VT, with or without syncope \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ICD (Class I) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Spontaneous type 1 ECG pattern + VT/VF induced by EPS</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">ICD (Class IIb)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Syncope + Spontaneous type 1 ECG pattern \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ICD (Class IIa) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Electrical/arrhythmic storm<a class="elsevierStyleCrossRef" href="#tblfn0020">b</a></td><td class="td" title="table-entry " align="left" valign="top">Isoprenaline<a class="elsevierStyleCrossRef" href="#tblfn0025">c</a> (Class IIa) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Type 1 ECG pattern induced by drugs and family history of SCD</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">ICD (Class III)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Quinidine<a class="elsevierStyleCrossRef" href="#tblfn0030">d</a> (Class IIa) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Individuals who are eligible for ICD but present a contraindication or refuse ICD and/or present with a history of supraventricular arrhythmias that require treatment</td><td class="td" title="table-entry " align="left" valign="top">Quinidine (Class IIa) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Individuals diagnosed with BrS and history of electrical/arrhythmic storms or (appropriate) repetition shocks due to ICD</td><td class="td" title="table-entry " align="left" valign="top">Catheter ablation – RF (Class IIb) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1702791.png" ] ] ] "notaPie" => array:4 [ 0 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "a" "nota" => "The clinical manifestations associated with BrS may include ventricular fibrillation, “aborted” sudden death, syncope, palpitations, chest discomfort and nocturnal agonal breathing." ] 1 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "b" "nota" => "Defined as more than 2 VT/VF episodes in 24 hours." ] 2 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "c" "nota" => "May be useful to suppress electrical/arrhythmic storms." ] 3 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "d" "nota" => "May be useful in individuals diagnosed with BrS and history of electrical/arrhythmic storms. Adapted from Priori et al. (2013)<a class="elsevierStyleCrossRef" href="#bib0620">46</a> and Steinfurt et al. (2015).<a class="elsevierStyleCrossRef" href="#bib0710">64</a>" ] ] ] "descripcion" => array:1 [ "en" => "Recommendations for the treatment of Brugada syndrome." ] ] 16 => array:8 [ "identificador" => "tbl0040" "etiqueta" => "Table 8" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at8" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "(-): loss of function; (+): gain of function; ATS: Andersen-Tawil syndrome; ICa,L: Ca2+ currents through voltage-gated type-L calcium channels; IK-Ach: K+ current regulated by acetylcholine receptors; IKl: K+ entry current, rectifying; IKr: rapid component (internal rectification – K+ channels are open when potential is negative and closed when potential is less negative or positive) of the K+ “delayed rectifier” current (IKr); IKs: slow component of the K+ “delayed rectifier” current (IKr); INa: voltage-gated Na+ current; NCX: Na+/Ca2+ exchanger; TS: Timothy syndrome." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Name \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Gene \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Protein \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Current \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Effect on function \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="6" align="left" valign="top">Autosomal dominant inheritance (Romano-Ward)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LQTS1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KCNQ1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KV7.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IKs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40-55% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LQTS2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KCNH2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KV11.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IKr \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30-45% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LQTS3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN5A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NaV1.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">INa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5-10% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LQTS4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ANKB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ankyrin B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NCX exchanger, ATPase Na+/K+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LQTS5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KCNE1<a class="elsevierStyleCrossRef" href="#tblfn0035">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MinK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IKs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LQTS6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KCNE2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MiRP1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IKr \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LQTS7 (ATS) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KCNJ2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Kir2.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IKl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LQTS8 (TS) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CACNA1C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CaV1.2α1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ICa,L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LQTS9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CAV3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Caveolin-3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">INa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LQTS10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SCN4B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Subunit β4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">INa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Very rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LQTS11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AKAP9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yotiao \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IKs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Very rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LQTS12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SNTA1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Syntrophin-α1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">INa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Very rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LQTS13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KCNJ5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Kir 3.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IK-Ach \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Very rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LQTS14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CALM1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Calmodulin 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduction of affinity for Ca2+<a class="elsevierStyleCrossRef" href="#tblfn0040">**</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LQTS15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CALM2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Calmodulin 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduction of affinity for Ca2+<a class="elsevierStyleCrossRef" href="#tblfn0040">**</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="6" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="6" align="left" valign="top">Autosomal recessive inheritance (Jervell and Lange-Nielsen)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">JLN1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KCNQ1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KV7.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IKs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">JLN2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">KCNE1<a class="elsevierStyleCrossRef" href="#tblfn0035">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MinK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IKs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(-) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rare \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1702782.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0035" "etiqueta" => "a" "nota" => "Mutations in the KCNE1 gene may cause Romano-Ward syndrome (autosomal dominant; LQTS5) or, if homozygous or compound heterozygous, Jervell and Lange-Nielsen syndrome (autosomal recessive)." ] 1 => array:3 [ "identificador" => "tblfn0040" "etiqueta" => "**" "nota" => "Calmodulin dysfunction may alter the inactivation of Ca2+-gated L-type Ca2+ channels (increasing the depolarizing current during phase 2 of the action potential), but some calmodulin mutations may also be associated with an abnormality in the regulation of sodium channels. Extracted and adapted from Nakano and Shimizu (2016),<a class="elsevierStyleCrossRef" href="#bib0560">34</a> **Makita et al. (2014)<a class="elsevierStyleCrossRef" href="#bib0570">36</a> and *Mizusawa (2014).<a class="elsevierStyleCrossRef" href="#bib0735">69</a>" ] ] ] "descripcion" => array:1 [ "en" => "Subtypes of congenital LQTS." ] ] 17 => array:8 [ "identificador" => "tbl0045" "etiqueta" => "Table 9" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at9" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "♂: male; ♀: female; HR: heart rate; RR: RR interval.Extracted and adapted from Goldenberg et al. (2006).<a class="elsevierStyleCrossRef" href="#bib0755">73</a>" "tablatextoimagen" => array:2 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">1 – Method for correction of QT interval (formulas)</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bazett \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">QT/RR1/2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fridericia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">QT/RR1/3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Framingham \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">QT + 0.154 (1 - RR) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hodges \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">QT + 1.75 (HR - 60) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1702790.png" ] ] 1 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">2 – Normal, borderline and prolonged QTc values calculated with the Bazett formula</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Normal \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Borderline \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Prolonged \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1-15 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><440 ms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">440-460 ms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>460 ms \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Adult (♂) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><430 ms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">430-450 ms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>450 ms \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Adult (♀) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><450 ms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">450-470 ms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>470 ms \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1702788.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Assessment of the QT interval." ] ] 18 => array:8 [ "identificador" => "tbl0050" "etiqueta" => "Table 10" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at10" "detalle" => "Table 1" "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "ICD: implantable cardioverter defibrillator; LCSD: left cardiac sympathetic denervation; SCB: sodium channel blocker; SCD: sudden cardiac death; VF: ventricular fibrillation; VT: ventricular tachycardia." "tablatextoimagen" => array:2 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">General measures for lifestyle alterations</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Avoid drugs that prolong the QT interval \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(Class I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Identify and correct hydroelectrolytic disorders \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(Class I) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1702785.png" ] ] 1 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Risk stratification and specific treatment</th></tr><tr title="table-row"><th class="td" title="table-head " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Symptomatic individuals</th><th class="td" title="table-head " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Asymptomatic individuals</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Syncope \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">β-blockers (Class I) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">QTc ≥470 ms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">β-blockers (Class I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Documented VT/VF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">β-blockers (Class I) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">QTc ≤470 ms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">β-blockers (Class IIa) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">“aborted” SCD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ICD (Class I) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not treated with β-blockers<a class="elsevierStyleCrossRef" href="#tblfn0045">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ICD (Class III) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Recurrent syncope episodes during treatment with β-blockers \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ICD (Class IIa) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Individuals with a diagnosis of LQTS who present with events during treatment with β-blockers/ICD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LCSD (Class IIa) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">High-risk individuals with a diagnosis of LQTS who refuse ICD or for whom it is contraindicated and/or when β-blockers are not effective in preventing syncope/arrhythmias, are not tolerated, are contraindicated or are refused</td><td class="td" title="table-entry " align="left" valign="top">LCSD (Class I) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Individuals with type 3 LQTS and QTc >500 ms that decrease >40 ms after acute oral test with an SCB</td><td class="td" title="table-entry " align="left" valign="top">SCB (Class IIa) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1702779.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0045" "etiqueta" => "*" "nota" => "Except under special circumstances, the ICD is not indicated in asymptomatic individuals not undergoing treatment with β-blockers. 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Cardiac channelopathies: The role of sodium channel mutations

Canalopatias cardíacas: o papel das mutações nos canais de sódio

Diana João Fonseca

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mimed11120@med.up.pt

Corresponding author.

, Manuel Joaquim Vaz da Silva

Faculdade de Medicina da Universidade do Porto, Porto, Portugal

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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Diagnostic algorithm for Brugada syndrome&#46; There are three patterns of electrocardiographic abnormalities in the right precordial leads &#40;V1-V3&#41;&#46; Type 1 is considered to be diagnostic&#44; unlike types 2 and 3 &#40;in presence of which provocation tests with SCB must be performed&#41;&#46; Other electrocardiographic abnormalities that may be present in BrS are&#58; prolongation of the PR interval and right branch block&#46; A definitive diagnosis is made in presence of type 1 ST-segment elevation in at least one V1-V3 lead and when one of the clinical criteria presented in the figure is met&#46; AMI&#58; acute myocardial infarction&#59; ANS&#58; autonomic nervous system&#59; C&#47;ARVD&#58; cardiomyopathy&#47;arrhythmogenic right ventricular dysplasia&#59; CCB&#58; calcium channel blockers&#59; CNS&#58; central nervous system&#59; ECG&#58; electrocardiogram&#59; LVH&#58; left ventricular hypertrophy&#59; PTE&#58; pulmonary thromboembolism&#59; RV&#58; right ventricle&#59; RVOT&#58; right ventricular outflow tract&#59; SCB&#58; sodium channel blockers&#59; SSRIs&#58; selective serotonin reuptake inhibitors&#59; VF&#58; ventricular fibrillation&#59; VT&#58; ventricular tachycardia&#59; &#946;-blockers&#58; beta blockers&#46; &#42;May unmask genetic susceptibility to BrS&#46;</p> <p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Extracted and adapted from Berne and Brugada &#40;2012&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">51</span></a></p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Introduction</span><p id="par0180" class="elsevierStylePara elsevierViewall">Cardiac channelopathies constitute a heterogeneous group of inherited cardiac diseases caused by mutations in genes that encode for the ion channels expressed in the heart &#40;involved in Na<span class="elsevierStyleSup">&#43;</span> &#91;I<span class="elsevierStyleInf">Na</span>&#93;&#44; K<span class="elsevierStyleSup">&#43;</span> &#91;I<span class="elsevierStyleInf">K</span>&#93; and Ca<span class="elsevierStyleSup">2&#43;</span> &#91;I<span class="elsevierStyleInf">Ca</span>&#93; currents&#41; and&#47;or the proteins that regulate their function&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">1&#8211;3</span></a> These mutations result in different phenotypes according to the abnormalities induced in the sodium current and in other ion currents&#44; leading to a greater likelihood of occurrence of syncope&#44; seizures and arrhythmias&#44; although most of the time there are no underlying structural heart defects&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">4</span></a> This shows the importance of ion channels&#44; namely sodium channels &#40;NaC&#41;&#44; in the genesis and propagation of the action potential &#40;AP&#41;&#44; and consequently in heart