The cardio-ankle vascular index (CAVI) is a new index of the overall stiffness of the artery from the origin of the aorta to the ankle. The most conspicuous feature of CAVI is its independence of blood pressure at the time of measurement.
CAVI increases with age and in many arteriosclerotic diseases, such as coronary artery disease, carotid arteriosclerosis, chronic kidney disease and cerebrovascular disease, and is related to many coronary risk factors, such as hypertension, diabetes mellitus, dyslipidemia and smoking. Furthermore, CAVI decreases by controlling diabetes mellitus and hypertension, and also by abstaining from smoking. This suggests that CAVI is a physiological surrogate marker of athero- or arteriosclerosis, and also might be an indicator of lifestyle modification.
Recently, it has been reported that CAVI and several left ventricular functions are co-related, suggesting a connection between the heart muscle and vascular function.
This review covers the principles of CAVI and our current knowledge about CAVI, focusing on its roles and future outlook.

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Aim: Increased coronary plaque burden, which could be involved in the pathogenesis of atherothrombotic events, is difficult to evaluate in the three major coronary arteries. The purpose of this study was to quantify coronary plaque volume using 64-slice computed tomography (CT).
Methods: We measured coronary plaque volume with our new protocol in 23 consecutive patients (48% men; 66 ± 11 years old) who underwent cardiac CT for suspicion of coronary artery disease and had noncalcified plaques. We counted the total pixel volume of noncalcified plaques in the three major coronary arteries.
Results: The coronary plaque volume was 1.29 ± 0.56 cm³ in the right coronary artery, 1.29 ± 0.42cm³ in the left main coronary artery and left anterior descending artery, and 0.88 ± 0.32 cm³ in the left circumflex artery. The total coronary plaque burden (TCPB) was 3.45 ± 1.02 cm³/patient and had a positive correlation with waist circumference (r =0.44, p < 0.05) and insulin resistance (r = 0.46, p < 0.05). TCPB was significantly greater in men (3.89 ± 1.07 cm³ vs. 3.06 ± 0.82 cm³ in women, p < 0.05), patients with diabetes or impaired glucose tolerance (3.77 ± 0.94 cm³ vs. 2.86 ± 0.92 cm³ in non-diabetics, p < 0.05), and patients with metabolic syndrome (3.91 ± 0.95 cm³ vs. 3.03 ± 0.91 cm³ in patients without metabolic syndrome, p < 0.05).
Conclusions: Cardiac CT can provide a noninvasive assessment of TCPB, which was significantly associated with metabolic syndrome and its components. Measuring TCPB by CT could be an important strategy for identifying high-risk patients with suspected coronary artery disease.

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Aim: Carotid intima-media thickness (CIMT) measurements are used as a disease outcome in randomized controlled trials that assess the effects of lipid-modifying treatment. It is unclear whether common CIMT or mean maximum CIMT should be used as the primary outcome. We directly compared both measurements using aspects that are of great importance in deciding which is most favorable for use in clinical trials.
Methods: A literature search was performed (PUBMED, up to March 31, 2008). Fifteen trials with lipid-modifying treatment were identified that had information on both outcome measures. Common CIMT and mean maximum CIMT were compared on reproducibility, strength of relation with LDL and HDL cholesterol and congruency of their results (harm/neutral/beneficial) with data from event trials.
Results: Findings showed that the reported reproducibility was high for both measurements, although a direct comparison was not possible. The relationship between the achieved LDL-C and HDL-C levels with CIMT progression was modest and showed no difference in magnitude between CIMT measurements. CIMT progression rates differed across carotid segments with the highest progression rates observed in the bifurcation segment. Treatment effects differed across carotid segments without a clear preference pattern. Trials using mean maximum CIMT progression more often (12 out of 15 studies) paralleled the findings of event trials in contrast to the mean common CIMT (11 out of 15 studies), a difference not reaching statistical significance.
Conclusions: Based on the literature, with equal results for reproducibility (assumed), lipid relationship and congruency with event findings, but with treatment effects that differ across carotid segments that can not be predicted, the mean maximum CIMT as the primary outcome may be preferred in trials on the impact of lipid-modifying interventions. One advantage is that information on mean common CIMT can generally be obtained easily in protocols assessing mean maximum CIMT, but not the other way around.

