Background: This All Nippon AF in the Elderly (ANAFIE) Registry sub-analysis evaluated the impact of polypharmacy on 2-year outcomes in a large, elderly (aged ≥75 years) Japanese population with non-valvular atrial fibrillation (NVAF).

Methods and Results: The ANAFIE Registry was a multicenter, prospective, observational study with a 24-month follow-up period. Of 32,275 enrolled NVAF patients, 31,419 were grouped by the number of prescribed concomitant medications (other than oral anticoagulants [OACs]): 0–4 [38.8%], 5–8 [43.3%], and ≥9 [17.9%]). Patients receiving more concomitant medications were older, had poor renal function, and suffered more comorbidities than those receiving fewer concomitant medications. Several patient background factors, including diabetes mellitus, myocardial infarction, and chronic kidney disease, were significantly correlated with an increased number of concomitant medications. With increasing medications, OAC prescription rates decreased, but the warfarin prescription rate increased, and the cumulative incidence rates of stroke/systemic embolic events (SEE), major bleeding, gastrointestinal bleeding, fracture/falls, cardiovascular events, cardiovascular death, and all-cause death significantly increased (each, P<0.05). In multivariate analysis, increasing medications was independently associated with increases in these events, except for stroke/SEE. There were no significant interactions between the number of medications and anticoagulant treatment with direct OAC or warfarin concerning the incidence of these events.

Conclusions: Polypharmacy was frequent among elderly patients with NVAF who were older with more comorbidities, and was independently associated with a higher incidence of extracranial events.

Background: There is a dearth of evidence to characterize longitudinal changes in domain-specific cognitive function related to atrial fibrillation (AF).

Methods and Results: This study enrolled 2,844 participants from the Systolic Blood Pressure Intervention Trial (SPRINT). Cognitive function was assessed at baseline and biennially during the follow-up period. Declines in global function and 4 major cognitive domains (i.e., memory, processing speed, language, and executive function) were fitted and compared between participants with and without AF using robust linear mixed-effect models. There were 252 participants with prevalent AF (mean [±SD] age 72.0±8.5 years; 30% women) and 2,592 participants without AF (mean age 67.9±8.4 years; 38% women). The annual decline in global function scores was greater among participants with than without AF (−0.016 vs. −0.012 points); however, the difference was not statistically significant (P=0.33). Processing speed declined faster in participants with prevalent AF, with a distinct difference of –0.013 points/year (95% CI −0.024~−0.001 points/year; P=0.02). For the memory, executive function, and language domains, there were no significant differences in the rate of cognitive decline between participants with and without AF.

Conclusions: In this post hoc analysis of the SPRINT trial, processing speed was the most prominent cognitive domain affected by AF, which may be beneficial for the early screening of cognitive dysfunction.

Background: The mechanism underlying the sex differences in atrial fibrillation (AF) recurrence following pulmonary vein (PV) isolation is not fully understood. We hypothesized that non-PV foci and epicardial adipose tissue (EAT) play a key role.

Methods and Results: Data from 304 consecutive patients (75% males) who underwent contrast-enhanced computed tomography and catheter ablation of AF were reviewed. The EAT around the atrium was measured separately in 4 parts of the atrium. All patients underwent high-dose isoproterenol infusions to assess the non-PV foci. Significantly more non-PV foci and less EAT around the atrium were observed in female patients than in male patients. In males, those with non-PV foci on the left atrial (LA) anterior wall had significantly greater EAT for the same lesions than those without non-PV foci. During a median follow-up of 27 months, the predictors of AF recurrence after first catheter ablation were female sex, presence of non-PV foci, LA diameter, and septal EAT index. A sex-specific analysis revealed that LA diameter was a predictor only in males and that the presence of non-PV foci in the septal region was a strong predictor in males (hazard ratio [HR]: 2.24) and females (HR: 3.65).

Conclusions: Sex-specific differences were observed in non-PV foci sites and local EAT and in regard to the predictors of AF recurrence.

Background: The incidence and prevalence of atrial fibrillation (AF) are increasing. The white blood cell (WBC) count is an indicator of systemic inflammation and is related to increased cardiovascular disease risk. Using data from the Suita Study, we investigated the association between WBC count and AF risk in the general Japanese population.

