Serum cholesterol and triglyceride levels in normal Japanese have been determined by a joint study in 1960, 1970 and 1980 in the past twenty years. The data obtained in 1980 were compared with those in 1960 and 1970.
Total cholesterol level in average was 176mg/dl in 1960 in 6.977 normal subjects and was 187mg/dl in 1970 in 3.555 normal subjects.
In 1980 average total cholesterol of 10.977 normal subjects was 191mg/dl which was higher 15mg/dl in compared with in 1960.
Triglyceride levels in 1980 was also higher than those of 10 years ago by 10-20mg/dl.
HDL-cholesterol levels were highest at the 1st decade and declined gradually with age.
Total cholesterol and triglyceride levels of younger age (1st and 3rd decade) were slightly higher than those of American in 1972-76.
The increase of serum lipids levels may be caused by the westnized dietary habits.
It was concluded that serum lipid levels of normal Japanese have been increasing in the past twenty years and approaching to the levels of Americans which suggest that possible increase of the incidence of atherosclerotic ischemic heart diseases due to hyperlipidemia in the nearly future.

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Serum lipid levels of normal Japanese subjects in 1980 were determined by a joint study of 14 institutions located in 9 districts of Japan. As for the serum lipid levels of young Japanese subjects (1st to 3rd decade), the following results were obtained.
1) Serum total cholesterol (TC) levels in young Japanese subjects in 1980 were higher than those of 20 years ago by about 10mg/dl. The TC levels of the 1st and 2nd decade in Japanese were higher than those of Americans in 1972-76. The TC levels of the 3rd decade in Japanese was equal to that of Americans.
2) Serum triglyceride levels in Japanese of the 1st to 3rd decade also exceeded those of Americans in 1972-76.
3) Serum TC levels in the male subjects in junior high school in Kanazawa area were almost equal to those in Tokyo area but TC levels of the female subjects in Kanazawa were higher than those in Tokyo.
4) The total energy intake in 1980 was almost the same as in 1960, while the intakes of total fat, animal fat and animal protein in 1980 were about 2, 3 and 1.6 times larger than those in 1960, respectively.
These results suggested that the increase in serum lipid levels in young Japanese subjects may be due to the changes in the quality rather than the quantity of diet. It is essential that the dietary life of young Japanese subjects must be improved in order to prevent the possible increase in the incidence of atherosclerotic diseases caused by hyperlipidemia in near future.

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Smooth muscle cells (SMC) are well known to play an important role in producing the progressive atherosclerotic lesions and also the early atherosclerotic lesions.
In this study, SMC in various states of atherosclerotic lesions of experimental rabbits, fed with a diet containing 1.5% cholesterol for different durations (1M, 3M), were subjected to biochemical lipid analysis by thin-layer chromatography. Cells of intima-media from various states of atherosclerotic lesions were obtained from the same thoracic aorta according to the method described by Chamley et al.
The results obtained are as follows:
1) In the same vessels, various states of atherosclerotic lesions could be produced by the cholesterol feeding within same loading period.
2) In the cells of the intima-media, CE in-creased, and PL and TG decreased following to progression of atherosclerotic lesions.
3) In the tissue of the intima-media, same tendencies in the lipids compositions which observed in the cells of the intima-media, were appeared. But in this case, FC increased.
4) In regards to the phospholipid composition in the cells of the aortic intima-media, LPC, SPH and PE decreased and PC increased, following to the progression of the atherosclerotic lesions.
5) In the phospholipid composition in the tissue of the aortic intima-media, LPC, SPH and PC increased and PE decreased following to the progression of the atherosclerotic lesions.
6) In the atherosclerotic lesions which were produced by the different periods of cholesterol feeding in the different subject and showed same degree of development, PL and FC decreased, and TG, CE and PSH increased following to the prolong cholesterol feeding periods.
7)From the above results, it is concluded that changes in the composition of the membrane phospholipids appeared in the atherosclerotic lesions might be more influenced by the loading period of cholesterol and the extent of hyper-lipidemia than by the severity of the lesions.

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To clarify the possible mechanism of hyperlipidemia in uremia, we have determined serum lipid levels, serum apoprotein (apo) C-II and E levels and postheparin lipolytic activity which consists of lipoprotein lipase (LPL) and hepatic triglyceride lipase (H-TGL) activities in 15 patients on maintenance hemodialysis and in 15 sex, age or serum triglyceride (TG) levels-matched normal controls. In addition, the relationship among various parameters in each group was investigated.
There was a significant decrease in serum total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) levels and H-TGL activity in the patient group when compared to those of normal controls.
Both serum apo C-II and apo E levels did not show significant changes between two groups regardless of age or sex.
There was a significant positive relationship between serum apo C-II and apo E levels in two groups.
In both groups, serum apo C-II and apo E levels showed a significant positive correlation to serum TG and TC levels. The correlation of TG to the apoproteins was much higher than that of TC.
In the patient group, LPL activity showed a significant positive correlation to serum apo C-II and apo E levels but not in the control group. Moreover, the patient group had a significant negative relationship between H-TGL activity and serum apo E levels, while no significant changes were observed in the control group.
These findings suggest that serum apo C-II and apo E levels may play an important role in the regulation of LPL and H-TGL activities in patients on maintenance hemodialysis.

