According to mortality statistics, Japan ranks one of the most successful countries in accompolising significant reduction in mortality from ischemic heart disease in men and women. This statistics, however, contradicts clinical impression of recent remarkable increase in patients with acute myocardial infarction, particularly in young patients.
The purpose of the present study is to resolve such controversy using nation-wide data collected in “Patients Survey” by the Ministry of Health and Welfare.
Secular trend of number of patients with ischemic heart disease (IHD) aged 35 years and over, was analysed. “Patients Survey” is a national report on the patients taken care at about 10% sample of all the hospitals stratified by size and at about 1% of clinics randomly selected, on the 2nd Wednesday of July every year. The present analysis covers data obtained from 1971 through 1981.
Results of the analysis are summarized:
1. Number of patients with IHD and AMI has been increasing in all age groups, sexes, areas, types of medical facilities, and hospitalized or ambulant patients during the observation periods.
2. The rate of increase was generally smaller during earlier period and became larger recently. It was larger in the elderly and smaller in the young.
3. The rate of increase did not vary between other hospitals and teaching hospitals from which significant increase in young patients with AMI was often claimed. Such a conspicuous increase in the young was not observed on the national basis.
4. The ratio of AMI to stroke was higher in Tokyo than elsewhere but the rate of recent increase of AMI and IHD was less in Tokyo.
5. The observed general trend of increase in number of patients with IHD and AMI may not be caused only by an increase in incidence rate and/or a decline in case-fatality rate. Other factors such as increases in provision of emergency services, consultation rate particularly by the elderly, accuracy of diagnosis, frequency of medical consultations and duration of treatment and rehabilitation period are also possible causes. Therefore real increase in prevalence rate of patients would be less than face values. Exact share of contributions by each factor, however, remains unknown.

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Both hypercholesterolemia (HCh) and hypertension (HT) are major contributor to death from cardiovascular disease (CVD). Since death from CVD has been gradually increasing in Japan since 1965, prevention of any further increase has become a major concern.
Epidemiological studies have shown that saturated fatty acid (SFA) intake is associated with HCh and salt intake is associated with HT. As result, SFA or salt restriction have helped to control these diseases. In data from a national nutritional study in Japan, the average fat-intake in 1981 was 54.7g/day which was composed of 23% total calories and 12% animal fat. The average salt intake in 1981 was 13g/day. The question arises whether it may be necessary for even the average person in modern Japan to make abrupt changes in his dietary habits, let alone people with habit of excessive intake of SFA or salt, to prevent increase in HCh or HT incidence.
In a previous report from a epidemiological study in Japan, it was clearly shown that the average of serum cholesterol concentration and blood pressure in farming village has increased during the past 20 years, accompanying the increase in adipose tissue noted in sking folds. Based on this result from the epidemiological study, it may be likely that an accumulation of body-fat caused by excess calory-intake and physical inactivity enhances the relationship between SFA and HCH or salt and HT.
Experiment I:
Three hospitalized subjects, who suffered from HCh (2 of three were familial HCh), were kept on a formula diet (1, 300 Kcal/day containing 32g fat, P/S ratio=0.9) and the other three subjects with HCh (2 of three were familial HCh) were kept on another formula diet (1, 600 Kcal/day containing 39g fat, P/S=0.9) for 26 days. The subjects then consumed the experimental diet under isocalory in which 300 Kcal/day of rice in each diet was formula replaced with butter for 7 to 14 days. In an analysis of the experimental diet as consumed, the 1, 300 Kcal/day with 65g fat covered 45% of the total calories and the other experimental diet with 1, 600 Kcal/day with 75g fat covered 42% of the total calories. Reduction in the ratio of polyunsaturated to saturated fatty acids in both diets may be followed by an elevation in about 40 mg/dl of serum cholesterol conscentration in both experimental diets.
In the subjects who consumed 1, 600Kcal rich in SFA, LDL-cholesterol elevation was 25 against the final period of isocaloric formala diet. On the other hand, in the subjects who consumed 1, 300Kcal rich in SFA, LDL-cholesterol was not changed in spite of the same amount of SFA intake as 1, 600Kcal/day.
Conslusion: The cholesterol increasing effect of diets with a low P/S ratio may appear only relatively high calory intake.
Experiment II:
The thirteen hospitalized subjects with HT (aged 52.9&p6.0 years, mean blood pressure 157±12/91±Hg) consumed a formula diet until their blood pressure became stable. All subjects were then given 1, 000 Kcal/day containing 7-10g NaCl and allowed mild physical training (50W for 9 minutes/day ergometer) for 16 days. Body weight reduction during therapeutic period was from 69.2±14 to 67.3±13.6Kg, accompanied by 12mmHg of systolic pressure-reduction. During experimental stage Na excretion in urine was similar to the formula diet stage. An exercise test (gradually increasing from 25W to 75W by ergometer) was given in each period.
Before and after body weight reduction there was no difference in the elevation rate of blood pressure, O₂ consumption, and plasma lactate concentration during the exercise test, except a decrease in the recovery of increased plasma lactate concentration against initial level seen in the treatment period.

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It is most important problem for prevention of disease that its pathogenesis is brought to light.
The epideminological research is one of techniques for the investigation in pathogenesis. Many risk factors are led by these studies and a disease will be prevented by these studies.
Atherosclerosis is a silent disease; we can not determine its extent in any individual or vascular tree untill it produces signs or symptoms through occulsion or embolism. As much as two-thirds of the coronary lumen may be occuluded by atherosclerotic plaque without any signs or symptoms. The first sign of atherosclerosis is often the last sign. This fact means that we must think about acute risk factors to separate from chronic risk factors. It is well known that aging is the most important risk factor in chronic risk factors for atherosclerosis.
It is supposed that the platelet aggregation plays a much more important role as acute risk factors. It will be too late to begin our therapy after symptoms appeared.
Cardiovascular epidemiologists have spent the past 20 to 30 years defining cardiovascular risk factors. Cardiovascular physiologists have taken another equally important tack. There may be twe periods in process of atherosclerosis, it is to say, those are reversible and irreversible periods. We must detect the dissase before it becomes irreversible-one could diagnose coronary disease before heart attacks occur.
On the other side, some conditions of noninvasive techniques for finding aterosclerosis are required necessarily. It is so say, the conditions are expensiveness and length in examinations. It is necessary to diagnose or detect abnormal changes in many people for short terms.
In this paper, I reported the results regarding to relation ships between biological age and calenderage as a risk factor, the method for measurement of aggregability of platelet in blood and assessment diagnostic techniques (noninvasive) for atherosclerosis.

