Coronary artery calcification (CAC) is a well-established surrogate marker of the total burden of coronary atherosclerosis. The CAC score, as measured on coronary computed tomography (CT), is associated with the prevalence of coronary artery disease (CAD) as well as cardiovascular morbidity and mortality. The CAC score is used to reclassify coronary risks in asymptomatic individuals with intermediate risks. However, there are few clinical data regarding the usefulness of the CAC score for identifying high-risk Japanese patients. In this review article, we describe our previous studies of the prognostic value of the CAC score in patients with proven or suspected CAD. In addition, we reanalyzed our previous data for 723 patients with suspected CAD and found both all-cause and cardiovascular disease mortality to be significantly higher among the patients with a CAC score of ≥100 than among those with a CAC score of ＜100. Several studies from Japan have also shown that the CAC score is associated with the prevalence of obstructive CAD, as demonstrated on invasive coronary angiography or stress myocardial perfusion imaging. Furthermore, the CAC score provides useful information for performing coronary CT angiography, as asymptomatic patients without CAC are expected to have favorable outcomes. In contrast, the diagnostic accuracy is decreased in patients with a high CAC score (＞400 or 600). In conclusion, the CAC score may have useful clinical applications in symptomatic and asymptomatic Japanese individuals. However, further studies are required to evaluate the prognostic value of this parameter for predicting cardiovascular morbidity and mortality in population-based analyses of asymptomatic Japanese subjects.

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Aim: The aim of this study was to assess whether rs1333049 was associated with coronary heart disease (CHD) in Han Chinese.
Methods: This case-control study was involved with 599 CHD patients and 591 non-CHD controls. Meanwhile, a comprehensive meta-analysis was also conducted to establish the contribution of rs1333049 to CHD.
Results: Our results showed that rs1333049 increased the risk of CHD by 38% (OR=1.38, 95% CI=1.18-1.62). A breakdown analysis by gender further indicated that rs1333049 increased the risk of CHD in men by 29% (OR=1.29, 95% CI=1.05-1.58) and in women by 64% (OR=1.64, 95% CI=1.25-2.16). A follow-up subgroup analysis by age showed there was a significant association between rs1333049 and CHD in women younger than 65 (≤55 years: p=0.001, 55-65 years: p=0.008) and in men aged between 55 and 65 years (p=0.005). Our meta-analysis was involved with 21 studies (25 stages) among 20969 cases and 34114 controls. Our results showed that rs1333049 led to a significantly increased risk of CHD (OR=1.30, 95% CI=1.21-1.39). Further subgroup analyses by ethnicity showed rs1333049 increased the CHD risk by 30% in Europeans (OR=1.30, 95% CI=1.16-1.47) and 27% in Asians (OR=1.27, 95% CI=1.22-1.33).
Conclusions: Our case-control study and meta-analysis suggest that rs1333049 is a useful risk marker of CHD.

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Aim: Proton pump inhibitor (PPI) therapy has been shown to attenuate the antiplatelet effects of clopidogrel. The aim of this study was to compare the antiplatelet effects of cilostazol versus clopidogrel in patients co-administered a PPI.
Methods: We enrolled PPI-naïve stented patients treated with standard clopidogrel and aspirin therapy for at least six months (n=100). The patients were randomly assigned to receive either cilostazol at a dose of 100mg twice daily (CILO group) or clopidogrel at a dose of 75mg daily (CLPD group) in addition to lansoprazole (30mg daily). The platelet aggregation (PA) determined using light transmittance aggregometry and the platelet reactivity index (PRI) obtained using a vasodilator-stimulated phosphoprotein phosphorylation assay were measured before randomization and at the 14-day follow-up visit. The primary endpoint was the PRI value at follow-up.
Results: At follow-up, the CLPD group showed similar values of PRI as the CILO group (66.9±14.0% vs. 63.1±14.1%; mean difference: 3.9%; 95% confidence interval of difference: −1.7% to 9.4%; p=0.174). However, the 6μg/mL collagen- and 0.5mg/mL arachidonic acid-induced PA values in the CLPD group were higher than those observed in the CILO group (mean differences: 9.8% to 11.1%; all p values ＜0.001). CYP2C19 loss-of-function allele carriage was the major contributing factor associated with the PRI level in the absence of lansoprazole treatment (with a gene-dose effect); this association was not observed in the subjects receiving lansoprazole co-administration in the CLPD group.
Conclusions: During lansoprazole co-administration, cilostazol treatment achieves a more favorable platelet function profile than clopidogrel therapy. The use of combination treatment with cilostazol and aspirin deserves further attention with respect to the management of stable stented patients requiring PPI co-administration.

