Search

Objectives With an increase in globalization, the number of non-native-speaking citizens and tourists visiting local pharmacies is rapidly growing worldwide, creating linguistic and sociological problems. The aim of this study is to compare the effect of adding our original method, Original MethOd at pharmacy To ENhAnce Support for Health Improvement (OMOTENASHI), to the conventional medication counselling method (CMC) when counselling non-Japanese patients at the pharmacy. Methods The OMOTENASHI consists of tools written in multiple languages and illustrations to clarify the effects and side effects, and to confirm patients’ understanding. 71 non-Japanese patients were recruited and randomly assigned to the OMOTENASHI or to the CMC in a 1:1 ratio. Comprehension and satisfaction level were evaluated. Results The overall comprehension level was significantly higher in the OMOTENASHI than in the CMC (75% vs 38%, p = 0.002), with a prominent difference in the recognition of the name, effects, side effects, precautions, and how to deal with side effects of the prescribed medication. Conclusion The OMOTENASHI to be a helpful tool in providing essential information to non-native-speaking patients. Practice implication The study highlighted the need to ensure every patient’s safety and interests, and to avoid disadvantages caused by limited language proficiency in the globalization era.

Omega-3 polyunsaturated fatty acids (PUFAs) have been a hot topic since the Japan EPA Lipid Intervention Study (JELIS), the first landmark study using a highly purified eicosapentaenoic acid (EPA), indicated that EPA could decrease the incidence of cardiovascular events. Over 20 years have passed since the JELIS was conducted, and the standard treatment for dyslipidemia has altered significantly since then. The JELIS subjects did not undertake the current risk management especially current standard statins and did not exclusively target secondary prevention patients. In addition, the subjects included are relatively high EPA population. Furthermore, the clinical implication of the plasma EPA/arachidonic acid (AA) ratio as a biomarker has not yet been validated. Therefore, the Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy - Statin and EPA (RESPECT-EPA) was planned and is currently underway in Japan.The RESPECT-EPA comprises two parts: the open-label randomized controlled trial (RCT) and biomarker study (prospective cohort study design). The RCT included patients with a low EPA/AA ratio. These patients were then randomized to highly purified EPA (1800 mg/day) or control groups. The primary endpoint was cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, unstable angina pectoris, and clinically indicated coronary revascularization. The biomarker study assesses the EPA/AA ratio's usefulness as a biomarker for cardiovascular events prediction.In the RCT, a total of 2,460 patients were enrolled in 95 sites in Japan. Patients' baseline characteristics were similar between intervention and control groups in the RCT. The baseline median EPA/AA ratio was 0.243 and 0.235, respectively. A total of 1,314 patients were participated in the observational part, and the baseline median EPA/AA ratio was 0.577.After this study is completed, we will have further evidence on whether a highly purified EPA is effective in reducing cardiovascular events for secondary prevention or not, as well as whether if EPA/AA ratio is a predictor for future cardiovascular events. This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000012069).

Aims A sodium glucose cotransporter 2 (SGLT2) inhibitor was recently found to reduce heart failure hospitalization in the EMPA‐REG OUTCOME trial. We have hypothesized that autonomic nerve activity may be modulated by SGLT2 inhibition. The current study aims to investigate the impact of empagliflozin on sympathetic and parasympathetic nerve activity in patients with type 2 diabetes mellitus. Methods and results This ongoing study is a prospective, randomized, open‐label, multicentre investigation of 134 patients with type 2 diabetes mellitus. The patients are randomly allocated to receive either empagliflozin or sitagliptin with the treatment goal of the Japan Diabetes Society guidelines. Ambulatory electrocardiographic monitoring is performed at the baseline and at 12 and 24 weeks of treatment. Analyses of heart rate variability are conducted using the MemCalc method, which is a combination of the maximum entropy method for spectral analysis and the non‐linear least squares method for square analysis. The primary endpoint is the change in the low‐frequency (0.04–0.15 Hz)/high‐frequency (0.15–0.4 Hz) ratio from baseline to 24 weeks. Conclusions This investigation on the effect of EMPagliflozin on cardiac sYmpathetic and parasympathetic neRve activity in JapanEse pAtieNts with type 2 diabetes (EMPYREAN study) offers an important opportunity to understand the impact of SGLT2 inhibition on autonomic nerve activity in patients with type 2 diabetes.

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

Background The influence of uric acid (UA) on renal function and the significance of UA-lowering therapy are unclear. The purpose of the sub-analysis of the Assessment of Clinical Usefulness in chronic kidney disease patients with Atorvastatin (ASUCA) trial was to evaluate the influence of serum UA levels on renal function in Japanese chronic kidney disease patients with hyperlipidemia. Methods Of 344 participants in the ASUCA trial, 279 participants whose UA levels at both baseline and 24 months were available were included. Based on UA level at baseline or mean UA level during the trial period, they were divided into four groups: Results For baseline UA levels (2, respectively. A negative correlation between changes in eGFR after 24 months and baseline UA level was observed with adjustment for confounding factors. The relationship between changes in eGFR and mean UA levels during trial period showed a similar trend. Conclusion In CKD patients with dyslipidemia, hyperuricemia was an independent risk factor for CKD progression. An ongoing clinical trial (TARGET-UA, UMIN-ID 000,026,741) may reveal the significance of strict UA-lowering therapy in CKD patients.

AIMS To assess the benefits of intensive statin therapy on reducing cardiovascular (CV) events in patients with type 2 diabetes complicated with hyperlipidaemia and retinopathy in a primary prevention setting in Japan. In the intension-to-treat population, intensive therapy [targeting LDL cholesterol