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Rocket immunoelectrophoresis developed by Laurell is one of efficieint methods for a determination of serum levels of apolipoproteins. This paper describes the principle of the determination, detailed technical comments and comparison to the single radial immnodiffusion method. The determinations were carried out on six apoproteins, namely, A-I, A-II, B, C-III, E and A-IV. The antisera against each apoprotein were prepared in our laboratory. The measurements were reasonably accurate, sensitive and reproducible. Coefficient of correlations between apoprotein levels measured by rocket technique and SRID method were around 0.9.

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The concentrations of serum apolipoprotein A (M-Partigen-Apolipoprotein A, Behringwerke), A-I and A-II (Apolipoprotein A-I and A-II Plates, Daiichi pure chemicals) were determined in 27 normal and hyperlipidemic subjects by the commercially developed SRID method. Apolipoprotein A concentration was higher than sum of apolipoprotein A-I and A-II concentrations, and the apo A/apo A-I+A-II ratio was 1.29±0.02. Apo A correlated with apo A-I+A-II (r=0.98). The same results were obtained even though specially prepared standard serum for each methods were determined by the different method. These data suggested that the differences between apo A and apo A-I+A-II concentrations which observed in the human serum were indeed by the differences of indicated values of standard serum in each method.
Whole serum formed single precipitin arc with a migration similar to HDL on crossed immunoelectrophoresis with anti apo A (anti human α-lipoprotein) serum and anti apo A-I or anti apo A-II serum. Delipidated HDL formed precipitin arcs of apo A-I and apo A-II with mixture of anti apo A-I serum and anti apo A-II serum. Delipidated HDL formed single precipitin arc with anti apo A serum on immunoelectrophoresis, but not formed on rocket immunoelectrophoresis and Ouchterlony method. Delipidated HDL formed clear precipitin rings on apo A-I and A-II SRID plates, but formed unclear precipitin rings on apo A plate. These differences of the reactions between anti apo A serum and delipidated HDL seems to suggest that immunoreactivity of HDL was not identical with that of apo A-I or apo A-II.

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Apoproteins A-I, A-II, C-II and E were determined in 94 patients with various hyperlipidemias and 87 normal controls using single radial immunodiffusion (SRID) method recently developed by Daiich-Kagaku Co. Apo A-I and A-II correlated positively with HDL-cholesterol and correlation coefficient values (r) were 0.620 and 0.465 respctively. There was a strong correlationship between apo C-II and serum triglyceride (r=0.748). Apo E correlated with both of serum cholesterol and triglyceride and r values were 0.555 and 0.511 respectively. Apo C-II could not be detected in a case with type I hyperlipoproteinemia caused by Apo C-II deficiency, confirming that the anti-apo C-II serum used in the SRID plates was immunochemically pure. The ratio of Apo C-II over triglyceride correlated positively with HDL-cholesterol, suggesting this ratio might express the state of lipoprotein metabolism. Although apo E levels in type III hyperlipoproteinemia with apo E₃ deficiency was significantly higher than in normal and the other hyperlipidemic subjects in agreement with the previous papers, there were substantial overlaps of apo E levels between type III and the other hyperlipidemia such as type V. Howerer, when the ratio of apo E over total cholesteriol was calculated, type III hyperlipoproteinemia with apo E₃ deficiency could be clearly discriminated from the other hyperlipidemia and normal controls. Therefore, the ratio of apo E/total cholesterol, can be easily available for the diagnosis of type III hyperlipoproteinemia with apo E₃ definceency.

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Serum lipids, lipoprotein lipids, apolipoprotein (Apo A-I, Apo A-II, Apo B, Apo C-II and Apo E) were determined in 62 survivors of myocardial infarction (MI) and in healthy controls matched for age and sex. Survivors of MI had significantly higher levels of serum triglycerides (TG), HDL-TG, LDL-TG and every lipids of VLDL than controls, and significantly lower levels of HDL-C, HDL-Phospholipids (PL), Apo A-I, Apo A-II and Apo C-II. However, there were no differences in levels of serum total cholesterol (T. Chol), PL, Apo B and Apo E between both groups. Ratios of Apo B/Apo A-I and every lipoproteins-TG/ Apolipoproteins were significantly higher in survivors of MI than in controls.
Furthermore, normolipemic survious of MI had lower levels of Apo A-I and Apo C-II, and higher ratio of Apo B/Apo A-I than controls, even though there were no significant differences in levels of T. Chol, HDL-C and in ratio of TC/HDL-C between both groups.
These results suggest that apolipoproteins are not only good discriminators as lipids between survivors of MI and controls, but also better discriminators than lipids especially between normolipemic surivors of MI and controls.

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Hepatic microsomal 3-hydroxy-3-methylglu-taryl coenzyme A (HMG-CoA) reductase (EC. 1. 1. 1. 34) activities were measured in 4 patients with heterozygous familial hepercholesterolemia (FH). Percutaneous needle liver biopsies were performed in 13 patients, who were classified into heterozygous FH group (n=4), heperlipidemic group (>200mg/dl in cholesterol, and/or >150mg/dl in triglyceride, n=4) and normolipidemic group (≤200mg/dl in cholesterol, ≤150mg/dl in triglyceride, n=5). The tissues were utilized for histological diagnoses and preparations of liver microsomes.
The mean±SE of HMG-CoA reductase activities was 71.8±33.9pmoles/min, mg microsomal protein in heterozygous FH, 25.2±4.0 in hyperlipidemic group and 19.0±5.9 in normolipidemic group. There were no statistically significancies among these three groups, but the activities in two patients with heterozygous FH showed very high levels (126.1 and 134.8). There was a significant correlation between HMG-CoA reductase activities and plasma cholesterol levels of low density lipoprotein (r=0.723, p<0.01). The activities did not significantly correlate with plasma albumin concentrations.
These results indicate that the regulation of hepatic cholesterol synthesis in vivo is impaired to various degress in heterozygous FH.

