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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.

Sestrin2 is a stress-inducible antioxidant protein that plays a protective role against oxidative stress. However, blood sestrin2 concentrations in subjects with carotid atherosclerosis have not been elucidated.We investigated plasma sestrin2 concentrations in 152 subjects undergoing carotid ultrasonography. Plaque severity was evaluated as plaque score.Of the 152 subjects, plaque was found in 63 (41%). Plasma sestrin2 concentrations were higher in 63 subjects with plaque than in 89 without plaque (median 14.1 vs. 12.8 ng/ml, P 0.02). A stepwise increase in sestrin2 concentrations was found depending on plaque score: 12.8 ng/ml in score = 0 (n = 89), 12.7 ng/ml in score = 1 (n = 31), and 15.9 ng/ml in score ≥2 (n = 32)(P 0.005). Especially, sestrin2 concentrations in subjects with score ≥ 2 were higher than in score = 0 and score = 1 (P 0.05). Sestrin2 concentrations correlated with plaque score (r = 0.24, P 0.005). In multivariate analysis, sestrin2 concentration was an independent factor associated with score ≥ 2. Odds ratio for score ≥ 2 was 5.70 (95%CI = 1.99-16.35) for high sestrin2 concentration (13.0 ng/ml).Plasma sestrin2 concentrations were found to be high in subjects with carotid plaque and to be associated with plaque severity. High plasma sestrin2 concentrations in subjects with carotid plaque may reflect a protective response against the progression of carotid atherosclerosis.

Heme oxygenase-1 (HO-1) degrades heme to CO, iron, and biliverdin/bilirubin. Although serum bilirubin levels were often reported in patients with coronary artery disease (CAD), HO-1 levels in patients with CAD and the association between HO-1 and bilirubin levels have not been clarified.We measured plasma HO-1 and serum total bilirubin levels in 262 patients undergoing coronary angiography.HO-1 levels were higher in patients with CAD than without CAD (median 0.46 vs. 0.35 ng/mL, P 0.01), but bilirubin were lower in patients with CAD than without CAD (0.69 vs. 0.75 mg/dL, P 0.02). Notably, HO-1 levels in CAD(-), 1-vessel, 2-vessel, and 3-vessel disease were 0.35, 0.51, 0.45, and 0.44 ng/mL, and were highest in 1-vessel disease (P 0.05). Bilirubin levels in CAD(-), 1-vessel, 2-vessel, and 3-vessel disease were 0.75, 0.70, 0.68, and 0.66 mg/dL (P = NS). No correlation was found between HO-1 and bilirubin levels. In multivariate analysis, HO-1 levels were a significant factor for CAD independent of atherosclerotic risk factors and bilirulin levels. Odds ratio for CAD was 2.32 (95%CI = 1.29-4.17) for high HO-1 (0.35 ng/mL).Patients with CAD were found to have high HO-1 and low bilirubin levels in blood, but no correlation was found between HO-1 and bilirubin levels.

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.

Nesfatin-1 is a recently identified anorexigenic peptide mainly secreted from the brain and adipose tissue. Although nesfatin-1 may have pro-inflammatory and apoptotic properties, the association between plasma nesfatin-1 levels and coronary artery disease (CAD) has not been clarified yet. We investigated plasma nesfatin-1 levels in 302 patients undergoing elective coronary angiography. Of the 302 study patients, CAD was present in 172 (57%), of whom 67 had 1-vessel, 49 had 2-vessel, and 56 had 3-vessel disease. Compared with 130 patients without CAD, 172 with CAD had higher plasma nesfatin-1 levels (median 0.21 vs. 0.17 ng/mL, P 0.01). A stepwise increase in nesfatin-1 levels was found depending on the number of 50% stenotic coronary vessels: 0.17 in CAD(-), 0.20 in 1-vessel, 0.21 in 2-vessel, and 0.22 ng/mL in 3-vessel disease (P 0.05). A high nesfatin-1 level ( 0.19 ng/mL) was found in 43% of patients with CAD(-), 55% of those with 1-vessel, 55% of those with 2-vessel, and 68% of those with 3-vessel disease (P 0.05). Nesfatin-1 levels significantly correlated with the number of 50% stenotic coronary segments (r = 0.14, P 0.02). In multivariate analysis, plasma nesfatin-1 levels were a significant factor for CAD independent of atherosclerotic risk factors. The odds ratio for CAD was 1.71 (95% CI 1.01-2.91) for high nesfatin-1 level of 0.19 ng/mL (P 0.05). Thus, plasma nesfatin-1 levels were found to be high in patients with CAD and were associated with CAD independent of atherosclerotic risk factors, suggesting that high nesfatin-1 levels in patients with CAD may play a role in the development 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

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