Methods and Results: This prospective cohort study included 6,884 people, aged 30–84 years, with no baseline AF. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for AF incidence by WBC count quintile. Within a median follow-up period of 14.6 years, 312 AF cases were diagnosed. Compared with the lowest WBC count quintile, the highest quintile was associated with an increased AF risk (HR 1.57; 95% CI 1.07–2.29). The association was more pronounced among women than men (HR 2.16 [95% CI 1.10–4.26] and 1.55 [95% CI 0.99–2.44], respectively; P interaction=0.07), and among current than non-smokers (HR 4.66 [95% CI 1.89–11.50] and 1.61 [95% CI 1.01–2.57], respectively; P interaction=0.20). For each 1.0×10⁹-cells/L increment in WBC count, AF risk increased by 9% in men (9% in non-smokers, 10% in current smokers) and 20% in women (13% in non-smokers, 32% in current smokers).

Conclusions: A higher WBC count was positively associated with an elevated AF risk in the general Japanese population, especially in women who smoked.

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.

Background: Radiofrequency hotballoon (RHB) is an ablation device used for atrial fibrillation (AF) treatment. The efficacy and safety of RHB-based pulmonary vein isolation (PVI) in real-world practice are unknown.

Methods and Results: A multicenter, prospective registry study (UMIN000029567) enrolled AF patients who underwent RHB-PVI. The primary endpoint was the AF recurrence-free survival rate at 12 months after PVI. Of the 679 patients enrolled, 613 (90.3%; paroxysmal AF, n=370; persistent AF, n=136; long-standing AF, n=107) underwent initial RHB-PVI. Acute isolation using only the RHB was successful for 55.6% of patients and 83.5% of pulmonary veins (PVs). The acute isolation rate was higher for patients with paroxysmal AF and more experienced centers. Antiarrhythmic drugs were prescribed after 3 months for 47.5% of patients. The AF recurrence-free survival rate at 12 months was 83.7%. Procedure-related complications including atrio-esophageal fistula (n=1) and phrenic nerve injury (persistent; n=4, permanent; n=2) were observed in 19 (3.1%) patients. Five (1.7%) of the 302 patients who underwent pre-procedural and post-procedural multidetector computed tomography had severe PV stenosis.

Conclusions: The size-adjustable RHB has been used for the treatment of various AF types. The arrhythmia recurrence-free rate at 12 months, with the use of antiarrhythmic drugs in approximately half of the patients, was acceptable, but the acute isolation rate using the RHB requires further improvement.

Background: It is unknown whether early atrial tachyarrhythmia (ATA) recurrence occurring within 3 months after the Maze procedure predicts late ATA recurrence.

Methods and Results: This study involved 610 patients who underwent the modified Cryo-Maze procedure in conjunction with other cardiac surgery. The primary outcomes were late ATA recurrence, defined as occurring ≥3 months after surgery. The effects of early ATA recurrence on late ATA recurrence were analyzed using a Cox proportional hazards model. The following 11 covariates were considered explanatory variables: early ATA recurrence, age, sex, body surface area, preoperative duration of atrial fibrillation, preoperative left atrial diameter, and concomitant surgery (mitral valve replacement, mitral valve repair, aortic valve replacement, tricuspid annuloplasty, and left atrial appendage closure). Statistical analyses were performed with a 2-sided 5% significance level. Early ATA recurrence occurred in 174 patients (28.5%). Late ATA recurrence occurred in 167 patients (27.5%), with 595 events identified in these patients. The Cox proportional hazards model showed that early ATA recurrence was an independent predictor of late ATA recurrence (hazard ratio, 4.14; 95% confidence interval, 3.00–5.70; P<0.001)

Conclusions: Early ATA recurrence was an independent predictor of late ATA recurrence among patients undergoing the modified Cryo-Maze procedure. The blanking period might not be applied to patients undergoing the modified Cryo-Maze procedure.

Background: Radiofrequency catheter ablation (RFCA) is commonly performed in patients with non-paroxysmal atrial fibrillation (AF), but because very long-term follow-up results of RFCA are limited, we investigated the 10-year RFCA outcomes of non-paroxysmal AF.

Methods and Results: We retrospectively enrolled 100 patients (89 men, mean age 53.5±8.4years) with drug-refractory symptomatic non-paroxysmal AF who underwent 3D electroanatomic-guided RFCA. Procedural characteristics at index procedures and clinical outcomes were investigated. In the index procedures, all patients had pulmonary vein isolation, 56 (56.0%), 48 (48.0%), and 32 (32.0%) underwent additional linear, complex fractionated atrial electrogram (CFAE) and non-pulmonary vein (NPV) foci ablations, respectively. After 124.1±31.7 months, 16 (16%) patients remained in sinus rhythm after just 1 procedure (3 with antiarrhythmic drugs [AAD]) and after multiple (2.1±1.3) procedures in 53 (53.0%) patients (22 with AAD). Left atrial (LA) diameter (hazard ratio HR 1.061; 95% confidence interval (CI) 1.020 to 1.103; P=0.003), presence of NPV triggers (HR 1.634; 95% CI 1.019 to 2.623; P=0.042) and undergoing CFAE ablation (HR 2.003; 95% CI 1.262 to 3.180; P=0.003) in the index procedure were independent predictors for recurrent atrial tachyarrhythmia.

