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Brugada Syndrome: Cellular Mechanisms and Approaches to Therapy

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Electrical Diseases of the Heart

Abstract

Nearly 15 years have passed since Pedro and Josep Brugada introduced the syndrome of ST-segment elevation and right bundle branch block (RBBB) associated with a high incidence of ventricular tachycardia/ventricular fibrillation (VT/VF) as a new clinical entity.1 Over 16 years have transpired since the introduction of the concept of phase 2 reentry (induced by sodium channel block), the mechanism believed to underlie the development of arrhythmogenesis in this clinical syndrome.2,3 Thus, the entity, which in 1996 came to be known as the Brugada syndrome,4,5 evolved in the experimental laboratory and in the clinic along parallel but separate tracks until the late 1990s.6

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References

  1. Brugada P, Brugada J Right bundle branch block, persistent ST segment elevation and sudden cardiac death: A distinct clinical and electrocar-diographic syndrome: A multicenter report. J Am Coll Cardiol 1992;20:1391–1396.

    PubMed  CAS  Google Scholar 

  2. Krishnan SC, Antzelevitch C. Sodium channel block produces opposite electrophysiological effects in canine ventricular epicardium and endocardium. CircRes 1991;69:277–291.

    CAS  Google Scholar 

  3. Krishnan SC, Antzelevitch C. Flecainide-induced arrhythmia in canine ventricular epicardium. Phase 2 reentry? Circulation 1993;87:562–572.

    PubMed  CAS  Google Scholar 

  4. Yan GX, Antzelevitch C. Cellular basis for the electrocardiographic J wave. Circulation 1996;93:372–379.

    PubMed  CAS  Google Scholar 

  5. Miyazaki T, Mitamura H, Miyoshi S, Soejima K, Aizawa Y, Ogawa S. Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome.J Am Coll Cardiol 1996;27:1061–1070.

    Article  PubMed  CAS  Google Scholar 

  6. Antzelevitch C. The Brugada syndrome. J Cardiovasc Electrophysiol 1998;9:513–516.

    Article  PubMed  CAS  Google Scholar 

  7. Wilde AA, Antzelevitch C, Borggrefe M, Brugada J, Brugada R, Brugada P, Corrado D, Hauer RN, Kass RS, Nademanee K, Priori SG, Towbin JA. Proposed diagnostic criteria for the Brugada syndrome: Consensus report. Eur Heart J 2002;23:1648–1654.

    PubMed  CAS  Google Scholar 

  8. Wilde AA, Antzelevitch C, Borggrefe M, Brugada J, Brugada R, Brugada P, Corrado D, Hauer RN, Kass RS, Nademanee K, Priori SG, Towbin JA. Proposed diagnostic criteria for the Brugada syndrome: Consensus report. Circulation 2002;106:2514–2519.

    Article  PubMed  Google Scholar 

  9. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada Syndrome. Report of the Second Consensus Conference. Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005;1 11:659–6

    Article  Google Scholar 

  10. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: Report of the second consensus conference. Heart Rhythm 2005;2:429–440.

    Article  PubMed  Google Scholar 

  11. Brugada P, Brugada J, Brugada R. Arrhythmia induction by antiarrhythmic drugs. Pacing Clin Electrophysiol 2000;23:291–292.

    Article  PubMed  CAS  Google Scholar 

  12. Brugada R, Brugada J, Antzelevitch C, Kirsch GE, Potenza D, Towbin JA, Brugada P. Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. Circulation 2000;101:510–515.

    PubMed  CAS  Google Scholar 

  13. Antzelevitch C, Brugada R. Fever and the Brugada syndrome. Pacing Clin Electrophysiol 2002;25:1537–1539.

    Article  PubMed  Google Scholar 

  14. Shimizu W, Antzelevitch C, Suyama K, Kurita T, Taguchi A, Aihara N, Takaki H, Sunagawa K, Kamakura S. Effect of sodium channel blockers on ST segment, QRS duration, and corrected QT interval in patients with Brugada syndrome. J Cardiovasc Electrophysiol 2000;11:1320–1329.

    Article  PubMed  CAS  Google Scholar 

  15. Priori SG, Napolitano C, Gasparini M, Pappone C, Della BP, Brignole M, Giordano U, Giovannini T, Menozzi C, Bloise R, Crotti L, Terreni L, Schwartz PJ. Clinical and genetic heterogeneity of right bundle branch block and ST-segment elevation syndrome: A prospective evaluation of 52 families. Circulation 2000;102:2509–2515.

    PubMed  CAS  Google Scholar 

  16. Wolpert C., Echternach C, Veltmann C, Antzelevitch C, Thomas GP, Sphel S, Streitner F, Kuschyk J, Schimpf R, Haase KK, Borggrefe M. Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome. Heart Rhythm 2005;2:254–260.

    Article  PubMed  Google Scholar 

  17. Hong K, Brugada J, Oliva A, Berruezo-Sanchez A, Potenza D, Pollevick GD, Guerchicoff A, Matsuo K, Burashnikov E, Dumaine R, Towbin JA, Nesterenko VV, Brugada P, Antzelevitch C, Brugada R. Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations. Circulation 2004;110:3023–3027.

    Article  PubMed  Google Scholar 

  18. Itoh H, Shimizu M, Takata S, Mabuchi H, Imoto K. A novel missense mutation in the SCN5A gene associated with Brugada syndrome bidirectionally affecting blocking actions of antiarrhythmic drugs. J Cardiovasc Electrophysiol 2005;16:486–493.

    Article  PubMed  Google Scholar 

  19. Kalla H, Yan GX, Marinchak R. Ventricular fibrillation in a patient with prominent J (Osborn) waves and ST segment elevation in the inferior electrocardiographic leads: A Brugada syndrome variant? J Cardiovasc Electrophysiol 2000;11:95–98.

    Article  PubMed  CAS  Google Scholar 

  20. Ogawa M, Kumagai K, Yamanouchi Y, Saku K. Spontaneous onset of ventricular fibrillation in Brugada syndrome with J wave and ST-segment elevation in the inferior leads. Heart Rhythm 2005;2:97–99.

    Article  PubMed  Google Scholar 

  21. Horigome H, Shigeta O, Kuga K, Isobe T, Sakakibara Y, Yamaguchi I, Matsui A. Ventricular fibrillation during anesthesia in association with J waves in the left precordial leads in a child with coarctation of the aorta. J Electrocardiol 2003;36:339–343.

    Article  PubMed  Google Scholar 

  22. Shimizu W, Matsuo K, Takagi M, Tanabe Y, Aiba T, Taguchi A, Suyama K, Kurita T, Aihara N, Kamakura S. Body surface distribution and response to drugs of ST segment elevation in Brugada syndrome: Clinical implication of eightyseven-lead body surface potential mapping and its application to twelve-lead electrocardiograms. J Cardiovasc Electrophysiol 2000;11:396–404.

    Article  PubMed  CAS  Google Scholar 

  23. Sangwatanaroj S, Prechawat S, Sunsaneewitayakul B, Sitthisook S, Tosukhowong P, Tungsanga K. New electrocardiographic leads and the procainamide test for the detection of the Brugada sign in sudden unexplained death syndrome survivors and their relatives. Eur Heart J 2001;22:2290–2296.

    Article  PubMed  CAS  Google Scholar 

  24. Shin SC, Ryu S, Lee JH, Chang BJ, Shin JK, Kim HS, Heo JH, Yang DH, Park HS, Cho Y, Chae SC, Jun JE, Park WH. Prevalence of the Brugada-type ECG recorded from higher intercostal spaces in healthy Korean males. Circulation J 2005;69:1064–1067.

    Article  Google Scholar 

  25. Alings M, Wilde A. “Brugada” syndrome: Clinical data and suggested pathophysiological mechanism. Circulation 1999;99:666–673.

    PubMed  CAS  Google Scholar 

  26. Bezzina C, Veldkamp MW, van Den Berg MP, Postma AV, Rook MB, Viersma JW, Van Langen IM, Tan-Sindhunata G, Bink-Boelkens MT, Der Hout AH, Mannens MM, Wilde AA. A single Na(+) channel mutation causing both long-QT and Brugada syndromes. Circ Res 1999;85:1206–1213.