excitability&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">2&#44;3&#44;5&#8211;7</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Induced arrhythmias are potentially fatal&#44; and sudden cardiac death &#40;SCD&#41; frequently constitutes the first manifestation of these diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">4&#44;8</span></a> Sudden death &#40;SD&#41; is one of the most common causes of death due to cardiovascular pathologies and&#44; in the adult Western population&#44; cardiac channelopathies &#40;1-2&#37;&#41; are one of the most frequently diagnosed predisposing pathologies together with cardiomyopathies &#40;10-15&#37;&#41; and coronary disease &#40;75&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">9</span></a> In reality&#44; some studies show that cardiac channelopathies are responsible for approximately 1&#47;3 of the SD cases in young people with a negative autopsy&#44; and up to 50&#37; of the cases of arrhythmic SCD&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">10&#44;11</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">The main hereditary arrhythmias caused by ion channel dysfunctions are Brugada syndrome &#40;BrS&#41;&#44; long QT syndrome &#40;LQTS&#41;&#44; short QT syndrome &#40;SQTS&#41; and catecholaminergic polymorphic ventricular tachycardia &#40;PVT&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">4&#44;12</span></a> However&#44; their prevalence in the general population is difficult to estimate&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">11&#44;13&#8211;15</span></a> In addition to the pathologies mentioned above&#44; pre-excitation syndrome&#44; idiopathic ventricular fibrillation &#40;VF&#41; and rare cases of familial cardiomyopathies are also associated with ion channel mutations&#46;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">4&#44;12</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">In the last two decades&#44; the knowledge about the genetic and molecular mechanisms underlying arrhythmias &#40;especially those of hereditary nature &#8211; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; has vastly increased&#44; and various mutations and&#47;or genetic variants have been described&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">16&#44;17</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0200" class="elsevierStylePara elsevierViewall">Although many mutations in different ion channels affect the heart&#39;s electrical currents&#44; we only cover what concerns sodium currents in this literature review&#46; In particular&#44; we cover the structure of the NaC and their role in heart excitability&#44; mutations in the NaC complex&#44; the associated phenotypes and the implications of the relationship between genetic and clinical aspects at the level of diagnosis&#44; risk stratification&#44; prognosis and treatment&#44; namely of LQTS and BrS&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Methods</span><p id="par0205" class="elsevierStylePara elsevierViewall">A narrative review of the literature covering the topic <span class="elsevierStyleItalic">Cardiac channelopathies&#58; the role of sodium channel mutations</span> was conducted&#46; The online Pubmed<span class="elsevierStyleSup">&#174;</span> database was used to search for articles published in this field&#44; and the <span class="elsevierStyleItalic">MeSH database</span> was used to select the MeSH terms and to define the following query&#58; &#8220;Mutation &#91;Mesh&#93; AND Sodium Channels &#91;Mesh&#93; AND Heart Diseases &#91;Mesh&#93;&#8221;&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Applying the predefined inclusion criteria&#44; only articles published in the last 15 years&#44; written in English or in Portuguese&#44; and referring to research in human beings were included&#46; Additionally&#44; the impact factor was taken into consideration&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Other references were also included&#44; some with a publication date prior to 2002&#44; with the aim of widening the relevant content cited in the initially searched articles&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Structure and function of sodium channels</span><p id="par0220" class="elsevierStylePara elsevierViewall">The NaC are transmembrane proteins consisting of an &#945; subunit together with one or two &#946; subunits &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">2</span></a> There are various types of &#945; subunits&#44; which are differentially expressed according to the type of tissue and are encoded by a family of 10 different genes &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">18&#44;19</span></a> The main &#945; subunit expressed in the heart is called Nav1&#46;5 &#40;like the sodium channel it is part of&#41; and is encoded by the SCN5A &#40;<span class="elsevierStyleItalic">sodium channel&#44; voltage gated&#44; type V alpha subunit</span>&#41; gene&#44; which includes 28 exons and spans more than 100 kb in chromosome 3p22&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">18&#44;20</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0225" class="elsevierStylePara elsevierViewall">Regulation of transcription of the SCN5A gene is influenced by many factors&#44; including&#58; presence of three promoters&#44; transcription factors and microRNAs with post-transcriptional activity&#46; More than 10 isoforms resulting from splicing of this gene have been described&#44; and the most abundant isoform in the human heart is SCN5A-003 &#40;adult isoform&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">7&#44;18&#44;20</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">The &#945; subunit has about 227 kDa and consists of a transmembrane protein with four homologous domains &#40;DI-DIV&#41; connected by cytoplasmic loops&#44; each of them with six &#945;-helix transmembrane segments &#40;S1-6&#41; connected by intra- and extracellular loops&#46; It also has a C terminus &#40;carboxy&#41; and an N terminus &#40;amino&#41;&#44; both being cytoplasmic&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">5&#44;6&#44;21</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">The central pore is formed by the four S5 and S6 segments of subunit &#945;&#44; namely by the extracellular loops that connect them&#46; It is selectively permeable to sodium&#44; which travels through it according to the electrochemical gradient&#46; Segments S1 to S4 act as voltage sensors&#46; However&#44; the latter has the peculiarity of having a positive charge&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">2&#44;5&#44;18&#44;21</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">Like the other voltage-gated channels&#44; the NaC show conformational changes during a process called gating that enables defining three functional states for the channel &#40;open&#44; inactive or closed&#41;&#44; according to membrane potential&#46; These alterations occur in the &#945; subunit&#44; which is the main one responsible for regulation of depolarization of excitable cells membranes&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">2&#44;18&#44;22</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">The subunits are proteins of approximately 30-40 kDa&#44; with a single transmembrane segment&#44; an intracellular C terminus and an extracellular N terminus&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">5</span></a> These subunits associate with the &#945; subunit of the NaC &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#44; thus not only modulating their expression on the cell surface and the gating process&#44; but also enabling connection with the cytoskeleton and other interaction proteins&#46; In effect&#44; the subunits are capable of increasing the channels traffic to the cell membrane&#44; with subsequent increase in I<span class="elsevierStyleInf">Na</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">5&#44;18</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">There are four types of &#946; subunits &#40;&#946;1&#44; &#946;2&#44; &#946;3 and &#946;4&#41;&#44; encoded by the SCN1B&#44; SCN2B&#44; SCN3B and SCN4B genes&#44; respectively&#46; These are preferentially associated with different &#945; subunits according to the type of tissue where they are expressed&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">5&#44;18&#44;20&#44;23</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">In addition to the &#946; subunits&#44; there are other proteins with the ability to interfere and modulate Nav1&#46;5 function &#40;ankyrin-G&#44; calmodulin&#44; caveolin-3&#44; syntrophin &#945;1&#44; plakophilin-2&#44; Ran guanine nucleotide release factor &#91;MOG1&#93;&#44; glycerol-3-phosphate dehydrogenase 1-like &#91;GPD1L&#93;&#44; fibroblast growth factor homologous factor 1B &#91;FHF-1B&#93; and Nedd4-like ubiquitin ligases&#44; among others&#41; that integrate a macromolecular complex &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">5&#44;6&#44;18&#44;20&#44;21&#44;24&#44;25</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">The role of sodium channels in heart excitability</span><p id="par0260" class="elsevierStylePara elsevierViewall">The heart AP is generated by depolarizing &#40;I<span class="elsevierStyleInf">Na</span>&#59; I<span class="elsevierStyleInf">Ca</span>&#41; and re-polarizing &#40;I<span class="elsevierStyleInf">K</span>&#41; ion currents&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">22</span></a> NaC play an essential role in AP initiation through the generation of I<span class="elsevierStyleInf">Na</span>&#44; and they are expressed in the membrane of atrial and ventricular cardiomyocytes and in specialized conduction tissue&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">21&#8211;23</span></a> However&#44; although their expression is abundant in the bundle of His&#44; bundle branches and Purkinje fibers&#44; their expression is low or absent in the sinus and atrioventricular nodes&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">6&#44;21</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">In the ventricular myocardium&#44; during diastole&#44; the transmembrane electrical potential &#40;at rest&#41; is approximately -85 mV&#44; and the NaC are closed&#46; When a stimulus depolarizes the membrane&#44; the S4 segments of the four domains move simultaneously outside&#44; the channel opens and there is Na<span class="elsevierStyleSup">&#43;</span> movement to the intracellular medium&#44; according to the electrochemical gradient&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">5&#44;6&#44;18&#44;22</span></a> In addition&#44; I<span class="elsevierStyleInf">Na</span>&#44; the main agent responsible for the rapid AP depolarization phase &#40;phase 0&#41;&#44; is thus generated and then rapidly increases until it reaches its peak &#40;I<span class="elsevierStyleInf">Na</span><span class="elsevierStyleInf">peak</span>&#41; and decreases milliseconds later&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">18&#44;23</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">In NaC inactivation&#44; the loop between domains III and IV &#40;inactivation gate&#41; works as a &#8220;lid&#8221; and the channels gradually close in about 1 ms&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">18&#44;26</span></a> It should be noted that the NaC undergo various conformational changes that translate into different inactivation states &#40;rapid&#44; intermediate and slow inactivation&#41; which&#44; in turn&#44; have different recovery times&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">18&#44;22</span></a> However&#44; at the end of phase 0&#44; the majority &#40;&#8776;99&#37;&#41; of the NaC are inactivated&#44; precluding ion traffic&#46; They remain like this until the cell membrane is repolarized&#44; when they recover from inactivation and again become available to be activated during phase 4&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">5&#44;18</span></a></p><p id="par0275" class="elsevierStylePara elsevierViewall">Nevertheless&#44; during AP phase 2&#44; a small fraction of the NaC &#40;&#60;1&#37; of the total NaC available&#41; may maintain conductibility for Na<span class="elsevierStyleSup">&#43;</span> and reopen&#44; and thus a small I<span class="elsevierStyleInf">Na</span> called late current persists &#40;I<span class="elsevierStyleInf">Na</span><span class="elsevierStyleInf">late</span>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">5&#44;18&#44;27</span></a> Moreover&#44; some channels may reactivate during the repolarization phase &#40;phase 3&#41;&#44; when inactivation is not yet completed but the AP enables their reactivation&#44; generating a current called window current&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">18&#44;22</span></a> This current corresponds to less than 1&#37; of the sodium current peak&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">22</span></a> An important role in the ventricular arrhythmogenesis present in certain cardiac pathologies&#44; some of them covered in this review&#44; has been attributed to these two currents&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">5&#44;18&#44;22&#44;27</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">Under physiological conditions&#44; the NaC activation and inactivation processes are strictly regulated in order to ensure normal cardiac electrical activity&#46; Anomalies in the NaC cause significant abnormalities in heart electrophysiology and potentiate arrhythmogenesis&#44; which may result from alterations in gating properties or in I<span class="elsevierStyleInf">Na</span> kinetics&#46; These alterations change channel availability&#44; the amplitude of the I<span class="elsevierStyleInf">Na</span><span class="elsevierStyleInf">peak</span> or prevent adequate channel inactivation&#44; with maintenance of a persistent I<span class="elsevierStyleInf">Na</span> during the AP plateau&#46; Therefore&#44; the importance of the NaC in heart excitability is emphasized by the occurrence of potentially fatal arrhythmias &#40;e&#46;g&#46;&#44; ventricular tachycardia and VF&#41; in the presence of hereditary or acquired dysfunction in these channels&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">18&#44;21&#44;22</span></a></p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Mutations in sodium channels</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Mutations in subunit &#945;</span><p id="par0285" class="elsevierStylePara elsevierViewall">In the last few decades&#44; the knowledge about the function of the SNC5A gene at the molecular and electrophysiological level has greatly increased&#44; and various genetic studies show that mutations in this gene are associated with many heart diseases&#44; namely hereditary cardiac arrhythmias&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">1&#44;5&#44;16&#44;18&#44;21&#44;22&#44;28</span></a> In most cases&#44; the pathologies associated with NaC mutations are caused by mutations that alter channel permeability or the gating process&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">6&#44;21</span></a></p><p id="par0290" class="elsevierStylePara elsevierViewall">Mutations in the SCN5A gene leading to dysfunction of the Nav1&#46;5 NaC may be due to gain of function&#44; loss of function or both&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">7&#44;18</span></a></p><p id="par0295" class="elsevierStylePara elsevierViewall">The loss-of-function mutations result in decreased I<span class="elsevierStyleInf">Na</span> and are associated with BrS&#44; sinus node disease &#40;SND&#41;&#44; atrial fibrillation &#40;AF&#41;&#44; Lev-Len&#233;gre disease and dilated cardiomyopathy &#40;DCM&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">7&#44;18</span></a> The mechanism most frequently involved is decreased I<span class="elsevierStyleInf">Na</span><span class="elsevierStyleInf">peak</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">7&#44;18&#44;23</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0300" class="elsevierStylePara elsevierViewall">Gain-of-function mutations result in increased I<span class="elsevierStyleInf">Na</span> and are associated with LQTS3 &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#41;&#46; There are also some gain-of-function mutations associated with AF and DCM&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">7&#44;18</span></a> The most frequently involved mechanism consists of increased I<span class="elsevierStyleInf">Na</span><span class="elsevierStyleInf">late</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">7&#44;18&#44;23</span></a> However&#44; there are other mechanisms such as increased I<span class="elsevierStyleInf">Na</span> peak&#44; decreased inactivation rate or increased window current &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">18&#44;22</span></a></p><p id="par0305" class="elsevierStylePara elsevierViewall">Rarely&#44; the mutations may simultaneously cause reduced I<span class="elsevierStyleInf">Na</span><span class="elsevierStyleInf">peak</span> and increased I<span class="elsevierStyleInf">Na</span><span class="elsevierStyleInf">late</span>&#44; occurring with loss and gain of function&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">7&#44;23</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Mutations in &#946; subunits</span><p id="par0310" class="elsevierStylePara elsevierViewall">Mutations in the &#946;1 subunits were identified in patients with BrS&#44; AF and cardiac conduction disease &#40;CCD&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; The mechanism involved in these phenotypes is believed to occur with a decrease in I<span class="elsevierStyleInf">Na</span> density &#40;loss of function&#41;&#46; However&#44; given the limited number of patients with these mutations&#44; the mechanism involved or the genotype-phenotype relationship cannot be completely determined&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">20&#44;23&#44;25</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0315" class="elsevierStylePara elsevierViewall">The prevalence of potentially pathogenic variants of the genes for the &#946; subunits is similar to that of other minor genes involved in BrS&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">29&#44;30</span></a> Indeed&#44; even though in recent years the knowledge of the underlying mechanisms of BrS focuses mainly on the SCN5A gene&#44; the screening of the four &#946; subunits may lead to a potential increase in the genetic diagnosis of the syndrome&#44; up to approximately 5&#46;4&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">30</span></a></p><p id="par0320" class="elsevierStylePara elsevierViewall">Mutations in the &#946;1 and &#946;2 subunits