Difference in right and left cardio-ankle vascular index as a useful marker for evaluation of leg ischemia in patients with lower extremity arterial disease.

OBJECTIVES: Cardio-ankle vascular index (CAVI) is a blood pressure-independent measure of heart-ankle pulse wave velocity and is used as an indicator of arterial stiffness. However, there is a paradox that CAVI is inversely associated with leg ischemia in patients with lower extremity arterial disease (LEAD). The aim of this study was to clarify the significance of the absolute value of left and right difference in CAVI (diff-CAVI). METHODS: The subjects were 165 patients with LEAD who had received medication therapy. Relationships between diff-CAVI and leg ischemia were investigated. Leg ischemia was evaluated by decrease in leg arterial flow using ankle-brachial index (ABI) and by symptoms using the Rutherford classification. RESULTS: There was a significant inverse correlation between diff-CAVI and ABI. The odds ratio for low ABI of the 3rd versus 1st tertile groups of diff-CAVI was 7.03 with a 95% confidence interval of 2.71 ∼ 18.22. In ROC analysis, the cutoff value of diff-CAVI for low ABI was 1.05 with a sensitivity of 61.1% and a specificity of 87.1%. The median of diff-CAVI was significantly higher in subjects with grade 2 of the Rutherford classification than in subjects with its grade 1. CONCLUSIONS: diff-CAVI showed an inverse association with ABI and a positive association with symptoms of leg ischemia. Thus, diff-CAVI is thought to be a useful indicator of leg ischemia in LEAD patients.

Augmentation by resveratrol of the inhibitory effect of ethanol on platelet aggregation.

Ethanol and resveratrol have been shown to inhibit platelet aggregation. The aim of this study was to determine whether resveratrol has an additional effect on ethanol-induced inhibition of platelet aggregation. Ca2+ entry and subsequent aggregation of human platelets were measured by the fluorescence method and light transmittance method, respectively. Thromboxane B2 concentrations in media containing platelets were measured by using the enzyme-linked immunosorbent assay. Platelet aggregation induced by thrombin (0.025 U/ml) was significantly inhibited by preincubation of platelets with ethanol (0.5%). Preincubation with resveratrol (3.125 µM), which did not affect thrombin-induced platelet aggregation, significantly augmented the inhibitory effect of ethanol on platelet aggregation. Similar synergic effects of ethanol and resveratrol were found on aggregatory responses to collagen (2 µg/ml) and arachidonic acid (0.25 mM). On the other hand, the thrombin-induced increase in intracellular Ca2+ concentration ([Ca2+]i) was not affected by ethanol alone, resveratrol alone or both ethanol and resveratrol together. In nominally Ca2+-free medium, arachidonic acid (0.75 mM) caused a potent platelet aggregation, which was not affected by the presence of ethanol alone, resveratrol alone, or both of them together. Thromboxane B2 formation induced by thrombin was significantly inhibited by ethanol (0.5%) alone and resveratrol (3.125 µM) alone, and these inhibitory effects were significantly augmented in the presence of both ethanol and resveratrol together. Resveratrol shows an additive effect on ethanol-induced inhibition of platelet aggregation. This effect by resveratrol is partly explained by its inhibitory action on thromboxane A2 production in platelets. In addition, both ethanol and resveratrol attenuate platelet aggregation through acting on the Ca2+-dependent intra-platelet pathway after an increase in [Ca2+]i induced by thrombin.

VEGF-Independent Angiogenic Factors: Beyond VEGF/VEGFR2 Signaling.

Tumors induce angiogenesis to acquire oxygen and nutrition from their adjacent microenvironment. Tumor angiogenesis has been believed to be induced primarily by the secretion of vascular endothelial growth factor-A (VEGF-A) from various tumors. VEGF-A binds to VEGF receptor 2 (VEGFR2), resulting in subsequent activation of cellular substances regulating cell proliferation, survival, and angiogenesis. Antiangiogenic therapies targeting the VEGF-A/VEGFR2 axis, including bevacizumab and ramucirumab, humanized monoclonal antibodies against VEGF-A and VEGFR2, respectively, have been proposed as a promising strategy aimed at preventing tumor growth, invasion, and metastasis. Phase III clinical trials using bevacizumab and ramucirumab have shown that not all tumor patients benefit from such antiangiogenic agents, and that some patients who initially benefit subsequently become less responsive to these antibodies, suggesting the possible existence of VEGF-independent angiogenic factors. In this review, we focus on VEGF-independent and VEGFR2-dependent tumor angiogenesis, as well as VEGFR2-independent tumor angiogenesis. Additionally, we discuss VEGF-independent angiogenic factors which have been reported in previous studies. Various molecular targeting drugs are currently being evaluated as potential antitumor therapies. We expect that precision medicine will permit the development of innovative antiangiogenic therapies targeting individual angiogenic factors selected on the basis of the genetic screening of tumors.

