Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid (RESPECT-EPA).

BACKGROUND: Low plasma levels of eicosapentaenoic acid (EPA) are associated with cardiovascular events. This trial aimed to assess the clinical benefits of icosapent ethyl in patients with coronary artery disease, a low EPA/arachidonic acid (AA) ratio, and statin treatment. METHODS: In this prospective, multicenter, randomized, open-label, blinded end-point study, patients with stable coronary artery disease and a low EPA/AA ratio (<0.4) were randomized to EPA (1800 of icosapent ethyl administered daily) or control group. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina pectoris, and coronary revascularization. The secondary composite end points of coronary events included sudden cardiac death, fatal and nonfatal myocardial infarction, unstable angina requiring emergency hospitalization and coronary revascularization, or coronary revascularization. RESULTS: Overall, 3884 patients were enrolled at 95 sites in Japan. Among them, 2506 patients had a low EPA/AA ratio, and 1249 and 1257 patients were randomized to the EPA and control group, respectively. The median EPA/AA ratio was 0.243 (interquartile range, 0.180-0.314) and 0.235 (interquartile range, 0.163-0.310) in the EPA and control group, respectively. Over a median period of 5 years, the primary end point occurred in 112 of 1225 patients (9.1%) and 155 of 1235 patients (12.6%) in the EPA and control group, respectively (hazard ratio, 0.79 [95% CI, 0.62-1.00]; P=0.055). Meanwhile, the secondary composite end point of coronary events in the EPA group was significantly lower (81/1225 [6.6%] versus 120/1235 [9.7%] patients; hazard ratio, 0.73 [95% CI, 0.55-0.97]). Adverse events did not differ between the groups, but the rate of new-onset atrial fibrillation was significantly higher in the EPA group (3.1% versus 1.6%; P=0.017). CONCLUSIONS: Icosapent ethyl treatment resulted in a numerically lower risk of cardiovascular events that did not reach statistical significance in patients with chronic coronary artery disease, a low EPA/AA ratio, and statin treatment. REGISTRATION: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000012069.

Multicenter randomized controlled trial of intensive uric acid lowering therapy for CKD patients with hyperuricemia: TARGET-UA.

BACKGROUND: We investigate whether Intensive uric acid (UA)-lowering therapy (ULT) provides increased renal protection compared with standard therapy in chronic kidney disease (CKD) patients. METHODS: This was a multicenter randomized controlled trial. Only CKD patients with hyperuricemia were included in this study. The participants were randomly assigned to either the Intensive therapy group (target serum UA level ≥ 4.0 mg/dL and < 5.0 mg/dL) or the standard therapy group (serum UA level ≥ 6.0 mg/dL and < 7.0 mg/dL). ULT was performed using topiroxostat, a non-purine-type selective xanthine oxidase inhibitor. The primary endpoint was change in the logarithmic value of urine albumin to the creatinine ratio (ACR) between baseline and week 52 of the treatment. RESULTS: Three hundred fifty-two patients were included in the full analysis set. In the Standard therapy group, mean serum UA was 8.23 mg/dL at baseline and 6.13 mg/dL at 52 weeks. In the Intensive therapy group, mean serum UA was 8.15 mg/dL at baseline and 5.25 mg/dL at 52 weeks. There was no significant difference in changes in log ACR at 52 weeks between the Intensive therapy and the Standard therapy groups. CONCLUSION: This study did not reveal the benefit of Intensive ULT to improve albuminuria levels. (UMIN000026741 and jRCTs051180146).

Study protocol and baseline characteristics of Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid: RESPECT-EPA, the combination of a randomized control trial and an observational biomarker study.

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

Active Participation in Outpatient Cardiac Rehabilitation Is Associated With Better Prognosis After Coronary Artery Bypass Graft Surgery　- J-REHAB CABG Study.

