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Background: A recent randomized trial demonstrated that catheter ablation for atrial fibrillation (AF) in patients with heart failure with reduced ejection fraction (EF) is associated with a reduction in death or heart failure. However, the effect of catheter ablation for AF in patients with heart failure with mid-range or preserved EF is unclear., Methods and results: We screened 899 AF patients (72.4% male, mean age 68.4 years) with heart failure and left ventricular EF ≥40% from 2 Japanese multicenter AF registries: the Atrial Fibrillation registry to Follow the long-teRm Outcomes and use of aNTIcoagulants aftER Ablation (AF Frontier Ablation Registry) as the ablation group (525 patients who underwent ablation) and the Hokuriku-Plus AF Registry as the medical therapy group (374 patients who did not undergo ablation). Propensity score matching was performed in these 2 registries to yield 106 matched patient pairs. The primary endpoint was a composite of cardiovascular death and hospitalization for heart failure. At 24.6 months, the ablation group had a significantly lower incidence of the primary endpoint (hazard ratio 0.32; 95% confidence interval 0.13-0.70; P=0.004) than the medical therapy group., Conclusions: Compared with medical therapy, catheter ablation for AF in patients with heart failure and mid-range or preserved EF was associated with a significantly lower incidence of cardiovascular death or hospitalization for heart failure.

Introduction: Data are lacking on the extent to which patients with non-valvular atrial fibrillation (AF) who are aged ≥80 years benefit from ablation treatment. The question pertains especially to patients' postablation quality of life (QoL) and long-term clinical outcomes., Methods and Analysis: We are initiating a prospective, registry-based, multicentre observational study that will include patients aged ≥80 years with non-valvular AF who choose to undergo treatment by catheter ablation and, for comparison, such patients who do not choose to undergo ablation (either according to their physician's advice or their own preference). Study subjects are to be enrolled from 52 participant hospitals and three clinics located throughout Japan from 1 June 2022 to 31 December 2023, and each will be followed up for 1 year. The planned sample size is 660, comprising 220 ablation group patients and 440 non-ablation group patients. The primary endpoint will be the composite incidence of stroke/transient ischaemic attack (TIA) or systemic embolism (SE), another cardiovascular event, major bleeding and/or death from any cause. Other clinical events such as postablation AF recurrence, a fall or bone fracture will be recorded. We will collect standard clinical background information plus each patient's Clinical Frailty Scale score, AF-related symptoms, QoL (Five-Level Version of EQ-5D) scores, Mini-Mental State Examination (optional) score and laboratory test results, including measures of nutritional status, on entry into the study and 1 year later, and serial changes in symptoms and QoL will also be secondary endpoints. Propensity score matching will be performed to account for covariates that could affect study results., Ethics and Dissemination: The study conforms to the Declaration of Helsinki and the Ethical Guidelines for Clinical Studies issued by the Ministry of Health, Labour and Welfare, Japan. Results of the study will be published in one or more peer-reviewed journals., Trial Registration Number: UMIN000047023., Competing Interests: Competing interests: The following authors have potential conflicts of interest: YO received research funding from Bayer Healthcare, Daiichi-Sankyo, Bristol-Meyers Squibb, Nippon Boehringer Ingelheim, Pfizer and Boston Scientific Japan, and accepted remuneration from Bayer Healthcare, Daiichi-Sankyo and Bristol-Meyers Squibb. KNas accepted remuneration from Johnson & Johnson K.K. TK received lecture fees from Daiichi-Sankyo, Bristol-Myers Squibb, Bayer Healthcare, Boston Scientific and Medtronic Japan. HF accepted remuneration from Daiichi-Sankyo, Bayer Yakuhin, Nippon Boehringer Ingelheim, Johnson & Johnson K.K., Abbott Medical Japan, Medtronic Japan and Japan Lifeline. SN received speaker honoraria from Bayer Healthcare, Daiichi-Sankyo, Bristol-Meyers Squibb and Medtronic Japan. WS received grants from Daiichi Sankyo Co., Ltd, and Nippon Boehringer Ingelheim; and remuneration for lectures, presentations, speakers bureaus, manuscript writing or educational events from Daiichi Sankyo, Nippon Boehringer Ingelheim, Bristol-Meyers Squibb, K.K., Bayer Yakuhin, Pfizer, Ono Pharmaceutical and Medtronic Japan. YM received lecture fees from Bayer Healthcare, Daiichi-Sankyo, Bristol-Meyers Squibb, Nippon Boehringer Ingelheim, Johnson & Johnson K.K., Japan Lifeline K.K, Medtronic Japan, Pfizer and Boston Scientific Japan. SSu received research funding from Daiichi Sankyo and remuneration from Bristol-Myers Squibb and Daiichi Sankyo. MHar received research funding from BIOTRONIK Japan, Medtronic Japan, Abbott Japan, Japan Lifeline, Nihon Kohden and Boston Scientific Japan, and accepted remuneration from Nippon Boehringer Ingelheim, Daiichi-Sankyo, Bristol-Meyers Squibb, Medtronic Japan, Japan Life Line and Abbott Japan. TY received speaker honoraria from Medtronic Japan and Abbott Medical Japan. MTo received research funding from Japan Lifeline and consulting fee from Medtronic Japan. MTa belongs to the Section of Arrhythmia, Division of Cardiovascular Medicine, Department of Internal Medicine. This section supported by an endowment from Abbott Japan, Medtronic Japan and Boston Scientific Japan. MS is affiliated with an endowed division supported by BIOTRONIK Japan, Boston Scientific Japan K.K., Medtronic Japan and Abbott Medical Japan. AO taught courses endowed by BIOTRONIK, Abbott, Medtronic, Boston Scientific Japan and Japan Lifeline. KSa accepted remuneration from Abbott Japan, Medtronic Japan and Japan Lifeline. HKi accepted remuneration from Otsuka Pharmaceutical., AstraZeneca, Bristol-Meyers Squibb, Ono Pharmaceutical, Pfizer and Novo Nordisk. KMu received honoraria for Chugai Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, MSD, Kyowa Kirin, Yakult Pharmaceutical and Boehringer Ingelheim. KKus received speaker honoraria from Daiichi-Sankyo, Nippon Boehringer Ingelheim, Bayer Yakuhin, Pfizer and Medtronic Japan, and research grants from Medtronic Japan and JSR. KoM received speaker honoraria from Medtronic Japan and Abbott Japan, and research funding from Bristol-Meyers Squibb, Pfizer, Medtronic Japan, Japan Lifeline and Boston Scientific Japan., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Local impedance (LI) parameters of IntellaNav STABLEPOINT for successful pulmonary vein isolation (PVI) of atrial fibrillation (AF) remain unclear. The purpose of this study was to seek LI data achieving successful PVI., Methods: Consecutive AF patients who underwent catheter ablation with STABLEPOINT were prospectively enrolled in two centers. PVI was performed under a constant 35-or 40-watt power, 20-s duration, and >5-g contact force. The operators were blinded to the LI data. The characteristics of all ablation points with/without conduction gaps (Unsuccess or Success tags) after the first-attempt PVI were evaluated for the right/left PVs and anterior/posterior wall (RPV/LPV and AW/PW, respectively), and cutoff values of LI data were calculated for successful lesion formation., Results: A total of 5257 ablation points in 102 patients (65 [58-72] years old, 65.7% male) were evaluated. The LI drop values were higher in the Success tags than Unsuccess tags on the LPV-AW and RPV-AW/PW (p < .001), except for the LPV-PW (p = .105). The %LI drop values (LI drop/initial LI) were higher for the Success tags in all areas (15.8 [12.2%-19.6%] vs. 11.6 [9.7%-15.6%] in LPV-AW: p < .001, 15.0 [11.5%-19.3%] vs. 11.4 [8.7%-17.3%] in LPV-PW: p = .035, 15.3 [11.5%-19.4%] vs. 9.9 [8.1%-13.7%] in RPV-AW: p < .001, and 13.3 [10.1%-17.4%] vs. 8.1 [6.3%-9.5%] in RPV-PW, p < .001). The LI drop and %LI drop cutoff values were 20.0 ohms and 11.6%, respectively., Conclusions: An insufficient LI drop with STABLEPOINT was associated with a gap formation during PVI, and the best cutoff values for the LI drop and %LI drop were 20.0 ohms and 11.6%, respectively., (© 2022 Wiley Periodicals LLC.)