    PubMed  CAS  Google Scholar 

  27. Pitzalis MV, Anaclerio M, Iacoviello M, Forleo C, Guida P, Troccoli R, Massari F, Mastropasqua F, Sorrentino S, Manghisi A, Rizzon P. QT-interval prolongation in right precordial leads: An additional electrocardiographic hallmark of Brugada syndrome. J Am Coll Cardiol 2003;42:1632–1637.

    Article  PubMed  Google Scholar 

  28. Castro HJ, Antzelevitch C, Tornes BF, Dorantes SM, Dorticos BF, Zayas MR, Quinones Perez MA, Fayad RY. Tpeak-Tend and Tpeak-Tend dispersion as risk factors for ventricular tachycardia/ ventricular fibrillation in patients with the Brugada syndrome. J Am Coll Cardiol 2006;47:1828–1834.

    Article  Google Scholar 

  29. Smits JP, Eckardt L, Probst V, Bezzina CR, Schott JJ, Remme CA, Haverkamp W, Breithardt G, Escande D, Schulze-Bahr E, LeMarec H, Wilde AA. Genotype-phenotype relationship in Brugada syndrome: Electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. J Am Coll Cardiol 2002;40:350–356.

    Article  PubMed  CAS  Google Scholar 

  30. Kasanuki H, Ohnishi S, Ohtuka M, Matsuda N, Nirei T, Isogai R, Shoda M, Toyoshima Y, Hosoda S. Idiopathic ventricular fibrillation induced with vagal activity in patients without obvious heart disease. Circulation 1997;95:2277–2285.

    PubMed  CAS  Google Scholar 

  31. Proclemer A, Facchin D, Feruglio GA, Nucifora R. Recurrent ventricular fibrillation, right bundle-branch block and persistent ST-segment elevation in V1-V3: A new arrhythmia syndrome? A clinical case report (see comments). GItal Cardiol 1993;23:1211–1218.

    CAS  Google Scholar 

  32. Makiyama T, Akao M, Tsuji K, Doi T, Ohno S, Takenaka K, Kobori A, Ninomiya T, Yoshida H, Takano M, Makita N, Yanagisawa F, Higashi Y, Takeyama Y, Kita T, Horie M. High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations. J Am Coll Cardiol 2005;46:2100–2106.

    Article  PubMed  CAS  Google Scholar 

  33. Scornik FS, Desai M, Brugada R, Guerchicoff A, Pollevick GD, Antzelevitch C, Perez GJ. Functional expression of “cardiac-type” Na(v)1.5 sodium channel in canine intracardiac ganglia. Heart Rhythm 2006;3:842–850.

    Article  PubMed  Google Scholar 

  34. Shimada M, Miyazaki T, Miyoshi S, Soejima K, Hori S, Mitamura H, Ogawa S. Sustained monomorphic ventricular tachycardia in a patient with Brugada syndrome. Jpn Circ J 1996;60:364–370.

    Article  PubMed  CAS  Google Scholar 

  35. Pinar BE, Garcia-Alberola A, Martinez SJ, Sanchez Munoz JJ, Valdes CM. Spontaneous sustained monomorphic ventricular tachycardia after administration of ajmaline in a patient with Brugada syndrome [see comments]. Pacing Clin Electrophysiol 2000;23:407–409.

    Article  Google Scholar 

  36. Dinckal MH, Davutoglu V, Akdemir I, Soydinc S, Kirilmaz A, Aksoy M. Incessant monomorphic ventricular tachycardia during febrile illness in a patient with Brugada syndrome: Fatal electrical storm. Europace 2003;5:257–261.

    Article  PubMed  CAS  Google Scholar 

  37. Mok NS, Chan NY. Brugada syndrome presenting with sustained monomorphic ventricular tachycardia. Int J Cardiol 2004;97:307–309.

    Article  PubMed  Google Scholar 

  38. Probst V, Evain S, Gournay V, Marie A, Schott JJ, Boisseau P, Le MH. Monomorphic ventricular tachycardia due to Brugada syndrome successfully treated by hydroquinidine therapy in a 3-year-old child. J Cardiovasc Electrophysiol 2006;17:97–100.

    Article  PubMed  Google Scholar 

  39. Sastry BK, Narasimhan C, Soma RB. Brugada syndrome with monomorphic ventricular tachycardia in a one-year-old child. Indian Heart J 2001;53:203–205.

    PubMed  CAS  Google Scholar 

  40. Remme CA, Wever EFD, Wilde AAM, Derksen R, Hauer RNW. Diagnosis and long-term follow-up of Brugada syndrome in patients with idiopathic ventricular fibrillation. Eur Heart J 2001;22:400–409.

    Article  PubMed  CAS  Google Scholar 

  41. Brugada J, Brugada R, Antzelevitch C, Towbin J, Nademanee K, Brugada P. Long-term follow-up of individuals with the electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V(1) to V(3). Circulation 2002;105:73–

    Article  PubMed  Google Scholar 

  42. Priori SG, Napolitano C, Gasparini M, Pappone C, Della BP, Giordano U, Bloise R, Giustetto C, De Nardis R, Grillo M, Ronchetti E, Faggiano G, Nastoli J. Natural history of Brugada syndrome: Insights for risk stratification and management. Circulation 2002;105:1342–1347.

    Article  PubMed  Google Scholar 

  43. Brugada P, Brugada R, Brugada J. Patients with an asymptomatic Brugada electrocardiogram should undergo pharmacological and electrophysical testing. Circulation 2005;1 12:279–285.

    Article  Google Scholar 

  44. Priori SG, Napolitano C. Management of patients with Brugada syndrome should not be based on programmed electrical stimulation. Circulation 2005;1 12:285–2

    Google Scholar 

  45. 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. Circula tion 2005;111:257–263.

    Article  Google Scholar 

  46. Atarashi H, Ogawa S, for The Idiopathic Ventricular Fibrillation Investigators. New ECG criteria for high-risk Brugada syndrome. Circ J 2003;67:8–10.

    Article  PubMed  Google Scholar 

  47. Morita H, Takenaka-Morita S, Fukushima-Kusano K, Kobayashi M, Nagase S, Kakishita M, Nakamura K, Emori T, Matsubara H, Ohe T. Risk stratification for asymptomatic patients with Brugada syndrome. Circ J 2003;67:312–316.

    Article  PubMed  Google Scholar 

  48. Viskin S. Inducible ventricular fibrillation in the Brugada syndrome: Diagnostic and prognostic implications. J Cardiovasc Electrophysiol 2003;14:458–460.

    Article  PubMed  Google Scholar 

  49. Brugada J, Brugada R, Brugada P. Right bundlebranch block and ST-segment elevation in leads V1 through V3. A marker for sudden death in patients without demonstrable structural heart disease. Circulation 1998;97:457–460.

    PubMed  CAS  Google Scholar 

  50. Kanda M, Shimizu W, Matsuo K, Nagaya N, Taguchi A, Suyama K, Kurita T, Aihara N, Kamakura S. Electrophysiologic characteristics and implications of induced ventricular fibrillation in symptomatic patients with Brugada syndrome. J Am Coll Cardiol 2002;39:1799–1805.

    Article  PubMed  Google Scholar 

  51. Brugada J, Brugada R, Brugada P. Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest. Circulation 2003;108:3092–3096.

    Article  PubMed  Google Scholar 

  52. Eckardt L, Kirchhof P, Johna R, Haverkamp W, Breithardt G, Borggrefe M. Wolff-Parkinson-White syndrome associated with Brugada syndrome. Pacing Clin Electrophysiol 2001;24:1423–1424.

    Article  PubMed  CAS  Google Scholar 

  53. Carlsson J, Erdogan A, Schulte B, Neuzner J, Pitschner HF. Possible role of epicardial left ventricular programmed stimulation in Brugada syndrome. Pacing Clin Electrophysiol 2001;24:247–249.

    Article  PubMed  CAS  Google Scholar 

  54. 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.

    Article  PubMed  Google Scholar 

  55. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-Lopez R, Wang Z, Antzelevitch C, O’Brien RE, Schultze-Bahr E, Keating MT, Towbin JA, Wang Q. Genetic basis and molecular mechanisms for idiopathic ventricular fibrillation. Nature 1998;392:293–296.

    Article  PubMed  CAS  Google Scholar 

  56. Grant AO, Carboni MP, Neplioueva V, Starmer CF, Memmi M, Napolitano C, Priori SG. Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation. J Clin Invest 2002;1 10:1201–1209.

