Tsukasa Kamakura

Significance of Non-Type 1 Anterior Early Repolarization in Patients With Inferolateral Early Repolarization Syndrome

OBJECTIVES The aim of this study was to investigate the significance of non-type 1 anterior early repolarization (NT1-AER) combined with inferolateral early repolarization syndrome (ERS). BACKGROUND Inferolateral ERS might be a heterogeneous entity, although it excludes type 1 Brugada syndrome (BS). METHODS Of 84 patients with spontaneous ventricular fibrillation, 31 ERS patients were divided into 2 groups. The ERS(A)-group consisted of inferolateral ER and NT1-AER--that is, notching or slurring with J-wave ≥ 1 mm at the end of QRS to early ST segment in any of V1 to V3 leads, in which the ST-T segment did not change to a coved pattern in the standard and high costal (second and third) electrocardiographic recordings even after drug provocation tests (n = 12). The other, ERS(B)-group, showed only inferolateral ER (n = 19). Clinical characteristics and outcomes were compared between the ERS groups, 40 patients with type-1 BS (BS-group), and 13 patients with idiopathic ventricular fibrillation lacking J-wave (IVF-group). RESULTS Ventricular fibrillation occurred during sleep or near sleep in 10 of 12 patients in ERS(A)-group and in 22 of 40 patients in BS-group but in 2 of 19 patients in ERS(B)-group and in 1 of 13 patients in IVF-group (ERS[A] vs. ERS[B], p < 0.0001). Ventricular fibrillation recurrence was significantly higher in ERS(A)-group (58%), particularly in patients with J waves in the high lateral lead, and BS-group (55%), compared with ERS(B)-group (11%) and IVF-group (15%) (ERS[A] vs. ERS[B], p = 0.012). CONCLUSIONS Inferolateral ERS comprises heterogeneous ER subtypes with and without NT1-AER. Coexistence of NT1-AER was a key predictor of poor outcome in patients with ERS.

Risk stratification in patients with brugada syndrome without previous cardiac arrest – Prognostic value of combined risk factors

BACKGROUND Risk stratification in patients with Brugada syndrome for primary prevention of sudden cardiac death is still an unsettled issue. A recent consensus statement suggested the indication of implantable cardioverter defibrillator (ICD) depending on the clinical risk factors present (spontaneous type 1 Brugada electrocardiogram (ECG) [Sp1], history of syncope [syncope], and ventricular fibrillation during programmed electrical stimulation [PES+]). The indication of ICD for the majority of patients, however, remains unclear. METHODS AND RESULTS A total of 218 consecutive patients (211 male; aged 46 ± 13 years) with a type 1 Brugada ECG without a history of cardiac arrest who underwent evaluation for ICD including electrophysiological testing were examined retrospectively. During a mean follow-up period of 78 months, 26 patients (12%) developed arrhythmic events. On Kaplan-Meier analysis patients with each of Sp1, syncope, or PES+ suffered arrhythmic events more frequently (P=0.018, P<0.001, and P=0.003, respectively). On multivariate analysis Sp1 and syncope were independent predictors of arrhythmic events. When dividing patients according to the number of these 3 risk factors present, patients with 2 or 3 risk factors experienced arrhythmic events more frequently than those with 0 or 1 risk factor (23/93 vs. 3/125; P<0.001). CONCLUSIONS Syncope, Sp1, and PES+ are important risk factors and the combination of these risks well stratify the risk of later arrhythmic events.

Monomorphic ventricular tachycardia in patients with Brugada syndrome: A multicenter retrospective study

