Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.

BACKGROUND AND AIMS: Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries. METHODS: A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart. RESULTS: The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10-8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10-4), and their allelic effects were highly correlated across ancestries (Pearson's R = .91; P = 2.9 × 10-7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94-2.31); P = 1.2 × 10-61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway. CONCLUSIONS: This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries.

Flecainide Is Associated With a Lower Incidence of Arrhythmic Events in a Large Cohort of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia. METHODS: From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients. RESULTS: A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14-29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7-3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4-7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0-6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38-0.83]; P=0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31-0.77]; P=0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14-0.45]; P<0.001). CONCLUSIONS: For patients with catecholaminergic polymorphic ventricular tachycardia, adding flecainide to beta-blocker therapy was associated with a lower incidence of AEs in the overall cohort, in symptomatic patients, and particularly in patients with breakthrough AEs while on beta-blocker therapy.

Clinical Usefulness of the Active Fixation Quadripolar Left Ventricular Lead Compared With the Passive Fixation Quadripolar Lead in Cardiac Resynchronization Therapy.

BACKGROUND: This study compared the stability of the Medtronic Attain Stability Quad (ASQ), a novel quadripolar active fixation left ventricular (LV) lead with a side helix, to that of conventional quadripolar leads with passive fixation (non-ASQ) and evaluated their LV lead performance.Methods and Results: In all, 183 consecutive patients (69 ASQ, 114 non-ASQ) who underwent cardiac resynchronization therapy (CRT) between January 2018 and June 2021 were enrolled. Complications, including elevated pacing capture threshold (PCT) levels, phrenic nerve stimulation (PNS), and LV lead dislodgement, were analyzed during the postimplantation period until the first outpatient visit after discharge. The frequency of LV lead-related complications was significantly lower in the ASQ than non-ASQ group (14% vs. 30%, respectively; P=0.019). Specifically, LV lead dislodgement occurred only in the non-ASQ group, and elevated PCT levels were significantly lower in the ASQ group (7% vs. 23%; P=0.007). Kaplan-Meier analysis confirmed a significantly lower incidence of LV lead-related complications in the ASQ group (log-rank P=0.005). Cox multivariable regression analysis showed a significant reduction in lead-related complications associated with ASQ (hazard ratio 0.44; 95% confidence interval 0.23-0.83; P=0.011). CONCLUSIONS: The ASQ group exhibited fewer LV lead-related complications requiring reintervention and setting changes than the non-ASQ group. Thus, the ASQ may be a favorable choice for CRT device implantation.

Local dispersion of repolarization in the occurrence of ventricular fibrillation in Brugada syndrome: Possibility of phase 2 reentry?

To date, there have been no reports of recording epicardial electrograms at the onset of spontaneous ventricular fibrillation (VF) in patients with Brugada syndrome (BrS). In the case of BrS, unipolar and bipolar electrogram recording on the right ventricular epicardium revealed that dispersion of repolarization with delayed potential was associated with spontaneous occurrence of VF. Phase 2 reentry associated with shortening and dispersion of action potential could have been recorded for the first time in BrS. Epicardial unipolar mapping can guide accurate and appropriate ablation for the elimination of arrhythmia substrate in J wave syndrome.

Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry.

AIMS: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. CONCLUSION: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator.

An International Multicenter Cohort Study on ß-Blockers for the Treatment of Symptomatic Children With Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. ß-Blockers decrease this risk, but studies comparing individual ß-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of ß-blocker in a large cohort of symptomatic children with CPVT. METHODS: From 2 international registries of patients with CPVT, RYR2 variant-carrying symptomatic children (defined as syncope or sudden cardiac arrest before ß-blocker initiation and age at start of ß-blocker therapy <18 years), treated with a ß-blocker were included. Cox regression analyses with time-dependent covariates for ß-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope. RESULTS: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7-15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8-12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective ß-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a ß1-selective ß-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial ß-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for ß1-selective compared with nonselective ß-blockers (HR, 2.04 [95% CI, 1.31-3.17]; and HR, 1.99 [95% CI, 1.20-3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44-4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47-7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08-4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30-5.55]). CONCLUSIONS: ß1-selective ß-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective ß-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred ß-blocker for treating symptomatic children with CPVT.

