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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Brugada syndrome &#40;BrS&#41; was first described as a distinct clinical entity in 1992 by Pedro and Josep Brugada<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">1</span></a>&#46; Considered a primary electrical heart disease&#44; BrS is an inherited cardiac condition electrocardiographically characterized by a distinct coved-type ST segment configuration &#40;type 1&#41; in the right precordial leads in the absence of significant structural heart disease&#44; and typically presents a high risk of sudden cardiac death &#40;SCD&#41; secondary to polymorphic ventricular tachycardia &#40;PVT&#41; and&#47;or ventricular fibrillation &#40;VF&#41;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">2&#44;3</span></a>&#46; It is estimated to be responsible for at least 4&#37; of all sudden deaths and at least 20&#37; of sudden deaths in patients with structurally normal hearts<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">3</span></a>&#46; However&#44; this concept of the structurally normal heart in BrS has been challenged<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">4&#44;5</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The prevalence of BrS with a type 1 electrocardiogram &#40;ECG&#41; in adults is much higher in East Asian countries&#44; where the syndrome is endemic&#44; but in western countries the prevalence is lower<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46; It typically manifests during adulthood and is 8-10 times more prevalent in males than in females<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">3&#44;5</span></a>&#46; Most BrS patients are asymptomatic&#44; representing a majority &#40;around 63&#37;&#41; of newly diagnosed Brugada patients&#46; When present&#44; symptoms include ventricular tachycardia &#40;VT&#41;&#47;VF or aborted SCD&#44; syncope&#44; nocturnal agonal respiration&#44; palpitations&#44; or chest discomfort&#46; Unfortunately&#44; sudden cardiac arrest &#40;SCA&#41; or SCD can be the first manifestation&#44; frequently occurring without any preceding clinical sign<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#8211;8</span></a>&#46; These symptoms and arrhythmic events are more frequently observed at rest and during sleep&#44; typically between 12 am and 6 am&#44; and less frequently during the daytime<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">9</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">BrS displays autosomal dominant inheritance with incomplete penetrance&#46; The <span class="elsevierStyleItalic">SCN5A</span> gene&#44; which codes for the alpha subunit of the cardiac sodium channel Nav1&#46;5&#44; was the first gene found to be linked to BrS<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">10</span></a>&#46; To date&#44; more than 300 <span class="elsevierStyleItalic">SCN5A</span> gene variants related to BrS have been described&#44; accounting for 18-28&#37; of BrS cases&#46; Soon&#44; variants in other genes were found to be related to BrS&#44; now making up a total of 18 genes&#46; Mutations in these genes may result in a loss of function in cardiac sodium &#40;INa&#41; or calcium &#40;ICa&#41; channel currents&#44; or in a gain of function in transient outward &#40;Ito&#41; or adenosine-triphosphate-sensitive &#40;IK-ATP&#41; potassium currents<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The type 1 BrS ECG is often dynamic and sometimes concealed&#44; and may be unmasked during febrile states&#44; due to electrolyte imbalance&#44; or under vagotonic conditions such as at rest or during sleep &#40;but rarely during exercise&#41;&#44; or under the effect of certain agents&#44; such as sodium channel blockers &#40;class IA and IC antiarrhythmic drugs&#41;&#46; These modulating factors may not only induce a type 1 pattern but also predispose to associated malignant ventricular arrhythmias &#40;VAs&#41;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">3&#44;5&#44;11&#8211;15</span></a>&#46; Recently&#44; many other drugs&#44; including antidepressants&#44; antipsychotics&#44; anesthetics&#44; antihistamines and cocaine&#44; have also been implied in the induction of Brugada patterns&#44; which represents a considerable challenge for physicians in clinical practice because of their potential for arrhythmic events<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">16&#8211;19</span></a>&#46; Moreover&#44; not all induced Brugada patterns occur in patients with BrS&#44; existing the possibility for acquired Brugada patterns&#47;syndrome and Brugada phenocopies &#40;BrPs&#41;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;7&#44;16&#8211;20</span></a>&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The purpose of this paper was to review the literature on the modulators &#40;agents and conditions&#41; associated with induced type 1 Brugada pattern&#44; as possible causes of adverse events and arrhythmogenesis&#44; particularly in BrS itself&#44; and to describe some of the possible underlying mechanisms&#46; It also presents some of the confounding factors that could account for an ECG abnormality similar to type 1 Brugada pattern&#44; and discusses the concepts of acquired BrS and BrPs&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="par0035" class="elsevierStylePara elsevierViewall">The survey was conducted by searching the PubMed database for relevant Portuguese- and English-language studies published between January 1&#44; 2012 and December 31&#44; 2016&#44; using the following search terms&#58; &#40;&#40;&#8220;adverse effects&#8221;&#91;Subheading&#93; OR &#8220;acquired&#8221;&#91;All Fields&#93; OR &#8220;induced&#8221;&#91;All Fields&#93; OR &#8220;modulating&#8221;&#91;All Fields&#93; OR &#8220;iatrogenic disease&#8221;&#91;MeSH&#93; OR &#8220;drug-induced&#8221;&#91;All Fields&#93; OR &#8220;fever&#8221;&#91;MeSH&#93; OR &#8220;exercise&#8221;&#91;MeSH&#93; OR &#8220;water-electrolyte imbalance&#8221;&#91;MeSH&#93; OR &#8220;ethanol&#8221;&#91;MeSH&#93; OR &#8220;cocaine&#8221;&#91;MeSH&#93;&#41; AND &#40;&#8220;Brugada Syndrome&#8221;&#91;MeSH&#93; OR &#8220;brugada syndrome&#8221;&#91;All Fields&#93;&#41;&#41; OR &#8220;brugada phenocopy&#8221;&#91;All Fields&#93;&#44; which yielded 359 articles&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">An initial assessment of eligibility was made through titles and abstracts&#46; Potentially relevant articles were retrieved and their full text was reviewed independently by the authors for final decision on inclusion&#46; Unavailable and irrelevant articles were excluded&#46; Additional relevant papers found in the reference lists of the articles retrieved from the initial selection were also included&#46; A total of 93 articles made up the final study&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Brugada phenotype and diagnosis</span><p id="par0045" class="elsevierStylePara elsevierViewall">A pharmacologic challenge with one of the class I antiarrhythmic agents &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; which block INa&#44; may be used as a diagnostic tool for susceptible patients by unmasking the type 1 pattern<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;11&#44;16</span></a>&#46; The 2016 expert consensus on J-wave syndromes<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a> expresses concerns about the potential for overdiagnosis of BrS&#44; particularly in patients displaying a type 1 pattern only after a drug challenge&#44; contrasting with the previous 2013 consensus statement on inherited cardiac arrhythmias<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">6</span></a>&#46; Thus&#44; it is now suggested that development of a type 1 pattern with this test should be considered as probabilistic rather than binary in nature&#46; The same may apply to the interpretation of a genetic test<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">The 2016 consensus report<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a> recommends that only a type 1 &#40;coved-type&#41; ST-segment elevation is considered diagnostic of BrS &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#44; specifically an elevation of &#8805;2<span class="elsevierStyleHsp" style=""></span>mm &#40;0&#46;2<span class="elsevierStyleHsp" style=""></span>mV&#41; in &#8805;1 right precordial leads &#40;V1&#8211;V3&#41; positioned in the 4th&#44; 3rd&#44; or 2nd intercostal space&#46; Type 2 &#40;saddleback-type&#41; is characterized by ST-segment elevation of &#8805;0&#46;5<span class="elsevierStyleHsp" style=""></span>mm &#40;generally &#8805;2<span class="elsevierStyleHsp" style=""></span>mm in V2&#41; in &#8805;1 right precordial lead &#40;V1-V3&#41;&#44; followed by a convex ST&#44; and by a positive T wave in V2 and variable morphology in V1&#46; Type 3 pattern is characterized by either a saddleback or coved appearance with an ST-segment elevation of &#60;1<span class="elsevierStyleHsp" style=""></span>mm&#46; Type 2 or type 3 ST-segment elevation can be used for the diagnosis of BrS only if converted to type 1 with fever or pharmacologic challenge&#46; However&#44; when a type 1 ECG is unmasked using drug challenge&#44; diagnosis of BrS should require that the patient also present with at least one of the following&#58; documented VF or PVT&#44; syncope of probable arrhythmic cause&#44; a family history of SCD at &#60;45 years old with negative autopsy&#44; coved-type ECGs in family members&#44; or nocturnal agonal respiration&#46; A pharmacologic challenge may therefore be useful only when there is clinical suspicion of BrS in the absence of spontaneous type 1 ST-segment elevation&#46; Alternatively&#44; programmed ventricular stimulation inducing VT&#47;VF with one or two premature beats may also support the diagnosis when the above clinical features are present<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">It is recommended that electrocardiographic recordings be obtained in the standard and superior positions for the V1 and V2 leads&#44; because placement in more cranial positions &#40;in the 3rd or 2nd intercostal space&#41; increases the sensitivity of the ECG<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46; An alternative diagnostic tool&#44; the full stomach test&#44; in which ECGs are performed before and after a large meal&#44; has been proposed for diagnosing BrS<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">21</span></a>&#46; It is reasonable to assume that a spontaneous type 1 recorded by Holter at night or after a large meal has more diagnostic and prognostic value than a drug-induced type 1<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The criteria of the Proposed Shanghai BrS Score for the diagnosis of BrS are based on the ECG&#44; clinical history&#44; family history and genetic test results&#44; but this score needs to be validated in further studies<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Differential diagnosis of Brugada syndrome</span><p id="par0065" class="elsevierStylePara elsevierViewall">Other circumstances can produce a type 1 Brugada-like ECG &#40;ST-segment elevation mimicking a type 1 Brugada pattern&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;7&#44;8</span></a>&#46; These are separate clinical entities with different pathophysiologies and prognosis and can thus be interpreted as confounding factors&#59; they should be excluded before the establishment of a definitive diagnosis of BrS<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">3&#44;5&#44;8</span></a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Ionic and cellular mechanisms underlying Brugada syndrome</span><p id="par0070" class="elsevierStylePara elsevierViewall">The pathophysiology of BrS is only partially understood<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">8</span></a>&#46; There are two main theories&#44; the repolarization hypothesis and the depolarization hypothesis<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;22&#44;23</span></a>&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The repolarization theory suggests that a decrease in inward currents &#40;INa and ICa&#41; and&#47;or increase in outward currents &#40;Ito&#41; results in an outward shift in the balance of the ionic currents active at the end of phase 1 of the action potential &#40;AP&#41; in the right ventricular &#40;RV&#41; epicardium&#44; where Ito is prominent&#46; This results in loss of the AP dome and accentuation of the AP notch in the epicardium but not the endocardium&#44; creating a transmural voltage gradient manifested by the characteristic Brugada ST-segment elevation on the ECG and dispersion of repolarization within the epicardium and transmurally&#46; These repolarization abnormalities can precipitate the development of phase 2 reentry &#40;local re-excitation&#41;&#44; which in turn generates closely coupled premature beats as ventricular extrasystoles capable of precipitating PVT&#47;VF<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">23&#44;24</span></a>&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">According to the depolarization theory&#44; conduction slowing and delay&#44; particularly in the right ventricular outflow tract &#40;RVOT&#41;&#44; results in delayed and abnormal depolarization currents that may play a primary role in the pathophysiology and arrhythmic manifestations of the syndrome<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">22&#44;23</span></a>&#46; Mild structural changes&#44; such as increased collagen and fibrosis&#44; and reduced expression of the gap junction protein connexin-43 especially &#40;but not exclusively&#41; in the RVOT&#44; are a part of BrS and could account for the conduction abnormalities and also late potentials<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">4</span></a>&#46; Further evidence supporting delayed depolarization includes the observation of late potentials and low-voltage fragmented electrogram activity in the RVOT and the RV anterior wall&#44; and the beneficial effect of radiofrequency ablation on these epicardial sites of slow conduction in BrS patients<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">4&#44;25</span></a>&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Despite the controversy&#44; these two theories are not necessarily mutually exclusive and may indeed be synergistic<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;26</span></a>&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Agents and conditions associated with induced Brugada electrocardiographic pattern</span><p id="par0090" class="elsevierStylePara elsevierViewall">Certain agents and conditions &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41; may act as modulating factors by influencing and interfering with cardiac ion channel function&#44; unmasking the characteristic Brugada ECG pattern and possibly leading to fatal consequences&#44; particularly in BrS patients&#44; because of already impaired cardiac ion channel function<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">3&#44;5&#44;16&#44;17</span></a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Hyperthermia &#40;fever&#41;</span><p id="par0095" class="elsevierStylePara elsevierViewall">Fever is now recognized as being capable of unmasking BrS by promoting a type I Brugada ECG in susceptible individuals<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">15&#44;27&#8211;35</span></a>&#46; BrS is rarely identified in pediatric patients&#44; but most reported cases are unmasked after febrile episodes<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">29</span></a>&#46; A study by Adler et al&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">30</span></a> reported that type 1 Brugada ECG was 20 times more prevalent among patients with fever than in afebrile patients and that the prevalence of fever-induced BrS was 2&#37;&#46; Rattanawong et al&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">31</span></a> demonstrated an approximately five-fold higher prevalence of BrS in a febrile group compared to an afebrile group&#44; with a prevalence of 4&#37; in patients from endemic areas&#46; Fever has also been reported to trigger VAs<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">32&#8211;36</span></a>&#46; It was also demonstrated by Mizusawa et al&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">32</span></a> that asymptomatic patients with fever-induced type 1 ECG &#40;F-type 1&#41; carry a higher risk of arrhythmic events &#40;0&#46;9&#37;&#47;year&#41;&#44; and conclude that patients with BrS who develop F-type 1 are at risk of arrhythmic events such as SCD&#46; It has been observed that an <span class="elsevierStyleItalic">SCN5A</span> mutation identified in BrS patients leads to a loss of function of the sodium channel current that is accentuated at higher temperatures<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">37</span></a>&#46; Compared with a drug challenge-induced type 1 pattern&#44; an F-type 1 appears to have a more complex mechanism&#46; Alternatively&#44; other as yet unknown factors related to acute infection or increased temperature may be involved<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">32</span></a>&#46; Nevertheless&#44; fever is presumed to accelerate inactivation of INa and to accelerate recovery of Ito from inactivation<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Similarly to fever&#44; hypothermia may also induce or accentuate J waves&#44; probably by slowing activation of ICa&#44; leaving Ito unopposed<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46; However&#44; it seems more likely to provoke Brugada-like ECG abnormalities&#44; mimicking an actual BrS<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;38&#44;39</span></a>&#46; Moreover&#44; the