Effects of a surfactant on thromboatherosclerosis and cholesterol atherosclerosis

The objective was to study the effect of the surfactant polymer 30-oxyethylated t-octyl phenol formaldehyde tetramer on the severity and lipid accumulation of experimental cholesterol atherosclerosis in the arch and thoracic aorta induced by feeding 0.5 gm cholesterol per day, in comparison with its effect on fibrofatty type atherosclerosis developing from organized white mural thrombus in the abdominal aorta of the same rabbits. Cholesterol atherosclerosis at 12 weeks measured as percentage intimal area in the arch 74 ± 28 S.D.%, thoracic aorta 48 ± 22% was markedly reduced in severity in rabbits fed the same cholesterol diet and treated with the surfactant: arch 9 ± 21% (P < 0.001) and thoracic 3 ± 4% (P < 0.001). Cholesterol + cholesterol ester18 mg/100 mg dry aortic tissue in the control group was markedly reduced in the surfactant group to 5 mg/100 mg dry tissue. Severity of fibrofatty type lesions expressed in terms of weight were the same in both groups. Cholesterol + cholesterol ester 20 mg/100 mg fibrofatty lesions in the cholesterol group was not significantly different in the surfactant group where 21 mg cholesterol + cholesterol ester/100 mg tissue was found. It is concluded that this surfactant markedly reduces the severity and the lipid accumulation in fatty streak type cholesterol atherosclerosis but does not modify lipid accumulation in fibrofatty lesions developing from thrombus. This surfactant may be a useful agent to differentiate pathways of lipid accumulation in these two different types of lesions.     

Biochemistry of atherosclerosis produced by cholesterol feeding,thrombosis, and injury

Aortic atherosclerosis produced in rabbits by feeding them cholesterol was found to be biochemically and morphologically different from raised lesions developing from white mural nonocclusive thrombus and was also different from flat myointimal thickenings developing after catheter-induced endothelial injury with transient platelet adhesion in both the normolipidemic and hypercholesterolemic state. The three types of lesions differed in respect to the time of onset, intensity and time of decline of DNA synthesis (cell proliferation), collagen synthesis, collagen concentration, lipid profile, uptake of Evans blue, and uptake of colloidal thorium dioxide. Lesions of Evans blue positive endothelial injury in the normolipidemic state ultimately developed into flat myointimal thickenings with DNA, collagen, and lipid concentrations very similar to the normal aortic wall. Lesions from thrombus ultimately developed into raised thromboatherosclerotic lesions with a lipid and collagen profile very much higher and different from the normal aortic wall. The kinetics of DNA and collagen synthesis, collagen concentration, lipid profile, Evans blue and colloidal thorium dioxide uptake of the flat myointimal thickenings from injury, and the raised thromboatherosclerotic lesion from thrombus are different from the cholesterol atherosclerotic lesion from cholesterol feeding. Although these three types of lesions have many features of cell injury and repair in common and with wound healing in general, the biochemistry and morphology of the three types of lesions are distinctly different.     

Comparative primate atherosclerosis: II. A biochemical study of lipids,calcium, and collagen in atherosclerotic arteries

Arterial lipid, calcium, and collagen concentrations were determined for squirrel monkeys (Saimiri sciureus), African green monkeys (Cercopithecus aethiops), stump-tailed macaques (Macaca arctoides), and woolly monkeys (Lagothrix lagothricha) fed four types of diets with and without cholesterol for 42 mo. Comparisons were made with human arteries selected at several stages in the natural progression of atherosclerosis and the nonhuman primates were evaluated for their usefulness in the study of human atherosclerosis. Samples of normal artery, fatty streak, and plaque from the aortas of man and the nonhuman primates were fractionated by an ultracentrifugal method into a floating cholesterol layer termed “the nonbound cholesterol pool,” corresponding to the intra- and extracellular cholesterol thought to be capable of regression, and a “bound cholesterol pool” associated with the sedimenting arterial components such as membranes and connective tissue elements. The two physically distinct compartments of cholesterol were described and characterized within the atherosclerotic lesions.Most of the experimental diets fed the nonhuman primates increased the concentration of arterial lipids, especially esterified and nonesterified cholesterol. African green monkeys and stump-tailed macaques fed the atherogenic diet had greater accumulations of total cholesterol in the abdominal than thoracic aorta and were similar to man whereas squirrel monkeys were unlike man in that regard. Woolly monkeys fed the atherogenic diet had low concentrations of arterial cholesterol even though the arteries studied had intimal lesions. African green monkeys fed atherogenic diets had the most uniformly increased arterial calcium concentrations and were similar to man during the fourth and fifth decade of age as regards both arterial distribution and concentration. The stump-tailed macaques fed the atherogenic diet had 40–57% higher aortic hydroxyproline concentrations than controls indicating a very fibrous component comprising the lesion.Fatty streaks of African green monkeys, squirrel monkeys, and man had a similar concentration and distribution of total cholesterol in the lipid pools of aortic arch, thoracic aorta, and abdominal aorta; however, in that regard stump-tailed macaques were dissimilar and had low concentrations of cholesterol even though approximately 45% of the aorta was affected grossly with fatty streaks. Esterified cholesterol constituted the majority of the nonbound cholesterol pool of plaque in man and the nonhuman primates. On the basis of cholesterol distribution in atherosclerotic plaques, the stump-tailed macaque and the African green monkey seemed more similar to man.The results indicate that the African green monkey and the stump-tailed macaque would be the most useful of those species studied for investigating the lipid component of atherosclerosis. The African green monkey seems well suited for studies involving the mineral component of the lesion whereas the stump-tailed macaque appears useful for investigations on the proliferation of mesenchymal components of the artery wall and the resulting sclerogenic process.     

L-精氨酸对高胆固醇血症鹌鹑主动脉粥样斑块面积的影响

目的 初步探讨Ｌ－精氨酸对高胆固醇血症鹌鹑主动脉粥样斑块面积的影响。方法 选择健康雄性日本鹌鹑８０只,分为正常对照组,高脂组,Ｌ－Ａｒｇ组和安慰剂组,前８周高脂饮食,复制动脉粥样硬化模型,在此基础上,后８周Ｌ－Ａｒｇ组与安慰剂组停喂胆固醇和油脂,饮水补充２．２５％－Ｌ－精氨酸,后者饮自来水,在８周末,１６周末,取出主动脉,形态学观察动脉粥样硬化病变,计算斑块面积百分比,收集血清作生化分析。结果 （     

Lipid accumulation in prosthetic vascular grafts. Experimental study.

The present study demonstrates that the endoprosthetic tissue, developed at the contact of Dacron and Gore-Tex vascular prostheses replacing the infrarenal aortae of healthy dogs, presents a particular lipidic pattern as compared with the adjacent intimal arterial layer. The modified lipidic pattern is characterized by a significant increase in the total amounts of cholesterol, phospholipids, and triglycerides, despite a normal lipidic plasma profile. Histochemical studies showed that lipid droplets are accumulated in the cytoplasm of deeply situated cells and in the extracellular matrix. These findings support the idea that lipids may be trapped within the pseudo-intima of synthetic vascular grafts, even in the absence of a major plasma lipid disorder, and contribute to the prosthesis failure.     

Atherosclerotic lesions produced in baboons by feeding an atherogenic diet for four years

Baboons were fed a diet containing high levels of saturated fat and cholesterol for 49 months. Atherosclerotic lesions in the aorta and the major branches of the coronary arteries were examined grossly after staining with Sudan IV. Sections prepared from these arteries were examined histologically.In spite of only moderate elevation of serum cholesterol, fatty streaks and fibrous plaques were produced in both aorta and coronary arteries. Aortic fatty streaks contained both lipid filled intimal smooth muscle cells and foam cells together with variable amounts of extracellular lipid. The distribution of this lipid varied considerably among lesions and also from one area to another within a single lesion.Aortic fibrous plaques showed much collagen and elastin, contained seven to nine layers of smooth muscle cell and two to three layers of foam cells, and had large amounts of extracellular lipid. In some animals abdominal aortic fibrous plaques appeared to be formed to two distinct layers.The gross and histologic features of the lesions produced in these baboons by feeding an atherogenic diet for 49 months were similar to features of lesions observed in the human. This study provides further evidence that the baboon is an appropriate model and should continue to be used for the study of chronically induced atherosclerotic lesions.     