Background The effects of pharmacological blood-pressure-lowering on cardiovascular outcomes in individuals aged 70 years and older, particularly when blood pressure is not substantially increased, is uncertain. We compared the effects of blood-pressure-lowering treatment on the risk of major cardiovascular events in groups of patients stratified by age and blood pressure at baseline. Methods We did a meta-analysis using individual participant-level data from randomised controlled trials of pharmacological blood-pressure-lowering versus placebo or other classes of blood-pressure-lowering medications, or between more versus less intensive treatment strategies, which had at least 1000 persons-years of follow-up in each treatment group. Participants with previous history of heart failure were excluded. Data were obtained from the Blood Pressure Lowering Treatment Triallists' Collaboration. We pooled the data and categorised participants into baseline age groups (Findings We included data from 358 707 participants from 51 randomised clinical trials. The age of participants at randomisation ranged from 21 years to 105 years (median 65 years [IQR 59–75]), with 42 960 (12·0%) participants younger than 55 years, 128 437 (35·8%) aged 55–64 years, 128 506 (35·8%) 65–74 years, 54 016 (15·1%) 75–84 years, and 4788 (1·3%) 85 years and older. The hazard ratios for the risk of major cardiovascular events per 5 mm Hg reduction in systolic blood pressure for each age group were 0·82 (95% CI 0·76–0·88) in individuals younger than 55 years, 0·91 (0·88–0·95) in those aged 55–64 years, 0·91 (0·88–0·95) in those aged 65–74 years, 0·91 (0·87–0·96) in those aged 75–84 years, and 0·99 (0·87–1·12) in those aged 85 years and older (adjusted pinteraction=0·050). Similar patterns of proportional risk reductions were observed for a 3 mm Hg reduction in diastolic blood pressure. Absolute risk reductions for major cardiovascular events varied by age and were larger in older groups (adjusted pinteraction=0·024). We did not find evidence for any clinically meaningful heterogeneity of relative treatment effects across different baseline blood pressure categories in any age group. Interpretation Pharmacological blood pressure reduction is effective into old age, with no evidence that relative risk reductions for prevention of major cardiovascular events vary by systolic or diastolic blood pressure levels at randomisation, down to less than 120/70 mm Hg. Pharmacological blood pressure reduction should, therefore, be considered an important treatment option regardless of age, with the removal of age-related blood-pressure thresholds from international guidelines. Funding British Heart Foundation, National Institute of Health Research Oxford Biomedical Research Centre, Oxford Martin School.

Background The effects of pharmacological blood pressure lowering at normal or high-normal blood pressure ranges in people with or without pre-existing cardiovascular disease remains uncertain. We analysed individual participant data from randomised trials to investigate the effects of blood pressure lowering treatment on the risk of major cardiovascular events by baseline levels of systolic blood pressure. Methods We did a meta-analysis of individual participant-level data from 48 randomised trials of pharmacological blood pressure lowering medications versus placebo or other classes of blood pressure-lowering medications, or between more versus less intensive treatment regimens, which had at least 1000 persons-years of follow-up in each group. Trials exclusively done with participants with heart failure or short-term interventions in participants with acute myocardial infarction or other acute settings were excluded. Data from 51 studies published between 1972 and 2013 were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We pooled the data to investigate the stratified effects of blood pressure-lowering treatment in participants with and without prevalent cardiovascular disease (ie, any reports of stroke, myocardial infarction, or ischaemic heart disease before randomisation), overall and across seven systolic blood pressure categories (ranging from

Characteristics of high frequency (HF) component based on heart rate variability (HRV) in a large general population remain unclear, particularly on the relationship with daily physical activity. We aimed to characterize the distribution of HF component and examine the association with daily physical activity among community residents. We performed spectral analysis of HRV from 10-second ECG recordings among 9135 residents aged 30 to 74 years in Nagahama City, Japan. HF components were log-transformed to consider the distribution. Simple correlations between HF and age were determined. Age-adjusted mean values of HF component were calculated for each questionnaire item related to daily physical activity. Multiple regression analysis was performed to examine the effect of daily physical activity on HF component value. Mean values of logarithmically-transformed HF component (lnHF) were higher in women than in men (p < 0.001). lnHF was inversely associated with age (r = -0.40, -0.49 for men, women, respectively). Adjusted mean lnHF for physically active people was significantly higher than that in inactive people (p < 0.001). HF components from 10-second ECG recordings were moderately and negatively correlated with age in both sexes, and positively correlated with daily physical activity in the general adult population. Maintaining the level of daily physical activity, especially to exercise regularly could keep the parasympathetic function high.

Objective During the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial, patients with hypertension who received amlodipine had similar cardiovascular risks as those who received candesartan. We conducted a post-trial study, the Candesartan Antihypertensive Survival Evaluation in Japan 10-year follow-up (CASE-J 10). This study aimed to confirm the long-term cardiovascular effects of candesartan and amlodipine. Methods Case report forms were sent to CASE-J investigators who agreed to participate in the CASE-J 10. All the available information was retrospectively collected. The primary endpoint was a time-to-first event for a composite of cerebrovascular, cardiac, renal, and vascular events, and sudden death. Secondary endpoints included new-onset diabetes (NOD), cardiovascular mortality, and all-cause mortality. For each endpoint, treatment effect was compared on an intention-to-treat basis, according to previous randomization categories. Results A total of 1313 patients' data have been updated. The 10-year Kaplan-Meier rates of the primary endpoint were 14.7% for candesartan and 14.8% for amlodipine. After adjusting for baseline characteristics, the rates for the primary endpoint were similar between the two treatments (hazards ratioadj = 0.99, 95% CI 0.82-1.20). Candesartan had a lower Kaplan-Meier rate of NOD than amlodipine (8.3 vs. 11.1%), and when adjusted for clinical factors, candesartan remained an independent predictor for NOD prevention (hazard ratioadj = 0.71, 95% CI 0.52-0.98). Conclusion With more than 28 385 patient-years follow-up, we demonstrated that candesartan and amlodipine were comparable in reducing cardiovascular events in patients with high-risk hypertension. Additionally, our results may support candesartan's superiority in reducing NOD incidence compared with amlodipine even after the long-term follow-up.