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Monoclonal antibodies directed against lipoprotein lipase (LPL) have been prepared by immunization of mice with purified bovine milk LPL. Spleen cells from the mice were fused with the SP2/O-Ag14 line of mouse myeloma cells. Ten clones producing antibodies against LPL were isolated. Cross reactivities against human post-heparin plasma LPL were tested for six clones.
1) Two clones react strongly with bovine milk LPL but react weakly with human post-heparin plasma LPL.
2) Two clones react strongly with human post-heparin plasma LPL but weakly with bovine milk LPL.
3) The remaining two clones react only weakly to both antigens.
These monoclonal antibodies will be useful for quantification of post-heparin plasma LPL and also useful for studying synthesis of LPL by human monocyte-derived macrophages.

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We reported the exaggerated response to dietary cholesterol in the streptozotocin-induced diabetic rats, showing hypercholesterolemia and hypertriglyceridemia with the occurrence of β-VLDL, an increase in IDL and LDL and the appearance of HDLc (HDL with apo E).
The present study was designed to elucidate the role of lipoprotein receptor mechanisms of liver parenchymal cells in the diabetic dyslipoproteinemia. Rat β-VLDL obtained from cholesterol and propylthiouracil-fed rats, human LDL₂ and rat HDL₃ was fractionated by ultracentrifugation.
Isolated rat hepatocytes (5.0×10⁶ cells) were incubated with a fixed amount of ¹²⁵I-lipoprotein at 37°C for 60min in Krebs-Henseleit bicarbonate buffer, pH 7.4 with or without unlabelled lipoprotein. Binding was determined by radioactivity washed cells.
Scatchard analysis of binding data revealed nonlinearity of the binding which could be resolved into two components.
The apparent dissociation constant (Kd) and maximum β-VLDL binding (B_max) for the higher affiinty binding site in the diabetic rats (n=6) were (11.9±5.1)×10²ng/ml and 307.5±145.2ng/10⁶ cells, respectively. These binding characteristics of the diabetic rats were not significantly different from the control rats. Furthermore, There were no significant differences in the binding characteristics of human LDL₂ and rat HDL₃ between the isolated liver parenchymal cells from the diabetic rats and the control rats.
The data presented suggested that no significant role of alteration of lipoprotein receptor characteristics in liver parencymal cells is played in the diabetic dyslipoproteinemia.

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In order to elucidate the role of macrophages in atherosclerosis, sequential observations of cholesterol-induced rabbit aortic lesions were preformed by the immunoperoxidase technique using anti-monocyte-macrophage monoclonal antibody named SRM1.
Animals on the cholesterol diet for 8 weeks or longer showed increased accumulations of lipidfilled, SRM1 positive macrophages in the subendothelial space. In early stages in which no grossly visible alteration was manifested, macrophages with or without lipid vaculoes could be seen clinging to the endothelial surface and apparently penetrating the endothelium. A single line of 3 or 4 vacuolated macrophages was found in otherwise almost normal subendothelial zone, and, in flat lesions consisted of a few layers of foam cells, lipid-laden macrophages were cells predominated. It could be therefore indicated that circulating monocytes are the prime source of foam cells in these early fatty lesions.
After 16 weeks of cholesterol feeding intimal lesions further progressed. In advanced plaque lesions SRM1 negative, smooth muscle foam cells became remarkable and tended to be numerous in places. In these lesions, macrophage foam cells were predominated in the superficial layer and often arranged in a row under the endothelium, whereas smooth muscle foam cells were prevalent in the deeper areas. In addition, SRM1 negative, elongated cells were scattered throughout the lesion. In atheroma lesions SRM1 positive macrophages were notably seen within the area of necrosis, and, later, situated occasionally near the necrotic core of the atheroma. In addition, they were preferentially observed in the vicinity of SRM1 negative foam cells still lying in fibrous plaque leions; the spatial relationship of macrophages to SRM1 negative foam cells thus gave an impression that disintegration of the latter cells was apparently a nidus of activity.
After stopping the cholesterol diet, numbers of SRM1 positive macrophages in the atheroma lesion diminished remarkably, and SRM1 positive cells actually breaching the endothelium almost totally disappeared.
It seems likely that the defined role of macrophages in atherogenesis is to remove lipid from areas of lesion formation. The removal of lipid by macrophages, however, is not always so efficient to prevent medial cell involvement that, in a protracted course of hyperlipemia, fatty streak lesion may progress to advanced ones. The slow or absent resorption of lipid from atheromatous lesions may in part be attributed to the paucity of macrophages therein.

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When macrophages were incubated with VLDL-tri[1-¹⁴C] oleate (VLDL-TG-[¹⁴C]) and lipoprotein lipase (LpL), incorporation of lipid into macrophages was increased compared with in the absence of LpL. These results suggest that the metabolites of VLDL, especially FFA, might be easily incorporated into macrophages. But the calculated incorporation of metabolites except for FFA was also increased. These results indicate that the increase in incorporation into macrophages was due to the increase in incorporation of IDL or other altered lipoproteins. In the metabolism of FFA in the cells, cholesterol ester synthesis was increased by addition of LpL. The medium, which was incubated with VLDL-TG-(¹⁴C) in the presence or absence of LpL for 24 hours, was incubated with smooth muscle cells (SMC) for 24 hours. The medium which was derived from the condition with VLDL and LpL increased the incroporated radioactivity into SMC. In intracellular metabolism of lipid incorporated into cells, increase in phospholipid synthesis and decrease in cholesterol ester syntehsis were observed in the presence of LpL. These results suggest that the conditioned medium with LpL and macrophage regulated the incorporation of lipid into SMC and might regulate the metabolism in SMC.

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In the present study, serum HDL₂-C, HDL₃-C, apo A-I, and apo A-II levels were measured in 88 diabetics to investigate the matebolism of HDL subfractions in diabetics. Diabetics were divided into three groups, taking insulin, oral agent, and diet-only.
Serum HDL₂-C and HDL₃-C levels were compared between each therapeutic group of diabetics and normal group. Serum HDL₂-C levels in the insulin group were significantly higher than those in the normal group (p<0.01), while there was no difference between the serum HDL₂-C levels in the oral agent group or diet-only group and those in the normal group. And no difference was found between the serum HDL₃-C levels in each therapeutic group of diabetics and those in the normal group.
Then serum apo A-I and A-II levels were compared between each therapeutic group of diabetics and normal group. No significant differences in the serum apo A-I and apo A-II levels were found between each diabetic group and normal group. These findings suggest that in the insulin group the cholesterol/apoprotein ratio in the HDL is higher than that in the normal group.
Serum apo A-I and apo A-II levels were significantly lower in diabetics with coronary heart disease (CHD) than those in diabetics without CHD (p<0.05).
In normal subjects, HDL₂-C showed a significant correlation with apo A-I (r=0.43, p<0.01), while HDL₃-C demonstrated a significant correlation with apo A-I and apo A-II as well (r=0.50, p<0.01). From these results, it is guggested that HDL₂ contains apo A-I, and HDL₃ contains both of apo A-I and apo A-II.

