A topographical view of atherosclerotic lesions and the development of intimal thickening of branching sites, including internal carotid-anterior cerebral-middle cerebral arterial bifurcation and middle cerebral artery-first branch of humans, was studied. A fatty streak was observed in the second decade but its surface involvement did not develop with age. In contrast, a fibrous plaque first appeared in the fourth decade and progressed with age. The fibrous plaque revealed a distinct pattern with a high incidence on the outer walls of daughter vessels with bifurcations. The flow divider was free from fibrous plaques.
In newborns and infants, the focal cellular intima (intimal pad) began to appear on the outer walls of daughter vessels of bifurcations and was replaced by cellulofibrous intimal thickening after one year of age. In similar topographic sites, a heterogeneous, stratified cellulofibrous intimal thickening, consisting of cellular component-rich layer and fibrous component-rich layer occurred in subjects more than 40 years of age. This frequency increased with age. The intima/media ratio increased progressively in successive age groups, and more rapid development was detected in subjects over 30 years old. In cases younger than 40 year-old, foam cells and fatty changes of collagen fibers were not observed in the intima, but LDL deposits were observed. In cases over 40 year-old, foam cells and fatty changes of collagen fibers in the intima were observed with LDL deposition. The cells observed in both the cellular and cellulofibrous intimal thickening demonstrated myosin and vimentin positivity. But the cells in the stratified cellulofibrous intimal thickening were immunohistochemically heterogeneous; some of them did not stain with antibodies to myosin or vimentin, though they were intimal smooth muscle cells.
These findings suggest that the cellular and cellulofibrous intimal thickening, occurring on the outer wall of daughter vessels of bifurcations in young patients, may play an important nascent role as a lesion in atherogenesis.

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Seventy-nine abnormal alleles of low density lipoprotein receptor (LDLR) gene in unrelated Japanese patients with familial hypercholesterolemia (FH) were screened and the following results were obtained:
1. A new variant of the LDLR gene with a 6kb deletion was found in four patients (FH Tonami-1). In the family of one of these four, neonatal diagnosis of FH was possible by checking this deletion.
2. Another variant of LDLR gene with approximately 10kb deletion was detected in five patients (FH Tonami-2). Patient H. Y., whose LDLR activity showed the same level as “heterozygote”, was revealed to have two copies of this mutant alleles and to be “true homozygote”.
3. The frequencies of these large structural alterations in the LDLR gene were 5.1% (FH Tonami-1) and 7.6% (FH Tonami-2).

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We hypothesized that functional changes of prostacyclin receptors were involved in exerciseinduced activation of platelets in patients with ischemic heart disease (IHD). Submaximal treadmill test, using the modified Bruce protocol, was performed in 12 IHD patients (10 angina pectoris and 2 old MI) and 12 age- and sex-matched control subjects.
In IHD patients, plasma TXB₂ levels increased significantly after exercise (p<0.02), suggesting activation of platelets during exercise. However, in controls, TXB₂ levels either decreased or remained constant. Inhibition of platelet aggregation by prostacyclin was blunted after exercise in IHD patients (p<0.01), whereas in controls, inhibition by the agent was enhanced significantly (p<0.01). The changes of anti-aggregatory property of prostacyclin after exercise correlated with the change of activation of the AC by prostacyclin (r=0.766, p<0.05).
We conclude that impaired sensitivity of the platelets to prostacyclin might be relevant to platelet activation associated with exercise in IHD patients.

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Studies of an immune potentiation factor which was generated only during the early stage of inflammation lead us to conclude that this factor was mainly derived from exuded PMNs at the inflammatory site. The ultimately purified factor was identified as rabbit IL 1β. We assume that PMNs were triggered to express mRNA for both IL 1α and IL 1β shortly after exudation into the inflammatory site, although the expression of IL 1βmRNA was about 6 times greater than that of IL 1α. This may contribute in understanding the biologic function of IL 1 as an autacoid which acts only for a brief period during the early stage of the inflammation. Also, this result may give us an opportunity to propose a new concept of “neutrokine” as one of the mediators of inflammation.

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Studies with cultured human vascular endothelial cells have led to the identification of two endothelial-dependent mechanisms relevant to leukocyte adhesion: the inducible cell surface expression of “endothelial-leukocyte adhesion molecules” (e. g., ELAM-1) and the secretion of a soluble leukocyte adhesion inhibitor (LAI). The interplay of these two mechanisms may contribute to the local regulation of leukocyte-vessel wall interactions in various pathophysiologic settings in vivo. Further understanding of these and related endothelial-dependent mechanisms may provide new insights into the pathogenesis of inflammatory vascular disease processes and potential therapeutic interventions.

