International Journal of Cardiology 189 (2015) 88–90
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Is Brugada syndrome a variant of arrhythmogenic cardiomyopathy? S. Peters ⁎ St. Elisabeth Hospital Salzgitter, Germany
a r t i c l e
i n f o
Brugada syndrome is characterized by coved-type ST-segment elevation in right precordial leads after exclusion of structural heart disease. In the course of Brugada syndrome polymorphic ventricular tachycardia of primary ventricular fibrillation can appear, making sudden cardiac death the main clinical event. The only prophylaxis is up to now ICD implantation and, to a lesser extent, chinidine medication [1]. Monomorphic ventricular tachycardia is a rare, but possible finding [2]. In genetic screening SCN5A is the most relevant finding in about 20% of cases. Together with Ca++ and K+ mutations Brugada syndrome is called an ion channel disease.
Article history: Received 10 March 2015 Accepted 19 March 2015 Available online 28 March 2015 Keywords: Brugada syndrome Arrhythmogenic cardiomyopathy Connexome Plakophilin-2
Fig. 1. Epicardial mapping technique: QRS fragmentation and prolongation.
⁎ St. Elisabeth Hospital Salzgitter, Liebenhaller Str. 20, 38259 Salzgitter, Germany. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.ijcard.2015.03.394 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
S. Peters / International Journal of Cardiology 189 (2015) 88–90
Ablation success can only be secured when done epicardially in the region of the right ventricular outflow tract [3]. In epicardial mapping techniques QRS prolongation and fragmentation can be registered (Fig. 1). In several publications the amount of fibrosis in the right ventricular outflow tract is increased [4,5] and in a single publication in the few patients reduced gap junctions are described [6]. If in arrhythmogenic cardiomyopathy the right ventricular outflow tract is first involved and spontaneous or provoked coved type ST elevations can be seen before sudden cardiac death appears [7]. In 1989 Bruno Martini described a patient with coved-type ST elevation and aborted sudden cardiac death [8] and 4 years later the patient died. In the autopsy typical arrhythmogenic cardiomyopathy was evident with fibrofatty abnormalities also at atrioventricular and His bundle complexes. Four years ago echocardiography and right ventricular angiography were completely normal. An example of provoked ST-segment elevation in right precordial leads after resuscitation due to ventricular fibrillation is shown in a
89
54-year old female patient suffering of arrhythmogenic cardiomyopathy (Fig. 2) making Brugada syndrome as the first clinical event in developing arrhythmogenic cardiomyopathy possible [9]. Up to now in the clinical picture of arrhythmogenic cardiomyopathy desmosomal and non-desmosomal gene mutations were differentiated. There are five desmosomal gene mutations (plakoglobin, plakophilin-2, desmoplakin, desmoglein-2 and desmocollin-2) — a major finding in patients with arrhythmogenic cardiomyopathy. Meanwhile there are eight so-called non-desmosomal gene mutations (lamin A/C, titin, phospholamban, desmin, rynadonine-2-receptor, TGF beta 3, LBP 3 and TMEM protein 43), although TMEM protein 43 has an association to desmosomal gene mutations [10]. Presently, arrhythmogenic cardiomyopathy is defined as a disease of intercalated discs — a disease of reduced gap junctions, that can be measured by connexin 43 in endomyocardial biopsy [11]. Arrhythmogenic cardiomyopathy is generally characterised as myocardial atrophy surrounded by increased fibrosis as the main finding and fatty infiltration.
Fig. 2. Precordial leads in a patient with resuscitation without (left side) and with ajmaline administration (right side).