are associated with AF&#44; and the mechanism consists of alterations in gating and decreased I<span class="elsevierStyleInf">Na</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">6&#44;31</span></a> In 2011&#44; Olesen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">32</span></a> described mutations associated with AF&#44; also in the &#946;3 subunit&#46; These mutations decrease I<span class="elsevierStyleInf">Na</span>&#44; increasing the susceptibility for AF through one of two mechanisms&#58; conduction delay or decrease in the refractory period &#40;promoting the possibility of reentry circuits&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">32</span></a> Moreover&#44; mutations in SCN3B are also associated with BrS &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">8&#44;23</span></a></p><p id="par0325" class="elsevierStylePara elsevierViewall">Mutations in &#946;4 subunit have already been described in LQTS10 and confer gain of function&#44; whose most likely mechanism consists of increased I<span class="elsevierStyleInf">Na</span><span class="elsevierStyleInf">late</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">23&#44;25&#44;30&#44;33</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Mutations in proteins associated with sodium channels</span><p id="par0330" class="elsevierStylePara elsevierViewall">The NaC are part of a macromolecular complex that includes various proteins that participate in cell adhesion&#44; signal transduction pathways and the cytoskeleton &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">6&#44;7&#44;11</span></a> These proteins are directly or indirectly bound to the NaC and have the ability to modulate their expression&#44; traffic and function&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">6&#44;19&#44;23</span></a> Therefore&#44; their dysfunction contributes to the pathophysiology of the cardiac channelopathies&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">6&#44;22&#44;23&#44;28</span></a></p><p id="par0335" class="elsevierStylePara elsevierViewall">In fact&#44; mutations in several of these proteins are associated with LQTS or BrS &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">5&#44;22&#44;34&#8211;36</span></a> Caveolin-3 &#40;CAV3&#41; is an important protein in membrane traffic and in the positioning of the ion channels in the sarcoplasmatic membrane&#44; which regulates various ion currents in the heart such as I<span class="elsevierStyleInf">Na</span>&#46; Syntrophin &#945;1 &#40;SNTA1&#41; is a cytoskeleton protein that interacts with the NaC &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#46; Gain-of-function mutations described in CAV3 are associated with LQTS9&#44; whereas those described for SNTA1 are associated with a phenotype similar to LQTS3&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">6&#44;15&#44;22&#44;28&#44;37</span></a> On the other hand&#44; mutations in ankyrin-B&#44; whose function is to bind membrane proteins to cytoskeleton structures &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#44; are associated with LQTS4 and AF&#44; among others&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">15</span></a></p><p id="par0340" class="elsevierStylePara elsevierViewall">Mutations in the GPD1L gene&#44; which encodes the glycerol-3-phosphate dehydrogenase 1-like protein&#44; or in the MOG1 gene&#44; which encodes a molecule that affects protein traffic&#44; have already been described in BrS&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">6&#44;15&#44;23&#44;25</span></a> In addition&#44; mutations in plakophilin-2&#44; a desmosomal protein&#44; may decrease I<span class="elsevierStyleInf">Na</span> and therefore lead to a phenotype similar to BrS&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">15&#44;38&#44;39</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">&#8220;Cardiac&#8221; phenotypes associated with dysfunction in sodium channels and interacting proteins</span><p id="par0345" class="elsevierStylePara elsevierViewall">The numerous &#8220;cardiac&#8221; phenotypes associated with mutations in the genes encoding for the NaC and the proteins that make up its macromolecular complex are described in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#46; The most prevalent cardiac channelopathies are LQTS &#40;1&#58;2500&#41; and BrS &#40;1&#58;3300 to 1&#58;10<span class="elsevierStyleHsp" style=""></span>000&#41;&#44; which are partially associated with NaC dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">12</span></a> Therefore&#44; we will now cover only these two entities&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Brugada syndrome</span><p id="par0350" class="elsevierStylePara elsevierViewall">BrS was first described in 1992 as a syndrome characterized by a typical electrocardiographic pattern&#44; absence of structural heart anomalies and family history of SD&#46; Since then&#44; progress has been made in understanding its pathophysiology and in identifying its genetic basis&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">1&#44;40&#44;41</span></a></p><p id="par0355" class="elsevierStylePara elsevierViewall">BrS is a rare hereditary syndrome with an estimated prevalence of 1&#47;3300 to 1&#47;10<span class="elsevierStyleHsp" style=""></span>000&#44; and ethnic and geographic differences have already been described&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">12&#44;14&#44;42</span></a> It affects relatively young adults &#40;&#60;40 years old&#41;&#44; more frequently males&#44; with a family history of SD in 20-50&#37; of the cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">21&#44;43&#44;44</span></a> Moreover&#44; it is estimated that BrS is responsible for at least 4&#37; of all SD cases and for at least 20&#37; of all SD cases in individuals without structural heart abnormalities&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">8&#44;45</span></a></p><p id="par0360" class="elsevierStylePara elsevierViewall">The absence of structural heart anomalies was classically a characteristic of BrS&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">41</span></a> However&#44; mild structural anomalies in the right and left ventricles have been described in various studies&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">46</span></a></p><p id="par0365" class="elsevierStylePara elsevierViewall">Most individuals are asymptomatic at the time of diagnosis&#44; which is made following a routine ECG in approximately 58&#37; of cases or as a result of family screening in approximately 37&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">44</span></a> However&#44; SCD may be the first sign of the disease since these individuals are at increased risk for developing tachyarrhythmias&#44; namely PVT and VF&#46;<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">22&#44;47</span></a></p><p id="par0370" class="elsevierStylePara elsevierViewall">It is estimated that the rate of arrhythmia events per year in symptomatic individuals is about 0&#46;5&#37;&#44; occurring more frequently at rest and while sleeping&#44; but also in the presence of fever or after a heavy meal&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">1&#44;44&#44;48</span></a> In fact&#44; fever is one of the factors that may cause or exacerbate the electrocardiographic pattern of BrS&#44; triggering potentially fatal arrhythmias in about 27&#37; of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">21&#44;49</span></a></p><p id="par0375" class="elsevierStylePara elsevierViewall">Diagnosis is made using clinical criteria&#44; presence of a typical pattern of electrocardiographic abnormalities and exclusion of other etiologies that may mimic BrS&#44; namely because they trigger ST-segment elevation &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0615"><span class="elsevierStyleSup">45&#44;50&#44;51</span></a> Provocation tests with NaC-blocking agents &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41; may be performed to provoke the electrocardiographic abnormalities seen in BrS &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Figure 5</a>&#41;&#44; which enables diagnosing those individuals with transient electrocardiographic pattern&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">14&#44;41&#44;45&#44;52</span></a> In these cases&#44; Holter may also be used and&#44; through prolonged monitoring&#44; it may enable diagnosing intermittent abnormalities&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">1</span></a></p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0380" class="elsevierStylePara elsevierViewall">Genetic tests &#40;broad or specific for the SCN5A gene&#41; may also be useful for diagnosis in any case where there is strong clinical suspicion of BrS according to the family and medical history and the ECG&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">53</span></a> It should be noted that after identifying a pathogenic mutation in a BrS <span class="elsevierStyleItalic">case index</span>&#44; specific genetic screening of family members is indicated&#46;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">53&#44;54</span></a></p><p id="par0385" class="elsevierStylePara elsevierViewall">BrS presents high genetic complexity and there are various genes that may be mutated in this syndrome&#44; although only a few are associated with abnormalities in I<span class="elsevierStyleInf">Na</span> &#40;<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">43&#44;54&#44;55</span></a> As of today&#44; more than 300 mutations reducing I<span class="elsevierStyleInf">Na</span> amplitude through different mechanisms have been described&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">16&#44;43&#44;54&#44;56</span></a> The mutations occur more frequently in the SCN5A gene&#44; and usually occur in transmembrane segments S1-S4 and in the segments involved in pore formation &#40;S5-S6&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">16&#44;55</span></a> However&#44; only a few &#40;approximately 10-30&#37;&#41; of the total number of individuals diagnosed with BrS are positive for a mutation in this gene&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">21&#44;43&#44;56&#8211;58</span></a> Other genes &#40;<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>&#41; are involved in fewer than 5&#37; of the cases&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">55</span></a></p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><p id="par0390" class="elsevierStylePara elsevierViewall">In fact&#44; only 30-35&#37; of the individuals with a clinical diagnosis have a genetic diagnosis as well &#40;positive genotype&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">8</span></a> Therefore&#44; the majority of the individuals affected &#40;approximately 65&#37;&#41; remains genetically undetermined &#40;negative genotype&#41; and for this reason identifying new susceptibility genes for BrS is necessary&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">16&#44;56&#44;59</span></a></p><p id="par0395" class="elsevierStylePara elsevierViewall">Recently&#44; the SCN10A gene was identified as a susceptibility gene for BrS&#44; although its real prevalence has yet to be determined&#46;<a class="elsevierStyleCrossRefs" href="#bib0670"><span class="elsevierStyleSup">56&#44;60</span></a> The expression level and function of the Nav1&#46;8 NaC in the heart are still controversial&#46; However&#44; a study published in 2014 shows that the variants of this gene influence the duration of the PR and QRS interval&#44; heart rate &#40;HR&#41; and also the risk of arrhythmias&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">56</span></a></p><p id="par0400" class="elsevierStylePara elsevierViewall">A few recessive forms with homozygous or compound heterozygous mutations have been described&#44; but most of the known pathogenic mutations in the SCN5A gene present an autosomal dominant transmission pattern with variable&#44; and frequently incomplete&#44; penetrance&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">18&#44;43&#44;45</span></a></p><p id="par0405" class="elsevierStylePara elsevierViewall">The mechanism most frequently implicated is decreased I<span class="elsevierStyleInf">Na</span><span class="elsevierStyleInf">peak</span> due to mutations in the SCN5A gene &#40;loss of function&#41; and consequent slowing of cardiac conduction &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">7&#44;18&#44;60&#44;61</span></a> Nevertheless&#44; there are many hypotheses for the pathophysiological mechanisms of BrS that involve depolarization and repolarization abnormalities&#59; however&#44; the latter are not covered in this article&#46;<a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">40&#44;51&#44;54</span></a></p><p id="par0410" class="elsevierStylePara elsevierViewall">The genotype of individuals with BrS does not currently carry relevant implications for prognosis or treatment &#40;<a class="elsevierStyleCrossRef" href="#tbl0035">Table 7</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">9</span></a> Nonetheless&#44; its influence in the risk of arrhythmia and in prognosis is still under debate&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">54</span></a> In reality&#44; genetic data may constitute a complementary tool for risk stratification&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">43&#44;61</span></a> Nonsense mutations&#44; which result in truncated proteins&#44; have been associated with a poorer prognosis compared with other types of mutations with less marked repercussions in NaC function&#46;<a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">40&#44;43&#44;59&#44;61</span></a> A retrospective study published in 2009 shows that the phenotype is more severe in individuals with mutations associated with more significant I<span class="elsevierStyleInf">Na</span> reductions compared with individuals with mutations associated with lower reductions&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">61</span></a> The same is seen when the mutation is located in a transmembrane region of the NaC&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">61</span></a> Another study published in 2013 shows that different mutations in the SCN5A gene have a different impact on I<span class="elsevierStyleInf">Na</span>&#44; emphasizing the role of mutation characterization in the risk assessment for nonaffected family members&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">62</span></a> However&#44; it is still not clear to what extent different mutations confer a risk for arrhythmia events or SCD&#44; thus the risk is currently stratified only with clinical parameters&#46;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">53&#44;54</span></a></p><elsevierMultimedia ident="tbl0035"></elsevierMultimedia><p id="par0415" class="elsevierStylePara elsevierViewall">The only treatment available proven capable of preventing SCD in patients with BrS was the implementation of an implantable cardioverter defibrillator &#40;ICD&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">1&#44;9&#44;44&#44;46</span></a> This procedure&#44; however&#44; results in a considerable risk of complications&#44; which occur in approximately 9&#37; of patients&#47;year and&#44; although rarely life-threatening&#44; they are psychologically harmful&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">9&#44;54</span></a> Therefore&#44; a careful assessment of risks &#40;namely the risk of arrhythmia&#41; and benefits is a key process in this decision&#46;<a class="elsevierStyleCrossRefs" href="#bib0610"><span class="elsevierStyleSup">44&#44;54</span></a></p><p id="par0420" class="elsevierStylePara elsevierViewall">A 2003 study that included 547 individuals diagnosed with BrS&#44; showing a diagnostic electrocardiographic pattern but no prior &#8220;aborted&#8221; SCD&#44; was conducted with the aim of assessing the prognostic value of clinical&#44; electrocardiographic and electrophysiological variables&#46; The authors observed that the group with lower risk &#40;incidence of events&#58; 0&#46;5&#37;&#41; is characterized by absence of syncope episodes&#44; an electrocardiographic pattern only triggered by antiarrhythmics and absence of arrhythmia during programmed ventricular stimulation &#40;PVS&#41;&#46; However&#44; the group with higher risk &#40;incidence of events&#58; 27&#46;2&#37;&#41; is characterized by prior history of syncope episodes&#44; spontaneously abnormal ECG and presence of arrhythmias induced by PVS&#46; Moreover&#44; individuals with inducibility of arrhythmias in PVS have a six-fold higher risk of SCD or VF during the subsequent two years than those who do not have it&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">63</span></a></p><p id="par0425" class="elsevierStylePara elsevierViewall">Although some are controversial&#44; there are many risk factors for arrhythmia events&#44; and among them&#44; symptoms are one of the most important&#46;<a class="elsevierStyleCrossRefs" href="#bib0600"><span class="elsevierStyleSup">42&#44;46&#44;54&#44;64</span></a> In fact&#44; individuals diagnosed after an &#8220;aborted&#8221; SCD are at the highest risk&#44; and in approximately 60&#37; of these cases there is a new event 10 years after the diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">54</span></a> Individuals with syncope episodes have a rate of arrhythmia events of 1&#46;9&#37;&#47;year&#44; and the simultaneous presence of a type 1 electrocardiographic pattern is associated with a poor prognosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0620"><span class="elsevierStyleSup">46&#44;54</span></a> Additionally there are other electrocardiographic parameters that are associated with a poorer prognosis&#44; for example&#44; presence of QRS-interval fragmentation in the ECG&#44; identified in 30-40&#37; of the patients&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">54</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Long QT syndrome</span><p id="par0430" class="elsevierStylePara elsevierViewall">Congenital LQTS is an arrhythmia syndrome with a genetic&#47;hereditary etiology and incomplete penetrance&#44; whose prevalence in Caucasians is approximately 1&#58;2500&#44; a value much higher than what was previously expected&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">12&#44;13&#44;65</span></a> It represents a heterogeneous group of diseases and&#44; classically&#44; it is divided into two variants&#58; Romano-Ward syndrome and Jervell and Lange-Nielsen syndrome &#40;<a class="elsevierStyleCrossRef" href="#tbl0040">Table 8</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">1&#44;43&#44;65</span></a></p><elsevierMultimedia ident="tbl0040"></elsevierMultimedia><p id="par0435" class="elsevierStylePara