Atherosclerosis is a progressive disease characterized by the accumulation of lipids in medium to large sized arteries. Atherothrombosis is a term used to describe formation of a thrombus after rupture of an atherosclerotic plaque. Thrombosis can lead to myocardial infarction and stroke. Risk factors for atherosclerosis include hyperlipidemia, diabetes, smoking and hypertension all of which increase tissue factor (TF) expression. High levels of TF are present in atherosclerotic plaques due to expression by macrophages and vascular smooth muscle cells and the presence of cell-derived TF-positive microvesicles (MVs). In addition, hyperlipidemia leads to the formation of oxidized LDL, which induces TF expression in circulating monocytes and the release of TF-positive MVs. The major source of TF that drives thrombosis after plaque rupture is TF within the plaque. However, TF in the blood on monocytes and MVs may also contribute the thrombosis. Inhibition of the TF/factor VIIa complex is unlikely to be an effective strategy to reduce atherothrombosis due the essential role of the complex in hemostasis. However, selective blockade of pathologic TF without affecting protective TF may be effective in reducing atherothrombosis. For instance, statins have been shown to reduce TF expression in the plaque and in circulating monocytes, which would be expected to reduce thrombosis. Further studies are needed to determine safe strategies to reduce pathologic TF expression and atherothrombosis.
Aim: Prasugrel is a novel platelet P2Y12 receptor blocker with a faster onset of action and greater platelet inhibition with less response variability than clopidogrel. Our objective was to determine the optimal prasugrel dose in Japanese patients undergoing elective percutaneous coronary intervention (PCI) with respect to the incidence of bleeding and platelet inhibition. Methods: A total of 422 patients were randomly assigned to receive clopidogrel or prasugrel in two strata (standard group: ＜75 years of age and body weight ＞50 kg, n=312; high-risk group: ≥75 years of age and/or body weight ≤50 kg, n=110). The standard group received 20/3.75 or 20/5mg (loading/maintenance doses for three months) of prasugrel or 300/75mg of clopidogrel, while the high-risk group received 20/2.5 or 20/3.75mg of prasugrel or 300/75mg of clopidogrel. Results: The rates of TIMI major and minor bleeding (primary endpoint) were similar among the three treatment arms in the standard group (20/5mg of prasugrel: 0%; 20/3.75mg of prasugrel: 3.8%; 300/75mg of clopidogrel: 2.9%) and the high-risk group (20/3.75mg of prasugrel: 2.7%; 20/2.5mg of prasugrel: 0%; 300/75mg of clopidogrel: 2.8%). VerifyNow assays revealed sufficient levels of platelet inhibition at Weeks 4 and 12 in both the prasugrel arms of the standard group and the 20/3.75mg of prasugrel arm in the high-risk group. Platelet inhibition was not affected by the CYP2C19 phenotype in the prasugrel groups. Conclusions: The prasugrel dosing regimen of 20/3.75mg has strong antiplatelet effects and the risk of bleeding events is low in Japanese patients undergoing PCI.
Aims: High mobility group box 1 (HMGB1) is a DNA-binding protein secreted into the extracellular space from necrotic cells that acts as a cytokine. We examined the role of HMGB1 in angiogenesis from bone marrow-derived cells in the heart using transgenic mice exhibiting the cardiac-specific overexpression of HMGB1 (HMGB1-TG). Methods: HMGB1-TG mice and wild-type littermate (WT) mice were lethally irradiated and injected with bone marrow cells from green fluorescent protein mice through the tail vein. After bone marrow transplantation, the left anterior descending artery was ligated to induce myocardial infarction (MI). Results: Flow cytometry revealed that the levels of circulating endothelial progenitor cells (EPCs) mobilized from the bone marrow increased after MI in the HMGB-TG mice versus the WT mice. In addition, the size of MI was smaller in the HMGB1-TG mice than in the WT mice, and immunofluorescence staining demonstrated that the number of engrafted vascular endothelial cells derived from bone marrow in the border zones of the MI areas was increased in the HMGB1-TG mice compared to that observed in the WT mice. Moreover, the levels of cardiac vascular endothelial growth factor after MI were higher in the HMGB1-TG mice than in the WT mice. Conclusions: The present study demonstrated that HMGB1 promotes angiogenesis and reduces the MI size by enhancing the mobilization and differentiation of bone marrow cells to EPCs as well as their migration to the border zones of the MI areas and engraftment as vascular endothelial cells in new capillaries or arterioles in the infarcted heart.
