Late life-threatening arrhythmia in patients with Brugada syndrome: Results from long-term follow-up in a large Japanese cohort.

INTRODUCTION: Most patients with Brugada syndrome (BrS) are first diagnosed in their 40s, with sudden cardiac death (SCD) often occurring in their 50s. Ventricular fibrillation (VF) may occur in some patients with BrS despite having been asymptomatic for a long period. This study aimed to assess the incidence and risk factors for late life-threatening arrhythmias in patients with BrS. METHODS: Patients with BrS (n = 523; mean age, 51 ± 13 years; male, n = 497) were enrolled. The risk of late life-threatening arrhythmia was investigated in 225 patients who had experienced no cardiac events (CEs: SCD or ventricular tachyarrhythmia) for at least 10 years after study enrollment. The incidence of CEs during the follow-up period was examined. RESULTS: During the follow-up of the 523 patients, 59 (11%) experienced CEs. The annual incidences of CEs were 2.87%, 0.77%, and 0.09% from study enrollment to 3, 3-10, and after 10 years, respectively. Among 225 patients who had experienced no CEs for at least 10 years after enrollment, four patients (1.8%) subsequently experienced CEs. Kaplan-Meier analysis revealed significant differences in the incidence of late CEs between patients with and without a history of symptoms (p = .032). The positive and negative predictive values of late CEs for the programmed electrical stimulation (PES) test were 2.9% and 100%, respectively. CONCLUSION: Our results suggest that patients with BrS who are asymptomatic and have no ventricular tachycardia/VF inducibility by PES are at extremely low risk of experiencing late life-threatening arrhythmias.

A multicenter prospective randomized study comparing the incidence of periprocedural cerebral embolisms caused by catheter ablation of atrial fibrillation between cryoballoon and radiofrequency ablation (Embo-Abl study): Study design.

BACKGROUND: Although catheter ablation (CA) has become a standard therapeutic approach to atrial fibrillation (AF), it imposes a low but relevant risk of thromboembolic complications of around 0.5%-1%, including ischemic strokes, and has an additional risk of clinically silent cerebral embolisms (SCEs) of 10%-40%. Both cryoballoon (CB) and radiofrequency (RF) ablation are routinely used clinically worldwide, yet there are few prospective data comparing the incidence of cerebral embolism after CA of AF between CB and RF ablation. METHODS: The aim of the Embo-Abl study will be to compare the incidence of cerebral embolisms on 3 T diffusion-weighted image magnetic resonance imaging (MRI) after CA of AF between CB and RF ablation in patients with AF in a prospective, multicenter, open-label, controlled, randomized fashion. The primary endpoint of the Embo-Abl study will be the occurrence of MRI-detected SCE 1-3 days after CA. The patients will be registered and randomly assigned to either the CB or RF ablation group in a 1:1 ratio. The study cohort will include 230 patients with AF from a multicenter in Japan. RESULTS: The results of this study are currently under investigation. CONCLUSION: The Embo-Abl study will be the first to compare the incidence of periprocedural cerebral embolisms caused by CA of AF between CB and RF ablation in a prospective, multicenter, randomized, controlled fashion.

Analysis of site-specific late potentials using a novel Holter signal-averaged electrocardiography in patients with Brugada syndrome.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Genotype-Phenotype Correlation of SCN5A Genotype in Patients With Brugada Syndrome and Arrhythmic Events: Insights From the SABRUS in 392 Probands.

