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To predict mortality in patients with acute heart failure (AHF), we created and validated an internal clinical risk score, the KICKOFF score, which takes physical and social aspects, in addition to clinical aspects, into account. In this study, we validated the prediction model externally in a different geographic area.Methods and Results: There were 2 prospective multicenter cohorts (1,117 patients in Osaka Prefecture [KICKOFF registry]; 737 patients in Kochi Prefecture [Kochi YOSACOI study]) that had complete datasets for calculation of the KICKOFF score, which was developed by machine learning incorporating physical and social factors. The outcome measure was all-cause death over a 2-year period. Patients were separated into 3 groups: low risk (scores 0-6), moderate risk (scores 7-11), and high risk (scores 12-19). Kaplan-Meier curves clearly showed the score's propensity to predict all-cause death, which rose independently in higher-risk groups (P0.001) in both cohorts. After 2 years, the cumulative incidence of all-cause death was similar in the KICKOFF registry and Kochi YOSACOI study for the low-risk (4.4% vs. 5.3%, respectively), moderate-risk (25.3% vs. 22.3%, respectively), and high-risk (68.1% vs. 58.5%, respectively) groups.The unique prediction score may be used in different geographic areas in Japan. The score may help doctors estimate the risk of AHF mortality, and provide information for decisions regarding heart failure treatment.

Background In Japan, both the prevalence of the elderly and super‐elderly and those of acute heart failure (AHF) have been increasing rapidly. Methods This registry was a prospective multicenter cohort, which enrolled a total of 1253 patients with AHF. In this study, 1117 patients' follow‐up data were available and were categorized into three groups according to age

Background: This study investigated whether combination therapy (CT) with renin-angiotensin system inhibitors and β-blockers improved endpoints in acute heart failure (AHF). Methods and Results: AHF patients were recruited to this prospective multicenter cohort study between April 2015 and August 2017. Patients were divided into 3 categories based on ejection fraction (EF), namely heart failure (HF) with reduced EF (HFrEF), HF with midrange EF (HFmrEF), and HF with preserved EF (HFpEF), and a further into 2 groups according to physical status (those who could walk independently outdoors and those who could not). The composite endpoint included all-cause mortality and hospitalization for HF. Data at the 1-year follow-up were available for 1,018 patients. The incidence of the composite endpoint was significantly lower in the CT than non-CT group for HFrEF patients, but not among HFmrEF and HFpEF patients. For patients who could walk independently outdoors, a significantly lower rate of the composite endpoint was recorded only in the HFrEF group. The differences were maintained even after adjustment for comorbidities and prescriptions, with hazard ratios (95% confidence intervals) of 0.39 (0.20-0.76) and 0.48 (0.22-0.99), respectively. Conclusions: In this study, CT was associated with the prevention of adverse outcomes in patients with HFrEF. Moreover, CT prevented adverse events only among patients without a physical disorder, not among those with a physical disorder.

Kensuke Takabayashi, Kotaro Iwatsu, Tsutomu Ikeda, Yuko Morikami, Tahei Ichinohe, Takashi Yamamoto, Kotoe Takenaka, Hiroyuki Takenaka, Hiroyuki Muranaka, Ryoko Fujita, Miyuki Okuda, Osamu Nakajima, Hitoshi Koito, Yuka Terasaki, Tetsuhisa Kitamura, Shouji Kitaguchi, Ryuji Nohara, Clinical Characteristics and Outcomes of Heart Failure Patients With Long-Term Care Insurance ― Insights From the Kitakawachi Clinical Background and Outcome of Heart Failure Registry ―, Circulation Journal, 2020, Volume 84, Issue 9, Pages 1528-1535, Released August 25, 2020, [Advance publication] Released July 21, 2020, Online ISSN 1347-4820, Print ISSN 1346-9843, https://doi.org/10.1253/circj.CJ-20-0017, https://www.jstage.jst.go.jp/article/circj/84/9/84_CJ-20-0017/_article/-char/en, Background: In Japan, the long-term care insurance (LTCI) system has an important role in helping elderly people, but there have been no clinical studies that have examined the relationship between the LTCI and prognosis for patients with acute heart failure (HF). Methods and Results: This registry was a prospective multicenter cohort, 1,253 patients were enrolled and 965 patients with acute HF aged ≥65 years were comprised the study group. The composite endpoint included all-cause death and hospitalization for HF after discharge. We divided the patients into 4 groups: (i) patients without LTCI, (ii) patients requiring support level 1 or 2, (iii) patients with care level 1 or 2, and (iv) patients with care levels 3-5. The Kaplan-Meier analysis identified a lower rate of the composite endpoint in group (i) than in the other groups. After adjusting for potentially confounding effects using a Cox proportional regression model, the hazard ratio (HR) of the composite endpoint increased significantly in groups (iii) and (iv) (adjusted HR, 1.62; 95% confidence interval [CI], 1.22-1.98 and adjusted HR, 1.62; 95% CI, 1.23-2.14, respectively) when compared with group (i). However, there was no significant difference between groups (i) and (ii). Conclusions: The level of LTCI was associated with a higher risk of the composite endpoint after discharge in acute HF patients.

