Low Plasma Levels of Soluble Endoglin and Cardiovascular Events in Patients Undergoing Coronary Angiography.

TGF-ß is recognized as playing a protective role against atherosclerosis. Endoglin is a receptor for TGF-ß, and its expression is upregulated in atherosclerotic plaques. Endoglin is secreted from the cell membrane into the circulation as a soluble form (sEng). We previously reported that plasma sEng levels were low in patients with coronary artery disease (CAD). However, the prognostic value of sEng levels has not been clarified. We investigated the association between plasma sEng levels and cardiovascular events in 403 patients who had an elective coronary angiography and were then followed up. Cardiovascular events were defined as cardiovascular death, myocardial infarction, unstable angina, heart failure, stroke, or coronary revascularization. Of the 403 patients, 209 (52%) had CAD. Plasma sEng levels were lower in patients with CAD than in those without CAD (median 4.26 vs. 4.41 ng/mL, p < 0.025). During a mean follow-up period of 7.5 ± 4.5 years, cardiovascular events occurred in 79 patients. Compared with 324 patients without events, 79 with events had lower sEng levels (3.95 vs. 4.39 ng/mL) and more often had an sEng level < 3.9 ng/mL (47% vs. 28%) (p < 0.02). A Kaplan-Meier analysis showed lower event-free survival in patients with sEng < 3.9 ng/mL than in those with ≥3.9 ng/mL (p < 0.02). In a multivariate Cox proportional hazards analysis, the sEng level (<3.9 ng/mL) was an independent predictor of cardiovascular events (hazard ratio: 1.59; 95%CI: 1.01-2.49). Furthermore, only among the 209 patients with CAD, the sEng level was also a predictor of further cardiovascular events (hazard ratio: 2.07; 95%CI: 1.24-3.45). Thus, low plasma sEng levels were found to be associated with an increased risk of cardiovascular events in patients with CAD and patients undergoing coronary angiography.

Association between the Japanese Diet and Coronary Artery Disease in Patients Undergoing Coronary Angiography.

Several cohort studies have reported that the Japanese diet is associated with reduced cardiovascular disease mortality. However, the results were not always consistent, and most of those studies conducted dietary surveys around 1990. We investigated the association between the Japanese diet and coronary artery disease (CAD) in 802 patients undergoing coronary angiography. The Japanese diet score was defined as the sum of scores of the intakes of fish, soy products, vegetables, seaweed, fruits, and green tea. CAD was found in 511 patients, of whom 173 had myocardial infarction (MI). Intakes of fish, soy products, vegetables, seaweed, fruits, and green tea were lower in patients with CAD, especially in those with MI, than in those without CAD. As a result, the Japanese diet score was significantly lower in patients with CAD than in those without CAD (p < 0.001). To clarify the association between the Japanese diet and CAD, the 802 study patients were divided into three tertiles by the Japanese diet score. The proportion of CAD decreased with the Japanese diet score, reaching 72% in patients at T1 (lowest score), 63% at T2, and 55% at T3 (highest) (p < 0.05). The proportion of MI also decreased with the Japanese diet score, reaching 25% at T1, 24% at T2, and 15% at T3 (p < 0.05). In a multivariate analysis, compared with T1, the adjusted odds ratios for CAD and MI were 0.41 (95% confidence interval [CI]: 0.26-0.63) and 0.61 (95% CI: 0.38-0.99) for T3, respectively. Thus, the Japanese diet was found to be inversely associated with CAD in Japanese patients undergoing coronary angiography.

Plasma Concentrations of Vinculin versus Talin-1 in Coronary Artery Disease.

