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Endosialin, also called tumor endothelial marker-1 or CD248, is a transmembrane glycoprotein that is suggested to play a role in inflammation as well as tumor progression. Endosialin expression was also reported to be upregulated in human atherosclerotic lesions. However, no study has reported blood endosialin levels in patients with coronary artery disease (CAD).We investigated the association between plasma endosialin levels and the presence or severity of CAD in 376 patients who underwent elective coronary angiography for suspected CAD. The severity of CAD was represented as the numbers of stenotic coronary vessels and segments.Of the 376 study patients, CAD was found in 210 patients (one-vessel disease (1-VD), n = 90; two-vessel disease (2-VD), n = 65; and three-vessel disease (3-VD), n = 55). Compared with 166 patients without CAD, 210 patients with CAD had higher C-reactive protein (CRP) levels (median 0.57 vs. 0.43 mg/L, P = 0.007). However, endosialin levels did not significantly differ between patients with and without CAD (0.91 vs. 0.92 ng/mL, P = 0.693). A stepwise increase in CRP levels was found depending on the number of50% stenotic vessels: 0.43 in CAD(-), 0.52 in 1-VD, 0.57 in 2-VD, and 0.58 mg/L in 3-VD (P = 0.019). No marked difference was found in endosialin levels among four groups of CAD(-), 1-VD, 2-VD, and 3-VD (0.92, 0.89, 0.98, and 0.87 ng/mL, respectively, P = 0.785). Moreover, no significant correlation was found between endosialin levels and the numbers of50% and25% stenotic segments or CRP levels. In multivariate analysis, endosialin levels were not a significant factor associated with CAD independent of atherosclerotic risk factors.Plasma endosialin levels in patients with CAD were found to be not higher than in those without CAD and to be not significantly associated with the presence or severity of CAD.

Green tea and coffee contain various bioactive compounds (e.g., polyphenols), and their consumption has been proposed to decrease the risk of cardiovascular diseases. Here, we investigated the associations between the consumption of green tea and that of coffee and the prevalence of coronary artery disease (CAD) in Japanese patients. The study group was 612 patients who underwent coronary angiography at Tokyo Medical Center between July 2008 and February 2017. CAD was confirmed in 388 of the patients: one-vessel disease (1-VD, n=166); two-vessel disease (2-VD, n=112); three-vessel disease (3-VD, n=110). Myocardial infarction (MI) was found in 138 patients. After adjustment for well-known atherosclerotic risk factors and other dietary habits, greater green tea consumption was significantly inversely associated with CAD prevalence (p for trend=0.044), and the patients who drank3 cups/d had a lower prevalence of CAD compared to those who drank1 cup/d (odds ratio [OR]: 0.54, 95% CI: 0.30-0.98). Greater green tea consumption (3 cups/d) was also associated with a decreased prevalence of 3-VD (OR: 0.49, 95% CI: 0.24-0.98, p-trend=0.047) and MI (OR: 0.51, 95% CI: 0.27-0.97, p-trend=0.037). In contrast, coffee consumption was not associated with CAD or MI. In subgroup analyses, the inverse association between green tea consumption and CAD or MI was found in the high intake groups of vegetables or fruits but not in the low intake groups of vegetables or fruits. These results suggest a beneficial effect of green tea consumption, especially with a diet rich in vegetables and fruits, against coronary atherosclerosis in Japanese.

Follistatin-like protein 1 (FSTL1) is a secreted glycoprotein known for its role in inflammation. However, plasma FSTL1 levels in patients with coronary artery disease (CAD) have not been fully elucidated. Thus, in this study, we investigated the plasma FSTL1 levels of 350 patients who underwent elective coronary angiography. The severity of CAD was represented as the numbers of50% stenotic vessels and segments and the severity score. CAD was detected in 196 patients, of whom 84 had 1-vessel disease (1-VD), 62 had 2-VD, and 50 had 3-VD. Plasma high-sensitivity C-reactive protein (hsCRP) levels were higher in patients with CAD than in those without CAD (median 0.56 versus 0.44 mg/L, P0.01). Notably, plasma FSTL1 levels were higher in patients with CAD than in those without CAD (median 4.05 versus 3.47 ng/mL, P0.02). A stepwise increase in FSTL1 levels was found depending on the number of50% stenotic vessels: 3.47 in CAD (-), 3.74 in 1-VD, 4.42 in 2-VD, and 4.65 ng/mL in 3-VD (P0.05). FSTL1 levels also correlated with the number of50% stenotic segments and the severity score (r = 0.14 and r = 0.15, respectively, P0.005) and hsCRP levels (r = 0.10, P0.05). In the multivariate analysis, FSTL1 levels were an independent factor associated with CAD. The odds ratio for CAD was 1.61 (95% CI = 1.01-2.58) for high FSTL1 level of3.6 ng/mL (P0.05). In conclusion, plasma FSTL1 levels in patients with CAD were found to be high and associated with the presence and severity of CAD, thus, suggesting that FSTL1 may play a role in the progression of coronary atherosclerosis.