    Google Scholar 

  57. Antzelevitch C, Brugada P, Brugada J, Brugada R. The Brugada Syndrome: From Bench to Bedside. Oxford, UK: Blackwell Futura, 2005.

    Google Scholar 

  58. Balser JR. The cardiac sodium channel: Gating function and molecular pharmacology. J Mol Cell Cardiol 2001;33:599–613.

    Article  PubMed  CAS  Google Scholar 

  59. Schulze-Bahr E, Eckardt L, Breithardt G, Seidl K, Wichter T, Wolpert C, Borggrefe M, Haverkamp W. Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: Different incidences in familial and sporadic disease. Hum Mutat 2003;21:651–652.

    Article  PubMed  CAS  Google Scholar 

  60. Bezzina CR, Wilde AA, Roden DM. The molecular genetics of arrhythmias. Cardiovasc Res 2005;67:343–346.

    Article  PubMed  CAS  Google Scholar 

  61. Tan HL, Bezzina CR, Smits JP, Verkerk AO, Wilde AA. Genetic control of sodium channel function. Cardiovasc Res 2003;57:961–973.

    Article  PubMed  CAS  Google Scholar 

  62. Antzelevitch C, Brugada P, Brugada J, Brugada R. The Brugada syndrome. From cell to bedside. Curr Probl Cardiol 2005;30:9–54.

    Article  PubMed  Google Scholar 

  63. Dumaine R, Towbin JA, Brugada P, Vatta M, Nesterenko VV, Nesterenko DV, Brugada J, Brugada R, Antzelevitch C. Ionic mechanisms responsible for the electrocardiographic pheno-type of the Brugada syndrome are temperature dependent. Circ Res 1999;85:803–809.

    PubMed  CAS  Google Scholar 

  64. Saura D, Garcia-Alberola A, Carrillo P, Pascual D, Martinez-Sanchez J, Valdes M. Brugada-like electrocardiographic pattern induced by fever. Pacing Clin Electrophysiol 2002;25:856–859.

    Article  PubMed  Google Scholar 

  65. Porres JM, Brugada J, Urbistondo V, Garcia F, Reviejo K, Marco P. Fever unmasking the Brugada syndrome. Pacing Clin Electrophysiol 2002;25:1646–1648.

    Article  PubMed  Google Scholar 

  66. Mok NS, Priori SG, Napolitano C, Chan NY, Chahine M, Baroudi G. A newly characterized SCN5A mutation underlying Brugada syndrome unmasked by hyperthermia. J Cardiovasc Electrophysiol 2003;14:407–4

    Article  PubMed  Google Scholar 

  67. Ortega-Carnicer J, Benezet J, Ceres F. Feverinduced ST-segment elevation and T-wave alternans in a patient with Brugada syndrome. Resuscitation 2003;57:315–317.

    Article  PubMed  Google Scholar 

  68. Patruno N, Pontillo D, Achilli A, Ruggeri G, Critelli G. Electrocardiographic pattern of Brugada syndrome disclosed by a febrile illness: Clinical and therapeutic implications. Europace 2003;5:251–255.

    Article  PubMed  CAS  Google Scholar 

  69. Peng J, Cui YK, Yuan FH, Yi SD, Chen ZM, Meng SR. [Fever and Brugada syndrome: Report of 21 cases.]. Di Yi Jun Yi Da Xue Xue Bao 2005;25:432–434.

    PubMed  Google Scholar 

  70. Dulu A, Pastores SM, McAleer E, Voigt L, Halpern NA. Brugada electrocardiographic pattern in a postoperative patient. Crit Care Med 2005;33:1634–1637.

    Article  PubMed  Google Scholar 

  71. Aramaki K, Okumura H, Shimizu M. Chest pain and ST elevation associated with fever in patients with asymptomatic Brugada syndrome. Fever and chest pain in Brugada syndrome. Int J Cardiol 2005;103:338–3

    Article  PubMed  Google Scholar 

  72. Hong K, Guerchicoff A, Pollevick GD, Oliva A, Dumaine R, de Zutter M, Burashnikov E, Wu YS, Brugada J, Brugada P, Brugada R. Cryptic 5’ splice site activation in SCN5A associated with Brugada syndrome. J Mol Cell Cardiol 2005;38:555–560.

    Article  PubMed  CAS  Google Scholar 

  73. Bezzina CR, Shimizu W, Yang P, Koopmann TT, Tanck MW, Miyamoto Y, Kamakura S, Roden DM, Wilde AA. Common sodium channel promoter haplotype in Asian subjects underlies variability in cardiac conduction. Circulation 2006;113:338–344.

    Article  PubMed  CAS  Google Scholar 

  74. Weiss R, Barmada MM, Nguyen T, Seibel JS, Cavlovich D, Kornblit CA, Angelilli A, Villanueva F, McNamara DM, London B. Clinical and molecular heterogeneity in the Brugada syndrome. A novel gene locus on chromosome 3. Circulation 2002;105:707–7

    Article  PubMed  CAS  Google Scholar 

  75. London B, Sanyal S, Michalec M, Pfahnl AE, Shang LL, Kerchner BS, Lagana S, Aleong RG, Mehdi H, Gutmann R, Weiss R, Dudley SC. AB 16-1: A mutation in the glycerol-3-phosphate dehydrogenase 1-like gene (GPD1L) causes Brugada syndrome. Heart Rhythm 2006;3:S32 (abstract).

    Article  Google Scholar 

  76. Antzelevitch C, Sicouri S, Litovsky SH, Lukas A, Krishnan SC, Di Diego JM, Gintant GA, Liu DW. Heterogeneity within the ventricular wall. Electrophysiology and pharmacology of epicardial, endocardial, and M cells. Circ Res 1991;69:1427–1449.

    PubMed  CAS  Google Scholar 

  77. Antzelevitch C, Shimizu W, Yan GX, Sicouri S, Weissenburger J, Nesterenko VV, Burashnikov A, Di Diego JM, Saffitz J, Thomas GP. The M cell: Its contribution to the ECG and to normal and abnormal electrical function of the heart. J Cardiovasc Electrophysiol 1999;10:1124–1152.

    Article  PubMed  CAS  Google Scholar 

  78. Litovsky SH, Antzelevitch C. Transient outward current prominent in canine ventricular epicardium but not endocardium. Circ Res 1988;62:116–126.

    PubMed  CAS  Google Scholar 

  79. Liu DW, Gintant GA, Antzelevitch C. Ionic bases for electrophysiological distinctions among epicardial, midmyocardial, and endocardial myocytes from the free wall of the canine left ventricle. Circ Res 1993;72:671–687.

    PubMed  CAS  Google Scholar 

  80. Furukawa T, Myerburg RJ, Furukawa N, Bassett AL, Kimura S. Differences in transient outward currents of feline endocardial and epicardial myocytes. Circ Res 1990;67:1287–1291.

    PubMed  CAS  Google Scholar 

  81. Fedida D, Giles WR. Regional variations in action potentials and transient outward current in myocytes isolated from rabbit left ventricle. J Physiol (Lond) 1991;442:191–209.

    CAS  Google Scholar 

  82. Clark RB, Bouchard RA, Salinas-Stefanon E, Sanchez-Chapula J, Giles WR. Heterogeneity of action potential waveforms and potassium currents in rat ventricle. CardiovascRes 1993;27:1795–1799.

    Article  CAS  Google Scholar 

  83. Wettwer E, Amos GJ, Posival H, Ravens U. Transient outward current in human ventricular myocytes of subepicardial and subendocardial origin. Circ Res 1994;75:473–482.

    PubMed  CAS  Google Scholar 

  84. Nabauer M, Beuckelmann DJ, Uberfuhr P, Steinbeck G. Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle. Circulation 1996;93:168–177.

    PubMed  CAS  Google Scholar 

  85. Di Diego JM, Sun ZQ, Antzelevitch C. I to and action potential notch are smaller in left vs. right canine ventricular epicardium. Am J Physiol Heart Circ Physiol 1996;271:H548–H

    Google Scholar 

  86. Volders PG, Sipido KR, Carmeliet E, Spatjens RL, Wellens HJ, Vos MA. Repolarizing K+ currents ITO1 and IKs are larger in right than left canine ventricular midmyocardium. Circulation 1999;99:206–210.

