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Background: Although bisoprolol has been established to prevent heart failure (HF), finding the optimal dose remains a challenge. It is crucial to understand the distribution of bisoprolol plasma concentration (Bis-PC) and association with outcomes., Methods: This was a single-center observational study in 114 HF patients under once-daily bisoprolol. After obtaining trough Bis-PC, patients were followed-up for 1 year. The primary endpoint was worsening of HF. Patients were divided according to the tertiles of Bis-PC., Results: In multivariate logistic regression analysis, independent predictors of high Bis-PC (1st tertile: ≥ 5.38 ng/mL) were age, eGFR, and bisoprolol dose. The cumulative incidence rates of the primary endpoint were 10.5%/13.2%/26.3% in low/middle/high Bis-PC categories, respectively (log rank test, p = 0.087). Bis-PC was independently associated with the primary endpoint (hazard ratio [HR], 1.19 [per ng/mL], 95% CI 1.03-1.36). In subgroups, high Bis-PC was independently associated with the primary endpoint in elderly (HR 6.32, 95% CI 1.34-29.83) and HF with preserved ejection fraction (HFpEF) (HR 3.52, 95% CI 1.06-11.70)., Conclusions: Bis-PC was increased by age and renal dysfunction, and high Bis-PC was associated with worsening of HF in elderly and HFpEF patients. Care should be taken to avoid overdose., (Copyright © 2020 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Prothrombin time (PT) has been widely used for measuring anticoagulation intensity under rivaroxaban therapy, but precise information has not been well established yet. Consecutive 96 non-valvular atrial fibrillation (NVAF) under rivaroxaban between Jan/June, 2015 were recruited. Serum concentration (SC) and PT with 5 representative reagents available in Japan (Neoplastin Plus®, Thromborel S®, Thrombocheck PT®, Thrombocheck PT Plus®, and Recombiplastin®) at 2-4 hours after (peak) and before intake of rivaroxaban (trough) were measured at outpatient clinic in the cardiovascular institute (CVI ARO study 1). Nonlinear mixed-effects modelling was used to model the population pharmacokinetics and pharmacodynamics of rivaroxaban. An oral one-compartment model was employed to describe the population pharmacokinetics of rivaroxaban. The pharmacokinetics of rivaroxaban were affected by creatinine clearance, alanine aminotransferase, and use of CYP3A4 or P-gp inhibitors. PTs with 5 reagents were predicted by pharmacodinamic models with SC, hematocrit, serum albumin, and age, with medium predicting ability (highest/lowest R2 = 0.746/0.658 in Recombiplastin/Thromborel S, respectively). This population analysis in NVAF patients under rivaroxaban therapy demonstrated that pharmacokinetics of rivaroxaban was described by an oral one-compartment model with expected covariates, and can be assessed by PT with available reagents in Japan with medium predicting ability., (Copyright © 2018 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Background: The predictive role of E/e' on ischemic stroke (IS) and atrial fibrillation (AF) in Japanese patients without AF are unclear., Methods and Results: Shinken database includes all the new patients visiting the Cardiovascular Institute Hospital in Tokyo, Japan. E/e' has been routinely measured since 2007. Patients without AF for whom E/e' was measured at the initial visit between 2007 and 2014 (n=11 477, mean age 57.2 years old, men 59.5%) were divided into E/e' tertiles (<8.04, 8.04-11.00, >11.00). During the mean follow-up period of 1.8 years, 58 IS and 140 new appearances of AF were observed. High E/e' tertile was associated with more prevalence of atherothrombotic risks. The cumulative incidence of IS events and new appearance of AF at 6 years in low, middle, and high E/e' tertiles were 0.5%, 1.4%, and 3.0%/year (log-rank test, p<0.001), and 2.5%, 2.9%, and 4.2%/year (log-rank test, p=0.007), respectively. In multivariate analysis, high E/e' tertile was independently associated with IS (HR, 2.857, 95%CI 1.257-6.495, p=0.012). Although high E/e' tertile was independently associated with new appearance of AF when adjusted for coexistence of atherothrombotic risk factors (HR, 1.694, 95%CI, 1.097-2.616, p=0.017), the association was attenuated after adjustment for left atrial dimension., Conclusions: E/e' was significantly associated with incidence of IS and new appearance of AF in non-AF patients., (Copyright © 2018 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Atrial fibrosis is a hallmark of atrial structural remodeling leading to the persistence