Aim: Smoking and adiponectin are individually associated with cardiometabolic pathologies. The present systematic review was carried out in order to summarize the association between the smoking status and circulating adiponectin levels.
Methods: Original articles, restricted to epidemiological studies (by a cross-sectional, case-control and cohort study design) and intervention studies for adult humans, were screened for the years 1995-2010. All of the research group members then selected the eligible literature and assessed the articles in a structured systematic review manner.
Results: There were 11 key studies, which included 9 articles with a cross-sectional design and 2 articles with an intervention design. Most cross-sectional studies reported lower levels of adiponectin in current smokers than in non/never smokers and/or ex-smokers, while 2 studies reported a non-significant difference in adiponectin between male smokers and non-smokers. The two intervention studies, conducted in patients on 9-week bupropion treatment and 6-month non-pharmacological treatment, reported that smoking cessation increased the adiponectin levels.
Conclusion: This review suggests that there is a decreased adiponectin level in current smokers and this reduction can be reversed by quitting smoking. More studies are required to confirm the findings and elucidate the biological mechanisms underlying the association between the smoking status and adiponectin levels.

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Aim: We evaluated the impact of adherence to preferable behavior on serum lipid control assessed by a self-reported questionnaire in high-risk patients taking pravastatin for primary prevention of coronary artery disease.
Methods: High-risk patients taking pravastatin were followed for 2 years. Questionnaire surveys comprising 21 questions, including 18 questions concerning awareness of health, and current status of diet, exercise, and drug therapy, were conducted at baseline and after 1 year. Potential domains were established by factor analysis from the results of questionnaires, and adherence scores were calculated in each domain. The relationship between adherence scores and lipid values during the 1-year treatment period was analyzed by each domain using multiple regression analysis.
Results: A total of 5,792 patients taking pravastatin were included in the analysis. Multiple regression analysis showed a significant correlation in terms of “Intake of high fat/cholesterol/sugar foods” (regression coefficient −0.58, p=0.0105) and “Adherence to instructions for drug therapy” (regression coefficient −6.61, p<0.0001). Low-density lipoprotein cholesterol (LDL-C) values were significantly lower in patients who had an increase in the adherence score in the “Awareness of health” domain compared with those with a decreased score. There was a significant correlation between high-density lipoprotein (HDL-C) values and “Awareness of health” (regression coefficient 0.26; p= 0.0037), “Preferable dietary behaviors” (regression coefficient 0.75; p<0.0001), and “Exercise” (regression coefficient 0.73; p= 0.0002). Similar relations were seen with triglycerides.
Conclusion: In patients who have a high awareness of their health, a positive attitude toward lipid-lowering treatment including diet, exercise, and high adherence to drug therapy, is related with favorable overall lipid control even in patients under treatment with pravastatin.

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Aim: To investigate the association among insulin sensitivity, insulin secretion, beta cell function and coronary artery disease (CAD) in patients with normal glucose tolerance.
Methods: One hundred eighty-nine patients with normal glucose tolerance (NGT) participated in this study and underwent coronary angiography. We estimated the severity of CAD by counting the number of diseased vessels and Gensini score using coronary angiography. The HOMA-IR index and Matsuda index were used to estimate insulin sensitivity. Insulin secretion was assessed using the HOMA-β index, insulinogenic index and AUC-insulin/glucose. Beta cell function was assessed using the basal disposition index, early-phase disposition index and total disposition index. We finally determined the relationship between CAD and these indices.
Results: There were statistically significant differences in the HOMA-IR, Matsuda index, basal disposition index, early-phase disposition index and total disposition index both in the single- and multiple-diseased vessel groups when compared to the 0-diseased vessel group; however, there was no significant difference between the single- and multiple- diseased vessel groups. Moreover, HOMA-β, the insulinogenic index and AUC-ins/glu showed no significant difference among the three groups. Multivariate logistic regression analysis suggested that the HOMA-IR, Matsuda index, early-phase disposition index and total disposition index were independent risk factors for the presence of CAD.
Conclusion: Insulin resistance and beta cell function were closely related to the incidence of CAD in patients with normal glucose tolerance.