    PubMed  CAS  Google Scholar 

  87. Zicha S, Xiao L, Stafford S, Cha TJ, Han W, Varro A, Nattel S. Transmural expression of transient outward potassium current subunits in normal and failing canine and human hearts. J Physiol 2004;561:735–7

    Article  PubMed  CAS  Google Scholar 

  88. Rosati B, Pan Z, Lypen S, Wang HS, Cohen I, Dixon JE, McKinnon D. Regulation of KChIP2 potassium channel beta subunit gene expression underlies the gradient of transient outward current in canine and human ventricle. J Physiol 2001;533:119–125.

    Article  PubMed  CAS  Google Scholar 

  89. Costantini DL, Arruda EP, Agarwal P, Kim KH, Zhu Y, Zhu W, Lebel M, Cheng CW, Park CY, Pierce SA, Guerchicoff A, Pollevick GD, Chan TY, Kabir MG, Cheng SH, Husain M, Antzelevitch C, Srivastava D, Gross GJ, Hui CC, Backx PH, Bruneau BG. The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient. Cell 2005;123:347–358.

    Article  PubMed  CAS  Google Scholar 

  90. Takano M, Noma A. Distribution of the isoprenaline-induced chloride current in rabbit heart. Pflugers Arch 1992;420:223–226.

    Article  PubMed  CAS  Google Scholar 

  91. Zygmunt AC. Intracellular calcium activates chloride current in canine ventricular myocytes. Am J Physiol Heart Circ Physiol 1994;267:H1984–H1995.

    CAS  Google Scholar 

  92. Cordeiro JM, Greene L, Heilmann C, Antzelevitch D, Antzelevitch C. Transmural heterogeneity of calcium activity and mechanical function in the canine left ventricle. Am J Physiol Heart Circ Physiol 2004;286:H 1471–H1479.

    CAS  Google Scholar 

  93. Banyasz T, Fulop L, Magyar J, Szentandrassy N, Varro A, Nanasi PP. Endocardial versus epicardial differences in L-type calcium current in canine ventricular myocytes studied by action potential voltage clamp. Cardiovasc Res 2003;58:66–75.

    Article  PubMed  CAS  Google Scholar 

  94. Wang HS, Cohen IS. Calcium channel heterogeneity in canine left ventricular myocytes. J Physiol 2003;547:825–8

    Article  PubMed  CAS  Google Scholar 

  95. Sicouri S, Antzelevitch C. A subpopulation of cells with unique electrophysiological properties in the deep subepicardium of the canine ventricle. The M cell. Circ Res 1991;68:1729–1741.

    PubMed  CAS  Google Scholar 

  96. Anyukhovsky EP, Sosunov EA, Rosen MR. Regional differences in electrophysiologic properties of epicardium, midmyocardium and endocardium: In vitro and in vivo correlations. Circulation 1996;94:1981–1988.

    PubMed  CAS  Google Scholar 

  97. Liu DW, Antzelevitch C. Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. Circ Res 1995;76:351–365.

    PubMed  CAS  Google Scholar 

  98. Zygmunt AC, Eddlestone GT, Thomas GP, Nesterenko VV, Antzelevitch C. Larger late sodium conductance in M cells contributes to electrical heterogeneity in canine ventricle. Am J Physiol Heart Circ Physiol 2001;281:H689–H697.

    PubMed  CAS  Google Scholar 

  99. Zygmunt AC, Goodrow RJ, Antzelevitch C. I(NaCa) contributes to electrical heterogeneity within the canine ventricle. Am J Physiol Heart Circ Physiol 2000;278:H1671–H1678.

    PubMed  CAS  Google Scholar 

  100. Brahmajothi MV, Morales MJ, Reimer KA, Strauss HC. Regional localization of ERG, the channel protein responsible for the rapid component of the delayed rectifier, K+ current in the ferret heart. Circ Res 1997;81:128–135.

    PubMed  CAS  Google Scholar 

  101. Clements SD, Hurst JW. Diagnostic value of ECG abnormalities observed in subjects accidentally exposed to cold. Am J Cardiol 1972;29:729–734.

    Article  PubMed  Google Scholar 

  102. Thompson R, Rich J, Chmelik F, Nelson WL. Evolutionary changes in the electrocardiogram of severe progressive hypothermia. J Electrocardiol 1977;10:67–

    Article  PubMed  CAS  Google Scholar 

  103. RuDusky BM. The electrocardiogram in hypothermia—the J wave and the Brugada syndrome. Am J Cardiol 2004;93:671–672.

    Article  PubMed  Google Scholar 

  104. Kraus F. Ueber die wirkung des kalziums auf den kreislauf. Dtsch Med Wochenschr 1920;46:201–203.

    Article  Google Scholar 

  105. Sridharan MR, Horan LG. Electrocardiographic J wave of hypercalcemia. Am J Cardiol 1984;54:672–673.

    Article  PubMed  CAS  Google Scholar 

  106. Antzelevitch C, Sicouri S, Lukas A, Nesterenko VV, Liu DW, Di Diego JM. Regional differences in the electrophysiology of ventricular cells: Physiological and clinical implications. In: Zipes DP, Jalife J, Eds. Cardiac Electrophysiology: From Cell to Bedside, 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1995:228–

    Google Scholar 

  107. Eagle K. Images in clinical medicine. Osborn waves of hypothermia. N Engl J Med 1994;10:680.

    Google Scholar 

  108. Emslie-Smith D, Sladden GE, Stirling GR. The significance of changes in the electrocardiogram in hypothermia. Br Heart J 1959;21:343–351.

    Article  PubMed  CAS  Google Scholar 

  109. Osborn JJ. Experimental hypothermia: Respiratory and blood pH changes in relation to cardiac function. Am J Physiol 1953;175:389–398.

    PubMed  CAS  Google Scholar 

  110. Sridharan MR, Johnson JC, Horan LG, Sohl GS, Flowers NC. Monophasic action potentials in hypercalcemic and hypothermic “J” waves—a comparative study. Am Fed Clin Res 1983;31:219.

    Google Scholar 

  111. Di Diego JM, Antzelevitch C. High [Ca2+]-induced electrical heterogeneity and extrasystolic activity in isolated canine ventricular epicardium: Phase 2 reentry. Circulation 1994;89:1839–1850.

    PubMed  Google Scholar 

  112. Litovsky SH, Antzelevitch C. Rate dependence of action potential duration and refractoriness in canine ventricular endocardium differs from that of epicardium: Role of the transient outward current. J Am Coll Cardiol 1989;14:1053–1066.

    Article  PubMed  CAS  Google Scholar 

  113. Kilborn MJ, Fedida D. A study of the developmental changes in outward currents of rat ventricular myocytes. J Physiol (Lond) 1990;430:37–60.

    CAS  Google Scholar 

  114. Furukawa Y, Akahane K, Ogiwara Y, Chiba S. K+-channel blocking and anti-muscarinic effects of a novel piperazine derivative, INO 2628, on the isolated dog atrium. Eur J Pharm 1991;193:217–222.

    Article  CAS  Google Scholar 

  115. Lukas A, Antzelevitch C. Phase 2 reentry as a mechanism of initiation of circus movement reentry in canine epicardium exposed to simulated ischemia. Cardiovasc Res 1996;32:593–603.

    PubMed  CAS  Google Scholar 

  116. Di Diego JM, Antzelevitch C. Pinacidil-induced electrical heterogeneity and extrasystolic activity in canine ventricular tissues. Does activation of ATP-regulated potassium current promote phase 2 reentry? Circulation 1993;88:1177–1189.

    PubMed  Google Scholar 

  117. Antzelevitch C, Sicouri S, Lukas A, Di Diego JM, Nesterenko VV, Liu DW, Roubache JF, Zygmunt AC, Zhang ZQ, Iodice A. Clinical implications of electrical heterogeneity in the heart: The electrophysiology and pharmacology of epicardial, M, and endocardial cells. In: Podrid PJ, Kowey PR, Eds. Cardiac Arrhythmia: Mechanism, Diagnosis and Management. Baltimore, MD: William & Wilkins, 1995:88–107.

    Google Scholar 

  118. Yan GX, Lankipalli RS, Burke JF, Musco S, Kowey PR. Ventricular repolarization components on the electrocardiogram: Cellular basis and clinical significance. J Am Coll Cardiol 2003;42:401–409.

