Author + information
- Received June 5, 2014
- Revision received September 27, 2014
- Accepted October 21, 2014
- Published online January 20, 2015.
- Saagar Mahida, MD∗∗ (, )
- Nicolas Derval, MD∗,
- Frederic Sacher, MD∗,
- Antoine Leenhardt, MD†,
- Isabel Deisenhofer, MD‡,
- Dominique Babuty, MD§,
- Jürg Schläpfer, MD‖,
- Luc de Roy, MD¶,
- Robert Frank, MD#,
- Sinikka Yli-Mayry, MD∗∗,
- Philippe Mabo, MD††,
- Thomas Rostock, MD‡‡,
- Akihiko Nogami, MD§§,
- Jean-Luc Pasquié, MD, PhD‖‖,
- Christian de Chillou, MD, PhD¶¶,
- Josef Kautzner, MD, PhD##,
- Laurence Jesel, MD∗∗∗,
- Philippe Maury, MD†††,
- Benjamin Berte, MD∗,
- Seigo Yamashita, MD, PhD∗,
- Laurent Roten, MD∗,
- Han S. Lim, MBBS, PhD∗,
- Arnaud Denis, MD∗,
- Pierre Bordachar, MD∗,
- Philippe Ritter, MD∗,
- Vincent Probst, MD, PhD‡‡‡,
- Mélèze Hocini, MD∗,
- Pierre Jaïs, MD∗ and
- Michel Haïssaguerre, MD∗
- ∗Hôpital Cardiologique du Haut-Lévêque and Université Victor Segalen Bordeaux II, Bordeaux, France
- †AP-HP, Hôpital Bichat, Service de Cardiologie et Centre de Référence des Maladies Cardiaques Héréditaires, INSERM, U698, Université Paris Diderot, Paris, France
- ‡Deutsches Herzzentrum München, Munich, Germany
- §Centre Hospitalier Universitaire de Tours, Tours, France
- ‖Service de Cardiologie, CHUV, Lausanne, Switzerland
- ¶Clinique Mont Godinne Leuven, Leuven, Belgium
- #Groupe Hospitalier Pitié Salpêtrière, Paris, France
- ∗∗Tampere University Hospital, Tampere, Finland
- ††Centre Hospitalier Universitaire de Rennes, Rennes, France
- ‡‡Eppendorf Hospital, Hamburg, Germany
- §§University of Tsukuba, Tsukuba, Japan
- ‖‖Centre Hospitalier Universitaire de Montpellier, Montpellier, France
- ¶¶Centre Hospitalier Universitaire de Nancy, Nancy, France
- ##Institute for Clinical and Experimental Medicine, Department of Cardiology, Prague, Czech Republic
- ∗∗∗Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France
- †††Centre Hospitalier Universitaire de Toulouse, Toulouse, France
- ‡‡‡Centre Hospitalier Universitaire de Nantes, Nantes, France
- ↵∗Reprint requests and correspondence:
Dr. Saagar Mahida, Service de Rythmologie et Stimulation Cardiaque, Hôpital Cardiologique du Haut-Lévêque, Avenue de Magellan, 33604 Bordeaux-Pessac, France.
Background The early repolarization (ER) pattern is associated with an increased risk of arrhythmogenic sudden death. However, strategies for risk stratification of patients with the ER pattern are not fully defined.
Objectives This study sought to determine the role of electrophysiology studies (EPS) in risk stratification of patients with ER syndrome.
Methods In a multicenter study, 81 patients with ER syndrome (age 36 ± 13 years, 60 males) and aborted sudden death due to ventricular fibrillation (VF) were included. EPS were performed following the index VF episode using a standard protocol. Inducibility was defined by the provocation of sustained VF. Patients were followed up by serial implantable cardioverter-defibrillator interrogations.