OBJECTIVE Diabetes is associated with high risk of cardiovascular (CV) events, particularly in patients with dyslipidemia and diabetic complications. We investigated the incidence of CV events with intensive or standard lipid-lowering therapy in patients with hypercholesterolemia, diabetic retinopathy, and no history of coronary artery disease (treat-to-target approach). RESEARCH DESIGN AND METHODS In this multicenter, prospective, randomized, open-label, blinded end point study, eligible patients were randomly assigned (1:1) to intensive statin therapy targeting LDL cholesterol (LDL-C) RESULTS Mean follow-up was 37 ± 13 months. LDL-C at 36 months was 76.5 ± 21.6 mg/dL in the intensive group and 104.1 ± 22.1 mg/dL in the standard group (P < 0.001). The primary end point events occurred in 129 intensive group patients and 153 standard group patients (hazard ratio [HR] 0.84 [95% CI 0.67–1.07]; P = 0.15). The relationship between the LDL-C difference in the two groups and the event reduction rate was consistent with primary prevention studies in patients with diabetes. Exploratory findings showed significantly fewer cerebral events in the intensive group (HR 0.52 [95% CI 0.31–0.88]; P = 0.01). Safety did not differ significantly between the two groups. CONCLUSIONS We found no significant decrease in CV events or CV-associated deaths with intensive therapy, possibly because our between-group difference of LDL-C was lower than expected (27.7 mg/dL at 36 months of treatment). The potential benefit of achieving LDL-C

SummaryObjective To investigate the effects of monthly feedback of changes in visceral fat area (VFA) as measured by dual bioelectrical impedance analysis method and the importance of VFA in individuals with obesity. Methods Thirty-eight Japanese patients with obesity underwent VFA measurements. The feedback group was given feedback on VFA measurements each month for 4 months. The control group underwent VFA measurements at the beginning and end of the study but was not informed of the results. All the study participants completed eating behaviour and weight efficacy lifestyle questionnaires. Results Mean age was 53.9 (14.3) years; mean body mass index was 30.6 (4.3) kg m−2. At the 4-month follow-up, there was no significant difference in VFA reduction between the control and feedback groups (−4.4% vs. −3.0%; 95% CI, −3.8 to 5.5). In post-hoc analysis using the overall group irrespective of allocation, changes of eating style were significantly associated with a reduction in VFA at 4 months (p = 0.034). Conclusions Monthly feedback on changes in VFA does not reduce VFA. More frequent feedback may be required. In post-hoc analysis, changes of eating style were associated with a reduction in VFA.

Background: A sodium glucose cotransporter 2 (SGLT2) inhibitor was recently found to reduce heart failure hospitalization in the EMPA-REG OUTCOMES trial. We have hypothesized that autonomic nerve activity may be modulated by SGLT2 inhibition. The current study aims to investigate the impact of empagliflozin on sympathetic and parasympathetic nerve activity in patients with type 2 diabetes mellitus.Methods: This ongoing study is a prospective, randomized, open-label, multicenter investigation of 134 patients with type 2 diabetes mellitus. The patients are randomly allocated to receive either empagliflozin or sitagliptin with the treatment goal of the Japan Diabetes Society guidelines. Ambulatory electrocardiographic monitoring is performed at the baseline and at 12 and 24 weeks of treatment. Analyses of heart rate variability are performed using the MemCalc method, which is a combination of the maximum entropy method for spectral analysis and the non-linear least squares method for square analysis. The primary endpoint is the change in the low frequency (LF; 0.04-0.15 Hz) / high frequency (HF; 0.15-0.4 Hz) ratio from baseline to 24 weeks.Discussion: This investigation on the effect of EMPagliflozin on cardiac sYmpathetic and parasympathetic neRve activity in JapanEse pAtieNts with type 2 diabetes (EMPYREAN study) offers an important opportunity to understand the impact of SGLT2 inhibition on autonomic nerve activity in patients with type 2 diabetes.Trial Registration: UMIN Clinical Trials Registry identifier UMIN000029194. Registered 19 September 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000033375

As the glucose tolerance of patients with diabetes worsens, autonomic nervous system (ANS) function decreases. Only a few studies, using plasma glucose, have reported on this relationship in large general populations that include people with wide range of glycemia. This study aimed to examine correlates of ANS function with special reference to HbASpectral analysis was performed to assess heart rate variability (HRV) using 1-minute electrocardiogram RR interval data recordings from 7690 residents aged 35-79 years in Nagahama City, Japan. HRV parameters were log-transformed. Multiple regression analysis was performed using potential correlates.lnLF decreased with age (regression coefficient, -0.025; P 0.001), BMI (-0.010; P = 0.035), and HbAAlthough the associations were weak, age, BMI and HbA

We previously reported the secretion of C-type natriuretic peptide (CNP) from vascular endothelial cells and proposed the existence of a vascular natriuretic peptide system composed of endothelial CNP and smooth muscle guanylyl cyclase-B (GC-B), the CNP receptor, and involved in the regulation of vascular tone, remodeling, and regeneration. In this study, we assessed the functional significance of this system in the regulation of blood pressure in vivo using vascular endothelial cell–specific CNP knockout and vascular smooth muscle cell–specific GC-B knockout mice. These mice showed neither the skeletal abnormality nor the early mortality observed in systemic CNP or GC-B knockout mice. Endothelial cell–specific CNP knockout mice exhibited significantly increased blood pressures and an enhanced acute hypertensive response to nitric oxide synthetase inhibition. Acetylcholine-induced, endothelium-dependent vasorelaxation was impaired in rings of mesenteric artery isolated from endothelial cell–specific CNP knockout mice. In addition, endothelin-1 gene expression was enhanced in pulmonary vascular endothelial cells from endothelial cell–specific CNP knockout mice, which also showed significantly higher plasma endothelin-1 concentrations and a greater reduction in blood pressure in response to an endothelin receptor antagonist than their control littermates. By contrast, vascular smooth muscle cell–specific GC-B knockout mice exhibited blood pressures similar to control mice, and acetylcholine-induced vasorelaxation was preserved in their isolated mesenteric arteries. Nonetheless, CNP-induced acute vasorelaxation was nearly completely abolished in mesenteric arteries from vascular smooth muscle cell–specific GC-B knockout mice. These results demonstrate that endothelium-derived CNP contributes to the chronic regulation of vascular tone and systemic blood pressure by maintaining endothelial function independently of vascular smooth muscle GC-B.

Background Workers with coronary artery disease (CAD) require evidence-based care in order to return to work safely. We assessed the use of cardiac rehabilitation (CR) among workers with CAD, and identified the factors associated with CR use.Methods and Results:A retrospective cohort study based on data from a health insurance claims database was conducted. We identified workers aged ≥18 years who underwent percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) between 2006 and 2013, and reviewed the utilization of inpatient or outpatient CR. Logistic regression was used to identify the factors associated with CR use. A total of 1,699 patients were included. The frequency of inpatient and outpatient CR use was 23.7% (n=402) and 4.2% (n=72), respectively. Patients diagnosed with ST-elevated myocardial infarction were most likely to receive inpatient CR, and patients undergoing CABG were more likely to receive inpatient CR than those undergoing PCI. Moreover, inpatient CR use was associated with longer hospitalization duration, catecholamine use, and no history of chronic kidney disease. Furthermore, both unstable and stable angina were negatively correlated with outpatient CR use. Conclusions Most of the Japanese workers with CAD in this study did not undergo CR. The type of CAD was strongly associated with inpatient and outpatient CR use. Thus, a strong evidence-practice gap exists in secondary preventative care within this group of patients.

