A sensitive immunoassay system using a specific monoclonal antibody against lipoprotein lipase (LPL) recently demonstrated the presence of an LPL mass in preheparin serum. We reported that a preheparin serum LPL mass (pre-LPL mass) reflected the level of functioning LPL activity in the whole body and could be deeply involved in the progression of coronary atherosclerosis of stable organic angina pectoris. We examined the relation between the pre-LPL mass and acute myocardial infarction (AMI). We studied 44 males with AMI (AMI group) and 16 males with a normal coronary artery (NCA group), and measured the pre-LPL mass by enzyme-linked immunosorbent assay. Coronary risk factors including the pre-LPL mass were compared between the two groups and multiple regression analysis was performed for AMI. There were no significant differences in the lipid data, but the pre-LPL mass level was significantly low in the AMI group (52±16 vs 41±14 ng/ml, p=0.01), and a low pre-LPL mass concentration was observed in the small sized LDL group and/or the Midband positive group. Multiple regression analysis revealed that a low pre-LPL mass and hypertriglyceridemia were independent risk factors for AMI (t value=2.1, 2.4). The result indicates that a low pre-LPL mass may be an important risk factor for AMI and stable organic angina pectoris.

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Atherosclerotic plaques composed of foamed macrophages, smooth muscle cells and fibrous components in the twice-injured carotid artery from 1% cholesterol diet (HCD)-fed rabbits were prepared and the effects of all-cis-5, 8, 11, 14, 17-icosapentaenoic acid (EPA) on the histopathological properties of atherosclerotic lesions were examined. During the test period, there was no significant difference between the control and the EPA-treated groups in serum lipid levels. In the control group, atherosclerotic lesions were composed of foamed macrophages, smooth muscle cells and fibrous components. Some of the lesions had a large core of foamed macrophages covered with a thin cap of smooth muscle cells and fibrous components, and were morphologically similar to human vulnerable plaques. The classification of plaques, composing atherosclerotic lesions based on collagenous fiber density and foam cell size indicated that over 70% of plaques in the control group were poor in collagenous fiber, while about 20% of plaques contained only large foam cells. In contrast to the control group, over 70% of plaques in the EPA-treated group were rich in collagenous fiber and only 3% consisted of large foam cells. These results suggest that EPA changes certain aspects of pre-existing atherosclerotic lesions.

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Large-scale clinical trials have demonstrated significant reductions in cardiovascular events following statin therapy. The observed benefit of statin therapy, however, may be greater in these trials than is to be expected from lowering lipid levels alone. In order to clarify the mechanism by which statins prevent cardiovascular events in vascular wall cells, we investigated the changes in gene expression profiles after incubation with atorvastatin or pitavastatin in cultured human umbilical vein endothelial cells using DNA microarrays. Statins affected the expression levels of genes involved in inflammation, coagulation, and vascular constriction. The mRNA levels for interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) decreased after statin treatment. Statins reduced mRNA levels of plasminogen activator inhibitor-1 (PAI-1) and increased the mRNA levels of thrombomodulin. Statins reduced the mRNA levels of endothelin-1 and increased the mRNA levels of nitric oxide synthase-3 (eNOS). These results show that, statins are clinically effective because of their ability to change the gene expression profile of endothelial cells thereby preventing vascular events.

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Oxidative stress induced by reactive oxygen species (ROS) plays an important role in atherogenesis, and the redox state is determined by the balance between antioxidants and the ROS generating system. To defend against enhanced ROS, mammalian cells have a complex network of antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase. To clarify the role of the vascular antioxidant system, we investigated by immunohistochemistry the expressional changes of antioxidative enzymes in coronary arteries obtained from autopsied cases. In nonatherosclerotic coronary arteries, Cu/Zn SOD and Mn SOD were expressed in medial smooth muscle cells (SMC), whereas cytosolic GPx (GPx-1) was expressed mainly in endothelium and weakly in medial SMC. Catalase was expressed in medial SMC and endothelium. Progression of atherosclerosis did not result in an additional increase in the expression of antioxidative enzymes in SMC in the media or endothelium. However, migrating SMC and macrophages in atheromatous plaques expressed these four antioxidative enzymes intensively. Double staining with cell markers confirmed the cell-specific expression of the antioxidative enzymes. Thus, the expressional pattern showed regional heterogeneity. In response to oxidative stress, the vascular antioxidant system was upregulated in atherosclerotic lesions. The imbalance between vascular antioxidant and oxidant systems might play an important role in coronary atherogenesis.

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The relative importance of metabolic risk factors for coronary heart disease (CHD) in the Japanese is assessed by comparing their prevalence in patients with acute coronary syndrome (ACS) enrolled in the Asia-Pacific Collaboration on CHD Risk Factor Intervention (ASPAC) study to that obtained by a serum lipid survey carried out in 1990 and also by comparing them to the ASPAC data from other countries and regions in this area. Hypertension was the most prevalent risk factor among Japanese patients with ACS as in the other countries and regions. The prevalence of obesity with a body mass index (BMI) of 30 or more was several times higher than that in the general population, although the rate was still much lower than in New Zealand and Singapore. In addition to hypercholesterolemia, hypertriglyceridemia and diabetes mellitus were frequently found in Japanese patients with ACS. When the prevalence of metabolic risk factors was compared between people with and without hypertension in the general population, the most remarkable difference was seen in BMI, followed by triglyceride and total cholesterol. These results indicate that hypertriglyceridemia and diabetes mellitus may be more important CHD risk factors in the Japanese population than LDL-cholesterol.

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Elevated cardiovascular risk is associated with an increased number of small, dense low-density lipoprotein (LDL) particles, which exhibit increased susceptibility to lipid oxidation, however, the mechanism determining LDL particle size has never been fully elucidated. We have examined the association between the C242T polymorphism of the p22 phox gene, which is a small subunit of vascular NAD(P)H oxidase, and both LDL particle size and clinical characteristics in 260 healthy subjects. Peak LDL particle diameter (LDL-PPD) was measured by continuous disk polyacrylamide gel electrophoresis. Twenty-one of the 217 subjects with the CC genotype showed pattern B (median LDL-PPD under 25.5 nm), whereas, none of the 43 subjects with TC + TT genotypes showed pattern B. The pattern B fraction was significantly larger in the CC group than in the TC + TT group (p = 0.030). The subjects with the CC genotype also showed a significantly higher fasting glucose level, plasma insulin level, and insulin resistance index of homeostasis model assessment (HOMA-R) than those with the TC + TT genotype. Our data demonstrate that variation in the small NAD(P)H oxidase subunit p22 phox gene substantially influences LDL particle size and may also reflect differences in the insulin sensitivity of non-diabetic subjects.

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