Abstract
The Brugada Syndrome, introduced as a new clinical entity 20 years ago, has attracted great interest because of its prevalence and association with high risk of sudden death, especially in males as they enter their third and fourth decade of life. Consensus reports published in 2002 and 2005 focused on diagnostic criteria, risk stratification and approaches to therapy. More recently, the risk stratification approaches have been the subject of controversy and debate.
Over 21 years have transpired since the introduction of the concept of phase 2 reentry, the mechanism believed to underlie development of arrhythmogenesis in BrS. Thus, the entity initially introduced as “ST segment elevation and right bundle branch block (RBBB)”, which came to be known as Brugada syndrome in 1996, evolved in the experimental laboratory and in the clinic along parallel but separate tracks. While the electrocardiographic and arrhythmic manifestations of BrS are well explained by abnormal repolarization in the right ventricular outflow track (RVOT), recent data have suggested conduction impairment in the RVOT as the basis for BrS, thus generating a debate as to the basis for the pathogenicity of the syndrome.
This review provides an overview of the clinical, genetic, molecular and cellular aspects of the Brugada syndrome and the various approaches to therapy.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome: a multicenter report. J Am Coll Cardiol. 1992;20:1391–6.
Krishnan SC, Antzelevitch C. Sodium channel block produces opposite electrophysiological effects in canine ventricular epicardium and endocardium. Circ Res. 1991;69:277–91.
Krishnan SC, Antzelevitch C. Flecainide-induced arrhythmia in canine ventricular epicardium. Phase 2 reentry? Circulation. 1993;87:562–72.
Yan GX, Antzelevitch C. Cellular basis for the electrocardiographic J wave. Circulation. 1996;93:372–9.
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;27:1061–70.
Antzelevitch C. The Brugada syndrome. J Cardiovasc Electrophysiol. 1998;9:513–6.
Wilde AA, Antzelevitch C, Borggrefe M, Brugada J, Brugada R, Brugada P, et al. Proposed diagnostic criteria for the Brugada syndrome. Eur Heart J. 2002;23:1648–54.
Wilde AA, Antzelevitch C, Borggrefe M, Brugada J, Brugada R, Brugada P, et al. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation. 2002;106:2514–9.
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;111:659–70.
Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, et al. Brugada syndrome: report of the second consensus conference. Heart Rhythm. 2005;2:429–40.
Viskin S, Rogowski O. Asymptomatic Brugada syndrome: a cardiac ticking time-bomb? Europace. 2007;9:707–10.
Wilde AA, Viskin S. EP testing does not predict cardiac events in Brugada syndrome. Heart Rhythm. 2011;8:1598–600.
Wilde AA, Viskin S. Rebuttal to EP testing predicts cardiac events in patients with Brugada syndrome. Heart Rhythm. 2011;8:1797.
Brugada J, Brugada R, Brugada P. Electrophysiologic testing predicts events in Brugada syndrome patients. Heart Rhythm. 2011;8:1595–7.
Brugada J, Brugada R, Brugada P. Rebuttal to EP testing does not predict cardiac events in patients with Brugada syndrome. Heart Rhythm. 2011;8:1796.
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;86:91–4.
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;38:771–4.
Holst AG, Jensen HK, Eschen O, Henriksen FL, Kanters J, Bundgaard H, et al. Low disease prevalence and inappropriate implantable cardioverter defibrillator shock rate in Brugada syndrome: a nationwide study. Europace. 2012;14:1025–9.
Antzelevitch C. Brugada syndrome. Pacing Clin Electrophysiol. 2006;29:1130–59.
Brugada P, Brugada J, Brugada R. The Brugada syndrome. Card Electrophysiol Rev. 2002;6:45–8.
Brugada P, Brugada J, Brugada R. Arrhythmia induction by antiarrhythmic drugs. Pacing Clin Electrophysiol. 2000;23:291–2.
Brugada R, Brugada J, Antzelevitch C, Kirsch GE, Potenza D, Towbin JA, et al. 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;101:510–5.
Antzelevitch C, Brugada R. Fever and the Brugada syndrome. Pacing Clin Electrophysiol. 2002;25:1537–9.
Ikeda T, Abe A, Yusa S, Nakamura K, Ishiguro H, Mera H, et al. The full stomach test as a novel diagnostic technique for identifying patients at risk for Brugada syndrome. J Cardiovasc Electrophysiol. 2006;17:602–7.
Makimoto H, Nakagawa E, Takaki H, Yamada Y, Okamura H, Noda T, et al. Augmented ST-segment elevation during recovery from exercise predicts cardiac events in patients with Brugada syndrome. J Am Coll Cardiol. 2010;56:1576–84.
Mizumaki K, Fujiki A, Tsuneda T, Sakabe M, Nishida K, Sugao M, et al. Vagal activity modulates spontaneous augmentation of ST elevation in daily life of patients with Brugada syndrome. J Cardiovasc Electrophysiol. 2004;15:667–73.
Morita H, Zipes DP, Morita ST, Wu J. Temperature modulation of ventricular arrhythmogenicity in a canine tissue model of Brugada syndrome. Heart Rhythm. 2007;4:188–97.
Take Y, Morita H, Wu J, Nagase S, Morita S, Toh N, et al. Spontaneous electrocardiogram alterations predict ventricular fibrillation in Brugada syndrome. Heart Rhythm. 2011;8:1014–21.
Richter S, Sarkozy A, Veltmann C, Chierchia GB, Boussy T, Wolpert C, et al. Variability of the diagnostic ECG pattern in an ICD patient population with Brugada syndrome. J Cardiovasc Electrophysiol. 2009;20:69–75.
Richter S, Sarkozy A, Paparella G, Henkens S, Boussy T, Chierchia GB, et al. Number of electrocardiogram leads displaying the diagnostic coved-type pattern in Brugada syndrome: a diagnostic consensus criterion to be revised. Eur Heart J. 2010;31:1357–64.
Shimizu W, Antzelevitch C, Suyama K, Kurita T, Taguchi A, Aihara N, et al. Effect of sodium channel blockers on ST segment, QRS duration, and corrected QT interval in patients with Brugada syndrome. J Cardiovasc Electrophysiol. 2000;11:1320–9.
Priori SG, Napolitano C, Gasparini M, Pappone C, Della BP, 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;102:2509–15.
Wolpert C, Echternach C, Veltmann C, Antzelevitch C, Thomas GP, Sphel S, et al. Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome. Heart Rhythm. 2005;2:254–60.