elsevierViewall">In 1995 and 1996&#44; the three main genes conferring susceptibility to LQTS were identified&#58; KCNQ1&#44; KCNH2 and SCN5A&#46;<a class="elsevierStyleCrossRefs" href="#bib0720"><span class="elsevierStyleSup">66&#8211;68</span></a> These genes constitute about 75&#37; of the clinically defined LQTS and the remainder collectively represents only 5&#37; of these cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">43&#44;69</span></a> It should be noted that LQTS is associated with abnormalities in sodium currents only for types 3&#44; 9&#44; 10 and 12&#46;<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">22&#44;69</span></a></p><p id="par0440" class="elsevierStylePara elsevierViewall">LQTS is characterized by a delay in ventricular repolarization&#44; which translates echocardiographically as QT interval prolongation &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Figure 6</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">22&#44;65</span></a> The duration of the QT interval depends on NaC inactivation&#44; the alteration of which may trigger arrhythmias&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">26</span></a></p><p id="par0445" class="elsevierStylePara elsevierViewall">Mutations in the SCN5A gene associated with LQTS3 &#40;gain of function&#41; usually affect NaC inactivation&#44; which is slower&#44; unstable or incomplete&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">6&#44;18&#44;22&#44;26</span></a> Consequently&#44; there is an increase in I<span class="elsevierStyleInf">Na</span><span class="elsevierStyleInf">late</span> with prolongation of membrane depolarization and delay in repolarization&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">18&#44;26&#44;65&#44;70</span></a> Other mechanisms potentially involved are&#58; increased window current&#44; slower inactivation and increased I<span class="elsevierStyleInf">Na</span><span class="elsevierStyleInf">peak</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">6&#44;18&#44;22</span></a></p><p id="par0450" class="elsevierStylePara elsevierViewall">The first mutation associated with LQTS3 is found in the loop between domains III and IV&#44; corresponding to the inactivation gate&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">26</span></a> Since then&#44; multiple mutations causing abnormalities in inactivation have been identified and functionally characterized&#46; They may be located at different sites in the NaC structure&#44; namely in the C terminus&#44; to which a relevant function in this process has been attributed&#46;<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">22&#44;26</span></a></p><p id="par0455" class="elsevierStylePara elsevierViewall">Congenital LQTS occurs mainly in young&#44; healthy individuals without concomitant structural heart abnormalities and is associated with an increased risk of syncope and potentially fatal heart arrhythmias such as <span class="elsevierStyleItalic">Torsade de Pointes</span> &#40;TdP&#41;&#44; which degenerates into VF and causes cardiac arrest&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">6&#44;18&#44;66</span></a> In LQTS3 &#40;unlike LQTS1 and LQTS2 &#8211; <a class="elsevierStyleCrossRef" href="#fig0030">Figure 6</a>&#41;&#44; arrhythmias usually occur at rest&#44; particularly while sleeping &#40;low HR&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">6&#44;22&#44;43&#44;70</span></a> It should be noted that I<span class="elsevierStyleInf">Na</span><span class="elsevierStyleInf">late</span> is higher with slower stimulation frequencies&#44; suggesting that the intensity of this current may be a strong factor in determining the occurrence of arrhythmias&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">22</span></a></p><p id="par0460" class="elsevierStylePara elsevierViewall">The first cardiac event &#40;more frequently syncope&#41; usually occurs in adolescents &#40;16&#177;10 years old in LQTS3&#41; and earlier among males&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">9&#44;71</span></a> However&#44; in approximately 5-10&#37; of cases&#44; SCD is the initial event of the disease and&#44; actually&#44; LQTS is one of the main causes of SCD with negative autopsy&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">10&#44;72</span></a></p><p id="par0465" class="elsevierStylePara elsevierViewall">Diagnosis is mainly based on medical history and ECG &#40;<a class="elsevierStyleCrossRefs" href="#fig0030">Figures 6 and 7</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0715"><span class="elsevierStyleSup">65&#44;70</span></a> In ECGs&#44; the QT interval is the most relevant parameter &#40;<a class="elsevierStyleCrossRef" href="#tbl0045">Table 9</a>&#41;&#44; and is measured from the beginning of the QRS complex to the end of the T wave in the DII and V5 or V6 leads&#46;<a class="elsevierStyleCrossRefs" href="#bib0715"><span class="elsevierStyleSup">65&#44;73</span></a> The longest value is used&#44; generally corrected for HR &#40;QTc&#41; with the <span class="elsevierStyleItalic">Bazett formula</span> &#40;despite its limitations for particularly rapid or slow HR&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">1&#44;46&#44;65&#44;73</span></a></p><elsevierMultimedia ident="fig0030"></elsevierMultimedia><elsevierMultimedia ident="fig0035"></elsevierMultimedia><elsevierMultimedia ident="tbl0045"></elsevierMultimedia><p id="par0470" class="elsevierStylePara elsevierViewall">Additionally&#44; secondary causes for QT interval prolongation &#40;acquired LQTS&#41; must be ruled out&#44; for example&#58; drugs&#44; myocardial ischemia&#44; cardiomyopathy&#44; hypokalemia&#44; hypomagnesemia and hypothermia&#44; among others&#46;<a class="elsevierStyleCrossRefs" href="#bib0620"><span class="elsevierStyleSup">46&#44;65</span></a> Once ruled out&#44; the presence of a repetition of a QTc value &#8805;500 ms &#40;or 480-499 ms if conducted after an unexplained syncope episode&#41; in an electrocardiogram is considered to be diagnostic&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">43&#44;46</span></a> However&#44; LQTS types 1&#44; 2 and 3 may occur with normal QTc in the ECG at rest in 36&#37;&#44; 19&#37; and 10&#37; of cases&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">69</span></a></p><p id="par0475" class="elsevierStylePara elsevierViewall">A scoring system considering various clinical and electrocardiographic parameters was created for diagnosis and provides the likelihood for LQTS &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Figure 6</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">43&#44;46&#44;70</span></a> In addition&#44; Holter monitoring and the ECG obtained during an effort test or after adrenaline infusion may be useful in some particular cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">1&#44;46&#44;53&#44;65&#44;69</span></a></p><p id="par0480" class="elsevierStylePara elsevierViewall">Once the diagnosis is made or given the occurrence of unexplained SD in a young individual&#44; first-degree family members must be screened for LQTS&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">1&#44;65&#44;72</span></a> However&#44; LQTS cannot be ruled out in family members with a normal ECG&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">43</span></a> In fact&#44; after identifying a pathogenic mutation in an <span class="elsevierStyleItalic">index case</span>&#44; family members should undergo a genetic test specific for the mutation in question&#44; with the aim of identifying individuals with a normal QT interval&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">43&#44;53</span></a> This is important given the risk of arrhythmias&#44; which is estimated to occur in 10&#37; of asymptomatic carriers&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">1</span></a></p><p id="par0485" class="elsevierStylePara elsevierViewall">Moreover&#44; genetic tests specific for LQTS &#40;broad or specific for the three main genes&#41; are recommended for any patient when there is a strong clinical suspicion of LQTS &#40;based on the medical and family history and the ECG&#41;&#44; or for any asymptomatic patient with QT interval prolongation in the absence of other clinical conditions that may prolong this interval&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">53</span></a> In reality&#44; genetic tests play an important role&#44; not only in the diagnosis of LQTS &#40;namely of asymptomatic carriers&#41; and in ruling out disease for first-degree family members&#44; but also in risk stratification&#44; prognosis and treatment &#40;according to the genotype &#8211; <a class="elsevierStyleCrossRef" href="#fig0035">Figure 7</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">1&#44;43&#44;69&#44;70&#44;72</span></a></p><p id="par0490" class="elsevierStylePara elsevierViewall">Risk stratification takes into account phenotype and genotype and is conducted for all patients with regular clinical assessments &#40;<a class="elsevierStyleCrossRef" href="#fig0035">Figure 7</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0620"><span class="elsevierStyleSup">46&#44;65&#44;70</span></a> Risk varies according to genotype and&#44; additionally&#44; in the most common genetic types&#44; it is influenced by the specific type and location of the mutations&#44; as well as by the degree of dysfunction that they cause&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">43&#44;46</span></a></p><p id="par0495" class="elsevierStylePara elsevierViewall">Priori et al&#46; &#40;2003&#41;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">71</span></a> followed up 647 individuals with mutations in the genes for LQTS types 1&#44; 2 and 3&#44; for an average period of 28 years&#46; The authors found that 42&#37; of the individuals with LQTS3 developed a first cardiac event &#40;occurrence of syncope&#44; cardiac arrest or SCD&#41; before turning 40 years old and before starting treatment&#46; The incidence of cardiac arrest or SCD in patients with LQTS3 was about 16&#37;&#44; and men presented with symptoms earlier than women&#46; However&#44; given the small study sample&#44; no conclusions could be reached about this finding&#46; Additionally&#44; the authors found that the QTc interval of patients with cardiac events was significantly longer than that of asymptomatic patients &#40;LQTS3 subgroup&#58; 523&#177;55 ms vs&#46; 481&#177;38 ms&#44; p&#61;0&#46;003&#41;&#46; They also concluded that only a QTc value higher than 498 ms is associated with a markedly increased likelihood of cardiac events&#46; However&#44; the percentage of individuals in the LQTS3 subgroup with a normal QT interval and carrying a silent mutation was 10&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">71</span></a></p><p id="par0500" class="elsevierStylePara elsevierViewall">The result of the genetic tests is also important in the treatment and counseling of affected individuals and family members &#40;<a class="elsevierStyleCrossRef" href="#fig0035">Figure 7</a>&#59; <a class="elsevierStyleCrossRef" href="#tbl0050">Table 10</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">9&#44;43</span></a> It should be noted&#44; for example&#44; that LQTS1 involves higher risk during physical activity compared with LQTS2 and LQTS3&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">43&#44;74&#44;75</span></a></p><elsevierMultimedia ident="tbl0050"></elsevierMultimedia><p id="par0505" class="elsevierStylePara elsevierViewall">Mexiletine&#44; flecainide or ranolazine constitute &#8220;specific&#8221; therapeutic options for LQTS3 &#40;<a class="elsevierStyleCrossRef" href="#tbl0050">Table 10</a>&#41;&#44; for which &#946;-blockers may not be so effective&#44; since the adrenergic stress in this type is a trigger with less influence&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">1&#44;43&#44;70&#44;76</span></a> Mexiletine may be used as an add-on to &#946;-blockers&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">9&#44;43&#44;46&#44;50</span></a> However&#44; its effect depends on the type of mutation and may not be beneficial for all individuals with LQTS3&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">9&#44;12&#44;70</span></a></p><p id="par0510" class="elsevierStylePara elsevierViewall">In fact&#44; of the three main types of LQTS&#44; type 3 is the one that involves a higher arrhythmia recurrence rate in individuals receiving treatment with &#946;-blockers &#40;10-15&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">70</span></a> This justifies the need for individuals with LQTS3 to undergo other invasive procedures&#44; such as left cardiac sympathetic denervation and&#47;or ICD implantation more frequently &#40;<a class="elsevierStyleCrossRef" href="#tbl0050">Table 10</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">70</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conclusions</span><p id="par0515" class="elsevierStylePara elsevierViewall">Cardiac channelopathies are not common in clinical practice &#40;although they are more common than once thought&#41;&#44; but they have a significant impact on quality of life and survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">1&#44;13</span></a> The clinical approach constitutes a challenge&#44; owing to their high clinical and genetic heterogeneity&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">1&#44;76</span></a></p><p id="par0520" class="elsevierStylePara elsevierViewall">Although they were initially considered to be separate clinical entities with distinct phenotypes&#44; these syndromes may have overlapping clinical and genetic presentations &#40;<a class="elsevierStyleCrossRef" href="#fig0040">Figure 8</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">21</span></a> In fact&#44; in addition to strictly loss- or gain-of-function mutations&#44; there is a wide spectrum of mutations associated with various anomalies with different repercussions in NaC function&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">25</span></a> In some cases&#44; a single mutation in the SCN5A gene may result in multiple rhythm disorders&#44; and various phenotypes may thus coexist in the same family&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">6&#44;25</span></a></p><elsevierMultimedia ident="fig0040"></elsevierMultimedia><p id="par0525" class="elsevierStylePara elsevierViewall">Moreover&#44; some studies have recently reported structural heart anomalies secondary to mutations in this gene &#40;namely DCM&#41;&#44; although the underlying mechanism is unknown&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">6&#44;18&#44;22&#44;77</span></a></p><p id="par0530" class="elsevierStylePara elsevierViewall">The power of the genetic tests to identify mutations is currently 25&#37; for BrS and 80&#37; for LQTS &#40;<a class="elsevierStyleCrossRef" href="#fig0045">Figure 9</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">43&#44;78</span></a> The impact of genetics in clinical approach varies considerably depending on the underlying channelopathies&#44; and is more marked in LQTS&#44; where influence at the level of diagnosis&#44; prognosis and treatment is recognized&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">9&#44;43&#44;78</span></a></p><elsevierMultimedia ident="fig0045"></elsevierMultimedia><p id="par0535" class="elsevierStylePara elsevierViewall">Great progress has been made in understanding the genotype-phenotype relationship and its implications&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">43</span></a> However&#44; despite increased scientific knowledge in this field&#44; the genotype of a considerable number of affected individuals remains undetermined&#44; some mechanisms still need to be clarified and the treatment options currently available are still limited&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">12&#44;18&#44;72</span></a> A better understanding of molecular principles may contribute not only to increasing knowledge of these aspects&#44; but also to developing new specific treatment approaches for the gene or mutation&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">12&#44;43</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflicts of interest</span><p id="par0540" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "identificador" => "xres1005669"
          "titulo" => "Abstract"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "abst0005"
              "titulo" => "Introduction and objectives"
            ]
            1 => array:2 [
              "identificador" => "abst0010"
              "titulo" => "Methods"
            ]
            2 => array:2 [
              "identificador" => "abst0015"
              "titulo" => "Conclusions"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec965455"
          "titulo" => "Keywords"
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        2 => array:3 [
          "identificador" => "xres1005668"
          "titulo" => "Resumo"
          "secciones" => array:3 [
            0 => array:2 [
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              "titulo" => "Introdu&#231;&#227;o e objetivos"
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              "identificador" => "abst0025"
              "titulo" => "M&#233;todos"
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            2 => array:2 [
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              "titulo" => "Conclus&#245;es"
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          "titulo" => "Introduction"
        ]
        5 => array:3 [
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          "titulo" => "Methods"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Structure and function of sodium channels"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "The role of sodium channels in heart excitability"
            ]
          ]
        ]
        6 => array:3 [
          "identificador" => "sec0025"
          "titulo" => "Mutations in sodium channels"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Mutations in subunit &#945;"
            ]
            1 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Mutations in &#946; subunits"
            ]
            2 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Mutations in proteins associated with sodium channels"
            ]
            3 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "&#8220;Cardiac&#8221; phenotypes associated with dysfunction in sodium channels and interacting proteins"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Brugada syndrome"
        ]
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          "identificador" => "sec0055"
          "titulo" => "Long QT syndrome"
        ]
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          "identificador" => "sec0060"