Both heart failure (HF) and chronic obstructive pulmonary disease (COPD) are common diseases, but few studies have assessed the relationship between COPD and outcomes in patients with acute HF, especially in relation to age or ejection fraction (EF). The Kitakawachi Clinical Background and Outcome of Heart Failure Registry was a prospective, multicenter, community-based cohort and enrolled a total of 1,102 patients with acute HF between 2015 and 2017 in this study. The primary endpoint was defined as a composite endpoint that included all-cause mortality and hospitalization for HF. We stratified patients into two groups: those aged ≥ 80 years (elderly) and

The Short Physical Performance Battery (SPPB) has been reported to predict clinical outcomes in patients with heart failure (HF). However, whether the discriminative capacity of SPPB score for adverse outcomes varies according to the phenotypes of HF, such as HF with reduced, mid-range, and preserved left-ventricular ejection fraction (HFrEF, HFmrEF, and HFpEF) remains unclear. The aim of this study was to investigate the difference in discriminative capacity of SPPB score for predicting 2-year mortality among phenotypes of HF.We consecutively enrolled 542 adult patients admitted for HF (HFrEF, n = 187; HFmrEF, n = 94; HFpEF, n = 261). The patients underwent SPPB score when discharged from hospital. The primary endpoint was all-cause mortality during the 2 years after hospital discharge. We assessed the discriminative capacity of SPPB score for predicting mortality by using receiver operating characteristic (ROC) curve analysis.A total of 95 events (17.5%) occurred during the follow-up period. The area under the curve of ROC (95% confidence interval) was 0.80 (0.71-0.88) in HFrEF, 0.61 (0.46-0.76) in HFmrEF, and 0.70 (0.61-0.79) in HFpEF group. After adjustment for potential confounders, the hazard ratios (95% confidence interval) of the lower SPPB score were 5.38 (2.34-14.6) in HFrEF group, 1.12 (0.36-3.29) in HFmrEF group, and 3.19 (1.68-6.22) in HFpEF group.Prognostic value of SPPB score varies according to the HF phenotype. SPPB score predicts mortality in patients with HFrEF and HFpEF, but not in patients with HFmrEF. These findings lead to more precise risk prediction by SPPB score in patients with HF.

BACKGROUND There is little evidence regarding the effect of outpatient cardiac rehabilitation (CR) on exercise capacity or the long-term prognosis in patients after coronary artery bypass graft surgery (CABG). This study aimed to determine whether participation in outpatient CR improves exercise capacity and long-term prognosis in post-CABG Japanese patients in a multicenter cohort.Methods and Results:We enrolled 346 post-CABG patients who underwent cardiopulmonary exercise testing during early (2-3 weeks) and late (3-6 months) time points after surgery. They formed the Active (n=240) and Non-Active (n=106) CR participation groups and were followed for 3.5 years. Primary endpoint was a major adverse cardiac event (MACE): all-cause death or rehospitalization for acute myocardial infarction/unstable angina/worsening heart failure. Peak oxygen uptake at 3-5 months from baseline was significantly more increased in Active than in Non-Active patients (+26±24% vs. +19±20%, respectively; P

Home treatment for heart failure (HF) is one of the most important problems in patients after discharge as a secondary preventive measure for rehospitalization for HF. However, there are no detailed studies on gender differences in sociopsychological factors such as living alone for HF rehospitalization among patients with acute HF (AHF). This prospective multicenter cohort study enrolled patients with AHF between April 2015 and August 2017. Patients of each gender with first AHF were divided into those living alone and those not living alone. The primary endpoint was defined as rehospitalization for HF after discharge. Cox proportional hazard analysis was performed to determine the association between living alone and the endpoint. Overall, 581 patients were included in this study during the 3-year follow-up. The proportion of rehospi-talization for HF was significantly higher in patients living alone than in those not living alone among male pa-tients. However, female patients showed no difference in endpoints between the two groups. The difference was independently maintained even after adjusting for differences in social backgrounds in male patients (adjusted hazard ratio (HR) 2.02; 95% confidence interval (CI), 1.07-3.70). In female patients, the HR for rehospitaliza-tion for HF showed no difference between the two groups (adjusted HR, 0.99; 95% CI, 0.56-1.69). In this study population, male patients living alone after first AHF discharge had a higher risk of rehospi-talization for HF than those not living alone, but these differences were not observed in female patients.

