Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS).

BACKGROUND: Japan EPA Lipid Intervention Study (JELIS) was a large-scale clinical trial examining the effects of eicosapentaenoic acid (EPA) on coronary artery disease (CAD) in hypercholesterolemic patients. Herein, we focused on risk factors other than low-density lipoprotein cholesterol (LDL-C) to investigate the effects of EPA on CAD among JELIS primary prevention cases. METHODS: Hypercholesterolemic patients on statin therapy but without evidence of CAD (n=14,981) were randomly assigned to an EPA group (n=7503) or a control group (n=7478). The relationships between incident CAD, the number of CAD risk factors (hypercholesterolemia; obesity; high triglyceride (TG) or low high-density lipoprotein cholesterol (HDL-C); diabetes; and hypertension) and EPA treatment were investigated. RESULTS: For the control and EPA groups combined, a higher number of risk factors was directly associated with an increased incidence of CAD. Incidence was lower for the EPA group than for the control group regardless of the numbers of risk factors. Compared to patients with normal serum TG and HDL-C levels, those with abnormal levels (TG >or=150 mg/dL; HDL-C <40 mg/dL) had significantly higher CAD hazard ratio (HR: 1.71; 95% CI: 1.11-2.64; P=0.014). In this higher risk group, EPA treatment suppressed the risk of CAD by 53% (HR: 0.47; 95% CI: 0.23-0.98; P=0.043). CONCLUSIONS: Multiple risk factors besides cholesterol are associated with markedly increased incidence of CAD. High TG with low HDL-C represents a particularly potent risk factor. EPA was effective in reducing the incidence of CAD events for patients with this dyslipidemic pattern, suggesting that EPA may be especially beneficial in patients who with abnormal TG and HDL-C levels.

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.

Suppressive effects of cacao liquor polyphenols (CLP) on LDL oxidation and the development of atherosclerosis in Kurosawa and Kusanagi-hypercholesterolemic rabbits.

We investigated the properties of cacao liquor polyphenols (CLP), which have an antioxidative effect on low-density lipoprotein (LDL) and an anti-atherosclerotic effect in the spontaneous familial hypercholesterolemic model, the Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbit. After 6 months of dietary administration of CLP at 1% (w/w) to the KHC rabbits, a higher total cholesterol concentration was observed in the treatment group compared to the control group. However, no other effects were noted in lipid profiles in plasma or lipoproteins. The plasma concentration of thiobarbituric acid reactive substances (TBARS), which is a lipid-peroxidation index, was significantly decreased 1 month after the start of CLP administration compared to that of the control group. The antioxidative effect of CLP on LDL was observed from 2 to 4 months of administration. The area of atherosclerotic lesions in the aorta in the CLP group (32.01+/-1.58%) was significantly smaller than that in the control group (47.05+/-3.29%), and the tissue cholesterol and TBARS concentrations were lower in the CLP group than in the control group. The anti-atherosclerotic effect of CLP was confirmed both rheologically and histopathologically. An in vitro study using KHC rabbit-derived LDL revealed that CLP significantly prolonged the lag time of LDL oxidation that was induced by a lipophilic azo-radical initiator, 2,2'-azobis(4-methoxy)-2,4-dimethylvaleronitrile (V-70), or Cu(2+) from a low concentration of 0.1 microg/mL. The antioxidative effect of CLP was superior to those of the well-known antioxidative substances, vitamin C, vitamin E and probucol. Therefore, CLP suppressed the generation of atherosclerosis, and its antioxidative effect appeared to have an important role in its anti-atherosclerotic activity.

Effects of Dai-saiko-to (Da-Chai-Hu-Tang) on plasma lipids and atherosclerotic lesions in female heterozygous heritable Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits.