of atrial fibrillation. Although fibroblasts play a major role in atrial fibrosis, their source in the adult atrium is unclear. We tested the hypothesis that endothelial cells contribute to fibroblast accumulation through an endothelial-mesenchymal transition in the atrium of patients with atrial fibrillation., Methods and Results: The study group consisted of patients with atrial fibrillation and valvular disease or atrial septal defect who underwent left atrial appendectomy during cardiac surgery (n=38). The amount of fibrotic depositions in the left atrium positively correlated with left atrial dimension. Furthermore, snail and S100A4, indicative of endothelial-mesenchymal transition, were quantified in the left atrium using western blot analysis, which showed statistically significant correlations with left atrial dimension. Immunofluorescence assay of the left atrial tissue identified snail and S100A4 being expressed within the endocardium which is composed of CD31 + cells. The snail-positive endocardium also showed the expression of membrane type 1-matrix metalloproteinase. Immunofluorescence multi-labeling experiments identified that heat shock protein 47, prolyl-4-hydroxylase, and procollagen type 1 co-localized with snail and S100A4 within the endothelial cells of the left atrium, indicating the mesenchymal phenotype to produce collagen., Conclusions: In this study, we showed that the endothelial-mesenchymal transition occurs in the atrium of patients with atrial fibrillation. This observation should help in constructing a novel therapeutic approach for preventing atrial structural remodeling., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: Low ankle-brachial index (ABI) is associated with increased mortality and an increased incidence of cardiovascular events. The purpose of this study was to investigate the value of borderline ABI in predicting clinical outcomes., Methods and Results: The data were derived from the Shinken Database 2004-2012, from a single hospital-based cohort study (N = 19,994). ABI was measured in 5205 subjects; 4756 subjects whose ABI was 0.91-1.39 and having no history of peripheral artery disease were enrolled. The subjects were classified into two groups as follows: borderline ABI (0.91-1.00; n = 324) and normal ABI (1.01-1.39; n = 4432). Subjects in the borderline ABI group had more comorbidities, including diabetes mellitus, aortic disease, and stroke. Moreover, the borderline ABI group was associated with higher levels of hemoglobin A1c and brain natriuretic peptide, larger diameters of left atrium and left ventricle, and lower levels of estimated glomerular filtration rate and left ventricular ejection fraction. All-cause death and cardiovascular death occurred in 9.3% and 4.6% of subjects in the borderline ABI group, and in 2.0% and 0.8% of subjects in the normal ABI group, respectively. An adjusted Cox regression model showed that borderline ABI was associated with a higher incidence of all-cause death (hazard ratio [HR] 2.27, p = 0.005) and cardiovascular death (HR 3.47, p = 0.003)., Conclusion: A borderline ABI was independently associated with worse clinical outcomes in relatively high risk population. Our data should be confirmed in larger populations including those with low risk profiles., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Selective separation and sensitive detection of dissolved silicon and boron (DSi and DB) in aqueous solution was achieved by combining an electrodialytic ion isolation device (EID) as a salt remover, an ion-exclusion chromatography (IEC) column, and a corona charged aerosol detector (CCAD) in sequence. DSi and DB were separated by IEC on the H(+)-form of a cation exchange resin column using pure water eluent. DSi and DB were detected after IEC separation by the CCAD with much greater sensitivity than by conductimetric detection. The five-channel EID, which consisted of anion and cation acceptors, cathode and anode isolators, and a sample channel, removed salt from the sample prior to the IEC-CCAD. DSi and DB were scarcely attracted to the anion accepter in the EID and passed almost quantitatively through the sample channel. Thus, the coupled EID-IEC-CCAD device can isolate DSi and DB from artificial seawater and hot spring water by efficiently removing high concentrations of Cl(-) and SO4(2-) (e.g., 98% and 80% at 0.10molL(-1) each, respectively). The detection limits at a signal-to-noise ratio of 3 were 0.52μmolL(-1) for DSi and 7.1μmolL(-1) for DB. The relative standard deviations (RSD, n=5) of peak areas were 0.12% for DSi