Aim: Betatrophin, a recently identified circulating adipokine, affects lipid and glucose metabolism. However, association between plasma betatrophin levels and atherosclerotic diseases, such as coronary artery disease (CAD) and peripheral artery disease (PAD), has not been elucidated. Methods: We investigated plasma betatrophin levels in 457 patients undergoing elective coronary angiography who also had ankle-brachial index (ABI) test for PAD screening. Results: Of the 457 study patients, CAD was present in 241 patients (53%) (1-vessel [1-VD], n = 99; 2-vessel [2-VD], n = 71; 3-vessel disease [3-VD], n = 71). Compared to 216 patients without CAD, 241 with CAD had higher betatrophin levels (median 1120 vs. 909 pg/mL, p < 0.001). A stepwise increase in betatrophin levels was found depending on the number of > 50% stenotic coronary vessels: 909 in CAD(-), 962 in 1-VD, 1097 in 2-VD, and 1393 pg/ml in 3-VD (p < 0.001). Betatrophin levels correlated with the number of > 25% stenotic segments (r = 0.24, p < 0.001). PAD (ABI < 0.9) was found in 41 patients (9%). Plasma betatrophin levels were also significantly higher in 41 patients with PAD than in 416 without PAD (1354 vs. 981 pg/mL, p < 0.001). In the multivariate analysis, betatrophin levels were not a factor for CAD, but they were a significant factor for 3-VD and PAD independent of atherosclerotic risk factors. The odds ratios for 3-VD and PAD were 1.06 (95%CI = 1.01–1.11) and 1.07 (95%CI = 1.01–1.13) for a 100-pg/mL increase in betatrophin levels, respectively (p < 0.05). Conclusion: Plasma betatrophin levels were associated with the presence and severity of CAD and PAD, suggesting betatrophin has a role in atherosclerosis.

Aim: Osteoglycin is one of proteoglycans that are biologically active components of vascular extracellular matrix. However, the role of osteoglycin in atherosclerosis remains unclear. Methods: We investigated plasma osteoglycin levels and the presence, severity, and lesion morphology of coronary artery disease (CAD) in 462 patients undergoing elective coronary angiography. Results: Of 462 patients, 245 had CAD. Osteoglycin levels were higher in patients with CAD than without CAD (median 29.7 vs. 25.0 ng/mL, P < 0.05). However, osteoglycin levels did not differ among patients with one-vessel, two-vessel, or three-vessel disease (30.8, 30.6, and 29.4 ng/mL, respectively) and did not correlate with the number of stenotic segments. Among 245 CAD patients, 41 had complex coronary lesions, and 70 had total occlusion, of whom 67 had good collateralization. Between 70 patients with occlusion and 175 without occlusion, osteoglycin levels did not differ (30.4 vs. 29.5 ng/mL). Notably, osteoglycin levels were lower in 41 patients with complex lesions than in 204 without such lesions (24.2 vs. 31.6 ng/mL, P < 0.02). In multivariate analysis, osteoglycin levels were an independent factor for complex lesion but not for CAD. Odds ratio for complex lesion was 0.80 (95%CI = 0.67–0.96) for each 10 ng/mL increase in osteoglycin levels (P < 0.02). Conclusion: Although plasma osteoglycin levels were high in patients with CAD, they did not correlate with the severity of CAD and were not an independent factor for CAD. Notably, osteoglycin levels were low in patients with complex lesions and were a factor for complex lesions, suggesting that osteoglycin plays a role in coronary plaque stabilization.

Aims. Atherosclerotic disease, such as coronary artery disease (CAD), is recognized to be associated with inflammation and oxidative stress. We investigated the association between CAD and plasma levels of sestrin2 which is one of the stress-inducible antioxidant proteins. Methods. We measured plasma sestrin2 levels in 304 patients undergoing elective coronary angiography. The severity of CAD was represented as the numbers of >50% stenotic coronary vessels and segments and the severity score. Results. CAD was found in 175 patients, of whom 73 had 1-vessel (1-VD), 59 had 2-vessel (2-VD), and 43 had 3-vessel disease (3-VD). Plasma sestrin2 levels were significantly higher in 175 patients with CAD than in 129 without CAD (median 16.4 vs. 14.2 ng/mL, P<0.05). A stepwise increase in sestrin2 levels was found depending on the number of >50% stenotic coronary vessels: 14.2 in CAD(-), 15.4 in 1-VD, 17.3 in 2-VD, and 17.7 ng/mL in3-VD (P<0.05). High sestrin2 level (>16.0 ng/mL) was present in 38% of patients with CAD(-), 47% of 1-VD, 66% of 2-VD, and 53% of 3-VD (P<0.005). Sestrin2 levels significantly, but weakly, correlated with the number of >50% stenotic segments and the severity score (rs=0.12 and rs=0.13, P<0.05). In the multivariate analysis, sestrin2 levels were a significant factor associated with CAD independent of atherosclerotic risk factors. The odds ratio for CAD was 1.79 (95%CI=1.09‐2.95) for high sestrin2 level of >16.0 ng/mL (P<0.025). Conclusions. Plasma sestrin2 levels in patients with CAD were found to be high and to be associated with the severity of CAD. High sestrin2 levels in patients with CAD may reflect a protective response against the progression of CAD.

Aims. Heme oxygenase-1 (HO-1) is an intracellular enzyme that catalyzes the oxidation of heme to generate CO, biliverdin, and iron. Since these products have antiatherogenic properties, HO-1 may play a protective role against the progression of atherosclerosis. However, plasma HO-1 levels in patients with atherosclerotic diseases, such as coronary artery disease (CAD) and peripheral artery disease (PAD), have not been clarified yet. Methods. We investigated plasma HO-1 levels by ELISA in 410 consecutive patients undergoing elective coronary angiography who also had an ankle-brachial index (ABI) test for PAD screening. Results. Of the 410 study patients, CAD was present in 225 patients (55%) (1-vessel (1-VD), n=91; 2-vessel (2-VD), n=66; 3-vessel disease (3-VD), n=68). PAD (ABI P<0.02). After excluding the 36 patients with PAD, HO-1 levels were significantly higher in 192 patients with CAD than in 182 without CAD (0.45 versus 0.35 ng/mL, P<0.05). HO-1 levels in 4 groups of CAD(−), 1-VD, 2-VD, and 3-VD were 0.35, 0.49, 0.44, and 0.44 ng/mL, respectively, and were highest in 1-VD (P<0.05). In the multivariate analysis, HO-1 levels were inversely associated with PAD, whereas they were also associated with CAD. The odds ratios for PAD and CAD were 2.12 (95% CI = 1.03–4.37) and 0.65 (95% CI = 0.42–0.99) for the HO-1 level of Conclusions. Plasma HO-1 levels were found to be low in patients with PAD, in contrast to high levels in patients with CAD.