Structural characteristics of patients with superior vena cava foci initiating atrial fibrillation: Analysis with electrocardiogram-triggered computed tomography.

INTRODUCTION: The superior vena cava (SVC) is the most common source of non-pulmonary vein foci in atrial fibrillation (AF); therefore, predicting the existence of non-pulmonary vein foci before the catheter ablation procedure helps construct a proper ablation strategy in preparation for SVC isolation. This study aimed to clarify the structural characteristics of patients with SVC foci initiating AF. METHODS: We enrolled 331 consecutive patients with AF who underwent cardiac computed tomography imaging before radiofrequency catheter ablation treatment, and they were divided into SVC (+) and (-) groups based on the presence or absence of SVC foci initiating AF. RESULTS: The SVC (+) group (n = 27) exhibited SVC crescent signs-defined as a curve-shaped SVC with two narrow pointed ends-more frequently (37% vs. 9%, p < .001), and larger right atrial volume (95.6 ± 20.8 vs. 80.5 ± 26.1 mL, p = .004) than the SVC (-) group (n = 304). Multivariate logistic regression analysis revealed that the SVC crescent sign (odds ratio, 8.88; 95% confidence interval [CI], 3.21-24.60) and right atrial volume (odds ratio, 1.03; 95% CI, 1.01-1.04) were independent predictors of SVC foci. CONCLUSION: Patients with SVC foci exhibited more frequent SVC crescent signs and larger right atrial volumes, and these characteristics may help clinicians choose the appropriate ablation technology.

Prediction of the Presence of Ventricular Fibrillation From a Brugada Electrocardiogram Using Artificial Intelligence.

BACKGROUND: Brugada syndrome is a potential cause of sudden cardiac death (SCD) and is characterized by a distinct ECG, but not all patients with A Brugada ECG develop SCD. In this study we sought to examine if an artificial intelligence (AI) model can predict a previous or future ventricular fibrillation (VF) episode from a Brugada ECG.Methods and Results: We developed an AI-enabled algorithm using a convolutional neural network. From 157 patients with suspected Brugada syndrome, 2,053 ECGs were obtained, and the dataset was divided into 5 datasets for cross-validation. In the ECG-based evaluation, the precision, recall, and F1score were 0.79±0.09, 0.73±0.09, and 0.75±0.09, respectively. The average area under the receiver-operating characteristic curve (AUROC) was 0.81±0.09. On per-patient evaluation, the AUROC was 0.80±0.07. This model predicted the presence of VF with a precision of 0.93±0.02, recall of 0.77±0.14, and F1score of 0.81±0.11. The negative predictive value was 0.94±0.11 while its positive predictive value was 0.44±0.29. CONCLUSIONS: This proof-of-concept study showed that an AI-enabled algorithm can predict the presence of VF with a substantial performance. It implies that the AI model may detect a subtle ECG change that is undetectable by humans.

Clinical Significance of Atrial Tachyarrhythmia Duration for Ventricular Arrhythmia in Patients With Cardiac Resynchronization Therapy.