BACKGROUND Isolated cases of monomorphic ventricular tachycardia (MVT) in patients with Brugada syndrome (BrS) have been reported. OBJECTIVE We aimed to describe the incidence and characteristics of MVT in a cohort of patients with BrS who had received an implantable cardioverter-defibrillator (ICD). METHODS Data from 834 patients with BrS implanted with an ICD in 15 tertiary hospitals between 1993 and 2014 were included. RESULTS The mean age of enrolled patients was 45.3 ± 13.9 years; 200 patients (24%) were women. During a mean follow-up of 69.4 ± 54.3 months, 114 patients (13.7%) experienced at least 1 appropriate ICD intervention, with MVT recorded in 35 patients (4.2%) (sensitive to antitachycardia pacing in 15 [42.8%]). Only QRS width was an independent predictor of MVT in the overall population. Specifically, 6 (17.1%) patients presented with right ventricular outflow tract tachycardia (successfully ablated from the endocardium in 4 and epicardial and endocardial ablation in 1), 2 patients with MVT arising from the left ventricle (1 successfully ablated in the supra lateral mitral annulus), and 2 (5.7%) patients with bundle branch reentry ventricular tachycardia. Significant structural heart disease was ruled out by echocardiography and/or cardiac magnetic resonance imaging. CONCLUSION In this retrospective study, 4.2% of patients with BrS implanted with an ICD presented with MVT confirmed as arising from the right ventricular outflow tract tachycardia in 6, patients with MVT arising from the left ventricle in 2, and patients with bundle branch reentry ventricular tachycardia in 2. Endocardial and/or epicardial ablation was successful in 80% of these cases. These data imply that the occurrence of MVT should not rule out the possibility of BrS. This finding may also be relevant for ICD model selection and programming.

Evaluation of the Necessity for Cardioverter-Defibrillator Implantation in Elderly Patients With Brugada Syndrome

Background—The clinical characteristics and prognosis of elderly patients with Brugada syndrome (BrS) are largely unknown. The purpose of this study was to evaluate the risks and benefits of implantable cardioverter defibrillator (ICD) in elderly patients with BrS based on a long follow-up. Methods and Results—A total of 120 BrS patients with ICD (90 for aborted sudden cardiac arrest or syncope, mean age, 46.6±12.2 years; 50 with age ≥60 years at the last follow-up) were included in this study. During 102±68 months of follow-up, 31 patients (26%) experienced appropriate shocks. Age at the first attack of ventricular fibrillation (VF) was <70 years in all patients (mean, 45.0±12.1 years), the incidence of VF decreased with age, and VF did not recur after 70 years of age except in 2 patients with ischemic heart disease. Eleven of 28 patients with supraventricular tachycardia experienced inappropriate shocks. These inappropriate shocks increased with age and reached a peak in patients who were in their sixties. Lead failures occurred in later stages after implantation in 10 of 120 patients (8%). Conclusions—Long-term follow-up of high-risk BrS patients with ICD showed a low incidence of VF in those aged >70 years. Considering the increasing risk of inappropriate shocks because of the relatively late onset of supraventricular tachycardia and lead failures, avoidance of ICD implantation, or replacement may be considered in elderly BrS patients who remain free from VF until 70 years of age.

Patient-specific Human Induced Pluripotent Stem Cell Model Assessed with Electrical Pacing Validates S107 as a Potential Therapeutic Agent for Catecholaminergic Polymorphic Ventricular Tachycardia

Introduction Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. However, it is not invariably successful to recapitulate the disease phenotype because of the immaturity of hiPSC-derived cardiomyocytes (hiPSC-CMs). The purpose of this study was to establish and analyze iPSC-based model of catecholaminergic polymorphic ventricular tachycardia (CPVT), which is characterized by adrenergically mediated lethal arrhythmias, more precisely using electrical pacing that could promote the development of new pharmacotherapies. Method and Results We generated hiPSCs from a 37-year-old CPVT patient and differentiated them into cardiomyocytes. Under spontaneous beating conditions, no significant difference was found in the timing irregularity of spontaneous Ca2+ transients between control- and CPVT-hiPSC-CMs. Using Ca2+ imaging at 1 Hz electrical field stimulation, isoproterenol induced an abnormal diastolic Ca2+ increase more frequently in CPVT- than in control-hiPSC-CMs (control 12% vs. CPVT 43%, p<0.05). Action potential recordings of spontaneous beating hiPSC-CMs revealed no significant difference in the frequency of delayed afterdepolarizations (DADs) between control and CPVT cells. After isoproterenol application with pacing at 1 Hz, 87.5% of CPVT-hiPSC-CMs developed DADs, compared to 30% of control-hiPSC-CMs (p<0.05). Pre-incubation with 10 μM S107, which stabilizes the closed state of the ryanodine receptor 2, significantly decreased the percentage of CPVT-hiPSC-CMs presenting DADs to 25% (p<0.05). Conclusions We recapitulated the electrophysiological features of CPVT-derived hiPSC-CMs using electrical pacing. The development of DADs in the presence of isoproterenol was significantly suppressed by S107. Our model provides a promising platform to study disease mechanisms and screen drugs.

