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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.

The purpose of this study was to conduct a factual survey to evaluate the type of clinical research support offered by service providers (supporters) in Japanese academic research organizations (AROs). From September to October 2018, we conducted an online questionnaire targeting researchers and supporters of AROs, including individuals supporting research and development (R&D) planning, as well as those involved in study management, biostatistics, coordination, data management, monitoring, and auditing. The number of responses was tabulated for each survey item. For items with written descriptions, we compiled summaries using the inductive regression method of qualitative research. Responses were obtained from 124 researchers, 258 supporters, and 40 AROs. None of the institutions responded that they had a performance index for all types of service providers, whereas 47% of institutions had an index for 1–3 types of service providers, and 40% of institutions had no index. Many institutions responded that they had a performance index for coordinators and data management, but few responded that there was a performance index for individuals engaged in R&D and study management. Furthermore, for all evaluations of AROs and researchers, the level of supporter satisfaction was low at only 20%. There was a discrepancy between the levels of researcher expectations and the actual contribution of R&D in the process of research planning. Our survey revealed that there is currently no performance index for services supporting clinical research. In future studies, we need to examine a performance index that accurately reflects the researcher attitudes revealed in this study.

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 Previous large trials of trastuzumab (TZM) demonstrated improved outcomes in patients with HER2-positive early breast cancer. However, its effectiveness and safety in Japanese patients is not yet clear. Recently, new anti-HER2 agents were developed to improve treatment outcomes, but the patient selection criteria remain controversial. Purpose The aim of this study was to evaluate the long-term effectiveness of TZM therapy as perioperative therapy for HER2-positive operable breast cancer in daily clinical practice and to create a recurrence prediction model for therapeutic selection. Methods An observational study was conducted in Japan (UMIN000002737) to observe the prognosis of women (n = 2024) with HER2-positive invasive breast cancer who received TZM for stage I–III C disease between July 2009 and June 2011. Moreover, a recurrence-predicting model was designed to evaluate the risk factors for recurrence. Results The 5- and 10-year disease-free survival (DFS) rates were 88.9 (95% CI 87.5–90.3%) and 82.4% (95% CI 79.2–85.6%), respectively. The 5- and 10-year overall survival (OS) rates were 96% (95% CI 95.1–96.9%) and 92.7% (95% CI 91.1–94.3%), respectively. Multivariate analysis revealed that the risk factors for recurrence were an age of ≥ 70 years, T2 or larger tumors, clinically detected lymph node metastasis, histological tumor diameter of > 1 cm, histologically detected lymph node metastasis (≥ n2), and the implementation of preoperative treatment. The 5-year recurrence rate under the standard treatment was estimated to be > 10% in patients with a score of 3 or greater on the recurrence-predicting model. Conclusion The recurrence-predicting model designed in this study may improve treatment selection of patients with stage I–III C disease. However, further studies are needed to validate the scores generated by this model.

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.

Introduction: Repetitive peripheral magnetic stimulation (rPMS) therapy is an innovative and minimally invasive neurorehabilitative technique and has been shown to facilitate neural plasticity. However, there is at present no research that clarifies the dose–response of rPMS therapy on the recovery of upper limb hemiparesis after stroke. This trial aims to clarify the dose–response of rPMS therapy combined with intensive occupational therapy (OT) for chronic stroke patients with moderate to severe upper limb hemiparesis. Methods and analysis: This multicenter, prospective, assessor-blinded, randomized controlled study with 3 parallel groups will be conducted from January 20, 2020 to September 30, 2022. Fifty patients will be randomly assigned in a ratio of 1:2:2 to the control group, the group receiving daily 2400 pulses of rPMS, or the group receiving daily 4800 pulses of rPMS, respectively. From the day after admission (Day 1), rPMS therapy and intensive OT will be initiated. The primary outcome is the change in the motor function of the affected upper extremity (Fugl-Meyer Assessment) between the time of admission (Day 0) and the day after 2 weeks of treatment (Day 14). Secondary outcomes will include the changes in spasticity, active range of motion, motor evoked potential, and activity of daily living. Ethics and dissemination: The study was approved by the Jikei University Certified Review Board for all institutions (reference number: JKI19–020). Results of the primary and secondary outcomes will be published in a peer-reviewed journal and presented at international congresses. The results will also be disseminated to patients. Trial registration number: jRCTs032190191.

