Inherited ion channel diseases: a brief review

Transcription

1 Europace (2015) 17, ii1 ii6 doi: /europace/euv105 SUPPLEMENT: REVIEW Inherited ion channel diseases: a brief review Krystien V.V. Lieve 1 and Arthur A.M. Wilde 1,2 * 1 Heart Centre, Department of Clinical and Experimental Cardiology, Academic Medical Centre, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands; and 2 Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia Received 12 February 2015; accepted after revision 24 March 2015 Ion channelopathies are diseases caused by dysfunctional ion channels that may lead to sudden death. These diseases can be either acquired or inherited. The main phenotypes observed in patients carrying these heritable arrhythmia syndromes are congenital long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome. In the recent years, tremendous progress has been made in the recognition, mechanisms, and treatment of these diseases. The goal of this review is to provide an overview of the main phenotypes, genetic underpinnings, risk stratification, and treatment options for these so-called cardiac ion channelopathies Keywords Genetic Inherited channelopathies Sudden death Introduction Inherited ion channel diseases, although rare, have attracted enormous attention in recent years. They are one by one associated with unexpected sudden death of individuals and timely and appropriate therapy may prevent such dramatic events. The identification of genes underlying these disease entities has enabled pre-symptomatic identification of individuals at risk and has led to more sophisticated risk stratification (also in symptomatic individuals). In addition, it has led to targeted therapy with some gene-specific elements. This brief review aims to focus on some of these recent developments. Long QT syndrome Clinical presentation In 2009, an Italian population study aimed to investigate the prevalence of the long QTsyndrome (LQTS). Electrocardiogram(ECG) screening was performed in neonates. If neonatesthat were found to have a prolonged corrected QT (QTc) intervals (.450 ms), the ECG was repeated within 2 weeks. If the QTc remained prolonged after the second measurement (a QTc.470 ms or between 461 and 470 ms), genetic testing(types1 7)wasperformed.Thisled to anestimated prevalence of a little over 1: Long QT syndrome is an inherited cardiac arrhythmia disorder characterized by a prolonged QT interval on resting 12-lead surface ECG, due to delayed cardiac repolarization, in the absence of structural heart disease. Clinically, LQTS presents with syncope, aborted cardiac arrest (ACA), or sudden cardiac death (SCD). These symptoms are due to ventricular arrhythmias, in particular, torsades de pointes, the hallmark of the disease, which may subsequently deteriorate to ventricular fibrillation (VF). In 10 15% of LQTS patients, the first and only symptom is SCD. 2 A significant percentage of the patients, however, remains asymptomatic during their whole life. Of the individuals that do become symptomatic, 50% experience their first cardiac event by the age of 12 and 90% by the age of Genetic background A pathogenic mutation can be identified in 60% of the LQTS patients. 4 Mostly, these are inherited as an autosomal dominant trait. The rare and highly malignant Jervell and Lange-Nielsen syndrome, which affects between 1: and 1: individuals, is inherited in an autosomal recessive manner with compound heterozygous or homozygous mutations in either KCNQ1 or KCNE2. 