and 4.3% for DB., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: The prognostic impact of worsening renal function (WRF) in acute coronary syndrome (ACS) patients is not fully understood in Japanese clinical practice, and clinical implication of persistent versus transient WRF in ACS patients is also unclear., Methods: With a single hospital-based cohort in the Shinken database 2004-2012 (n=19,994), we followed 604 ACS patients who underwent percutaneous coronary intervention (PCI). WRF was defined as an increase in creatinine during hospitalization of ≥0.3mg/dl above admission value. Persistent WRF was defined as an increase in creatinine during hospitalization of ≥0.3mg/dl above admission value and maintained until discharge, whereas transient WRF was defined as that WRF resolved at hospital discharge., Results: WRF occurred in 78 patients (13%), persistent WRF 35 patients (6%) and transient WRF 43 patients (7%). WRF patients were older and had a higher prevalence of chronic kidney disease, history of myocardial infarction (MI), and ST elevation MI. WRF was associated with elevated inflammatory markers and reduced left ventricular (LV) ejection fraction in acute, chronic phase. Incidence of all-cause death and major adverse cardiac events (MACE: all-cause death, MI, and target lesion revascularization) was significantly higher in patients with WRF. Moreover, in the WRF group, incidences of all-cause death and MACE were higher in patients with persistent WRF than those with transient WRF. A multivariate analysis showed that as well as older age, female gender, and intubation, WRF was an independent determinant of the all-cause death in ACS patients who underwent PCI., Conclusions: In conclusion, WRF might have a prognostic impact among Japanese ACS patients who underwent PCI in association with enhanced inflammatory response and LV remodeling. Persistent WRF might portend increased events, while transient WRF might have association with favorable outcomes compared with persistent WRF., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: We previously reported a cross-sectional analysis regarding the relationship between smoking and atrial fibrillation (AF) in a single hospital-based cohort with Japanese patients, but the effect of cessation of smoking and/or total tobacco consumption were unclear., Methods and Results: We used data from the Shinken Database 2004-2011 (men/women, n=10,714/6803, respectively), which included all new patients attending the Cardiovascular Institute between June 2004 and March 2012. After excluding those previously diagnosed with AF (n=2296), 15,221 patients (men/women, n=9016/6205) were analyzed. During the follow-up period of 2.0±2.1 years (range 0.0-8.1), the incidence rates of new AF in smokers and non-smokers were 9.0 and 5.0 per 1000 patient-years, respectively. In adjusted models with Cox regression analysis, smokers were independently associated with new AF [hazard ratio (HR) 1.47, 95% confidence interval (CI) 1.09-2.00]. Also, current smokers (HR 1.81, 95% CI 1.17-2.79) and smokers with Brinkman index ≥800 (HR 1.69, 95% CI 1.05-2.70) were independently associated with new AF. However, in current smokers, the HRs were not different by Brinkman index (Brinkman index <800/≥800; HR 1.81/1.82, 95% CI 1.07-3.05/0.94-3.51, respectively)., Conclusions: Smoking was independently associated with the first-appearance of AF in patients in sinus rhythm, especially when the patients continued their smoking habit. However, in patients who continued smoking, difference by total tobacco consumption was not observed, suggesting the significance of cessation of smoking for preventing AF. Our data are limited because of a single hospital-based nature and a relatively short observation period., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Seasonal variations in cardiovascular disease is well recognized. However, little is known about the presentations and outcomes of Japanese heart failure (HF) patients in the winter season., Methods and Results: We used a single hospital-based cohort from the Shinken Database 2004-2012, comprising all new patients (n=19,994) who visited the Cardiovascular Institute Hospital. A total of 375 patients who were admitted owing to acute decompensated HF were included in the analysis. Of these patients, 136 (36%) were admitted in winter. Winter was defined as the period between December and February. The HF patients admitted in winter were older, and had a higher prevalence of hypertension and diabetes mellitus than the patients admitted in other seasons. Patients