Human aortic homogenates taken from normal, fatty streak, and atheromatous lesions were examined respectively for lipoperoxide content.
A positive correlation were seen between the severity of atherosclerotic changes and lipoperoxide content.
We tried to stain lipoperoxide and superoxide by the histochemical methods. For lipoperoxide, fresh cryostat sections of aortic tissues taken from normal, fatty streak, and atheromatous lesions were treated with Schiff's reagent without HIO₄ directly at 36°C, for 2 hours. The reaction products could be detected in atheromas as droplets or doughnut like figures often tangling with ceroid substances. Many authors have suggested that this reaction products were produced by the polymerization of dialdehydes produced by oxidation of unsaturated fatty acids. We concluded that this Schiff's method is most suitable technique for the staining lipoperoxide in tissues. Though ceroid which reveals prominent fluorescence is not stained by Schiff's reagent, non-flurescent lipoperoxide is Schiff-positive without periodic acid oxidation, and the substances that weakly fluorescence and weakly react with Schiff's reagent, were thought to be Hartroft's “interceroid.”
The frozen sections of the same aortic lesions were treated also by superoxide staining solution which contained superoxide-dismutase, peroxidase, and diaminobenzidine. The brown reaction products were detected in atheromas. It could suggest the places where superoxides were produced.

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Serum levels of TBA value were observed in connection with that of organs of atherosclerosis diseases and experimental animals. Furthermore, superoxide dependent platelet-leukocyte reaction was studied. Conclusively, following results were obtained.
1. Serum lipoperoxide elevated in cases of acute vascular accident. Its origin was conceived at diseased brain or heart and organs such as liver and so on.
2. In contrast to the abrupt increase of lipoperoxide, antioxidative activities, such as SOD (superoxide dismutase), glutathione peroxidase, ascorbate, vitamine E decreased in serum and organs.
3. Leukocyte gathering around the lesions released superoxide and a series of active oxygens which could damage endothelial cells and induce aggregation of platelets and leukocytes. These reactions might promote local thromogenesis.
4. Lipoperoxide occurred in liver would be outfluxed to blood in early stage, but clearance from blood might be rather slow.
5. Lipoperoxide in blood is used to be elevated in chronic metabolic disorder like diabetes mellitus or in the state of deficient antioxidative activity which was associated with diseases, nutritional imbalance of other restrictions. Though it might below, its longstanding elevation would aggravate the vascular derrangement. Liver was supposed to be one of main sources of lipoperoxide in these state, too.

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The purpose of these studies was to seek for the role of lipid peroxides (thiobarbituric acid method: TBA) in atherosclerosis.
1) Serum TBA value in atherosclerotic diseases was higher than that in healthy controls.
2) In hypertensive rats (Goldblatt's two kidney type) the TBA value of aortic wall was not different from that of the controls.
3) In cholesterol-fed guinea pigs the TBA value of aortic wall tended to decrease, compared to that in the controls.
4) In the rabbits fed 1% cholesterol diet for twelve weeks the serum TBA value increased, compared to that in the rabbits fed normal basal diet.
The TBA value of serum and aortic wall was not different between the rabbits fed basal diet and those fed basal diet plus aspirin 30 or 100mg/kg/day.
While there were no differences in the grade of atherosclerotic lesions in the aorta, the TBA value of aortic wall of the rabbits fed 1% cholesterol diet plus aspirin was significantly lower than that of the rabbits fed 1% cholesterol diet only.

