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Sensitivity and specificity of sodium channel blocking test in the diagnosis of Brugada syndrome
International Journal of Cardiology 141 (2010) e31 – e33 www.elsevier.com/locate/ijcard
Letter to the Editor
Sensitivity and specificity of sodium channel blocking test in the diagnosis of Brugada syndrome Gerasimos Gavrielatos a,⁎, Konstantinos P. Letsas b , Loukas K. Pappas a , Michalis Efremidis a , Antonios Sideris a , Fotios Kardaras a a
Second Department of Cardiology, Evangelismos General Hospital of Athens, 10676 Athens, Greece b Arrhythmia Service, Herz-Zentrum, 79189 Bad Krozingen, Germany Received 9 July 2008; accepted 25 November 2008 Available online 13 January 2009
Abstract The ECG features of Brugada syndrome are dynamic and frequently concealed. Sodium channels blockers are widely used to unmask the Brugada electrocardiographic (ECG) pattern. The sensitivity and specificity of INa channel blocking test varies significantly. A negative INa blocking test does not exclude the presence of a SCN5A mutation, which is responsible for the phenotype of Brugada syndrome. Herein, we describe the case of a 65-years-old asymptomatic male who underwent a INa channel blocking test, seven years ago due to a type 2 ECG pattern (saddleback configuration) which failed to induce the diagnostic type 1 ECG pattern. Diagnostic considerations at a molecular level and their clinical relevance are being discussed. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Brugada electrocardiographic pattern; Sodium channel blockers; Diagnostic test
Dear Editor,
The Brugada syndrome (BS) is a genetically determined cause of sudden cardiac death in individuals without structural heart disease [1]. The characteristic electrocardiographic (ECG) pattern of BS consists of complete or incomplete right bundle branch block (RBBB) and STsegment elevation in leads V1 through V3 [2]. Three types of ECG repolarization pattern have been recognized. Type 1 is diagnostic of BS and is characterized by a coved ST-segment elevation ≥ 2 mm followed by a negative T wave. Type 2 STsegment elevation displays a saddleback configuration with a high takeoff ST-segment elevation of ≥ 2 mm, a trough displaying ≥ 1 mm ST elevation, and either a positive or ⁎ Corresponding author. Second Department of Cardiology, Evangelismos General Hospital of Athens 45-47 Ipsilantou St., 10676 Athens, Greece. Fax: +302107217687. E-mail address: [email protected] (G. Gavrielatos). 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.11.147
biphasic T wave. Type 3 has either a saddleback or coved appearance with an ST-segment elevation of ≤ 1 mm [3]. The ECG features of BS are dynamic and frequently concealed. The administration of sodium channel (INa) blocking agents (ajmaline, flecainide, pilsicainide, procainamide) is widely used to accentuate the ST-segment elevation or unmask the diagnostic pattern when it is initially absent [1,3]. The diagnosis of BS is therefore considered positive when the baseline type 2 or type 3 pattern is converted to the diagnostic type 1 ECG pattern (ST-segment elevation ≥ 2 mm) [3]. Mutations of the SCN5A gene encoding for the α subunit of INa channel have been reported as the genetic basis of the disease [1,3]. Herein, we report the case of a 65-years-old asymptomatic male without structural heart disease exhibiting a spontaneous type 1 ECG pattern of BS (Fig. 1a). Eight years ago due to a type 2 ECG pattern (saddleback configuration) (Fig. 1b), he underwent a INa channel blocking test with procainamide (10 mg/kg body weigh) which failed to induce the diagnostic type 1 ECG pattern. In the meanwhile, he has
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Fig. 1. a. Spontaneous type 1 ECG pattern of BS recorded in 2008. b. Spontaneous type 2 ECG pattern of BS (saddleback configuration) recorded in 2001. Sodium channel blocking test with procainamide failed to induce the diagnostic type 1 ECG pattern at that time of period.
