Associations between visceral obesity and renal impairment in health checkup participants: a retrospective cohort study.

BACKGROUND: Obesity is a risk factor for chronic kidney disease. Although body mass index (BMI) or waist circumference is indicators of obesity, actual measurements of visceral fat area (VFA) more accurately reflect the amount of visceral fat. We aimed to determine the most sensitive obesity indicator for predicting renal impairment among VFA, BMI, waist circumference, waist-to-height ratio, and visceral-to-subcutaneous fat ratio (VSR). METHODS: Subjects who underwent VFA measurements during health checkups in 2012 were included. Obesity was defined using a separate baseline value for each indicator [VFA (100 cm2), BMI (25 kg/m2), waist circumference (85 cm for men and 90 cm for women), waist-to-height ratio (0.5), VSR (0.4)]. Changes in estimated glomerular filtration rate (eGFRcr) and time to new-onset proteinuria were measured. The relationships between obesity indicators and eGFRcr were evaluated using a linear mixed-effects model. The relationships between obesity indicators and new-onset proteinuria were evaluated using Poisson regression analysis. RESULTS: Analysis was performed on 2753 subjects (mean age 50.3 years). The VFA ≥ 100 cm2 group exhibited a larger annual difference in eGFRcr compared to the < 100 cm2 group (- 0.24 mL/min/1.73 m2, P = 0.03). There was a statistically significant difference in the proteinuria incidence rate ratio, which was 1.54 times (95% confidence interval 1.01-2.35) in the VFA ≥ 100 cm2 group. Statistically significant correlations were not observed with any of the other obesity indicators. CONCLUSION: VFA is suggested to be the most sensitive obesity indicator for decline in kidney function and new-onset proteinuria.

The association between uric acid levels and renal function of CKD patients with hyperlipidemia: a sub-analysis of the ASUCA trial.

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: < 5.0, 5.0-6.0, 6.0-7.0, or ≥ 7.0 mg/dL, irrespective of allocation. Changes in the estimated glomerular filtration rate (eGFR) after 24 months were compared among the groups in relation to baseline or mean UA levels. RESULTS: For baseline UA levels (< 5.0, 5.0-6.0, 6.0-7.0, or ≥ 7.0 mg/dL), the change in eGFR after 24 months was - 1.32 ± 10.3, - 1.74 ± 8.94, - 2.53 ± 7.34, and - 3.51 ± 9.10 mL/min/1.73 m2, 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.

Effects of atorvastatin on renal function in patients with dyslipidemia and chronic kidney disease: assessment of clinical usefulness in CKD patients with atorvastatin (ASUCA) trial.

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.

Reciprocal expression of MRTF-A and myocardin is crucial for pathological vascular remodelling in mice.

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 ß1, 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.

Effects of nocturnal oxygen therapy in patients with chronic heart failure and central sleep apnea: CHF-HOT study.

It was previously reported that nocturnal home oxygen therapy (HOT) significantly improved not only sleep disordered breathing (SDB), but also quality of life (QOL) and left ventricular ejection fraction (LVEF) in two trials. To strengthen the statistical reliability of the above efficacies of HOT and to assess the effects of 12-week nocturnal HOT on suppression of ventricular arrhythmias, we combined the two trials and undertook a post hoc analysis. Ninety-seven patients with chronic heart failure (CHF) and central sleep apnea were assigned to receive HOT (45 patients) or not (52 patients). HOT resulted in greater reduction in the apnea-hypopnea index (AHI) (-11.4 ± 11.0 vs. -0.2 ± 7.6 events/h, p < 0.01), which is associated with greater improvement in the Specific Activity Scale (0.8 ± 1.2 vs. 0.0 ± 0.6, p < 0.01), New York Heart Association (NYHA) functional class (p < 0.01), and LVEF (p = 0.06). Median number of premature ventricular contraction (PVC) at baseline was 17 beats per hour in both the HOT and the control groups. Overall improvements of PVCs were not different either in the HOT group or in the control. However, in 12 patients with NYHA >III and AHI >20 events/h, PVC was significantly improved by HOT with a marked reduction in AHI and a substantial increase in LVEF. In conclusion, among patients with CHF and CSA, HOT improves SDB, QOL, and cardiac function. The effectiveness of HOT for ventricular arrhythmias was not observed in the overall analysis, but only in a limited number of patients with severe CHF and SDB. To clarify the effects of HOT on ventricular arrhythmias in patients with CHF and SDB, a further study is needed.