Background Living status is an important factor to manage the conditions of acute heart failure (AHF) patients after discharge. In patients with heart failure (HF), a frailty is a common and serious complication. However, the association between living alone and the outcome in HF patients have not been well described. Purpose The purpose of this study is to identify the association between living alone and following outcomes. Furthermore, we reveal the impact of living alone combined with physical or cognitive frailty in AHF patient after discharge. Methods We have enrolled 1117 discharged patients with AHF in the Kitakawachi Clinical Background and Outcome of Heart Failure Registry (KICKOFF Registry; 13 hospitals in a city in Japan) from April 2015 to January 2017. The KICKOFF Registry is a prospective multicenter community-based cohort of AHF patients. We defined physical frailty as impossible outdoor walking and cognitive frailty as dementia. We divided into three groups, living without alone (non-alone, n=898), living alone without frailty (alone without frailty, n=148) and living alone with physical or cognitive frailty (alone with frailty, n=71). We compared the clinical characteristics and outcomes between three groups. We defined a primary outcome as a composite endpoint that included all-cause mortality and hospitalization for HF. Results During the follow-up period whose median was 573 days, a total of 548 patients (49.1%) had the composite endpoint, and the highest proportion of the composite endpoint was in alone with frailty, 63.4%. This was followed by 49.2% in non-alone, and 41.2% in alone without frailty. In the Kaplan-Meier analyses, the composite endpoint was a significantly higher in alone with frailty than the other groups (Figure A), but there was no significant difference between all patients with living alone and those without living alone (Figure B). After adjustment by gender, age, and the other co-morbidities (HF, coronary artery disease, valvular disease, hypertension, diabetes, atrial fibrillation and chronic kidney disease) in the Cox proportional hazard model, the composite endpoint hazard ratio (HR) increased significantly in the factor of alone with frailty when compared with the others (adjusted HR, 1.38; 95% confidence interval, 1.00–1.86; p=0.048). Conclusion In this study, the patients with only living alone have not independently prognostic impact, but those with living alone combined physical frailty or cognitive frailty have independently prognostic impact after discharged AHF. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This research was supported by research funding from Nakajima Steel Pipe Company Limited.

Introduction: It is essential to characterize patients with dyspnea while walking. This experiment is one of the resources that can aid in gaining a better understanding of dyspnea while walking. Aims and Objectives: We aimed to determine the clinical characteristics of patients with chronic obstructive pulmonary disease (COPD) and age- and oxygen saturation-matched patients with interstitial pneumonia (IP) during a 6-minute walk test, as a means for the assessment of dyspnea during walking. Methods: We studied 15 COPD patients (mean age: 70.3 ± 10.9 years, mean %FEV1: 54.7% ± 23.8%) and 16 IP patients (mean age: 71.8 ± 8.6 years, mean %VC 64.1% ± 16.3%). All performed a 6-minute walk test with a portable spirometer. VE, RR, VT, IC, SpO2, PR, and modified Borg scale were assessed. These parameters were used to identify the differences between COPD and IP and the changes over time within the groups. Results: An aspect characteristic of COPD was a significant decrease in IC before and after 6 min of walking (p Conclusion: During the 6-minute walk test, dynamic hyperinflation was observed with COPD but not with IP. Rapid shallow breathing was observed with IP but not with COPD. In addition, each characteristic was observed to appear within 3 min after the start of walking.

AIM In Japan, the long-term care insurance (LTCI) system is important for elderly people living at home; however, no clinical studies have revealed a relationship between home- or community-based services and outcomes in patients with acute heart failure (AHF). METHODS This was a prospective multicenter cohort study of patients with AHF enrolled between April 2015 and August 2017. Patients aged ≥65 years with LTCI were divided into those receiving home- and community-based services (service users) and without home and community-based services (service non-users). The endpoint was defined as a composite endpoint, which included all-cause mortality and hospitalization for heart failure after discharge. Subgroup analyses were performed for elderly patients (

Background Polypharmacy creates an increased patient's burden by drug-drug interactions and poor adherence. However, there are very few studies available evaluating the association of polypharmacy with hospital readmission in patients with heart failure (HF). Purpose The aim of this study was to investigate the impact of polypharmacy on hospital readmission for HF. Methods We enrolled 1253 patients who were hospitalized with acute heart failure (AHF) or acute exacerbation of chronic heart failure in the Kitakawachi Clinical Background and Outcome of Heart Failure Registry (KICKOFF Registry) from April 2015 to July 2018 (age 78.1±11.5 years, male 51.4%). Our Registry is a prospective multicenter community-based cohort study of HF patients in Japan. The inclusion criteria for the registry was a diagnosis of HF during hospitalization according to the Framingham criteria, and there were no exclusion criteria. From data at discharge, we collected data on clinical characteristics, medication schedule, and social backgrounds. We defined polypharmacy as the use of seven or more medications. The primary end point was HF rehospitalization within 1 year after discharge. Cox proportional hazards regression analysis was used to describe the association between polypharmacy and 1-year HF rehospitalization, controlling for potential confounding factors. Results In this study, the prevalence of polypharmacy was 59.7% of all patients. Patients with polypharmacy were more likely to have comorbidities such as hypertension, dyslipidemia, diabetes, chronic kidney disease, coronary artery disease and dementia. They also had lower EF (50.9±0.64 vs 53.6±0.80, p Conclusion Polypharmacy is an independent predictor of hospital readmission for HF. Our study suggests the need for developing an effective strategy to choose the appropriate drugs in patients with HF. Acknowledgement/Funding Nakajima Steel Pipe

