Aim:The effects of exercise intervention and to assess its long-term efficacy in preventing subsequent cardiovascular events in patients with type 2 diabetes were little known on randomized controlled trial. Methods: Thirty-eight type 2 diabetic patients (21 men and 17 women) were assigned to either the exercise group (n 21) or the control group without exercise training (n 17) by simple randomization. The exercise training group was scheduled for aerobic and resistance exercise programs for 3 months. After the 3-month, we investigated endothelial function, insulin resistance, adipocytokines and inflammatory markers. The endothelial function was evaluated by examining a flow-mediated endothelium-dependent vasodilatation (FMD). Furthermore, we followed the incidence of cardiovascular events for 24 months. Results: After 3-month, HbA1C was decreased significantly in both groups. FMD was increased from 7.3 4.7% to 10.9 6.2% only in the exercise group ( p 0.05). Long-term follow-up data showed that the control group developed cardiovascular events more frequently than did the exercise group ( p 0.05). Conclusions: Exercise improves endothelial dysfunction independently of glycemic control and insulin sensitivity in patients with type 2 diabetes. The beneficial effects of 3-month exercise to reduce cardiovascular events persist for 24 months. J Atheroscler Thromb, 2010; 17:828-833.

BACKGROUND The adipose tissue renin–angiotensin system (RAS) has been implicated in the pathophysiology of obesity and dysfunction of adipose tissue. However, neither regulation of angiotensinogen (AGT) expression in adipose tissue nor secretion of adipose tissue–derived AGT has been fully elucidated in humans. METHODS Human subcutaneous abdominal adipose tissue (SAT) biopsies were performed for 46 subjects with a wide range of body mass index (BMI). Considering the mRNA level of AGT and indices of body fat mass, the amount of adipose tissue–derived AGT secretion (A-AGT-S) was estimated. Using a mouse model of obesity and weight reduction, plasma AGT levels were measured with a newly developed enzyme-linked immunosorbent assay (ELISA), and the contribution of A-AGT-S to plasma AGT levels was assessed. RESULTS A-AGT-S was substantially increased in obese humans and the value was correlated with the plasma AGT level in mice. A-AGT-S and plasma AGT were higher in obese mice, whereas lower in mice with weight reduction. However, the AGT mRNA levels in the liver, kidney, and aorta were not altered in the mouse models. In both humans and mice, the AGT mRNA levels in mature adipocytes (MAs) were comparable to those in stromal-vascular cells. Coulter Multisizer analyses revealed that AGT mRNA levels in the MAs were inversely correlated with the average size of mature adipocytes. CONCLUSIONS This study demonstrates that adipose tissue–derived AGT is substantially augmented in obese humans, which may contribute considerably to elevated levels of circulating AGT. Adipose tissue–specific regulation of AGT provides a novel insight into the clinical implications of adipose tissue RAS in human obesity.

Background: The long-term efficacy and safety of low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus are still inconclusive. Methods: The JPAD trial (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes) was a randomized, open-label, standard care–controlled trial examining whether low-dose aspirin affected cardiovascular events in 2539 Japanese patients with type 2 diabetes mellitus and without preexisting cardiovascular disease. Patients were randomly allocated to receive aspirin (81 or 100 mg daily; aspirin group) or no aspirin (no-aspirin group) in the JPAD trial. After that trial ended in 2008, we followed up with the patients until 2015, with no attempt to change the previously assigned therapy. Primary end points were cardiovascular events, including sudden death, fatal or nonfatal coronary artery disease, fatal or nonfatal stroke, and peripheral vascular disease. For the safety analysis, hemorrhagic events, consisting of gastrointestinal bleeding, hemorrhagic stroke, and bleeding from any other sites, were also analyzed. The primary analysis was conducted for cardiovascular events among patients who retained their original allocation (a per-protocol cohort). Analyses on an intention-to-treat cohort were conducted for hemorrhagic events and statistical sensitivity. Results: The median follow-up period was 10.3 years; 1621 patients (64%) were followed up throughout the study; and 2160 patients (85%) retained their original allocation. Low-dose aspirin did not reduce cardiovascular events in the per-protocol cohort (hazard ratio, 1.14; 95% confidence interval, 0.91–1.42). Multivariable Cox proportional hazard model adjusted for age, sex, glycemic control, kidney function, smoking status, hypertension, and dyslipidemia showed similar results (hazard ratio, 1.04; 95% confidence interval, 0.83–1.30), with no heterogeneity of efficacy in subgroup analyses stratified by each of these factors (all interaction P >0.05). Sensitivity analyses on the intention-to-treat cohort yielded consistent results (hazard ratio, 1.01; 95% confidence interval, 0.82–1.25). Gastrointestinal bleeding occurred in 25 patients (2%) in the aspirin group and 12 (0.9%) in the no-aspirin group ( P =0.03), and the incidence of hemorrhagic stroke was not different between groups. Conclusions: Low-dose aspirin did not affect the risk for cardiovascular events but increased risk for gastrointestinal bleeding in patients with type 2 diabetes mellitus in a primary prevention setting. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00110448.

on behalf of the J-RHYTHM Registry Investigators* Background--To clarify the influence of hypertension and blood pressure (BP) control on thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J-RHYTHM Registry was performed.

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