text, 紀要論文 / Departmental Bulletin Paper

text, 紀要論文 / Departmental Bulletin Paper

Objective— Transforming growth factor-β inhibits migration and proliferation of endothelial and smooth muscle cells. Endoglin is a transmembrane receptor for transforming growth factor-β1 and transforming growth factor-β3. Endoglin is released into blood as a soluble form (soluble endoglin [sEng]), but plasma sEng levels in patients with coronary artery disease (CAD) have not been elucidated. Approach and Results— We measured plasma sEng levels in 244 patients undergoing coronary angiography. The severity of coronary atherosclerosis was evaluated as the numbers of >50% stenotic vessels and segments. CAD was found in 147 patients, of whom 55 had 1-vessel, 42 had 2-vessel, and 50 had 3-vessel disease. Compared with 97 patients without CAD, 147 with CAD had lower sEng levels (median 4.04 versus 4.37 ng/mL; P P r =−0.25; P P P Conclusions— Plasma sEng levels were low in patients with CAD, especially 3-vessel disease, and were inversely associated with the severity of coronary atherosclerosis.

Aim: The degradation of the vascular extracellular matrix is important for atherosclerosis. The cysteine protease legumain was shown to be upregulated in atherosclerotic plaques, especially unstable plaques. However, no study has reported blood legumain levels in patients with coronary artery disease (CAD). Methods: We investigated plasma legumain and C-reactive protein (CRP) levels in 372 patients undergoing elective coronary angiography. Results: CAD was found in 225 patients. Compared with patients without CAD, those with CAD had higher CRP levels (median 0.60 [0.32, 1.53] vs. 0.46 [0.22, 0.89] mg/L, P < 0.001), but no difference was found in legumain levels between patients with and without CAD (median 5.08 [3.87, 6.82] vs. 4.99 [3.84, 6.88] ng/mL). A stepwise increase in CRP was found depending on the number of > 50% stenotic vessels: 0.55 mg/L in 1-vessel, 0.71 mg/L in 2-vessel, and 0.86 mg/L in 3-vessel diseases (P < 0.001). However, legumain did not differ among 1-, 2-, and 3-vessel diseases (5.20, 4.93, and 5.01 ng/mL, respectively). Of 225 patients with CAD, 40 (18%) had complex lesions. No difference was found in CRP levels between patients with CAD with and without complex lesions (0.60 [0.34, 1.53] vs. 0.60 [0.32, 1.51] mg/L). Notably, legumain levels were higher in patients with CAD with complex lesions than without such lesions (6.05 [4.64, 8.64] vs. 4.93 [3.76, 6.52] ng/mL, P < 0.01). In multivariate analysis, legumain levels were not a factor for CAD, but were a factor for complex lesions. The odds ratio for complex lesions was 2.45 (95% CI = 1.26–4.79) for legumain > 5.5 ng/mL. Conclusion: Plasma legumain levels were associated with the presence of complex coronary lesions.

Aims. Betatrophin is a recently identified circulating adipokine that may affect lipid and glucose metabolism. However, the association between plasma betatrophin levels and carotid atherosclerosis has not been elucidated. Methods. We investigated plasma betatrophin levels in 153 subjects undergoing carotid ultrasonography. The severity of plaque was evaluated as plaque score. Results. Of the 153 subjects, plaque was found in 63 (41%). Plasma betatrophin levels were higher in 63 subjects with plaque than in 90 without plaque (median 906 vs. 729 pg/mL, P<0.025). A stepwise increase in betatrophin levels was found depending on the plaque score: 729 pg/mL in score=0 (n=90), 802 pg/mL in score=1 (n=31), and 978 pg/mL in score≥2 (n=32) (P<0.01). In particular, betatrophin levels in subjects with score≥2 were higher than in those with score=0 (P<0.05). Moreover, betatrophin levels correlated with plaque score (r=0.23, P<0.01), but no significant correlation was found between betatrophin levels and triglyceride or HbA1c levels. The percentage of subjects with betatrophin>800 pg/mL was higher in subjects with plaque than in those without plaque (65% vs. 44%) and was highest in score≥2 (78%) (P<0.005). In the multivariate analysis, betatrophin level was not a significant factor for the presence of plaque but was a significant factor for plaque score≥2, independent of atherosclerotic risk factors. The odds ratio for score≥2 was 4.9 (95% CI=1.9-12.8) for betatrophin>800 pg/mL. Conclusions. Plasma betatrophin levels were found to be high in subjects with carotid plaque and to be associated with the severity of plaque. Betatrophin may play a role in the progression of carotid atherosclerosis.