development of arrhythmias in BrS appears to be promoted only by fever&#44; unlike early repolarization syndrome&#44; in which hypothermia appears to induce VA<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46; It is noteworthy that hypothermia can even diminish the manifestation of a BrS ECG pattern when already present<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">40</span></a>&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Drugs</span><p id="par0105" class="elsevierStylePara elsevierViewall">An increasing number of drugs prescribed in routine clinical practice have been reported to induce or unmask the characteristic type 1 BrS pattern&#44; predisposing to malignant VAs<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">16&#8211;19</span></a>&#46; In view of the potential hazardous effects of certain drugs in BrS individuals&#44; Postema et al&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">16</span></a> developed a website &#40;<a href="http://www.brugadadrugs.org/">www&#46;brugadadrugs&#46;org</a>&#41; with the goal of ensuring worldwide accessibility of information on safe drug use in BrS&#46; Two broad categories of agents capable of unmasking a drug-induced type 1 &#40;D-type 1&#41; ECG were defined&#58; one group that have a clear association with malignant VAs&#44; to be avoided by BrS patients &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#44; and another group&#44; preferably to be avoided&#44; for which there is as yet no substantial evidence that these drugs cause malignant arrhythmias as well as the D-type 1 phenotype &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">16</span></a>&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">The mechanisms by which some of these drugs can induce a type 1 ECG and proarrhythmic effects are not yet fully clarified&#46; However&#44; most of them are either confirmed or believed to act through INa blockage&#44; and a few may also act on other cardiac channels&#44; by promoting a decrease in ICa or an increase in Ito currents<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">18&#44;19&#44;41&#8211;56</span></a>&#46; The agents with INa blocking properties most strongly associated with a D-type 1 ECG and with clear evidence of proarrhythmic effects include ajmaline&#44; flecainide&#44; pilsicainide and propafenone &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">16</span></a>&#46; Other antiarrhythmic agents include amiodarone which&#44; although predominantly a potassium blocking agent &#40;class III&#41;&#44; also has INa blocking properties &#40;as a class IA antiarrhythmic drug&#41;&#44; especially in the acute phase of administration<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">42</span></a>&#46; Vernakalant&#44; which acts predominantly as a voltage- and rate-dependent INa blocker&#44; has also recently been associated with Brugada ECG phenotype<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">43</span></a>&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Psychotropic and anesthetic drugs are among the non-cardiac drugs most commonly involved in drug-induced BrS<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">19&#44;41</span></a>&#46; Tricyclic antidepressants &#40;TCAs&#41; have been shown to produce a D-type 1 pattern and even VAs at therapeutic or supratherapeutic doses&#46; TCAs&#44; including amitriptyline&#44; have been reported&#44; among other actions&#44; to block INa&#44; thereby inducing the BrS phenotype&#46; However&#44; they can also potentially inhibit Ito&#44; preventing its development<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">18&#44;19&#44;44</span></a>&#46; Minoura et al&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">44</span></a> demonstrated that amitriptyline has a relatively potent inhibitory effect on INa and little inhibition of Ito at concentrations close to the therapeutic range&#44; thus unmasking type 1 ECG and promoting arrhythmogenesis only in cases of a genetic predisposition&#46; Similarly&#44; blockage of INa by therapeutic as well as supratherapeutic dosages of nortriptyline has been demonstrated to be critical and cause life-threatening arrhythmias when other causes of INa block are also present&#44; such as genetic variants and&#47;or functional factors&#59; the use of nortriptyline in the general population is associated with a 4&#46;6-fold increased risk for SCA<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">45</span></a>&#46; Lithium may also cause potent INa blockade in a dose-dependent manner&#44; inducing a Brugada phenotype even at therapeutic dosages&#46; Selective serotonin reuptake inhibitors at therapeutic or supratherapeutic doses have been implicated in D-type 1 ECG without associated VA&#44; probably by INa blockade&#46; As well as supratherapeutic doses of certain antipsychotics causing a D-type 1 pattern&#44; therapeutic doses of loxapine and trifluoperazine have been associated with VF<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">18&#44;19&#44;41</span></a>&#46; Some antiepileptic agents&#44; including lamotrigine&#44; are also capable of inducing a D-type 1 pattern&#44; presumably acting on cardiac INa as well as the sodium channels in the cerebral cortex<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">19&#44;46</span></a>&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Propofol is a widely used anesthetic agent with few significant side effects&#46; However&#44; at high doses&#44; it may be associated with SCD&#44; in a condition termed propofol infusion syndrome&#44; whose mechanism of arrhythmogenesis is thought to be similar to that responsible for VA in BrS&#44; probably by blocking INa<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">18&#44;19&#44;41&#44;47</span></a>&#46; Procaine&#44; which produces anesthesia by sodium channel blockade&#44; was recently reported to have unmasked BrS and contributed to SCA in a young male individual<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">48</span></a>&#46; Tramadol is a commonly prescribed synthetic opioid analgesic that in overdose may produce INa blockade and a D-type 1 pattern<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">49</span></a>&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">A D-type 1 ECG has also been elicited in patients treated with antihistamines &#40;mainly first-generation&#41;&#46; No associated VAs have been reported with their use in isolation<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">18&#44;19</span></a>&#46; Leiria et al&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">50</span></a> described an interesting case of a 44-year-old man in whom BrS was diagnosed after experiencing a syncopal episode associated with the use of over-the-counter cold medicine &#40;brompheniramine &#43; phenylephrine&#41;&#46; The mechanism by which adrenergic agonists can trigger BrS is not entirely understood&#44; but one hypothesis is a sudden increase in vagal tone once the adrenergic effect has worn off&#46; Alternatively&#44; brompheniramine appears to directly alter the expression of the <span class="elsevierStyleItalic">SCN5A</span> gene and to reduce the INa current<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">50</span></a>&#46; Alcohol intoxication has been shown to induce the Brugada ECG pattern along with VA&#46; The exact mechanism is not clear&#44; but increased parasympathetic nervous activity and inhibition of ICa currents have been proposed as possible underlying causes<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">19&#44;51</span></a>&#46; Similarly&#44; acetylcholine and ergonovine have also been reported to decrease ICa currents and possibly to induce VF in BrS patients<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">52</span></a>&#46; In addition to sympathomimetic actions that can result in acute ischemic events&#44; cocaine has a potent direct blocking effect on INa that&#44; particularly at relatively low doses&#44; can trigger VF in genetically predisposed individuals with BrS<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">19&#44;41&#44;53</span></a>&#46; Cannabis has also been reported to be associated with the Brugada pattern&#46; The mechanisms of this interaction are unclear&#44; but may be related to a late vagotonic effect after cannabis exposure<a class="elsevierStyleCrossRefs" href="#bib0735"><span class="elsevierStyleSup">54&#44;55</span></a>&#46; The Red Bull<span class="elsevierStyleSup">&#174;</span> energy drink was recently reported to have induced SCA with VF in a young individual who was eventually diagnosed with BrS&#46; Red Bull contains taurine&#44; which could suppress INa&#44; ICa and Ito channels&#44; and high levels of caffeine&#44; which could disrupt calcium homeostasis and lead to cytoplasmic calcium overload&#44; thus potentiating VA<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">56</span></a>&#46; Several antianginal drugs may also be associated with a D-type 1 pattern&#44; but evidence is lacking on the existence and nature of this relationship<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">16&#44;18&#44;57</span></a>&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Vagotonic conditions and maneuvers</span><p id="par0130" class="elsevierStylePara elsevierViewall">Vagal tone is recognized as an important factor capable of precipitating VAs in BrS&#44; which explains why VF and SCD are more frequent at night&#44; at rest&#44; and at low levels of physical activity<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">9&#44;12&#8211;14</span></a>&#44; since these situations are related to higher levels of vagal tone and slower heart rates&#46; Specifically&#44; vagal tone is thought to directly inhibit ICa and indirectly increase Ito due to slowing of heart rate&#46; This autonomic modulation of ion channel currents underlying the early phases of the epicardial AP may therefore contribute to the characteristically dynamic ECG in BrS<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;9&#44;12&#8211;14</span></a>&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Large meals have similarly been implicated in unmasking BrS and precipitating VA in BrS patients&#44; some even going so far as to propose that they could play a role in the diagnosis of BrS in suspected cases<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">21&#44;58&#44;59</span></a>&#46; Vel&#225;zquez-Rodr&#237;guez et al&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">58</span></a> recently demonstrated the reproducibility&#44; efficacy and safety of the dextrose-insulin metabolic test in the differential diagnosis of patients with non-diagnostic ECG patterns&#46; The spontaneous J wave and ST-segment elevation seen after meals may reflect changes in autonomic modulation due to a full stomach&#44; with consequent increase in vagal activity&#44; and may also be a consequence of high glucose concentrations and insulin release<a class="elsevierStyleCrossRefs" href="#bib0755"><span class="elsevierStyleSup">58&#44;59</span></a>&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The increase in vagal tone that occurs immediately after exercise appears to be the reason that the Brugada pattern can be seen in BrS patients with exercise&#44; especially early in the recovery phase&#46; Besides worsening ST-segment elevation in BrS&#44; exercise can produce associated VAs&#46; Exercise testing may also be helpful in unmasking BrS<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">14&#44;60&#44;61</span></a>&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Hormones</span><p id="par0145" class="elsevierStylePara elsevierViewall">Apart from insulin as mentioned above&#44; other hormones may also play a role in the manifestation of the Brugada ECG pattern&#44; associated VA and BrS itself&#46; Testosterone is thought to modulate ion currents underlying the epicardial AP notch&#44; possibly by promoting an increase in Ito or a decrease in ICa currents<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;62&#44;63</span></a>&#46; In addition to the presence of a more prominent Ito current in males&#44; higher testosterone levels associated with less visceral fat also appears to have a significant role in the Brugada phenotype and in the male predominance in BrS<a class="elsevierStyleCrossRefs" href="#bib0775"><span class="elsevierStyleSup">62&#44;63</span></a>&#46; Moreover&#44; thyroxine may alter membrane currents&#44; including Ito and ICa&#44; thus contributing to triggering the Brugada pattern and BrS<a class="elsevierStyleCrossRefs" href="#bib0775"><span class="elsevierStyleSup">62&#44;64</span></a>&#46; Recently&#44; Korte et al&#46;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">64</span></a> reported a case of SCA as a presentation of BrS unmasked by a thyroid storm in a young male&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Electrolyte imbalance</span><p id="par0150" class="elsevierStylePara elsevierViewall">It has been speculated that certain electrolyte disturbances can amplify the Ito-mediated AP notch with loss of the AP dome in the epicardium of the RVOT&#44; thereby precipitating the Brugada ECG pattern&#44; and even related VAs in BrS patients<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">3&#44;5&#44;36&#44;65</span></a>&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Hyperkalemia may induce the Brugada pattern by decreasing the resting membrane potential&#44; which inactivates the INa current and leads to a predominantly Ito current that is most pronounced in the RV epicardium&#44; resulting in type 1 Brugada ECG<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">24&#44;65</span></a>&#46; Postema et al&#46;<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">66</span></a> also reported a case of diabetic ketoacidosis with concomitant hyperkalemia that uncovered a typical Brugada pattern&#44; and further pharmacologic challenge in the patient and his son confirmed familial BrS&#46; The concomitant acidosis may also have played an important part because of its similar effect in decreasing INa currents<a class="elsevierStyleCrossRefs" href="#bib0795"><span class="elsevierStyleSup">66&#44;67</span></a>&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Hypokalemia is also known to accentuate the Brugada ECG pattern&#44; possibly by enhancing Ito with an increase in transmural or epicardial dispersion of repolarization in the RV&#44; which may increase the risk for VF in patients with BrS<a class="elsevierStyleCrossRefs" href="#bib0750"><span class="elsevierStyleSup">57&#44;68</span></a>&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Furthermore&#44; hypercalcemia may also unmask the Brugada-type ECG&#44; probably through transmural differences in the magnitude of the AP notch due to an increase in the calcium-activated chloride current and to a reduction of INa and ICa<a class="elsevierStyleCrossRefs" href="#bib0810"><span class="elsevierStyleSup">69&#44;70</span></a>&#46; However&#44; it is unknown whether hypercalcemia-induced J-point elevation increases the risk of VA<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">70</span></a>&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Hyponatremia is believed to diminish the ion gradient and thereby reduce the INa current&#44; leaving Ito unopposed&#44; which may cause loss of the AP dome in the RV epicardium&#46; However&#44; whether induction of the Brugada pattern by severe hyponatremia is associated with increased susceptibility to VA is currently uncertain<a class="elsevierStyleCrossRef" href="#bib0820"><span class="elsevierStyleSup">71</span></a>&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Brugada phenocopies</span><p id="par0175" class="elsevierStylePara elsevierViewall">BrPs are clinical entities that have visually similar or even identical ECG patterns to true congenital BrS but are etiologically distinct&#44; being elicited by a variety of other clinical circumstances<a class="elsevierStyleCrossRefs" href="#bib0750"><span class="elsevierStyleSup">57&#44;72&#44;73</span></a>&#46; The term phenocopy describes a phenotype which is caused by environmental conditions that matches one determined by a gene&#44; and so the absence of any apparent genetic abnormality is central to the concept of BrP&#59; the environmental factors alone are sufficient to result in a BrS pattern rather than unmasking latent BrS<a class="elsevierStyleCrossRefs" href="#bib0750"><span class="elsevierStyleSup">57&#44;73&#8211;75</span></a>&#46; These factors may include myocardial ischemia&#44; hyponatremia&#44; hyperkalemia &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#41;&#44; hypokalemia&#44; hypophosphatemia &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>&#41;&#44; pulmonary embolism&#44; concomitant alcohol and heroin overdose&#44; hypothermia&#44; hypopituitarism&#44; mechanical mediastinal compression&#44; electrocution &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>&#41;&#44; and poor ECG filters&#59; they are categorized by etiology in <a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a><a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">38&#44;73&#8211;87</span></a>&#46; The website <a href="http://www.brugadaphenocopy.com/">www&#46;brugadaphenocopy&#46;com</a> was recently created to establish an online international database of BrP cases to allow for longitudinal follow-up of these conditions and to develop a better understanding of BrP<a class="elsevierStyleCrossRef" href="#bib0835"><span class="elsevierStyleSup">74</span></a>&#46; Notably&#44; a recent report of recurrent hypokalemia demonstrated clinically reproducible BrP&#44; contributing to the evolution of the concept<a class="elsevierStyleCrossRef" href="#bib0860"><span class="elsevierStyleSup">79</span></a>&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><p