BACKGROUND: Atrial tachyarrhythmias (ATAs) are reportedly associated with ventricular arrhythmias (VAs). However, little is known about the association between ATA duration and the risk of VA. We investigated the relationship between ATA duration and subsequent VA in patients with a cardiac resynchronization therapy defibrillator (CRT-D).Methods and Results: We investigated associations between the longest ATA duration during the first year after cardiac resynchronization therapy (CRT) implantation and VA and VA relevant to ATA (VAATA) in 160 CRT-D patients. ATAs occurred in 63 patients in the first year. During a median follow-up of 925 days from 1 year after CRT implantation, 40 patients experienced 483 VAs. Kaplan-Meier analysis showed a significantly higher risk of VA in patients with than without ATA in the first year (log rank P=0.0057). Hazard ratios (HR) of VA (HR 2.36, 2.10, and 3.04 for ATA >30s, >6 min and >24 h, respectively) and only VAATA (HR 4.50, 5.59, and 11.79 for ATA >30s, >6 min and >24 h, respectively) increased according to the duration of ATA. In multivariate analysis, ATA >24 h was an independent predictor of subsequent VA (HR 2.42; P=0.02). CONCLUSIONS: Patients with ATA >24 h in the first year after CRT had a higher risk of subsequent VA and VAATA. The risk of VA, including VAATA, increased with the longest ATA duration.

Transvenous lead extraction versus surgical lead extraction or conservative treatment for cardiac implantable electronic device infections: Propensity score-weighted analyses of a nationwide claim-based database.

INTRODUCTION: Infection is one of the most important complications associated with cardiac implantable electronic device (CIED) therapy. The number of reports comparing the outcomes of transvenous lead extraction (TLE), surgical lead extraction, and conservative treatment for CIED infections using a real-world database is limited. This study investigated the association between the treatment strategies for CIED infections and their outcomes. METHODS: We performed a retrospective analysis of 3605 patients with CIED infections admitted to 681 hospitals using a nationwide claim-based database collected between April 2012 and March 2018. RESULTS: We divided the 3605 patients into TLE (n = 938 [26%]), surgical lead extraction (n = 182 [5.0%]), and conservative treatment (n = 2485 [69%]) groups. TLE was performed more frequently in younger patients and at larger hospitals (p for trend < .001 for both). The rate of TLE increased during the study period, whereas that of surgical lead extraction decreased (p for trend < .001 for both). TLE was associated with lower in-hospital mortality (vs. surgical lead extraction: odds ratio [OR], 0.20; 95% CI, 0.06-0.70; vs. conservative treatment: OR, 0.45; 95% CI: 0.22-0.94) and lower 30-day readmission rates (vs. surgical lead extraction: OR, 0.18; 95% CI: 0.06-0.56; vs. conservative treatment: OR, 0.06; 95% CI, 0.03-0.13) in propensity score-weighted analyses. CONCLUSIONS: Only 26% of patients hospitalized for CIED infections received TLE. TLE was associated with significantly lower in-hospital mortality and 30-day recurrence rates than surgical lead extraction and conservative treatment, suggesting that TLE should be more widely recommended as a first-line treatment for CIED infections.

Impact of nocturnal hypoxemia on the recurrence of atrial tachyarrhythmia after catheter ablation of atrial fibrillation.

Factors causing atrial tachyarrhythmia recurrence after catheter ablation (CA) of atrial fibrillation (AF) remain undetermined. This study aimed to investigate the effect of nocturnal hypoxemia on the recurrence of atrial tachyarrhythmia after CA of AF. Among 594 patients with AF who underwent an ambulatory sleep study at the National Cerebral and Cardiovascular Center, Suita, Osaka, Japan (2014-2019), 365 underwent CA of AF; 290 patients who underwent CA were followed up for > 3 months. Multivariate Cox regression analysis was used to calculate hazard ratios (HRs) using clinical variables, to identify the independent predictors of atrial tachyarrhythmia recurrence after the final CA. Atrial tachyarrhythmia recurred in 45 of 290 (15.5%) patients during the median follow-up period of 479 days (interquartile range 225-1002). On the performing multivariate analysis of the data of patients who did not receive continuous positive airway pressure (CPAP), severe nocturnal hypoxemia [defined as the percentage of sleep time spent with SaO2 of < 90% (T90) over 20%] [HR 8.53, 95% confidence interval (CI) 1.872-38.814; P < 0.01] and an 1 mL/m2 increase in the left atrial volume index (HR 1.02, 95% CI 1.004-1.044; P = 0.02) were found to be independently associated with the recurrence of atrial tachyarrhythmia. In addition, the rates of freedom from atrial tachyarrhythmia after the final AF ablation with CPAP were significantly lower in the group with more severe nocturnal hypoxemia (Log-rank P = 0.03). In conclusion, it is necessary to consider both, AHI and nocturnal hypoxia while performing an ambulatory sleep apnea study. CA may be less effective in patients with more severe nocturnal hypoxia, despite the administration of CPAP.