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

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.

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 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.

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.

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

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.

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.

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 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.

The objective of this study was to compare the safety and efficacy of high-dose and low-dose intravenous (iv) glucocorticoid (GC) therapy in patients with Graves' ophthalmopathy (GO) and to investigate which factors may help determine appropriate iv GC doses. The medical records of 43 patients who received different doses of iv GCs for GO were retrospectively reviewed. Twenty patients received high-dose iv GCs (HD group, cumulative dose 9.0-12.0 g) and 18 received low-dose iv GCs (LD group, cumulative dose 4.5 g). Five patients with previous treatment for GO were excluded. Changes in ophthalmic parameters after treatment and frequencies of adverse effects due to GCs of the 2 groups were compared. We also reviewed the incidence of GO progression and hepatic dysfunction after patients were discharged. We evaluated correlations among pretreatment (before treatment) ophthalmic parameters and investigated useful predictive factors for determining iv GC doses. There were no significant differences in ophthalmic parameters reflecting treatment efficacy or overall safety between the groups. Among baseline ophthalmic parameters, corrected signal intensity ratio (cSIR) correlated well with magnetic resonance imaging findings and were more strongly associated with changes in ophthalmic parameters after treatment in the HD group than in the LD group, indicating that pretreatment cSIR might be useful for determining iv GC doses. In conclusion, there were no significant differences in overall safety and efficacy between high-dose and low-dose iv GC therapy in patients with active GO. Further randomized clinical trials with longer observation periods are required to establish the optimal treatment regimen of GO.

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.

The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial assessed cardiovascular outcomes in high-risk hypertensive patients receiving either candesartan or amlodipine. The aim of this study was to examine the role of pre-existing diabetes or obesity on these outcomes as a sub-analysis of the trial. We examined the influence of pre-existing diabetes on cardiovascular morbidity and mortality using a multivariate Cox regression model. The cardiovascular morbidity and mortality of candesartan and amlodipine were compared between subgroups with or without pre-existing diabetes or by body mass index (BMI) category, and new-onset diabetes was compared by BMI category. Pre-existing diabetes greatly increased the cardiovascular mortality and morbidity, regardless of the allocated drugs. Furthermore, all-cause mortality was significantly higher with amlodipine than with candesartan among patients with BMI >or=27.5 kg m(-2) (adjusted hazard ratio (HR)=0.32; range=0.13-0.75; P=0.009). New-onset diabetes occurred significantly less frequently with candesartan than with amlodipine, with an adjusted HR of 0.66 (P=0.043). Furthermore, the increase in new-onset diabetes was dependent on BMI among patients receiving amlodipine, whereas no such dependency was observed for candesartan (interaction P=0.016). In conclusion, preexisting diabetes increased the risk of experiencing a cardiovascular event among high-risk Japanese hypertensive patients. Candesartan treatment may suppress all-cause death and reduce the incidence of new-onset diabetes in patients with obesity.

OBJECTIVE Hypertensive patients have an increased risk of developing diabetes. Accumulating evidence suggests a close relation between metabolic disturbance and increased arterial stiffness. Here, we examined the association between pulse pressure and the risk of new-onset diabetes in high-risk Japanese hypertensive patients. RESEARCH DESIGN AND METHODS The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial examined the effects of candesartan and amlodipine on the incidence of cardiovascular events in 4,728 high-risk Japanese hypertensive patients. In the present study, we analyzed the relationship between pulse pressure at baseline and new-onset diabetes in 2,685 patients without diabetes at baseline (male 1,471; mean age 63.7 years; mean BMI 24.8 kg/m2) as a subanalysis of the CASE-J trial. RESULTS During 3.3 ± 0.8 years of follow-up, 97 patients (3.6%) developed diabetes. In multiple Cox regression analysis, pulse pressure was an independent predictor for new-onset diabetes (hazard ratio [HR] per 1 SD increase 1.44 [95% CI 1.15–1.79]) as were male sex, BMI, and additional use of diuretics, whereas age and heart rate were not. Plots of HRs for new-onset diabetes considering both systolic and diastolic blood pressure (DBP) revealed that a higher pulse pressure with a lower DBP, indicating that the increased pulse pressure was largely due to increased arterial stiffness, was strongly associated with the risk of new-onset diabetes. CONCLUSIONS Pulse pressure is an independent predictor of new-onset diabetes in high-risk Japanese hypertensive patients. Increased arterial stiffness may be involved in the development of diabetes.