Background Perceived social isolation (SI), the subjective sense of feelings of loneliness or isolation, has a negative impact on health outcomes, particularly in older adults. Although SI may also contribute to poor prognosis in patients with HF, evidence on the relationship between SI and outcomes in patients with HF is limited. Purpose The aim of this study was to investigate the relationship between SI and hospital readmission in patients with HF. Methods This study was a single center prospective cohort study. We consecutively enrolled 203 patients (mean age 72.9±11.7) who admitted for acute HF or exacerbation of chronic HF. At hospital discharge, we assessed perceived SI by using Lubben Social Network Scale - 6 (LSNS-6). Lower scores in LSNS-6 represents greater SI. Study outcome was rehospitalization for worsening HF within 180 days after discharge. We selected the optimal cutoff point of LSNS-6 that predict a worse outcome by the receiver operating characteristic (ROC) curve analysis. We investigate the association between SI and 180-days HF rehospitalization by using Cox proportional-hazard models, controlling for potential confounding factors. Results During follow up, A total of 40events (19.7%) were observed. The optimal cut-off point of LSNS-6 score was 17 points (the area under the ROC curve: 0.62, p Conclusion The present study shows that SI is a independent predictor of HF rehospitalization in patients with HF. Assessing SI in the clinical practice with a brief screening tool may help identify patients with heart failure at greater risk of rehospitalization.

Background Sarcopenia is a geriatric syndrome characterized by loss of muscle mass and muscle function. As the population ages, there is a growing worldwide interest in the intersection of sarcopenia and heart failure (HF). However, estimates of the prevalence of sarcopenia in HF vary widely because of difference in diagnostic criteria. Although the Asian Working Group of Sarcopenia (AWGS) has announced a consensus on the diagnostic criteria of sarcopenia in Asian people, the prevalence and prognostic impact of sarcopenia based on AWGS criteria in patients with HF remains unclear. Purpose The aim of this study was to investigate the prevalence and predictive value of sarcopenia identified according to AWGS definition in non-dependent elderly patients with HF. Methods This study was a prospective, single-center cohort study in Japan. We consecutively enrolled 274 patients, aged 65 years or older, hospitalized due to acute HF or acute exacerbation of chronic HF and who were able to walk at least 20 m at discharge. Patients with severe cognitive or psychiatric disorders were excluded. Patients with implantable cardiac pacemaker or cardioverter defibrillator were also excluded because skeletal muscle mass was estimated by using bioimpedance analysis. At hospital discharge, we collected data on age, gender, left ventricular ejection fraction, brain natriuretic peptide, estimate glomerular filtration rate, body mass index and sarcopenia. Sarcopenia was diagnosed according to the AWGS criteria: low skeletal muscle index ( Results In this study, a total of 199 patents (43.4%) fulfilled sarcopenia criteria at discharge. During follow-up, 57 patients (20.8%) readmitted for HF. Kaplan-Meier survival curves showed that patients with sarcopenia had significantly lower event-free survival than those without sarcopenia (Figure). After adjusting for other prognostic factors, sarcopenia was independently associated with HF rehospitalization (hazard ratio: 2.31, 95% confidence interval: 1.20–4.53). Conclusion Based on AWGS criteria, sarcopenia is highly prevalent even among non-dependent elderly HF patients, and is an independent strong predictor of rehospitalization for worsening HF. AWGS criteria for sarcopenia may be useful for risk prediction in HF.

Kensuke Takabayashi, Akihiro Ikuta, Yoshinori Okazaki, Mariko Ogami, Kotaro Iwatsu, Koichi Matsumura, Tsutomu Ikeda, Tahei Ichinohe, Yuko Morikami, Takashi Yamamoto, Ryoko Fujita, Kotoe Takenaka, Hiroyuki Takenaka, Yoshisumi Haruna, Hiroyuki Muranaka, Masaaki Ozaki, Tetsuhisa Kitamura, Shouji Kitaguchi, Ryuji Nohara, Clinical Characteristics and Social Frailty of Super-Elderly Patients With Heart Failure ― The Kitakawachi Clinical Background and Outcome of Heart Failure Registry ―, Circulation Journal, 2017, Volume 81, Issue 1, Pages 69-76, Released December 22, 2016, [Advance publication] Released November 30, 2016, Online ISSN 1347-4820, Print ISSN 1346-9843, https://doi.org/10.1253/circj.CJ-16-0914, https://www.jstage.jst.go.jp/article/circj/81/1/81_CJ-16-0914/_article/-char/en, Background: Social background is important in preventing admission/readmission of heart failure (HF) patients. However, few clinical studies have been conducted to assess the social background of these patients, especially elderly patients. Methods and Results: The Kitakawachi Clinical Background and Outcome of Heart Failure (KICKOFF) Registry is a prospective multicenter community-based cohort of HF patients, established in April 2015. We compared the clinical characteristics and social background of the super-elderly group (≥85 years old) and the non-super-elderly group (

Although activities of daily living (ADL) are recognized as being pertinent in averting relevant readmission of heart failure (HF) and mortality, little research has been conducted to assess a correlation between a decline in ADL and outcomes in HF patients.The Kitakawachi Clinical Background and Outcome of Heart Failure Registry is a prospective, multicenter, community-based cohort of HF patients. We categorized the patients into four types of ADL: independent outdoor walking, independent indoor walking, indoor walking with assistance, and abasia. We defined a decline in ADL (decline ADL) as downgrade of ADL and others (non-decline ADL) as preservation of ADL before discharge compared with admission.Among 1253 registered patients, 923 were eligible, comprising 98 (10.6%) with decline ADL and 825 (89.4%) with non-decline ADL. Decline ADL exhibited a higher risk of hospitalization for HF and mortality compared with non-decline ADL. A multivariate analysis revealed that decline ADL emerged as an independent risk factor of hospitalization for HF [hazard ratio (HR), 1.42; 95% confidence interval (CI): 1.01-1.96; p=0.046] and mortality (HR, 1.95; 95% CI: 1.23-2.99; p0.01). Although 66.3% of patients with decline ADL were registered for long-term care insurance, few received daycare services (32.7%) or home-visit medical services (8.2%).Decline in ADL is a predictor of hospitalization for HF and mortality in HF patients.