BACKGROUND: Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene, SCN5A. However, genetic studies of patients with BrS with arrhythmic events have been limited. We sought to compare various clinical, ECG, and electrophysiological parameters according to SCN5A genotype in a large cohort of BrS probands with first arrhythmic event. METHODS: Survey on Arrhythmic Events in Brugada Syndrome is a survey of 10 Western and 4 Asian countries, gathering 678 patients with BrS with first arrhythmic event. Only probands were included, and SCN5A genotype adjudicated. Patients without appropriate genetic data were excluded. Associations of genotype with clinical features were analyzed. RESULTS: The study group comprised 392 probands: 92 (23.5%) SCN5A+(44 pathogenic/likely pathogenic [P/LP] and 48 variants of unknown significance) and 300 (76.5%) SCN5A-.SCN5A missense variants and the patients hosting them were similar regardless of adjudication. A higher proportion of patients with P/LP were pediatric (<16 years) compared with SCN5A- (11.4% versus 3%, P=0.023). The proportion of females was higher among patients with P/LP compared with SCN5A- (18.2% versus 6.3%, P=0.013). P/LP probands were more likely to have a family history of sudden cardiac death compared with SCN5A- (41.9% versus 16.8%, P<0.001). A higher proportion of patients with P/LP were White compared with SCN5A- (87.5% versus 47%, P<0.001). Ethnicity (odds ratio, 5.41 [2.8-11.19], P<0.001) and family history of sudden cardiac death (odds ratio, 2.73 [1.28-5.82], P=0.009) were independent variables associated with P/LP genotype following logistic regression. CONCLUSIONS: The genetic basis of BrS has a complex relationship with gender, ethnicity, and age. Probands hosting a P/LP variant tended to experience their first arrhythmic event at a younger age and to have events triggered by fever compared with patients with SCN5A-. In addition, they were more likely to be White and to have family history of sudden cardiac death. Among females, a P/LP variant suggests an increased risk of being symptomatic. This association should be further studied on an ethnically specific basis in large prospectively collected international cohorts.

Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome.

AIMS: The prognostic value of genetic variants for predicting lethal arrhythmic events (LAEs) in Brugada syndrome (BrS) remains controversial. We investigated whether the functional curation of SCN5A variations improves prognostic predictability. METHODS AND RESULTS: Using a heterologous expression system and whole-cell patch clamping, we functionally characterized 22 variants of unknown significance (VUSs) among 55 SCN5A mutations previously curated using in silico prediction algorithms in the Japanese BrS registry (n = 415). According to the loss-of-function (LOF) properties, SCN5A mutation carriers (n = 60) were divided into two groups: LOF-SCN5A mutations and non-LOF SCN5A variations. Functionally proven LOF-SCN5A mutation carriers (n = 45) showed significantly severer electrocardiographic conduction abnormalities and worse prognosis associated with earlier manifestations of LAEs (7.9%/year) than in silico algorithm-predicted SCN5A carriers (5.1%/year) or all BrS probands (2.5%/year). Notably, non-LOF SCN5A variation carriers (n = 15) exhibited no LAEs during the follow-up period. Multivariate analysis demonstrated that only LOF-SCN5A mutations and a history of aborted cardiac arrest were significant predictors of LAEs. Gene-based association studies using whole-exome sequencing data on another independent SCN5A mutation-negative BrS cohort (n = 288) showed no significant enrichment of rare variants in 16 985 genes including 22 non-SCN5A BrS-associated genes as compared with controls (n = 372). Furthermore, rare variations of non-SCN5A BrS-associated genes did not affect LAE-free survival curves. CONCLUSION: In vitro functional validation is key to classifying the pathogenicity of SCN5A VUSs and for risk stratification of genetic predictors of LAEs. Functionally proven LOF-SCN5A mutations are genetic burdens of sudden death in BrS, but evidence for other BrS-associated genes is elusive.

Reassessment of practical usage and accumulation of real-world data of wearable cardioverter defibrillator (WCD) in Japan-Design paper for J-WCDR study.

Although implantable cardioverter defibrillators (ICDs) are a powerful preventive therapy for cardiac sudden death, there are some populations in whom ICDs cannot be applied because of a lack of a definitive indication (grey-zone patients), such as in patients during the acute phase of cardiac injury with a susceptible risk for lethal arrhythmias. In such patients, wearable cardioverter defibrillators (WCDs) provide safer bridging period during the acute phase until the final decision-making for the ICD use and it may eliminate any inappropriate overuse of ICDs in the subacute phase. The JCS/JHRS practical guidelines provide the criteria for WCD use in Japan. Nevertheless, the evidence for that is totally limited in Japan and is dependent on the accumulation of actual real-world data from other countries in order to be able to discuss the appropriate criteria for WCD use. This study will be conducted retrospectively and/or prospectively, and is an observational and multicenter study among Japanese institutions (J-WCDR, Japan WCD Registry). This will provide evidence for WCD use in our own country and contribute to upcoming updates for the future guideline revisions.