id="par0180" class="elsevierStylePara elsevierViewall">In order to differentiate BrP from true congenital BrS&#44; the criteria summarized in <a class="elsevierStyleCrossRef" href="#tbl0035">Table 7</a> can be used to assist with recognition and diagnosis of BrP&#46; Unlike in BrS&#44; in BrP there is usually an identifiable and reversible underlying condition&#44; resolution of which is accompanied by prompt normalization of the ECG&#46; Additionally&#44; these patients have low clinical probability for BrS&#44; as indicated by the absence of a documented personal history of SCA or syncope&#44; or family history of SCD&#46; Finally&#44; drug challenge testing is negative&#44; while in BrS patients this tends to be positive<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">73&#44;74</span></a>&#46; The differences in ECG response to drug challenge denote pathophysiological differences between BrP and BrS&#44; suggesting alternative underlying mechanisms with various genetic&#44; structural and environmental interactions that are yet to be elucidated<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">73</span></a>&#46; While high-risk patients with BrS may be candidates for an implantable cardioverter-defibrillator &#40;ICD&#41;&#44; the clinical implications of BrP&#44; and hence the correlation between BrP and malignant VA&#44; remain unknown<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;57&#44;73</span></a>&#46; At this time&#44; the recommended approach for BrP is mainly based on systematic diagnostic procedures &#40;to differentiate BrP from BrS&#41; and resolution of the underlying condition<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">73&#44;74</span></a>&#46;</p><elsevierMultimedia ident="tbl0035"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Discussion and Conclusion</span><p id="par0185" class="elsevierStylePara elsevierViewall">The congenital BrS ECG pattern is often dynamic and concealed&#44; but it can be unmasked&#44; modulated or precipitated by a wide range of agents and conditions&#44; which are summarized in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a><a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">3&#44;5&#44;8</span></a>&#46; Associated malignant VAs can develop under most of these circumstances in BrS patients&#44; because these individuals already have impaired cardiac ion channel function<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">3&#44;5&#44;17</span></a>&#46; This association with VA and SCD is more evident with fever<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">15&#44;32&#8211;36</span></a>&#44; with certain drugs that are indicated to be avoided by BrS patients &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">16</span></a> and energy drinks<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">56</span></a>&#44; under vagotonic conditions<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">9&#44;12&#44;13</span></a> such as a large meal<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">21&#44;58&#44;59</span></a> or the recovery phase of exercise<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">14&#44;60&#44;61</span></a>&#44; with hypertestosteronemia<a class="elsevierStyleCrossRefs" href="#bib0775"><span class="elsevierStyleSup">62&#44;63</span></a> or hyperthyroidism<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">64</span></a>&#44; and possibly with potassium imbalance<a class="elsevierStyleCrossRefs" href="#bib0790"><span class="elsevierStyleSup">65&#8211;68</span></a>&#46; Fever is recognized as a major risk factor in BrS and can even outperform drug challenge in unmasking a type 1 ECG<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;28&#44;32</span></a>&#46; Junttila et al&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">36</span></a> reported that patients presenting with a Brugada ECG during an acute event&#44; including fever&#44; treatment with medication affecting INa&#44; drug overdose or electrolyte imbalances&#44; should be considered to have a higher risk of life-threatening VA and SCD&#44; even in the absence of an <span class="elsevierStyleItalic">SCN5A</span> mutation&#46; It is also plausible that the cardiac electrophysiological mechanisms involved in acidosis and ischemic heart disease may potentiate those of BrS&#44; resulting in increased risk for VA in BrS patients<a class="elsevierStyleCrossRefs" href="#bib0725"><span class="elsevierStyleSup">52&#44;67&#44;88</span></a>&#46; In most of such cases&#44; the type 1 pattern and associated VAs presumably result from induced or exacerbated decrease in inward currents &#40;INa and ICa&#41; or increase in outward currents &#40;Ito or IK-ATP&#41;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">3&#44;5&#44;20</span></a>&#46; There is now a growing consensus that apart from genetic factors&#44; the expression of BrS is also multifactorial&#44; the underlying genetic predisposition being modulated by diverse environmental factors and even morphologic cardiac changes<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">4&#44;5</span></a>&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Equally important&#44; there are also cases of acquired forms of BrS in which&#44; theoretically&#44; an intervention &#40;such as administration of a pharmacologic agent&#41; could have caused a sufficient imbalance of inward and outward currents in the RVOT to induce a Brugada pattern<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">17&#8211;20&#44;75</span></a>&#46; These patients are typically asymptomatic&#44; without a personal or family history of VA&#44; and may test positive on drug challenge&#46; It is not yet established whether this requires an underlying genetic predisposition or actually represents latent BrS<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">18&#44;75</span></a>&#46; However&#44; the susceptibility of these individuals may be due to genetic polymorphisms rather than pathogenic mutations<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">17&#44;75&#44;89</span></a>&#46; Such a genetic predisposition or subclinical form &#40;forme fruste&#41; may result in increased latent ion channel dysfunction that favors induction of a Brugada pattern&#44; particularly when there is a specific combination of stressors and comorbidities&#44; similar to what is observed with acquired long QT syndrome &#40;LQTS&#41;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">17&#44;18&#44;75&#44;90</span></a>&#46; However&#44; the likelihood of arrhythmias is still unclear<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">18&#44;75</span></a>&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">In principle&#44; a risk profile for a D-type 1 pattern and VA could be drawn up based on various factors such as male gender&#44; genetic predisposition and modulating polymorphisms&#44; specific electrolyte disturbances&#44; fever&#44; kidney and liver dysfunction&#44; cardiac comorbidities&#44; the use or excessive doses of specific drugs&#44; electrocardiographic characteristics&#44; and previous arrhythmias<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">17&#44;91</span></a>&#46; Konigstein et al&#46;<a class="elsevierStyleCrossRef" href="#bib0925"><span class="elsevierStyleSup">92</span></a> recently documented that the D-type 1 ECG associated with non-cardiac drugs is seen mostly in adult males&#44; is frequently due to drug toxicity&#44; and develops late after the onset of therapy&#46; However&#44; it would be difficult to apply these data to a specific individual&#44; because of the wide variability in response to a specific drug&#44; and because its possible effects may change over time depending on treatment duration&#44; age&#44; or developing comorbidities&#46; Furthermore&#44; most of the evidence supporting the association with VAs comes from a limited number of case reports&#44; laboratory studies and cohort analyses<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">16&#44;17</span></a>&#46; It would therefore be difficult to predict the likelihood of drug-induced BrS in routine clinical practice<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">17&#44;19&#44;91</span></a>&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Clinical presentation is still the strongest predictor of risk in BrS&#44; and in asymptomatic patients the arrhythmic risk is low &#40;0&#46;5&#37; per year&#41;&#46; Furthermore&#44; asymptomatic patients with a type 1 pattern that only develops following drug challenge have a lower risk of arrhythmic events during follow-up than those with a spontaneous type 1 at diagnosis<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;93</span></a>&#46; Unlike high-risk BrS patients&#44; who may have indication for an ICD&#44; asymptomatic patients with a type 1 pattern only disclosed by drug challenge may be indicated for close follow-up only<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;6</span></a>&#46; The prognosis of asymptomatic patients with a D-type 1 pattern but without a family history of SCD appears to be relatively benign once the offending agent is discontinued<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;18</span></a>&#46; Nevertheless&#44; it may be prudent not to ignore the risk&#44; particularly during exposure to the agent<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">16&#8211;19&#44;36&#44;41&#44;91</span></a>&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">There is considerable debate concerning the appropriate terminology for BrP&#44; mainly because it is very difficult to rule out a genetic predisposition&#46; Antzelevitch et al&#46; have accordingly proposed that these conditions be designated acquired forms of Brugada ECG pattern or BrS&#44; as more in line with the terminology used in LQTS&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a> At this stage&#44; there is a need to clarify the concepts and real significance of acquired Brugada patterns and BrP as clinical entities&#44; especially in terms of arrhythmic risks and prognosis&#44; and to gain a better understanding of their underlying mechanisms and the possible genetic predisposition in the case of acquired BrS&#46; Thus&#44; more systematic&#44; population-based&#44; observational and experimental studies are needed to clarify these concepts and to better differentiate them from each other and from BrS itself&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Nevertheless&#44; in a patient with an induced type 1 Brugada pattern&#44; it seems prudent to proceed with a systematic diagnostic approach&#44; excluding confounding factors &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; identifying possible underlying modulators &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#44; investigating whether the ECG normalizes on resolution of possible environmental factors&#44; investigating personal and family history of symptoms and arrhythmias &#40;including SCD&#41;&#44; performing a drug challenge &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; and possibly undertaking genetic study&#44; including of the patient&#39;s family<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;8&#44;19&#44;73</span></a>&#46; Additionally&#44; distinguishing true BrS from BrP is crucial&#44; because the type 1 pattern in BrS can be transient and indistinguishable from BrP and possibly provoked by the same conditions&#44; such as hyperkalemia<a class="elsevierStyleCrossRefs" href="#bib0795"><span class="elsevierStyleSup">66&#44;72&#8211;74&#44;78</span></a>&#46; Moreover&#44; the propensity for VA in BrS is established&#44; whereas this is not the case for BrP<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">73&#44;74</span></a>&#46; Since the prognosis of BrP may be related to the evolution of the underlying condition<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">73&#44;74</span></a>&#44; and a type 1 Brugada ECG may itself be an indicator of increased risk for arrhythmias<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">17</span></a>&#44; it makes sense to screen for and promptly correct any underlying conditions or possible modulating factors<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;73&#44;74</span></a>&#46; Fever in BrS patients should be treated aggressively with antipyretics&#44; and they should avoid the substances listed in <a class="elsevierStyleCrossRefs" href="#tbl0020">Tables 4 and 5</a> and be familiar with the effects of a large meal&#44; especially after a long fasting period<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;16&#8211;19&#44;59</span></a>&#46; Data on the risks of exercise in BrS are currently too limited to make recommendations concerning exercise<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;60</span></a>&#46; However&#44; it is suggested that BrS patients should avoid vigorous exercise<a class="elsevierStyleCrossRefs" href="#bib0765"><span class="elsevierStyleSup">60&#44;61</span></a>&#46;</p></span></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Brugada syndrome is an inherited cardiac condition with the potential for development of life-threatening arrhythmias in relatively young individuals without significant structural cardiac abnormalities&#46; The condition is characterized by a distinct coved-type ST segment elevation in the right precordial leads &#40;V1-V3&#41;&#46; This hallmark pattern &#40;type 1&#41; is often dynamic and sometimes concealed&#44; and may be unmasked in certain conditions or under the effect of certain agents&#44; which include variation of sympathovagal balance&#44; hormones&#44; metabolic factors and drugs&#46; These factors may not only modulate electrocardiographic morphology and induce the characteristic type 1 pattern&#44; but also predispose to ventricular arrhythmias&#46; The risk of malignant arrhythmias in acute events with induced type 1 pattern may be imminent&#44; particularly if the patient in fact has Brugada syndrome&#46; The physician should be aware of the modulating factors that may underlie a Brugada pattern&#44; and be able to recognize&#44; identify and promptly correct them&#46; The mechanisms responsible for the type 1 pattern and possible associated ventricular arrhythmias induced by these modulating factors have attracted growing attention and interest&#46; Furthermore&#44; not all induced Brugada ECG patterns are observed in patients with Brugada syndrome&#44; existing the possibility for acquired Brugada patterns&#47;syndrome and Brugada phenocopies&#46; This paper reviews the modulating factors associated with induced type 1 pattern as possible causes of arrhythmogenesis&#44; particularly in Brugada syndrome patients&#44; describes some of the probable underlying mechanisms&#44; and discusses the concepts of acquired Brugada syndrome and Brugada phenocopies&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A s&#237;ndrome de Brugada &#233; um dist&#250;rbio card&#237;aco cong&#233;nito com o potencial para o desenvolvimento de arritmias fatais em indiv&#237;duos relativamente jovens sem anomalias estruturais card&#237;acas grosseiras&#46; Essa condi&#231;&#227;o &#233; caracterizada por uma distinta eleva&#231;&#227;o do segmento-ST com concavidade superior &#40;tipo 1&#41; nas deriva&#231;&#245;es precordiais &#40;V1-V3&#41;&#46; Esse peculiar padr&#227;o tipo 1 &#233; frequentemente din&#226;mico e por vezes dissimulado&#44; podendo ser desmascarado em certas condi&#231;&#245;es ou sobre o efeito de alguns agentes que coletivamente envolvem e incluem o equil&#237;brio simpatovagal&#44; hormonas&#44; fatores metab&#243;licos e agentes farmacol&#243;gicos&#46; N&#227;o s&#243; esses fatores podem modular a morfologia eletrocardiogr&#225;fica e induzir o caracter&#237;stico padr&#227;o tipo 1&#44; como tamb&#233;m predispor a arritmias ventriculares&#46; Esse risco de arritmias malignas em eventos agudos pode ser iminente e possivelmente presente&#44; particularmente se o paciente apresentar uma efetiva s&#237;ndrome de Brugada&#46; O cl&#237;nico dever&#225; estar ciente&#44; reconhecer&#44; identificar e prontamente corrigir esses poss&#237;veis fatores modeladores que possam estar subjacentes a um padr&#227;o de Brugada&#46; Os mecanismos respons&#225;veis por esses padr&#245;es induzidos do tipo 1 e poss&#237;veis arritmias ventriculares associadas por esses fatores moduladores t&#234;m igualmente trazido crescente aten&#231;&#227;o e interesse&#46; Ademais&#44; nem todos os padr&#245;es de Brugada induzidos ocorrem em pacientes com s&#237;ndrome de Brugada&#44; existindo a possibilidade para padr&#245;es&#47;s&#237;ndrome adquirida e fenoc&#243;pias de Brugada&#46; Este artigo faz uma revis&#227;o dos fatores moduladores associados ao padr&#227;o tipo 1 induzido&#44; como poss&#237;veis fontes para arritmog&#233;nese&#44; particularmente em pacientes com s&#237;ndrome de Brugada&#44; descreve alguns dos prov&#225;veis mecanismos subjacentes e aborda os conceitos de s&#237;ndrome de Brugada adquirida e fenoc&#243;pias&#46;</p></span>"
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                  \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">Mode of administration&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&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">Intravenous&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 over 5-10 min&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">Intravenous&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 over 10 min&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">Oral &#40;41 hour&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">150-300 mg&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">Intravenous&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 over 5-10 min&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">Intravenous&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 over 5-10 min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Provocative agents used in drug challenge for diagnosis of Brugada syndrome&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
