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EDITORIAL COMMENTARY
Everybody has Brugada syndrome until proven otherwise? Sami Viskin, MD,* Raphael Rosso, MD,* Limor Friedensohn, MD,* Ofer Havakuk, XX,* Arthur Wilde, MD† From the *Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel, and † Heart Center, Academic Medical Center, Amsterdam, The Netherlands.
Brugada syndrome is a genetic arrhythmogenic disorder manifesting itself in a peculiar electrocardiogram (ECG) and an increased risk of cardiac arrest from ventricular fibrillation (VF).1 The diagnostic ECG, demonstrating J-point elevation and 42-mm coved ST-segment elevation in the right precordial leads, is termed type I Brugada ECG.2 This diagnostic ECG, however, has such day-to-day variability that among high-risk patients undergoing numerous ECG recordings over time, only every third ECG is diagnostic while every third ECG is normal.3 Several maneuvers are therefore used to increase the diagnostic sensitivity of the ECG: (1) The use of “high electrodes” (placing the recording right-precordial ECG electrodes not only on the standard fourth intercostal space but also on the second and the third intercostal space) increases the odds of identifying a type I ECG by 30%–40%.4 (2) The use of 12-lead Holter recordings (particularly with high electrodes as described above) further increases the odds of recognizing the diagnostic ST-segment elevation at times when vagal tone is elevated, primarily at night5 but also after meals.6 (3) Recognition that sodium channel blockers temporarily worsen the conduction and repolarization abnormalities of Brugada syndrome7 led to the use of these drugs to unravel the diagnostic ECG.8 Miyazaki et al7 were the first to test the effects of sodium channel blockers on the ECG of Brugada syndrome (in 1996) by injecting disopyramide or procainamide into 3 patients with nondiagnostic ECG: all 3 developed type I Brugada ECG within seconds.7 Shortly thereafter, Brugada et al8 tested 34 cardiac arrest survivors with an intermittent Brugada ECG pattern and demonstrated a 100% sensitivity for unraveling the type I Brugada ECG in this patient subgroup. In the same study, there was a 100% concordance between a positive ajmaline test and the presence of a given sodium channel mutation in 13 relatives of probands with Brugada syndrome.8 The excellent sensitivity of these results paved the path for what would become widespread use of sodium channel blockers for diagnosing Brugada syndrome. Today, Brugada syndrome is diagnosed, under the right circumstances, “in patients with ST segment elevation with Address reprint requests and correspondence: Dr Sami Viskin, Department of Cardiology, Tel Aviv Medical Center, Weizman 6, Tel Aviv 64239, Israel. E-mail address: [email protected].
1547-5271/$-see front matter B 2015 Heart Rhythm Society. All rights reserved.
type 1 morphology… either spontaneously or after provocative drug test with a sodium channel blocker.”9 The medical community embraced this new diagnostic test, even though data on its specificity was limited. Not only diagnostic decisions but also therapeutic choices with long-term implications were adopted worldwide before the potential for false-positive results of the ajmaline test was fully appreciated. In Europe, E70% of patients diagnosed with “asymptomatic Brugada syndrome” received this diagnosis after a positive ajmaline test.10 Today, the most common reason for implantable cardioverter-defibrillator (ICD) implantation for Brugada syndrome in asymptomatic patients is “a positive ajmaline test with inducible VF during electrophysiologic studies.”11,12 Considering the low rate of appropriate ICD interventions in asymptomatic individuals, in particular in those who only have a drug-induced type I ECG,10 and the high risk for ICD-related complications, including 16%12–37%11 rates of inappropriate shocks, it is about time we critically reappraise what we know about the specificity of the sodium channel blocker challenge test. The above-mentioned article by Brugada et al8 demonstrating the high sensitivity of the ajmaline test (and to a lesser degree flecainide and procainamide) for diagnosing Brugada syndrome also included a control group of 53 patients without Brugada syndrome. The fact that none of them developed a type I ECG during the drug challenge allowed portraying a test with 100% specificity. This control group, however, was problematic for several reasons: (1) Eight of the controls had right ventricular dysplasia. Later studies with more patients demonstrated a 16% false-positive rate of the ajmaline test in right ventricular dysplasia.13,14 (2) Ten controls had complete right bundle branch block, a condition that may mask or hide the type I ECG.15,16 As a result of the small size of the “true control group” (only 35 patients had a normal ECG),8 the 95% confidence intervals for a test showing nil results reaches 8.5%.17 Furthermore, none of the controls had their ECG recording electrodes placed on the third or second intercostal space, which is now common practice. Adding such high electrodes almost doubles the sensitivity of the test18,19 and is unrealistic to expect that such a maneuver would not reduce specificity. Shimizu et al20 performed an intravenous drug challenge with flecainide, disopyramide, and mexiletine in 10 patients http://dx.doi.org/10.1016/j.hrthm.2015.04.017