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Plasma concentrations of apolipoproteins (apo) A-I, A-II and B in the 52 noninsulin-dependent (type II) diabetics were measured. The diabetics consisted of 35 patients treated with insulin (insulin group), 10 patients treated with oral hypoglycemic agents (mostly glibenclamide: oral drug group), 3 patients on dietary treatment alone (diet group) and 4 untreated patients. Mean (±SE) age were 60.4±13.8, 65.9±11.4, 58.3±9.6 and 65.3±11.2 in insulin group, oral drug group, diet group and untreated diabetics, respectively. Fasting blood glucose levels and HbA₁ levels in parenthesis were 158.5±67.3mg/dl (10.5±2.0%), 116.3±23.5mg/dl (9.3±0.6%), 144.5±64.3mg/dl (10.0±6.1%) and 170±54.5mg/dl (10.7±0.5%) in insulin group, oral drug group, diet group, and untreated diabetics, respectively. HDL was fractionated by the method of heparin-MnCl₂ precipitation. Plasma apo A-I, A-II and B were measured by single radial immunodiffusion using the commercially available plate. Plasma triglycerides were significantly higher in insulin group (163.1±23.5mg/dl) and oral drug group (171.4±29.9mg/dl) than control (106.5±5.3mg/dl). HDL-C was significantly lower in insulin group (46.5±1.9mg/dl) than control (55.8±1.4mg/dl). Plasma apo B concetrations were significantly increased in the diabetics (insulin group: 104.3±4.5mg/dl, oral drug group: 117.0±8.5mg/dl, diet group: 116.0±8.9mg/dl vs. control group: 91.3±2.8mg/dl). Plasma apo A-I were significantly lower in insulin group (94.8±2.9mg/dl), oral drug group (111.4±6.0mg/dl) than control (126.3±2.9mg/dl). Plasma apo A-II also decreased significantly in insulin group (22.0±0.8mg/dl) and oral drug group (24.6±2.3mg/dl) as compared to control (31.3±0.7mg/dl). Therefore, apo B/apo A-I+apo A-II were significantly increased in insulin group (0.92±0.05mg/dl) and oral drug group (0.94±0.09mg/dl) compared to control (0.59±0.22mg/dl). Apo A-I showed a positive correlation to HDL-C. The present study suggested the usefulness of plasma apo A-I, A-II and B measurement for understanding the derangement of lipoprotein metabolism in the diabetics.

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Serum HDL₂- and HDL₃-cholesterol (HDL₂-C and HDL₃-C) levels and Apoprotein A-I and A-II (Apo A-I and Apo A-II) levels were measured in 226 healthy subjects (136 males, 90 females, age ranging 20 to 79 years) and 20 neonates (10 males, 10 females). Serum lipids of the neonates were determined by umbilical cord blood.
Ultracentrifugation has been used to separate HDL and its subclasses. Apo A-I and A-II were determined by SRID method.
Results:
1) The total cholesterol (T-C) level was lowest in the newborns. In the adults, it increased with age especially in famales. As a result, females showed higher T-C values than in males in their fifties and sixties.
2) Females demonstrated higher HDL-C values than males of the same age group. This difference seemed to be caused by the difference in HDL₂-C level.
3) Excluding the neonates, Apo A-I was relatively constant and showed no sex difference. The Apo A-II level was slightly higher in males than in females in the younger subjects. The Apo A-II level of the males showed a gradual decrease after the fourth decade, resulting in no apparent sex difference.
4) In the neonates, the levels of T-C, HDL-C, HDL₂-C, HDL₃-C, Apo A-I and Apo A-II were statistically significantly lower than any other age group. These levels of males were significantly lower than those of females.

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Serum apolipoprotein A-I and A-II concentrations were lower in type I hyperlipidemia, LCAT deficiency and sever hepatitis, and higher in cholestasis than in normolipidemics. The discrepancies of serum apolipoprotein A concentrations with high density lipoprotein (HDL) cholesterol were observed in some dyslipoproteinemias, especially in the patients with hypertriglyceridemias.
There were some differences in the compositions of HDL among various dyslipoproteinemias. Therefore, the faults may occure, when only one component of HDL, for example HDL cholesterol, is used for the evaluation of serum HDL or atherogenic index.

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Abnormalities of very low density lipoprotein (VLDL) compositions separated by ultracentrifugation were observed in some dyslipoproteinemias, for example in type I and III hyperlipidemias, LCAT deficiency or hyperalpha-lipoproteinemias. The percentage of apo C-II subclass in apo C lipoproteins of VLDL from LCAT deficiency was higher than that from normolipidemics, which indicated the changes of apolipoprotein components in VLDL from this disease.
Although the concentrations of apo C-II and E protein were parallel to serum triglyceride or VLDL, some cases of hypertriglyceridemias had low apo C-II concentration. C-II/triglyceride ratio tended to decrease in remarkable hypertriglyceridemias.