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A 14-year-old girl was admitted to our hospital, complaining of abdominal pain. Her serum was milkish, the triglyceride (TG) level was 3, 548mg/dl and the total cholesterol (T-Ch) level was 316mg/dl. Agarose gel electrophoresis and sequential preparative ultracentrifugation revealed markedly increased levels of chylomicron and VLDL. Postheparin plasma (PHP) lipoprotein lipase (LPL) activity was 0.93μmol/ml/hr (control: 9.23±0.67) and serum level of apolipoprotein C-II (Apo C-II) was 9.2mg/dl (control: 3.0±0.8). Oral glucose tolerance test was normal.
Laboratory examinations showed the increased levels of serum TG in her parents, although her mother's hypertriglyceridemia was later normalized. Serum lipid levels of her two sisters were within normal limits. Serum lipoprotein fractionation of her father also demonstrated high levels of chylomicron and VLDL. PHP LPL activity was very low (1.16μmol/ml/hr) in her father and moderately decreased in her mother and second sister (5.1 and 3.2μmol/ml/hr). Her father's subcutaneous adipose tissue LPL activity was 3.35μmol/g/hr (control: 2.46±1.82). Hence, this family was diagnosed as having primary type I hyperlipoproteinemia.
Primary type I hyperlipoproteinemia is currently considered to have three subclasses: 1) familial LPL deficiency, 2) familial Apo C-II deficiency, and 3) a circulating inhibitor of LPL activity. The presence of normal or high levels of serum Apo C-II excluded the possibility of a familial Apo C-II deficiency. Despite the normal LPL activity in her father's adipose tissue, his PHP LPL activity was markedly decreased, leading us to examine an inhibitor of LPL activity according to Brunzell's method. Normal postheparin lipolytic activities were inhibited by about 20% and 10% by the addition of 0.4ml of patient's and her father's lipoprotein free sera, respectively. Hence, we concluded that the patient and her father had primary type I hyperlipoproteinemias due, to a circulating inhibitor of LPL activity. However, it was difficult to explain the following two points: 1) PHP LPL activity was also low in her mother and second sister, and 2) inhibiting activities of the patient's and her father's sera on LPL activity were not sufficiently potent compared with the extremely low PHP LPL activities. For these points, we proposed the possibility that in addition to LPL inhibitor this family had familial LPL deficiency which was transmitted to the parents and second sister in heterozygous form.

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Hypercholesterolemia is well known to be one of the most important promoting factors on atherosclerosis. Intravenous alimentation (IVA) was performed to 6 patients of familial hypercholesterolemia (FH). IVA solution consisted of 80% of the carories from glucose and 20% from amino acid hydrolysate. Total 1, 200 Kcal solution was infused daily to the patients for 4 weeks.
Plasma total cholesterol and LDL cholesterol decreased significantly (p<0.001, respectively). Plasma triglyceride tended to increase. HDL cholesterol (p<0.02), apo A-I (p<0.05), apo C-II (p<0.02) and apo E (p<0.05) reduced significantly, but apo A-II showed no change. The increase of the apo C-II/C-III₁ area ratio in VLDL was shown by isoelectric focusing.
Blood glucose, IRI and FFA showed no circadian variation. Blood glucose kept the normal fasting level and IRI kept the two-fold basal level but FFA kept the extremely low level.
In conclusion, it was suggested that lipid restriction and parenteral alimentation of nutrients caused the absolute reduction of LDL precursor such as chylomicron and VLDL, resulting in the decrease of total and LDL cholesterol.

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Rat apo E isoform patterns were determined by two-dimensional gel electrophoreisis (2-D. G. E.). Apo E in rat VLDL and HDL was separated into 3 bands by SDS gradient polyacrylamide gel and into 4 to 5 bands by IEF. On the 2-D. G. E., 4 to 5 different apo E isoforms (designated as E₃, E₄, etc) with isoproteins differing in MW (designated as E_3a, E_3b, E_3c) existed as shown in Fig. 2. Rat VLDL and HDL separated by ultracentrifugation had similar apo E isoform pattern. After 4weeks of feeding with atherogenic diet, mean plasma chol and PL were increased with decrease in plasma TG. The changes in plasma lipids were accompanied with increase in chol and PL of VLDL and IDL+LDL and with decrease in VLDL-TG. Then plasma lipoproteins were isolated by 6% agarose column chromatography to exclude the loss of apo E from lipoproteins after ultracentrifugations. Distribution pattern of column-isolated lipoproteins showed decrease of VLDL peak with increasing of IDL+LDL peak in atherogenic diet group. When looked at apo E bands of isolated IDL+LDL of atherogenic diet group on SDS gel, larger particles in terms of column isolation contained high MW apo E and smaller particles contained low MW apo E proportionaly.

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Plasma triglyceride, insulin, triglyceride secretion rate (TGSR) and postheparin plasma lipoprotein lipase (LPL) were determined in rats with ventromedial hypothalamic (VMH) lesions after 1 and 12weeks, respectively.
The results were as follows:
1) 12weeks after VMH operations, VMH lesioned rats showed significantly higher over-night-fasting plasma triglyceride concentrations than controls, wheares no difference was found between these two groups 1week after VMH operations.
2) VMH lesioned rats showed significantly higher TGSR, and blood insulin concentrations than controls both 1 and 12weeks after VMH operations. There was a positive correlation between serum insulin levels and TGSR in VMH lesioned rats.
3) VMH lesioned rats showed significantly higher LPL activity and serum insulin concentration than controls both 1 and 12weeks after VMH operations. There was a positive correlation between plasma insulin levels and LPL activity in VMH lesioned rats.
In these results, we presume that in rats with one week after VMH lesions the adipose tissue has enough capacity of depositing overproduced circulatory triglyceride, however in rats with 12weeks after VMH lesions, the adipose tissue has restricted capacity due to full deposition of the triglyceride, developing hypertriglyceridaemia.

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We investigated the effects of high-cholesterol diet on lipid metabolism in MSG-rat in the following four groups.
(1) MSG (-), Normal diet.
(2) MSG (-), High-cholesterol diet.
(3) MSG (+), Normal diet.
(4) MSG (+), High-cholesterol diet.
In lipoprotein profil, VLDL-triglyceride was increased in MSG (+) groups, (3) and (4). VLDL-cholesterol were increased in high-cholesterol diet administered groups, (2) and (4). In the liver, content of cholesterol ester, free cholesterol and triglyceride were increased in high-cholesterol diet groups, (2) and (4), compared with those in normal diet groups, (1) and (3), respectively. Triglyceride content was higher in MSG (+) groups, (3) and (4), than that in MSG (-) groups, (1) and (2), respectively. Free fatty acid uptake into cholesterol ester in liver was higher in (3) than that in (1). It was increased in control rats (2), but decreased in MSG rats (4), by administration of high-cholesterol diet. Free fatty acid uptake into triglyceride in liver was increased by high-cholesterol diet administration in both MSG (4) and control rats (2). Acid cholesterol esterase activity in aorta was also increased by high-cholesterol diet administration in MSG (4) rats in as same degree as in control rats (2).