Aims: The analysis of heart rate (HR) changes, such as the HR variability or HR turbulence, has been reported as a marker of cardiovascular events during sinus rhythm; however, those relationships during atrial fibrillation (AF) remain controversial, and those parameters are not commonly used in AF patients. We sought to investigate the relationship between a simple index focused on the HR and heart failure (HF) events in patients with permanent AF., Methods and Results: We enrolled 198 patients with permanent AF and evaluated the HR range, defined as the maximum HR minus the minimum HR on 24-h Holter electrocardiogram recordings. The patients were divided into two groups, i.e., the larger (n = 101) and smaller (n = 97) HR range (HRR) groups, determined by the median value. The HF events were defined as hospitalizations for HF or urgent hospital visits due to exacerbations of one's HF status. The observation period of this study was set at 5 years from registration. The median age was 73 (68-77) years, and 29% were female. The median HRR was 84 (63-118) beats per minutes (bpm). During the observational period of 1825 days (median), HF events occurred in 37 (0.047 per patient-year) patients. In a log-rank test, the larger HRR group had more frequent HF events than the smaller HRR group (P = 0.0078). In the adjusted Cox proportional hazards model using the significantly different factors from the univariate analysis (Model 1) and factors and medications associated with HF (Model 2), the larger HRR group had a higher prevalence of HF events than the smaller HRR group for both models [Model 1, adjusted hazard ratio = 3.21, 95% confidence interval (CI) 1.593-6.708, P = 0.0009; Model 2, adjusted hazard ratio = 3.12, 95% CI 1.522-6.685, P = 0.002]. When analysed using the time-dependent Cox proportional hazards model, the HRR was associated with HF with a statistically significant difference in both the univariate and multivariate analyses [hazard ratio = 1.01, 95% CI 1.006-1.020, P = 0.0002; Model 1, adjusted hazard ratio = 1.02, 95% CI 1.011-1.027, P < 0.0001; Model 2, adjusted hazard ratio = 1.01, 95% CI 1.008-1.021, P = 0.0003). There was no significant difference in the chronotropic medications between the two groups., Conclusions: In patients with permanent AF, a larger HRR was associated with HF events., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: Direct comparison studies about the incidence of esophagogastric complications between radiofrequency (RF) and cryoballoon (CB) catheter ablation (CA) for atrial fibrillation (AF) have been scarce. We sought to elucidate the relationship between the pulmonary vein isolation (PVI) modalities and esophagogastric complications., Methods: The study population consisted of 254 patients who underwent CA for AF from November 2017 to October 2018. Finally, 160 patients were enrolled and divided into the RF and CB groups. Esophageal ulcers, gastric hypomotility, and exfoliative esophagitis detected by esophagogastroduodenoscopy were defined as esophagogastric complications in this study., Results: The median age was 68 years old, with 34% being females. Esophagogastric complications were observed in 42.5% of patients who underwent CA. According to the detailed esophagogastric complications, the RF group had a higher prevalence of esophageal ulcers than the CB group (19% vs. 0%, p < .0001). There was no significant difference between the two groups regarding gastric hypomotility and exfoliative esophagitis (18% vs. 28%; p = .15 and 16% vs. 21%; p = .42, respectively)., Conclusion: Asymptomatic esophagogastric complications were common in CA for AF. The incidence of esophageal ulcers was higher in the RF group than in the CB group, whereas the other esophagogastric complications did not significantly differ., (© 2022 Wiley Periodicals LLC.)

Background: Atrial fibrillation (AF) is associated with an increased risk of heart failure (HF), stroke, and death. Although fibrillation cycle length (FCL) is used as a surrogate for atrial refractoriness, its impact on outcomes remains unclear. This study aimed to identify predictors of cardiovascular events, including FCL, in patients with long-standing persistent AF., Methods: The study included 190 consecutive patients with long-standing persistent AF (mean age 74 years, 74% male). Patients with valvular AF or hemodialysis-dependent end-stage renal disease and those on anti-arrhythmic drugs were excluded. The primary composite outcome was occurrence of cardiovascular events (myocardial infarction, HF), cerebrovascular events (stroke, transient ischemic attack), and all-cause death. FCL was calculated by fast Fourier transformation analysis of fibrillation waves in the surface electrocardiogram., Results: Over a median follow-up of 2.6 years, the primary outcome occurred in 31 patients (cardiovascular events, n = 18; cerebrovascular events, n = 8; all-cause death, n = 5). In multivariate analysis, longer FCL and history of HF were independent predictors of these outcomes. In a Cox proportional hazards model adjusted for age, sex, and history of HF, patients with an FCL > 160 ms (cut-off determined by receiver-operating characteristic curve analysis) were at increased risk of the outcome (hazard ratio 12.9; 95% confidence interval 4.99-44.10; p < 0.001)., Conclusions: FCL was independently associated with cardiovascular outcomes in patients with long-standing persistent AF., (© 2021. Springer Japan KK, part of Springer Nature.)

The recurrence of atrial fibrillation (AF) after catheter ablation (CA) is still an unsolved issue. Although structural remodeling is relatively well defined, the method to assess electrical remodeling of the atrium is not well established. In this study, we evaluated the relationship between atrial conduction properties and recurrence after CA for AF. One hundred six consecutive patients (66 ± 11 years old, male: 68%) who underwent CA for AF with a CARTO system from July 2016 to July 2019 were enrolled in this study. An activation map of both atria was constructed to precisely evaluate the total conduction time, distance, and conduction velocity between the earliest and latest activation sites during sinus rhythm. All parameters were compared between the patients with or without AF recurrence. Of the patients, 27 had an AF recurrence (Rec group). The left atrial (LA) conduction velocity was significantly slower in the Rec group than in the non-Rec group (101.2 ± 17.9 vs. 116.9 ± 18.0 cm/s, P < 0.01). Likewise, the right atrial (RA) conduction velocity was significantly slower in the Rec group than in the non-Rec group (81.1 ± 17.5 vs. 103.6 ± 25.4 cm/s, P < 0.01). A multivariate logistic analysis demonstrated that the LA and RA conduction velocities were independent predictors of AF recurrence, with adjusted odds ratios of 0.95 (95% confidential interval: 0.91-0.98, P < 0.01) and 0.94 (0.89-0.98, P < 0.01), respectively. In conclusion, slower conduction velocity of the atrium was associated with AF recurrence after pulmonary vein isolation., (© 2021. Springer Japan KK, part of Springer Nature.)

The impact of catheter ablation for atrial fibrillation (AF) on cardiovascular events and mortality is controversial. We investigated the impact of sinus rhythm maintenance on major adverse cardiac and cerebrovascular events after AF ablation from a Japanese multicenter cohort of AF ablation. We investigated 3326 consecutive patients (25.8% female, mean age 63.3 ± 10.3 years) who underwent catheter ablation for AF from the atrial fibrillation registry to follow the long-term outcomes and use of anti coagulants after ablation (AF frontier ablation registry). The primary endpoint was a composite of stroke, transient ischemic attack, cardiovascular events, and all-cause death. During a mean follow-up of 24.0 months, 2339 (70.3%) patients were free from AF after catheter ablation, and the primary composite endpoint occurred in 144 (4.3%) patients. The AF nonrecurrence group had a significantly lower incidence of the primary endpoint (1.8 per 100 person-years) compared with the AF recurrence group (3.0 per 100 person-years, p = 0.003). The multivariate analysis revealed that freedom from AF (hazard ratio 0.61, 95% confidence interval 0.44-0.86, p = 0.005) was independently associated with the incidence of the composite event. In the multicenter cohort of AF ablation, sinus rhythm maintenance after catheter ablation was independently associated with lower rates of major adverse cardiac and cerebrovascular events., (© 2021. Springer Japan KK, part of Springer Nature.)

Background: It is unclear whether there are differences in the clinical factors between atrial fibrillation (AF) recurrence and adverse clinical events (AEs), including stroke/transient ischemic attack (TIA), major bleeding, and death, after AF ablation., Methods and results: We examined the data from a retrospective multicenter Japanese registry conducted at 24 cardiovascular centers between 2011 and 2017. Of the 3,451 patients (74.1% men; 63.3±10.3 years) who underwent AF ablation, 1,046 (30.3%) had AF recurrence and 224 (6.5%) suffered AEs (51 strokes/TIAs, 71 major bleeding events, and 36 deaths) over a median follow-up of 20.7 months. After multivariate adjustment, female sex, persistent and long-lasting persistent AF (vs. paroxysmal AF), and stepwise increased left atrial diameter (LAd) quartiles were significantly associated with post-ablation recurrences. A multivariate analysis revealed that an age ≥75 years (vs. <65 years), body weight <50 kg, diabetes, vascular disease, left ventricular (LV) ejection fraction <40% (vs. ≥50%), Lad ≥44 mm (vs. <36 mm), and creatinine clearance <50 mL/min were independently associated with AE incidences, but not with recurrences., Conclusions: This study disclosed different determinants of post-ablation recurrence and AEs. Female sex, persistent AF, and enlarged LAd were determinants of post-ablation recurrence, whereas an old age, comorbidities, and LV and renal dysfunction rather than post-ablation recurrence were AEs determinants. These findings will help determine ablation indications and post-ablation management.