Hong K, Brugada J, Oliva A, Berruezo-Sanchez A, Potenza D, Pollevick GD, et al. Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations. Circulation. 2004;110:3023–7.
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;16:486–93.
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;11:95–8.
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;2:97–9.
Horigome H, Shigeta O, Kuga K, Isobe T, Sakakibara Y, Yamaguchi I, et al. 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;36:339–43.
Kamakura S, Ohe T, Nakazawa K, Aizawa Y, Shimizu A, Horie M, et al. Long-term prognosis of probands with Brugada-pattern ST-elevation in leads V1-V3. Circ Arrhythm Electrophysiol. 2009;2:495–503.
Nam GB, Kim YH, Antzelevitch C. Augmentation of J waves and electrical storms in patients with early repolarization. N Engl J Med. 2008;358:2078–9.
Nam GB, Ko KH, Kim J, Park KM, Rhee KS, Choi KJ, et al. Mode of onset of ventricular fibrillation in patients with early repolarization pattern vs. Brugada syndrome. Eur Heart J. 2010;31:330–9.
Antzelevitch C, Yan GX. J wave syndromes. Heart Rhythm. 2010;7:549–58.
Shimizu W, Matsuo K, Takagi M, Tanabe Y, Aiba T, Taguchi A, et al. Body surface distribution and response to drugs of ST segment elevation in Brugada syndrome: clinical implication of eighty-seven-lead body surface potential mapping and its application to twelve-lead electrocardiograms. J Cardiovasc Electrophysiol. 2000;11:396–404.
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;22:2290–6.
Shimeno K, Takagi M, Maeda K, Tatsumi H, Doi A, Yoshiyama M. Usefulness of multichannel Holter ECG recording in the third intercostal space for detecting type 1 Brugada ECG: comparison with repeated 12-lead ECGs. J Cardiovasc Electrophysiol. 2009;20:1026–31.
Shin SC, Ryu S, Lee JH, Chang BJ, Shin JK, Kim HS, et al. Prevalence of the Brugada-type ECG recorded from higher intercostal spaces in healthy Korean males. Circ J. 2005;69:1064–7.
Alings M, Wilde A. “Brugada” syndrome: clinical data and suggested pathophysiological mechanism. Circulation. 1999;99:666–73.
Bezzina C, Veldkamp MW, van Den Berg MP, Postma AV, Rook MB, Viersma JW, et al. A single Na+ channel mutation causing both long-QT and Brugada syndromes. Circ Res. 1999;85:1206–13.
Pitzalis MV, Anaclerio M, Iacoviello M, Forleo C, Guida P, Troccoli R, et al. QT-interval prolongation in right precordial leads: an additional electrocardiographic hallmark of Brugada syndrome. J Am Coll Cardiol. 2003;42:1632–7.
Castro Hevia J, Antzelevitch C, Tornés Bárzaga F, Dorantes Sánchez M, Dorticós Balea F, Zayas Molina R, et al. 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;47:1828–34.
Smits JP, Eckardt L, Probst V, Bezzina CR, Schott JJ, Remme CA, et al. Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. J Am Coll Cardiol. 2002;40:350–6.
Morita H, Kusano KF, Miura D, Nagase S, Nakamura K, Morita ST, et al. Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome. Circulation. 2008;118:1697–704.
Priori SG, Gasparini M, Napolitano C, Della BP, 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;59:37–45.
Kasanuki H, Ohnishi S, Ohtuka M, Matsuda N, Nirei T, Isogai R, et al. Idiopathic ventricular fibrillation induced with vagal activity in patients without obvious heart disease. Circulation. 1997;95:2277–85.
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. G Ital Cardiol. 1993;23:1211–8.
Makiyama T, Akao M, Tsuji K, Doi T, Ohno S, Takenaka K, et al. High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations. J Am Coll Cardiol. 2005;46:2100–6.
Scornik FS, Desai M, Brugada R, Guerchicoff A, Pollevick GD, Antzelevitch C, et al. Functional expression of “cardiac-type” Nav1.5 sodium channel in canine intracardiac ganglia. Heart Rhythm. 2006;3:842–50.
Patruno N, Pontillo D. Brugada syndrome and vasovagal syncope. Pacing Clin Electrophysiol. 2006;29:215.
Shimada M, Miyazaki T, Miyoshi S, Soejima K, Hori S, Mitamura H, et al. Sustained monomorphic ventricular tachycardia in a patient with Brugada syndrome. Jpn Circ J. 1996;60:364–70.
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. Pacing Clin Electrophysiol. 2000;23:407–9.
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;5:257–61.
Mok NS, Chan NY. Brugada syndrome presenting with sustained monomorphic ventricular tachycardia. Int J Cardiol. 2004;97:307–9.
Probst V, Evain S, Gournay V, Marie A, Schott JJ, Boisseau P, et al. 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.
Sastry BK, Narasimhan C, Soma Raju B. Brugada syndrome with monomorphic ventricular tachycardia in a one-year-old child. Indian Heart J. 2001;53:203–5.
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;22:400–9.
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 V1 to V3. Circulation. 2002;105:73–8.
Priori SG, Napolitano C, Gasparini M, Pappone C, Della BP, Giordano U, et al. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation. 2002;105:1342–7.
Brugada P, Brugada R, Brugada J. Patients with an asymptomatic Brugada electrocardiogram should undergo pharmacological and electrophysical testing. Circulation. 2005;112:279–85.
Priori SG, Napolitano C. Management of Patients with Brugada syndrome should not be based on programmed electrical stimulation. Circulation. 2005;112:285–91.
Eckardt L, Probst V, Smits JP, Bahr ES, Wolpert C, Schimpf R, et al. Long-term prognosis of individuals with right precordial ST-segment-elevation Brugada syndrome. Circulation. 2005;111:257–63.
Atarashi H, Ogawa S, Idiopathic Ventricular Fibrillation Investigators. New ECG criteria for high-risk Brugada syndrome. Circ J. 2003;67:8–10.
Junttila MJ, Brugada P, Hong K, Lizotte E, de Zutter M, Sarkozy A, et al. Differences in 12-lead electrocardiogram between symptomatic and asymptomatic Brugada syndrome patients. J Cardiovasc Electrophysiol. 2008;19:380–3.
Morita H, Takenaka-Morita S, Fukushima-Kusano K, Kobayashi M, Nagase S, Kakishita M, et al. Risk stratification for asymptomatic patients with brugada syndrome. Circ J. 2003;67:312–6.