Background Dyslipidemia is a risk factor for the progression of chronic kidney disease (CKD). While conventional lipid lowering therapy provides a benefit to CKD management, the effect of statins on eGFR remains unclear. Methods A prospective, multi-center, open-labeled, randomized trial. Total of 349 CKD patients with hyperlipidemia were randomized into 2 groups, and followed for 2 years. Group A included patients who were treated with atorvastatin. Group C were treated with conventional lipid lowering drugs other than statin. Primary endpoint was changes in eGFR. Secondary endpoints included changes in urinary albumin excretion, serum LDL-C, serum triglyceride, cardio-vascular events and all-cause mortality. Results As the primary endpoint, eGFR decreased by 2.3 ml/min/1.73 m2 in Group A and by 2.6 ml/min/1.73 m2 in Group C, indicating that there was no difference in change of eGFR between the two groups. As secondary endpoints, atorvastatin succeeded to reduce serum LDL-C level significantly and rapidly, but conventional therapy did not. In fact, mean LDL-C level did not reach the target level of 100 mg/dl in Group C. Serum triglyceride was lowered only by atorvastatin, but not conventional drugs. The number of cardiovascular events and all-cause mortality did not differ between in two groups. Conclusion The ASUCA (Assessment of Clinical Usefulness in CKD Patients with Atorvastatin) trial demonstrated that atorvastatin failed to exhibit reno-protections compared to conventional therapy in Japanese patients with dyslipidemia and CKD. It would be due in part to the ability of atorvastatin to more potently reduce serum LDL and triglycerides compared to conventional therapy.

Aims As the glucose tolerance of patients with diabetes worsens, autonomic nervous system (ANS) function decreases. Only a few studies, using plasma glucose, have reported on this relationship in large general populations that include people with wide range of glycemia. This study aimed to examine correlates of ANS function with special reference to HbA1c which is more stable than plasma glucose among community residents. Methods Spectral analysis was performed to assess heart rate variability (HRV) using 1-minute electrocardiogram RR interval data recordings from 7690 residents aged 35–79 years in Nagahama City, Japan. HRV parameters were log-transformed. Multiple regression analysis was performed using potential correlates. Results lnLF decreased with age (regression coefficient, −0.025; P Conclusions Although the associations were weak, age, BMI and HbA1c were inversely correlated with parasympathetic activity, while positively correlated with sympathetic activity among general residents.

Background: Over the past few years, the rate of success for smoking cessation has improved markedly owing to the widespread availability of drug therapy; however, the quit rate 1 year after the beginning of therapy remains low at approximately 50%. Previous studies have demonstrated that exercise can relieve mental stress during continuous abstinence from smoking and curb the resumption of smoking. Nonetheless, very few studies have examined the effects of exercise therapy combined with continuous abstinence from smoking; those studies involved only a handful of patients. Thus, this study will examine continuous abstinence from smoking coupled with instructions on specific forms of exercise in individuals who are attempting to quit smoking but do not exercise. We aimed to determine the effects of implementing an intervention in the form of exercise instruction after smoking cessation therapy completion on continuous abstinence from smoking. If this study finds that exercise instruction increases the continuous abstinence rate, widespread implementation of the intervention is expected to reduce public smoking rate, promote health, reduce medical expenses, and greatly benefit the public. Methods: We will enroll patients visiting a smoking cessation clinic (over a 3-month period) who have abstained from smoking in the second month after their initial visit as potential subjects and patients aged 20–75 years who do not exercise and who consent to participation in this study as subjects. We aim to enroll 300 patients. Subjects will be randomly assigned to one of the following two groups: an intervention group actively given exercise instruction in addition to the standard instruction and a control group given the standard instruction. The status of the two groups will be assessed after 9 months. The intervention group will receive instruction on exercises that can be incorporated into their daily lives. Additionally, members of this group will be lent a pedometer and encouraged to record their daily step count, level of activity, and weight during follow-up. The control group will be followed during the standard smoking cessation support program. The primary endpoint will be the continuous abstinence rate, and secondary endpoints will be weight, blood pressure, exhaled carbon monoxide concentration, psychological state, and blood test results. These indices will be compared between the intervention and control groups; the study will be conducted over a 9-month period. Discussion: By examining the effects of exercise instruction after 12-weeks smoking cessation therapy completion (covered by the National Health Insurance), this study will yield quality information for the development of protocols to improve the continuous abstinence rate and inhibit weight gain after smoking cessation therapy. Trial registration: The study is registered at UMIN Clinical Trials Registry (UMIN000014615). Registered on 1st October, 2014. Keywords: Smoking cessation, exercise, weight gain, obesity

Background The blood pressure (BP) variability (BPV) is a predictor of cardiovascular disease, independently of the BP itself. In addition, visceral fat accumulation can trigger atherosclerotic disease through various mechanisms. Methods and results We examined the association between fat accumulation and day-to-day BPV in 61 adult hypertensive patients. Visceral fat area (VFA) was measured using the dual bioelectrical impedance analysis method. Participants were divided into three groups based on VFA. The standard deviation (SD) in home systolic BP (SBP) for 7 consecutive days was significantly lower in the high VFA tertile (low VFA, 8.40±4.15 mmHg; intermediate VFA, 8.47±2.80 mmHg; and high VFA, 5.84±2.37 mmHg, p of One-way ANOVA = 0.017, p for trend = 0.0126). A similar association was observed between the coefficient of variance (CV) of home SBP and the VFA tertile. Multiple-regression analysis adjusted for age, sex, antihypertensive drug, diabetes, habitual drinking, and SBP level also showed a significant association between the VFA tertile and the SD or CV of home SBP. The adjusted coefficient of regression for the SD of home SBP was -3.28 (95%CI: -5.60 to -0.97, p = 0.008) and the CV of home SBP was -2.51 (95%CI: -4.31 to -0.71, p = 0.008) for the highest VFA tertile as compared to the lowest VFA tertile. Conclusions These results show for the first time negative correlation between VFA and day-to-day BPV. The degree of obesity should be taken into account when evaluating the value of BPV.