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In order to investigate whether lipid peroxide may play a initial role to development of atherosclerosis or not, following observation were made in this study.
Materials and methods; Lipid peroxide was prepared from linoleic acid incubated with soybean lipoxygenase as the method described by Funk et al. Adult male rabbits weighing between 2.5kg and 3.0kg were divided into 2 groups. In the first group, 10mg/kg of the lipid peroxide dissolved in 2ml of rabbit's serum was administered intravenously as one shot administration through the lateral ear vein. In the second group, 1mg/kg of the lipid peroxide was injected daily foe 7 days. As controls, same doses of untreated linoleic acid were administerd for two groups of rabbits. Then, intima of thoracic aorta was investigated by scanning and transmission electron microscopy. At the same time, in order to observe the changes of the permeability of endothelial cells, ferritin was utilized. Results and discussions; 1) In the scanning electron microscopic observation of endothelial cells of first group, the first sign of changes was formation of marked bulges in the nuclei and loss of rhomboidal shape of endothelial cells. More severe change included incidence of stomata. Some parts of changed endothelium showed adhering of platelets and fibrin. 2) In the transmission electron microscopic observation of second group, proliferation of many smooth muscle cells into subendothelial space was caused by administration of lipid peroxide. These migrated smooth muscle cells could be called as modified smooth muscle cells. These findings seems to be almost consistent with intimal thickning of initial change observed in the development of atherosclerosis. Other changes included enlargement of endoplasmic reticulums, incidence of myelin bodies and marked increasing of pinocytotic vesicles of endothelial cell. Furthermore, in order to investigate the change of permeability of endothelial cell, 1000mg/kg of ferritin was injected intravenously 15 minutes before the fixation in situ. Uptake of ferritin was increased by administration of lipid peroxide. These findings may suggest that enhancement of permeability of endothelial cell was caused by lipid peroxide. Moreover lipid accumulation around injured endothelium was proved by the technique of lipid staining.
Conclusion: Above observations indicate that endothelial injury caused by the lipid peroxide may be considered as one of initial steps in which atheroma formation develops.

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Lipid peroxides in serum and aortic tissues of 19 albino rabbits were studied. Eight rabbits were fed 1% cholesterol for 67 days, while 11 constituted the control group. Serum cholesterol levels elevated in the cholesterol fed group from 51 to 1097mg/dl, serum lipoperoxide from 0.43 to 1.47nmol/ml. In the control rabbits serum lipid peroxides distributed 99% in HDL, while in cholesterol-fed group: 49% of the increased lipoperoxides was found in HDL and 51% in VLDL+LDL fraction.
In aortic lesions, the lipids increased about 4 times and the lipid peroxides 15 times when compared with the control. The increased lipoperoxides in aortic tissues were distributed 51% in lipid inclusions, and 49% in the tissue residue fractions.
These indicate that lipid peroxides may have a role in pathogenesis of atherosclerosis, though the precise mechanism and origin of peroxides elevated in the lesion tissue are not known yet.

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Human endothelial cells derived from the umbilical cord veins were cultured using Gimbrone's method followed by identification of the cells by phase contrast and electron microscopy. Incubation of intact cultured cells with platelet rich plasma for 5 minutes prior to the addition of ADP demonstrated inhibition of ADP-induced platelet aggregation suggesting release of prostacyclin from the cultured endothelial cells. Endothelial cells cultured with the medium contain tolbutamide showed less inhibitory effect on the ADP-induced platelet aggregation than those cultured without it. These results suggest that tolbutamide may interfere with the production of prostacyclin in endothelial cells.

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The analysis of lipid-laden lysosomes (light lysosomes) in atherosclerotic lesions of human aorta was carried out by the application of biochemical assay techniques. This paper suggests that there is an obvious relationships between severity of atherosclerosis and the levels of lipid laden lysosomes. In addition a relative insufficiency of lysosomal acid cholesteryl esterase in light lysosomes was observed. Another important change in the process of atherosclerotic transformation was the alteration of lysosomal membranes. The amount of free cholesterol in light lysosomal membrane fraction was found to be very high.
In this paper, we discussed the reason why choresteryl ester accumulates in arterial wall from the connection of insufficiency of acid cholesteryl esterase and alteration of lysosomal membranes.

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Hepatic triglyceride lipase obtained from postheparin plasma is first stimulated and then progressively inhibited by addition of an increasing amount of serum. To solve the mechanism of this modification, serum fractions isolated by ultracentrifugation were added to the assay mixture and their effects on H-TGL activity were determined. We demonstrated that the addition of the d=1.21 bottom fraction together with HDL almost fully reproduces the effect of the whole serum.

