Impact of atrial fibrillation type (paroxysmal vs. non-paroxysmal) on long-term clinical outcomes: The RAFFINE registry subanalysis.

BACKGROUND: The type of atrial fibrillation (AF) (paroxysmal or non-paroxysmal) is important in determining its therapeutic management. However, the prognostic impact of AF type on the incidence of cardiovascular events remains uncertain. METHODS: We investigated patients with AF who were selected from an observational, multicenter, prospective registry (RAFFINE) comprising 4 university hospitals and 50 general hospitals/clinics in Japan between 2013 and 2015. In this subanalysis study, patients were divided into two groups according to their AF pattern at the time of enrollment. The primary outcome was the composite of death, ischemic stroke, and heart-failure-related hospitalization. RESULTS: Among 3845 patients, 1472 (38.3 %) and 2373 (61.7 %) had paroxysmal and non-paroxysmal type AF, respectively. Patients with non-paroxysmal AF were older and had higher CHADS2 score and prevalence of comorbidities. During median follow-up of 3.7 years, 681 (17.7 %) primary endpoints were identified. Cumulative incidences of the primary endpoint were significantly higher in the non-paroxysmal AF group; however, rates of bleeding events were not significantly different between the groups. Multivariate Cox hazard analysis showed that non-paroxysmal AF had significantly higher risk of cardiovascular events compared with paroxysmal AF (hazard ratio, 1.38; 95 % confidence interval, 1.17-1.64; p = 0.0002). CONCLUSIONS: Non-paroxysmal AF was significantly associated with cardiovascular events. Long-term clinical outcomes might be improved if transition from paroxysmal to non-paroxysmal AF can be prevented.

Comparison of primary and secondary stroke prevention in patients with nonvalvular atrial fibrillation: Results from the RAFFINE registry.

OBJECTIVES: Clinical outcome data of primary and secondary prevention in patients with nonvalvular atrial fibrillation (NVAF) after the introduction of direct oral anticoagulant (DOAC) therapy are limited. MATERIALS AND METHODS: A subgroup analysis of the RAFFINE registry, an observational, multicenter, prospective registry of Japanese patients with AF, was performed. Incidence rates of stroke or systemic embolism, all-cause death, major bleeding, and intracranial hemorrhage were compared between patients with and without a history of stroke or transient ischemic attack (TIA). RESULTS: Of 3,706 NVAF patients at baseline, 557 (15.0%) had a history of ischemic stroke or TIA (secondary prevention group), and 3,149 (85.0%) had no history of ischemic stroke or TIA (primary prevention group). The proportion of patients receiving oral anticoagulants was 87.2% (42.5% warfarin, 44.7% DOACs). The secondary prevention group had higher rates of stroke or systemic embolism (2.6% vs 1.0%/year, p<0.001), all-cause death (3.6% vs 2.4%/year, p<0.01), and major bleeding (2.0% vs 1.3%/year, p<0.01), and similar rates of intracranial hemorrhage (0.6% vs 0.5%/year, p=0.66) compared with the primary prevention group. A Cox proportional hazards model showed that a history of ischemic stroke or TIA was independently associated with an increased risk of stroke or systemic embolism (adjusted hazard ratio, 2.22; 95% confidence interval, 1.57 - 3.15; p<0.001). CONCLUSIONS: In a contemporary cohort of NVAF patients, a history of ischemic stroke or TIA was still an independent predictor of stroke or systemic embolism, despite advances in anticoagulation therapy.

Trends of anticoagulant use and outcomes of patients with non-valvular atrial fibrillation: Findings from the RAFFINE registry.

BACKGROUND: The management of non-valvular atrial fibrillation (AF) has evolved with the development of direct oral anticoagulants (DOACs). However, data regarding the effectiveness and safety of DOACs outside clinical trial settings are limited, and off-label dosing of DOACs has not been thoroughly investigated. METHODS: We examined the clinical outcomes of patients with non-valvular AF in the RAFFINE registry, a prospective registry of Japanese patients with AF who were followed-up for more than 3 years. RESULTS: Among 3706 patients with non-valvular AF, 42.5% received warfarin and 44.7% received DOACs at baseline. The administration of DOACs increased annually. The mean CHADS2 and HAS-BLED scores were significantly higher in the warfarin group. The unadjusted all-cause mortality, cardiovascular mortality, and incidence of major bleeding events were higher in the warfarin group. The incidence of ischemic stroke/systemic embolism was not different between groups. After adjustment for baseline characteristics, the incidence of these events was not different between groups. Off-label dosing was performed for 32% of patients in the DOAC group, but this did not affect clinical outcomes. CONCLUSIONS: The all-cause mortality, cardiovascular mortality, and incidence of major bleeding events were higher in the warfarin group than in the DOAC group. After adjustment, warfarin use was not associated with an increase in these events. Off-label dosing of DOACs is not rare and is not associated with reduced effectiveness. The impact of off-label dosing of each DOAC on clinical events should be assessed using a larger population.

