Inflammation plays a key role in atherosclerosis and plaque vulnerability, and monocyte/macrophage activation contributes to these processes. Neopterin, a by-product of the guanosine triphosphate pathway, is produced by activated macrophages on stimulation with interferon-γ released from T lymphocytes, and is an activation marker for monocytes/macrophages. Coronary angiographic studies have shown a relationship between increased circulating levels of neopterin and the presence of complex coronary lesions in patients with unstable angina pectoris (UAP). Furthermore, in an immunohistochemical study performed using coronary atherectomy specimens, a significantly higher prevalence of neopterin-positive macrophages was found in culprit lesions in patients with UAP than in those with stable angina pectoris (SAP). We recently clarified that the presence of complex carotid plaques detected by carotid ultrasound was related to increased circulating levels of neopterin, and immunohistochemical localization of neopterin was observed in complex carotid lesions obtained from carotid endarterectomy in patients with SAP. These findings suggest that neopterin is an important biomarker of plaque instability in both coronary and carotid atherosclerotic lesions.

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Aim: Pre-procedural platelet reactivity (PR) in Korean patients may be greater because the CYP2C19^*2 and ^*3 variant alleles are more common in Korean patients than in Caucasians. We investigated the level of PR and the prevalence of high post-clopidogrel platelet reactivity (HPPR) after a routine loading dose (LD) of clopidogrel in Korean patients.
Methods: We assessed the PR level at 12 to 24 hours after a 300-mg LD of clopidogrel in 215 patients undergoing scheduled percutaneous coronary intervention (PCI) (available CYP2C19 genotyping: n =176). PR was measured by conventional aggregometry and VerifyNow. Based on a previous study, HPPR was defined as a 5 µmol/L ADP-induced maximal PR >50%.
Results: With 5 and 20 µmol/L ADP stimuli, maximal PR were 48.7±17.1% and 62.1±15.7%, respectively, and the prevalence of HPPR reached 52.1%. The highest quartile cut-offs of 5 and 20 µmol/L ADP-induced PR_max were 64% and 75%, respectively. P2Y12 reaction unit (PRU) was 274±76, and 69.8% (n =150) showed PRU ≥240. A carrier of at least one CYP2C19 variant allele showed higher PRs than non-carriers. In multivariate regression analysis, carriage of the CYP2C19 variant allele (^*2 or ^*3) was determined to be a significant predictor of HPPR (odds ratio 4.202, 95% confidence interval 1.996 to 8.850, p< 0.001).
Conclusions: Korean patients undergoing scheduled PCI cannot achieve adequate pre-procedural platelet inhibition from a 300-mg LD of clopidogrel, which is related with a higher prevalence of the CYP2C19 mutant allele.

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Aim: No previous studies have evaluated the long-term anti-atherosclerotic effects of pioglitazone in Asian patients with type 2 diabetes. Therefore, the present study investigated the protective effects of pioglitazone on the progression of carotid intima-media thickness (IMT), an established surrogate marker of cardiovascular events in Japanese type 2 diabetic patients without a recent history of cardiovascular morbidity.
Methods: This 2.5?4-year, randomized, open-label, blinded endpoint study was conducted in 6 centers across Japan. Patients received pioglitazone with or without other oral glucose-lowering drugs (excluding another thiazolidinedione) (n=89) or oral glucose-lowering drugs, excluding thiazolidinediones (n=97). Treatment was adjusted to achieve HbA_1c <6.5%. The primary endpoints of the study were the absolute changes from the baseline to final visit in max- and mean-IMT in the average of bilateral common carotid arteries.
Results: Pioglitazone induced carotid IMT regression compared to baseline measurements (from 1.060±0.2368 to 0.992±0.1921 mm; p=0.0042 in max-IMT and from 0.839±0.1873 to 0.780±0.1571 mm; p=0.0019 in mean-IMT). Although the between-group difference did not reach statistical significance, the regression of carotid IMT values was greater in the pioglitazone-treatment group than in the non-pioglitazone group, (max-IMT: -0.069±0.2199 mm vs -0.031±0.2327 mm, respectively; p=NS, mean-IMT: -0.058±0.1718 mm vs -0.043±0.1644 mm, respectively; p=NS).
Conclusions: Pioglitazone induced and maintained the long-term regression of carotid IMT in Japanese type 2 diabetic patients. This suggests that pioglitazone may inhibit the progression of atherosclerosis in this patient group. Further studies are required to verify these findings.