with conditions categorized as clinical scenario 1 tended to be admitted more commonly in winter. HF with preserved left ventricular ejection fraction (LVEF) was more common in HF patients admitted in winter than in those admitted in other seasons. Beta-blocker use at hospital discharge was more common in the patients admitted in other seasons. Kaplan-Meier curves and log-rank test results indicated that the incidences of all-cause death, cardiovascular death, and HF admission were comparable between the patients admitted in winter and those admitted in other seasons., Conclusions: HF admission was frequently observed in the winter season and HF patients admitted in the winter season were older, and had higher prevalence of hypertension and diabetes mellitus, and preserved LVEF suggesting that we might need to pay more attention for elderly patients with hypertension, diabetes mellitus, and HF with preserved LVEF to decrease HF admissions in the winter season., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Both the prevalence of atrial fibrillation and coronary artery disease (CAD) is increasing in aged societies. However, limited data are available regarding the prevalence of CAD and the incidence of coronary events in Japanese patients with nonvalvular atrial fibrillation (NVAF)., Methods and Results: The data in this study were derived from Shinken Database 2004-2010, which includes 15,227 new patient visitors to the Cardiovascular Institute between June 2004 and March 2011. In the database, 1835 patients were diagnosed with NVAF (mean age 63 years, mean CHADS2 score 1.1 ± 1.1, and 75% were men). The prevalence of CAD at the initial visit was 118 patients (6.4%). They were older age and had a greater prevalence of men, more history of congestive heart failure and more history of cardiovascular risk factors rather than those without. During the follow-up period of 532 ± 599 days, coronary events (myocardial infarction, unstable angina, and stable angina) occurred in 51 patients (1.9%/year). Multivariate analysis showed that a history of CAD (p<0.001) and older age (p=0.024) were independent predictors of the incidence of future coronary events., Conclusions: In Japanese patients with NVAF, both the presence of CAD and the occurrence of coronary events are not uncommon. History of CAD and older age are strongly associated with the incidence of coronary events., (Copyright © 2013. Published by Elsevier Ltd.)

Background: A blue letter (safety advisory) for dabigatran was issued by the Japanese Ministry of Health, Labour and Welfare in August 2011. Changes in physicians' attitudes toward dabigatran use before and after the blue letter have not been previously reported., Methods and Results: Between March 2011 and July 2012, dabigatran was prescribed to 404 Japanese patients with nonvalvular atrial fibrillation at The Cardiovascular Institute (Tokyo, Japan). Patients were divided into three groups according to the first prescription date: phase I (before the blue letter, n=135); phase II (after the blue letter and before permission for longer-term prescriptions, n=112); and phase III (after permission for longer-term prescriptions, n=157). In phase II, dabigatran use tended to be avoided for patients with older age, renal dysfunction, receiving antiplatelet medication, or p-glycoprotein inhibitors. Measurement of activated partial thromboplastin time significantly increased from phase I to III. In phase III, the tendencies seen in phase II were reversed: dabigatran use in patients with older age and renal dysfunction tended to increase, but decreased or remained the same in patients receiving antiplatelet medications or p-glycoprotein inhibitors., Conclusions: We described the changes in the attitudes of attending physicians toward dabigatran prescription after the blue letter in a specialized hospital for cardiovascular care in Japan, which, we believe, involve useful information for safe use of dabigatran in a real-world clinical setting. However, a true impact or effect of the blue letter should be ascertained in a nationwide, multicenter study., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Clinical data on the mortality and morbidity of unselected Japanese patients with heart failure (HF) are limited. In this study, we aimed to determine the clinical characteristics, long-term outcomes, and prognostic factors of Japanese HF patients with preserved or reduced left ventricular ejection fraction (LVEF)., Methods and Results: We used a single hospital-based cohort from the Shinken Database 2004-2011 that