Reiko Ohmori

Plasma osteopontin levels are associated with the presence and extent of coronary artery disease

Recently, osteopontin (OPN) mRNA was reported to be highly expressed in atherosclerotic plaques, most strikingly in calcified plaques. We examined if plasma OPN levels are associated with coronary stenosis and calcification in patients with coronary artery disease (CAD). We measured plasma OPN levels in 178 patients undergoing coronary angiography. Compared with 71 patients without CAD, 107 with CAD had higher OPN levels (616+/-308 ng/ml versus 443+/-237 ng/ml, P<0.001). A stepwise increase in OPN levels was found depending on the number of >50% stenotic coronary vessels: 540+/-293 ng/ml in 1-vessel, 615+/-230 ng/ml in 2-vessel, and 758+/-416 ng/ml in 3-vessel disease. OPN levels also correlated with the numbers of >50% and >25% stenotic segments (r=0.35 and 0.43, respectively, P<0.001). In multivariate analysis, OPN levels were significantly associated with CAD (odds ratio=1.21, 95% CI=1.05-1.39 for a 100 ng/ml increase) independent of traditional risk factors. Coronary calcification was found in 86 patients. OPN levels were higher in patients with calcification than in those without calcification (608+/-328 ng/ml versus 490+/-246 ng/ml, P<0.01) and correlated with the number of calcified segment (r=0.26, P<0.001). However, OPN levels were not independently associated with coronary calcification. Thus, plasma OPN levels were found to be associated with the presence and extent of CAD.

Tocotrienol Suppresses Adipocyte Differentiation and Akt Phosphorylation in 3T3-L1 Preadipocytes

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.

Antioxidant activity of various teas against free radicals and LDL oxidation

Tea is a widely consumed beverage throughout the world. We assessed the antioxidant activity of six teas, including the aqueous extracts of green tea and oolong tea (Camellia sinensis), tochu (Eucommia ulmoides), Gymnema sylvestre, Japanese mugwort (Artemisia princeps), and barley (Hordeum vulgare), against 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals and LDL oxidation, and examined the association of LDL oxidizability with the plasma catechin levels in 10 healthy volunteers with a single dose of 5 g green tea powder. In vitro, the inhibitory effects of DPPH radicals and LDL oxidation were found to be strongest in the extract of green tea and weakest in that of barley. After the ingestion of green tea powder, the lag time increased from basal 52.2±4.1 to 60.3±4.2 min at 1 h and 59.5±4.1 min at 2 h, and then returned to the baseline lag time (51.9±1.4 at 4 h and 52.1±4.7 min at 6 h). Regarding the plasma catechin levels, epigallocatechingallate and epicatechingallate significantly increased from basal 3.7±1.3 and 0.8±0.8 ng/mL to 65.7±11.6 and 54.6±12.6 ng/mL at 1 h, and 74.4±18.6 and 49.4±7.1 ng/mL at 2 h, respectively. Green tea therefore showed the strongest antioxidant activity among the six different teas, and the inhibitory effects of green tea on LDL oxidation depended on the plasma catechin levels.

High plasma levels of matrix metalloproteinase-8 in patients with unstable angina

