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Ion Channel Diseases: an Update for 2016

  • Arrhythmia (D Spragg, Section Editor)
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Opinion statement

Ion channelopathies are a frequent cause of sudden cardiac death (SCD) in patients with structurally normal hearts. These are generally Mendelian inherited electrical disorders with variable penetrance and expressivity. The ability to predict the development of life threatening arrhythmias in these patients is challenging. This chapter will present an update on the genetics, the role of genetic testing, and management of the inherited cardiac channelopathies with a focus on the relatively more common syndromes associated with an increased risk of SCD.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Zheng ZJ, Croft JB, Giles WH, Mensah GA. Sudden cardiac death in the United States, 1989 to 1998. Circulation. 2001;104(18):2158–63.

    Article  CAS  PubMed  Google Scholar 

  2. Nichol G, Thomas E, Callaway CW, Hedges J, Powell JL, Aufderheide TP, et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA. 2008;300(12):1423–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chugh SS, Jui J, Gunson K, Stecker EC, John BT, Thompson B, et al. Current burden of sudden cardiac death: multiple source surveillance versus retrospective death certificate-based review in a large U.S. community. J Am Coll Cardiol. 2004;44(6):1268–75.

    Article  PubMed  Google Scholar 

  4. Kong MH, Fonarow GC, Peterson ED, Curtis AB, Hernandez AF, Sanders GD, et al. Systematic review of the incidence of sudden cardiac death in the United States. J Am Coll Cardiol. 2011;57(7):794–801.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Myerburg RJ, Junttila MJ. Sudden cardiac death caused by coronary heart disease. Circulation. 2012;125(8):1043–52.

    Article  PubMed  Google Scholar 

  6. Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death. Structure, function, and time-dependence of risk. Circulation. 1992;85(1 Suppl):I2–10.

    CAS  PubMed  Google Scholar 

  7. Watkins H, Ashrafian H, Redwood C. Inherited cardiomyopathies. N Engl J Med. 2011;364(17):1643–56.

    Article  CAS  PubMed  Google Scholar 

  8. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, et al. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990;62(5):999–1006.

    Article  CAS  PubMed  Google Scholar 

  9. Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell. 1995;80(5):805–11.

    Article  CAS  PubMed  Google Scholar 

  10. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995;80(5):795–803.

    Article  CAS  PubMed  Google Scholar 

  11. Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet. 1996;12(1):17–23.

    Article  PubMed  Google Scholar 

  12. Brink PA, Crotti L, Corfield V, Goosen A, Durrheim G, Hedley P, et al. Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population. Circulation. 2005;112(17):2602–10.

    Article  PubMed  Google Scholar 

  13. Marjamaa A, Salomaa V, Newton-Cheh C, Porthan K, Reunanen A, Karanko H, et al. High prevalence of four long QT syndrome founder mutations in the Finnish population. Ann Med. 2009;41(3):234–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tester DJ, Ackerman MJ. Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice. Circulation. 2011;123(9):1021–37.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Bezzina CR, Lahrouchi N, Priori SG. Genetics of sudden cardiac death. Circ Res. 2015;116(12):1919–36. This is a timely and comprehensive review of diseases associated with sudden death inherited in Mendelian and more complex manners.

    Article  CAS  PubMed  Google Scholar 

  16. Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013;15(7):565–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Behr ER, Dalageorgou C, Christiansen M, Syrris P, Hughes S, Tome Esteban MT, et al. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. Eur Heart J. 2008;29(13):1670–80.

    Article  PubMed  Google Scholar 

  18. Nunn LM, Lambiase PD. Genetics and cardiovascular disease--causes and prevention of unexpected sudden adult death: the role of the SADS clinic. Heart. 2011;97(14):1122–7.

    Article  CAS  PubMed  Google Scholar 

  19. Ingles J, Yeates L, Semsarian C. The emerging role of the cardiac genetic counselor. Heart Rhythm. 2011;8(12):1958–62.

    Article  PubMed  Google Scholar 

  20. Hofman N, Tan HL, Alders M, van Langen IM, Wilde AA. Active cascade screening in primary inherited arrhythmia syndromes: does it lead to prophylactic treatment? J Am Coll Cardiol. 2010;55(23):2570–6.

