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.

Long-Term Outcomes of Brugada Substrate Ablation: A Report from BRAVO (Brugada Ablation of VF Substrate Ongoing Multicenter Registry).

BACKGROUND: Treatment options for high-risk Brugada syndrome (BrS) with recurrent ventricular fibrillation (VF) are limited. Catheter ablation is increasingly performed but a large study with long-term outcome data is lacking. We report the results of the multicenter, international BRAVO (Brugada Ablation of VF Substrate Ongoing Registry) for treatment of high-risk symptomatic BrS. METHODS: We enrolled 159 patients (median age 42 years; 156 male) with BrS and spontaneous VF in BRAVO; 43 (27%) of them had BrS and early repolarization pattern. All but 5 had an implantable cardioverter-defibrillator for cardiac arrest (n=125) or syncope (n=34). A total of 140 (88%) had experienced numerous implantable cardioverter-defibrillator shocks for spontaneous VF before ablation. All patients underwent a percutaneous epicardial substrate ablation with electroanatomical mapping except for 8 who underwent open-thoracotomy ablation. RESULTS: In all patients, VF/BrS substrates were recorded in the epicardial surface of the right ventricular outflow tract; 45 (29%) patients also had an arrhythmic substrate in the inferior right ventricular epicardium and 3 in the posterior left ventricular epicardium. After a single ablation procedure, 128 of 159 (81%) patients remained free of VF recurrence; this number increased to 153 (96%) after a repeated procedure (mean 1.2±0.5 procedures; median=1), with a mean follow-up period of 48±29 months from the last ablation. VF burden and frequency of shocks decreased significantly from 1.1±2.1 per month before ablation to 0.003±0.14 per month after the last ablation (P<0.0001). The Kaplan-Meier VF-free survival beyond 5 years after the last ablation was 95%. The only variable associated with a VF-free outcome in multivariable analysis was normalization of the type 1 Brugada ECG, both with and without sodium-channel blockade, after the ablation (hazard ratio, 0.078 [95% CI, 0.008 to 0.753]; P=0.0274). There were no arrhythmic or cardiac deaths. Complications included hemopericardium in 4 (2.5%) patients. CONCLUSIONS: Ablation treatment is safe and highly effective in preventing VF recurrence in high-risk BrS. Prospective studies are needed to determine whether it can be an alternative treatment to implantable cardioverter-defibrillator implantation for selected patients with BrS. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04420078.

First-Line Catheter Ablation of Monomorphic Ventricular Tachycardia in Cardiomyopathy Concurrent With Defibrillator Implantation: The PAUSE-SCD Randomized Trial.

BACKGROUND: Catheter ablation as first-line therapy for ventricular tachycardia (VT) at the time of implantable cardioverter defibrillator (ICD) implantation has not been adopted into clinical guidelines. Also, there is an unmet clinical need to prospectively examine the role of VT ablation in patients with nonischemic cardiomyopathy, an increasingly prevalent population that is referred for advanced therapies globally. METHODS: We conducted an international, multicenter, randomized controlled trial enrolling 180 patients with cardiomyopathy and monomorphic VT with an indication for ICD implantation to assess the role of early, first-line ablation therapy. A total of 121 patients were randomly assigned (1:1) to ablation plus an ICD versus conventional medical therapy plus an ICD. Patients who refused ICD (n=47) were followed in a prospective registry after stand-alone ablation treatment. The primary outcome was a composite end point of VT recurrence, cardiovascular hospitalization, or death. RESULTS: Randomly assigned patients had a mean age of 55 years (interquartile range, 46-64) and left ventricular ejection fraction of 40% (interquartile range, 30%-49%); 81% were male. The underlying heart disease was ischemic cardiomyopathy in 35%, nonischemic cardiomyopathy in 30%, and arrhythmogenic cardiomyopathy in 35%. Ablation was performed a median of 2 days before ICD implantation (interquartile range, 5 days before to 14 days after). At 31 months, the primary outcome occurred in 49.3% of the ablation group and 65.5% in the control group (hazard ratio, 0.58 [95% CI, 0.35-0.96]; P=0.04). The observed difference was driven by a reduction in VT recurrence in the ablation arm (hazard ratio, 0.51 [95%CI, 0.29-0.90]; P=0.02). A statistically significant reduction in both ICD shocks (10.0% versus 24.6%; P=0.03) and antitachycardia pacing (16.2% versus 32.8%; P=0.04) was observed in patients who underwent ablation compared with control. No differences in cardiovascular hospitalization (32.0% versus. 33.7%; hazard ratio, 0.82 [95% CI, 0.43-1.56]; P=0.55) or mortality (8.9% versus 8.8%; hazard ratio, 1.40 [95% CI, 0.38-5.22]; P=0.62]) were observed. Ablation-related complications occurred in 8.3% of patients. CONCLUSIONS: Among patients with cardiomyopathy of varied causes, early catheter ablation performed at the time of ICD implantation significantly reduced the composite primary outcome of VT recurrence, cardiovascular hospitalization, or death. These findings were driven by a reduction in ICD therapies. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02848781.