Trend in Age at the Initial Pacemaker Implantation in Patients With Bradyarrhythmia　- A 50-Year Analysis (1970-2019) in Japan.

BACKGROUND: This study investigated whether the age of patients undergoing pacemaker implantation is increasing.Methods and Results: This study retrospectively reviewed the consecutive cases of 3,582 patients who underwent an initial pacemaker implantation at our hospitals because of symptomatic bradyarrhythmias between 1970 and 2019. The exclusion criteria were: patients with AV block due to cardiac surgery or AV junction ablation, and patients aged <20 years. The patients were divided into 5×10-year groups: those treated in the 1970s (1970-1979), 1980s (1980-1989), 1990s (1990-1999), 2000s (2000-2009), and 2010s (2010-2019). A total of 3,395 patients satisfied the study criteria. The average age at which the patients underwent a first pacemaker implantation increased across the 10-year periods: 63.7±13.2 years in the 1970s, 66.2±12.6 years (1980s), 69.1±12.4 years (1990s), 72.0±11.1 years (2000s), and 75.8±10.0 years (2010s) and advanced significantly in the 1990s, 2000s, and 2010s compared to the 1970s (all P<0.001). The ratio of patients aged ≥80 and ≥90 years increased from 10.6% and 0% in the 1970 s to 38.2% (P<0.001) and 5.2% (P= 0.017) in the 2010s, respectively. CONCLUSIONS: The average age at initial pacemaker implantation increased by 12.1 years over the last 50 years in Japan. In particular, the ratios of ≥80 and ≥90 years as the patients age increased significantly.

Prognosis of Japanese Patients With Coronary Artery Disease Who Underwent Implantable Cardioverter Defibrillator Implantation　- The JID-CAD Study.

Background: There has been no large multicenter clinical trial on the prognosis of implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy with a defibrillator (CRT-D) in Japanese patients with coronary artery disease (CAD). The aim of the present study was to compare differences in the prognoses of Japanese patients with CAD between primary and secondary prevention, and to identify potential predictors of prognosis. Methods and Results: We investigated 392 CAD patients (median age 69 years, 90% male) treated with ICD/CRT-D enrolled in the Japan Implantable Devices in CAD (JID-CAD) Registry. The primary endpoint was all-cause death, and the secondary endpoint was appropriate ICD therapies. Endpoints were assessed by dividing patients into primary prevention (n=165) and secondary prevention (n=227) groups. The mean (±SD) follow-up period was 2.1±0.9 years. The primary endpoint was similar in the 2 groups (P=0.350). Conclusions: The mortality rate in Japanese patients with CAD who underwent ICD/CRT-D implantation as primary prevention was not lower than that of patients who underwent ICD/CRT-D implantation as secondary prevention, despite the lower cardiac function in the patients undergoing ICD/CRT-D implantation as primary prevention.

Effects of Cardiac Massage and ß-Blocker Pretreatment on the Success Rate of Cardiopulmonary Resuscitation Assessed by the Canine Ischemia/Reperfusion-Induced Ventricular Fibrillation Model.

BACKGROUND: Effects of rapid electrical defibrillation and ß-blockade on coronary ischemia/reperfusion-induced ventricular fibrillation (VF) during cardiopulmonary resuscitation (CPR) remain unknown.Methods and Results:After induction of VF by 30 min of ischemia followed by reperfusion, animals were treated with defibrillation alone (Group A, n=13), 2 min of open-chest cardiac massage followed by defibrillation (Group B, n=11), or the same therapy to Group B with propranolol (1 mg/kg, i.v.) treatment before ischemia/reperfusion (Group C, n=11). If return of spontaneous circulation (ROSC) was not attained, each therapy was repeated ≤3 times (Set-1). When ROSC was not obtained within Set-1, cardiac massage was applied to all animals followed by defibrillation, which was repeated ≤3 times (Set-2). ROSC after Set-1 was 8% in Group A, 82% in Group B and 82% in Group C, whereas that after Set-2 was 62% in Group A, 100% in Group B and 82% in Group C. Each animal with ROSC in Groups A (n=8) and B (n=11) showed sinus rhythm, whereas those in Group C (n=9) had sinus rhythm (n=5), atrial fibrillation (n=1), accelerated idioventricular rhythm (n=2) and atrioventricular block (n=1). Post ROSC heart rate and mean arterial pressure were significantly lower in Group C. CONCLUSIONS: Cardiac massage increased the likelihood of ROSC vs. rapid defibrillation, but ß-blocker pretreatment may worsen hemodynamics and electrical stability after ROSC.