never received medications known to accentuate the STsegment elevation or unmask the diagnostic pattern. Transthoracic echocardiography revealed a non hypertrophic left ventricle with normal ejection fraction. Ischemic heart disease was excluded. The sensitivity and specificity of INa channel blocking test varies significantly. Brugada et al. have demonstrated that intravenous administration of ajmaline, procainamide, or flecainide successfully unmasked the diagnostic ECG type in 34 patients with BS [4]. The sensitivity and specificity of flecainide testing, calculated among SCN5A-positive probands and their family members, were 77% and 80%, and its positive and negative predictive values 96% and 36%, respectively [5]. In a similar study, the sensitivity, specificity, and positive and negative predictive values of ajmaline challenge among 35 genetic carriers were 80%, 94.4%, 93.3%, and 82.9%, respectively [6]. Ιn a recent study comparing the diagnostic value of flecainide and ajmaline, a coved-type ST-segment elevation in right precordial leads was induced or enhanced in 22 of 22 patients following ajmaline administration. Among the 22 patients, only 15 patients showed positive response to flecainide, resulting in a positive concordance of 68%. Greater inhibition of Ito current by flecainide may render it less effective [7]. Psilicanaide, a pure class 1C agent, is considered more effective than flecanaide [8]. On the contrary, procainamide exhibits a less use-dependent block of the fast INa channel, and therefore is less effective compared to all other agents [8]. A combined sodium and calcium channel block has been reported to be more effective than INa channel blocking test alone in unmasking the ECG features of BS. Flecainide, ajmaline, and procainamide failed to generate polymorphic ventricular tachycardia except when combined with verapamil [9]. A negative INa blocking test does not exclude the presence of a SCN5A mutation [5,6]. Several explanations have been proposed: the lack of power of some INa channel
blocking agents such as observed with procainamide in the present case; the overlap between BS and other syndromes associated with SCN5A mutations where INa channel blockers do not necessarily provoke ST elevation; and the presence of specific SCN5A mutations that might provoke variable clinical phenotypes resulting in combinations of different diseases [5]. In conclusion, the INa channel blocking test is valuable in the diagnosis of SCN5A carriers. The sensitivity and specificity of ajmaline testing in the diagnostic work-up of BS appears superior compared to other INa blocking agents. However, clinicians should always remember that a negative INa blocking test does not exclude BS. Acknowledgements The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [10]. References [1] Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference. Heart Rhythm 2005;2:429–40. [2] 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. [3] Rossenbacker T, Priori SG. The Brugada syndrome. Curr Opin Cardiol 2007;22:163–70. [4] Brugada R, Brugada J, Antzelevitch C. 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. [5] Meregalli PG, Ruijter JM, Hofman N, Bezzina CR, Wilde AA, Tan HL. Diagnostic value of flecainide testing in unmasking SCN5Arelated Brugada syndrome. J Cardiovasc Electrophysiol 2006;17: 857–64.
G. Gavrielatos et al. / International Journal of Cardiology 141 (2010) e31–e33 [6] Hong K, Brugada J, Oliva A, et al. Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations. Circulation 2004;110:3023–7. [7] Wolpert C, Echternach C, Veltmann C, et al. Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome. Heart Rhythm 2005;2:254–60.
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[8] Shimizu W. The Brugada syndrome–an update. Intern Med 2005;44: 1224–31. [9] Fish JM, Antzelevitch C. Role of sodium and calcium channel block in unmasking the Brugada syndrome. Heart Rhythm 2004;1:210–7. [10] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131: 149–50.
Letter to the Editor
Sensitivity and specificity of sodium channel blocking test in the diagnosis of Brugada syndrome Gerasimos Gavrielatos a,⁎, Konstantinos P. Letsas b , Loukas K. Pappas a , Michalis Efremidis a , Antonios Sideris a , Fotios Kardaras a a
Second Department of Cardiology, Evangelismos General Hospital of Athens, 10676 Athens, Greece b Arrhythmia Service, Herz-Zentrum, 79189 Bad Krozingen, Germany Received 9 July 2008; accepted 25 November 2008 Available online 13 January 2009
Abstract The ECG features of Brugada syndrome are dynamic and frequently concealed. Sodium channels blockers are widely used to unmask the Brugada electrocardiographic (ECG) pattern. The sensitivity and specificity of INa channel blocking test varies significantly. A negative INa blocking test does not exclude the presence of a SCN5A mutation, which is responsible for the phenotype of Brugada syndrome. Herein, we describe the case of a 65-years-old asymptomatic male who underwent a INa channel blocking test, seven years ago due to a type 2 ECG pattern (saddleback configuration) which failed to induce the diagnostic type 1 ECG pattern. Diagnostic considerations at a molecular level and their clinical relevance are being discussed. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Brugada electrocardiographic pattern; Sodium channel blockers; Diagnostic test
Dear Editor,
The Brugada syndrome (BS) is a genetically determined cause of sudden cardiac death in individuals without structural heart disease [1]. The characteristic electrocardiographic (ECG) pattern of BS consists of complete or incomplete right bundle branch block (RBBB) and STsegment elevation in leads V1 through V3 [2]. Three types of ECG repolarization pattern have been recognized. Type 1 is diagnostic of BS and is characterized by a coved ST-segment elevation ≥ 2 mm followed by a negative T wave. Type 2 STsegment elevation displays a saddleback configuration with a high takeoff ST-segment elevation of ≥ 2 mm, a trough displaying ≥ 1 mm ST elevation, and either a positive or ⁎ Corresponding author. Second Department of Cardiology, Evangelismos General Hospital of Athens 45-47 Ipsilantou St., 10676 Athens, Greece. Fax: +302107217687. E-mail address: [email protected] (G. Gavrielatos). 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.11.147
biphasic T wave. Type 3 has either a saddleback or coved appearance with an ST-segment elevation of ≤ 1 mm [3]. The ECG features of BS are dynamic and frequently concealed. The administration of sodium channel (INa) blocking agents (ajmaline, flecainide, pilsicainide, procainamide) is widely used to accentuate the ST-segment elevation or unmask the diagnostic pattern when it is initially absent [1,3]. The diagnosis of BS is therefore considered positive when the baseline type 2 or type 3 pattern is converted to the diagnostic type 1 ECG pattern (ST-segment elevation ≥ 2 mm) [3]. Mutations of the SCN5A gene encoding for the α subunit of INa channel have been reported as the genetic basis of the disease [1,3]. Herein, we report the case of a 65-years-old asymptomatic male without structural heart disease exhibiting a spontaneous type 1 ECG pattern of BS (Fig. 1a). Eight years ago due to a type 2 ECG pattern (saddleback configuration) (Fig. 1b), he underwent a INa channel blocking test with procainamide (10 mg/kg body weigh) which failed to induce the diagnostic type 1 ECG pattern. In the meanwhile, he has
e32
G. Gavrielatos et al. / International Journal of Cardiology 141 (2010) e31–e33
Fig. 1. a. Spontaneous type 1 ECG pattern of BS recorded in 2008. b. Spontaneous type 2 ECG pattern of BS (saddleback configuration) recorded in 2001. Sodium channel blocking test with procainamide failed to induce the diagnostic type 1 ECG pattern at that time of period.