Long-term prognosis in patients with non-type 1 Brugada electrocardiogram: Results from a large Japanese cohort of idiopathic ventricular fibrillation.

BACKGROUND: Brugada syndrome (BrS) is diagnosed in patients with ST-segment elevation with spontaneous, drug-induced, or fever-induced type 1 morphology. Prognosis in type 2 or 3 Brugada electrocardiogram (Br-ECG) patients remains unknown. The purpose of this study is to evaluate long-term prognosis in non-type 1 Br-ECG patients in a large Japanese cohort of idiopathic ventricular fibrillation (The Japan Idiopathic Ventricular Fibrillation Study [J-IVFS]). METHODS: From 567 patients with Br-ECG in J-IVFS, a total of 28 consecutive non-type 1 patients who underwent programmed electrical stimulation (PES) (median age: 58 years, all male, previous sustained ventricular tachyarrhythmias [VTs] 1, syncope 11, asymptomatic 16) were enrolled. Cardiac events (CEs: sudden cardiac death or sustained VT/ventricular fibrillation) during the follow-up period were examined. RESULTS: During a median follow-up of 136 months, four patients (14%) had CEs. None of patients with PES- have experienced CEs. There was no statistically significant clinical risk factor for the development of CEs. Using the Kaplan-Meier method, the event-free rate significantly decreased in a group with all 3 risk factors (symptom, wide QRS complex in lead V2 , and positive PES) (p = .01). CONCLUSIONS: Our study revealed long-term prognosis in patients with non-type 1 Br-ECG. The combination analysis of these risk factors may be useful for the risk stratification of CEs in non-type 1 Br-ECG patients. The present study suggests that the patients with all these parameters showed high risk for CEs and need to be carefully followed.

Risk stratification in asymptomatic patients with Brugada syndrome: Utility of multiple risk factor combination rather than programmed electrical stimulation.

BACKGROUND: The prognostic value of programmed electrical stimulation (PES) in Brugada syndrome (BrS) remains controversial. Asymptomatic BrS patients generally have a better prognosis than those with symptoms. The purpose of this study was to evaluate the value of nonaggressive PES with up to two extra stimuli and predict clinical factors for risk stratification in asymptomatic BrS patients. METHODS: The study enrolled 193 consecutive asymptomatic BrS patients with type 1 ECG (mean age: 50 ± 13 years, 180 males) who underwent PES using a nonaggressive uniform protocol. Cardiac events (CEs: sudden cardiac death or ventricular tachyarrhythmia) during the follow-up period were examined. RESULTS: During a mean follow-up of 101 ± 48 months, seven asymptomatic patients (3.6%) had a CE. The incidence of CEs was not different between patients with and without inducible ventricular tachyarrhythmia by PES (p = .51). The clinical significance of risk factor combinations, including spontaneous type 1 ECG, family history of sudden cardiac death, QRS duration in lead V2 , and presence of J wave, was evaluated. Using the Kaplan-Meier method according to the number of risk factors, the prevalence of CE in patients with three or four risk factors was determined to be significantly higher than in those with one risk factor (p = .02 and p = .004, respectively). CONCLUSIONS: The present study suggests that inducibility of ventricular tachyarrhythmia does not predict future CEs in asymptomatic BrS patients. Combination analysis of the other four clinical risk parameters may be effective for risk assessment.

A multicenter study comparing the outcome of catheter ablation of atrial fibrillation between cryoballoon and radiofrequency ablation in patients with heart failure (CRABL-HF): Study design.