          "titulo" => "Conclusions"
        ]
        10 => array:2 [
          "identificador" => "sec0065"
          "titulo" => "Conflicts of interest"
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          "titulo" => "References"
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      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec965455"
          "palabras" => array:5 [
            0 => "Mutations"
            1 => "Sodium channels"
            2 => "Heart diseases"
            3 => "Heart arrhythmias"
            4 => "Sudden cardiac death"
          ]
        ]
      ]
      "pt" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palavras-chave"
          "identificador" => "xpalclavsec965456"
          "palabras" => array:5 [
            0 => "Muta&#231;&#245;es"
            1 => "Canais de S&#243;dio"
            2 => "Doen&#231;as card&#237;acas"
            3 => "Arritmias card&#237;acas"
            4 => "Morte s&#250;bita card&#237;aca"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The importance of sodium channels for the normal electrical activity of the heart is emphasized by the fact that mutations &#40;inherited or de novo&#41; in genes that encode for these channels or their associated proteins cause arrhythmogenic syndromes such as the Brugada syndrome and the long QT syndrome &#40;LQTS&#41;&#46; The aim of this study is to conduct a review of the literature on the mutations in the sodium channel complex responsible for heart disease and the implications of a close relationship between genetics and the clinical aspects of the main cardiac channelopathies&#44; namely at the level of diagnosis&#44; risk stratification&#44; prognosis&#44; screening of family members and treatment&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The online Pubmed<span class="elsevierStyleSup">&#174;</span> database was used to search for articles published in this field in indexed journals&#46; The <span class="elsevierStyleItalic">MeSH database</span> was used to define the following query&#58; &#8220;Mutation &#91;Mesh&#93; AND Sodium Channels &#91;Mesh&#93; AND Heart Diseases &#91;Mesh&#93;&#8221;&#44; and articles published in the last 15 years&#44; written in English or Portuguese and referring to research in human beings were included&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Conclusions</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">In the past few years&#44; significant advances have been made to clarify the genetic and molecular basis of these syndromes&#46; A greater understanding of the underlying pathophysiological mechanisms showed the importance of the relationship between genotype and phenotype and led to progress in the clinical approach to these patients&#46; However&#44; it is still necessary to improve diagnostic capacity&#44; optimize risk stratification&#44; and develop new specific treatments according to the genotype-phenotype binomial&#46;</p></span>"
        "secciones" => array:3 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction and objectives"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Conclusions"
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      ]
      "pt" => array:3 [
        "titulo" => "Resumo"
        "resumen" => "<span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introdu&#231;&#227;o e objetivos</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">A import&#226;ncia dos canais de s&#243;dio para a normal atividade el&#233;trica do cora&#231;&#227;o &#233; enfatizada pelo facto de as muta&#231;&#245;es &#40;heredit&#225;rias ou de novo&#41; nos genes que codificam esses canais ou as prote&#237;nas a esses associadas provocarem s&#237;ndromes arritmog&#233;nicas como a s&#237;ndrome de Brugada e a s&#237;ndrome do QT longo&#46; O objetivo deste trabalho &#233; proceder a uma revis&#227;o bibliogr&#225;fica sobre as muta&#231;&#245;es no complexo dos canais de s&#243;dio respons&#225;veis por doen&#231;a card&#237;aca e as implica&#231;&#245;es da rela&#231;&#227;o estrita entre a gen&#233;tica e a cl&#237;nica das principais canalopatias card&#237;acas&#44; nomeadamente no n&#237;vel do diagn&#243;stico&#44; da estratifica&#231;&#227;o do risco&#44; do progn&#243;stico&#44; do rastreio de parentes e terap&#234;utica&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">M&#233;todos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Foi usada a base de dados online Pubmed&#174; para pesquisar os artigos publicados nessa &#225;rea&#44; em revistas indexadas&#46; Recorreu-se &#224; <span class="elsevierStyleItalic">MeSH Database</span> para definir a seguinte <span class="elsevierStyleItalic">query</span>&#58; &#8220;Mutation &#91;Mesh&#93; AND Sodium Channels &#91;Mesh&#93; AND Heart Diseases &#91;Mesh&#93;&#8221; e inclu&#237;ram-se artigos publicados nos &#250;ltimos 15 anos&#44; escritos em ingl&#234;s ou portugu&#234;s e referentes &#224; investiga&#231;&#227;o em humanos&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conclus&#245;es</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Nos &#250;ltimos anos&#44; grandes avan&#231;os foram feitos no esclarecimento da base gen&#233;tica e molecular dessas s&#237;ndromes&#46; A maior compreens&#227;o dos mecanismos fisiopatol&#243;gicos subjacentes demonstrou a import&#226;ncia da rela&#231;&#227;o entre o gen&#243;tipo e o fen&#243;tipo e permitiu efetuar progressos na abordagem cl&#237;nica desses pacientes&#46; Todavia&#44; &#233; ainda necess&#225;rio melhorar a capacidade de diagn&#243;stico&#44; aprimorar a estratifica&#231;&#227;o do risco e desenvolver novas terap&#234;uticas espec&#237;ficas de acordo com o bin&#243;mio gen&#243;tipo-fen&#243;tipo&#46;</p></span>"
        "secciones" => array:3 [
          0 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Introdu&#231;&#227;o e objetivos"
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            "identificador" => "abst0025"
            "titulo" => "M&#233;todos"
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            "titulo" => "Conclus&#245;es"
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    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0065">Please cite this article as&#58; Fonseca DJNdO&#44; Silva MJLVd&#46; Canalopatias card&#237;acas&#58; o papel das muta&#231;&#245;es nos canais de s&#243;dio&#46; Rev Port Cardiol&#46; 2018&#59;37&#58;179&#8211;199&#46;</p>"
      ]
    ]
    "nomenclatura" => array:1 [
      0 => array:3 [
        "identificador" => "nom0005"
        "titulo" => "<span class="elsevierStyleSectionTitle" id="sect0055">List of abbreviations</span>"
        "listaDefinicion" => array:1 [
          0 => array:1 [
            "definicion" => array:35 [
              0 => array:2 [
                "termino" => "AF"
                "descripcion" => "<p id="par0005" class="elsevierStylePara elsevierViewall">atrial fibrillation</p>"
              ]
              1 => array:2 [
                "termino" => "AP"
                "descripcion" => "<p id="par0010" class="elsevierStylePara elsevierViewall">action potential</p>"
              ]
              2 => array:2 [
                "termino" => "BrS"
                "descripcion" => "<p id="par0015" class="elsevierStylePara elsevierViewall">Brugada syndrome</p>"
              ]
              3 => array:2 [
                "termino" => "Ca<span class="elsevierStyleSup">2&#43;</span>"
                "descripcion" => "<p id="par0020" class="elsevierStylePara elsevierViewall">calcium ion</p>"
              ]
              4 => array:2 [
                "termino" => "CAV3"
                "descripcion" => "<p id="par0025" class="elsevierStylePara elsevierViewall">caveolin-3</p>"
              ]
              5 => array:2 [
                "termino" => "CCD"
                "descripcion" => "<p id="par0030" class="elsevierStylePara elsevierViewall">cardiac conduction disease</p>"
              ]
              6 => array:2 [
                "termino" => "CPVT"
                "descripcion" => "<p id="par0035" class="elsevierStylePara elsevierViewall">catecholaminergic polymorphic ventricular tachycardia</p>"
              ]
              7 => array:2 [
                "termino" => "DCM"
                "descripcion" => "<p id="par0040" class="elsevierStylePara elsevierViewall">dilated cardiomyopathy</p>"
              ]
              8 => array:2 [
                "termino" => "ECG"
                "descripcion" => "<p id="par0045" class="elsevierStylePara elsevierViewall">electrocardiogram</p>"
              ]
              9 => array:2 [
                "termino" => "EPS"
                "descripcion" => "<p id="par0050" class="elsevierStylePara elsevierViewall">electrophysiological study</p>"
              ]
              10 => array:2 [
                "termino" => "HR"
                "descripcion" => "<p id="par0055" class="elsevierStylePara elsevierViewall">heart rate</p>"
              ]
              11 => array:2 [
                "termino" => "I<span class="elsevierStyleInf">Ca</span>"
                "descripcion" => "<p id="par0060" class="elsevierStylePara elsevierViewall">calcium current</p>"
              ]
              12 => array:2 [
                "termino" => "I<span class="elsevierStyleInf">K</span>"
                "descripcion" => "<p id="par0065" class="elsevierStylePara elsevierViewall">potassium current</p>"
              ]
              13 => array:2 [
                "termino" => "I<span class="elsevierStyleInf">Na</span>"
                "descripcion" => "<p id="par0070" class="elsevierStylePara elsevierViewall">sodium current</p>"
              ]
              14 => array:2 [
                "termino" => "I<span class="elsevierStyleInf">Na late</span>"
                "descripcion" => "<p id="par0075" class="elsevierStylePara elsevierViewall">late&#44; persistent or sustained sodium current</p>"
              ]
              15 => array:2 [
                "termino" => "I<span class="elsevierStyleInf">Na peak</span>"
                "descripcion" => "<p id="par0080" class="elsevierStylePara elsevierViewall">peak sodium current</p>"
              ]
              16 => array:2 [
                "termino" => "K<span class="elsevierStyleSup">&#43;</span>"
                "descripcion" => "<p id="par0085" class="elsevierStylePara elsevierViewall">potassium ion</p>"
              ]
              17 => array:2 [
                "termino" => "LQTS"
                "descripcion" => "<p id="par0090" class="elsevierStylePara elsevierViewall">long QT syndrome</p>"
              ]
              18 => array:2 [
                "termino" => "LQTS1"
                "descripcion" => "<p id="par0095" class="elsevierStylePara elsevierViewall">long QT syndrome type 1</p>"
              ]
              19 => array:2 [
                "termino" => "LQTS2"
                "descripcion" => "<p id="par0100" class="elsevierStylePara elsevierViewall">long QT syndrome type 2</p>"
              ]
              20 => array:2 [
                "termino" => "LQTS3"
                "descripcion" => "<p id="par0105" class="elsevierStylePara elsevierViewall">long QT syndrome type 3</p>"
              ]
              21 => array:2 [
                "termino" => "ms"
                "descripcion" => "<p id="par0110" class="elsevierStylePara elsevierViewall">milliseconds</p>"
              ]
              22 => array:2 [
                "termino" => "Na<span class="elsevierStyleSup">&#43;</span>"
                "descripcion" => "<p id="par0115" class="elsevierStylePara elsevierViewall">sodium ion</p>"
              ]
              23 => array:2 [
                "termino" => "NaC"
                "descripcion" => "<p id="par0120" class="elsevierStylePara elsevierViewall">sodium channels</p>"
              ]
              24 => array:2 [
                "termino" => "PVS"
                "descripcion" => "<p id="par0125" class="elsevierStylePara elsevierViewall">programmed ventricular stimulation</p>"
              ]
              25 => array:2 [
                "termino" => "PVT"
                "descripcion" => "<p id="par0130" class="elsevierStylePara elsevierViewall">polymorphic ventricular tachycardia</p>"
              ]
              26 => array:2 [
                "termino" => "QTc"
                "descripcion" => "<p id="par0135" class="elsevierStylePara elsevierViewall">QT interval corrected for heart rate</p>"
              ]
              27 => array:2 [
                "termino" => "SCD"
                "descripcion" => "<p id="par0140" class="elsevierStylePara elsevierViewall">sudden cardiac death</p>"
              ]
              28 => array:2 [
                "termino" => "SD"
                "descripcion" => "<p id="par0145" class="elsevierStylePara elsevierViewall">sudden death</p>"
              ]
              29 => array:2 [
                "termino" => "SNP"
                "descripcion" => "<p id="par0150" class="elsevierStylePara elsevierViewall">single nucleotide polymorphism</p>"
              ]
              30 => array:2 [
                "termino" => "SNTA1"
                "descripcion" => "<p id="par0155" class="elsevierStylePara elsevierViewall">syntrophin</p>"
              ]
              31 => array:2 [
                "termino" => "SQTS"
                "descripcion" => "<p id="par0160" class="elsevierStylePara elsevierViewall">short QT syndrome</p>"
              ]
              32 => array:2 [
                "termino" => "TdP"
                "descripcion" => "<p id="par0165" class="elsevierStylePara elsevierViewall">Torsade de pointes</p>"
              ]
              33 => array:2 [
                "termino" => "VF"
                "descripcion" => "<p id="par0170" class="elsevierStylePara elsevierViewall">ventricular fibrillation</p>"
              ]
              34 => array:2 [
                "termino" => "VT"
                "descripcion" => "<p id="par0175" class="elsevierStylePara elsevierViewall">ventricular tachycardia</p>"
              ]
            ]
          ]
        ]
      ]
    ]
    "multimedia" => array:19 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Protein macromolecular complex&#44; &#945; subunits and life cycle of the Nav1&#46;5 sodium channels&#46; <span class="elsevierStyleBold">&#40;A&#41;</span> The Nav1&#46;5 channel is part of a macromolecular complex interacting with various proteins such as&#58; &#946; subunits&#44; caveolin-3&#44; MOG1&#44; ankyrin&#44; syntrophin and cytoskeleton&#46; Extracted and adapted from Liu et al&#46; &#40;2014&#41;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">7</span></a> and Amin et al&#46; &#40;2010&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">22</span></a><span class="elsevierStyleBold">&#40;B&#41;</span> The life cycle of Nav1&#46;5 starts in the nucleus&#44; where transcription of the SCN5A gene and the respective regulation by transcription factors &#40;FOXO1&#44; NF-KB and TBX5&#41; occur&#46; However&#44; microRNAs also regulate mRNA levels&#46; In the endoplasmic reticulum proteins are translated and&#44; after appropriate protein folding and assembly&#44; they are transported to the cell membrane &#40;trafficking&#41;&#46; Mutations or splicing variants may lead to a misfolded Nav1&#46;5 protein&#44; which may activate the PERK pathway for downregulation of their mRNA levels&#46; PKA&#44; PKC&#44; oxidative stress &#40;ROS&#41; and metabolic states &#40;NADH and NAD<span class="elsevierStyleSup">&#43;</span>&#41; may modulate channel trafficking&#46; NEDD4 regulates ubiquitin-mediated degradation&#46; Extracted and adapted from Liu et al&#46; &#40;2014&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">7</span></a></p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">CAV3&#58; caveolin-3&#59; FOXO1&#58; forkhead box protein O1&#59; MOG1&#58; Ran guanine nucleotide release factor&#59; NaChIP&#58; Na<span class="elsevierStyleSup">&#43;</span>-channel-interacting protein&#59; NEDD4&#58; E3 ubiquitin-protein ligase NEDD4&#59; NF-&#954;B&#58; nuclear factor NF-&#954;B&#59; PERK&#58; eukaryotic translation initiation factor 2&#945;-kinase 3&#59; PKA&#58; AMPc-dependent protein kinase &#40;protein kinase A&#41;&#59; PKC&#58; protein kinase C&#59; ROS&#58; reactive oxygen species&#59; TBX5&#58; T-box transcription factor TBX5&#46;</p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Clinical phenotypes associated with mutations in Nav1&#46;5 sodium channels&#46;</p> <p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Extracted and adapted from Liu et al&#46; &#40;2014&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">7</span></a></p>"
        ]
      ]
      2 => array:7 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Abnormalities in action potential and sodium currents associated with gain- and loss-of-function mutations in Nav1&#46;5 channels&#46; <span class="elsevierStyleBold">&#40;1A&#41;</span> Gain-of-function mutations are associated with an increase in the duration of the action potential and may trigger arrhythmic events&#46; <span class="elsevierStyleBold">&#40;1B&#41;</span> Various mechanisms may be associated with gain of function in the sodium current&#46; The most common mechanism is increased late sodium current &#40;abnormally sustained increase of INa during the AP phase 2 with prolonged membrane depolarization and delayed repolarization&#41;&#44; which may be due to incomplete or slowed inactivation&#46; Other less common mechanisms are increased window current and increased INa peak &#40;increase in influx of Na<span class="elsevierStyleSup">&#43;</span> in AP phase 0&#41;&#46; <span class="elsevierStyleBold">&#40;1C&#41;</span> The mechanism of sodium current increase more frequently results from incomplete inactivation of the sodium channels &#40;green circles&#41;&#46; <span class="elsevierStyleBold">&#40;1D&#41;</span> In the mechanism of window current increase &#40;green circles&#41;&#44; inactivation occurs in more positive AP states&#44; &#8220;delaying&#8221; and broadening the amplitude of voltages during which NaC may be reactivated&#46; <span class="elsevierStyleBold">&#40;2A&#41;</span> In loss-of-function mutations&#44; decreased peak sodium current decreases the upstroke speed of the AP phase 0&#44; slowing down electrical conduction in the heart&#46;</p> <p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Extracted and adapted from Amin et al&#46; &#40;2010&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">22</span></a></p>"
        ]
      ]
