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.

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.

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.

Efficacy of Precordial Percussion Pacing Assessed in a Cardiac Standstill Microminipig Model.

BACKGROUND: Potential cardiovascular benefits of precordial percussion pacing (PPP) during cardiac standstill are unknown.Methods and Results:A cardiac standstill model in amicrominipigwas created by inducing complete atrioventricular block with a catheter ablation technique (n=7). Next, the efficacy of cardiopulmonary resuscitation by standard chest compressions (S-CPR), PPP and ventricular electrical pacing in this model were analyzed in series (n=4). To assess the mechanism of PPP, a non-selective, stretch-activated channel blocker, amiloride, was administered during PPP (n=3). Peak systolic and diastolic arterial pressures during S-CPR, PPP and ventricular electrical pacing were statistically similar. However, the duration of developed arterial pressure with PPP was comparable to that with ventricular electrical pacing, and significantly greater than that with S-CPR. Amiloride decreased the induction rate of ventricular electrical activity by PPP in a dose-related manner. Each animal survived without any neurological deficit at 24, 48 h and 1 week, even with up to 2 h of continuous PPP. CONCLUSIONS: In amicrominipigmodel of cardiac standstill, PPP can become a novel means to significantly improve physiological outcomes after cardiac standstill or symptomatic bradyarrhythmias in the absence of cardiac pacing. Activation of the non-selective stretch-activated channels may mediate some of the mechanophysiological effects of PPP. Further study of PPP by itself and together with S-CPR is warranted using cardiac arrest models of atrioventricular block and asystole.

Impacts of Surgically Performed Renal Denervation on the Cardiovascular and Electrophysiological Variables in the Chronic Atrioventricular Block Dogs　- Comparison With Those of Amiodarone Treatment.

BACKGROUND: In order to begin to precisely clarify the impact of renal denervation on the blood pressure, atrial fibrillation and ventricular tachyarrhythmias, in addition to proarrhythmic potential, its cardiovascular effects were assessed by using the chronic complete atrioventricular block dogs. METHODS AND RESULTS: Cardiohemodynamic and electrophysiological effects, together with neurohumoral factors and/or electrolytes, were assessed before and 4 weeks after either renal denervation (n=5) or amiodarone treatment (n=6). Amiodarone hydrochloride was given orally to the animals every day in a dose of 200 mg/day for the first 7 days followed by 100 mg/day for the following 21 days. The renal denervation decreased the systolic pressure, idioventricular rate, prolonged ventricular effective refractory period, and slightly suppressed the adrenergic tone and the renin-angiotensin-aldosterone system, but hardly affected the atrial effective refractory period and terminal repolarization period. Amiodarone prolonged the atrial effective refractory period, whereas no significant change was detected in the other variables. CONCLUSIONS: Surgically performed renal denervation may possess the anti-ventricular tachyarrhythmic rather than anti-atrial fibrillatory potentials, and it also modestly decreased the blood pressure. Thus, currently obtained information may be used as guidance for better understanding the utility and limitation of renal denervation against various types of cardiovascular diseases. (Circ J 2016; 80: 1556-1563).

Increased extracellular and intracellular Ca²âº lead to adipocyte accumulation in bone marrow stromal cells by different mechanisms.

Mesenchymal stem cells found in bone marrow stromal cells (BMSCs) are the common progenitors for both adipocyte and osteoblast. An increase in marrow adipogenesis is associated with age-related osteopenia and anemia. Both extracellular and intracellular Ca(2+) ([Ca(2+)]o and [Ca(2+)]i) are versatile signaling molecules that are involved in the regulation of cell functions, including proliferation and differentiation. We have recently reported that upon treatment of BMSCs with insulin and dexamethasone, both high [Ca(2+)]o and high [Ca(2+)]i enhanced adipocyte accumulation, which suggested that increases in [Ca(2+)]o caused by bone resorption may accelerate adipocyte accumulation in aging and diabetic patients. In this study, we used primary mouse BMSCs to investigate the mechanisms by which high [Ca(2+)]o and high [Ca(2+)]i may enhance adipocyte accumulation. In the process of adipocyte accumulation, two important keys are adipocyte differentiation and the proliferation of BMSCs, which have the potential to differentiate into adipocytes. Use of MTT assay and real-time RT-PCR revealed that high [Ca(2+)]i (ionomycin)-dependent adipocyte accumulation is caused by enhanced proliferation of BMSCs but not enhanced differentiation into adipocytes. Using fura-2 fluorescence-based approaches, we showed that high [Ca(2+)]o (addition of CaCl2) leads to increases in [Ca(2+)]i. Flow cytometric methods revealed that high [Ca(2+)]o suppressed the phosphorylation of ERK independently of intracellular Ca(2+). The inhibition of ERK by U0126 and PD0325901 enhanced the differentiation of BMSCs into adipocytes. These data suggest that increased extracellular Ca(2+) provides the differentiation of BMSCs into adipocytes by the suppression of ERK activity independently of increased intracellular Ca(2+), which results in BMSC proliferation.