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.

Background Lifestyle interventions can substantially improve obesity and cardiometabolic risks. However, evidence of long-term benefits of national intervention is sparse. We aimed to evaluate the long-term effectiveness of a nationwide program for abdominal obesity. Methods A retrospective cohort study was performed using a longitudinal nationwide individual data in subjects aged 40–74 years who underwent checkups in fiscal year (FY) 2008. Lifestyle interventions were provided via interview in subjects with abdominal obesity and at least one cardiometabolic risk factor. Subjects who attended the lifestyle intervention (participants) were compared to those who did not attend (non-participants). Outcomes were waist circumferences (WC) and body mass index (BMI) reduction, reversal of metabolic syndrome (MetS), and changes in cardiometabolic risks. We used a three-step process with robust analytic approaches to account for selection bias that included traditional multivariate analysis, propensity-score matching and instrumental variable (IV) analyses. Results Of 19,969,722 subjects, 4,370,042 were eligible for analyses; 111,779 participants and 907,909 non-participants. A higher percentage of participants had ≥5% reductions in obesity profiles at year 3, compared to non-participants (WC, 21.4% vs 16.1%; BMI, 17.6% vs 13.6%; p

Aims Dysregulation of autonomic nervous system activity can trigger ventricular arrhythmias and sudden death in patients with heart failure. N-type Ca2+ channels (NCCs) play an important role in sympathetic nervous system activation by regulating the calcium entry that triggers release of neurotransmitters from peripheral sympathetic nerve terminals. We have investigated the ability of NCC blockade to prevent lethal arrhythmias associated with heart failure. Methods and results We compared the effects of cilnidipine, a dual N- and L-type Ca2+ channel blocker, with those of nitrendipine, a selective L-type Ca2+ channel blocker, in transgenic mice expressing a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). In this mouse model of dilated cardiomyopathy leading to sudden arrhythmic death, cardiac structure and function did not significantly differ among the control, cilnidipine, and nitrendipine groups. However, cilnidipine dramatically reduced arrhythmias in dnNRSF-Tg mice, significantly improving their survival rate and correcting the imbalance between cardiac sympathetic and parasympathetic nervous system activity. A β-blocker, bisoprolol, showed similar effects in these mice. Genetic titration of NCCs, achieved by crossing dnNRSF-Tg mice with mice lacking CACNA1B , which encodes the α1 subunit of NCCs, improved the survival rate. With restoration of cardiac autonomic balance, dnNRSF-Tg; CACNA1B +/− mice showed fewer malignant arrhythmias than dnNRSF-Tg; CACNA1B +/+ mice. Conclusions Both pharmacological blockade of NCCs and their genetic titration improved cardiac autonomic balance and prevented lethal arrhythmias in a mouse model of dilated cardiomyopathy and sudden arrhythmic death. Our findings suggest that NCC blockade is a potentially useful approach to preventing sudden death in patients with heart failure.

We thank Donzelli et al. (1) for their interest in our article (2). The report of the EMPATHY study (2) showed no significant difference between the intensive group and the standard group for the primary end point, but the difference was significant for cerebral events, which was one of the secondary end points. Our study did not adjust for multiplicity of secondary end points. We thus agree with the authors of the letter (1) that these results do not provide substantial evidence that aggressive LDL cholesterol (LDL-C)–lowering therapy prevents cerebral events. This is why we identified our investigation of cerebral events as an exploratory analysis. Our study focused particularly on the assessment of effects of stains on atherosclerotic events. Thus, we established the secondary end point of stroke (cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage) and assessed the data within that context. We believe that our findings support those of previous studies (3) that statins do not …

Chronic kidney disease (CKD) is not merely a disorder featuring renal dysfunction, but also accelerates the progression of cardiovascular disease. Recently, the prevalence of CKD has been increasing in parallel with that of metabolic syndrome, suggesting that these two disorders are closely related. Metabolic syndrome is generally characterized by several metabolic and cardiovascular features, including obesity, insulin resistance and hypertension, all of which are known to cause renal impairment. Hence, it is likely that metabolic syndrome could be a key factor in the development of renal disease. Among several factors associated with metabolic syndrome, lipid abnormality, in particular a high level of serum low-density lipoprotein, has been emerging as a cause of kidney injury. Accumulating evidence has demonstrated that statin therapy for treating hyperlipidemia could slow the progression of renal disease, indicating that a treatment for lipid abnormality might prevent the progression of renal disease. In other words, statin therapy might be renoprotective in addition to its beneficial effect on the cardiovascular system. We are carrying out a clinical trial, the ASUCA trial, in which we examine whether statins might slow the progression of CKD in the Japanese population. We organized the multi-center clinical trial to investigate the effect of atorvastatin on estimated glomerular filtration rate in patients with CKD and lipid abnormality. In this paper, we discuss the outline and significance of this trial.

Background:The safety of exercise-based cardiac rehabilitation (CR) has not been investigated in Japan, so a nationwide survey was conducted to investigate the incidence of adverse events (AEs) associated with CR and exercise testing.Methods and Results:In total, 136 hospitals reported operating recovery-phase CR programs, amounting to 383,096 patient-hours of exercise training. The incidence rates of all AEs and life-threatening AEs (LAE: death, cardiac arrest, acute myocardial infarction, cardiac rupture) during exercise sessions were 12 and 1 event/383,096 patient-hours (3.13 and 0.26 events/100,000patient-hours), respectively. When CR programs were categorized as “Formal” in which an exercise prescription based on exercise testing was issued to individual patients or “Non-formal” without exercise prescription, the incidence of AEs during and within the 24 h after an exercise session was significantly lower in the Formal than the Non-formal CR programs (P