Contribution of platelet-derived microRNAs to serum microRNAs in healthy men.

Platelets are a major source of microRNAs (miRNAs) in blood. Relationships between circulating platelet-derived miRNAs were investigated to elucidate their significance as biomarkers. Total miRNAs in serum were analyzed using the 3D-Gene miRNA Oligo chip. Among 22 miRNAs that are included in platelets and play functional roles, sufficient miRNA levels for comparison were detected for 11 miRNAs (let-7b-5p, miR-16-5p, miR-17-5p, miR-24-3p, miR-107, miR-126-3p, miR-150-3p, miR-191-5p, miR-197-3p, miR-223-3p, and miR-326). Among 55 pairs prepared by these miRNAs, relatively strong correlations (Spearman's correlation coefficient >0.8) were shown between miRNAs of 7 pairs including let-7b-5p and miR-16-5p, let-7b-5p and miR-17-5p, let-7b-5p and miR-107, miR-16-5p and miR-17-5p, miR-16-5p and miR-107, miR-17-5p and miR-107, and miR-107 and miR-126-3p. In principal component analysis, the first principal component consisted of let-7b-5p, miR-16-5p, miR-17-5p, miR-107, miR-126-3p, and miR-191-5p. These six miRNAs may be useful biomarkers that reflect platelet condition and function.

Relationship of urinary liver-type fatty acid-binding protein with cardiovascular risk factors in the Japanese population without chronic kidney disease: Sasayama study.

BACKGROUND: Urinary liver-type fatty acid-binding protein (L-FABP) is a well-known marker of proximal tubular impairment. We evaluated the relationship between cardiovascular disease (CVD) risk factors and levels of L-FABP in a cross-sectional community-based study. Participants with normoalbuminuria and normal estimated glomerular filtration rate (eGFR), that is, non-chronic kidney disease (non-CKD), were enrolled in this study. To the best of our knowledge, this is the first study to focus on the association between CVD risk factors and a proximal tubular marker in the Japanese general population with normoalbuminuria and normal eGFR. METHODS: The present study is part of the Sasayama study. The participants included 1000 community residents (447 men and 553 women) aged 40-64 years without a history of CVD or renal dysfunction. Out of these participants 375 men and 477 women, defined as non-CKD, were included for further analysis. In each sex, the highest quintile group was considered to have high-normal L-FABP levels. A multiple logistic regression model was used to evaluate the relationship between risk factors for CVD and high-normal L-FABP levels in the non-CKD participants. We performed a similar analysis using the high-normal urinary albumin to creatinine ratio (UACR) as a dependent variable instead of L-FABP. RESULTS: Among the non-CKD participants, in the highest quintile group (Q5, top 20%), L-FABP was ≥2.17 µg/gCre in men and ≥ 2.83 µg/gCre in women. In women, the multivariate odds ratio was 3.62 (1.45-9.00) for high-normal L-FABP in the presence of diabetes mellitus (DM) compared with that in the group without DM. However, the relationship between DM and the UACR level was not significant. In men, DM was significantly associated with high-normal UACR. However, the relationship with L-FABP levels was not significant. CONCLUSIONS: The presence of DM was more strongly related to high-normal L-FABP levels than to high-normal UACR in women even at the stage of normoalbuminuria and normal eGFR. Our results were also consistent with the findings of a previous study where women were more prone to nonalbuminuric renal impairment compared to men, although further studies are required to confirm the results.

Platelet count in men with a habit of alcohol drinking.