text, 紀要論文 / Departmental Bulletin Paper

text, 紀要論文 / Departmental Bulletin Paper

text, 紀要論文 / Departmental Bulletin Paper

text, 紀要論文 / Departmental Bulletin Paper

Resistin is an adipocytokine that may link inflammation and atherosclerosis.We studied the associations of resistin levels with cardiovascular events and restenosis.We measured pre-procedural serum resistin levels in 140 patients with coronary artery disease undergoing elective percutaneous coronary intervention (PCI), of whom 97 had a stent. Restenosis was defined as50% stenosis at follow-up angiography. Patients were followed for 3 years for major adverse cardiovascular events (MACE).At 8±6 months after PCI, reangiography was performed in 94 (67%) patients, of whom 42 had restenosis. Between 42 patients with restenosis and 52 without restenosis, resistin (4.5±2.6 vs. 4.5±2.5 ng/mL) and Creactive protein (CRP) (median 0.70 vs. 0.70 mg/L) levels did not differ. During 3-year follow-up, MACE occurred in 24 patients (1 death, 21 unstable angina, 2 stroke). Compared with 116 patients without MACE, 24 with MACE had higher resistin (5.4±2.4 vs. 4.3±2.5 ng/mL) and CRP (1.30 vs. 0.60 mg/L) levels (p0.05). Patients with MACE more often had resistin4.0 ng/mL than without MACE (75% vs. 35%, p0.001). Resistin correlated with CRP levels (r= 0.31). To clarify the association between MACE and resistin, patients were divided into 2 groups by resistin levels. Kaplan-Meier analysis showed a lower event-free survival rate in patients with resistin4.0 ng/mL than without it (p0.001). On multivariate analysis, resistin, but not CRP, was an independent predictor of MACE. The hazard ratio for MACE was 3.6 (95%CI=1.4-9.2) for resistin4.0 ng/mL.Serum resistin levels were found to be associated with further cardiovascular events in patients undergoing PCI.

text, 紀要論文 / Departmental Bulletin Paper

alpha-Tocopherol (alpha-Toc) is abundant in LDL and thought to prevent the oxidation of LDL together with various water-soluble antioxidants. Recently, it was reported that alpha-Toc and gamma-Toc metabolites, alpha-carboxyethyl-6-hydroxychromans (CEHC) and gamma-CEHC, are water-soluble antioxidants. In this study, we investigated the interaction between alpha-Toc and CEHC against 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radicals and LDL oxidation. We administered 600 mg of alpha-Toc to healthy male volunteers to obtain LDL including high levels of alpha-Toc before antioxidant administration. The alpha-Toc content of their LDL was increased after consumption at 24 h (18.3 microg/mL) above the level before consumption (6.6 microg/mL). The lag time of LDL at 24 h after alpha-Toc consumption (alpha-Toc rich LDL) with alpha-CEHC (98.5+/-8.2 min) or gamma-CEHC (101.3+/-9.0 min) was longer than that of only alpha-Toc-rich LDL (78.1+/-9.0 min). Furthermore, we examined the interaction of LDL with CEHC and alpha-Toc in vitro (5-20 microg/mL). The lag times of 5 and 10 microg/mL alpha-Toc were 65.5+/-18.9 min and 69.5+/-15.5 min, and that of 20 microg/mL alpha-Toc (83.5+/-20.2 min) was longer than the control value (55.7+/-14.1 min). The lag time of 20 microg/mL alpha-Toc with alpha-CEHC (98.7+/-25.7 min) or gamma-CEHC (100.6+/-25.3 min) was longer than that of only alpha-Toc (83.5+/-20.2 min). These results suggest that CEHC has the potential to delay the oxidation of LDL, while enhancing the antioxidative activity of alpha-Toc both in vitro and ex vivo.

Cholesteryl ester transfer protein (CETP) is understood to play a regulatory role in HDL cholesterol (HDLC) metabolism. In this study, the effect of CETP genotypes on plasma lipid and lipoprotein levels in 348 Vietnamese girls (aged 7-9) with different nutritional conditions was analyzed. The two mutations, intron 14 G(+1)-to-A (I14A) and Asp 442 to Gly within exon 15 (D442G), and the TaqIB polymorphism in the CETP gene were identified by an Invader assay. The D442G mutation was present with a frequency of 0.034, while the I14A mutation was absent. HDLC levels were significantly higher in carriers of the D442G mutation than in noncarriers, regardless of the nutritional status. Low-density lipoprotein (LDL) cholesterol and triglyceride levels were not significantly lower in carriers of D442G mutation. The frequency of the TaqIB2 allele was 0.34, which was lower than that observed in other Asian populations. TaqIB2B2 carriers also had significantly higher HDLC levels, but this association was weaker than that of the D442G mutation. Overall, genetic variations at the CETP gene locus may account for a significant proportion of HDLC variation in Vietnamese children.

Background: A lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) is the major receptor of oxidized LDL in endothelial cells. The expression of LOX-1 was shown to be upregulated in atherosclerotic lesions. Recently, LOX-1 gene polymorphism (G501C) was reported to be associated with myocardial infarction (MI). Hypothesis: Our study was undertaken to elucidate the association between this polymorphism and coronary artery disease (CAD). Methods: We evaluated LOX-1 gene polymorphism using Invader assay in 586 patients undergoing coronary angiography. Results: Study patients were categorized into three groups: normal/minimal stenosis (≤25%) (n = 128); mild stenosis (26-50%) (n = 39); and significant stenosis (> 50%) (n = 419). Of the 419 patients with significant stenosis, 163 had single-vessel, 165 had double-vessel, and 91 had triple-vessel disease. Myocardial infarction was present in 171 patients. The frequency of LOX-1 gene variants (C/C or C/G) was lower in patients with significant than in those with normal/minimal stenosis (36 vs. 49%, p < 0.01). The frequency of LOX-1 gene variants did not differ between patients with and without MI (34 vs. 37%). However, a stepwise decrease in the frequency of such variants was found depending on the severity of CAD: 49% in normal/minimal stenosis, 41% in mild stenosis, 39% in single-vessel, 35% in double-vessel, and 32% in triple-vessel disease. Multivariate analysis demonstrated LOX-1 gene variants to be inversely associated with the presence of significant stenosis (odds ratio = 0.61; 95% confidence interval = 0.41-0.92). Conclusions: The LOX-1 gene variants at 501 were found to be inversely associated with the severity of CAD. This polymorphism may be modifying the severity of CAD.

