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Prevalence of Type 1 Brugada Electrocardiographic Pattern Evaluated by Twelve-Lead Twenty-Four-Hour Holter Monitoring
Prevalence of Type 1 Brugada Electrocardiographic Pattern Evaluated by Twelve-Lead Twenty-Four-Hour Holter Monitoring Natascia Cerrato, MDa, Carla Giustetto, MDa,*, Elena Gribaudo, MDa, Elena Richiardi, MDb, Lorella Barbonaglia, MDc, Chiara Scrocco, MDa, Domenica Zema, MDa, and Fiorenzo Gaita, MDa Patients with drug-induced type 1 Brugada electrocardiograms (BrECGs) are considered to have good prognosis. Spontaneous type 1 is, instead, considered a risk factor; however, it is probably underestimated because of the BrECG fluctuations. The aim of this study was to analyze, in a large population of patients with Br, the real prevalence of type 1 BrECG using 12-lead 24-hour Holter monitoring (12L-Holter) and its correlation with the time of the day. We recorded 303 12L-Holter in 251 patients. Seventy-five (30%) patients exhibited spontaneous type 1 BrECG at 12-lead ECG (group 1) and 176 (70%) had only druginduced type 1 (group 2). Type 1 BrECG was defined as “persistent” (>85% of the recording), “intermittent” (<85%), or “absent.” In group 1, 12% showed persistent type 1 at 12L-Holter, 57% intermittent type 1%, and 31% never had type 1; in group 2, none had persistent type 1, 20% had intermittent type 1%, and 80% never showed type 1. To evaluate the circadian fluctuations of BrECG, 4 periods in the day were considered. Type 1 BrECG was more frequent between 12-noon and 6 P.M. (52%, p <0.001). In conclusion, in patients with drug-induced type 1, spontaneous type 1 BrECG can be detected more frequently with 12L-Holter than with conventional follow-up with periodic ECGs and this has important implications in the risk stratification. 12L-Holter recording might avoid 20% of the pharmacological challenges with sodium channel blockers, which are not without risks, and should thus be considered as the first screening test, particularly in children or in presence of borderline diagnostic basal ECG. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;115:52e56) Brugada (Br) syndrome is an inherited arrhythmogenic disorder characterized by ST-segment elevation in the right precordial leads and an increased risk of sudden death due to ventricular fibrillation, mostly in young and otherwise healthy adults. There are 2 electrocardiographic patterns: type 1, that is, coved ST-segment elevation 2 mm, followed by a negative T wave in at least 1 right precordial lead and type 2, saddle-back ST elevation.1e5 Type 1 is diagnostic, whereas in type 2, drug test with sodium channel blockers is needed to confirm the diagnosis. The authors agree in considering spontaneous type 1 electrocardiographic pattern (Br electrocardiogram [BrECG]) as a risk factor.6e8 It is, however, likely that type 1 BrECG is underestimated by recording only sporadic 12-lead ECGs, due to the well-known Br electrocardiographic fluctuations.9 a Division of Cardiology, Department of Medical Sciences, Città della Salute e della Scienza Hospital, University of Torino, Torino, Italy; b Division of Cardiology, Gradenigo Hospital, Torino, Italy; and cDivision of Cardiology, Sant’Andrea Hospital, Vercelli, Italy. Manuscript received August 20, 2014; revised manuscript received and accepted October 5, 2014. The authors Drs. Cerrato and Giustetto contributed equally to the study. This work was supported by the PRIN grant, 2010BWY8E9_006, of the Ministero Italiano dell’Istruzione, dell’Università e della Ricerca. See page 55 for disclosure information. *Corresponding author: Tel: (þ39) 347 6004390; fax: (þ39) 011 2366656. E-mail address: [email protected] (C. Giustetto).