Alcohol inhibits platelet function, and platelet count is often reduced in individuals with alcohol use disorder. However, the relation of habitual alcohol drinking with platelet count in a general population remains to be determined. The participants were 6508 men (30 ~ 69 years old) who had received annual health checkup examinations, and most of them (98.6%) were nondrinkers or drinkers with an average ethanol intake of less than 66 g per day. Relationships of platelet count with alcohol intake were investigated by using analysis of covariance and multivariate linear and logistic regression analyses. Platelet count was significantly correlated with age, smoking, γ-glutamyl transpeptidase, body mass index and leukocyte count, which were thus used as explanatory variables in the multivariate analyses. Mean platelet counts in light (<22 g of ethanol per day), moderate (≥22 and <44 g ethanol per day) and heavy (≥44 g ethanol per day) drinkers were not significantly different from that in nondrinkers. Odds ratios vs. nondrinkers of light, moderate and heavy drinkers for low platelet count (<15 x 104/µl) were not significantly different from the reference level. In conclusion, there is no association between habitual alcohol drinking and platelet count in a general population. Further studies using data for heavier drinkers are needed to confirm the relationship between alcohol use disorder and platelet count.

Resveratrol inhibits Ca2+ signals and aggregation of platelets.

BACKGROUND: Resveratrol has been shown to inhibit platelet aggregation. However, the mechanism for this action of resveratrol remains to be clarified. The purpose of this study was to elucidate the Ca2+-related mechanism for the inhibitory action of resveratrol on platelet aggregation. METHODS: Ca2+ entry and subsequent aggregation of human platelets induced by different stimulants including thrombin, thapsigargin, and 1-oleoyl-2-acetylglycerol (OAG) were measured by the fluorescence method and light transmittance method, respectively. Each stimulant was added to a nominally Ca2+-free medium containing platelets, and then CaCl2 was added to the medium to induce Ca2+ influx into platelets. RESULTS: Thapsigargin-induced Ca2+ entry into platelets and subsequent platelet aggregation were significantly inhibited in the presence of resveratrol at 6.25 µM or higher concentrations, while OAG-induced Ca2+ entry and subsequent platelet aggregation were not affected by resveratrol at concentrations up to 50 µM. In the nominally Ca2+-free medium, thrombin induced a small transient increase in intracellular Ca2+ concentrations, which was attenuated in the presence of resveratrol at 12.5 µM or higher concentrations. Thrombin-induced Ca2+ entry into platelets and subsequent platelet aggregation were significantly inhibited in the presence of resveratrol at 12.5 µM or higher concentrations. CONCLUSIONS: The results suggest that resveratrol inhibits thrombin-induced platelet aggregation through decreasing Ca2+ release from its stores and inhibiting store-operated Ca2+ influx into platelets.

Deletion of diacylglycerol kinase ε confers susceptibility to obesity via reduced lipolytic activity in murine adipocytes.

Lipid metabolism is closely involved with signal transduction and energy homeostasis. Excess calorie intake causes abnormal lipid metabolism, promoting obesity and insulin resistance. Diacylglycerol (DG) represents not only a lipidic second messenger but also an intermediate metabolite for triglyceride metabolism in the endoplasmic reticulum (ER). However, it remains undetermined how the roles of DG in signaling and energy homeostasis is regulated within the cell. Of DG kinases (DGKs), which are enzymes that phosphorylate DG, DGKε resides in the ER. This study examined how DGKε is implicated in signal transduction and lipid homeostasis. DGKε-deficient mice were fed a high-fat diet (HFD) for 40 d. We observed that DGKε deficiency promotes fat accumulation in adipocytes and subsequently promotes insulin resistance in mice fed an HFD. This abnormal fat metabolism is mediated by down-regulation of lipolytic activities, such as adipose triglyceride lipase and hormone-sensitive lipase. In addition, activation of DG-sensitive PKC leads to insulin resistance in adipose tissue, which may be caused by delayed metabolism of DG. Our data suggest that DGKε links the second messenger signaling system to energy homeostasis in adipocytes and that its deficiency results in abnormal lipid metabolism such as obesity and insulin resistance.-Nakano, T., Seino, K., Wakabayashi, I., Stafforini, D. M., Topham, M. K., Goto, K. Deletion of diacylglycerol kinase ε confers susceptibility to obesity via reduced lipolytic activity in murine adipocytes.