    Article  PubMed  Google Scholar 

  119. Aizawa Y, Tamura M, Chinushi M, Naitoh N, Uchiyama H, Kusano Y, Hosono H, Shibata A. Idiopathic ventricular fibrillation and bradycardia-dependent intraventricular block. Am Heart J 1993;126:1473–14

    Article  PubMed  CAS  Google Scholar 

  120. Aizawa Y, Tamura M, Chinushi M, Niwano S, Kusano Y, Naitoh N, Shibata A, Tohjoh T, Ueda Y, Joho K. An attempt at electrical catheter ablation of the arrhythmogenic area in idiopathic ventricular fibrillation. Am Heart J 1992;123:257–260.

    Article  PubMed  CAS  Google Scholar 

  121. Bjerregaard P, Gussak I, Kotar Sl, Gessler JE. Recurrent syncope in a patient with prominent J-wave. Am Heart J 1994;127:1426–1430.

    Article  PubMed  CAS  Google Scholar 

  122. Lukas A, Antzelevitch C. Differences in the electrophysiological response of canine ventricular epicardium and endocardium to ischemia: Role of the transient outward current. Circulation 1993;88:2903–2915.

    PubMed  CAS  Google Scholar 

  123. Thomsen PE, Joergensen RM, Kanters JK, Jensen TJ, Haarbo J, Hagemann A, Vestergaard A, Saermark K. Phase 2 reentry in man. Heart Rhythm 2005;2:797–803.

    Article  Google Scholar 

  124. Antzelevitch C. In vivo human demonstration of phase 2 reentry. Heart Rhythm 2005;2:804–806.

    Article  PubMed  Google Scholar 

  125. Litovsky SH, Antzelevitch C. Differences in the electrophysiological response of canine ventricular subendocardium and subepicardium to acetylcholine and isoproterenol. A direct effect of acetylcholine in ventricular myocardium. Circ Res 1990;67:615–6

    PubMed  CAS  Google Scholar 

  126. Tsuchiya T, Ashikaga K, Honda T, Arita M. Prevention of ventricular fibrillation by cilostazol, an oral phosphodiesterase inhibitor, in a patient with Brugada syndrome. J Cardiovasc Electrophysiol 2002;13:698–7

    Article  PubMed  Google Scholar 

  127. Yan GX, Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST segment elevation. Circulation 1999;100:1660–1666.

    PubMed  CAS  Google Scholar 

  128. Pertsov AM, Davidenko JM, Salomonsz R, Baxter WT, Jalife J. Spiral waves of excitation underlie reentrant activity in isolated cardiac muscle. Circ Res 1993;72:631–650.

    PubMed  CAS  Google Scholar 

  129. Asano Y, Davidenko JM, Baxter WT, Gray RA, Jalife J. Optical mapping of drug-induced polymorphic arrhythmias and torsade de pointes in the isolated rabbit heart. J Am Coll Cardiol 1997;29:831–842.

    Article  PubMed  CAS  Google Scholar 

  130. Fish JM, Antzelevitch C. Role of sodium and calcium channel block in unmasking the Brugada syndrome. Heart Rhythm 2004;1:210–217.

    Article  PubMed  Google Scholar 

  131. Tukkie R, Sogaard P, Vleugels J, De Groot IK, Wilde AA, Tan HL. Delay in right ventricular activation contributes to Brugada syndrome. Circulation 2004;109:1272–1277.

    Article  PubMed  Google Scholar 

  132. Antzelevitch C, Fish J, Di Diego JM. Cellular mechanisms underlying the Brugada syndrome. In: Antzelevitch C, Brugada P, Brugada J, Brugada R, Eds. The Brugada Syndrome: From Bench to Bedside. Oxford, UK: Blackwell Futura, 2004:52–77.

    Google Scholar 

  133. Antzelevitch C. The Brugada syndrome: Ionic basis and arrhythmia mechanisms. J Cardiovasc Electrophysiol 2001;12:268–272.

    Article  PubMed  CAS  Google Scholar 

  134. Antzelevitch C. The Brugada syndrome: Diagnostic criteria and cellular mechanisms. Eur Heart J 2001;22:356–3

    Article  PubMed  CAS  Google Scholar 

  135. Gussak I, Antzelevitch C, Bjerregaard P, Towbin JA, Chaitman BR. The Brugada syndrome: Clinical, electrophysiologic and genetic aspects. J Am Coll Cardiol 1999;33:5–15.

    Article  PubMed  CAS  Google Scholar 

  136. Shimizu W, Aiba T, Kamakura S. Mechanisms of disease: Current understanding and future challenges in Brugada syndrome. Nat Clin Pract Cardiovasc Med 2005;2:408–414.

    Article  PubMed  CAS  Google Scholar 

  137. Antzelevitch C, Brugada P, Brugada J, Brugada R, Shimizu W, Gussak I, Perez Riera AR. Brugada syndrome. A decade of progress. Circ Res 2002;91:1114–1119.

    Article  PubMed  CAS  Google Scholar 

  138. Kurita T, Shimizu W, Inagaki M, Suyama K, Taguchi A, Satomi K, Aihara N, Kamakura S, Kobayashi J, Kosakai Y. The electrophysiologic mechanism of ST-segment elevation in Brugada syndrome. J Am Coll Cardiol 2002;40:330–334.

    Article  PubMed  Google Scholar 

  139. Futterman LG, Lemberg L. Brugada. Am J Crit Care 2001;10:360–364.

    PubMed  CAS  Google Scholar 

  140. Fujiki A, Usui M, Nagasawa H, Mizumaki K, Hayashi H, Inoue H. ST segment elevation in the right precordial leads induced with class IC antiarrhythmic drugs: Insight into the mechanism of Brugada syndrome. J Cardiovasc Electrophysiol 1999;10:214–2

    Article  PubMed  CAS  Google Scholar 

  141. Antzelevitch C. Late potentials and the Brugada syndrome. J Am Coll Cardiol 2002;39:1996–1999.

    Article  PubMed  Google Scholar 

  142. Nagase S, Kusano KF, Morita H, Fujimoto Y, Kakishita M, Nakamura K, Emori T, Matsubara H, Ohe T. Epicardial electrogram of the right ventricular outflow tract in patients with the Brugada syndrome: Using the epicardial lead. J Am Coll Cardiol 2002;39:1992–1995.

    Article  PubMed  Google Scholar 

  143. Eckardt L, Bruns HJ, Paul M, Kirchhof P, Schulze-Bahr E, Wichter T, Breithardt G, Borggrefe M, Haverkamp W. Body surface area of ST elevation and the presence of late potentials correlate to the inducibility of ventricular tachyarrhythmias in Brugada syndrome. J Cardiovasc Electrophysiol 2002;13:742–749.

    Article  PubMed  Google Scholar 

  144. Ikeda T, Takami M, Sugi K, Mizusawa Y, Sakurada H, Yoshino H. Noninvasive risk stratification of subjects with a Brugada-type electrocardiogram and no history of cardiac arrest. Ann Noninvasive Electrocardiol 2005;10:396–403.

    Article  PubMed  Google Scholar 

  145. Shimizu W, Aiba T, Kurita T, Kamakura S. Paradoxic abbreviation of repolarization in epicardium of the right ventricular outflow tract during augmentation of Brugada-type ST segment elevation. J Cardiovasc Electrophysiol 2001;12:1418–1421.

    Article  PubMed  CAS  Google Scholar 

  146. Kandori A, Shimizu W, Yokokawa M, Noda T, Kamakura S, Miyatake K, Murakami M, Miyashita T, Ogata K, Tsukada K. Identifying patterns of spatial current dispersion that characterise and separate the Brugada syndrome and complete right-bundle branch block. Med Biol Eng Comput 2004;42:236–244.

    Article  PubMed  CAS  Google Scholar 

  147. Watanabe H, Chinushi M, Osaki A, Okamura K, Izumi D, Komura S, Hosaka Y, Tanabe Y, Furushima H, Washizuka T, Aizawa Y. Elimination of late potentials by quinidine in a patient with Brugada syndrome. J Electrocardiol 2006;39:63–66.