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Aims: Renal dysfunction is a major public health problem, but there have been few investigations of the relationship between serum high molecular weight (HMW) adiponectin and renal function in Japanese community-dwelling adults.
Methods: We randomly recruited a sample of 1,849 adult Japanese (793 men aged 60±14 (mean±standard deviation; range, 20-89) years and 1,056 women aged 62±12 (range, 21-88) years) during their annual health examination in a single community. Participants with an eGFR of ≥ 60 mL/ min/1.73 m² were divided into four groups based on quartiles of serum HMW adiponectin levels, and it was investigated whether serum HMW adiponectin is independently associated with eGFR.
Results: Mean eGFR was significantly higher in the highest quartile than the lowest quartile of serum HMW adiponectin levels. Stepwise multiple linear regression analysis using eGFR as an objective variable, adjusted for confounding factors as explanatory variables, showed that serum HMW adiponectin (β=0.068) as well as age (β=-0.361), prevalence of antihypertensive medication (β=-0.115), triglycerides (β=-0.063), low-density lipoprotein cholesterol (β=-0.094), and fasting plasma glucose (β=0.148) were independently associated with eGFR. The multivariate-adjusted odds ratio for mild renal dysfunction of an eGFR < 70 mL/min/1.73 m² was 0.62 (95% CI, 0.42-0.91) for the highest quartile compared with participants with the lowest serum adiponectin quartile.
Conclusions: We conclude that a higher serum HMW adiponectin level is associated with a reduced odds ratio of mild renal dysfunction in Japanese adults.

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Aim: Peroxisome proliferator-activated receptor (PPAR) α is a nuclear receptor that through sensing fatty acid metabolites as ligands regulates genes involved in lipid transport and metabolism (Atherosclerosis 205: 413, 2009). Disruption of the PPARα gene, however, may not lead to apparent changes in phenotypes, perhaps due to compensation by other members of the nuclear receptor superfamily. We characterized cholesterol homeostasis in PPARα-null mice on a C57BL/6 background with a focus on HDL metabolism.
Methods and Results: PPARα-null mice gained weight significantly more than wild-type mice, with more prominence in females, without changing the HDL-apoprotein clearance rate. Clearance of plasma HDL-cholesteryl ester was retarded, more prominently in females. Uptake of HDL-cholesteryl ester by the adrenal glands and ovaries was found to be decreased in female mutant mice. The ATP binding cassette transporter A1 (ABCA1), liver X receptor α and PPARδ mRNAs were decreased in the liver, and that encoding scavenger receptor B1 (SR-B1) decreased in the adrenal glands of these mice. Although the plasma lipoprotein profile did not show major differences, some subtle changes were found in the mutants, including HDL properties being consistent with its slow turnover. Cholesterol content in the organs was not significantly influenced except for a paradoxical increase in gonad glands.
Conclusions: We conclude that the plasma HDL turnover rate is retarded in PPARα-null mice, perhaps more prominently in females.

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Aim: To examine the effects of supervised aerobic exercise training on serum adiponectin and lipids, including triglyceride (TG)-rich lipoproteins, in moderate dyslipidemic subjects.
Methods: Twenty-five dyslipidemic patients [mean body mass index (BMI)=24.6 kg/m²; mean age= 39 years; mean total cholesterol=226 mg/dL; mean TG=149 mg/dL] without metabolic syndrome, diabetes, and hypertension underwent supervised aerobic exercise training (60 min/day, 2 to 3 times/week) at an intensity of 60-80% of age-predicted maximal heart rate for 16 weeks. Lipoprotein cho-lesterol levels were measured by our established anion-exchange HPLC method.
Results: Aerobic exercise training significantly decreased BMI, cholesterol levels of LDL- and IDL-, and markedly reduced VLDL-cholesterol at week 8 (-45%) and week 16 (-50%), but changes in TG and HDL-cholesterol were not significant. Adiponectin significantly increased by 51% and HOMA-R was significantly decreased at week 16, although changes in these parameters were not sig-nificant at week 8. There was no significant relationship between changes in adiponectin and in VLDL- or IDL- cholesterol, but changes in adiponectin were inversely but insignificantly associated with changes in BMI (r=-0.343, p=0.095).
Conclusions: These results suggest that supervised aerobic exercise training two to three times/week in the presence of body weight loss increases serum adiponectin with an improved lipid profile and insulin sensitivity at week 16 in non-obese moderate dyslipidemic patients, and that VLDL-choles-terol is markedly decreased by supervised aerobic exercise training.