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.

Impact of Pre-Ablation Direct Current Cardioversion for Persistent Atrial Fibrillation to Predict Recurrence of Atrial Fibrillation after Catheter Ablation.

The efficacy of direct current (DC) cardioversion before catheter ablation (CA) for persistent atrial fibrillation (PerAF) patients remains controversial. We hypothesized that maintenance of sinus rhythm (SR) by pre-ablation DC cardioversion may predict the outcome of CA in patients with PerAF. A total of 383 PerAF patients with no or mild symptoms (EHRA I/II) who had undergone DC cardioversion before CA (301 males, 65 ± 10 years old, mean atrial fibrillation (AF) duration: 25 ± 47 months) were retrospectively enrolled. Whether or not SR was maintained at least 24 hour after DC cardioversion, patients were divided into two groups, namely, the DC-SR group and DC-AF group, and then all were followed until AF recurrence after CA. After DC cardioversion, 281 (73%) patients were categorized into the DC-SR group, and 102 (27%) were categorized into the DC-AF group. A total of 195 patients underwent CA at an average of 83 (54-145) days after DC cardioversion, including 161 (83%) in the DC-SR group and 34 (17%) in the DC-AF group. During follow-up (median: 15 [10-25] months), the number of patients who were free from AF was significantly higher in the DC-SR group compared with the DC-AF group (61.5% versus 38.3%, P < 0.0001). Multivariate analysis revealed that the DC-SR group (hazard ratio [HR]: 0.45, 95% confidence interval [CI]: 0.21-0.99, P = 0.047) and age at first AF diagnosis (HR: 0.95, 95% CI: 0.91-1.00, P = 0.039) were the independent predictors for being AF-free after CA. In conclusion, the 24-hour rhythm outcome of pre-ablation DC cardioversion and age at first AF diagnosis may predict the recurrence of AF after CA in patients with PerAF.

An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

BACKGROUND: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. METHODS: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. RESULTS: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). CONCLUSIONS: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

High-risk atrioventricular block in Brugada syndrome patients with a history of syncope.

BACKGROUND: Determining the etiology of syncope is challenging in Brugada syndrome (BrS) patients. Implantable cardioverter defibrillator placement is recommended in BrS patients who are presumed to have arrhythmic syncope. However, arrhythmic syncope in BrS patients can occur in the setting of atrioventricular block (AVB), which should be managed by cardiac pacing. The clinical characteristics of BrS patients with high-risk AVB remain unknown. METHODS: This study included 223 BrS patients with a history of syncope from two centers. The clinical characteristics of patients with high-risk AVB (Mobitz type II second-degree AVB, high-degree AVB, or third-degree AVB) were investigated. RESULTS: During the 99 ± 78 months of follow-up, we identified six BrS patients (2.7%) with high-risk AVB. Three of the six patients (50%) with AVB presented with syncope associated with prodromes or specific triggers. Four patients (67%) were found to have paroxysmal third-degree AVB during the initial evaluation for BrS and syncope, while two patients developed third-degree AVB during the follow-up period. The incidence of first-degree AVB was significantly higher in AVB patients than in non-AVB patients (83% vs. 15%; p = .0005). There was no significant difference in the incidence of ventricular fibrillation between AVB and non-AVB patients (AVB [17%], non-AVB [12%]; p = .56). CONCLUSION: High-risk AVB can occur in BrS patients with various clinical presentations. Although rare, the incidence is worth considering, especially in BrS patients with first-degree AVB.