We investigated the usefulness of Holter monitoring to detect cardiac disease and predict future cardiovascular risk in asymptomatic diabetic patients. This is a multi-centre, prospective study in 406 asymptomatic diabetic patients. They were categorized into three groups based on findings of Holter monitoring. A total of 377 met inclusion criteria and were classified as low ( n = 172), moderate ( n = 136) and high risk ( n = 69). In total, 86 in moderate and 53 in high risk receive further evaluation. In total, 29 in moderate and 25 in high risk were diagnosed as cardiac disease and 12 required additional treatment, including coronary intervention. Over 1.8 years of mean follow-up, 11 (16.5 per 1000 person-years) experienced cardiovascular events. The cumulative incidence in moderate and high risk was higher than that in low risk ( p = 0.029 and p = 0.014, respectively). Our study suggests that Holter monitoring may be a useful screening tool to detect cardiac disease and predict future cardiovascular risk in asymptomatic diabetic patients.

Introduction Several reports have described the usefulness of a high-flow nasal cannula (HFNC). However, the physiological mechanisms of this system are unclear. In the current study, various methods were used to investigate the physiological mechanisms of an HFNC in healthy volunteers. Methods The physiological mechanisms of the constant-flow and constant-pressure models of HFNC were studied in 10 healthy volunteers by the oesophageal balloon method, the electrical impedance method and the forced oscillation technique (FOT). Results The tidal volume (TV) increased markedly during HFNC (off, 30 L/min, 50 L/min: 685.6±236.5 mL, 929.8±434.7 mL, 968.8±451.1 mL). The end-inspiratory oesophageal pressure (EIOP) was not significantly different, but there was a tendency for it to decrease. HFNC 30 L/min and 50 L/min, the increment in TV and the difference in EIOP showed strong negative correlations (p=0.0025, 0.003). The end-expiratory oesophageal pressure (EEOP) increased. The respiratory system reactance at 5 Hz (X5) by FOT decreased significantly. There was a flow rate-dependent EEOP increase, and the positive end-expiratory pressure (PEEP) effect of HFNC was confirmed. There was a correlation between the difference in X5 and the difference in EEOP during HFNC 30 L/min and 50 L/min, with correlation coefficients of 0.534 and 0.404 (p=0.112, 0.281). The amount of change in EEOP and the fluctuation in X5 were positively correlated. Conclusions The PEEP effect of HFNC was confirmed by the electrical impedance method and FOT. The increment in TV and the difference in EIOP of HFNC showed strong negative correlations.

The prevalence, intensity, safety, and efficacy of oral anticoagulation (OAC) in addition to dual antiplatelet therapy (DAPT) in “real-world” patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) have not yet been fully evaluated. In the Coronary REvascularization Demonstrating Outcome Study in Kyoto registry cohort-2, a total of 1,057 patients with AF (8.3%) were identified among 12,716 patients undergoing first PCI. Cumulative 5-year incidence of stroke was higher in patients with AF than in no-AF patients (12.8% vs 5.8%, p

Aim This subanalysis aimed to clarify whether intensive lipid-lowering therapy with statins slows the progression of atherosclerosis in Japanese subjects under treatment for primary prevention of cardiovascular disease. Methods This was a subanalysis of the Justification for Atherosclerosis Regression Treatment (JART) Study. We compared the efficacy of intensive lipid-lowering therapy and conventional therapy with respect to changes in the mean intima-media thickness (IMT) and serum lipid levels. We also evaluated changes in the mean IMT over 24 months of treatment and assessed the relationship between these changes and reductions in the LDL-C levels using a post-hoc analysis. Results Intensive lipid-lowering therapy with rosuvastatin was associated with significantly smaller changes in the mean IMT and a greater reduction in the serum lipid levels in comparison to conventional therapy with pravastatin. The average net change in the mean IMT was 0.010 mm (n=121) at 12 months and -0.004 mm (n=56) at 24 months. A decrease in LDL-C was found to be associated with a smaller change in the mean IMT (p=0.0009; Jonckheere-Terpstra trend test). A greater reduction in serum LDL-C was found to be associated with a smaller change in the mean IMT. Similar associations were observed for the serum TC and non-HDL-C levels and LDL-C/HDL-C ratio. There were no notable differences in the incidence of serious adverse events among the LDL-C quartiles. Conclusions Lowering the LDL-C level with intensive lipid-lowering therapy is associated with reduced changes in the IMT among Japanese subjects at moderate to high risk under treatment for primary prevention. Subjects suitable for primary prevention may receive cardiovascular benefits from intensive lipid-lowering therapy, in association with significantly slower IMT progression than that observed with conventional therapy.

