Aim: In an insulin-resistant state, excess lipids may accumulate in various non-adipose tissues, leading to histological and functional damage. It has been suggested that peroxisome proliferator-activated receptor-gamma (PPARγ) may ameliorate disorganized lipid balance. In the current study, we analyzed whether pioglitazone, an agonist of PPARγ, reduces angiotensin II-induced vascular lipid accumulation.
Methods: Angiotensin II was infused into rats at doses of 0.7 mg/kg/day via a subcutaneously implanted osmotic minipump for 7 consecutive days. Pioglitazone was orally given at a dose of 2.5 mg/kg/day for 7 days.
Results: Pioglitazone significantly reduced angiotensin II-induced enhanced lipid deposition and superoxide production in the adventitia of the aorta, as detected by oil red O and dihydroethidium (DHE) staining, respectively. Increased DHE signals, some observed at the site of lipid deposition, were mainly localized in ED-1-positive monocytes/macrophages. Angiotensin II-induced upregulation of the expression of LDL receptor and Nox1 was inhibited by pioglitazone treatment. In addition, angiotensin II significantly reduced the expression of PCSK9, and this reduction was ameliorated by pioglitazone. On the other hand, pioglitazone did not significantly alter the expression of the phosphorylated forms of AMPKα and ACC, which was downregulated by angiotensin II.
Conclusions: Pioglitazone treatment suppressed excess lipid accumulation and superoxide production in the aorta in an angiotensin II-induced rat model of hypertension.

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Aim: To determine the lipid lowering effectiveness, cost effectiveness, and safety of rosuvastatin compared with pitavastatin in dyslipidemic patients with concurrent renal disorders.
Methods: This single-center, prospective, open-label, randomized, 12-month study evaluated rosuvastatin (2.5 mg) and pitavastatin (1 or 2 mg) in 134 dyslipidemic patients with concurrent chronic kidney disease (CKD; rosuvastatin group, n=68; pitavastatin group, n=66). Lipid parameters [i.e., low density lipoprotein cholesterol (LDL-C), etc.], renal function parameters [i.e., estimated glomerular filtration rate (eGFR), etc.], glycated hemoglobin (HbA1c), and high-sensitivity C-reactive protein (hs-CRP) were measured at enrollment (baseline), month 6, and month 12.
Results: The mean daily dose of rosuvastatin and pitavastatin was 2.5 mg and 1.4 mg, respectively. All lipid parameters were significantly more improved in the rosuvastatin group. eGFR improved from baseline in the rosuvastatin group (p＜0.0001) and showed no tendency to worsen in the pitavastatin group (p=0.2232). In multiple regression analysis (n=134), it was significantly associated with a percent change in total cholesterol (β=0.2296; p=0.0112), smoking (β=0.1927; p=0.0224), and HbA1c (β=-0.1606; p=0.0585). Hs-CRP was significantly improved in both groups. An analysis eliminating the influence of antidiabetic medication showed a significant difference between groups in the change of HbA1c at month 6 from baseline (p=0.0016). No subjects in either group had new onset of diabetes mellitus. The cost of statin medication required to reduce LDL-C by 10 mg/dL was significantly lower for 2.5 mg of rosuvastatin (p=0.0116).
Conclusions: Rosuvastatin 2.5 mg had superior lipid lowering and cost effectiveness in dyslipidemic patients with concurrent CKD.(UMIN ID: UMIN000005812)

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Aims: Patients with chronic kidney disease (CKD) undergoing hemodialysis (HD) have a high prevalence of cardiovascular diseases (CVD). Arterial sclerosis plays an important role in the pathogenesis of CVD. However, to date, there have been no reports of assessment of the association between retinal arterial sclerosis and CVD in patients with CKD on HD. The aim of this study was to assess retinal arterial sclerosis and to investigate the relationship between retinal arterial changes in patients with CKD on HD and arterial stiffness/past history of CVD.
Methods: We examined the data of 44 patients (21 female, 23 male) with CKD receiving HD treatment at Saiseikai Kurihashi Hospital. The relationship between ophthalmological changes and arterial stiffness [pulse wave velocity (PWV)] or past history of CVD was evaluated. All medications being taken were recorded, and biochemical parameters were analyzed.
Results: Significant correlations were found between the presence of arteriosclerotic retinopathy [Scheie classification S grade (grade 0: 7 patients, grade 1: 18 patients, grade 2: 14 patients, grade 3: 4 patients, and grade 4: 1 patient)] and results of the evaluation of arterial stiffness (PWV) and past history of CVD (p=0.001, p=0.045). Other ophthalmological findings were not associated with a history of CVD or arterial stiffness.
Conclusion: We showed that the classification (Scheie S grade) of retinopathy on ophthalmoscopic examination may be a useful tool for predicting arterial stiffness and its association with CVD.