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Serum apolipoprotein A-I and A-II levels were determined after oral and intravenous fat administration to elucidate the correlation between lipid metabolism and high density lipoprotein. For oral fat administration, four normal adult males ingested 55g of butter after an overnight fast. For intravenous fat administration, five normal adult males and eleven patients with liver disease were injected 1ml of 10% fat emulsion (Intralipid) per kg of body weight after an overnight fast. The A-I and A-II measurement was carried out by the rocket immunoelectrophoresis. Serial blood specimens were taken and measured for their concentration of A-I, A-II and triglyceride.
Serum apo A-I and A-II levels scarcely varied after intravenous fat administration, but in some cases decreased slightly. On the other hand, the apoprotein levels increased after oral fat administration and peaked after 60 minutes. Serum apo A-I and A-II levels varied concomitantly, therefore, the ratio of apo A-I/apo A-II remained constant. These results suggested that serum apolipoprotein A-I and A-II levels were influenced partially by their synthesis in the small intestine.

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Lipoprotein lipid and serum LCAT activity were studied in 20 patients with chronic renal failure treated or untreated by hemodialysis.
Serum cholesterol, HDL₂-cholesterol, HDL₃-cholesterol and HDL₃-phospholipid were reduced in patients without hemodialysis. In patients with hemodialysis, serum triglyceride and VLDL lipids were raised, but HDL₂-cholesterol, HDL₃-cholesterol and HDL₃-phospholipid were reduced. HDL₂-cholesterol was negatively correlated with VLDL-triglyceride in normal subjects, but not related in patients with chronic renal failure. The cholesterol/triglyceride and cholesterol/phospholipid ratios in LDL and HDL were decreased in chronic renal failure.
The molar LCAT activities were reduced in patients without hemodialysis and normal in patients with hemodialysis. But, the fractional LCAT rates were reduced in both. LCAT activities were postively correlated especially to VLDL lipids.
These results suggest that the decreases of HDL₂ and HDL₃ in CRF are probably due to impaired catabolism of chylomicron or VLDL.

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Recently, it is hypothesized that HDL in plasma results from the catabolism of the TG rich lipoprotein. And it is of great importance to measure α, pre β and β-lipoprotein cholesterol separately.
In this study, we measured each lipoprotein cholesterol in healthy controls, primary hyper-lipoproteinemics and diabetics by the gas liquid chromatography of extracts of fractions separated by agarose gel electrophoresis.
Hypertriglyceridemics (Type IIb or Type IV), in both primary hyperlipoproteinemics and diabetics, had significantly lower α-chol levels and higher pre β-chol levels than healthy controls. These results suggest that there may be some metabolic relationship between α-chol and serum triglyceride. Then, we observed changes of cholesterol levels in each lipoprotein fraction under the accelerated condition of the catabolism of pre β-lipoprotein by the heparin administration. Serum samples were collected before, 10 min, and 30 min after heparin administration. (10U/Kg body weight)
Both α and β-chol increased mildly but significantly (paired test, P<0.001) after heparin administration.
There was not significant change in plasma total cholesterol.
Pre β-chol levels decreased 10 min after heparin administration. But 30 min after, we observed different pattern in the response of pre β-chol levels according to its preinjection levels. In the subjects with higher preinjection levels, pre β-chol levels still decreased 30 min after, whereas, in the subjects with normal preinjection levels, they increased and returned to the preinjection levels approximately. These results suggest that in the former group, there may be delayed pre β-lipoprotein catabolism.

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Using single radial immunodiffusion method and coagulation method, the changes of immunological and biological activities of Antithrombin III during heparin therapy on cerebral thrombosis, myocardial infarction and disseminated intravascular coagulation (DIC) were investigated. A good correlation between immunological and biological activity was observed on 30 healthy persons. The discrepancy between immunological and biological activity of Antithrombin III was seen before and after 24 hours of heparin injection on pathologic states. After injection of heparin, immunological activity was decreased but biological activity was increased in patients with cerebral thrombosis and myocardial infraction. But in patients with DIC both activities, immunological and biological, were increased. This can be due to inhibition of Antithrombin III consumption following heparin therapy.

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Ultrawatersoluble lipoprotein were measured in 10 healthy persons, 20 old cerebral thrombosis and 6 old cerebral haemorrhage. And also ultrawatersoluble lipoprotein by using 136 serum were fractionated by water dialysis, sephadex G-100, bio-gel p-300 and bio-gel p-2 column chromatography.
1) Although significant differences were not found in serum cholesterol and triglyceride between healthy persons and old cerebral stroke, clear differences were found in cholesterol and triglyceride of ultrawatersoluble lipoprotein.
2) There are many ultrawatersoluble lipoproteins with high or low molecular size in serum lipoprotein. The following ultrawatersoluble lipoproteins were separated, namely, low molecular sugar-triglyceride compounds without cholesterol and phospholipid, low molecular sugar-cholesterol-triglyceride-phospholipid compound, high molecular sugar-cholesterol-triglyceride compound without phospholipid and high molecular sugar-triglyceride compound without cholesterol and phospholipid.
3) The measurements of ultrawatersoluble lipoprotein are useful for investigating the pathogenesis of arteriosclerosis.

