- Email: [email protected]
The history of Brugada syndrome — Continuum with arrhythmogenic cardiomyopathy or lone disease?
International Journal of Cardiology 211 (2016) 84–85
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
The history of Brugada syndrome — Continuum with arrhythmogenic cardiomyopathy or lone disease? Stefan Peters St. Elisabeth Hospital gGmbH Salzgitter, Liebenhaller Str. 20, 38259 Salzgitter, Germany
a r t i c l e
i n f o
Article history: Received 12 December 2015 Received in revised form 10 February 2016 Accepted 28 February 2016 Available online 2 March 2016 Keywords: Brugada syndrome Arrhythmogenic cardiomyopathy Coved-type ST-segment elevation Low amplitude ECG
Right bundle branch block and coved-type ST segment elevation in patients with polymorphic ventricular tachycardia or ventricular fibrillation were first described by Bortolo Martini and Andrea Nava in 1989 [1], nowadays known as Brugada syndrome published by Pedro und Josep Brugada in 1992 [2]. In the following years Andrea Nava described together with Bortolo Martini or alone multiple cases of Brugada syndrome, which are in close association with a subtle form of arrhythmogenic right ventricular cardiomyopathy localised to the right ventricular outflow tract [3–5]. Pedro Brugada together with his brothers Josep and, later, Ramon Brugada has sampled nearly 1000 patients with the exclusion of structural heart disease by echocardiography only [6]. Right ventricular angiography or MRI was used in rare cases [7,8]. They described in nearly all cases a primarily electrical disease due to current-to-load mismatch, based on activation block at different sides, with primary repolarisation disorder [9], based on transmural dispersion in repolarization of the right ventricle ((RV)/RVOT. A few years later Dutch scientists like Arthur Wilde considered depolarisation disorders with, in particular, recording of fractionated and late potentials, the main cause of Brugada syndrome [10]. Last year a very interesting publication on Brugada syndrome was in the focus of interest. The whole heart of patients with Brugada syndrome, who all died, was analysed with special interest in the right ventricular outflow tract. Fibrosis, reduction of gap junctions, and conduction abnormalities were described in the right ventricular outflow tract. These findings are very similar to those of arrhythmogenic E-mail address: [email protected].
http://dx.doi.org/10.1016/j.ijcard.2016.02.132 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
cardiomyopathy [11]. The association with a subtle form of arrhythmogenic right ventricular cardiomyopathy was not mentioned in a word. In the text fatty infiltration in right ventricular myocardium without fibrosis by Italian authors is mentioned [12]. This statement is totally wrong, as Martini et al. [1] and Corrado et al. [3] published histologic pictures demonstrating fibrofatty replacement of the right ventricular myocardium. Recently, a continuum between arrhythmogenic cardiomyopathy and Brugada syndrome has been described [13]. The same working group described plakophilin-2 as encoding gene in isolated Brugada syndrome in about 2.5% of cases [14]. PKP-2 is the most frequent gene causing arrhythmogenic cardiomyopathy [15]. A few more genes have been described in Brugada syndrome and in arrhythmogenic cardiomyopathy: desmoglein-2 [16] in about 5%, and recently, desmoplakin [17] in about 17%. The so-called connexome as an association between gap junctions, desmosomal