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Seven hundred fifty mg of cholesterol were fed daily to 32 patients of the ischemic heart disease (IHD) for 2 weeks. Cholesterol amounts in VLDL, LDL, HDL, HDL₂ and HDL₃ were estimated on the 0th, 7th and 14th days of cholesterol load. Plasma apoprotein A-I, A-II, B, C-II, E levels were also measured in 16 from 32 IHD subjects. Apoprotein levels were estimated by a method of single radial immunodiffusion (SRID). Before cholesterol administration, cholesterol amounts in VLDL, LDL, HDL, HDL₂ and HDL₃ were 15.9±7.5mg/dl (mean±SD), 150.9±58.1mg/dl 43.8±9.6mg/dl, 16.4±5.8mg/dl and 24.9±6.3mg/dl respectively. Plasma apoprotein A-I, A-II, B, C-II and E levels were 81.7±22.0 mg/dl, 15.1±5.4mg/dl, 93.7±36.0mg/dl, 3.83±1.00mg/dl and 4.29±1.36mg/dl respectively. After 2 weeks' cholesterol feeding, all plasma lipoprotein cholesterol and apoprotein levels did not change significantly. Correlation coefficients between plasma apoprotein and lipoprotein cholesterol levels were calculated. Apoprotein A-I and A-II correlated with HDL-C (r=0.348), HDL₂-C (r=0.612) and HDL₃ (r=0.569). Apoprotein B correlated with total cholesterol (TC) (r=0.610), VLDL-C (r=0.341), LDL-C (r=0.726), HDL-C (r=0.432) and HDL₂-C (r=0.465). Apoprotein C-II correlated with TC (r=0.765), TG (r=0.679), VLDL-C (r=0.651), LDL-C (r=0.461) and HDL₂-C (r=0.326). Apoprotein E correlated with TC (r=0.580), TG (r=0.575) and VLDL-C (r=0.666). Interapoprotein's correlations were also calculated. Apoprotein A-I correlated with apoprotein A-II (r=0.468). Apoprotein B correlated with apoprotein C-II (r=0.393). Apoprotein C-II correlated with apoprotein B (r=0.393) and E (r=0.549). Apoprotein E only correlated with apoprotein C-II (r=0.549).

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The aim of this study is to examine the relation between Very Low Density Lipoprotein (VLDL) apoprotein E isoforms and coronary atherosclerosis. Ninety eight subjects were allocated into two groups: 77 patients with coronary atherosclerosis (group 1) and 21 controls with normal intact coronary artery (group 2). All subjects were diagnosed by selective cornary angiography. Apoprotein E isoforms were analyzed by isoelectric focusing electrophoresis and determined semiquantitatively by densitometry.
Apo E₂/E₃ ratio in group 1 was significantly higher than that in group 2 (group 1: 0.60±0.20, group 2: 0.51±0.09, p<0.05: Wilcoxon's rank sum test). In group 1, 27 patients (35%) had more than 0.7 of Apo E₂/E₃ ratio, but all controls in group 2 had less than 0.69. The incidence of Apo E₄ was 24.7% in group 1 and 23.8% in group 2, there being no singificant difference between two groups.
VLDL Apo E₂/E₃ ratio is clinically useful indicator of coronary aterosclerosis.

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The purpose of the present study was to characterize the properties of cholesterol esterase (CEase) in human skin fibroblasts and monocyte-derived macrophages. Acid and neutral CEases exist in lysosome and microsome, respectively in both cells. Acid CEase activity was higher than neutral CEase activity. Other properties of acid and neutral CEase of fibroblasts and macrophages were similar with respect to Km, effect of phospholipids and divalent cations for phosphatidyl choline (PC) emulsified cholesterol ester (CE).
But optimal pH of CE hydrolysing activity in low density lipoprotein (LDL) was located at pH 4.5 and was not detected at neutral or alkaline range, whereas there was two pH optima for CEase activity when PC emulsified CE was used as substrate. This result suggests that LDL-CE hydrolysis can be performed only in lysosome. The uptake and hydrolysis by fibroblasts of ¹²⁵I-LDL were determined. The uptake of LDL in fibroblasts of familial hypercholesterolemic patients (FHC) was lesser than that of normals, but the hydrolysis of LDL was increased. The amount of uptake of a-LDL in macrophages of FHC was not different from that of normals, but the hydrolysis of LDL was decreased.

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We have Postulated that lysosomal acid cholesterol esterase involved in the accumulation of cholesterol ester in atheromatous aorta. We found that cholesterol ester in cultured smooth muscle cells increased 12.68 times of control in the presence of LDL (220μg cholesterol equivalent) and esterastin (500μM) as an inhibitor of acid cholesterol esterase. These experiments may help to elucidate the mechanism of accumulation of cholesterol ester in smooth muscle cells in vitro.

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We previously reported that hypoxic incubation (2% O₂) promoted the cellular cholesterol (especially esterified form) accumulation in cultured rabbit arterial smooth muscle cells in the presence of diet induced hyperlipemic serum.
Present study was designed to examine cholesterol and other lipids accumulation in cultured rabbit fibroblasts under different degree of hypoxic conditions (2% O₂ and 5% O₂), and to investigate the role of LDL-receptor in cellular lipids accumulation using cultured fibroblasts from WHHL-rabbit.
After 48 hours incubation of normal fibrobasts in the medium with 20% normolipemic rabbit serum (NLS), free fatty acid level increased slightly and triglyceride level increased markedly in hypoxic group. While in the medium with 20% hyperlipemic rabbit serum (HLS), in addition to the increased free fatty acid and triglyceride levels, free cholesterol level increased slightly and esterified cholesterol level increased markedly in hypoxic group. And these increases were correlated with O₂ concentration inversely.
Moreover, in WHHL fibroblasts, which lacked LDL-receptor, cellular lipids accumulation were also observed after 48 hours incubation in the medium with 20% HLS, and hypoxic incubation enhanced the cellular lipids accumulation, as in normal fibroblasts.
These results suggest that under hyperlipemic condition, receptor non-mediated uptake of lipoproteins plays an important role in cellular lipids deposition in peripheral cells, and tissue hypoxia may promote the lipids accumulation in peripheral cells including vascular smooth muscle cells by LDL-receptor independent mechanism.

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Endothelial changes in the renal and femoral arteries of rabbits induced by repeated electrical stimulation with 3.5 volt pulse wave were examined byelectron microscope. The stimulation period ranged from 15 minutes to 14 days. The animals were divided into three groups; (1) Electrical stimulated rabbits. (2) Electrical stimulated plus 1% cholesterol fed rabbits. (3) Normal controls and sham operated rabbits.
In the electrical stimulated group, scanning electron microscopic examination revealed various endothelial changes as irregularity of cell orientation, adherence of leukocytes and platelets, swelling of marginal fold and appearence of microvillied cells. The numbers and degree of these changes increased gradually and consequently a small intimal proliferation of 1-2 cell-layers modified smooth muscle cells appeared within 7 days.
In the electrical stimulated plus cholesterol fed group, endothelial changes were intenser compared with only electrical stimulation group. Foam cells appeared in the subendothelial space within 3 days and early atherosclerosis was observed within 7 days. But any foam cells were not observed in controls and sham operated arteries.
These results suggested that arterial spasm was significant as an initiating factor of atherosclerosis and that severe endothelial damages and hyperlipoidemia played the role of developing the sclerotic lesions.