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A patient with nephrotic syndrome and morbus Kimura (eosinophilic granuloma) showed chylous ascites. Ascites chylomicron was analyzed and further subjected to study the substrate specificity of lipoprotein lipase and hepatic triglyceride lipase. Ascites triglyceride and cholesterol concentrations were 191 ans 12mg/dl, respectively. Both apo CII and apo CIII contents in ascites were approximately one-third of those of plasma from normal subjects. Ascites chylomicron was incubated with either lipoprotein lipase or hepatic triglyceride lipase, which were prepared from human postheparin plasma using heparin-Sepharose affinity chromatography. Lipoprotein lipase hydrolyzed ascites chylomicron, while hepatic triglyceride lipase was unable to do that. These results suggest different functions of these two lipases in chylomicron catabolism.

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In order to establish a standardized method for the determination of serum lipid peroxide using thiobarbituric acid (TBA) reaction, problems in the TBA reaction and the sequence of TBA reaction of poly unsaturated fatty acid (PUFA) hydroperoxide, which were enzymatically prepared, were investigated and the following results were obtained.
1) Lipid peroxide values in the serum determined using TBA reaction varied by the change of deproteinnizing reagents used in the assay, such as 10% TCA, 0.33N HC10₃, 10% sodium-tungstate and 10% phosphotungstate.
2) Use of a crude TBA reagent, which is determined by the existence of a spot with Rf-value of 0.68-0.70 on the analysis with thin layer chromatography, resulted in a lowered value of serum lipid peroxide.
This crude TBA reagent was purified by a recrystalization procedure using boiling water.
3) Optimum pH values for PUFA hydroperoxides, such as linoleic acid hydroperoxide, linolenic acid hydroperoxide and archidonic acid hydroperoxide were found to be 3.5, 3.0 and 3.0, respectively.
The reaction of serum to the TBA reagent was found to be decreased, when the pH value was increased.
4) The TBA reaction with the PUFA hydroperoxides, such as linoleic acid hydroperoxide and arachidonic acid hydroperoxide as well as standard solution was found to be completed in 20, 60 and 60 minutes, respectively.
The TBA reaction with serum, however, was found not to be completed following an incubation period of 120 minutes.
5) The malondialdehyde (MDA) amounts, which were generated from PUFA hydroperioxides, such as linoleic acid hydroperoxide of 156μM, linolenic acid hydroperoxide of 150μM and archidonic acid hydroperoxide of 150μM by the TBA reaction, were 4.0, 6.3 and 7.8nM/ml, respectively.
This shows that the MDA generated by the TBA reaction varied by the changes in the number of carbon atoms and the double bonds in the PUFA hydroperoxide molecule.
6) Levels of serum lipid peroxide determined using TBA reaction varied by the change in the determination method for absorbance. Using serum levels lipid peroxide were found to be 5.48nM/ml by the mono-wavelength (532)nm), 2.34nM/ml by the two-wavelength (532, 575nm) and 3.84nM/ml by the fluorometric method. The precision (CV) of the determined values were found to be 3.26, 4.24 and 9.53%, respectively.
7) On the basis of the present analysis, levels of the serum lipid peroxide determined using TBA reaction varied to a considerable extent and the biological meanings of the determined values have to be analyzed with recognition of the problems existing in the determiniation method.

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We have had an idea that the serum lipids and lipid peroxide (LPO) are an important factor to be the cause of athero sclerosis. However, the relationship among these factors have been known almost nothing. The purpose of this study is to make up a relationship between LPO and lipoprotein-lipids in diabetics.
There were markedly difference of the LPO concentration among the 3 lipoprotein fractions, i. e., the mean value of HDL-LPO was significantly below one of VLDL-LPO and LDL-LPO, whereas LDL-LPO level was statistically highest in these fractions. As far as a correlation between the serum concentration of LPO and other lipids is concerned, many reports were positive in denying. It is possible that the mean is explained by our results as follows; there were statistically significant correlation between lipids and LPO level in the both fraction, VLDL and LDL. However, a significant correlation was not found in HDL fraction.
In this study, these results gave us the conclusion that serum LPO level may depend on the LPO level in VLDL and LDL. And also it is possible that the difference of LPO level among 3 lipoprotein fractions depend on the difference of their binding affinity between lipoprotein-lipids and lipoprotein-proteins.

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With intension of noninvasive, quantitative analysis of arteriosclerosis of carotid artery, we design ultrasonic, phase-locked echo tracking system. (Materials and method) Materials are consisted of 169 cases from 3 to 59 years old. Measuring system is shown in Fig. (2). The measured portions are four points along the common carotid artery containing carotid sinus. Fig. (2). We use stiffness parameterβ by Hayashi as a index of elastic property of artery. We can calculate it by following equation. β=ln Pmax/Pmin·D/ΔD, where Pmax is maximum pressure, Pmin is minimum pressure, D is diastolic diameter, and ΔD is the diameter change during the heart cycle. Now we fix the probe softly on the measuring position. The electric pulses are sonified into the body of the object through transducer as 5MHZ ultrasonic pulses. Then pulses reflected from the vessel walls are monitored on A-scope screen. Two tracking gates are set to follow automatically the movement of the echoes corresponding to the wall motion. Such behavior of the wall is recorded by the pen recorder. Fig. (3). Thus giving us the diameter change (ΔD) of the vessel during the heart cycle as well as diastolic diameter (D). Blood pressure are measured on the upper arm. (Result) 1. The each diameter of common carotid artery is almost same along the portions (B, C, D, ) and that of sinus (E) is a little larger than the others. In any portions the diameters are became larger with aging. Fig. (4). 2. We calculate stiffness parameterβ at each portion on common carotid artery in each individuals. Fig. (5), Fig. (6). β is increased with aging in any portions. But under 29 years old, we can find no difference between four portions on carotid artery, and the difference between each individuals is small. Over 30 years old, β is became higher with remarkable difference between four portions. Over 40, β of carotid sinus is became higher pecuriarly than the others (B, C, D, ). We can find this tendency more clearly over 50 years old. 3. The standard deviation of β at carotid sinus over 40 is higher than that of the other portions clearly. We can recognize the appearance of material change in common carotid artery.

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The occulusive coronary segments of 7cases of the acute myocardial infraction in post-acute stage were examined morphologically by serial step sections with 50μ intervals, in which 5cases had died from sudden cardiac death such as ventricular fibrillation or acute heart failure. The clinical course of these cases had progressed rather favorly after the final attacks.
New occulusive coronary thrombi of the recent stage were superimposed on the former thrombi in 5cases. No obvious reinfarction and/or new ischemic foci were observed both in the myocardium and in the conducting system.
These findings suggest that the new thrombi may be one of the causes of the sudden death in the post-acute stage of the myocardial infraction.

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Atherosclerotic changes in 711 aortas and 292 coronary arteries of Japanese under 40 years of age, which were autopsied during recent 5 years, were observed macroscopically. Relationship between extent and severity of atherosclerotic changes and age, sex, living area, blood pressure and serum cholesterol were also investigated.
1) Surface involvement (S. I.) of aorta showed more extensive involvement in the cases in west Japan than in east Japan in each decade, and showed no sex predilection. Atherosclerotic index (A. I.) of aorta in the cases in east Japan showed higher than those in west Japan in each decade. A.I. of male was higher than female in each decade, especially after 30 years of age.
2) Aorta in the cases in east Japan showed higher A. I. than in west in male.
3) In aortas, cloudy thickening was mainly seen in childhood, and decreased in relative involvement by age, and fatty streaks increased by age, but was nearly fixed over 20 years of age, and plaques appeared over 10 years old and increased in extent by age.
4) Positive relation was noted between S. I. of aorta and blood pressure, and A. I. of aorta and blood pressure and serum cholesterol. Positive relation was noted between A. I. of aorta and blood pressure in male, and serum cholesterol in female cases.
5) A. I. of coronary artery in the cases in west Japan was usually higher than that in those in east Japan in each decade, but difference between the cases in east and west Japan decreased in the cases over 30 years of age. A. I. of coronary artery showed no sex predilection under 30 years of age, but was higher in male than in female in the cases 30 years of age.
6) A. I. of coronary arteries was higher in the cases in west than in those in east Japan under 30 years of age, but was higher in the male cases in east than in west Japan in the cases over 30 years of age. A. I. of coronary artery was higher in the cases in west than in those in east Japan in female cases of each decade.