Background: Vascular endothelial growth factor (VEGF) has been implicated in both angiogenesis and ischemia. However, the relationship between plasma VEGF level and coronary artery disease remains unknown. Hypothesis: Plasma VEGF level may be associated with severe coronary artery disease and other cardiovascular risk factors. Methods: We examined plasma VEGF concentration and coronary risk factors in 73 patients who underwent coronary angiography and 70 apparently healthy control subjects. According to the number of the three major coronary vessels with significant (≥ 75%) stenosis, we divided the patients into two groups: the mild stenosis group (0- and single-vessel disease, n = 36) and the severe stenosis group (double- and triple-vessel disease, n = 37). Results: The log VEGF value of the severe stenosis group was significantly higher than that of the mild stenosis (p < 0.05) and control groups (p < 0.05). Furthermore, there was a significant positive trend in the log VEGF value according to the number of vessels with significant stenosis (p = 0.016). However, there was no significant difference in log VEGF value between the mild stenosis and control groups. Soluble vascular cellular adhesion molecule, soluble intracellular adhesion molecule, and other coronary risk factors were found to be associated with the presence of vessel stenosis. Conclusion: Unlike established coronary risk factors, the plasma VEGF level may be associated with only severe coronary ischemia such as multiple coronary vessel disease.

Oxidized low-density lipoprotein (LDL) is considered a risk factor in atherosclerosis, and polyphenols are the potential agents to inhibit the oxidation of LDL. We determined the polyphenol contents and the antioxidant activities of commonly consumed vegetables in Vietnam and assessed the quantity of the polyphenol intake from vegetables in the current Vietnamese diet. The polyphenol contents in 30 kinds of vegetables was determined by the Folin-Ciocalteu method. The antioxidant activities of vegetables were evaluated by measuring the oxidation of LDL and the reduction of the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical. In this study, some herbs and edible wild vegetables possessed high contents of polyphenols and antioxidant activities. Among green vegetables, sweet potato leaves showed both a high polyphenol content and antioxidant activity. The mean polyphenol daily intake of the Vietnamese was a 595 mg catechin equivalent. Water spinach, a kind of green vegetable, contributed the highest amount (45%) of the total polyphenol intake, followed by other green vegetables. Neither herbs nor edible wild vegetables contributed significantly to the total polyphenol intake due to their low consumption. Green vegetables are therefore considered very important sources of polyphenol intake for the Vietnamese.

Interleukin (IL)-27, one of cytokines in the IL-12 family, is considered to have both pro- and anti-inflammatory properties. However, blood IL-27 levels in coronary artery disease (CAD) have not been fully elucidated yet. This cross-sectional study was done to elucidate the association between blood IL-27 levels and CAD. We investigated plasma IL-27 and high-sensitivity C-reactive protein (hsCRP) levels in 274 consecutive patients who underwent elective coronary angiography for suspected CAD. CAD was present in 177 patients [30 acute coronary syndrome (ACS) and 147 stable CAD]. Compared with 97 patients without CAD, 177 patients with CAD had higher IL-27 (median 0.26 vs 0.22 ng/mL, P 50% stenotic coronary vessels: 0.22 in CAD(-), 0.22 in 1-vessel disease, 0.31 in 2-vessel disease, and 0.27 ng/mL in 3-vessel disease (P

High levels of osteopontin (OPN) mRNA and proteins were reported in atherosclerotic plaques [1–3]. OPN-overexpressing transgenic mice developed marked atherosclerotic lesions [4]. These suggest that OPN plays an important role in atherosclerosis. Regarding blood OPN levels, we reported plasma OPN levels to be higher in patients with coronary artery disease (CAD) than without CAD [5]. However, some overlap in OPN levels was found between patients with and without CAD. Since atherosclerotic process is a generalized process that may involve the entire vasculature, we hypothesized that plasma OPN levels may reflect not only coronary atherosclerosis but also atherosclerosis in other vascular beds.

Chronic kidney disease (CKD) is considered to be associated with increased risk of coronary artery disease (CAD). To elucidate the associations between kidney dysfunction (KD) and the severity of coronary and aortic atherosclerosis, we performed aortic black-blood MRI in 149 patients (pts) (age 64±9 yrs) undergoing coronary angiography. Regarding MRI, 9 slices of thoracic and 9 slices of abdominal aorta were obtained at 12-mm intervals. Plaque extent in each slice was scored. Severity of aortic atherosclerosis was represented as the sum of scores. On coronary angiograms, severity of coronary atherosclerosis was represented as the numbers of stenotic vessels and segments. KD was evaluated by eGFR. RESULTS: The 149 pts were divided into tertiles by eGFR: 51±10 (T1), 60±3 (T2) and 86±12 ml/min/1.73 2 (T3). CKD (eGFR50% stenosis) and thoracic and abdominal aortic plaques were found in 105 (70%), 95 (64%) and 136 (91%) pts, respectively. Regarding coronary atherosclerosis, the number of >25% stenotic coronary segments correlated with eGFR (r=-0.25, P50% stenotic vessels was found depending on eGFR tertiles: 1.5±1.0 (T1), 1.3±1.2 (T2) and 0.9±0.8 (T3) (PCONCLUSION: The severity of coronary and thoracic, but not abdominal, aortic atherosclerosis correlated with the degree of KD. However, KD was an independent factor for coronary atherosclerosis but not for aortic atherosclerosis. KD is more likely to be associated with coronary atherosclerosis than aortic atherosclerosis.

