To demonstrate the reasons for low morbidity and mortality from coronary artery disease (CAD) and reconfirm the effectiveness of the Japanese dietary lifestyle for preventing CAD, we herein review the CAD risk transition, and post-war changes in Japanese food and nutrient intake. Large-scale cohort studies in Japan were selectively reviewed. Low serum total cholesterol contributed to preventing CAD, and decreased blood pressure was the major factor favoring stroke reduction. Japanese consumed more plant and marine origin foods, but fewer animal foods with saturated fatty acids (SFA) during the 1960-70s than in recent decades. Adequate control of total energy with restriction of saturated fatty acids from animal foods, increased intake of n-3 polyunsaturated fatty acids, including fish, soybean products, fruits and vegetables together with low salt intake are responsible for promoting CAD and stroke prevention. A diet with adequate total calories and increased intake of fish and plant foods, but decreased intake of refined carbohydrates and animal fat, a so-called Japan diet, appears to be quite effective for prevention of CAD risk factors and is recommended as dietary therapy for preventing CAD.

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Aim: The waist circumference (WC) cut-off values in the diagnostic criteria of metabolic syndrome (MetS) established in Japan (Japanese criteria) differ from those established by the International Diabetes Federation (IDF) for Asians (IDF criteria).
Methods: To settle this contradiction, a cross-sectional study of Japanese aged 20-65 years was performed. After excluding subjects suffering from significant diseases other than those constituting MetS, excessive drinkers, and regular smokers, 835 males and 1,304 females were examined. WC was measured at the umbilical level (UWC) and midway between the ribs and iliac crest (MWC) according to both criteria in each subject.
Results: Upper limits of reference intervals of MWC estimated in subjects free from MetS were 84.6 and 84.3 cm in older (40-65 years) and younger (20-39) males, and 78.4 and 70.5 cm in older and younger females, respectively; those of UWC were 86.4, 86.2, 87.9 and 78.9 cm, respectively. Receiver operating characteristic (ROC) curves for MWC to predict UWC reproduced the relationships of the two types of cut-off values in each population.
Conclusion: WC cut-off values in the Japanese and IDF criteria have the potential to be valid as cut-off values of UWC and MWC in Japanese, respectively. Their difference can be explained by the variation in the WC definition, and they can stand together without inconsistency. Acceptance of the recently prevailing view that the WC standard in IDF for Asian males should be 85 cm and the introduction of new criteria for younger females in consideration of their generation differences in both criteria could facilitate their higher compatibility.

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Aims: To investigate whether endothelial dysfunction assessed by brachial artery flow-mediated dilation (FMD) is associated with urinary albumin excretion (UAE) and is interrelated with carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) in type 2 diabetes.
Methods: We measured FMD, IMT and PWV in 158 subjects with type 2 diabetes (normo- 49, micro- 64, macroalbuminuria 45), explored the determinants of FMD, and analyzed the relationship of FMD with traditional cardiovascular risk factors according to IMT and PWV levels.
Results: Microalbuminuria was significantly associated with lower FMD, higher IMT and higher PWV compared to normoalbuminuria (p < 0.001 for all). FMD was significantly correlated with IMT and PWV, and also with traditional risk factors, UAE, glomerular filtration rate, diabetic retinopathy, and neuropathy. Multivariate regression analysis revealed that UAE remained a significant determinant of FMD independent of traditional risk factors, metabolic control, and renal function. The relationship of FMD with IMT and PWV was less pronounced in subjects with increased IMT and PWV.
Conclusions: In individuals with type 2 diabetes, FMD is impaired in subjects with microalbuminuria and is associated with IMT and PWV only when these values are not increased, i.e., at an early stage of atherosclerosis.