Objective: Patients with coronary artery disease (CAD) and atrial fibrillation (AF) can be treated with multiple antithrombotic therapies including antiplatelet and anticoagulant therapies; however, this has the potential to increase bleeding risk. Here, we aimed to evaluate the efficacy and safety of P2Y 12 inhibitors and aspirin in patients also receiving anticoagulant therapy., Methods: We evaluated patients from the Atrial Fibrillation and Ischaemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial who received rivaroxaban plus an antiplatelet agent; the choice of antiplatelet agent was left to the physician's discretion. The primary efficacy and safety end points, consistent with those of the AFIRE trial, were compared between P2Y 12 inhibitors and aspirin groups. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularisation or death from any cause. The primary safety end point was major bleeding according to the International Society on Thrombosis and Haemostasis criteria., Results: A total of 1075 patients were included (P2Y 12 inhibitor group, n=297; aspirin group, n=778). Approximately 60% of patients were administered proton pump inhibitors (PPIs) and there was no significant difference in PPI use in the groups. There were no significant differences in the primary end points between the groups (efficacy: HR 1.31; 95% CI 0.88 to 1.94; p=0.178; safety: HR 0.79; 95% CI 0.43 to 1.47; p=0.456)., Conclusions: There were no significant differences in cardiovascular and bleeding events in patients with AF and stable CAD taking rivaroxaban with P2Y 12 inhibitors or aspirin in the chronic phase., Trial Registration Number: UMIN000016612; NCT02642419., Competing Interests: Competing interests: HF reports personal fees from Nippon Boehringer Ingelheim and Daiichi Sankyo. JA reports personal fees from Bayer Yakuhin and Sanofi, and grants and personal fees from Daiichi Sankyo. SY reports grants from Takeda Pharmaceutical, Abbott and Boston Scientific, and personal fees from Daiichi Sankyo and Bristol-Meyers. KKa reports Grants-in-Aid for Scientific Research (20K08451) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and grants and personal fees from Bayer Yakuhin and Daiichi Sankyo. MA reports grants from the Japan Agency for Medical Research and Development (AMED), personal fees from Bristol-Myers Squibb and Nippon Boehringer Ingelheim, and grants and personal fees from Bayer Yakuhin and Daiichi Sankyo. TM reports grants from the Japan Cardiovascular Research Foundation and personal fees from Nippon Boehringer Ingelheim, Daiichi Sankyo, AstraZeneca and Bayer Yakuhin. MN reports grants and personal fees from Bayer Yakuhin, Daiichi Sankyo and Sanofi, and personal fees from Bristol-Myers Squibb and Nippon Boehringer Ingelheim. KMi reports personal fees from Amgen Astellas BioPharma, Astellas Pharma, MSD, Bayer Yakuhin, Sanofi, Takeda Pharmaceutical, Daiichi Sankyo, Nippon Boehringer Ingelheim and Bristol-Myers Squibb. NH reports grants and personal fees from Bayer Yakuhin, grants from Nippon Boehringer Ingelheim and personal fees from Bristol-Myers Squibb. KKi reports grants from the Japan Cardiovascular Research Foundation; grants and personal fees from Bayer Yakuhin, Daiichi Sankyo, Sanofi, MSD and AstraZeneca; and personal fees from Bristol-Myers Squibb and Nippon Boehringer Ingelheim. AH reports grants and personal fees from Boston Scientific Japan, Otsuka Pharmaceutical, Sanofi, Astellas Pharma, Bristol-Myers Squibb, Daiichi Sankyo and Bayer Yakuhin; grants from Fukuda Denshi, Abbott Japan, Japan Lifeline, Takeda Pharmaceutical and Sumitomo Dainippon Pharma; and personal fees from Toa Eiyo, Nippon Boehringer Ingelheim, Amgen Astellas BioPharma and AstraZeneca. HO reports personal fees from Towa Pharmaceutical, Bristol-Meyers Squibb, Pfizer, Toa Eiyo, Bayer Yakuhin and Novartis Pharma. All other authors declare no financial relationships relevant to the contents of this paper., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although the coexistence of heart failure (HF) with atrial fibrillation (AF) exhibits poor outcomes, the correlation between AF status and outcomes after exercise-based cardiac rehabilitation (CR) remains unclear in older individuals with HF., Objective: This retrospective study aimed to investigate the impact of AF on changes in physical function and prognosis after CR in older individuals with HF., Methods: We enrolled consecutive individuals with HF who were ≥ 60 years old who received 5-month CR. Exercise-based CR involved moderate-intensity aerobic exercises tailored to each participant. Isometric quadriceps strength (QS) and 6-min walk distance (6MWD) were measured as physical function, at baseline and 5 months thereafter. We compared QS and 6MWD changes from baseline to the 5-month observation period (QS and 6MWD) between sinus rhythm and AF. We examined composite incidence of all-cause death or unplanned readmission after 5-month CR and analysed the association of QS and 6MWD with clinical events, estimating adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs)., Results: Of the 764 participants, 476 (62%) had sinus rhythm, and 288 (38%) had AF. AF was associated with lower QS and 6MWD at baseline. The 2 groups did not differ in QS and 6MWD after adjusting for clinical confounders. With sinus rhythm, greater change in QS and 6MWD was significantly associated with reduced incidence of clinical events (QS tertile: aHR 0.75 [95% CI 0.60-0.92]; 6MWD tertile: aHR 0.59 [95% CI 0.46-0.76]); however, with AF, this association was observed for only 6MWD and not QS (QS: aHR 0.92 [95% CI 0.72-1.17]; 6MWD: aHR 0.73 [95% CI 0.54-0.98])., Conclusion: AF in older individuals with HF is associated with reduced physical function at baseline but not response to exercise-based CR. Furthermore, positive response of physical function after CR is associated with better prognosis regardless of AF, which suggests that exercise-based CR is potentially effective in older individuals with HF and AF., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Purpose: Ablation index (AI) is a useful tool of the CARTO® system to make effective lesions during pulmonary vein isolation (PVI) for atrial fibrillation (AF). However, the optimal distance between neighboring ablation points (interlesion distance (ILD)) is still unclear. Here, we evaluated the optimal ILDs in the AI-guided PVI., Methods: Forty-nine AF patients who underwent AI-guided PVI in our institute from July 2018 to March 2019 were retrospectively enrolled in this study. Target AI was set at 500 and 400 for anterior and posterior walls, respectively, and we compared the ILDs with and without electrical gaps after a first encircling PVI., Results: In both PV, the ILDs with electrical gaps were longer than those without electrical gaps. The best cutoff values of ILD to detect the electrical gaps using the ROC curve were 5.4 mm for the RPV anterior wall (AUC, 0.67; sensitivity, 0.42; specificity, 0.84, P < 0.01) and 4.4 mm for the RPV posterior wall (AUC, 0.68; sensitivity, 0.91; specificity, 0.39, P < 0.01). Similarly, the best cutoff values of ILD were 5.5 mm for the LPV anterior wall (AUC, 0.74; sensitivity, 0.65; specificity, 0.82, P < 0.01) and 5.1 mm for the LPV posterior wall (AUC, 0.67; sensitivity, 0.79; specificity, 0.53, P =0.03)., Conclusion: The optimal interlesion distances for PVI were different in each PV segment. To achieve the first-pass isolation, less than 5.4/4.4 mm for the RPV anterior/posterior and 5.5/5.1 mm for the LPV anterior/posterior walls of interlesion distances were the best cutoff values in the patients with AF., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Whether ablation for atrial fibrillation (AF) is, in terms of clinical outcomes, beneficial for Japanese patients has not been clarified. Drawing data from 2 Japanese AF registries (AF Frontier Ablation Registry and SAKURA AF Registry), we compared the incidence of clinically relevant events (CREs), including stroke/transient ischemic attack (TIA), major bleeding, cardiovascular events, and death, between patients who underwent ablation (n = 3451) and those who did not (n = 2930). We also compared propensity-score matched patients (n = 1414 in each group). In propensity-scored patients who underwent ablation and those who did not, mean follow-up times were 27.2 and 35.8 months, respectively. Annualized rates for stroke/TIA (1.04 vs. 1.06%), major bleeding (1.44 vs. 1.20%), cardiovascular events (2.15 vs. 2.49%) were similar (P = 0.96, 0.39, and 0.35, respectively), but annualized death rates were lower in the ablation group than in the non-ablation group (0.75 vs.1.28%, P = 0.028). After multivariate adjustment, the risk of CREs was statistically equivalent between the ablation and non-ablation groups (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.71-1.11), but it was significantly low among patients who underwent ablation for paroxysmal AF (HR 0.68 [vs. persistent AF], 95% CI 0.49-0.94) and had a CHA 2 DS 2 -VASc score  < 3 (HR 0.66 [vs. CHA 2 DS 2 -VASc score ≥ 3], 95% CI 0.43-0.98]). The 2-year risk reduction achieved by ablation may be small among Japanese patients, but AF ablation may benefit those with paroxysmal AF and a CHA 2 DS 2 -VASc score < 3.