Relationship between electrical gaps after Maze procedure and atrial tachyarrhythmias and ablation outcomes after cardiac surgery and concomitant Maze procedure.

Atrial tachycardia (AT) and atrial fibrillation (AF) commonly occur after cardiac surgeries (CSs). This study investigated the mechanisms and long-term outcomes of AT and AF ablation after various Maze procedures, particularly whether atrial tachyarrhythmias after the Maze procedure occur due to gaps in the Maze lines. We analyzed 37 consecutive cases with atrial tachyarrhythmias after the Maze procedures and concomitant CSs between 2007 and 2019. Fifty-nine atrial tachyarrhythmias were induced in 37 consecutive cases, and 49 of those atrial tachyarrhythmias were mappable ATs. Forty ATs were related to the Maze procedures in the 49 mappable ATs (81.6%). All 37 consecutive cases had residual electrical conductions (gaps) in the Maze lines (88 gaps; 2.4 ± 1.2 gaps/patient). Forty of 88 gaps (45.5%) were associated with gap-related ATs. The common ATs in this study were 1. peri-mitral atrial flutter due to gaps at pulmonary vein isolation (PVI) line to mitral valve annulus (MVA) (20 cases), and 2. peri-tricuspid atrial flutter due to gaps at right atrial incision to the tricuspid valve annulus (TVA) (10 cases). Forty-seven of 49 ATs (95.9%) were successfully ablated at the first session, and there were no complications. The mean follow-up period after ablation was 3.6 ± 3.2 (median, 2.1; interquartile range, 0.89-6.84) years. The Kaplan-Meier analysis of freedom from recurrent atrial tachyarrhythmias after Maze procedure was 82.7% at 1-year follow-up and 75.5% at 4-year follow-up after a single procedure. Reentry was the main mechanism of ATs after Maze procedures and concomitant CSs, and ATs were largely related to the gaps on the Maze lines between the PVI line and the MVA or those on the lines between right atrial incision to the TVA. Long-term follow-up data suggest that catheter ablation of atrial tachyarrhythmias after various Maze procedures is effective and safe.

Differential diagnosis between LQT1 and LQT2 by QT/RR relationships using 24-hour Holter monitoring: A multicenter cross-sectional study.

BACKGROUND: The clinical course and therapeutic strategies in the congenital long QT syndrome (LQTS) are genotype-specific. However, accurate estimation of LQTS genotype is often difficult from the standard 12-lead ECG. OBJECTIVES: This study aims to evaluate the utility of QT/RR slope analysis by the 24-hour Holter monitoring for differential diagnosis of LQTS genotype between LQT1 and LQT2. METHODS: This cross-sectional study enrolled 54 genetically identified LQTS patients (29 LQT1 and 25 LQT2) recruited from three medical institutions. The QT-apex (QTa) interval and the QT-end (QTe) interval at each 15-second were plotted against the RR intervals, and the linear regression (QTa/RR and QTe/RR slopes, respectively) was calculated from the entire 24-hour and separately during the day or night-time periods of the Holter recordings. RESULTS: The QTe/RR and QTa/RR slopes at the entire 24-hour were significantly steeper in LQT2 compared to those in LQT1 patients (0.262 ± 0.063 vs. 0.204 ± 0.055, p = .0007; 0.233 ± 0.052 vs. 0.181 ± 0.040, p = .0002, respectively). The QTe interval was significantly longer, and QTe/RR and QTa/RR slopes at daytime were significantly steeper in LQT2 than in LQT1 patients. The receiver operating curve analysis revealed that the QTa/RR slope of 0.211 at the entire 24-hour Holter was the best cutoff value for differential diagnosis between LQT1 and LQT2 (sensitivity: 80.0%, specificity: 75.0%, and area under curve: 0.804 [95%CI = 0.68-0.93]). CONCLUSION: The continuous 24-hour QT/RR analysis using the Holter monitoring may be useful to predict the genotype of congenital LQTS, particularly for LQT1 and LQT2.