Unidirectional conduction characterizing epicardial connections in patients with atrial tachyarrhythmias.

INTRODUCTION: Electrophysiological characteristics of epicardial connections (ECs) in atria and pulmonary veins (PVs) are unclear despite their important contributions to atrial fibrillation (AF). Unidirectional conduction associated with source-sink mismatch can occur in ECs due to their fine fibers with abrupt changes in orientation. We detailed the prevalence and electrophysiological characteristics of unidirectional conduction in the atria and investigated its association with the clinical manifestation of AF. METHODS: This study retrospectively reviewed electrophysiological studies and radiofrequency catheter ablation in 261 consecutive patients with AF. RESULTS: Unidirectional conduction was observed during ablation encircling the PVs in eight (3.1%) patients, and all occurred in the suspected (N = 4) or definitively (N = 4) recognized ECs. These ECs included three intercaval bundles, four septopulmonary bundles, and one Marshall bundle, and were first manifested in a second procedure in 6 (75%) patients. The unidirectional property was from PV to atrium (exit conduction) in all intercaval bundles and three septopulmonary bundles, and from atrium to PV (entrance conduction) in the remaining two bundles. Intercaval bundles acted as a limb of bi-atrial macro-reentrant tachycardia (50%, three of the six including previous cases). Ablation of the exit outside the PVs, including the right atrium, eliminated ECs in three (38%) patients. All patients remain free from arrhythmia recurrence after a mean 13-month follow-up. CONCLUSION: A unidirectional conduction property was closely associated with the EC, as estimated by histological findings. Recognition of this fact by electrophysiologists may help to clarify mechanisms for AF and atrial tachycardia and guide the creation of efficient and safe ablation lesion sets.

Acute and mid-term outcomes of ablation for atrial fibrillation with VISITAG SURPOINT: the Japan MIYABI registry.

AIMS: The effectiveness of pulmonary vein isolation (PVI) guided by VISITAG SURPOINT (VS) has been demonstrated in Western populations. However, data for Asian populations are limited. VS settings may differ for Asians, given their smaller body size. This study aimed to describe outcomes of radiofrequency atrial fibrillation (AF) ablation guided by VS in a large Asian population. METHODS AND RESULTS: The prospective, observational, multicentre MIYABI registry collected real-world data from patients undergoing VS-guided AF ablation using ThermoCool SmartTouch and ThermoCool SmartTouch SF catheters from 50 Japanese centres. All patients had paroxysmal AF or persistent AF for <6 months. Primary adverse events (PAEs) were evaluated for safety. The primary efficacy endpoint was the proportion of patients with PVI at the end of the procedure. Mid-term effectiveness (up to 12 months) was evaluated by freedom from documented atrial arrhythmias. Of the 1011 patients enrolled, 1002 completed AF ablation. The mean number of VS values per procedure was 428.8 on the anterior wall and 400.4 on the posterior wall. Nine patients (0.9%) experienced PAEs. Upon procedure completion, 99.7% of patients had PVI. Twelve-month freedom from atrial arrhythmia recurrence was 88.5%; 5.7% of patients were re-ablated. At repeat ablation, 54% of RSPV, 73% of RIPV, 70% of LSPV, and 86% of LIPV evaluated remained durably isolated. CONCLUSION: Despite lower anterior wall VS values compared with the CLOSE protocol (≥550), the present study demonstrated comparable efficacy outcomes, indicating that a VS of ≥550 for the anterior wall may not be necessary for Asian patients.

