The prognostic value of early repolarization (J wave) and ST-segment morphology after J wave in Brugada syndrome: Multicenter study in Japan

doi:10.1016/j.hrthm.2012.12.023

Heart Rhythm

Volume 10, Issue 4, April 2013, Pages 533-539

https://doi.org/10.1016/j.hrthm.2012.12.023 Get rights and content

Background

The prognostic value of a J wave and ST-segment morphology after J wave in inferolateral leads in Brugada syndrome (BS) is still unknown.

Objective

To evaluate the prognostic value of a J wave and ST-segment morphology after J wave in a large Japanese cohort of BS.

Methods

A total of 460 consecutive patients with BS (mean age 52±14 years, 432 men) were enrolled. The presence and location of leads showing a J wave, ST-segment morphology after J wave, and clinical outcomes were evaluated in patients with documented ventricular fibrillation (VF) (N = 84), those with syncope without documented VF (N = 109), and subjects without symptoms (N = 267).

Results

The prevalence of a J wave in the inferior and/or lateral leads was 12% (53 cases). The prevalence of a J wave among the 3 groups was not different. The incidence of cardiac events (sudden cardiac death or VF) during a mean follow-up period of 50±32 months was not different in patients with (11%) or without (8%) a J wave. Patients with a J wave in both inferior and lateral leads or with horizontal ST-segment morphology after J wave showed a higher incidence of cardiac events than those without (P = .04 and .02, respectively). Multivariate analysis revealed symptoms, QRS duration in lead V₂>90 ms, and inferolateral J wave and/or horizontal ST-segment morphology after J wave were important for predicting cardiac events.

Conclusion

The presence of a J wave in multiple leads and horizontal ST-segment morphology after J wave may indicate a highly arrhythmogenic substrate in patients with BS.

Introduction

J wave syndrome is suggested to have a certain similarity of cellular and ionic mechanism to Brugada syndrome (BS), which is characterized by J point and ST-segment elevation in leads V₁–V₃ and a high propensity toward sudden cardiac death (SCD).1, 2, 3 Previous studies have examined the prognosis of BS with a J wave in inferolateral leads, but the results were controversial.4, 5, 6 Recently, the presence of a J wave followed by horizontal ST-segment configuration has been reported to be associated with arrhythmic death in a large cohort of a middle-aged general population⁷ and in patients with idiopathic ventricular fibrillation (VF).⁸

The Japan Idiopathic Ventricular Fibrillation Study (J-IVFS) is a multicenter study for a prospective survey started in 2002 with the aim of exploring clinical characteristics, risk stratification, and prospective survival of patients with idiopathic VF including BS. The J-IVFS database was used to investigate the prevalence and prognostic value of the J wave and ST-segment morphology after J wave in inferolateral leads in Japanese patients with BS.

Section snippets

Study population

Consecutive individuals with type 1 BS electrocardiogram (ECG) (n = 460, mean age 52±14 years, 432 men) were enrolled in J-IVFS between February 2002 and January 2011. The patients were probands from 460 different families, followed for a period of greater than 1 year, and meeting the following inclusion criteria: (1) either spontaneous or sodium channel blocker induced type 1 ECG in at least 2 of 3 right precordial leads (V₁–V₃) on resting 12-lead ECG, as previously reported⁹; (2) the absence

Clinical profile of patients

Of the 460 enrolled patients, a family history of SCD was noted in 107 cases (23%), past documented history of AF in 64 cases (14%), and spontaneous type 1 BS ECG in 290 cases (63%).

The clinical, electrocardiographic, and electrophysiologic characteristics of patients for the 3 groups are presented in Table 1. Male predominance and incidence of a history of paroxysmal AF were higher in the VF group than in the syncope and As groups. There were no differences among the 3 groups in age,

Discussion

The present study is the largest survey of patients with BS in Japan. Our series is large and indeed representative of the patient population of BS because incidences in most clinical parameters were similar to those in previous studies.12, 13, 14 This suggests that our findings are applicable to the patient population with BS.