    Article  PubMed  Google Scholar 

  21. Christiaans I, van Langen IM, Birnie E, Bonsel GJ, Wilde AA, Smets EM. Genetic counseling and cardiac care in predictively tested hypertrophic cardiomyopathy mutation carriers: the patients' perspective. Am J Med Genet A. 2009;149A(7):1444–51.

    Article  PubMed  Google Scholar 

  22. Bai R, Napolitano C, Bloise R, Monteforte N, Priori SG. Yield of genetic screening in inherited cardiac channelopathies: how to prioritize access to genetic testing. Circ Arrhythm Electrophysiol. 2009;2(1):6–15.

    Article  CAS  PubMed  Google Scholar 

  23. van der Werf C, Hofman N, Tan HL, van Dessel PF, Alders M, van der Wal AC, et al. Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the young: the experience of a tertiary referral center in The Netherlands. Heart Rhythm. 2010;7(10):1383–9.

    Article  PubMed  Google Scholar 

  24. van Langen IM, Birnie E, Leschot NJ, Bonsel GJ, Wilde AA. Genetic knowledge and counselling skills of Dutch cardiologists: sufficient for the genomics era? Eur Heart J. 2003;24(6):560–6.

    Article  PubMed  Google Scholar 

  25. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10(12):1932–63. This is the most recent guideline document that presents the criteria for diagnosis and treatment recommendations for inherited arrhythmia syndromes.

    Article  PubMed  Google Scholar 

  26. Schwartz PJ, Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation. 2011;124(20):2181–4.

    Article  PubMed  Google Scholar 

  27. Dessertenne F. La tachycardie ventriculaire a deux foyers opposes variables. Arch Mal Coeur. 1966;59:263–72.

    CAS  PubMed  Google Scholar 

  28. 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(1):89–95.

    Article  CAS  PubMed  Google Scholar 

  29. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. 2011;8(8):1308–39.

    Article  PubMed  Google Scholar 

  30. 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(10):2929–34.

    Article  CAS  PubMed  Google Scholar 

  31. 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(19):1866–74.

    Article  PubMed  Google Scholar 

  32. 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(18):1761–7.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Nyegaard M, Overgaard MT, Sondergaard 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(4):703–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Crotti L, Johnson CN, Graf E, De Ferrari GM, Cuneo BF, Ovadia M, et al. Calmodulin mutations associated with recurrent cardiac arrest in infants. Circulation. 2013;127(9):1009–17.

    Article  CAS  PubMed  Google Scholar 

  35. Liu JF, Jons C, Moss AJ, McNitt S, Peterson DR, Qi M, et al. Risk factors for recurrent syncope and subsequent fatal or near-fatal events in children and adolescents with long QT syndrome. J Am Coll Cardiol. 2011;57(8):941–50.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Zareba W, Moss AJ, Locati EH, Lehmann MH, Peterson DR, Hall WJ, et al. Modulating effects of age and gender on the clinical course of long QT syndrome by genotype. J Am Coll Cardiol. 2003;42(1):103–9.

    Article  PubMed  Google Scholar 

  37. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell. 2004;119(1):19–31.

    Article  CAS  PubMed  Google Scholar 

  38. Moss AJ, Shimizu W, Wilde AA, Towbin JA, Zareba W, Robinson JL, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007;115(19):2481–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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(10):1537–43.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Goldenberg I, Horr S, Moss AJ, Lopes CM, Barsheshet A, McNitt S, et al. Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals. J Am Coll Cardiol. 2011;57(1):51–9.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Zhang C, Kutyifa V, McNitt S, Zareba W, Goldenberg I, Moss AJ. Identification of low-risk adult congenital LQTS patients. J Cardiovasc Electrophysiol. 2015;26(8):853–8.

    Article  PubMed  Google Scholar 

  42. Johnson JN, Ackerman MJ. Competitive sports participation in athletes with congenital long QT syndrome. JAMA. 2012;308(8):764–5.

    Article  CAS  PubMed  Google Scholar 

  43. Ackerman MJ, Zipes DP, Kovacs RJ, Maron BJ: Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 10: The Cardiac Channelopathies: A Scientific Statement From the American Heart Association and American College of Cardiology. Circulation 2015. This is a recent guidelines document that covers questions regarding the sports participation of patients with inherited diseases of ion channels. The document includes not only prohibitions but some of the recommendations for safe participation.