Results Despite a recent history of aborted sudden death, VF was inducible in only 18 of 81 (22%) patients. During follow-up of 7.0 ± 4.9 years, 6 of 18 (33%) patients with inducible VF during EPS experienced VF recurrences, whereas 21 of 63 (33%) patients who were noninducible experienced recurrent VF (p = 0.93). VF storm occurred in 3 patients from the inducible VF group and in 4 patients in the noninducible group. VF inducibility was not associated with maximum J-wave amplitude (VF inducible vs. VF noninducible; 0.23 ± 0.11 mV vs. 0.21 ± 0.11 mV; p = 0.42) or J-wave distribution (inferior, odds ratio [OR]: 0.96 [95% confidence interval (CI): 0.33 to 2.81]; p = 0.95; lateral, OR: 1.57 [95% CI: 0.35 to 7.04]; p = 0.56; inferior and lateral, OR: 0.83 [95% CI: 0.27 to 2.55]; p = 0.74), which have previously been demonstrated to predict outcome in patients with an ER pattern.
Conclusions Our findings indicate that current programmed stimulation protocols do not enhance risk stratification in ER syndrome.
The early repolarization (ER) pattern on the surface electrocardiogram (ECG) is characterized by elevation of the J-point, with slurring or notching of the terminal portion of the QRS complex (1). The reported prevalence of the ER pattern in the general population is variable and ranges between 1% and 13% (2–4), with a higher prevalence reported among young patients (5). The ER pattern has traditionally been regarded as a benign ECG variant. However, in recent years, this paradigm has been challenged, and multiple studies have reported that the ER pattern is associated with an increased risk of malignant ventricular arrhythmias and sudden cardiac death (6–9). The presence of an ER pattern on the ECG with otherwise unexplained ventricular arrhythmia is commonly referred to as ER syndrome (10).
Despite the reports linking the ER pattern with sudden cardiac death, the vast majority of patients with the ECG pattern are asymptomatic and have a low arrhythmic risk (11). Identification of the small subset of patients with a high arrhythmic risk represents a significant challenge. To date, much of the research in the field has focused on variants of the ER pattern that confer an increased risk of sudden death. More “malignant” variants of the ER pattern are characterized by widespread distribution of J waves, higher J-wave amplitude, and horizontal or descending ST-segment morphology (3,6,12–15). However, the absolute risk conferred by each of these variants is small, and strategies for risk stratification remain suboptimal. Furthermore, predictors of recurrent arrhythmic events in patients with ER syndrome who have previously experienced aborted sudden death are not known.
The role of electrophysiology studies (EPS) in risk stratification of patients with the ER pattern is currently not defined. In this large, multicenter study, we sought to determine the diagnostic utility of programmed ventricular stimulation in patients with ER syndrome and the potential role of the technique in predicting risk of recurrent ventricular fibrillation (VF) following aborted cardiac arrest.
From February 2007 to February 2014, patients with ER syndrome were recruited into the International Registry of Idiopathic Ventricular Fibrillation from 44 tertiary cardiac centers worldwide (6). Of note, a number of patients recruited at the initiation of the study had previous follow-up data from their respective institutions.
All patients underwent echocardiography to exclude structural cardiac abnormalities. Additional imaging with cardiac magnetic resonance (CMR) imaging or right ventricular angiography was performed in patients in whom echocardiographic imaging was suboptimal. To reduce the probability of selecting patients with subclinical structural heart disease, all patients over the age of 60 years were excluded from the study. Coronary angiography or myocardial perfusion scintigraphy was performed to exclude underlying ischemic heart disease. Provocation testing with class I antiarrhythmic drugs, isoprenaline, or exercise stress testing was performed at the investigating physician’s discretion in patients in whom there was any clinical suspicion of Brugada syndrome (BS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). A diagnosis of idiopathic VF was based on an absence of structural cardiac abnormalities, coronary artery disease, or arrhythmia syndromes such as BS, long or short QT syndromes, and CPVT.
Criteria for inclusion in the study were as follows: 1) presence of ≥0.1 mV of J-point elevation in ≥2 contiguous inferior (II, III, and aVF) and/or lateral leads (I, aVL, and V4 to V6), with the presence of either notching in the S-wave or QRS slurring (Figure 1); 2) a history of aborted sudden cardiac death with documented VF; 3) structurally normal heart as determined by echocardiography, CMR, and/or cardiac catheterization; 4) absence of ECG features suggestive of BS, long or short QT syndromes, or CPVT; and 5) diagnostic EPS with programmed ventricular stimulation performed following the episode of aborted sudden death. The respective institutional review boards at all participating centers approved the study.