Our findings indicated that symptomatic patients with VF or syncope had higher recurrence rates of cardiac events than did As individuals, which were similar to the

Conclusions

This largest survey of Japanese patients with BS demonstrated that symptoms, QRS duration in lead V₂>90 ms, and inferolateral J wave and/or horizontal ST segment were associated with cardiac events by multivariate analysis. The location of J waves in the inferior and lateral leads and horizontal ST-segment morphology after J wave may be related to a highly arrhythmogenic substrate in patients with BS.

Appendix

The following executive committee participated in the J-IVFS: Tachikawa Medical Center, Nagaoka: Y. Aizawa; Nippon Medical School Tama Nagayama Hospital, Tama: H. Atarashi; University of Toyama, Toyama: H. Inoue; The Sakakibara Heart Institute of Okayama, Okayama: T. Ohe; International University of Health and Welfare, Mita Hospital, Tokyo: S. Ogawa; Hirosaki University School of Medicine, Hirosaki: K. Okumura; Tokyo Women’s Medical University, Tokyo: H. Kasanuki; National Cerebral and

Acknowledgment

The authors thank Prof Jonathan C. Makielski for his support to edit our manuscript.

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Numerous studies have demonstrated that a type I Brugada electrocardiographic (ECG) pattern, history of syncope, prior sudden cardiac arrest, and previously documented ventricular tachyarrhythmias are still insufficient to stratify the risk of sudden cardiac death in Brugada syndrome (BrS). Several auxiliary risk stratification parameters are pursued to yield a better prognostic model. Our aim was to assess the association between several ECG markers (wide QRS, fragmented QRS, S-wave in lead I, aVR sign, early repolarization pattern in inferolateral leads, and repolarization dispersion pattern) with the risk of developing poor outcomes in BrS. A systematic literature search from several databases was conducted from database inception until August 17th, 2022. Studies were eligible if it investigated the relationship between the ECG markers with the likelihood of acquiring major arrhythmic events (MAE). This meta-analysis comprised 27 studies with a total of 6552 participants. Our study revealed that wide QRS, fragmented QRS, S-wave in lead I, aVR sign, early repolarization pattern in inferolateral leads, and repolarization dispersion ECG pattern were associated with the incremental risk of syncope, ventricular tachyarrhythmias, implantable cardioverter-defibrillator shock, and sudden cardiac death in the future, with the risk ratios ranging from 1.41 to 2.00. Moreover, diagnostic test accuracy meta-analysis indicated that the repolarization dispersion ECG pattern had the highest overall area under curve (AUC) value amid other ECG markers regarding our outcomes of interest. A multivariable risk assessment approach based on the prior mentioned ECG markers potentially improves the current risk stratification models in BrS patients.
Brugada Syndrome as a Major Cause of Sudden Cardiac Death in Asians
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Brugada syndrome (BrS) is one of the main inherited arrhythmia syndromes causing ventricular fibrillation (VF) and sudden cardiac death in young to middle-aged men, especially in Asians. The diagnosis of BrS is based on spontaneous or drug-provoked type 1 Brugada electrocardiogram. The current reliable therapy for BrS patients with VF history is the implantation of an implantable cardioverter-defibrillator. As for BrS patients without VF history, how asymptomatic BrS patients should effectively be treated is still uncertain because risk stratification of the BrS is still inadequate. Various parameters and combinations of several parameters have been reported for risk stratification of BrS. The SCN5A gene is believed to be the only gene that is responsible for BrS, and it has been reported to be useful for risk stratification. This review focuses on risk stratification of BrS patients, and focuses specifically on BrS patients of Asian descent.
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Citation Excerpt :