BACKGROUND: Catheter ablation of atrial fibrillation (AF) is increasingly performed worldwide in patients with heart failure (HF). However, it has been recently emphasized that AF ablation in patients with HF is associated with increased risks of procedure-related complications and mortality. There are little data about the differences in the efficacy and safety between cryoballoon (CB) and radiofrequency (RF) ablation of AF in patients with HF. METHODS: The CRABL-HF study is designed as a prospective, multicenter, open-label, controlled, and randomized clinical trial comparing the efficacy and safety of AF ablation between CB and RF ablation in patients with HF (LVEF ≤40%) (UMIN Clinical Trials Registry UMIN000032433). The CRABL-HF study will consist of 110 patients at multicenter in Japan. The patients will be registered and randomly assigned to either the CB ablation or RF ablation group with a 1:1 allocation. The primary endpoint of this study is the occurrence of atrial tachyarrhythmias (ATs) at 1 year with a blanking period of 90 days after ablation. Key secondary endpoints are the success rate of the pulmonary vein isolation, total procedural time, left atrial dwelling time, total fluoroscopy time, radiation exposure, complication rate, composite of all-cause mortality or HF hospitalizations, cardiovascular events, change in left ventricular ejection fraction, and change in quality of life. RESULTS: The results of this study are currently under investigation. CONCLUSION: The CRABL-HF study is being conducted to compare the efficacy and safety of catheter ablation of AF between CB and RF ablation in patients with HF.

Ethnic differences in patients with Brugada syndrome and arrhythmic events: New insights from Survey on Arrhythmic Events in Brugada Syndrome.

BACKGROUND: There is limited information on ethnic differences between patients with Brugada syndrome (BrS) and arrhythmic events (AEs). OBJECTIVE: The purpose of this study was to compare clinical, electrocardiographic (ECG), electrophysiological, and genetic characteristics between white and Asian patients with BrS and AEs. METHODS: The Survey on Arrhythmic Events in Brugada Syndrome is a multicenter survey from Western and Asian countries, gathering 678 patients with BrS and first documented AE. After excluding patients with other (n = 14 [2.1%]) or unknown (n = 30 [4.4%]) ethnicity, 364 (53.7%) whites and 270 (39.8%) Asians comprised the study group. RESULTS: There was no difference in AE age onset (41.3 ± 16.1 years in whites vs 43.3 ± 12.3 years in Asians; P = .285). Higher proportions of whites were observed in pediatric and elderly populations. Asians were predominantly men (98.1% vs 85.7% in whites; P < .001) and frequently presented with aborted cardiac arrest (71.1% vs 56%; P < .001). Asians tended to display more spontaneous type 1 BrS-ECG pattern (71.5% vs 64.3%; P = .068). A family history of sudden cardiac death was noted more in whites (29.1% vs 11.5%; P < .001), with a higher rate of SCN5A mutation carriers (40.1% vs 13.2% in Asians; P < .001), as well as more fever-related AEs (8.5% vs 2.9%; P = .011). No difference was observed between the 2 groups regarding history of syncope and ventricular arrhythmia inducibility. CONCLUSION: There are important differences between Asian and white patients with BrS. Asian patients present almost exclusively as male adults, more often with aborted cardiac arrest and spontaneous type 1 BrS-ECG. However, they have less family history of sudden cardiac death and markedly lower SCN5A mutation rates. The striking difference in SCN5A mutation rates should be tested in future studies.

Characterization and Management of Arrhythmic Events in Young Patients With Brugada Syndrome.