Background and Purpose Angiotensin II has been implicated in the development of various cardiovascular ailments, including cardiac hypertrophy and heart failure. The fact that inhibiting its signalling reduced the incidences of both sudden cardiac death and heart failure in several large-scale clinical trials suggests that angiotensin II is involved in increased cardiac arrhythmogenicity during the development of heart failure. However, because angiotensin II also promotes structural remodelling, including cardiomyocyte hypertrophy and cardiac fibrosis, it has been difficult to assess its direct contribution to cardiac arrhythmogenicity independently of the structural effects. Experimental Approach We induced cardiac hypertrophy in wild-type (WT) and angiotensin II type 1a receptor knockout (AT1aR-KO) mice by transverse aortic constriction (TAC). The susceptibility to ventricular tachycardia (VT) assessed in an in vivo electrophysiological study was compared in the two genotypes. The effect of acute pharmacological blockade of AT1R on the incidences of arrhythmias was also assessed. Key Results As described previously, WT and AT1aR-KO mice with TAC developed cardiac hypertrophy to the same degree, but the incidence of VT was much lower in the latter. Moreover, although TAC induced an increase in tyrosine phosphorylation of connexin 43, a critical component of gap junctional channels, and a reduction in ventricular levels of connexin 43 protein in both genotypes, the effect was significantly ameliorated in AT1aR-KO mice. Acute pharmacological blockade of AT1R also reduced the incidence of arrhythmias. Conclusions and Implications Our findings demonstrate that AT1aR-mediated signalling makes a direct contribution to the increase in arrhythmogenicity in hypertrophied hearts independently of structural remodelling.

Objectives Cardiac rehabilitation is underused and its quality in practice is unclear. A quality indicator is a measurable element of clinical practice performance. This study aimed to propose a set of quality indicators for cardiac rehabilitation following an acute coronary event in the Japanese population and conduct a small-size practice test to confirm feasibility and applicability of the indicators in real-world clinical practice. Design and setting This study used a modified Delphi technique (the RAND/UCLA appropriateness method), a consensus method which involves an evidence review, a face-to-face multidisciplinary panel meeting and repeated anonymous rating. Evidence to be reviewed included clinical practice guidelines available in English or Japanese and existing quality indicators. Performance of each indicator was assessed retrospectively using medical records at a university hospital in Japan. Participants 10 professionals in cardiac rehabilitation for the consensus panel. Results In the literature review, 23 clinical practice guidelines and 16 existing indicators were identified to generate potential indicators. Through the consensus-building process, a total of 30 indicators were assessed and finally 13 indicators were accepted. The practice test (n=39) revealed that 74% of patients underwent cardiac rehabilitation. Median performance of process measures was 93% (IQR 46–100%). ‘Communication with the doctor who referred the patient to cardiac rehabilitation’ and ‘continuous participation in cardiac rehabilitation’ had low performance (32% and 38%, respectively). Conclusions A modified Delphi technique identified a comprehensive set of quality indicators for cardiac rehabilitation. The single-site, small-size practice test confirmed that most of the proposed indicators were measurable in real-world clinical practice. However, some clinical processes which are not covered by national health insurance in Japan had low performance. Further studies will be needed to clarify and improve the quality of care in cardiac rehabilitation.

Objective: To clarify whether the L-/N-type calcium channel blocker (CCB) cilnidipine is more renoprotective than the L-type CCB amlodipine in patients with early-stage diabetic nephropathy. Methods: In this prospective, multicenter, open-labeled, randomized trial, the antialbuminuric effects of cilnidipine and amlodipine were examined in renin-angiotensin system (RAS) inhibitor-treated patients with hypertension (blood pressure [BP]: 130-180/80-110 mmHg), type 2 diabetes, and microalbuminuria (urinary albumin to creatinine [Cr] ratio [UACR]: 30-300 mg/g). Results: Patients received cilnidipine (n = 179, final dose: 10.27 ± 4.13 mg/day) or amlodipine (n = 186, 4.87 ± 2.08 mg/day) for 12 months. Cilnidipine and amlodipine equally decreased BP. The UACR values for the cilnidipine and amlodipine groups were 111.50 ± 138.97 and 88.29 ± 63.45 mg/g, respectively, before treatment and 107.93 ± 130.23 and 89.07 ± 97.55 mg/g, respectively, after treatment. The groups showed similar changes for the natural logarithm of the UACR, serum Cr, and estimated glomerular filtration rate. Conclusions: Cilnidipine did not offer greater renoprotection than amlodipine in RAS inhibitor-treated hypertensive patients with type 2 diabetes and microalbuminuria.

Objective The present study was undertaken to establish a useful range for the B-type natriuretic peptide (BNP) level, with the ultimate goal of determining a cut-off BNP level that will make it possible to identify patients with clinically important organic heart disorders among patients encountered in clinical practice. Methods A total of 11,967 outpatients were evaluated for this study, and, after applying the exclusion criteria, 361 patients were finally recruited for the analysis. Compared to the factors of gender and body mass index, aging was considered to be an indispensable factor in this analysis. The 'median' plasma BNP level was found to increase slowly with age, but remained lower than 30 pg/mL, even in patients aged 60 years or older. In contrast, the overall '95th percentile' of the plasma BNP level in the patients younger than 60 years was 41 pg/mL, which increased to 139.8 pg/mL in the patients aged 60 years or older. Conclusion These findings suggest that the lower range of the BNP level allowing for identification of patients with clinically important organic heart disorders increases with age; however, it might be appropriate to adopt a level of approximately 40 pg/mL, even in elderly patients, in order to avoid any possible age-related effects of diastolic dysfunction or other factors.

Myocardin-related transcription factor (MRTF)-A is a Rho signalling-responsive co-activator of serum response factor (SRF). Here, we show that induction of MRTF-A expression is key to pathological vascular remodelling. MRTF-A expression was significantly higher in the wire-injured femoral arteries of wild-type mice and in the atherosclerotic aortic tissues of ApoE−/− mice than in healthy control tissues, whereas myocardin expression was significantly lower. Both neointima formation in wire-injured femoral arteries in MRTF-A knockout (Mkl1−/−) mice and atherosclerotic lesions in Mkl1−/−; ApoE−/− mice were significantly attenuated. Expression of vinculin, matrix metallopeptidase 9 (MMP-9) and integrin β1, three SRF targets and key regulators of cell migration, in injured arteries was significantly weaker in Mkl1−/− mice than in wild-type mice. In cultured vascular smooth muscle cells (VSMCs), knocking down MRTF-A reduced expression of these genes and significantly impaired cell migration. Underlying the increased MRTF-A expression in dedifferentiated VSMCs was the downregulation of microRNA-1. Moreover, the MRTF-A inhibitor CCG1423 significantly reduced neointima formation following wire injury in mice. MRTF-A could thus be a novel therapeutic target for the treatment of vascular diseases.