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with Brugada syndrome and 10 healthy controls. In contrast to mexiletine, which did not cause ST-segment elevation in patients or controls, flecainide, and to a lesser degree disopyramide, caused some degree of ST-segment elevation in both groups. ST-segment elevation was more prominent in patients with Brugada syndrome, who also had more ST-segment elevation at baseline. Nevertheless, ST-segment elevation increased by E1 mm in virtually all controls20; in fact, the mean ST-segment elevation after flecainide injection in controls was 2.2 ⫾ 0.4 mm, a degree that could be counted as “diagnostic of Brugada syndrome” during clinical (uncontrolled) use of the test,21 particularly in less experienced centers. The largest series using genetic results as the criterion standard for determining the specificity of the ajmaline test was published by Hong et al.22 In 71 members of 4 families with an identified SCN5A mutation, the false-positive rate of the ajmaline test was 5.6%, but these results were obtained using only standard precordial electrode placement22; it is likely that higher false-positive rates would be recorded with high electrodes, which is now common practice. In a similar study from Amsterdam including 35 members of families with identified SCN5A mutations,19 24 tested individuals had a positive ajmaline test and the false-positive rate by this criterion was 4%. Here too, because of the small study sample, the 95% confidence intervals of this finding reach 12%, meaning that if a sufficiently large population was studied, up to 12% could end up having a false-positive ajmaline test. In addition, this particular study design (ie, selection of a small number of members within families with identified mutations as the study cohort) led to overestimation of the positive predictive value of the ajmaline test (with inevitable underestimation of its false-positive rate). This is due to that fact that the positive predictive value of any test is predictably magnified by a high disease prevalence,23 which in this study group was 86%, as 30 of the 35 subjects tested had an SCN5A mutation. Finally, accepting an SCN5A mutation as the criterion standard for defining Brugada syndrome during evaluation of a diagnostic test would be considered problematic nowadays. The classical concept of Brugada syndrome as a trait that is controlled by a single locus in an inheritance pattern has now been challenged.24 Accordingly, sodium channel defects may be one of the contributory causes of Brugada syndrome but not necessarily the main one.25 Because of the incertitude surrounding the specificity of the ajmaline test, one should look at the study by Hasdemir et al,26 published in this issue of HeartRhythm, on the high prevalence of “concealed Brugada syndrome” in patients with atrioventricular (AV) nodal reentry tachycardia (AVNRT) with due caution. Hasdemir et al performed the ajmaline test in 96 patients undergoing radiofrequency ablation for typical AVNRT and 66 controls. Their results are intriguing: 27% of patients with AVNRT and 5% of controls developed a type I Brugada ECG in response to the ajmaline challenge. The statistically significant results led the authors to conclude that AVNRT is
Heart Rhythm, Vol 0, No 0, Month 2015 a manifestation of Brugada syndrome and that 1 of 4 patients with AVNRT have concealed Brugada syndrome. As a matter of fact, all these patients with positive ajmaline tests (27% of patients with typical AVNRT) would be defined as patients with asymptomatic Brugada syndrome by present consensus documents. Extrapolation of these results to the general population (as done by the authors) would lead to the conclusion that concealed Brugada syndrome is a disease of pandemic proportions. Thus, before we embrace their conclusions, a critical analysis of the data presented by Hasdemir et al26 is mandatory. First, none of their patients with AVNRT and a positive ajmaline test had clinical clues or family history even remotely suggestive of Brugada syndrome. Second, the ajmaline test protocol used was standard (1 mg/kg infused over 5 minutes), but the continuous ECG included recordings with high electrodes, unquestionably affecting their results. As a matter of fact, 60% of all their ajmaline-induced type I Brugada ECGs were seen only on recordings with high electrodes. Third, the investigators performing and interpreting the test were aware of patient allotting, inevitably creating bias. The importance of this potential bias is best demonstrated by the following fact: Over a decade ago, the group from Milan tested the reproducibility of the flecainide test in 20 patients with Brugada syndrome and found it to be 100%.27 However, and here is the point, in the same study, flecainide was also injected into 25 patients after ablation of AVNRT and none of these patients with AVNRT—this time serving as “controls” instead of “patients”—developed a type I Brugada ECG.27 Even after taking into consideration that flecainide is less sensitive than ajmaline for