Background: Recently, it was reported from the Justification for Atherosclerosis Regression Treatment (JART) Study that intensive therapy with rosuvastatin significantly slowed progression of carotid intima-media thickness (IMT) compared with conventional therapy with pravastatin at 12 months. To assess the long-term efficacy of intensive therapy, the present extension study was conducted. Methods and Results: Subjects in the intensive therapy group of the JART Study were asked to participate in the extension study and to continue rosuvastatin treatment. A total of 113 subjects were enrolled into the extension study and were included in the analysis. At 24 months, the mean daily dose of rosuvastatin (±SD) was 7.9±2.9mg. Mean change in mean IMT was –0.005mm (range, –0.024 to 0.015mm) at 24 months (P=0.633, compared with baseline). Rosuvastatin lowered low-density lipoprotein cholesterol (mean±SD) by 46.4±13.8% and elevated high-density lipoprotein cholesterol (mean±SD) by 8.9±24.0% at 24 months compared with baseline. Gray scale median was measured in 25 subjects. It increased by 16.93±33.12 (mean±SD) % at 12 months and by 22.50±52.83% at 24 months from baseline (P=0.017, P=0.044, respectively). Conclusions: Two-year treatment with rosuvastatin inhibited progression of carotid IMT. Rosuvastatin also improved the plaque composition, and this qualitative change occurred relatively early after starting therapy. (Circ J 2013; 77: 1526–1533)

Background Gliptins should have beneficial effects beyond glycemic control, potentially on the pathophysiology of cardiovascular (CV) diseases, with some basic studies demonstrating this possibility. However, we are yet to answer whether there are any direct CV effects in the clinical setting. We aimed to examine the beneficial effects of sitagliptin in Japanese patients with diabetes and high CV risk for 12 months. Methods This was a prospective, multicenter, observational study of 205 patients with type 2 diabetes. All participants had more than one major CV risk factor and were treated with sitagliptin for 12 months. At 3 or 12 months, we examined the effects of treatment on glycemic control, CV function (by electrocardiography, echocardiography, and reactive hyperemia-peripheral arterial tonometry), and CV biomarkers. Results Patients were predominantly elderly (68.8 ± 9.9 years) and male (71.5 %) and typically had more than three CV risk factors (79.2 %). Treatment with sitagliptin significantly reduced the hemoglobin A1c (HbA1c) level from 7.09 % ± 0.81 % at baseline to 6.67 % ± 0.69 % at 3 months and 6.68 % ± 0.73 % at 12 months (both P

Background— There still remain safety concerns on surgical procedures after coronary drug-eluting stents (DES) implantation, and optimal management of perioperative antiplatelet therapy (APT) has not been yet established. Methods and Results— During 3-year follow-up of 12 207 patients (DES=6802 patients and bare-metal stent [BMS] only=5405 patients) who underwent coronary stent implantation in the CREDO-Kyoto registry cohort-2, surgical procedures were performed in 2398 patients (DES=1295 patients and BMS=1103 patients). Surgical procedures (early surgery in particular) were more frequently performed in the BMS group than in the DES group (4.4% versus 1.9% at 42-day and 23% versus 21% at 3-year, log-rank P =0.0007). Cumulative incidences of death/myocardial infarction (MI)/stent thrombosis (ST) and bleeding at 30 days after surgery were low, without differences between BMS and DES (3.5% versus 2.9%, P =0.4 and 3.2% versus 2.1%, P =0.2, respectively). The adjusted risks of DES use relative to BMS use for death/MI/ST and bleeding were not significant (hazard ratio: 1.63, 95% confidence interval: 0.93 to 2.87, P =0.09 and hazard ratio: 0.6, 95% confidence interval: 0.34 to 1.06, P =0.08, respectively). The risks of perioperative single- and no-APT relative to dual-APT for both death/MI/ST and bleeding were not significant; single-APT as compared with dual-APT tended to be associated with lower risk for death/MI/ST (hazard ratio: 0.4, 95% confidence interval: 0.13 to 1.01, P =0.053). Conclusions— Surgical procedures were commonly performed after coronary stent implantation, and the risk of ischemic and bleeding complications in surgical procedures was low. In patients selected to receive DES or BMS, there were no differences in outcomes. Perioperative administration of dual-APT was not associated with lower risk for ischemic events.