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Aim: It has been reported that oxidized low-density lipoprotein (oxLDL) forms a stable and non-dissociable complex with β₂-glycoprotein I (β₂GPI) and that IgG anti-β₂GPI autoantibodies are able to recognize this complex, thus facilitating macrophage-derived foam cell formation in patients with antiphospholipid syndrome (APS). However, the immunopathological mechanisms of oxLDL/β₂GPI complexes in promoting foam cell formation are not fully understood. In this study, we examined the role of toll-like receptor 4 (TLR4) in the oxLDL/β₂GPI/anti-β₂GPI complex-induced transformation of mouse peritoneal macrophages to foam cells.
Methods: Oil red O staining and optical density (OD) measurements of intracellular stained oil red O solution were used to monitor the transformation of peritoneal macrophages to foam cells in TLR4-competent C3H/HeN and TLR4-mutant C3H/HeJ mice. During foam cell formation induced by the oxLDL/β₂GPI/anti-β₂GPI complex, the expression of TLR4 and activation of nuclear factor kappa B (NF-κB) were confirmed by analyzing the protein and mRNA levels of these compounds. Furthermore, the related active molecule expression during foam cell formation induced by the oxLDL/β₂GPI/anti-β₂GPI complex was examined in the presence or absence of TLR4.
Results: The data showed that treatment with the oxLDL/β₂GPI/anti-β₂GPI complex markedly increased foam cell formation, the TLR4 expression, NF-κB activation, the tissue factor (TF) expression and tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1) secretion in the C3H/HeN mice. However, the transformation of macrophages to foam cells and the expression levels of phosphorylated NF-κB, TF, TNF-α and MCP-1 were significantly reduced in the C3H/HeJ mice treated with the oxLDL/β₂GPI/anti-β₂GPI complex. In addition, compared with that achieved by oxLDL alone, the oxLDL/β₂GPI complex decreased foam cell formation and the related signaling molecule expression in the C3H/HeN mice.
Conclusions: Our results indicate that TLR4 plays an important role in the process of oxLDL/β₂GPI/anti-β₂GPI complex-induced transformation of macrophages to foam cells, which may accelerate the development of atherosclerosis in the setting of APS. However, β₂GPI alone functions as an antiatherogenic protein by preventing the foam cell formation induced by oxLDL.

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Aim: The levels of lipids, especially triglycerides (TG), and obesity are associated with diabetes mellitus (DM). Although typically measured in fasting individuals, non-fasting lipid measurements play an important role in predicting future DM. This study compared the predictive efficacy of lipid variables according to the fasting status and body mass index (BMI) category.
Methods: Data were collected for 39,196 nondiabetic men and 87,980 nondiabetic women 40-79years of age who underwent health checkups in Ibaraki-Prefecture, Japan in 1993 and were followed through 2007. The hazard ratios (HRs) for DM in relation to sex, the fasting status and BMI were estimated using a Cox proportional hazards model.
Results: A total of 8,867 participants, 4,012 men and 4,855 women, developed DM during a mean follow-up of 5.5 years. TG was found to be an independent predictor of incident DM in both fasting and non-fasting men and non-fasting women. The multivariable-adjusted HR for DM according to the TG quartile (Q) 4 vs. Q1 was 1.18 (95% confidence interval (CI): 1.05, 1.34) in the non-fasting men with a normal BMI (18.5-24.9). This trend was also observed in the non-fasting women with a normal BMI. That is, the multivariable-adjusted HRs for DM for TG Q2, Q3 and Q4 compared with Q1 were 1.07 (95% CI: 0.94, 1.23), 1.17 (95%CI: 1.03, 1.34) and 1.48 (95%CI: 1.30, 1.69), respectively.
Conclusions: The fasting and non-fasting TG levels in men and non-fasting TG levels in women are predictive of future DM among those with a normal BMI. Clinicians must pay attention to those individuals at high risk for DM.