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Aim: The enlargement of visceral adipose tissue (VAT) is considered to mediate the close relationship between obesity and insulin resistance. We aimed to determine whether a stronger association of VAT compared to subcutaneous adipose tissue (SAT) with insulin resistance could be confirmed and generalized in non-diabetic Japanese men and women.
Methods: Participants were 912 non-diabetic Japanese (636 men and 276 women, mean age 52.4±7.0 years, and mean BMI 24.9±3.1 kg/m²). VAT and SAT were measured through the use of computed tomography scanning. Homeostatic model for the assessment of insulin resistance (HOMA-IR) and Matsuda insulin sensitivity index (ISI) were calculated based on results from the oral glucose tolerance test.
Results: For both genders, subjects in higher tertiles of SAT as well as VAT showed significantly higher levels of HOMA-IR and lower levels of Matsuda ISI (p<0.001). In multiple regression analyses with VAT and SAT included in the model, only VAT, but not SAT, was independently associated with Matsuda ISI in women (p<0.001), whereas both SAT and VAT were independently associated with HOMA-IR and with Matsuda ISI in men (p<0.001). When VAT and waist circumference were jointly included in the model, only VAT, but not waist circumference, was independently associated with Matsuda ISI in women (p<0.001) but not in men.
Conclusion: VAT had a stronger association with insulin resistance than SAT or waist circumference in women but not in men. BMI showed a comparable association with insulin resistance to VAT in this population.

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Aim: Apolipoprotein A-I (apoA-I), the major component of high-density lipoprotein (HDL), has been recently found to suppress inflammation. This study was to investigate the effects and potential mechanisms of apoA-I on the CD40/CD40 ligand (CD40L) proinflammatory signaling pathway.
Methods: Human THP-1 macrophage-derived foam cells were treated with sCD40L alone or in the presence of apoA-I. Secretion of proinflammatory cytokines was performed by enzyme-linked immunosorbent assay(ELISA). The proteins and mRNA expression were examined by western-blot and real-time PCR analysis, respectly Cholesterol efflux was assessed by liquid scintillation counting. Cholesterol depletion of macrophages was performed with methylated β-cyclodextrin.
Results: ApoA-I inhibits the inflammatory response stimulated by soluble CD40L (sCD40L) in macrophages. In addition, apoA-I inhibited the sCD40L-stimulated activation of nuclear factor-kB (NF-kB). The apoA-I-induced NF-kB deactivation was related to the decreased recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF-6), a crucial adapter protein for CD40 in macrophages, to lipid rafts after being treated by sCD40L. When interfering the expression of ATP-binding cassette transporter A1 (ABCA1), a major cholesterol transporter for apoA-I in macrophages, it could significantly diminish the effect of apoA-I on the sCD40L-stimulated inflammatory response.
Conclusion: ApoA-I suppresses CD40 proinflammatory signaling in macrophages by preventing TRAF-6 translocation to lipid rafts through ABCA1-dependent regulation of free cholesterol (FC) efflux, which may present a novel mechanism of apoA-I-mediated inflammation inhibition in macrophages.

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Aim: To understand the differences between histopathological characteristics related to PTX3 (pentraxin 3) and CRP (C-reactive protein) in coronary atherosclerotic plaques.
Methods and Results: To assess the localization of PTX3 and CRP in coronary plaque, immunohistochemistry was performed using 157 coronary artery specimens from 45 autopsied cases. Overall, immunoreactivity to CRP was more intense than that to PTX3 in lipid rich plaque; however, PTX3 was notably abundant in areas of intraplaque hemorrhage, in which CRP was quite sparse. On quantitative analysis, complicated plaques showed more immunopositive area of PTX3 than fibroatheroma, but with CRP, this trend disappeared. In addition, we examined the phenotype of macrophages in PTX3- and CRP-rich areas using CD163 staining (M2 macrophages). Consequently, these areas were differently characterized by the accumulation of macrophages with high and low magnitude of CD163 positivity, respectively. Next, we immunohistochemically investigated relationships among PTX3, CRP, histological components and clinical presentation in 73 coronary atherectomy specimens obtained from 35 and 38 patients with unstable (UAP) and stable angina pectoris (SAP), respectively. Both PTX3 and CRP were more intense in culprit plaques from patients with UAP than with SAP, and they significantly correlated with CD68 (pan macrophage)-positive areas; however, there was no correlation between PTX3 and CRP.
Conclusion: Although PTX3 and CRP were more enhanced in unstable than in stable coronary plaques, their distribution distinctly differed, suggesting that they play distinct biological roles in unstable plaques.

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Aim: The combination of ezetimibe and a statin provides greater LDL-C reduction by inhibiting both intestinal cholesterol absorption and endogenous production of cholesterol. The present study was designed to examine the influence of ageing, gender, BMI, levels of LDL-C, and HbA1c on the response to ezetimibe add-on therapy.
Methods: Patients who had been taking a statin for >3 months at the usual dose and whose LDL-C was >120 mg/dL were eligible for this study. Patients were assigned to receive add-on ezetimibe at 10 mg once daily for 12 weeks.
Results: Adding ezetimibe to basal statin therapy resulted in a further 15.0% reduction of TC, 20.5% reduction of LDL-C, and 19.7% reduction of non-HDL-C. The change in TC was significantly greater in males than in females. The change in TG was significantly greater in patients with a baseline TG level ≥150 mg/dL. Multivariate regression analysis showed that male sex and LDL-C ≥140 mg/dL were independent predictors of TC reduction after adjustment for age, BMI, and HbA1c. A baseline TG ≥150 mg/dL was also an independent predictor of TG reduction.
Conclusion: Addition of ezetimibe to ongoing statin therapy was effective in patients with type 2 diabetes. Male sex and baseline LDL-C levels are independent predictors of marked TC reduction by ezetimibe treatment.