Background: There are little data on the usefulness of trastuzumab (TZM) retreatment as the first-line treatment for patients with HER2 (human epidermal growth factor receptor 2)–positive breast cancer recurrence after perioperative treatment with TZM. Aim: To clarify the outcome and safety of TZM retreatment in patients with recurrent HER2-positive breast cancer. Method: An observational study was conducted on patients who relapsed after primary systemic therapy with TZM using the central registration system. The primary end point was progression-free survival (PFS). Secondary end points consisted of the response rate, overall survival (OS), and safety. Result: In total, 34 patients were registered between July 2009 and June 2012. The median follow-up time was 23.7 months (2-24 months). The 1- and 2-year PFS rates were 46.9% (95% confidence interval (95% CI): 29.2%-62.9%) and 29.8% (95% CI: 15.0%-46.3%), respectively (median 10.6 months). The median PFS time for patients receiving TZM combined with CTx was 13.9 months. The 1-and 2-year OR rates were 93.9 (95% CI: 77.9%-98.4%) and 84.8% (95% CI: 67.4%-93.4%). Trastuzumab-induced grade 3/4 adverse events were not observed. Conclusions: This study suggests that the PFS and OS in Japanese patients who relapsed after perioperative TZM therapy improved or were similar to those in previous reports. Differences in patient backgrounds and treatments must be considered when interpreting the results. Trastuzumab should be used combination with CTx and/or HTx for retreatment. Retreatment with TZM is safe. Trial registration: UMIN000002738.

Background: In this subanalysis of the CASE-J, which was conducted to compare the effects of candesartan and amlodipine in Japanese high-risk hypertensive patients, the association of left ventricular hypertrophy (LVH) with renal function is clarified. Methods and Results: Patients were divided into 2 groups: 1,082 patients with LVH and 2,119 patients without LVH. The primary endpoint was the change in the estimated glomerular filtration rate (eGFR). The eGFRs were increased from 63.6 to 65.1 ml · min-1 · 1.73 m-2 in patients with LVH and from 63.6 to 68.5 ml · min-1 · 1.73 m-2 in those without LVH. The improvement in the eGFR was greater in patients without LVH than in those with LVH (P=0.004). In patients with chronic kidney disease (CKD) patients, the eGFR increased from 52.7 to 60.5 ml · min-1 · 1.73 m-2 in patients without LVH, but from 53.1 to 57.2 ml · min-1 · 1.73 m-2 in those with LVH (P

Objectives We assessed whether a combination of summed stress scores (SSS) using exercise myocardial perfusion SPECT (Ex-SPECT) and maximal heart rate accurately predicts cardiac events through a sub-analysis of J-ACCESS (Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated SPECT) which was conducted to evaluate the prognosis of Japanese patients with suspected ischemic heart disease. Methods In J-ACCESS, 2, 373 patients with suspected coronary artery disease not receiving beta-blocker treatment underwent Ex-SPECT. These patients were categorized into the following four groups: Group A [achieved target heart rate (THR) and SSS < 4: n = 631], B (did not achieve THR and SSS < 4: n = 612), C (achieved THR and SSS ≥ 4: n = 570), and D (did not achieve THR and SSS ≥ 4: n = 560). We evaluated the incidence rate of cardiac events including cardiac death, myocardial infarction, and heart failure requiring hospital admission during a 3-year period. Results In Group A, B, C, and D, 9 of 631 (1.4%), 15 of 612 (2.4%), 23 of 570 (4.0%) and 30 of 560 (5.4%) patients experienced cardiac events, respectively. Although the hazard ratio of the SSS ≥ 4 was 2.45 (p < 0.001) and that of the attained THR was 0.69 (p = 0.10) in the multiple Cox regression analysis, Kaplan–Meier curves showed that the cardiac events rate was lower in the order of A, B, C, and D (p < 0.001). Conclusion The combination of SSS using Ex-SPECT and the maximal heart rate is a useful predictor of cardiac events in patients with suspected coronary artery disease.