comprised all new patients (n=17,517) visiting the Cardiovascular Institute Hospital. A total of 1,525 patients diagnosed with symptomatic HF at the initial visit were included in the analysis. Of these, 1121 patients (74%) exhibited a preserved LVEF (>50%) and 404 patients (26%) had a reduced LVEF (≤ 50%). HF patients with preserved LVEF (HFpEF) were older and more often female than patients with reduced LVEF (HFrEF). Kaplan-Meier curves and log-rank test results showed that HFpEF patients had a better prognosis than HFrEF patients. However, there were no significant differences in clinical outcomes between HFpEF and HFrEF patients when the analysis was limited to inpatients. Cox regression analysis showed that HFpEF patients had a significantly lower risk of all-cause death (p=0.027; hazard ratio, 0.547, 95% confidence interval, 0.321-0.933). Multivariate analyses performed separately showed that the independent predictors of all-cause death in HFrEF were advanced age, lower body mass index, diabetes mellitus, and the absence of statin treatment, whereas those for HFpEF were advanced age, absence of dyslipidemia, anemia, and left ventricular hypertrophy., Conclusions: This prospective cohort study identified the clinical characteristics, long-term outcomes, and prognostic factors of Japanese HF patients with reduced and preserved ejection fractions in a real-world clinical setting., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: The impact of obesity on Japanese patients who undergo primary percutaneous coronary intervention (PCI) remains unclear., Methods and Results: Within a single hospital-based cohort in the Shinken Database 2004-2010, which comprised all new patients (n=15227) who visited the Cardiovascular Institute, we followed patients who underwent PCI. Major adverse cardiac events (MACE)-death, myocardial infarction, or target lesion revascularization (TLR)-were defined as the composite endpoint. A total of 1205 patients were included in this study (median follow-up of 1037±703 days): 92 lean [body-mass-index (BMI)<20]; 640 normal-weight (BMI=20-24.9); 417 overweight (BMI=25-29.9); and 56 obese (BMI≥30). Mean age decreased and male gender increased with increasing BMI. Classic coronary risk factors were more common in overweight and obese patients than in normal-weight and lean patients. Chronic kidney disease (CKD) was more common in lean patients than in overweight and obese patients. Patients taking dual antiplatelet therapy, statins, beta-blockers, and renin-angiotensin-system inhibitors increased in a BMI-dependent manner. Obese patients had a significantly lower frequency of MACE, all-cause death, cardiac death, and hospital admission for heart failure than lean patients. Multivariate analysis showed that BMI category was independently associated with all-cause death after PCI., Conclusion: Over-weight and obese patients were independently associated with favorable long-term clinical outcomes after PCI, suggesting that obesity paradox was applicable to Japanese patients after PCI in real-world clinical setting., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Several reports have identified that decline in renal function and presence of proteinuria are closely associated with incidence of atrial fibrillation (AF). However, it is still unclear whether these kidney-related markers are associated with the progression of AF from paroxysmal to persistent form., Methods and Results: Among the new patients who visited the Cardiovascular Institute Hospital between 2004 and 2010 (Shinken Database 2004-2010, n=15,227), both estimated glomerular filtration rate (eGFR) and proteinuria were measured in 1074 AF patients (paroxysmal/persistent 579/495, respectively), who were divided into tertiles of eGFR (the borderlines were 60.07 and 73.67 ml[min(-1)]1.73[m(-2)], respectively), and then further divided into the two categories with/without proteinuria. The average value of eGFR was lower (63.1 ml[min(-1)]1.73[m(-2)] vs. 68.8 ml[min(-1)]1.73[m(-2)], p<0.001) and the detection rate of proteinuria was higher (13.7% vs. 8.5%, p=0.006) in patients with persistent AF than in those with paroxysmal AF, respectively. In the multivariate analysis without parameters of echocardiography [left ventricular ejection fraction (LVEF) and left atrial dimension (LAD)], both eGFR and proteinuria were independently associated with persistent AF, but the association was abolished when the model included LAD and LVEF., Conclusions: In the present analysis with cross-sectional design, both eGFR and proteinuria were apparently