The association between impairment of HDL cholesterol efflux capacity and atrial remodeling in atrial fibrillation.

This cross-sectional study enrolled 202 patients with atrial fibrillation (AF) who had undergone catheter ablation and evaluated the association between high-density lipoprotein (HDL) functionality, cholesterol efflux capacity (CEC) of HDL, and the pathophysiology of left atrial structural remodeling. Participants were divided into two groups, based on their left atrial volume index (LAVI) (< 34 mL/m2, n = 60 vs. LAVI ≥ 34 mL/m2, n = 142). We quantified three types of HDL CECs by the presence or absence of cyclic-AMP, as entire, and CEC dependent or not dependent on ATP binding cassette transporter A1 (ABCA1) and termed them Global CEC, ABCA1 CEC, and Non-ABCA1 CEC, respectively. Consequently, Global and Non-ABCA1 CECs were significantly impaired in patients with an enlarged LA (Global CEC: p = 0.039, Non-ABCA1 CEC: p = 0.022). Logistic regression analyses demonstrated that Non-ABCA1 CEC was significantly associated with an enlarged LA after adjusting for the conventional risk factors of AF. Furthermore, the association of higher Non-ABCA1 CEC with an enlarged LA was independent of serum levels of HDL cholesterol and serum myeloperoxidase (Odds ratio of 1 standard deviation higher: 0.64, 95% confidence interval: 0.43-0.95, p = 0.027). The findings of this study indicate the potential contribution of reduced Non-ABCA1 CEC in HDL to the pathophysiology in left atrial structural remodeling of patients with AF.

Enhanced monocyte migratory activity in the pathogenesis of structural remodeling in atrial fibrillation.

BACKGROUND AND AIMS: Pathophysiological roles of monocytes in atrial fibrillation (AF), particularly for the progression of structural remodeling of the left atrium (LA), remain elusive. This study examined the association between the characteristics of circulating and local monocytes and extent of structural remodeling in LA, gauged by LA size, in AF patients. METHODS: First, 161 AF patients who were referred for catheter ablation were enrolled and divided into two groups according to the median of LA diameter (≤39 mm: normal LA group, >39 mm: enlarged LA group). As a control group, 22 patients underwent catheter ablation for paroxysmal supraventricular tachycardia (PSVT) without history of AF were analyzed. Blood samples were collected for flow cytometric analyses to evaluate monocyte subsets based on the levels of CD14 and CD16. Moreover, monocytes were isolated from blood to measure CC chemokine receptor 2 (CCR2) transcripts and protein levels, and migratory activity toward monocyte chemoattractant protein 1 (MCP-1). Second, to characterize the local monocytes in the atrial wall in AF, the resected left atrial appendages (LAA) in AF patients underwent cardiac surgery were histologically evaluated (n = 20). RESULTS: The proportions of monocyte subsets based on CD14 and CD16 expressions were not significantly different between the normal and enlarged LA group. Both transcripts and total protein levels of CCR2 in monocytes were higher in the enlarged LA group compared to those in the normal LA group. In the enlarged LA group, monocytes exhibited more enhanced migratory activity than the normal LA group. Moreover, we found a significantly higher number of CCR2-positive monocytes/macrophages in the LAA in the enlarged LA group. CONCLUSION: Enhanced migratory activity in circulating and local monocytes may play a pivotal role in the pathogenesis of progression in atrial remodeling in AF patients.

A case of paroxysmal atrioventricular block with atrial pacemaker shift during ventricular arrest.

We present a case of paroxysmal atrioventricular block with atrial pacemaker shift, focusing on the change of P-wave morphology.

Implementing the European Society of Cardiology 0-h/1-h algorithm in patients presenting very early after chest pain.