Methods Aortic MRI was performed on Signa 1.5T Cvi using a phased-array body coil in 159 patients at high-risk for CAD. However, since statins affect LDL- and HDL-cholesterol levels, 64 patients who were taking statin were excluded from this study. Transverse PDW and T2W images of thoracic descending and abdominal aortas were obtained using an ECG-gated, double-inversionrecovery FSE sequence: TR=2 RR intervals, TE=10ms (PDW) and 60ms (T2W), 20-cm FOV, 4-mm slice thickness, 8-mm inter-slice gap, 256x256 acquisition matrix, and 32 echo-train. For each patient, 9 slices of thoracic aorta and 9 slices of abdominal aorta were obtained at 12-mm intervals, which each covered about 10-cm portion of thoracic aorta below the arch and 10-cm portion of abdominal aorta above the bifurcation of iliac artery. Plaque extent in each slice was scored 0 to 4 points by the percentage of luminal surface involved by plaque. The severity of aortic atherosclerosis was represented as sum of scores (plaque score). Results Among the 95 study patients without statin (age 63±9 years), thoracic and abdominal aortic plaques were found in 60 (63%) and 84 (88%) patients, respectively. The severities of both thoracic and abdominal aortic atherosclerosis correlated with age and blood pressures. Regarding lipid parameters, the severity of thoracic aortic atherosclerosis correlated with LDL-cholesterol (r=0.30) and HDL-cholesterol (r=-0.26) levels (P

Focal chorioretinal atrophy observed in untreated Sprague-Dawley rats was clinically and histopathologically described. On ophthalmoscopical examination, the lesion consisted of discrete, hyperreflective, frequently rectangular foci with sharp margins. Petechial hemorrhages preceded to the development of these foci. No particular predilection sites were evident in the fundus. Histopathological characteristics on the perfusion-fixed eyes included: 1) the affected region was focal and well demarcated, 2) the retina in the lesion was devoid of the external layers, 3) in contrast, the internal retinal layers were unaffected, 4) abrupt disappearance of the underlying retinal pigment epithelium and choroid capillaries coincides with the retinal change, and 4) very little inflammatory cell response. These findings suggest that the primary defect may be either in the retinal pigment epithelium or choroid capillaries with subsequent retinal atrophy.

Aim: Limited correlations between C-reactive protein (CRP) and coronary artery disease (CAD) have been reported. Recently, MRI became a useful tool for non-invasively evaluating atherosclerotic plaques in thoracic and abdominal aortas.Methods: To elucidate the associations between plasma CRP levels and the severities of coronary and aortic atherosclerosis, we performed aortic black-blood MRI in 136 patients undergoing coronary angiography. For each patient, 9 slices of thoracic aorta and 9 slices of abdominal aorta were obtained at 12-mm intervals, and the plaque extent in each slice was scored. The degree of aortic atherosclerosis is represented as the sum of scores. The degree of coronary atherosclerosis is represented as the number of >50% stenotic vessels and >25% stenotic segments.Results: CAD (>50% stenosis) was present in 96 patients. Patients with CAD had higher CRP levels than those without CAD (median 0.78 vs. 0.48 mg/L, p

Methods Aortic MRI was performed on Signa 1.5 T in 143 patients undergoing coronary angiography. Transverse PDW and T2W images of thoracic descending and abdominal aortas were obtained using double-inversion-recovery FSE sequence: TR = 2 RR intervals, TE = 10 ms (PDW) and 60 ms (T2W), 20-cm FOV, 4-mm slice thickness, and 8-mm inter-slice gap. For each patient, 9 slices of thoracic aorta and 9 slices of abdominal aorta were obtained at 12-mm intervals. Plaque extent in each slice was scored 0-4 points by the percentage of luminal surface involved by plaque. The severity of aortic atherosclerosis was represented as sum of scores (plaque score). On coronary angiograms, the severity of coronary atherosclerosis was represented as the numbers of > 50% stenotic vessels and > 25% stenotic segments.

In vivo studies show that alpha-tocotrienol and gamma-tocotrienol accumulate in adipose tissue. Furthermore, a recent study reports that the oral administration of gamma-tocotrienol from a tocotrienol-rich fraction from palm oil (TRF) decreases body fat levels in rats. The objective of this study was to evaluate the effect of TRF and its components on adipocyte differentiation in 3T3-L1 preadipocytes, which differentiated into adipocytes in the presence of 1.8 micromol/L insulin. TRF suppressed the insulin-induced mRNA expression of adipocyte-specific genes such as PPARgamma, adipocyte fatty acid-binding protein (aP2), and CCAAT/enhancer-binding protein-alpha (C/EBPalpha) compared with the differentiation of 3T3-L1 preadipocytes into adipocytes only in the presence of insulin. To confirm the suppressive effect of TRF, the major components of TRF, such as alpha-tocotrienol, gamma-tocotrienol, and alpha-tocopherol, were investigated. Alpha-tocotrienol and gamma-tocotrienol decreased the insulin-induced PPARgamma mRNA expression by 55 and 90%, respectively, compared with insulin, whereas alpha-tocopherol increased the mRNA expression. In addition, gamma-tocotrienol suppressed the insulin-induced aP2 and C/EBPalpha mRNA expression, triglyceride accumulation, and PPARgamma protein levels compared with insulin. The current results also revealed that gamma-tocotrienol inhibited the insulin-stimulated phosphorylation of Akt but not extracellular signal-regulated kinase (ERK)1/2 in the insulin signaling pathway of 3T3-L1 preadipocytes. Thus, the antiadipogenic effect of TRF depends on alpha-tocotrienol and gamma-tocotrienol, and gamma-tocotrienol may be a more potent inhibitor of adipogenesis than alpha-tocotrienol. Therefore, the results of this study suggest that tocotrienol suppresses insulin-induced differentiation and Akt phosphorylation in 3T3-L1 preadipocytes. Furthermore, tocotrienol could act as an antiadipogenic vitamin in the nutrient-mediated regulation of body fat through its effects on differentiation.