Matrix metalloproteinases (MMPs) play a role in collagen breakdown, leading to plaque instability. High levels of MMPs mRNA and proteins, especially MMP-1, MMP-2, MMP-8, MMP-9, and MMP-13, were shown in human atherosclerotic plaques. However, among various MMPs, only MMP-1, MMP-8 and MMP-13, so-called interstitial collagenases, can initiate collagen breakdown. To elucidate whether MMP-1, MMP-8 and MMP-13 levels in blood were high in patients with unstable angina (UAP), we measured serum MMP-1 and plasma MMP-8 and MMP-13 levels in 45 patients with UAP, 175 with stable coronary artery disease (CAD), and 45 controls. Plasma C-reactive protein levels tended to be higher in patients with UAP than in those with stable CAD and controls (median 0.94 vs. 0.69 and 0.51mg/l). Regarding blood levels of MMPs, MMP-13 levels were above the lower detection limit in only one patient with UAP (2%), one with stable CAD (1%), and none in controls. MMP-1 levels did not differ among patients with UAP, stable CAD, and controls (median 4.8, 5.3, and 5.4ng/ml). Notably, MMP-8 levels were higher in patients with stable CAD than in controls (median 3.5ng/ml vs. 2.8ng/ml, P<0.005), however, MMP-8 levels in patients with UAP were much higher than those in stable CAD (3.9ng/ml vs. 3.5ng/ml, P<0.05). In multivariate analysis, MMP-8 level was an independent factor for UAP. Thus, plasma MMP-8 levels were found to be high in patients with UAP, suggesting that MMP-8 levels in UAP may reflect coronary plaque instability and that MMP-8 is a promising biomarker for UAP.

Prognostic value of plasma high-sensitivity C-reactive protein levels in Japanese patients with stable coronary artery disease: The Japan NCVC-Collaborative Inflammation Cohort (JNIC) Study

High-sensitivity C-reactive protein (hsCRP) levels can predict cardiovascular events among apparently healthy individuals and patients with coronary artery disease (CAD). However, hsCRP levels vary among ethnic populations. We previously reported hsCRP levels in Japanese to be much lower than in Western populations. We investigated the prognostic value of hsCRP levels in Japanese patients with stable CAD. The hsCRP levels were measured in 373 Japanese patients who underwent elective coronary angiography and thereafter decided to receive only medical treatment. Patients were followed up for 2.9+/-1.5 years for major cardiovascular events (death, myocardial infarction, unstable angina, stroke, aortic disease, peripheral arterial disease, or heart failure). The median hsCRP level was 0.70 mg/l. During the follow-up, cardiovascular events occurred in 53 (14%) of the 373 patients. Compared with 320 patients without events, 53 with events had higher hsCRP levels (median 1.06 vs. 0.67 mg/l, P<0.05). To clarify the association between hsCRP levels and cardiovascular events, the 373 study patients were divided into tertiles according to hsCRP levels: lower (<0.4 mg/l), middle (0.4-1.2mg/l), and higher (>1.2mg/l). The Kaplan-Meier analysis demonstrated a significant difference in the event-free survival rate between higher vs. middle or lower tertiles (P<0.05). In multivariate Cox regression analysis, the hsCRP level of >1.0mg/l was an independent predictor for cardiovascular events (hazard ratio, 2.0; 95%CI, 1.1-3.4; P<0.05). Thus, in Japanese patients with stable CAD who received only medical treatment, higher hsCRP levels, even >1.0mg/l, were found to be associated with a significantly increased risk for further cardiovascular events.

Effect of lipid-lowering therapy with atorvastatin on atherosclerotic aortic plaques: a 2-year follow-up by noninvasive MRI

Background Using MRI, we reported plaque regression in thoracic aorta and retardation of plaque progression in abdominal aorta by 1-year atorvastatin. However, association between serial plaque changes and LDL-cholesterol levels was not fully elucidated. Design A prospective, randomized, open-label trial. Methods We investigated the long-term effect of 20 versus 5-mg atorvastatin on thoracic and abdominal plaques and the association between plaque progression and on-treatment LDL-cholesterol levels in 36 hypercholesterolemia patients. MRI was performed at baseline and 1 and 2 years of treatment. Vessel wall area change was evaluated. Results The 20-mg dose markedly reduced LDL-cholesterol levels (−47%) versus 5-mg (−35%) dose. After 2 years of treatment, regression of thoracic plaques was found in the 20-mg group (−15% vessel wall area reduction), but not in the 5-mg group (+7%). Although the 20-mg dose induced plaque regression (−14%) from baseline to 1 year, no further regression was seen from 1 to 2 years of treatment (−1%). Regarding abdominal plaques, progression was found in the 5-mg group (+10%), but not in the 20-mg group (+2%). Plaque progression in the 5-mg group was found from baseline to 1 year (+8%), but not from 1 to 2 years (+2%). The degree of thoracic plaque regression correlated with LDL-cholesterol reduction (r = 0.61), whereas thoracic plaque change from 1 to 2 years correlated with on-treatment LDL-cholesterol levels (r = 0.64). Conclusion Twenty milligrams of atorvastatin regressed thoracic plaques. However, maintaining low LDL-cholesterol levels was needed to prevent plaque progression. In abdominal aorta, only retardation of plaque progression was found after 2 years of 20-mg treatment. Eur J Cardiovasc Prev Rehabil 16:222-228

