Kazuo Kondo’s research while affiliated with Ochanomizu University and other places

Several Japanese cohort studies have reported that the intakes of plant foods, such as vegetables, fruits, seaweed, and soy products, are inversely associated with coronary artery disease (CAD). However, the results of these studies have been inconsistent. We investigated the association between CAD and the intakes of plant foods in 802 Japanese patients undergoing coronary angiography. The intakes of vegetables, fruits, seaweed, and soy products were determined by 3 categories (<3, 3–4, and >4 times/wk). CAD was found in 511 patients, of whom 173 had myocardial infarction (MI). Patients with higher vegetable and fruit intakes had a significantly lower prevalence of CAD and tended to have a lower prevalence of MI. However, no significant difference was found in the prevalence of CAD or MI among the 3 groups of seaweed and soy product intakes. In the multivariate analyses, the prevalence of CAD decreased depending on the intakes of vegetables and fruits. The odds ratios (OR) for >4 times/wk intakes of vegetables and fruits relative to <3 times/wk were 0.46 (95%CI: 0.29–0.74) and 0.62 (0.40–0.95), respectively. Thus, in Japanese patients undergoing coronary angiography, the intakes of vegetables and fruits were found to be inversely associated with CAD but not with MI. However, no significant association was found between the intakes of seaweed or soy products and CAD or MI.

Atherosclerotic diseases, like coronary artery disease (CAD), are recognized to be associated with oxidative stress and inflammation. Sestrin2 is a stress-inducible protein that has anti-oxidant and anti-inflammatory properties. We previously reported that plasma sestrin2 levels were high in patients with CAD. However, no study has shown their prognostic value in patients with CAD. We investigated the association between plasma sestrin2 levels and major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, unstable angina, coronary revascularization, heart failure, or stroke) in 320 patients undergoing coronary angiography, of whom 191 had CAD. During a mean follow-up of 7.0 ± 4.2 years, 58 patients had MACE. Plasma sestrin2 levels were higher in patients with CAD than without CAD (median 16.4 versus 14.2 ng/mL, P < 0.05). Notably, patients with MACE had higher sestrin2 levels (19.5 versus 14.9 ng/mL) and more often had sestrin2 > 15.0 ng/mL (79% versus 49%) than those without MACE (P < 0.001). Kaplan-Meier analysis showed lower event-free survival in patients with sestrin2 > 15.0 ng/mL than in those with ≤ 15.0 ng/mL (P < 0.001). In multivariate Cox hazards analysis, sestrin2 level (> 15.0 ng/mL) was a significant predictor of MACE (hazard ratio: 2.44; 95%CI: 1.28-4.67), independent of CAD and atherosclerotic risk factors. Moreover, among 191 patients with CAD, sestrin2 level was also a significant predictor of MACE (hazard ratio: 2.51; 95%CI: 1.28-4.82), independent of the severity of CAD and coronary revascularization. Thus, high plasma levels of sestrin2 at baseline angiography were found to be associated with an increased risk of cardiovascular events in patients with CAD and patients undergoing coronary angiography.

Background: The function of olive oil polyphenols in suppressing the oxidation of low-density lipoprotein (LDL) is well-known in Europeans. However, it remains unclear whether olive oil polyphenols exert antioxidant effects in Japanese people. Objectives: The objective of this study was to determine whether the ingestion of olive oil polyphenols suppresses LDL oxidation in the Japanese population and whether this effect depends on age. Methods: This randomized controlled double-blind crossover trial with a 2-week washout enrolled 80 healthy Japanese men aged 35–64 years. Participants ingested either 14 g of extra virgin olive oil containing 5.0 mg of olive oil polyphenols (test food) or 14 g of refined olive oil containing 0.3 mg of olive oil polyphenols (control food) for 3 weeks. The primary outcome was oxidized LDL (malondialdehyde-modified LDL; MDA-LDL). Subgroup analyses based on age (35–50 and 51–64 years) were also performed. Results: In all of the participants (35–64 years), there were no significant differences in MDA-LDL between the control and test groups. However, in the 35–50 years subgroup, ingestion of olive oil polyphenols led to a significantly larger reduction in MDA-LDL as compared with the control group (p < 0.025). Conclusions: The significantly lower dietary total polyphenol intake of the 35–50 years subgroup compared to the 51–64 years subgroup suggests that the suppressive function of olive oil polyphenol intake on LDL oxidation in Japanese men is influenced by dietary habits and is more clearly demonstrated in the younger age population with a relatively low total polyphenol intake.