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Aim: Coronary artery calcium (CAC) score has a role in stratifying cardiovascular risk in patients with diabetes. Cardio-ankle vascular index (CAVI) is also a useful method to detect coronary artery calcification. This study compares CAC score with CAVI in the prediction of cardiovascular events in patients with diabetes.
Methods: From August 2006 to June 2008, a total of 626 patients with diabetes who received CAC score assessment with concomitant tests of ankle-brachial index and CAVI were included in this study.
Results: During 4 years of follow-up, 98 participants developed cardiovascular events. There is an increased incidence of coronary revascularization and total cardiovascular events with higher categories of CAC score (P＜0.05 when CAC score ≥100). The logistic regression analyses revealed pooled odd ratios for coronary revascularization, and total cardiovascular events were 1.25 [95% confidence interval (CI) 1.03– 1.51, P =0.021] and 1.23 (95% CI 1.07–1.42, P = 0.005), respectively, for high versus low CAVI (CAVI ≥9.0 vs CAVI ＜9.0). The logistic regression model revealed that a CACscore of ≥1000 rather than a CAVI of ≥9.0 had a higher predictive value for total cardiovascular events.
Conclusions: A CAC score of ≥100 or a CAVI of ≥9.0 predicts future total cardiovascular events in asymptomatic patients with type 2 diabetes. Considering the advantages of CAVI, it can be used as one of the screening tools to reflect coronary atherosclerosis in these patients.

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Aim: Pulse wave velocity (PWV) is a simple and valid clinical method for assessing arterial stiffness. Coronary artery calcification (CAC) is an intermediate stage in the process leading to overt cardiovascular disease (CVD) and an established determinant of coronary artery disease. This study aimed to examine the association between PWV and CAC in a population-based sample of Japanese men.
Methods: This is a cross-sectional study of 986 randomly selected men aged 40-79 years from Shiga, Japan. CVD-free participants were examined from 2006 to 2008. Brachial-ankle PWV (baPWV) was measured using an automatic waveform analyzer. CAC was assessed using computed tomography. Agatston scores ≥ 10 were defined as the presence of CAC.
Results: Prevalence of CAC progressively increased with rising levels of baPWV: 20.6%, 41.7%, 56.3%, and 66.7% across baPWV quartiles ＜1378, 1378-1563, 1564-1849, and ＞1849 cm/s (P＜ 0.001 for trend). Associations remained significant after adjusting for age and other factors, including body mass index, systolic blood pressure, pulse rate, total and high-density lipoprotein cholesterol, hemoglobin A1c, drinking, smoking and exercise status, and the use of medication to treat hypertension, dyslipidemia and diabetes (P=0.042 for trend). The optimal cutoff level of baPWV to detect CAC was 1612 cm/s using receiver operating characteristic curve analysis.
Conclusions: Arterial stiffness as defined by an elevated baPWV is associated with an increased prevalence of CAC in a general population-based setting among Japanese men.