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Aim: Increased levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been observed in patients with cardiovascular risk factors and atherosclerosis and in patients with a history of stroke. The role of ADMA and its analogue symmetric dimethylarginine (SDMA) in acute ischemic stroke is yet unclear. We hypothesized that plasma dimethylarginine levels increase in the hyper-acute phase after ischemic stroke and that their time course is related to stroke outcome.
Methods: Plasma dimethylarginines ADMA and SDMA and L-arginine levels were measured in 67 patients at 6, 12, 24 hours, as well as 3 and 7 days after stroke onset using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS). Data were compared to control data from 32 age-adjusted healthy volunteers. Clinical outcome was assessed using the modified Rankin Scale (mRS) at 90 days after stroke.
Results: At baseline, plasma ADMA levels were higher in stroke patients than in controls, whereas plasma SDMA and L-arginine levels did not differ from control subjects. The time courses of ADMA and SDMA were related to the clinical outcome. Binary logistic regression analysis showed that ADMA levels of ≥ 0.566 µmol/L at day 3, ≥ 0.530 µmol/L at day 7 and SDMA levels of ≥ 0.59 µmol/L at 24 hours predicted an unfavorable clinical outcome.Conclusions: An increase of both ADMA and SDMA plasma levels within the first 72 hours after the onset of ischemic stroke predicts a poor outcome.

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Aim: Thrombin induces vascular responses including the promotion of tissue factor (TF) and plas-minogen activator inhibitor-1 (PAI-1) protein expression, which is modulated by small GTPases RhoA and Rac1, Ca²⁺ signaling and reactive oxygen species (ROS). Recent studies have shown that membrane type 1 matrix metalloproteinase (MT1-MMP) functions not only as a protease but also as a signaling molecule. In this study, we hypothesized that MT1-MMP may mediate RhoA and Rac1 activation and their downstream events in thrombin-stimulated endothelial cells.
Methods: We used cultured human aortic endothelial cells (HAECs). MT1-MMP was silenced by small interfering RNA (siRNA). RhoA was inhibited by C3 exoenzyme, whereas adenovirus-mediated gene transfection of dominant negative RhoA and Rac1 was used for the inhibition of RhoA and Rac1. RhoA and Rac1 activation was determined by pull-down assays. Intracellular Ca²⁺ concentrations ([Ca²⁺]_i) were fluorescently measured by fura-2 assay. NADPH oxidase activity was determined by lucigenin-enhanced chemiluminescence.
Results: Inhibition of RhoA attenuated thrombin-triggered [Ca²⁺]_i increase and TF and PAI-1 expression in HAECs, whereas thrombin-triggered ROS generation and TF and PAI-1 expression were blocked by inhibition of Rac1. Silencing of MT1-MMP attenuated thrombin-triggered RhoA and Rac1 activation, resulting in the attenuation of downstream events including Ca²⁺ signaling, NADPH oxidase activity, ROS generation, and TF and PAI-1 expression.
Conclusions: The present study shows that MT1-MMP mediates the RhoA/Ca²⁺ and Rac1/NADPH oxidase-dependent signaling pathways in thrombin-induced vascular responses.

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Aim: Endothelial cell (EC) dysfunction contributes to insulin resistance in diabetes and is characterized by reduced nitric oxide (NO) release, increased nitroxidative stress and enhanced inflammation. The purpose of this study was to test the effect of improved postprandial glucose control on EC function in insulin-resistant rats as compared to fasting glucose (FG) changes.
Methods: Obese Zucker rats were treated with 10 mg/kg/day saxagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, for 4 or 8 weeks and compared to lean rats. NO and peroxynitrite (ONOO^-) release from aortic and glomerular ECs was measured ex vivo using amperometric approaches and correlated with FG, postprandial glucose, insulin, soluble CD40 (sCD40) and L-citrulline levels.
Results: Saxagliptin treatment improved NO production and reduced ONOO^- release prior to any observed changes in FG levels. In untreated obese animals, NO release from aortic and glomerular ECs decreased by 22% and 31%, respectively, while ONOO^- release increased by 26% and 40%. Saxagliptin increased aortic and glomerular NO release by 18% and 31%, respectively, with comparable reductions in ONOO^- levels; the NO/ONOO^- ratio, an indicator of NO synthase coupling, increased by >40%. Improved glycemic control was further associated with a reduction in sCD40 levels by more than ten-fold (from 300 ± 206 to 22 ± 22 pg/mL, p < 0.001).
Conclusion: These findings indicate that enhanced glycemic control with DPP4 inhibition improved NO release and reduced inflammation in a manner not predicted by FG changes alone.