5,6 Up to now, over 15 genetically distinct types of LQTS have been described. 7 However, almost 90% of the mutations are found in three genes: KCNQ1 (encoding Kv7.1), KCNH2 (encoding Kv11.1), and SCN5A (encoding Nav 1.5) causing LQT1, LQT2, and LQT3, respectively. 8 These three subtypes can be identified by T wave morphology (Figure 1) on the ECG and by the specific triggers that provoke symptoms. Type 1 is characterized by broad-based T waves and symptoms typically occur during exercise. 9,10 Type 2 has low amplitude notched or biphasic T waves and auditory noise trigger symptoms. 9,11 Finally, the LQTS type 3 ECG has a long isoelectric segment followed by a narrow-based T wave while symptoms mostly occur during rest. 9,10,12 The remaining pathogenic mutations are found in genes encoding for other ion channels or ion channel interacting proteins. 7 * Corresponding author. Tel: address: a.a.wilde@amc.uva.nl Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 ii2 K.V.V. Lieve et al. Diagnosis The diagnosis of LQTS is based on criteria expressed in a recent consensus document endorsed by the, worldwide, three main EP societies. 13 Central in the diagnosis consensus is the updated Schwartz score (Table 1); a diagnosis of LQTS can be made with a score 3.5 points if a secondary cause for QT prolongation has been excluded. 13,14 In 75% of the cases with a Schwartz score 4, a pathogenic mutation can be identified. 8 By means of the updated Schwartz score, LQTS can be easily diagnosed for the extremes of the curve (patients with either a low or a high Schwartz score). When using this score, one should keep in mind +35% of LQT1, +20% of LQT2, and +10% of LQT3, respectively, have a normal QT interval. 15 Risk stratification and current management Patients with a prolonged QTc interval 500 ms and a history of syncope are at high risk for SCD. 15 More recently, studies have identified risk factors tailored to the specific underlying genetic substrate. Long QT syndrome type 1 patients with missense cytoplasmic-loop mutations seem at increased risk (hazard ratio vs. non-missense mutations ¼ 2.75; 95% confidence interval, ; P ¼ 0.009) for ACA/SCD. 16 Females are at greater risk for ACA/ SCD in LQTS2 (26 vs. 14%; P, 0.001) as well men with a pore-loop mutation, in particular missense mutations. 17,18 Beta-blocker therapy is the first choice for LQTS. 13 However, effectiveness might vary for the different subtypes. Long QT syndrome type 1 patients probably benefit most of b-blocker therapy 10 while it is somewhat less effective in LQTS2. 19 Furthermore, not all subtypes of b-blockers are equally effective in LQTS: propanolol and nadolol seem to be the most effective. 20 These findings are, however, challenged by a recent report suggesting there may actual be no difference between the b-blocker subtypes. 21 In LQTS3, preliminary data suggest that b-blockers are also highly effective. 22 For LQTS3, mexiletine and more recently ranolazine have proved to be beneficial and can be used adjunct to b-blocker therapy. 23,24 Long-term followup is, however, not available. Figure 1 Characteristic ECGs of the various cardiac channelopathies. The main cardiac ion channels involved in inherited ion channel diseases. Loss-of-function mutations in KCNQ1 and KCNH2 lead tot LQTS1 (A) and LQTS2 (B), respectively. Gain-of-function mutations in KCNQ1 or KCNH2 lead to SQTS (D). Gain-of-function mutations in SCN5A lead to LQTS3 (C), loss-of-function mutations lead to BrS (E). Loss-of-function mutations in RYR2 lead to CPVT (F).