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Studies on the usefulness of aortic pulse wave velocity (PWV) method, a non-invasive diagnostic method of arteriosclerosis have been published so far by the authors, and in this study the authors aimed at clarifying how tissue impairments due to arteriosclerosis influence PWV values by comparisons of antemortem PWV values with aortic tissues. Subjects were aorta of 30 patients; 18 males and 12 females of 24-82 years of age whose antemortem PWV values were determined and autopsy was made. Areas occupied by atheroma and calcification were determined by the point counting method, and the amounts of intimomedial elastin and collagen, by the microspectrophotometric procedure for comparison with PWV values. Intimal atheroma and calcification appeared from level of PWV 8m/sec. and 9m/sec., respectively. A PWV elevation coupled with an increase in collagen amount were found while the amount of elastin remained unchanged in the intima. In the media, PWV showed high values along with a decrease in elastin and collagen amounts.

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Acidic glycosaminoglycans (AGAG) in arterial tissues may play a role in the process of atherosclerosis as negatively charged substances. Previous work shows that arterial AGAG possess anti-atherogenic, anti-thrombogenic and anticoagulant properties. Little biochemical information is available on the AGAG composition of coronary arteries. In analytical processing of AGAG, we succeeded in precisely analyzing AGAG by microenzymatic assay methods, using chondroitinases, hyaluronidase and heparitinase. The data obtained indicated that the AGAG compositions of coronary arteries differ both according to the topographical site and the degree of atherosclerosis. The AGAG content of coronary arteries was relatively higher in the main branches than in their distal parts, and it decreased with increasing severity of atherosclerosis.
Fresh human coronary arteries were prepared from 48 male subjects in their fifth decade, and then divided into three parts: the left and right branches and their distal parts. The specimens, thus prepared, were then classified into 3 grades on the basis of the severity of atherosclerosis. The preparation of AGAG from coronary arteries were performed principally by the method reported in previous papers. The specimens were digested with pronase and treated with 4M sodium hydroxide and trichloroacetic acid. After the specimens were centrifuged, the supernatant was dialyzed against running tap and distilled water. The undialyzed AGAG were completely precipitated by addition of 5% cetylpyridinium chloride. The yield of uronic acid in units of AGAG was determined; it varied between 3 and 5.5mg/g defatted dry tissue weight. The AGAG thus prepared were applied onto a Dowex 1-X2 column (0.7×20cm) and eluted with 0.25M and 3.0M NaCI. The latter eluate was desalted by passing through a Sephadex G-10 column (0.7×25cm) and then used for the subsequent chemical analysis.
Thus, the acidic glycosaminoglycans (AGAG) of the human coronary arteries (the left and right branches and their distal parts) were analyzed by enzymatic methods employing chondroitinases, hyaluronidase and heparitinase. The AGAG content of human coronary arteries was highest in the left branch, intermediate in the right branch and lowest in the distal parts. Some compositional differences in AGAG were found in these three parts. The amount of AGAG in the coronary arterial tree decreased with increasing severity of atherosclerosis. The main AGAG were heparan sulfate (HS) and chondroitin 6-sulfate (C-6S), constituting 33-38% and 24-36% of the total AGAG, respectively. Dermatan sulfate (DS) and chondroitin 4-sulfate (C-4S) each comprised 1/5-1/10 of the total AGAG. Hyaluronic acid (HA) and oversulfated DS comprised smaller proportions of the total AGAG. A small amount of heparin was occasionally detected in the coronary arteries, particularly in the distal parts. The lipid content of the main branches was increased in mildly atherosclerotic parts but diminished in severely affected parts. The water content was relatively higher in the main branches and decreased with severity of atherosclerosis. A possible function of these AGAG in atherosclerosis is discussed with respect to the compositional changes.

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The cases observed cholesterol emboli in arteries were found 38 cases (4.75%) out of 800 consecutive autopsy cases from June 1977 to October 1983 at National Cardiovascular Center. Average age in those cases was 69.8 years old and male: female ratio was 32: 6. All cases showed complicated lesion in atherosclerotic lesion, 19 cases (50%) of them were accompanied with aortic aneurysm. Hypertension was documented in 29 cases (76.3%) and diabetes mellitus 8 cases (21.1%).
Thirty-eight cases were divided into two groups by their pathoetiology, one is a group induced by definite etiology including cardiac catheterization (5 cases), intraaortic baloon pumping; IABP (4 cases), and surgical procedure (12 cases), the other is unknown etiology group (17 cases). Cardiac catheterization group was consisted with male with history of hypertension, but diabetes mellitus was only two cases. IABP group was also composed of cases with history of hypertension, and diabetes mellitus was seen in three cases. It is posturated that cholesterol embolization in definite etiology groups were not only due to mechanical injury onto the surface of aortic atherosclerotis, but also due to the cotrast (76% Urografin) and fibrinolytic therapy.
Embolization rate (organs observed cholesterol emboli/all organs examined) was as follows; cardiac catheterization group 61.8%, IABP group 63.9%, surgical procedure group 37.4%, unknown etiology group 55.1%. The kidney seemed to be most frequently affected, followed with diminishing frequency by the spleen, pancreas, liver, adrenal gland, stomach and brain. Infarction rate (infarcted organs/organs found cholesterol emboli) was as follows; cardiac catheterization group 82.4%, IABP group 44%, surgical procedure group 42.1%, and unknown etiology group 31.3%. From the aspect of organ affected by infarction, brain, spinal cord and gallbladder were 100% in definite etiology group, and in 38 cases followed with diminishing frequency by the brain, intestine, stomach, gallbladder, kidney, spinal cord, and spleen.

