Atherosclerosis has been recognized as an inflammatory disease of the arterial wall, involving innate and adaptive immunity. Effector T cells are differentiated from naïve T cells stimulated by antigen-presenting cells such as macrophages and dendritic cells (DCs) and play critical roles in atherogenesis. Accumulating evidence revealed that several subsets of regulatory T cells (Tregs) inhibit atherosclerotic lesion formation via inhibiting the inflammatory response of effector T cells. In addition, the contribution of DCs to atherogenesis has been demonstrated. DCs have different functions for either stimulating or inhibiting T cell function depending on their origin and maturation stage. In particular, immature DCs, which have potential for inducing Tregs and inhibiting effector T cells, are sometimes called ‘tolerogenic DCs’ and suppress immune responses. Epidemiological studies have highlighted the increasing prevalence of vitamin D₃ deficiency and its association with increased risks of cardiovascular diseases. Some studies have raised interest in the immunomodulatory properties of vitamin D₃ beyond its well-established role in bone and calcium metabolism. The active form of vitamin D₃ (calcitriol) induces Tregs and tolerogenic DCs, which are both involved in maintaining immunologic tolerance to self and harmless antigens. Interestingly, recent evidence suggested that DCs in the intestinal immune system are involved in inducing Tregs; modulating the function of DCs and Tregs in the intestinal immune system might have beneficial effects on atherosclerosis. In this review, we focus on the function of DCs in vascular diseases and discuss vitamin D₃ therapy for the prevention of atherosclerosis.

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Aim: Factor VII activating protease (FSAP) is a plasma serine protease involved in hemostasis and remodeling processes. Increased levels of circulating FSAP during pregnancy and in women using oral contraceptives (OCs) indicate that the hormonal status critically influences FSAP expression. In this respect, the aim of this study was to quantify nicotine modulation of FSAP expression in human monocytes/macrophages isolated from healthy female smokers and non-smokers, and from women who use OCs and smoke.
Methods: FSAP concentration and activity were measured in plasma samples obtained from healthy non-pregnant, pre-menopausal, non-smoking women who did not use OCs (n=69), non-pregnant, pre-menopausal women who currently smoke and use OCs (n=43), and women who are only smokers (n=40) or currently use OCs (n=48). Expressions of FSAP mRNA and protein in monocytes isolated from healthy non-pregnant female or healthy male donors were analyzed.
Results: Strongest circulating FSAP concentration and activity occurred in women with combined smoking and use of OCs compared to the control group. Enhanced FSAP levels were also observed in smoking women when compared to non-smokers. Ex vivo experiments demonstrated enhanced FSAP expression in monocytes isolated from women using OCs and currently smoking. Nicotine enhanced FSAP mRNA and protein levels in monocytes.
Conclusions: Monocytes from healthy female smokers show a constitutively enhanced FSAP expression and this effect could be replicated in vitro by stimulating monocytes with nicotine. The upregulation of FSAP due to nicotine and OC usage may be linked to a higher incidence of arteriothromboembolic diseases related to their usage.

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Aim: The SYNTAX score is a semi-quantitative angiographic tool used to determine the extent and severity of coronary artery disease (CAD). Automatic computer-assisted measurement of the brachial-ankle pulse wave velocity (baPWV) is a reproducible and valid method by which to assess arterial stiffness. Limited information is available for the association between the SYNTAX score and arterial stiffness in a CAD patient. We aim to assess the association between arterial stiffness determined by PWV and CAD severity assessed by angiography and the SYNTAX score.
Methods: 321 subjects underwent measurement of both baPWV and angiography from 2010 to 2011. BaPWV was divided into tertiles. Multiple logistic and linear regression analyses were used to evaluate the relationship between the SYNTAX score and baPWV.
Results: After adjusting for age, body mass index, smoking habits, family history of CAD, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), total cholesterol, triglycerides, LDL-cholesterol, fasting glucose, serum creatinine, uric acid and cysteine proteinase, analyses revealed that baPWV groups were significantly associated with the SYNTAX score. Compared with the lowest baPWV tertile, the adjusted odds ratios (ORs) of having a SYNTAXHIG for the MID and HIG baPWV tertiles were 4.76 (95% confidence interval: 1.71-6.33) and 4.13 (95% confidence interval: 1.12-5.27), respectively. We also used multiple linear regression analyses to assess the association between baPWV and the SYNTAX score, which showed that baPWV was associated with the SYNTAX score.
Conclusion: Arterial stiffness determined by PWV is related to CAD severity assessed by angiography and the SYNTAX score.