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A quantitative analysis of inflammatory lesions in the coronary arterial adventitia in addition to intimal lesions (luminal narrowing, thrombus) is described in a group of 14 autopsy cases with clinical history of angina at rest (6 succumbed from acute myocardial infarction, 6 suddenly from anginal attacks, 2 from non-cardiac reasons). Cross-sections were examined histologically, especially with meticulous attention to the adventitia in a total 308 sections of 14 study patients (2 from each of 11 segments from each heart), compared with 396 sections of 18 control subjects.
Of the 154 segments in the study patients 47 (31%) were 76 to 100 percent narrowed by atherosclerotic plaques (control 1%), and 23 (15%) had occlusive thrombi. Of the 308 sections in the study patients 97 (31%) showed infiltration of small round cells in the adventitia (control 9%). Involvement of vascular nerve fibers was noticed approximately one half of the sections of inflammatory lesions.
These findings in the adventitia may correlate to the vasospastic component of angina at rest.

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We examined the platelet-induced contractions of aortic strips from normal rabbits and atherosclerotic rabbits.
In cholesterol-fed rabbits whose aortae revealed only slight atherosclerotic changes, the contraction induced by platelet was almost same as that in normal rabbits.
On the other hand, in the severely atherosclerotic rabbits whose thoracic aortae had been scratched with a balloon catheter and then fed a high cholesterol diet, the platelet-induced vascular contraction was depressed in comparison with normal rabbits. There was no difference between the contraction of normal aortic strips by normal platelet and that by platelet from atherosclerotic rabbits.
It therefore appears that as the atherosclerotic changes progresses, the vascular contraction induced by platelet decreases and becomes less concerned in the cause of the damage of organ blood supply.

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Recently it has experimentally and clinically become evident that spasm may occur in coronary arteries of some species of experimental animals and also of human. This study was attempted to elucidate if coronary spasm could be more easily induced in arteries which had been involved by organic diseases such as athero-sclerosis before drug-induction of spasm in experimental animals.
Swine had been pretreated with denuding of endothelium of left anterior descending branch of coronary arteries by brushing through coronary catheterization, and then fed with a high fat diet for 14 weeks at the longest. After coronary arteriosclerosis was proven to have been produced by a coronary angiography and ECG monitoring was set, methacholine was injected intramuscularly.
Among 9 swine in the experimental group with pre-existing coronary arteriosclerosis, 6 developed coronary arterial spasm, which was confirmed angiographically and in which ECG changes such as ST elevation in 4 animals or depression in 2. Spasm appeared in the period between 10 seconds to 20 minutes after the injection. In contrast, control group without the pretreatment to produce arteriosclerosis had 2 swine, which developed coronary spasm in 9 animals.
Coronary arterial spasm generally persisted from couples of minutes to over ten minutes. The animals to show ST elevation on ECG tended to develop stronger spastic changes on arteriography, while others to have ST depression had weaker lumen narrowing or localized spasm to certain focal segments.
Immunohistochemistry with use of anti-swine fibrinogen antibody revealed deposition of reaction products in subendothelial areas of intima, and also in cytoplasm of smooth muscle cells in the segments of the coronary arteries, where arteriosclerosis had been artificially produced. In the segments where spasm had been proven on angiography only very slight deposits of reaction product were demonstrated in subendothelial layer. This did not indicate intensified vascular permeability in those segments at one time spasm. Repeated arterial spasm may lead to accelerate vascular permeability, but further investigations would be needed to prove that.
This result of the experiment leads to a conclusion that preexistence of some organic diseases in coronary arteries may play a role in induction of coronary spasm by neurohumoral factors.

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Three groups of male Japanese rabbits weighing about 2.7Kg each were given experimental diets consisting of high cholesterol chow and fluid skim milk, yogurt or water, and were bled every four weeks to measure serum lipids. After 12 weeks they were killed and concentrations of total cholesterol and atheromatous areas dyed with Oil Red O were determined in the aorta to evaluate the development of atherosclerosis. At 8 and 12 weeks, the skim milk group showed significantly lower levels of serum total cholesterol, LDL cholesterol and triglyceride than the control group. Although no significant difference between the yogurt and control groups in concentrations of serum lipids was observed, total cholesterol concentrations in the aorta were significantly lower in both the skim milk and the yogurt groups than in the control group. The atheromatous areas of the skim milk group (38±34%) were significantly smaller than those of the control group (75±25%). No significant difference, however, was found between the yogurt group (51±22%) and the control group. Concentrations of total cholesterol in the liver did not differ among the three groups. These results suggest that skim milk may have a preventive effect on the development of atherosclerosis.

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Hypertriglyceridemia (HTG) is considered to be a risk factor for development of ischemic heart disease. Previously, the authors reported on a simplified intravenous fat emulsion tolerance test (FETT). In the present study, FETT is applied for the analysis of the pathogenesis of HTG and to determine the nutrient composition of a diet in HTG treatment.
The subjects were 9 patients with primary HTG and one with secondary HTG and obesity. The serum triglyceride level was determined before treatment, and subjects were admitted to the hospital for two weeks. The effects of two kinds of diet (A and B) were compared in terms of serum triglyceride (Table 2).
Diet A consisted of 20% calories as fat, 60% as carbohydrate, and 20% as protein. Diet B consisted of 40% calories as fat, 40% as carbohydrate, and 20% as protein. Total diet calory intake was limited to 25-30kcal/kg of ideal b. w. per day. After one week of diet treatment (either one), the serum TG levels of patients were determined for 24hr.
FETT was done as follows: After an overnight fast, an indwelling catheter was inserted into an antebrachial vein, and 0.25ml 10% Intralipid/kg b. w. was injected intravenously in 90 seconds.
Time measurements were started at midpoint of injection, and blood was sampled at 2-3, 5, 7, 9, 11, 14, 17 and 20min, respectively. Light scattering index (LSI) of serum diluted 1:100 in physiological saline, was determined by the nephelometric method. The zero-time value was then subtracted from the value for each post-injection sample. Removal rate was calculated by the method of least squares, using the logarithmic values of LSI. The TG levels in all subjects improved with either diet A or B (Fig. 1). In cases 1, 2, 3, 4, 5 and 6, the TG levels improved more in a day with diet B than diet A (Fig. 2). Cases 7 and 8 showed more TG improvement on diet A (Fig. 2).
Assuming that a multiplication of total serum TG by K₂ is a crude estimate of VLDL-TG production, HTG in cases 1 and 2 might be caused by increased VLDL-TG production, and HTG in cases 3, 4 and 5 by both increased VLDL production and decreased VLDL removal from circulation. In the serum of cases 7 and 8 on diet A, chylomicrons of the layer overlying a turbid infranatant layer were observed to correspond to a TG peak concentration in the serum following the meal. HTG in cases 7 and 8 may have been caused by both decreased VLDL removal and decreased chylomicron removal from the circulation.
From these results, diet A with less fat (20% of total calories) should be given to HTG patients with a K₂ level under 2%/min. The pathogenesis of HTG could be known by FETT. And FETT is a useful method to determine the nutrient composition of the diet to be used in treating HTG.

