The levels of total and LDL-cholesterol are important risk factors for coronary atherosclerosis and recent clinical trials have shown that LDL-cholesterol lowering is benefical in both the primary and the secondary prevention of CAD. HMG-CoA reductase inhibitor is a potent drug reducing LDL-cholesterol levels, but sufficient reduction of LDL-cholesterol could not be always achieved using its currently recommended dosage in Japan. Accordingly, we studied the efficacy and safety of combined therapy using two kinds of HMGCoA reductase inhibitors, pravastatin and simvastatin, in 20patients (men/women=16/4, mean age 54 years) with heterozygous familial hypercholesterolemia whose LDLcholesterol was more than 160mg/dl and had a coronary atherosclerosis. Three patients had been treated by HMG-CoA reductase inhibitor alone, 3 patients by HMG-CoA reductase inhibitor and bezafibrate, 13 patients by HMG-CoA reductase inhibitor and cholestyramine, 1 patient by HMG-CoA reductase inhibitor and LDL-apheresis. In 12 patients, 5mg/day of simvastatin was added to 20mg/day of pravastatin (simvastatin group). By contrast, in 8 patients, 10mg/day pravastatin was added to 10mg/day of simvastatin (pravastatin group).
Mean levels of total cholesterol significantly decreased from 272±44mg/dl (mean±SD) at week 0 to 244±35mg/dl (-10%) at week 12. Mean levels of LDL-cholesterol also significantly decreased from 196±40mg/dl at week 0 to 166±30mg/dl (-15%) at week 12. The mean % changes of total and LDL-cholesterol were -35% and -45% as compared to baseline values, respectively. Decrease of trygliceride levels and increase of HDL-cholesterol levels did not reach statistical significance. Mean levels of apolipoprotein B significantly decreased from 165±32mg/dl at week 0 to 146±27mg/dl (-12%) at week 12, but apolipoproteinsA I and E showed no significant alterations. In pravastatin group, mean levels of LDL-cholesterol decreased from 204±54 at week 0 to 179±39mg/dl (-12%) at week 12. Mean levels of LDL-cholesterol decreased from 202±29 to 159±20mg/dl (-21%) in simvastatin group. There were no difference in mean % changes of total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglyceride between pravastatin group and simvastatin group. During whole study period, there were no adverse events including elevation of CPK, liver injury, and renal dysfunction. We concluded that combined therapy using two kinds of HMG-CoA reductase inhibitors is useful and safe to achieve significant further reduction of LDL-cholesterol in heterozygous familial hypercholesterolemia.

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To verify the accuracy of data obtained in the Pravastatin Antiatherosclerosis Trial in the Elderly (PATE Study), and thus to add further support to its conclusions regarding the impact of pravastatin on the incidence of cardiovascular disease in the elderly, we standardized serum total cholesterol (TC) measurements made at the participating laboratories. TC measurements made at 44 laboratories in the PATE Study were evaluated and standardized according to the Protocols of the Centers for Disease Control and Prevention (CDC) and the US Cholesterol Reference Method Laboratory Network (CRMLN) in September of 1995. The results revealed a %bias, in accuracy, of -1.78±2.24% (mean±standard deviation) compared to the CDC standardized reference value for the 44 laboratories as a whole. Precision, measured as a coefficient of variation, was 0.85±0.66%, with a total error of 3.92±2.38%. The certification rate was 72.7%, which is similar to international certification rates. These findings suggest that the measurement errors accompanying the dispersed measurement method are unlikely to have had any effect on the validity of the PATE data.

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Cilostazol is registered for the treatment of chronic atherosclerotic diseases such as arteriosclerosis obliterans and diabetes mellitus. Recently, the lipid lowering effects of cilostazol in hyperlipidemic subjects have also attracted attention. We investigated the effects of cilostazol on lipoprotein metabolism in 12 NIDDM subjects with dyslipoproteinemia. Eight NIDDM patients with dyslipoproteinemia were also investigated as control subjects. One hundred fifty mg per day of cilostazol was administered orally for three 4-week periods. Serum lipid and apolipoprotein concentrations were measured at the end of each 4-week period. Cholesterol content in the remnant-like particles (RLP-c) was measured by using monoclonal anti apo B-100 and anti apo A-I immunoaffinity mixed gels. LDL particle size was analyzed based on a new parameter, LDL-migration index (LDL-MI), which was calculated by dividing the distance from the VLDL peak to the LDL peak by the distance from the VLDL peak to the HDL peak on a PAGE densitogram. Serum concentrations of TC and LDL-c did not change, while the TG content in serum decreased significantly and the HDL-c content increased significantly. No significant changes of the lipid levels were found in the control subjects. Apo C-III and E decreased significantly. RLP-c also decreased from 11.4 to 5.1mg/dl. LDL-MI showed a significant decrease from 0.40 to 0.36, while LDL-MI showed no change in the control group. These results suggest that cilostazol may have some beneficial effects on lipoprotein metabolism by normalizing LDL particle size in NIDDM patients with dyslipoproteinemia.