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Aim: Fractalkine (CX3CL1), a chemokine, and its receptor CX3CR1 (expressed on T lymphocytes), have been shown to be abnormal in atherosclerosis. We investigated whether CX3CL1 levels and CX3CR1 expression were altered in patients with chronic kidney disease (CKD) and their association with common carotid artery intima-media thickness (CCA-IMT)
. Methods: CX3CR1 expression on CD4⁺ T cells was analyzed by flow cytometry in 62 healthy controls (HC) and 128 Stage III-V CKD subjects. Fractalkine and highly sensitive C-reactive protein (hsCRP) were analyzed by ELISA. CCA-IMT was measured by ultrasound.
Results: Compared to HC, CKD patients exhibited a 2.5-fold increase in the CD4⁺CX3CR1⁺ T cell population (14.8±0.6 vs 5.9±0.34%, p < 0.0001). The expression of CX3CR1 was largely restricted to those CD4⁺ cells that lacked CD28 co-stimulatory molecule. Fractalkine (pg/mL) and hsCRP (µg/mL) levels were increased in CKD subjects (510.6±61.6 vs. 239.7±9.67, p =0.003, and 93.8± 5.3 vs. 48.4±6.8, p < 0.0001), as was the CCA-IMT (0.71±0.01 vs. 0.56±0.01 mm, p < 0.0001). There was a significant relationship between CD4⁺CX3CR1⁺ T cells and fractalkine levels (r = 0.2, p =0.01). CCA-IMT correlated positively with CX3CR1⁺ T cells (r =0.34, p < 0.0001), CD4⁺ CX3CR1⁺ T cells (r =0.39, p < 0.0001), CD4⁺CD28^nullCX3CR1⁺ T cells (r =0.23, p =0.02), fractalkine (r =0.3, p =0.001), age (r =0.33, p < 0.0001) and diabetes (p =0.01). On multiple regression, only CD4⁺CX3CR1⁺ T cells and the presence of diabetes continued to show an association with IMT (p < 0.0001 and 0.0029 respectively).
Conclusions: CKD subjects showed an increase in CD4⁺CX3CR1⁺ T cell population, plasma fractalkine and IMT; the association of CD4⁺CX3CR1⁺ T cells and plasma fractalkine with CCA-IMT indicates that the fractalkine-CX3CR1 pathway may be important in the development and/or progression of atherosclerosis in CKD.

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Aim: Mesenchymal stem cells (MSCs) are a multipotent cell type that can differentiate into non-hematopoietic cells, such as adipocytes. Adipocyte tissue is central to the regulation of energy balance. Two functionally different types of fat are present in mammals. White adipose tissue is the primary site for triglyceride storage, while brown adipose tissue is specialized in energy expenditure. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) controls several aspects of mitochondrial biogenesis. In this study, we hypothesized that PGC-1α plays a role in brown fat differentiation of MSCs.
Methods: Immortalized human MSCs were infected with adenovirus carrying PGC-1α cDNA to create PGC-1α-expressing MSCs.
Results: The genetic profiling of PGC-1α-expressing MSCs shows the significant increase of genes related to mitochondrial functions and lipid metabolism compared to that of MSCs. When expressed in MSCs, PGC-1α activates robust mitochondrial biogenesis and respiration. The increase of oxygen consumption and reactive oxygen species represents a cellular readout of increased activity of the respiratory chain. The expression of thermogenic markers, such as cytochrome C and complex II, was significantly increased in MSCs with treatment of adenovirus expressing PGC-1α. Moreover, PGC-1α markedly inhibited the osteogenesis of MSCs under osteogenic induction. During adipogenesis, PGC-1α-expressing MSCs showed a significant increase in brown fat markers and a decrease in white fat markers. Notably, PGC-1α knockdown inhibited adipocyte differentiation of MSCs.
Conclusions: In summary, our data reveal an important role of PGC-1α in promoting brown fat differentiation of MSCs, and provide a new therapeutic approach for the treatment of obesity.

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Aim: The aim of this study was to determine the impact of the lifestyles of adolescents and their parents on the levels of cardiovascular (CV) risk factors in the adolescents.
Methods: A total of 755 volunteers (331 male, 424 female) aged 15 to 18 years were included. Abdominal obesity, hypertension, elevated triglyceride levels, decreased high density lipoprotein-cholesterol levels, and hyperglycemia were considered to be CV risk factors. Self-reported lifestyle, including participation in school-based extracurricular (EC) physical activities, time spent on physical activity or watching television (TV), and average daily food intake were assessed. Parental information on weight status and lifestyle was also obtained.
Results: Multivariate regression analyses showed that participation in EC physical activities, time spent watching TV, regular breakfast consumption, total energy intake, fiber intake per 1,000 Kcal, and parental BMI were independently associated with the levels of one or more CV risk factors in adolescents. Among these, participation in EC physical activities had a profound effect on adolescent CV risk factor levels. The risk of male adolescent obesity was associated with paternal obesity, but not with maternal obesity. Conversely, the risk of female adolescent obesity was associated with maternal obesity but not with paternal obesity.
Conclusions: Participation in EC physical activities may be the first-line approach for adolescents to maintain favorable CV risk factor levels. An association between paternal or maternal obesity and adolescent obesity differs between adolescent genders in Japan; thus, approaches focusing on parents should take the gender of the adolescent into consideration.