90
S. Peters / International Journal of Cardiology 189 (2015) 88–90
Ablation success can be reached by epicardial approach (80–90% success rate) better than endocardial approach (about 30–40% success rate) [12]. In the follow-up of patients with typical arrhythmogenic cardiomyopathy and provocable Brugada syndrome in four out of eight patients ajmaline testing was no longer positive [13]. This can be due in part to initial myocarditis provoking positive ajmaline challenge — a mechanism which explains spontaneous or provocable Brugada syndrome in nearly 40% in cases [14]. In the other cases ajmaline testing is no longer positive and typical arrhythmogenic cardiomyopathy has developed. In typical Brugada syndrome plakophilin-2 is in about 2.5% of cases of the gene mutation of interest after exclusion of any relevant Brugada syndrome genes. Plakophilin-2 produces sodium deficit thus producing typical features of Brugada syndrome [15]. Delmar and coworkers described the so-called “connexome” — an association between desmosomal proteins, gap junctions and sodium channel complexes [16] making a continuum between arrhythmogenic cardiomyopathy and Brugada syndrome more likely. References [1] K. Hasegawa, T. Ashihara, H. Kimura, H. Jo, H. Itoh, T. Yamamoto, et al., Long-term pharmacological therapy of Brugada syndrome: is J-wave attenuation a marker of drug efficacy ? Intern. Med. 53 (2014) 1523–1526. [2] A. Georgios, S. Georgios, T. Nikolitsa, K. Persefoni, M. Andreas, An atypical case of Brugada syndrome, Ann. Noninvasive Electrocardiol. 16 (2011) 412–414. [3] K. Nademanee, G. Veerakul, P. Chandanamattha, L. Shaothawee, A. Ariyachaipanich, K. Jirasiriroganakorn, et al., Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium, Circulation 123 (2011) 1270–1279. [4] R. Coronel, S. Cassini, T.T. Koopmann, F.J. Wilms-Schopman, A.O. Verkerk, et al., Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada
[5]
[6]
[7]
[8]
[9] [10]
[11] [12]
[13]
[14]
[15]
[16]
syndrome: a combined electrophysiological, genetic, histopathologic, and computational study, Circulation 112 (2005) 2769–2777. K. Ohkubo, I. Watanabe, Y. Okumura, Y. Takagi, S. Ashino, M. Kofune, et al., Right ventricular histological substrate and conduction delay in patients with Burgada syndrome, Int. Heart J. 51 (2010) 17–23. H. Raju, S.V. de Noronha, S. Rothery, L. Ronbinson, M. Papadakis, S. Sharma, et al., The Brugada syndrome and cardiomyopathy: altered collagen and gap junction expression, Europace (2014), http://dx.doi.org/10.1093/europace/euu237.11. F. Rouzet, V. Algalarraido, S. Burg, P. Nassar, L. Sarda-Mantel, P. Aouate, et al., Contraction delay of the RV outflow tract in patients with Brugada syndrome is dependent on the spontaneous ST-segment elevation pattern, Heart Rhythm. 8 (2011) 1905–1912. B. Martini, A. Nava, G. Thiene, G.F. Buja, B. Canciani, R. Scognamiglio, et al., Ventricular fibrillation without apparent heart disease: description of six cases, Am. Heart J. 118 (1989) 1203–1209. S. Peters, Is early sudden death in the course of arrhythmogenic cardiomyopathy due to initial Brugada syndrome ? Int. J. Cardiol. 182C (2014) 107–108. V. Siragam, X. Cui, S. Masse, C. Ackerley, S. Aafaqi, L. Strandberg, et al., TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy, PLoS One 9 (2014) e109128. A. Rampazzo, M. Calore, J. van Hengel, F. van Roy, Intercalated discs and arrhythmogenic cardiomyopathy, Circ. Cardiovasc. Genet. 7 (2014) 930–940. C.M. Tschabrunn, F.E. Marchlinski, Ventricular tachycardia mapping and ablation in arrhythmogenic right ventricular cardiomyopathy/dysplasia: lessons learned, World J. Cardiol. 6 (2014) 959–967. S. Peters, Arrhythmogenic right ventricular dysplasia-cardiomyopathy and provocable coved-type ST-segment elevation in right precordial leads: clues from long-term follow-up, Europace 10 (2008) 816–820. A. Frustaci, S.G. Priori, M. Pieroni, C. Chimenti, C. Napolitano, I. Rivolta, et al., Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome, Circulation 112 (2005) 3680–3687. 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. E. Agullo-Pascual, M. Cerrone, M. Delmar, Arrhythmogenic cardiomyopathy and Brugada syndrome: diseases of the connexome, FEBS Lett. 588 (2014) 1322–1330.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Is Brugada syndrome a variant of arrhythmogenic cardiomyopathy? S. Peters ⁎ St. Elisabeth Hospital Salzgitter, Germany
a r t i c l e
i n f o
Brugada syndrome is characterized by coved-type ST-segment elevation in right precordial leads after exclusion of structural heart disease. In the course of Brugada syndrome polymorphic ventricular tachycardia of primary ventricular fibrillation can appear, making sudden cardiac death the main clinical event. The only prophylaxis is up to now ICD implantation and, to a lesser extent, chinidine medication [1]. Monomorphic ventricular tachycardia is a rare, but possible finding [2]. In genetic screening SCN5A is the most relevant finding in about 20% of cases. Together with Ca++ and K+ mutations Brugada syndrome is called an ion channel disease.