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In order to examine the effect of dietary iron on the atherosclerosis, male rabbits were fed with diet containing 1.3g/kg iron as experimental group and 0.3g/kg iron as the control group for 18 weeks. At 14 weeks, noradrenalin was injected for 14 days and after a cessation of 14 days they were sacrificed.
The level of plasma essential metals (calcium, magnesium, iron, zinc and copper) and lipids (triglyceride, total-cholesterol, phospholipid and lipoperoxide) were analyzed and the pathological severity of atherosclerotic lesions were observed.
The results were obtained as follow:
1. Grossly visible atherosclerotic lesions were seen 3 out of 4 animals in the experimental group and 3 out of 5 animals in the control group.
2. The level of plasma iron in the experimental group were not significantly different from that of the control group. The level of iron in the liver was significantly increased (p<0.05), and in the aorta tended to decrease in the experimental group, respectively.
3. Plasma lipoperoxide, triglyceride and totalcholesterol were not significantly different between in the two groups by feeding.
4. The contents of triglyceride and calcium in the thoracic aorta from rabbits with grossly visible atherosclerotic lesions were remarkably increased. The level of totalcholesterol in the abdominal aorta in the experimental group were significantly increased (p<0.05) and the level of triglyceride in the liver in the experimental group were increased.
5. As pathological finding, a severe split and stretch of elastic fiber caused by calcification were diffusely observed in the thoracic aorta of the experimental group.
6. From the above results, it was concluded that intaked iron may play an important role indirectly in the pathogenesis of atherosclerosis, because the increased content of iron in the liver damaged the function of reticuloendotherial system-cells.

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To study the blood flow induced fibrosis in the vascular wall, an arterio-venous shunt was constructed in the canine carotid artery using 57 mongrel dogs (9-15kg). They were kept for acute (1 day, 3 days and 7 days), subacute (2 to 4 weeks) and chronic experiments (4 to 6 months). After the measurements of the blood flow in the shunted (fs) and control (fc) common carotid arteries, these arteries were fixed by 2.5% glutaraldehyde solution in phosphate buffer normotensively (22 dogs) and nontensionly (35 dogs). They were cut longitudinally and transversely to the long axis of the vessel and were examined histologically and ultrastructurally.
Blood flow ratio (fs/fc) was used for the index of the relative blood flow change. In acute experiments, the artery showed no fibrosis. In subacute experiments, the arterial media showed slight increase of elastic fibers in the animals which showed high blood flow ratio (over 3). In chronic experiments, the arterial media showed moderate increase of elastic lamina and fibers in the animals which showed slightly to moderately high blood flow rate (over 1.5). These arteries showed wide interstitium consisting of increased elastic fibers and collagen fibers by transmission electron microscopy. The smooth muscle cells were irregular in the margin and seemed shrinked.
To realize the increasement of the elastic fibers in the media, counting of elastic laminae and fibers was tried using ×500 B & W photograph of elastica van Gieson's stain. Elastic lamina ratio (number of elastic lamina of the shunted artery/that of the control artery) is increased slightly according to the blood flow ratio in the chronic experiments (r=0.60, n: 9), but it is not significant. Elastic fiber ratio (number of elastic fiber of the shunted artery/that of the control artery) is increased moderately according to the blood flow ratio (r=0.67, n: 9). It is significant (p<0.05). No significant correlation was found in the acute and subacute experiments.
We consider these arterial media fibrosis in the chronic experiments might be a kind of adaptive regulatory change to the blood flow. However, when the blood flow increased remarkably and the adaptive regulatory mechanism was not sufficient, the arterial fibrosis would mean sclerosis of the arterial wall.

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Renal hypertensive rats were divided into two groups. Group 1 rats were fed cholesterol rich diet and group 2 rats fed same diet and were intramuscularly injected the elastase. The effect of elastase on the mesenteric arteries was examined pathologically.
Body weight and blood pressure did not show any differences between the two groups. Serum, β-lipoprotein of group 2 was lower than group 1.
Histologically many mesenteric arteries of group 2 rats showed healed stage of arterionecrosis. Lipid infiltration into the arterial wall was severe in the early stage, but the arteries showing large amount of fibrinoid deposition in the intima or thickened intima resulted from absorption of fibrinoid substance showed little lipid deposition.
Fibronectin deposited in the luminal side of intima showing large amount of fibrinoid deposition and thickened intima with abundant acid mucopolysaccharides.
Impairment of plasma infiltration into the injured wall was discussed.

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The present study was performed to examine the prophylatic effect of dl-α-tocopheryl nicotinate (TN, Eisai), in the induction of an experimental atherosclerosis in rats. The experimental hypercholesterolemia and then atherosclerosis (Ch group) was induced in rats by administering Vit. D₂ (3.33×10⁵units/kg. B. W./day) for 4 days and then with an atherogenic diet for 5 weeks. Rats in E group were treated with TN (200 I. U./kg diet) in addition to the normal basal diet for a week and then were treated with the Vit. D₂ and TN (500 I. U./kg diet) in addition to the atherogenic diet for 5 weeks.
The following results were observed:
1) Serum and liver α-tocopherol levels were significantly higher, and lipoperoxide level was lower in the E group.
2) Serum HDL-cholesterol level was higher in the E group than in the Ch group.
3) Cholesterol levels in the aortic elastin fraction was lower in the E group than in the Ch group.
It may be suggested that TN primarily inhibits the formation of lipoperoxides. Disturbed lipoprotein metabolism due to hyperlipidemia may be improved by the administration of TN and lipid deposition on the elastin fraction may be minimized. Thus TN may exert its anti-atherosclerotic effect.

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In the study of arteriosclerosis, when it is questioned whether a physiological change or a lesional change, the mean aging trend, individual characteristics by age and individual changes with passage of time are essential to solve the question.
In this paper aortic properties were evaluated noninvasively by a method of aortic pulse wave velocity measurement, and characteristics by aging, individual and sex as well as long-term individual changes with passage of time on aortosclerosis were studied.
Subjects
(1) Aging and Individual Characteristics
The 114 in- and outpatients of both sexes with myocardial infarction or cerebral infarction, as well as 428 in- and outpatients of both sexes with diabetes under treatment for longer than 3 years were used, having 41, 046 healthy Japanese from 0 to the seventies in their age including the personnels of Toho University Hospital and Social Insurance Omiya General Hospital and their family members and those showing none of abnormalities upon the group examination conducted by the Epidemic Institute of Arteriosclerosis, Health and Welfare Association as the control.
(2) Sex
The subject used was the same as the abovementioned control with their age being ranged from the twenties to the seventies including 17, 914 males and 5, 155 females, 23, 069 in total.
(3) Long-term Individual Characteristics with Passage of Time
The subject used was 368 male and female exaxminees of the group examination with their age being ranged from the thirties to the seventies. Pulse wave velocity was measured regularly once a year together with the measurements of urine sugar, urine albumin, ophthalmodynamography, ECG and blood pressure for many consecutive years, namely, from 5 to 12 years.
Results
(1) Mean values of the aortic pulse wave velocity gradually increased as the age advanced, and after 40 years of age the standard deviations also increased rapidly. It explains that although aortosclerosis increases as the age advances, individual characteristics become more accurate after the forties and fifties.
(2) Although slightly, sexual characteristics were observed on distribution by age of aortosclerosis.
(3) Between the individuals the time course change patterns of aortic pulse wave velocities were compared. Regardless of age, sex and the initial value, the individual difference was large, ranging widely from that with no increase after 10 years to that with an increase of 3 m/sec, from 8m/sec to 11m/sec.
(4) Arteriosclerosis developed at a sharp gradient with advance of age, and significant difference was noted between that before the forties and that after the fifties.