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        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Adapted from Antzelevitch et al&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a> ARVD&#58; arrhythmogenic right ventricular dysplasia&#59; ECG&#58; electrocardiogram&#59; RVOT&#58; right ventricular outflow tract&#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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Acute myocardial ischemia or infarction &#40;especially of the right ventricle&#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">Acute pericarditis&#47;myocarditis&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">ARVD&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">Artifacts secondary to low-pass filtering&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">Atypical right bundle branch 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">Central and autonomic nervous system abnormalities&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">Dissecting aortic aneurysm&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">Duchenne muscular dystrophy&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">Early repolarization &#40;especially in athletes&#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">Friedreich ataxia&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">Hypothermia&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">Mechanical compression of the RVOT &#40;e&#46;g&#46;&#44; by pectus excavatum&#44; mediastinal tumor&#44; hemopericardium&#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">Myotonic dystrophy&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">Post-defibrillation ECG&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">Prinzmetal angina&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">Pulmonary thromboembolism&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">Spinobulbar muscular atrophy&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">Ventricular hypertrophy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Differential diagnosis of Brugada pattern&#46;</p>"
        ]
      ]
      6 => 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" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Adapted from Antzelevitch et al&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a> and www&#46;brugadadrugs&#46;org&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">16</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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Hyperthermia &#40;fever&#41;</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="elsevierStyleItalic">Substances</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>Antiarrhythmic drugs&#58; sodium channel blockers &#40;class IC and IA&#41;&#44; calcium channel blockers&#44; beta-blockers&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>Psychotropic drugs&#58; unicyclic&#47;tricyclic&#47;tetracyclic antidepressants&#44; antipsychotics&#44; selective serotonin reuptake inhibitors&#44; lithium&#44; antiepileptics&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>Anesthetics&#47;analgesics&#58; bupivacaine&#44; procaine&#44; propofol&#44; ketamine&#44; tramadol&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>Others&#58; histamine H1 antagonists&#44; alcohol&#44; cocaine&#44; cannabis&#44; ergonovine&#44; energy drinks&#44; acetylcholine&#44; edrophonium&#44; fexofenadine&#44; indapamide&#44; metoclopramide&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="elsevierStyleItalic">Vagotonic conditions and maneuvers&#58; at night&#47;rest&#44; recovery phase of exercise&#44; large meals</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="elsevierStyleItalic">Hormones&#58; hypertestosteronemia&#44; thyroid storm &#40;hyperthyroidism&#41;&#44; increased insulin level</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="elsevierStyleItalic">Electrolyte abnormalities&#58;</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>Hyperkalemia&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>Hypokalemia&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>Hypercalcemia&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>Hyponatremia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab1624741.png"
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Agents and conditions modulating Brugada syndrome&#46;</p>"
        ]
      ]
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        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
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        "detalles" => array:1 [
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            "identificador" => "at4"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Adapted from www&#46;brugadadrugs&#46;org<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">16</span></a> &#40;last consulted on December 31&#44; 2016&#41;&#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">Category&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">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">Clinical use&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">Antiarrhythmic drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " 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">Class IA antiarrhythmic &#40;Na-blocker&#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  " 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">Allapinin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IC antiarrhythmic &#40;Na-blocker&#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  " 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">Ethacizine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IC antiarrhythmic &#40;Na-blocker&#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  " 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">Flecainide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IC antiarrhythmic &#40;Na-blocker&#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  " 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">Pilsicainide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IC antiarrhythmic &#40;Na-blocker&#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  " 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">Procainamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IA antiarrhythmic &#40;Na-blocker&#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  " 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">Propafenone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IC antiarrhythmic &#40;Na-blocker&#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">Psychotropic drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Amitriptyline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tricyclic antidepressant&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">Clomipramine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tricyclic antidepressant&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">Desipramine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tricyclic antidepressant&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">Lithium&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antidepressant&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">Loxapine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antipsychotic&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">Nortriptyline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tricyclic antidepressant&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">Oxcarbazepine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anti-epileptic&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">Trifluoperazine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antipsychotic &#40;phenothiazine&#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">Anesthetics&#47;analgesics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bupivacaine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anesthetic&#47;analgesic&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">Procaine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Analgesic&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">Propofol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anesthetic&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">Other substances&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acetylcholine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cholinergic&#47;vasospastic intracoronary&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">Alcohol intoxication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Other substances&#47;beverage&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">Cannabis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Other substances&#47;illicit drugs&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">Cocaine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Other substances&#47;illicit drugs&#47;anesthetic&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">Ergonovine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Vasospastic intracoronary&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Agents to be avoided by Brugada syndrome patients &#40;associated with type 1 ECG and related arrhythmias&#41;&#46;</p>"
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        "identificador" => "tbl0025"
        "etiqueta" => "Table 5"
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          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">SSRI&#58; selective serotonin reuptake inhibitor&#46;</p><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Adapted from www&#46;brugadadrugs&#46;org<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">16</span></a> &#40;last consulted on December 31&#44; 2016&#41;&#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">Category&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">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">Clinical use&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">Antiarrhythmic drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Amiodarone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class III antiarrhythmic &#40;also IA&#44; II&#44; and IV effects&#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  " 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">Cibenzoline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IA antiarrhythmic &#40;Na-blocker&#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  " 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">Disopyramide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IA antiarrhythmic &#40;Na-blocker&#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  " 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">Lidocaine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IB antiarrhythmic &#40;Na-blocker&#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  " 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">Propranolol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class II antiarrhythmic &#40;beta-blocker&#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  " 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">Verapamil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IV antiarrhythmic &#40;Ca-blocker&#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  " 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">Vernakalant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class I and III antiarrhythmic&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">Psychotropic drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bupropion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Monocyclic antidepressant&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">Carbamazepine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anticonvulsant&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">Clothiapine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antipsychotic&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">Cyamemazine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antipsychotic &#40;phenothiazine&#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  " 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">Dosulepin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tricyclic antidepressant&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">Doxepin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tricyclic antidepressant&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">Fluoxetine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antidepressant &#40;SSRI&#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  " 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">Fluvoxamine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antidepressant &#40;SSRI&#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  " 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">Imipramine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tricyclic antidepressant&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">Lamotrigine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anti-epileptic&#47;bipolar and depressive disorders&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">Maprotiline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tricyclic antidepressant&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">Paroxetine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antidepressant &#40;SSRI&#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  " 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">Perphenazine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antipsychotic &#40;phenothiazine&#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  " 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">Phenytoin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anticonvulsant&#47;antiarrhythmic&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">Thioridazine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antipsychotic&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">Anesthetics&#47;analgesics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ketamine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anesthetic&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">Tramadol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Narcotic analgesic&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">Other substances&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dimenhydrinate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antiemetic&#47;histamine H1 antagonist&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">Diphenhydramine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Histamine H1 antagonist&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">Edrophonium&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cholinergic&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">Indapamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Diuretic&#47;antihypertensive&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">Metoclopramide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antiemetic&#47;dopamine antagonist&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">Terfenadine&#47;Fexofenadine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antihistamine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Agents preferably avoided by Brugada syndrome patients &#40;associated with type 1 ECG&#44; but without substantial evidence that&#44; apart from inducing the ECG phenotype&#44; they also cause malignant arrhythmias&#41;&#46;</p>"
        ]
      ]
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          "leyenda" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Adapted from Anselm et al&#46;<a class="elsevierStyleCrossRef" href="#bib0895"><span class="elsevierStyleSup">86</span></a></p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Metabolic conditions&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">Mechanical compression&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">Ischemia and pulmonary embolism&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">Myocardial and pericardial disease&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">BrS&#58; Brugada syndrome&#59; ECG&#58; electrocardiographic&#46;</p><p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Adapted from Anselm et al&#46;<a class="elsevierStyleCrossRef" href="#bib0900"><span class="elsevierStyleSup">87</span></a></p><p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">Criteria 1-5 are mandatory&#44; except for criterion 5 if there was surgical manipulation of the right ventricular outflow tract within 96<span class="elsevierStyleHsp" style=""></span>hours of the presenting Brugada ECG pattern&#46;</p>"
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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">3&#46; The ECG pattern resolves after resolution of the underlying condition&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">4&#46; There is a low clinical pretest probability of true BrS determined by lack of symptoms&#44; medical history&#44; and family history&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">5&#46; The results of drug challenge with a sodium channel blocker such as ajmaline&#44; flecainide&#44; pilsicainide or procainamide are negative&nbsp;\t\t\t\t\t\t\n
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Review Article
Induced Brugada syndrome: Possible sources of arrhythmogenesis
Síndrome de Brugada induzida: possíveis fontes de arritmogénese
Gonçalo Toméa,
Autor para correspondência
goncalo.ltcf@gmail.com

Corresponding author.
