Westernization of the Japanese lifestyle has been steadily progressing, and the percent energy intake as fat has increased 3.8 fold over the past 50 years. Although the serum cholesterol (C) level has also increased, the death rate due to coronary artery disease (CAD) is not increasing. Consumption of dietary fat in the United States (US) is decreasing and serum C levels are also decreasing. Although the death rate due to CAD is markedly decreasing in men and women in the US, it is still 4 times higher than that of Japanese. The percent energy intake as fat in Japanese migrants to the US (Japanese-American: JA) lies between that of native Japanese and US populations, and their C values are higher than those of native Japanese. Compared with native Japanese, JA showed a significant increase in carotid intima-media wall thickness, and deaths from CAD are also higher than those of Japanese in Japan. Although the death rate due to CAD has not yet increased in Japan, Japanese have the potential for further progression of atherosclerosis and increasing CAD.
Recent findings regarding the roles of cytokines, inflammation and immunity during the development of atherosclerosis were reviewed. Especially, the relationships among pro-inflammatory cytokines such as interleukin (IL)-1, IL-18 and osteopontin, and anti-inflammatory cytokines such as IL-1 receptor antagonist, IL-10 and IL-18 binding protein to inflammation and atherosclerosis were investigated and are described in detail. In addition, helicobacter pylori and C pneumoniae infections to inflammations regarding the persistence of inflammation have been pointed out. A pro-inflammatory genotype or haplotype and toll-like receptors have been shown to be involved in human atherosclerosis. Atherosclerosis might therefore be a specific form of the chronic inflammatory process. In addition to hyperlipidemia, infections, cytokines and immunity might also be involved in the development of atherosclerosis. Certain treatments that reduce coronary risk also limit inflammation. Statins possess multiple pleiotropic effects such as an anti-inflammatory effect in addition to a lipid-lowering effect.
The development of the remnant like particle (RLP) method for conveniently measuring serum remnant lipoprotein levels in 1993 promoted much research on atherogenic significance and metabolism of remnant lipoproteins. This research brought about many results as the following. A novel apolipoprotein B48 receptor incorporating remnant lipoproteins into macrophages in arterial wall was discovered and the structure of the gene of the receptor was clarified. The expression of apolipoprotein B100 was recognized in the human small intestine, suggesting that dietary very low density lipoproteins (VLDL) might be synthesized in the human small intestine and converted into VLDL remnants and low density lipoproteins (LDL). It is recognized that the atherosclerotic risk of postprandial hyperlipidemia is derived from an increase of remnant lipoproteins and that measurement of serum RLP levels in postprandial state is more sensitive and necessary for evaluating an atherosclerotic risk because serum RLP levels remain high all day in patients with diabetes mellitus or coronary heart disease. The relation between postprandial hyperlipidemia and insulin resistance was clarified.
Evaluation of carotid intima media wall thickness (IMT) by using ultrasonography is a validated quantitative method for assessing atherosclerosis, and is closely correlated with pathological findings observed in the carotid artery. Furthermore, the appearance of atherosclerosis in the carotid artery has been highly associated with atherosclerosis in the aorta and a close relationship has been observed between IMT and the incidence of coronary heart disease. In the present study, we investigated the association of risk factors for atherosclerosis with pre-clinical atherosclerosis as evaluated by IMT in native Japanese and Japanese Americans living in the United States.
Forty Type IIb or IV hyperlipidemic patients (serum triglyceride concentrations were higher than 150 mg/dl) were treated with fenofibrate (300 mg/day) for 12 weeks. Lipid profile and uric acid metabolism were evaluated before and after the treatment; the serum concentrations of total cholesterol and triglyceride respectively decreased from 224 ± 41.9 mg/dl to 199 ± 35.2 mg/dl and from 205 ± 71.7 mg/dl to 134 ± 67.5 mg/dl (p < 0.001). The uric acid concentrations in the serum also significantly decreased from 7.0 ± 1.58 mg/dl to 5.2 ± 1.57 mg/dl (p < 0.001). Fenofibrate treatment did not cause any change in the serum xanthine and hypoxanthine concentrations. Instead the urinary concentrations of uric acid decreased from 7.0 ± 1.58 mg/dl to 5.2 ± 1.57 mg/dl (p < 0.01), while the clearance ratio of uric acid and creatinin increased from 6.1 ± 2.56 to 9.9 ± 3.87 (p = 0.02) by the fenofibrate treatment. Fenofibrate decreases uric acid concentrations in the serum not as a result of inhibition of uric acid production but by increasing the urinary excretion of uric acid.
To clarify whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statin) increases lipoprotein lipase mass in preheparin plasma (preheparin LPL mass), we observed the change in preheparin LPL mass during administration of atorvastatin and pravastatin to type 2 diabetes mellitus patients with hypercholesterolemia. The subjects were randomly divided into two groups. One group was 24 patients given atorvastatin (10 mg/day), and the other was 23 patients given pravastatin (20 mg/day) for 4 months. After 4 months of administration, no significant change of HbA1c was observed. TC significantly decreased in the atorvastatin group compared to the pravastatin group. TG significantly decreased in the atorvastatin group. Low density lipoprotein cholesterol level significantly decreased in both groups (− 36.3%, p < 0.01 in atorvastatin, − 24.3%, p < 0.01 in pravastatin). Preheparin LPL mass slightly increased in both groups after 4 months of administration. Especially in patients who showed low preheparin LPL mass (less than 50 ng/ml) before statin administration, preheparin LPL mass significantly increased in both groups (+ 25.8% in the atorvastatin group, + 24.39% in the pravastatin group). These results suggested that administration of atorvastatin and pravastatin to type 2 diabetic patients with hypercholesterolemia increased serum preheparin LPL mass concentration. Especially, its effect was remarkable in patients who showed low preheparin LPL mass.
The pathophysiology of aortic aneurysm is complex and it has remained unclear how frequently arteriomegaly, a diffuse dilatation of the artery, is associated with aneurysm. Therefore, ultrasonic study of the carotid artery was conducted to clarify this issue in a large number of subjects. Carotid ultrasonography was performed in 1,108 Japanese men aged 50 or older, and the results of 379 patients with arteriosclerotic aortic aneurysm (AA) were compared with those of 211 patients with peripheral arterial disease, 65 patients with aortic dissection, 232 hypertensive subjects, and 221 normotensive subjects. The carotid diameter was measured bilaterally at two points on the common carotid artery, and we defined carotid arteriomegaly as an arterial diameter in the 95th percentile or above that in the normotensive control group according to the relevant age subgroups. The incidence of carotid arteriomegaly in the AA group (25.9%) was significantly higher than in the other groups (p < 0.01) even when adjusted for body height and blood pressure. In the arteriomegaly subgroup, hypertension and cigarette smoking was significantly more frequent than in the non-dilated artery subgroup. This study demonstrates that one fourth of patients with aortic aneurysm have arteriomegaly as a generalized systemic abnormality in the arterial wall.
We have investigated whether the oral administration of vitamin C could prevent smoking-induced acceleration of arterial stiffness in healthy volunteers. Subjects were pretreated with 2 g vitamin C and their heart rate (HR), mean blood pressure (MBP), and brachial-ankle pulse wave velocity (baPWV) were measured before and after smoking. Smoking significantly increased the HR, MBP, baPWV (13, 6.4, 7.0%). Vitamin C treatment significantly reduced the smoking-induced elevation in baPWV at 0 min (− 58.5%, p = 0.0002) without affecting HR or MBP. These findings suggest that oral vitamin C treatment prevents smoking-induced acceleration in arterial stiffness through reducing endothelial dysfunction.