Relationships of Habitual Alcohol Intake with Erythrocyte-Related Indices in Middle-Aged Japanese Men.

BACKGROUND: Anemia is induced by chronic alcohol abuse. However, it remains to be clarified whether a habitual alcohol intake affects erythrocyte-related indices in a general population. METHODS: The subjects were 16,014 Japanese male workers aged 30-65 years. The subjects were divided into non-, occasional, and regular drinkers based on the frequency of alcohol consumption. Regular drinkers were further quantitatively divided based on their daily alcohol consumption into light, moderate, and heavy drinkers. Relationships between alcohol drinking and erythrocyte-related indices were investigated. RESULTS: Erythrocyte counts and hemoglobin levels tended to be lower and higher, respectively, with increases in the frequency and amount of drinking. In logistic regression analysis, the odds ratios (OR) for abnormally low erythrocyte counts of moderate and heavy drinkers vs. nondrinkers were significantly higher than the reference level of 1.00 and the values tended to be higher with an increase in the alcohol intake. The OR vs. nondrinkers for abnormally low levels of hemoglobin and hematocrit were significantly lower than the reference level in all of the drinker groups and they were lowest in light drinkers among the drinker groups. CONCLUSION: A habitual alcohol intake has different associations with erythrocyte counts and hemoglobin and with low erythrocyte counts and low hemoglobin. Thus, alcohol is thought to have diverse effects on erythropoiesis.

Inhibition by Ethanol of Shear Stress-Induced Formation of Platelet Thrombi in Whole Blood.

AIMS: The risk of thromboatherosclerotic disease is lower in moderate drinkers than in non-drinkers. We investigated the effects of ethanol on platelet aggregation under a condition with shear stress. SHORT SUMMARY: Shear stress-induced formation of platelet thrombi is inhibited by ethanol at its attainable concentrations after drinking. This effect is prominent at the early stage of thrombus formation, being in agreement with inhibitory actions of ethanol on the initial steps of platelet activation such as Ca2+ entry and phospholipase A2 activation. METHODS: Platelet aggregation was evaluated by using a total thrombus-formation analysis system, and shear rates of 1000 s-1 (low), 1500 s-1 (middle) and 2000 s-1 (high) were loaded to whole blood. The times required to generate increases in flow pressure of 10 kPa (T10), 30 kPa (T30) and 50 kPa (T50) in microchips containing the blood, which depend on the degree of thrombus generation, were recorded. RESULTS: Under the conditions of the low-grade and middle-grade shear rates, T10 and T30 were significantly longer in the presence of ethanol at 0.25-1% than in the absence of ethanol. T10 under the condition of the low-grade shear rate and T30 under the conditions of the low-grade and middle-grade shear rates were also significantly longer in the presence of ethanol at 0.125% than in the absence of ethanol. On the other hand, T50 under the conditions of the low-grade and middle-grade shear rates was not significantly different in the absence and presence of ethanol at 0.125, 0.25 and 0.5%. Under the condition of the high-grade shear rate, T10, T30 and T50 were not significantly different in the absence and presence of ethanol at its lower concentrations. CONCLUSIONS: Ethanol at attainable concentrations inhibits platelet thrombus formation induced by shear stress, and the inhibitory effect of ethanol is prominent at the early stage of thrombus formation.

Comparison of discrimination for cardio-metabolic risk by different cut-off values of the ratio of triglycerides to HDL cholesterol.