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From stiffness parameter beta obtained by ultrasonic deviometry, local abdominal aortosclerosis was diagnosed quantitatively, and its relation to space and constructive mean velocity from aortic ostium to total ilioaortic pulsation was studied. Seventy-two in- and outpatients with various diseases of the attached hospital to Toho University School of Medicine, their age being ranged from 33 to 78, were used as the subject. As a result the following 4 points were clarified:
(1) Sclerosis of common carotid artery was significantly higher in diabetes and cerebral infarction than that of the normal.
(2) Sclerosis of abdominal aorta was remarkable in its individual characteristics.
(3) Sclerosis of abdominal aorta was higher than that of common carotid artery.
(4) A high value was noted in correlation of the pulse wave velocity as space and constructive mean velocity with the beta value in axial direction of local abdominal aorta (r=0.611).
It can be considered that determination of common carotid arteriosclerosis and abdominal aortosclerosis from the distribution characteristics of common carotid artery and abdominal aorta stiffness parameter beta measured non-invasively by ultrasonic deviometer as well as aortosclerosis by aortic pulse wave velocity simultaneously is an extremely effective diagnosis clinicoepidemiologically as noninvasive and quantitative method.

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To investigate the effect of glucocorticoid administration on lipoprotein metabolism, the changes of serum triglyceride levels in collagen disease patients, who were administered glucocorticoid, were studied.
Serum triglyceride levels were increased by administration of prednisolone, and the amount of elevated triglyceride was well correlated with the dose of administered prednisolone from 7.5 to 100mg/day. Efficacy unit of prednisolone for increment of triglyceride, of which value was obtained by dividing the amount of integrated rise of Δ triglyceride by total amount of administered prednisolone in that period, was about 2mg triglyceride/dl/mg prednisolone.
Next, the effect of dexamethasone on very low density lipoproteins (VLDL) secretion from isolated rat hepatocytes was studied. When isolated rat hepatocytes were incubated with radioactive [¹⁴C] glucose in DME medium containing 10 fetal calf serum, [¹⁴C] labelled VLDL was increased in the medium time-dependently up to 48hr. By the addition of dexamethasone from 5×10^-8 to 5×10^-7M in the medium, incorporation of [¹⁴C] glucose and [¹⁴C] fatty acid into VLDL in the medium was increased dose-dependently. Radioactivity was found mainly in triglyceride fraction.
These results suggested that dexamethasone increased the synthesis and secretion of VLDL from hepatocytes. Among other steroids, estradiol (10^-7M) had an increasing effect, but others (ex. aldosterone, testosterone and progesterone) had little effect on VLDL secretion into the medium. Glycyrrhzin, which is reported to have a hypolipidemic action, had a little decreasing effect. These different effects of various kind of steroids on secretion of VLDL in culture system were well correlated with the effects of these kind of steroids on serum lipid contents observed in clinical studies.

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To investigate the possible mechanism of serum lipoprotein (LP) abnormalities in cirrhotics, the following in vitro experiment was carried out. Serum LPs from the patient were isolated by sequential ultracentrifugation at d. 1.21g/ml and inactivated by heat treatment at 56°C 30min after subsequent dialysis against saline. LP deficient fraction (LPDF) from serum and postheparin plasma (PHP) from a healthy control was obtained by the same procedure at 4°C. The LPs were incubated with equal amount of the LPDF at 37°C for 6hr. The activity of lipoprotein lipase (LPL) and lecithin: cholesterol acyltransferase (LCAT) was inhibited by 1M NaCl and 2mM parachloromercuriphenyl sulfonate respectively. The resulting mixtures were isolated to record LP profiles and to perform chemical analyses by single-step density gradient ultra-centrifugation.
Most significant changes among the mixtures were observed in a PHP·LPDF containing system which possessed LPL, hepatic triglyceride lipase (H-TGL) and LCAT, wheareas there were no appreciable changes in other systems.
The results from the PHP·LPDF containing system were as follows.
1) In LP profiles, the absorbance of low density lipoproteins₂ (LDL₂) and high density lipoproteins₂ (HDL₂) shifted to heavier density and HDL₃ peak which was not usually detectable in cirrhotics appeared.
2) Total amount of LPs showed parallel changes with the LP profiles.
3) With respect to the percent chemical composition of each LP fraction, the significant changes were an increase in protein of very low density lipoprotein (VLDL)+intermediate density lipoprotein (IDL), an increase in total cholesterol (TC) and a decrease in triglycerides (TG) of LDL₂, an increase in protein and a decrease in TG of HDL₂ and an increase in protein and a decrease in TG and phospholipids of HDL₃. In addition, an elevation in cholesteryl ester/TC ratio was found in LDL₂, HDL₂ and HDL₃.
4) Apoprotein (apo) A-I/A-II ratio was elevated in both HDL₂ and HDL₃ subfractions.
These in vitro results suggest that lipoprotein abnormalities in cirrhotics could be partially normalized by the treatment with LPDF from healthy PHP which contains LPL, H-TGL and LCAT.