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Aim: There is increasing evidence of a strong link between erectile dysfunction and atherosclerosis. The aim of this study was to evaluate the relationships between the 5-item version of the International Index of Erectile Function (IIEF-5) score and albuminuria as well as markers of subclinical atherosclerosis in men with type 2 diabetes.
Methods: We evaluated the relationship of the IIEF-5 score with the degree of urinary albumin excretion, pulse wave velocity, ankle-brachial index or toe-brachial index (n = 125) as well as with major cardiovascular risk factors, including age, blood pressure, serum lipid concentration and hemoglobin A1c, body mass index, severity of diabetic retinopathy or nephropathy, and presence of neuropathy or cardiovascular disease in 197 men with type 2 diabetes.
Results: The mean IIEF-5 score was 10.0 ± 6.9. The IIEF-5 score was inversely correlated with age or duration of diabetes, and positively correlated with diastolic blood pressure or serum total cholesterol concentration. The IIEF-5 score inversely correlated with log (urinary albumin excretion; r =−0.190, p =0.0078) or pulse wave velocity (r =−0.255, p =0.0003), and positively correlated with the toe-brachial index (r = 0.379, p < 0.0001). The IIEF-5 score was lower in patients with proliferative diabetic retinopathy than in patients with no diabetic retinopathy, and in patients with macroalbuminuria than in patients with normoalbuminuria. The IIEF-5 score was also lower in patients with neuropathy or cardiovascular disease than without.
Conclusions: The IIEF-5 score correlated with diabetic micro- and macroangiopathy in men with type 2 diabetes.

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Aims: N-acetylcysteine (NAC) has antioxidant and anti-inflammatory properties. To explore the mechanisms underlying atherosclerotic plaque stabilization induced by NAC, we examined the effects of NAC administration in apoE-deficient mice on the expression of the receptor of advanced glycation end products (RAGE), matrix metalloproteinases (MMPs) and the activation of nuclear factor kappa B (NF-κB) in atherosclerotic plaques.
Methods: 10-week-old ApoE^-/- mice fed with atherogenic diet were treated with NAC (200 mg/kg/ day) for 8 weeks. Serum lipid, glucose and malondialdehyde (MDA) were detected. The size and composition of atherosclerotic plaques were measured by en face analysis, Movat staining, immunofluorescence and immunohistochemistry, respectively. Reactive oxygen species (ROS) generation in aortic root was tested by DHE staining. The levels of vascular cell adhesion molecule-1(VCAM-1), NF-κB, phosphor-NF-κB, I-κB, phosphor-I-κB, RAGE, MMP2 and MMP9 in descending arteries were analyzed by Western blot.
Results: ApoE^-/- mice administrated with NAC displayed reduced serum MDA level and impaired ROS generation in aortic root. However, NAC did not affect the levels of plasma glucose, lipids and the size of atherosclerotic lesions. Analysis of plaque composition showed decreased amounts of macrophages, lipid deposition, but not smooth muscle cells, and increased collagen content in atherosclerotic lesions in apoE^-/- mice administered with NAC. Moreover, we found that NAC down-regulated the expression of VCAM-1, MMP2 and MMP9, accompanied by inhibition of NF-κB activation and reduced expression of RAGE.
Conclusion: In the present study, we show novel data to suggest that NAC promotes atherosclerotic plaque stabilization through suppression of RAGE, MMPs and NF-κB in apoE^-/- mice.