    Article  PubMed  Google Scholar 

  148. Marquez MF, Bisteni A, Medrano G, De Micheli A, Guevara M, Iturralde P, Colin L, Hermosillo G, Cardenas M. Dynamic electrocardiographic changes after aborted sudden death in a patient with Brugada syndrome and rate-dependent right bundle branch block. J Electrocardiol 2005;38:256–259.

    Article  PubMed  Google Scholar 

  149. Nishizaki M, Fujii H, Sakurada H, Kimura A, Hiraoka M. Spontaneous T wave alternans in a patient with Brugada syndrome—responses to intravenous administration of class I antiarrhythmic drug, glucose tolerance test, and atrial pacing. J Cardiovasc Electrophysiol 2005;16:217–220.

    Article  PubMed  Google Scholar 

  150. Tada H, Nogami A, Shimizu W, Naito S, Nakatsugawa M, Oshima S, Taniguchi K. ST segment and T wave alternans in a patient with Brugada syndrome. Pacing Clin Electrophysiol 2000;23:413–415.

    Article  PubMed  CAS  Google Scholar 

  151. Chinushi M, Washizuka T, Okumura H, Aizawa Y. Intravenous administration of class I antiarrhythmic drugs induced T wave alternans in a patient with Brugada syndrome. J Cardiovasc Electrophysiol 2001;12:493–495.

    Article  PubMed  CAS  Google Scholar 

  152. Chinushi Y, Chinushi M, Toida T, Aizawa Y. Class I antiarrhythmic drug and coronary vasospasminduced T wave alternans and ventricular tachyarrhythmia in a patient with Brugada syndrome and vasospastic angina. J Cardiovasc Electrophysiol 2002;13:191–194.

    Article  PubMed  Google Scholar 

  153. Takagi M, Doi A, Takeuchi K, Yoshikawa J. Pilsicanide-induced marked T wave alternans and ventricular fibrillation in a patient with Brugada syndrome. J Cardiovasc Electrophysiol 2002;13: 837.

    Article  PubMed  Google Scholar 

  154. Ohkubo K, Watanabe I, Okumura Y, Yamada T, Masaki R, Kofune T, Oshikawa N, Kasamaki Y, Saito S, Ozawa Y, Kanmatsuse K. Intravenous administration of class I antiarrhythmic drug induced T wave alternans in an asymptomatic Brugada syndrome patient. Pacing Clin Electrophysiol 2003;26:1900–1903.

    Article  PubMed  Google Scholar 

  155. Morita H, Morita ST, Nagase S, Banba K, Nishii N, Tani Y, Watanabe A, Nakamura K, Kusano KF, Emori T, Matsubara H, Hina K, Kita T, Ohe T. Ventricular arrhythmia induced by sodium channel blocker in patients with Brugada syndrome. J Am Coll Cardiol 2003;42:1624–1631.

    Article  PubMed  CAS  Google Scholar 

  156. Morita H, Nagase S, Kusano K, Ohe T. Spontaneous T wave alternans and premature ventricular contractions during febrile illness in a patient with Brugada syndrome. J Cardiovasc Electrophysiol 2002;13:816–818.

    Article  PubMed  Google Scholar 

  157. Morita H, Zipes DP, Lopshire J, Morita ST, Wu J. T wave alternans in an in vitro canine tissue model of Brugada syndrome. Am J Physiol Heart Circ Physiol 2006;291:H421–H428.

    Article  PubMed  CAS  Google Scholar 

  158. Babaliaros VC, Hurst JW. Tricyclic antidepressants and the Brugada syndrome: An example of Brugada waves appearing after the administration of desipramine. Clin Cardiol 2002;25:395–398.

    Article  PubMed  Google Scholar 

  159. Goldgran-Toledano D, Sideris G, Kevorkian JP. Overdose of cyclic antidepressants and the Brugada syndrome. N Engl J Med 2002;346:1591–1592.

    Article  PubMed  Google Scholar 

  160. Tada H, Sticherling C, Oral H, Morady F. Brugada syndrome mimicked by tricyclic antidepressant overdose. J Cardiovasc Electrophysiol 2001;12: 275.

    Article  PubMed  CAS  Google Scholar 

  161. Pastor A, Nunez A, Can tale C, Cosio FG. Asymptomatic Brugada syndrome case unmasked during dimenhydrinate infusion. J Cardiovasc Electrophysiol 2001;12:1192–1194.

    Article  PubMed  CAS  Google Scholar 

  162. Ortega-Carnicer J, Bertos-Polo J, Gutierrez-Tirado C. Aborted sudden death, transient Brugada pattern, and wide QRS dysrrhythmias after massive cocaine ingestion. J Electrocardiol 2001;34: 345–349.

    Article  PubMed  CAS  Google Scholar 

  163. Nogami A, Nakao M, Kubota S, Sugiyasu A, Doi H, Yokoyama K, Yumoto K, Tamaki T, Kato K, Hosokawa N, Sagai H, Nakamura H, Nitta J, Yamauchi Y, Aonuma K. Enhancement of J-ST-segment elevation by the glucose and insulin test in Brugada syndrome. Pacing Clin Electrophysiol 2003;26:332–337.

    Article  PubMed  Google Scholar 

  164. Araki T, Konno T, Itoh H, Ino H, Shimizu M. Brugada syndrome with ventricular tachycardia and fibrillation related to hypokalemia. Circ J 2003;67:93–95.

    Article  PubMed  Google Scholar 

  165. Akhtar M, Goldschlager NF. Brugada electrocardiographic pattern due to tricyclic antidepressant overdose. J Electrocardiol 2006;39:336–339.

    Article  PubMed  Google Scholar 

  166. Darbar D, Yang T, Churchwell K, Wilde AA, Roden DM. Unmasking of Brugada syndrome by lithium. Circulation 2005;112:1527–1531.

    Article  PubMed  Google Scholar 

  167. Noda T, Shimizu W, Taguchi A, Satomi K, Suyama K, Kurita T, Aihara N, Kamakura S. ST-segment elevation and ventricular fibrillation without coronary spasm by intracoronary injection of acetylcholine and/or ergonovine maleate in patients with Brugada syndrome. J Am Coll Cardiol 2002; 40:1841–1847.

    Article  PubMed  Google Scholar 

  168. Chinushi M, Furushima H, Tanabe Y, Washizuka T, Aizawaz Y. Similarities between Brugada syndrome and ischemia-induced ST-segment elevation. Clinical correlation and synergy. J Electrocardiol 2005;38(Suppl.):18–21.

    Article  PubMed  Google Scholar 

  169. Nimmannit S, Malasit P, Chaovakul V, Susaengrat W, Vasuvattakul S, Nilwarangkur S. Pathogenesis of sudden unexplained nocturnal death (lai tai) and endemic distal renal tubular acidosis. Lancet 1991;338:930–932.

    Article  PubMed  CAS  Google Scholar 

  170. Proclemer A, Facchin D, Feruglio GA, Nucifora R. Recurrent ventricular fibrillation, right bundlebranch block and persistent ST segment elevation in V1-V3: A new arrhythmia syndrome? A clinical case report (see comments). G Ital Cardiol 1993; 23:1211–1218.

    PubMed  CAS  Google Scholar 

  171. Mizumaki K, Fujiki A, Tsuneda T, Sakabe M, Nishida K, Sugao M, Inoue H. Vagal activity modulates spontaneous augmentation of ST elevation in daily life of patients with Brugada syndrome. J Cardiovasc Electrophysiol 2004;15:667–673.

    Article  PubMed  Google Scholar 

  172. Wichter T, Matheja P, Eckardt L, Kies P, Schafers K, Schulze-Bahr E, Haverkamp W, Borggrefe M, Schober O, Breithardt G, Schafers M. Cardiac autonomic dysfunction in Brugada syndrome. Circulation 2002;105:702–706.

    Article  PubMed  Google Scholar 

  173. Ikeda T, Abe A, Yusa S, Nakamura K, Ishiguro H, Mera H, Yotsukura M, Yoshino H. The full stomach test as a novel diagnostic technique for identifying patients at risk for Brugada syndrome. J Cardiovasc Electrophysiol 2006;17:602–607.

    Article  PubMed  Google Scholar 

  174. Gonzalez Rebollo G, Madrid H, Carcia A, Garcia de Casto A, Moro AM. Reccurrent ventricular fibrillation during a febrile illness in a patient with the Brugada syndrome. Rev Esp Cardiol 2000;53: 755–757.