  44. 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(20):2092–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Moss AJ, Zareba W, Schwarz KQ, Rosero S, McNitt S, Robinson JL. Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome. J Cardiovasc Electrophysiol. 2008;19(12):1289–93.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Windle JR, Geletka RC, Moss AJ, Zareba W, Atkins DL. Normalization of ventricular repolarization with flecainide in long QT syndrome patients with SCN5A:DeltaKPQ mutation. Ann Noninvasive Electrocardiol. 2001;6(2):153–8.

    Article  CAS  PubMed  Google Scholar 

  47. Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantu F, Towbin JA, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. Circulation. 1995;92(12):3381–6.

    Article  CAS  PubMed  Google Scholar 

  48. Jons C, Moss AJ, Goldenberg I, Liu J, McNitt S, Zareba W, et al. Risk of fatal arrhythmic events in long QT syndrome patients after syncope. J Am Coll Cardiol. 2010;55(8):783–8.

    Article  PubMed  Google Scholar 

  49. Zareba W, Moss AJ, Daubert JP, Hall WJ, Robinson JL, Andrews M. Implantable cardioverter defibrillator in high-risk long QT syndrome patients. J Cardiovasc Electrophysiol. 2003;14(4):337–41.

    Article  PubMed  Google Scholar 

  50. Schwartz PJ, Spazzolini C, Priori SG, Crotti L, Vicentini A, Landolina M, et al. Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: data from the European Long-QT Syndrome Implantable Cardioverter-Defibrillator (LQTS ICD) Registry. Circulation. 2010;122(13):1272–82.

    Article  PubMed  Google Scholar 

  51. Monnig G, Kobe J, Loher A, Wasmer K, Milberg P, Zellerhoff S, et al. Role of implantable cardioverter defibrillator therapy in patients with acquired long QT syndrome: a long-term follow-up. Europace. 2012;14(3):396–401.

    Article  PubMed  Google Scholar 

  52. Berul CI, Van Hare GF, Kertesz NJ, Dubin AM, Cecchin F, Collins KK, et al. Results of a multicenter retrospective implantable cardioverter-defibrillator registry of pediatric and congenital heart disease patients. J Am Coll Cardiol. 2008;51(17):1685–91.

    Article  PubMed  Google Scholar 

  53. Kaufman ES, McNitt S, Moss AJ, Zareba W, Robinson JL, Hall WJ, et al. Risk of death in the long QT syndrome when a sibling has died. Heart Rhythm. 2008;5(6):831–6.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Odero A, Bozzani A, De Ferrari GM, Schwartz PJ. Left cardiac sympathetic denervation for the prevention of life-threatening arrhythmias: the surgical supraclavicular approach to cervicothoracic sympathectomy. Heart Rhythm. 2010;7(8):1161–5.

    Article  PubMed  Google Scholar 

  55. De Ferrari GM, Dusi V, Spazzolini C, Bos JM, Abrams DJ, Berul CI, et al. Clinical management of catecholaminergic polymorphic ventricular tachycardia: the role of left cardiac sympathetic denervation. Circulation. 2015;131(25):2185–93.

    Article  PubMed  Google Scholar 

  56. Li J, Wang L, Wang J. Video-assisted thoracoscopic sympathectomy for congenital long QT syndromes. Pacing Clin Electrophysiol. 2003;26(4 Pt 1):870–3.

    Article  PubMed  Google Scholar 

  57. Bos JM, Bos KM, Johnson JN, Moir C, Ackerman MJ: Left cardiac sympathetic denervation in long QT syndrome: analysis of therapeutic non-responders. Circ Arrhythm Electrophysiol 2013.

  58. Collura CA, Johnson JN, Moir C, Ackerman MJ. Left cardiac sympathetic denervation for the treatment of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia using video-assisted thoracic surgery. Heart Rhythm. 2009;6(6):752–9.