Since dyslipidemia has been shown to be an independent risk factor for the progression of chronic kidney disease (CKD), low-density lipoprotein cholesterol (LDL-C)-lowering therapy can be potentially associated with inhibition of CKD progression. The ASsessment of clinical Usefulness in CKD patients with Atorvastatin (ASUCA) trial was designed to determine whether atorvastatin has protective effects on renal function in patients with dyslipidemia and CKD.We decided to carry out a prospective multi-center, open-labeled, randomized trial to compare the reno-protective effects between diet therapy alone and atorvastatin plus diet therapy in patients with dyslipidemia (LDL-C ≥ 140 mg/dL if not treated or LDL-C ≥ 100 mg/dL if treated with lipid-lowering drugs in subjects taking dyslipidemia-treating agents other than statins) and CKD [estimated glomerular filtration rate (eGFR)60 mL/min/1.73 m(2)]. The primary endpoint is the change in eGFR (mL/min/1.73 m(2)) as calculated by the modified MDRD equation for Japanese after 2 years of treatment.Enrollment began in April 2009 and was completed in March 2011. A total of 334 patients (213 male and 121 female) were randomly assigned to either diet therapy alone or atorvastatin plus diet therapy and included in an intent-to-treat population. In the atorvastatin and control groups, the mean ages were 63.2 and 63.1 years, mean eGFRs were 55.9 and 54.0 mL/min/1.73 m(2), and median urinary albumin/creatinine ratios were 24.9 and 29.1 mg/g, respectively.This study distinguishes itself from similar studies by increasing statistical accuracy derived from its significantly larger sample size and longitudinal magnitude. The results of this study will help to determine whether atorvastatin has reno-protective effects in patients with dyslipidemia and CKD.

SummaryBackground and purposeThere have been no large-scale studies on the impact of diabetes mellitus (DM) on outcomes in Japanese patients undergoing coronary artery bypass grafting (CABG).Methods and subjectsA multi-institutional retrospective cohort study was conducted in 14 Japanese centers. All adult patients who underwent isolated CABG from 2007 to 2008 were included (n=1522, mean age: 68.5years). The definitions of DM were all patients admitted with diagnosis of DM and preoperative glycated hemoglobin (Hb) A1c≥6.5%. Univariate and multivariate analyses were performed to identify the risk of morbidity and mortality.ResultsThere were 849 DM and 572 non-DM patients. Preoperative mean HbA1c were 7.1% in the DM group and 5.7% in the non-DM group (p

Hypertension is one of the most prevalent disorders and the largest contributor to global mortality. The aim of antihypertensive treatment is to reduce the risk of cardiovascular morbidity and mortality by lowering increased blood pressure (BP) to target levels. Despite progress in antihypertensive drug development, BP control remains suboptimal. Accumulating evidence has shown that fixed-dose combination therapy is better in terms of BP control than increasing the dose of one drug or its corresponding combination. Fixed-dose combinations of an angiotensin receptor blocker, candesartan cilexetil, and a calcium channel blocker, amlodipine besilate (candesartan/amlodipine 8/2.5 or 8/5 mg), were approved in Japan for once-daily oral administration in hypertensive patients. Recent data showed that a fixed-dose combination of candesartan and amlodipine lowered BP safely and rapidly, providing a potential opportunity to improve the rate of BP control. Further studies are needed to determine whether this will lead to improvements in long-term clinical outcomes.

Objective: To investigate the significance of intra-abdominal fat area (IAFA) on new onset of individual components of the metabolic syndrome: high blood pressure, dyslipidemia, or hyperglycemia. Methods: We conducted a longitudinal study using checkup data of a hospital from 1994 to 2010. Of 25,255 subjects, we examined 1,380 Japanese, who underwent computed tomography to measure IAFA and had no metabolic syndrome components at baseline. Results: During 3.6 years of the mean follow-up period, one of metabolic syndrome components occurred in 752 subjects. Of three components, high blood pressure was more prevalent. The multiple Cox regression analysis disclosed that IAFA is significantly associated with onset of metabolic syndrome components (HR: 1.05 per 10 cm2, 95%CI: 1.03–1.07). This finding was independent of BMI, and significant even in non-obese individuals with body mass index

In the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial, comparable efficacy was noted between candesartan and amlodipine in the incidence of cardiovascular (CV) morbidity and mortality during 3.2 years of follow up. Candesartan suppressed new-onset diabetes more effectively than amlodipine. In this observational study, we investigated whether or not the efficacy of the two drugs is sustainable for another 3 years beyond the experimental period of the CASE-J trial. Of the 4728 high-risk hypertensive patients initially enrolled in the CASE-J trial, 2232 agreed to further follow up. The primary endpoint was a composite of CV morbidity and mortality. The distribution of demographic characteristics for the 2232 patients in the CASE-J extension was similar to that in the initial 4703 patients in the CASE-J trial. Both drugs controlled blood pressure well over the relatively long period of time. The incidence of CV events was 15.5/1000 patient years in the candesartan group and 16.3/1000 patient years in the amlodipine group (Hazard ratio (HR)=0.95, 95% confidence interval (CI)=0.77-1.18; P=0.650). The incidence of new-onset diabetes was significantly lower in the candesartan group (9.5/1000 patient years) than in the amlodipine group (13.3/1000 patient years), representing a 29% risk reduction for new-onset diabetes (HR=0.71, 95% CI=0.51-1.00, P=0.0495). In conclusion, candesartan and amlodipine showed comparable efficacy against CV events beyond the experimental period of the CASE-J trial in high-risk hypertensive patients. In addition, the effects of candesartan on new-onset diabetes observed during the CASE-J trial were sustained in the CASE-J extension. The CASE-J extension, which covered a 3-year extension of follow-up from the original trial, corroborated the results of the CASE-J trial.