Impact of Interatrial Epicardial Connections on the Dominant Frequency of Atrial Fibrillation.

BACKGROUND: An epicardial connection (EC) between the right-sided pulmonary venous (RtPV) carina and right atrium (RA) may preclude PV isolation, but its electrophysiological role during atrial fibrillation (AF) remains unknown.Methods and Results: This prospective observational study included 98 consecutive patients undergoing catheter ablation for AF, subdivided into the EC group (n=17) and non-EC group (n=80) based on observation of RA posterior wall breakthrough during RtPV pacing. Mean left atrial (LA) dominant frequency (mean DFLA) was defined as the averaged DFs at the right and left PVs and LA appendage. The regional DF was higher in the EC group vs. the non-EC group except at the left PV antrum. The DF at the RA appendage (RAA) and mean DFLAwere equivocal (6.5±0.7 vs. 6.6±0.7 Hz) in the EC group, but the mean DFLAwas significantly higher than that at the RAA (5.8±0.6 vs. 6.1±0.5 Hz, P=0.001) in the non-EC group, suggesting an LA-to-RA DF gradient. A significant correlation of DF between the RtPV antrum and RAA was observed in the EC group (P<0.001, r=0.84) but not in the non-EC group. CONCLUSIONS: An electrophysiological link via interatrial ECs might attenuate the hierarchical nature of activation frequencies of AF, leading to advanced electrical remodeling of the atria.

Long-QT Syndrome with Peripartum Cardiomyopathy Causing Fatal Ventricular Arrhythmia after Delivery.

Although rare, long QT syndrome (LQTS) and peripartum cardiomyopathy (PPCM) are the major causes of maternal cardiovascular death. We herein present a case study of a 23-year-old woman with LQTS, pregnancy-induced hypertension, and PPCM. During the postpartum period, her left ventricular systolic function had severely decreased, requiring the administration of loop diuretics. Diuretics cause several changes in the circulating blood volume, electrolyte balance, and hormonal status during pregnancy, delivery, and the peripartum period. Extreme QTc prolongation and fatal ventricular arrhythmia require frequent defibrillation. For the patient in this study, we corrected her electrolyte abnormality, and eventually, we controlled the arrhythmia by administering a ß-blocker and Na-channel blocker. Although the arrhythmia subsided, she continued on medication after discharge to prevent the recurrence of fatal arrhythmia. In conclusion, close attention should be paid to patients with LQTS, especially when some changes that may lead to QTc prolongation could occur during the peripartum period.

The R Wave Amplitude in Lead aVL Could Predict Successful Catheter Ablation of Ventricular Arrhythmias Originating below the His Bundle Region of the Right Ventricle.

Radiofrequency catheter ablation (RFCA) to treat ventricular arrhythmias (VAs) originating below the His bundle (HB) region of the right ventricular (RV) septum could impair the atrioventricular node conduction. This study aimed to clarify the parameters of the 12-lead electrocardiography that predict successful RFCA of VAs originating from this region. This study included 20 consecutive patients (13 men; mean age, 68 ± 7 years) with monomorphic VAs in whom the earliest ventricular activation during the VA was below the HB region of the RV septum. According to the ablation results, the patients were divided into two groups: successful ablation (S-group; n = 10) and failed ablation groups (F-group; n = 10). The electrocardiographic parameters during the VAs and RFCA results were assessed. The R wave amplitudes in leads aVL (P = 0.001) and I (P = 0.010) in the S-group were both smaller than those in the F-group. In addition, the S-group had smaller negative deflection amplitudes in leads III (P = 0.002) and aVF (P = 0.003) than the F-group. According to the receiver operating characteristic curve analysis, the most useful electrocardiographic parameter for predicting successful ablation was the R wave amplitude in lead aVL (area under the curve, 0.895; P < 0.001); a cutoff value of < 1.3 mV predicted a successful RFCA with the highest accuracy (sensitivity, 90%; specificity, 80%; positive predictive value, 82%; negative predictive value, 89%). The R wave amplitude in lead aVL was the most useful parameter for predicting a successful RFCA to treat VAs originating below the HB region of the RV septum.