OBJECTIVE We prospectively investigated the efficacy of the screening methods for asymptomatic coronary heart disease (CHD) in Japanese patients with type 2 diabetes using the treadmill tolerance test (TTT) as a first-line test or the American Diabetes Association (ADA) guidelines. METHODS The subjects included consecutive inpatients with type 2 diabetes (n=331) assessed with both electrocardiogram (ECG) at rest and TTT. Subjects with abnormal TTT findings were evaluated using stress myocardial perfusion scintigraphy (MPS). RESULTS A total of 60 out of 69 subjects with positive TTT findings underwent MPS, among whom a total of 22 subjects (6.6% of the total number of subjects) had positive MPS results. Among those with positive MPS results, a total of 14 subjects underwent coronary angiography, eight of whom were determined to have significant coronary artery stenosis. The prevalence rates of hypertension and micro/macroalbuminuria were significantly higher in the MPS-positive group (77.3% and 54.5%, respectively) than in the TTT-negative group (44.7% and 27.1%, respectively). Among the subjects with positive MPS results, 68.2% met the 1998 ADA criteria. CONCLUSION Neither the TTT as a first-line test nor the ADA guidelines are sufficiently adequate screening methods to detect asymptomatic CHD in Japanese subjects with type 2 diabetes. Conducting routine screening for asymptomatic CHD in Japanese patients with type 2 diabetes may therefore not be very useful.

Background The ankle-brachial pressure index (ABI), the ratio of the systolic blood pressure of the ankle to the systolic brachial pressure, is commonly measured at rest, but ABI values post-exercise enhance the sensitivity of the test and can be used to identify atherosclerotic vascular damage. However, it has not been established whether or not enhanced post-exercise ABI is also associated with endothelial dysfunction. We hypothesized that a decrease in post-exercise ABI is related to impaired endothelial function. Purpose To investigate alterations in post-exercise ABI values and endothelial dysfunction in the elderly. Methods The study population comprised 35 men and women aged 51–77 years (mean age: 66 years). Patients with peripheral arterial disease or a history of heart failure were excluded. The ABI was estimated at rest and immediately after exercise. The exercise protocol comprised 2.5 min of active pedal flexion exercises at a speed of 60 times/min. Endothelial function was assessed by measuring flow-mediated vasodilation (FMD) in the brachial artery using ultrasound imaging. Results No correlation was found between FMD and the ABI at rest. However, a weak correlation was found between FMD and post-exercise ABI (r = 0.46, P = 0.06). A strong correlation was observed between FMD and a decrease in post-exercise ABI compared to baseline readings (r = –0.52, P = 0.01). Multiple linear regression analysis was used to generate a prediction equation for FMD using the percentage decrease in post-exercise ABI. Significant correlations were observed between the ultrasound imaging-measured FMD and the predicted FMD (R2 = 0.27, P = 0.001). Conclusions Post-exercise ABI appears to be a simple surrogate marker for endothelial function in the elderly, although larger studies are required for validation.

Long-term safety and efficacy of drug-eluting stents remains controversial. The CREDO-Kyoto registry cohort-2 is a physician-initiated non-company sponsored multi-center registry enrolling consecutive patients undergoing first coronary revascularization in 26 centers in Japan. We compared 3-year outcome between patients treated with sirolimus-eluting stent (SES) only (5092 patients) and bare-metal stent (BMS) only (5405 patients). SES-use as compared with BMS-use was associated with significantly lower adjusted risk for all-cause death [hazard ratio (HR) [95% confidence interval (CI)] 0.72 (0.59–0.87), P = 0.0007], which was mainly driven by the reduction in non-cardiac death [HR (95% CI) 0.64 (0.48–0.85), P = 0.002]. The risk of cardiac death [HR (95% CI) 0.82 (0.63–1.07), P = 0.15], myocardial infarction [HR (95% CI) 0.73 (0.51–1.03), P = 0.07] and definite stent thrombosis [HR (95% CI) 0.62 (0.35–1.09), P = 0.1] was not different between the two groups. Despite longer duration of thienopyridine administration, SES-use was associated with significantly lower risk for bleeding [HR (95% CI) 0.75 (0.6–0.95), P = 0.02] and similar risk for stroke [HR (95% CI) 1.0 (0.75–1.34), P = 1.0]. The risk for target-lesion revascularization (TLR) was markedly lower in the SES group [HR (95% CI) 0.42 (0.36–0.48), P < 0.0001]. The direction and magnitude of the effect of SES relative to BMS in patients presenting acute myocardial infarction (AMI) were similar to those in patients presenting otherwise. In conclusion, SES-use as compared with BMS-use was associated with marked reduction of TLR without any increases in death, myocardial infarction, stent thrombosis, stroke and bleeding in real world clinical practice regardless of clinical presentation including AMI.

Previous studies have shown inconsistent results regarding the effects of concomitant use of clopidogrel and proton pump inhibitors (PPI) on cardiovascular outcomes. We sought to evaluate the clinical impact of PPI-use in patients treated with thienopyridines after percutaneous coronary intervention (PCI) in a large Japanese observational database. Among 12446 patients discharged alive on thienopyridines (ticlopidine 90.4% and clopidogrel 9.6%), 3223 patients were treated with PPIs and 9223 patients without PPI at the time of hospital discharge. The PPI group included more patients with co-morbidities than the non-PPI group. The adjusted hazard ratio (HR) of PPI-use for a composite of cardiovascular death, myocardial infarction, and stroke was 1.26 (95% confidence interval (CI) 1.09-1.47, p = 0.002). The adjusted HR of PPI-use for bleeding was 1.26 (95% CI 1.05-1.52, p = 0.013). Cardiovascular and bleeding outcomes were not different among the three groups receiving three different types of PPI. The negative effect of PPI on cardiovascular outcome was consistently seen in both drug-eluting stent (DES) [HR 1.31 (95% CI 1.07-1.6, p = 0.0097)] and non-DES strata [HR 1.25 (95% CI: 0.99-1.57, p = 0.057)] (Interaction p = 0.79) despite the fact that the duration of thienopyridine administration was significantly longer in patients receiving DES. In conclusion, cardiovascular outcomes after PCI were significantly worse in patients with PPI than in patients without PPI in the Japanese real clinical practice. However, the observed poorer cardiovascular outcome in patients receiving PPI was most likely to be related to residual confounding and seemed not causally related to attenuation of antiplatelet effect of thienopyridine through interaction with PPI.