Objective To evaluate the associations of left ventricular hypertrophy (LVH) and its changes with the incidence of cardiovascular events and the time-course of serum creatinine (sCr) levels in high-risk hypertensive patients who participated in the Candesartan Antihypertensive Survival Evaluation in Japan trial. Methods We analysed data of 1447 patients who underwent echocardiography at enrolment as an observational study irrespective of allocation. According to the left ventricular mass index (LVMI) at the baseline, they were divided into two groups (without LVH, LVMI < 125g/m 2 ; n = 607 and with LVH, LVMI≥ 125 g/m 2 ; n = 840) and four categories on the basis of LVMI at the baseline and 1 year: absence of LVH (n = 285), development of LVH (n = 97), regression of LVH (n = 155), and persistence of LVH (n = 418). Results During 3.3 ± 0.8 years, cardiovascular events occurred in 20 (3.3%) patients without LVH and in 67 (8.0%) patients with LVH (hazard ratio: 2.58; 95% confidence interval: 1.54-4.33; P < 0.001 Among the four categories, absence of LVH was associated with lower risk of cardiovascular events than persistence of LVH (hazard ratio: 0.30; 95% confidence interval: 0.13-0.71; P= 0.006), but development or regression of LVH was not. Only in persistence of LVH did the sCr level significantly increase over time (baseline vs. 3 years; 0.92 vs. 1.02 mg/dl, P < 0.001). Adjusted sCr level of absence and regression of LVH at 3 years was significantly lower than that of persistence of LVH (0.89 and 0.90 vs. 0.97 mg/dl, P < 0.001, P= 0.002, respectively), but that of development of LVH was not. Conclusion Protection against LVH is associated with a reduced risk of cardiovascular events and may be related to the preservation of renal function in high-risk hypertensive patients.

Background: The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial compared the effects of candesartan and amlodipine on cardiovascular events in Japanese high-risk hypertensive patients. The present study aimed to clarify the effect of cardiac complications on cardiovascular events in patients enrolled in CASE-J. Methods and Results: Cardiac complications were defined as left ventricular hypertrophy (LVH) and ischemic heart disease (IHD). The primary endpoint was a composite of sudden death, cerebrovascular, cardiac, renal and vascular events. The study group was divided into 2,030 and 2,673 patients with and without cardiac complications. During 3.2 follow-up years, cardiovascular events occurred for a rate of 13.6 per 1000 patient-years in patients without cardiac complications, and 23.1 per 1000 patient-years in patients with cardiac complications (adjusted hazard ratio (HR): 2.22; P

Background Aortic regurgitation (AR) causes left ventricular (LV) volume overload, leading to progressive LV dilatation and dysfunction. In the present study it was examined whether blockade of angiotensin II type 1 receptor (AT1) could improve survival in cases of chronic severe AR. Methods and Results AR was induced by puncturing the aortic valves of wild-type (WT) and AT1a knockout (KO) mice. Mice that survived for 4 weeks after the operation were deemed to be a model of chronic severe AR and were followed up for 50 weeks (WT, n=29; KO, n=31). Baseline measurements made 4 weeks after surgery showed similar LV cavity and function in both genotypes. These conditions progressively worsened in both genotypes, but 16 weeks after baseline, KO mice showed significantly less LV dilatation, hypertrophy and interstitial fibrosis than WT mice. Cardiac mRNA expression of B-type natriuretic peptide and type I collagen was lower in KO than WT mice. The 50-week mortality rate was significantly lower among KO (45.2%) than WT (86.2%) mice, and postmortem findings indicated that the lower mortality was attributable to a lower incidence of congestive heart failure. Conclusions In cases of chronic severe AR, blockade of AT1 attenuates the progression of LV dilatation, hypertrophy and fibrosis, thereby mitigating heart failure and improving long-term survival. (Circ J 2007; 71: 1310 - 1316)