Background: Gastric hypomotility (GH) is a possible complication of catheter ablation (CA) for atrial fibrillation (AF). However, it is unclear which factors are associated with GH. We sought to elucidate the relationship between the CA procedure and GH., Methods: The study population consisted of 254 patients who underwent CA for AF from November 2017 to October 2018. Finally, 119 patients were enrolled and divided into two groups: with or without GH (GH or non-GH groups). To evaluate the association with GH, the clinical backgrounds and procedure characteristics of the radiofrequency CA (RFCA) were compared between the two groups., Results: The median age was 69 years old with 34% of female. GH were observed in 27.7% of patients who underwent RFCA, which was significantly higher than that in the cohort of patients who underwent esophago-gastro-duodenoscopy during the same time period (1.9%: 151 in 8063 patients, p < 0.0001). According to the detailed RFCA procedure, additional posterior wall isolation with pulmonary vein isolation (PVI) had a higher prevalence of GH than that with only PVI (54.8% vs. 18.2%; odds ratio 5.46, 95%CI 2.24-13.32, p = 0.0002). After an adjustment using a multivariate logistic analysis, a posterior wall isolation with the PVI was identified as the only independent predictor for GH (odds ratio 5.01, 95%CI 1.94-13.43, p = 0.0009)., Conclusions: Additional posterior wall isolation with PVI was associated with gastric hypomotility., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background Recent clinical trials have demonstrated the possible pleiotropic effects of SGLT2 (sodium-glucose cotransporter 2) inhibitors in clinical cardiovascular diseases. Atrial electrical and structural remodeling is important as an atrial fibrillation (AF) substrate. Methods and Results The present study assessed the effect of canagliflozin (CAN), an SGLT2 inhibitor, on atrial remodeling in a canine AF model. The study included 12 beagle dogs, with 10 receiving continuous rapid atrial pacing and 2 acting as the nonpacing group. The 10 dogs that received continuous rapid atrial pacing for 3 weeks were subdivided as follows: pacing control group (n=5) and pacing+CAN (3 mg/kg per day) group (n=5). The atrial effective refractory period, conduction velocity, and AF inducibility were evaluated weekly through atrial epicardial wires. After the protocol, atrial tissues were sampled for histological examination. The degree of reactive oxygen species expression was evaluated by dihydroethidium staining. The atrial effective refractory period reduction was smaller ( P =0.06) and the degree of conduction velocity decrease was smaller in the pacing+CAN group compared with the pacing control group ( P =0.009). The AF inducibility gradually increased in the pacing control group, but such an increase was suppressed in the pacing+CAN group ( P =0.011). The pacing control group exhibited interstitial fibrosis and enhanced oxidative stress, which were suppressed in the pacing+CAN group. Conclusions CAN and possibly other SGLT2 inhibitors might be useful for preventing AF and suppressing the promotion of atrial remodeling as an AF substrate.

Direct oral anticoagulants (DOACs) are sometimes prescribed at off-label under-doses for patients who have undergone ablation for atrial fibrillation (AF). This practice may be an attempt to balance the risk of bleeding against that of stroke or AF recurrence.We examined outcomes of 1163 patients who continued use of a DOAC after ablation. The patients were enrolled in a large (3530 patients) multicenter registry in Japan. The study patients were classified as 749 (64.4%) appropriate standard-dose DOAC users, 216 (18.6%) off-label under-dose DOAC users, and 198 (17.0%) appropriate low-dose DOAC users.Age and CHA 2 DS 2 -VASc scores differed significantly between DOAC dosing regimens, with patients given an appropriate standard-dose being significantly younger (63.3 ± 9.4 versus 64.8 ± 9.5 versus 73.2 ± 6.8 years, P < 0.0001) and lower (2.1 ± 1.5 versus 2.4 ± 1.6 versus 3.4 ± 1.4, P < 0.0001) than those given an off-label under-dose or an appropriate low-dose. During the median 19.0-month follow-up period, the AF recurrence rate was similar between the appropriate standard-dose and off-label under-dose groups but relatively low in the appropriate low-dose group (42.5% versus 41.2% versus 35.4%, P = 0.08). Annualized rates of thromboembolic events, major bleeding, and death from any cause were 0.47%, 0.70%, and 0.23% in the off-label under-dose group, while those rates were 0.74%, 0.73%, and 0.65% in the appropriate standard-dose, and 1.58%, 2.12%, and 1.57% in the appropriate low-dose groups.In conclusion, the clinical adverse event rates for patients on an off-label under-dose DOAC regimen after ablation, predicated on careful patient evaluations, was not high as seen with that of patients on a standard DOAC dosing regimen.

Optimal antithrombotic strategy for atrial fibrillation (AF) patients with a history of percutaneous coronary intervention (PCI) has been under debate. The actual prescription trend of antithrombotic therapy for these patients remains unclear, especially in chronic phase.Patients with AF having at least a 1-year history of PCI were retrospectively evaluated in 2010, 2012, 2014, and 2016. A total of 266 patients were finally enrolled in this study. The proportion of patients prescribed with oral anticoagulants (OACs) gradually increased over the study period (56%, 67%, 73%, and 74% in 2010, 2012, 2014, and 2016, respectively). According to the type of OACs, the proportion of direct oral anticoagulant (DOAC), launched in 2011, increased compared with warfarin (DOAC versus warfarin = 3% versus 64% in 2012, 24% versus 49% in 2014, and 32% versus 42% in 2016). Single antiplatelet therapy (SAPT) with OAC was the most popular prescription every year, and its proportion increased over the study period (41%, 44%, 55%, and 59%, respectively). The proportion of OAC monotherapy gradually increased (2%, 3%, 8%, and 9%, respectively), whereas that of triple therapy, i.e., dual antiplatelet therapy with OAC, gradually decreased (14%, 22%, 8%, and 5% in 2010, 2012, 2014, and 2016, respectively).Antithrombotic therapy trends for AF patients with a history of PCI were changing every year. The prescription rate of triple therapy gradually decreased, in contrast, that of OAC monotherapy gradually increased from 2010 to 2016. However, the evidence for OAC monotherapy in these patients remains insufficient.

Background: The safety of discontinuing oral anticoagulant (OAC) after ablation for atrial fibrillation (AF) in Japanese patients has not been clarified., Methods and results: A study based on the Atrial Fibrillation registry to Follow the long-teRm Outcomes and use of aNTIcoagulants aftER Ablation (AF Frontier Ablation Registry) was conducted. Data were collected from 3,451 consecutive patients (74.1% men; age, 63.3±10.3 years) who had undergone AF ablation at any of 24 cardiovascular centers in Japan between August 2011 and July 2017. During a 20.7-month follow-up period, OAC therapy was discontinued in 1,836 (53.2%) patients; 51 patients (1.5%) suffered a stroke/transient ischemic attack (TIA), 71 (2.1%) suffered major bleeding, and 36 (1.0%) died. Patients in whom OAC therapy was discontinued were significantly younger than those in whom OACs were continued, and their CHA 2 DS 2 -VASc scores were significantly lower. The incidences of stroke/TIA, major bleeding, and death were significantly lower among these patients. Upon multivariate adjustment, stroke events were independently associated with relatively high baseline CHA 2 DS 2 -VASc scores but not with OAC status., Conclusions: Although the incidences of stroke/TIA, major bleeding, and death were relatively low among patients for whom OAC therapy was discontinued, stroke/TIA occurrence was strongly associated with a high baseline stroke risk rather than with OAC status. Thus, discontinuation of OAC therapy requires careful consideration, especially in patients with a high baseline stroke risk.

We have shown that a dipeptidyl peptidase 4 (DPP-4) inhibitor suppresses atrial remodeling in a canine atrial fibrillation (AF) model. Glucagon-like peptide-1 (GLP-1) is increased by DPP-4 inhibitors. However, it is not clear whether GLP-1 is involved in the suppression of atrial remodeling. In this study, we evaluated the effect of liraglutide (a GLP-1 analog) on atrial electrophysiological changes using the same canine AF model. We established a canine AF model using continuous 3-week rapid atrial stimulation in seven beagle dogs divided into two groups: a liraglutide group with four dogs (3-week atrial pacing with liraglutide (150 µg/kg/day) administration) and a pacing control group with three dogs (3-week pacing without any medicine). We evaluated the atrial effective refractory period (AERP), conduction velocity (CV), and AF inducibility every week during the protocol using implanted epicardial wires against the surfaces of both atria. In the pacing control group, the AERP was gradually shortened and the CV was decreased along the time course. In the liraglutide group, the AERP was similarly shortened as in the pacing control group (94 ± 4% versus 85 ± 2%, respectively; p = 0.5926), but the CV became significantly higher than that in the pacing control group after 2 and 3 weeks (95 ± 4 versus 83 ± 5%, respectively; p = 0.0339). The AF inducibility was gradually increased in the pacing control group, but it was suppressed in the liraglutide group (5 ± 9% versus 73 ± 5%; p = 0.0262). Liraglutide suppressed electrophysiological changes such as AF inducibility and CV decrease in our canine AF model.