Viskin S. Inducible ventricular fibrillation in the Brugada syndrome: diagnostic and prognostic implications. J Cardiovasc Electrophysiol. 2003;14:458–60.
Brugada J, Brugada R, Brugada P. Right bundle-branch block and ST-segment elevation in leads V1 through V3. A marker for sudden death in patients without demonstrable structural heart disease. Circulation. 1998;97:457–60.
Kanda M, Shimizu W, Matsuo K, Nagaya N, Taguchi A, Suyama K, et al. Electrophysiologic characteristics and implications of induced ventricular fibrillation in symptomatic patients with Brugada syndrome. J Am Coll Cardiol. 2002;39:1799–805.
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;108:3092–6.
Eckardt L, Kirchhof P, Johna R, Haverkamp W, Breithardt G, Borggrefe M. Wolff-Parkinson-White syndrome associated with Brugada syndrome. Pacing Clin Electrophysiol. 2001;24:1423–4.
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;24:247–9.
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;17:577–83.
Paul M, Gerss J, Schulze-Bahr E, Wichter T, Vahlhaus C, Wilde AA, et al. Role of programmed ventricular stimulation in patients with Brugada syndrome: a meta-analysis of worldwide published data. Eur Heart J. 2007;28:2126–33.
Yamagata K, Horie M, Ogawa S, Aizawa Y, Kusano KF, Ohe T, et al. Clinical phenotype and prognosis of probands with Brugada syndrome in relation to SCN5A mutation Japanese Brugada Syndrome Multicenter Registry. Circulation. 2009;120:S697.
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;121:635–43.
Makimoto H, Kamakura S, Aihara N, Noda T, Nakajima I, Yokoyama T, et al. Clinical impact of the number of extrastimuli in programmed electrical stimulation in patients with Brugada type 1 electrocardiogram. Heart Rhythm. 2012;9(2):242–8.
Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, et al. Genetic basis and molecular mechanisms for idiopathic ventricular fibrillation. Nature. 1998;392:293–6.
Antzelevitch C, Viskin S. Brugada syndrome: cellular mechanisms and approached to therapy. In: Gussak I, Antzelevitch C, editors. Electrical diseases of the heart: genetics, mechanisms, treatment, prevention. London: Springer; 2008. p. 500–35.
Grant AO, Carboni MP, Neplioueva V, Starmer CF, Memmi M, Napolitano C, et al. Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation. J Clin Invest. 2002;110:1201–9.
Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, et al. An international compendium of mutations in the SCN5A encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm. 2010;7:33–46.
Balser JR. The cardiac sodium channel: gating function and molecular pharmacology. J Mol Cell Cardiol. 2001;33:599–613.
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;21:651–2.
Bezzina CR, Wilde AA, Roden DM. The molecular genetics of arrhythmias. Cardiovasc Res. 2005;67:343–6.
Tan HL, Bezzina CR, Smits JP, Verkerk AO, Wilde AA. Genetic control of sodium channel function. Cardiovasc Res. 2003;57:961–73.
Antzelevitch C, Brugada P, Brugada J, Brugada R. Brugada syndrome: from cell to bedside. Curr Probl Cardiol. 2005;30:9–54.
Dumaine R, Towbin JA, Brugada P, Vatta M, Nesterenko DV, Nesterenko VV, et al. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res. 1999;85:803–9.
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;25:856–9.
Porres JM, Brugada J, Urbistondo V, Garcia F, Reviejo K, Marco P. Fever unmasking the Brugada syndrome. Pacing Clin Electrophysiol. 2002;25:1646–8.
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;14:407–11.
Ortega-Carnicer J, Benezet J, Ceres F. Fever-induced ST-segment elevation and T-wave alternans in a patient with Brugada syndrome. Resuscitation. 2003;57:315–7.
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;5:251–5.
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;25:432–4.
Dulu A, Pastores SM, McAleer E, Voigt L, Halpern NA. Brugada electrocardiographic pattern in a postoperative patient. Crit Care Med. 2005;33:1634–7.
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;103:338–9.
Hong K, Guerchicoff A, Pollevick GD, Oliva A, Dumaine R, de Zutter M, et al. Cryptic 5′ splice site activation in SCN5A associated with Brugada syndrome. J Mol Cell Cardiol. 2005;38:555–60.
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;113:338–44.
Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007;115:442–9.
Burashnikov E, Pfeiffer R, Barajas-Martinez H, Delpon E, Hu D, Desai M, et al. Mutations in the cardiac L-type calcium channel associated J wave syndrome and sudden cardiac death. Heart Rhythm. 2010;7:1872–82.
London B, Michalec M, Mehdi H, Zhu X, Kerchner L, Sanyal S, et al. Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias. Circulation. 2007;116:2260–8.
Watanabe H, Koopmann TT, Le Scouarnec S, Yang T, Ingram CR, Schott JJ, et al. Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. J Clin Invest. 2008;118:2260–8.
Delpón E, Cordeiro JM, Núñez L, Thomsen PEB, Guerchicoff A, Pollevick GD, et al. Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome. Circ Arrhythm Electrophysiol. 2008;1:209–18.
Medeiros-Domingo A, Tan BH, Crotti L, Tester DJ, Eckhardt L, Cuoretti A, et al. Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes. Heart Rhythm. 2010;7:1466–71.
Giudicessi JR, Ye D, Tester DJ, Crotti L, Mugione A, Nesterenko VV, et al. Transient outward current (Ito) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome. Heart Rhythm. 1032;8:1024.
Cranefield PF, Hoffman BF. Conduction of the cardiac impulse. II. Summation and inhibition. Circ Res. 1971;28:220–33.
Kattygnarath D, Maugenre S, Neyroud N, Duthoit G, Denjoy I, Martins RP, et al. MOG1 mutations associated with Brugada syndrome electrocardiogram pattern. Circulation. 2009;120:S686 (Abstract).
Kattygnarath D, Maugenre S, Neyroud N, Balse E, Ichai C, Denjoy I, et al. MOG1: a new susceptibility gene for Brugada syndrome. Circ Cardiovasc Genet. 2011;4:261–8.
Tester DJ, Ackerman MJ. Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice. Circulation. 2011;123:1021–37.