Whole-body periodic acceleration (WBPA) has been developed as a passive exercise device capable of improving endothelial function by applying pulsatile shear stress to vascular endothelium. We hypothesized that treatment with WBPA improves exercise capacity, myocardial ischemia, and left ventricular (LV) function because of increased coronary and peripheral vasodilatory reserves in patients with angina. Twenty-six patients with angina who were not indicated for percutaneous coronary intervention and/or coronary artery bypass grafting were randomly assigned to remain sedentary (sedentary group) or undergo 20 sessions of WBPA with the motion platform for 4 weeks (WBPA group) in addition to conventional medical treatment. WBPA was applied at 2 to 3 Hz and approximately ±2.2 m/s(2) for 45 minutes. We repeated the symptom-limited treadmill exercise test and adenosine sestamibi myocardial scintigraphy. In the WBPA group, the exercise time until 0.1-mV ST-segment depression increased by 53% (p

Aim In Japan, heart disease and cerebral ischemic disease are major causes of death. A decrease in the level of low-density lipoprotein cholesterol (LDL-C) through intensive treatment with statins positively correlates with a reduction in the volume of plaques in patients with cardiovascular disease. The METEOR trial, evaluating the effect of rosuvastatin on carotid intima-media thickness (IMT), was conducted only in Europe and the US. Here we planned another trial, the Justification for Atherosclerosis Regression Treatment (JART) study, to clarify the efficacy of intensive lipid-lowering therapy with rosuvastatin in Japanese with atherosclerosis. Methods and results Four hundred patients with hypercholesterolemia (LDL-C >or=140 mg/dL) and a maximum IMT of >or=1.1 mm will be treated for 24 months either with intensive lipid-lowering therapy with rosuvastatin (target LDL-C levels: 80 mg/dL for primary prevention, and 70 mg/dL for secondary prevention) or conventional lipid-lowering therapy with pravastatin (target LDL-C level: complying with JASGL2007). The primary endpoint will be the percent change of mean-IMT and the objectives of the study are to compare the two protocols. Conclusion The JART trial is a prospective, randomized, open-label, blinded end-point evaluation, multi-center, parallel-group, comparative study to examine the regressive effect of intensive lipid-lowering therapy with statins on atherosclerosis by evaluating IMT in the Japanese population.

Calcium ion is one of the most important second messengers of cellular signal transduction including hypoxia-elicited signals. In this study, we investigated the effects of the L-type calcium channel blockers such as nifedipine, efonidipine cilnidipine, diltiazem, and verapamil, on the activity of hypoxia-inducible factor-1 (HIF-1), a key transcription factor in control of hypoxia-induced gene expression. Using the lung carcinoma cell line A549 cells, human aortic smooth muscle cells, and human umbilical vein endothelial cells, we demonstrated that cilnidipine exclusively suppressed HIF-1 activity and the expressions of downstream genes in a cell-type specific manner. We also demonstrated that cilnidipine blocked the synthesis of the HIF-1alpha protein not by affecting activity of the intracellular hypoxia-sensing element prolyl hydroxylases but inhibiting activity of Akt and mitogen-activated protein kinase and that the inhibition is not dependent on the effect on calcium homeostasis.

The S100A8/A9 complex is expressed in a subset of activated neutrophils and macrophages in acute inflammatory lesions associated with various diseases.To investigate (a) whether serum S100A8/A9 levels are increased in patients with unstable angina (UA); and (b) whether S100A8/A9 expression is upregulated in coronary atherosclerotic plaques of patients with UA.Serum S100A8/A9 levels in 39 patients with stable angina (SA) and 53 patients with UA were measured. In addition, the presence of the S100A8/A9 complex in directional coronary atherectomy specimens was studied immunohistochemically. Cell types which stain positive for S100A8/A9 were identified by immunodouble staining with neutrophils and macrophages.Mean (SD) serum S100A8/A9 levels were significantly higher in patients with UA than in those with SA (3.25 (3.08) microg/ml vs 0.77 (0.31) microg/ml, p0.05). In patients with UA, immunodouble staining clearly showed that the S100A8/A9 complex was expressed in infiltrated neutrophils and occasional macrophages. The S100A8/A9-positive area was significantly higher in UA than in SA (mean (SD) 18.3 (14.2)% vs 1.3 (2.4)%, respectively, p0.001).The S100A8/A9 complex may be involved in the inflammatory process of coronary atherosclerotic plaques in patients with UA.