Osteopontin (OPN) mRNA is highly expressed in atherosclerotic plaques and plasma OPN levels are high in patients with coronary artery disease and in those with restenosis. OPN-overexpressing transgenic mice show markedly increased neointimal formation after arterial injury.The prognostic significance of the preprocedural plasma OPN level was investigated in 130 patients undergoing percutaneous coronary intervention (PCI). Patients were followed up for restenosis and major adverse cardiovascular events (MACE). At 7+/-3 months after PCI, angiography was performed again in 91 patients, of whom 40 had restenosis. Between patients with and without restenosis, OPN (492+/-200 vs 482+/-224 ng/ml) and C-reactive protein (CRP: 0.78 vs 0.70 mg/L) levels did not differ. During a 3-year follow-up, MACE occurred in 21 patients, who had higher OPN (586+/-230 vs 438+/-195 ng/ml) and CRP (1.30 vs 0.70 mg/L) levels than those without MACE (P0.005). Both OPN and CRP levels were independent predictors for MACE. Hazard ratios for MACE were 1.3 (95% confidence interval (CI) 1.1-1.5) for a 100 ng/ml increase in OPN and 3.6 (95%CI 1.4-9.3) for CRP1.0 mg/L.In patients undergoing PCI, the preprocedural OPN and CRP levels are independent predictors for further cardiovascular events, but not for restenosis.

The association between coronary artery disease (CAD) and thoracic aortic plaques has often been reported using transesophageal echocardiography. However, studies showing the association between CAD and abdominal aortic plaques are scarce. CMR can visualize plaques in both the thoracic and abdominal aortas. Using CMR, we investigated the associations of thoracic and abdominal aortic plaques with the presence and extent of coronary artery stenosis in 146 patients undergoing coronary angiography, of whom 108 had CAD. The prevalence of thoracic and abdominal aortic plaques was higher in patients with CAD than in those without CAD (73% and 94% vs. 32% and 79%, p 50% and > 25% stenotic coronary segments (rs = 0.30 and 0.41). Plaque extent in the abdominal aorta also correlated with ...

Osteopontin (OPN) mRNA was shown to be highly expressed in atherosclerotic plaques. We reported plasma OPN levels to be high in patients (pts) with coronary artery disease. Moreover, OPN levels were recently shown to be high in acute coronary syndrome. Increased OPN mRNA expression was also shown in rat arteries after balloon injury. OPN transgenic mice showed markedly increased neointimal formation after arterial injury. OPN may play a role in the development of restenosis after percutaneous coronary intervention (PCI). Methods: We investigated the prognostic value of pre-procedural plasma OPN levels by ELISA on restenosis and clinical outcome in 130 pts undergoing PCI, of whom 89 (68%) had bare metal stent. Pts with AMI were excluded. Restenosis was defined as >50% diameter stenosis at follow-up angiography. Pts were followed up for 3 years for major adverse cardiovascular events (MACE) (death, MI, unstable angina, stroke). Results: At 7±3 months after PCI, re-angiography was performed in 91 (70%) pts, of whom 40 had restenosis. Between 40 pts with restenosis and 51 without it, plasma OPN (492±200 vs 482±224 ng/ml) and C-reactive protein (CRP) (median 0.78 vs 0.70 mg/l) levels did not differ. In multivariate analysis, reference diameter and smoking were independent predictors for angiographic restenosis, but OPN or CRP levels were not. During the 3-year follow-up, MACE occurred in 21 pts. Compared with 109 pts without MACE, 21 with it had higher OPN (586±230 vs 438±195 ng/ml, P500 ng/ml (62% vs 35%) and CRP >3.0 mg/l (33% vs 12%) than without it (P500 ng/ml than those without it (P500 ng/ml and 4.3 (1.3–14.0) for CRP >3.0 mg/l. Conclusion: Plasma levels of OPN as well as CRP were found to be independent predictors for cardiovascular events in pts undergoing PCI, but they were not predictors for restenosis.

Unilateral hypoplasia of the retina and optic nerve was found in a male Sprague-Dawley rats. The lesion was first suspected on the electroretinographic examination. There was very little response from the left eye to the light stimulus, whereas the right eye was normal. On the ophthalmic examination, the fundus of the left eye had faint retinal vessels. At necropsy, the left optic nerve and right optic tract were thin. Microscopically, the retina of the left eye was not fully developed showing undifferentiated photoreceptor, outer and inner granular, inner plexiform and ganglion cell layers, and a complete lack of the outer plexiform layer.