BACKGROUND: There is little evidence regarding the effect of outpatient cardiac rehabilitation (CR) on exercise capacity or the long-term prognosis in patients after coronary artery bypass graft surgery (CABG). This study aimed to determine whether participation in outpatient CR improves exercise capacity and long-term prognosis in post-CABG Japanese patients in a multicenter cohort.Methods and Results:We enrolled 346 post-CABG patients who underwent cardiopulmonary exercise testing during early (2-3 weeks) and late (3-6 months) time points after surgery. They formed the Active (n=240) and Non-Active (n=106) CR participation groups and were followed for 3.5 years. Primary endpoint was a major adverse cardiac event (MACE): all-cause death or rehospitalization for acute myocardial infarction/unstable angina/worsening heart failure. Peak oxygen uptake at 3-5 months from baseline was significantly more increased in Active than in Non-Active patients (+26±24% vs. +19±20%, respectively; P<0.05), and the MACE rate was significantly lower in Active than Non-Active patients (3.4% vs. 10.5%, respectively; P=0.02). Multivariate Cox proportional hazard analysis showed that participation in outpatient CR was a significant prognostic determinant of MACE (P=0.03). CONCLUSIONS: This unique study showed that a multicenter cohort of patients who underwent CABG and actively participated in outpatient CR exhibited greater improvement in exercise capacity and better survival without cardiovascular events than their counterparts who did not participate.

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.

Achieving LDL cholesterol target levels <1.81 mmol/L may provide extra cardiovascular protection in patients at high risk: Exploratory analysis of the Standard Versus Intensive Statin Therapy for Patients with Hypercholesterolaemia and Diabetic Retinopathy study.

AIMS: To assess the benefits of intensive statin therapy on reducing cardiovascular (CV) events in patients with type 2 diabetes complicated with hyperlipidaemia and retinopathy in a primary prevention setting in Japan. In the intension-to-treat population, intensive therapy [targeting LDL cholesterol <1.81 mmol/L (<70 mg/dL)] was no more effective than standard therapy [LDL cholesterol ≥2.59 to <3.10 mmol/L (≥100 to <120 mg/dL)]; however, after 3 years, the intergroup difference in LDL cholesterol was only 0.72 mmol/L (27.7 mg/dL), and targeted levels were achieved in <50% of patients. We hypothesized that the intergroup difference in CV events would have been statistically significant if more patients had been successfully treated to target. MATERIALS AND METHODS: This exploratory post hoc analysis focused on intergroup data from patients who achieved their target LDL cholesterol levels. The primary endpoint was the composite incidence of CV events. A Cox proportional hazards model was used to estimate hazard ratios (HRs) for incidence of the primary endpoint in patients who achieved target LDL cholesterol levels in each group. RESULTS: Data were analysed from 1909 patients (intensive: 703; standard: 1206) who achieved target LDL cholesterol levels. LDL cholesterol at 36 months was 1.54 ± 0.30 mmol/L (59.7 ± 11.6 mg/dL) in the intensive group and 2.77 ± 0.46 mmol/L (107.1 ± 17.8 mg/dL) in the standard group (P < 0.05). After adjusting for baseline prognostic factors, the composite incidence of CV events or deaths associated with CV events was significantly lower in the intensive than the standard group (HR 0.48; 95% confidence interval 0.28-0.82; P = 0.007). CONCLUSIONS: This post hoc analysis suggests that achieving LDL cholesterol target levels <1.81 mmol/L may more effectively reduce CV events than achieving target levels ≥2.59 to <3.10 mmol/L in patients with hypercholesterolaemia and diabetic retinopathy.

Underuse of Cardiac Rehabilitation in Workers With Coronary Artery Disease　- Claims Database Survey in Japan.

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

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.

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.

Safety of exercise-based cardiac rehabilitation and exercise testing for cardiac patients in Japan: a nationwide survey.

BACKGROUND: The safety of exercise-based cardiac rehabilitation (CR) has not been investigated in Japan, so a nationwide survey was conducted to investigate the incidence of adverse events (AEs) associated with CR and exercise testing. METHODS AND RESULTS: In total, 136 hospitals reported operating recovery-phase CR programs, amounting to 383,096 patient-hours of exercise training. The incidence rates of all AEs and life-threatening AEs (LAE: death, cardiac arrest, acute myocardial infarction, cardiac rupture) during exercise sessions were 12 and 1 event/383,096 patient-hours (3.13 and 0.26 events/100,000patient-hours), respectively. When CR programs were categorized as "Formal" in which an exercise prescription based on exercise testing was issued to individual patients or "Non-formal" without exercise prescription, the incidence of AEs during and within the 24 h after an exercise session was significantly lower in the Formal than the Non-formal CR programs (P<0.001), despite similar hospital size and coronary intervention volumes between the 2 category hospitals. Moreover, LAEs did not occur in 277,721 patient-hours in Formal CR, whereas 2 LAEs occurred in 105,375 patient-hours in Non-formal CR (P<0.05). During 469,215 exercise testing sessions, 3 LAEs (0.64 event/100,000tests) and 31 non-LAEs (6.61 events/100,000tests) occurred. CONCLUSIONS: This first nationwide survey in Japan revealed that both exercise-based CR and exercise testing are generally safe, and that Formal CR, in which an individual exercise prescription is determined by exercise testing, is particularly safe.