Article history: Received 10 March 2015 Accepted 19 March 2015 Available online 28 March 2015 Keywords: Brugada syndrome Arrhythmogenic cardiomyopathy Connexome Plakophilin-2
Fig. 1. Epicardial mapping technique: QRS fragmentation and prolongation.
⁎ St. Elisabeth Hospital Salzgitter, Liebenhaller Str. 20, 38259 Salzgitter, Germany. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.ijcard.2015.03.394 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
S. Peters / International Journal of Cardiology 189 (2015) 88–90
Ablation success can only be secured when done epicardially in the region of the right ventricular outflow tract [3]. In epicardial mapping techniques QRS prolongation and fragmentation can be registered (Fig. 1). In several publications the amount of fibrosis in the right ventricular outflow tract is increased [4,5] and in a single publication in the few patients reduced gap junctions are described [6]. If in arrhythmogenic cardiomyopathy the right ventricular outflow tract is first involved and spontaneous or provoked coved type ST elevations can be seen before sudden cardiac death appears [7]. In 1989 Bruno Martini described a patient with coved-type ST elevation and aborted sudden cardiac death [8] and 4 years later the patient died. In the autopsy typical arrhythmogenic cardiomyopathy was evident with fibrofatty abnormalities also at atrioventricular and His bundle complexes. Four years ago echocardiography and right ventricular angiography were completely normal. An example of provoked ST-segment elevation in right precordial leads after resuscitation due to ventricular fibrillation is shown in a
89
54-year old female patient suffering of arrhythmogenic cardiomyopathy (Fig. 2) making Brugada syndrome as the first clinical event in developing arrhythmogenic cardiomyopathy possible [9]. Up to now in the clinical picture of arrhythmogenic cardiomyopathy desmosomal and non-desmosomal gene mutations were differentiated. There are five desmosomal gene mutations (plakoglobin, plakophilin-2, desmoplakin, desmoglein-2 and desmocollin-2) — a major finding in patients with arrhythmogenic cardiomyopathy. Meanwhile there are eight so-called non-desmosomal gene mutations (lamin A/C, titin, phospholamban, desmin, rynadonine-2-receptor, TGF beta 3, LBP 3 and TMEM protein 43), although TMEM protein 43 has an association to desmosomal gene mutations [10]. Presently, arrhythmogenic cardiomyopathy is defined as a disease of intercalated discs — a disease of reduced gap junctions, that can be measured by connexin 43 in endomyocardial biopsy [11]. Arrhythmogenic cardiomyopathy is generally characterised as myocardial atrophy surrounded by increased fibrosis as the main finding and fatty infiltration.
Fig. 2. Precordial leads in a patient with resuscitation without (left side) and with ajmaline administration (right side).