0002-9149/14/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.10.007
For this reason, aim of this study was to analyze, in a large population of patients with Br, the prevalence of type-1 BrECG using 12-lead 24-hour Holter monitoring (12L-Holter) and the correlation of type 1 BrECG with the time of the day. Methods Of 684 patients included in the Brugada Registry of the Piedmont region of Italy from 2001 to 2013, we considered in this study 251 patients who underwent 12L-Holter at least once during the follow-up, starting from 2008. All the patients gave their informed consent to the inclusion in the registry. Type 1 Br pattern at baseline ECG was defined as coved-type ST-segment elevation 0.2 mV, followed by a negative T wave1,2 in at least 1 right precordial lead,3 including recordings from the second or third intercostal space (ICS).10 This typical electrocardiographic pattern could be recorded either spontaneously or after Class 1 antiarrhythmic drug challenge (intravenous ajmaline 1 mg/kg in 5 minutes or flecainide 2 mg/kg in 10 minutes).2 The pharmacological test was performed in patients presenting with a saddle-back ST elevation in V1-V21,2 recorded in the standard position or in the second ICS or in the presence of a rounded, wide r’ wave in V1 andV2 and a QRS duration longer in the right precordial leads than in V6.4,5 All the patients signed an informed consent before undergoing the test. Two groups were considered. Group 1 consisted in patients with spontaneous type 1 BrECG before the 12L-Holter. Group 2 included www.ajconline.org
Arrhythmias and Conduction Disturbances/Twelve-Lead Holter Monitoring in Brugada Patients
53
Figure 1. 12L-Holter strip showing spontaneous type 1 at both second and fourth ICS.
Figure 3. BrECG fluctuations throughout the day.
Figure 2. Percentage of patients presenting type 1 Br pattern at 12L-Holter in group 1 (patients with spontaneous type 1 at basal ECG) and group 2 (patients with drug-induced type 1).
patients with only drug-induced type 1 BrECG before the 12L-Holter. Patients were classified as symptomatic if they had a history of aborted sudden death or syncope, otherwise they were considered asymptomatic. In all patients, 12L-Holter was recorded in the right precordial leads both at the fourth and the second ICS during 24-hour periods of ordinary daily life (recording systems: Mortara H12þ High Fidelity [Mortara Instrument Europe S.r.l., Casalecchio di Reno, Bologna, Italy] and Esaote Lifecard CF 12 [Esaote S.p.A., Firenze, Italy] Holter
recorders). V1 and V2 electrodes were attached in the second ICS, V3 and V4 electrodes in the fourth ICS (on the right and left parasternal line), and V5 and V6 in the fifth ICS in their standard position. Before the examination, we recorded a fourth and a second ICS strip during standing and supine positions to evaluate changes in ST-segment morphology related to the position. All 12L-Holter were analyzed independently by 2 cardiologists. The type 1 pattern was searched scrolling the 12L-Holter traces from the beginning to the end. Type 1 Br pattern on 12L-Holter was defined as for 12-lead ECG (Figure 1). The Br electrocardiographic burden was arbitrarily defined as follows: “persistent,” when the type 1 BrECG was present for >85% of the 24-hour Holter recording, “intermittent,” corresponding to a type 1 burden <85% of the recording, “absent,” when type 1 was never recorded. To evaluate the circadian fluctuations of the Br electrocardiographic pattern, we divided the day into 4
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periods: 12 midnight to 6 A.M., 6 A.M. to 12 noon, 12 noon to 6 P.M., and 6 P.M. to 12 midnight. The presence of spontaneous type 1 BrECG on 12L-Holter was compared between symptomatic and asymptomatic patients. Moreover, the correlation with arrhythmic events at follow-up was searched. Arrhythmic events during follow-up were defined as documented sustained (>30 seconds) ventricular arrhythmias or appropriate implantable cardioverter defibrillator shock. Continuous variables are presented as mean SD. Comparisons between groups were performed using the chisquare test (maximum-likelihood chi-square test) for qualitative variables. Comparisons of quantitative variables were carried out with Student t test and nonparametric MannWhitney test for 2 distributions. All probability values were 2-sided, with p <0.05 considered significant. Analyses were performed using SPSS 20 (IBM, Armonk, New York). Results Three hundred and three 12L-Holter were recorded in 251 patients with Br. Mean age was 46 15 years, 72% of the patients were men. Seventy-five