An experienced examiner analyzed ECGs. Calipers were used to measure the J-wave amplitude, PR interval, QRS duration, and QT interval. The QT interval was corrected for heart rate using Bazett’s formula. In addition to analysis of the degree of J-point elevation, the ST-segment was characterized. ST-segment analysis was performed in the inferior and/or lateral leads, depending on the distribution of ER. A horizontal or descending ST-segment was described as an ST-segment amplitude ≤0.1 mV relative to the baseline 100 ms after the J-point.
EPS were performed using a standard stimulation protocol. Programmed ventricular stimulation was performed at 2 different right ventricular sites. In all patients, 1, 2, and 3 extrastimuli were used with a minimal coupling interval of 180 to 200 ms (unless ventricular arrhythmia was induced or the ventricular effective refractory period was reached). Inducibility was defined as the provocation of sustained VF requiring external direct current (DC) cardioversion to terminate the arrhythmia. Noninducibility was determined on the basis of an absence of sustained VF with completion of the induction protocol.
Follow-up data were obtained from all participating centers. All patients included in the study underwent insertion of an implantable cardioverter-defibrillator (ICD). Appropriate and inappropriate ICD shocks were documented. During the follow-up period, patients were regarded as having an arrhythmic event if they had an ICD shock due to sustained ventricular arrhythmia or sudden cardiac death.
Data analysis was performed using the PASW Statistics 18 package (version 18.0.0, SPSS Inc., Chicago, Illinois). Continuous variables were expressed as mean ± SD. Kaplan-Meier analysis was performed to estimate freedom from VF. A log-rank test was performed to compare event rates between patients with and without inducible VF. Logistic regression analyses were performed to determine whether VF inducibility during EPS predicted subsequent ICD intervention, whether different baseline J-wave distribution patterns predicted inducibility during EPS, and whether the ST-segment morphology predicted VF inducibility. The Student t test was used to analyze continuous variables. A p value ≤0.05 was considered to be statistically significant.
Clinical characteristics of ER syndrome cohort
Over the past 7 years, 367 patients with idiopathic VF were recruited into the International Registry of Idiopathic Ventricular Fibrillation. Of these patients, 138 had a definitive diagnosis of ER syndrome, and 81 of these ER syndrome patients underwent a diagnostic EPS following the index VF episode (Online Figure 1). All patients underwent a standard programmed ventricular stimulation protocol with minor differences between participating centers.
In the 81 ER syndrome patients included in the study, the mean age at presentation with aborted sudden death due to VF was 36 ± 13 years. Patients were predominantly male (male to female ratio 3:1). Twenty-one patients (26%) had a previous history of unexplained syncope. A family history of sudden cardiac death was present in 18 patients (22%). All patients had structurally normal hearts on echocardiography. Due to suboptimal echocardiographic images, additional imaging with CMR and/or right ventricular angiography was performed in 36 patients (44%) and 25 patients (31%), respectively.
Cardiac catheterization was performed in 76 patients (94%) and demonstrated normal coronary arteries. Six patients (7%) underwent myocardial perfusion scintigraphy, which did not demonstrate evidence of coronary ischemia. In 64 patients (79%) in whom there was any suspicion of BS, ajmaline/flecainide provocation testing was performed to exclude the diagnosis. To exclude catecholaminergic arrhythmias, 62 patients (76%) had either isoprenaline infusion or exercise stress testing. Patient characteristics are summarized in Table 1.