We investigated the antihypercholesterolemic effects of traditional Japanese herbal medicine Dai-saiko-to (Da-Chai-Hu-Tang in Chinese) in female heritable Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits. The plasma total cholesterol levels increased for up to 12 weeks after beginning a diet containing 0.1% cholesterol then reached a plateau of about 603 mg dl(-1). Dai-saiko-to was administered at doses of 0.5-1.0 g kg(-1) per day or pravastatin 10 mg kg(-1) per day for 24 weeks. Plasma total cholesterol levels were significantly decreased in the groups administered Dai-saiko-to 1.0 g kg(-1) per day or pravastatin for 4-24 weeks, whereas there were no change with plasma phospholipid and triglyceride levels. However, Dai-saiko-to 1.0 g kg(-1) per day significantly decreased plasma LDL cholesterol levels, but had no effect on either VLDL- or HDL-cholesterol levels. Moreover, LDL-receptor mRNA levels in the liver were significantly increased in the Dai-saiko-to 1.0 g kg(-1) per day group compared with those of animals receiving the 0.1% cholesterol diet. In addition, both groups receiving Dai-saiko-to 1.0 g kg(-1) per day and pravastatin showed a significantly reduced percentage of intimal surface area of thoracic aorta involved with atheromatous plaques in the thoracic aorta at 24 weeks. These results indicated that Dai-saiko-to 1.0 g kg(-1) per day significantly decreased the plasma cholesterol levels and atheromatous plaque area due to expression of the LDL mRNA gene in the liver.

Evaluation of Rhubarb using antioxidative activity as an index of pharmacological usefulness.

We attempted to estimate the pharmacological activity by measuring the concentrations of a composition ingredient using a multivariate statistical analysis method. Medicinal herb of Rhubarb has been many largely unrecognized biochemical and pharmacological effect components. Therefore, we attempted to estimate the antioxidative activity of Rhubarb on low-density lipoprotein (LDL) of its components. Thirty specimens of Rhubarb from various origins were used, chose nine components of anthraquinones, two components of anthrones, two components of flavan-3-ols, one component of procyanidin, one component of naphthalene, two components of phenylbutanones and one component of stilbene. Quantitative analysis of 18 components was performed with high-performance liquid chromatography (HPLC) and antioxidative activities were measured with plasma taken from spontaneous familial hypercholesterolemia model rabbits. There was considerable variation among the specimens in the concentration of components and antioxidative activities on LDL. As a result of multiple regression analysis, significant multiple correlation coefficient for antioxidative activities on LDL (R=0.914, P<0.01) was found in relation to the concentrations of five components: aloe-emodin, chrysophanol, emodin 1-O-beta-D-glucoside, lindleyin and 6-hydroxymusizin 8-O-beta-D-glucoside. Three of the five components were not active in promoting antioxidative activity and there was no significant correlation between the concentrations of the most active component and the activity. We consider this a useful method for selecting of Rhubarb and propose a new scientific approach for the selection of natural medicines.

Effects of Lentinus edodes mycelia on dietary-induced atherosclerotic involvement in rabbit aorta.

Lentinus edodes mycelia lowers cholesterol levels and acts as an immunomodulator and tumor-inhibitor in animal models. Lentinus edodes mycelia contains eritadenine (C(9)H(11)O(4)N(5)) and glucans among other biological compounds. However, whether or not Lentinus edodes mycelia is anti-atherogenic remains unknown. We examined the effect of Lentinus edodes mycelia (L.E.M) on atherosclerosis in a rabbit model. Thirty-two Japanese white male rabbits were fed with 1.0% cholesterol for 8 weeks, then divided into groups and given 1) 1.0% cholesterol for over 8 weeks (control), 2) 1.0% cholesterol and 1.0% L.E.M for over 8 weeks, 3) 1.0% cholesterol and 2.0% L.E.M for over 8 weeks, and 4) 1.0% cholesterol and 4.0% L.E.M for over 8 weeks (n=8 each group). Total cholesterol (TC) was measured periodically throughout the experiment. After the experimental periods, the aortas were removed and atherosclerotic lesions were examined histologically, immunohistochemically and morphometrically to determine surface involvement (SI) and an atherosclerotic index (AI). Body weight and TC did not significantly differ among the four groups. Decreases in SI were significant in the 1% L.E.M (26.2+/-10.8%) and 2% L.E.M (29.3+/-15.7%) groups compared with the control (48.7+/-15.3%; p < 0.05). The AI was significantly decreased in the 1% L.E.M (6.62+/-4.31) and 2% L.E.M (7.49+/-3.49) groups compared with the control (16.96+/-9.21; p < 0.05). Foam cells aggregated in thickened intima of dietary-induced atherosclerotic lesions in the rabbit aorta. In contrast, the numbers of foam cells in the intima decreased in the experimental group. No-cholesterol-lowering action or dose-dependant effects of L.E.M were determined in this study, but atherosclerotic development was significantly inhibited, indicating that L.E.M had anti-atherogenic properties. L.E.M may inhibit atherosclerotic development in rabbit aorta and be beneficial as a nutritional supplement.