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42 diabetic patient with hyperlipidemia were treated with γ-oryzanol of 300mg/day for 16 weeks, and the changes of serum lipid levels was followed.
Significant reduction of cholesterol, triglyceride, malondialdehyde and atherogenic index was appeared following medication as 270 to 238 mg/dl (p was less than 0.01), 250 to 173mg/dl (p was less than 0.05), 3.6 to 2.1n mol/ml (p was less than 0.01) and 5.0 to 3.4 (p was less than 0.001), respectively.
The HDL-cholesterol increased significantly from 47 to 56mg/dl (p was less than 0.001) in both hypo and hyper HDL-cholesterolemic groups.

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Our previous report showed that when experimental rats were subjected to arteriosclerosis by artificially raising the cholesterol contents of their food-intake. ⁴⁵Ca deposits were found on the aorta.
This study was undertaken to discover if ⁴⁵Ca deposits can be prevented from forming (Experiment A) or removed once presents, in the aorta of rats suffering from arteriosclerosis (Experiment B), by the use of such known antiarteriosclerotic drugs as vitamin E, clofibrate and elastase, which each have a biochemically different function.
Elastase was found to prevent the formation of ⁴⁵Ca deposits and the accumulation of the cholesterol in the aorta of the rats. In the case of vitamin E and clofibrate, their influence on the ⁴⁵Ca and cholesterol was minimal more furthermore elastase, which was shown to have the most effect in preventing the formation of ⁴⁵Ca deposits, was also used successfully to remove ⁴⁵Ca deposits which had already formed in the aorta of the rats. In both the experiments using elastase, the elastin contents of the aorta were found to increase, whereas there was not marked change in the elastin contents when using vitamin E or clofibrate.

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Arteriosclerosis is one of the most important disorders in clinical medicine, but at the present time there are only a few method for detecting the severity of the disorder without any surgical procedures.
In biophysical sense, arteriosclerosis can be understood as a loss of elasticity of the arterial wall. Therefore, arteriosclerosis can be reflected on a pulse wave velocity (PWV) of the artery along its longitudinal axis according to the Moens-Korteweg's equation. In this view point, we have studied a method measuring PWV of the aorta in living subjects. And there are fairy good correlation between the PWV and the pathological changes of the aorta and the difference between in ante- and post mortem in 169 cases was negligible with 0.86 by multivariate statistical analysis.
Thus, these facts indicated that the grade of sclerosis of the aorta of living subjects could be estimated by measuring PWV which could be done non invasively and quantitatively.
This paper represents the evaluation of effect of antisclerotic agent Elazyme by measuring aortic PWV for 18 to 24 months.
Materials were 46 patients with coronary sclerosis, hypertension, hyperlipidemia, aortic sclerosis and others aged from 39 to 80 years old, the mean PWV was 9.16±1.16m/sec with advanced sclerotic grade. The second materials were of 69 control subjects. These two groups were measured PWV, ECG, blood pressure and serum lipid periodically. Results:
1. The mean PWV of patients who were given the antisclerotic agent Elaszym decreased from 9.16±1.15m/sec to 8.81±0.91m/sec (after 6 months. P<0.05), 8.69±0.97m/sec (after 12 months, P<0.05), 8.68±0.82m/sec (after 18 months. P<0.05) and 8.52±0.81m/sec (after 24 months, P<0.05) respectively.
2. The mean PWV of control subjects did not showed significant changes; 8.43±1.12m/sec (0 month), 8.51±0.99m/sec (after 12 months. N. S.), 8.42±0.96m/sec (after 24 months, N. S.) 8.44±0.72m/sec (after 36 months, N. S.)
3. The mean values of serum lipids such as total cholesterol, trigly-ceride and β-lipoprotein decreased significantly.

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