    PubMed  CAS  Google Scholar 

  175. Madle A, Kratochvil Z, Polivkova A. [The Brugada syndrome]. Vnitr Lek 2002;48:255–258.

    PubMed  CAS  Google Scholar 

  176. Kum L, Fung JWH, Chan WWL, Chan GK, Chan YS, Sanderson JE. Brugada syndrome unmasked by febrile illness. Pacing Clin Electrophysiol 2002;25:1660–1661.

    Article  PubMed  Google Scholar 

  177. Keller DI, Huang H, Zhao J, Frank R, Suarez V, Delacretaz E, Brink M, Osswald S, Schwick N, Chahine M. A novel SCN5A mutation, F1344S, identified in a patient with Brugada syndrome and fever-induced ventricular fibrillation. Cardiovasc Res 2006;70:521–529.

    Article  PubMed  CAS  Google Scholar 

  178. Di Diego JM, Cordeiro JM, Goodrow RJ, Fish JM, Zygmunt AC, Perez GJ, Scornik FS, Antzelevitch C. Ionic and cellular basis for the predominance of the Brugada syndrome phenotype in males. Circulation 2002; 106:2004–2011.

    Article  PubMed  Google Scholar 

  179. Brugada J, Brugada R, Brugada P. Pharmacological and device approach to therapy of inherited cardiac diseases associated with cardiac arrhythmias and sudden death. J Electrocardiol 2000;33(Suppl.):41–47.

    Article  PubMed  Google Scholar 

  180. Brugada P, Brugada R, Brugada J, Geelen P. Use of the prophylactic implantable cardioverter defibrillator for patients with normal hearts. Am J Cardiol 1999;83:98D–100D.

    Article  PubMed  CAS  Google Scholar 

  181. Haissaguerre M, Extramiana F, Hocini M, Cauchemez B, Jais P, Cabrera JA, Farre G, Leenhardt A, Sanders P, Scavee C, Hsu LF, Weerasooriya R, Shah DC, Frank R, Maury P, Delay M, Garrigue S, Clementy J. Mapping and ablation of ventricular fibrillation associated with long-QT and Brugada syndromes. Circulation 2003;108:925–928.

    Article  PubMed  Google Scholar 

  182. Kron J, Herre J, Renfroe EG, Rizo-Patron C, Raitt M, Halperin B, Gold M, Goldner B, Wathen M, Wilkoff B, Olarte A, Yao Q. Lead-and devicerelated complications in the antiarrhythmics versus implantable defibrillators trial. Am Heart J 2001;141:92–98.

    Article  PubMed  CAS  Google Scholar 

  183. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. N Engl J Med 1997; 337:1576–1583.

    Article  Google Scholar 

  184. Belhassen B, Viskin S, Antzelevitch C. The Brugada syndrome: Is an implantable cardioverter defibrillator the only therapeutic option? Pacing Clin Electrophysiol 2002;25:1634–1640.

    Article  PubMed  Google Scholar 

  185. Antzelevitch C, Fish JM. Therapy for the Brugada syndrome. In: Kass R, Clancy CE, Eds. Handbook of Experimental Pharmacology. New York: Springer-Verlag, 2006:305–330.

    Google Scholar 

  186. Chinushi M, Aizawa Y, Ogawa Y, Shiba M, Takahashi K. Discrepant drug action of disopyramide on ECG abnormalities and induction of ventricular arrhythmias in a patient with Brugada syndrome. J Electrocardiol 1997;30:133–136.

    Article  PubMed  CAS  Google Scholar 

  187. Antzelevitch C, Brugada P, Brugada J, Brugada R, Nademanee K, Towbin JA. Clinical Approaches to Tachy arrhythmias. The Brugada Syndrome. Armonk, NY: Futura Publishing Company, Inc., 1999.

    Google Scholar 

  188. Grant AO. Electrophysiological basis and genetics of Brugada syndrome. J Cardiovasc Electrophysiol 2005;16(Suppl. 1):S3–S7.

    Article  PubMed  Google Scholar 

  189. Alings M, Dekker L, Sadee A, Wilde A. Quinidine induced electrocardiographic normalization in two patients with Brugada syndrome. Pacing Clin Electrophysiol 2001;24:1420–1422.

    Article  PubMed  CAS  Google Scholar 

  190. Belhassen B, Viskin S. Pharmacologic approach to therapy of Brugada syndrome: Quinidine as an alternative to ICD therapy? In: Antzelevitch C, Brugada P, Brugada J, Brugada R, Eds. The Brugada Syndrome: From Bench to Bedside. Oxford, UK: Blackwell Futura, 2004:202–211.

    Google Scholar 

  191. Marquez MF, Rivera J, Hermosillo AG, Iturralde P, Colin L, Moragrega JL, Cardenas M. Arrhythmic storm responsive to quinidine in a patient with Brugada syndrome and vasovagal syncope. Pacing Clin Electrophysiol 2005;28:870–873.

    Article  PubMed  Google Scholar 

  192. Belhassen B, Viskin S, Fish R, Glick A, Setbon I, Eldar M. Effects of electrophysiologic-guided therapy with Class IA antiarrhythmic drugs on the long-term outcome of patients with idiopathic ventricular fibrillation with or without the Brugada syndrome. J Cardiovasc Electrophysiol 1999;10: 1301–1312.

    Article  PubMed  CAS  Google Scholar 

  193. 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.

    Article  PubMed  CAS  Google Scholar 

  194. Mok NS, Chan NY, Chi-Suen CA. Successful use of quinidine in treatment of electrical storm in Brugada syndrome. Pacing Clin Electrophysiol 2004;27:821–823.

    Article  PubMed  Google Scholar 

  195. Marquez MF, Rivera J, Hermosillo AG, Iturralde P, Colin L, Moragrega JL, Cardenas M. Arrhythmic storm responsive to quinidine in a patient with Brugada syndrome and vasovagal syncope. Pacing Clin Electrophysiol 2005;28:870–873.

    Article  PubMed  Google Scholar 

  196. Mizusawa Y, Sakurada H, Nishizaki M, Hiraoka M. Effects of low-dose quinidine on ventricular tachyarrhythmias in patients with Brugada syndrome: Low-dose quinidine therapy as an adjunctive treatment. J Cardiovasc Pharmacol 2006;47: 359–364.

    PubMed  CAS  Google Scholar 

  197. Fish JM, Extramiana F, Antzelevitch C. Tedisamil abolishes the arrhythmogenic substrate responsible for VT/VF in an experimental model of the Brugada syndrome. Heart Rhythm 2004;1(1S): S158 (abstract).

    Google Scholar 

  198. Zeltser D, Justo D, Halkin A, Prokhorov V, Heller K, Viskin S. Torsade de pointes due to noncardiac drugs: Most patients have easily identifiable risk factors. Medicine (Baltimore) 2003;82:282–290.

    Article  Google Scholar 

  199. Antzelevitch C, Shimizu W. Cellular mechanisms underlying the long QT syndrome. Curr Opin Cardiol 2002;17:43–51.

    Article  PubMed  Google Scholar 

  200. Belardinelli L, Antzelevitch C, Vos MA. Assessing predictors of drug-induced torsade de pointes. Trends Pharmacol Sci 2003;24:619–625.

    Article  PubMed  CAS  Google Scholar 

  201. Fish JM, Extramiana F, Antzelevitch C. AVE0118, an I to and I Kur blocker, suppresses VT/VF in an experimental model of the Brugada syndrome. Circulation 2004;110(17):III–193 (abstract).

    Google Scholar 

  202. Suzuki H, Torigoe K, Numata O, Yazaki S. Infant case with a malignant form of Brugada syndrome. J Cardiovasc Electrophysiol 2000;11:1277–1280.

    Article  PubMed  CAS  Google Scholar 

  203. Tanaka H, Kinoshita O, Uchikawa S, Kasai H, Nakamura M, Izawa A, Yokoseki O, Kitabayashi H, Takahashi W, Yazaki Y, Watanabe N, Imamura H, Kubo K. Successful prevention of recurrent ventricular fibrillation by intravenous isoproterenol in a patient with Brugada syndrome. Pacing Clin Electrophysiol 2001;24:1293–1294.