BACKGROUND: The ratio of triglycerides to HDL cholesterol (TG/HDL-C ratio) is known as a good predictor for cardiovascular disease. The purpose of this study was to compare discrimination for cardiovascular risk by different cut-off values of the TG/HDL-C ratio. METHODS: Receiver operating characteristic (ROC) analysis was performed for the relationship between TG/HDL-C ratio and accumulation of cardio-metabolic risk factors including visceral obesity, hypertension and diabetes. Logistic regression analysis was performed for the relationships of TG/HDL-C ratio with cardio-metabolic risk factors using the cut-off values obtained by ROC analysis and conventional cut-off values (men, 3.75; women, 3.00). RESULTS: In ROC analysis, the optimal cut-off values for TG/HDL-C ratio were 2.967 in men and 2.237 in women, which were much smaller than the conventional cut-of values. Odds ratios for multiple cardio-metabolic risk factors of subjects with vs. subjects without a high TG/HDL-C ratio in men and women were 5.75 (4.43-7.46) and 18.76 (10.32-34.13), respectively, by using the new cut-off values and they were 5.03 (3.96-6.39) and 16.11 (9.20-28.20), respectively, by using the conventional cut-off values. The odds ratios for visceral obesity, hypertension and diabetes were comparable when using these two different cut-off values. CONCLUSION: Cut-off values should be ideally calculated by ROC analysis. However, the discrimination power of cut-off values for the TG/HDL-C ratio calculated by ROC analysis for cardio-metabolic risk was similar to those by using the conventional cut-off values. Further studies using cardiovascular events as outcomes in the analysis may be needed to determine more suitable cut-off values of the TG/HDL-C ratio.

Proneness to high blood lipid-related indices in female smokers.

BACKGROUND: Smoking is a major risk factor for dyslipidemia. However, it remains to be clarified whether light smoking in Asian women affects lipid profiles and lipid-related indices. The aim of this study was to determine the relationships between lipid-related indices and smoking in Japanese women. Alcohol drinking influences blood lipid levels and is a potent confounder for the relationship between smoking and blood lipids. Thus, analysis for the relationships between smoking and blood lipid-related indices was also performed after stratification of drinking status. METHODS: The participants were 18,793 Japanese women aged 35-70 years. A cross-sectional study was performed using a local population-based database. The relationships of smoking with each index were investigated by using analysis of covariance and logistic regression analysis with adjustment for age and other lifestyle factors such as alcohol drinking and regular exercise. RESULTS: In multivariate logistic regression analysis, odds ratios of smokers vs. nonsmokers for high ratio of LDL cholesterol to HDL cholesterol (LDL-C/HDL-C), high ratio of triglycerides to HDL cholesterol (TG/HDL-C), high lipid accumulation product (LAP) and high cardio metabolic index (CMI) were significantly higher than the reference level of 1.00 in overall participants (2.17 [1.78-2.66], 1.70 [1.47-1.97], 1.17 [1.08-1.27] and 1.41 [1.30-1.53], respectively), nondrinking participants (2.29 [1.80-2.91], 1.68 [1.39-2.02], 1.21 [1.08-1.36] and 1.46 [1.30-1.63], respectively), and drinking participants (1.96 [1.35-2.85], 1.76 [1.39-2.21], 1.13 [1.01-1.27] and 1.38 [1.22-1.55], respectively). In overall participants, nondrinking participants, and drinking participants, LDL-C/HDL-C, TG/HDL-C, LAP and CMI were significantly higher in smokers than in nonsmokers. In nondrinking participants, triglycerides and LDL cholesterol were significantly higher in smokers than in nonsmokers, while the ratio of waist circumference to height and HDL cholesterol were significantly lower in smokers than in nonsmokers. CONCLUSION: In women, all of the four lipid-related indices tested were higher in smokers than in nonsmokers, and these associations were independent of alcohol drinking. The high levels of the lipid-related indices in smokers result from the detrimental effects of smoking on levels of blood lipids such as triglycerides, HDL cholesterol and LDL cholesterol.

Relationships of oxidized HDL with blood coagulation and fibrinolysis in patients with type 2 diabetes mellitus.