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.

Enhanced accumulation of adipocytes in bone marrow stromal cells in the presence of increased extracellular and intracellular [Ca²âº].

The bone marrow stroma contains osteoblasts and adipocytes that have a common precursor: the pluripotent mesenchymal stem cell found in bone marrow stromal cells (BMSCs). Local bone marrow Ca(2+) levels can reach high concentrations due to bone resorption, which is one of the notable features of the bone marrow stroma. Here, we describe the effects of high [Ca(2+)](o) on the accumulation of adipocytes in the bone marrow stroma. Using primary mouse BMSCs, we evaluated the level of adipocyte accumulation by measuring Oil Red O staining and glycerol-3-phosphate dehydrogenase (GPDH) activity. High [Ca(2+)](o) enhanced the accumulation of adipocytes following treatment with both insulin and dexamethasone together but not in the absence of this treatment. This enhanced accumulation was the result of both the accelerated proliferation of BMSCs and their differentiation into adipocytes. Using the fura-2 method, we also showed that high [Ca(2+)](o) induces an increase in [Ca(2+)](i). An intracellular Ca(2+) chelator suppressed the enhancement in adipocyte accumulation due to increased [Ca(2+)](o) in BMSCs. These data suggest a new role for extracellular Ca(2+) in the bone marrow stroma: increased [Ca(2+)](o) induces an increase in [Ca(2+)](i) levels, which in turn enhances the accumulation of adipocytes under certain conditions.

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.

Azelnidipine and amlodipine anti-coronary atherosclerosis trial in hypertensive patients undergoing coronary intervention by serial volumetric intravascular ultrasound analysis in Juntendo University (ALPS-J).

BACKGROUND: A previous study reported that amlodipine retarded coronary plaque progression in patients with coronary artery disease. The goal of this multicenter study was to determine which calcium-channel blockers (CCBs) other than amlodipine attenuated the progression of plaque volume (PV) accessed by intravascular ultrasound (IVUS). METHODS AND RESULTS: ALPS-J was a prospective, randomized open-label study conducted at 5 centers. Patients who had hypertension and were scheduled for coronary intervention were enrolled. Subjects were randomly assigned to receive 16 mg/day of azelnidipine or 5mg/day of amlodipine administered for 48 weeks. The primary endpoint was the percent change in coronary PV measured by IVUS. Between 2007 and 2009, 199 patients were enrolled; 115 had evaluable IVUS images at both baseline and after 48 weeks of treatment. Blood pressure significantly reduced to 128/68 mmHg at follow-up. The lipid profiles in the 2 groups were comparable (low-density lipoprotein cholesterol: 97 mg/dl). The %change in PV showed a significant regression of 4.67 and 4.85% in the azelnidipine and amlodipine groups, respectively. The upper limit of the 95% confidence interval of the mean difference in %change PV between the 2 groups (0.18%, 95% confidence interval 4.62 to 4.98%) did not exceed the pre-defined non-inferiority margin of 6.525%. CONCLUSIONS: ALPS-J demonstrated that azelnidipine was not inferior to amlodipine for primary efficacy. In addition to standard medical therapy, dihydropyridine CCBs will retard PV progression in hypertensive patients.

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.

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.

Clinical characteristics of defecation syncope compared with micturition syncope.