BACKGROUND: Information on young patients with Brugada syndrome (BrS) and arrhythmic events (AEs) is limited. OBJECTIVES: The purpose of this study was to describe their characteristics and management as well as risk factors for AE recurrence. METHODS: A total of 57 patients (age ≤20 years), all with BrS and AEs, were divided into pediatric (age ≤12 years; n = 26) and adolescents (age 13 to 20 years; n = 31). RESULTS: Patients' median age at time of first AE was 14 years, with a majority of males (74%), Caucasians (70%), and probands (79%) who presented as aborted cardiac arrest (84%). A significant proportion of patients (28%) exhibited fever-related AE. Family history of sudden cardiac death (SCD), prior syncope, spontaneous type 1 Brugada electrocardiogram (ECG), inducible ventricular fibrillation at electrophysiological study, and SCN5A mutations were present in 26%, 49%, 65%, 28%, and 58% of patients, respectively. The pediatric group differed from the adolescents, with a greater proportion of females, Caucasians, fever-related AEs, and spontaneous type-1 ECG. During follow-up, 68% of pediatric and 64% of adolescents had recurrent AE, with median time of 9.9 and 27.0 months, respectively. Approximately one-third of recurrent AEs occurred on quinidine therapy, and among the pediatric group, 60% of recurrent AEs were fever-related. Risk factors for recurrent AE included sinus node dysfunction, atrial arrhythmias, intraventricular conduction delay, or large S-wave on ECG lead I in the pediatric group and the presence of SCN5A mutation among adolescents. CONCLUSIONS: Young BrS patients with AE represent a very arrhythmogenic group. Current management after first arrhythmia episode is associated with high recurrence rate. Alternative therapies, besides defibrillator implantation, should be considered.

The unstable pacing thresholds of the leadless transcatheter pacemaker affected by body positions in subacute phase after implant.

BACKGROUND: If the threshold at implant of leadless transcatheter pacemakers (LTPs) is less than 2.0 V, pacing thresholds reportedly decrease significantly by 1 month and maintain an optimal value of less than 1.0 V by 6 months. CASE SUMMARY: We report a case series of two patients with unstable pacing thresholds of the LTPs in the subacute phase after implant. The first patient (77-year-old man) was implanted an LTP for sick sinus syndrome. At that time of implant, the pacing threshold was 0.9 V at 0.24 ms. At 1 week and 1 month later, the threshold had increased to more than 2.0 V at 0.24 ms. We investigated the trend data for the week and found variations in the threshold. The second patient (81-year-old man) was implanted an LTP for bradycardia and atrial fibrillation. The pacing threshold at implantation was 0.63 V at 0.24 ms. One week later, the threshold had increased in supine position and decreased in sitting position. The trend data for the week were fluctuating greatly. DISCUSSION: The pacing threshold may increase to more than 2.0 V with significant fluctuation on assessment at 1 week and 1 month after implantation in association with changes in body position, even though we confirmed a stable threshold at implant. If an increased threshold is observed, it is necessary to check the trend data and threshold in each body position.

A Decision Tree-Based Survival Analysis of Patients with a History of Inappropriate Implantable Cardioverter-Defibrillator Therapy.

Implantable cardioverter-defibrillators (ICDs) improve survival in patients who are at risk of sudden death. However, inappropriate therapy is commonly given to ICD recipients, and this situation may be associated with an increased risk of death. This study aimed to construct a risk stratification scheme by using decision tree analysis in patients who received inappropriate ICD therapy.Mortality was calculated from a retrospective data analysis of a multicenter cohort involving 417 ICD recipients. Inappropriate therapy was defined as therapy for nonventricular arrhythmias, including sinus tachycardia, supraventricular tachycardia, atrial fibrillation/flutter, oversensing, and lead failure. Inappropriate therapy included antitachycardia pacing, cardioversion, and defibrillation. The prognostic factors were identified by a Cox proportional hazards regression analysis, and we constructed a decision tree.During an average follow-up of 5.2 years, 48 patients (12%) had all-cause death. A multivariate Cox hazard model revealed that the age (hazard ratio [HR] 1.06, P < 0.001), ln B-type natriuretic peptide (BNP) (HR 1.47, P = 0.02), nonsinus rhythm at implantation (HR 2.70, P < 0.05), and inappropriate therapy occurring during sedentary/awake conditions (HR 3.51, P = 0.001) correlated with an increased risk of mortality. An inappropriate therapy due to abnormal sensing (HR 0.16, P = 0.04) decreased the risk of mortality. Furthermore, a decision tree analysis stratified the patients well by using 4 covariates: BNP, activity at the time of inappropriate therapy, mechanism of inappropriate therapy, and baseline rhythm at ICD implantation (log-rank test, P < 0.0001).We identified the predictors of mortality in inappropriate ICD therapy recipients and constructed a risk stratification scheme by using decision tree analysis.