Vinculin and talin-1, which are cytoskeletal proteins affecting focal adhesions, were reported to be down-expressed in atherosclerotic lesions. Recently, we reported high concentrations of plasma talin-1 in patients with coronary artery disease (CAD). However, blood vinculin concentrations in CAD patients have not been clarified. Plasma vinculin concentrations as well as talin-1 were studied in 327 patients in whom coronary angiography was performed. CAD was proven in 177 patients (1-vessel, n = 79; 2-vessel, n = 57; 3-vessel disease, n = 41). However, vinculin concentrations were not markedly different between the CAD(-) and CAD groups (median 122.5 vs. 119.6 pg/mL, p = 0.325) or among patients with CAD(-), 1-, 2-, and 3-vessel diseases (122.5, 112.8, 107.9, and 137.2 pg/mL, p = 0.202). In contrast, talin-1 concentrations were higher in CAD than the CAD(-) group (0.29 vs. 0.23 ng/mL, p = 0.006) and increased stepwise in the number of stenotic vessels: 0.23 in CAD(-), 0.28 in 1-vessel, 0.29 in 2-vessel, and 0.33 ng/mL in 3-vessel disease (p = 0.043). No correlation was observed between vinculin and talin-1 concentrations. In multivariate analysis, vinculin concentrations were not a factor for CAD. In conclusion, plasma vinculin concentrations in patients with CAD were not high and were not associated with the presence or severity of CAD.

High Plasma Levels of Fortilin in Patients with Coronary Artery Disease.

Excessive apoptosis is known to be a common feature of atherosclerotic lesions. Fortilin is recognized to have potent antiapoptotic properties. An increased fortilin expression was demonstrated in atherosclerotic lesions, and fortilin knockout mice developed less atherosclerosis. However, no study has reported blood fortilin levels in patients with coronary artery disease (CAD). We investigated plasma fortilin levels in 384 patients undergoing coronary angiography. CAD severity was evaluated as the numbers of stenotic vessels and segments. CAD was found in 208 patients (one-vessel (1VD), n = 86; two-vessel (2VD), n = 68; and three-vessel disease (3VD), n = 54). Plasma C-reactive protein (CRP) levels were higher in patients with CAD than without CAD (median 0.60 vs. 0.45 mg/L, p < 0.01). Notably, fortilin levels were higher in patients with CAD than without CAD (75.1 vs. 69.7 pg/mL, p < 0.02). A stepwise increase in fortilin was found according to the number of stenotic vessels: 69.7 in CAD(−), 71.1 in 1VD, 75.7 in 2VD, and 84.7 pg/mL in 3VD (p < 0.01). Fortilin levels also correlated with the number of stenotic segments (r = 0.16) and CRP levels (r = 0.24) (p < 0.01). In a multivariate analysis, fortilin levels were independently associated with 3VD. The odds ratio for 3VD was 1.93 (95%CI = 1.01−3.71) for a high fortilin level (>70.0 pg/mL). Thus, plasma fortilin levels in patients with CAD, especially those with 3VD, were found to be high and to be associated with the severity of CAD.

No Significant Association Between Plasma Endosialin Levels and the Presence or Severity of Coronary Artery Disease.

Background: 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). Methods: 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. Results: 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 of > 50% 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 of > 50% and > 25% stenotic segments or CRP levels. In multivariate analysis, endosialin levels were not a significant factor associated with CAD independent of atherosclerotic risk factors. Conclusions: 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.

Association between Plasma Follistatin-like Protein 1 Levels and the Presence and Severity of Coronary Artery Disease.

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 of > 50% 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, P < 0.01). Notably, plasma FSTL1 levels were higher in patients with CAD than in those without CAD (median 4.05 versus 3.47 ng/mL, P < 0.02). A stepwise increase in FSTL1 levels was found depending on the number of > 50% stenotic vessels: 3.47 in CAD (-), 3.74 in 1-VD, 4.42 in 2-VD, and 4.65 ng/mL in 3-VD (P < 0.05). FSTL1 levels also correlated with the number of > 50% stenotic segments and the severity score (r = 0.14 and r = 0.15, respectively, P < 0.005) and hsCRP levels (r = 0.10, P < 0.05). 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 of > 3.6 ng/mL (P < 0.05). 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.

Associations Between Plasma Kinin B1 Receptor Levels and the Presence and Severity of Coronary Artery Disease.

