Brugada Syndrome in Children
2007; Lippincott Williams & Wilkins; Volume: 115; Issue: 15 Linguagem: Inglês
10.1161/circulationaha.106.686758
ISSN1524-4539
Autores Tópico(s)Cardiac Arrhythmias and Treatments
ResumoHomeCirculationVol. 115, No. 15Brugada Syndrome in Children Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBBrugada Syndrome in ChildrenDon't Ask, Don't Tell? Sami Viskin, MD Sami ViskinSami Viskin From the Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Originally published17 Apr 2007https://doi.org/10.1161/CIRCULATIONAHA.106.686758Circulation. 2007;115:1970–1972In recent years, numerous asymptomatic individuals worldwide have undergone electrophysiological studies "only" because they have a pathological ECG indicative of Brugada syndrome.1 Furthermore, at least 1 of 3 of these individuals had inducible ventricular fibrillation (VF) and underwent implantation of a cardioverter defibrillator (ICD).2 "Asymptomatic Brugada syndrome with inducible VF" became an accepted indication for ICD implantation because data from a single large study showed that 12% of such patients develop spontaneous VF within 3 years of diagnosis.3 More recent (albeit smaller) studies, however, suggested that the risk for spontaneous VF in asymptomatic patients is lower.4 In fact, the most recent studies show that only 3%5 to 4%6 of individuals undergoing ICD implantation for "asymptomatic Brugada syndrome with inducible VF" developed spontaneous VF within 3 years of implantation. At the same time, as many as 28% of them developed ICD-related complications.6 The realization that we have done more harm than good to many asymptomatic individuals has reopened the debate on the optimal management of asymptomatic Brugada syndrome. Indeed, defining the role of electrophysiological testing in asymptomatic Brugada syndrome is probably the most heated debate in arrhythmology nowadays.7,8 Fortunately, children have been spared from this debate because Brugada syndrome has been reported only rarely in minors, at least until now.Article p 2042In this issue of Circulation, Probst et al9 describe 30 children and adolescents (≤16 years of age) with Brugada syndrome. Their mean age was 8±5 years; 22 of them were <12 years of age. The circumstances leading to diagnosis of Brugada syndrome are important; in only 11 children (37%) was the Brugada-type ECG recognized during an evaluation for arrhythmia-related symptoms (cardiac arrest in 1, syncope in 10).9 The majority of children (60%) were asymptomatic, and their Brugada-type ECG was noted during family screening. This pediatric patient population behaved similarly to the more commonly described adult population in several ways: (1) Symptoms were more prevalent among patients with pathological ECG at baseline; (2) arrhythmias generally occurred at rest, often during febrile episodes; (3) VF was induced with programmed ventricular stimulation; and (4) no arrhythmias occurred among patients treated with quinidine. On the other hand, children with Brugada syndrome differed from the typical adult patient in their gender distribution. More than 90% of adults with symptoms are male4; in contrast, no obvious male predominance existed among symptomatic or asymptomatic children with Brugada syndrome.9Considering that Brugada syndrome is a genetic disorder with autosomal-dominant inheritance, males and females are expected to inherit the defective gene equally, and it is not easy to explain why the majority of carriers who actually develop arrhythmias are adults (mean age, 34 to 53 years)4 and almost invariably (≥90%) male.4 The prevailing explanation is that hormonal changes taking place during puberty worsen the already unbalanced flow of ion currents that underlies Brugada syndrome.10For the action potential to remain normal, a delicate balance between inflow (sodium and calcium) currents and outflow (potassium) currents must prevail. In Brugada syndrome, this balance is spoiled because mutations in the gene encoding the sodium channel reduce the inward sodium current. In areas with prominent transient outward (Ito) potassium currents like the right ventricular epicardium, unopposed outward currents cause a disproportional shortening of the action potential.11 This shortening of the action potential (and refractory period) in