Anticoagulants are prescribed for prevention of thromboembolic events (TE) of atrial fibrillation (AF), however, their effects have a negative impact on disastrous bleeding outcomes. Idarucizumab was developed to reverse the anticoagulation effects of dabigatran. This study aimed to retrospectively investigate the clinical efficacy and safety of idarucizumab in the setting of progressive emergent bleeding events associated with catheter ablation (CA). Dabigatran is given uninterruptedly as an anticoagulant in patients undergoing CA of AF. The capacity of idarucizumab to reverse the anticoagulant effects of dabigatran in patients with cardiac tamponade associated with CA was examined by measuring the activated partial thromboplastin time (aPTT), active clotting time (ACT), and prothrombin international normalizing ratio (PT-INR). The primary endpoint was effective hemostasis. This analysis included 21 patients receiving idarucizumab, given for restoration of hemostasis. In all 21 patients, hemostasis was restored at a median of 205.6 ± 14.8 min. Normal intraoperative cessation of bleeding was reported in 16 patients, and completion of hemostasis was also ascertained in the remaining four within 5 h. No TEs occurred within 72 h after the idarucizumab administration. Despite a significant reduction in the aPTT and ACT, no significant change was observed in PT-INR after administering idarucizumab. In emergency situations, idarucizumab was able to reverse dabigatran within a relatively short period without any serious adverse events.

Background: The relationship between atrial high-rate episode (AHRE) burden (i.e., the frequency of atrial tachyarrhythmia) and heart failure (HF) risk is unclear. We hypothesized that new-onset and higher burden of AHRE are associated with HF., Methods and results: We included 104 consecutive patients with cardiac implantable electronic devices (CIEDs) capable of continuous atrial rhythm monitoring. Patients with AF history were excluded. To stratify patients, AHREs were evaluated only during the initial 1 year after CIED implantation. The primary endpoint was all-cause death or new-onset or worsening HF that required unplanned hospitalization or readjustment of HF drug therapy. At 1 year after CIED implantation, 34/104 patients (33%) exhibited AHREs. No difference in basal clinical characteristics except for left ventricular ejection fraction between patients with and without new-onset AHREs was found. AHRE groups had more HF events than the non-AHRE group. All patients were divided into 3 groups based on AHRE burden: none, low, and high. Worsening HF was observed in 12 patients (12%). Cox hazard analysis revealed that AHRE and higher AHRE burden were independent predictive factors for worsening HF. The high group showed a higher risk for HF than the non-AHRE groups, but no significant difference was found between the low- and non-AHRE groups., Conclusions: New-onset higher AHRE burden was associated with subsequent risk for HF in patients with CIEDs.

Dipeptidyl peptidase 4 (DPP-4) inhibitors have recently been reported to exhibit additional cardioprotective effects; however, their effect in atrial remodeling, such as in atrial fibrillation (AF), remains unclear. In this study, the effect of linagliptin on atrial electrical and structural remodeling was evaluated in a canine AF model. Sixteen beagle dogs with 3-week atrial rapid stimulation were divided into the linagliptin group (9 mg/kg/day, n = 8) and pacing control group (n = 8). Three additional dogs without rapid pacing were assigned into non-pacing group, which was used as sham in this study. In the dogs with rapid pacing, the atrial effective refractory period (AERP), conduction velocity (CV), and AF inducibility were evaluated and blood was sampled every week. After the entire protocol, atrial tissue was sampled for histological examinations using HE, Azan, and dihydroethidium (DHE) staining to evaluate any tissue damage or oxidative stress. The pacing control group exhibited a gradual AERP shortening and CV decrease along the time course as previously reported. In the linagliptin group, the AERP shortening was not affected, but the CV decrease was suppressed in comparison to the control group (p < 0.05). The AF inducibility was increased in the control group and suppressed in the linagliptin group (p < 0.05). The control group exhibited tissue fibrosis, the degree of which was suppressed in the linagliptin group. DHE staining exhibited suppression of the reactive oxygen species expression in the linagliptin group in comparison to the pacing control group. Linagliptin, a DPP-4-inhibitor, suppressed the AF inducibility, CV decrease, and overexpression of oxidative stress in the canine AF model. Such suppressive effects of linagliptin on AF in the canine model may possibly be related to the anti-oxidative effect.

In a canine rapid atrial stimulation model of atrial fibrillation (AF), we have demonstrated an increased production of reactive oxygen species (ROS) along with electrical and structural remodeling. In the present study, we hypothesized that antioxidants can suppress atrial remodeling canines with AF. We therefore evaluated the effect of febuxostat, a xanthine oxidase (XO) inhibitor and a pure antioxidant, on atrial remodeling.AF was produced by performing a 3-week rapid atrial pacing (400 bpm) in 13 dogs divided into three groups: pacing + febuxostat group (n = 5; atrial pacing with 50 mg/day of febuxostat (administration); pacing control group (n = 5; atrial pacing without any drug administration); and non-pacing group (n = 3). Electrophysiological studies were conducted in the first 2 groups every week. Atrial tissue fibrosis was evaluated by Azan and immunofluorescent staining of fibronectin. Oxidative stress was evaluated by DHE and FCF-DA staining.Shortening of the refractory period and increase in AF inducibility appeared gradually in the pacing control group, but such changes were suppressed in the pacing + febuxostat group (P = 0.05). The pacing control group showed increase in fibrosis, which was suppressed in the febuxostat group. In DHE and DCF-DA staining, the pacing control group showed an increase in oxidative stress, which was suppressed in the pacing + febuxostat group. The pacing control group exhibited fibronectin expression, which was suppressed in the pacing + febuxostat group.The antioxidant effect of febuxostat may achieve an inhibition of new-onset AF in canines.

Background: Distinction of paroxysmal atrial fibrillation (PAF) from non-PAF is important in clinical practice, but this is often difficult at the time of first documented AF. Given that fibrillation cycle length (FCL) is longer in PAF than in non-PAF, the aim of this study was to compare various clinical parameters including FCL to establish a scoring system to distinguish PAF and non-PAF., Methods and results: The subjects consisted of 382 consecutive patients with AF on digital ECG at the present institute between 2008 and 2011. They were divided into PAF and non-PAF groups according to the following clinical course. Propensity score matching yielded 88 matched patient pairs with similar mean age and gender between the 2 groups. FCL was evaluated using customized fibrillation wave analyzer with fast Fourier transform analysis. On multivariate analysis, higher HR, longer FCL, and smaller LAD were independent predictors of PAF. For the scoring, cut-offs for each parameter were determined according to highest sensitivity and specificity on the ROC curves, and 1 point assigned for each parameter. Using this scoring system, 2 points detected PAF with 64% sensitivity and 84% specificity., Conclusions: We propose a scoring system including FCL to distinguish PAF from non-PAF. Further studies are needed to validate the results.

Background: Dabigatran etexilate (DE), an effective direct oral anticoagulant for patients with atrial fibrillation (AF), should be carefully used in patients with renal insufficiency. Data on the safety of DE in Japanese "real world" patients with mildly impaired renal function are limited. We hypothesized that low-dose DE (110mg, twice daily) could be safely used in Japanese AF patients with mildly impaired renal function compared to those with preserved renal function., Methods and Results: One hundred ninety-six consecutive AF patients taking low-dose DE were retrospectively enrolled in this study, and were divided into two groups: preserved creatinine clearance (CCr ≥50ml/min; n=127) and reduced CCr (30-49ml/min; n=69). Baseline characteristics including CHADS 2 , CHA 2 DS 2 -VASc, and HAS-BLED scores were evaluated. Activated partial thromboplastin time (aPTT) was measured as a surrogate marker of the anticoagulant activity of DE, which was evaluated at 661 time points in total and the data were divided into five time windows after the last DE intake. The incidence of bleeding complications was compared between the two groups of reduced and preserved CCr. Reduced CCr group showed higher age (76.9±6.3 years vs. 67.6±6.7 years), higher CHADS 2 (2.6±1.4 vs. 1.8±1.2), higher CHA 2 DS 2 -VASc (4.3±1.6 vs. 3.2±1.6), and higher HAS-BLED (2.3±1.0 vs. 2.0±1.0) scores in comparison with preserved CCr group (p<0.01, respectively). There was no difference in aPTT over the entire time windows between the two groups. The incidence of total bleeding events was not significantly different between the two groups (reduced vs. preserved CCr=2/69 vs. 2/127)., Conclusion: Low-dose DE was safe in AF patients with mildly reduced CCr., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Aliskiren, a direct renin inhibitor is expected to achieve sufficient suppression of renin-angiotensin system. We evaluated the effect of aliskiren on the electrical and structural remodeling in a canine atrial fibrillation (AF) model. Twenty-eight dogs were divided into three groups: (1) pacing control group (n = 12), with continuous atrial rapid pacing for 3 or 6 weeks, (2) pacing + aliskiren group (n = 12), with oral aliskiren (30 mg/kg/day), and (3) sham group (n = 4), no pacing nor drug administration. Electrophysiological properties and AF inducibility were evaluated every week. After the protocol, the left atrial tissue was sampled for the further histological and mRNA analysis. The electrical remodeling, AF inducibility, the left atrial enlargement and interstitial fibrosis were observed in pacing control group and were more prominent in the 6-week protocol (vs. 3 week, p < 0.05). The mRNA expressions of matricellular proteins exhibited upregulation in 3-week pacing control, but these upregulations became insignificant in 6 weeks. In contrast, collagen type 3 exhibited significant upregulation in 6 week but not in 3-week protocol. These changes were suppressed in the pacing + aliskiren group. Aliskiren suppressed the atrial remodeling in a canine AF model. This effect was accompanied by the suppression of tissue fibrosis.