3 Inherited ion channel diseases: a brief review ii3 Table LQTS diagnostic criteria Points... Electrocardiographic findings a A QTc b 480 ms ms ms (in males) 1 B QTc b fourth minute of recovery from exercise 1 stress test 480 ms C Torsades de pointes c 2 D T wave alternans 1 E Notched T wave in three leads 1 F Low heart rate for age d 0.5 Clinical history A Syncope c With stress 2 Without stress 1 B Congenital deafness Family history A Family members with definite LQTS e 1 B Unexplained SCD below age 30 among immediate 0.5 family members e Score: 1 point: low probability of LQTS; points: intermediate probability of LQTS; 3.5 points: high probability. a In the absence of medications or disorders known to affect these electrocardiographic features. b QTc calculated by Bazett s formula where QTcQT/RR. c Mutually exclusive. d Resting heart rate below the second percentile for age. e The same family member cannot be counted in A and B. Implantable cardioverter-defibrillator (ICD) therapy can be used for those who have suffered ACA, have syncopal episodes on b-blocker therapy, or are at extremely high risk of SCD, based, for example, on very long QTc (.550 ms) intervals. 13 Left cardiac sympathetic denervation (LCSD) can be used as an adjunctive therapy for severely affected patients who are refractory to b-blocker therapy. In this surgical procedure, the lower two-thirds of the left stellate ganglion is ablated together with the thoracic ganglia T2 T4 to denervate cardiac sympathetic innervation to the heart. 25 Left cardiac sympathetic denervation has been shown to reduce cardiac events significantly in LQTS with a reasonable long-term cardiac-event-free survival (46%/5 years). 25 Short QT syndrome Short QT syndrome (SQTS) is rare entity included in the group of inherited primary electric disorders without structural heart disease. Patients are at increased risk of atrial fibrillation, VF, and SCD. The exact prevalence of SQTS is unknown. 26,27 A QT interval 330 ms is considered diagnostic in the absence of tachycardia or bradycardia (Figure 1). 13 Gain-of-function mutations in three genes encoding potassium channels, KCNQ1, KCNH2, and KCNJ2 have been associated with the SQTS. Short QT syndrome is associated with a high incidence of SCD; therefore, prophylactic ICD therapy is appropriate. 26,31 Adjunctive pharmacological therapy in the form of quinidine related to its QT interval prolonging properties seems to be beneficial in a subset of these patients. 32 Brugada syndrome Clinical presentation Brugada syndrome (BrS) was originally described as ST elevation with successive negative T wave in the right precordial leads without structural cardiac abnormalities. 13,33 Clinically, it presents with syncope or cardiac arrest due to VF. The vast majority of the patients remain asymptomatic. The incidence and prevalence of BrS varies around the world but is estimated to be 5 20 in every , with the highest prevalence in south east Asia. 34 Mean age of patients with VF is years and this occurs predominantly in males. Nevertheless, arrhythmic events have been reported from the age of 2 up to Arrhythmias typically occur while sleeping or at rest or may occur after large, heavy meals; all this is believed to be due to a high vagal tone. 36 Furthermore, fever is an important risk factor for ECG changes that subsequently may lead to VF. 37 Genetic background In up to 35% of the cases, a causal mutation can be identified, 4 most of them involving the SCN5A gene (encoding the alpha subunit of the cardiac sodium channel Nav1.5). 38 The disease is inherited as an autosomal dominant trait with incomplete penetrance. 39 Mutations in the SCN5A gene are linked to various clinical phenotypes including LQTS3 and conduction disorders. It therefore did not come as a complete surprise that several SCN5A mutations manifest clinically as an overlap syndrome (i.e. combinations of BrS, LQTS, conduction disorders, and sick sinus syndrome). 40 In the past years, many mutations in several genes have been published; however, these genes have merely been found in single families and are only responsible for 5% of the BrS cases. 41 Recently, genetic studies suggested a oligogenetic inheritance pattern, an inheritance pattern in which more than one causal gene is needed in order to establish a clinical phenotype (i.e. the multiple genetic hit hypothesis ), underlying BrS. 42 Typical electrocardiogram and diagnosis The diagnosis of BrS involves the detection of the typical ECG abnormality in a single lead at any position on the RV thorax. 13 Coved-type ST-segment elevation and negative T wave in any of the right precordial leads with or without a drug challenge test in the 12-lead ECG is the hallmark of diagnosis (Figure 1). In the recent past, together with