Antzelevitch C, Sicouri S, Litovsky SH, Lukas A, Krishnan SC, DiDiego JM, et al. Heterogeneity within the ventricular wall. Electrophysiology and pharmacology of epicardial, endocardial, and M cells. Circ Res. 1991;69:1427–49.
Antzelevitch C, Shimizu W, Yan GX, Sicouri S, Weissenburger J, Nesterenko VV, et al. The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart. J Cardiovasc Electrophysiol. 1999;10:1124–52.
Litovsky SH, Antzelevitch C. Transient outward current prominent in canine ventricular epicardium but not endocardium. Circ Res. 1988;62:116–26.
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;72:671–87.
Furukawa T, Myerburg RJ, Furukawa N, Bassett AL, Kimura S. Differences in transient outward currents of feline endocardial and epicardial myocytes. Circ Res. 1990;67:1287–91.
Fedida D, Giles WR. Regional variations in action potentials and transient outward current in myocytes isolated from rabbit left ventricle. J Physiol. 1991;442:191–209.
Clark RB, Bouchard RA, Salinas-Stefanon E, Sanchez-Chapula J, Giles WR. Heterogeneity of action potential waveforms and potassium currents in rat ventricle. Cardiovasc Res. 1993;27:1795–9.
Wettwer E, Amos GJ, Posival H, Ravens U. Transient outward current in human ventricular myocytes of subepicardial and subendocardial origin. Circ Res. 1994;75:473–82.
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;93:168–77.
Glukhov AV, Fedorov VV, Lou Q, Ravikumar VK, Kalish PW, Schuessler RB, et al. Transmural dispersion of repolarization in failing and nonfailing human ventricle. Circ Res. 2010;106:981–91.
Antzelevitch C. M cells in the human heart. Circ Res. 2010;106:815–7.
Di Diego JM, Sun ZQ, Antzelevitch C. Ito and action potential notch are smaller in left vs. right canine ventricular epicardium. Am J Physiol. 1996;271:H548–61.
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;99:206–10.
Zicha S, Xiao L, Stafford S, Cha TJ, Han W, Varro A, et al. Transmural expression of transient outward potassium current subunits in normal and failing canine and human hearts. J Physiol. 2004;561:735–48.
Rosati B, Pan Z, Lypen S, Wang HS, Cohen I, Dixon JE, et al. Regulation of KChIP2 potassium channel beta subunit gene expression underlies the gradient of transient outward current in canine and human ventricle. J Physiol. 2001;533:119–25.
Costantini DL, Arruda EP, Agarwal P, Kim KH, Zhu Y, Zhu W, et al. The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient. Cell. 2005;123:347–58.
Takano M, Noma A. Distribution of the isoprenaline-induced chloride current in rabbit heart. Pflugers Arch. 1992;420:223–6.
Zygmunt AC. Intracellular calcium activates chloride current in canine ventricular myocytes. Am J Physiol. 1994;267:H1984–95.
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:H1471–9.
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.
Wang HS, Cohen IS. Calcium channel heterogeneity in canine left ventricular myocytes. J Physiol. 2003;547:825–33.
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;68:1729–41.
Anyukhovsky EP, Sosunov EA, Rosen MR. Regional differences in electrophysiologic properties of epicardium, midmyocardium and endocardium: in vitro and in vivo correlations. Circulation. 1996;94:1981–8.
Liu DW, Antzelevitch C. Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell. Circ Res. 1995;76:351–65.
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. 2001;281:H689–97.
Zygmunt AC, Goodrow RJ, Antzelevitch C. INaCa contributes to electrical heterogeneity within the canine ventricle. Am J Physiol Heart Circ Physiol. 2000;278:H1671–8.
Brahmajothi MV, Morales MJ, Reimer KA, Strauss HC. Regional localization of HERG, the channel protein responsible for the rapid component of the delayed rectifier, K+ current in the ferret heart. Circ Res. 1997;81:128–35.
Clements SD, Hurst JW. Diagnostic value of ECG abnormalities observed in subjects accidentally exposed to cold. Am J Cardiol. 1972;29:729–34.
Thompson R, Rich J, Chmelik F, Nelson WL. Evolutionary changes in the electrocardiogram of severe progressive hypothermia. J Electrocardiol. 1977;10:67–70.
RuDusky BM. The electrocardiogram in hypothermia-the J wave and the Brugada syndrome. Am J Cardiol. 2004;93:671–2.
Kraus F. Ueber die wirkung des kalziums auf den kreislauf. Dtsch Med Wochenschr. 1920;46:201–3.
Sridharan MR, Horan LG. Electrocardiographic J wave of hypercalcemia. Am J Cardiol. 1984;54:672–3.
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, editors. Cardiac electrophysiology: from cell to bedside. 2nd ed. Philadelphia: W.B. Saunders Co; 1994. p. 228–45.
Eagle K. Images in clinical medicine. Osborn waves of hypothermia. N Engl J Med. 1994;10:680.
Emslie-Smith D, Sladden GE, Stirling GR. The significance of changes in the electrocardiogram in hypothermia. Br Heart J. 1959;21:343–51.
Osborn JJ. Experimental hypothermia: respiratory and blood pH changes in relation to cardiac function. Am J Physiol. 1953;175:389–98.
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.
Di Diego JM, Antzelevitch C. High [Ca2+]-induced electrical heterogeneity and extrasystolic activity in isolated canine ventricular epicardium. Phase 2 reentry. Circulation. 1994;89:1839–50.
Yan GX, Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST segment elevation. Circulation. 1999;100:1660–6.
Antzelevitch C, Yan GX. Cellular and ionic mechanisms responsible for the Brugada syndrome. J Electrocardiol. 2000;33(Suppl):33–9.
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;42:401–9.
Fish JM, Antzelevitch C. Role of sodium and calcium channel block in unmasking the Brugada syndrome. Heart Rhythm. 2004;1:210–7.
Morita H, Morita ST, Nagase S, Banba K, Nishii N, Tani Y, et al. Ventricular arrhythmia induced by sodium channel blocker in patients with Brugada syndrome. J Am Coll Cardiol. 2003;42:1624–31.
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.
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;88:1177–89.
Antzelevitch C, Sicouri S, Lukas A, Di Diego JM, Nesterenko VV, Liu DW, et al. Clinical implications of electrical heterogeneity in the heart: the electrophysiology and pharmacology of epicardial, M, and endocardial cells. In: Podrid PJ, Kowey PR, editors. Cardiac arrhythmia: mechanism, diagnosis and management. Baltimore: William & Wilkins; 1995. p. 88–107.
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.
Thomsen PE, Joergensen RM, Kanters JK, Jensen TJ, Haarbo J, Hagemann A, et al. Phase 2 reentry in man. Heart Rhythm. 2005;2:797–803.
Antzelevitch C. In vivo human demonstration of phase 2 reentry. Heart Rhythm. 2005;2:804–6.
Postema PG, van Dessel PF, Kors JA, Linnenbank AC, van Harpen G, Ritsema van Eck HJ, et al. Local depolarization abnormalities are the dominant pathophysiologic mechanism for type 1 electrocardiogram in Brugada syndrome: a study of electrocardiograms, vectorcardiograms, and body surface potential maps during ajmaline provocation. J Am Coll Cardiol. 2010;55:789–97.
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;123:1270–9.
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;49:543–53.
Futterman LG, Lemberg L. Brugada. Am J Crit Care. 2001;10:360–4.
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;10:214–8.
Antzelevitch C. Late potentials and the Brugada syndrome. J Am Coll Cardiol. 2002;39:1996–9.
Nagase S, Kusano KF, Morita H, Fujimoto Y, Kakishita M, Nakamura K, et al. Epicardial electrogram of the right ventricular outflow tract in patients with the Brugada syndrome: using the epicardial lead. J Am Coll Cardiol. 2002;39:1992–5.
Eckardt L, Bruns HJ, Paul M, Kirchhof P, Schulze-Bahr E, Wichter T, et al. 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;13:742–9.
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.
Mizobuchi M, Enjoji Y, Nakamura S, Muranishi H, Utsunomiya M, Funatsu A, et al. Ventricular late potential in patients with apparently normal electrocardiogram; predictor of Brugada syndrome. Pacing Clin Electrophysiol. 2010;33:266–73.
Takagi M, Aihara N, Kuribayashi S, Taguchi A, Shimizu W, Kurita T, et al. Localized right ventricular morphological abnormalities detected by electron-beam computed tomography represent arrhythmogenic substrates in patients with the Brugada syndrome. Eur Heart J. 2001;22:1032–41.
Antzelevitch C. Brugada syndrome: historical perspectives and observations. Eur Heart J. 2002;23:676–8.
Esperer HD, Hoos O, Hottenrott K. Syncope due to Brugada syndrome in a young athlete. Br J Sports Med. 2007;41:180–1.
Guevara-Valdivia ME, Iturralde Torres P, De Micheli A, Colin Lizalde L, Medeiros Domingo A, Gonzalez-Hermosillo JA. Electrocardiographic changes during stress test in a patient with “Brugada syndrome”. Arch Cardiol Mex. 2001;71:66–72.
Stix G, Bella PD, Carbucicchio C, Schmidinger H. Spatial and temporal heterogeneity of depolarization and repolarization may complicate implantable cardioverter defibrillator therapy in Brugada syndrome. J Cardiovasc Electrophysiol. 2000;11:516–21.
Amin AS, de Groot EAA, Ruijter JM, Wilde AAM, Tan HT. Exercise-induced ECG changes in Brugada syndrome. Circ Arrhythm Electrophysiol. 2009;2:531–9.
Das MK, El Masry H. Fragmented QRS and other depolarization abnormalities as a predictor of mortality and sudden cardiac death. Curr Opin Cardiol. 2010;25:59–64.
Antzelevitch C, Brugada P, Brugada J, Brugada R, Shimizu W, Gussak I, et al. Brugada syndrome: a decade of progress. Circ Res. 2002;91:1114–9.
Kurita T, Shimizu W, Inagaki M, Suyama K, Taguchi A, Satomi K, et al. The electrophysiologic mechanism of ST-segment elevation in Brugada syndrome. J Am Coll Cardiol. 2002;40:330–4.
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, editors. The Brugada syndrome: from bench to bedside. Oxford: Blackwell Futura; 2004. p. 202–11.
Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation. 2004;110:1731–7.
Watanabe H, Chinushi M, Osaki A, Okamura K, Izumi D, Komura S, et al. Elimination of late potentials by quinidine in a patient with Brugada syndrome. J Electrocardiol. 2006;39:63–6.
Fish JM, Antzelevitch C. Cellular and ionic basis for the sex-related difference in the manifestation of the Brugada syndrome and progressive conduction disease phenotypes. J Electrocardiol. 2003;36:173–9.
Aiba T, Shimizu W, Hidaka I, Uemura K, Noda T, Zheng C, et al. Cellular basis for trigger and maintenance of ventricular fibrillation in the Brugada syndrome model: high-resolution optical mapping study. J Am Coll Cardiol. 2006;47:2074–85.
Shimizu W, Yan GX, Antzelevitch C. The Brugada syndrome: clinical findings and cellular mechanism. In: Sekiguchi M, Fontaine G, editors. Arryth-mogenic Right Ventricular Cardiomyopathy: ARVC and Related Disorders. Springer-Verlag, Tokyo, Japan: Springer; 2009.
Aiba T, Hidaka I, Shimizu W, Uemura K, Inagaki M, Sugimachi M, et al. Steep repolarization gradient is required for development of phase 2 reentry and subsequent ventricular tachyarrhythmias in a model of the Brugada syndrome: high-resolution optical mapping study. Circulation. 2004;110:III–318 (Abstract).
Morita H, Zipes DP, Fukushima-Kusano K, Nagase S, Nakamura K, Morita ST, et al. Repolarization heterogeneity in the right ventricular outflow tract: correlation with ventricular arrhythmias in Brugada patients and in an in vitro canine Brugada model. Heart Rhythm. 2008;5:725–33.
Morita H, Zipes DP, Morita ST, Wu J. Genotype-phenotype correlation in tissue models of Brugada syndrome simulating patients with sodium and calcium channelopathies. Heart Rhythm. 2010;7:820–7.
Di Diego JM, Antzelevitch C. Cellular basis for ST-segment changes observed during ischemia. J Electrocardiol. 2003;36(Suppl):1–5.
Di Diego JM, Fish JM, Antzelevitch C. Brugada syndrome and ischemia-induced ST-segment elevation. Similarities and differences. J Electrocardiol. 2005;38:14–7.
Childers R. R wave amplitude in ischemia, injury, and infarction. J Electrocardiol. 1996;29:171–8.