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Aim: The aim of this study, the YOung TAiwanese Cohort (YOTA) Study, was to investigate the relationship between a childhood overweight/obese status and young adult preclinical atherosclerosis, including assessments of the carotid intima-media thickness (CIMT) and prehypertension or hypertension.
Methods: From among children who participated in the 1992-2000 mass urine screening program in Taiwan, we recruited 303 subjects with an elevated blood pressure (EBP) and 486 subjects with a normal BP in childhood during the period of 2006-2008. These 789 young adults received health check-ups for cardiovascular health, including examinations of blood and urine parameters, anthropometrics, BP and the CIMT, a subclinical cardiovascular risk index. Data analyses were used to evaluate the associated risks in both childhood and young adulthood.
Results: The school students with a childhood overweight/obese status had a higher risk of prehypertension or hypertension, with a relative risk of 3.20 (1.40-7.33) for being overweight and 6.51 (3.36-12.63) for being obese in young adulthood at an average age of 21. A childhood overweight/obese status also predicted a higher risk of having a thicker CIMT, with a relative risk of 2.82 (1.26-6.28) and 4.17 (2.21-7.85) for being overweight and obese in adulthood, respectively, after a mean follow-up of 8.5 years. The body mass index exhibited a consistent trend from childhood to adulthood, with an adjusted R square of 0.551. The participants who were not overweight/obese in childhood also demonstrated a higher risk of prehypertension or hypertension if they became overweight or obese in adulthood.
Conclusions: This study highlights the importance of preventing and treating an overweight or obese status in childhood for the primary prevention of cardiovascular disease in adulthood.

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Aim: Peripheral arterial disease (PAD), particularly critical limb ischemia (CLI), is a severe cause of amputation and mortality. More than 50% of diabetic patients with CLI die within four to five years. The development of novel stem cell therapies may bring new hope to these patients. We aimed to assess the efficacy of autologous bone marrow cell therapy for treating CLI using a meta-analysis.
Methods: We searched the literature in PubMed, the Cochrane Central Registry of Controlled Trials, the Elsevier database and EBSCO for trials of autologous cell therapy in patients with severe PAD published before October 30, 2013. We chose objective clinical endpoints to assess the efficacy of therapy in the meta-analysis, including changes in the ankle-brachial index (ABI), transcutaneous oxygen tension (TcO₂), pain scale (0-10 scale) and amputation-free survival (AFS).
Results: Thirty-one articles reporting clinical trials involving a total of 1,214 patients treated with bone marrow stem cell-based therapy were collected for the meta-analysis, in which the randomized controlled trials (RCTs) and other trials (non-RCTs) were classified into two groups. Regarding the efficacy of stem cell therapy, the ABI showed significant increases (P＜0.05) at 12 , 24 and 48 weeks after therapy in the non-RCT and RCT groups, but not after four to eight weeks in the non-RCT group. The TcO₂ values also increased in the RCT group at four to eight weeks after therapy and 24 weeks after therapy (P＜0.001) and in the non-RCT group at four to eight weeks after therapy (P= 0.01), although no significant increases were observed in the RCT group at 12 weeks after therapy or the non-RCT group at 24 weeks after therapy. Meanwhile, pain was significantly reduced (P＜0.05) at four to eight weeks and 24 weeks after therapy in both the non-RCT and RCT groups, but not at four to eight weeks or 12 weeks after therapy in the RCT group. In addition, the long-term clinical trials demonstrated that the AFS rate improved after therapy with bone marrow stem cells (one-year AFS, P＜0.00001; three-year AFS, P=0.0003).
Conclusions: The present results suggest that autologous bone marrow stem cells have an advantageous therapy effect in PAD patients who are not eligible for revascularization.

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Aim: Vitamin A plays a major role in lipid metabolism. Previously, we reported that chronic vitamin A feeding (129 mg/kg) for two months normalized the abnormally high plasma HDL-cholesterol (HDL-C) levels in hypercholesterolemic obese rats by upregulating the hepatic scavenger receptor class B type 1 (SR-BI) expression. In this report, we hypothesize that the administration of a dose less than 129 mg of vitamin A/kg would also be effective in lowering the plasma HDL-C levels in these rats.
Methods: Changes in the activity and expression of proteins related to RCT were analyzed together with blood parameters in five-month-old male lean and obese rats supplemented with 2.6 (control group), 26, 52 and 129 mg of vitamin A/kg as retinyl palmitate for 20 weeks.
Results: Vitamin A supplementation in the obese rats decreased the plasma HDL-C levels with a concomitant increase in the hepatic SR-BI expression and lipase activity compared to that observed in the control diet-fed obese rats treated with 2.6 mg of vitamin A/kg diet. Furthermore, vitamin A supplementation at doses of 52 and 129 mg/kg diet reduced the plasma lecithin cholesterol acyltransferase activity and increased the hepatic ATP-binding cassette transporter protein A1 expression in the obese rats. Interestingly, most of these changes were not observed in the lean rats fed a vitamin A-enriched diet.
Conclusions: Chronic feeding of a vitamin A-enriched diet in hypercholesterolemic obese rats normalizes the plasma HDL-C level and presumably improves RCT, with an effective dose of 52 mg/kg diet. Further studies should focus on the pharmacological potential of vitamin A supplementation to correct an abnormal human obesity-associated lipoprotein metabolism.