Conclusions: The 10-year outcomes of single RFCA in non-paroxysmal AF were unsatisfactory. Enlarged LA, presence of NPV triggers, and undergoing CFAE ablation in the index procedure independently predicted single-procedure recurrence. Multiple procedures are required to achieve adequate rhythm control.

Background: The prospective observational Nippon Storm Study aggregated clinical data from Japanese patients receiving implantable cardioverter-defibrillator (ICD) therapy. This study investigated the usefulness of prophylactic ICD therapy in patients with non-ischemic heart failure (NIHF) enrolled in the study.

Methods and Results: We analyzed 540 NIHF patients with systolic dysfunction (left ventricular ejection fraction <50%). Propensity score matching was used to select patient subgroups for comparison; 126 patients were analyzed in each of the primary (PP) and secondary (SP) prophylaxis groups. The incidence of appropriate ICD therapy during follow-up in the PP and SP groups was 21.4% and 31.7%, respectively (P=0.044). The incidence of electrical storm (ES) was higher in SP than PP patients (P=0.024). Cox proportional hazard analysis revealed that increased serum creatinine in SP patients (hazard ratio [HR] 1.18; 95% confidence interval [CI] 1.02–1.33; P=0.013) and anemia in PP patients (HR 0.92; 95% CI 0.86–0.98; P=0.008) increased the likelihood of appropriate ICD therapy, whereas long-lasting atrial fibrillation in PP patients (HR, 0.64 [95% CI, 0.45–0.91], P=0.013) decreased that likelihood.

Conclusions: In propensity score-matched Japanese NIHF patients, the incidence of appropriate ICD therapy and ES was significantly higher in SP than PP patients. Impaired renal function in SP patients and anemia in PP patients increased the likelihood of appropriate ICD therapy, whereas long-lasting atrial fibrillation reduced that likelihood in PP patients.

Background: Although surgical approaches for infected or failing cardiac implantable electronic device (CIED) leads are more invasive than transvenous approaches, they are still required for patients considered unsuitable for transvenous procedures. In this study, surgical management with transvenous equipment for CIED complications was examined in patients unsuitable for transvenous lead extraction.

Methods and Results: We retrospectively examined 152 consecutive patients who underwent CIED extraction between April 2009 and December 2021 at the Department of Cardiovascular Surgery, Nippon Medical School. Nine patients (5.9%; mean [±SD] age 61.7±16.7 years) who underwent open heart surgery were identified as unsuitable for the isolated transvenous approach. CIED types included 5 pacemakers and 4 implantable cardioverter-defibrillators; the mean [±SD] lead age was 19.5±7.0 years. Indications for surgical management according to Heart Rhythm Society guidelines included failed prior to transvenous CIED extraction (n=6), intracardiac vegetation (n=2), and severe lead adhesion (n=1). Transvenous CIED extraction tools were used in all patients during or before surgery. Additional surgical procedures with CIED extraction included epicardial lead implantation (n=4) and tricuspid valve repair (n=3). All patients were discharged; during the follow-up period (mean 5.7±3.7 years), only 1 patient died (non-cardiac cause).

Conclusions: Surgical procedures and transvenous extraction tools were combined in the removal strategy for efficacious surgical management of CIED leads. Intensive surgical procedures were safely performed in patients unsuitable for transvenous extraction.

Background: Idiopathic bradyarrhythmia is considered to be due to pathological degeneration of the cardiac conduction system (CCS) during aging. There appears to have been no comprehensive genetic investigations in patients with idiopathic bradyarrhythmia.

Methods and Results: Ten autopsy cases with advanced bradyarrhythmia (6 men and 4 women; age: 70–94 years, 81.5±6.9 years; 5 cases each of sinus node dysfunction [SND] and complete atrioventricular block [CAVB]) were genetically investigated by using whole-exome sequencing. Morphometric analysis of the CCS was performed with sex-, age- and comorbidity-matched control cases. As a result, severe loss of nodal cells and distal atrioventricular conduction system were found in SND and CAVB, respectively. However, the conduction tissue loss was not significant in either the atrioventricular node or the proximal bundle of His in CAVB cases. A total of 13 heterozygous potential variants were found in 3 CAVB and 2 SND cases. Of these 13 variants, 4 were missense in the known progressive cardiac conduction disease-related genes: GATA4 and RYR2. In the remaining 9 variants, 5 were loss-of-function mutation with highly possible pathogenicity.