linked to the persistent form of AF, but their role in the pathogenesis does not seem to exceed the atrial stretch and remodeling, represented by LAD and LVEF., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Objectives: This study aimed to test the hypothesis that the range of 24-h total heart beats (24 h-tHB) correlates with cardiac outcomes (cardiac death and incidence of hospitalization with heart failure) in patients with permanent atrial fibrillation (AF)., Methods and Results: We divided 252 consecutive outpatients with permanent AF into 4 groups according to their 24 h-tHB and examined clinical outcomes. Initial 24 h-tHB at enrollment was significantly associated with patient characteristics including age, sex, presence of structural heart diseases, and left ventricular ejection fraction (EF). The cumulative incidence of heart failure was high in the lowest 24 h-tHB group compared with other groups and significantly different from the highest one (23.9% vs. 7.2% at 5 years, p=0.0074). Multivariate analysis showed that 24 h-tHB<100,000 was associated with cardiac events [hazard ratio, 2.45; 95% confidence interval (CI), 1.09-5.49; p=0.03), along with structural heart disease (hazard ratio, 9.81; 95% CI, 3.34-28.83; p=0.0001) and EF (hazard ratio, 0.97; 95% CI, 0.94-0.99; p=0.002)., Conclusions: Surprisingly, low but not high heart rate was significantly associated with higher incidence of heart failure in Japanese patients. This finding should be further evaluated in future prospective studies., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: The presence of heart failure (HF) with preserved ejection fraction (HFPEF) is increasingly recognized. However, prognostic factors for HFPEF remain unclear., Methods and Results: The data were derived from Shinken Database 2004-2010, a prospective cohort study (n=15,227). We examined 301 consecutive HFPEF patients (New York Heart Association Class II or greater) and tracked them for an average 3.5 years. Cardiopulmonary exercise testing (CPX), blood exams, and ultrasound cardiogram (UCG) were performed at the first medical examination. Acute decompensated HF (ADHF) admission was observed in 19 patients (6.3%). CPX showed that the anaerobic threshold was lower (7.3±4.8mL/min/kg vs. 9.7±4.3mL/min/kg, p=0.02) and slope of the increase in ventilation to the increase in CO(2) output (VE-VCO(2) slope) was higher (40.6±8.5 vs. 34.6±7.9, p<0.01) in patients with ADHF admission than those without. Serum brain natriuretic peptide (BNP) tended to be higher and left atrial (LA) dimension was significantly greater (47.0±15.8mm vs. 41.0±9.9mm, p=0.01) in patients with ADHF admission than those without. Multivariate analysis showed that higher VE-VCO(2) slope and greater LA dimension were independent determinants of ADHF admission., Conclusion: An aggravated CPX parameter and LA dilatation were associated with ADHF admission in patients with symptomatic HFPEF, suggesting the prognostic role of cardiopulmonary dysfunction during exercise and LA remodeling in the pathogenesis of decompensated HF development in HFPEF., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: In Japan, the recent status of the mortality of atrial fibrillation (AF) patients is still unclear., Methods and Results: We used a single-hospital based cohort database in an urban city (Tokyo) in Japan, including all the new visitors from 2004 to 2009 (n=13,228). The non-adjusted death rates of AF patients for all-cause, stroke, and cardiovascular death were 1091, 97, and 727 per 100,000 patient-years, and the age-adjusted ones were 317 (95% CI, 316-318), 16 (95% CI, 16-16), and 238 (95% CI, 237-239), respectively. The age-adjusted relative risk of AF on all-cause mortality was 1.7 in the particular population., Conclusions: The present study provides the most recent data about the characteristics and the mortality of AF patients in Tokyo, thus serving as the basic information for finding problems to solve regarding Japanese AF patients., (Copyright © 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Diabetes mellitus promotes atrial structural remodeling, thereby producing atrial arrhythmogenicity, where advanced glycation endproducts (AGEs) and their receptor (RAGE) are implicated to play a role in the pathogenesis., Purpose: We investigated the effects of candesartan, an angiotensin type II receptor blocker, on the diabetes-induced atrial structural change., Methods and Results: Diabetes was induced in 8-week-old female Sprague-Dawley rats by intraperitoneal injection of streptozotocin at 70 mg/kg. Osmotic