, João Freitasb
a Universidade do Porto, Faculdade de Medicina, Departamento de Medicina, Porto, Portugal
b Centro Hospitalar de São João EPE, Serviço de Cardiologia, Porto, Portugal
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Brugada syndrome &#40;BrS&#41; was first described as a distinct clinical entity in 1992 by Pedro and Josep Brugada<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">1</span></a>&#46; Considered a primary electrical heart disease&#44; BrS is an inherited cardiac condition electrocardiographically characterized by a distinct coved-type ST segment configuration &#40;type 1&#41; in the right precordial leads in the absence of significant structural heart disease&#44; and typically presents a high risk of sudden cardiac death &#40;SCD&#41; secondary to polymorphic ventricular tachycardia &#40;PVT&#41; and&#47;or ventricular fibrillation &#40;VF&#41;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">2&#44;3</span></a>&#46; It is estimated to be responsible for at least 4&#37; of all sudden deaths and at least 20&#37; of sudden deaths in patients with structurally normal hearts<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">3</span></a>&#46; However&#44; this concept of the structurally normal heart in BrS has been challenged<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">4&#44;5</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The prevalence of BrS with a type 1 electrocardiogram &#40;ECG&#41; in adults is much higher in East Asian countries&#44; where the syndrome is endemic&#44; but in western countries the prevalence is lower<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46; It typically manifests during adulthood and is 8-10 times more prevalent in males than in females<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">3&#44;5</span></a>&#46; Most BrS patients are asymptomatic&#44; representing a majority &#40;around 63&#37;&#41; of newly diagnosed Brugada patients&#46; When present&#44; symptoms include ventricular tachycardia &#40;VT&#41;&#47;VF or aborted SCD&#44; syncope&#44; nocturnal agonal respiration&#44; palpitations&#44; or chest discomfort&#46; Unfortunately&#44; sudden cardiac arrest &#40;SCA&#41; or SCD can be the first manifestation&#44; frequently occurring without any preceding clinical sign<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#8211;8</span></a>&#46; These symptoms and arrhythmic events are more frequently observed at rest and during sleep&#44; typically between 12 am and 6 am&#44; and less frequently during the daytime<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">9</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">BrS displays autosomal dominant inheritance with incomplete penetrance&#46; The <span class="elsevierStyleItalic">SCN5A</span> gene&#44; which codes for the alpha subunit of the cardiac sodium channel Nav1&#46;5&#44; was the first gene found to be linked to BrS<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">10</span></a>&#46; To date&#44; more than 300 <span class="elsevierStyleItalic">SCN5A</span> gene variants related to BrS have been described&#44; accounting for 18-28&#37; of BrS cases&#46; Soon&#44; variants in other genes were found to be related to BrS&#44; now making up a total of 18 genes&#46; Mutations in these genes may result in a loss of function in cardiac sodium &#40;INa&#41; or calcium &#40;ICa&#41; channel currents&#44; or in a gain of function in transient outward &#40;Ito&#41; or adenosine-triphosphate-sensitive &#40;IK-ATP&#41; potassium currents<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The type 1 BrS ECG is often dynamic and sometimes concealed&#44; and may be unmasked during febrile states&#44; due to electrolyte imbalance&#44; or under vagotonic conditions such as at rest or during sleep &#40;but rarely during exercise&#41;&#44; or under the effect of certain agents&#44; such as sodium channel blockers &#40;class IA and IC antiarrhythmic drugs&#41;&#46; These modulating factors may not only induce a type 1 pattern but also predispose to associated malignant ventricular arrhythmias &#40;VAs&#41;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">3&#44;5&#44;11&#8211;15</span></a>&#46; Recently&#44; many other drugs&#44; including antidepressants&#44; antipsychotics&#44; anesthetics&#44; antihistamines and cocaine&#44; have also been implied in the induction of Brugada patterns&#44; which represents a considerable challenge for physicians in clinical practice because of their potential for arrhythmic events<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">16&#8211;19</span></a>&#46; Moreover&#44; not all induced Brugada patterns occur in patients with BrS&#44; existing the possibility for acquired Brugada patterns&#47;syndrome and Brugada phenocopies &#40;BrPs&#41;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;7&#44;16&#8211;20</span></a>&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The purpose of this paper was to review the literature on the modulators &#40;agents and conditions&#41; associated with induced type 1 Brugada pattern&#44; as possible causes of adverse events and arrhythmogenesis&#44; particularly in BrS itself&#44; and to describe some of the possible underlying mechanisms&#46; It also presents some of the confounding factors that could account for an ECG abnormality similar to type 1 Brugada pattern&#44; and discusses the concepts of acquired BrS and BrPs&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="par0035" class="elsevierStylePara elsevierViewall">The survey was conducted by searching the PubMed database for relevant Portuguese- and English-language studies published between January 1&#44; 2012 and December 31&#44; 2016&#44; using the following search terms&#58; &#40;&#40;&#8220;adverse effects&#8221;&#91;Subheading&#93; OR &#8220;acquired&#8221;&#91;All Fields&#93; OR &#8220;induced&#8221;&#91;All Fields&#93; OR &#8220;modulating&#8221;&#91;All Fields&#93; OR &#8220;iatrogenic disease&#8221;&#91;MeSH&#93; OR &#8220;drug-induced&#8221;&#91;All Fields&#93; OR &#8220;fever&#8221;&#91;MeSH&#93; OR &#8220;exercise&#8221;&#91;MeSH&#93; OR &#8220;water-electrolyte imbalance&#8221;&#91;MeSH&#93; OR &#8220;ethanol&#8221;&#91;MeSH&#93; OR &#8220;cocaine&#8221;&#91;MeSH&#93;&#41; AND &#40;&#8220;Brugada Syndrome&#8221;&#91;MeSH&#93; OR &#8220;brugada syndrome&#8221;&#91;All Fields&#93;&#41;&#41; OR &#8220;brugada phenocopy&#8221;&#91;All Fields&#93;&#44; which yielded 359 articles&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">An initial assessment of eligibility was made through titles and abstracts&#46; Potentially relevant articles were retrieved and their full text was reviewed independently by the authors for final decision on inclusion&#46; Unavailable and irrelevant articles were excluded&#46; Additional relevant papers found in the reference lists of the articles retrieved from the initial selection were also included&#46; A total of 93 articles made up the final study&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Brugada phenotype and diagnosis</span><p id="par0045" class="elsevierStylePara elsevierViewall">A pharmacologic challenge with one of the class I antiarrhythmic agents &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; which block INa&#44; may be used as a diagnostic tool for susceptible patients by unmasking the type 1 pattern<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;11&#44;16</span></a>&#46; The 2016 expert consensus on J-wave syndromes<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a> expresses concerns about the potential for overdiagnosis of BrS&#44; particularly in patients displaying a type 1 pattern only after a drug challenge&#44; contrasting with the previous 2013 consensus statement on inherited cardiac arrhythmias<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">6</span></a>&#46; Thus&#44; it is now suggested that development of a type 1 pattern with this test should be considered as probabilistic rather than binary in nature&#46; The same may apply to the interpretation of a genetic test<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">The 2016 consensus report<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a> recommends that only a type 1 &#40;coved-type&#41; ST-segment elevation is considered diagnostic of BrS &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#44; specifically an elevation of &#8805;2<span class="elsevierStyleHsp" style=""></span>mm &#40;0&#46;2<span class="elsevierStyleHsp" style=""></span>mV&#41; in &#8805;1 right precordial leads &#40;V1&#8211;V3&#41; positioned in the 4th&#44; 3rd&#44; or 2nd intercostal space&#46; Type 2 &#40;saddleback-type&#41; is characterized by ST-segment elevation of &#8805;0&#46;5<span class="elsevierStyleHsp" style=""></span>mm &#40;generally &#8805;2<span class="elsevierStyleHsp" style=""></span>mm in V2&#41; in &#8805;1 right precordial lead &#40;V1-V3&#41;&#44; followed by a convex ST&#44; and by a positive T wave in V2 and variable morphology in V1&#46; Type 3 pattern is characterized by either a saddleback or coved appearance with an ST-segment elevation of &#60;1<span class="elsevierStyleHsp" style=""></span>mm&#46; Type 2 or type 3 ST-segment elevation can be used for the diagnosis of BrS only if converted to type 1 with fever or pharmacologic challenge&#46; However&#44; when a type 1 ECG is unmasked using drug challenge&#44; diagnosis of BrS should require that the patient also present with at least one of the following&#58; documented VF or PVT&#44; syncope of probable arrhythmic cause&#44; a family history of SCD at &#60;45 years old with negative autopsy&#44; coved-type ECGs in family members&#44; or nocturnal agonal respiration&#46; A pharmacologic challenge may therefore be useful only when there is clinical suspicion of BrS in the absence of spontaneous type 1 ST-segment elevation&#46; Alternatively&#44; programmed ventricular stimulation inducing VT&#47;VF with one or two premature beats may also support the diagnosis when the above clinical features are present<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">It is recommended that electrocardiographic recordings be obtained in the standard and superior positions for the V1 and V2 leads&#44; because placement in more cranial positions &#40;in the 3rd or 2nd intercostal space&#41; increases the sensitivity of the ECG<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46; An alternative diagnostic tool&#44; the full stomach test&#44; in which ECGs are performed before and after a large meal&#44; has been proposed for diagnosing BrS<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">21</span></a>&#46; It is reasonable to assume that a spontaneous type 1 recorded by Holter at night or after a large meal has more diagnostic and prognostic value than a drug-induced type 1<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The criteria of the Proposed Shanghai BrS Score for the diagnosis of BrS are based on the ECG&#44; clinical history&#44; family history and genetic test results&#44; but this score needs to be validated in further studies<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Differential diagnosis of Brugada syndrome</span><p id="par0065" class="elsevierStylePara elsevierViewall">Other circumstances can produce a type 1 Brugada-like ECG &#40;ST-segment elevation mimicking a type 1 Brugada pattern&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;7&#44;8</span></a>&#46; These are separate clinical entities with different pathophysiologies and prognosis and can thus be interpreted as confounding factors&#59; they should be excluded before the establishment of a definitive diagnosis of BrS<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">3&#44;5&#44;8</span></a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Ionic and cellular mechanisms underlying Brugada syndrome</span><p id="par0070" class="elsevierStylePara elsevierViewall">The pathophysiology of BrS is only partially understood<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">8</span></a>&#46; There are two main theories&#44; the repolarization hypothesis and the depolarization hypothesis<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;22&#44;23</span></a>&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The repolarization theory suggests that a decrease in inward currents &#40;INa and ICa&#41; and&#47;or increase in outward currents &#40;Ito&#41; results in an outward shift in the balance of the ionic currents active at the end of phase 1 of the action potential &#40;AP&#41; in the right ventricular &#40;RV&#41; epicardium&#44; where Ito is prominent&#46; This results in loss of the AP dome and accentuation of the AP notch in the epicardium but not the endocardium&#44; creating a transmural voltage gradient manifested by the characteristic Brugada ST-segment elevation on the ECG and dispersion of repolarization within the epicardium and transmurally&#46; These repolarization abnormalities can precipitate the development of phase 2 reentry &#40;local re-excitation&#41;&#44; which in turn generates closely coupled premature beats as ventricular extrasystoles capable of precipitating PVT&#47;VF<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">23&#44;24</span></a>&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">According to the depolarization theory&#44; conduction slowing and delay&#44; particularly in the right ventricular outflow tract &#40;RVOT&#41;&#44; results in delayed and abnormal depolarization currents that may play a primary role in the pathophysiology and arrhythmic manifestations of the syndrome<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">22&#44;23</span></a>&#46; Mild structural changes&#44; such as increased collagen and fibrosis&#44; and reduced expression of the gap junction protein connexin-43 especially &#40;but not exclusively&#41; in the RVOT&#44; are a part of BrS and could account for the conduction abnormalities and also late potentials<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">4</span></a>&#46; Further evidence supporting delayed depolarization includes the observation of late potentials and low-voltage fragmented electrogram activity in the RVOT and the RV anterior wall&#44; and the beneficial effect of radiofrequency ablation on these epicardial sites of slow conduction in BrS patients<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">4&#44;25</span></a>&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Despite the controversy&#44; these two theories are not necessarily mutually exclusive and may indeed be synergistic<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;26</span></a>&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Agents and conditions associated with induced Brugada electrocardiographic pattern</span><p id="par0090" class="elsevierStylePara elsevierViewall">Certain agents and conditions &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41; may act as modulating factors by influencing and interfering with cardiac ion channel function&#44; unmasking the characteristic Brugada ECG pattern and possibly leading to fatal consequences&#44; particularly in BrS patients&#44; because of already impaired cardiac ion channel function<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">3&#44;5&#44;16&#44;17</span></a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Hyperthermia &#40;fever&#41;</span><p id="par0095" class="elsevierStylePara elsevierViewall">Fever is now recognized as being capable of unmasking BrS by promoting a type I Brugada ECG in susceptible individuals<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">15&#44;27&#8211;35</span></a>&#46; BrS is rarely identified in pediatric patients&#44; but most reported cases are unmasked after febrile episodes<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">29</span></a>&#46; A study by Adler et al&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">30</span></a> reported that type 1 Brugada ECG was 20 times more prevalent among patients with fever than in afebrile patients and that the prevalence of fever-induced BrS was 2&#37;&#46; Rattanawong et al&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">31</span></a> demonstrated an approximately five-fold higher prevalence of BrS in a febrile group compared to an afebrile group&#44; with a prevalence of 4&#37; in patients from endemic areas&#46; Fever has also been reported to trigger VAs<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">32&#8211;36</span></a>&#46; It was also demonstrated by Mizusawa et al&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">32</span></a> that asymptomatic patients with fever-induced type 1 ECG &#40;F-type 1&#41; carry a higher risk of arrhythmic events &#40;0&#46;9&#37;&#47;year&#41;&#44; and conclude that patients with BrS who develop F-type 1 are at risk of arrhythmic events such as SCD&#46; It has been observed that an <span class="elsevierStyleItalic">SCN5A</span> mutation identified in BrS patients leads to a loss of function of the sodium channel current that is accentuated at higher temperatures<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">37</span></a>&#46; Compared with a drug challenge-induced type 1 pattern&#44; an F-type 1 appears to have a more complex mechanism&#46; Alternatively&#44; other as yet unknown factors related to acute infection or increased temperature may be involved<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">32</span></a>&#46; Nevertheless&#44; fever is presumed to accelerate inactivation of INa and to accelerate recovery of Ito from inactivation<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Similarly to fever&#44; hypothermia may also induce or accentuate J waves&#44; probably by slowing activation of ICa&#44; leaving Ito unopposed<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46; However&#44; it seems more likely to provoke Brugada-like ECG abnormalities&#44; mimicking an actual BrS<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;38&#44;39</span></a>&#46; Moreover&#44; the