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Aim: To evaluate whether plaque scoring measurements are able to track changes in atherosclerotic plaque burden over time and to study whether this is affected by lipid-lowering therapy.
Methods: Data used were from METEOR (Measuring Effects on Intima-Media Thickness: an Evaluation Of Rosuvastatin), a randomized controlled trial of rosuvastatin 40 mg among 984 low-risk patients with modest carotid intima-media thickening (CIMT). In this analysis, duplicate ultrasound images from 12 carotid sites were collected at the baseline and end of the study from 495 European patients and were evaluated for plaque presence and severity. Plaques were scored from near and far walls of the 12 sites (0= none; 1= minimal; 2= moderate; 3= severe) and plaque scores (PS) were combined into two summary measures for each examination. The MeanMaxPS is the mean over the 12 carotid sites of the maximum score at each site and the MaxMaxPS reflects the most severe lesion at any site.
Results: Baseline MeanMaxPS and MaxMaxPS were 0.31 (SD: 0.20) and 1.15 (SD: 0.51), respectively. Changes in MeanMaxPS and MaxMaxPS significantly differed between rosuvastatin and placebo (mean difference: −0.03 [SE: 0.01; p =0.016] and −0.09 [SE: 0.04; p =0.027], respectively). In contrast to rosuvastatin, which demonstrated no change from the baseline, placebo showed significant progression in MeanMaxPS and MaxMaxPS (p =0.002; both).
Conclusion: The plaque-scoring method proved capable of assessing the change in atherosclerotic plaque burden over time and proved useful to evaluate lipid-lowering in asymptomatic individuals with a low risk of cardiovascular disease and subclinical atherosclerosis.

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Aims: Advanced oxidation protein products (AOPPs) are new independent risk factor for coronary artery disease. This study was to determine the effects and potential mechanisms of AOPPs on cholesterol efflux from human macrophage foam cells.
Methods: Human THP-1 monocytes were preincubated with Phorbol-12-myristate- 13-acetate (PMA) and oxidized low density lipoprotein (ox-LDL) to form foam cells. The protein and mRNA expression were examined by western immunoblotting assays and real-time quantitative PCR, respectively. Cellular cholesterol content was measured by HPLC. The cholesterol efflux was assessed by liquid scintillation counting.
Results: AOPPs significantly decreased the expression of ATP-binding membrane cassette transporter A-1 (ABCA1) and liver X receptor α (LXRα) and reduced cholesterol efflux from THP-1 macrophage- derived foam cells. AOPPs substantially activated NADPH oxidase and activated Janus kinase/signal transducers and activators of transcription (JAK/STAT) signal pathway in THP-1-derived foam-like cells. Inhibiting NADPH oxidase by diphenyliodonium (DPI) effectively abolished the AOPPs-induced decrease in cholesterol efflux and the expression of ABCA1. Inhibiting JAK/STAT activation by its specific inhibitor AG-490 or by siRNA could also block AOPPs action on THP-1 cells.
Conclusions: AOPPs may first down-regulate the expression of LXRα and ABCA1 through JAK/STAT signal pathway activation and then inhibit cholesterol efflux in THP-1-derived foam-like cells; therefore, our study may be useful for understanding the critical effects of AOPPs on the pathogenesis of atherosclerosis.