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        "etiqueta" => "Figure 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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            "imagen" => "gr4.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Diagnostic algorithm for Brugada syndrome&#46; There are three patterns of electrocardiographic abnormalities in the right precordial leads &#40;V1-V3&#41;&#46; Type 1 is considered to be diagnostic&#44; unlike types 2 and 3 &#40;in presence of which provocation tests with SCB must be performed&#41;&#46; Other electrocardiographic abnormalities that may be present in BrS are&#58; prolongation of the PR interval and right branch block&#46; A definitive diagnosis is made in presence of type 1 ST-segment elevation in at least one V1-V3 lead and when one of the clinical criteria presented in the figure is met&#46; AMI&#58; acute myocardial infarction&#59; ANS&#58; autonomic nervous system&#59; C&#47;ARVD&#58; cardiomyopathy&#47;arrhythmogenic right ventricular dysplasia&#59; CCB&#58; calcium channel blockers&#59; CNS&#58; central nervous system&#59; ECG&#58; electrocardiogram&#59; LVH&#58; left ventricular hypertrophy&#59; PTE&#58; pulmonary thromboembolism&#59; RV&#58; right ventricle&#59; RVOT&#58; right ventricular outflow tract&#59; SCB&#58; sodium channel blockers&#59; SSRIs&#58; selective serotonin reuptake inhibitors&#59; VF&#58; ventricular fibrillation&#59; VT&#58; ventricular tachycardia&#59; &#946;-blockers&#58; beta blockers&#46; &#42;May unmask genetic susceptibility to BrS&#46;</p> <p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Extracted and adapted from Berne and Brugada &#40;2012&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">51</span></a></p>"
        ]
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        "etiqueta" => "Figure 5"
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        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 2859
            "Ancho" => 2333
            "Tamanyo" => 607751
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Electrocardiographic patterns in BrS&#58; spontaneous <span class="elsevierStyleBold">&#40;1&#41;</span> and after provocation test with ajmaline <span class="elsevierStyleBold">&#40;2&#41;</span>&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "fig0030"
        "etiqueta" => "Figure 6"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr6.jpeg"
            "Alto" => 3472
            "Ancho" => 3167
            "Tamanyo" => 814266
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Long QT syndrome &#8211; main characteristics and diagnostic criteria&#46; <span class="elsevierStyleBold">&#40;B&#41;</span> Scoring system used in the diagnosis of LQTS based on the findings in the electrocardiogram&#44; medical history &#40;symptoms&#41; and family history&#46; QTc is calculated using the Bazett formula&#46; Scoring&#58; &#8804;1 &#8211; low likelihood of LQTS&#59; 1&#46;5 to 3 &#8211; intermediate likelihood of LQTS&#59; &#8805;3&#46;5 &#8211; high likelihood of LQTS&#46; LQTS is diagnosed in individuals with a score &#8805;3&#46;5 in whom there are no secondary causes for QT interval prolongation&#46;</p> <p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">&#9794;&#58; male individuals&#59; &#9792;&#58; female individuals&#59; HR&#58; heart rate&#46;</p> <p id="spar0090" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">&#35;</span>Mutually exclusive&#46; <span class="elsevierStyleSup">¿</span>Both cannot be accounted for in the same family&#46;</p> <p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">&#42;&#42;HR at rest below the 2nd percentile for age&#46;</p> <p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">&#42;&#42;&#42;The low risk associated with exercise in LQTS2 and LQTS3 patients is explained by the fact that both have a normal IK current&#44; stimulated by activation of the sympathetic nervous system&#44; which in turn results in shortening of the ventricular repolarization whenever the heart rate increases&#44; thus avoiding the likelihood of ventricular tachyarrhythmias during exercise&#46;</p> <p id="spar0105" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">&#40;A&#41;</span> Extracted and adapted from Furst and Aziz &#40;2016&#41;<a class="elsevierStyleCrossRef" href="#bib0765"><span class="elsevierStyleSup">75</span></a> and &#42;Schwartz et al&#46; &#40;2001&#41;<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">74</span></a>&#59; <span class="elsevierStyleBold">&#40;B&#41;</span> Extracted and adapted from Schwartz et al&#46; &#40;2013&#41;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">43</span></a>&#59; <span class="elsevierStyleBold">&#40;C&#41;</span> and <span class="elsevierStyleBold">&#40;D&#41;</span> Extracted and adapted from Giudicessi and Ackerman &#40;2013&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">70</span></a></p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "fig0035"
        "etiqueta" => "Figure 7"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr7.jpeg"
            "Alto" => 3738
            "Ancho" => 2917
            "Tamanyo" => 887120
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Diagnostic approach&#44; risk stratification and guidance for the treatment of long QT syndrome&#46;</p> <p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">USV&#58; undetermined significance variant&#46; Extracted and adapted from Giudessi and Ackerman &#40;2013&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">70</span></a></p>"
        ]
      ]
      7 => array:7 [
        "identificador" => "fig0040"
        "etiqueta" => "Figure 8"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr8.jpeg"
            "Alto" => 1690
            "Ancho" => 2505
            "Tamanyo" => 184098
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0120" class="elsevierStyleSimplePara elsevierViewall">Diagram illustrating the overlap between BrS&#44; LQTS&#44; SQTS&#44; SND&#44; ERS and ARVC&#46; The sodium channel macromolecular complex genes are in bold&#46;</p> <p id="spar0125" class="elsevierStyleSimplePara elsevierViewall">ARVC&#58; arrhythmogenic right ventricular cardiomyopathy&#59; ERS&#58; early repolarization syndrome&#59; LQTS&#58; long QT syndrome&#59; SND&#58; sinus node disease&#59; SQTS&#58; short QT syndrome&#46;</p> <p id="spar0130" class="elsevierStyleSimplePara elsevierViewall">Extracted and adapted from Sarquella-Brugada &#40;2016&#41;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">8</span></a> and Fernandez-Falgueras &#40;2017&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">35</span></a></p>"
        ]
      ]
      8 => array:7 [
        "identificador" => "fig0045"
        "etiqueta" => "Figure 9"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr9.jpeg"
            "Alto" => 858
            "Ancho" => 1413
            "Tamanyo" => 48393
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0135" class="elsevierStyleSimplePara elsevierViewall">Cardiac channelopathies&#58; positivity of the genetic tests in individuals clinically diagnosed with BrS and LQTS&#46;</p> <p id="spar0140" class="elsevierStyleSimplePara elsevierViewall">Data presented in the charts from Schwartz and Dagradi &#40;2016&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">78</span></a></p>"
        ]
      ]
      9 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0150" class="elsevierStyleSimplePara elsevierViewall">Extracted and adapted from Mizusawa &#40;2016&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">9</span></a>&#44; <span class="elsevierStyleSup">&#42;</span>Imbrici et al&#46; &#40;2016&#41;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">12</span></a> and Ackerman et al&#46; &#40;2011&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">53</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Pathology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genes &#40;&#37; of involvement&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Prevalence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Hereditary arrhythmias in the absence of structural heart defects</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Brugada syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN5A &#40;20-30&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#58;3300 to 1&#58;10<span class="elsevierStyleHsp" style=""></span>000<span class="elsevierStyleSup">&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Long QT syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNQ1 &#40;30-35&#37;&#41;&#44; KCNH2 &#40;25-30&#37;&#41;&#44; SCN5A &#40;5-10&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#58;2500<span class="elsevierStyleSup">&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Catecholaminergic polymorphic ventricular tachycardia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RYR2 &#40;60-65&#37;&#41;&#44; CASQ2 &#40;&#60;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#58;10<span class="elsevierStyleHsp" style=""></span>000<span class="elsevierStyleSup">&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cardiac conduction disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN5A &#40;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Short QT syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None of the 3 known genes represents &#62;5&#37; of the disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Atrial fibrillation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None of the known genes represents &#62;5&#37; of the disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Hereditary arrhythmias in the presence of structural heart defects</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Right ventricular arrhythmogenic cardiomyopathy&#47;Right ventricular arrhythmogenic dysplasia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PKP2 &#40;25-40&#37;&#41;&#44; DSG2 &#40;5-10&#37;&#41;&#44; DSP &#40;2-12&#37;&#41;&#44; DSC2 &#40;2-7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Dilated cardiomyopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TTN &#40;&#8776;25&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hypertrophic cardiomyopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MYBPC3 &#40;30-40&#37;&#41;&#44; MYH7 &#40;20-30&#37;&#41;&#44; TNNT2 &#40;10&#37;&#41;&#44; TNNI3 &#40;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1702784.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0145" class="elsevierStyleSimplePara elsevierViewall">Main genes associated with hereditary arrhythmias&#46;</p>"
        ]
      ]
      10 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0160" class="elsevierStyleSimplePara elsevierViewall">CNS&#58; central nervous system&#59; PNS&#58; peripheral nervous system&#46;</p><p id="spar0165" class="elsevierStyleSimplePara elsevierViewall">Extracted and adapted from England and Groot &#40;2009&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">19</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Protein&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Tissue with major expression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Chromosome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CNS and PNS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN1A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2q24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CNS and PNS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN2A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2q23-24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CNS and PNS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN3A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2q24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Skeletal muscle&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN4A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17q23-25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Heart&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN5A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3p21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CNS and PNS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN8A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12q13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PNS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN9A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2q24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PNS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN10A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3p21-24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PNS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN11A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3p21-24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nav2&#46;1 &#40;Nax&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Glial cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN6&#47;7A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2q21-23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0155" class="elsevierStyleSimplePara elsevierViewall">Sodium channel &#945; subunits&#46;</p>"
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          "leyenda" => "<p id="spar0175" class="elsevierStyleSimplePara elsevierViewall">&#216;&#58; failure&#59; &#40;&#8593;&#41;&#58; increase&#59; &#40;&#8595;&#41;&#58; decrease&#59; &#40;&#43;&#41;&#58; depolarizing shift&#59; &#40;-&#41;&#58; hyperpolarizing shift&#59; AF&#58; atrial fibrillation&#59; BrS&#58; Brugada syndrome&#59; CCD&#58; cardiac conduction disease&#59; ISDS&#58; infant sudden-death syndrome&#59; LQTS&#58; long QT syndrome&#59; Rec&#46;R&#58; recovery rate&#59; Ref&#46;P&#58; refractory period&#59; RP&#46;ST&#58; ST segment in right precordial leads&#59; SSI&#58; steady state inactivation&#59; VF&#58; ventricular fibrillation&#46;</p><p id="spar0180" class="elsevierStyleSimplePara elsevierViewall">Extracted and adapted from Adsit et al&#46; &#40;2013&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">23</span></a></p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Protein&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Normal effect on I<span class="elsevierStyleInf">Na</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mutations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mutation effect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Phenotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="5" align="left" valign="top">SCN1B</td><td class="td" title="table-entry  " rowspan="5" align="left" valign="top">&#946;1</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> late&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Trp179X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#216;-&#41; Activation&#44; &#40;&#216;-&#41; SSI&#44; &#40;&#216;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BrS&#44; CCD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8593;&#41; Rec&#46;R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">E87Q&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#216;-&#41; Activation&#44; &#40;&#216;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BrS&#44; CCD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">R85H&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41; Activation&#44; SSI&#44; &#40;&#216;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Familial AF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">D153N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#216;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Familial AF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">R214Q&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#216;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BrS&#44; Familial AF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">SCN2B</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">&#946;2</td><td class="td" title="table-entry  " align="left" valign="top">State of sialylation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">R28Q&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41; Activation&#44; &#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Familial AF &#40;&#8593;&#41; PR&#44; &#40;&#8593;&#41; RP&#46;ST&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8593;&#41; Late current&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">R28W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41; SSI&#44; &#40;&#43;&#41; Activation&#44; &#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Familial AF &#40;&#8593;&#41; PR&#44; &#40;&#8593;&#41; RP&#46;ST&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">SCN3B</td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">&#946;3</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span>&#44; &#40;&#8593;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">R6K&#44; L10P and M161T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mixed&#44; &#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&#44; &#40;-&#41; SSI&#44; &#40;&#8595;&#41; Rec&#46;R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Familial AF<br>BrS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rec&#46;R&#44; &#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A130V&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Familial AF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SSI&#44; &#40;&#8593;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">V54G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak &#40;&#8595;&#41; Trafficking&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Idiopathic VF&#44; ISDS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ref&#46;P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">V36M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak &#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> late&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ISDS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">SCN4B</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">&#946;4</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8593;&#41; Speed of AP upstroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">S206L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> late&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ISDS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#43;&#41; SSI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">L179F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8593;&#41; Window current&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">LQTS10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">CAV3</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Caveolin 3</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Scaffolding&#44; &#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> late</td><td class="td" title="table-entry  " align="left" valign="top">F97C&#44; S141R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> late&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">LQTS9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">V14L&#44; T78M and L79R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> late&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ISDS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">GPD1L</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">GPD1L</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> by phosphorylation</td><td class="td" title="table-entry  " align="left" valign="top">A280V&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BrS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">E83K&#44; I124V&#44; R273C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ISDS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">RANGRF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MOG1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8593;&#41; Surface density&#44; &#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">E83D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak<br>&#40;&#8595;&#41; Trafficking&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BrS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">SNTA1</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Syntrophin &#945;1</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Scaffolding</td><td class="td" title="table-entry  " align="left" valign="top">A390V&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> peak&#44; &#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> late&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">LQTS12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">S287R&#44; T372M&#44; G460S&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> peak&#44; &#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> late&#44; &#40;&#43;&#41; SSI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ISDS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0170" class="elsevierStyleSimplePara elsevierViewall">Mutations in proteins of the sodium channel macromolecular complex&#46;</p>"