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We investigated the changes in triglyceride metabolism induced by various lipid loading in aged and young rats in order to elucidate the mechanism of hyperlipidemia in the aged. 24 month-old rats were used as the aged and were compared with 2 month-old rats. Serum triglyceride in the aged rats were higher than those of the young rats. After oral oil loading, serum triglyceride was increased more accurately in aged rats than in young rats. There are three possible mechanisms by which serum triglyceride was increased.
(1) Increase in triglyceride absorption from intestine. (2) Increase in triglyceride synthesis in liver. (3) Decrease in triglyceride clearance from serum. As to the possibility of (1), it may be excluded because decrease in triglyceride absorption from intestine according to aging was reported. As to the possibility of (2), activities of Acetyl-CoA carboxylase, Acyl-CoA synthetase and Triglyceride Synthesis were measured in the liver of the aged or the young rats. These three activities were not different in the aged and the young rats. As to the possibility of (3), decrease in triglyceride clearance from serum was observed in the aged rats after intravenous administration of lipid. One of the most important factors which regulate triglyceride clearance from serum is lipoprotein lipase activity in vascular wall. We discussed the capacity of this enzymatical activity by measuring post heparin lipolytic activity (PHLA) and heparin releasable lipoprotein lipase activity in epididymal adipose tissue in the aged or the young rats. The both activities were decreased in the aged rats compared with the young rats. Above results suggest that hypertriglyceridemia in the aged might depend on the decrease in the capacity or adaptability of lipoprotein lipase activity to postprandial increase in serum lipid.

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Two experiments were designed to investigate the effect of inhibition of the sympathetic nervous system on the metabolism of acid mucopolysaccharides (AMPS) in blood vessels.
In the first experiment, tyrosine hydroxylase inhibitor, α-methyltyrosine (α-MT) was administered to normotensive male Wistar rats for ten days.
Total AMPS contents in the rat aortas were significantly decreased and when subfractions of AMPS were measured, mono-sulfated AMPS were significantly decreased.
In the second experiment, bilateral adrenal demedullation was undertaken in male spontaneously hypertensive rats (SHR, Okamoto and Aoki), which were then chemically sympathectomized by 6-hydroxydopamine (6-OHDA) for nine weeks.
Total AMPS contents in the aortas of SHRs were significantly decreased and all of the subfractions—non-, mono- and highly-sulfated AMPS—were significantly decreased.
In both experiments, blood pressure of the treated animals were not different from those of control Wistar rats or untreated SHRs.
The results suggest that the sympathetic nervous system may affect on the metabolism of AMPS in blood vessels.

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To clarify the thromobolytic mechanism, the thrombi of 11 cases taken at surgery and autopsy were morphologyically investigated by using urokinase (HMW 54, 000) and plasminogen. These included fresh and old organized thrombi, which were divided into two groups so as to examine whether the thrombolysis due to urokinase depend upon its dose or its incubation time. As a result, the thrombolysis mainly depended upon the incubation time rather than dose of urokinase, furthermore plasminogen was proved to be effective for the thrombolysis.
Morphological findings on these experiments showed that the superfficial fibrin membranes initially disappeared and then each thrombus had porous surface, from which urokinase and plasminogen would get into the thrombi to lyse fibrin. Ultrastructural observation disclosed disappearance, irregularity, shortening, and thinning of fibrin.
It is of great interest that the organized, at least more than 5 days old, thrombi also showed thrombolysis by urokinase and plaminogen.
In the thrombolytic effects on the artificial thrombi, it was the most effective to treat with urokinase and plasminogen from outside similtaneously. As the thrombi were lysed, some of thrombi showed fragmentation, which would lead clinically to hemorrhagic infacrt and/or microinfarct because of traveling of small fragmented thrombi.

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In addition to hypoglycemic effect, gliclazide decreases platelet aggregation and inhibits progression of diabetic retinopathy. Moreover, in Japan, recent study showed that gliclazide has stronger hypolipidemic effect than glibenclamide. In order to clarify this hypolipidemic mechanism of this drug we carried out a crossover trial from glibenclamide to gliclazide and examined the change in not only lipoprotein profile but also apoprotein concentration in plasma.
We examined eight Type II diabetic subjects. Their mean age was 55 and had been administered glibenclamide at least one year before the beginning of this study. All subjects were examined on out patient basis. They ate a regular diet and were advised to maintain a constant dietary intake. Patients with thyroid, renal or hepatic diseases and those taking steroid or hypolipidemic drugs were excluded. After the first blood sampling, glibenclamide was alternated to gliclazide on a comparable dose. The second blood sampling was performed 3 to 6 weeks later. Blood samples were obtained after 16-hour overnight fast. Very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) were isolated by sequential ultracentrifugation at appropriate densities. The VLDL (Sf 60-400) was separated in a Beckman SW 40 rotor by exactly 2 hour ultracentrifugation at 29, 000RPM at 18°C. IDL was divided into two subclasses at Sf 20.: IDL₁ (Sf 20-60) and IDL₂ (Sf 12-20) was centrifuged in a Beckman 50 Ti rotor at 39, 000RPM for 18 and 20 hours at d=1.006 and at d=1.019, respectively. The separation of high density lipoprotein (HDL) from low density lipoprotein (LDL) was done by phosphotungstic acid precipitation. Cholesterol and triglyceride in whole serum and in the lipoprotein fraction were determined by an enzymatic method. Apolipoprotein A-I, A-II, C-II and E concentration were determined by a single radial immunodiffusion method using commercially available kits.
There was no significant change in total-, VLDL-, IDL₁ and IDL₂-triglyceride levels during gliclazide administration. On the other hand, we found significant fall in total- and IDL₂- cholesterol levels. LDL- and HDL-cholesterol and each of apolipoprotein showed no significant change during this period of observation.
Thus, gliclazide effectively lowers plasma cholesterol concentration in Type II diabetic subjects without changing triglyceride and apolipoprotein concentrations. Its action appeares to be directed towards lowering cholesterol in intermediate density lipoprotein fraction. The mechanisms whereby these effects are achieved are not yet known but suppression of lipoprotein cholesterol secretion from the liver is suggested.

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1) Nine male rabbits 38 months old were concurrently loaded with 3 different treatments i. e., N₂ gas inhalation, norepinephrine in injection and cholesterol oral administration, and left coronary anterior descending branch (LCA 5) was observed histochemically and determined for smooth muscle cell, elastin, collagen, acid mucopolysaccharides and glycoproteien in comparison with 8 healthy normal rabbits of the same age.
2) The histology of the indurative group presented obivious histo-lesional findings such as atrophy and necrosis of the smooth muscle cells (SMC), swelling and stratified rupture of the inner elastic membrane, loses in content of medial elastin (EL) and collagen (CL) and their transfer from the tunica externa, and compensatory increases in content of acid mucopolysaccharides (AMPS) and glycoprotein (GP).
3) The results of the determination made of these 5 constituents revealed that the healthy normal group and the indurative group showed 65.4±7.9 and 46.7±7.5 (p<0.001) of SMC, 9.6±0.88 and 12.2±2.78 (p<0.05) of EL 25.7±4.02 and 35.6±3.86 (p<0.001) of CL, 14.4±1.7 and 20.2±2.85 (p<0.001) of AMPS and 22.8±5.9 and 31.6±7.5% E of GP, respectively, the indurative group showed significantly less content of SMC and significantly more contents of EL, CL, AMPS and GP than the healthy normal group.

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In studying the drug treatment of dyslipidemias or dyslipoproteinemias, we observed several patterns of reactions common to the different kinds of drugs and populations. They were: (i) when we classified dyslipidemias according to the grade of severity, higher the grade of severity, always greater the response to a treatment, (ii) namely, higher the baseline level, greater the change in reduction, (iii) there was a turning point of effect where the reaction to the drug treatment became zero and hereafter the sign of the reaction reversed, (iv) if we treated hypolipidemias with the same lipid lowering drug, they reacted to the drug in the direction to raise the low serum lipids.
These patterns of the reactions indicated that there exists a certain level where all the dyslipidemias tend to converge as the result of drug treatment. We formulated the method to estimate the convergent level and considered it as a homeostatic level of human serum lipid and lipoproteins.

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We have developed a method of pulse wave velocity (PWV) determination for an aid of noninvasive diagnosis of arteriosclerosis, and have studied the principle of pulse generation and theory of wave transfer, its relation to the quantitative histological findings, organ specific distribution of arteriosclerosis, and other basic, clinical and epidemiological problems on PWV,
In the present paper, features of the complicated arteriosclerosis with hypertension were examined using PWV based on the epidemiological interests. Subjects:
Epidemiological subjects: Among 128, 127 male subjects examined in the occasion of mass physical examinations for 30 to 60s of age without the of cerebral apoplexy and cardiac attack, 12, 231 cases with history of hypertension, 7, 253 cases without history of hypertension but hypertension with maximum blood pressure more than 180 and/or minimum blood pressure more than 100mmHg being found in the mass physical examination, and 108, 643 cases of the control with no hypertensive history, showing less than 158 and/or less than 88mmHg of blood pressure were the subjects of epidemiological examination.
Results:
The PWV values of the epidemiological subjects (having history of hypertension, and hypertensive subjects) were higher than those in the control subjects. However, the PWV values in the hypertensive history bearing and hypertensive patients in the epidemiological examination were not significantly different among various age group, and considering the fact that the hypertensive history bearing cases had recived some treatments, treatment of hypertension might not be directly and positively effective in the improvement of arteriosclerosis.

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The effect of KCD-232, a new hypolipidemic compound with a structure of 4-(4'-cholorobenzyloxy) benzyl nicotinate, on cholesterol absorption was studied by an isotope ratio method (IRM) in rats fed a normal diet and a high cholesterol diet (HCD). To validate this method, we also compared cholesterol absorption by a fecal radioactive method (FRM) with that simultaneously mesured by IRM. KCD-232 was orally administered once daily for 15 days. The following results were obtained.
1) Ratios of cholesterol absorption by IRM were almost constant values (range: 52-57, 58-61%) from 24h to 96h after isotope dosage in rats.
2) There was good to excellent agreement (r=0.9495, p<0.001) in cholesterol absorption indicated by IRM and FRM in the same rats.
3) KCD-232 inhibited both cholesterol absorption and serum cholesterol level in a dosedependent manner (37.5-300mg/kg/day) in normal rats and significantly reduced the former at dosage levels over 70mg/kg/day and the latter at over 37.5mg/kg/day, respectively. High positive correlations were also found between the administered dose of KCD-232 and the inhibition percent of cholesterol absorption (r=0.9982, p<0.001) and between the administered dose of KCD-232 and the inhibitory percent of serum cholesterol level (r=0.9750, p<0.001).
By contrast, colestipol (300mg/kg/day) used as a reference also inhibited cholesterol absorption but did not decrease serum cholesterol level at all.
4) Hypercholesterolemic rats fed a HCD have a slightly lower cholesterol absorption ratio and significantly decreased radioactivity of [³H] cholesterol intravenously administered in plasma compared with normocholesterolemic rats fed a normal diet.
KCD-232 (300mg/kg/day) significantly inhibited the elevation of serum total cholesterol (TCH) and TCH-(HDL-CH) levels by 86.4% and 89.3%, respectively, but increased the HDL-CH level by 24.7% (p<0.001), and consequently significantly improved the “Atherogenic index” indicated by the [TCH-(HDL-CH)]/HDL-CH ratio in rats fed a HCD.
KCD-232 significantly decreased further the lower cholesterol absorption by 22.5% (p<0.05) and stimulated the ratio of disappearance of [³H] cholesterol intravenously administered from the blood stream by 42.9% (p<0.001) in rats fed a HCD.
From these results, it can be assumed that the hypocholesterolemic activities of KCD-232 are in some part due to the inhibitory effect of cholesterol absorption from the intestine and in addition, might be due to the stimulated excretion of cholesterol from the blood stream in hypercholesterolemic rats.

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