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There has been conflicting data as to the role of cholesterol ester transfer protein (CETP), which show that it is atherogenic or anti-atherogenic by the HDLcholesterol catabolism. Accordingly, further investigations are necessary as to the role of CETP. This study was conducted to determine the role of CETP for lipid metabolism in normotriglyceridemia. Methods Plasma lipid levels, apolipoprotein concentration and CETP activities were measured in 31 male and 19 female subjects (aged 30 to 80 years). Further more, their relationships to coronary heart disease (CHD) prevalence was analyzed. Patients with hepatic and thyroidal dysfunction and diabetes mellitus were excluded from this study. CETP activities were measured by the method of Katoh et al Results: A positive correlation between LDL-cholesterol and CETP activity (r=0.46, p<0.01) was found, but no correlation was found between HDL-cholesterol and CETP activity. There was no relationship between the incidence of CHD and CETP activity. Conclusion: It is suggested that CETP also plays an important role in the metabolism of LDL-cholesterol, in addition to in the transfer of HDLcholesterol. However, it remains unknown whether CETP is atherogenic or anti-atherogenic.

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We developed a rabbit model of atherosclerosis showing increased triglycerides, blood pressure, plasma glucose and insulin levels, and presenting with sclerotic lesions in the aorta, coronary artery and cerebral artery without cholesterol loading. This model is considered to closely reflect atherosclerosis in humans. The relation between the extent of aortic medial smooth muscle cells outgrowth (COG) in the aorta and vascular wall tissue disorder has not yet been thoroughly investigated in the human aorta. In this regard, we used this Syndrome X-like atherosclerosis rabbit model to assess COG in atherosclerosis. We compared the percent of COG with the quantitated values (%Extinction) of various histochemical arterial wall components (smooth muscle cells, elastin, collagen type III, type I, hyaluronic acid, glycoproteins, Alcian Blue-positive substance, PASpositive substance, calcium and cholesterol) which reflect arterial wall tissue disorder, using two-dimensional patterns.
Since eicosapentaenoic acid (EPA), an omega-3 polyvalent unsaturated fatty acid contained in fish oil, is known to have anti-atherosclerosis effects, the influence of EPA on COG and wall components was also investigated by comparing the two-dimensional patterns of COG and wall components in rabbits with atherosclerosis (atherosclerosis group), rabbits with atherosclerosis administered EPA (300mg/rabbit/day; EPA group) and healthy rabbits fed a standard diet (control group).
It is said that the percent of COG increases in proportion to the severity of vascular wall tissue disorder in rabbits in which atherosclerosis is induced by a high cholesterol diet. However, we observed that COG increased in the initial to middle stage of the vascular disorder, then decreased from the middle to terminal stage in our rabbit model.
According to the two-dimensional patterns of COG and wall components, the EPA group definitely differed from the atherosclerotic group in comparison with the status assessed based on wall component alone and was distributed in a position closer to the control group, indicating more clearly the anti-atherosclerotic action of EPA.