BACKGROUND: Defecation syncope (DS) and micturition syncope (MS) are daily excretion-related syndromes that are both classified as situational. However, their clinical features seem to be very different, so the present comparative study aimed to clarify those of DS. METHODS AND RESULTS: The study population consisted of 20 consecutive patients with DS and 37 consecutive patients with MS. The DS patients were significantly older than the MS patients (63+/-15 vs 52+/-17 years, P=0.026). Gender was significantly different (P=0.026): women predominated in the DS group (60%) whereas men more commonly had MS (70%). The diurnal distribution of syncope differed (P=0.0054): 88% of MS episodes occurred between 6 pm and 6 am, whereas DS occurred almost equally throughout the 24 h. Syncope after drinking alcohol was less common with DS (10%) than with MS (60%) (P=0.0003), whereas gastrointestinal tract (GIT) symptoms as a premonitory sign were more common with DS (55%) than with MS (3%) (P<0.0001). Positive responses to head-up tilt testing did not differ between the DS and MS groups. CONCLUSIONS: DS tends to occur in elderly women and without any significant daily distribution. Alcohol-related syncope was uncommon in patients with DS, and preceding GIT symptoms may be important as predictors or triggering factors.

Prevalence of the Brugada-type electrocardiogram and incidence of Brugada syndrome in patients with sick sinus syndrome.

BACKGROUND: In the present study, clarification of the prevalence of the Brugada-type electrocardiogram (ECG) and the incidence of spontaneous ventricular fibrillation (VF) that occurred with the Brugada-type ECG in patients with sick sinus syndrome (SSS) was determined. METHODS AND RESULTS: A total of 487 consecutive patients (men 45%, mean age 69.9+/-12.3 years), who were defined as having an indication for cardiac pacemaker (PM) for SSS, were investigated. The ECG before an initial PM implantation and occurrence of VF or sudden cardiac death (SCD) was examined retrospectively. Brugada-type ECG was found in 14 patients (2.87%) including 4 (0.82%) with type 1 and 10 (2.05%) with type 2. During the follow-up period of 7.2+/-5.4 years, 2 out of the 4 patients with type 1 ECG had experienced a VF episode after the device implantation. In 10 patients with type 2 ECG, none had VF or SCD. The incidence of spontaneous VF (Brugada syndrome) in SSS patients was calculated as 14.1 per 100 person-years with type 1 ECG. CONCLUSIONS: The prevalence of typical Brugada-type (type 1) ECG in SSS patients seems to be higher compared with the general population. In addition, SSS patients with the typical Brugada-type ECG might be a high risk for spontaneous VF.

Effects of nicorandil on the cAMP-dependent Cl- current in guinea-pig ventricular cells.

In guinea-pig cardiomyocytes, a cAMP-dependent Cl(-) current (I(Cl,cAMP)) flows through a cardiac isoform of the cystic fibrosis transmembrane conductance regulator (CFTR), which belongs to a family of the ATP-binding cassette (ABC) proteins. Although several K(+)-channel openers and sulfonylurea ATP-sensitive K(+) (K(ATP))-channel blockers reportedly inhibit I(Cl,cAMP), effects of nicorandil on the Cl(-) current have not been evaluated. This study was conducted to examine the effects of nicorandil on I(Cl,cAMP) in isolated guinea-pig ventricular cells using patch clamp techniques. Nicorandil in concentrations higher than 300 microM enhanced the I(Cl,cAMP) preactivated by 0.1 microM isoproterenol. The isoproterenol-induced I(Cl,cAMP) was inhibited by 100 microM glibenclamide, but not by 100 microM pinacidil. SNAP (S-nitroso-N-acetyl-D,L-penicillamine, 10 microM), a nitric oxide (NO) donor, similarly enhanced the isoproterenol-induced I(Cl,cAMP). However, SG-86, a denitrated metabolite possessing K(+ )channel-opening action, failed to enhance the Cl(-) current. When the I(Cl,cAMP) was activated by 3-isobutyl-1-methylxanthine (IBMX, 30 microM), either nicorandil or SNAP failed to enhance the isoproterenol-induced I(Cl,cAMP). Thus, nicorandil enhances I(Cl,cAMP) in guinea-pig cardiomyocytes through an increase in intracellular cGMP, although direct modulation of I(Cl,cAMP) by NO cannot be completely excluded.

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.