Novel preventive effect of isorhamnetin on electrical and structural remodeling in atrial fibrillation.

Isorhamnetin, a natural flavonoid, has strong antioxidant and antifibrotic effects, and a regulatory effect against Ca2+-handling. Atrial remodeling due to fibrosis and abnormal intracellular Ca2+ activities contributes to initiation and persistence of atrial fibrillation (AF). The present study investigated the effect of isorhamnetin on angiotensin II (AngII)-induced AF in mice. Wild-type male mice (C57BL/6J, 8 weeks old) were assigned to three groups: (1) control group, (2) AngII-treated group, and (3) AngII- and isorhamnetin-treated group. AngII (1000 ng/kg/min) and isorhamnetin (5 mg/kg) were administered continuously via an implantable osmotic pump for two weeks and intraperitoneally one week before initiating AngII administration, respectively. AF induction and electrophysiological studies, Ca2+ imaging with isolated atrial myocytes and HL-1 cells, and action potential duration (APD) measurements using atrial tissue and HL-1 cells were performed. AF-related molecule expression was assessed and histopathological examination was performed. Isorhamnetin decreased AF inducibility compared with the AngII group and restored AngII-induced atrial effective refractory period prolongation. Isorhamnetin eliminated abnormal diastolic intracellular Ca2+ activities induced by AngII. Isorhamnetin also abrogated AngII-induced APD prolongation and abnormal Ca2+ loading in HL-1 cells. Furthermore, isorhamnetin strongly attenuated AngII-induced left atrial enlargement and atrial fibrosis. AngII-induced elevated expression of AF-associated molecules, such as ox-CaMKII, p-RyR2, p-JNK, p-ERK, and TRPC3/6, was improved by isorhamnetin treatment. The findings of the present study suggest that isorhamnetin prevents AngII-induced AF vulnerability and arrhythmogenic atrial remodeling, highlighting its therapeutic potential as an anti-arrhythmogenic pharmaceutical or dietary supplement.

Combined endo- and epicardial pace-mapping to localize ventricular tachycardia isthmus in ischaemic and non-ischaemic cardiomyopathy.

AIMS: A high-density pace-mapping can depict an abrupt transition in paced QRS morphology from a poor to excellent match, unmasking the critical component of ventricular tachycardia (VT) isthmus from the entrance to exit. We sought to assess pace-mapping at multiple sites within the endo- and epicardial scars to identify the VT isthmus in patients with ischaemic (ICM) and non-ischaemic cardiomyopathy (NICM). METHODS AND RESULTS: Colour-coded maps correlating to the percentage matches between 12-lead electrocardiograms during VT and pace-mapping [referred to as correlation score maps (CSMs)] were analysed. We studied 115 CSMs (80 endo- and 35 epicardial CSMs) in 37 patients (17 ICM, 20 NICM). The CSM with an abrupt change (AC) in pacemap score (AC-type) on the endocardium was more frequently observed in ICM than in NICM [11/39 (28%) vs. 1/41 (2%); P = 0.001]. Among 35 CSMs that were analysed by the combined endo- and epicardial mapping, 10 (29%) CSMs exhibited non-AC-type on the endocardium; however, AC-type was present on the opposite epicardium. Although 24 (69%) CSMs did not show AC-type on both the endocardium and epicardium, 16 of them had either an excellent (>90%) or poor (<0%) correlation score on either side, associated with isthmus exit or entrance, respectively. However, the remaining eight CSMs had neither excellent nor poor scores. CONCLUSION: The CSM may provide electrophysiological information to localize the endo- and epicardial VT isthmus. The absence of AC-type CSM on the endocardium, which is frequently observed in NICM, appears to indicate the sub-epicardial or intramural course of the critical isthmus.

Real-World Investigation on Anticoagulation Management Before and After Catheter Ablation for Atrial Fibrillation in Japan　- Periprocedural and Long-Term Outcomes.