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Apolipoprotein E (apoE) polymorphism is an important genetic factor associated with lipid metabolism. We examined how an environmental factor influenced the association between apoE polymorphism and lipid metabolism or insulin resistance in 540 Japanese women living in Hiroshima (JH) and 635 Japanese-American women (JA) living in Hawaii and Los Angeles originally from Hiroshima. ApoE phenotype was determined in serum samples by isoelectric focusing followed by immunoblotting. Phenotypes were subdivided into three groups: E2 phenotype (E2/2+E3/2), E3 phenotype (E3/3), and E4 phenotype (E4/3+E4/4). In JH, total serum cholesterol (TC) and serum triglycerides (TG) were the lowest in subjects with the E2 phenotype and the highest in those with the E4 phenotype, and HDL-cholesterol (HDL-C) was the lowest in those with the E4 phenotype, after adjustment for age and BMI. In JA, TC was the lowest in those with the E2 phenotype and the highest in those with the E4 phenotype, and TG was the lowest in subjects with the E3 phenotype, higher in those with the E2 phenotype, and the highest in those with the E4 phenotype, and HDL-C was the lowest in those with the E4 phenotype after adjustment for age and BMI. The average effect according to the formula of Sing & Davignon of the ε4 allele was to raise TG in JH, whereas the average effect of the ε2 allele as well as that of the ε4 allele was to raise TG in JA. Fasting insulin (FIRI) was significantly higher in JA than JH in all subjects of apo E phenotype. Furthermore, FIRI was positively associated with TG after adjusting for age and BMI in JH with the E2, E3, and E4 phenotypes. On the other hand, FIRI was correlated with TG with the E3 and E4 phenotypes, but not the E2 phenotype in JA. Thus, a westernized lifestyle increased TG and insulin resistance despite apo E polymorphism in Japanese women. Furthermore, an association of insulin resistance and TG metabolism was modified by a westernized lifestyle, dietary, and hormonal factors in subjects with the ε2 allele.

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To investigate the relationship between micro- and macroangiopathy (MA) in diabetic subjects, prevalence, and clinical characteristics of cardiac, cerebral, and peripheral vascular disease were studied in 842 subjects with NIDDM. Stages of nephropathy were defined as normoalbuminuria (N=471), microalbuminuria (N=250), overt proteinuria (N=75), and chronic renal failure (s-Cr≥2mg-dl, N=46). Prevalence of ischemic heart disease (IHD), cerebral infarction (CI), and arteriosclerosis obliterans (ASO) in the 4 groups showed a significant correlation with the degree of nephropathy, and occurred most frequently in subjects with renal failure. Aging, duration of diabetes, hypertension, and reduced concentrations of HDL-C, which were common risk factors for these MA patients, were also related to the stages of nephropathy. In addition, multivariate analysis indicated that the urinary albumin excretion rate itself could be an independent risk factor for MA, especially IHD and ASO. The mortality rate of subjects with renal failure surpassed that of these with normoalbuminuria by about 15-fold because of renal dysfunction and/or complications of MA. These results suggest that diabetic nephropathy is closely correlated with MA of the heart, brain, and lower extremities. Glycemic control, other means of risk factor management, and evaluation of systemic MA using a noninvasive approach is important for subjects with nephropathy, especially end-stage renal disease, to improve life prognosis.

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A large number of basic and clinical studies have demonstrated that triglyceride-rich lipoproteins (TRLP) are atherogenenic. Some have also demonstrated that the metabolism of exogenous lipoproteins containing apolipoprotein (apo) B48 in postprandial lipemia is related to the development of atherosclerosis. The purpose of this study is to investigate whether triglyceride (TG)-rich remnant lipoproteins are related to atherosclerotic coronary artery disease (CAD) and whether this relationship is affected by metabolic states in which apo B48 remains in fasting plasma. We evaluated the levels of lipids, apoproteins, and cholesterol (C) levels of VLDL, IDL, and LDL fractions that were separated by ultracentrifugation (VLDL-C, IDL-C, LDL-C) in fasting plasma from 209 consecutive patients who underwent coronary angiography. We also examined apo B48 in VLDL fractions by SDS-PAGE to detect the presence of chylomicron remnants. Patients taking lipid-lowering Burgs were excluded. Patients with CAD (+), defined as≥50% stenosis in the major coronary artery (n=159, mean age 60), were older than CAD (-) (n=50, mean age 55). CAD (+) had significantly higher levels of apo B and lower levels of HDL-C and apo AT compared to CAD (-). The total-C, TG and lipoprotein (a) levels were not significantly different. Although the VLDL-C levels were not significantly different, the levels of IDL-C and LDL-C were significantly higher in CAD (+) than in CAD (-). The presence of apo B48 tended to be more frequent in CAD patients and was significantly related to elevated levels of total-C, TG, VLDL-C, and reduced levels of HDL-C, respectively. In multiple logistic regression analysis, IDL-C and HDL-C were significantly and independently associated with CAD. In conclusion, elenated IDI-C of TRLP and reduced HDL-C are independent predictors of CAD. Furthermore, metabolic disorder of apo B48 containing exogenous lipoproteins may contribute to increasing atherogenic of endogenous lipoproteins.

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