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Aim: Diastolic dysfunction is a common problem in patients with obesity, hypertension, diabetes, or coronary artery disease. The purpose of this study was to evaluate the association of left ventricular diastolic dysfunction with an abnormal coronary artery calcium score (CAC score).
Methods: This study considered a cohort of patients ≥18 years of age with normal ejection fraction who were admitted to the hospital with chest pain. All patients underwent regadenoson myocardial perfusion stress imaging and had no evidence of ischemia or infarction. Patients then underwent cardiac CT for measurement of CAC score. Patients were excluded if they had prior history of coronary artery disease, ECG findings diagnostic of an acute coronary syndrome, an elevated troponin level, or hemodynamic instability.
Results: A total of 114 patients were included and 52 (45.6%) patients had echocardiographic evidence of diastolic dysfunction. Patients with diastolic dysfunction were more likely to have an abnormal calcium score (79.6% vs 20%; OR 15.10, 95% CI 5.70 to 43.85; p＜0.001). In multivariable analysis, the presence of diastolic dysfunction on echocardiogram was significantly associated with an abnormal calcium score (OR 13.82, 95% CI 5.57 to 37.37; p＜0.001) after adjusting for Framingham Risk Score or clinical risk factors (age, gender, diabetes mellitus, dyslipidemia, and obesity; OR 19.06,95% CI 4.66 to 107.97; p＜0.001).
Conclusions: Our study demonstrates that left ventricular diastolic dysfunction is associated with an abnormal CAC score even after adjusting for Framingham Risk Score or clinical risk factors. Patients without known coronary artery disease that present with chest pain and have normal perfusion imaging with evidence of abnormal diastolic function on echocardiogram may warrant more thorough evaluation for coronary atherosclerotic disease with CAC score assessment.

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Aim: To assess the prevalence of high-risk atherosclerotic cardiovascular disease (ASCVD, defined as history of acute coronary syndrome [hACS], cerebrovascular atherosclerotic disease [CeVAD], peripheral artery disease [PAD], or coronary artery disease w/diabetes [CADD]) and associated costs and cardiovascular (CV) events in Japan.
Methods: A retrospective analysis was conducted using the Japan Medical Data Center (JMDC) database (2006–2011). ASCVD prevalence was estimated on the basis of diagnoses for CeVAD, PAD, CADD, and hACS (ACS claim ＞30–≤365 days after ACS-related hospitalization) during 1/1/ 2008–12/31/2009. Population denominators used in the prevalence estimations were provided by JMDC. A subcohort with an insurance coverage for ≥12 months before and ≥24 months after first/index ASCVD claim during 1/1/2008–12/31/2009 were analyzed on the basis of costs (in 2012 US dollars) and events.
Results: ASCVD prevalence was 1,869/100,000 population. In total, 8,112 patients met inclusion criteria for the cost and CV event analyses. Among these patients, 4.0% experienced any event (myocardial infarction, stroke, coronary revascularization, hospitalization for unstable angina) in the year after ASCVD diagnosis, which decreased to 2.2% in year 2. First-year event rates were highest (22%) in patients with hACS. Mean [SD] all-cause costs per patient in year 1 were $7,031 [$14,359] for all patients with ASCVD combined. Extrapolated to the entire employed population, total first-year costs were estimated at $8.2 billion.
Conclusions: ASCVD is not rare in Japan, even within a relatively young population of employed persons. Further, the total direct first-year cost burden of ASCVD in the employed Japanese population is high. These data may inform future economic assessments of new ASCVD treatments.

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Aim: Prediabetes is an independent risk factor for future stroke. However, no effective treatment has yet been established for the recurrence of stroke in patients with prediabetes. Here we investigated the effects of pioglitazone, a potent peroxisome proliferator-activated receptor-gamma agonist, for the reduction of recurrent stroke in patients with prediabetes.
Methods: Participants were patients who had a symptomatic ischemic stroke or transient ischemic attack (TIA) without a history of type 2 diabetes mellitus and who were diagnosed to have IGT or newly diagnosed diabetes by a 75-g oral glucose tolerance test. These patients were randomized to either receive or not receive pioglitazone. The primary endpoint was a recurrence of ischemic stroke.
Results: A total of 120 patients were enrolled in the study. Sixty-three patients received pioglitazone and 57 were enrolled in the control group that did not receive pioglitazone. The majority of patients (68.3%) were prescribed 15 mg of pioglitazone, while the remaining patients (31.7%) were treated with 30 mg of pioglitazone. Over a median follow-up period of 2.8 years, treatment with pioglitazone was found to be associated with a lower rate of the primary endpoint (recurrence of stroke) than that observed in the control group [event rate=4.8% pioglitazone vs 10.5% control, hazard ratio=0.62, 95% confidence interval 0.13–2.35, p=0.49]. However, differences were not statistically significant.
Conclusions: While this study was too underpowered to determine the effect of pioglitazone, the result failed to show beneficial effects in patients of ischemic stroke or TIA with impaired glucose tolerance and newly diagnosed diabetes.