BACKGROUND: Optimal periprocedural oral anticoagulant (OAC) therapy before catheter ablation (CA) for atrial fibrillation (AF) and the safety profile of OAC discontinuation during the remote period (from 31 days and up to 1 year after CA) have not been well defined.Methods and Results: The RYOUMA registry is a prospective multicenter observational study of Japanese patients who underwent CA for AF in 2017-2018. Of the 3,072 patients, 82.3% received minimally interrupted direct-acting OACs (DOACs) and 10.2% received uninterrupted DOACs. Both uninterrupted and minimally interrupted DOACs were associated with an extremely low thromboembolic event rate. Female, long-standing persistent AF, low creatinine clearance, hepatic disorder, and high intraprocedural heparin dose were independent factors associated with periprocedural major bleeding. At 1 year after CA, DOAC was continued in 55.9% of patients and warfarin in 56.4%. The incidence of thromboembolic and major bleeding events for 1 year was 0.3% and 1.2%, respectively. Age ≥73 years, dementia, and AF recurrence were independently associated with major bleeding events. Univariate analyses revealed that warfarin continuation and off-label overdose of DOACs were risk factors for major bleeding after CA. CONCLUSIONS: High intraprocedural dose of heparin was associated with periprocedural major bleeding events. At 1 year after CA, over half of the patients had continued OAC therapy. Thromboembolic events were extremely low; however, major bleeding occurred in 1.2%. Age ≥73 years, dementia, and AF recurrence were independently associated with major bleeding after CA.

Catheter ablation of ventricular tachycardia in dilated-phase hypertrophic cardiomyopathy: Substrate characterization and ablation outcome.

INTRODUCTION: Catheter ablation is a therapeutic option to suppress ventricular tachycardia (VT) in the setting of dilated-phase hypertrophic cardiomyopathy (DHCM). However, the characteristics of the arrhythmogenic substrate and the ablation outcome are not fully illustrated. METHOD: A total of 23 ablation procedures for drug-refractory sustained monomorphic VTs in 13 DHCM patients (60 ± 11 years, one female, the left ventricular [LV] ejection fraction 39% ± 9%, the LV mass index 156 ± 39 g/m2 ) were performed. The distribution of VT substrate as endocardial or epicardial/intramural was based on detailed mapping and ablation response during VT. RESULT: Two patients underwent ablation of sustained monomorphic VT that was not scar-mediated tachycardia. Of the remaining 11 patients, eight (73%) patients had VT substrate in the basal regions, most frequently at the epicardial and/or intramural basal antero-septum. None of the patients had VT substrate located at the LV inferolateral region. Ablation at the right ventricular septum and the aortic cusps was done in four and five patients, respectively. Other approaches including bipolar and chemical ablations, were done in three and two patients, respectively. Six (55%) out of 11 patients (two patients lost follow-up) had VT recurrence. All the six patients had basal substrate. However, anti-tachycardia pacing was sufficient for VT termination except in one patient. CONCLUSION: Catheter ablation of VT in patients with DHCM is challenging because of the predominant basal anteroseptal epicardial/intramural location of arrhythmogenic substrate. An ablation approach from multiple sites and/or adjunctive interventional techniques are often required.

Right bundle branch block and risk of cardiovascular mortality: the Ibaraki Prefectural Health Study.

Historically, a right bundle branch block has been considered a benign finding in asymptomatic individuals. However, this conclusion is based on a few old studies with small sample sizes. We examined the association between a complete right bundle branch block (CRBBB) and subsequent cardiovascular mortality in the general population in Japan. In this large community-based cohort study, data of 90,022 individuals (mean age, 58.5 ± 10.2 years; 66.2% women) who participated in annual community-based health check-ups were assessed. Subjects were followed up from 1993 to the end of 2016. Cox proportional hazards' models and log-rank tests were used for the data analysis. CRBBB was documented in 1,344 participants (1.5%). Among all included participants, CRBBB was associated with an increased risk of cardiovascular mortality after adjustment for all potential confounders (hazard ratio [HR] 1.21; 95% confidence interval [CI] 1.06-1.38). The increased risk of cardiovascular mortality was particularly evident in women aged < 65 years (HR 2.00; 95% CI 1.34-2.98) and men aged ≥ 65 years (HR 1.28; 95% CI 1.06-1.55). CRBBB is associated with an increased risk of cardiovascular mortality in women aged < 65 years and men aged ≥ 65 years. Clinicians should be aware of the presence of CRBBB in young women and elderly men, even if they exhibit no symptoms.