An ECG inclusion criterion of ≥0.1 mV of J-point elevation in contiguous inferior (II, III, and aVF) and/or lateral leads (I, aVL, and V4 to V6) was used in the study. J-point elevation in the inferior leads only was present in 40 patients (49%). J-point elevation in the lateral leads only was present in 12 patients (15%). J-point elevation in both the inferior and lateral leads was present in 29 patients (36%). The maximum J-point elevation was 0.22 ± 0.11 mm. Isolated slurring of the QRS complex was present in 28 patients (35%). Eighteen patients (22%) displayed isolated notching of the J-wave, whereas 35 patients (43%) displayed both slurring and notching. Fifty-five patients (68%) had a horizontal or descending ST-segment morphology, whereas the remaining 32% had an ascending ST-segment. The mean corrected QT interval was 389 ± 26 ms, and QRS duration was 86 ± 11 ms. PR intervals were normal in all patients. J-point characteristics in the ER syndrome cohort are summarized in Table 2.
Despite the fact that all 81 ER syndrome patients had a recent history of aborted sudden death with documented VF, only 18 patients (22%) had inducible VF during programmed stimulation. In all but 3 patients, triple extrastimuli were necessary to induce VF. None of the patients had inducible monomorphic VT. The clinical characteristics of patients with inducible ventricular arrhythmias are summarized in Table 3.
Of the 63 patients who did not have inducible VF, we captured the coupling interval of the spontaneous ventricular ectopic that precipitated VF on the surface ECG (coupling interval 302 ± 72 ms) in 11 patients. Of note, despite delivering premature ventricular extrastimuli with similar or shorter coupling intervals to the spontaneous VF-inducing ectopics, we were unable to induce VF. A representative example of a surface ECG and EPS is included in Figure 2.
There were no significant differences in the maximum J-wave amplitude between patients with inducible VF as compared to those with no inducible VF (VF inducible vs. VF noninducible: 0.23 ± 0.11 mV vs. 0.21 ± 0.11 mV; p = 0.42). J-wave distribution was not associated with VF inducibility (inferior J waves, odds ratio [OR]: 0.96 [95% confidence interval (CI): 0.33 to 2.81]; p = 0.95; lateral J waves, OR: 1.57 [95% CI: 0.35 to 7.04]; p = 0.56; inferior and lateral J waves, OR: 0.83 [95% CI: 0.27 to 2.55]; p = 0.74). ST-segment morphology was also not associated with VF inducibility (OR: 1.3 [95% CI: 0.41 to 4.13]; p = 0.66). Data on baseline HV intervals was available in 59 of 81 ER syndrome patients (73%). None of the patients displayed baseline conduction abnormalities (HV interval 45 ± 7 ms).
All patients underwent ICD implantation following the index VF episode and were followed for 7.0 ± 4.9 years post-ICD implantation. Due to a recurrence of VF, 27 of the 81 patients (33%) had appropriate ICD shocks. The characteristics of individuals with VF-related ICD shocks are included in Table 4. Of these patients, 21 experienced more than 1 shock (range 1 to >100 shocks), 7 experienced VF storms, and sudden death occurred in 2, both of whom had experienced VF storms. The event rates in the ER syndrome cohort are summarized in Online Figure 1. Due either to atrial tachycardias or ICD lead fractures, 10 patients (12%) experienced inappropriate ICD shocks.
As illustrated in the Kaplan-Meier curve in Figure 3, there were no significant differences in event rates between patients who had inducible VF during programmed stimulation and those who were noninducible (log rank p = 0.93) during the follow-up period. Specifically, 6 of the 18 (33%) patients with inducible VF experienced VF-related ICD shocks, whereas 21 of 63 (33%) ER syndrome patients with no inducible VF experienced VF-related ICD shocks. Inducibility of VF was also not a predictor of recurrent arrhythmic events as determined by logistic regression analysis (OR: 1.0 [95% CI: 0.33 to 3.04]; p = 1.00). Overall, the presence of inducible ventricular arrhythmias during programmed stimulation had a sensitivity of 22% and a specificity of 78%. The positive predictive value for recurrent VF was 33%, whereas the negative predictive value was 67%.
Analysis of ER syndrome patients with no EPS
To assess for potential selection bias, clinical characteristics of the patients who underwent EPS were compared with 57 ER syndrome patients who did not undergo EPS from our registry. In 7 patients, there was either insufficient information or the ECGs were not of adequate quality; therefore, these patients were excluded from further analysis. There were no significant differences in clinical and ECG characteristics of the remaining 50 ER syndrome patients who did not have EPS compared with the 81 patients who had EPS (summarized in Online Table 1). Follow-up data were available for 32 of the 50 patients who did not have EPS. As demonstrated in Online Figure 2, there were no differences in event rates between ER syndrome patients with and without EPS. Overall, EP studies were performed at the investigating physician’s discretion, with some variation between centers.