Overall safety and efficacy of high-dose and low-dose intravenous glucocorticoid therapy in patients with moderate-to-severe active Graves' ophthalmopathy.

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.

Outcomes of trastuzumab therapy in HER2-positive early breast cancer patients.

BACKGROUND: Previous large trials with trastuzumab (TZM) showed improved outcome in patients with HER2-positive early-stage breast cancer. However, the efficacy and safety of TZM in Japanese patients have not been fully evaluated. We have therefore conducted an observational study in Japan. METHODS: This was a retrospective and a prospective observational study in which data on women with histologically confirmed HER2-positive invasive breast cancer who received TZM for stage I-IIIC disease were collected from 56 institutions that participated in the Japan Breast Cancer Research Group and the efficacy of each treatment regimen analyzed. RESULTS: A total of 2,024 patients treated between July 2009 and June 2011 were initially enrolled in this study; in August 2013, the patient cohort comprised 2,009 patients. Of these, 142 (7.5 %) were aged ≥70 years, 1,097 (58.1 %) had clinically node-negative (cN0) breast cancer, and 883 (47.4 %) were estrogen receptor-positive. Treatment options were neoadjuvant therapy (662 patients) and adjuvant therapy with TZM (1,228 patients). Three-year overall survival (OS) rates in the entire cohort and in the neoadjuvant and adjuvant cohorts, respectively, were 98.9 [95 % confidence interval (CI) 98.2-99.3], 98.3 (95 % CI 96.8-99.1 %), and 99.2 % (95 % CI 98.4-99.6), respectively. Three-year disease-free survival (DFS) rates in the entire cohort and in the neoadjuvant and adjuvant cohorts, respectively were 94.2 (95 % CI 93.0-95.2), 94.8 (95 % CI 93.0-95.9), and 93.1 (95 % CI 90.7-94.9 %), respectively. Multivariate analysis showed that age and nodal status negatively correlated with DFS. Age was the only factor which correlated with OS rate. Adverse events (AEs) associated with TZM and grade 3/4 AEs were reported in 356 (18.8 %) and 14 (0.6 %) patients, respectively. Grade 3/4 cardiac toxicities were reported in 11 patients. CONCLUSION: Based on data from our patient cohort of Japanese women with HER2-positive early-stage breast cancer, the efficacy and safety of systemic therapy with TZM are comparable to data from previously conducted large trials. Progress in anti-HER2 therapy for patients aged ≥70 years who have a poorer prognosis is needed.

Preoperative chronic kidney disease as a strong predictor of postoperative infection and mortality after coronary artery bypass grafting.

BACKGROUND: The aim of this study was to determine the influence of preoperative kidney dysfunction (ie, chronic kidney disease (CKD)) on postoperative cardiovascular events, infection, acute kidney injury and hospital mortality in patients undergoing coronary artery bypass grafting (CABG). METHODS AND RESULTS: A multi-institutional retrospective study was performed at 14 hospitals of adult patients undergoing isolated CABG from 2007 to 2008 (n=1,522). We classified CKD level according to preoperative estimated glomerular filtration rate (eGFR): normal, eGFR >90 ml·min(-1)·1.73 m(-2); mild, eGFR 60-90 ml·min(-1)·1.73 m(-2); moderate, eGFR 30-59 ml·min(-1)·1.73 m(-2); and severe, eGFR <30 ml·min(-1)·1.73 m(-2), and assessed postoperative outcome. Preoperative CKD distribution was as follows: normal, n=121 (8%); mild, n=713 (47%); moderate, n=515 (34%); and severe, n=169 (11%). Risk of infection was strongly correlated with CKD level (normal, 3.3%; mild, 7.0%; moderate, 8.3%; severe, 17.0%; P<0.01). The risk of in-hospital death was also strongly correlated with CKD level (normal, 1.7%; mild, 1.0%; moderate, 1.6%; severe, 5.9%; P<0.01). On multivariate logistic regression analysis, CKD level was identified as a significant risk factor for postoperative infection, acute kidney injury, and in-hospital death. CONCLUSIONS: Advanced preoperative CKD is a strong predictor of postoperative infection, acute kidney injury and in-hospital death after CABG.

