Epidemiological studies have shown that the incidence of coronary artery disease increases as the LDL- C, TC1-9), and TG10, 11) levels rise and the HDL-C level lowers5, 8, 12) both in Japan and in Western countries (Fig.1). At present, prevalence of coronary artery disease in Japan is much lower than that in Western countries13-16). However, recent increases in the LDL-C and TC levels in Japanese associated with so-called Westernization of diet implies future increases in coronary artery disease. In this guideline, therefore, criteria for the diagnosis of dyslipidemia were defined as in Table 1, with a greater emphasis on the prevention of coronary artery disease. The first step in this diagnostic procedure is to measure TC, TG, and HDL-C levels after overnight fasting. LDL-C level is then calculated by use of the Friedewald equation (LDL-C=TC – HDL-C – TG/5). The LDL-C level may be measured by a homogenous method especially in the case of postprandial examination or when the TG level is 400 mg/dL or higher.
Atherosclerotic disease is the most prevalent cause of death worldwide. The ratio of coronary heart disease/cerebrovascular disease differs between Japan and Western countries and the incidence of hemorrhagic stroke and gastrointestinal bleeding is higher in Japan. Thus, the threshold for aspirin administration for primary prevention has been controversial in Japan. Much anecdotal data from Western countries and from Japan has implied that the threshold for administering aspirin to those with risk factors for coronary heart disease is higher than that recommended in Western countries, and that the potential candidates for primary prevention in Japan seem to be diabetic patients. The Japanese primary Prevention of atherosclerosis with Aspirin for Diabetes (JPAD) trial involving 2,530 patients with type 2 diabetes started in December 2002. Compared to other primary prevention trials, this trial offered an acceptable sample size, a standard aspirin dosage, and gender balance. Because stroke is the most significant component of all atherosclerotic diseases in Japan, the impact of primary prevention with aspirin on stroke should be understood. Thus, the JPAD trial should generate reliable data on primary prevention with aspirin for diabetic patients that would also be relevant to other countries.
Aim: The aim of this study is to analyze the effect of apolipoprotein E (apo E) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms on serum lipid and homocysteine levels in the general Japanese population. Methods: We analyzed the polymorphisms in individuals randomly selected from among participants of Serum Lipid Survey 2000. Results: The frequency of the ε2, ε3, and ε4 alleles of APOE was 4.2, 85.3, and 10.5%, respectively. Individuals with the genotype ε4/ε4 had the highest total and low-density lipoprotein (LDL) cholesterol levels, while those with ε2/ε2 had the lowest. Individuals with the ε2/ε2 and ε2/ε4 genotypes had higher remnant-like particles (RLP)-cholesterol levels than those with ε2ε3, ε3ε3, and ε3ε4. There was a trend for individuals with the ε2/ε4 and ε2/ε2 genotypes to have higher triglyceride levels, although the difference was not significant. The presence of the T allele in a MTHFR polymorphism (C667T) was associated with higher homocysteine levels, which is more prominent in men than in women. Conclusion: Thus in our large-scale analysis we have shown that RLP-cholesterol is better associated with, APOE genotype than triglyceride and the effect of the T allele on MTHFR polymorphism (C667T) homocysteine levels is more prominent in men than in women among Japanese.
en-abstract=Aim: The present study aimed to clarify the clinical impact of modified NCEP-ATP III criteria for metabolic syndrome (MS) and Framingham Risk Score (FRS) on carotid atherosclerosis in 615 Japanese adults (319 men and 296 women) including 307 with type 2 diabetes. Methods: Waist circumference was the only component from the original NCEP-ATP III criteria based on Japanese criteria. The intima-medial thickness (IMT) and stiffness parameter β of the carotid artery were measured by ultrasound. Results: Both IMT and stiffness parameter β were significantly increased with the number of coexisting components of MS, and higher in subjects with MS than in those without MS (all Ps < 0.0001). In a logistic regression analysis with each component of MS as independent factors, hyperglycemia and hypertension had the highest odds ratio for progressors of IMT and stiffness parameter β , respectively. Univariate odds ratios of MS for both IMT and stiffness parameter β were comparable with that of an increase of 10% in 10-year coronary heart disease (CHD) risk by FRS (CHD risk/ 10%) but inferior to CHD risk by FRS ≥ 20%. Conclusion: The modified NCEP-ATP III criteria for MS revealed an additive predictive impact on carotid atherosclerosis but no superiority to FRS.