4 ii4 K.V.V. Lieve et al. the ECG abnormality, one of the following criteria was necessary: (i) a history of ventricular tachycardia (VT)/VF, (ii) a family history of SCD, (iii) a family history of coved-type ECG, (iv) agonal respiration during sleep, or (v) inducibility of VT/VF during electrophysiological study. 35 In order to be consistent with the diagnosis of LQTS, these criteria were abandoned in the most recent consensus. 13 In cases where BrS is suspected, but the ECG lacks the diagnostic criteria, a drug challenge can be performed using a sodium channel blocking agent. 13 Confounding factors (ischaemic heart disease, myocarditis, hyperkalaemia, hypercalcaemia, arrhythmogenic right ventricular dysplasia, pulmonary embolism, or mechanical compression of the RVOT) need to be excluded before the definite diagnosis of BrS can be made. 35 Risk stratification and current management In the past years, several indicators for risk in BrS have been identified. Patients with a history of VT/VF or syncope suggestive of malignant arrhythmia origin and spontaneous coved-type ST-segment elevations are at risk for future arrhythmic events. For asymptomatic patients, however, risk stratification is still ill-defined. Even though male patients more often present with VF, it has not proved to be a consistent risk factor for future arrhythmic events. 43,44 The role of electrophysiology study for risk stratification remains an ongoing debate. 45,46 Marked spontaneous variation of the ST segment and fractionation of the QRS complex is potential important markers for future arrhythmic events. 47 An ICD is the first-line therapy for patients with BrS with a history of VT/VF or syncope, suggestive of malignant arrhythmia origin. 13 For patients with a definite or suspected diagnosis of BrS, caution is needed in the usage of specific drugs since these can provoke the type 1 ECG and subsequently lead to arrhythmias. A full list of drugs-to-avoid can be found on 48 Catecholaminergic polymorphic ventricular tachycardia Clinical presentation Catecholaminergic polymorphic ventricular tachycardia (CPVT) typically presents at the mean age of 10 with syncope or cardiac arrest triggered by exercise or emotion. 49 While the baseline ECG is normal, exercise provokes, very reproducibly, the diagnostic polymorphic ventricular arrhythmias, and in a minority of patients the characteristic bidirectional VT (Figure 1), which can be observed during exercise testing or Holter recording. 49 Catecholaminergic polymorphic ventricular tachycardia is a rare disorder and has an estimated prevalence of 1: Even though it is rare, recognition of CPVT is vital importance due to its high mortality rate of up to 50% in affected untreated individuals up to the age of In autopsynegative studies of young sudden death victims, a pathogenic ryanodine receptor 2 (RYR2) mutation was identified in 11.6% of the cases. 50 Hence, CPVT potentially plays an important role in autopsynegative sudden death of young patients. Genetic background A number of genetic subtypes have been recognized for this disorder. Catecholaminergic polymorphic ventricular tachycardia type 1, accounting for 65% of index cases, 51 is caused by mutations in the gene encoding the cardiac RYR2 and segregates as an autosomal dominant trait. Catecholaminergic polymorphic ventricular tachycardia type 2 is associated with mutations in the cardiac calsequestrin gene (CASQ2), mostly shows an autosomal recessive inheritance pattern, and accounts for a few per cent of index cases. 52 RYR2 and CASQ2 are proteins involved in calcium homeostasis of the cardiomyocyte. A leakage in the RYR2 receptor results in inappropriate diastolic calcium release from the sarcoplasmic reticulum, leading to delayed after-depolarizations and ventricular arrhythmias. Catecholaminergic polymorphic ventricular tachycardia has also been associated with mutations in KCNJ2 (CPVT3). Recently, triadin (TRDN) 53 and calmodulin (CALM1) 54 have been identified as new CPVT genes. Typical electrocardiogram and diagnosis It is characterized by exercise- or emotion-induced ventricular arrhythmias, including VT or VF in the absence of resting electrocardiographic or structural cardiac abnormalities. 