genes and sodium channel complexes could be assessed in the continuum between these two diseases [13]. The latest publication of Dutch authors could show that in endocardial and epicardial mapping techniques low amplitude ECG and QRS fragmentation after ajmaline administration together with coved-type ST-segment elevation in the right precordial leads could demonstrate abnormal myocardium [18]. This is a very good hint to suspected arrhythmogenic cardiomyopathy, but not mentioned in the text. The same phenomenon could be demonstrated in surface ECG recordings (Stefan Peters, not yet published), contributing to the theory of a continuum between Brugada syndrome and arrhythmogenic cardiomyopathy. Brugada ECG, Brugada phenocopy or Brugada syndrome can be caused by drugs (anti-psychotic agents, propofol etc.), fever, ischemia, hyperkalemia, chest abnormalities or other neurological diseases caused by current-to-load mismatch producing coved-type STsegment elevation. The proportion of patients with current-to-load mismatch is not yet known. In some patients with sudden cardiac death as the first manifestation of arrhythmogenic cardiomyopathy Brugada syndrome can be provoked by ajmaline administration in developing arrhythmogenic cardiomyopathy [19]. In patients with “false Brugada syndrome”, not fulfilling the criteria published by Bayes de Luna [20] or low amplitude ECG and QRS fragmentation [21] together with coved-type ST-segment elevation the definite diagnosis is arrhythmogenic cardiomyopathy. In cases with provocable coved-type ST-segment elevation without low amplitude ECG and QRS fragmentation there is a mixture between
S. Peters / International Journal of Cardiology 211 (2016) 84–85
arrhythmogenic cardiomyopathy and Brugada syndrome demonstrating the so-called continuum. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] B. Martini, A. Nava, G. Thiene, et al., Ventricular fibrillation without apparent heart disease: description of six cases, Am. Heart J. 118 (1989) 1203–1209. [2] P. Brugada, J. Brugada, 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. 20 (1992) 1361–1366. [3] D. Corrado, C. Basso, G. Buja, A. Nava, L. Rossi, G. Thiene, Right bundle branch block, right precordial ST-segment elevation, and sudden death in young people, J. Am. Coll. Cardiol. 27 (1996) 443–448. [4] B. Martini, A. Nava, 1988–2003. Fifteen years after the first Italian description by Nava-Martini-Thiene and colleaques of a new syndrome (different form the Brugada syndrome?) in the Giornale Italiano di Cardiologica: do we relly know everything in this entity? Ital. Heart J. 5 (2004) 52–60. [5] B. Martini, A. Nava, Unexplained syncope, Brugada-like ECG and minimal structural right ventricular abnormalities: which is the right diagnosis? J. Cardiovasc. Med. 10 (2009) 819. [6] J. Brugada, P. Brugada, Further characterization of the syndrome of right bundle branch block, ST segment elevation, sand sudden death, J. Cardiovasc. Electrophysiol. 8 (1997) 325–331. [7] B. Pinamonti, F. Brun, L. Mestroni, G. Sinagra, Arrhythmogenic right ventricular cardiomyopathy: from genetics to diagnostic and therapeutic challenges, World J. Cardiol. 6 (2014) 1234–1244. [8] W. De Wilde, L. Boersma, P. Pollet, B. Scholzel, E. Wever, Y. Vandekerckhove, Symtomatic arrhythmogenic right ventricular dysplasia/cardiomyopathy. A two-centre retrospective study of 15 symptomatic ARVD/C cases and focus on the diagnostic value of MRI in symptomatic ARVD/C patients, Acta Cardiol. 63 (2008) 181–189.