Aim: Vitamin D deficiency, which is prevalent among young women in Middle Eastern populations, has been linked to cardiovascular disease. Epicardial adipose tissue (EAT) has also been found to be associated with coronary artery disease. However, data on the relationship between vitamin D status and epicardial adiposity is limited. This study aims to investigate the effect of vitamin D deficiency and replacement therapy on EAT thickness in healthy, young premenopausal women. Methods: Thirty-one premenopausal women with vitamin D deficiency and 31 age-matched women with normal vitamin D levels were enrolled in this study. EAT thickness was measured echocardiographically. Measurements were performed at baseline in both groups and were repeated at the 6-month follow-up in vitamin D deficient subjects after vitamin D replacement therapy. Results: The baseline plasma 25-hydroxyvitamin D levels were lower in the vitamin D deficient group compared to the control group and were significantly improved following replacement therapy. EAT thickness was significantly higher in the vitamin D deficient group, and no significant change occurred following replacement therapy. In the linear regression analysis, waist circumference (β=0.031 [0.005-0.057], p=0.020) and 25(OH)D level (β=－0.020 [(－0.028)－(－0.013)], p＜0.001) independently correlated with EAT thickness. Conclusion: Vitamin D deficiency is associated with a significant increase in EAT thickness in premenopausal women; however, a net beneficial response to adequate replacement therapy was not observed during the short period of therapy during our study. Longer periods of replacement therapy and follow-up may be useful to demonstrate the potential beneficial effects of vitamin D replacement on epicardial adiposity.
Aim: To examine whether the inflammatory markers C-reactive protein (CRP) and fibrinogen are associated with biomarkers of atherosclerosis [carotid intima-media thickness (IMT) and coronary artery calcification (CAC)] in the general male population, including Asians. Methods: Population-based samples of 310 Japanese, 293 Japanese-American and 297 white men 40-49 years of age without clinical cardiovascular disease underwent measurement of IMT, CAC and the CRP and fibrinogen levels as well as other conventional risk factors using standardized methods. Statistical associations between the variables were evaluated using multiple linear or logistic regression models. Results: The Japanese group had significantly lower levels of inflammatory markers and subclinical atherosclerosis than the Japanese-American and white groups (P-values all ＜0.001). The mean level of CRP was 0.66 vs. 1.11 and 1.47 mg/L, while that of fibrinogen was 255.0 vs. 313.0 and 291.5 mg/dl, respectively. In addition, the mean carotid IMT was 0.61 vs. 0.73 and 0.68 mm, while the mean prevalence of CAC was 11.6% vs. 32.1% and 26.3%, respectively. Body mass index (BMI) showed significant positive associations with both the CRP and fibrinogen levels. Although CRP showed a significant positive association with IMT in the Japanese men, this association became non-significant following adjustment for traditional risk factors or BMI. In all three populations, CRP was not found to be significantly associated with the prevalence of CAC. Similarly, fibrinogen did not exhibit a significant association with either IMT or the prevalence of CAC. Conclusions: The associations between inflammatory markers and subclinical atherosclerosis may merely reflect the strong associations between BMI and the levels of inflammatory markers and incidence of subclinical atherosclerosis in both Eastern and Western populations.
Aim: Macrophage-derived chemokine (CCL22) is a member of the CC-family of chemokines synthesized by monocyte-derived macrophages. Previous studies have reported a relationship between CCL22 and atherosclerosis and the role of histamine in this pathway. Histamine ncreases the CCL22 expression in human monocytes via the H2 receptor. In this study, we investigated the effects of CCL22 and the role of histamine in mouse monocytes with respect to atherosclerosis. Methods and Results: The expression of CCL22 was investigated in apolipoprotein E (apoE)-deficient mice. The mice had high serum concentrations of CCL22 and their atherosclerotic lesions contained abundant levels of CCL22. In addition, when the mouse monocyte cell line (J774A.1 cells) differentiated into macrophage-like cells, the cells showed a similar expression of CCL22 and reduced expression of H2 receptors. Histamine is synthesized from l-histidine by histidine decarboxylase (HDC) in a single enzymatic step. HDC knockout mice were compared with apoE/HDC double knockout mice. The findings indicated that the expression of CCL22 in atherosclerosis models is under the influence of histamine. In addition, in vitro studies using J774A.1 cells and an in vivo study using histamine receptor knockout mice showed that histamine stimulates the CCL22 expression via the histamine H2 receptor. Conclusions: The current results support our previous CCL22 studies in the setting of human atherosclerosis and suggest that this molecule is involved in the atherogenic processes in a mouse model of atherosclerosis.