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Aims: Although several surrogate measures of insulin resistance have been proposed, their associations with cardiovascular disease (CVD) have not been evaluated sufficiently.
Methods: A total of 2,356 community-dwelling Japanese individuals aged 40 to 79 years who underwent a 75 g oral glucose tolerance test were followed up for 14 years. The status of insulin resistance was estimated by using the Matsuda index or homeostasis model assessment of insulin resistance (HOMA-IR).
Results: During follow-up, 260 subjects developed CVD. The age- and sex-adjusted hazard ratios of CVD significantly decreased with an increasing Matsuda index and rose with increasing HOMA-IR levels (both p for trend <0.05). After adjustment for age, sex, serum total cholesterol, electrocardiogram abnormalities, proteinuria, smoking habits, alcohol intake, and regular exercise, the risk of CVD was significantly lower in the third to fifth quintiles of the Matsuda index and higher in the fifth quintile of HOMA-IR values compared with the first quintile of the corresponding index (Matsuda index Q3: hazard ratio (HR)= 0.59 [95% confidence interval 0.40-0.87]; Q4: HR= 0.66 [0.45-0.97]; and Q5: HR= 0.67 [0.47-0.97]; HOMA-IR Q5: HR= 1.55 [1.05-2.29]); however, these associations were attenuated after further adjustment for the metabolic syndrome status. In regard to CVD subtypes, the risks for stroke and coronary heart disease significantly decreased with an increasing Matsuda index, while elevated HOMA-IR levels were a significant risk factor for stroke, but not for coronary heart disease.
Conclusion: Our findings suggest that insulin resistance significantly increases the risk of incident CVD through metabolic syndrome in Japanese.

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Aim: No prior studies have investigated the effects of dietary cholesterol oxidation products (oxysterols) on atherosclerotic plaque destabilization and rupture. We used an atherosclerotic mouse model with histological features similar to those seen in ruptured human plaques to test the hypothesis that (1) dietary oxysterols accelerate plaque destabilization and rupture and (2) a NPC1L1 inhibitor, ezetimibe, has therapeutic effects on these processes.
Methods and Results: Advanced atherosclerotic plaques were examined in innominate arteries of ApoE^-/- mice that were fed either a regular high-fat diet (HFD) or HFD containing oxysterols (oxysterol-HFD; 6.8% of added cholesterol was oxidized) and infused with angiotensin II. Compared with HFD, oxysterol-HFD did not affect plasma lipid levels but did accelerate plaque destabilization and rupture, which was associated with increased monocyte infiltration/activation, monocyte chemoattractant protein-1 (MCP-1) expression, and matrix metalloproteinase (MMP) activity. Dietary oxysterol-induced plaque destabilization and rupture were blunted in ApoE^-/- CCR2^-/- mice. Oral treatment with ezetimibe, significantly decreased plasma lipid levels and prevented the acceleration of plaque destabilization and rupture induced by dietary oxysterol. These data indicate a primary role for monocyte-mediated inflammation via the MCP-1-CCR2 pathway and the resultant increase in MMP activity in plaque destabilization and rupture induced by dietary oxysterols in ApoE^-/- mice. These data also provide a mechanism by which dietary oxysterols are connected with the pathogenesis of plaque destabilization and rupture.
Conclusions: These data suggest that inhibition of the absorption of oxysterols by ezetimibe may be useful for the treatment of high-risk patients with high oxysterol intake.

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Aim: To determine whether there is a significant correlation between optic nerve head circulation determined by pulse wave analysis of laser speckle flowgraphy (LSFG), and the cardio-ankle vascular index (CAVI), left ventricular (LV) function, and age.
Methods: Forty-nine men who visited the Vascular Function Section of Toho University Sakura Medical Center, Chiba, Japan were studied. The mean age of the subjects was 60.7±10.6 years (range 29 to 80 years). The CAVI, left ventricular ejection fraction (LVEF) as a function of the systolic LV function, early diastolic mitral annulus velocity (e'), and the ratio of transmitral early peak velocity (E) to e' (E/e' ratio) as the diastolic LV function, and the optic nerve head circulation determined by pulse wave analysis of the LSFG. This parameter was named the blowout time (BOT).
Results: The BOT was significantly correlated with age, heart rate, body mass index (BMI), triglyceride, LVEF, e' velocity, E/e' ratio, and CAVI. The results of multiple regression analysis showed that age was significantly associated with CAVI (r= 0.36, p=0.002), BOT (r=−0.30, p=0.01) and e' velocity (r=−0.21, p=0.04).
Conclusions: The BOT of the optic nerve head circulation determined by LSFG was significantly correlated with age but was independent of cardiac diastolic function and arterial stiffness. This suggests that the damage to different organs increases with age. Our results confirmed that BOT can be helpful in evaluating physiological aging of the microcirculation.

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Aim: Visceral fat accumulation is associated with obesity-related cardiovascular risk factor accumulation and atherosclerosis. The present study investigated whether one-year reduction of the visceral fat area (VFA) correlates with a decrease in the number of such factors in Japanese with or without visceral fat accumulation.
Methods: The study subjects comprised 5,347 Japanese, who underwent health check-ups in 2007 and 2008, including measurements of VFA and subcutaneous fat area (SFA) by computed tomography at 9 centers in Japan. Subjects with one or more such factor(s) were categorized into tertiles based on the one-year change in VFA. We investigated the multivariate age, sex, and one-year change in SFA-adjusted odds ratios (ORs) and 95% confidence intervals (CI) for reductions in the number of risk factors in each of the three categories based on the one-year change in VFA, in subjects with one or more such factors (n= 3,648).
Results: In the entire group (n=3,648), the OR and 95%CI for reductions in the number of risk factors in the first tertile were 0.804 (0.673-0.962, p=0.0172), compared with the second tertile set at 1.0. Subjects with VFA <100cm² showed no reduction in the number of risk factors. In subjects with VFA≥100 cm², OR in the first tertile was 0.788 (0.639-0.972, p=0.0257) relative to the second tertile set at 1.0.
Conclusions: In subjects with multiple cardiovascular risk factors, visceral fat reduction correlated with a decrease in the number of such factors in subjects with VFA≥100cm², but not in those with VFA<100cm².