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The effect of apolipoprotein C-II (apo C-II) on the bovine milk lipoprotein lipase (LPL)-catalysed hydrolysis of a homogeneous series of saturated phosphatidylcholines (PC) was examined with respect to the fatty acyl chain length of the substrates. Dilauryl-, dimyristoyl-, dipalmitoyl-, and distearoylphophatidylcholine (diC₁₂PC, diC₁₄PC, diC₁₆PC and diC₁₈PC, respectively) solubilized by Triton X-100 were used as substrates. The maximal rate of the LPL-catalysed hydrolysis of each of these lipids was determined in the absence and presence of apo C-II. The activation factor (the ratio of enzyme activity with apo C-II to that without the activator protein) increased with increasing mol ratio of apo C-II to LPL and was maximal at a ratio of about 50. At all apo C-II/ LPL mol ratio tested, the activation factor increased as a function of fatty acyl chain length.
When LPL activities were determined between 16C and 40C, no systematic relationship between substrate fatty acyl chain length and either the rates or the activation energies for hydrolysis in the presence or absence of apo C-II was observed. However, there was a linear relationship between fatty acyl chain length and both the logarithm of the activation factor and the difference in activation energy in the presence and absence of apo C-II.
These relationship were not the result of an alteration in the physical form of the substrate, since a mixture of diC₁₄PC and diC₁₆PC gave activation factors for each PC which were the same as those obtained for each individual lipid. From the temperature dependence of the activation factor, thermodynamic functions of the apo C-II-induced change in the reaction pathway were calculated. The free energy of activation decreased linearly with increasing chain length as the result of a linear increase in activation entropy which more than offset the unfavorable increase in activation enthalpy. We propose that the apo C-II mediated increase in the rate of LPL-catalysed hydrolysis of phosphatidylcholine is associated with transfer of a fatty acyl chain of the substrate or product to a more hydrophobic environment within the transition state complex.

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We investigated the relationship between lipoprotein fractions separated by ultracentrifugal method and lipoprotein lipase and hepatic triglyceride lipase in postheparin plasma. Postheparin lipolytic activity was measured by sensitive nonradioisotopic method we had developed recently.
The following results were obtained in this study.
1) H-TGL activity is inversely correlated with IDL-cholesterol, and patients with high IDL-cholesterol concentration have lower H-TGL activity than with normal IDL-cholesterol concentration.
2) H-TGL activity is inversely correlated with the ratio HDL₂ cholesterol/HDL₃ cholesterol. The relationship between H-TGL activity and HDL₂ cholesterol is not significant statistically.
3) LPL activity is positively correlated with HDL₂ fraction, as previously reported.
These findings provide further evidence that low H-TGL activity contributes to the IDL accumulation even without apoprotein E disorder.

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Binding of ¹²⁵I-VLDL to endothelial cells was investigated before and after the treatment of cells with glycosaminoglycan (GAG) degrading enzymes. Treatment of the endothelial cell monolayer by heparitinase or chondroitinase ABC was found to remove all of the cell surface heparan sulfate or chondroitin sulfates, which accounted for 80% or 20% of cell surface GAGs respectively. No proteinase activity was demonstrated.
Binding of VLDL to endothelial cells reached equilibrium at 4°C by 2hr and, was saturable at VLDL concentration of 100μg protein/ml. Neither heparitinase nor chondroitinase treatment affected the amount of cell surface binding and cellular uptake of VLDL.
These results do not support the concept that endothelial cell surface GAGs contribute to the attachment of VLDL to the surface of the endothelium.

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The interaction of lysosomal cholesterol esterase with liposome-CHL-E composed of PC and PE at various ratios was investigated. Liposomes were prepared by sonicating lyophilized cholesteryl-1-[¹⁴C]-oleate with phospholipids (1: 66) at various ratios of PC to PE (PC only, 25, 10, 3, 1, 0.5). Rat liver lysosomal fraction, guinea pig peritoneal macrophages and the ring of rat thoracic aorta were used to examine the interaction of the liposomes with the enzyme, cells and tissues, respectively. The hydrolytic rates of liposome-CHL-E by cholesterol esterase in rat liver lysosomal fraction were markedly changed with varying ratios of PC to PE in the liposomes. The largest V_max and the smallest Km were obtained with the liposome with the ratio of PC/PE: 1. V_max and K_m were getting less and greater, respectively, in the order of the ratio: 1, 0.5, 3, 10 and 25.
The uptake and degradation of liposome-CHL-E by guinea pig peritoneal macrophages during 24hr incubation, was greatest in the liposome with the ratio 1, followed by those with the ratio: 0.5, 3, and 10, 25, PC only. However, the rate of degradation of liposome-CHL-E to the uptake was in almost the same degree with various liposomes. A similar result was obtained when the liposomes were incubated with rabbit aortic ring preparation, in which the rate of the degradation was less than in the macrophages, especially of the liposomes with the ratios larger than 10.
The ratio of PC/PE in VLDL-LDL fraction of cholesterol fed-rabbit serum was analyzed to examine if a change in the ratio would occur during atherogenesis. PC/PE ratios were getting greater with an increase in cholesterol level in the fraction, and there was a significant linear correlation between them (r=0.507). These results suggest that the metabolic rate of LDL-CHL-E, a native substrate for cholesterol esterase, changes with the composition of phospholipids in the particles, and that the change in the composition in LDL will occur in certain pathological conditions.

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The role of serum carboxyl esterase on lipoprotein metabolism was investigated. Serum carboxylesterase levels were well correlated with the level of total cholesterol and triglyceride, suggesting that carboxyl esterase is secreted from the liver accompanying with the secretion of very low density lipoprotein. VLDL are catabolized into IDL by LpL and a part of IDL are taken up by macrophages. The possibility that carboxylesterase is incorporated into macrophage and works as acid lipase was tested. ¹²⁵I-carboxyl esterase was incorporated into rat peritoneal macrophage, and transferred to the area where acid lipase existed. Incubation with carboxyl esterase and macrophages induced an increase in acid lipase activity in macrophages. These results indicated that serum carboxyl esterase is incorporated into macrophage, and exerts acid lipase activity.