Aim: Both an overweight status and obesity are associated with high cardiovascular morbidity and mortality. The aim of this study was to examine the effects of obesity on different underlying mechanisms, i.e. inflammation, fibrinolysis and a prothrombotic state, in a young high-risk population in the Mediterranean area. Methods: The study population included 237 subjects (median age: 44 years). We recorded the presence of cardiovascular risk factors and premature ischaemic heart disease and performed weight stratification using the body mass index (BMI) according to the established World Health Organization (WHO) criteria. We also measured the serum/plasma lipid, fibrinogen, D-dimer, von Willebrand factor, tissue plasminogen activator antigen (t-PA), plasminogen activator inhibitor-1 antigen (PAI-1) and high-sensitivity C-reactive protein (CRP-hs) levels in samples of peripheral blood. Results: The subjects with premature ischaemic heart disease and hypertension had higher BMI values (p＜0.01), and the subjects with an increased weight showed an unadjusted detrimental lipid profile, with a proinflammatory, prothrombotic state and abnormal fibrinolytic parameters. According to a multivariate analysis, the HDL-cholesterol (r2=0.176; p＜0.001), t-PA antigen (r2=0.235; p＜0.001), PAI-1 antigen (r2=0.164; p＜0.001) and CRP-hs (r2=0.096; p=0.019) levels were significantly related to the weight stratification. Conclusions: A high BMI is a common finding in young populations at high risk of cardiovascular disease. In the current study, the patients with an increased BMI demonstrated an unhealthy lipid profile, as well as a proinflammatory and prothrombotic state and abnormal fibrinolytic parameters.
Aim: Whether there are differences among statins in their effect on the kidney function in diabetic patients remains controversial. In this report, we aimed to examine the comparative effects of statins on the kidney function in a long-term follow-up study. Methods: This was a single-center longitudinal observational historical cohort study. We enrolled 326 Japanese adult ambulatory patients with type 2 diabetes who were newly prescribed one of four statins (pravastatin, rosuvastatin, atorvastatin and pitavastatin) and who had an estimated glomerular filtration rate (eGFR) of ≥30 mL/min/1.73m2. The outcome measurement was the annual rate of change in eGFR. We used the standardized inverse probability of treatment weighted (IPTW) method based on the propensity score to adjust for the effects of confounding factors. Furthermore, in order to take into account the variety in the number and spacing of eGFR measurements and the duration of the follow-up period for each individual, we conducted a linear mixed-effects model regression analysis. Results: The median follow-up period was 4.3years (range, 3.0-7.1years). In an analysis using the IPTW method, the mean (±standard error) annual rate of change in eGFR among the patients treated with pravastatin (−0.86±0.28 mL/min/1.73m2/year) was significantly lower than that observed among the patients treated with rosuvastatin (−1.80±0.27, p=0.02), atorvastatin (−1.99± 0.28, p=0.004) and pitavastatin (−2.23±0.49, p=0.02). Similar results were obtained in the linear mixed-effects model regression analysis. Conclusions: Pravastatin may be superior to rosuvastatin, atorvastatin and pitavastatin in preserving the kidney function in patients with type 2 diabetes.