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Aim: Heterozygous patients of familial hypercholesterolemia (FH) are known to have a high risk of coronary artery disease (CAD). Early diagnosis and prompt treatment are necessary to prevent their CAD. In this study we tried to amend the Japanese diagnostic criteria of FH for general practitioners by examining each component of the current criteria.
Methods: A multicenter study was performed, which included 1356 dyslipidemic patients at 6 centers. Pretreatment demographic information including LDL-cholesterol (LDL-C), Achilles tendon thickness (ATT), family history of FH and premature CAD and the result of genetic analysis were analyzed.
Results: Of 1356 patients, 419 were diagnosed with FH by criteria in 1988, which were used as a golden standard. We tried to define FH according to 3 conventional major items, i.e., 1) LDL-C, 2) ATT and/or cutaneous nodular xanthomas (CX), 3) family history of FH and/or family history of premature CAD. We then determined the cutoff of LDL-C using the new criteria. When we used 180 mg/dL as the cutoff of LDL-C, 94.3% of FH patients and 0.85% of non-FH satisfied 2 or more criteria. When we used 190 mg/dL, 92.1% of FH and 0.85% of non-FH satisfied 2 or more criteria; therefore, we chose 180 mg/dL for the cutoff of LDL-C in the new criteria and proposed that the diagnosis of definite FH can be made if 2 or more criteria are satisfied.
Conclusions: We examined each component for the diagnosis of heterozygous FH in a multicenter study in Japan.

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Aim: High-sensitivity C-reactive protein (hs-CRP) identifies individuals at risk for cardiovascular disease (CVD) without an increased level of low-density lipoprotein cholesterol (LDL-C). The present study was performed to compare hs-CRP and LDL-C in association with the cardio-ankle vascular index (CAVI) in Japanese community dwellers considered to be at low risk for atherosclerosis from their level of traditional CVD risk factors.
Methods: A community-based study involving 386 healthy Japanese (261 men and 125 women) without a history of CVD and medications for hypertension, diabetes, and dyslipidemia was performed. Multiple adjustments were performed with linear regression models to estimate the association between CAVI and hs-CRP or LDL-C levels. The participants were divided into four groups on the basis of whether they were above or below the median hs-CRP and LDL-C values, and CAVI was compared among the four groups by analysis of covariance after adjusting for confounders.
Results: In multiple linear regression models, hs-CRP showed a significant positive association with CAVI; however, no clear association was observed between CAVI and LDL-C. These results were similar in the analyses among the participants with LDL-C <140 mg/dL or hs-CRP <1.0 mg/L. CAVI was higher in the groups with high hs-CRP than in those with low hs-CRP, irrespective of LDL-C; however, CAVI was highest in the group with high LDL-C and high hs-CRP.
Conclusions: The present study suggests that hs-CRP could be a better risk factor assessor for atherosclerosis than LDL-C in individuals considered to be at low risk for atherosclerosis assessed by their traditional CVD risk factors.

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Aim: Understanding factors that contribute to changes in arterial stiffness over time is important as this may lead to therapies that can abrogate cardiovascular risk. We compared the contribution of pulsatile stress and inflammation to changes in arterial stiffness in middle-aged men using a 1-year follow-up study design.
Methods: Arterial stiffness was derived from brachial-ankle pulse wave velocity (baPWV) in 107 men (mean age 53±6 yrs) on two separate occasions. The changes in outcome variables were calculated as the difference between the first and second examinations (mean interval 403±122 days). Pulsatile stress was calculated as the product of heart rate and brachial pulse pressure. C-reactive protein (CRP), white blood cell count (WBC) and fibrinogen were measured as inflammatory markers.
Results: At baseline, baPWV was significantly correlated with pulsatile stress (r=0.37, p<0.01), WBC (r=0.19, p<0.05), HbA1c (r=0.39, p<0.01), HDL-C (r=.0.20, p<0.05), but not CRP (r= 0.06, p=0.56), or fibrinogen (r=0.12, p=0.21). The change in baPWV over 1 year was associated with the change in pulsatile stress (r=0.26, p<0.01) and HbA1c (r=0.19, p<0.05) over that same time period. Change in baPWV was not associated with the change in WBC (r=0.18, p=0.06) or CRP (r=0.05, p=0.62).
Conclusions: These results demonstrate that both pulsatile stress and inflammation may be associated with arterial stiffness at any given moment in time, but change in pulsatile stress is a better predictor of change in arterial stiffness over time.

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