Although oxidization of LDL is known to be a crucial step for atherosclerotic progression, the significance of oxidized HDL remains to be clarified. The purpose of this study was to determine the relationships of oxidized HDL with blood coagulation and fibrinolysis in patients with diabetes. The subjects were outpatients with type 2 diabetes (n = 163; median hemoglobin A1c, 6.9%). Activities of blood coagulation and fibrinolysis were evaluated by levels of thrombin-anti-thrombin complex (TAT) and plasmin-α2 plasmin inhibitor complex (PIC), respectively. Relationships of oxidized HDL with TAT and PIC were investigated by using linear regression analysis and logistic regression analysis. Oxidized HDL showed a significant inverse correlation with TAT and a marginally significant correlation with PIC (Spearman's rank correlation coefficient: TAT, - 0.205 [p < 0.01]; PIC, - 0.135 [p = 0.087]). Prevalence of high TAT was significantly lower in the 3rd tertile group for oxidized HDL than in its 1st tertile (20.4 vs. 5.6%, p < 0.05), and prevalence of high PIC was marginally significantly lower in the 3rd tertile group for oxidized HDL than in its 1st tertile (40.7 vs. 24.1%, p = 0.099). In multivariate logistic regression analysis using age, gender, smoking, alcohol drinking, BMI, hemoglobin A1c, therapy for dyslipidemia, therapy for diabetes and anti-coagulation therapy as explanatory variables, odds ratios for high TAT and high PIC in the 3rd tertile group for oxidized HDL versus its 1st tertile group were significantly lower than the reference level of 1.00 (high TAT: 0.19 [0.04-0.99], p < 0.05; high PIC: 0.33 [0.12-0.95], p < 0.05). The frequency of high TAT or high PIC was lower in the higher tertile group for oxidized HDL than in its lower tertile group. Thus, oxidized HDL is thought to be inversely associated with both blood coagulation and fibrinolysis in patients with type 2 diabetes.

Effects of methanol and formic acid on human platelet aggregation.

BACKGROUND: Although ethanol is known to inhibit platelet aggregation, the effects of another variant of alcohol, methanol, have not been reported. The purpose of this study was to determine whether methanol and its metabolite, formic acid, affect Ca2+ entry into and subsequent aggregation of platelets in vitro. METHODS: Ca2+ entry into and aggregation of human platelets were measured by spectrofluorometry using Fura-2/AM as an indicator and the light transmission method, respectively. RESULTS: Thrombin-induced platelet aggregation was significantly augmented by methanol at pharmacological concentrations (0.5-2%) in a concentration-dependent manner. Methanol at 2% significantly attenuated thapsigargin-induced platelet aggregation, which was not significantly affected by lower concentrations (0.5 and 1%) of methanol. Methanol (0.5-2%) did not significantly affect platelet aggregation induced by 1-oleoyl-2-acetyl-sn-glycerol (OAG), or Ca2+ entry into platelets induced by thrombin, thapsigargin, or OAG. Platelet aggregation induced by thrombin, thapsigargin, or OAG was significantly inhibited by formic acid at toxic concentrations (0.01% or higher). Ca2+ entry into platelets induced by thrombin or thapsigargin was also significantly inhibited by formic acid at 0.01% or higher, while that induced by OAG was not affected by formic acid at 0.005 and 0.01% and augmented by that at 0.02%. CONCLUSIONS: Methanol at pharmacological doses has diverse effects on platelet aggregation, depending on the aggregation stimuli, without affecting Ca2+ entry into platelets. Formic acid at toxic concentrations has an inhibitory action on platelets aggregation, which was partly explained by the reduction of Ca2+ entry into platelets.

Selective induction of anti-inflammatory monocyte-platelet aggregates in a model of pulsatile blood flow at low shear rates.

In patients with cardiovascular abnormalities or immunological disorders, an increased number of circulating leukocyte-platelet aggregates is observed. Leukocyte-platelet aggregates play an essential role in linking the hemostatic and immune systems. High shear stress and pro-coagulant and pro-inflammatory stimulants are known to activate platelets and promote the formation of aggregates. Pulsatile blood flow under low shear stress can also induce platelet activation in comparatively mild conditions. However, the effect of such events on leukocyte-platelet aggregates has not yet been investigated. To determine whether low shear stress affects the formation of aggregates, we established a simple "inverting rotation" method of inducing periodic changes in the direction of blood flow in combination with low shear stress. We demonstrated that after the inverting rotation treatment for 10-20 min more than 70% of monocytes selectively aggregated with platelets. The formation of monocyte-platelet complexes was inhibited by an anti-CD162 (PSGL-1) monoclonal antibody or a Ca(2+) chelator. The phagocytic activity of monocytes was augmented by inverting rotation, whereas phagocytosis mediated by granulocytes remained unaffected. Interestingly, the formation of monocyte-platelet complexes suppressed the production of pro-inflammatory cytokines such as interleukin (IL)-1ß. At the same time, monocyte-platelet complexes augmented the expression of the anti-inflammatory cytokine IL-10. Our results suggest that platelet-bound monocytes show an anti-inflammatory phenotype under low shear stress conditions. Thus, our method provided new insights into the mechanisms of monocyte-platelet aggregate formation and regulation.