development of arrhythmias in BrS appears to be promoted only by fever&#44; unlike early repolarization syndrome&#44; in which hypothermia appears to induce VA<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a>&#46; It is noteworthy that hypothermia can even diminish the manifestation of a BrS ECG pattern when already present<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">40</span></a>&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Drugs</span><p id="par0105" class="elsevierStylePara elsevierViewall">An increasing number of drugs prescribed in routine clinical practice have been reported to induce or unmask the characteristic type 1 BrS pattern&#44; predisposing to malignant VAs<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">16&#8211;19</span></a>&#46; In view of the potential hazardous effects of certain drugs in BrS individuals&#44; Postema et al&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">16</span></a> developed a website &#40;<a href="http://www.brugadadrugs.org/">www&#46;brugadadrugs&#46;org</a>&#41; with the goal of ensuring worldwide accessibility of information on safe drug use in BrS&#46; Two broad categories of agents capable of unmasking a drug-induced type 1 &#40;D-type 1&#41; ECG were defined&#58; one group that have a clear association with malignant VAs&#44; to be avoided by BrS patients &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#44; and another group&#44; preferably to be avoided&#44; for which there is as yet no substantial evidence that these drugs cause malignant arrhythmias as well as the D-type 1 phenotype &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">16</span></a>&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">The mechanisms by which some of these drugs can induce a type 1 ECG and proarrhythmic effects are not yet fully clarified&#46; However&#44; most of them are either confirmed or believed to act through INa blockage&#44; and a few may also act on other cardiac channels&#44; by promoting a decrease in ICa or an increase in Ito currents<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">18&#44;19&#44;41&#8211;56</span></a>&#46; The agents with INa blocking properties most strongly associated with a D-type 1 ECG and with clear evidence of proarrhythmic effects include ajmaline&#44; flecainide&#44; pilsicainide and propafenone &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">16</span></a>&#46; Other antiarrhythmic agents include amiodarone which&#44; although predominantly a potassium blocking agent &#40;class III&#41;&#44; also has INa blocking properties &#40;as a class IA antiarrhythmic drug&#41;&#44; especially in the acute phase of administration<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">42</span></a>&#46; Vernakalant&#44; which acts predominantly as a voltage- and rate-dependent INa blocker&#44; has also recently been associated with Brugada ECG phenotype<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">43</span></a>&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Psychotropic and anesthetic drugs are among the non-cardiac drugs most commonly involved in drug-induced BrS<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">19&#44;41</span></a>&#46; Tricyclic antidepressants &#40;TCAs&#41; have been shown to produce a D-type 1 pattern and even VAs at therapeutic or supratherapeutic doses&#46; TCAs&#44; including amitriptyline&#44; have been reported&#44; among other actions&#44; to block INa&#44; thereby inducing the BrS phenotype&#46; However&#44; they can also potentially inhibit Ito&#44; preventing its development<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">18&#44;19&#44;44</span></a>&#46; Minoura et al&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">44</span></a> demonstrated that amitriptyline has a relatively potent inhibitory effect on INa and little inhibition of Ito at concentrations close to the therapeutic range&#44; thus unmasking type 1 ECG and promoting arrhythmogenesis only in cases of a genetic predisposition&#46; Similarly&#44; blockage of INa by therapeutic as well as supratherapeutic dosages of nortriptyline has been demonstrated to be critical and cause life-threatening arrhythmias when other causes of INa block are also present&#44; such as genetic variants and&#47;or functional factors&#59; the use of nortriptyline in the general population is associated with a 4&#46;6-fold increased risk for SCA<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">45</span></a>&#46; Lithium may also cause potent INa blockade in a dose-dependent manner&#44; inducing a Brugada phenotype even at therapeutic dosages&#46; Selective serotonin reuptake inhibitors at therapeutic or supratherapeutic doses have been implicated in D-type 1 ECG without associated VA&#44; probably by INa blockade&#46; As well as supratherapeutic doses of certain antipsychotics causing a D-type 1 pattern&#44; therapeutic doses of loxapine and trifluoperazine have been associated with VF<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">18&#44;19&#44;41</span></a>&#46; Some antiepileptic agents&#44; including lamotrigine&#44; are also capable of inducing a D-type 1 pattern&#44; presumably acting on cardiac INa as well as the sodium channels in the cerebral cortex<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">19&#44;46</span></a>&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Propofol is a widely used anesthetic agent with few significant side effects&#46; However&#44; at high doses&#44; it may be associated with SCD&#44; in a condition termed propofol infusion syndrome&#44; whose mechanism of arrhythmogenesis is thought to be similar to that responsible for VA in BrS&#44; probably by blocking INa<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">18&#44;19&#44;41&#44;47</span></a>&#46; Procaine&#44; which produces anesthesia by sodium channel blockade&#44; was recently reported to have unmasked BrS and contributed to SCA in a young male individual<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">48</span></a>&#46; Tramadol is a commonly prescribed synthetic opioid analgesic that in overdose may produce INa blockade and a D-type 1 pattern<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">49</span></a>&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">A D-type 1 ECG has also been elicited in patients treated with antihistamines &#40;mainly first-generation&#41;&#46; No associated VAs have been reported with their use in isolation<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">18&#44;19</span></a>&#46; Leiria et al&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">50</span></a> described an interesting case of a 44-year-old man in whom BrS was diagnosed after experiencing a syncopal episode associated with the use of over-the-counter cold medicine &#40;brompheniramine &#43; phenylephrine&#41;&#46; The mechanism by which adrenergic agonists can trigger BrS is not entirely understood&#44; but one hypothesis is a sudden increase in vagal tone once the adrenergic effect has worn off&#46; Alternatively&#44; brompheniramine appears to directly alter the expression of the <span class="elsevierStyleItalic">SCN5A</span> gene and to reduce the INa current<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">50</span></a>&#46; Alcohol intoxication has been shown to induce the Brugada ECG pattern along with VA&#46; The exact mechanism is not clear&#44; but increased parasympathetic nervous activity and inhibition of ICa currents have been proposed as possible underlying causes<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">19&#44;51</span></a>&#46; Similarly&#44; acetylcholine and ergonovine have also been reported to decrease ICa currents and possibly to induce VF in BrS patients<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">52</span></a>&#46; In addition to sympathomimetic actions that can result in acute ischemic events&#44; cocaine has a potent direct blocking effect on INa that&#44; particularly at relatively low doses&#44; can trigger VF in genetically predisposed individuals with BrS<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">19&#44;41&#44;53</span></a>&#46; Cannabis has also been reported to be associated with the Brugada pattern&#46; The mechanisms of this interaction are unclear&#44; but may be related to a late vagotonic effect after cannabis exposure<a class="elsevierStyleCrossRefs" href="#bib0735"><span class="elsevierStyleSup">54&#44;55</span></a>&#46; The Red Bull<span class="elsevierStyleSup">&#174;</span> energy drink was recently reported to have induced SCA with VF in a young individual who was eventually diagnosed with BrS&#46; Red Bull contains taurine&#44; which could suppress INa&#44; ICa and Ito channels&#44; and high levels of caffeine&#44; which could disrupt calcium homeostasis and lead to cytoplasmic calcium overload&#44; thus potentiating VA<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">56</span></a>&#46; Several antianginal drugs may also be associated with a D-type 1 pattern&#44; but evidence is lacking on the existence and nature of this relationship<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">16&#44;18&#44;57</span></a>&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Vagotonic conditions and maneuvers</span><p id="par0130" class="elsevierStylePara elsevierViewall">Vagal tone is recognized as an important factor capable of precipitating VAs in BrS&#44; which explains why VF and SCD are more frequent at night&#44; at rest&#44; and at low levels of physical activity<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">9&#44;12&#8211;14</span></a>&#44; since these situations are related to higher levels of vagal tone and slower heart rates&#46; Specifically&#44; vagal tone is thought to directly inhibit ICa and indirectly increase Ito due to slowing of heart rate&#46; This autonomic modulation of ion channel currents underlying the early phases of the epicardial AP may therefore contribute to the characteristically dynamic ECG in BrS<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;9&#44;12&#8211;14</span></a>&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Large meals have similarly been implicated in unmasking BrS and precipitating VA in BrS patients&#44; some even going so far as to propose that they could play a role in the diagnosis of BrS in suspected cases<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">21&#44;58&#44;59</span></a>&#46; Vel&#225;zquez-Rodr&#237;guez et al&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">58</span></a> recently demonstrated the reproducibility&#44; efficacy and safety of the dextrose-insulin metabolic test in the differential diagnosis of patients with non-diagnostic ECG patterns&#46; The spontaneous J wave and ST-segment elevation seen after meals may reflect changes in autonomic modulation due to a full stomach&#44; with consequent increase in vagal activity&#44; and may also be a consequence of high glucose concentrations and insulin release<a class="elsevierStyleCrossRefs" href="#bib0755"><span class="elsevierStyleSup">58&#44;59</span></a>&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The increase in vagal tone that occurs immediately after exercise appears to be the reason that the Brugada pattern can be seen in BrS patients with exercise&#44; especially early in the recovery phase&#46; Besides worsening ST-segment elevation in BrS&#44; exercise can produce associated VAs&#46; Exercise testing may also be helpful in unmasking BrS<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">14&#44;60&#44;61</span></a>&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Hormones</span><p id="par0145" class="elsevierStylePara elsevierViewall">Apart from insulin as mentioned above&#44; other hormones may also play a role in the manifestation of the Brugada ECG pattern&#44; associated VA and BrS itself&#46; Testosterone is thought to modulate ion currents underlying the epicardial AP notch&#44; possibly by promoting an increase in Ito or a decrease in ICa currents<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;62&#44;63</span></a>&#46; In addition to the presence of a more prominent Ito current in males&#44; higher testosterone levels associated with less visceral fat also appears to have a significant role in the Brugada phenotype and in the male predominance in BrS<a class="elsevierStyleCrossRefs" href="#bib0775"><span class="elsevierStyleSup">62&#44;63</span></a>&#46; Moreover&#44; thyroxine may alter membrane currents&#44; including Ito and ICa&#44; thus contributing to triggering the Brugada pattern and BrS<a class="elsevierStyleCrossRefs" href="#bib0775"><span class="elsevierStyleSup">62&#44;64</span></a>&#46; Recently&#44; Korte et al&#46;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">64</span></a> reported a case of SCA as a presentation of BrS unmasked by a thyroid storm in a young male&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Electrolyte imbalance</span><p id="par0150" class="elsevierStylePara elsevierViewall">It has been speculated that certain electrolyte disturbances can amplify the Ito-mediated AP notch with loss of the AP dome in the epicardium of the RVOT&#44; thereby precipitating the Brugada ECG pattern&#44; and even related VAs in BrS patients<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">3&#44;5&#44;36&#44;65</span></a>&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Hyperkalemia may induce the Brugada pattern by decreasing the resting membrane potential&#44; which inactivates the INa current and leads to a predominantly Ito current that is most pronounced in the RV epicardium&#44; resulting in type 1 Brugada ECG<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">24&#44;65</span></a>&#46; Postema et al&#46;<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">66</span></a> also reported a case of diabetic ketoacidosis with concomitant hyperkalemia that uncovered a typical Brugada pattern&#44; and further pharmacologic challenge in the patient and his son confirmed familial BrS&#46; The concomitant acidosis may also have played an important part because of its similar effect in decreasing INa currents<a class="elsevierStyleCrossRefs" href="#bib0795"><span class="elsevierStyleSup">66&#44;67</span></a>&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Hypokalemia is also known to accentuate the Brugada ECG pattern&#44; possibly by enhancing Ito with an increase in transmural or epicardial dispersion of repolarization in the RV&#44; which may increase the risk for VF in patients with BrS<a class="elsevierStyleCrossRefs" href="#bib0750"><span class="elsevierStyleSup">57&#44;68</span></a>&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Furthermore&#44; hypercalcemia may also unmask the Brugada-type ECG&#44; probably through transmural differences in the magnitude of the AP notch due to an increase in the calcium-activated chloride current and to a reduction of INa and ICa<a class="elsevierStyleCrossRefs" href="#bib0810"><span class="elsevierStyleSup">69&#44;70</span></a>&#46; However&#44; it is unknown whether hypercalcemia-induced J-point elevation increases the risk of VA<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">70</span></a>&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Hyponatremia is believed to diminish the ion gradient and thereby reduce the INa current&#44; leaving Ito unopposed&#44; which may cause loss of the AP dome in the RV epicardium&#46; However&#44; whether induction of the Brugada pattern by severe hyponatremia is associated with increased susceptibility to VA is currently uncertain<a class="elsevierStyleCrossRef" href="#bib0820"><span class="elsevierStyleSup">71</span></a>&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Brugada phenocopies</span><p id="par0175" class="elsevierStylePara elsevierViewall">BrPs are clinical entities that have visually similar or even identical ECG patterns to true congenital BrS but are etiologically distinct&#44; being elicited by a variety of other clinical circumstances<a class="elsevierStyleCrossRefs" href="#bib0750"><span class="elsevierStyleSup">57&#44;72&#44;73</span></a>&#46; The term phenocopy describes a phenotype which is caused by environmental conditions that matches one determined by a gene&#44; and so the absence of any apparent genetic abnormality is central to the concept of BrP&#59; the environmental factors alone are sufficient to result in a BrS pattern rather than unmasking latent BrS<a class="elsevierStyleCrossRefs" href="#bib0750"><span class="elsevierStyleSup">57&#44;73&#8211;75</span></a>&#46; These factors may include myocardial ischemia&#44; hyponatremia&#44; hyperkalemia &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#41;&#44; hypokalemia&#44; hypophosphatemia &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>&#41;&#44; pulmonary embolism&#44; concomitant alcohol and heroin overdose&#44; hypothermia&#44; hypopituitarism&#44; mechanical mediastinal compression&#44; electrocution &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>&#41;&#44; and poor ECG filters&#59; they are categorized by etiology in <a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a><a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">38&#44;73&#8211;87</span></a>&#46; The website <a href="http://www.brugadaphenocopy.com/">www&#46;brugadaphenocopy&#46;com</a> was recently created to establish an online international database of BrP cases to allow for longitudinal follow-up of these conditions and to develop a better understanding of BrP<a class="elsevierStyleCrossRef" href="#bib0835"><span class="elsevierStyleSup">74</span></a>&#46; Notably&#44; a recent report of recurrent hypokalemia demonstrated clinically reproducible BrP&#44; contributing to the evolution of the concept<a class="elsevierStyleCrossRef" href="#bib0860"><span class="elsevierStyleSup">79</span></a>&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><p id="par0180" class="elsevierStylePara elsevierViewall">In order to differentiate