A Possible Association Between Coronary Plaque Instability and Complex Plaques in Abdominal Aorta

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<0.025). In multivariate analysis, abdominal complex plaques were associated with MI (odds ratio [OR], 4.5; 95% CI, 1.5 to 13.8). Among patients without MI, thoracic and abdominal complex plaques were more prevalent in patients with than without complex coronary lesions (22% and 33% versus 2% and 7%; P<0.05). Abdominal complex plaques were also associated with complex coronary lesions (OR, 9.8; 95% CI, 1.1 to 85.9). Conclusion—Complex plaques in abdominal aorta were associated with MI and complex coronary lesions, suggesting a link between coronary and aortic plaque instability.

Associations between serum lipoprotein(a) levels and the severity of coronary and aortic atherosclerosis

To elucidate the associations between Lp(a) levels and coronary and aortic atherosclerosis, we performed aortic MRI in 143 patients undergoing coronary angiography. Severity of aortic atherosclerosis was represented as plaque scores. Of the 143 patients, 104 had coronary artery disease (CAD). Thoracic and abdominal aortic plaques were found in 89 and 131 patients. Lp(a) levels increased stepwise with the number of stenotic coronary vessels: 15.7 (CAD(-)), 21.2 (1-vessel), 21.4 (2-vessel), and 22.9 mg/dl (3-vessel) (P<0.05). For aortic atherosclerosis, 143 patients were divided into quartiles by plaque scores. Lp(a) did not differ among quartiles of thoracic plaques: 17.1, 19.0, 23.5, and 21.2 mg/dl (P=NS), whereas Lp(a) increased stepwise with quartiles of abdominal plaques: 17.1, 19.2, 19.1, and 24.0 mg/dl (P<0.05). Lp(a) was an independent factor for CAD and abdominal aortic plaques, but not thoracic plaques. Thus, Lp(a) levels were associated with aortic atherosclerosis, especially in abdominal aorta, as well as coronary atherosclerosis.

Associations between plasma osteopontin levels and the severities of coronary and aortic atherosclerosis

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.

Effect of Atorvastatin on Plasma Osteopontin Levels in Patients With Hypercholesterolemia

To the Editor High levels of osteopontin (OPN) mRNA and proteins were reported in atherosclerotic plaques.1,2 OPN-transgenic mice developed marked atherosclerosis.3 We reported plasma OPN levels to be high in patients with coronary artery disease (CAD) and to correlate with the severity of CAD.4 We also reported high plasma levels of OPN in patients with restenosis.5 These suggest that OPN plays a role in the development of atherosclerosis. In vitro, Takemoto et al6 demonstrated statins to reduce OPN mRNA in cultured aortic smooth muscle cells and upregulated OPN mRNA in aorta of diabetic rats. We investigated the effects of 20 mg/d versus 5 mg/d atorvastatin on plasma OPN levels in 40 hypercholesterolemic patients without any history of cardiovascular disease. Our study was approved by institutional ethics committee. If patients were taking statins, these were discontinued. After 4-week washout period, fasting blood samples were taken after informed consent was obtained. If LDL-cholesterol >150 mg/dL, patients …