pumps were simultaneously set to infuse candesartan at a subdepressor dose of 0.05 mg/kg/day. Twelve weeks after the induction of diabetes, the blood glucose and glycated hemoglobin A1c were significantly higher in streptozotocin-injected rats than those in control rats, and were not affected by candesartan treatment. The atria of diabetic rats showed remarkable diffuse interstitial fibrosis with more enhanced protein expressions of RAGE and connective tissue growth factor (CTGF) compared with control ones. The treatment with candesartan significantly reduced CTGF expression and effectively suppressed the development of fibrotic deposition in diabetic animals., Conclusions: Candesartan reduced CTGF expression and attenuated the fibrosis in diabetic rat atria. These results implied the protective effects of candesartan on diabetes-related atrial arrhythmias., (Copyright © 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: The effect of early statin initiation on secondary prevention remains uncertain in unselected Japanese populations with coronary artery disease (CAD)., Methods: We investigated the mortality and morbidity in CAD patients according to presence or absence of statins within 3 months after the diagnosis of CAD in the Shinken Database cohort study. The primary endpoint was all-cause mortality., Results: Data were available on 789 Japanese patients with CAD (male 78.8%). Among those, 351 patients (44.5%) received a statin. The mean (SD) baseline low-density lipoprotein (LDL)-cholesterol levels were 113.6 (35.7) mg/dL in the statin group and 113.6 (26.4) mg/dL in the non-statin group (p=0.992). Unadjusted 2-year survival in patients with or without statins was 98.4% and 92.1%, respectively (p<0.001). Among a prespecified subgroup of patients undergoing percutaneous coronary intervention (PCI) (n=238 with statins and n=183 without statins), a consistent effect of statins on 2-year survival was observed (98.5% and 90.9%, respectively, p<0.001). However, there was no significant difference in 2-year target lesion revascularization-free survival (77.9% in statins versus 73.7% in non-statins, respectively, p=0.298). The age- and gender-adjusted survival in the PCI subgroup was significantly higher in the statin group [hazard ratio (HR) 0.29, 95% confidence interval (CI) 0.095-0.913] compared to non-statin. Multivariate analysis showed statins significantly reduced mortality (HR 0.27, 95%CI 0.078-0.944), but not revascularization (HR 0.91, 95%CI 0.589-1.406)., Conclusions: This study suggested that statin therapy initiated early after the diagnosis of CAD can decrease the risk of fatal events in Japanese CAD patients., (Copyright © 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Several hospital-based investigations have reported that a high proportion of patients with heart failure (HF) have preserved left ventricular ejection fraction (LVEF). The purpose of this study was to determine the prevalence, prognosis, and predictors for mortality of Japanese HF patients with preserved versus reduced LVEF in a prospective cohort fashion., Methods and Results: Our hospital-based database including inpatients and also outpatients was used for analysis. Out of 4255 new patients, 597 patients (male/female 414/183, age 65.1+/-12.9 years) were diagnosed as having symptomatic HF at the initial visit. Among 589 HF patients undergoing echocardiography, 398 (67.6%) showed a preserved LVEF (>50%) and 191 (32.4%) had a reduced LVEF (< or =50%). Patients with preserved LVEF were older (p=0.004) and more likely to be female (p=0.002). During follow-up of an average 539 days, 34 cardiovascular deaths occurred, and patients with preserved LVEF showed a better prognosis than those with reduced LVEF (3.2% vs. 7.4% per year, p=0.0097). Multivariate Cox hazards analysis identified LVEF as an independent predictor in all HF patients. Also, separated group analysis showed that presence of chronic kidney disease was independently associated with poor prognosis irrespective of HF types., Conclusions: This prospective cohort study identified prevalence and prognosis of HF in Japanese in- and outpatients, where patients with preserved LVEF showed a better prognosis than those with reduced LVEF., (2009 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Mortality and morbidity after acute coronary syndrome (ACS) in Japan appear to be different from those in Western countries due to different social healthcare systems, races, geographical locations, and interventional procedures, although data are limited in Japan., Methods: With a hospital-based