Pulmonary Vein Isolation and Pacemaker Implantation in a Patient with Dextrocardia Situs Inversus.

A 70-year-old female with dextrocardia with situs inversus (DSI) totalis and inferior vena cava occlusion underwent radiofrequency catheter ablation because she had symptomatic paroxysmal atrial fibrillation (AF). Careful preoperative examination made successful pulmonary vein isolation through the left jugular vein approach. One-year later, however, AF recurred, and symptomatic sinus bradycardia or junctional bradycardia often occurred. Then, the pacemaker was implanted. We here reported a rare case of congenital abnormality, DSI with inferior vena cava occlusion who had undergone successful pulmonary vein isolation and pacemaker implantation without any complications.

Improved Risk Stratification of Patients With Brugada Syndrome by the New Japanese Circulation Society Guideline　- A Multicenter Validation Study.

BACKGROUND: The new guideline (NG) published by the Japanese Circulation Society (JCS) places emphasis on previous arrhythmic syncope and inducibility of ventricular fibrillation (VF) by ≤2 extrastimuli during programmed electrical stimulation (PES) for deciding the indication of an implantable cardioverter-defibrillator in patients with Brugada syndrome (BrS). This study evaluated the usefulness of the NG and compared it with the former guideline (FG) for risk stratification of patients with BrS.Methods and Results:This was a multicenter (7 Japanese hospitals) retrospective study involving 234 patients with BrS who underwent PES at baseline (226 males; mean age at diagnosis: 44.9±13.4 years). At diagnosis, 46 patients (20%) had previous VF, 100 patients (43%) had previous syncope, and 88 patients (37%) were asymptomatic. We evaluated the difference in the incidence of VF in each indication according to the new and FGs. During the follow-up period (mean: 6.9±5.2 years), the incidence of VF was higher in patients with Class IIa indication according to the NG (NG: 16/45 patients [35.6%] vs. FG: 16/104 patients [15.4%]), while the incidence of VF in patients with other than class I or IIa indication was similarly low in both guidelines (NG: 2/143 patients [1.4%] vs. FG: 2/84 patients [2.4%]). CONCLUSIONS: This study validated the usefulness of the NG for risk stratification of BrS patients.

Novel Non-Invasive Index for Prediction of Responders in Cardiac Resynchronization Therapy Using High-Resolution Magnetocardiography.

BACKGROUND: Approximately one-third of patients with advanced heart failure (HF) do not respond to cardiac resynchronization therapy (CRT). We investigated whether the left ventricular (LV) conduction pattern on magnetocardiography (MCG) can predict CRT responders.Methods and Results:This retrospective study enrolled 56 patients with advanced HF (mean [±SD] LV ejection fraction [LVEF] 23±8%; QRS duration 145±19 ms) and MCG recorded before CRT. MCG-QRS current arrow maps were classified as multidirectional (MDC; n=28) or unidirectional (UDC; n=28) conduction based on a change of either ≥35° or <35°, respectively, in the direction of the maximal current arrow after the QRS peak. Baseline New York Heart Association functional class and LVEF were comparable between the 2 groups, but QRS duration was longer and the presence of complete left bundle branch block and LV dyssynchrony was higher in the UDC than MDC group. Six months after CRT, 30 patients were defined as responders, with significantly more in the UDC than MDC group (89% vs. 14%, respectively; P<0.001). Over a 5-year follow-up, Kaplan-Meyer analysis showed that adverse cardiac events (death or implantation of an LV assist device) were less frequently observed in the UDC than MDC group (6/28 vs. 15/28, respectively; P=0.027). Multivariate analysis revealed that UDC on MCG was the most significant predictor of CRT response (odds ratio 69.8; 95% confidence interval 13.14-669.32; P<0.001). CONCLUSIONS: Preoperative non-invasive MCG may predict the CRT response and long-term outcome after CRT.