Do statins play a role in renoprotection?

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.

Effects of atorvastatin on renal function in patients with dyslipidemia and chronic kidney disease: rationale and design of the ASsessment of clinical Usefulness in CKD patients with Atorvastatin (ASUCA) trial.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Intra-abdominal fat area is a predictor for new onset of individual components of metabolic syndrome: MEtabolic syndRome and abdominaL ObesiTy (MERLOT study).

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 cm(2), 95%CI: 1.03-1.07). This finding was independent of BMI, and significant even in non-obese individuals with body mass index <25 kg/m(2). CONCLUSIONS: MERLOT study demonstrates that IAFA is an independent predictor for new onset of individual components of the metabolic syndrome, even in non-obese healthy Japanese.

[Clinical implications from the results of the CASE-J extension].

The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial was conducted to compare the effects of the angiotensin II receptor blocker (ARB) candesartan and the calcium channel blocker (CCB) amlodipine on the incidence of cardiovascular events in Japanese high-risk hypertensive patients. The CASE-J Extension (CASE-J Ex) was an observational study designed to evaluate the long-term effects of ARB candesartan and CCB amlodipine, incorporating an additional 3-year follow-up of the CASE-J trial. As in the CASE-J trial, no statistically significant difference was observed in the incidence of primary cardiovascular events, all-cause mortality, or cardiovascular death between the two groups. The superiority of candesartan over amlodipine in reducing new-onset diabetes was sustained in the three-year-long CASE-J Ex, thereby corroborating the results of the CASE-J trial.

The effect of the Original MethOd at pharmacy To ENhAnce Support for Health Improvement in the limited Japanese proficiency patients visiting local community pharmacy: A randomized controlled trial.

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.

Bortezomib-cyclophosphamide-dexamethasone induction/consolidation and bortezomib maintenance for transplant-eligible newly diagnosed multiple myeloma: phase 2 multicenter trial.

OBJECTIVES: We conducted a phase II trial to prospectively evaluate the efficacy and safety of bortezomib-cyclophosphamide-dexamethasone (VCD) induction, autologous stem cell transplantation (ASCT), VCD consolidation, and bortezomib maintenance in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients in Japan (UMIN000010542). METHODS: From 2013 to 2016, 42 patients with a median age of 58 (range 42-65) years with NDMM were enrolled in 15 centers. The primary endpoint was the complete response (CR) /stringent CR (sCR) rate after transplantation, and overall/progression-free survival rates were also evaluated. RESULTS: Following induction therapy, the overall response rate was obtained in 71% of patients, including a CR/sCR of 10% and a very good partial response (VGPR) of 26%. Twenty-six of the 42 patients completed ASCT following the protocol and CR/sCR and VGPR rate 100 days after ASCT was 26% and 17%, respectively. During consolidation therapy, 3 of the 24 patients achieved deeper responses. Eight of the 18 patients completed 2-year bortezomib maintenance without disease progression and grade 3/4 toxicities. Five patients were VGPR or partial response after ASCT but maintained response with 2-year bortezomib maintenance. Two-year overall and progression-free survival rates were 92.5% (95% confidence interval [CI]: 78.5%-97.5%) and 62.6% (95% CI: 45.8%-75.5%), respectively. Grade 3/4 toxicities (≥ 10%) included neutropenia (19%) and anemia (17%) in induction, and thrombocytopenia (29%) in consolidation. CONCLUSION: VCD induction/consolidation and bortezomib maintenance with ASCT for NDMM resulted in a high CR/sCR rate and provided good overall/progression-free survival in Japan.