    Article  PubMed  Google Scholar 

  59. Schwartz PJ. Cardiac sympathetic denervation to prevent life-threatening arrhythmias. Nat Rev Cardiol. 2014;11(6):346–53. This is a review of the role of sympathetic denervation in the treatment of patients at high-risk for malignant ventricular arrhythmia. The review covers the indications, basic methodology and side effects.

    Article  PubMed  Google Scholar 

  60. Miyasaka Y, Tsuji H, Yamada K, Tokunaga S, Saito D, Imuro Y, et al. Prevalence and mortality of the Brugada-type electrocardiogram in one city in Japan. J Am Coll Cardiol. 2001;38(3):771–4.

    Article  CAS  PubMed  Google Scholar 

  61. Hermida JS, Lemoine JL, Aoun FB, Jarry G, Rey JL, Quiret JC. Prevalence of the brugada syndrome in an apparently healthy population. Am J Cardiol. 2000;86(1):91–4.

    Article  CAS  PubMed  Google Scholar 

  62. Sakabe M, Fujiki A, Tani M, Nishida K, Mizumaki K, Inoue H. Proportion and prognosis of healthy people with coved or saddle-back type ST segment elevation in the right precordial leads during 10 years follow-up. Eur Heart J. 2003;24(16):1488–93.

    Article  PubMed  Google Scholar 

  63. 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(5):659–70.

    Article  PubMed  Google Scholar 

  64. Priori SG, Gasparini M, Napolitano C, Della Bella P, Ottonelli AG, Sassone B, et al. Risk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) registry. J Am Coll Cardiol. 2012;59(1):37–45.

    Article  PubMed  Google Scholar 

  65. Probst V, Wilde AA, Barc J, Sacher F, Babuty D, Mabo P, et al. SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome. Circ Cardiovasc Genet. 2009;2(6):552–7.

    Article  CAS  PubMed  Google Scholar 

  66. Gottschalk BH, Anselm DD, Brugada J, Brugada P, Wilde AA, Chiale PA, Perez-Riera AR, Elizari MV, De Luna AB, Krahn AD, Tan HL et al.: Expert cardiologists cannot distinguish between Brugada phenocopy and Brugada syndrome electrocardiogram patterns. Europace 2015.

  67. Bezzina CR, Shimizu W, Yang P, Koopmann TT, Tanck MW, Miyamoto Y, et al. Common sodium channel promoter haplotype in Asian subjects underlies variability in cardiac conduction. Circulation. 2006;113(3):338–44.

    Article  CAS  PubMed  Google Scholar 

  68. Di Diego JM, Cordeiro JM, Goodrow RJ, Fish JM, Zygmunt AC, Perez GJ, et al. Ionic and cellular basis for the predominance of the Brugada syndrome phenotype in males. Circulation. 2002;106(15):2004–11.

    Article  PubMed  Google Scholar 

  69. Shimizu W, Matsuo K, Kokubo Y, Satomi K, Kurita T, Noda T, et al. Sex hormone and gender difference—role of testosterone on male predominance in Brugada syndrome. J Cardiovasc Electrophysiol. 2007;18(4):415–21.

    Article  PubMed  Google Scholar 

  70. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998;392(6673):293–6.

    Article  CAS  PubMed  Google Scholar 

  71. Yan GX, Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation. 1999;100(15):1660–6.

    Article  CAS  PubMed  Google Scholar 

  72. Wilde AA, Postema PG, Di Diego JM, Viskin S, Morita H, Fish JM, et al. The pathophysiological mechanism underlying Brugada syndrome: depolarization versus repolarization. J Mol Cell Cardiol. 2010;49(4):543–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Schulze-Bahr E, Eckardt L, Breithardt G, Seidl K, Wichter T, Wolpert C, et al. Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: different incidences in familial and sporadic disease. Hum Mutat. 2003;21(6):651–2.

    Article  PubMed  CAS  Google Scholar 

  74. Priori SG, Napolitano C, Gasparini M, Pappone C, Della Bella P, Brignole M, et al. Clinical and genetic heterogeneity of right bundle branch block and ST-segment elevation syndrome: A prospective evaluation of 52 families. Circulation. 2000;102(20):2509–15.