Relationship between Smoking and Cardiometabolic Index in Middle-Aged Men.

BACKGROUND: Cardiometabolic index (CMI) is a new index for discriminating diabetes mellitus and has been demonstrated to be associated with the degree of atherosclerosis in patients with peripheral arterial disease. The purpose of this study was to clarify the relationship of CMI with smoking, a major risk factor for atherosclerotic disease. METHODS: The subjects included 31,742 Japanese men (35 - 60 years old) receiving health-checkup examinations at their workplaces. CMI was calculated as a product of waist-to-height ratio and triglycerides-to-HDL cholesterol ratio. Relationships between CMI and smoking were investigated by using analysis of covariance and logistic regression analysis after adjusting for age and histories of alcohol drinking and regular exercise. RESULTS: Odds ratios (with their confidence intervals) vs. nonsmokers for high CMI (> 1.748) were 1.16 (1.10 - 1.23, p < 0.01) in light smokers (< or = 20 cigarettes/day), 1.60 (1.49 - 1.70, p < 0.01) in heavy smokers (> 20 and 5 40 cigarettes/day), and 2.34 (1.77 - 3.09, p < 0.01) in very heavy smokers (> 40 cigarettes/day). CMI was significantly higher in each smoker group than in the nonsmoker group and tended to be higher with an increase in amount of smoking. The odds ratio (with its confidence interval) for diabetes of subjects with vs. those without high CMI was 2.27 (2.06 - 2.50, p < 0.01) in overall subjects and was not significantly different in each smoker group compared with the odds ratio in the nonsmoker group. CONCLUSIONS: There was a dose-dependent relationship between CMI and amount of smoking, while the association between CMI and diabetes was not different in smokers and nonsmokers. Thus, CMI was suggested to be useful for discriminating diabetes both in smokers and nonsmokers.

A U-shaped relationship between alcohol consumption and cardiometabolic index in middle-aged men.

BACKGROUND: Cardiometabolic index (CMI) is a new index for discriminating diabetes. The purpose of this study was to determine whether CMI is affected by habitual alcohol drinking. METHODS: The subjects were 21572 men (35-60 years) receiving annual health checkups. They were divided by average daily ethanol consumption into non-, light (< 22 g), moderate (≥ 22 and < 44 g), heavy (≥ 44 and < 66 g) and very heavy (≥ 66 g) drinkers. Relationship between alcohol intake and CMI was investigated with adjustment for age and histories of smoking and regular exercise. RESULTS: Log-transformed CMI was significantly lower in light, moderate and heavy drinkers than in nondrinkers and was lowest in light drinkers, while there was no significant difference in log-transformed CMI of nondrinkers and very heavy drinkers. Odds ratio vs. nondrinkers for high CMI was significantly lower than the reference level of 1.00 in light, moderate and heavy drinkers and was lowest in light drinkers but was not significantly different from the reference level in very heavy drinkers. Odds ratio of subjects with vs. those without high CMI for hyperglycemia was significantly higher than the reference level in all of the alcohol groups and was significantly lower in moderate drinkers but was not significantly different in the other drinker groups when compared with the nondrinker group. CONCLUSION: There is a U-shaped relationship between alcohol consumption and CMI, and moderate drinking but not excessive drinking attenuates the association between CMI and hyperglycemia.

Recombinant human soluble thrombomodulin attenuates FK506-induced endothelial dysfunction through prevention of Akt inactivation.

Thrombomodulin (TM), a transmembrane glycoprotein on vascular endothelial cells, is a naturally occurring anticoagulant. Recombinant human soluble TM (rTM), composed of the extracellular domain of TM, also shows anti-coagulant and anti-inflammatory activity, but the effects of rTM on microangiopathy remain unclear. We reported that FK506 induced endothelial dysfunction through inactivation of Akt and extracellular-regulated kinase 1/2 using a three-dimensional culture blood vessel model. In the present study, we examined the effects of rTM on FK506-induced endothelial dysfunction. We found that rTM suppressed FK506-induced endothelial cell death, but not the breakdown of capillary-like tube structures. rTM prevented FK506-induced inactivation of Akt, but not of extracellular-regulated kinase 1/2. Akt inhibition by LY294002 abrogated the preventive effect of rTM on FK506-induced Akt inactivation and the suppressive effect of rTM on FK506-induced cell death. These results suggest that rTM attenuates FK506-induced endothelial dysfunction through prevention of Akt inactivation.