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        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0190" class="elsevierStyleSimplePara elsevierViewall">AF&#58; atrial fibrillation&#59; AV&#58; atrioventricular&#59; BrS&#58; Brugada syndrome&#59; CCD&#58; cardiac conduction disease&#59; DCM&#58; dilated cardiomyopathy&#59; ISDS&#58; infant sudden death syndrome&#59; LQTS&#58; long QT syndrome&#59; SND&#58; sinus node disease&#46;</p><p id="spar0195" class="elsevierStyleSimplePara elsevierViewall">Extracted and adapted from Wilde and Brugada &#40;2011&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">5</span></a> Remme &#40;2013&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">6</span></a> Abriel &#40;2010&#41;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">15</span></a> and Adsit et al&#46; &#40;2013&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">23</span></a></p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Protein&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Abnormalities in I<span class="elsevierStyleInf">Na</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">&#8220;Cardiac&#8221; phenotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Sodium channel</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="11" align="left" valign="middle"><span class="elsevierStyleHsp" style=""></span>SCN5A</td><td class="td" title="table-entry  " rowspan="11" align="left" valign="middle">Na<span class="elsevierStyleInf">v</span>1&#46;5</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> by different mechanisms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Type 1 BrS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> late&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Type 3 LQTS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> by different mechanisms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CCD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> by different mechanisms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lev-Len&#233;gre disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> by different mechanisms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Congenital AV block&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Atrial standstill&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Different and mismatched molecular phenotypes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Different and mismatched molecular phenotypes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DCM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> late&#47;&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ISDS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Combination of molecular phenotypes present in other clinical entities&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Overlap Syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Proteins of sodium channel macromolecular complex</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>SCN1B</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Subunit &#946;1</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Type 5 BrS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CCD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>SCN2B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Subunit &#946;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="5" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>SCN3B</td><td class="td" title="table-entry  " rowspan="5" align="left" valign="top">Subunit &#946;3</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Type 7 BrS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CCD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&#47;&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> late&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ISDS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Idiopathic VF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>SCN4B</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Subunit &#946;4</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> late&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Type 10 LQTS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> late&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ISDS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>SNTA</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Syntrophin &#945;1</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> late&#47;&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span>peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Type 12 LQTS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> late&#47;&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span>peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ISDS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>RANGRF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MOG1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Type 8 BrS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CAV3</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Caveolin-3</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> late&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Type 9 LQTS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8593;&#41; I<span class="elsevierStyleInf">Na</span> late&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ISDS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>GPD1L</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Glycerol-3-phosphate dehydrogenase 1-like</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Type 2 BrS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#40;&#8595;&#41; I<span class="elsevierStyleInf">Na</span> peak&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ISDS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>PTPH1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tyrosine phosphatase H1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>NEDD4L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nedd4-2&#47;Nedd4-like&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CALM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Calmodulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CAMK2D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Calcium&#47;Calmodulin-dependent protein kinase II delta&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>SAP97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SAP97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>YWHAH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14-3-3-a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>FGF13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">FGF13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>ANK3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ankyrin-G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>ACTN2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Actinin &#945;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>PKP2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Plakophilin-2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Arrhythmogenic cardiomyopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>DSG2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Desmoglein-2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Arrhythmogenic cardiomyopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>TCAP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Telethonin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>ZASP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Z band&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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          "en" => "<p id="spar0185" class="elsevierStyleSimplePara elsevierViewall">&#8220;Cardiac&#8221; phenotypes associated with dysfunction of sodium channels and related proteins&#46;</p>"
        ]
      ]
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        "etiqueta" => "Table 5"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0205" class="elsevierStyleSimplePara elsevierViewall">IV&#58; intravenous&#59; PO&#58; <span class="elsevierStyleItalic">per os</span>&#46;</p><p id="spar0210" class="elsevierStyleSimplePara elsevierViewall">Extracted and adapted from Antzelevitch et al&#46; &#40;2005&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">45</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dose and duration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Route of administration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ajmaline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 mg&#47;kg for 5 minutes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Flecainide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 mg&#47;kg for 10 minutes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">400 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PO&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pilsicainide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 mg&#47;kg for 10 minutes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Procainamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 mg&#47;kg for 10 minutes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0200" class="elsevierStyleSimplePara elsevierViewall">Drugs used in provocation tests to &#8220;unmask&#8221; Brugada syndrome&#46;</p>"
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        "etiqueta" => "Table 6"
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          "leyenda" => "<p id="spar0220" class="elsevierStyleSimplePara elsevierViewall">AD&#58; autosomal dominant&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Phenotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Locus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Protein&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Effect on function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Inheritance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">Sodium channels and associated proteins</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN5A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3p21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nav1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11-28&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN10A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3p22&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nav1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#46;0-16&#46;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN1B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19q13&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Subunit &#946;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN2B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11q23&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Subunit &#946;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN3B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11q24&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Subunit &#946;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GPD1L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3p22&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Glycerol-3-phosphate dehydrogenase 1-like&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RANGRF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17p13&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">MOG1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SLMAP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3p14&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Protein associated with sarcolemma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PKP2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12p11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Plakophilin 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I<span class="elsevierStyleInf">Na</span> deficit<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#35;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">HEY2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6q22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nav1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">Calcium channels</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CACNA1C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12p13&#46;33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#945;1c subunit of voltage-gated L-type calcium channel &#40;Cav1&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#46;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CACNB2B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10p12&#46;33-p12&#46;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#946;2 subunit of voltage-gated L-type calcium channel &#40;Cav &#946;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CACNA2D1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7q21&#46;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#945;2&#47;&#948;1 subunits of voltage-gated calcium channel &#40;Cav&#945;2&#948;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TRPM4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19q13&#46;33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8220;<span class="elsevierStyleItalic">Transient receptor potential cation channel subfamily M member 4</span>&#8221;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">Potassium channels</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCND3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1p13&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Voltage-gated potassium channel subfamily D member 3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNE3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11q13&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Voltage-gated potassium channel subfamily E member 3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNJ8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12p12&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inward rectifier potassium channel 8 sensitive to ATP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">HCN4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15q24&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8220;<span class="elsevierStyleItalic">Potassium&#47;sodium hyperpolarization-activated cyclic nucleotide-gated channel 4</span>&#8221;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNE5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Xq22&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Voltage-gated potassium channel subfamily E &#8220;regulatory &#946;&#8221; subunit 5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">X-linked&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNH2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7q35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Kv11&#46;1&#44; IKr</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1-2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BrS21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ABCC9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12p12&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SUR2A &#40;subunit 2A of the sulfonylurea receptor&#41;&#44; IK-ATP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4-5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "&#35;"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Plakophilin causes I<span class="elsevierStyleInf">Na</span> deficit&#46;</p> <p class="elsevierStyleNotepara" id="npar0010">Extracted and adapted from Sarquella-Brugada-et al&#46; &#40;2016&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">8</span></a> Sieira et al&#46; &#40;2016&#41;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">54</span></a> and Juang and Horie &#40;2016&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">60</span></a></p>"
            ]
          ]
        ]
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          "en" => "<p id="spar0215" class="elsevierStyleSimplePara elsevierViewall">Mutated genes in Brugada syndrome&#46;</p>"
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      ]
