Japan's age-adjusted rate for mortality from stroke increased after the Second World War until 1965 and then showed a significant decline until 1990; however, the age-adjusted rate for mortality from all heart disease and coronary heart disease (CHD) increased until 1970 and then declined slowly. A puzzling question is why the rate of mortality from CHD declined in spite of an increase in serum total cholesterol level following an increase in fat consumption.
It was confirmed that CHD incidence was far lower in several Japanese populations compared to Western countries in the “ Monitoring Trends and Determinants in Cardiovascular Disease ” (MONICA) project; therefore, the lower CHD mortality in Japan stems from the lower CHD incidence. CHD risk factors based on epidemiologic cohort studies in Japan were no different from those of other industrialized countries: hypertension, hypercholesterolemia, smoking and diabetes mellitus (DM). So, how can we explain this phenomenon?
There are three possible explanations. One is the decline in population blood pressure level and the prevalence of hypertension during the years 1965-1990; the second is the decline in smoking rate in men and women; the third is that the serum total cholesterol level for middle-aged and elderly populations remains 5-15 mg/dL lower than that of the US elderly counterpart, although men aged 40-49 in Japan and the US had similar serum total cholesterol levels. It was also noted that elderly people in Japan, as observed in the Seven Countries Study, had far lower serum total cholesterol levels in midlife, i.e., around 160 mg/dL in the 1960s. This was not the case for elderly in the US where a higher serum total cholesterol level was observed in midlife.
In conclusion, the lower serum cholesterol level in the past of Japanese middle-aged and elderly people compared to Western counterparts helps to maintain the low CHD incidence and mortality supported by the declining trend in blood pressure level and smoking rate for both men and women.

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Aim: We established an external quality control (QC) program for high-sensitivity C-reactive protein (hs-CRP) for a collaborative epidemiological study.
Methods: External QC was performed 3 times in 3 years to follow hs-CRP performance for precision and accuracy.
Results: For precision, the mean coefficient of variation (CV) of the internal QC by 9 laboratories was 2.2% and 1.9% in the 1st and 2nd tests, respectively. The mean CV of the external QC by 4 laboratories was 2.7% in the three tests. The CV of both the internal and external QC satisfied the acceptable range specified by the AHA/CDC Scientific Statement, CV < 10%. For accuracy, the mean values of the 1st external QC by 9 laboratories were set as the consensus value and the acceptable range was set to within ± 10% from it. The mean accuracy by 9 laboratories was 0.51% in the 2nd external QC. The mean accuracy by 4 laboratories was – 0.37% in the 3rd external QC. These findings demonstrated that the initial consensus value was valid in the continued external QC, and hs-CRP was stable for 3 years.
Conclusion: We demonstrated both the precision and accuracy of hs-CRP by an external QC program applied for 3 years in a collaborative epidemiological study.

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Aim: Recent clinical studies using intra-vascular ultrasound have clarified that coronary artery plaque already exists in subjects with normal coronary artery which is diagnosed by coronary angiography; furthermore, culprit lesion on acute coronary syndrome often occurs in mild to moderate angiographical stenotic lesion. The aim of this study is to clarify relationship between metabolic syndrome and early stage coronary atherosclerosis using a 3-dimensional intra-vascular ultrasound.
Methods: 70 subjects with normal coronary artery diagnosed by coronary angiography were enrolled. Proxymal range of left anterior descending coronary artery was observed by intra-vascular ultrasound using autopullback methods.
Results: Subjects with metabolic syndrome had significantly high percent plaque volume (31 ± 8% vs 21 ± 8%, p < 0.0001) and frequently detected abnormal plaque quality such as eccentricity, calcification and lipid pool into plaque than those without metabolic syndrome. Multivariate analysis showed that serum adiponectin concentration was the most strongest variable for percent plaque volume (t value= − 3.0, p < 0.01). On the other hand, subjects with hypoadiponectinemia were detected high incidence of mild calcification into plaque.
Conclusion: Metabolic syndrome needs to be detected and treated as early as possible. Furthermore, measurement of serum adiponectin concentration and appropriate treatment would prevent acute coronary syndrome.

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Aim: Endothelial dysfunction is considered an early event in the development of atherosclerosis. The present study was undertaken to determine whether the accumulation of cardiovascular risk factors and insulin resistance are associated with endothelial function in diabetic patients.
Methods: 101 patients with type 2 diabetes without macroangiopathy stratified by the number of cardiovascular risk factors (dyslipidemia, hypertension, obesity) and 9 normal control subjects were studied for vascular endothelial functions by measuring flow-mediated vasodilation (FMD) using a high-resolution ultrasound method, brachial-ankle pulse wave velocity (baPWV), carotid intima-media thickness (IMT), and the ankle-brachial index (ABI).
Results: FMD negatively correlated with baPWV and carotid IMT, and positively correlated with ABI. FMD was significantly lower in diabetic patients associated with 3 other risk factors than in those with diabetes alone. In subjects with fasting plasma glucose ≤ 140mg/dL, FMD showed significant negative correlations with fasting insulin levels and homeostasis model assessment (HOMA)-R. Multivariate analysis revealed that insulin resistance as represented by HOMA-R and systolic blood pressure showed a significant association with impaired FMD.
Conclusion: The present results suggest that the accumulation of cardiovascular risk factors is associated with endothelial dysfunction in diabetic patients, and that insulin resistance as well as high blood pressure could play a pathogenic role in the development of endothelial dysfunction.