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The purpose of the present study was to clarify the mechanism of the interaction of smooth muscle cells (SMC) and macrophages in accumulation of cholesterol ester in those cells. The internalization of β-migrating very low density lipoprotein (β-VLDL) was increased two-fold to four-fold when it was preconditioned with macrophages. So we investigated the metabolites of β-VLDL by macrophages. β-VLDL was internalized and degradaded by macrophages and its metabolites were secreted into the medium. The separation of β-VLDL macrophage conditioned medium by zonalutracentrifugation demonstrated two peaks. Peak I represented the same characteristics with β-VLDL and was considered to be the non degradaded β-VLDL. Peak II was present at a density of 1.12 and was elutioned at the same band with LDL. It contained free cholesterol and cholesterol ester and formed a new lipid-protein particle, which was considered to be the metabolite of β-VLDL. This particle was internalized into SMC and acid cholesterol esterase activity and cholesterol ester content were increased. These results suggest that β-VLDL was internalized and degradaded by macrophages and that its metabolites increased cholesterol ester content in SMC.

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Rapidly-frozen, etched replica of atheromatous aorta of WHHL rabbit was examined. In foam cells, lipid droplets were seen in two sites; membrane-bounded droplets in lysosomes and cytoplasmic droplets without membranes surrounded by 10nm filaments. The latter droplets, which were frequently observed, showed concentric lamellar structure like an onion and may correspond to cholesterol ester-rich lipid inclusion isolated by
Lang& Insull (J. Clin. Invest. 1970) and us (Takano, T. et al. Biochem. Int. 1982).

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The effects of porcine pancreatic elastase on post heparin lipolytic activity in rabbit plasma have been studied.
The results were as follows:
1) The direct stimulating action of porcine pancreatic elastase on lipoprotein lipase activity in post heparin plasma was not observed.
2) From the experiment presented with rabbit normal plasma, it appears that porcine pancreatic elastase biologically releases the stimulating factors of lipoprotein lipase activity.
3) The enhancement of lipoprotein lipase activity in post heparin plasma by α-chymotrypsin, trypsin and carboxypeptidase A_γ was not observed.

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Effects of Elaszym was tested on lipid metabolism and atherosclerosis in genetically restrictedovulator chickens with endogenous hyperlipidemia. A total of 12 eight month-old non-laying hens and 6 eight month-old roosters were used in this study. Non-laying hens were divided into 2 groups: Cont-NL group (without any treatment) and EL-NL group (With Elaszym). Elaszym was orally administered 3 times per week for 4 month. EL-NL group consisted of 6 non-laying hens, each of which received 5400 EL of Elaszym for the first 2 months, 1800 EL of Elaszym for the third month and 5400EL of Elaszym again for the last month of this study. Marked reductions in the serum triglyceride and cholesterol levels were noted in the EL-NL group compared to the Cont-NL group. The lipid and calcium content in the aortic tissue also decreased in the EL-NL group. The EL-NL group displayed a lesser degree of intimal thickening of the abdominal aortas than the Cont-NL group or roosters. Lipid-containing cells and extracellular lipid deposition were more prevalent in the aortas of the Cont-NL group than in those of the EL-NL group or roosters.

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We investigated the effect of age upon coronary atherosclerosis in eldery patients based on 2, 780 consecutive autopsies. Twenty-two hundred and fifteen patients who had no myocardial infarction on postmortem examination were classified as group A. The other 565 patients who had myocardial infarction were classified as group B. The coronary arteries were cross sectioned at 5mm interval, and the coronary stenotic index was defined as the sum of the highest stenotic scores in each major coronary artery; 0: without stenosis, 1: coronary atherosclerosis without stenosis, 2:25% narrowing of cross sectional area, 3:50%, 4:75%, 5: pinhole or complete occlusion. According to the number of 75% or greater narrowing of major coronary arteries, 0, 1, 2, and 3 vessel disease was defined.
The overall incidence of myocardial infarction was 20.3%; the incidence increased above the age of 70. In group A, the coronary stenotic index was relativety low in comparison with group B and increased with age. The mean±SD of coronary stenotic index was 6.3±3.8 in sixties, 7.0±3.6 in seventies, 7.6±3.3 in eighties, and 7.8±3.1 in nineties (p<0.01, between each decades except nineties). However, in group B, the coronary stenotic index remained at the same level; 10.9±3.6 in sixties, 11.1±3.1 in seventies, 10.8±3.1 in eighties, and 10.6±3.3 in nineties. The mean coronary stenotic index increased with the size of myocardial infarction, 12.0 in large size, 10.8 in middle size, and 9.3 in small size infarction. However, no agewise increase of coronary stenotic index was observed within each infarction size. In group A, the incidence of 0 vessel disease was 69.4% in sixties, and it decreased with advancing of ages until 58.7% in nineties. In group B, the overall incidence of 0 vessel disease was 17.2%, and it remained at the same level with advancing of ages. The progression of low grade coronary atherosclerosis with advancing of ages in group A may imply physiological aging process. On the other hand, in group B, high grade coronary atherosclerosis which was independent of the age may imply pathological process and may have consisted the direct cause of death.

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Using human umbilical vein endothelial cell, the effect of vitamin E on the morphological feature and prostacyclin synthesis in the endothelial cell incubated with linoleic acid hydroperoxide were investigated. In the cell specimens incubated with 1.0nmol/ml of linoleic acid hydroperoxide, a increase in number of cell organelle, well-developed rough endoplasmic reticulum, and a decrease of electron density in some mitochondrial matrix were observed electron microscopically. Prostacyclin synthesis of the cell incubated with 1.0nmol/ml of linoleic acid hydroperoxide was markedly decreased as compared to the control value. When the endothelial cell was pre-incubated with the medium containing 30.0μg/ml of dl-α-tocopherol dissolved in ethanol, the similar morphological changes and a decrease of prostacyclin synthesis were not exhibited. On the other hand, in the cell specimens pre-incubated with 50.0μg/ml of dl-α-tocopherol dissolved in the solvent containing HCO-60, propylene glycol, glucose, and sesame oil, the inhibition of dl-α-tocopherol on the injury caused by linoleic acid hydroperoxide were not exhibit. The result suggested that the solvent inhibited the transport of dl-α-tocopherol into the cultured endothelial cell.