Aside from resuscitated cardiac arrest, the clinical factors that have the greatest impact on SAEs in patients with BrS are a history of cardiogenic syncope and the presence of a spontaneous type 1 ECG, which is validated in both pediatric and adult cohorts (Table 3).85,86,123,124 Consistent evidence from multiple studies have found that a history of cardiogenic syncope results in a 2.5-5x relative risk for SAEs even when adjusting for other factors.125-132 In a pooled analysis of prospective studies involving 1,312 patients, Sroubek et al67 found that patients with BrS and syncope had a 2.5% annual incidence of SAEs compared with 0.7% for those who did not have syncope.
Brugada syndrome (BrS) is an “inherited” condition characterized by predisposition to syncope and cardiac arrest, predominantly during sleep. The prevalence is ∼1:2,000, and is more commonly diagnosed in young to middle-aged males, although patient sex does not appear to impact prognosis. Despite the perception of BrS being an inherited arrhythmia syndrome, most cases are not associated with a single causative gene variant. Electrocardiogram (ECG) findings support variable extent of depolarization and repolarization changes, with coved ST-segment elevation ≥2 mm and a negative T-wave in the right precordial leads. These ECG changes are often intermittent, and may be provoked by fever or sodium channel blocker challenge. Growing evidence from cardiac imaging, epicardial ablation, and pathology studies suggests the presence of an epicardial arrhythmic substrate within the right ventricular outflow tract. Risk stratification aims to identify those who are at increased risk of sudden cardiac death, with well-established factors being the presence of spontaneous ECG changes and a history of cardiac arrest or cardiogenic syncope. Current management involves conservative measures in asymptomatic patients, including fever management and drug avoidance. Symptomatic patients typically undergo implantable cardioverter defibrillator insertion, with quinidine and epicardial ablation used for patients with recurrent arrhythmia. This review summarizes our current understanding of BrS and provides clinicians with a practical approach to diagnosis and management.
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The utility of late potentials on signal-averaged electrocardiography (SAECG) for risk stratification in patients with Brugada syndrome (BrS) remains controversial. Late potentials on conventional SAECG with Frank leads may be insufficiently sensitive to detect site-specific late potentials in right precordial leads.
The purpose of this study was to evaluate the utility of site-specific late potentials using a novel unipolar Holter-SAECG system for risk stratification in patients with BrS.
Consecutive symptomatic (n = 20) and asymptomatic (n = 21) patients with BrS who underwent investigation using conventional SAECG and a novel unipolar Holter-SAECG system were enrolled. We evaluated clinical characteristics and outcomes and compared late potentials on the 2 SAECGs between both groups and patients with and without cardiac events (CEs) (sudden cardiac death or sustained ventricular tachyarrhythmias) during the follow-up period.
During mean follow-up of 76 months, 10 patients (24%) had CEs. There were no significant differences in late potentials on conventional SAECG between symptomatic and asymptomatic patients. On the Holter-SAECG system, RMS40 in lead V₂ in the third intercostal space (3L-V₂) at the nighttime was significantly lower in the symptomatic group than in the asymptomatic group (5.5 ± 0.8 μV and 8.2 ± 0.8 μV, respectively; P = .027). Univariate analysis of predictive values for CE showed that hazard ratios of daytime and nighttime RMS40 in lead 3L-V₂ of <7.7 μV and <6.1 μV were 7.58 and 6.14, respectively.
Site-specific late potentials in lead 3L-V₂ measured using the novel Holter-SAECG system may be a useful marker for high-risk patients with BrS.
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PAR syncope and a spontaneous type 1 Brugada ECG pattern remain independent predictors of VA/SCD compatible with the findings of numerous BrS studies (2,6,17–19). Interestingly, the presence of ER and a type 1 Brugada ECG pattern in peripheral leads, which has previously only been assessed in a few studies, were shown to be independent predictors of VA/SCD in this cohort (12,20–22). This study is the first, to the best of our knowledge, that assessed all 16 proposed risk factors in a single study; others have only assessed the role of <10 proposed risk factors (2,17,18,23).