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[9] C.X. Yan, C. Antzelevitch, Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation, Circulation 100 (1999) 1660–1666. [10] P.G. Meregalli, A.A. Wilde, H.L. Tan, Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more? Cardiovasc. Res. 15 (2005) 367–378. [11] A. Asimaki, A.G. Kleber, J.E. Saffitz, Pathogenesis of arrhythmogenic cardiomyopathy, Can. J. Cardiol. 31 (2015) 1313–1321. [12] K. Nademanee, H. Raju, S.V. de Noronha, M. Papadakis, L. Robinson, S. Rothery, et al., Fibrosis, connexin-43, and conduction abnormalities in the Brugada syndrome, J. Am. Coll. Cardiol. 66 (2015) 1976–1986. [13] M. Cerrone, M. Delmar, Desmosomes and the sodium channel complex: implications for arrhythmogenic cardiomyopathy and Brugada syndrome, Trends Cardiovasc. Med. 24 (2014) 184–190. [14] M. Cerrone, X. Lin, M. Zhang, E. Agullo-Pascual, A. Pfenniger, H. Chkourko-Gusky, et al., Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype, Circulation 129 (2014) 1092–1103. [15] B. Gerull, A. Heuser, T. Wichter, M. Paul, C.T. Basson, D.A. McDermott, et al., Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy, Nat. Genet. 36 (2004) 1162–1164. [16] C. DiResta, A. Pietrelli, S. Sala, P. Della Bella, G. DeBellis, M. Ferrari, et al., Highthroughput characterization of a cohort of Brugada syndrome patients, Hum. Mol. Genet. 24 (2015) 5828–5835. [17] Q. Zhao, Y. Chen, L. Peng, R. Gao, N. Liu, R. Jiang, et al., Identification of rare variants of DSP gene in sudden unexplained nocturnal death syndrome in the southern Chinese Han population, Int. J. Legal Med. 130 (2016) 317–322. [18] J.N. Ten Sande, R. Coronel, C.E. Conrath, A.H. Driessen, J.R. de Groot, H.L. Tan, et al., ST-segment elevation and fractionated electrograms in Brugada syndrome patients arise from the same structurally abnormal subepicardial RVOT area but have a different mechanism, Circ. Arrhythm. Electrophysiol. 8 (2015) 1382–1392. [19] S. Peters, Is early sudden death in the course of arrhythmogenic cardiomyopathy due to initial Brugada syndrome? Int. J. Cardiol. 182 (2015) 107–108. [20] A. Bayes de Luna, J. Garcia-Niebla, A. Baranchuk, New electrocardiographic features in Brugada syndrome, Curr. Cardiol. Rev. 10 (2014) 175–180. [21] J. Zhang, F. Sacher, K. Hoffmayer, T. O'Hara, M. Strom, P. Cuculich, et al., Cardiac electrophysiologic substrate underlying the ECG phenotype and electrogram abnormalities in Brugada syndrome patients, Circulation 131 (2015) 1950–1959.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
The history of Brugada syndrome — Continuum with arrhythmogenic cardiomyopathy or lone disease? Stefan Peters St. Elisabeth Hospital gGmbH Salzgitter, Liebenhaller Str. 20, 38259 Salzgitter, Germany
a r t i c l e
i n f o
Article history: Received 12 December 2015 Received in revised form 10 February 2016 Accepted 28 February 2016 Available online 2 March 2016 Keywords: Brugada syndrome Arrhythmogenic cardiomyopathy Coved-type ST-segment elevation Low amplitude ECG
Right bundle branch block and coved-type ST segment elevation in patients with polymorphic ventricular tachycardia or ventricular fibrillation were first described by Bortolo Martini and Andrea Nava in 1989 [1], nowadays known as Brugada syndrome published by Pedro und Josep Brugada in 1992 [2]. In the following years Andrea Nava described together with Bortolo Martini or alone multiple cases of Brugada syndrome, which are in close association with a subtle form of arrhythmogenic right ventricular cardiomyopathy localised to the right ventricular outflow tract [3–5]. Pedro Brugada together with his brothers Josep and, later, Ramon Brugada has sampled nearly 1000 patients with the exclusion of structural heart disease by echocardiography only [6]. Right ventricular angiography or MRI was used in rare cases [7,8]. They described in nearly all cases a primarily electrical disease due to current-to-load mismatch, based on activation block at different sides, with primary repolarisation disorder [9], based on transmural dispersion in repolarization of the right ventricle ((RV)/RVOT. A few years later Dutch scientists like Arthur Wilde considered depolarisation disorders with, in particular, recording of fractionated and late potentials, the main cause of Brugada syndrome [10]. Last year a very interesting publication on Brugada syndrome was in the focus of interest. The whole heart of patients with Brugada syndrome, who all died, was analysed with special interest in the right ventricular outflow tract. Fibrosis, reduction of gap junctions, and conduction abnormalities were described in the right ventricular outflow tract. These findings are very similar to those of arrhythmogenic E-mail address: [email protected].