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Aim: Not all genetic factors predisposing phenotypic features of dyslipidemia have been identified. We studied the association between the low density lipoprotein-related protein 2 gene (LRP2) and levels of plasma total cholesterol (T-Cho) and LDL-cholesterol (LDL-C) among 352 adults in Japan.
Methods: Subjects were obtained from among participants in a cohort study that was carried out with health-check screening in an area of east-central Japan. We selected 352 individuals whose LDL-C levels were higher than 140 mg/dL from the initially screened 22,228 people. We assessed the relation between plasma cholesterol levels and single-nucleotide polymorphisms (SNPs) in the LRP2 gene.
Results: We identified significant correlations between plasma cholesterol levels and two of 19 examined SNPs in LRP2, c.+193826T/C and IVS55 – 147A/G. In particular, the association of c.+193826T/C with the T-Cho level was prominent (p=0.003), showing a co-dominant effect of the minor C-allele on lowering T-Cho and LDL-C levels: for 24 homozygous C-allele carriers, T-Cho=240.7 ± 24.2 mg/dL and LDL-C=166.1 ± 21.0 mg/dL); for 130 heterozygous carriers, 248.5 ± 23.5 mg/dL and 166.6 ± 19.3 mg/dL; and for 196 homozygous T-allele carriers, 253.9 ± 23.5 mg/dL and 172.0 ± 21.0 mg/dL. Linkage disequilibrium (LD) analyses based on 19 selected SNPs showed that c.+193826T/C and IVS55 – 147A/G were in tight LD and that both were located in an LD block covering the genomic sequence from exon 55 to exon 61.
Conclusion: We confirm the association between LRP2 and levels of T-Cho and LDL-C in human plasma. The results suggest that genetic variations in LRP2 are important factors affecting lipoprotein phenotypes of patients with hypercholesterolemia.

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Aim: Vascular calcification is a common feature in patients with advanced atherosclerosis, postmenopausal women and patients with renal failure, which results in reduced elasticity of arteries. Pamidronate, a bisphosphonate, is used as a therapeutic agent for anti-osteoporosity, although there are adverse side effects, such as renal damage and aortic inflamed plaque rupture. In the present study, we demonstrated the effects of vitamin K₂ alone or in combination with pamidronate in an arterial calcification model induced using inorganic phosphate in cultured bovine aortic smooth muscle cells (BASMCs).
Methods: Calcification was induced by the addition of Pi (3 mM) in BASMCs. Calcium deposition was determined by Calcium C-test Wako and von Kossa staining. mRNA expression was assessed by semi-quantitative reverse transcription-polymerase chain reaction.
Results: Calcium deposition assay and von Kossa staining showed that calcification could be inhibited in a dose-dependent manner by treatment with vitamin K₂ alone, and that its inhibitory effect was enhanced when combined with pamidronate. It was found that the expression of tropoelastin mRNA was synergistically enhanced by combined treatment with vitamin K₂ and pamidronate, and the expression matrix Gla protein mRNA and osteopontin mRNA expression were also enhanced and suppressed, respectively, by treatment with vitamin K₂ or pamidronate. Moreover, our data showed that the suppression of TE expression by siRNA significantly increased Pi-induced vascular calcification.
Conclusion: Taken together, our study suggests that vitamin K₂ in combination with pamidronate synergistically inhibits arterial calcification via the increased expression of tropoelastin, which would be a useful marker for developing effective therapeutic or prophylactic agents for arterial calcification.

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Aim: Since atherosclerosis was recognized as an inflammatory disease in 1990, the infiltration of macrophages and T lymphocytes has been reported to be predominant in human atherosclerotic lesions. Although adventitis accompanying atherosclerosis was also described in many reports, it is still unclear whether T lymphocytes or B lymphocytes are predominant in the adventitis. In this study, the authors immunohistochemically investigated the correlation between the transition of infiltrating inflammatory cells in the adventitia with atherosclerosis and the type of coronary atherosclerosis.
Methods: Sixty-four coronary atherosclerotic lesions from a surgical specimen and 47 autopsy cases were used for immunohistochemical study of CD45RO, CD20, CD68 and others. Atherosclerosis was classified into type I, II, III, IV according to the 1995 AHA classification.
Results: T lymphocyte infiltration in the adventitia was predominantly recognized in about 80% (38/48) of cases, but B lymphocyte infiltration was occasionally recognized in about 20% (10/48). Among 10 cases with B lymphocyte infiltration, small lymph follicles formed in 3 cases. This inflammatory response in adventitia subsided in type III and augmented again in type IV.
Conclusion: This result suggested that other inflammatory stimuli were induced in the adventitia in type IV coronary atherosclerosis.

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