Significance of electrocardiogram recording in high intercostal spaces in patients with early repolarization syndrome

AIMS Published reports regarding inferolateral early repolarization (ER) syndrome (ERS) before 2013 possibly included patients with Brugada-pattern electrocardiogram (BrP-ECG) recorded only in the high intercostal spaces (HICS). We investigated the significance of HICS ECG recording in ERS patients. METHODS AND RESULTS Fifty-six patients showing inferolateral ER in the standard ECG and spontaneous ventricular fibrillation (VF) not linked to structural heart disease underwent drug provocation tests by sodium channel blockade with right precordial ECG (V1-V3) recording in the 2nd-4th intercostal spaces. The prevalence and long-term outcome of ERS patients with and without BrP-ECG in HICS were investigated. After 18 patients showing type 1 BrP-ECG in the standard ECG were excluded, 38 patients (34 males, mean age; 40.4 ± 13.6 years) were classified into four groups [group A (n = 6;16%):patients with ER and type 1 BrP-ECG only in HICS, group B (n = 5;13%):ERS with non-type 1 BrP-ECG only in HICS, group C (n = 8;21%):ERS with non-type 1 BrP-ECG in the standard ECG, and group D (n = 19;50%):ERS only, spontaneously or after drug provocation test]. During follow-up of 110.0 ± 55.4 months, the rate of VF recurrence including electrical storm was significantly higher in groups A (4/6:67%), B (4/5:80%), and C (4/8:50%) compared with D (2/19:11%) (A, B, and C vs. D, P < 0.05). CONCLUSIONS Approximately 30% of the patients with ERS who had been diagnosed with the previous criteria showed BrP-ECG only in HICS. Ventricular fibrillation mostly recurred in patients showing BrP-ECG in any precordial lead including HICS; these comprised 50% of the ERS cohort.

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Associated With Ryanodine Receptor (RyR2) Gene Mutations – Long-Term Prognosis After Initiation of Medical Treatment –

BACKGROUND The long-term prognosis of cardiac ryanodine receptor (RyR2) positive catecholaminergic polymorphic ventricular tachycardia (CPVT) patients after initiation of medical therapy has not been well investigated. This study aimed to assess the recurrence of fatal cardiac event after initiation of medical therapy inRyR2-positive CPVT patients. METHODSANDRESULTS Thirty-fourRyR2-positive CPVT patients with a history of cardiac events were enrolled. All patients had medical treatment initiated after the first symptom or diagnosis. Exercise stress tests (ESTs) were performed to evaluate the efficacy of the medical therapy. Even after the initiation of medical therapy, high-risk ventricular arrhythmias (VAs), including premature ventricular contraction couplets, bigeminy, and ventricular tachycardia, were still induced in the majority of patients (80.6%). During 7.4 years of follow-up after the diagnosis, 7 of the 34 (20.6%) patients developed fatal cardiac events. Among those 7 patients, 6 (85.7%) were not compliant with either exercise restriction or medication therapy at the time of the events. CONCLUSIONS Even after initiation of medical treatment, high-risk VAs were induced during EST in mostRyR2-positive CPVT patients. Most fatal recurrent cardiac events occurred in patients who were noncompliant with exercise restriction and/or medical therapy. Medical management including strict exercise restriction should be emphasized to prevent recurrent cardiac event in mostRyR2-positive CPVT patients. (Circ J 2016; 80: 1907-1915).

T-Wave Oversensing in Patients With Brugada Syndrome: True Bipolar Versus Integrated Bipolar Implantable Cardioverter Defibrillator Leads Multicenter Retrospective Study