Zinc-finger protein 90 negatively regulates neuron-restrictive silencer factor-mediated transcriptional repression of fetal cardiac genes.

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.

p300 plays a critical role in maintaining cardiac mitochondrial function and cell survival in postnatal hearts.

RATIONALE: It is known that the transcriptional coactivator p300 is crucially involved in the differentiation and growth of cardiac myocytes during development. However, the physiological function of p300 in the postnatal hearts remains to be characterized. OBJECTIVE: We have now investigated the physiological function of p300 in adult hearts. METHODS AND RESULTS: We analyzed transgenic mice exhibiting cardiac-specific overexpression of a dominant-negative p300 mutant lacking the C/H3 domain (p300DeltaC/H3 transgenic [TG] mice). p300DeltaC/H3 significantly inhibited p300-induced activation of GATA- and myocyte enhancer factor 2-dependent promoters in cultured ventricular myocytes, and p300DeltaC/H3-TG mice showed cardiac dysfunction that was lethal by 20 weeks of age. The numbers of mitochondria in p300DeltaC/H3-TG myocytes were markedly increased, but the mitochondria were diminished in size. Moreover, cardiac mitochondrial gene expression, mitochondrial membrane potential and ATP contents were all significantly disrupted in p300DeltaC/H3-TG hearts, suggesting that mitochondrial dysfunction contributes to the progression of the observed cardiomyopathy. Transcription of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, a master regulator of mitochondrial gene expression, and its target genes was significantly downregulated in p300DeltaC/H3-TG mice, and p300DeltaC/H3 directly repressed myocyte enhancer factor 2C-dependent PGC-1alpha promoter activity and disrupted the transcriptional activity of PGC-1alpha in cultured ventricular myocytes. In addition, myocytes showing features of autophagy were observed in p300DeltaC/H3-TG hearts. CONCLUSIONS: Collectively, our findings suggest that p300 is essential for the maintenance of mitochondrial integrity and for myocyte survival in the postnatal left ventricular myocardium.

Influence of coronary risk factors on coronary events in Japanese high-risk hypertensive patients. - Primary and secondary prevention of ischemic heart disease in a subanalysis of the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial-.

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 previous 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.

Performance Index for Types of Clinical Research Support Service Providers for Academic Research Organizations in Japan: A Cross-Sectional Survey.

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.

T-type Ca2+ channel blockade prevents sudden death in mice with heart failure.

BACKGROUND: Pharmacological interventions for prevention of sudden arrhythmic death in patients with chronic heart failure remain limited. Accumulating evidence suggests increased ventricular expression of T-type Ca(2+) channels contributes to the progression of heart failure. The ability of T-type Ca(2+) channel blockade to prevent lethal arrhythmias associated with heart failure has never been tested, however. METHODS AND RESULTS: We compared the effects of efonidipine and mibefradil, dual T- and L-type Ca(2+) channel blockers, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, on survival and arrhythmogenicity in a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), which is a useful mouse model of dilated cardiomyopathy leading to sudden death. Efonidipine, but not nitrendipine, substantially improved survival among dnNRSF-Tg mice. Arrhythmogenicity was dramatically reduced in dnNRSF-Tg mice treated with efonidipine or mibefradil. Efonidipine acted by reversing depolarization of the resting membrane potential otherwise seen in ventricular myocytes from dnNRSF-Tg mice and by correcting cardiac autonomic nervous system imbalance. Moreover, the R(-)-isomer of efonidipine, a recently identified, highly selective T-type Ca(2+) channel blocker, similarly improved survival among dnNRSF-Tg mice. Efonidipine also reduced the incidence of sudden death and arrhythmogenicity in mice with acute myocardial infarction. CONCLUSIONS: T-type Ca(2+) channel blockade reduced arrhythmias in a mouse model of dilated cardiomyopathy by repolarizing the resting membrane potential and improving cardiac autonomic nervous system imbalance. T-type Ca(2+) channel blockade also prevented sudden death in mice with myocardial infarction. Our findings suggest T-type Ca(2+) channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.