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Comparative studies on arteriosclerosis and phlebosclerosis had been done with 50 autopsied cases and in addition to 4 cases with long term AC bypass venous grafts, and 2 surgically obtained gallbladders with cholesterosis and 4 xanthomata of gastric mucosa, by light and electron microscopies with X ray metal analyzer, and by thin layer chromatography for lipid. Following results were obtained.
1. Intimal thickening of phlebosclerosis did not followed by risk factors of atherogenesis, but densely related with phlebothrombosis deriving from hyperbiscosity of circulating blood or disturbances of venous flow.
2. Neither electron microscopy nor thin layerr chromatography disclosed atheromatous changes; lipid accumulation of veins in any individuals.
3. Spherical paracrystal bodies often contained Ca, Fe or Zn compounds were characteristic in markedly thickened intima of veins and long term AC bypass venous grafts.
4. Fibroelastic thickening, similar to arteriosclerosis was not performed in long-term, experimental and human AC bypass venous grafts.
5. Neither ultrastructural differences nor differences with thin layer chromatography were found on the modes of each lipid accumulation in arterial atherosclerosis, atheromatous plaque of AC bypass venous grafts, xanthoma of gastric mucosa and gall bladder with cholesterosis.
We conclude that phlebosclerosis is essentially different from arteriosclerosis in promortion and progression, and its risk factors for Intimal thickening were different from the artery's. Atheromatous plaque appeared in long-term AC bypass venous grafts could not prove to be true arterialization of the vein grafts.

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The effect of CS514 (an HMG-CoA reductase inhibitor) on LDL receptors was investigated with cultured chicken embryo hepatocytes. The increase of LDL receptors was demonstrated by CS514 treatment suggesting that the induction of hepatic LDL receptor by CS514 may have an important role in reducing serum cholesterol level.

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Dai-saiko-toh (Tsumura juntendo, Tokyo) is one of traditional Chinese drugs which has recently gained attention in Japan. Following administration, aortae and coronary arteries obtained from spontaneously hypertensive rats (SHR) were studied concerning its effect as an anti-athero-genesity. Sixty SHR were divided into three groups; A group: Dai-saiko-toh administration (900mg/kg/day), B group: Saiko-karyukotsu-borei-toh (900mg/kg/day) and C group: vehicle feeding. The groups were orally fed with one of them for 3, 6, 9, 12 months respectively, under identical environmental conditions. Blood pressure and body weight were monitored weekly until the subjects were sacrificed. After administration of these drugs, serum levels of Trace elements in SHR detected by ICP-Plasma Emission Analysis.
There were significant differences in serum Zn concentration at 9 and 12 months between the Saiko-Karyukotsu-borei-toh and the control group, and serum Fe concentration at 9 and 12 months between the Dai-saiko-toh and control group. Also, between the Saiko-Karyukotsu-borei-toh and control group at 12 months. SHR had high concentrations of serum Cu, Zn, Mg, K, Na and Fe as compared with WKY, fed with the vehicle feed at 3 months.

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An animal experiment adopting three heterozygous WHHL rabbits (A and two others) was carried out in order to evaluate the efficacy of repetitive LDL apheresis using an LDL adsorption module filled with polyvinyl alcohol gels on plasma and lipoprotein cholesterol (C) concentrations, and on aortic atherosclerosis in vivo. LDL apheresis was performed once a week for 2 months. Plasma total-C concentration of rabbit A was 266mg/dl at the beginning of the study. Mean removal rates of IDL-(39.5±5.0%) and LDL-C (42.9±4.2%) were significantly higher than those of VLDL-(28.3±5.8%) and HDL₃-C (21.3±6.6%) after eight plasmapheretic treatments (mean±SEM, p<0.05). There might be a decreasing tendency of C concentrations in plasma, VLDL, IDL and LDL along with the treatment course. In contrast, HDL₂- and HDL₃-C concentrations showed a tendency to continue increasing. The experiments in other two rabbits showed the same tendency.
Comparison between aortic specimens from a non-treated control rabbit and rabbit A exhibited an area ratio of atherosclerotic lesion to whole aorta nearly 1.8-fold higher in the former (14.1%) than in the latter (7.9%).
These results suggest that repetitive LDL apheresis may be effective for maintaining lower levels of atherogenic lipoprotein cholesterols and suppressing the progression of atherosclerotic lesions in vivo.

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This study investigated the relationship between maximal oxygen uptake (V_o2 max) and concentrations of plasma lipid and lipoprotein in men. V_o2 max was measured and blood sample taken for the analysis of plasma lipid and lipoprotein concentrations in 149 volunteers, including 106 trained and 43 untrained men, aged from 30 to 80 yr. T_o2 max significantly decreased with advance of age (r=-0.573, p<0.01, regression line: V_o2 max (ml/kg/min)=-0.488×Age (yr)+74.5). The trained runners had higher V_o2 max and more favorable plasma lipid and lipoprotein profile than the untrained men regardless of age (HDL cholesterol: 77±14 vs. 56±14mg/dl, p<0.01, triglyceride: 78±34 vs. 100±42 mg/dl, p<0.01, total cholesterol/HDL cholesterol ratio: 2.77± 0.50 vs. 3.79± 1.03, p<0.01). We also observed large interindividual variations in the coronary heart disease (CHD) risk factors. Although among all subjects, including runners and untrained men there were significant correlations between V_o2 max and the CHD risk factors, no significant correlation was observed within the respective group. These results indicate that a given level of V_o2 max is not an appropriate index for evaluating a risk of CHD in middle-aged and older men.

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The effects of fat emulsion (Intralipid®) on HDL in primary hypertriglyceridemia were studied in vivo. Following a 14-h fast, five primary hypertriglyceridemic male patients (HTG) and six healthy male subjects (N) received intralipid® over a 4-h infusion. Apo A-I and A-II in HDL₂ and HDL₃ were estimated and polyacrylamide gradient gel electrophoresis of lipoprotein (density<1.225g/ml) was performed before, at 4h and 6h after the start of the infusion. HDL subpopulations were observed using terminology by Blanche et al.
At 4h, Apo A-I and A-II in HDL₂ increased significantly, while HDL₃ decreased significantly. Significant increases were noted in HDL_2b and HDL_2a percentages and significant decreases in HDL_3a and HDL_3b. However, most of these dramatic changes at 4h disappeared by 6h.
In HTG at 4h and 6h, no significant changes of apo A-I and A-II i n both HDL₂ and HDL₃ were observed. In addition, no changes in HDL_2b and HDL_3a percentages were observed in HTG at 4h. However, three large HDL peaks were revealed by stained gel densitometry. The degree of change in particle size over time of HDL occupying peak 2 and peak 3 was less for HTG than N.
These results suggest that reverse conversion between HDL₂ and HDL₃ over time and among HDL subpopulations is impaired in HTG.

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We investigated the relationship between fatty liver and serum lipids using electrocardiogram (ECG) findings in patients with glucose intolerance.
The cases with glucose intolerance diagnosed by 75g OGTT were 40 to 65 years old. Fatty liver was determined by brightness through abdominal echography.
1. 1) 26 male cases with fatty liver and 59 cases without were 46.1±11.9 (M±SD) years old and 49.6±11 years old, respectively and 106.9 and 101.4% on an average in relative body weight ratio (RBWR). GPT and TG/HDL-C ratio increased significantly in cases with fatty liver as compared to cases without, while HDL-C decreased. 2) 9 female cases with fatty liver and 15 cases without were 52.9±9 years old and 56.7±4.1 years old, and 107.4% and 100.8% in RBWR. GPT and apo C-III increased significantly in cases with fatty liver. 3) 15 male cases with fatty liver and 47 cases without, who showed the normal ranges of serum transaminases, were 49±11 years old and 45±11 years old, and 110% and 100.7 in RBWR (p<0.005). HDL-C decreased significantly in cases with fatty liver, while atherogenic index, TG/HDL-C ratio and apo E increased. 4) In cases not given medical agents, there were significant positive correlations (r=0.53, 0.53, 0.71 or 0.52) between body weight changes and the changes of GPT, GOT, FBS or cholesterol. 5) There were significant positive correlations (r=0.75, 0.8 or 0.72) between carbohydrate intakes and GPT, GOT or γ-GTP in cases with fatty liver, while a significant negative correlation (r=-0.87) between protein intake and GOT.
2. Seven cases consisting of 5 males and 2 females, who resulted in the disappearance of the previous fatty liver during the period of 12.4±6.9 months, showed the significant decrements of serum cholesterol and LDL cholesterol.
3. 24 male cases with fatty liver and 26 cases without were 51.3±7.7 years old and 52.3±7.1 years old, and 119.9±13.5% and 117.1±6.8% in RBWR. The horizontal ST depression of resting ECG and the positive Master double exercise test were 20.8% and 4.8% respectively in cases with fatty liver, while 0% and 0% in cases without. From these findings, the cases with fatty liver tended to be accompanied with the increments of GPT, cholesterol, LDL-cholesterol, atherogenic index or RBWR or with the decrements of HDL-cholesterol, indicating the tendency of arteriosclerosis in fatty liver.