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Aim: Little is known about the impact of having one cardiovascular (CV) risk factor on the levels of other CV risk factors in the general adolescent population. We hypothesized that when adolescents have one CV risk factor, the levels of other CV risk factors worsen simultaneously.
Methods: Subjects consisted of 1,257 healthy adolescent volunteers (549 males and 708 females) aged 15-18 years. Abdominal obesity, hypertension, raised triglyceride levels, decreased HDL-cholesterol levels and hyperglycemia were used as CV risk factors. Homeostasis assessment of insulin resistance (HOMA-IR) was used as a surrogate marker of insulin resistance. Levels of four biomarkers, leptin, adiponectin, high-sensitive C-reactive protein, and desacyl-ghrelin, were also determined. Cut-offs for gender-specific individual CV risk factor levels were based on the 90th (or 10th) percentile values of the subjects in the present study.
Results: The levels of all CV risk factors and HOMA-IR significantly and simultaneously worsened when adolescents had one CV risk factor in both genders. Having any one CV risk factor indicated the development of other CV risk factors in adolescents; in particular, we found that the development of abdominal obesity in male subjects had a harmful effect on the levels of other CV risk factors and was associated with the worsening of all four biomarkers examined.
Conclusions: It is important to determine the presence or absence of these CV risk factors before and/or during adolescence, because having one CV risk factor indicates the start of an accumulation of CV risk factors in the general adolescent population.

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Aim: To evaluate the effects of HMG-CoA reductase inhibitor (statin) treatment on serum inflammatory markers using data from the National Health and Nutrition Examination Survey (NHANES 1999-2004).
Methods and Results: A total of 9,128 individuals aged 40 and older participated in the NHANES. The inflammatory markers studied were white blood cell counts (WBC), high sensitivity C-reactive protein (CRP) and ferritin. Other covariables were: age, gender, race/ethnicity, body mass index, prescription or nonprescription medication use within the previous 30 days (statins, anti-inflammatory drugs, antibiotics). Four analytic groups for drug use were defined: Statin users; AI/Antibiotic users (use of either anti-inflammatory or antibiotic drugs); Combination group (use of both Statins and anti-inflammatory or antibiotic drugs), and a Non-use group (taking none of the listed drugs). The mean CRP level was significantly lower in the Statin use group than the Non-use group (0.3 mg/dL, 95%CI: 0.3-0.3 and 0.4 mg/dL, 95%CI: 0.4-0.5). In multivariable regression modeling, the Statin use group had significantly lower predicted mean WBC (Beta Coeff: -0.2, p < 0.05) and CRP (Beta Coeff: -0.1, p < 0.01) values than the Non-use group.
Conclusions: Treatment with statins was significantly associated with decreased WBC and CRP levels in this large population-based sample.

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Aims: We studied the effect of insulin on HDL-mediated cholesterol efflux from macrophages. The potential involvement of cholesteryl ester hydrolysis and membrane cholesterol transport was also addressed.
Methods: Human monocyte-derived THP-1 cells were developed into macrophages. Cholesterol efflux was measured by incubating macrophages, labeled with [³H]-cholesterol, with HDL for 24 h. The cells were treated with insulin (0-500 nM) for 30 min prior to the addition of HDL. To investigate the molecular mechanisms of the effect of insulin, the expressions of neutral cholesteryl ester hydrolase (nCEH) and ATP-binding cassette transporter (ABC) G1 were analyzed.
Results: Insulin inhibited, in a concentration-dependent manner, HDL-mediated cholesterol efflux from macrophages. Insulin also inhibited the enzyme activity of nCEH and its mRNA and protein expression in cells. Insulin also suppressed the expressions of mRNA and protein for ABCG1.
Conclusions: Insulin inhibits HDL-mediated cholesterol efflux from macrophages, which may result from the suppression of nCEH and ABCG1 expressions. Our findings show part of the potential molecular mechanism of atherogenesis in type 2 diabetes with hyperinsulinemia.

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Aim: Determination of the functional capability of the peripheral arteries is increasingly used as an early marker of vessel disease. The aim of this study was to evaluate flow-mediated (FMD) and glyceryl trinitrate-mediated (NMD) dilation of the brachial artery in patients with idiopathic venous thrombosis (VT).
Methods: Flow-mediated brachial artery dilatation and the dilatation response to glyceryl trinitrate were measured using high-resolution ultrasound in 97 subjects (49 eligible patients of both sexes, mean age 51.5±14.6 years, with idiopathic venous thrombosis, and 48 age-matched healthy controls).
Results: Compared to the control group, FMD was significantly reduced in the group of patients with idiopathic venous thrombosis -4.9% (95% CI 1.1-8.7%) vs. 12.7% (95% CI 7.8-17.6%), p<0.001. Patients also had diminished NMD of the brachial artery -12.5% (95% CI 6.6-18.4%) vs. 18.5% (95% CI 10.1-26.9%), p<0.001. In patients, significantly higher levels of circulatory markers (P-selectin, von Willebrand factor) of endothelial dysfunction were registered.
Conclusions: Idiopathic venous thrombosis is associated with impaired flow- and GTN-mediated vasodilatory response of the brachial artery. This may suggest involvement of the functional deterioration of the vessel wall in the pathogenesis of idiopathic VT and indicate a relationship between VT and atherothrombosis.

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