In the present study, we demonstrate that despite a recent history of aborted sudden death secondary to VF, only a small proportion of ER syndrome patients have inducible ventricular arrhythmias during programmed electrical stimulation. Furthermore, inducibility of VF during programmed stimulation does not predict risk of recurrent arrhythmic events during long-term follow-up. VF inducibility is also not correlated with the degree of J-point elevation, the distribution of J waves, or the ST-segment morphology on the surface ECG, all of which are risk factors for ventricular arrhythmia in patients with the ER pattern (3). Taken together, these findings suggest that EPS using current protocols does not have a role in risk stratification and management of patients with ER syndrome (Central Illustration).
The protocols used for programmed ventricular stimulation are designed primarily for induction of ventricular tachycardia and risk stratification in patients with structural heart disease. However, the arrhythmogenic mechanisms underlying VF are distinct. The relevance of inducible VF, especially in the context of structurally normal hearts, is uncertain. Multiple studies have demonstrated that induction of VF during programmed stimulation, even with double extrastimuli, is likely to be a nonclinical response and does not predict risk of recurrent VF episodes (16–18). Furthermore, even in a high-risk subset of patients with inherited VF syndromes such as long and short QT syndrome, VF inducibility has been reported to be a nonclinical response that does not predict future arrhythmic events (19). These reports are consistent with the findings of the present study demonstrating that VF induction is a poor predictor of arrhythmic risk in ER syndrome patients.
ER syndrome demonstrates considerable overlap with BS, and the 2 are commonly collectively referred to as J-wave syndromes (11). The role of programmed stimulation in patients with BS has been the subject of significant interest. Consistent with the findings of the present study, 7 relatively large studies and 2 meta-analyses reported that EPS does not predict outcome in BS (20–28). In contrast, earlier studies from Brugada et al. (29–31) and a series from Guistetto et al. (32) reported that the inducibility of ventricular arrhythmias during EPS is a predictor of adverse outcome. Overall, although there is some controversy regarding the role of EPS in J-wave syndromes, our and other studies indicate that they do not enhance risk stratification. It is important to note, however, that despite similar results in terms of the prognostic value of EPS, VF inducibility rates in BS patients have been reported to be significantly higher (20–23). Specifically, in the aforementioned studies, BS patients undergoing EPS had VF induction rates of between 34% and 66%, which is 2- to 3-fold higher than those observed in the present study. Furthermore, although the majority of ER syndrome patients required triple extrastimuli to induce VF, not uncommonly, BS patients required only 2 extrastimuli. These observations highlight the point that there are significant differences between BS and ER syndrome in terms of the response to programmed stimulation.
From a mechanistic perspective, J-point elevation in ER syndrome patients has been proposed to be a manifestation of augmented transmural repolarization heterogeneity (11,33). Previous studies have demonstrated that VF in ER syndrome patients is triggered by ventricular ectopics with short coupling intervals (6). Therefore, it is likely that VF is initiated by an interaction between triggering premature ventricular beats and a susceptible ventricular substrate, which is prone to transmural re-entry. However, our results demonstrate that programmed delivery of premature ventricular beats fails to induce VF in the majority of high-risk ER syndrome patients, including premature beats delivered at the inferior wall with similar coupling intervals as spontaneous ventricular ectopics that are known to induce VF. These observations suggest that, in addition to short-coupled ventricular ectopics, induction of VF is dependent upon a specific transmural ventricular gradient, which is likely to be dynamic. This point is underscored by the observation that J-point elevation is augmented prior to VF episodes in ER syndrome patients (6). Therefore, during an EPS, which is typically performed days after the spontaneous VF episodes, the substrate is likely to be unfavorable for transmural re-entry. However, at this stage, this proposed mechanism is speculative.