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Aim: Complement C3 (C3) is one of the major mediators of inflammation. Serum C3 has been shown to be correlated with the presence of atherosclerosis. We examined whether the serum C3 level might be correlated with the severity of renal arteriolosclerosis in patients with chronic kidney disease (CKD).
Methods: Non-diabetic CKD (stages 1-3) patients who underwent renal biopsy were enrolled in this study. Renal arteriolosclerosis was defined by the presence of hyaline changes and vessel wall thickening in the renal biopsy specimens. We examined whether the serum C3 level might be correlated with the severity of renal arteriolosclerosis in CKD patients.
Results: A total of 208 CKD patients (age 36.0±13.6 years; 94 male) who underwent renal biopsy were included. Univariate analysis showed that the serum C3 level was positively correlated with age, body mass index, blood pressure and the serum triglyceride, LDL cholesterol and CRP (p<0.001). The serum C3 level was also inversely correlated with serum HDL cholesterol (p<0.001). Multiple regression analysis identified that the serum C3 (p=0.043) as well as age (p<0.001), serum uric acid (p=0.009) and eGFR (p= 0.025) were independently associated with the severity of renal arteriolosclerosis.
Conclusion: Our results suggest that the serum C3 level is a reliable marker of renal arteriolosclerosis. Components of metabolic syndrome were also correlated with the serum C3 level. Inflammation or metabolic syndrome may contribute to CKD through influencing the rate of progression of renal arteriolosclerosis.

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Aim: Remnant lipoproteins are atherogenic and are accumulated in patients with type III hyperlipidemia (HL). Although type III HL is diagnosed by phenotyping apolipoprotein (apo) E, this procedure is time-consuming and inconvenient for routine clinical use. Clinical indices for screening type III HL in untreated HL patients have been proposed; however, in clinical settings, HL patients are promptly treated with lipid-lowering agents without diagnosing the underlying cause. We investigated whether existing clinical indices for screening type III HL as well as the apo B-48/triglyceride (TG) ratio, which was suggested to be related to the accumulation of small chylomicron (CM) remnants, are useful after the initiation of lipid-lowering therapies.
Methods: In 25 normolipidemic subjects and 191 treated HL patients (type I, n =6; IIa, 62; IIb, 66; III, 12; IV, 22; and V, 23) from Osaka University Hospital and related hospitals, fasting low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), TG, and apolipoproteins were measured and clinical indices were evaluated statistically.
Results: Apo B-48 levels were significantly higher in patients with type I, III, and V HL, and TG levels were significantly higher in patients with type I and V HL. The apo B-48/TG ratio was significantly higher only in patients with type III HL compared with other types of HL (p<0.001), and was statistically significant among the other clinical indices (AUC-ROC value, 0.895; cut-off value, 0.110).
Conclusion: The apo B-48/TG ratio is a novel and useful marker for detecting type III HL even after the initiation of lipid-lowering interventions.

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Aim: Few population-based studies have assessed the risk factors of and gender differences in intima-media thickness (IMT) at the common carotid artery (CCA) for different age groups.
Objective: Factors determining age and gender differences in IMT were studied in ethnic Chinese participants of the Chin-Shan Community Cardiovascular Cohort in Taiwan.
Methods: From July 1994 through August 1996, the CCA-IMT of 1203 men and 1487 women aged 35 years or more was measured using high-resolution B-mode carotid ultrasound. Cardiovascular risk factors were recorded for each subject.
Results: The CCA-IMT consistently increased with age and was more in men than in women. For participants aged 55 years or more, women showed a more rapid increase in systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL) than men. The gender difference in CCA-IMT became insignificant after 75 years of age. The major determinants of CCA-IMT in addition to age and gender were body mass index at 35-44 years of age, LDL in both genders and SBP in women at 45-54 years old, SBP at 55-64 and 65-74 years old, and women with left ventricular hypertrophy, hypertension with medication, and high LDL levels at 65-74 years old after multivariate linear regression analysis. For those aged over 75 years, SBP was an important determinant of CCA-IMT.
Conclusions: The CCA-IMT increases with age and its determinants are associated with age and gender. The rapid increase in cardiovascular risk factors in women after 55 years of age attenuates the female advantage in CCA-IMT.

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