13 Risk stratification and current management Risk stratification in CPVT is virtually non-existent. Male gender, younger age at the time of diagnosis, history of ACA, arrhythmias while treated with b-blockers, and location of the mutation in the c-terminus of the gene have been suggested as potential risk factors for arrhythmic events. 51,55,56 Since risk stratification is ill-defined, the current consensus is to offer active treatment to every clinically or genetically diagnosed CPVT patient (including the genotypepositive, phenotype-negative patients). 13 First-line therapy consists of b-blockers at the highest tolerable dose. 57 Up until a few years ago, the only alternative for patients with significant ventricular arrhythmias and/or cardiac events despite b-blocker therapy was ICD implantation. However, in the past years, significant advances have been made in developing new treatment alternatives for CPVT. For patients with significant ventricular arrhythmias despite adequate b-blocker dose, flecainide can be added to the therapy. 58 There are several theories about the arrhythmia-reducing properties of flecainide: some reports state that flecainide reduces the arrhythmias by directly blocking the RYR2 channel, 59 other reports have demonstrated that the reduced arrhythmia burden is due to the direct effects of sodium-dependent modulation of intracellular calcium handling that impairs the RYR2 dysfunction. 60 In addition, flecainide inhibits delayed after-depolarizations through its sodium channel blocking properties and hereby prevents triggered beats. 59 For severely affected patients, LCSD has been demonstrated to be an effective treatment. 61 Implantable cardioverter-defibrillator therapy should be used with caution since a shock from an ICD can lead to catecholamine release due to pain or fear that subsequently can lead to ventricular storms. 62

5 Inherited ion channel diseases: a brief review ii5 Conclusion and perspectives Owing to extensive research in the past years, our knowledge on cardiac ion channelopathies has grown extensively. This is especially true for LQTS, where gene-specific risk stratification and genespecific treatment options have emerged. However, an ongoing debate for practically all of the channelopathies remains in place on how to treat genotype-positive, phenotype-negative cases. Secondly, a significant percentage of the SCD/ACA cases, especially those in the age group,35 years of age, remains of complete unknown origin: idiopathic VF. Even with the addition of molecular autopsy, a percentage as high as 65% remains of unknown cause. Finally, the success rates in genetic testing vary considerably between the channelopathies: 30 70% of the cases remain elusive. These facts underscore the importance of future clinical studies and gene discovery for the cardiac channelopathies. Funding We acknowledge the support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences. Conflict of interest: none declared. References 1. Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G et al. Prevalence of the congenital long-qt syndrome. Circulation 2009;120: Ackerman MJ. Cardiac channelopathies: it s in the genes. Nat Med 2004;10: Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati EH, MacCluer J et al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation 1991;84: Hofman N, Tan HL, Alders M, Kolder I, de Haij S, Mannens MMAM et al. Yield of molecular and clinical testing for arrhythmia syndromes: report of 15 years experience. Circulation 2013;128: Splawski I, Timothy KW, Vincent GM, Atkinson DL, Keating MT. Molecular basis of the long-qt syndrome associated with deafness. N Engl J Med 1997;336: Schulze-Bahr E, Wang Q, Wedekind H, Haverkamp W, Chen Q, Sun Y et al. KCNE1 mutations cause Jervell and Lange-Nielsen syndrome. Nat Genet 1997;17: Mizusawa Y, Horie M, Characteristics C. Genetic and clinical advances in congenital long QT syndrome. 2014; Tester DJ, Will ML, Haglund CM, Ackerman MJ. Effect of clinical phenotype on yield of long QT syndrome genetic testing. J Am Coll Cardiol 2006;47: Moss AJ, Zareba W, Benhorin J, Locati EH, Hall WJ, Robinson JL et al. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation 1995;92: Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C et al. Genotype-phenotype correlation in the long-qt syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001;103: Wilde AA, Jongbloed RJ, Doevendans PA, Düren DR, Hauer RN, van Langen IM et al. Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). J Am Coll Cardiol 1999; 33: Takigawa M, Kawamura M, Noda T, Yamada Y, Miyamoto K, Okamura H et al. Seasonal and circadian distributions of cardiac events in genotyped patients with congenital long QT syndrome. Circ J 2012;76: Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C et al. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Europace 2013;15: Schwartz PJ, Crotti L. QTc behavior during exercise and genetic testing for the long-qt syndrome. Circulation 2011;124: Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M et al. Risk stratification in the long-qt syndrome. N Engl J Med 2003;348: Barsheshet A, Goldenberg I, O-Uchi J, Moss AJ, Jons C, Shimizu W et al. Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to b-blocker therapy in type 1 long-qt syndrome. Circulation 2012;125: Shimizu W, Moss AJ, Wilde AAM, Towbin JA, Ackerman MJ, January CT et al. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol 2009; 54: Migdalovich D, Moss AJ, Lopes CM, Costa J, Ouellet G, Barsheshet A et al. Mutation and gender-specific risk in type 2 long QT syndrome: implications for risk stratification for life-threatening cardiac events in patients with long QT syndrome. Heart Rhythm 2011;8: Priori SG, Napolitano C, Schwartz PJ, Grillo M, Bloise R, Ronchetti E et al. Association of long QT syndrome loci and cardiac events among patients treated with betablockers. JAMA 2004;292: Chockalingam P, Crotti L, Girardengo G, Johnson JN, Harris KM, van der Heijden JF et al. Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol. J Am Coll Cardiol 2012;60: Abu-Zeitone A, Peterson DR, Polonsky B, McNitt S, Moss AJ. Efficacy of different beta-blockers in the treatment of long QT syndrome. J Am Coll Cardiol 2014;64: Wilde AA, Kaufman ES, Shimizu W, Moss AJ, Benhorin J, Lopes CM et al..sodium channel mutations, risk of cardiac events, and efficacy of beta-blocker therapy in type 3 long QT syndrome. Heart Rhythm 2012;9(Suppl):S Ruan Y, Liu N, Bloise R, Napolitano C, Priori SG. Gating properties of SCN5A mutations and the response to mexiletine in long-qt syndrometype 3 patients. Circulation 2007;116: Antzelevitch C, Burashnikov A, Sicouri S, Belardinelli L. Electrophysiologic basis for the antiarrhythmic actions of ranolazine. Heart Rhythm 2011;8: Schwartz PJ, Priori SG, Cerrone M, Spazzolini C, Odero A, Napolitano C et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-qt syndrome. Circulation 2004;109: Patel C, Yan G-X, Antzelevitch C. Short QT syndrome: from bench to bedside. Circ Arrhythm Electrophysiol 2010;3: Bjerregaard P, Gussak I. Short QT syndrome: mechanisms, diagnosis and treatment. Nat Clin Pract Cardiovasc Med 2005;2: Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M et al. Sudden death associated with short-qt syndrome linked to mutations in HERG. Circulation 2004; 109: Bellocq C, van Ginneken ACG, Bezzina CR, Alders M, Escande D, Mannens MMAM et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 2004;109: Priori SG, Pandit SV, Rivolta I, Berenfeld O, Ronchetti E, Dhamoon A et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res 2005;96: Giustetto C, Di Monte F, Wolpert C, Borggrefe M, Schimpf R, Sbragia P et al. Short QT syndrome: clinical findings and diagnostic-therapeutic implications. Eur Heart J 2006;27: Gaita F, Giustetto C, Bianchi F, Schimpf R, Haissaguerre M, Calò L et al. Short QT syndrome: pharmacological treatment. J Am Coll Cardiol 2004;43: BrugadaP, Brugada J. Right bundle branchblock, persistentst segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol 1992;20: Juang J-M, Huang SKS. Brugada syndrome an under-recognized electrical disease in patients with sudden cardiac death. Cardiology 2004;101: Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005;111: Takigawa M, Noda T, Shimizu W, Miyamoto K, Okamura H, Satomi K et al. Seasonal and circadian distributions of ventricular fibrillation in patients with Brugada syndrome. Heart Rhythm 2008;5: Amin AS, Meregalli PG, Bardai A, Wilde AAM, Tan HL. Fever increases the risk for cardiac arrest in the Brugada syndrome. Ann Intern Med 2008;149: Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm 2010;7: Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P et al. Genetic basis and molecular mechanism for idiopathicventricular fibrillation. Nature 1998;392: Remme CA, Wilde AAM, Bezzina CR. Cardiac sodium channel overlap syndromes: different faces of SCN5A mutations. Trends Cardiovasc Med 2008;18:78 87.