    Article  PubMed  CAS  Google Scholar 

  204. Haghjoo M, Arya A, Heidari A, Sadr-Ameli MA. Suppression of electrical storm by oral quinidine in a patient with Brugada syndrome. J Cardiovasc Electrophysiol 2005;16:674.

    Article  PubMed  Google Scholar 

  205. Fish JM, Welchons DR, Kim YS, Lee SH, Ho WK, Antzelevitch C. Dimethyl lithospermate B, an extract of danshen, suppresses arrhythmogenesis associated with the Brugada syndrome. Circulation 2006;113:1393–1400.

    Article  PubMed  CAS  Google Scholar 

  206. Nademanee K, Veerakul G, Schwab M. Predisposing factors in the Brugada syndrome. In: Antzelevitch C, Brugada P, Eds. Brugada Syndrome. Elmsford, UK: Blackwell Publishing, 2004: 157–165.

    Google Scholar 

  207. Krishnan SC, Josephson ME. ST segment elevation induced by class IC antiarrhythmic agents: Underlying electrophysiologic mechanisms and insights into drug-induced proarrhythmia. J Cardiovasc Electrophysiol 1998;9:1167–1172.

    Article  PubMed  CAS  Google Scholar 

  208. Gasparini M, Priori SG, Mantica M, Napolitano C, Galimberti P, Ceriotti C, Simonini S. Flecainide test in Brugada syndrome: A reproducible but risky tool. Pacing Clin Electrophysiol 2003;26:338–341.

    Article  PubMed  Google Scholar 

  209. Takenaka S, Emori T, Koyama S, Morita H, Fukushima K, Ohe T. Asymptomatic form of Brugada syndrome. Pacing Clin Electrophysiol 1999;22:1261–1263.

    Article  PubMed  CAS  Google Scholar 

  210. Matana A, Goldner V, Stanic K, Mavric Z, Zaputovic L, Matana Z. Unmasking effect of pro-pafenone on the concealed form of the Brugada phenomenon. Pacing Clin Electrophysiol 2000;23: 416–418.

    Article  PubMed  CAS  Google Scholar 

  211. Rolf S, Bruns HJ, Wichter T, Kirchhof P, Ribbing M, Wasmer K, Paul M, Breithardt G, Haverkamp W, Eckardt L. The ajmaline challenge in Brugada syndrome: Diagnostic impact, safety, and recommended protocol. Eur Heart J 2003;24:1104–1112.

    Article  PubMed  CAS  Google Scholar 

  212. Sarkozy A, Caenepeel A, Geelen P, Peytchev P, de Zutter M., Brugada P. Cibenzoline induced Brugada ECG pattern. Europace 2005;7:537–539.

    Article  PubMed  Google Scholar 

  213. Aouate P, Clerc J, Viard P, Seoud J. Propranolol intoxication revealing a Brugada syndrome. J Cardiovasc Electrophysiol 2005;16:348–351.

    Article  PubMed  Google Scholar 

  214. Matsuo K, Shimizu W, Kurita T, Inagaki M, Aihara N, Kamakura S. Dynamic changes of 12-lead electrocardiograms in a patient with Brugada syndrome. J Cardiovasc Electrophysiol 1998;9:508–512.

    Article  PubMed  CAS  Google Scholar 

  215. Bigwood B, Galler D, Amir N, Smith W. Brugada syndrome following tricyclic antidepressant overdose. Anaesth Intensive Care 2005;33:266–270.

    PubMed  CAS  Google Scholar 

  216. Bolognesi R, Tsialtas D, Vasini P, Conti M, Manca C. Abnormal ventricular repolarization mimicking myocardial infarction after heterocyclic antidepressant overdose. Am J Cardiol 1997;79:242–245.

    Article  PubMed  CAS  Google Scholar 

  217. Rouleau F, Asfar P, Boulet S, Dube L, Dupuis JM, Alquier P, Victor J. Transient ST segment elevation in right precordial leads induced by psychotropic drugs: Relationship to the Brugada syndrome. J Cardiovasc Electrophysiol 2001;12:61–65.

    Article  PubMed  CAS  Google Scholar 

  218. Lopez-Barbeito B, Lluis M, Delgado V, Jimenez S, az-Infante E, Nogue-Xarau S, Brugada J. Diphenhydramine overdose and Brugada sign. Pacing Clin Electrophysiol 2005;28:730–732.

    Article  PubMed  Google Scholar 

  219. Littmann L, Monroe MH, Svenson RH. Brugada-type electrocardiographic pattern induced by cocaine. Mayo Clin Proc 2000;75:845–849.

    Article  PubMed  CAS  Google Scholar 

  220. Shimizu W. Acquired forms of the Brugada syndrome. J Electrocardiol 2005;38(Suppl.):22–25.

    Article  PubMed  Google Scholar 

  221. van Den Berg MP, Wilde AA, Viersma TJW, Brouwer J, Haaksma J, van der Hout AH, Stolte-Dijkstra I, Bezzina TCR, Van Langen IM, Beaufort-Krol GC, Cornel JH, Crijns HJ. Possible bradycardic mode of death and successful pacemaker treatment in a large family with features of long QT syndrome type 3 and Brugada syndrome. J Cardiovasc Electrophysiol 2001;12:630–636.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Masonic Medical Research Laboratory, Utica, NY

    Charles Antzelevitch PhD, FACC, FAHA, FHRS (Executive Director and Director of Research, Gordon K. Moe Scholar, Professor of Pharmacology)

  2. Upstate Medical University, Syracuse, NY, USA

    Charles Antzelevitch PhD, FACC, FAHA, FHRS (Executive Director and Director of Research, Gordon K. Moe Scholar, Professor of Pharmacology)

  3. Cardiac Hospitalization Tel Aviv Sourasky Medical Center, Sackler School of Medicine Tel Aviv University, Tel Aviv, Israel

    Sami Viskin MD (Director)

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  1. Charles Antzelevitch PhD, FACC, FAHA, FHRS
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  2. Sami Viskin MD
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Editors and Affiliations

  1. Cardiovascular Boehringer Ingelheim Pharmaceuticals Ridgefield, CT, USA

    Ihor Gussak MD, PhD, FACC (Deputy Therapeutic Area Head, Professor of Pharmacology) (Deputy Therapeutic Area Head, Professor of Pharmacology)

  2. Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Bridgewater, NJ, USA

    Ihor Gussak MD, PhD, FACC (Deputy Therapeutic Area Head, Professor of Pharmacology) (Deputy Therapeutic Area Head, Professor of Pharmacology)

  3. Gordon K. Moe Scholar Masonic Medical Research Laboratory, Utica, NY, USA

    Charles Antzelevitch PhD, FACC, FAHA, FHRS (Executive Director and Director of Research) (Executive Director and Director of Research)

  4. Upstate Medical University, Syracuse, NY, USA

    Charles Antzelevitch PhD, FACC, FAHA, FHRS (Executive Director and Director of Research) (Executive Director and Director of Research)

  5. Heart Failure Research Center Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands

    Arthur A. M. Wilde MD, PhD, FESC, FAHA (Professor) (Professor)

  6. Mayo Clinic College of Medicine, Rochester, MN, USA

    Paul A. Friedman MD (Professor of Medicine) & Michael J. Ackerman MD, PhD, FACC (Professor of Medicine, Pediatrics and Pharmacology, Consultant Cardiovascular Disease and Pediatric Cardiology, Director Long QT Syndrome Clinic and the Mayo Clinic Windland Smith Rice Sudden Death Genomics) (Professor of Medicine) &  (Professor of Medicine, Pediatrics and Pharmacology, Consultant Cardiovascular Disease and Pediatric Cardiology, Director Long QT Syndrome Clinic and the Mayo Clinic Windland Smith Rice Sudden Death Genomics)

  7. Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN, USA

    Win-Kuang Shen MD (Consultant, Professor of Medicine) (Consultant, Professor of Medicine)

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Antzelevitch, C., Viskin, S. (2008). Brugada Syndrome: Cellular Mechanisms and Approaches to Therapy. In: Gussak, I., Antzelevitch, C., Wilde, A.A.M., Friedman, P.A., Ackerman, M.J., Shen, WK. (eds) Electrical Diseases of the Heart. Springer, London. https://doi.org/10.1007/978-1-84628-854-8_35

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  • DOI: https://doi.org/10.1007/978-1-84628-854-8_35

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