detecting Brugada syndrome,28 one would expect some patients within the Milan group of patients with AVNRT to have a positive response.27 Finally, genetic testing was performed in only 17 patients: 10 with concealed Brugada syndrome and 7 with previous diagnosis of Brugada syndrome who also had AVNRT.26 Although, in general, the yield of mutation identification in a Brugada syndrome cohort is at most 30%,29 in this cohort it was unexpectedly high (70%)26 and the pathogenicity of the variants reported here could not be demonstrated. Furthermore, the fact that conduction intervals (PR, HV, and QRS) were normal in the present Brugada syndrome cohort, where half the patients (13 of 26) harbored a “mutation” mainly affecting sodium channel function (in 10 of 13), argues against a major role of genes impacting the sodium current because patients with SCN5A-associated Brugada syndrome characteristically have prolonged conduction intervals.30 Unfortunately, genetic screening of the control group was not performed, so the impact of the “genetic background noise”31 cannot be determined. One cannot emphasize enough that the identification of a mutation is not proof for the diagnosis of Brugada syndrome. AVNRT is a common arrhythmia with a characteristically benign long-term prognosis. True, Eckardt et al32 reported that 5 of 35 patients with Brugada syndrome (14%) had AVNRT, but the arrhythmia was induced (during electrophysiological studies) rather than spontaneously recorded in
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Editorial Commentary
3 of the 5. Furthermore, when the same authors expanded their analysis to 115 consecutive patients with Brugada syndrome, the percentage with AVNRT decreased to 7%. When one considers a common disease (AVNRT) and a rare disorder (Brugada syndrome), it is predictable to find patients who have both. Only large population controlled studies can prove if such a “link” exists. This will be difficult to prove because dual AV nodal physiology, the substrate for AVNRT, is present—when sought during electrophysiological studies—in 15% of children33 and 440% of adolescents33 and adults.34 It is nevertheless worth considering a true association between the 2 identities. Almost 10 years ago the Amsterdam group proposed as a potential mechanism of right precordial ST-segment elevation the existence of remnants of AV nodal tissue in the right ventricular outflow tract area.35 These remnants would act as the substrate for slowed conduction in this area.35,36 Hypothetically, altered expression of slow conduction AV nodal tissue (around the AV ring) could provide a more vulnerable substrate for AVNRT and thus could link the 2 entities. The study by Hasdemir et al26 suggests that the specificity of the ajmaline test is not as high as we thought. Not all patients developing QT prolongation after receiving strong potassium channel blockers have a congenital long QT syndrome and it is time to question whether all patients showing a type I Brugada ECG, when challenged with potent sodium channel blockers, indeed have Brugada syndrome. It is also important to emphasize that the test is not risk free. Life-threatening ventricular arrhythmias, including VF that is rarely recurrent or refractory, have been reported in 0.3%,21 1.3%,37 and up to 1.8%38 of patients tested. This small risk of iatrogenic arrhythmias is significant because numerous studies have shown that the long-term risk of spontaneous VF in patients diagnosed with asymptomatic Brugada syndrome by virtue of a positive ajmaline test is small—even if they also have inducible VF during subsequent electrophysiological studies. For example, the multicenter ICD study on Brugada syndrome with the longest available follow-up period11 enrolled 166 asymptomatic patients, including 92 with spontaneous- and 74 with drug-induced type I ECG. After a follow-up period of 7 ⫾ 3 years, 8 patients of the former group (8.6%) but only 4 patients of the latter group (5.4%) had an appropriate ICD intervention. Thus, the average risk for spontaneous VF in patients with asymptomatic Brugada syndrome revealed by a drug challenge test was 0.8% per year, not different from the immediate risk for VF resulting from the diagnostic test itself. This “risk stratification paradox” is of particular consequence for children: On the one hand, children are at particularly high risk of developing ventricular arrhythmias during the ajmaline test. In one series,39 10% of children undergoing the ajmaline test, including 3% of the asymptomatic subgroup, developed on-site VF. On the other hand, none of the children with ajmaline-based diagnosis of Brugada syndrome had spontaneous VF during 7 years of follow-up.39 Even if their longterm risk is low, asymptomatic patients with positive ajmaline
3 tests are left with the knowledge that they have a potentially lethal disease and the provoked emotional stress is not inconsequential, particularly if such patients are then left untreated (a common practice in some experienced centers). Based on all of the above, it is time to pause and think before performing any additional tests with sodium channel blockers before the specificity of the test is clearly defined by large controlled studies.