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Aim: Interleukin-1 receptor antagonist (IL-1Ra) negatively regulates IL-1 signaling by blocking the functional receptor. We previously demonstrated that IL-1Ra-deficient (IL-1Ra-/-) mice exhibit marked neointimal formation after injury. IL-1Ra is expressed on bone marrow (BM)-derived cells as well as non-BM intrinsic arterial cells. However, the importance of various cell types as sources of IL-1Ra remains unknown. The aim of this study was to test the hypothesis that IL-1Ra originating from BM-derived cells and non-BM intrinsic cells helps to suppress both inflammation and neointimal formation after vascular injury using a model of BM cell transplantation (BMT).
Methods: In order to determine the contribution of IL-1Ra-deficient (Ra-/-) and wild-type (WT) BM cells to neointimal formation, we developed four types of BM chimeric mice (BMT^WT→WT (n=12), BMT^Ra-/-→WT (n=12), BMT^WT→Ra-/- (n=12) and BMT^{Ra-/-→Ra-/-} (n=12)). At four weeks after BMT, we induced vascular injury by placing a non-occlusive cuff around the femoral artery. Histological analyses were subsequently performed two weeks after injury.
Results: Neointimal formation was decreased in the BMT^WT→Ra-/- mice compared with that observed in the BMT^{Ra-/-→Ra-/-} mice (p＜0.001), but significantly more so in the BMT^Ra-/-→WT (p＜0.01) and BMT^WT→WT (p＜0.01) mice. In contrast, the neointimal formation in the BMT^Ra-/-→WT mice was significantly increased compared with that noted in the BMT^WT→WT mice (p＜0.05). In addition, immunostaining revealed that Mac3-positive areas were significantly increased in the BMT^{Ra-/-→Ra-/-} mice compared with those seen in the other three groups (p＜0.001), with a significantly decreased percentage of alpha-SMA-positive areas in the neointima in the BMT^{Ra-/-→Ra-/-} mice compared with that found in the remaining groups (p＜0.001). Furthermore, IL-1Ra staining demonstrated the IL-1Ra expression in several inflammatory cells in the adventitia in the BMT^WT→WT and BMT^WT→Ra-/- mice, compared to the neointima in the BMT^WT→WT and BMT^Ra-/-→WT mice.
Conclusions: The IL-1Ra present in BM-derived cells and non-BM cells helps to suppress arterial inflammation, resulting in decreased neointimal formation after injury. These findings shed new light on the mechanisms underlying the development of atherosclerosis and restenosis after angioplasty.

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Aim: The Pan-Asian CEPHEUS study assessed low-density lipoprotein cholesterol (LDL-C) goal attainment among patients under lipid-lowering therapy. We compared Korean and other Asian data in order to investigate international variations in clinical practice in the field of cardiology.
Methods: Hypercholesterolemic patients ≥18 years of age who had been on lipid-lowering treatment for ≥3 months were recruited from eight Asian countries. The lipid concentrations were measured, and demographic and other relevant data were collected. In addition, the cardiovascular risk was determined using criteria established in the updated 2004 NCEP guidelines.
Results: In Korea, 92 cardiologists enrolled 1,584 patients. The data of these patients were compared with those for 2,060 patients enrolled by 135 cardiologists from other Asian countries in the CEPHEUS study. The proportion of high-risk patients, frequency of use of more potent LDL-C-lowering regimens and rate of LDL-C goal attainment were significantly greater in the Korean subjects than those observed in the other Asian populations. In addition, the Korean patients were more likely to achieve the LDL-C target (odds ratio=1.37, 95% confidence interval 1.11-1.70) after adjusting for the LDL-C target level, use of potent LDL-C-lowering regimens, the baseline LDL-C level, age and systolic blood pressure.
Conclusions: There was a significant difference in the goal attainment rate between Korea and the other Asian countries. Korean cardiologists appear to be relatively more aggressive with lipid-lowering treatment than other Asian cardiologists.

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