90
S. Peters / International Journal of Cardiology 189 (2015) 88–90
Ablation success can be reached by epicardial approach (80–90% success rate) better than endocardial approach (about 30–40% success rate) [12]. In the follow-up of patients with typical arrhythmogenic cardiomyopathy and provocable Brugada syndrome in four out of eight patients ajmaline testing was no longer positive [13]. This can be due in part to initial myocarditis provoking positive ajmaline challenge — a mechanism which explains spontaneous or provocable Brugada syndrome in nearly 40% in cases [14]. In the other cases ajmaline testing is no longer positive and typical arrhythmogenic cardiomyopathy has developed. In typical Brugada syndrome plakophilin-2 is in about 2.5% of cases of the gene mutation of interest after exclusion of any relevant Brugada syndrome genes. Plakophilin-2 produces sodium deficit thus producing typical features of Brugada syndrome [15]. Delmar and coworkers described the so-called “connexome” — an association between desmosomal proteins, gap junctions and sodium channel complexes [16] making a continuum between arrhythmogenic cardiomyopathy and Brugada syndrome more likely. References [1] K. Hasegawa, T. Ashihara, H. Kimura, H. Jo, H. Itoh, T. Yamamoto, et al., Long-term pharmacological therapy of Brugada syndrome: is J-wave attenuation a marker of drug efficacy ? Intern. Med. 53 (2014) 1523–1526. [2] A. Georgios, S. Georgios, T. Nikolitsa, K. Persefoni, M. Andreas, An atypical case of Brugada syndrome, Ann. Noninvasive Electrocardiol. 16 (2011) 412–414. [3] K. Nademanee, G. Veerakul, P. Chandanamattha, L. Shaothawee, A. Ariyachaipanich, K. Jirasiriroganakorn, et al., Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium, Circulation 123 (2011) 1270–1279. [4] R. Coronel, S. Cassini, T.T. Koopmann, F.J. Wilms-Schopman, A.O. Verkerk, et al., Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada
[5]
[6]
[7]
[8]
[9] [10]
[11] [12]
[13]
[14]
[15]
[16]
syndrome: a combined electrophysiological, genetic, histopathologic, and computational study, Circulation 112 (2005) 2769–2777. K. Ohkubo, I. Watanabe, Y. Okumura, Y. Takagi, S. Ashino, M. Kofune, et al., Right ventricular histological substrate and conduction delay in patients with Burgada syndrome, Int. Heart J. 51 (2010) 17–23. H. Raju, S.V. de Noronha, S. Rothery, L. Ronbinson, M. Papadakis, S. Sharma, et al., The Brugada syndrome and cardiomyopathy: altered collagen and gap junction expression, Europace (2014), http://dx.doi.org/10.1093/europace/euu237.11. F. Rouzet, V. Algalarraido, S. Burg, P. Nassar, L. Sarda-Mantel, P. Aouate, et al., Contraction delay of the RV outflow tract in patients with Brugada syndrome is dependent on the spontaneous ST-segment elevation pattern, Heart Rhythm. 8 (2011) 1905–1912. B. Martini, A. Nava, G. Thiene, G.F. Buja, B. Canciani, R. Scognamiglio, et al., Ventricular fibrillation without apparent heart disease: description of six cases, Am. Heart J. 118 (1989) 1203–1209. S. Peters, Is early sudden death in the course of arrhythmogenic cardiomyopathy due to initial Brugada syndrome ? Int. J. Cardiol. 182C (2014) 107–108. V. Siragam, X. Cui, S. Masse, C. Ackerley, S. Aafaqi, L. Strandberg, et al., TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy, PLoS One 9 (2014) e109128. A. Rampazzo, M. Calore, J. van Hengel, F. van Roy, Intercalated discs and arrhythmogenic cardiomyopathy, Circ. Cardiovasc. Genet. 7 (2014) 930–940. C.M. Tschabrunn, F.E. Marchlinski, Ventricular tachycardia mapping and ablation in arrhythmogenic right ventricular cardiomyopathy/dysplasia: lessons learned, World J. Cardiol. 6 (2014) 959–967. S. Peters, Arrhythmogenic right ventricular dysplasia-cardiomyopathy and provocable coved-type ST-segment elevation in right precordial leads: clues from long-term follow-up, Europace 10 (2008) 816–820. A. Frustaci, S.G. Priori, M. Pieroni, C. Chimenti, C. Napolitano, I. Rivolta, et al., Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome, Circulation 112 (2005) 3680–3687. 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. E. Agullo-Pascual, M. Cerrone, M. Delmar, Arrhythmogenic cardiomyopathy and Brugada syndrome: diseases of the connexome, FEBS Lett. 588 (2014) 1322–1330.