Discrimination between paroxysmal and persistent atrial fibrillation (PAF and persistent AF) is important for determining the therapeutic strategy in patients with new-onset AF. We evaluated various clinical factors and P wave morphology to discriminate PAF and persistent AF patients in patients with new-onset AF.The study population consisted of 79 patients with new-onset AF (70.3 ± 10.8 years, female:male 33:46) who were retrospectively selected from 8,632 AF patients in the Kitasato University Hospital ECG storing system. PAF (n = 38) and persistent AF (n = 41) patients were diagnosed by whether the initial PAF episode continued for 1 week. The P wave morphologies were analyzed using the most recent 12 lead-ECG recording of sinus rhythm. P wave dispersion was defined as the difference between the maximum and minimum durations of all leads. Along with these data, various clinical factors were evaluated and compared between PAF and persistent AF patients.Multivariate analysis identified P wave dispersion (56.6 ± 14.8 versus 66.5 ± 12.8 msec, P = 0.002) and left atrial dimension (LAD: 40.2 ± 7.0 versus 47.7 ± 8.2 mm, P < 0.001) as independent factors for discrimination between PAF and persistent AF patients. Combining these two parameters achieved a specificity of 88.9%, a positive predictive value of 81.8%, a sensitivity of 95.3%, and a negative predictive value of 88.9%.In patients with new-onset AF, P wave dispersion and LAD were independent factors for discrimination between PAF and persistent AF.

It is unknown whether 12-lead ECG can predict new-onset AF. In the present study, we identified patients with new onset AF from our digitally stored ECG database, and the P wave morphologies were analyzed in their preceding sinus rhythm recordings as the precursor state for AF. The P wave was analyzed in the most recent ECG recording of sinus rhythm preceding new onset AF within 12 months. The duration and amplitude of P waves were analyzed in 12 leads and compared between the 2 groups with the other clinical parameters. The study population consisted of 68 patients with new-onset AF and 68 age and sex-matched controls. Multivariate analysis revealed that the P wave amplitude in leads II and V1 (0.157 ± 0.056 versus 0.115 ± 0.057 mV, P = 0.032, and 0.146 ± 0.089 versus 0.095 ± 0.036 mV, P = 0.002) and P wave dispersion (56.9 ± 14.8 versus 33.5 ± 12.9 ms, P = 0.001) were significant independent factors for the prediction of new-onset AF. By using these factors, new-onset AF could be predicted with a sensitivity of 69.1% and specificity of 88.2%. P wave analysis is useful for predicting new onset AF.

Patients with recently diagnosed atrial fibrillation (AF) tend to exhibit a longer fibrillation cycle length (FCL) than those having a longer clinical history. However, the electrophysiological properties of new-onset AF may vary because of the clinical background of patients. In this study, we evaluated clinical factors to identify the determinants of FCL in new-onset AF. Electrocardiograms (ECGs) recorded from 2008 through 2011 were analyzed using our digital ECG-profiling system. In the 1,578 AF episodes recorded, 466 new-onset AF episodes were identified using clinical referral history and previous ECGs. After evaluating FCL in these new-onset AF episodes, using a customized fibrillation wave analyzer with fast Fourier transform analysis, we divided the patients into a longer-FCL group and a shorter-FCL group using the median FCL (158 ms). Propensity score matching yielded 135 matched pairs of patients with comparable mean ages between the two groups. Four factors (brain natriuretic peptide levels, and use of angiotensin receptor blockers, calcium channel blockers or statins) exhibited a significant difference between the two groups. Multivariate analysis revealed that statin use was the only significant independent predictor of longer FCL (Odds ratio, 3.86; 95% CI, 1.659.63; P = 0.003). Among various clinical parameters, statin use was related to longer FCL at the time of new-onset AF in patients with AF.

Aims: Remodelling of the extracellular matrix (ECM) plays an important role in the production of arrhythmogenic substrate for atrial fibrillation (AF), and is considered to be promoted by the connective tissue growth factor (CTGF). Our objective was to assess the relationship between CTGF and ECM synthesis, and the effect of olmesartan on these processes., Methods and Results: Fifteen canine AF models were produced by rapid atrial stimulation. They were divided into three groups: pacing control (n = 5): 6-week pacing, pacing + olmesartan (n = 5): pacing with olmesartan (2 mg/kg/day), and non-pacing group (n = 5). In the pacing control group, messenger ribonucleic acid expressions of CTGF and collagen types 1 and 3 were up-regulated in comparison with the non-pacing group (P < 0.05) while transforming growth factor-β (TGF-β) did not exhibit a significant difference. In the pacing + olmesartan group, these up-regulations were suppressed (P < 0.05). In fluorescent immunostaining, the expression of CTGF was localized in the cytoplasm. The protein level of collagen type 3 was increased in the pacing control and it was suppressed in the pacing + olmesartan group., Conclusions: CTGF and associated genes were up-regulated in the atria with the appearance of fibrosis. Because this up-regulation was independent of TGF-β and suppressed by olmesartan, CTGF up-regulation was considered to be mediated by angiotensin II.

Background: Recent reports suggest angiotensin receptor blockers (ARBs) and some antiarrhythmic agents affect atrial remodeling in atrial fibrillation (AF). We evaluated the effect of combination therapy with olmesartan (Olm) and bepridil (Bep) in a canine model of AF., Methods and Results: An atrial stimulation device was implanted in 10 dogs undergoing 6-week pacing at 400 bpm. They were divided into Olm (2 mg/kg/day) (n=5) and Olm+Bep (Olm, 2 mg/kg/day; Bep, 10 mg/kg/day) groups (n=5). Atrial effective refractory period (AERP), conduction velocity (CV), and AF inducibility were evaluated weekly, and hemodynamics, atrial histology, and mRNA expression and protein expression of ion-channel and gap junction-related molecules at 6 weeks. Data were compared between groups and with non-pacing control and pacing-control groups from our previous report. The pacing-control group exhibited shortened AERP, decreased CV, increased AF inducibility and tissue fibrosis, and down-regulated L-type Ca(2+) channel (LCC), SCN5A, Kv4.3 and connexin43 (Cx43). By comparison, the Olm group exhibited suppression of the decrease in CV and of the increase in AF inducibility, but no change in AERP shortening. The Olm+Bep group exhibited suppression of AERP shortening as well as the greatest decrease in AF inducibility. Histologically, tissue fibrosis was suppressed in Olm and Olm+Bep groups. Down-regulation of Cx43 was partly suppressed in the Olm group while that of LCC, SCN5A, and Cx43 was suppressed in the Olm+Bep group., Conclusion: Olm and Bep in combination suppressed AF inducibility more strongly than Olm alone, and may be more useful in the suppression of AF., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Spectral analysis of the fibrillation waves was performed in patients with persistent atrial fibrillation (PAF) to clarify the usefulness of this method of predicting the efficacy of antiarrhythmic agents., Methods and Results: The 59 patients with PAF were randomly assigned to pilsicainide (150 mg/day) or bepridil (200 mg/day) therapy for 4 weeks under optimal anticoagulation therapy. When the first therapy did not interrupt PAF, the drugs were changed in a cross-over manner. The fibrillation cycle length (FCL) was calculated using spectral analysis of the fibrillation waves on the body-surface ECG every 2 weeks. Pilsicainide and bepridil were effective in 19 and 20 patients, respectively. The FCL at the basic state was longest in the pilsicainide-effective group, moderate in the bepridil-effective group and shortest in the failure group (P<0.05). The change in FCL with drug administration (DeltaFCL) was larger in the effective than in the ineffective cases (P<0.01). Successful interruption of the atrial fibrillation (AF) with pilsicainide could be expected for patients with a FCL >148 ms (sensitivity =0.917, specificity =0.612, P=0.007) and DeltaFCL >41 ms (sensitivity =0.875, specificity =0.833, P=0.001)., Conclusions: The FCL reflects the electrophysiological properties of the AF substrate and is considered useful for predicting the efficacy of antiarrhythmic agents.