some areas but not others allows the onset of reentrant polymorphic ventricular tachycardia in Brugada syndrome.11 Male adults (at least in animal models) have more prominent outward currents (increased Ito,10 IKr,12 and IKs13 current density), and testosterone also reduces inward calcium currents.13 These electrophysiological effects of testosterone would facilitate the onset of arrhythmias in Brugada syndrome by further shortening the action potential in the right ventricular epicardium.10 Conversely, the female hormone estradiol modulates calcium current (ICa-L) density.14 The estradiol-mediated increase of inflow current would be "antiarrhythmic" in the Brugada syndrome.14 The hormonal changes that take place in puberty and their electrophysiological consequences explain why (in patients with Brugada mutations) the risk of spontaneous arrhythmias increases after puberty only in males. However, because most males who develop arrhythmias do so between the age of 34 and 53 years4 rather than shortly after puberty, additional proarrhythmic factors must come into play during adulthood. One such factor could be the progressive structural degeneration of myocytes that appears to take place in Brugada syndrome and is associated with conduction slowing.15 Although the repolarization abnormalities (explained above) facilitate the onset of polymorphic ventricular tachycardia, it is the depolarization disturbance (conduction slowing leading to wave break of the reentrant wave) that allows the ventricular tachycardia to become sustained and to degenerate to VF.16 In addition, recent data suggest that adult men with Brugada syndrome have higher levels of testosterone than age-matched healthy men,17 and it is not clear when this abnormal testosterone rise takes place.Many electrophysiologists adopted a "don't ask, don't tell" policy toward the need for screening the offspring of adults with Brugada syndrome. This policy resulted from 2 factors: the perception that carriers of Brugada mutations almost never develop arrhythmias during childhood and the fact that prophylactic ICD implantation in children incurs significant morbidity. The present series of Brugada syndrome in children9 could lead to a reversal of this conservative approach. Thus, a few points are noteworthy. First, only through the collaboration of investigators from 13 different referral centers in 3 European countries was it possible to report 30 children.9 This means that during the 15 years that passed since the original description of the Brugada syndrome, 1500 adults with Brugada syndrome have been reported.4 Thus, this series supports, rather than contradicts, the notion that symptomatic Brugada syndrome is rare in children. Second, having a history of familial sudden death has not been shown to be of prognostic value in adults4 and does not appear to be of prognostic value in children either.9 Third, asymptomatic adults who have a type I Brugada ECG only when challenged with sodium-channel blockers are at low risk for arrhythmic events (during follow-up periods of ≈3 years) even if they have inducible VF.4 In the present series, only 1 of 13 children (8%) who had their Brugada ECG unraveled by drug challenge actually developed symptoms. Thus, although the drug challenge test appeared to be safe in children,9 one should carefully consider whether the limited new information derived from such test merits the anxiety resulting from a positive test in a child. Finally, quinidine is extremely effective for preventing inducible VF in the electrophysiological laboratory18 and appears to be effective for preventing spontaneous arrhythmias in adults with symptomatic18 and asymptomatic18,19 Brugada syndrome. The few children who received quinidine in this series did well.9How should we implement these new data when advising parents with Brugada syndrome? First, we ought to acknowledge that we do not know enough about prognosis or risk stratification of Brugada syndrome in children. Because of our limited knowledge, some parents may prefer not to know if their asymptomatic children have a Brugada-type ECG, and we ought to respect such decision. Other parents may take the opposite attitude, insisting on doing "whatever it takes" to prevent arrhythmic death. In practical terms, however, doing "everything possible" to prevent sudden death starts with ECG recording but may culminate in prophylactic ICD implantation. It is imperative that such parents comprehend that the alarmingly high rate of ICD-related complications reported for young adults with Brugada syndrome6 is likely to be worse among children. Because of their smaller vessel diameter and cardiac size, infants with intravenous defibrillator leads often develop venous obstruction and tricuspid regurgitation,20 whereas epicardial defibrillator patches require extensive surgery and are associated with high defibrillation thresholds.20 Moreover, disruption of the fixed leads eventually occurs as children grow.20 Although novel ICD implantation techniques are being developed,21 the need for repeated surgical revision continues to be a serious problem. Totally extracardiac ICD systems delivering only shock therapy will soon be available, and children with Brugada syndrome may end up deriving the greatest benefit from such systems. In the meantime, relatives of patients with Brugada syndrome should be taught the art of cardiopulmonary resuscitation and be informed of the availability of external automatic defibrillators. In addition, because fever is an important trigger for arrhythmias in Brugada syndrome, it makes sense to use antipyretics liberally and to hospitalize children during febrile episodes,9 particularly when fever causes additional ST-segment elevation. Finally, the possibility of drug therapy should be discussed. Because sentences like "the ICD is the only effective therapy for Brugada syndrome" appear in every review of the topic, many physicians may not even consider drug therapy. One should recall, however, that children with congenital long-QT syndrome have received drug therapy with β-blockers for many years, and in large patient subgroups, this therapy proved to be effective in preventing arrhythmic death. Ironically, many of these now youngsters with congenital long-QT syndrome were "saved from the ICD" simply because these devices were not available when the long-QT syndrome was described. Because of its strong Ito-blocking capabilities,22 its efficacy in preventing inducible and spontaneous VF,18,19 and its efficacy in terminating VF storms,23 quinidine therapy has been proposed as a "bridge to ICD" for symptomatic children with Brugada syndrome23 (to prevent VF recurrence until infants grow sufficiently to undergo ICD implantation safely). It is too early to recommend universal prophylactic quinidine therapy for asymptomatic children with Brugada syndrome, but for parents and physicians willing to adopt an active approach, it is an option to consider.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.DisclosuresNone.FootnotesReprint requests to Sami Viskin, MD, Department of Cardiology, Tel Aviv Sourasky Medical Center, Weizman 6, Tel Aviv 64239, Israel. E-mail [email protected] References 1 Viskin S. Inducible ventricular fibrillation in the Brugada syndrome: diagnostic and prognostic implications. J Cardiovasc Electrophysiol. 2003; 14: 458–460.CrossrefMedlineGoogle Scholar2 Paul M, Schulze-Bahr E, Vahlhaus C, Gerss V, Breithardt G, Wichter T, Eckardt L. Impact of programmed ventricular stimulation in patients with Brugada syndrome: a meta-analysis of worldwide published data. Heart Rhythm. 2006; 3: S79. Abstract.Google Scholar3 Brugada P, Geelen P, Brugada R, Mont L, Brugada J. Prognostic value of electrophysiologic investigations in Brugada syndrome. J Cardiovasc Electrophysiol. 2001; 12: 1004–1007.CrossrefMedlineGoogle Scholar4 Gehi AK, Duong TD, Metz LD, Gomes JA, Mehta D. Risk stratification of individuals with the Brugada electrocardiogram: a meta-analysis. J Cardiovasc Electrophysiol. 2006; 17: 577–583.CrossrefMedlineGoogle Scholar5 Eckardt L, Probst V, Smits JP, Bahr ES, Wolpert C, Schimpf R, Wichter T, Boisseau P, Heinecke A, Breithardt G, Borggrefe M, LeMarec H, Bocker D, Wilde AA. Long-term prognosis of individuals with right precordial ST-segment-elevation Brugada syndrome. Circulation. 2005; 111: 257–263.LinkGoogle Scholar6 Sacher F, Probst V, Iesaka Y, Jacon P, Laborderie J, Mizon-Gerard F, Mabo P, Reuter S, Lamaison D, Takahashi Y, O'Neill MD, Garrigue S, Pierre B, Jais P, Pasquie JL, Hocini M, Salvador-Mazenq M, Nogami A, Amiel A, Defaye P, Bordachar P, Boveda S, Maury P, Klug D, Babuty D, Haissaguerre M, Mansourati J, Clementy J, Le Marec H. Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study. Circulation. 2006; 114: 2317–2324.LinkGoogle Scholar7 Brugada P, Brugada R, Brugada J. Should patients with an asymptomatic Brugada electrocardiogram undergo pharmacological and electrophysiological testing? Patients with an asymptomatic Brugada electrocardiogram should undergo pharmacological and electrophysiological testing. Circulation. 2005; 112: 279–285.LinkGoogle Scholar8 Priori SG, Napolitano C. 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Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation. 1999; 100: 1660–1666.CrossrefMedlineGoogle Scholar12 Liu XK, Katchman A, Whitfield BH, Wan G, Janowski EM, Woosley RL, Ebert SN. In vivo androgen treatment shortens the QT interval and increases the densities of inward and delayed rectifier potassium currents in orchiectomized male rabbits. Cardiovasc Res. 2003; 57: 28–36.CrossrefMedlineGoogle Scholar13 Bai CX, Kurokawa J, Tamagawa M, Nakaya H, Furukawa T. Nontranscriptional regulation of cardiac repolarization currents by testosterone. Circulation. 2005; 112: 1701–1710.LinkGoogle Scholar14 Pham TV, Robinson RB, Danilo P Jr, Rosen MR. Effects of gonadal steroids on gender-related differences in transmural dispersion of L-type calcium current. Cardiovasc Res. 2002; 53: 752–762.CrossrefMedlineGoogle Scholar15 Frustaci A, Priori SG, Pieroni M, Chimenti C, Napolitano C, Rivolta I, Sanna T, Bellocci F, Russo MA. Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome. Circulation. 2005; 112: 3680–3687.LinkGoogle Scholar16 Aiba T, Shimizu W, Hidaka I, Uemura K, Noda T, Zheng C, Kamiya A, Inagaki M, Sugimachi M, Sunagawa K. Cellular basis for trigger and maintenance of ventricular fibrillation in the Brugada syndrome model: high-resolution optical mapping study. J Am Coll Cardiol. 2006; 47: 2074–2085.CrossrefMedlineGoogle Scholar17 Shimizu W, Matsuo K, Kokubo Y, Satomi K, Kurita T, Noda T, Nagaya N, Suyama K, Aihara N, Kamakura S, Inamoto N, Akahoshi M, Tomoike H. Sex hormone and gender difference: role of testosterone on male predominance in Brugada syndrome. J Cardiovasc Electrophysiol. 2007; 18: 415–421.CrossrefMedlineGoogle Scholar18 Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation. 2004; 110: 1731–1737.LinkGoogle Scholar19 Hermida JS, Denjoy I, Clerc J, Extramiana F, Jarry G, Milliez P, Guicheney P, Di Fusco S, Rey JL, Cauchemez B, Leenhardt A. Hydroquinidine therapy in Brugada syndrome. J Am Coll Cardiol. 2004; 43: 1853–1860.CrossrefMedlineGoogle Scholar20 Silka MJ, Bar-Cohen Y. Pacemakers and implantable cardioverter-defibrillators in pediatric patients. Heart Rhythm. 2006; 3: 1360–1366.CrossrefMedlineGoogle Scholar21 Stephenson EA, Batra AS, Knilans TK, Gow RM, Gradaus R, Balaji S, Dubin AM, Rhee EK, Ro PS, Thogersen AM, Cecchin F, Triedman JK, Walsh EP, Berul CI. A multicenter experience with novel implantable cardioverter defibrillator configurations in the pediatric and congenital heart disease population. J Cardiovasc Electrophysiol. 2006; 17: 41–46.CrossrefMedlineGoogle Scholar22 Antzelevitch C. The Brugada syndrome: ionic basis and arrhythmia mechanisms. 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Medeiros-Domingo A, Tan B, Iturralde-Torres P, Tester D, Tusié-Luna T, Makielski J and Ackerman M (2009) Unique mixed phenotype and unexpected functional effect revealed by novel compound heterozygosity mutations involving SCN5A, Heart Rhythm, 10.1016/j.hrthm.2009.04.034, 6:8, (1170-1175), Online publication date: 1-Aug-2009. Antzelevitch C and Nof E (2008) Brugada syndrome: Recent advances and controversies, Current Cardiology Reports, 10.1007/s11886-008-0060-y, 10:5, (376-383), Online publication date: 1-Sep-2008. Campuzano O, Sarquella‐Brugada G, Brugada R, Brugada J and Brugada P (2013) Brugada Syndrome eLS, 10.1002/9780470015902.a0003634.pub2 April 17, 2007Vol 115, Issue 15 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.106.686758PMID: 17438161 Originally publishedApril 17, 2007 KeywordstachyarrhythmiasgeneticsEditorialsdeath, suddenelectrical stimulationBrugada syndromeantiarrhythmia agentsPDF download Advertisement SubjectsArrhythmias
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