Background—It is thought that dedicated bipolar are more susceptible to T-wave oversensing when compared with integrated bipolar leads. This could be of extreme importance in patients with Brugada syndrome (BrS) because T-wave oversensing in this population is more frequent when compared with other implantable cardioverter defibrillator (ICD) recipients without BrS. We aimed to compare the incidence of T-wave oversensing in patients with BrS according to the type of lead (integrated bipolar versus true/dedicated bipolar). Methods and Results—All patients diagnosed with BrS with an ICD implant in 10 tertiary hospitals between 1993 and 2013 were included in the study. A total of 480 patients were included (mean age, 45.6±14 years). During a mean follow-up of 74.9±51.7 months (median, 69; range, 2–236), 28 patients had T-wave oversensing (5.8%), leading to inappropriate shock in 18 (3.8%). All these events occurred in patients with true bipolar ICD leads (P=0.01) and in 2 patients it was solved instantaneously by changing the configuration from a dedicated to an integrated bipolar sensing configuration. In the stepwise multivariate models, only integrated bipolar ICD leads (hazard ratio, 0.34; 95% confidence interval, 0.171–0.675; P=0.002) was independent predictor of non–T-wave oversensing. Conclusions—T-wave oversensing is a potential reason of inappropriate shocks in patients with BrS receiving ICDs. In the vast majority it can be solved by reprogramming. However, in some patients it still requires invasive intervention. Importantly, incidence is significantly lower using an integrated bipolar lead system when compared with a dedicated bipolar lead system and hence the latter should be routinely used in BrS cases.

T-Wave Oversensing in Patients with Brugada Syndrome - True Bipolar Versus Integrated Bipolar ICD Leads: A Multicenter Retrospective Study

Background—It is thought that dedicated bipolar are more susceptible to T-wave oversensing when compared with integrated bipolar leads. This could be of extreme importance in patients with Brugada syndrome (BrS) because T-wave oversensing in this population is more frequent when compared with other implantable cardioverter defibrillator (ICD) recipients without BrS. We aimed to compare the incidence of T-wave oversensing in patients with BrS according to the type of lead (integrated bipolar versus true/dedicated bipolar). Methods and Results—All patients diagnosed with BrS with an ICD implant in 10 tertiary hospitals between 1993 and 2013 were included in the study. A total of 480 patients were included (mean age, 45.6±14 years). During a mean follow-up of 74.9±51.7 months (median, 69; range, 2–236), 28 patients had T-wave oversensing (5.8%), leading to inappropriate shock in 18 (3.8%). All these events occurred in patients with true bipolar ICD leads (P=0.01) and in 2 patients it was solved instantaneously by changing the configuration from a dedicated to an integrated bipolar sensing configuration. In the stepwise multivariate models, only integrated bipolar ICD leads (hazard ratio, 0.34; 95% confidence interval, 0.171–0.675; P=0.002) was independent predictor of non–T-wave oversensing. Conclusions—T-wave oversensing is a potential reason of inappropriate shocks in patients with BrS receiving ICDs. In the vast majority it can be solved by reprogramming. However, in some patients it still requires invasive intervention. Importantly, incidence is significantly lower using an integrated bipolar lead system when compared with a dedicated bipolar lead system and hence the latter should be routinely used in BrS cases.

Age of First Arrhythmic Event in Brugada Syndrome: Data From the SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) in 678 Patients

Background Data on the age at first arrhythmic event (AE) in Brugada syndrome are from limited patient cohorts. The aim of this study is 2-fold: (1) to define the age at first AE in a large cohort of patients with Brugada syndrome, and (2) to assess the influence of the mode of AE documentation, sex, and ethnicity on the age at first AE. Methods and Results A survey of 23 centers from 10 Western and 4 Asian countries gathered data from 678 patients with Brugada syndrome (91.3% men) with first AE documented at time of aborted cardiac arrest (group A, n=426) or after prophylactic implantable cardioverter–defibrillator implantation (group B, n=252). The vast majority (94.2%) of the patients were 16 to 70 years old at the time of AE, whereas pediatric (<16 years) and elderly patients (>70 years) comprised 4.3% and 1.5%, respectively. Peak AE rate occurred between 38 and 48 years (mean, 41.9±14.8; range, 0.27–84 years). Group A patients were younger than in Group B by a mean of 6.7 years (46.1±13.2 versus 39.4±15.0 years; P<0.001). In adult patients (≥16 years), women experienced AE 6.5 years later than men (P=0.003). Whites and Asians exhibited their AE at the same median age (43 years). Conclusions SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) presents the first analysis on the age distribution of AE in Brugada syndrome, suggesting 2 age cutoffs (16 and 70 years) that might be important for decision-making. It also allows gaining insights on the influence of mode of arrhythmia documentation, patient sex, and ethnic origin on the age at AE.