patients (30%) exhibited spontaneous type 1 BrECG at basal ECG (group 1); of these, 11 (15%) had previous syncope and 1 aborted sudden death, and the remaining were asymptomatic. One hundred seventysix subjects (70%) had drug-induced type 1 (group 2); 21 (12%) were symptomatic for syncope, and the remaining 154 (88%) were asymptomatic. In group 1, 52 (69%) of 75 patients showed type 1 at 12L-Holter, 43 (57%) had intermittent type 1, 9 (12%) had persistent type 1, and 23 (31%) never had type 1 at 12LHolter (Figure 2). In this latter group, there were 6 patients in whom the type 1 Br pattern at basal ECG had been documented only during fever. In group 2, 35 (20%) of 176 patients developed intermittent type 1 BrECG at 12L-Holter, and in the remaining 80%, type 1 BrECG was never recorded (Figure 2). One patient showed type 1 BrECG both at basal ECG and at 12L-Holter during antidepressant therapy with mirtazapine; he did not show anymore the diagnostic pattern after discontinuation of the therapy. Forty-five (18%) 12L-Holter were recorded in subjects with family history of BrECG. Thirty-seven (82%) belonged to group 2 and 6 (16%) of them exhibited type 1 at 12L-Holter. Type 1 BrECG on 12L-Holter was present in 12 of 33 symptomatic patients (33%) and in 75 of 218 asymptomatic patients (34%; p ¼ NS). Type 1 BrECG was most frequently recorded from 12 noon to 6 P.M. (52%), followed by 6 P.M. to 12 midnight (32%), 6 A.M. to 12 noon (9%), and 12 midnight to 6 A.M. (7%, p <0.001; Figure 3). Mean heart rate was respectively 90 8 beats/min, 82 11 beats/min, 63 13 beats/min, and 69 7 beats/min. Mean heart rate was significantly lower from 12 midnight to 6 A.M. than in the other periods (p <0.001). Thirty-eight subjects had 2 or more 12L-Holter (mean 1.2 Holter per patient); between one 12L-Holter and the other, about 12 months elapsed. The repeated recording allowed identifying the type 1 pattern in other 3 out of 20 subjects (15%) with drug-induced type 1 BrECG, who were negative at the first monitoring. At a mean follow-up of 38 26 months, no patient had arrhythmic events.
Discussion All the studies have reported that the presence of spontaneous type 1 Br electrocardiographic pattern is a risk factor for arrhythmic events at follow-up, whereas druginduced type 1 BrECG identifies subjects with a good prognosis.6e8,11e13 It is also known that the ST-segment morphology in patients with Br exhibits daily fluctuations, so that both diagnosis and risk may be underestimated.9 Indeed, performing only sporadic 12-lead ECGs, a spontaneous intermittent type 1 pattern might never be seen. The strength of this study is the large number of patients with Br with 12L-Holter recordings, compared with the previous studies.14e16 We demonstrate that 12L-Holter monitoring allows to identify, in group 2, at least 20% of subjects with spontaneous type 1 BrECG, who would have been considered at low risk, based on periodic 12-lead ECGs, because of the presence of only drug-induced Br pattern. Increasing further the recording time by repeating 12L-Holter, it is possible to identify the type 1 pattern in another 15% of subjects, who are negative at the first monitoring. Our study confirms the importance of the electrocardiographic recording duration to increase the sensitivity in detecting spontaneous type 1 BrECG and demonstrates that a follow-up with repeated 12L-Holter is better than only periodic ECGs. Considering that the pharmacological test with sodium channel blockers is not without risks,17,18 12L-Holter monitoring might be considered as the first screening test, particularly in children, in presence of a borderline diagnostic basal ECG and in the evaluation of family members of affected subjects, as type 1 BrECG identified at 12L-Holter has the same diagnostic meaning of spontaneous type 1 at basal ECG. Moreover, as a consistent number of patients, who were considered to have only a drug-induced type 1 BrECG, have indeed a spontaneous type 1 pattern, these results indicate the need for a reappraisal of the criteria for risk stratification of the patients with Br. On the contrary, in group 1, 12L-Holter confirms the presence of spontaneous type 1 in 69% of the patients, 57% with intermittent, and 12% with persistent type 1, but in 31% the 12L-Holter does not show the type 1 BrECG in the 24 hours recording time. In particular, the 6 patients who came to the observation for spontaneous type 1 BrECG recorded during fever never exhibited spontaneous type 1 neither at 12L-Holter nor in other 12-lead ECGs recorded during the follow-up. Fever increases sodium channel dysfunction, accelerating the late sodium current inactivation.19 There are a large number of reports documenting the ability of fever to unmask type 1 BrECG in susceptible subjects and also to trigger ventricular arrhythmias.20e22 To date, these are the first data on 12L-Holter monitoring in subjects with fever-induced type 1 BrECG. In our study, we found a significantly higher prevalence of spontaneous type 1 BrECG from 12 noon to 6 P.M. (Figure 3). This might be due to the autonomic variations related to the lunch, which is generally the main meal in our country. It is known that the BrECG can be unmasked by a fast and large meal23 and can also be influenced by glucose intake and insulin plasmatic levels.24 The mean heart rate in the period 12 noon to 6 P.M. was 90 beats/min, higher than
Arrhythmias and Conduction Disturbances/Twelve-Lead Holter Monitoring in Brugada Patients
that recorded in the other 3 periods. Episodes of ventricular fibrillation in Br syndrome are detected significantly more frequently at night (from 6 P.M. to 6 A.M.), particularly during sleep,25 and this has been attributed to the proarrhythmic effect of the increased nocturnal vagal activity. It has also been reported that an enhanced vagal tone can emphasize the type 1 pattern.26,27 The relation between type 1 burden and arrhythmic risk has not been fully established so far. It is possible that the actual level of vagal tone cannot be measured only on the base of the entity of the ST-segment elevation in the right precordial leads16; moreover, other factors, such as bradycardia, ventricular premature beats,26 and poor QT adaptation to lower heart rates28 could favor the onset of ventricular arrhythmias. In our study, it was not possible to highlight a higher incidence of nocturnal arrhythmic events, because no events occurred at follow-up. We did not find a significant difference in the presence of type 1 BrECG at 12L-Holter between symptomatic and asymptomatic patients. At difference, Extramiana et al16 found a greater—although non statistically significant— type 1 burden in symptomatic subjects. One possible explanation for these discordant results could be the different characteristics of our population compared with that of Extramiana et al,16 which was composed by a greater proportion of patients with spontaneous type 1 and symptoms at the diagnosis. Indeed, in our series 12L-Holter was mainly used as a tool to better assess the prognosis of subjects considered at low risk, particularly the asymptomatic or patients with only drug-induced type 1 BrECG. Our results are in line with those of Shimeno et al,14 who also failed to demonstrate a significant difference in the presence and duration of spontaneous type 1 between the 15 symptomatic and the 45 asymptomatic patients. We think that the presence of type 1 BrECG at 12L-Holter in patients with drug-induced type 1 identify a subgroup of patients with an increased arrhythmic risk. However, it is difficult to establish whether these subjects have a risk as high as those with spontaneous type 1 recorded at 12-lead ECG, as the type 1 burden might be much lower in this newly identified group. It has been hypothesized that a persistent type 1 ST-segment elevation may have prognostic implications.29,30 We were unable to confirm this hypothesis, because in our study 8 of the 9 patients with persistent type 1 Br pattern were asymptomatic at presentation and none had symptoms during the follow-up. Disclosures
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The authors have no conflicts of interest to disclose. 1. Wilde AA, Antzelevitch C, Borggrefe M, Brugada J, Brugada R, Brugada P, Corrado D, Hauer RN, Kass RS, Nademanee K, Priori SG, Towbin JA. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation 2002;106:2514e2519. 2. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the second consensus conference. Heart Rhythm 2005;2: 429e440. 3. Richter S, Sarkozy A, Paparella G, Henkens S, Boussy T, Chierchia GB, Brugada R, Brugada J, Brugada P. Number of electrocardiogram leads displaying the diagnostic coved-type pattern in Brugada
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syndrome: a diagnostic consensus criterion to be revised. Eur Heart J 2010;31:1357e1364. Bayes de Luna A, Brugada J, Baranchuk A, Borggrefe M, Breithardt G, Goldwasser D, Lambiase P, Riera AP, Garcia-Niebla J, Pastore C, Oreto G, McKenna W, Zareba W, Brugada R, Brugada P. Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report. J Electrocardiol 2012;45:433e442. Oreto G, Corrado D, Delise P, Fedele F, Gaita F, Gentile F, Giustetto C, Michelucci A, Padeletti L, Priori S. Dubbi del cardiologo davanti ad un elettrocardiogramma che presenta in V1-V3 complessi QRS con onda positiva terminale e sopraslivellamento del segmento ST. Consensus Conference promossa dalla Società Italiana di Cardiologia. G Ital Cardiol 2010;11:3Se22S. Brugada J, Brugada R, Antzelevitch C, Towbin J, Nademanee K, Brugada P. Long-term follow-up of individuals with the electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V(1) to V(3). Circulation 2002;105: 73e78. Priori SG, Napolitano C, Gasparini M, Pappone C, Della Bella P, Giordano U, Bloise R, Giustetto C, De Nardis R, Grillo M, Ronchetti E, Faggiano G, Nastoli J. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation 2002;105: 1342e1347. Eckardt L, Probst V, Smits JP, Bahr ES, Wolpert C, Schimpf R, Wichter T, Boisseau P, Heinecke A, Breithardt G, Borggrefe M, LeMarec H, Böcker D, Wilde AA. Long-term prognosis of individuals with right precordial ST-segment-elevation Brugada syndrome. Circulation 2005;111:257e263. Veltmann C, Schimpf R, Echternach C, Eckardt L, Kuschyk J, Streitner F, Spehl S, Borggrefe M, Wolpert C. A prospective study on spontaneous fluctuations between diagnostic and non-diagnostic ECGs in Brugada syndrome: implication for correct phenotyping and risk stratification. Eur Heart J 2006;27:2544e2552. Miyamoto K, Yokokawa M, Tanaka K, Nagai T, Okamura H, Noda T, Satomi K, Suyama K, Kurita T, Aihara N, Kamakura S, Shimizu W. Diagnostic and prognostic value of a type 1 Brugada electrocardiogram at higher (third or second) V1 to V2 recording in men with Brugada syndrome. Am J Cardiol 2007;99:53e57. Brugada J, Brugada R, Brugada P. Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest. Circulation 2003;108: 3092e3096. Probst V, Veltmann C, Eckardt L, Meregalli PG, Gaita F, Tan HL, Babuty D, Sacher F, Giustetto C, Schulze-Bahr E, Borggrefe M, Haissaguerre M, Mabo P, Le Marec H, Wolpert C, Wilde AA. Longterm prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry. Circulation 2010;121: 635e643. Priori SG, Gasparini M, Napolitano C, Della Bella P, Ottonelli AG, Sassone B, Giordano U, Pappone C, Mascioli G, Rossetti G, De Nardis R, Colombo M. Risk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) registry. J Am Coll Cardiol 2012;59:37e45. 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;20: 1026e1031. Extramiana F, Seitz J, Maison-Blanche P, Badilini F, Haggui A, Takatsuki S, Milliez P, Denjoy I, Cauchemez B, Beaufils P, Leenhardt A. Quantitative assessment of ST segment elevation in Brugada patients. Heart Rhythm 2006;3:1175e1181. Extramiana F, Maison-Blanche P, Badilini F, Messali A, Denjoy I, Leenhardt A. Type 1 electrocardiographic burden is increased in symptomatic patients with Brugada syndrome. J Electrocardiol 2010;43:408e414. Conte G, Sieira J, Sarkozy A, de Asmundis C, Di Giovanni G, Chierchia GB, Ciconte G, Levinstein M, Casado-Arroyo R, Baltogiannis G, Saenen J, Saitoh Y, Pappaert G, Brugada P. Life-threatening ventricular arrhythmias during ajmaline challenge in patients with Brugada syndrome: incidence, clinical features, and prognosis. Heart Rhythm 2013;10:1869e1874. Morita H, Morita ST, Nagase S, Banba K, Nishii N, Tani Y, Watanabe A, Nakamura K, Kusano KF, Emori T, Matsubara H, Hina K, Kita T,
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The American Journal of Cardiology (www.ajconline.org) Ohe T. Ventricular arrhythmia induced by sodium channel blocker in patients with Brugada syndrome. J Am Coll Cardiol 2003;42: 1624e1631. Dumaine R, Towbin J, Brugada P, Vatta M, Nesterenko DV, Nesterenko VV, Brugada J, Brugada R, Antzelevitch C. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res 1999;85: 803e809. Probst V, Denjoy I, Meregalli PG, Amirault JC, Sacher F, Mansourati J, Babuty D, Villain E, Victor J, Schott JJ, Lupoglazoff JM, Mabo P, Veltmann C, Jesel L, Chevalier P, Clur SA, Haissaguerre M, Wolpert C, Le Marec H, Wilde AA. Clinical aspects and prognosis of Brugada syndrome in children. Circulation 2007;115: 2042e2048. Amin AS, Meregalli PG, Bardai A, Wilde AA, Tan HL. Fever increases the risk of cardiac arrest in the Brugada syndrome. Ann Int Med 2008;149:216e218. Adler A, Topaz G, Heller K, Zeltser D, Ohayon T, Rozovski U, Halkin A, Rosso R, Ben-Shachar S, Antzelevitch C, Viskin S. Fever-induced Brugada pattern: how common is it and what does it mean? Heart Rhythm 2013;10:1375e1382. Ikeda T, Abe A, Yusu S, Nakamura K, Ishiguro H, Mera H, Yotsukura M, Yoshino H. The full stomach test as a novel diagnostic technique for identifying patients at risk of Brugada syndrome. J Cardiovasc Electrophysiol 2006;17:602e607.
24. Nishizaki M, Sakurada H, Ashikaga T, Yamawake N, Fujii H, Arita M, Isobe M, Hiraoka M. Effects of glucose-induced insulin secretion on ST segment elevation in the Brugada syndrome. J Cardiovasc Electrophysiol 2003;14:243e249. 25. Matsuo K, Kurita T, Inagaki M, Kakishita M, Aihara N, Shimizu W, Taguchi A, Suyama K, Kamakura S, Shimomura K. The circadian pattern of the development of ventricular fibrillation in patients with Brugada syndrome. Eur Heart J 1999;20:465e470. 26. Yan GX, Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation 1999;100:1660e1666. 27. Mizumaki K, Fujiki A, Tsuneda T, Sakabe M, Nishida K, Sugao M, Inoue H. Vagal activity modulates spontaneous augmentation of ST elevation in the daily life of patients with Brugada syndrome. J Cardiovasc Electrophysiol 2004;15:667e673. 28. Fujiki A, Sugao M, Nishida K, Sakabe M, Tsuneda T, Mizumaki K, Inoue H. Repolarization abnormality in idiopathic ventricular fibrillation: assessment using 24-hour QT-RR and QaT-RR relationships. J Cardiovasc Electrophysiol 2004;15:59e63. 29. Viskin S, Adler A, Rosso R. Brugada burden in Brugada syndrome: the way to go in risk stratification? Heart Rhythm 2013;10:1019e1020. 30. Take Y, Morita H, Wu J, Nagase S, Morita S, Toh N, Nishii N, Nakamura K, Kusano KF, Ohe T, Ito H, Zipes DP. Spontaneous electrocardiogram alterations predict ventricular fibrillation in Brugada syndrome. Heart Rhythm 2011;8:1014e1021.
0002-9149/14/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.10.007
For this reason, aim of this study was to analyze, in a large population of patients with Br, the prevalence of type-1 BrECG using 12-lead 24-hour Holter monitoring (12L-Holter) and the correlation of type 1 BrECG with the time of the day. Methods Of 684 patients included in the Brugada Registry of the Piedmont region of Italy from 2001 to 2013, we considered in this study 251 patients who underwent 12L-Holter at least once during the follow-up, starting from 2008. All the patients gave their informed consent to the inclusion in the registry. Type 1 Br pattern at baseline ECG was defined as coved-type ST-segment elevation 0.2 mV, followed by a negative T wave1,2 in at least 1 right precordial lead,3 including recordings from the second or third intercostal space (ICS).10 This typical electrocardiographic pattern could be recorded either spontaneously or after Class 1 antiarrhythmic drug challenge (intravenous ajmaline 1 mg/kg in 5 minutes or flecainide 2 mg/kg in 10 minutes).2 The pharmacological test was performed in patients presenting with a saddle-back ST elevation in V1-V21,2 recorded in the standard position or in the second ICS or in the presence of a rounded, wide r’ wave in V1 andV2 and a QRS duration longer in the right precordial leads than in V6.4,5 All the patients signed an informed consent before undergoing the test. Two groups were considered. Group 1 consisted in patients with spontaneous type 1 BrECG before the 12L-Holter. Group 2 included www.ajconline.org
Arrhythmias and Conduction Disturbances/Twelve-Lead Holter Monitoring in Brugada Patients
53
Figure 1. 12L-Holter strip showing spontaneous type 1 at both second and fourth ICS.
Figure 3. BrECG fluctuations throughout the day.
Figure 2. Percentage of patients presenting type 1 Br pattern at 12L-Holter in group 1 (patients with spontaneous type 1 at basal ECG) and group 2 (patients with drug-induced type 1).
patients with only drug-induced type 1 BrECG before the 12L-Holter. Patients were classified as symptomatic if they had a history of aborted sudden death or syncope, otherwise they were considered asymptomatic. In all patients, 12L-Holter was recorded in the right precordial leads both at the fourth and the second ICS during 24-hour periods of ordinary daily life (recording systems: Mortara H12þ High Fidelity [Mortara Instrument Europe S.r.l., Casalecchio di Reno, Bologna, Italy] and Esaote Lifecard CF 12 [Esaote S.p.A., Firenze, Italy] Holter
recorders). V1 and V2 electrodes were attached in the second ICS, V3 and V4 electrodes in the fourth ICS (on the right and left parasternal line), and V5 and V6 in the fifth ICS in their standard position. Before the examination, we recorded a fourth and a second ICS strip during standing and supine positions to evaluate changes in ST-segment morphology related to the position. All 12L-Holter were analyzed independently by 2 cardiologists. The type 1 pattern was searched scrolling the 12L-Holter traces from the beginning to the end. Type 1 Br pattern on 12L-Holter was defined as for 12-lead ECG (Figure 1). The Br electrocardiographic burden was arbitrarily defined as follows: “persistent,” when the type 1 BrECG was present for >85% of the 24-hour Holter recording, “intermittent,” corresponding to a type 1 burden <85% of the recording, “absent,” when type 1 was never recorded. To evaluate the circadian fluctuations of the Br electrocardiographic pattern, we divided the day into 4
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The American Journal of Cardiology (www.ajconline.org)
periods: 12 midnight to 6 A.M., 6 A.M. to 12 noon, 12 noon to 6 P.M., and 6 P.M. to 12 midnight. The presence of spontaneous type 1 BrECG on 12L-Holter was compared between symptomatic and asymptomatic patients. Moreover, the correlation with arrhythmic events at follow-up was searched. Arrhythmic events during follow-up were defined as documented sustained (>30 seconds) ventricular arrhythmias or appropriate implantable cardioverter defibrillator shock. Continuous variables are presented as mean SD. Comparisons between groups were performed using the chisquare test (maximum-likelihood chi-square test) for qualitative variables. Comparisons of quantitative variables were carried out with Student t test and nonparametric MannWhitney test for 2 distributions. All probability values were 2-sided, with p <0.05 considered significant. Analyses were performed using SPSS 20 (IBM, Armonk, New York). Results Three hundred and three 12L-Holter were recorded in 251 patients with Br. Mean age was 46 15 years, 72% of the patients were men. Seventy-five patients (30%) exhibited spontaneous type 1 BrECG at basal ECG (group 1); of these, 11 (15%) had previous syncope and 1 aborted sudden death, and the remaining were asymptomatic. One hundred seventysix subjects (70%) had drug-induced type 1 (group 2); 21 (12%) were symptomatic for syncope, and the remaining 154 (88%) were asymptomatic. In group 1, 52 (69%) of 75 patients showed type 1 at 12L-Holter, 43 (57%) had intermittent type 1, 9 (12%) had persistent type 1, and 23 (31%) never had type 1 at 12LHolter (Figure 2). In this latter group, there were 6 patients in whom the type 1 Br pattern at basal ECG had been documented only during fever. In group 2, 35 (20%) of 176 patients developed intermittent type 1 BrECG at 12L-Holter, and in the remaining 80%, type 1 BrECG was never recorded (Figure 2). One patient showed type 1 BrECG both at basal ECG and at 12L-Holter during antidepressant therapy with mirtazapine; he did not show anymore the diagnostic pattern after discontinuation of the therapy. Forty-five (18%) 12L-Holter were recorded in subjects with family history of BrECG. Thirty-seven (82%) belonged to group 2 and 6 (16%) of them exhibited type 1 at 12L-Holter. Type 1 BrECG on 12L-Holter was present in 12 of 33 symptomatic patients (33%) and in 75 of 218 asymptomatic patients (34%; p ¼ NS). Type 1 BrECG was most frequently recorded from 12 noon to 6 P.M. (52%), followed by 6 P.M. to 12 midnight (32%), 6 A.M. to 12 noon (9%), and 12 midnight to 6 A.M. (7%, p <0.001; Figure 3). Mean heart rate was respectively 90 8 beats/min, 82 11 beats/min, 63 13 beats/min, and 69 7 beats/min. Mean heart rate was significantly lower from 12 midnight to 6 A.M. than in the other periods (p <0.001). Thirty-eight subjects had 2 or more 12L-Holter (mean 1.2 Holter per patient); between one 12L-Holter and the other, about 12 months elapsed. The repeated recording allowed identifying the type 1 pattern in other 3 out of 20 subjects (15%) with drug-induced type 1 BrECG, who were negative at the first monitoring. At a mean follow-up of 38 26 months, no patient had arrhythmic events.
Discussion All the studies have reported that the presence of spontaneous type 1 Br electrocardiographic pattern is a risk factor for arrhythmic events at follow-up, whereas druginduced type 1 BrECG identifies subjects with a good prognosis.6e8,11e13 It is also known that the ST-segment morphology in patients with Br exhibits daily fluctuations, so that both diagnosis and risk may be underestimated.9 Indeed, performing only sporadic 12-lead ECGs, a spontaneous intermittent type 1 pattern might never be seen. The strength of this study is the large number of patients with Br with 12L-Holter recordings, compared with the previous studies.14e16 We demonstrate that 12L-Holter monitoring allows to identify, in group 2, at least 20% of subjects with spontaneous type 1 BrECG, who would have been considered at low risk, based on periodic 12-lead ECGs, because of the presence of only drug-induced Br pattern. Increasing further the recording time by repeating 12L-Holter, it is possible to identify the type 1 pattern in another 15% of subjects, who are negative at the first monitoring. Our study confirms the importance of the electrocardiographic recording duration to increase the sensitivity in detecting spontaneous type 1 BrECG and demonstrates that a follow-up with repeated 12L-Holter is better than only periodic ECGs. Considering that the pharmacological test with sodium channel blockers is not without risks,17,18 12L-Holter monitoring might be considered as the first screening test, particularly in children, in presence of a borderline diagnostic basal ECG and in the evaluation of family members of affected subjects, as type 1 BrECG identified at 12L-Holter has the same diagnostic meaning of spontaneous type 1 at basal ECG. Moreover, as a consistent number of patients, who were considered to have only a drug-induced type 1 BrECG, have indeed a spontaneous type 1 pattern, these results indicate the need for a reappraisal of the criteria for risk stratification of the patients with Br. On the contrary, in group 1, 12L-Holter confirms the presence of spontaneous type 1 in 69% of the patients, 57% with intermittent, and 12% with persistent type 1, but in 31% the 12L-Holter does not show the type 1 BrECG in the 24 hours recording time. In particular, the 6 patients who came to the observation for spontaneous type 1 BrECG recorded during fever never exhibited spontaneous type 1 neither at 12L-Holter nor in other 12-lead ECGs recorded during the follow-up. Fever increases sodium channel dysfunction, accelerating the late sodium current inactivation.19 There are a large number of reports documenting the ability of fever to unmask type 1 BrECG in susceptible subjects and also to trigger ventricular arrhythmias.20e22 To date, these are the first data on 12L-Holter monitoring in subjects with fever-induced type 1 BrECG. In our study, we found a significantly higher prevalence of spontaneous type 1 BrECG from 12 noon to 6 P.M. (Figure 3). This might be due to the autonomic variations related to the lunch, which is generally the main meal in our country. It is known that the BrECG can be unmasked by a fast and large meal23 and can also be influenced by glucose intake and insulin plasmatic levels.24 The mean heart rate in the period 12 noon to 6 P.M. was 90 beats/min, higher than
Arrhythmias and Conduction Disturbances/Twelve-Lead Holter Monitoring in Brugada Patients
that recorded in the other 3 periods. Episodes of ventricular fibrillation in Br syndrome are detected significantly more frequently at night (from 6 P.M. to 6 A.M.), particularly during sleep,25 and this has been attributed to the proarrhythmic effect of the increased nocturnal vagal activity. It has also been reported that an enhanced vagal tone can emphasize the type 1 pattern.26,27 The relation between type 1 burden and arrhythmic risk has not been fully established so far. It is possible that the actual level of vagal tone cannot be measured only on the base of the entity of the ST-segment elevation in the right precordial leads16; moreover, other factors, such as bradycardia, ventricular premature beats,26 and poor QT adaptation to lower heart rates28 could favor the onset of ventricular arrhythmias. In our study, it was not possible to highlight a higher incidence of nocturnal arrhythmic events, because no events occurred at follow-up. We did not find a significant difference in the presence of type 1 BrECG at 12L-Holter between symptomatic and asymptomatic patients. At difference, Extramiana et al16 found a greater—although non statistically significant— type 1 burden in symptomatic subjects. One possible explanation for these discordant results could be the different characteristics of our population compared with that of Extramiana et al,16 which was composed by a greater proportion of patients with spontaneous type 1 and symptoms at the diagnosis. Indeed, in our series 12L-Holter was mainly used as a tool to better assess the prognosis of subjects considered at low risk, particularly the asymptomatic or patients with only drug-induced type 1 BrECG. Our results are in line with those of Shimeno et al,14 who also failed to demonstrate a significant difference in the presence and duration of spontaneous type 1 between the 15 symptomatic and the 45 asymptomatic patients. We think that the presence of type 1 BrECG at 12L-Holter in patients with drug-induced type 1 identify a subgroup of patients with an increased arrhythmic risk. However, it is difficult to establish whether these subjects have a risk as high as those with spontaneous type 1 recorded at 12-lead ECG, as the type 1 burden might be much lower in this newly identified group. It has been hypothesized that a persistent type 1 ST-segment elevation may have prognostic implications.29,30 We were unable to confirm this hypothesis, because in our study 8 of the 9 patients with persistent type 1 Br pattern were asymptomatic at presentation and none had symptoms during the follow-up. Disclosures
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