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Aim: The anti-oxidant enzyme copper/zinc superoxide dismutase (CuZnSOD) metabolizes superoxide anion (O₂^-) in vascular cells. However, the role of CuZnSOD in vascular injury remains poorly understood.
Methods: Using CuZnSOD-deficient (CuZnSOD^-/-) mice and wild-type (WT) mice, we investigated morphometric changes and the role of O₂^- in vascular remodeling after femoral artery injury induced by an external vascular cuff model.
Results: Three days post-injury, inflammatory cell infiltration increased significantly. Moreover, the percent positive area of tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in media were higher in CuZnSOD^-/- mice than in WT mice (TNF-α: 34.8±8.4% versus 18.8±5.6%, p < 0.05, ICAM-1: 29.6±6.5% versus 11.0±2.8%, p < 0.05, VCAM-1: 23.5±7.5% versus 3.7±1.1%, p < 0.05). mRNA expression of iNOS was markedly increased in CuZnSOD^-/- mice with cuff injury. Dihydroethidine staining revealed increased levels of vascular O₂^- in media from CuZnSOD^-/- mice. Although neointimal formation remained unchanged, 14 days postinjury, we observed degeneration of the media, and the media/vessel wall ratio increased in CuZnSOD^-/- mice (40.4±2.1% versus 26.8±1.4%, p < 0.05). Furthermore, SMemb/MHC-B-stained lesions increased markedly in CuZnSOD^-/- mice.
Conclusions: CuZnSOD-deficiency promoted inflammation, expressed adhesion molecules, and altered the structure of the media post-injury. Our results suggest that O₂^- participates importantly in the progression of early stage vascular inflammation, resulting in vascular remodeling in media but not neointimal formation, post-injury.

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Aim: We aimed to assess the effects of rosuvastatin treatment on lipid levels, a biomarker of oxidative stress, albuminuria, and kidney function in patients with diabetic nephropathy.
Methods: We conducted a prospective, open-label, parallel group, controlled study of 104 patients with diabetic nephropathy, low-density lipoprotein cholesterol (LDL-C) levels of > 120 mg/dL, and well-controlled blood pressure who were undergoing treatment with renin angiotensin system inhibitors. Patients were randomly assigned to two groups: the rosuvastatin group (n = 52; 2.5 mg/day rosuvastatin, increased to 10 mg/day) and the control group (n = 52; no rosuvastatin administered). We determined the efficacy of rosuvastatin by monitoring serum lipid profiles, high sensitivity C-reactive protein (hs-CRP), malondialdehyde-modified LDL (MDA-LDL), and cystatin C levels. In addition, urinary albumin, 8-hydroxydeoxyguanosine (8-OHdG) and liver-type fatty acid-binding protein (L-FABP) levels were measured before and 6 months after rosuvastatin was added to the treatment.
Results: Rosuvastatin effectively reduced total cholesterol, LDL-C, triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C) levels, and the LDL-C/ HDL-C ratio in the rosuvastatin group. These parameters remained unchanged in patients who were not treated with rosuvastatin. Although there was no significant change in the estimated glomerular filtration rate level, serum cystatin C levels and urinary albumin excretion rates were significantly decreased in the rosuvastatin group. In addition, rosuvastatin significantly reduced hs-CRP and MDA-LDL levels. Moreover, urinary 8-OHdG and L-FABP levels at baseline (13.5±5.1 and 41.7±26.1 ng/mgCr, respectively) decreased significantly at 6 months (11.5±4.0 and 26.9±13.4 ng/mgCr, respectively), and there was a significant correlation (r = 0.48, p < 0.01). Multivariate analysis revealed that albuminuria was significantly correlated with only rosuvastatin use (p = 0.0006, R²= 0.53).
Conclusion: Rosuvastatin administration reduced albuminuria, oxidative stress, and serum cystatin C levels, independent of blood pressure and lipid levels.

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According to many prospective cohort studies and meta-analyses of those studies, physical inactivity and/or low levels of physical fitness are associated with an elevated risk for the development of metabolic syndrome, type 2 diabetes, hypertension, coronary artery disease (CAD), and stroke, and with an increased risk of cardiovascular disease (CVD) mortality and all-cause mortality. Most of these analyses, however, were conducted on non-Japanese populations in the West. This report summarizes prospective observational and clinical studies in Japan. The annual national nutrition survey has shown a gradual decline in the number of walking steps in both genders and in all age groups over the last 10 years. While exercise habits have been gradually increasing in the elderly, only one-fifth of young and middle-aged people undertake leisure-time physical activity. Prospective cohort studies have shown that increased physical fitness and greater physical activity in either daily life or leisure time are of benefit in preventing all-cause mortality and CVD mortality. The daily number of walking steps is positively associated with HDL cholesterol levels and negatively associated with triglyceride levels. According to a random-effects model meta-analysis of 4 randomized controlled trials comparing supervised aerobic exercise training with non-exercise control in subjects without CAD, exercise resulted in a significant increase in HDL-cholesterol (10.01 mg/dL, 95% CI 5.38 to 14.65, p< 0.0001). While this confirms the importance of physical activity in preventing CVD mortality and all-cause mortality, the levels of physical activity are on a declining trend in Japan, particularly among the young.

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