Objective— Coronary plaque instability causes myocardial infarction (MI). Angiographic lesions with such instability are complex lesions. Complex carotid plaques were reported to be prevalent in unstable angina. We investigated associations between coronary plaque instability, such as MI and angiographic complex coronary lesions, and aortic plaques. Methods and Results— Aortic MRI was performed in 146 patients undergoing coronary angiography, of whom 108 had coronary artery disease (CAD) and 44 also had MI. Prevalence of plaques in thoracic and abdominal aortas was higher in patients with than without CAD (73% and 94% versus 32% and 79%), but it was similar in CAD patients with and without MI. Notably, complex plaques in abdominal aorta were more prevalent in CAD patients with than without MI (36% versus 14%; P P Conclusion— Complex plaques in abdominal aorta were associated with MI and complex coronary lesions, suggesting a link between coronary and aortic plaque instability.

To the Editor: High levels of osteopontin (OPN) mRNA and proteins were reported in atherosclerotic plaques.1,2 Recently, we reported plasma OPN levels to be high in patients with coronary artery disease (CAD) and to correlate with the severity of CAD.3 However, no association between plasma OPN levels and restenosis after percutaneous coronary intervention (PCI) has yet been demonstrated. We measured plasma OPN levels in 90 patients with CAD undergoing elective coronary angiography for suspected restenosis. They had undergone PCI 0.6±0.4 years ago, of whom 52 (58%) had been treated with bare metal stents. OPN levels were also measured in 60 age- and gender-matched CAD patients with no history of PCI. Patients with acute coronary syndrome were excluded. Our study was approved by institutional ethics committee. After informed consent was obtained, fasting blood samples were taken. Plasma OPN levels were measured by ELISA (Human OPN …

Background Interstitial collagen, especially type I, is a major component of atherosclerotic plaques and the matrix metalloproteinases (MMP) 1, 8 and 13 can initiate collagen breakdown. MMP-8 degrades type I collagen preferentially and more potently than MMP-1 or MMP-13. Although MMP-8 was thought to be produced only by neutrophils, it was recently reported to also be produced by endothelial cells, smooth muscle cells and macrophages in plaques. Methods and Results Plasma MMP-8 concentrations were measured in 250 patients undergoing coronary angiography for coronary artery disease (CAD: >50% stenosis), which was found in 181 patients, of whom 69 had 1-vessel, 66 had 2-vessel, and 46 had 3-vessel disease. Compared with 69 patients without CAD, the 181 with CAD had higher MMP-8 concentrations (3.5 vs 3.0 ng/ml, p

Background Interleukin (IL)-12 is thought to play an important role in the development of atherosclerosis and recently, polymorphism of the 3'-untranslated region of the IL-12 p40 gene (A1188C) was reported to be associated with diabetes and multiple sclerosis. However, the association between this genetic polymorphism and coronary artery disease (CAD) has not been studied. Methods and Results The frequency of this polymorphism was investigated in 555 patients undergoing coronary angiography: 395 had CAD, of whom 161 also had a myocardial infarction (MI). With regard to the IL-12 p40 polymorphism, 125 had the A/A, 268 had the A/C, and 162 had the C/C genotype. The prevalence of CAD did not differ among the groups (71%, 73%, and 69%, respectively; p= NS). The prevalence of MI was also similar among the groups (28%, 27%, and 33%, respectively; p= NS). Moreover, the number of >50% stenotic vessels, >50% stenotic segments, and ≤50% stenotic segments did not differ among the 3 groups. Conclusions Polymorphism of IL-12 p40 gene was not found to be associated with the presence or severity of CAD, suggesting that it does not play an important role in the development of this disease. (Circ J 2005; 69: 793 - 797)

To the Editor: We read with great interest the study by Iacoviello et al.1 They investigated IL-1β gene polymorphism (−511C/T) in 406 patients with myocardial infarction (MI) at young age and 419 controls and reported the TT genotype to be inversely associated with MI. Moreover, they demonstrated mononuclear cells with TT homozygote to show decreased IL-1β production compared with those with CC homozygote. They concluded …

Background: A lectin‐like oxidized low‐density lipoprotein (LDL) receptor‐1 (LOX‐1) is the major receptor of oxidized LDL in endothelial cells. The expression of LOX‐1 was shown to be upregulated in atherosclerotic lesions. Recently, LOX‐1 gene polymorphism (G501C) was reported to be associated with myocardial infarction (MI). Hypothesis: Our study was undertaken to elucidate the association between this polymorphism and coronary artery disease (CAD). Methods: We evaluated LOX‐1 gene polymorphism using Invader assay in 586 patients undergoing coronary angiography. Results: Study patients were categorized into three groups: normal/minimal stenosis (≤25%) (n = 128); mild stenosis (26‐50%) (n = 39); and significant stenosis (> 50%) (n = 419). Of the 419 patients with significant stenosis, 163 had single‐vessel, 165 had double‐vessel, and 91 had triple‐vessel disease. Myocardial infarction was present in 171 patients. The frequency of LOX‐1 gene variants (C/C or C/G) was lower in patients with significant than in those with normal/minimal stenosis (36 vs. 49%, p < 0.01). The frequency of LOX‐1 gene variants did not differ between patients with and without MI (34 vs. 37%). However, a stepwise decrease in the frequency of such variants was found depending on the severity of CAD: 49% in normal/minimal stenosis, 41% in mild stenosis, 39% in single‐vessel, 35% in double‐vessel, and 32% in triple‐vessel disease. Multivariate analysis demonstrated LOX‐1 gene variants to be inversely associated with the presence of significant stenosis (odds ratio = 0.61; 95% confidence interval = 0.41‐0.92). Conclusions: The LOX‐1 gene variants at 501 were found to be inversely associated with the severity of CAD. This polymorphism may be modifying the severity of CAD.