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Aim: Interleukin-1 receptor-associated kinase 1 (IRAK1) and IRAK4 play essential roles in the induction of inflammatory gene products. We aimed to investigate the effect of the inhibition of IRAK1 and IRAK4 kinase activities on neointimal formation in rats with carotid artery balloon injuries using the IRAK1/4 inhibitor N-(2-Morpholinylethyl)-2-(3-nitrobenzoylamido)-benzimidazole, a cell-permeable benzimidazole compound.
Methods: Wistar rats and vascular smooth muscle cells (VSMCs) isolated from the thoracic aortas were used. Toll-like receptor 4 (TLR4)-mediated nuclear factor kappa B (NFκB) signaling pathway was revealed by microarrays analysis. In addition, the differential expression of the TLR4 pathway genes, including TLR4, IRAK1, IκBα, and interleukin-1β (IL-1β), was confirmed by quantitative real-time polymerase chain reaction. Immunohistochemical staining, elastic-van Gieson and Masson staining, 5-ethynyl-2´-deoxyuridine staining, enzyme-linked immunosorbent assay, transwell migration assay and western blotting were also contributed for relevant detection.
Results: The expression of TLR4 protein gradually increased at days 1, 3, 7, and 21 after balloon injury compared with the uninjured group. The dual inhibition of IRAK1 and IRAK4 attenuated neointimal formation and fibrotic remodeling after injury in vivo and suppressed VSMC proliferation and migration in vitro. The production of mediators such as tumor necrosis factor-α and IL-1β in injured arteries were also reduced by the inhibition of IRAK1 and IRAK4. The expression of NFκB p65- and F4/80-positive cells in inhibitor rats were fewer than those in control rats at day 7, while IRAK1 expression was markedly higher at day 3 in inhibitor rats. Furthermore, western blotting analysis revealed that the IRAK1/4 inhibitor suppressed the IRAK1 and IRAK4 kinase activities and the activation of the TLR4-mediated NFκB pathway in vivo and in vitro.
Conclusions: This study suggested that IRAK1/4 could serve as a potential therapeutic target to suppress neointimal formation in carotid arteries after balloon injury through the TLR4/NFκB signaling pathway.

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Aim: Fibroblast growth factor 23 (FGF23) and α-Klotho have been recently identified to play a crucial role in calcium/phosphate metabolism. We herein investigated the possible relation between serum FGF23/α-Klotho levels and coronary artery calcification (CAC) and aortic valve calcification (AVC).
Methods: Among subjects with diagnosed or suspected coronary artery disease (CAD), CAC and AVC were estimated via the Agatston score of 320-detector computed tomography images, and serum FGF23 and α-Klotho levels were measured.
Results: In total, 157 subjects were enrolled (75 women and 82 men). We performed logistic regression using CAC as a dependent variable; the highest FGF23 tertile (＞52.5 pg/mL) was significantly positively associated with CAC with an odds ratio of 6.61 versus the lowest FGF23 tertile (＜35.3 pg/mL) in women after the adjustment for potential confounding variables including age, renal function, hypertension, statin use, diuretic use, and calcium/phosphate metabolism related factors. In addition, the highest α-Klotho tertile (＞561 pg/mL) was significantly associated with AVC with an odds ratio of 6.31 versus the lowest α-Klotho tertile (＜306 pg/mL) in men after adjusting for the same variables. On the other hand, the association between FGF23 and CAC/AVC in men or that between α-Klotho and CAC/AVC in women was nonsignificant.
Conclusion: Among subjects with diagnosed or suspected CAD, serum FGF23 was positively associated with CAC in women and serum α-Klotho was positively associated with AVC in men independent of the confounding variables, including the renal function and calcium/phosphate metabolism-related factors.

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