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.

A Randomized Controlled Trial of Betamethasone on Fatigue in Patients With Advanced Cancer.

CONTEXT: Fatigue is one of the most uncomfortable physical symptoms seen in patients with advanced cancer. Previous studies have reported on the efficacy of corticosteroids from Western countries. OBJECTIVES: To assess the effectiveness of 4mg betamethasone improving fatigue among Japanese patients with advanced cancer. METHODS: A randomized, double-blind, placebo-controlled trial enrolled eligible patients with advanced cancer expected to survive 1-2 months, with an Eastern Cooperative Oncology Group Performance Status of 2-3, and experiencing fatigue according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-15-palliative criteria. Participants received twice-daily oral administration of 2 mg betamethasone (4 mg/d) or placebo for seven days, with fatigue assessed using EORTC QLQ-C15-PAL subscale and numerical rating scale (NRS) score (at baseline and day seven). The trial was registered under the University Hospital Medical Information Network (UMIN)000011913. RESULTS: Among the 267 screened patients, 81 were eligible, of which 70 were evaluable (betamethasone, 33; placebo, 37). The mean difference in the EORTC-QLQ-C15-PAL fatigue subscale was -8.2 (95% CIs: -22.3, 0.0; P = 0.178) and in a NRS for fatigue was -1.2 (95% CIs: -2.5, -0.01; P = 0.048), respectively. Emotional function, appetite loss, and global-health were slightly better in the betamethasone group than in the placebo group. CONCLUSION: The impact of betamethasone 4 mg/d on alleviating fatigue in patients with advanced cancer in the last weeks of life did not reach statistical significance in the EORTC-QLQ-C15-PAL as the primary endpoint, however, it was significant in the NRS, the secondary endpoint.

Comparison of the antialbuminuric effects of L-/N-type and L-type calcium channel blockers in hypertensive patients with diabetes and microalbuminuria: the study of assessment for kidney function by urinary microalbumin in randomized (SAKURA) trial.

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

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.

Inhibition of TRPC6 channel activity contributes to the antihypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart.

RATIONALE: Atrial and brain natriuretic peptides (ANP and BNP, respectively) exert antihypertrophic effects in the heart via their common receptor, guanylyl cyclase (GC)-A, which catalyzes the synthesis of cGMP, leading to activation of protein kinase (PK)G. Still, much of the network of molecular mediators via which ANP/BNP-GC-A signaling inhibit cardiac hypertrophy remains to be characterized. OBJECTIVE: We investigated the effect of ANP-GC-A signaling on transient receptor potential subfamily C (TRPC)6, a receptor-operated Ca(2+) channel known to positively regulate prohypertrophic calcineurin-nuclear factor of activated T cells (NFAT) signaling. METHODS AND RESULTS: In cardiac myocytes, ANP induced phosphorylation of TRPC6 at threonine 69, the PKG phosphorylation site, and significantly inhibited agonist-evoked NFAT activation and Ca(2+) influx, whereas in HEK293 cells, it dramatically inhibited agonist-evoked TRPC6 channel activity. These inhibitory effects of ANP were abolished in the presence of specific PKG inhibitors or by substituting an alanine for threonine 69 in TRPC6. In model mice lacking GC-A, the calcineurin-NFAT pathway is constitutively activated, and BTP2, a selective TRPC channel blocker, significantly attenuated the cardiac hypertrophy otherwise seen. Conversely, overexpression of TRPC6 in mice lacking GC-A exacerbated cardiac hypertrophy. BTP2 also significantly inhibited angiotensin II-induced cardiac hypertrophy in mice. CONCLUSIONS: Collectively, these findings suggest that TRPC6 is a critical target of antihypertrophic effects elicited via the cardiac ANP/BNP-GC-A pathway and suggest TRPC6 blockade could be an effective therapeutic strategy for preventing pathological cardiac remodeling.

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.