Aim: Takayasu arteritis (TA) is associated with increased cardiovascular morbidity and mortality, and the degree of arterial stiffness is an independent predictor of cardiovascular mortality in a variety of diseases. In addition, the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of ventricular dysfunction, have been found to be higher in patients with TA than in healthy controls. In this study, we aimed to investigate the relationship between the plasma NT-proBNP levels and arterial stiffness in patients with TA. Methods: Seventy-two patients with TA were recruited in this study. The participants were analyzed with respect to the NT-proBNP levels, cardiovascular risk factors, TA-related variables and arterial stiffness assessed according to the brachial-ankle pulse wave velocity (baPWV). The patients were divided into two groups based on the mean baPWV, and the association between the NT-proBNP and baPWV values was tested using uni- and multivariate analyses. Results: Twenty-four patients (33.3%) were classified into the high-baPWV group. The body mass index (p=0.035), systolic blood pressure (p＜0.001), diastolic blood pressure (p=0.001), mean blood pressure (p＜0.001), plasma NT-proBNP levels (p=0.036) and total cholesterol levels (p=0.030) were significantly higher in the high-baPWV group than in the low-baPWV group. A stepwise multiple linear regression analysis revealed the mean blood pressure (p＜0.001), age (p=0.002), and NT-proBNP level (p=0.002) to be independent determinants of the ba-PWV after adjusting for other confounding factors. Conclusions: The plasma NT-proBNP levels are independently associated with the degree of arterial stiffness measured according to the baPWV in patients with TA.
Aim: The purpose of this study was to determine whether arterial stiffness can be used to predict one-year changes in the cognitive function in Japanese community-dwelling elderly subjects. Methods: A total of 103 Japanese community-dwelling elderly patients joined this study. Information regarding the age, height, weight, gender and past medical history of each participant was obtained. Additionally, arterial stiffness was determined according to the cardio-ankle vascular index (CAVI), and the cognitive function was assessed with the Mini-Mental State Examination (MMSE). One year later, we performed the MMSE in the same subjects. After dividing the cohort according to the 80th percentile of the CAVI (normal and arterial stiffness [AS] groups), we examined whether the degree of cognitive decline, as determined using the pre- and post-MMSE, was significantly different based on the severity of arterial stiffness, adjusted for age, BMI, gender and the pre-MMSE scores. Results: Of the 103 subjects who participated in the pre-data collection, 74 (38 men and 36 women, 73.4±4.0 years) joined the post-data collection. We found a significant difference in the change in the post-MMSE scores between the normal and AS groups (pre-MMSE: normal group [27.4±2.1] and AS group [26.9±2.4] and post-MMSE: normal group [27.2±2.1] and AS group [25.5±2.3], F=5.95, p=0.02). For each domain of the MMSE, the changes in MMSE-attention-and-calculation (F=5.11, p=0.03) and MMSE-language (F=4.32, p=0.04) were significantly different according to an ANCOVA. Conclusions: We found that arterial stiffness predicts cognitive decline in Japanese community-dwelling elderly subjects regardless of the initial level of the global cognitive function. This finding indicates the potential use of the degree of arterial stiffness as an indicator for preventing or delaying the onset of dementia in the elderly.
Aim: To investigate the acute effects of the ingestion of a fructose-containing beverage combinedwith fat on postprandial lipoprotein metabolism. Methods: Twelve young healthy Japanese women with apolipoprotein E phenotype 3/3 were enrolled in this study. At each of four sessions, the subjects ingested one of four sugar beverages containing fructose and/or glucose (total: 0.5g/kg body weight) combined with OFTT cream (1g/kg, 0.35g/kg as fat) in a randomized crossover design. The four sugar beverages were as follows: 100% (w/w) fructose (F100), 90% fructose+10% glucose (F90G10), 55% fructose+45% glucose (F55G45) and 100% glucose (G100). Venous blood samples were obtained at baseline and 0.5, one, two, four and six hours after ingestion. Results: The serum concentrations of TG in the F100, F90G10 and F55G45 trials were significantlyhigher than each fasting value at two and four hours, and returned to baseline at six hours, except inthe F100 trial. The concentrations at four hours and the incremental areas under the curve for thehepatic triglyceride-rich lipoprotein-triglyceride (VLDL-TGTM) levels in the F100 and F90G10 trialswere significantly higher and larger, respectively, than those observed in the G100 trial. Meanwhile,the concentrations of RLP-TG and apolipoprotein B-48 peaked at two hours in the G100 trial, versusfour hours in the other trials, and did not return to baseline at six hours, except in the G100 trial.At four hours, the ⊿apoB48 tended to be higher in the F100 trial than in the G100 trial. Conclusions: The ingestion of a high-fructose-containing beverage with fat cream delays the clearance of chylomicron and its remnant derived from the intestine and enhances the secretion of triglyceride-rich lipoprotein particles from the liver, thereby inducing postprandial lipidemia, even in young healthy women.