We recently reported that a transcriptional repressor, neuron-restrictive silencer factor (NRSF), represses expression of fetal cardiac genes, including atrial and brain natriuretic peptide (ANP and BNP), by recruiting class I histone deacetylase (HDAC) and that attenuation of NRSF-mediated repression contributes to the reactivation of fetal gene expression during cardiac hypertrophy. The molecular mechanism by which the activity of the NRSF-HDAC complex is inhibited in cardiac hypertrophy remains unresolved, however. In the present study, we show that class II HDACs (HDAC4 and 5), which are Ca/calmodulin-dependent kinase (CaMK)-responsive repressors of hypertrophic signaling, associate with NRSF and participate in NRSF-mediated repression. Blockade of the CaMK-class II HDAC signaling pathway using a CaMK-resistant HDAC5 mutant, a CaMK inhibitor (KN62) or a dominant-negative CaMK mutant inhibited ET-1-inducible ANP and BNP promoter activity, but that inhibitory effect was abolished by mutation of the neuron-restrictive silencer element (NRSE) within the ANP and BNP promoter. In addition, adenovirus-mediated expression of a dominant-negative NRSF mutant abolished the inhibitory effect of KN62 on ET-1-inducible endogenous ANP gene expression in ventricular myocytes. Finally, the interaction between NRSF and class II HDACs was decreased in both in vitro and in vivo models of cardiac hypertrophy. These findings show that ET-1-induced CaMK signaling disrupts class II HDAC-NRSF repressor complexes, thereby enabling activation of ANP and BNP gene transcription in ventricular myocytes, and shed light on a novel mechanism by which the fetal cardiac gene program is reactivated.

Background Stimulation of angiotensin II type 1 (AT1) receptors has been shown to generate the arrhythmogenic substrate in ventricular hypertrophy. We examined whether candesartan, an AT1 receptor blocker, has antiarrhythmic effects on mouse model of left ventricular hypertrophy created by transverse aorta constriction (TAC). Methods and Results Forty-eight male mice were divided into 3 groups: TAC, candesartan (TAC plus candesartan) and control groups. Echocardiographic examination was performed before the operation and 2 and 4 weeks after the operation. Four weeks after the operation, electrophysiological studies were conducted by inserting a 1.7 F octapolar electrode catheter through the right external jugular vein into the right ventricle. The effective refractory period of the atrioventricular node (AVNERP) in TAC group was significantly prolonged, and short episodes of ventricular tachycardia (VT) and atrial fibrillation (AF) could be induced in 12 of 16 mice (75%) and 8 of 16 (50%), respectively. In contrast, in candesartan group, the incidence of VT was significantly reduced (12.5%) and no AF was induced. Moreover, the drug produced a significant left ventricular hypertrophy regression and restored the AVNERP to normal. Conclusions Candesartan reduced both ventricular and atrial arrhythmias in the TAC mice, presumably by preventing the electrical remodeling by inhibiting the AT1 receptor. (Circ J 2006; 70: 335 - 341)

Although plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are elevated early after myocardial infarction (MI), the significance is not fully understood. We therefore investigated the function of natriuretic peptides after induction of MI in knockout (KO) mice lacking the natriuretic peptide receptor guanylyl cyclase-A, the receptor for ANP and BNP. KO and wild-type (WT) mice were subjected to left coronary artery ligation and then followed up for 4 weeks. Irrespective of genotype, almost all deaths occurred within 1 week after induction of MI. KO mice showed significantly higher mortality because of a higher incidence of acute heart failure, which was associated with diminished water and sodium excretion and with higher cardiac levels of mRNAs encoding ANP, BNP, transforming growth factor-β1, and type I collagen. By 4 weeks after infarction, left ventricular remodeling, including myocardial hypertrophy and fibrosis, and impairment of left ventricular systolic function were significantly more severe in KO than WT mice. Notably, the enhanced myocardial fibrosis seen in KO mice was virtually absent in infarcted double-KO mice, lacking guanylyl cyclase-A and angiotensin II type 1a receptors, although there was no improvement in survival and no attenuation of cardiac hypertrophy. Thus, guanylyl cyclase-A activation by endogenous cardiac natriuretic peptides protects against acute heart failure and attenuates chronic cardiac remodeling after MI. These beneficial effects are mediated partly through inhibition of the renin-angiotensin system (RAS), although RAS-independent protective actions of guanylyl cyclase-A are also suggested.

gp130-dependent signaling is known to play a critical role in the onset of heart failure. In that regard, cardiotrophin-1 (CT-1) activates several signaling pathways via gp130, and induces hypertrophy in neonatal rat cardiomyocytes. Among the mediators activated by CT-1, STAT3 is thought to be important for induction of cell hypertrophy, though its precise function in the CT-1 signaling pathway is not fully understood. In the present study, therefore, to better understand the significance of STAT3 activity in CT-1 signaling, we infected cultured cardiomyocytes with adenoviral vectors harboring a dominant-negative STAT3 mutant or one of two endogenous negative regulators of cytokine signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways [suppressor of cytokine signaling (SOCS) 1 and 3] and then examined their effects on three indexes of CT-1-induced cell hypertrophy: protein synthesis, secretion of brain natriuretic peptide and changes in cell surface area. In control cells, CT-1-induced both STAT3 phosphorylation and cell hypertrophy. Overexpression of dominant-negative STAT3 mutant suppressed CT-1-induced STAT3 phosphorylation, but did not affect cell hypertrophy. On the other hand overexpression of SOCS1 or SOCS3 inhibited both CT-1-induced STAT3 phosphorylation and cell hypertrophy. CT-1 also induced phosphorylations of ERK1/2 and ERK5 in cardiomyocytes, and those, too, were suppressed by overexpression of SOCSs. CT-1-induced cell hypertrophy was suppressed by overexpression of a dominant-negative MEK5 mutant, and not by overexpression of a dominant-negative MEK1 mutant. These findings indicate that the major pathway responsible for the hypertrophic responses to CT-1 is not JAK-STAT3 pathway nor MEK1-ERK1/2 pathway, but MEK5-ERK5 pathway.

Background— Recent clinical trials have shown that systemic infusion of nesiritide, a recombinant human brain natriuretic peptide (BNP), improves hemodynamic parameters in acutely decompensated hearts. This suggests that BNP exerts a direct cardioprotective effect and might thus be a useful therapeutic agent with which to treat acute myocardial infarction (MI). In the present study, we used BNP-transgenic (BNP-Tg) mice with elevated plasma BNP to determine whether and how BNP contributes to left ventricular remodeling and healing after MI. Methods and Results— We examined the accumulation of neutrophils and the expression and activation of matrix metalloproteinase (MMP)-9 in the ventricles of male BNP-Tg mice and their nontransgenic (non-Tg) littermates during the early phase after acute MI. The numbers of neutrophils infiltrating the infarcted area were significantly increased in BNP-Tg mice 3 days after MI. In addition, both the gene expression and zymographic activity of MMP-9, but not MMP-2, were significantly higher in BNP-Tg than non-Tg mice. Double immunostaining revealed that neutrophils are the main source of the MMP-9, although doxycycline, an MMP inhibitor, had no effect on neutrophil infiltration of the infarcted area in BNP-Tg mice. Conclusions— These results demonstrate that elevated plasma BNP facilitates neutrophil infiltration of the infarcted area after MI and increases the activity of the MMP-9 they produce. This suggests that BNP plays a key role in the processes of extracellular matrix remodeling and wound-healing during the early phase after acute MI.