    Article  CAS  PubMed  Google Scholar 

  75. Bezzina CR, Barc J, Mizusawa Y, Remme CA, Gourraud JB, 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(9):1044–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Probst V, Veltmann C, Eckardt L, Meregalli PG, Gaita F, Tan HL, et al. Long-term prognosis of patients diagnosed with Brugada syndrome: Results from the FINGER Brugada Syndrome Registry. Circulation. 2010;121(5):635–43.

    Article  CAS  PubMed  Google Scholar 

  77. Tokioka K, Kusano KF, Morita H, Miura D, Nishii N, Nagase S, et al. Electrocardiographic parameters and fatal arrhythmic events in patients with Brugada syndrome: combination of depolarization and repolarization abnormalities. J Am Coll Cardiol. 2014;63(20):2131–8.

    Article  PubMed  Google Scholar 

  78. Kusano KF, Taniyama M, Nakamura K, Miura D, Banba K, Nagase S, et al. Atrial fibrillation in patients with Brugada syndrome relationships of gene mutation, electrophysiology, and clinical backgrounds. J Am Coll Cardiol. 2008;51(12):1169–75.

    Article  PubMed  Google Scholar 

  79. Morita H, Kusano-Fukushima K, Nagase S, Fujimoto Y, Hisamatsu K, Fujio H, et al. Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome. J Am Coll Cardiol. 2002;40(8):1437–44.

    Article  PubMed  Google Scholar 

  80. Kakishita M, Kurita T, Matsuo K, Taguchi A, Suyama K, Shimizu W, et al. Mode of onset of ventricular fibrillation in patients with Brugada syndrome detected by implantable cardioverter defibrillator therapy. J Am Coll Cardiol. 2000;36(5):1646–53.

    Article  CAS  PubMed  Google Scholar 

  81. Schweizer PA, Becker R, Katus HA, Thomas D. Successful acute and long-term management of electrical storm in Brugada syndrome using orciprenaline and quinine/quinidine. Clin Res Cardiol. 2010;99(7):467–70.

    Article  PubMed  Google Scholar 

  82. Maury P, Couderc P, Delay M, Boveda S, Brugada J. Electrical storm in Brugada syndrome successfully treated using isoprenaline. Europace. 2004;6(2):130–3.

    Article  CAS  PubMed  Google Scholar 

  83. Watanabe A, Fukushima Kusano K, Morita H, Miura D, Sumida W, Hiramatsu S, et al. Low-dose isoproterenol for repetitive ventricular arrhythmia in patients with Brugada syndrome. Eur Heart J. 2006;27(13):1579–83.

    Article  CAS  PubMed  Google Scholar 

  84. Haissaguerre M, Extramiana F, Hocini M, Cauchemez B, Jais P, Cabrera JA, et al. Mapping and ablation of ventricular fibrillation associated with long-QT and Brugada syndromes. Circulation. 2003;108(8):925–8.

    Article  PubMed  Google Scholar 

  85. Nademanee K, Veerakul G, Chandanamattha P, Chaothawee L, Ariyachaipanich A, Jirasirirojanakorn K, et al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation. 2011;123(12):1270–9.

    Article  PubMed  Google Scholar 

  86. Reid DS, Tynan M, Braidwood L, Fitzgerald GR. Bidirectional tachycardia in a child. A study using His bundle electrography. Br Heart J. 1975;37(3):339–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 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(5):1512–9.

    Article  CAS  PubMed  Google Scholar 

  88. Sumitomo N, Harada K, Nagashima M, Yasuda T, Nakamura Y, Aragaki Y, et al. Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death. Heart. 2003;89(1):66–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Priori SG, Napolitano C, Memmi M, Colombi B, Drago F, Gasparini M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2002;106(1):69–74.

    Article  CAS  PubMed  Google Scholar 

  90. Hayashi M, Denjoy I, Extramiana F, Maltret A, Buisson NR, Lupoglazoff JM, et al. Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia. Circulation. 2009;119(18):2426–34.

    Article  CAS  PubMed  Google Scholar 

  91. Tester DJ, Kopplin LJ, Will ML, Ackerman MJ. Spectrum and prevalence of cardiac ryanodine receptor (RyR2) mutations in a cohort of unrelated patients referred explicitly for long QT syndrome genetic testing. Heart Rhythm. 2005;2(10):1099–105.