Excessive apoptosis and its insufficient clearance is characteristic of atherosclerotic plaques. Fortilin has potent antiapoptotic property and is abundantly expressed in atherosclerotic plaques. Fortilin-deficient mice had less atherosclerosis with more macrophage apoptosis. Recently, we reported that plasma fortilin levels were high in patients with coronary artery disease (CAD). However, its prognostic value has not been elucidated. We investigated plasma fortilin levels and major adverse cardiovascular events (MACE) in 404 patients (mean age 68 ± 12 years; 276 males) undergoing coronary angiography for suspected CAD. MACE was defined as cardiovascular death, myocardial infarction, unstable angina, heart failure, stroke, or coronary revascularization. Of the 404 patients, 218 (54%) had CAD. Plasma fortilin levels were higher in patients with CAD than without CAD (median 74.9 vs. 70.9 pg/mL, p < 0.05). During a mean follow-up of 5.7 ± 4.2 years, MACE was observed in 59 (15%) patients. Notably, patients with MACE had higher fortilin levels (median 83.0 vs. 71.4 pg/mL) and more often had fortilin level > 80.0 pg/mL (54% vs. 36%) than those without MACE (p < 0.025). A Kaplan-Meier analysis showed lower event-free survival in patients with fortilin > 80.0 pg/mL than in those with ≤ 80.0 pg/mL (p < 0.001). In multivariate Cox proportional hazards analysis, fortilin level (> 80.0 pg/mL) was an independent predictor of MACE (hazard ratio: 2.29, 95%CI: 1.36–3.85, p < 0.002). Among the 218 patients with CAD, fortilin level was also a significant predictor of MACE (hazard ratio: 2.48; 95%CI: 1.34–4.61, p < 0.005). Thus, high plasma fortilin levels were found to be associated with cardiovascular events in patients with CAD as well as those undergoing coronary angiography.

Atherosclerotic disease, including coronary heart disease (CHD), is one of the chronic inflammatory conditions, and an imbalance between pro-inflammatory and anti-inflammatory cytokines plays a role in the process of atherosclerosis. Interleukin (IL)-27, one of the IL-12 family members, is recognized to play a dual role in regulating immune responses with both pro-inflammatory and anti-inflammatory properties. IL-27 is secreted from monocytes, T cells, and endothelial cells, and its expression is upregulated in atherosclerotic plaques. We previously reported that no significant difference was observed in plasma IL-27 levels between patients with stable CHD and those without it. However, the prognostic value of IL-27 levels has not been fully elucidated. We studied the relation of plasma IL-27 levels to cardiovascular events in 402 patients undergoing elective coronary angiography for suspected CHD. We defined cardiovascular events as cardiovascular death, myocardial infarction, unstable angina, stroke, or coronary revascularization. Of the 402 study patients, CHD was present in 209 (52%) patients. Plasma IL-27 levels were not markedly different between patients with CHD and those without it (median 0.23 vs. 0.23 ng/mL). During a follow-up of 7.6 ± 4.5 years, cardiovascular events were observed in 70 patients (17%). In comparison to the 332 patients with no event, the 70 patients who had cardiovascular events showed significantly higher IL-27 levels (median 0.29 vs. 0.22 ng/mL) and more frequently had an IL-27 level of >0.25 ng/mL (59% vs. 40%) (p < 0.01). The Kaplan–Meier analysis demonstrated a lower event-free survival rate in patients with an IL-27 level >0.25 ng/mL than in those with an IL-27 level ≤0.25 ng/mL (p < 0.02). The multivariate Cox proportional hazards regression analysis showed that IL-27 level (>0.25 ng/mL) was a significant predictor for cardiovascular events (hazard ratio: 1.82; 95%CI: 1.13–2.93, p < 0.02), independent of CHD. Thus, high IL-27 levels in plasma were related to an increased risk of further cardiovascular events in patients who underwent elective coronary angiography.