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.

A simple pacing maneuver to unmask an epicardial connection involving the right-sided pulmonary veins.

INTRODUCTION: An epicardial connection (EC) between the right-sided pulmonary venous (PV) carina and right atrium (RA) is one of the mechanisms for which carinal ablation is required for right-sided PV isolation. The purpose of the study was to devise a simple pacing maneuver to differentiate an EC from a residual conduction gap on the antral ablation line during radiofrequency catheter ablation. METHODS AND RESULTS: This study included 133 consecutive patients. After one round of ablation, electrograms at the posterior antrum outside the ablation line were recorded during sinus rhythm (SR) and coronary sinus (CS) pacing, and intervals between the antral and PV potentials were measured in each rhythm. The ΔintervalSR-CS was calculated as the difference between the interval during SR and that during CS pacing. Presence of an EC was confirmed by observation of a RA posterior wall breakthrough during right-sided PV pacing, which was then targeted for ablation. Patients with nonachievement of first-pass isolation (N = 35) and with PV reconnection during the procedure (N = 9) were classified into the EC-group (N = 20) and gap-group (N=24), respectively. The prevalence of carina breakthrough during SR was higher in the EC-group than the gap-group (18 [95%] vs. 1 [4%] patients, p < .0001). The ΔintervalSR-CS was larger in the EC-group versus gap-group (71 [interquartile range, 57-97] vs. 6 [2-9] ms, p < .0001). In all patients with an EC, RA ablation resulted in delay (32 [20-40] ms) (N = 15) or elimination of PV potentials (N = 5). CONCLUSION: An EC can be efficiently discriminated from a conduction gap by a simple pacing maneuver.

Xanthine oxidase inhibitor febuxostat reduces atrial fibrillation susceptibility by inhibition of oxidized CaMKII in Dahl salt-sensitive rats.

Oxidative stress could be a possible mechanism and a therapeutic target of atrial fibrillation (AF). However, the effects of the xanthine oxidase (XO) inhibition for AF remain to be fully elucidated. We investigated the effects of a novel XO inhibitor febuxostat on AF compared with allopurinol in hypertension rat model. Five-week-old Dahl salt-sensitive rats were fed either low-salt (LS) (0.3% NaCl) or high-salt (HS) (8% NaCl) diet. After 4 weeks of diet, HS diet rats were divided into three groups: orally administered to vehicle (HS-C), febuxostat (5 mg/kg/day) (HS-F), or allopurinol (50 mg/kg/day) (HS-A). After 4 weeks of treatment, systolic blood pressure (SBP) was significantly higher in HS-C than LS, and it was slightly but significantly decreased by treatment with each XO inhibitor. AF duration was significantly prolonged in HS-C compared with LS, and significantly suppressed in both HS-F and HS-A (LS; 5.8 ± 3.5 s, HS-C; 33.9 ± 23.7 s, HS-F; 15.0 ± 14.1 s, HS-A; 20.1 ± 11.9 s: P<0.05). Ca2+ spark frequency was obviously increased in HS-C rats and reduced in the XO inhibitor-treated rats, especially in HS-F group. Western blotting revealed that the atrial expression levels of Met281/282-oxidized Ca2+/Calmodulin-dependent kinase II (CaMKII) and Ser2814-phosphorylated ryanodine receptor 2 were significantly increased in HS-C, and those were suppressed in HS-F and HS-A. Decreased expression of gap junction protein connexin 40 in HS-C was partially restored by treatment with each XO inhibitor. In conclusion, XO inhibitor febuxostat, as well as allopurinol, could reduce hypertension-related increase in AF perpetuation by restoring Ca2+ handling and gap junction.

Mapping and Ablation of Ventricular Fibrillation Associated With Early Repolarization Syndrome.