http://dx.doi.org/10.1016/j.ijcard.2016.02.132 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
cardiomyopathy [11]. The association with a subtle form of arrhythmogenic right ventricular cardiomyopathy was not mentioned in a word. In the text fatty infiltration in right ventricular myocardium without fibrosis by Italian authors is mentioned [12]. This statement is totally wrong, as Martini et al. [1] and Corrado et al. [3] published histologic pictures demonstrating fibrofatty replacement of the right ventricular myocardium. Recently, a continuum between arrhythmogenic cardiomyopathy and Brugada syndrome has been described [13]. The same working group described plakophilin-2 as encoding gene in isolated Brugada syndrome in about 2.5% of cases [14]. PKP-2 is the most frequent gene causing arrhythmogenic cardiomyopathy [15]. A few more genes have been described in Brugada syndrome and in arrhythmogenic cardiomyopathy: desmoglein-2 [16] in about 5%, and recently, desmoplakin [17] in about 17%. The so-called connexome as an association between gap junctions, desmosomal genes and sodium channel complexes could be assessed in the continuum between these two diseases [13]. The latest publication of Dutch authors could show that in endocardial and epicardial mapping techniques low amplitude ECG and QRS fragmentation after ajmaline administration together with coved-type ST-segment elevation in the right precordial leads could demonstrate abnormal myocardium [18]. This is a very good hint to suspected arrhythmogenic cardiomyopathy, but not mentioned in the text. The same phenomenon could be demonstrated in surface ECG recordings (Stefan Peters, not yet published), contributing to the theory of a continuum between Brugada syndrome and arrhythmogenic cardiomyopathy. Brugada ECG, Brugada phenocopy or Brugada syndrome can be caused by drugs (anti-psychotic agents, propofol etc.), fever, ischemia, hyperkalemia, chest abnormalities or other neurological diseases caused by current-to-load mismatch producing coved-type STsegment elevation. The proportion of patients with current-to-load mismatch is not yet known. In some patients with sudden cardiac death as the first manifestation of arrhythmogenic cardiomyopathy Brugada syndrome can be provoked by ajmaline administration in developing arrhythmogenic cardiomyopathy [19]. In patients with “false Brugada syndrome”, not fulfilling the criteria published by Bayes de Luna [20] or low amplitude ECG and QRS fragmentation [21] together with coved-type ST-segment elevation the definite diagnosis is arrhythmogenic cardiomyopathy. In cases with provocable coved-type ST-segment elevation without low amplitude ECG and QRS fragmentation there is a mixture between
S. Peters / International Journal of Cardiology 211 (2016) 84–85
arrhythmogenic cardiomyopathy and Brugada syndrome demonstrating the so-called continuum. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] B. Martini, A. Nava, G. Thiene, et al., Ventricular fibrillation without apparent heart disease: description of six cases, Am. Heart J. 118 (1989) 1203–1209. [2] P. Brugada, J. Brugada, 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. 20 (1992) 1361–1366. [3] D. Corrado, C. Basso, G. Buja, A. Nava, L. Rossi, G. Thiene, Right bundle branch block, right precordial ST-segment elevation, and sudden death in young people, J. Am. Coll. Cardiol. 27 (1996) 443–448. [4] B. Martini, A. Nava, 1988–2003. Fifteen years after the first Italian description by Nava-Martini-Thiene and colleaques of a new syndrome (different form the Brugada syndrome?) in the Giornale Italiano di Cardiologica: do we relly know everything in this entity? Ital. Heart J. 5 (2004) 52–60. [5] B. Martini, A. Nava, Unexplained syncope, Brugada-like ECG and minimal structural right ventricular abnormalities: which is the right diagnosis? J. Cardiovasc. Med. 10 (2009) 819. [6] J. Brugada, P. Brugada, Further characterization of the syndrome of right bundle branch block, ST segment elevation, sand sudden death, J. Cardiovasc. Electrophysiol. 8 (1997) 325–331. [7] B. Pinamonti, F. Brun, L. Mestroni, G. Sinagra, Arrhythmogenic right ventricular cardiomyopathy: from genetics to diagnostic and therapeutic challenges, World J. Cardiol. 6 (2014) 1234–1244. [8] W. De Wilde, L. Boersma, P. Pollet, B. Scholzel, E. Wever, Y. Vandekerckhove, Symtomatic arrhythmogenic right ventricular dysplasia/cardiomyopathy. A two-centre retrospective study of 15 symptomatic ARVD/C cases and focus on the diagnostic value of MRI in symptomatic ARVD/C patients, Acta Cardiol. 63 (2008) 181–189.