Background: The antiarrhythmic or reverse remodeling effects of bepridil, a multi-ion channel blocker, have been recently reported, but inhomogeneity of the electrical remodeling and effects of bepridil have been observed in previous reports. In this study, the effect of long-term administration of bepridil on atrial electrical remodeling was evaluated in a comparison of the right and left atrium (RA and LA) in a canine rapid atrial stimulation model., Methods and Results: In 10 beagle dogs, rapid atrial pacing (400 beats/min) was delivered for 6 weeks and the atrial effective refractory period (AERP), conduction velocity (CV) and inducibility of atrial fibrillation (AF) were evaluated every week. In 5 of the pacing dogs, bepridil (10 mg . kg(-1) . day(-1)) was administered orally, starting 2 weeks after the initiation of the rapid pacing. At the end of the protocol, the hemodynamic parameters and extent of tissue fibrosis were evaluated and the mRNA of SCN5A, Kv4.3, the L-type Ca2+ channel (LCC) and connexin (Cx) 40, 43, and 45 in both atria were examined by quantitative real-time reverse transcriptase-polymerase chain reaction. In the pacing control group, AERP shortening, decreased CV, increased AF inducibility and downregulation of the expression of SCN5A and LCC were observed. In the bepridil group, the AERP exhibited a relatively quick recovery after bepridil was started in the first week and continued to recover gradually until the end of the protocol, but that recovery was smaller in the LA than in the RA. The CV was not affected by bepridil administration. AF inducibility was well suppressed in the RA in the bepridil group, but the induction of short-duration AF could not be suppressed in the LA. The mRNA downregulation of the LCC and SCN5A was negated by bepridil administration in the RA; but not in the LA; however, the data showed similar tendencies. There were no significant differences in the hemodynamic parameters or tissue fibrosis and the mRNA expression of Kv4.3, Cx40, 43, and 45 between the pacing control and bepridil groups., Conclusion: Bepridil exhibited an anti-electrical remodeling effect in this study as previously reported, but the effect was inhomogeneous between the RA and LA, with the LA appearing to be more resistant to the effect of bepridil.

Aims: The electrical remodelling is considered to play a role in promoting arrhythmogenic substrate of atrial fibrillation (AF), and intracellular calcium overload may play a key role, especially in its early phase. The effect of oral verapamil on repetitive paroxysmal AF (PAF) was evaluated in clinical cases., Methods and Results: Thirty-five patients with repetitive PAF (total PAF duration >2/24 h) were divided into two groups with and without verapamil administration (240 mg/day) and they were followed-up for 12 months. Before and after the follow-up period, 24 h Holter ECG was recorded. In each Holter recording, total PAF duration and the longest PAF duration was evaluated and spectral analysis was performed for fibrillation waves in PAF episodes to evaluate the fibrillatory frequency. Total PAF duration was prolonged by 45 +/- 79 min in the control group (n = 18) whereas shortened by 25 +/- 55 min in the verapamil group (n = 17, P = 0.005). The fibrillatory frequency was increased from 5.66 +/- 1.05 to 6.73 +/- 1.02 Hz in the control group and was unchanged in the verapamil group. There was inverse relationship between Deltatotal PAF duration and Deltafibrillatory frequency (P = 0.0002)., Conclusion: Verapamil prevented the increase in fibrillatory frequency in PAF patients in relatively long-term observation. Verapamil might be effective for prevention of the electrophysiological change and increase in PAF episodes at least in specific type of PAF cases.

Background: Continuous rapid atrial stimulation causes atrial remodeling, but little is known about the difference in the arrhythmogenicity of the left (LA) and right atria (RA)., Methods and Results: In 14 beagle dogs, continuous rapid pacing (400 beats/min) was delivered from the right (n=7) or left (n=7) atrial appendage (RAA or LAA) for 2 weeks. The atrial effective refractory period (ERP), ERP dispersion, and inducibility of atrial fibrillation (AF) were evaluated along the time course from 4 atrial sites: (1) RAA, (2) area close to the inferior vena cava (IVC), (3) Bachmann's bundle (BB) and (4) LA. The ERP exhibited progressive shortening at all sites, but the degree of shortening differed among them. In the RA stimulation group, ERP shortening was more prominent in the RAA and LA than in the IVC or BB. In contrast, in the LA stimulation group, ERP shortening was more prominent in the LA than in the other sites. As a result, ERP dispersion was larger in the LA stimulation group than in the RA stimulation group and the AF inducibility was higher in the LA stimulation group than in the RA stimulation group, especially at the LA site (p<0.05)., Conclusion: LAA stimulation was more arrhythmogenic than RAA stimulation in this model. This result may partly explain the importance of premature contractions occurring from the pulmonary veins in clinical cases of AF.

Background: Previous studies have identified noninvasive methods for predicting atrial fibrillation (AF) recurrence after catheter ablation (CA). We assessed the association between AF recurrence and atrial late potentials (ALPs), which were measured using P‐wave signal‐averaged electrocardiography (P‐SAECG). Methods: Consecutive patients with paroxysmal AF who underwent their first CA at our institution between August 2015 and August 2019 were enrolled. P‐SAECG was performed before CA. Two ALP parameters were evaluated: the root‐mean‐square voltage during the terminal 20 ms (RMS20) and the P‐wave duration (PWD). Positive ALPs were defined as an RMS20 <2.2 μV and/or a PWD >115 ms. Patients were allocated to either the recurrence or nonrecurrence group based on the presence of AF recurrence at the 1‐year follow‐up post‐CA. Results: Of the 190 patients (age: 65 ± 11 years, 37% women) enrolled in this study, 21 (11%) had AF recurrence. The positive ALP rate was significantly higher in the recurrence group than in the nonrecurrence group (86% vs. 64%, p =.04), despite the absence of differences in other baseline characteristics between the two groups. In the multivariate analysis, positive ALP was an independent predictor of AF recurrence (odds ratio: 3.83, 95% confidence interval: 1.05–14.1, p =.04). Conclusions: Positive ALP on pre‐CA P‐SAECG is associated with AF recurrence after CA. [ABSTRACT FROM AUTHOR]

Background: Each direct oral anticoagulant (DOAC) has different dose reduction criteria. Here, we evaluated the differences in the doses of three anti‐Xa DOACs and clinical events based on the dose reduction criteria in patients with atrial fibrillation (AF). Methods: Consecutive AF patients prescribed with anti‐Xa DOACs [rivaroxaban (Riva), apixaban (Apix), and edoxaban (Edox)] between April 2011 and May 2016 were retrospectively evaluated. The incidences of thromboembolic and bleeding events were evaluated by the end of December 2020, focusing on the dose proportion. Results: A total of 786 patients (72 ± 10 years old, 66.9% male) were enrolled in this study [Riva (n = 337), Apix (n = 239), and Edox (n = 210)]. The proportion of reduced dose prescriptions was significantly greater for Edox (79.2%) than Riva (38.7%) or Apix (31.9%). A Kaplan–Meier analysis showed that the incidence of minor bleeding was significantly higher in the Apix than other groups (p <.001), even after propensity score matching. The standard dose of Apix had significantly higher bleeding events than the other DOACs (p <.001). Moreover, 23.2% and 51.6% of the patients with a standard dose of Apix were fulfilled with the dose reduction criteria for Riva and Edox and had more minor bleeding events than the unfulfilled ones (p =.046). Conclusions: The patients with a standard dose of Apix had a higher incidence of minor bleeding events than the other dosages. A reduced dose of apixaban was not prone to being chosen because of the dose reduction criteria, which may have been associated with a higher minor bleeding rate in patients with Apix. [ABSTRACT FROM AUTHOR]

Objective: Patients with coronary artery disease (CAD) and atrial fibrillation (AF) can be treated with multiple antithrombotic therapies including antiplatelet and anticoagulant therapies; however, this has the potential to increase bleeding risk. Here, we aimed to evaluate the efficacy and safety of P2Y12 inhibitors and aspirin in patients also receiving anticoagulant therapy.Methods: We evaluated patients from the Atrial Fibrillation and Ischaemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial who received rivaroxaban plus an antiplatelet agent; the choice of antiplatelet agent was left to the physician's discretion. The primary efficacy and safety end points, consistent with those of the AFIRE trial, were compared between P2Y12 inhibitors and aspirin groups. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularisation or death from any cause. The primary safety end point was major bleeding according to the International Society on Thrombosis and Haemostasis criteria.Results: A total of 1075 patients were included (P2Y12 inhibitor group, n=297; aspirin group, n=778). Approximately 60% of patients were administered proton pump inhibitors (PPIs) and there was no significant difference in PPI use in the groups. There were no significant differences in the primary end points between the groups (efficacy: HR 1.31; 95% CI 0.88 to 1.94; p=0.178; safety: HR 0.79; 95% CI 0.43 to 1.47; p=0.456).Conclusions: There were no significant differences in cardiovascular and bleeding events in patients with AF and stable CAD taking rivaroxaban with P2Y12 inhibitors or aspirin in the chronic phase.Trial Registration Number: UMIN000016612; NCT02642419. [ABSTRACT FROM AUTHOR]