BACKGROUND: We conducted a multicenter study to evaluate mapping and ablation of ventricular fibrillation (VF) substrates or VF triggers in early repolarization syndromes (ERS) or J-wave syndrome (JWS). METHODS: We studied 52 patients with ERS (4 women; median age, 35 years) with recurrent VF episodes. Body surface electrocardiographic imaging and endocardial and epicardial electroanatomical mapping of both ventricles were performed during sinus rhythm and VF for localization of triggers, substrates, and drivers. Ablations were performed on VF substrates, defined as areas that had late depolarization abnormalities characterized by low-voltage fractionated late potentials, and VF triggers. RESULTS: Fifty-one of the 52 patients had detailed mapping that revealed 2 phenotypes: group 1 had late depolarization abnormalities predominantly at the right ventricular (RV) epicardium (n=40), and group 2 had no depolarization abnormalities (n=11). Group 1 can be subcategorized into 2 groups: Group 1A included 33 patients with ERS with Brugada electrocardiographic pattern, and group 1B included 7 patients with ERS without Brugada electrocardiographic pattern. Late depolarization areas colocalize with VF driver areas. The anterior RV outflow tract/RV epicardium and the RV inferior epicardium are the major substrate sites for group 1. The Purkinje network is the leading underlying VF trigger in group 2 that had no substrates. Ablations were performed in 43 patients: 31 and 5 group 1 patients had only VF substrate ablation and VF substrates plus VF trigger, respectively (mean, 1.4±0.6 sessions); 6 group 2 patients and 1 patient without group classification had only Purkinje VF trigger ablation (mean, 1.2±0.4 sessions). Ablations were successful in reducing VF recurrences (P<0.0001). After follow-up of 31±26 months, 39 (91%) had no VF recurrences. CONCLUSIONS: There are 2 phenotypes of ERS/J-wave syndrome: one with late depolarization abnormality as the underlying mechanism of high-amplitude J-wave elevation that predominantly resides in the RV outflow tract and RV inferolateral epicardium, serving as an excellent target for ablation, and the other with pure ERS devoid of VF substrates but with VF triggers that are associated with Purkinje sites. Ablation is effective in treating symptomatic patients with ERS/J-wave syndrome with frequent VF episodes.

Catheter Ablation of Refractory Ventricular Fibrillation Storm After Myocardial Infarction.

BACKGROUND: Ventricular fibrillation (VF) storm after myocardial infarction (MI) is a life-threatening condition that necessitates multiple defibrillations. Catheter ablation is a potentially effective treatment strategy for VF storm refractory to optimal medical treatment. However, its impact on patient survival has not been verified in a large population. METHODS: We conducted a multicenter, retrospective observational study involving consecutive patients who underwent catheter ablation of post-MI refractory VF storm without preceding monomorphic ventricular tachycardia. The target of ablation was the Purkinje-related ventricular extrasystoles triggering VF. The primary outcome was in-hospital and long-term mortalities. Univariate logistic regression and Cox proportional-hazards analysis were used to evaluate clinical characteristics associated with in-hospital and long-term mortalities, respectively. RESULTS: One hundred ten patients were enrolled (age, 65±11years; 92 men; left ventricular ejection fraction, 31±10%). VF storm occurred at the acute phase of MI (4.5±2.5 days after the onset of MI during the index hospitalization for MI) in 43 patients (39%), the subacute phase (>1 week) in 48 (44%), and the remote phase (>6 months) in 19 (17%). The focal triggers were found to originate from the scar border zone in 88 patients (80%). During in-hospital stay after ablation, VF storm subsided in 92 patients (84%). Overall, 30 (27%) in-hospital deaths occurred. The duration from the VF occurrence to the ablation procedure was associated with in-hospital mortality (odds ratio for each 1-day increase, 1.11 [95% CI, 1.03-1.20]; P=0.008). During follow-up after discharge from hospital, only 1 patient developed recurrent VF storm. However, 29 patients (36%) died, with a median survival time of 2.2 years (interquartile range, 1.2-5.5 years). Long-term mortality was associated with left ventricular ejection fraction <30% (hazard ratio, 2.54 [95% CI, 1.21-5.32]; P=0.014), New York Heart Association class ≥III (hazard ratio, 2.68 [95% CI, 1.16-6.19]; P=0.021), a history of atrial fibrillation (hazard ratio, 3.89 [95% CI, 1.42-10.67]; P=0.008), and chronic kidney disease (hazard ratio, 2.74 [95% CI, 1.15-6.49]; P=0.023). CONCLUSIONS: In patients with MI presenting with focally triggered VF storm, catheter ablation of culprit triggers is lifesaving and appears to be associated with short- and long-term freedom from recurrent VF storm. Mortality over the long-term follow-up is associated with the severity of underlying cardiovascular disease and comorbidities in this specific patient population.