In addition to the previously mentioned findings relating to EPS, an interesting observation in the present study was that ER syndrome patients have a relatively high prevalence of previous syncope. More than one-quarter of the ER syndrome patients in our cohort had a previous history of syncope. This finding further confirms the original observation of Haïssaguerre et al. (6) in a significantly larger cohort of ER syndrome patients. The implication of these observations is that unexplained syncope in patients with an ER pattern, particularly patients with a “malignant variant” of the pattern, may be an important predictor of future arrhythmic events. However, further research is necessary to determine the role of syncope in the context of risk stratification of ER.
We also observed a high familial aggregation of sudden death in our ER syndrome patients. Specifically, one-fifth of ER syndrome patients had a family history of sudden death. These findings are consistent with a number of studies indicating that ER syndrome has a significant heritable component (6,34). The significance of a positive family history for risk stratification is currently not defined. Our findings and those from other studies suggest that family history may also be a mediator of risk. Studies in larger cohorts of symptomatic and asymptomatic patients with the ER pattern are necessary to address this question. Furthermore, genetic studies in ER syndrome cohorts with familial clustering may also identify risk variants underlying the trait.
ER syndrome patients were recruited from multiple centers around the world. Therefore, there was some variation in the investigation of patients following episodes of aborted sudden death. Although all centers used a standard protocol for programmed ventricular stimulation, there were minor methodological differences, which could potentially have introduced bias. Finally, because the study was restricted to patients with previous VF and aborted sudden death, the role of programmed stimulation in asymptomatic patients with the ER pattern is not known. However, on the basis of our findings, programmed stimulation is likely to be of limited value in these patients.
Our findings indicate that current protocols for programmed ventricular stimulation do not have a significant role in risk stratification of ER syndrome patients.
COMPETENCY IN MEDICAL KNOWLEDGE: Among patients with ER syndrome, programmed stimulation does not predict future ventricular arrhythmic events and, therefore, does not improve risk stratification.
TRANSLATIONAL OUTLOOK: It would be necessary to identify novel provocative tests that better identify patients with the ER pattern who are at high risk of arrhythmic sudden death.
In addition to the list of authors, the following physicians have kindly contributed to data collection. From France: Gabriel Laurent, MD (Dijon), Frederic Anselme, MD (Rouen), Pascal Defaye, MD (Grenoble), Dominique Lacroix, MD (Lille), Patrice Scanu, MD (Caen), Paul Bru, MD (La Rochelle), Nicolas Delarche, MD (Pau), Maurice Pornin, MD (Paris), Jean Vidal, MD (Niort), Pascal Chavernac, MD (Castres), Julien Laborderie, MD (Bayonne), and Lacroix Dominique, MD (Lille). From Japan: Nohiriro Komiya, MD (Nagasaki), Yoshifusa Aizawa, MD (Niigata), and Seiichiro Matsuo, MD (Tokyo). From the United Kingdom: Pier Lambiase, MD (London). From Germany: Thomas Arentz, MD (Bad Krozingen). From Italy: Roberto Mantovan, MD (Treviso). From Sweden: Piotr Platonov, MD, PhD (Lund).
For a supplemental table and figures, please see the online version of this article.
This work was supported by a grant from the Programme Hospitalier de Recherche Clinique PROG/09/62. Dr. Kautzner is a member of the advisory board for Biosense Webster, Boston Scientific, Medtronic, St. Jude Medical, GE Healthcare, and Siemens Healthcare; and has received speakers honoraria from Biotronik, Boston Scientific, Biosense Webster, Medtronic, and St. Jude Medical. Dr. Ritter has served as a consultant for Sorin Group and Medtronic. Dr. Haïssaguerre is a stockowner in and consultant to CardioInsight Inc.; and has received lecture fees from Biosense Webster and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- confidence interval
- cardiac magnetic resonance
- catecholaminergic polymorphic ventricular tachycardia
- electrophysiology study/studies
- early repolarization
- implantable cardioverter-defibrillator
- odds ratio
- ventricular fibrillation
- Received June 5, 2014.
- Revision received September 27, 2014.
- Accepted October 21, 2014.
- American College of Cardiology Foundation
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