cohort study comprising all the new patients who had visited our hospital between 2004 and 2007 (n=6562), we identified all-cause mortality, the composite endpoint of cardiac death, non-fatal myocardial infarction (MI), or target vessel revascularization and the predictors., Results: Of the total, 293 patients were included with a discharge diagnosis of ACS (median follow-up of 24.5 months). Non-ST elevation-ACS (NSTE-ACS) (unstable angina and non-ST elevation MI) and ST elevation MI (STEMI) were observed in 165 (56.3%) and 128 (43.7%) patients, respectively. Percutaneous coronary intervention or coronary artery bypass graft surgery was performed in 72.7% and 14.5% of NSTE-ACS patients, respectively and in 82.8% and 10.2% of STEMI patients. The use of aspirin, ticlopidine, and beta-blockers for NSTE-ACS patients were 93.3%, 66.9%, and 38.0%, respectively, with corresponding rates of 96.0%, 75.4%, and 57.1% for STEMI patients. All-cause mortality rates in NSTE-ACS and STEMI were 1.8% and 5.5% at 30 days, respectively, and 6.3% and 12.9% at 2 years, with corresponding rates of 3.7% and 8.7% at 30 days, respectively, and 23.4% and 35.6% at 2 years for the composite endpoint. Multivariate analysis showed that predictors for mortality were older age (hazard ratio [HR] 1.13, 95% confidence interval [CI] 1.018-1.244) and estimated glomerular filtration rate value (HR 0.96, 95% CI 0.929-0.988) in NSTE-ACS, and older age (HR 1.10, 95% CI 1.011-1.119) and congestive heart failure on admission (HR 20.0, 95% CI 2.439-164.4) in STEMI., Conclusions: The present study identified long-term mortality, morbidity, and predictors of adverse events for Japanese patients with ACS., (2009 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Hydrophobic interaction electrokinetic chromatography was used to simultaneously determine seven active ingredients (diphenhydramine hydrochloride, dibucaine hydrochloride, chlorhexidine hydrochloride, phenylephrine hydrochloride, hydrocortisone acetate, allantoin and tocopherol acetate) in an ointment. Not only hydrophobic but also ionic compounds were successfully separated by use of a separation solution composed of acetonitrile-water (80:20, v/v), tetradecylammonium salt and ammonium chloride. The migration behavior of the hydrophobic compound depended on tetradecylammonium concentration, while that of the ionic compounds depended on ammonium chloride concentration. An addition of triethylamine to the separation solution markedly improved the reproducibility of the peak areas of cations with a relative standard deviation (RSD) of less than 1.7% (n=6). The established method was validated and confirmed to be applicable to the determination of the active ingredients in a commercial ointment. Sample preparation was performed by liquid-liquid extraction and no interference from the formulation excipients was observed. Good linearities were obtained, with correlation coefficients above 0.999. Recoveries and precisions ranged from 98.0 to 100.8%, and from 0.4 to 2.9% RSD, respectively. These results suggest that hydrophobic interaction electrokinetic chromatography can be used for the determination of ionic compounds as well as hydrophobic compounds in ointment.

Cyclodextrin-modified micellar electrokinetic chromatography was applied to determine simultaneously 11 active ingredients in ophthalmic solutions. All the ingredients were successfully separated by using the mixed carrier system containing sodium dodecyl sulfate with beta-cyclodextrin and tetrabutylammonium phosphate. The effects of the cyclodextrin type on selectivity were also examined. Excellent separation of the all ingredients was obtained by the use of dimethyl-beta-cyclodextrin. The established method was validated and confirmed to be applicable to the determination of the active ingredients in a commercial ophthalmic solution. These results suggest that capillary electrophoresis can be applied to the quantitative analysis as well as qualitative analysis in pharmaceuticals.

A simple and precise ion-pair high-performance liquid chromatographic method was developed for the determination of sennoside A and B in Rhei Rhizoma. A reversed-phase chromatographic system consisting of a chemically bonded ODS silica gel column with an acetate buffer (pH 5.0)-acetonitrile (68:32), containing 5 mM tetra-n-heptylammonium bromide, as the mobile phase was used. Sennoside A and B in this crude drug were separated and determined within 20 min after direct injection of the solution extracted with 70% methanol. The results for various samples are presented.