Multicenter Study of the Validity of Additional Freeze Cycles for Cryoballoon Ablation in Patients With Paroxysmal Atrial Fibrillation: The AD-Balloon Study.

BACKGROUND: Pulmonary vein isolation (PVI) is a cornerstone of catheter ablation in patients with paroxysmal atrial fibrillation, and balloon-based ablation has been recently performed worldwide. The second-generation cryoballoon (CB2) ablation has proven to be highly effective in achieving freedom from paroxysmal atrial fibrillation. However, there are some debatable questions, including the ideal number of freeze cycles. METHODS: The AD-Balloon study (Multicenter Study of the Validity of Additional Freeze Cycles for Cryoballoon Ablation) was designed as a prospective, multicenter, and randomized clinical trial for investigation of the optimal strategy of freeze cycles for the CB2 ablation. One hundred and ten consecutive patients (aged 64±11 years) were randomly assigned to 2 groups after achieving a PVI by the CB2 ablation: 3-minute freeze cycles were added to each pulmonary vein (AD group: n=55) or not (non-AD group: n=55). Delayed-enhancement magnetic resonance imaging was also performed 1 to 2 months after the PVI to assess the ablation lesions. RESULTS: The patient characteristics did not differ between the 2 groups. A complete PVI was achieved in all patients. The total number of freeze cycles and durations for all pulmonary veins were significantly shorter in the non-AD group than in the AD group (5.7±1.6 versus 9.1±1.6 cycles, P<0.0001, and 932±244 versus 1483±252 seconds, P<0.0001). The cumulative freedom from any atrial tachyarrhythmia at 1 year was 87.3% in the AD group and 89.1% in the non-AD group (log-rank test P=0.78). There was no significant difference in the frequency of gaps on the PVI lines in the delayed-enhancement magnetic resonance imaging (46% in the AD group versus 36% in the non-AD group; P=0.38). CONCLUSIONS: No benefit was found in the patients receiving additional 3-minute freeze cycles after the complete PVI with the CB2 ablation, suggesting that an insurance freeze after achieving a PVI with the CB2 may be unnecessary and time consuming.

Prognostic factors for long-term outcomes in acute decompensated heart failure patients under tolvaptan treatment.

Inconsistent results have been reported concerning the effect of tolvaptan treatment on long-term prognostic outcomes in patients with acute decompensated heart failure (ADHF) and data are limited on prognostic factors affecting this patient population. We investigated prognostic factors influencing long-term clinical outcomes in patients with ADHF treated with tolvaptan in a real-world setting. A total of 263 consecutive patients hospitalized for ADHF and treated with tolvaptan were retrospectively enrolled. The patients were stratified into those who developed the combined event of cardiac death or rehospitalization for worsening heart failure within 1 year (n = 108) and those who were free of this combined event within 1 year (n = 155). Adjusted multivariate Cox proportional hazards model revealed that change in serum sodium level between pre-treatment and 24 h after tolvaptan administration [hazard ratio (HR) 0.913, 95% confidence interval (CI) 0.841-0.989, p = 0.025] and the time taken for tolvaptan initiation from admission (HR 1.043, 95% CI 1.009-1.074, p = 0.015) were independent predictors of combined event occurrence within 1 year. Moreover, change in serum sodium level > 1 mEq/L between pre-treatment and 24 h after administration and initiation of tolvaptan < 5 days after admission correlated significantly with the incidence of the combined event (log-rank test p = 0.003 and p = 0.002, respectively). In conclusion, increased serum sodium level early after administration and early initiation of tolvaptan are possibly useful for assessing the long-term prognosis after tolvaptan treatment in patients with ADHF.