BrP from true congenital BrS&#44; the criteria summarized in <a class="elsevierStyleCrossRef" href="#tbl0035">Table 7</a> can be used to assist with recognition and diagnosis of BrP&#46; Unlike in BrS&#44; in BrP there is usually an identifiable and reversible underlying condition&#44; resolution of which is accompanied by prompt normalization of the ECG&#46; Additionally&#44; these patients have low clinical probability for BrS&#44; as indicated by the absence of a documented personal history of SCA or syncope&#44; or family history of SCD&#46; Finally&#44; drug challenge testing is negative&#44; while in BrS patients this tends to be positive<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">73&#44;74</span></a>&#46; The differences in ECG response to drug challenge denote pathophysiological differences between BrP and BrS&#44; suggesting alternative underlying mechanisms with various genetic&#44; structural and environmental interactions that are yet to be elucidated<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">73</span></a>&#46; While high-risk patients with BrS may be candidates for an implantable cardioverter-defibrillator &#40;ICD&#41;&#44; the clinical implications of BrP&#44; and hence the correlation between BrP and malignant VA&#44; remain unknown<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;57&#44;73</span></a>&#46; At this time&#44; the recommended approach for BrP is mainly based on systematic diagnostic procedures &#40;to differentiate BrP from BrS&#41; and resolution of the underlying condition<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">73&#44;74</span></a>&#46;</p><elsevierMultimedia ident="tbl0035"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Discussion and Conclusion</span><p id="par0185" class="elsevierStylePara elsevierViewall">The congenital BrS ECG pattern is often dynamic and concealed&#44; but it can be unmasked&#44; modulated or precipitated by a wide range of agents and conditions&#44; which are summarized in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a><a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">3&#44;5&#44;8</span></a>&#46; Associated malignant VAs can develop under most of these circumstances in BrS patients&#44; because these individuals already have impaired cardiac ion channel function<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">3&#44;5&#44;17</span></a>&#46; This association with VA and SCD is more evident with fever<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">15&#44;32&#8211;36</span></a>&#44; with certain drugs that are indicated to be avoided by BrS patients &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">16</span></a> and energy drinks<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">56</span></a>&#44; under vagotonic conditions<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">9&#44;12&#44;13</span></a> such as a large meal<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">21&#44;58&#44;59</span></a> or the recovery phase of exercise<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">14&#44;60&#44;61</span></a>&#44; with hypertestosteronemia<a class="elsevierStyleCrossRefs" href="#bib0775"><span class="elsevierStyleSup">62&#44;63</span></a> or hyperthyroidism<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">64</span></a>&#44; and possibly with potassium imbalance<a class="elsevierStyleCrossRefs" href="#bib0790"><span class="elsevierStyleSup">65&#8211;68</span></a>&#46; Fever is recognized as a major risk factor in BrS and can even outperform drug challenge in unmasking a type 1 ECG<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;28&#44;32</span></a>&#46; Junttila et al&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">36</span></a> reported that patients presenting with a Brugada ECG during an acute event&#44; including fever&#44; treatment with medication affecting INa&#44; drug overdose or electrolyte imbalances&#44; should be considered to have a higher risk of life-threatening VA and SCD&#44; even in the absence of an <span class="elsevierStyleItalic">SCN5A</span> mutation&#46; It is also plausible that the cardiac electrophysiological mechanisms involved in acidosis and ischemic heart disease may potentiate those of BrS&#44; resulting in increased risk for VA in BrS patients<a class="elsevierStyleCrossRefs" href="#bib0725"><span class="elsevierStyleSup">52&#44;67&#44;88</span></a>&#46; In most of such cases&#44; the type 1 pattern and associated VAs presumably result from induced or exacerbated decrease in inward currents &#40;INa and ICa&#41; or increase in outward currents &#40;Ito or IK-ATP&#41;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">3&#44;5&#44;20</span></a>&#46; There is now a growing consensus that apart from genetic factors&#44; the expression of BrS is also multifactorial&#44; the underlying genetic predisposition being modulated by diverse environmental factors and even morphologic cardiac changes<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">4&#44;5</span></a>&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Equally important&#44; there are also cases of acquired forms of BrS in which&#44; theoretically&#44; an intervention &#40;such as administration of a pharmacologic agent&#41; could have caused a sufficient imbalance of inward and outward currents in the RVOT to induce a Brugada pattern<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">17&#8211;20&#44;75</span></a>&#46; These patients are typically asymptomatic&#44; without a personal or family history of VA&#44; and may test positive on drug challenge&#46; It is not yet established whether this requires an underlying genetic predisposition or actually represents latent BrS<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">18&#44;75</span></a>&#46; However&#44; the susceptibility of these individuals may be due to genetic polymorphisms rather than pathogenic mutations<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">17&#44;75&#44;89</span></a>&#46; Such a genetic predisposition or subclinical form &#40;forme fruste&#41; may result in increased latent ion channel dysfunction that favors induction of a Brugada pattern&#44; particularly when there is a specific combination of stressors and comorbidities&#44; similar to what is observed with acquired long QT syndrome &#40;LQTS&#41;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">17&#44;18&#44;75&#44;90</span></a>&#46; However&#44; the likelihood of arrhythmias is still unclear<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">18&#44;75</span></a>&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">In principle&#44; a risk profile for a D-type 1 pattern and VA could be drawn up based on various factors such as male gender&#44; genetic predisposition and modulating polymorphisms&#44; specific electrolyte disturbances&#44; fever&#44; kidney and liver dysfunction&#44; cardiac comorbidities&#44; the use or excessive doses of specific drugs&#44; electrocardiographic characteristics&#44; and previous arrhythmias<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">17&#44;91</span></a>&#46; Konigstein et al&#46;<a class="elsevierStyleCrossRef" href="#bib0925"><span class="elsevierStyleSup">92</span></a> recently documented that the D-type 1 ECG associated with non-cardiac drugs is seen mostly in adult males&#44; is frequently due to drug toxicity&#44; and develops late after the onset of therapy&#46; However&#44; it would be difficult to apply these data to a specific individual&#44; because of the wide variability in response to a specific drug&#44; and because its possible effects may change over time depending on treatment duration&#44; age&#44; or developing comorbidities&#46; Furthermore&#44; most of the evidence supporting the association with VAs comes from a limited number of case reports&#44; laboratory studies and cohort analyses<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">16&#44;17</span></a>&#46; It would therefore be difficult to predict the likelihood of drug-induced BrS in routine clinical practice<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">17&#44;19&#44;91</span></a>&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Clinical presentation is still the strongest predictor of risk in BrS&#44; and in asymptomatic patients the arrhythmic risk is low &#40;0&#46;5&#37; per year&#41;&#46; Furthermore&#44; asymptomatic patients with a type 1 pattern that only develops following drug challenge have a lower risk of arrhythmic events during follow-up than those with a spontaneous type 1 at diagnosis<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;93</span></a>&#46; Unlike high-risk BrS patients&#44; who may have indication for an ICD&#44; asymptomatic patients with a type 1 pattern only disclosed by drug challenge may be indicated for close follow-up only<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;6</span></a>&#46; The prognosis of asymptomatic patients with a D-type 1 pattern but without a family history of SCD appears to be relatively benign once the offending agent is discontinued<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;18</span></a>&#46; Nevertheless&#44; it may be prudent not to ignore the risk&#44; particularly during exposure to the agent<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">16&#8211;19&#44;36&#44;41&#44;91</span></a>&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">There is considerable debate concerning the appropriate terminology for BrP&#44; mainly because it is very difficult to rule out a genetic predisposition&#46; Antzelevitch et al&#46; have accordingly proposed that these conditions be designated acquired forms of Brugada ECG pattern or BrS&#44; as more in line with the terminology used in LQTS&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a> At this stage&#44; there is a need to clarify the concepts and real significance of acquired Brugada patterns and BrP as clinical entities&#44; especially in terms of arrhythmic risks and prognosis&#44; and to gain a better understanding of their underlying mechanisms and the possible genetic predisposition in the case of acquired BrS&#46; Thus&#44; more systematic&#44; population-based&#44; observational and experimental studies are needed to clarify these concepts and to better differentiate them from each other and from BrS itself&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Nevertheless&#44; in a patient with an induced type 1 Brugada pattern&#44; it seems prudent to proceed with a systematic diagnostic approach&#44; excluding confounding factors &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; identifying possible underlying modulators &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#44; investigating whether the ECG normalizes on resolution of possible environmental factors&#44; investigating personal and family history of symptoms and arrhythmias &#40;including SCD&#41;&#44; performing a drug challenge &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; and possibly undertaking genetic study&#44; including of the patient&#39;s family<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;8&#44;19&#44;73</span></a>&#46; Additionally&#44; distinguishing true BrS from BrP is crucial&#44; because the type 1 pattern in BrS can be transient and indistinguishable from BrP and possibly provoked by the same conditions&#44; such as hyperkalemia<a class="elsevierStyleCrossRefs" href="#bib0795"><span class="elsevierStyleSup">66&#44;72&#8211;74&#44;78</span></a>&#46; Moreover&#44; the propensity for VA in BrS is established&#44; whereas this is not the case for BrP<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">73&#44;74</span></a>&#46; Since the prognosis of BrP may be related to the evolution of the underlying condition<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">73&#44;74</span></a>&#44; and a type 1 Brugada ECG may itself be an indicator of increased risk for arrhythmias<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">17</span></a>&#44; it makes sense to screen for and promptly correct any underlying conditions or possible modulating factors<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;73&#44;74</span></a>&#46; Fever in BrS patients should be treated aggressively with antipyretics&#44; and they should avoid the substances listed in <a class="elsevierStyleCrossRefs" href="#tbl0020">Tables 4 and 5</a> and be familiar with the effects of a large meal&#44; especially after a long fasting period<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;16&#8211;19&#44;59</span></a>&#46; Data on the risks of exercise in BrS are currently too limited to make recommendations concerning exercise<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">5&#44;60</span></a>&#46; However&#44; it is suggested that BrS patients should avoid vigorous exercise<a class="elsevierStyleCrossRefs" href="#bib0765"><span class="elsevierStyleSup">60&#44;61</span></a>&#46;</p></span></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Brugada syndrome is an inherited cardiac condition with the potential for development of life-threatening arrhythmias in relatively young individuals without significant structural cardiac abnormalities&#46; The condition is characterized by a distinct coved-type ST segment elevation in the right precordial leads &#40;V1-V3&#41;&#46; This hallmark pattern &#40;type 1&#41; is often dynamic and sometimes concealed&#44; and may be unmasked in certain conditions or under the effect of certain agents&#44; which include variation of sympathovagal balance&#44; hormones&#44; metabolic factors and drugs&#46; These factors may not only modulate electrocardiographic morphology and induce the characteristic type 1 pattern&#44; but also predispose to ventricular arrhythmias&#46; The risk of malignant arrhythmias in acute events with induced type 1 pattern may be imminent&#44; particularly if the patient in fact has Brugada syndrome&#46; The physician should be aware of the modulating factors that may underlie a Brugada pattern&#44; and be able to recognize&#44; identify and promptly correct them&#46; The mechanisms responsible for the type 1 pattern and possible associated ventricular arrhythmias induced by these modulating factors have attracted growing attention and interest&#46; Furthermore&#44; not all induced Brugada ECG patterns are observed in patients with Brugada syndrome&#44; existing the possibility for acquired Brugada patterns&#47;syndrome and Brugada phenocopies&#46; This paper reviews the modulating factors associated with induced type 1 pattern as possible causes of arrhythmogenesis&#44; particularly in Brugada syndrome patients&#44; describes some of the probable underlying mechanisms&#44; and discusses the concepts of acquired Brugada syndrome and Brugada phenocopies&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A s&#237;ndrome de Brugada &#233; um dist&#250;rbio card&#237;aco cong&#233;nito com o potencial para o desenvolvimento de arritmias fatais em indiv&#237;duos relativamente jovens sem anomalias estruturais card&#237;acas grosseiras&#46; Essa condi&#231;&#227;o &#233; caracterizada por uma distinta eleva&#231;&#227;o do segmento-ST com concavidade superior &#40;tipo 1&#41; nas deriva&#231;&#245;es precordiais &#40;V1-V3&#41;&#46; Esse peculiar padr&#227;o tipo 1 &#233; frequentemente din&#226;mico e por vezes dissimulado&#44; podendo ser desmascarado em certas condi&#231;&#245;es ou sobre o efeito de alguns agentes que coletivamente envolvem e incluem o equil&#237;brio simpatovagal&#44; hormonas&#44; fatores metab&#243;licos e agentes farmacol&#243;gicos&#46; N&#227;o s&#243; esses fatores podem modular a morfologia eletrocardiogr&#225;fica e induzir o caracter&#237;stico padr&#227;o tipo 1&#44; como tamb&#233;m predispor a arritmias ventriculares&#46; Esse risco de arritmias malignas em eventos agudos pode ser iminente e possivelmente presente&#44; particularmente se o paciente apresentar uma efetiva s&#237;ndrome de Brugada&#46; O cl&#237;nico dever&#225; estar ciente&#44; reconhecer&#44; identificar e prontamente corrigir esses poss&#237;veis fatores modeladores que possam estar subjacentes a um padr&#227;o de Brugada&#46; Os mecanismos respons&#225;veis por esses padr&#245;es induzidos do tipo 1 e poss&#237;veis arritmias ventriculares associadas por esses fatores moduladores t&#234;m igualmente trazido crescente aten&#231;&#227;o e interesse&#46; Ademais&#44; nem todos os padr&#245;es de Brugada induzidos ocorrem em pacientes com s&#237;ndrome de Brugada&#44; existindo a possibilidade para padr&#245;es&#47;s&#237;ndrome adquirida e fenoc&#243;pias de Brugada&#46; Este artigo faz uma revis&#227;o dos fatores moduladores associados ao padr&#227;o tipo 1 induzido&#44; como poss&#237;veis fontes para arritmog&#233;nese&#44; particularmente em pacientes com s&#237;ndrome de Brugada&#44; descreve alguns dos prov&#225;veis mecanismos subjacentes e aborda os conceitos de s&#237;ndrome de Brugada adquirida e fenoc&#243;pias&#46;</p></span>"
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                  \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">Mode of administration&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&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">Intravenous&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 over 5-10 min&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">Intravenous&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 over 10 min&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">Oral &#40;41 hour&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">150-300 mg&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">Intravenous&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 over 5-10 min&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">Intravenous&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 over 5-10 min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1624739.png"
              ]