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Aim: Limited epidemiological studies have investigated the relationship between ischemic vascular disease and periodontitis in non-Western populations. We investigated this relationship in a Japanese cohort by measuring serum titers of antibodies to periodontopathic bacteria.
Methods: As part of the Tokamachi-Nakasato cohort study, we followed up 7021 participants regarding cardiovascular events over 5 years, and observed 99 ischemic vascular events: 66 cerebral infarctions and 33 cases of ischemic heart disease (IHD). For a nested case-control study, we selected 495 sex- and age-matched control subjects. Conditional logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) of ischemic vascular events associated with antibody titers to Porphyromonas gingivalis FDC381 and SU63. Multivariable models were adjusted for traditional cardiovascular risk factors using propensity scores.
Results: The highest tertile category of antibody titers to P. gingivalis FDC381 in men was significantly associated with an increased risk of cerebral infarction in only the crude model. The 2nd and 3rd tertile categories of antibody titers to P. gingivalis SU63 were significantly associated with an increased risk of cerebral infarction in men (multivariable ORs (95% CIs) were 7.12 (1.51-33.5) and 9.03 (1.97-41.5), respectively). The association was not appreciably modified when we further adjusted for serum high-sensitivity C-reactive protein levels. Antibody titers to P. gingivalis were not dose-dependently associated with the risk of IHD.
Conclusion: High serum antibody titers to P. gingivalis SU63 could be a predictor of cerebral infarction in Japanese men independent of traditional risk factors and inflammation.

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Aim: We have recently demonstrated that the circulating level of LOX-1 ligand containing apoB (LAB) predicts the risk of cardiovascular events; however, as is the case in other assays measuring oxidized LDL (oxLDL), chemical unstability and inter-lot variance of standard oxLDL may limit the utility of measuring LAB. This study aimed to develop an alternative protein standard that is simultaneously recognized by LOX-1 and anti-apoB antibody instead of copper-oxidized LDL.
Methods and Results: cDNAs encoding the variable regions of anti-LOX-1 monoclonal antibody were cloned from hybridomas and reorganized to express anti-LOX-1 single-chain variable fragment (Fv). cDNAs of four regions of human apoB (B1 to B4), which were reported to be epitopes of many anti-apoB antibodies, were also cloned. After confirming the respective reactivity of Fv and apoB fragments to LOX-1 and anti-apoB antibodies, cDNAs of Fv and apoB fragments were connected to express Fv-ApoB chimeric proteins. These fusion proteins were found to be recognized by both LOX-1 and anti-apoB antibodies. Among them, the fusion proteins of Fv-B1 and Fv-B3 gave saturable binding curves against immobilized LOX-1 when detected by anti-apoB antibodies. The binding curves of different Fv-B1 preparations to LOX-1 were almost identical while those of oxLDL varied among the preparations, suggesting better quality control of Fv-B1 preparations.
Conclusions: The fusion proteins composed of Fv-form anti-LOX-1 antibody and apoB fragment are useful alternatives to copper-oxidized LDL in determining LAB, which would facilitate the application of modified LDL analyses to the clinical diagnosis and risk evaluation of cardiovascular disease.

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We report the case of a 28-year-old woman taking contraceptives diagnosed with pulmonary embolism with a mass in the right atrium demonstrated by trans-thoracic echocardiogram that was not recognized on a previous angio-CT. Initially, it was thought to be a thrombus, but trans-oesophageal echocardiography and cardiac MRI showed data suggestive of cardiac neoplasm. Pericardial effusion and adjacent myocardial wall thickening noted on trans-oesophageal echocardiography were reported as signs that supported the possibility of malignancy, although cardiac MRI did not show wall infiltration signs. On the contrary, it demonstrated enhancement, which excludes the thrombotic nature of the mass and supports the diagnosis of neoplasm. The patient underwent surgery and biopsy proved that the mass was a myxoma. While myxomas are the most common among primary cardiac tumors, its attachment to the atrium free wall, far from the inter-atrium septum, the bi-lobed shape and accompanying pericardial effusion were atypical.

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