The goal of this study was to develop a risk score model for patients with Brugada syndrome (BrS).
Risk stratification in BrS is a significant challenge due to the low event rates and conflicting evidence.
A multicenter international cohort of patients with BrS and no previous cardiac arrest was used to evaluate the role of 16 proposed clinical or electrocardiogram (ECG) markers in predicting ventricular arrhythmias (VAs)/sudden cardiac death (SCD) during follow-up. Predictive markers were incorporated into a risk score model, and this model was validated by using out-of-sample cross-validation.
A total of 1,110 patients with BrS from 16 centers in 8 countries were included (mean age 51.8 ± 13.6 years; 71.8% male). Median follow-up was 5.33 years; 114 patients had VA/SCD (10.3%) with an annual event rate of 1.5%. Of the 16 proposed risk factors, probable arrhythmia–related syncope (hazard ratio [HR]: 3.71; p < 0.001), spontaneous type 1 ECG (HR: 3.80; p < 0.001), early repolarization (HR: 3.42; p < 0.001), and a type 1 Brugada ECG pattern in peripheral leads (HR: 2.33; p < 0.001) were associated with a higher risk of VA/SCD. A risk score model incorporating these factors revealed a sensitivity of 71.2% (95% confidence interval: 61.5% to 84.6%) and a specificity of 80.2% (95% confidence interval: 75.7% to 82.3%) in predicting VA/SCD at 5 years. Calibration plots showed a mean prediction error of 1.2%. The model was effectively validated by using out-of-sample cross-validation according to country.
This multicenter study identified 4 risk factors for VA/SCD in a primary prevention BrS population. A risk score model was generated to quantify risk of VA/SCD in BrS and inform implantable cardioverter-defibrillator prescription.
The role of clinical assessment and electrophysiology study in Brugada syndrome patients with syncope
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Cardiogenic syncope in Brugada syndrome (BrS) increases the risk of major events. Nevertheless, clinical differentiation between cardiogenic and vasovagal syncope can be challenging. We characterized the long-term incidence of major events in a large cohort of BrS patients who presented with syncope.
From a total of 474 patients, syncope was the initial manifestation in 135 (28.5%) individuals (43.9 ± 13.9 years, 71.1% male). The syncope was classified prospectively as cardiogenic, vasovagal, or undefined if unclear characteristics were present. Clinical, electrocardiographic, genetic, and electrophysiologic features were analyzed. Cardiogenic syncope, sustained ventricular arrhythmias, and sudden death were considered major events in follow-up.
In 66 patients (48.9%), the syncope was cardiogenic; in 51 (37.8%), vasovagal and in 18 (13.3%); undefined. The electrophysiology study (EPS) inducibility was more frequent in patients with cardiogenic syncope and absent in all patients with undefined syncope (28 [53.8%] vs 5 [12.2%] vs 0 [0%]; P < .01). During follow-up (7.7 ± 5.6 years), only patients with cardiogenic syncope presented major events (16 [11.9%]). Among patients with inducible EPS, 7 (21.2%) presented major events (P = .04). The negative predictive value of the EPS for major events was 92.4%. The incidence rate of major events was 2.6% person-year. Parameters associated with major events included cardiogenic syncope (hazard ratio [HR] 6.3; 95% CI 1.1-10.4; P = .05), spontaneous type 1 electrocardiogram (HR 3.7; 95% CI 1.3-10.5; P = .01), and inducible EPS (HR 2.8; 95% CI 1.1-8.8; P = .05).
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The prognostic value of early repolarization (J wave) and ST-segment morphology after J wave in Brugada syndrome: Multicenter study in Japan

Background

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Study population

Clinical profile of patients

Discussion

Conclusions

Appendix

Acknowledgment

J Electrocardiol

J Electrocardiol

Heart Rhythm

Heart Rhythm

J Am Coll Cardiol

Heart Rhythm

Heart Rhythm

J Am Coll Cardiol

J Mol Cell Cardiol

Genetic, molecular and cellular mechanisms underlying the J wave syndromes

Circ J