en-abstract=Aim: A number of adipocytokines have been suggested to be involved in the disruption of glucose metabolism, and also in the development of various diabetic complications. We attempted to identify and analyze additional adipocytokines, to better understanding the roles of adipocytes and adipocytokines. Methods: An oligo-capping signal sequence trap, developed in our laboratory for screening the cDNAs of secretory proteins, was used to sreen cDNAs expressed in mouse white adipose tissue. Profiles of the genes identified in mice and cultured cells were further investigated by northern blotting and luciferase assay. Results: A cDNA fragment of interferon-stimulated gene 12b (ISG12b) was obtained in the search. A northern blot analysis revealed ISG12b to be highly expressed in white adipose tissue. Interferon α (IFNα) was shown to induce ISG12b expression in the adipose tissue of BL6 mice in vivo, and also in a 3T3-L1 preadipocyte cell line in vitro. The level of ISG12b was higher in mature adipocytes than in preadipocytes. A promoter analysis demonstrated that the 369bp upstream from the transcription initiation site of ISG12b mRNA contain strong promoter activity, and the interferon-stimulated response elements (ISREs) were not present within the 5593bp upstream region. Conclusion: ISG12b is an additional candidate for a adipocytokine induced to express in adipose tissue by interferon.
Aim: Hepatocyte growth factor (HGF) is known to stimulate endothelial cell proliferation. However, re-endothelialization is not enhanced when the native protein is administered to the injured artery, probably due to the short half-life of HGF at the site of injury. Therefore, the effects of an HGF fusion protein having collagen-binding activity (CBD-HGF) on re-endothelialization and neointimal formation was studied in the balloon-injured rat carotid artery. Methods: The left common carotid artery of male Sprague-Dawley rats was injured with an inflated balloon catheter, and then treated with CBD-HGF (10 µ g/mL), HGF (10 µ g/mL) or saline (control) for 15 min. After 14 days, the rats were injected with Evans blue and sacrificed. Results: The re-endothelialized area was significantly greater in the CBD-HGF- treated rats than in the control or HGF -treated rats. Neointimal formation was significantly more pronounced in the CBD-HGF treated rats than in other rat groups. Both HGF and CBD-HGF stimulated proliferation of vascular smooth muscle cells as well as endothelial cells in vitro. Consistent with this, cultured smooth muscle cells were shown to express the HGF receptor (c-Met). Conclusion: CBD-HGF accelerates re-endothelialization and neointimal formation in vivo. CBD fusion protein is a useful vehicle to deliver vascular growth factors to injured arteries.
Aim: Endothelial lipase (EL) is a member of the lipoprotein lipase family that regulates HDL metabolism. EL is known to act as a bridging molecule for monocytes or lipoproteins in vascular endothelial cells. We investigated the role and regulatory mechanisms of EL expression in macrophages. Methods: Macrophages originating from wild-type (EL+/+) and EL-deficient (EL-/-) mice were stimulated with lipopolysaccharide (LPS). The expression of EL mRNA was evaluated by northern blotting. DiI-LDL was used to measure the uptake of native low-density lipoprotein (nLDL). Results: LPS increased EL mRNA levels by increasing intracellular oxidative stress in the macrophages. LPS did not affect EL expression in macrophages derived from Toll-like receptor 4 (TLR4) gene mutant mice, C3H/HeJ. The uptake of nLDL after LPS-treatment was significantly lower in macrophages from EL-/- mice than those from EL+/+ mice. Simvastatin suppressed the LPS-induced upregulation of EL expression and uptake of nLDL. Conclusions: EL expression is upregulated by LPS via TLR4 and promotes the uptake of nLDL by macrophages. Simvastatin inhibits the LPS-induced up-regulation and uptake in macrophages. Thus, our findings provide a novel role for EL in lipoprotein metabolism and would expand the range of anti-atherogenic effects of statins.
Aim: An evaluation of the relation between small dense low-density lipoprotein cholesterol (sd-LDL-C) levels measured by the heparin-magnesium precipitation method and metabolic syndrome (MetS). Methods: We have prospectively measured sd-LDL-C levels by the heparin-magnesium precipitation method in 112 Japanese patients (male/female=80/32) with coronary artery disease (CAD) who received percutaneous coronary intervention (PCI). Patients were diagnosed with MetS according to modified Japanese criteria. Results: A total of 36 patients (32%) met the criteria for MetS. Sd-LDL-C levels were significantly higher in the MetS group than non-MetS group (20.7 ± 1.5 mg/dL vs. 17.1 ± 1.0 mg/dL, p=0.042), especially among patients without lipid-lowering therapy (26.4 ± 2.6 mg/dL vs. 17.5 ± 1.5 mg/dL, p= 0.0034). Sd-LDL-C levels gradually increased with the number of components used to define MetS (0; 14.5 ± 1.8 mg/dL, 1; 16.5 ± 1.8 mg/dL, 2; 16.7 ± 1.3 mg/dL, 3; 19.3 ± 1.7 mg/dL, 4; 23.1 ± 2.1 mg/dL, 5; 40.0 mg/dL, p=0.0071). High-sensitivity C-reactive protein (hs-CRP) levels were significantly higher in the patients with MetS (1.09 ± 0.17 mg/L vs. 0.67 ± 0.09 mg/L, p=0.0204). Conclusion: The sd-LDL-C level measured by the heparin-magnesium precipitation method is a useful marker of MetS in Japanese patients with CAD.