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Effects of probucol on experimental atherosclerosis in cholesterol-fed rabbits were studied. Male New Zealand white rabbits weighing 1.5kg were divided in 4 groups. Group 1 rabbits (n=17) received 200mg of probucol and 400mg of cholesterol per kg body weight in the chow. Animals in group 2 (n=12) were fed the same doses of cholesterol but without probucol. Those in group 3 (n=11) were fed the same dosage of probucol as group 1 but without cholesterol. Group 4 (n=12) rabbits were fed standard chow. Serum lipid concentrations were determined every 4 weeks. 16 weeks after the start of the experiment, the animals were sacrificed and the percentage surface area of visible plaques in the thoracic aorta was measured. Separate tissues from the thoracic aorta and cornea were used for microscopic study.
The following results were obtained:
1) Serum total cholesterol in group 1 and 2 was significantly higher than in group 3 and 4. But the difference between group 1 and 2 was not significant (Table 1).
2) Percentage surface area of plaques in group 1 (33±22%) was significantly lower than in group 2 (75±23%) (p<0.001) (Fig. 1).
3) Histological study revealed a decrease in number of foam cells and spindle cells in atheromatous plaque in group 1 as compared with group 2 (Fig. 3-A, B).
4) Corneal opacity with angiogenesis was observed in animals in group 1, but not in groups 3 and 4. In group 2 animals, corneal arcus was observed (Fig. 4-A, B, C).
5) Histologically the corneal opacity in group 1 had marked angiogenesis with perivascular foam cells in the all layers of corneal stroma (Fig. 5A). The corneal arcus in group 2 had less marked angiogenesis with foam cells in just the anterior portion of corneal stroma (Fig. SB). In both groups sudanophilia was located in foam cell bodies (Fig. 5-E, F).
Thus, probucol prevents the progression of atherosclerosis without lowering serum total cholesterol. It may be concluded that probucol has a benefit in preventing atherosclerosis but some attention should be paid to the generation of ocular lesions in the experimental hypercholesterolemia.

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The relationship between running speed which brings blood lactate accumulation of 4 m mol×1^-1 (SP-OBLA) and serum lipids and apolipoproteins was investigated in 9 top-runners, 9 runners, and 9 controls. SP-OBLA was determined by intermittent, step-wise running test.
SP-OBLA were significantly higher in runners in the following order top-runners<runners>controls (p<0.001). HDL-C levels of top-runners and runners were significantly higher than that of controls (p<0.001). SP-OBLA were positively correlated with HDL-C, Apo A-I and Apo A-I/A-II (p<0.001). However, Apo C-II/C-III and atherogenic indexes (TC/HDL-C, LDL-C/HDL-C and Apo B/A-I) were negatively correlated with SP-OBLA (p<0.01 or p<0.001).
These results suggest that habitual running which induces hi-oxidative capacity of skeletal muscle will be useful for the prevention of atherosclerosis.

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We investigated the relationship between glycation (the Maillard reaction) aging and arteriosclerosis by measuring the glycation levels of collagen in the aorta. Using fluorescence, we measured late-stage products of the Maillard reaction. The degree of arteriosclerosis of the aorta was classed macroscopically. In non-diabetics, fluorescence levels were significantly correlated with age (r=0.79, p<0.001), and with the grade of arteriosclerosis (r=0.52, p<0.001). Fluorescence levels in diabetics were much higher than those in non-diabetics. These results suggest that an increase in the glycation of collagen in the aorta may play an etiological role in aging and arteriosclerosis. Diabetes may accelerate these pathophysiological conditions.

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