AIM: Kinin B1 receptor (KB1R) was shown to be up-regulated in human carotid atherosclerotic lesions. Serum KB1R levels were also reported to be high in patients with stroke. However, KB1R deficiency increased atherosclerotic lesions. Therefore, the role of KB1R in atherosclerosis remains unclear. Moreover, no study has reported blood KB1R levels in patients with coronary artery disease (CAD). METHODS: We measured plasma KB1R levels in 375 patients undergoing coronary angiography. The severity of CAD was represented as the numbers of ＞50% stenotic vessels and segments and the severity score. RESULTS: CAD was found in 197 patients, of whom 89 had 1-vessel disease (1-VD), 62 had 2-VD, and 46 had 3-VD. Plasma KB1R levels were higher in 197 patients with CAD than in 178 without CAD (median 83.3 vs. 73.7 pg/mL, p＜0.01). A stepwise increase in KB1R levels was found depending on the number of stenotic vessels: 77.1 in 1-VD, 87.8 in 2-VD, and 88.5 pg/mL in 3-VD (p＜0.025). A high KB1R level (＞90.0 pg/mL) was present in 30% of patients with CAD(-), 39% of 1-VD, 50% of 2-VD, and 48% of 3-VD (p＜0.025). KB1R levels correlated with the number of stenotic segments and the severity score (r=0.14 and r=0.17, p＜0.01). In multivariate analysis, KB1R levels were an independent factor associated with CAD. Odds ratio for CAD was 1.62 (95%CI=1.02-2.58) for high KB1R level ＞90.0 pg/mL. CONCLUSION: Plasma KB1R levels in patients with CAD were high and were associated with the presence and severity of CAD independent of atherosclerotic risk factors.

Associations between Green Tea Consumption and Coffee Consumption and the Prevalence of Coronary Artery Disease.

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 drank >3 cups/d had a lower prevalence of CAD compared to those who drank <1 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.

Association between Plasma Sestrin2 Levels and the Presence and Severity of Coronary Artery Disease.

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.

High Plasma Levels of Soluble Talin-1 in Patients with Coronary Artery Disease.

AIMS: Talin-1 is a cytoskeletal protein that binds integrin, thereby leading to integrin activation and affecting focal adhesions. Recently, talin-1 expression was reported to be downregulated in human atherosclerotic plaques. However, blood levels of soluble talin-1 (sTalin-1) in patients with atherosclerotic disease, such as coronary artery disease (CAD), have not been elucidated. METHODS: We measured plasma sTalin-1 levels in 349 patients undergoing elective coronary angiography. The severity of CAD was represented as the number of stenotic coronary vessels and segments. RESULTS: Of the 349 study patients, CAD was found in 194 patients, of whom 88 had 1-vessel disease (1-VD), 60 had 2-vessel disease (2-VD), and 46 had 3-vessel disease (3-VD). Plasma sTalin-1 levels were higher in 194 patients with CAD than in 155 without CAD (CAD(-) group) (median 0.30 vs. 0.23 ng/mL, P < 0.005). A stepwise increase in sTalin-1 levels was found depending on the number of >50% stenotic coronary vessels: 0.23 in CAD(-), 0.29 in 1-VD, 0.30 in 2-VD, and 0.32 ng/mL in 3-VD group, respectively, (P < 0.05). High sTalin-1 level (>0.28 ng/mL) was found in 36% of CAD(-), 51% of 1-VD, 53% of 2-VD, and 59% of 3-VD group (P < 0.025). sTalin-1 levels also correlated with the number of >50% stenotic segments (r = 0.14, P < 0.02). The multivariate analysis revealed that sTalin-1 levels were independently associated with CAD. The odds ratio for CAD was 1.83 (95%CI = 1.14 - 2.93) for high sTalin-1 level (>0.28 ng/mL) (P < 0.02). CONCLUSIONS: Plasma sTalin-1 levels in patients with CAD were found to be high and to be associated with the presence and severity of CAD, suggesting a role of sTalin-1 in the progression of coronary atherosclerosis.

High Plasma Levels of Legumain in Patients with Complex Coronary Lesions.

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.