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This study was undertaken to determine the effect of hyperinsulinemia and/or sucrose-feeding on lipoprotein metabolism in rats. Sixty male Wistar rats with a mean body weight of 350g were used in this study. They received gradually increasing dose of NPH insulin subcutaneously for 11 days. There were four groups of rats; sucroseinsulin (SI), sucrose-control (SC), chow-insulin (CI) and chow-control (CC). SI and SC groups were given 5% sucrose solution as drinking water (to avoid hypoglycemia after insulin injection). The final insulin dose was 6U and 4U in SI and CI group, respectively. At noon time (approximately 17 hr after insulin injection) of day 11, blood was obtained with EDTA from the abdominal aorta of 3hr fasted rats anesthetized with sodium pentobarbital. Each separated plasma pool was prepared from two equal volume of rat plasma. Lipoprotein fractionation was done by preparative ultracentrifugation. Each floating fraction was obtained by slicing and served for triglyceride and cholesterol assay.
There were no significant differences in plasma insulin and glucose levels between each experimental group and CC group. High density lipoprotein (HDL)-cholesterol concentration in SI group was the highest of all 4 groups and significantly differed from that of CC group. On the other hand, low density lipoprotein (LDL)-cholesterol in SI group was the lowest of all groups. CI group showed no remarkable differences in triglyceride and cholesterol concentration in each lipoprotein fraction compared to those of CC group.
It was suggested from the present data that the combination of hyperinsulinemia and sucrosefeeding raises HDL-cholesterol and suppresses LDL-cholesterol level in rats. Such a kind of hyperinsulinemic rats can be a good model for experimental hyper-α-lipoproteinemia.

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HWA 285 expected to have an anti-arteriosclerotic activity for its inhibitory action on the cyclic AMP phosphodiesterase. The inhibitory activity on the enzyme resulted in improving vasodilative function and erythrocyte deformity as well as repressing platelet coagulation. We have investigated the anti-arteriosclerotic activity of HWA 285 on the following study using arteriosclerotic rabbits: histochemical examinations of six structural components from aorta and one biophysical characteristics of aorta, i. e., the pulse wave velocity (PWV).
Material and methods: twenty eight Japanese albino domesticated rabbits, 38 months old male, were divided into three groups; 13 rabbits for healthy group (H), 9 for arteriosclerosis (S) and 6 for HWA 285 treated (A). Lesions on both intima and media in aorta were made by nitrogen inhalation, intramuscular injection of norepinephrine and cholesterol peroral ingestion. Group A received one dose of HWA 285, 3mg/kg/day, through intravenous injection at the same time the load test was started. An external loop of carotid artery was made and used for measuring both PWV and blood pressure. All animals were sacrificed 16 weeks later and examined for the following items in their thoracic media by MSP method; smooth muscle cell (SMC), nuclear DNA (DNA), elastin (EL), collagen (CL), acid mucopolysacharides (AMPS), glycoprotein (GP) and calcium phosphate (CA). The differences in the six structural materials among three groups were evaluated with the principale component analysis.
Results: The H group showed PWV between 7 and 8m/sec and the S group exhibited it gradual increase to 9m/sec. Whereas, the A group had a declining trend in PWV and significantly lower values than that of the S group (p<0.001). The average regression coefficiencies for the H, S and A group were 0.0109, 0.0626, and -0.056m/sec/ wk, respectively. The S group clearly showed some lesions on SMC, reduction in the amount of EL and CL, increase in diseased connective tissues and deposition of CA under histochemical studies. Among the A group, however in both tissues and the amount of components were observed only in slight. Since HWA 285 has more than three times of efficacy than its analogue, pentoxifylline, further clinical evaluation on this drug should be forthcoming. Besides HWA 285 has the anti-arteriosclerotic function observed in this study, we believe that it has some activity which acts directly on metabolism in smooth muscle cells of aortic wall and connective tissues.

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We have investigated the anti-arteriosclerotic activity of Cinnarizine (Aplactan^®) with histochemical study on six structural components of aorta and one of its biophysical characteristics, the aortic pulse wave velocity (PWV) using arteriosclerotic rabbits.
Materials and methods: Japanese albino domesticated rabbits, 38 months old male, were divided into three groups; 13 for healthy, 9 for arteriosclerosis and 5 for Cinnarizine treated group, a total of 27. Three methods were used for inducing arteriosclerosis; nitrogen inhalation, intramuscular injection of norepinephrine and peroral ingestion of cholesterol (0.5g). An external loop of common carotid artery made before the study and used for measuring both PWV and blood pressure. All animals sacrificed 16 weeks later and examined for the following six items by microspectrophotometric method (MSP); smooth muscle cell (SMC), nuclear DNA (DNA), acid mucopolysacharides (AMPS), glycoprotein (GP), elastin (EL), collagen (CL) and calcium phosphate (CA). The differences in them among three groups were compared. Results: The healthy group showed constantly PWV between 7 and 8m/sec and an average regression coefficiency was 0.0101m/sec/wk. On the other hand, the sclerotic group increased gradually from 8 to 9m/sec with a high average regression coefficiency of 0.063m/sec/wk. Whereas, the treated group decreased in PWV 8 to 7m/sec and its regression coefficiency was in negative value of -0.033m/sec/wk. The changes in PWV (ΔPWV) after 16 weeks among the three groups were 0.1m/sec for the healthy, 1.2 m/sec for the sclerotic and -1.2m/sec for the treated which was significantly lower than that of the sclerotic group (p<0.01). Under the histochemical observations, the sclerotic group exhibited hypertrophy, swelling, necrosis and disappearance of SMC, cleavages and narrowings in EL and CL, un-uniform growth in both AMPS and GP and deposition of CA on EL and SMC. However, the treated group displayed little of these abnormalities and kept the basic structure well. The amount of each component for the healthy, sclerotic and treated group were, respectively, SMC; 40.6, 32.6 and 38.0% E: DNA; 293, 283 and 280% E: EL; 52.8, 42.3 and 45.0% E: CL; 38.3, 33.3 and 35.0% E: AMPS; 28.4, 35.7 and 30.0% E and GP; 28.4, 35.7 and 30.0% E. The result of this study indicated that the Cinnarizine had supressing activity of organic arteriosclerotic changes.

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