6 ii6 K.V.V. Lieve et al. 41. Crotti L, Marcou CA, Tester DJ, Castelletti S, Giudicessi JR, Torchio M et al. Spectrum and prevalence of mutations involving BrS1-through BrS12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing: implications for genetic testing. J Am Coll Cardiol 2012;60: Bezzina CR, Barc J, Mizusawa Y, Remme CA, Gourraud J-B, Simonet F et al. Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nat Genet 2013;45: 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: ProbstV, Veltmann C, Eckardt L, Meregalli PG, Gaita F, TanHL et al. Long-term prognosis of patients diagnosed with Brugada syndrome: Results from the FINGER Brugada Syndrome Registry. Circulation 2010;121: Wilde AAM, Viskin S. Rebuttal to EP testing predicts cardiac events in patients with Brugada syndrome. Heart Rhythm 2011;8: Brugada J, Brugada R, Brugada P. Electrophysiologic testing predicts events in Brugada syndrome patients. Heart Rhythm 2011;8: Morita H, Kusano KF, Miura D, Nagase S, Nakamura K, Morita ST et al. Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome. Circulation 2008;118: Postema PG, Wolpert C, Amin AS, Probst V, Borggrefe M, Roden DM et al. Drugs and Brugada syndrome patients: review of the literature, recommendations, and an up-to-date website ( Heart Rhythm 2009;6: Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation 1995;91: Tester DJ, Medeiros-Domingo A, Will ML, Haglund CM, Ackerman MJ. Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsy-negative sudden unexplained death referred for postmortem genetic testing. Mayo Clin Proc 2012;87: Priori SG, Napolitano C, Memmi M, Colombi B, Drago F, Gasparini M et al. Clinical and molecularcharacterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002;106: Lahat H, Pras E, Olender T, Avidan N, Ben-Asher E, Man O et al. A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel. Am J Hum Genet 2001;69: Roux-Buisson N, Cacheux M, Fourest-Lieuvin A, Fauconnier J, Brocard J, Denjoy I et al. Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human. Hum Mol Genet 2012;21: Nyegaard M, Overgaard MT, Søndergaard MT, Vranas M, Behr ER, Hildebrandt LL et al. Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death. Am J Hum Genet 2012;91: Vander Werf C, NederendI, HofmanN, van Geloven N, Ebink C, Frohn-Mulder IME et al. Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives. Circ Arrhythm Electrophysiol 2012;5: Hayashi M, Denjoy I, Extramiana F, Maltret A, Buisson NR, Lupoglazoff J-M et al. Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia. Circulation 2009;119: Van der Werf C, Zwinderman AH, Wilde AA. Therapeutic approach for patients with catecholaminergic polymorphic ventricular tachycardia: state of the art and future developments. Europace 2012;14: Van der Werf C, Kannankeril PJ, Sacher F, Krahn AD, Viskin S, Leenhardt A et al. Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol 2011;57: Watanabe H, Chopra N, Laver D, Hwang HS, Davies SS, Roach DE et al. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat Med 2009;15: Bannister ML, Thomas NL, Sikkel MB, Mukherjee S, Maxwell CE, MacLeod KT et al. The mechanism offlecainide actionincpvt doesnotinvolveadirecteffect onryr2. Circ Res Wilde AAM, BhuiyanZA, CrottiL, Facchini M, De Ferrari GM, Paul Tet al. Left cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia. N Engl J Med 2008;358: Mohamed U, Gollob MH, Gow RM, Krahn AD. Sudden cardiac death despite an implantable cardioverter-defibrillatorinayoungfemalewith catecholaminergic ventricular tachycardia. Heart Rhythm 2006;3: