Volume 13, Issue 1, Pages (January 2016)

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Volume 13, Issue 1, Pages 299-310 (January 2016) Risk stratification in Brugada syndrome: Clinical characteristics, electrocardiographic parameters, and auxiliary testing  Arnon Adler, MD, Raphael Rosso, MD, Ehud Chorin, MD, Ofer Havakuk, MD, Charles Antzelevitch, PhD, Sami Viskin, MD  Heart Rhythm  Volume 13, Issue 1, Pages 299-310 (January 2016) DOI: 10.1016/j.hrthm.2015.08.038 Copyright © 2016 Heart Rhythm Society Terms and Conditions

Figure 1 Arrhythmic event rates (ventricular fibrillation or appropriate implantable cardioverter-defibrillator shock) during follow-up in initially asymptomatic patients with spontaneous (A) and drug-induced (B) type I Brugada ECG. Note that in every study, the risk is higher for patients with spontaneous (as opposed to drug-induced) type I ECG (A vs B). Also, note that more recent series show lower event rates. Event rates of the studies by Brugada (1998), Brugada (2003), and Delise (2011) include all asymptomatic patients (both spontaneous and drug-induced type 1 ECG) because the data were not available separately. (Reproduced with permission from Mizusawa Y, Wilde AA. Brugada syndrome. Circ Arrhythm Electrophysiol 2012;5:606–616.) Heart Rhythm 2016 13, 299-310DOI: (10.1016/j.hrthm.2015.08.038) Copyright © 2016 Heart Rhythm Society Terms and Conditions

Figure 2 Importance of QRS fractionation in Brugada syndrome. Examples of fractionated QRS complexes (f-QRS) in 2 patients with Brugada syndrome as defined by Morita et al62 (panel I) and Priori et al24 (panel II). Small arrows point to the QRS fragmentation. Panel I also shows ventricular fibrillation (VF)-free survival curves according to the presence or absence of f-QRS (A), late potentials (LP) (B), SCN5A mutation (C), and VF induced with programmed electrical stimulation (PES) (D) in the study by Morita.62 Panel II shows freedom from arrhythmic events during follow-up according to the presence or absence of (1) syncope, (2) spontaneous vs drug-induced type I ECG, (3) f-QRS, and (4) VF induced during with PES in the study by Priori et al.24 Note that in both studies, f-QRS was superior in distinguishing among patients with and those without arrhythmic events than other risk stratification strategies. (Reproduced with permission from Morita H, Kusano KF, Miura D, et al. Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome. Circulation 2008;118:1697–1704; and Priori SG, Gasparini M, Napolitano C, et al. Risk stratification in Brugada syndrome: results of the PRELUDE [PRogrammed ELectrical stimUlation preDictive valuE] registry. J Am Coll Cardiol 2012;59:37–45.) Heart Rhythm 2016 13, 299-310DOI: (10.1016/j.hrthm.2015.08.038) Copyright © 2016 Heart Rhythm Society Terms and Conditions

Figure 3 A: ECG of one of our patients with Brugada syndrome who has type I ST-segment elevation in leads V1 and aVR as well as ST-segment depression in the inferior leads. B: Type I ST elevation in leads V1–V2 and early repolarization (arrows) with horizontal ST segment in the inferior leads. (Reproduced with permission from Kaneko Y, Horie M, Niwano S, et al. Electrical storm in patients with Brugada syndrome is associated with early repolarization. Circ Arrhythm Electrophysiol 2014;7:1122–1128.) Heart Rhythm 2016 13, 299-310DOI: (10.1016/j.hrthm.2015.08.038) Copyright © 2016 Heart Rhythm Society Terms and Conditions

Figure 4 A: Data from recent large studies,12,13,81 including a total of 781 patients with Brugada syndrome who were asymptomatic at presentation, underwent electrophysiologic study (EPS), and were then followed for 4–5 years. Note the discrepancy between the results reported by Brugada et al (numbers in red) and the results obtained in large multicenter studies. (Modified from Viskin S, Rosso R. Risk of sudden death in asymptomatic Brugada syndrome: not as high as we thought and not as low as we wished...but the contrary. J Am Coll Cardiol 2010;56:1585–1588.) B: Data from recent 5 studies with a total of 512 patients presenting with syncope who underwent EPS and were followed for 3–5 years.11,21,23,88 VF = ventricular fibrillation. Heart Rhythm 2016 13, 299-310DOI: (10.1016/j.hrthm.2015.08.038) Copyright © 2016 Heart Rhythm Society Terms and Conditions

Figure 5 Arrhythmia-free survival curves for patients with Brugada syndrome and no prior cardiac arrest according to different risk stratification strategies. Makimoto et al85 (A, C) and Priori et al24 (B, D) show conflicting results. According to Makimoto et al85 (A), the risk of spontaneous ventricular fibrillation (VF) is higher for patients who had VF induced with single or double (SD) extrastimulation than for patients with VF induced with triple extrastimulation (T) or for patients with no inducible VF (N). In contrast, Priori et al24 (B) show identical survival curves regardless of the number of extrastimuli required for inducing VF during the electrophysiologic study. In the study by Priori et al,24 patients with ventricular refractory period (VRP) <200 ms had higher risk for spontaneous VF (D). In the study by Makimoto et al,85 the event-free survival curve for patients with VF induced with extrastimulation using coupling intervals <200 ms (suggesting a short refractory period) was not different from that of patients who had VF induced with longer coupling interval (C). (Reproduced with permission from 24. Priori SG, Gasparini M, Napolitano C, et al. Risk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) registry. J Am Coll Cardiol 2012;59:37–45; and Makimoto H, Kamakura S, Aihara N, et al. Clinical impact of the number of extrastimuli in programmed electrical stimulation in patients with Brugada type 1 electrocardiogram. Heart Rhythm 2012;9:242–248.) Heart Rhythm 2016 13, 299-310DOI: (10.1016/j.hrthm.2015.08.038) Copyright © 2016 Heart Rhythm Society Terms and Conditions

Figure 6 Prognostic value of combined risk factors in different studies. A: In a study by Okamura et al,54 including 218 patients with no prior cardiac arrest (40% with syncope), the risk factors considered were: a history of syncope, spontaneous type I ECG, and inducible ventricular fibrillation (VF) at electrophysiologic study. The risk increased according to the number of risk factors. B: In the study by Delise et al,51 including 320 patients with no prior cardiac arrest (syncope in 34%), the risk for spontaneous VF among patients with spontaneous type I ECG was higher when ≥2 risk factors were present. The risk factors considered here were familial history of sudden death, history of syncope, and inducible VF. C: In the study by Tokioka et al,50 including 246 patients (with a history of syncope or cardiac arrest in 16% and 5% of patients, respectively), the arrhythmia-free survival curves varied according to the presence or absence of fragmented QRS complexes (f-QRS) and early repolarization (ER) in the inferolateral leads. Heart Rhythm 2016 13, 299-310DOI: (10.1016/j.hrthm.2015.08.038) Copyright © 2016 Heart Rhythm Society Terms and Conditions

Figure 7 Schematic representation of the information available regarding the prognostic value of different tests in Brugada syndrome. “Thumbs up” denotes that a statistically significant association exists between the results of a given test and an arrhythmic event. “Thumbs down” denotes that such an association was tested and proved to be negative. The number of “thumbs” (up and down) denotes the number of studies looking at this association (the maximum number of thumbs per test is 5 even if there were more studies looking at a given test). Note that the figure does not take into consideration the number of patients included in each study or whether or not the predictive value of a given test was independent from other parameters. EPS = electrophysiologic study; VF = ventricular fibrillation. Heart Rhythm 2016 13, 299-310DOI: (10.1016/j.hrthm.2015.08.038) Copyright © 2016 Heart Rhythm Society Terms and Conditions