Neuron-restrictive silencer factor (NRSF) is a zinc-finger transcription factor that binds to specific DNA sequences (NRSE) to repress transcription. By down-regulating the transcription of its target genes, NRSF contributes to the regulation of various biological processes, including neuronal differentiation, carcinogenesis and cardiovascular homeostasis. We previously reported that NRSF regulates expression of the cardiac fetal gene program, and that attenuation of NRSF-mediated repression contributes to genetic remodeling in hearts under pathological conditions. The precise molecular mechanisms and signaling pathways via which NRSF activity is regulated in pathological conditions of the heart remain unclear, however. In this study, to search for regulators of NRSF, we carried out yeast two-hybrid screening using NRSF as bait and identified zinc-finger protein (Zfp) 90 as a novel NRSF-binding protein. NRSF and Zfp90 colocalized in the nucleus, with the zinc-finger DNA-binding domain of the former specifically interacting with the latter. Zfp90 inhibited the repressor activity of NRSF by inhibiting its binding to DNA, thereby derepressing transcription of NRSF-target genes. Knockdown of Zfp90 by siRNA led to reduced expression of NRSF-target fetal cardiac genes, atrial and brain natriuretic peptide genes, and conversely, overexpression of Zfp90 in ventricular myocardium resulted in significant increases in the expression of these genes. Notably, expression of Zfp90 mRNA was significantly upregulated in mouse and human hearts with chronic heart failure. Collectively, these results suggest that Zfp90 functions as a negative regulator of NRSF and contributes to genetic remodeling during the development of cardiac dysfunction.

Background: The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial was conducted to compare the effects of candesartan and amlodipine on cardiovascular events in Japanese high-risk hypertensive patients. The aim of the present subanalysis was to evaluate the influence of coronary risk factors on coronary events in these patients as an observational study irrespective of allocated drugs. Methods and Results: The adjusted hazard ratios (HRs) of the association of baseline risk factors including gender, age, allocated drugs, body mass index, systolic/diastolic blood pressure (SBP/DBP), diabetes mellitus (DM), hyperlipidemia (HL), smoking, left ventricular hypertrophy, previous ischemic heart disease (IHD), previous cerebrovascular events, and chronic kidney disease (CKD) with coronary events in 4,703 patients who were enrolled in the CASE-J trial, were examined. The coronary events occurred in 83 patients, and were significantly associated with previous IHD, DM, male sex, CKD, and low DBP. Significant predictors were previous IHD (HR, 3.89), DM (HR, 3.10), male sex (HR, 1.81), CKD (HR, 1.60), and low DBP (HR, 1.36), respectively. In 4,107 patients without pre-vious IHD, DM (HR, 4.88), HL (HR, 2.67), and DBP (HR, 1.39) were significantly associated with the risk of coronary events, while male sex (HR, 3.03), CKD (HR, 2.44), and DM (HR, 2.15) were in 596 patients with previous IHD. Conclusions: DM is the important factor in both primary and secondary prevention of coronary events. Comprehensive risk management including surveillance of DM, CKD and HL is needed for preventing coronary events, in addition to blood pressure control. (Circ J 2011; 75: 2411-2416)

Background: Three drug combinations are the standard treatment for newly diagnosed multiple myeloma (NDMM). However, induction, consolidation, and maintenance therapy have not been standardized in Japan. Therefore, in this single arm Phase II study, we evaluated bortezomib-based induction, autologous stem cell transplantation (ASCT), bortezomib-based consolidation, and bortezomib maintenance in transplant eligible NDMM patients and assessed clinical outcomes as well as the minimal residual disease (MRD) status. Methods: Patients received four cycles of CyBorD induction therapy with bortezomib 1.3 mg/m2 and cyclophosphamide 300 mg/m2 on day 1, 8, 15, and 22 and dexamethasone 40 mg on day 1-3, 8-10, 15-17, and 22-24 for the first two cycles and day 1, 8, 15, and 22 for the last two cycles of four 28-day cycles. Peripheral blood stem cells were collected after cyclophosphamide 2 g/m2 for 2 days, which was followed by melphalan 200 mg/m2 and ASCT. Three months after ASCT, patients received consolidation treatment with three cycles of CyBorD identical to the last two cycles of the induction therapy followed by maintenance therapy with bortezomib 1.3 mg/m2 on day 1 and 15 of a 28-day cycle, for 24 months. The primary end-point was the complete response (CR) rate after consolidation therapy and assessed as an interim analysis. Responses were assessed according to the International Myeloma Working Group (IMWG) criteria. MRD was assessed using an allele-specific oligonucleotide real-time quantitative polymerase chain reaction (qPCR). The toxicity was evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Results: From August 2013 to May 2016, 42 (25 male and 17 female) patients with a median age of 58 (range 42-65) years with NDMM were found eligible and enrolled in 15 centers in Japan. The International Staging System (ISS) values were 1 in 17 (40%), 2 in 20 (48%), and 3 in 5 patients (12%). Adverse cytogenetics of 17p deletion, t(4;14), and t(14;16) were observed in 20%, 18%, and 3% of the evaluable patients, respectively. Following four induction cycles of CyBorD, the overall response rate (ORR) was obtained in 71% of patients, including a CR/sCR of 10% and very good partial response (VGPR) of 26%. One of the evaluable 11 patients showed MRD negativity after induction therapy. Four patients discontinued the protocol during the induction therapy because of grade 4 interstitial pneumonia (n = 2), prolonged grade 3 drug eruption (n = 1), and grade 1 delirium (n = 1). Four patients discontinued the protocol due to doctor judgement (inadequate efficacy, n = 2; repetitive infection, n = 1; grade 3 neutropenia, n = 1). A total of 26 of the 42 patients completed ASCT following the protocol and 18 achieved VGPR/CR, including CR in 10 patients. Three of the evaluable 10 patients showed MRD negativity after ASCT. The 2-year overall and progression-free survival rates were 93% (95% confidence interval [CI], 76%-98%) and 81% (95% CI, 51%-94%), respectively (Figure 1). Conclusions: CyBorD with ASCT for NDMM resulted in relatively high CR rates in the investigated Japanese population, although a relatively high incidence of discontinuation of therapy was observed. Dose and schedule modification of induction therapy may be necessary in Japanese populations. Clinical trial information: UMIN000010542. Figure 1. Figure 1. Disclosures Imada: Celgene: Honoraria; Bristol-Meyers Squibb: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Nippon Shinyaku: Honoraria; MSD: Honoraria; Chugai: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Kyowa Hakko Kirin: Honoraria; Shire Japan: Honoraria; Ono: Honoraria; Mundipharma: Honoraria. Takaori-Kondo:Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Janssen Pharmaceuticals: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria.