Journal of Rare Cardiovascular Diseases

Brugada syndrome (BrS) is a cardiac channelopathy associated with ventricular arrhythmias and sudden cardiac death. Diagnosis of BrS is based on type 1 BrS electrocardiogram (ECG) pattern (coved pattern) presence, observed spontaneously or after provocation test. The worldwide prevalence of BrS ECG patterns is estimated to reach 0.4% and strongly depends on the population studied. BrS results from various genetic mutations of sodium, calcium and potassium channels and/or associated proteins affecting ion currents. SCN5A mutations are the most prevalent in BrS. Pathogenesis of BrS is explained by the depolarization theory, the repolarization theory and the neural crest theory, which seem to be complimentary, at least partially. This review summarizes current diagnostic criteria of BrS and epidemiology of BrS ECG patterns. We also discuss the recent understanding of BrS pathophysiology and the role of genetic testing in BrS. JRCD 2017; 3 (3): 73–80.

Brugada syndrome; diagnostics; epidemiology; genetic testing; mechanisms; rare disease

Priori SG, Napolitano C, Gasparini M, et al. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation 2002; 105: 1342–1347.

Georgopoulos S, Letsas KP, Liu T, et al. A meta-analysis on the prognostic significance of inferolateral early repolarization pattern in Brugada syndrome. Europace 2017; DOI: 10.1093/europace/euw394. [Epub ahead of print].

Kim SH, Nam GB, Yun SC, et al. Variants of Brugada Syndrome and Early Repolarization Syndrome: An Expanded Concept of J-Wave Syndrome. Pacing Clin Electrophysiol 2017; 40: 162–174.

Antzelevitch C, Yan GX. J wave syndromes. Heart Rhythm 2010; 7: 549–558.

Antzelevitch C, Patocskai B. Brugada Syndrome: Clinical, Genetic, Molecular, Cellular, and Ionic Aspects. Curr Probl Cardiol 2016; 41: 7–57.

Priori SG, Blomstrom-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015; 36: 2793–2867.

Bayes de Luna A, Brugada J, Baranchuk A, et al. Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report. J Electrocardiol 2012; 45: 433–442.

Matusik PT. Insights into channelopathies: progress in clinical practice and research. J Electrocardiol 2017. doi: 10.1016/j.jelectrocard.2017.02.003. [Epubahead of print].; 50: 534–535.

Matusik PT, Komar M, Podolec J, Karkowski G, Lelakowski J, Podolec P. Exercise ECG unmasked Brugada sign: manifestation of the risk of sports-associated sudden cardiac arrest. J Rare Cardiovasc Dis 2017; 3: 50–56.

Writing Group Members, Mozaffarian D, Benjamin EJ, et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation 2016; 133: e38-360.

Mizusawa Y, Wilde AA. Brugada syndrome. Circ Arrhythm Electrophysiol 2012; 5: 606-616.

Juang JM, Chen CY, Chen YH, et al. Prevalence and prognosis of Brugada electrocardiogram patterns in an elderly Han Chinese population: a nation-wide community-based study (HALST cohort). Europace 2015; 17 Suppl 2: ii54-62.

Quan XQ, Li S, Liu R, et al. A meta-analytic review of prevalence for Brugada ECG patterns and the risk for death. Medicine (Baltimore) 2016; 95: e5643.

Gehi AK, Duong TD, Metz LD, et al. Risk stratification of individuals with the Brugada electrocardiogram: a meta-analysis. J Cardiovasc Electrophysiol 2006; 17: 577–583.

Casado-Arroyo R, Berne P, Rao JY, et al. Long-Term Trends in Newly Diagnosed Brugada Syndrome: Implications for Risk Stratification. J Am Coll Cardiol 2016; 68: 614–623.

Antzelevitch C. Brugada syndrome. Pacing Clin Electrophysiol 2006; 29: 1130–1159.

Ikeda T, Abe A, Yusu S, et al. The full stomach test as a novel diagnostic technique for identifying patients at risk of Brugada syndrome. J Cardiovasc Electrophysiol 2006; 17: 602–607.

Fernandez-Falgueras A, Sarquella-Brugada G, Brugada J, et al. Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances. Biology (Basel) 2017; 6. DOI: 10.3390/biology6010007

Brugada R, Campuzano O, Sarquella-Brugada G, et al. Brugada syndrome. Methodist Debakey Cardiovasc J 2014; 10: 25–28.

Juang JJ, Horie M. Genetics of Brugada syndrome. J Arrhythm 2016; 32: 418–425.

Rudic B, Schimpf R, Veltmann C, et al. Brugada syndrome: clinical presentation and genotype-correlation with magnetic resonance imaging parameters. Europace 2016; 18: 1411–1419.

Priori SG, Napolitano C, Gasparini 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: 2509–2515.

Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA. Europace 2011; 13: 1077–1109.

Hu D, Barajas-Martinez H, Pfeiffer R, et al. Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome. J Am Coll Cardiol 2014; 64: 66–79.

Liu H, Chatel S, Simard C, et al. Molecular genetics and functional anomalies in a series of 248 Brugada cases with 11 mutations in the TRPM4 channel. PLoS One 2013; 8: e54 131.

Foss-Nieradko B, Franaszczyk M, Spiewak M, et al. Novel truncating desmoplakin mutation as a potential cause of sudden cardiac death in a family. Pol Arch Med Wewn 2016; 126: 704–707.

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: 1391–1396.

Brugada P, Brugada J, Roy D. Brugada syndrome 1992–2012: 20 years of scientific excitement, and more. Eur Heart J 2013; 34: 3610–3615.

Hoogendijk MG, Opthof T, Postema PG, et al. The Brugada ECG pattern: a marker of channelopathy, structural heart disease, or neither? Toward a unifying mechanism of the Brugada syndrome. Circ Arrhythm Electrophysiol 2010; 3: 283–290.

Coronel R, Casini S, Koopmann TT, et al. Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study. Circulation 2005; 112: 2769–2777.

Nademanee K, Veerakul G, Chandanamattha P, et al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation 2011; 123: 1270–1279.

Jastrzebski M, Kukla P. Ventricular fibrillation with a 2:1 conduction block over the right ventricle in a Brugada syndrome patient. Kardiol Pol 2013; 71: 991.

Elizari MV, Levi R, Acunzo RS, et al. Abnormal expression of cardiac neural crest cells in heart development: a different hypothesis for the etiopathogenesis of Brugada syndrome. Heart Rhythm 2007; 4: 359–365.

Holst AG, Jensen HK, Eschen O, et al. Low disease prevalence and inappropriate implantable cardioverter defibrillator shock rate in Brugada syndrome: a nationwide study. Europace 2012; 14: 1025–1029.

Schukro C, Berger T, Stix G, et al. Regional prevalence and clinical benefit of implantable cardioverter defibrillators in Brugada syndrome. Int J Cardiol 2010; 144: 191–194.

Pecini R, Cedergreen P, Theilade S, et al. The prevalence and relevance of the Brugada-type electrocardiogram in the Danish general population: data from the Copenhagen City Heart Study. Europace 2010; 12: 982–986.

Sinner MF, Pfeufer A, Perz S, et al. Spontaneous Brugada electrocardiogram patterns are rare in the German general population: results from the KORA study. Europace 2009; 11: 1338–1344.

Gallagher MM, Forleo GB, Behr ER, et al. Prevalence and significance of Brugada-type ECG in 12,012 apparently healthy European subjects. Int J Cardiol 2008; 130: 44–48.

Letsas KP, Gavrielatos G, Efremidis M, et al. Prevalence of Brugada sign in a Greek tertiary hospital population. Europace 2007; 9: 1077–1080.

Blangy H, Sadoul N, Coutelour JM, et al. Prevalence of Brugada syndrome among 35,309 inhabitants of Lorraine screened at a preventive medicine centre. Arch Mal Coeur Vaiss 2005; 98: 175–180.

Junttila MJ, Raatikainen MJ, Karjalainen J, et al. Prevalence and prognosis of subjects with Brugada-type ECG pattern in a young and middle-aged Finnish population. Eur Heart J 2004; 25: 874–878.

Juang JM, Phan WL, Chen PC, et al. Brugada-type electrocardiogram in the Taiwanese population – is it a risk factor for sudden death? J Formos Med Assoc 2011; 110: 230–238.

Uhm JS, Hwang IU, Oh YS, et al. Prevalence of electrocardiographic findings suggestive of sudden cardiac death risk in 10,867 apparently healthy young Korean men. Pacing Clin Electrophysiol 2011; 34: 717–723.

Wajed A, Aslam Z, Abbas SF, et al. Frequency of Brugada-type ECG pattern (Brugada sign) in an apparently healthy young population. J Ayub Med Coll Abbottabad 2008; 20: 121–124.

Gervacio-Domingo G, Isidro J, Tirona J, et al. The Brugada type 1 electrocardiographic pattern is common among Filipinos. J Clin Epidemiol 2008; 61: 1067–1072.

Tsuji H, Sato T, Morisaki K, et al. Prognosis of subjects with Brugada-type electrocardiogram in a population of middle-aged Japanese diagnosed during a health examination. Am J Cardiol 2008; 102: 584–587.

Bigi MA, Aslani A, Shahrzad S. Prevalence of Brugada sign in patients presenting with palpitation in southern Iran. Europace 2007; 9: 252–255.

Bozkurt A, Yas D, Seydaoglu G, et al. Frequency of Brugada-type ECG pattern (Brugada sign) in Southern Turkey. Int Heart J 2006; 47: 541–547.

Shin SC, Ryu HM, Lee JH, et al. Prevalence of the Brugada-type ECG recorded from higher intercostal spaces in healthy Korean males. Circ J 2005; 69: 1064–1067.

Miyasaka Y, Tsuji H, Yamada K, et al. Prevalence and mortality of the Brugada-type electrocardiogram in one city in Japan. J Am Coll Cardiol 2001; 38: 771–774.

Furuhashi M, Uno K, Tsuchihashi K, et al. Prevalence of asymptomatic ST segment elevation in right precordial leads with right bundle branch block (Brugada-type ST shift) among the general Japanese population. Heart 2001; 86: 161–166.

Patel SS, Anees S, Ferrick KJ. Prevalence of a Brugada pattern electrocardiogram in an urban population in the United States. Pacing Clin Electrophysiol 2009; 32: 704–708.

Donohue D, Tehrani F, Jamehdor R, et al. The prevalence of Brugada ECG in adult patients in a large university hospital in the western United States. Am Heart Hosp J 2008; 6: 48–50.

Ito H, Yano K, Chen R, et al. The prevalence and prognosis of a Brugada type electrocardiogram in a population of middle-aged Japanese-American men with follow-up of three decades. Am J Med Sci 2006; 331: 25–29.

Greer RW, Glancy DL. Prevalence of the Brugada electrocardiographic pattern at the Medical Center of Louisiana in New Orleans. J La State Med Soc 2003; 155: 242–246.

Ouali S, Ben Salem H, Hammas S, et al. Prevalence of Brugada-type ECG pattern and early ventricular repolarization pattern in Tunisian athletes. Open Access J Sports Med 2011; 2: 33–40.

Watanabe H, Koopmann TT, Le Scouarnec S, et al. Sodium channel beta1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. J Clin Invest 2008; 118: 2260–2268.

Riuro H, Beltran-Alvarez P, Tarradas A, et al. A missense mutation in the sodium channel beta2 subunit reveals SCN2B as a new candidate gene for Brugada syndrome. Hum Mutat 2013; 34: 961–966.

Hu D, Barajas-Martinez H, Burashnikov E, et al. A mutation in the beta 3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype. Circ Cardiovasc Genet 2009; 2: 270–278.

Antzelevitch C, Pollevick GD, Cordeiro JM, 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: 442–449.

Giudicessi JR, Ye D, Tester DJ, et al. Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome. Heart Rhythm 2011; 8: 1024–1032.

Delpon E, Cordeiro JM, Nunez L, et al. Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome. Circ Arrhythm Electrophysiol 2008; 1: 209–218.

Barajas-Martinez H, Hu D, Ferrer T, et al. Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8. Heart Rhythm 2012; 9: 548–555.

Hu D, Barajas-Martinez H, Terzic A, et al. ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene. Int J Cardiol 2014; 171: 431–442.

Kattygnarath D, Maugenre S, Neyroud N, et al. MOG1: a new susceptibility gene for Brugada syndrome. Circ Cardiovasc Genet 2011; 4: 261–268.

Olesen MS, Jensen NF, Holst AG, et al. A novel nonsense variant in Nav1.5 cofactor MOG1 eliminates its sodium current increasing effect and may increase the risk of arrhythmias. Can J Cardiol 2011; 27: 523 e517-523.

London B, Michalec M, Mehdi H, et al. Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias. Circulation 2007; 116: 2260–2268.

Ishikawa T, Sato A, Marcou CA, et al. A novel disease gene for Brugada syndrome: sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5. Circ Arrhythm Electrophysiol 2012; 5: 1098–1107.

Cerrone M, Lin X, Zhang M, et al. Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype. Circulation 2014; 129: 1092–1103.

Bezzina CR, Barc J, Mizusawa Y, et al. Common variants at SCN5A‑SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nat Genet 2013; 45: 1044–1049.

Wang Q, Ohno S, Ding WG, et al. Gain‑of‑function KCNH2 mutations in patients with Brugada syndrome. J Cardiovasc Electrophysiol 2014; 25: 522–530.

Itoh H, Sakaguchi T, Ashihara T, et al. A novel KCNH2 mutation as a modifier for short QT interval. Int J Cardiol 2009; 137: 83–85.

Ohno S, Zankov DP, Ding WG, et al. KCNE5 (KCNE1L) variants are novel modulators of Brugada syndrome and idiopathic ventricular fibrillation. Circ Arrhythm Electrophysiol 2011; 4: 352–361.

Ueda K, Hirano Y, Higashiuesato Y, et al. Role of HCN4 channel in preventing ventricular arrhythmia. J Hum Genet 2009; 54: 115–121.

Ueda K, Nakamura K, Hayashi T, et al. Functional characterization of a trafficking‑defective HCN4 mutation, D553N, associated with cardiac arrhythmia. J Biol Chem 2004; 279: 27 194–27 198.

Crotti L, Marcou CA, Tester DJ, et al. Spectrum and prevalence of mutations involving BrS1- through BrS12‑susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing: implications for genetic testing. J Am Coll Cardiol 2012; 60: 1410–1418.