Cordeiro JM, Mazza M, Goodrow R, Ulahannan N, Antzelevitch C, Di Diego JM. Functionally distinct sodium channels in ventricular epicardial and endocardial cells contribute to a greater sensitivity of the epicardium to electrical depression. Am J Physiol Heart Circ Physiol. 2008;295:H154–62.
Kandori A, Shimizu W, Yokokawa M, Noda T, Kamakura S, Miyatake K, et al. Identifying patterns of spatial current dispersion that characterise and separate the Brugada syndrome and complete right-bundle branch block. Med Biol Eng Comput. 2004;42:236–44.
Hoogendijk MG, Potse M, Linnenbank AC, Verkerk AO, Den Ruijter HM, van Amersfoorth SC, et al. Mechanism of right precordial ST-segment elevation in structural heart disease: Excitation failure by current-to-load mismatch. Heart Rhythm. 2010;7:238–48.
Marquez MF, Bisteni A, Medrano G, De Micheli A, Guevara M, Iturralde P, et al. Dynamic electrocardiographic changes after aborted sudden death in a patient with Brugada syndrome and rate-dependent right bundle branch block. J Electrocardiol. 2005;38:256–9.
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;67:615–27.
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;13:698–701.
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;88:2903–15.
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;16:217–20.
Tada H, Nogami A, Shimizu W, Naito S, Nakatsugawa M, Oshima S, et al. ST segment and T wave alternans in a patient with Brugada syndrome. Pacing Clin Electrophysiol. 2000;23:413–5.
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;12:493–5.
Chinushi Y, Chinushi M, Toida T, Aizawa Y. Class I antiarrhythmic drug and coronary vasospasm-induced T wave alternans and ventricular tachyarrhythmia in a patient with Brugada syndrome and vasospastic angina. J Cardiovasc Electrophysiol. 2002;13:191–4.
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.
Ohkubo K, Watanabe I, Okumura Y, Yamada T, Masaki R, Kofune T, et al. Intravenous administration of class I antiarrhythmic drug induced T wave alternans in an asymptomatic Brugada syndrome patient. Pacing Clin Electrophysiol. 2003;26:1900–3.
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;13:816–8.
Fish JM, Antzelevitch C. Cellular mechanism and arrhythmogenic potential of T-wave alternans in the Brugada syndrome. J Cardiovasc Electrophysiol. 2008;19:301–8.
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:H421–8.
Morita H, Zipes DP, Wu J. Brugada syndrome: insights of ST elevation, arrhythmogenicity, and risk stratification from experimental observations. Heart Rhythm. 2009;6:S34–43.
Tada T, Kusano KF, Nagase S, Banba K, Miura D, Nishii N, et al. Clinical significance of macroscopic T-wave alternans after sodium channel blocker administration in patients with Brugada syndrome. J Cardiovasc Electrophysiol. 2008;19:56–61.
Babaliaros VC, Hurst JW. Tricyclic antidepressants and the Brugada syndrome: an example of Brugada waves appearing after the administration of desipramine. Clin Cardiol. 2002;25:395–8.
Goldgran-Toledano D, Sideris G, Kevorkian JP. Overdose of cyclic antidepressants and the Brugada syndrome. N Engl J Med. 2002;346:1591–2.
Tada H, Sticherling C, Oral H, Morady F. Brugada syndrome mimicked by tricyclic antidepressant overdose. J Cardiovasc Electrophysiol. 2001;12:275.
Pastor A, Nunez A, Cantale C, Cosio FG. Asymptomatic Brugada syndrome case unmasked during dimenhydrinate infusion. J Cardiovasc Electrophysiol. 2001;12:1192–4.
Ortega-Carnicer J, Bertos-Polo J, Gutierrez-Tirado C. Aborted sudden death, transient Brugada pattern, and wide QRS dysrhythmias after massive cocaine ingestion. J Electrocardiol. 2001;34:345–9.
Nogami A, Nakao M, Kubota S, Sugiyasu A, Doi H, Yokoyama K, et al. Enhancement of J-ST-segment elevation by the glucose and insulin test in Brugada syndrome. Pacing Clin Electrophysiol. 2003;26:332–7.
Araki T, Konno T, Itoh H, Ino H, Shimizu M. Brugada syndrome with ventricular tachycardia and fibrillation related to hypokalemia. Circ J. 2003;67:93–5.
Akhtar M, Goldschlager NF. Brugada electrocardiographic pattern due to tricyclic antidepressant overdose. J Electrocardiol. 2006;39:336–9.
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;9:1167–72.
Gasparini M, Priori SG, Mantica M, Napolitano C, Galimberti P, Ceriotti C, et al. Flecainide test in Brugada syndrome: a reproducible but risky tool. Pacing Clin Electrophysiol. 2003;26:338–41.
Takenaka S, Emori T, Koyama S, Morita H, Fukushima K, Ohe T. Asymptomatic form of Brugada syndrome. Pacing Clin Electrophysiol. 1999;22:1261–3.
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;12:1418–21.
Matana A, Goldner V, Stanic K, Mavric Z, Zaputovic L, Matana Z. Unmasking effect of propafenone on the concealed form of the Brugada phenomenon. Pacing Clin Electrophysiol. 2000;23:416–8.
Fragakis N, Iliadis I, Papanastasiou S, Lambrou A, Katsaris G. Brugada type electrocardiographic changes induced by concomitant use of lithium and propafenone in patient with Wolff-Parkinson-White syndrome. Pacing Clin Electrophysiol. 2007;30:823–5.
Chutani S, Imran N, Grubb B, Kanjwal Y. Propafenone-induced Brugada-like ECG changes mistaken as acute myocardial infarction. Emerg Med J. 2008;25:117–8.
Rolf S, Bruns HJ, Wichter T, Kirchhof P, Ribbing M, Wasmer K, et al. The ajmaline challenge in Brugada syndrome: diagnostic impact, safety, and recommended protocol. Eur Heart J. 2003;24:1104–12.
Sarkozy A, Caenepeel A, Geelen P, Peytchev P, de Zutter M, Brugada P. Cibenzoline induced Brugada ECG pattern. Europace. 2005;7:537–9.
Chinushi M, Tagawa M, Nakamura Y, Aizawa Y. Shortening of the ventricular fibrillatory intervals after administration of verapamil in a patient with Brugada syndrome and vasospastic angina. J Electrocardiol. 2006;39:331–5.
Aouate P, Clerc J, Viard P, Seoud J. Propranolol intoxication revealing a Brugada syndrome. J Cardiovasc Electrophysiol. 2005;16:348–51.