Degradation of vascular extracellular matrix is important in atherosclerosis. Cysteine protease legumain is upregulated in atherosclerotic plaques. We recently reported that plasma legumain levels are high in patients with complex coronary lesions. This study investigated the association between legumain levels and cardiovascular events in 372 patients undergoing coronary angiography. Patients with acute coronary syndrome were excluded. Of the 372 patients, 225 had coronary artery disease (CAD). During a mean follow-up of 7.0 ± 4.3 years, cardiovascular events occured in 62 patients. Compared with 310 patients without events, 62 with events tended to have higher prevalence of complex lesions (15% vs. 10%). Notably, patients with events had higher legumain levels (median 5.51 vs. 4.90 ng/mL, P < 0.01) than those without events. A Kaplan-Meier analysis showed lower event-free survival in patients with legumain > 5.0 ng/mL than in those with ≤ 5.0 ng/mL (P < 0.01). In multivariate Cox regression analysis, legumain level was an independent predictor of cardiovascular events. The hazard ratio for legumain > 5.0 ng/mL for cardiovascular events was 2.18 (95%CI = 1.27–3.77, P < 0.01). Only among 225 patients with CAD, patients with events had higher legumain levels (5.49 vs. 4.73 ng/mL) than without events (P < 0.02). Legumain level was also a predictor of cardiovascular events in patients with CAD. Thus, high plasma legumain levels were associated with an increased risk of cardiovascular events in patients undergoing coronary angiography and those with stable CAD.

Endosialin, also known as tumor endothelial marker-1, is a transmembrane glycoprotein that plays a role in inflammation and tumor progression. Endosialin is upregulated in atherosclerotic lesions. To elucidate the association between blood endosialin levels and cardiovascular events, we measured plasma endosialin levels in 389 patients undergoing coronary angiography who were followed up for a mean follow-up of 6.4 ± 4.2 years for cardiovascular events (cardiovascular death, myocardial infarction, unstable angina, heart failure, stroke, or need for coronary revascularization). Of the 389 patients, 223 had coronary artery disease (CAD). No significant difference was found in plasma endosialin levels between patients with and without CAD (median 0.92 vs. 0.92 ng/mL). During the follow-up, cardiovascular events occurred in 62 patients. Compared with patients without events, those with events had higher endosialin levels (1.12 vs. 0.89 ng/mL), and more often had endosialin level of > 1.1 ng/mL (53% vs. 31%) (P < 0.01). A Kaplan-Meier analysis showed lower event-free survival in patients with endosialin > 1.1 ng/mL than those with ≤ 1.1 ng/mL (P < 0.01). In a multivariate Cox regression analysis, endosialin > 1.1 ng/mL was an independent predictor of cardiovascular events (hazard ratio = 2.00; 95%CI = 1.21–3.32; P < 0.01). Thus, high plasma endosialin levels were associated with an increased risk of cardiovascular events in patients undergoing coronary angiography.

TGF-β is recognized as playing a protective role against atherosclerosis. Endoglin is a receptor for TGF-β, 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.

Vanin-1 is a pantetheinase that hydrolyzes pantetheine to pantothenic acid and cysteamine. Vanin-1 has become recognized to be associated with oxidative stress and inflammation. In animal models, vanin-1 was reported to accelerate atherosclerosis. However, no study has reported blood vanin-1 concentrations in patients with coronary artery disease (CAD). We investigated plasma vanin-1 concentrations in 388 patients undergoing elective coronary angiography for suspected CAD. Patients with acute coronary syndrome were excluded. Of the 388 study patients, CAD was found in 207 patients [1-vessel (1-VD), n = 88; 2-vessel (2-VD), n = 66; and 3-vessel disease (3-VD), n = 53]. Plasma vanin-1 concentrations were higher in patients with CAD than in those without CAD (median 0.59 vs. 0.46 ng/mL, P < 0.005). Vanin-1 concentrations in patients without CAD and those with 1-VD, 2-VD, and 3-VD were 0.46, 0.58, 0.57, and 0.61 ng/mL, respectively, and were highest in 3-VD (P < 0.05). A high vainin-1 concentration (> 0.48 ng/mL) was found in 46% of patients without CAD, 61% of 1-VD, 65% of 2-VD, and 66% of 3-VD (P < 0.01). Vanin-1 concentrations significantly correlated with the number of stenotic coronary segments (r = 0.14, P < 0.02). In the multivariate analysis, vanin-1 concentration was a significant factor associated with CAD independent of atherosclerotic risk factors. The odds ratio for CAD was 1.63 (95%CI = 1.04–2.55) for the high vanin-1 concentration of > 0.48 ng/mL. Thus, plasma vanin-1 concentrations in patients with CAD were found to be high and to be associated with the presence and severity of CAD.