Background: Although the lesion size index (LSI) has been well established, it is sometimes difficult to achieve first‐pass pulmonary vein isolation (PVI) and to avoid acute pulmonary vein reconnections, even with LSI‐guided procedures. The purpose of this study was to assess the predictive accuracy of a novel parameter, the optimized lesion size index (o‐LSI), to perform PVI. Methods: The voltage maps created by the Advisor™ high‐density (HD) grid catheter before PVI in 35 atrial fibrillation (AF) patients were examined for an association between the voltage amplitude and insufficient ablation sites (IAS), which were defined as either (i) spontaneous reconnection sites, (ii) dormant PV conduction sites unmasked with 20 mg of adenosine triphosphate disodium hydrate (ATP) injection, or (iii) PV‐LA gap sites after the initial PVI. Results: IAS was observed in 25/1417 of the total ablation sites. IAS was significantly associated with higher bipolar voltage areas (4.20 ± 2.68 vs 2.43 ± 1.93 mV, P <.0001) but not with LSI. A novel index, o‐LSI (defined as LSI/bipolar voltage), was significantly lower in IAS than in others (1.14 [0.82, 1.81] vs 2.35 [1.31, 4.80] LSI/mV). By receiver operating characteristic analysis, an o‐LSI of 2.04 was the best cutoff value for the prediction of IAS (88% sensitivity and 55% specificity, P <.0001, areas under the curve: 0.742). Conclusion: Low o‐LSI was strongly associated with IAS, potentially providing a novel index to improve first‐pass PV isolation. [ABSTRACT FROM AUTHOR]

A 61-year-old male was referred to our hospital to receive catheter ablation of paroxysmal atrial fibrillation. Since no anatomical abnormalities were detected by preoperative computed tomography of left atrium and pulmonary veins (PVs), he underwent a cryoballoon ablation for a PV isolation. We performed single, 3-min freeze applications to all four PVs while monitoring the esophageal temperature. Immediately after the procedure, he complained of nausea, followed by a body weight loss of 9 kg over 2 months. Since no structural abnormalities were detected even through careful evaluation, he was diagnosed with hypoperistalsis caused by the cryoballoon ablation. Although his symptoms partially improved, they persisted over a year. The cryoballoon procedure is believed to be relatively safe, but even just a simple 3-min freeze application caused severe hypoperistalsis in the present case. Operators should recognize the risk of such complications. < Learning objective: Cryoballoon ablation is thought to be a safe procedure, however, there are important complications. Asymptomatic or mild-symptomatic hypoperistalsis after cryoballoon ablation is not uncommon. In this case, even just a single 3-min freeze for each pulmonary vein caused severe hypoperistalsis. Repetitive or longer freezes are reported as a risk for this complication, therefore, the operator should recognize the risk of this complication, and a shorter freeze time may be considered instead of a fixed 3-min freeze.> [ABSTRACT FROM AUTHOR]

Key Clinical Message: Esophageal injury is a major concern during catheter ablation of atrial fibrillation. Operators avoid radiofrequency applications on the esophagus by changing ablation line; however, it is unavoidable in patients with a dilated esophagus, such as esophageal achalasia. Steerable esophageal thermometer is useful for evaluating precise temperatures to prevent esophageal injury. [ABSTRACT FROM AUTHOR]

A seventy year-old male was referred to our hospital to undergo radiofrequency catheter ablation (RFCA) for drug-refractory paroxysmal atrial fibrillation (AF). Pre-operative three-dimensional computed tomography revealed a unique left atrial (LA) roof vein. Electrophysiological findings showed expansion of the myocardial sleeve and local firing in the LA roof vein. We performed isolation of this arrhythmogenic abnormal vein concomitant with general pulmonary vein isolation in this case, and AF did not recur after the procedure. [ABSTRACT FROM AUTHOR]

It is known that the efficacy of catheter ablation for atrial fibrillation (AF) is high, but cardiac tamponade may occur in 1–2% cases. Even in such cases, fatal condition can be avoided by appropriate drainage, but reversal of anticoagulation therapy might also be necessary. Here, we report a case of use of idarucizumab for cardiac tamponade during AF ablation. Although the drainage with pericardial centesis should be selected, we could not perform because echo free space was too thin at least at the precordial or apical side of the ventricle. Fortunately, dabigatran reversal by idarucizumab suppressed cardiac tamponade progress and the patient recovered without undergoing any invasive procedures. The pericardial drainage must be the principal therapy for cardiac tamponade, but reversal of anticoagulant might be helpful for patients' recovery. It might be thought that dabigatran, the only direct oral anticoagulant with a specific reversal agent, should be the safest choice in case of risk for bleeding complications such as AF ablation. < Learning objective: Cardiac tamponade is one of the complications of catheter ablation for atrial fibrillation (AF). In such cases, fatal condition can be avoided by appropriate drainage, but reversal of anticoagulation therapy might be necessary. Drainage with pericardial centesis was not selected because echo free space was too thin. Dabigatran reversal by idarucizumab suppressed cardiac tamponade progress. It was thought that dabigatran would be the safest choice in case of bleeding complications during AF ablation.> [ABSTRACT FROM AUTHOR]

Aims Remodelling of the extracellular matrix (ECM) plays an important role in the production of arrhythmogenic substrate for atrial fibrillation (AF), and is considered to be promoted by the connective tissue growth factor (CTGF). Our objective was to assess the relationship between CTGF and ECM synthesis, and the effect of olmesartan on these processes. Methods and results Fifteen canine AF models were produced by rapid atrial stimulation. They were divided into three groups: pacing control (n = 5): 6-week pacing, pacing + olmesartan (n = 5): pacing with olmesartan (2 mg/kg/day), and non-pacing group (n = 5). In the pacing control group, messenger ribonucleic acid expressions of CTGF and collagen types 1 and 3 were up-regulated in comparison with the non-pacing group (P < 0.05) while transforming growth factor-β (TGF-β) did not exhibit a significant difference. In the pacing + olmesartan group, these up-regulations were suppressed (P < 0.05). In fluorescent immunostaining, the expression of CTGF was localized in the cytoplasm. The protein level of collagen type 3 was increased in the pacing control and it was suppressed in the pacing + olmesartan group. Conclusions CTGF and associated genes were up-regulated in the atria with the appearance of fibrosis. Because this up-regulation was independent of TGF-β and suppressed by olmesartan, CTGF up-regulation was considered to be mediated by angiotensin II. [ABSTRACT FROM PUBLISHER]

Background: Antiarrhythmic agents may affect electrical remodeling but little is known regarding clinical cases. We evaluated fibrillation cycle length (FCL) of atrial fibrillation (AF) by spectral analysis of fibrillation waves (FW) in surface ECG for patients on antiarrhythmic agents. Methods and Results: 18 patients (14 males; 58 ± 2 year-old) with paroxysmal AF (pAF) lasting over 30 minutes recorded by Holter ECG were enrolled. FW was purified by subtraction of QRS-T, and calculated by fast Fourier transformation analysis. FCL was defined as reciprocal of mean peak frequency. Temporal variability was expressed as FCL coefficient of variation (FCL-CV). FCL and FCL-CV were calculated at 0, 1, 5, 10, and 30 minutes after the onset of AF. We evaluated three groups: control group (6 patients with no medication), class I group (6 patients with pilsicainide or flecainide), and bepridil group (6 patients with bepridil). FCL showed quick-shortening at first minute in control group (p < 0.001), and relatively slow-shortening in class I group. In bepridil group, FCL was not significantly shortened within 30 minutes. FCL-CV did not change, but was significantly larger in bepridil group. Conclusions: FCL of pAF showed significant shortening in control group, but FCL shortening was suppressed and FCL-CV was larger in bepridil group. This result may indicate the specific effect of bepridil for electrical changes in early phase of pAF. [Copyright &y& Elsevier]

Aims: The electrical remodelling is considered to play a role in promoting arrhythmogenic substrate of atrial fibrillation (AF), and intracellular calcium overload may play a key role, especially in its early phase. The effect of oral verapamil on repetitive paroxysmal AF (PAF) was evaluated in clinical cases. [ABSTRACT FROM PUBLISHER]