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Provocative agents used in drug challenge for diagnosis of Brugada syndrome&#46;</p>"
        ]
      ]
      5 => 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="spar0050" class="elsevierStyleSimplePara elsevierViewall">Adapted from Antzelevitch et al&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a> ARVD&#58; arrhythmogenic right ventricular dysplasia&#59; ECG&#58; electrocardiogram&#59; RVOT&#58; right ventricular outflow tract&#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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Acute myocardial ischemia or infarction &#40;especially of the right ventricle&#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">Acute pericarditis&#47;myocarditis&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">ARVD&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">Artifacts secondary to low-pass filtering&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">Atypical right bundle branch 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">Central and autonomic nervous system abnormalities&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">Dissecting aortic aneurysm&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">Duchenne muscular dystrophy&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">Early repolarization &#40;especially in athletes&#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">Friedreich ataxia&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">Hypothermia&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">Mechanical compression of the RVOT &#40;e&#46;g&#46;&#44; by pectus excavatum&#44; mediastinal tumor&#44; hemopericardium&#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">Myotonic dystrophy&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">Post-defibrillation ECG&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">Prinzmetal angina&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">Pulmonary thromboembolism&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">Spinobulbar muscular atrophy&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">Ventricular hypertrophy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab1624737.png"
              ]
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Differential diagnosis of Brugada pattern&#46;</p>"
        ]
      ]
      6 => 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" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Adapted from Antzelevitch et al&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a> and www&#46;brugadadrugs&#46;org&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">16</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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Hyperthermia &#40;fever&#41;</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="elsevierStyleItalic">Substances</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>Antiarrhythmic drugs&#58; sodium channel blockers &#40;class IC and IA&#41;&#44; calcium channel blockers&#44; beta-blockers&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>Psychotropic drugs&#58; unicyclic&#47;tricyclic&#47;tetracyclic antidepressants&#44; antipsychotics&#44; selective serotonin reuptake inhibitors&#44; lithium&#44; antiepileptics&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>Anesthetics&#47;analgesics&#58; bupivacaine&#44; procaine&#44; propofol&#44; ketamine&#44; tramadol&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>Others&#58; histamine H1 antagonists&#44; alcohol&#44; cocaine&#44; cannabis&#44; ergonovine&#44; energy drinks&#44; acetylcholine&#44; edrophonium&#44; fexofenadine&#44; indapamide&#44; metoclopramide&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="elsevierStyleItalic">Vagotonic conditions and maneuvers&#58; at night&#47;rest&#44; recovery phase of exercise&#44; large meals</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="elsevierStyleItalic">Hormones&#58; hypertestosteronemia&#44; thyroid storm &#40;hyperthyroidism&#41;&#44; increased insulin level</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="elsevierStyleItalic">Electrolyte abnormalities&#58;</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>Hyperkalemia&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>Hypokalemia&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>Hypercalcemia&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>Hyponatremia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1624741.png"
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Agents and conditions modulating Brugada syndrome&#46;</p>"
        ]
      ]
      7 => 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"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Adapted from www&#46;brugadadrugs&#46;org<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">16</span></a> &#40;last consulted on December 31&#44; 2016&#41;&#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">Category&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">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">Clinical use&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">Antiarrhythmic drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " 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">Class IA antiarrhythmic &#40;Na-blocker&#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  " 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">Allapinin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IC antiarrhythmic &#40;Na-blocker&#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  " 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">Ethacizine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IC antiarrhythmic &#40;Na-blocker&#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  " 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">Flecainide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IC antiarrhythmic &#40;Na-blocker&#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  " 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">Pilsicainide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IC antiarrhythmic &#40;Na-blocker&#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  " 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">Procainamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IA antiarrhythmic &#40;Na-blocker&#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  " 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">Propafenone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IC antiarrhythmic &#40;Na-blocker&#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">Psychotropic drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Amitriptyline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tricyclic antidepressant&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">Clomipramine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tricyclic antidepressant&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">Desipramine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tricyclic antidepressant&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">Lithium&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antidepressant&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">Loxapine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antipsychotic&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">Nortriptyline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tricyclic antidepressant&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">Oxcarbazepine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anti-epileptic&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">Trifluoperazine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antipsychotic &#40;phenothiazine&#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">Anesthetics&#47;analgesics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bupivacaine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anesthetic&#47;analgesic&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">Procaine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Analgesic&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">Propofol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anesthetic&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">Other substances&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acetylcholine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cholinergic&#47;vasospastic intracoronary&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">Alcohol intoxication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Other substances&#47;beverage&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">Cannabis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Other substances&#47;illicit drugs&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">Cocaine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Other substances&#47;illicit drugs&#47;anesthetic&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">Ergonovine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Vasospastic intracoronary&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Agents to be avoided by Brugada syndrome patients &#40;associated with type 1 ECG and related arrhythmias&#41;&#46;</p>"
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        "etiqueta" => "Table 5"
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          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">SSRI&#58; selective serotonin reuptake inhibitor&#46;</p><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Adapted from www&#46;brugadadrugs&#46;org<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">16</span></a> &#40;last consulted on December 31&#44; 2016&#41;&#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">Category&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">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">Clinical use&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">Antiarrhythmic drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Amiodarone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class III antiarrhythmic &#40;also IA&#44; II&#44; and IV effects&#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  " 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">Cibenzoline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IA antiarrhythmic &#40;Na-blocker&#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  " 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">Disopyramide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IA antiarrhythmic &#40;Na-blocker&#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  " 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">Lidocaine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IB antiarrhythmic &#40;Na-blocker&#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  " 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">Propranolol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class II antiarrhythmic &#40;beta-blocker&#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  " 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">Verapamil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class IV antiarrhythmic &#40;Ca-blocker&#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  " 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">Vernakalant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Class I and III antiarrhythmic&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">Psychotropic drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bupropion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Monocyclic antidepressant&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">Carbamazepine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anticonvulsant&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">Clothiapine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antipsychotic&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">Cyamemazine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antipsychotic &#40;phenothiazine&#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  " 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">Dosulepin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tricyclic antidepressant&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">Doxepin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tricyclic antidepressant&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">Fluoxetine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antidepressant &#40;SSRI&#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  " 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">Fluvoxamine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antidepressant &#40;SSRI&#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  " 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">Imipramine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tricyclic antidepressant&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">Lamotrigine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anti-epileptic&#47;bipolar and depressive disorders&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">Maprotiline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tricyclic antidepressant&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">Paroxetine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antidepressant &#40;SSRI&#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  " 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">Perphenazine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antipsychotic &#40;phenothiazine&#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  " 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">Phenytoin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anticonvulsant&#47;antiarrhythmic&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">Thioridazine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antipsychotic&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">Anesthetics&#47;analgesics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ketamine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anesthetic&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">Tramadol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Narcotic analgesic&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">Other substances&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dimenhydrinate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antiemetic&#47;histamine H1 antagonist&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">Diphenhydramine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Histamine H1 antagonist&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">Edrophonium&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cholinergic&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">Indapamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Diuretic&#47;antihypertensive&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">Metoclopramide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antiemetic&#47;dopamine antagonist&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">Terfenadine&#47;Fexofenadine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antihistamine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Agents preferably avoided by Brugada syndrome patients &#40;associated with type 1 ECG&#44; but without substantial evidence that&#44; apart from inducing the ECG phenotype&#44; they also cause malignant arrhythmias&#41;&#46;</p>"
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          "leyenda" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Adapted from Anselm et al&#46;<a class="elsevierStyleCrossRef" href="#bib0895"><span class="elsevierStyleSup">86</span></a></p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Metabolic conditions&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">Mechanical compression&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">Ischemia and pulmonary embolism&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">Myocardial and pericardial 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">ECG modulation&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">Miscellaneous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Possible etiological categories of Brugada phenocopies&#46;</p>"
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          "leyenda" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">BrS&#58; Brugada syndrome&#59; ECG&#58; electrocardiographic&#46;</p><p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Adapted from Anselm et al&#46;<a class="elsevierStyleCrossRef" href="#bib0900"><span class="elsevierStyleSup">87</span></a></p><p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">Criteria 1-5 are mandatory&#44; except for criterion 5 if there was surgical manipulation of the right ventricular outflow tract within 96<span class="elsevierStyleHsp" style=""></span>hours of the presenting Brugada ECG pattern&#46;</p>"
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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">2&#46; The patient has an underlying condition that is identifiable&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">3&#46; The ECG pattern resolves after resolution of the underlying condition&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">4&#46; There is a low clinical pretest probability of true BrS determined by lack of symptoms&#44; medical history&#44; and family history&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">5&#46; The results of drug challenge with a sodium channel blocker such as ajmaline&#44; flecainide&#44; pilsicainide or procainamide are negative&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">6&#46; The results of genetic testing are negative &#40;desirable but not mandatory&#44; because an <span class="elsevierStyleItalic">SCN5A</span> mutation is identifiable in only 18-28&#37; of probands affected by true BrS&#41;&nbsp;\t\t\t\t\t\t\n
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