Conclusions: In addition to degenerative changes of selectively vulnerable areas in the heart during advancing age, the vulnerability of the CCS, which may be associated with “rare variants of small effect,” may also be a contributing factor to the degeneration of CCS, leading to “idiopathic” bradyarrhythmia.

Background: We assessed the awareness of multidisciplinary healthcare professionals of the challenges related to implementation of molecular autopsy (MA) for sudden cardiac death (SCD) among children and young adults.

Methods and Results: We conducted 11 focus groups with 31 multidisciplinary healthcare professionals, and categorized them into 2 themes: values, and challenges of MA implementation. The participants recognized 2 different values of MA: discovering the unknown cause of SCD, and SCD prevention among family members of victims. The coexistence of these values makes the MA process and role of professionals more complex. Participants were concerned about the psychological burden for bereaved family members and mentioned challenges in each process of the MA delivery system: obtaining consent, cause of death investigation, disclosing results, and preventive intervention.

Conclusions: MA is a valuable procedure both in terms of forensic and preventive medicine. However, the dual meanings and complex characteristics of genetic information is a potential source of concern and confusion among healthcare professionals as well as bereaved family members. Increasing awareness among healthcare professionals of the MA process is essential for connecting all related areas of expertise.

Background: The prospective Control of HEART rate in inFant and child tachyarrhythmia with reduced cardiac function Using Landiolol (HEARTFUL) study investigated the effectiveness and safety of landiolol, a short-acting β₁ selective blocker, in children.

Methods and Results: Twenty-five inpatients aged ≥3 months to <15 years who developed supraventricular tachyarrhythmias (atrial fibrillation, atrial flutter, supraventricular tachycardia, and inappropriate sinus tachycardia) were treated with landiolol. The primary endpoint, the percent of patients with a reduction in heart rate ≥20% from the initial rate of tachycardia, or termination of tachycardia at 2 h after starting landiolol, was achieved in 12/25 patients (48.0%; 95% CI 28.4–67.6), which exceeded the predetermined threshold (38.0%). At 2 h after starting landiolol administration, heart rate had decreased by ≥20% in 45.8% (11/24) and recovery to sinus rhythm was achieved in 40.0% (6/15) of the patients. Adverse reactions (ARs) occurred in 24.0% (6/25) of patients, and the study was discontinued in 4.0% (1/25) of the patients; however, none of these ARs were considered serious. The most common AR was hypotension (20.0% [5/25] of patients).

Conclusions: The HEARTFUL study has demonstrated the efficacy of landiolol, by reducing heart rate or terminating tachycardia, in pediatric patients with supraventricular tachyarrhythmias. Although serious ARs and concerns were not identified in this study, physicians should be always cautious of circulatory collapse due to hypotension.

Background: Most of the factors and prediction models of sudden cardiac death (SCD) have been developed without considering the Asia population. The purpose of this study is to construct a point-based prediction model for the general population in Asia.

Methods and Results: Chin-Shan Community Cardiovascular Cohort (CCCC) is a community-based longitudinal cohort initiated between 1990 and 1991, enrolling participants aged ≥35 years and following them up until 2005. Participants with coronary artery disease (CAD) or a left ventricular ejection fraction (LVEF) of 35% were excluded from this study. The Framingham risk score function was used to derive a simple point-based prediction model. Based on bootstrapping, a novel model (CCCC-SCD-Score) was validated. A total of 2,105 participants were analyzed. The incidence rate of SCD was 0.406 per 1,000 person-years. The CCCC-SCD-Score score was calculated using age groups (maximal points=4), left ventricular hypertrophy, hypertension, left ventricular ejection fraction <40%, aortic flow rate >190 cm/s, and carotid plaque scores ≥5 (point=1 for each risk factor). The C-index of the CCCC-SCD-Score in predicting SCD risks was 0.888 (95% confidence interval: 0.807–0.969).

Conclusions: For the general Asian population without a history of CAD or a LVEF <35% and who are aged >35 years, the novel model-based scoring system effectively identifies the risk for SCD using the clinical factors, electrocardiographic and echocardiographic data.