85
[9] C.X. Yan, C. Antzelevitch, Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation, Circulation 100 (1999) 1660–1666. [10] P.G. Meregalli, A.A. Wilde, H.L. Tan, Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more? Cardiovasc. Res. 15 (2005) 367–378. [11] A. Asimaki, A.G. Kleber, J.E. Saffitz, Pathogenesis of arrhythmogenic cardiomyopathy, Can. J. Cardiol. 31 (2015) 1313–1321. [12] K. Nademanee, H. Raju, S.V. de Noronha, M. Papadakis, L. Robinson, S. Rothery, et al., Fibrosis, connexin-43, and conduction abnormalities in the Brugada syndrome, J. Am. Coll. Cardiol. 66 (2015) 1976–1986. [13] M. Cerrone, M. Delmar, Desmosomes and the sodium channel complex: implications for arrhythmogenic cardiomyopathy and Brugada syndrome, Trends Cardiovasc. Med. 24 (2014) 184–190. [14] M. Cerrone, X. Lin, M. Zhang, E. Agullo-Pascual, A. Pfenniger, H. Chkourko-Gusky, et al., Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype, Circulation 129 (2014) 1092–1103. [15] B. Gerull, A. Heuser, T. Wichter, M. Paul, C.T. Basson, D.A. McDermott, et al., Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy, Nat. Genet. 36 (2004) 1162–1164. [16] C. DiResta, A. Pietrelli, S. Sala, P. Della Bella, G. DeBellis, M. Ferrari, et al., Highthroughput characterization of a cohort of Brugada syndrome patients, Hum. Mol. Genet. 24 (2015) 5828–5835. [17] Q. Zhao, Y. Chen, L. Peng, R. Gao, N. Liu, R. Jiang, et al., Identification of rare variants of DSP gene in sudden unexplained nocturnal death syndrome in the southern Chinese Han population, Int. J. Legal Med. 130 (2016) 317–322. [18] J.N. Ten Sande, R. Coronel, C.E. Conrath, A.H. Driessen, J.R. de Groot, H.L. Tan, et al., ST-segment elevation and fractionated electrograms in Brugada syndrome patients arise from the same structurally abnormal subepicardial RVOT area but have a different mechanism, Circ. Arrhythm. Electrophysiol. 8 (2015) 1382–1392. [19] S. Peters, Is early sudden death in the course of arrhythmogenic cardiomyopathy due to initial Brugada syndrome? Int. J. Cardiol. 182 (2015) 107–108. [20] A. Bayes de Luna, J. Garcia-Niebla, A. Baranchuk, New electrocardiographic features in Brugada syndrome, Curr. Cardiol. Rev. 10 (2014) 175–180. [21] J. Zhang, F. Sacher, K. Hoffmayer, T. O'Hara, M. Strom, P. Cuculich, et al., Cardiac electrophysiologic substrate underlying the ECG phenotype and electrogram abnormalities in Brugada syndrome patients, Circulation 131 (2015) 1950–1959.