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;9:508–12.
Sicouri S, Antzelevitch C. Sudden cardiac death secondary to antidepressant and antipsychotic drugs. Expert Opin Drug Saf. 2008;7:181–94.
Bigwood B, Galler D, Amir N, Smith W. Brugada syndrome following tricyclic antidepressant overdose. Anaesth Intensive Care. 2005;33:266–70.
Monteban-Kooistra WE, van Den Berg MP, Tulleken JE, Ligtenberg JJ, Meertens JH, Zijlstra JG. Brugada electrocardiographic pattern elicited by cyclic antidepressants overdose. Intensive Care Med. 2006;32:281–5.
Meert A, Vermeersch N, Beckers R, Hoste W, Brugada P, Hubloue I. Brugada-like ECG pattern induced by tricyclic antidepressants. Eur J Emerg Med. 2010;17:325–7.
Bolognesi R, Tsialtas D, Vasini P, Conti M, Manca C. Abnormal ventricular repolarization mimicking myocardial infarction after heterocyclic antidepressant overdose. Am J Cardiol. 1997;79:242–5.
Rouleau F, Asfar P, Boulet S, Dube L, Dupuis JM, Alquier P, et al. Transient ST segment elevation in right precordial leads induced by psychotropic drugs: relationship to the Brugada syndrome. J Cardiovasc Electrophysiol. 2001;12:61–5.
Yap YG, Behr ER, Camm AJ. Drug-induced Brugada syndrome. Europace. 2009;11:989–94.
Darbar D, Yang T, Churchwell K, Wilde AA, Roden DM. Unmasking of Brugada syndrome by lithium. Circulation. 2005;112:1527–31.
Chandra PA, Chandra AB. Brugada syndrome unmasked by lithium. South Med J. 2009;102:1263–5.
Pirotte MJ, Mueller JG, Poprawski T. A case report of Brugada-type electrocardiographic changes in a patient taking lithium. Am J Emerg Med. 2008;26:113.
Strohmer B, Schernthaner C. Brugada syndrome unmasked by lithium therapy. Wien Klin Wochenschr. 2007;119:282.
Laske C, Soekadar SR, Laszlo R, Plewnia C. Brugada syndrome in a patient treated with lithium. Am J Psychiatry. 2007;164:1440–1.
Josephson IR, Lederer WJ, Hartmann HA. Letter regarding article by Darbar et al, “unmasking of Brugada syndrome by lithium”. Circulation. 2006;113:e408.
Lopez-Barbeito B, Lluis M, Delgado V, Jimenez S, Diaz-Infante E, Nogue-Xarau S, et al. Diphenhydramine overdose and Brugada sign. Pacing Clin Electrophysiol. 2005;28:730–2.
Littmann L, Monroe MH, Svenson RH. Brugada-type electrocardiographic pattern induced by cocaine. Mayo Clin Proc. 2000;75:845–9.
Vernooy K, Delhaas T, Cremer OL, Di Diego JM, Oliva A, Timmermans C, et al. Electrocardiographic changes predicting sudden death in propofol-related infusion syndrome. Heart Rhythm. 2006;3:131–7.
Vaccarella A, Vitale P, Presti CA. General anaesthesia in a patient affected by Brugada syndrome. Minerva Anestesiol. 2008;74:149–52.
Phillips N, Priestley M, Denniss AR, Uther JB. Brugada-type electrocardiographic pattern induced by epidural bupivacaine. Anesth Analg. 2003;97:264–7.
Vernooy K, Sicouri S, Dumaine R, Hong K, Oliva A, Burashnikov E, et al. Genetic and biophysical basis for bupivacaine-induced ST segment elevation and VT/VF. Anesthesia unmasked Brugada syndrome. Heart Rhythm. 2006;3:1074–8.
Noda T, Shimizu W, Taguchi A, Satomi K, Suyama K, Kurita T, et al. 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;40:1841–7.
Nishizaki M, Fujii H, Ashikaga T, Yamawake N, Sakurada H, Hiraoka M. ST-T wave changes in a patient complicated with vasospastic angina and Brugada syndrome: differential responses to acetylcholine in right and left coronary artery. Heart Vessels. 2008;23:201–5.
Oliva A, Hu D, Viskin S, Carrier T, Cordeiro JM, Barajas-Martinez H, et al. SCN5A mutation associated with acute myocardial infarction. Leg Med (Tokyo). 2009;11 Suppl 1:S206–9.
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.
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;338:930–2.
Wichter T, Matheja P, Eckardt L, Kies P, Schafers K, Schulze-Bahr E, et al. Cardiac autonomic dysfunction in Brugada syndrome. Circulation. 2002;105:702–6.
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;53:755–7.
Madle A, Kratochvil Z, Polivkova A. The Brugada syndrome. Vnitr Lek. 2002;48:255–8.
Kum L, Fung JWH, Chan WWL, Chan GK, Chan YS, Sanderson JE. Brugada syndrome unmasked by febrile illness. Pacing Clin Electrophysiol. 2002;25:1660–1.
Keller DI, Huang H, Zhao J, Frank R, Suarez V, Delacretaz E, et al. A novel SCN5A mutation, F1344S, identified in a patient with Brugada syndrome and fever-induced ventricular fibrillation. Cardiovasc Res. 2006;70:521–9.
Di Diego JM, Cordeiro JM, Goodrow RJ, Fish JM, Zygmunt AC, Peréz GJ, et al. Ionic and cellular basis for the predominance of the Brugada syndrome phenotype in males. Circulation. 2002;106:2004–11.
Ezaki K, Nakagawa M, Taniguchi Y, Nagano Y, Teshima Y, Yufu K, et al. Gender differences in the ST segment: effect of androgen-deprivation therapy and possible role of testosterone. Circ J. 2010;74:2448–54.
Antzelevitch C. The Brugada syndrome: diagnostic criteria and cellular mechanisms. Eur Heart J. 2001;22:356–63.
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):41–7.
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;108:925–8.
van Den Berg MP, Wilde AA, Viersma TJW, Brouwer J, Haaksma J, van der Hout AH, et al. 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;12:630–6.
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;30:133–6.
Sharif-Kazemi MB, Emkanjoo Z, Tavoosi A, Kafi M, Kheirkhah J, Alizadeh A, Sadr-Ameli MA.Electrical storm in Brugada syndrome during pregnancy. Pacing Clin Electrophysiol. 2011; 34(2):e18–21.