BACKGROUND: The European Society of Cardiology (ESC) recommends a 0-h/1-h (0/1-h) algorithm to classify patients with suspected non-ST-segment elevation myocardial infarction (NSTEMI). However, reliable evidence about patients who present early after the onset of symptoms is limited, likely because high-sensitivity cardiac troponin (hs-cTn) values cannot increase sufficiently within that time. This study aimed to evaluate the outcomes in real-world situations that utilized the 0/1-h algorithm. METHODS: In a prospective, international, multicenter cohort study that enrolled 1638 patients presenting with acute chest pain to the emergency department, we assessed the performance of the 0/1-h algorithm using hs-cTnT and the associated 30-day rates of major adverse cardiac events: death and acute myocardial infarction (AMI). RESULTS: Among 1074 patients, the prevalence of AMI was 16.0%. An approximately 60.1% (n = 645) of patients visited the hospital within 3 h after onset of chest pain (less than 1 h; 18.2% [n = 196], less than 2 h; 27.5% [n = 295], and less than 3 h; 14.3% [n = 154]). Moreover, the prevalence rates of AMI were similar at all times (1 h, 16.8%; 1-2 h, 20.7%; 2-3 h, 18.2%; p = .5). According to the ESC 0/1-h algorithm, the distribution patterns of rule-out, observe, and rule-in groups were similar; however, none of the patients was diagnosed with AMI or cardiac death in the rule-out group. CONCLUSION: This study revealed the applicability of the 0/1-h algorithm for the management of early presenters.

Sex-Dependent Phenotypic Variability of an SCN5A Mutation: Brugada Syndrome and Sick Sinus Syndrome.

Background Brugada syndrome ( BS ) is known to be 9 times more prevalent in males than females. However, little is known about the development of sick sinus syndrome in female members with familial BS . Methods and Results Familial BS patients and family members, both from our institutions and collaborating sites that specialize in clinical care of BS , participated in this study. We collected information on their clinical and genetic background, along with the inheritance patterns of BS . Detailed information on each case with familial BS is described. A total of 7 families, including 25 BS patients (12 females and 13 males), were included. Seven were probands and 18 were family members. Ten out of the 12 female patients and none of the 13 male patients developed sick sinus syndrome. Sudden death or spontaneous ventricular fibrillation occurred in 7 out of 13 male patients and 2 out of 12 female patients. Conclusions Familial BS existed in which female patients developed sick sinus syndrome but male patients did not. Some of those female patients with sick sinus syndrome had unrecognized BS . Information should be collected not only regarding a family history of sudden death or BS , but also whether a pacemaker was implanted in female members.

Stability of intrinsic rhythm in pacemaker-dependent patients during pacemaker replacement: Can we predict the need for temporary pacing?

BACKGROUND: In pacemaker-dependent patients, the risk of asystole must be managed during device replacement. This study aimed to examine whether we could predict the indication for temporary pacing (TP) during the generator replacement. METHODS: We studied 105 consecutive patients who underwent pacemaker replacement due to battery depletion at Juntendo Nerima Hospital between September 2005 and December 2016. We examined the relationship between the stability of the intrinsic rhythm (IR) during pacemaker replacement and several clinical factors including age, gender, sick sinus syndrome or atrioventricular (AV) block, duration of pacing, structural heart disease, use of anti-arrhythmic drugs, and the presence/absence of a stable IR (>40 bpm) at the outpatient clinic (OPC) just before pacemaker replacement. RESULTS: Of the 105 patients, we excluded 1 patient who required TP because of bradycardia-dependent torsades de points. Therefore, we evaluated 104 patients for the indication for TP. TP was underwent in 19 patients (18%) because of an absence or instability of the IR during pacemaker replacement. The indication for TP was significantly correlated with AV block (84% vs 48%, P = .0044) and the absence of a stable IR at the last OPC visit (89% vs 24%, P < .0001). For predicting the indication for TP, the following values of no stable IR at the last OPC visit were obtained: 89% sensitivity, 77% specificity, 46% positive predictive value, and 97% negative predictive value. CONCLUSIONS: The presence of a stable IR at the last OPC visit was a good predictor (97%) of no indication for TP during pacemaker replacement.

Brugada syndrome and sinus node dysfunction.