References 1. Mizusawa Y, Wilde AA. Brugada syndrome. Circ Arrhythm Electrophysiol 2012;5:606–616. 2. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference. Heart Rhythm 2005;2:429–440. 3. Richter S, Sarkozy A, Veltmann C, et al. Variability of the diagnostic ECG pattern in an ICD patient population with Brugada syndrome. J Cardiovasc Electrophysiol 2009;20:69–75. 4. Veltmann C, Papavassiliu T, Konrad T, et al. Insights into the location of type I ECG in patients with Brugada syndrome: correlation of ECG and cardiovascular magnetic resonance imaging. Heart Rhythm 2012;9:414–421. 5. 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. XX:XX–XX. 6. 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. 7. 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;27:1061–1070. 8. Brugada R, Brugada J, Antzelevitch C, 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;101:510–515. 9. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;10:1932–1963. 10. Probst V, Veltmann C, Eckardt L, et al. Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry. Circulation 2010;121:635–643. 11. Sacher F, Probst V, Maury P, et al. Outcome after implantation of a cardioverterdefibrillator in patients with Brugada syndrome: a multicenter study, part 2. Circulation 2013;128:1739–1747. 12. Conte G, Sieira J, Ciconte G, et al. Implantable cardioverter-deibrillator therapy in Brugada syndrome: a 20-year single-center experience. J Am Coll Cardiol 2015;65:879–888. 13. Peters S, Trummel M, Denecke S, Koehler B. Results of ajmaline testing in patients with arrhythmogenic right ventricular dysplasia-cardiomyopathy. Int J Cardiol 2004;95:207–210. 14. Peters S. Arrhythmogenic right ventricular dysplasia-cardiomyopathy and provocable coved-type ST-segment elevation in right precordial leads: clues from long-term follow-up. Europace 2008;10:816–820. 15. Chiale PA, Garro HA, Fernandez PA, Elizari MV. High-degree right bundle branch block obscuring the diagnosis of Brugada electrocardiographic pattern. Heart Rhythm 2012;9:974–976. 16. Baranchuk A, Sicouri S, Elizari MV, Chiale PA. Pause-dependent normalization of ST-segment elevation during the ajmaline test in a patient with Brugada syndrome. Heart Rhythm 2014;11:707–709. 17. Newman TB. If almost nothing goes wrong, is almost everything all right? Interpreting small numerators. J Am Med Assoc 1995;274:1013. 18. Govindan M, Batchvarov VN, Raju H, et al. Utility of high and standard right precordial leads during ajmaline testing for the diagnosis of Brugada syndrome. Heart 2010;96:1904–1908. 19. Meregalli PG, Ruijter JM, Hofman N, Bezzina CR, Wilde AA, Tan HL. Diagnostic value of flecainide testing in unmasking SCN5A-related Brugada syndrome. J Cardiovasc Electrophysiol 2006;17:857–864. 20. Shimizu W, Antzelevitch C, Suyama K, 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;11:1320–1329. 21. Veltmann C, Wolpert C, Sacher F, et al. Response to intravenous ajmaline: a retrospective analysis of 677 ajmaline challenges. Europace 2009;11:1345–1352.
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22. 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;110:3023–3027. 23. Altman DG, Bland JM. Diagnostic tests 2: predictive values. BMJ 1994;309:102. 24. 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. 25. Probst V, Wilde AA, Barc J, et al. SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome. Circ Cardiovasc Genet 2009;2:552–557. 26. Hasdemir C, Payzin S, Kocabas U, et al. High prevalence of concealed Brugada syndrome among patients with atrioventricular nodal reentrant tachycardia. Heart Rhythm 2015. XXXX:XX–XX. 27. Gasparini M, Priori SG, Mantica M, et al. Flecainide test in Brugada syndrome: a reproducible but risky tool. Pacing Clin Electrophysiol 2003;26:338–341. 28. Wolpert C, Echternach C, Veltmann C, et al. Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome. Heart Rhythm 2005;2:254–260. 29. Hofman N, Tan HL, Alders M, et al. Yield of molecular and clinical testing for arrhythmia syndromes: report of 15 years’ experience. Circulation 2013;128: 1513–1521. 30. Smits JP, Eckardt L, Probst V, et al. Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. J Am Coll Cardiol 2002;40:350–356.
Heart Rhythm, Vol 0, No 0, Month 2015 31. Landstrom AP, Ackerman MJ. The Achilles’ heel of cardiovascular genetic testing: distinguishing pathogenic mutations from background genetic noise. Clin Pharmacol Ther 2011;90:496–499. 32. Eckardt L, Kirchhof P, Loh P, et al. Brugada syndrome and supraventricular tachyarrhythmias: a novel association? J Cardiovasc Electrophysiol 2001;12:680–685. 33. Cohen MI, Wieand TS, Rhodes LA, Vetter VL. Electrophysiologic properties of the atrioventricular node in pediatric patients. J Am Coll Cardiol 1997;29:403–407. 34. Farshidi A, Josephson ME, Horowitz LN. Electrophysiologic characteristics of concealed bypass tracts: clinical and electrocardiographic correlates. Am J Cardiol 1978;41:1052–1060. 35. Meregalli PG, Wilde AA, Tan HL. Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more? Cardiovasc Res 2005;67:367–378. 36. Boukens BJ, Christoffels VM, Coronel R, Moorman AF. Developmental basis for electrophysiological heterogeneity in the ventricular and outflow tract myocardium as a substrate for life-threatening ventricular arrhythmias. Circ Res 2009;104:19–31. 37. Rolf S, Bruns HJ, Wichter T, et al. The ajmaline challenge in Brugada syndrome: diagnostic impact, safety, and recommended protocol. Eur Heart J 2003;24:1104–1112. 38. Conte G, Sieira J, Sarkozy A, et al. Life-threatening ventricular arrhythmias during ajmaline challenge in patients with Brugada syndrome: incidence, clinical features, and prognosis. Heart Rhythm 2013;10:1869–1874. 39. Conte G, Dewals W, Sieira J, et al. Drug-induced Brugada syndrome in children: clinical features, device-based management, and long-term follow-up. J Am Coll Cardiol 2014;63:2272–2279.
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EDITORIAL COMMENTARY
Everybody has Brugada syndrome until proven otherwise? Sami Viskin, MD,* Raphael Rosso, MD,* Limor Friedensohn, MD,* Ofer Havakuk, XX,* Arthur Wilde, MD† From the *Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel, and † Heart Center, Academic Medical Center, Amsterdam, The Netherlands.
Brugada syndrome is a genetic arrhythmogenic disorder manifesting itself in a peculiar electrocardiogram (ECG) and an increased risk of cardiac arrest from ventricular fibrillation (VF).1 The diagnostic ECG, demonstrating J-point elevation and 42-mm coved ST-segment elevation in the right precordial leads, is termed type I Brugada ECG.2 This diagnostic ECG, however, has such day-to-day variability that among high-risk patients undergoing numerous ECG recordings over time, only every third ECG is diagnostic while every third ECG is normal.3 Several maneuvers are therefore used to increase the diagnostic sensitivity of the ECG: (1) The use of “high electrodes” (placing the recording right-precordial ECG electrodes not only on the standard fourth intercostal space but also on the second and the third intercostal space) increases the odds of identifying a type I ECG by 30%–40%.4 (2) The use of 12-lead Holter recordings (particularly with high electrodes as described above) further increases the odds of recognizing the diagnostic ST-segment elevation at times when vagal tone is elevated, primarily at night5 but also after meals.6 (3) Recognition that sodium channel blockers temporarily worsen the conduction and repolarization abnormalities of Brugada syndrome7 led to the use of these drugs to unravel the diagnostic ECG.8 Miyazaki et al7 were the first to test the effects of sodium channel blockers on the ECG of Brugada syndrome (in 1996) by injecting disopyramide or procainamide into 3 patients with nondiagnostic ECG: all 3 developed type I Brugada ECG within seconds.7 Shortly thereafter, Brugada et al8 tested 34 cardiac arrest survivors with an intermittent Brugada ECG pattern and demonstrated a 100% sensitivity for unraveling the type I Brugada ECG in this patient subgroup. In the same study, there was a 100% concordance between a positive ajmaline test and the presence of a given sodium channel mutation in 13 relatives of probands with Brugada syndrome.8 The excellent sensitivity of these results paved the path for what would become widespread use of sodium channel blockers for diagnosing Brugada syndrome. Today, Brugada syndrome is diagnosed, under the right circumstances, “in patients with ST segment elevation with Address reprint requests and correspondence: Dr Sami Viskin, Department of Cardiology, Tel Aviv Medical Center, Weizman 6, Tel Aviv 64239, Israel. E-mail address: [email protected].
1547-5271/$-see front matter B 2015 Heart Rhythm Society. All rights reserved.
type 1 morphology… either spontaneously or after provocative drug test with a sodium channel blocker.”9 The medical community embraced this new diagnostic test, even though data on its specificity was limited. Not only diagnostic decisions but also therapeutic choices with long-term implications were adopted worldwide before the potential for false-positive results of the ajmaline test was fully appreciated. In Europe, E70% of patients diagnosed with “asymptomatic Brugada syndrome” received this diagnosis after a positive ajmaline test.10 Today, the most common reason for implantable cardioverter-defibrillator (ICD) implantation for Brugada syndrome in asymptomatic patients is “a positive ajmaline test with inducible VF during electrophysiologic studies.”11,12 Considering the low rate of appropriate ICD interventions in asymptomatic individuals, in particular in those who only have a drug-induced type I ECG,10 and the high risk for ICD-related complications, including 16%12–37%11 rates of inappropriate shocks, it is about time we critically reappraise what we know about the specificity of the sodium channel blocker challenge test. The above-mentioned article by Brugada et al8 demonstrating the high sensitivity of the ajmaline test (and to a lesser degree flecainide and procainamide) for diagnosing Brugada syndrome also included a control group of 53 patients without Brugada syndrome. The fact that none of them developed a type I ECG during the drug challenge allowed portraying a test with 100% specificity. This control group, however, was problematic for several reasons: (1) Eight of the controls had right ventricular dysplasia. Later studies with more patients demonstrated a 16% false-positive rate of the ajmaline test in right ventricular dysplasia.13,14 (2) Ten controls had complete right bundle branch block, a condition that may mask or hide the type I ECG.15,16 As a result of the small size of the “true control group” (only 35 patients had a normal ECG),8 the 95% confidence intervals for a test showing nil results reaches 8.5%.17 Furthermore, none of the controls had their ECG recording electrodes placed on the third or second intercostal space, which is now common practice. Adding such high electrodes almost doubles the sensitivity of the test18,19 and is unrealistic to expect that such a maneuver would not reduce specificity. Shimizu et al20 performed an intravenous drug challenge with flecainide, disopyramide, and mexiletine in 10 patients http://dx.doi.org/10.1016/j.hrthm.2015.04.017
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with Brugada syndrome and 10 healthy controls. In contrast to mexiletine, which did not cause ST-segment elevation in patients or controls, flecainide, and to a lesser degree disopyramide, caused some degree of ST-segment elevation in both groups. ST-segment elevation was more prominent in patients with Brugada syndrome, who also had more ST-segment elevation at baseline. Nevertheless, ST-segment elevation increased by E1 mm in virtually all controls20; in fact, the mean ST-segment elevation after flecainide injection in controls was 2.2 ⫾ 0.4 mm, a degree that could be counted as “diagnostic of Brugada syndrome” during clinical (uncontrolled) use of the test,21 particularly in less experienced centers. The largest series using genetic results as the criterion standard for determining the specificity of the ajmaline test was published by Hong et al.22 In 71 members of 4 families with an identified SCN5A mutation, the false-positive rate of the ajmaline test was 5.6%, but these results were obtained using only standard precordial electrode placement22; it is likely that higher false-positive rates would be recorded with high electrodes, which is now common practice. In a similar study from Amsterdam including 35 members of families with identified SCN5A mutations,19 24 tested individuals had a positive ajmaline test and the false-positive rate by this criterion was 4%. Here too, because of the small study sample, the 95% confidence intervals of this finding reach 12%, meaning that if a sufficiently large population was studied, up to 12% could end up having a false-positive ajmaline test. In addition, this particular study design (ie, selection of a small number of members within families with identified mutations as the study cohort) led to overestimation of the positive predictive value of the ajmaline test (with inevitable underestimation of its false-positive rate). This is due to that fact that the positive predictive value of any test is predictably magnified by a high disease prevalence,23 which in this study group was 86%, as 30 of the 35 subjects tested had an SCN5A mutation. Finally, accepting an SCN5A mutation as the criterion standard for defining Brugada syndrome during evaluation of a diagnostic test would be considered problematic nowadays. The classical concept of Brugada syndrome as a trait that is controlled by a single locus in an inheritance pattern has now been challenged.24 Accordingly, sodium channel defects may be one of the contributory causes of Brugada syndrome but not necessarily the main one.25 Because of the incertitude surrounding the specificity of the ajmaline test, one should look at the study by Hasdemir et al,26 published in this issue of HeartRhythm, on the high prevalence of “concealed Brugada syndrome” in patients with atrioventricular (AV) nodal reentry tachycardia (AVNRT) with due caution. Hasdemir et al performed the ajmaline test in 96 patients undergoing radiofrequency ablation for typical AVNRT and 66 controls. Their results are intriguing: 27% of patients with AVNRT and 5% of controls developed a type I Brugada ECG in response to the ajmaline challenge. The statistically significant results led the authors to conclude that AVNRT is
Heart Rhythm, Vol 0, No 0, Month 2015 a manifestation of Brugada syndrome and that 1 of 4 patients with AVNRT have concealed Brugada syndrome. As a matter of fact, all these patients with positive ajmaline tests (27% of patients with typical AVNRT) would be defined as patients with asymptomatic Brugada syndrome by present consensus documents. Extrapolation of these results to the general population (as done by the authors) would lead to the conclusion that concealed Brugada syndrome is a disease of pandemic proportions. Thus, before we embrace their conclusions, a critical analysis of the data presented by Hasdemir et al26 is mandatory. First, none of their patients with AVNRT and a positive ajmaline test had clinical clues or family history even remotely suggestive of Brugada syndrome. Second, the ajmaline test protocol used was standard (1 mg/kg infused over 5 minutes), but the continuous ECG included recordings with high electrodes, unquestionably affecting their results. As a matter of fact, 60% of all their ajmaline-induced type I Brugada ECGs were seen only on recordings with high electrodes. Third, the investigators performing and interpreting the test were aware of patient allotting, inevitably creating bias. The importance of this potential bias is best demonstrated by the following fact: Over a decade ago, the group from Milan tested the reproducibility of the flecainide test in 20 patients with Brugada syndrome and found it to be 100%.27 However, and here is the point, in the same study, flecainide was also injected into 25 patients after ablation of AVNRT and none of these patients with AVNRT—this time serving as “controls” instead of “patients”—developed a type I Brugada ECG.27 Even after taking into consideration that flecainide is less sensitive than ajmaline for detecting Brugada syndrome,28 one would expect some patients within the Milan group of patients with AVNRT to have a positive response.27 Finally, genetic testing was performed in only 17 patients: 10 with concealed Brugada syndrome and 7 with previous diagnosis of Brugada syndrome who also had AVNRT.26 Although, in general, the yield of mutation identification in a Brugada syndrome cohort is at most 30%,29 in this cohort it was unexpectedly high (70%)26 and the pathogenicity of the variants reported here could not be demonstrated. Furthermore, the fact that conduction intervals (PR, HV, and QRS) were normal in the present Brugada syndrome cohort, where half the patients (13 of 26) harbored a “mutation” mainly affecting sodium channel function (in 10 of 13), argues against a major role of genes impacting the sodium current because patients with SCN5A-associated Brugada syndrome characteristically have prolonged conduction intervals.30 Unfortunately, genetic screening of the control group was not performed, so the impact of the “genetic background noise”31 cannot be determined. One cannot emphasize enough that the identification of a mutation is not proof for the diagnosis of Brugada syndrome. AVNRT is a common arrhythmia with a characteristically benign long-term prognosis. True, Eckardt et al32 reported that 5 of 35 patients with Brugada syndrome (14%) had AVNRT, but the arrhythmia was induced (during electrophysiological studies) rather than spontaneously recorded in
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Editorial Commentary
3 of the 5. Furthermore, when the same authors expanded their analysis to 115 consecutive patients with Brugada syndrome, the percentage with AVNRT decreased to 7%. When one considers a common disease (AVNRT) and a rare disorder (Brugada syndrome), it is predictable to find patients who have both. Only large population controlled studies can prove if such a “link” exists. This will be difficult to prove because dual AV nodal physiology, the substrate for AVNRT, is present—when sought during electrophysiological studies—in 15% of children33 and 440% of adolescents33 and adults.34 It is nevertheless worth considering a true association between the 2 identities. Almost 10 years ago the Amsterdam group proposed as a potential mechanism of right precordial ST-segment elevation the existence of remnants of AV nodal tissue in the right ventricular outflow tract area.35 These remnants would act as the substrate for slowed conduction in this area.35,36 Hypothetically, altered expression of slow conduction AV nodal tissue (around the AV ring) could provide a more vulnerable substrate for AVNRT and thus could link the 2 entities. The study by Hasdemir et al26 suggests that the specificity of the ajmaline test is not as high as we thought. Not all patients developing QT prolongation after receiving strong potassium channel blockers have a congenital long QT syndrome and it is time to question whether all patients showing a type I Brugada ECG, when challenged with potent sodium channel blockers, indeed have Brugada syndrome. It is also important to emphasize that the test is not risk free. Life-threatening ventricular arrhythmias, including VF that is rarely recurrent or refractory, have been reported in 0.3%,21 1.3%,37 and up to 1.8%38 of patients tested. This small risk of iatrogenic arrhythmias is significant because numerous studies have shown that the long-term risk of spontaneous VF in patients diagnosed with asymptomatic Brugada syndrome by virtue of a positive ajmaline test is small—even if they also have inducible VF during subsequent electrophysiological studies. For example, the multicenter ICD study on Brugada syndrome with the longest available follow-up period11 enrolled 166 asymptomatic patients, including 92 with spontaneous- and 74 with drug-induced type I ECG. After a follow-up period of 7 ⫾ 3 years, 8 patients of the former group (8.6%) but only 4 patients of the latter group (5.4%) had an appropriate ICD intervention. Thus, the average risk for spontaneous VF in patients with asymptomatic Brugada syndrome revealed by a drug challenge test was 0.8% per year, not different from the immediate risk for VF resulting from the diagnostic test itself. This “risk stratification paradox” is of particular consequence for children: On the one hand, children are at particularly high risk of developing ventricular arrhythmias during the ajmaline test. In one series,39 10% of children undergoing the ajmaline test, including 3% of the asymptomatic subgroup, developed on-site VF. On the other hand, none of the children with ajmaline-based diagnosis of Brugada syndrome had spontaneous VF during 7 years of follow-up.39 Even if their longterm risk is low, asymptomatic patients with positive ajmaline
3 tests are left with the knowledge that they have a potentially lethal disease and the provoked emotional stress is not inconsequential, particularly if such patients are then left untreated (a common practice in some experienced centers). Based on all of the above, it is time to pause and think before performing any additional tests with sodium channel blockers before the specificity of the test is clearly defined by large controlled studies.
References 1. Mizusawa Y, Wilde AA. Brugada syndrome. Circ Arrhythm Electrophysiol 2012;5:606–616. 2. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference. Heart Rhythm 2005;2:429–440. 3. Richter S, Sarkozy A, Veltmann C, et al. Variability of the diagnostic ECG pattern in an ICD patient population with Brugada syndrome. J Cardiovasc Electrophysiol 2009;20:69–75. 4. Veltmann C, Papavassiliu T, Konrad T, et al. Insights into the location of type I ECG in patients with Brugada syndrome: correlation of ECG and cardiovascular magnetic resonance imaging. Heart Rhythm 2012;9:414–421. 5. 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. XX:XX–XX. 6. 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. 7. 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;27:1061–1070. 8. Brugada R, Brugada J, Antzelevitch C, 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;101:510–515. 9. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;10:1932–1963. 10. Probst V, Veltmann C, Eckardt L, et al. Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry. Circulation 2010;121:635–643. 11. Sacher F, Probst V, Maury P, et al. Outcome after implantation of a cardioverterdefibrillator in patients with Brugada syndrome: a multicenter study, part 2. Circulation 2013;128:1739–1747. 12. Conte G, Sieira J, Ciconte G, et al. Implantable cardioverter-deibrillator therapy in Brugada syndrome: a 20-year single-center experience. J Am Coll Cardiol 2015;65:879–888. 13. Peters S, Trummel M, Denecke S, Koehler B. Results of ajmaline testing in patients with arrhythmogenic right ventricular dysplasia-cardiomyopathy. Int J Cardiol 2004;95:207–210. 14. Peters S. Arrhythmogenic right ventricular dysplasia-cardiomyopathy and provocable coved-type ST-segment elevation in right precordial leads: clues from long-term follow-up. Europace 2008;10:816–820. 15. Chiale PA, Garro HA, Fernandez PA, Elizari MV. High-degree right bundle branch block obscuring the diagnosis of Brugada electrocardiographic pattern. Heart Rhythm 2012;9:974–976. 16. Baranchuk A, Sicouri S, Elizari MV, Chiale PA. Pause-dependent normalization of ST-segment elevation during the ajmaline test in a patient with Brugada syndrome. Heart Rhythm 2014;11:707–709. 17. Newman TB. If almost nothing goes wrong, is almost everything all right? Interpreting small numerators. J Am Med Assoc 1995;274:1013. 18. Govindan M, Batchvarov VN, Raju H, et al. Utility of high and standard right precordial leads during ajmaline testing for the diagnosis of Brugada syndrome. Heart 2010;96:1904–1908. 19. Meregalli PG, Ruijter JM, Hofman N, Bezzina CR, Wilde AA, Tan HL. Diagnostic value of flecainide testing in unmasking SCN5A-related Brugada syndrome. J Cardiovasc Electrophysiol 2006;17:857–864. 20. Shimizu W, Antzelevitch C, Suyama K, 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;11:1320–1329. 21. Veltmann C, Wolpert C, Sacher F, et al. Response to intravenous ajmaline: a retrospective analysis of 677 ajmaline challenges. Europace 2009;11:1345–1352.
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22. 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;110:3023–3027. 23. Altman DG, Bland JM. Diagnostic tests 2: predictive values. BMJ 1994;309:102. 24. 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. 25. Probst V, Wilde AA, Barc J, et al. SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome. Circ Cardiovasc Genet 2009;2:552–557. 26. Hasdemir C, Payzin S, Kocabas U, et al. High prevalence of concealed Brugada syndrome among patients with atrioventricular nodal reentrant tachycardia. Heart Rhythm 2015. XXXX:XX–XX. 27. Gasparini M, Priori SG, Mantica M, et al. Flecainide test in Brugada syndrome: a reproducible but risky tool. Pacing Clin Electrophysiol 2003;26:338–341. 28. Wolpert C, Echternach C, Veltmann C, et al. Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome. Heart Rhythm 2005;2:254–260. 29. Hofman N, Tan HL, Alders M, et al. Yield of molecular and clinical testing for arrhythmia syndromes: report of 15 years’ experience. Circulation 2013;128: 1513–1521. 30. Smits JP, Eckardt L, Probst V, et al. Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. J Am Coll Cardiol 2002;40:350–356.
Heart Rhythm, Vol 0, No 0, Month 2015 31. Landstrom AP, Ackerman MJ. The Achilles’ heel of cardiovascular genetic testing: distinguishing pathogenic mutations from background genetic noise. Clin Pharmacol Ther 2011;90:496–499. 32. Eckardt L, Kirchhof P, Loh P, et al. Brugada syndrome and supraventricular tachyarrhythmias: a novel association? J Cardiovasc Electrophysiol 2001;12:680–685. 33. Cohen MI, Wieand TS, Rhodes LA, Vetter VL. Electrophysiologic properties of the atrioventricular node in pediatric patients. J Am Coll Cardiol 1997;29:403–407. 34. Farshidi A, Josephson ME, Horowitz LN. Electrophysiologic characteristics of concealed bypass tracts: clinical and electrocardiographic correlates. Am J Cardiol 1978;41:1052–1060. 35. Meregalli PG, Wilde AA, Tan HL. Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more? Cardiovasc Res 2005;67:367–378. 36. Boukens BJ, Christoffels VM, Coronel R, Moorman AF. Developmental basis for electrophysiological heterogeneity in the ventricular and outflow tract myocardium as a substrate for life-threatening ventricular arrhythmias. Circ Res 2009;104:19–31. 37. Rolf S, Bruns HJ, Wichter T, et al. The ajmaline challenge in Brugada syndrome: diagnostic impact, safety, and recommended protocol. Eur Heart J 2003;24:1104–1112. 38. Conte G, Sieira J, Sarkozy A, et al. Life-threatening ventricular arrhythmias during ajmaline challenge in patients with Brugada syndrome: incidence, clinical features, and prognosis. Heart Rhythm 2013;10:1869–1874. 39. Conte G, Dewals W, Sieira J, et al. Drug-induced Brugada syndrome in children: clinical features, device-based management, and long-term follow-up. J Am Coll Cardiol 2014;63:2272–2279.
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