Association between serum long-chain n-3 and n-6 polyunsaturated fatty acid profiles and glomerular filtration rate assessed by serum creatinine and cystatin C levels in Japanese community-dwellers.

BACKGROUND: Plasma concentration of n-3 polyunsaturated fatty acids (PUFAs) has been reported to be associated with renal function in Western populations. However, few studies have investigated the association between serum long-chain n-3 and n-6 PUFA profiles and renal function in a Japanese population with high marine-derived long-chain n-3 PUFA intake. METHODS: A cross-sectional study was performed in 549 Japanese rural community-dwellers aged 40 to 64 years. In adjusted analysis of covariance, we assessed the relationship between estimated glomerular filtration rate (eGFR) and tertiles of serum long-chain n-3 and n-6 PUFA profiles ([eicosapentaenoic acid {EPA} + docosahexaenoic acid {DHA}]:arachidonic acid [AA]). GFR was estimated by Japanese specific equations using serum creatinine and cystatin C (eGFRcre and eGFRcys). Using multivariate-adjusted linear regression models, we also assessed the relationships between eGFRs and several n-3 and n-6 PUFAs, which have been suggested to be associated with renal function. RESULTS: In all participants, higher dietary fish intake as assessed by a semi-quantitative questionnaire was associated with higher serum value of (EPA+DHA):AA. Participants in the higher (EPA+DHA):AA tertiles had non-significantly higher eGFRcre and significantly higher eGFRcys (P = 0.016). In addition, eGFRcys in T2+T3 of (EPA+DHA):AA was significantly higher than that in T1 (adjusted mean eGFRcys, T1: 87 ml/min/1.73 m(2), T2+T3: 91 ml/min/1.73 m(2); P < 0.01). Among the PUFAs, only (EPA+DHA) was significantly associated with eGFRcys. CONCLUSIONS: Serum (EPA+DHA):AA, which reflects an individual's fish intake, might be associated with eGFRcys in Japanese community-dwellers.

Frequency of heavy alcohol drinking and risk of metabolic syndrome in middle-aged men.

BACKGROUND: Frequency of alcohol drinking is known to influence cardiovascular risk. However, little is known regarding the relationship between frequency of drinking and metabolic syndrome (MetS). The aim of this study was to determine how frequency of heavy drinking modifies the prevalence of MetS. METHODS: The subjects were middle-aged male nondrinkers and occasional or regular heavy drinkers (ethanol intake: ≥66 g per drinking day). Odds ratios (ORs) for MetS and each component comprising MetS were calculated with adjustment for age and histories of smoking and regular exercise. RESULTS: ORs versus nondrinkers for MetS defined by the criteria of the National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATP III) or the International Diabetes Federation (IDF) were significantly higher than the reference level of 1.00 in occasional heavy drinkers (NCEP-ATP III, 1.94 [confidence interval (CI): 1.54 to 2.45]; IDF, 1.97 [CI: 1.56 to 2.49]) and regular heavy drinkers (NCEP-ATP III, 1.48 [CI: 1.19 to 1.84]; IDF, 1.50 [CI: 1.20 to 1.86]). When compared with the reference level, OR versus nondrinkers for large waist circumference was significantly higher in occasional heavy drinkers (1.96 [CI: 1.63 to 2.35]), but not in regular heavy drinkers (1.12 [CI: 0.96 to 1.32]), while OR versus nondrinkers for hyperglycemia was significantly lower in regular heavy drinkers (0.66 [CI: 0.46 to 0.95]), but not in occasional heavy drinkers (0.86 [CI: 0.60 to 1.24]). CONCLUSIONS: There is a positive association between heavy drinking and MetS, which is stronger in occasional drinkers than in regular drinkers. This difference may be explained by a positive association between occasional heavy drinking and central obesity and an inverse association between regular heavy drinking and hyperglycemia. The results suggest that heavy drinking, even if occasionally, is a cardiovascular risk factor.