never received medications known to accentuate the STsegment elevation or unmask the diagnostic pattern. Transthoracic echocardiography revealed a non hypertrophic left ventricle with normal ejection fraction. Ischemic heart disease was excluded. The sensitivity and specificity of INa channel blocking test varies significantly. Brugada et al. have demonstrated that intravenous administration of ajmaline, procainamide, or flecainide successfully unmasked the diagnostic ECG type in 34 patients with BS [4]. The sensitivity and specificity of flecainide testing, calculated among SCN5A-positive probands and their family members, were 77% and 80%, and its positive and negative predictive values 96% and 36%, respectively [5]. In a similar study, the sensitivity, specificity, and positive and negative predictive values of ajmaline challenge among 35 genetic carriers were 80%, 94.4%, 93.3%, and 82.9%, respectively [6]. Ιn a recent study comparing the diagnostic value of flecainide and ajmaline, a coved-type ST-segment elevation in right precordial leads was induced or enhanced in 22 of 22 patients following ajmaline administration. Among the 22 patients, only 15 patients showed positive response to flecainide, resulting in a positive concordance of 68%. Greater inhibition of Ito current by flecainide may render it less effective [7]. Psilicanaide, a pure class 1C agent, is considered more effective than flecanaide [8]. On the contrary, procainamide exhibits a less use-dependent block of the fast INa channel, and therefore is less effective compared to all other agents [8]. A combined sodium and calcium channel block has been reported to be more effective than INa channel blocking test alone in unmasking the ECG features of BS. Flecainide, ajmaline, and procainamide failed to generate polymorphic ventricular tachycardia except when combined with verapamil [9]. A negative INa blocking test does not exclude the presence of a SCN5A mutation [5,6]. Several explanations have been proposed: the lack of power of some INa channel
blocking agents such as observed with procainamide in the present case; the overlap between BS and other syndromes associated with SCN5A mutations where INa channel blockers do not necessarily provoke ST elevation; and the presence of specific SCN5A mutations that might provoke variable clinical phenotypes resulting in combinations of different diseases [5]. In conclusion, the INa channel blocking test is valuable in the diagnosis of SCN5A carriers. The sensitivity and specificity of ajmaline testing in the diagnostic work-up of BS appears superior compared to other INa blocking agents. However, clinicians should always remember that a negative INa blocking test does not exclude BS. Acknowledgements The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [10]. References [1] Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference. Heart Rhythm 2005;2:429–40. [2] 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. [3] Rossenbacker T, Priori SG. The Brugada syndrome. Curr Opin Cardiol 2007;22:163–70. [4] Brugada R, Brugada J, Antzelevitch C. 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. [5] Meregalli PG, Ruijter JM, Hofman N, Bezzina CR, Wilde AA, Tan HL. Diagnostic value of flecainide testing in unmasking SCN5Arelated Brugada syndrome. J Cardiovasc Electrophysiol 2006;17: 857–64.
G. Gavrielatos et al. / International Journal of Cardiology 141 (2010) e31–e33 [6] Hong K, Brugada J, Oliva A, et al. Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations. Circulation 2004;110:3023–7. [7] Wolpert C, Echternach C, Veltmann C, et al. Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome. Heart Rhythm 2005;2:254–60.
e33
[8] Shimizu W. The Brugada syndrome–an update. Intern Med 2005;44: 1224–31. [9] Fish JM, Antzelevitch C. Role of sodium and calcium channel block in unmasking the Brugada syndrome. Heart Rhythm 2004;1:210–7. [10] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131: 149–50.