    Article  PubMed  Google Scholar 

  92. Tester DJ, Spoon DB, Valdivia HH, Makielski JC, Ackerman MJ. Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained death: a molecular autopsy of 49 medical examiner/coroner's cases. Mayo Clin Proc. 2004;79(11):1380–4.

    Article  CAS  PubMed  Google Scholar 

  93. Laitinen PJ, Brown KM, Piippo K, Swan H, Devaney JM, Brahmbhatt B, et al. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation. 2001;103(4):485–90.

    Article  CAS  PubMed  Google Scholar 

  94. Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2001;103(2):196–200.

    Article  CAS  PubMed  Google Scholar 

  95. 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(6):1378–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rooryck C, Kyndt F, Bozon D, Roux-Buisson N, Sacher F, Probst V, et al. New Family With Catecholaminergic Polymorphic Ventricular Tachycardia Linked to the Triadin Gene. J Cardiovasc Electrophysiol. 2015;26(10):1146–50.

    Article  PubMed  Google Scholar 

  97. 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(12):2759–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Makita N, Yagihara N, Crotti L, Johnson CN, Beckmann BM, Roh MS, et al. Novel calmodulin mutations associated with congenital arrhythmia susceptibility. Circ Cardiovasc Genet. 2014;7(4):466–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Venetucci L, Denegri M, Napolitano C, Priori SG. Inherited calcium channelopathies in the pathophysiology of arrhythmias. Nat Rev Cardiol. 2012;9(10):561–75.

    Article  CAS  PubMed  Google Scholar 

  100. van der Werf C, Nederend I, Hofman N, van Geloven N, Ebink C, Frohn-Mulder IM, 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(4):748–56.

    Article  PubMed  CAS  Google Scholar 

  101. Wilde AA, Bhuiyan ZA, Crotti L, Facchini M, De Ferrari GM, Paul T, et al. Left cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia. N Engl J Med. 2008;358(19):2024–9.

    Article  CAS  PubMed  Google Scholar 

  102. Kaneshiro T, Naruse Y, Nogami A, Tada H, Yoshida K, Sekiguchi Y, et al. Successful catheter ablation of bidirectional ventricular premature contractions triggering ventricular fibrillation in catecholaminergic polymorphic ventricular tachycardia with RyR2 mutation. Circ Arrhythm Electrophysiol. 2012;5(1):e14–17.

    Article  PubMed  Google Scholar 

  103. 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(4):380–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 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(22):2244–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Rosso R, Kalman JM, Rogowski O, Diamant S, Birger A, Biner S, et al. Calcium channel blockers and beta-blockers versus beta-blockers alone for preventing exercise-induced arrhythmias in catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm. 2007;4(9):1149–54.

    Article  PubMed  Google Scholar 

  106. Kobayashi S, Yano M, Uchinoumi H, Suetomi T, Susa T, Ono M, et al. Dantrolene, a therapeutic agent for malignant hyperthermia, inhibits catecholaminergic polymorphic ventricular tachycardia in a RyR2(R2474S/+) knock-in mouse model. Circ J. 2010;74(12):2579–84.

    Article  CAS  PubMed  Google Scholar 

  107. Jung CB, Moretti A, Mederos y Schnitzler M, Iop L, Storch U, Bellin M, et al. Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia. EMBO Mol Med. 2012;4(3):180–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Penttinen K, Swan H, Vanninen S, Paavola J, Lahtinen AM, Kontula K, et al. Antiarrhythmic Effects of Dantrolene in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia and Replication of the Responses Using iPSC Models. PLoS One. 2015;10(5):e0125366.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Gussak I, Bjerregaard P. Short QT syndrome--5 years of progress. J Electrocardiol. 2005;38(4):375–7.

    Article  PubMed  Google Scholar 

  110. Gussak I, Brugada P, Brugada J, Wright RS, Kopecky SL, Chaitman BR, et al. Idiopathic short QT interval: a new clinical syndrome? Cardiology. 2000;94(2):99–102.

    Article  CAS  PubMed  Google Scholar 

  111. Gaita F, Giustetto C, Bianchi F, Wolpert C, Schimpf R, Riccardi R, et al. Short QT Syndrome: a familial cause of sudden death. Circulation. 2003;108(8):965–70.

    Article  PubMed  Google Scholar 

  112. Gollob MH, Redpath CJ, Roberts JD. The short QT syndrome: proposed diagnostic criteria. J Am Coll Cardiol. 2011;57(7):802–12.

    Article  PubMed  Google Scholar 

  113. Giustetto C, Schimpf R, Mazzanti A, Scrocco C, Maury P, Anttonen O, et al. Long-term follow-up of patients with short QT syndrome. J Am Coll Cardiol. 2011;58(6):587–95.

    Article  PubMed  Google Scholar 

  114. Guerrier K, Kwiatkowski D, Czosek RJ, Spar DS, Anderson JB, Knilans TK: Short QT Interval Prevalence and Clinical Outcomes in a Pediatric Population. Circ Arrhythm Electrophysiol 2015.

  115. Gaita F, Giustetto C, Bianchi F, Schimpf R, Haissaguerre M, Calo L, et al. Short QT syndrome: pharmacological treatment. J Am Coll Cardiol. 2004;43(8):1494–9.

    Article  CAS  PubMed  Google Scholar 

  116. Junttila MJ, Sager SJ, Freiser M, McGonagle S, Castellanos A, Myerburg RJ. Inferolateral early repolarization in athletes. J Interv Card Electrophysiol. 2011;31(1):33–8.

    Article  PubMed  Google Scholar 

  117. Noseworthy PA, Tikkanen JT, Porthan K, Oikarinen L, Pietila A, Harald K, et al. The early repolarization pattern in the general population: clinical correlates and heritability. J Am Coll Cardiol. 2011;57(22):2284–9.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Haissaguerre M, Derval N, Sacher F, Jesel L, Deisenhofer I, de Roy L, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med. 2008;358(19):2016–23.

    Article  CAS  PubMed  Google Scholar 

  119. Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, Kerola T, Rissanen HA, et al. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med. 2009;361(26):2529–37.

    Article  CAS  PubMed  Google Scholar 

  120. Sinner MF, Reinhard W, Muller M, Beckmann BM, Martens E, Perz S, et al. Association of early repolarization pattern on ECG with risk of cardiac and all-cause mortality: a population-based prospective cohort study (MONICA/KORA). PLoS Med. 2010;7(7):e1000314.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Haruta D, Matsuo K, Tsuneto A, Ichimaru S, Hida A, Sera N, et al. Incidence and prognostic value of early repolarization pattern in the 12-lead electrocardiogram. Circulation. 2011;123(25):2931–7.

    Article  PubMed  Google Scholar 

  122. Rosso R, Kogan E, Belhassen B, Rozovski U, Scheinman MM, Zeltser D, et al. J-point elevation in survivors of primary ventricular fibrillation and matched control subjects: incidence and clinical significance. J Am Coll Cardiol. 2008;52(15):1231–8.

    Article  PubMed  Google Scholar 

  123. Derval N, Simpson CS, Birnie DH, Healey JS, Chauhan V, Champagne J, et al. Prevalence and characteristics of early repolarization in the CASPER registry: cardiac arrest survivors with preserved ejection fraction registry. J Am Coll Cardiol. 2011;58(7):722–8.

    Article  PubMed  Google Scholar 

  124. Macfarlane PW, Antzelevitch C, Haissaguerre M, Huikuri HV, Potse M, Rosso R, et al. The Early Repolarization Pattern: A Consensus Paper. J Am Coll Cardiol. 2015;66(4):470–7.

    Article  PubMed  Google Scholar 

  125. Krahn AD, Healey JS, Chauhan V, Birnie DH, Simpson CS, Champagne J, et al. Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER). Circulation. 2009;120(4):278–85.

    Article  PubMed  Google Scholar 

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Correspondence to Gordon F. Tomaselli MD.

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Gordon F. Tomaselli and Andreas S. Barth each declare no potential conflicts of interest.

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Tomaselli, G.F., Barth, A.S. Ion Channel Diseases: an Update for 2016. Curr Treat Options Cardio Med 18, 21 (2016). https://doi.org/10.1007/s11936-016-0442-1

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