Brugada syndrome (BrS) is a well-known catastrophic disease first reported in 1992 by the Brugada brothers. Ventricular fibrillation (VF) is an essential arrhythmia in BrS. An association between BrS and atrial tachyarrhythmias is not uncommon. However, sinus node dysfunction (SND) associated with BrS has not been well discussed. In this review, we focus on the association between BrS and SND. Based on previous reports describing clinical, epidemiological, and genetic evidence, SND is not a rare concomitant disorder in BrS. BrS may be a multiple conduction or arrhythmogenic disorder including not only the His-Purkinje system and right ventricle, but also the sinus node and atrium, derived from ion channel mutations.

Sunitinib does not acutely alter left ventricular systolic function, but induces diastolic dysfunction.

PURPOSE: Cancer chemotherapies have improved the prognosis of cancer patients in recent years; however, their side effects on the cardiovascular systems have emerged as a major concern in the field of both cardiology and oncology. In particular, multi-targeted tyrosine kinase inhibitors are known to induce various types of cardiovascular adverse events including hypertension, QT-interval prolongation and heart failure, but their underlying mechanisms remain elusive. To explore how to better predict such drug-induced cardiovascular adverse events, we assessed the electropharmacological effects of sunitinib using the halothane-anesthetized dogs (n = 5), while plasma concentrations of cardiac enzymes including aspartate aminotransferase, lactate dehydrogenase, creatinine kinase and cardiac troponin I  were measured. METHODS: Sunitinib was intravenously administered at 0.01 and 0.1 mg/kg for 10 min with 20 min interval. RESULTS: Sunitinib decreased the amplitude of maximum downstroke velocity of the left ventricular pressure, prolonged the isovolumic relaxation time and increased the left ventricular end-diastolic pressure in a dose-related manner without affecting the other cardiohemodynamic and electrophysiological variables. More importantly, sunitinib significantly elevated cardiac troponin I level for 30-60 min after the high dose without altering the other biomarkers. CONCLUSIONS: Monitoring of the cardiac diastolic function together with cardiac troponin I after the start of sunitinib administration may become a reliable measure to predict the onset of sunitinib-induced cardiovascular adverse events.

Registry of Japanese patients with atrial fibrillation focused on anticoagulant therapy in the new era: The RAFFINE registry study design and baseline characteristics.

BACKGROUND: The management of atrial fibrillation (AF) has evolved with the development of direct oral anticoagulants (DOACs), but data on their clinical effectiveness and safety outside clinical trial settings are limited. METHOD: The RAFFINE registry is an observational, multicenter, prospective registry of Japanese patients with AF, designed to follow clinical events over 3 years. Patient enrollment was conducted from 2013 to 2015 at university hospitals, general hospitals, and private clinics to ensure inclusion of a broad spectrum of representative AF patients. The primary outcome events in this study will be ischemic stroke, systemic embolism, and major bleeding. RESULT: We enrolled 3901 ambulatory patients with AF from 4 university hospitals and 50 general hospitals/clinics in Japan. The mean patient age was 72.6 years and 68.5% were male. The type of AF was paroxysmal in 37.8%, persistent in 9.3%, and permanent in 51.7%. Major coexisting diseases were hypertension (72.7%), diabetes mellitus (30.3%), congestive heart failure (23.8%), history of ischemic stroke or transient ischemic attack (15.1%), and coronary artery disease (13.7%). Of the entire cohort, 44.6% were treated with warfarin and 43.0% were treated with DOACs. The prescription of DOACs exceeded that of warfarin in the general hospitals and clinics. Risk scores such as CHADS2 score, CHA2DS2-VASc score, and HAS-BLED score were higher in patients at university hospitals than in patients at general hospitals or clinics. CONCLUSION: The RAFFINE registry at baseline described the current status of anticoagulation therapy in Japan and long-term follow-up data will identify how outcomes vary between stratified groups in patients with AF in the DOAC era (UMIN Clinical Trials Registry UMIN000009617).

Heart Failure with Hyperthyroidism Demonstrating Discrepancy between the Clinical Course and B-type Natriuretic Peptide Levels.

A 35-year-old Japanese man was emergently admitted to our hospital with chief complaints of palpitation and dyspnea. He has been treated for Basedow's disease. He was diagnosed with acute decompensated heart failure, atrial fibrillation and thyrotoxicosis. We started anti-thyroid agents and a treatment for heart failure with beta blockers and diuretics under anti-coagulation therapy. His B-type natriuretic peptide levels remained high, although the heart failure had been compensated and the heart rate was well controlled while hyperthyroidism still existed. We should bear in mind that a discrepancy can exist between the clinical course and the B-type natriuretic peptide level in heart failure patients complicated with hyperthyroidism.