Closed-loop stimulation as a physiological rate-modulated pacing approach based on intracardiac impedance to lower the atrial tachyarrhythmia burden in patients with sinus node dysfunction and atrial fibrillation.

INTRODUCTION: The effectiveness of rate-modulated pacing for the suppression of atrial fibrillation (AF) is controversial. Closed-loop stimulation (CLS) is a heart rate modulation technique based on the contractility of the right ventricle estimated by sensing myocardial impedance, and CLS can still adapt to the heart rate in conditions where there are no significant changes in acceleration or ventilation, such as emotional stress. We elucidated the association between CLS and atrial tachyarrhythmia (AT) burden in patients with sinus node dysfunction and paroxysmal AF history before pacemaker implantation. METHODS AND RESULTS: We retrospectively reviewed all consecutive patients who underwent pacemaker implantation for sinus node dysfunction with an AF history before implantation. Overall, 146 patients were analyzed, with fixed-rate pacing (FP) in 82, CLS in 31, and non-CLS rate modulation in 33 patients. The AF/AT episodes were detected in 98 patients during a 12-month period. The median AF/AT burden was 1.6% (interquartile: 0.0%, 11.0%) in FP; 0% (0.0%, 2.5%) in CLS, and 1.0% (0.1%, 9.3%) in non-CLS. The AF/AT burden was significantly lower for CLS than for FP and non-CLS rate modulation (P < .01 and P = .04, respectively). CLS was associated with lower risks of AF/AT occurrence (hazard ratio [HR], 0.31; P = .02) and AF/AT burden more than 5% (HR, 0.28; P = .05), even after adjusting for potential confounders. This association was independent of the percentage of atrial pacing. CONCLUSION: CLS was associated with lower AF/AT burden after pacemaker implantation in patients with sinus node dysfunction and AF history.

Preprocedural restoration of sinus rhythm and left atrial strain predict outcomes of catheter ablation for long-standing persistent atrial fibrillation.

INTRODUCTION: Catheter ablation (CA) for long-standing persistent atrial fibrillation (LS-AF) remains challenging. We aimed to explore whether sinus rhythm (SR) restoration and left atrium (LA) function after pretreatment with antiarrhythmic drugs (AAD's) and electrical cardioversion (ECV) predict procedural outcomes. METHODS AND RESULTS: We included 100 consecutive patients with LS-AF who were treated with AAD/ECV for at least 3 months before CA. The echocardiographic LA strain during reservoir phase (LASr) was assessed after pretreatment as a marker of LA fibrosis. The recurrence was recorded for ≥1 year after the last procedure. During a 34 ± 16-month follow-up period, the single and multiple procedures and pharmaceutically assisted success rates were 40% and 71%, respectively. Patients with preprocedural SR restoration and higher LASr showed a significantly higher recurrence-free probability after the last CA (logrank P = .001 and P < .001, respectively). Failure of preprocedural SR restoration and LASr ≤8.6% were independently associated with recurrence after the last CA (hazard ratio [HR]: 3.13, 95% confidence interval [CI]: 1.42-6.91, P = .005; HR: 3.89, 95% CI: 1.65-9.17, P = .002, respectively). These parameters added incrementally to the predictive value of AF duration and LA dilatation (P = .03 and P = .002, respectively) and improved the recurrence-risk stratification (net reclassification improvement = 0.39; 95% CI = 0.13-0.65; P = .003). CONCLUSION: In patients with LS-AF, the inability to restore SR and lower LASr after AAD/ECV treatment independently and incrementally predicts the recurrence after CA. These findings might be useful for determining LS-AF ablation candidates.