Kyriazis K, Bahlmann E, van der Schalk H, Kuck KH. Electrical storm in Brugada syndrome successfully treated with orciprenaline; effect of low-dose quinidine on the electrocardiogram. Europace. 2009;11:665–6.
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.
Alings M, Dekker L, Sadee A, Wilde A. Quinidine induced electrocardiographic normalization in two patients with Brugada syndrome. Pacing Clin Electrophysiol. 2001;24:1420–2.
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;10:1301–12.
Belhassen B, Viskin S, Antzelevitch C. The Brugada syndrome: is an implantable cardioverter defibrillator the only therapeutic option? Pacing Clin Electrophysiol. 2002;25:1634–40.
Hermida JS, Denjoy I, Clerc J, Extramiana F, Jarry G, Milliez P, et al. Hydroquinidine therapy in Brugada syndrome. J Am Coll Cardiol. 2004;43:1853–60.
Mok NS, Chan NY, Chi-Suen CA. Successful use of quinidine in treatment of electrical storm in Brugada syndrome. Pacing Clin Electrophysiol. 2004;27:821–3.
Kanlop N, Chattipakorn S, Chattipakorn N. Effects of cilostazol in the heart. J Cardiovasc Med (Hagerstown). 2011;12:88–95.
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).
Fish JM, Extramiana F, Antzelevitch C. AVE0118, an Ito and IKur blocker, suppresses VT/VF in an experimental model of the Brugada syndrome. Circulation. 2004;110(17):III-193 (Abstract).
de La Coussaye JE, Bassoul B, Brugada J, Albat B, Peray PA, Gagnol JP, et al. Reversal of electrophysiologic and hemodynamic effects induced by high dose of bupivacaine by the combination of clonidine and dobutamine in anesthetized dogs. Anesth Analg. 1992;74(5):703–11.
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;113:1393–400.
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–100.
Kron J, Herre J, Renfroe EG, Rizo-Patron C, Raitt M, Halperin B, et al. Lead- and device-related complications in the antiarrhythmics versus implantable defibrillators trial. Am Heart J. 2001;141:92–8.
AVID Investigators. 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;337:1576–83.
Sacher F, Probst V, Iesaka Y, Jacon P, Laborderie J, Mizon-Gerard F, et al. Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study. Circulation. 2006;114:2317–24.
Antzelevitch C, Brugada P, Brugada J, Brugada R. The Brugada syndrome: from bench to bedside. Oxford: Blackwell Futura; 2005.
Antzelevitch C, Fish JM. Therapy for the Brugada syndrome. Handb Exp Pharmacol. 2006;171:305–30.
Nakazato Y, Suzuki T, Yasuda M, Daida H. Manifestation of brugada syndrome after pacemaker implantation in a patient with sick sinus syndrome. J Cardiovasc Electrophysiol. 2004;15:1328–30.
Shah AJ, Hocini M, Lamaison D, Sacher F, Derval N, Haissaguerre M. Regional substrate ablation abolishes Brugada syndrome. J Cardiovasc Electrophysiol. 2011;22:1290–1.
Antzelevitch C, Brugada P, Brugada J, Brugada R, Nademanee K, Towbin JA. Clinical approaches to tachyarrhythmias. The Brugada syndrome. Armonk: Futura Publishing Company; 1999.
Grant AO. Electrophysiological basis and genetics of Brugada syndrome. J Cardiovasc Electrophysiol. 2005;16 Suppl 1:S3–7.
Minoura Y, Di Diego JM, Barajas-Martinez H, Zygmunt AC, Hu D, Sicouri S, et al. Ionic and cellular mechanisms underlying the development of acquired Brugada syndrome in patients treated with antidepressants. J Cardiovasc Electrophysiol. 2012;23:423–32.
Marquez MF, Rivera J, Hermosillo AG, Iturralde P, Colin L, Moragrega JL, et al. Arrhythmic storm responsive to quinidine in a patient with Brugada syndrome and vasovagal syncope. Pacing Clin Electrophysiol. 2005;28:870–3.
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;47:359–64.
Viskin S, Wilde AA, Tan HL, Antzelevitch C, Shimizu W, Belhassen B. Empiric quinidine therapy for asymptomatic Brugada syndrome: time for a prospective registry. Heart Rhythm. 2009;6:401–4.
Wu L, Guo D, Li H, Hackett J, Yan GX, Jiao Z, et al. Role of late sodium current in modulating the proarrhythmic and antiarrhythmic effects of quinidine. Heart Rhythm. 2008;5:1726–34.
Viskin S, Antzelevitch C, Marquez MF, Belhassen B. Quinidine: a valuable medication joins the list of ‘endangered species’. Europace. 2007;12:1105–6.
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;82:282–90.
Antzelevitch C, Shimizu W. Cellular mechanisms underlying the long QT syndrome. Curr Opin Cardiol. 2002;17:43–51.
Belardinelli L, Antzelevitch C, Vos MA. Assessing predictors of drug-induced torsade de pointes. Trends Pharmacol Sci. 2003;24:619–25.
Antzelevitch C. The Brugada syndrome: ionic basis and arrhythmia mechanisms. J Cardiovasc Electrophysiol. 2001;12:268–72.
Suzuki H, Torigoe K, Numata O, Yazaki S. Infant case with a malignant form of Brugada syndrome. J Cardiovasc Electrophysiol. 2000;11:1277–80.
Tanaka H, Kinoshita O, Uchikawa S, Kasai H, Nakamura M, Izawa A, et al. Successful prevention of recurrent ventricular fibrillation by intravenous isoproterenol in a patient with Brugada syndrome. Pacing Clin Electrophysiol. 2001;24:1293–4.
Acknowledgement.
Supported by grant HL47678 from NHLBI, grant C026424 from NYSTEM and NYS and Florida Grand Lodges F. & A. M.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer-Verlag London
About this chapter
Cite this chapter
Antzelevitch, C., Viskin, S. (2013). Brugada Syndrome: Cellular Mechanisms and Approaches to Therapy. In: Gussak, I., Antzelevitch, C. (eds) Electrical Diseases of the Heart. Springer, London. https://doi.org/10.1007/978-1-4471-4881-4_29
Download citation
DOI: https://doi.org/10.1007/978-1-4471-4881-4_29
Published:
Publisher Name: Springer, London
Print ISBN: 978-1-4471-4880-7
Online ISBN: 978-1-4471-4881-4
eBook Packages: MedicineMedicine (R0)