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        "etiqueta" => "Table 7"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0235" class="elsevierStyleSimplePara elsevierViewall">BrS&#58; Brugada syndrome&#59; ICD&#58; implantable cardioverter defibrillator&#59; RF&#58; radiofrequency&#59; RPCld&#58; right precordial leads&#59; SCD&#58; sudden cardiac death&#59; VF&#58; ventricular fibrillation&#59; VT&#58; ventricular tachycardia&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">General measures for lifestyle alterations</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Avoid drugs that may induce or worsen ST segment elevation in RPCld&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;Class I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Avoid excessive alcohol consumption&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;Class I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">In presence of fever&#44; promptly medicate with antipyretic drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;Class Ia&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Risk stratification and specific treatment</th></tr><tr title="table-row"><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Symptomatic individuals<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a></th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Asymptomatic individuals</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8220;aborted&#8221; SCD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ICD<br>&#40;Class I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Spontaneous type 1 electrocardiogram &#40;ECG&#41; pattern&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Quinidine<br>&#40;Class IIb&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Documented spontaneous VT&#44; with or without syncope&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ICD<br>&#40;Class I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Spontaneous type 1 ECG pattern &#43; VT&#47;VF induced by EPS</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">ICD<br>&#40;Class IIb&#41;</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Syncope &#43; Spontaneous type 1 ECG pattern&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ICD<br>&#40;Class IIa&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Electrical&#47;arrhythmic storm<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">b</span></a></td><td class="td" title="table-entry  " align="left" valign="top">Isoprenaline<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">c</span></a> &#40;Class IIa&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Type 1 ECG pattern induced by drugs and family history of SCD</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">ICD<br>&#40;Class III&#41;</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Quinidine<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">d</span></a><br>&#40;Class IIa&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Individuals who are eligible for ICD but present a contraindication or refuse ICD and&#47;or present with a history of supraventricular arrhythmias that require treatment</td><td class="td" title="table-entry  " align="left" valign="top">Quinidine<br>&#40;Class IIa&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Individuals diagnosed with BrS and history of electrical&#47;arrhythmic storms or &#40;appropriate&#41; repetition shocks due to ICD</td><td class="td" title="table-entry  " align="left" valign="top">Catheter ablation &#8211; RF<br>&#40;Class IIb&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              "identificador" => "tblfn0015"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">The clinical manifestations associated with BrS may include ventricular fibrillation&#44; &#8220;aborted&#8221; sudden death&#44; syncope&#44; palpitations&#44; chest discomfort and nocturnal agonal breathing&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Defined as more than 2 VT&#47;VF episodes in 24 hours&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0025"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0025">May be useful to suppress electrical&#47;arrhythmic storms&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0030"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0030">May be useful in individuals diagnosed with BrS and history of electrical&#47;arrhythmic storms&#46;</p> <p class="elsevierStyleNotepara" id="npar0035">Adapted from Priori et al&#46; &#40;2013&#41;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">46</span></a> and Steinfurt et al&#46; &#40;2015&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">64</span></a></p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0230" class="elsevierStyleSimplePara elsevierViewall">Recommendations for the treatment of Brugada syndrome&#46;</p>"
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0250" class="elsevierStyleSimplePara elsevierViewall">&#40;-&#41;&#58; loss of function&#59; &#40;&#43;&#41;&#58; gain of function&#59; ATS&#58; Andersen-Tawil syndrome&#59; I<span class="elsevierStyleInf">Ca&#44;L</span>&#58; Ca<span class="elsevierStyleSup">2&#43;</span> currents through voltage-gated type-L calcium channels&#59; I<span class="elsevierStyleInf">K-Ach</span>&#58; K<span class="elsevierStyleSup">&#43;</span> current regulated by acetylcholine receptors&#59; I<span class="elsevierStyleInf">Kl</span>&#58; K<span class="elsevierStyleSup">&#43;</span> entry current&#44; rectifying&#59; I<span class="elsevierStyleInf">Kr</span>&#58; rapid component &#40;internal rectification &#8211; K<span class="elsevierStyleSup">&#43;</span> channels are open when potential is negative and closed when potential is less negative or positive&#41; of the K<span class="elsevierStyleSup">&#43;</span> &#8220;delayed rectifier&#8221; current &#40;I<span class="elsevierStyleInf">Kr</span>&#41;&#59; I<span class="elsevierStyleInf">Ks</span>&#58; slow component of the K<span class="elsevierStyleSup">&#43;</span> &#8220;delayed rectifier&#8221; current &#40;I<span class="elsevierStyleInf">Kr</span>&#41;&#59; I<span class="elsevierStyleInf">Na</span>&#58; voltage-gated Na<span class="elsevierStyleSup">&#43;</span> current&#59; NCX&#58; Na<span class="elsevierStyleSup">&#43;</span>&#47;Ca<span class="elsevierStyleSup">2&#43;</span> exchanger&#59; TS&#58; Timothy syndrome&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Name&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Protein&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Current&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Effect on function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="6" align="left" valign="top"><span class="elsevierStyleItalic">Autosomal dominant inheritance &#40;Romano-Ward&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LQTS1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNQ1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">K<span class="elsevierStyleInf">V</span>7&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I<span class="elsevierStyleInf">Ks</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40-55&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LQTS2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNH2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">K<span class="elsevierStyleInf">V</span>11&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I<span class="elsevierStyleInf">Kr</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30-45&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LQTS3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN5A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Na<span class="elsevierStyleInf">V</span>1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I<span class="elsevierStyleInf">Na</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5-10&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LQTS4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ANKB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ankyrin B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NCX exchanger&#44; ATPase Na<span class="elsevierStyleSup">&#43;</span>&#47;K<span class="elsevierStyleSup">&#43;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LQTS5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNE1<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MinK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I<span class="elsevierStyleInf">Ks</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LQTS6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNE2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MiRP1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I<span class="elsevierStyleInf">Kr</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LQTS7 &#40;ATS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNJ2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Kir2&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I<span class="elsevierStyleInf">Kl</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LQTS8 &#40;TS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CACNA1C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ca<span class="elsevierStyleInf">V</span>1&#46;2&#945;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I<span class="elsevierStyleInf">Ca&#44;L</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LQTS9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CAV3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Caveolin-3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I<span class="elsevierStyleInf">Na</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LQTS10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCN4B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Subunit &#946;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I<span class="elsevierStyleInf">Na</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Very rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LQTS11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AKAP9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yotiao&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I<span class="elsevierStyleInf">Ks</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Very rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LQTS12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SNTA1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Syntrophin-&#945;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I<span class="elsevierStyleInf">Na</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Very rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LQTS13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNJ5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Kir 3&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I<span class="elsevierStyleInf">K-Ach</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Very rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LQTS14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CALM1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Calmodulin 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction of affinity for Ca<span class="elsevierStyleSup">2&#43;</span><a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LQTS15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CALM2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Calmodulin 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction of affinity for Ca<span class="elsevierStyleSup">2&#43;</span><a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="6" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="6" align="left" valign="top"><span class="elsevierStyleItalic">Autosomal recessive inheritance &#40;Jervell and Lange-Nielsen&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>JLN1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNQ1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">K<span class="elsevierStyleInf">V</span>7&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I<span class="elsevierStyleInf">Ks</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>JLN2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KCNE1<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MinK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I<span class="elsevierStyleInf">Ks</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;-&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab1702782.png"
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            0 => array:3 [
              "identificador" => "tblfn0035"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0040">Mutations in the KCNE1 gene may cause Romano-Ward syndrome &#40;autosomal dominant&#59; LQTS5&#41; or&#44; if homozygous or compound heterozygous&#44; Jervell and Lange-Nielsen syndrome &#40;autosomal recessive&#41;&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0040"
              "etiqueta" => "&#42;&#42;"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0045">Calmodulin dysfunction may alter the inactivation of Ca<span class="elsevierStyleSup">2&#43;</span>-gated L-type Ca<span class="elsevierStyleSup">2&#43;</span> channels &#40;increasing the depolarizing current during phase 2 of the action potential&#41;&#44; but some calmodulin mutations may also be associated with an abnormality in the regulation of sodium channels&#46;</p> <p class="elsevierStyleNotepara" id="npar0050">Extracted and adapted from Nakano and Shimizu &#40;2016&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">34</span></a> &#42;&#42;Makita et al&#46; &#40;2014&#41;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">36</span></a> and &#42;Mizusawa &#40;2014&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">69</span></a></p>"
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          "en" => "<p id="spar0245" class="elsevierStyleSimplePara elsevierViewall">Subtypes of congenital LQTS&#46;</p>"
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          "leyenda" => "<p id="spar0265" class="elsevierStyleSimplePara elsevierViewall">&#9794;&#58; male&#59; &#9792;&#58; female&#59; HR&#58; heart rate&#59; RR&#58; RR interval&#46;</p><p id="spar0270" class="elsevierStyleSimplePara elsevierViewall">Extracted and adapted from Goldenberg et al&#46; &#40;2006&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">73</span></a></p>"
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                0 => """
                  <table border="0" frame="\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">QT&#47;RR<span class="elsevierStyleSup">1&#47;2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fridericia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">QT&#47;RR<span class="elsevierStyleSup">1&#47;3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Framingham&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">QT &#43; 0&#46;154 &#40;1 - RR&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hodges&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">QT &#43; 1&#46;75 &#40;HR - 60&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">2 &#8211; Normal&#44; borderline and prolonged QTc values calculated with the Bazett formula</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;440 ms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">440-460 ms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;460 ms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Adult &#40;&#9794;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;430 ms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">430-450 ms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;450 ms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Adult &#40;&#9792;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;450 ms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">450-470 ms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;470 ms&nbsp;\t\t\t\t\t\t\n
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                  <table border="0" frame="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Documented VT&#47;VF&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8220;aborted&#8221; SCD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ICD<br>&#40;Class III&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ICD<br>&#40;Class IIa&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Individuals with a diagnosis of LQTS who present with events during treatment with &#946;-blockers&#47;ICD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">High-risk individuals with a diagnosis of LQTS who refuse ICD or for whom it is contraindicated and&#47;or when &#946;-blockers are not effective in preventing syncope&#47;arrhythmias&#44; are not tolerated&#44; are contraindicated or are refused</td><td class="td" title="table-entry  " align="left" valign="top">LCSD<br>&#40;Class I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Individuals with type 3 LQTS and QTc &#62;500 ms that decrease &#62;40 ms after acute oral test with an SCB</td><td class="td" title="table-entry  " align="left" valign="top">SCB<br>&#40;Class IIa&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0055">Except under special circumstances&#44; the ICD is not indicated in asymptomatic individuals not undergoing treatment with &#946;-blockers&#46;</p> <p class="elsevierStyleNotepara" id="npar0060">Adapted from Priori et al&#46; &#40;2013&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">46</span></a></p>"
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0275" class="elsevierStyleSimplePara elsevierViewall">Recommendations for the treatment of long QT syndrome&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
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          "bibliografiaReferencia" => array:78 [
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            1 => array:3 [
              "identificador" => "bib0400"
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Article information

ISSN: 21742049
Original language: English

DOI:10.1016/j.repce.2017.11.016

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2024 November	20	5	25
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2024 September	88	30	118
2024 August	117	40	157
2024 July	150	41	191
2024 June	82	43	125
2024 May	73	90	163
2024 April	63	41	104
2024 March	95	40	135
2024 February	81	45	126
2024 January	149	30	179
2023 December	88	41	129
2023 November	106	35	141
2023 October	106	29	135
2023 September	98	32	130
2023 August	88	20	108
2023 July	78	27	105
2023 June	67	17	84
2023 May	92	26	118
2023 April	82	25	107
2023 March	100	37	137
2023 February	92	30	122
2023 January	105	38	143
2022 December	107	51	158
2022 November	107	51	158
2022 October	112	50	162
2022 September	61	53	114
2022 August	59	36	95
2022 July	68	55	123
2022 June	85	43	128
2022 May	104	47	151
2022 April	74	44	118
2022 March	88	48	136
2022 February	75	44	119
2022 January	114	37	151
2021 December	62	35	97
2021 November	71	47	118
2021 October	145	82	227
2021 September	62	66	128
2021 August	64	44	108
2021 July	65	64	129
2021 June	66	62	128
2021 May	102	40	142
2021 April	138	136	274
2021 March	111	37	148
2021 February	107	31	138
2021 January	102	53	155
2020 December	80	18	98
2020 November	63	31	94
2020 October	47	37	84
2020 September	82	35	117
2020 August	64	23	87
2020 July	97	20	117
2020 June	85	27	112
2020 May	110	35	145
2020 April	87	25	112
2020 March	136	37	173
2020 February	187	61	248
2020 January	69	11	80
2019 December	95	24	119
2019 November	53	16	69
2019 October	97	17	114
2019 September	228	21	249
2019 August	73	16	89
2019 July	72	11	83
2019 June	96	24	120
2019 May	65	12	77
2019 April	56	21	77
2019 March	100	18	118
2019 February	115	10	125
2019 January	108	13	121
2018 December	100	29	129
2018 November	252	18	270
2018 October	353	33	386
2018 September	62	18	80
2018 August	74	19	93
2018 July	85	19	104
2018 June	85	26	111
2018 May	92	28	120
2018 April	163	50	213
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