Angiochemical and tissue cholesterol changes of Macaca fascicularis fed an atherogenic diet for 3 years.

Angiochemical and tissue cholesterol changes were investigated in Macaca fascicularis fed either an atherogenic containing 1 mg cholesterol/Cal or a control diet for 3 years. The thoracic and abdominal aortas and the carotid and femoral arteries were visually examined for the extensiveness of atherosclerosis and analyzed for lipid, collagen, elastin, and mineral content. Cholesterol accumulation in other tissues was assessed by measuring concentrations in liver, kidney, skin, and tendon. The cynomolgus macaques fed the atherogenic diet had between 77 and 97% of the intimal surface of all arteries studied affected with atherosclerotic lesions. The arteries of animals fed the atherogenic diet were between 1.6–2.5 times heavier than the arteries of control animals. This increased weight was attributed largely to collagen and elastin. When animals fed the atherogenic diet were compared with controls, significant increases in arterial total cholesterol, esterified cholesterol, phospholipid, calcium, phosphorus, and magnesium were seen. The liver, skin and tendon, but not the kidney, had significant increased concentrations of total and esterified cholesterol compared to control tissues. Comparison of our findings with the results of other studies of nonhuman primates indicates that the atherosclerotic plaques induced in the cynomolgus macaques are most nearly comparable to atherosclerosis in man, primarily because of the marked accumulation of mineral and connective tissue components.     

Detection of macrophages in atherosclerotic lesions with cytochrome oxidase.

The anaerobic metabolism of the arterial wall allows macrophages to be demonstrated therein by the cytochrome oxidase histochemical method. Monocytes (macrophages) in human fatty streaks (WHO grade I) or fibrofatty (WHO grade II) human atherosclerotic lesions are normally confined to subendothelial regions. Lesions complicated by ulceration, mural thrombosis or intimal haemorrhage (WHO grade III) showed numerous monocytes (macrophages) around newly-formed capillaries in focal areas of organization. By contrast with grades I and II atherosclerotic lesions, macrophages in lipid granulomas induced by subcutaneous injection of cholesterol oleate are more numerous and distributed throughout the lesion. The slow or absent resorption of lipid from atheromatous lesions may in part result from the paucity of macrophages therein.     

Effect of hypertension on the in vitro incorporation of [1-14C]-oleate into phospholipid and cholesterol ester in the aortae of normal-fed and cholesterol-fed rabbits

Summary The effect of prior hypertension on the in vitro incorporation of [1-¹⁴C]-oleate into phospholipid and cholesterol ester in aortae from cholesterolfed and normal fed rabbits was studied.Incorporation of [1-¹⁴C]-oleate into phospholipid was not increased in aortae from either hypertensive normal-fed or hypertensive cholesterol-fed rabbits when compared to the appropriate normotensive controls.In the normal-fed rabbits, incorporation of [1-¹⁴C]-oleate into cholesterol ester was increased by hypertension in all aortic regions. In cholesterol-fed rabbits cholesterol esterification was found to be proportional to the intimal cholesterol concentration, irrespective of the prior blood pressure or the particular aortic region studied.It is concluded that the increased lipid synthesis in atherosclerotic vessels from hypertensive rabbits is a consequence of the increased lipid accumulation produced by hypertension and not the result of hypertension directly stimulating arterial wall metabolism.     

Biochemical effects of moderate diet and clofibrate on swine atherosclerosis

Aortic atherosclerotic lesions were induced in swine by feeding them an atherogenic diet for 17 months. The effect of a moderate diet (up to 8 gm of cholesterol per day), with or without added clofibrate therapy, for the subsequent 12 months was assessed by biochemical analysis of carefully dissected lesions and adjacent nonlesion areas. The moderate diet alone prevented "progression," except for accumulation of free cholesterol and enhancement of total protein and collagen synthesis, and caused regression of DNA concentration to nonlesion levels. The addition of clofibrate therapy enhanced regression, with significant decreases in DNA and esterified cholesterol concentrations and in the rate of DNA synthesis. Extrapolation of these results to man suggests that a "sensible" level of dietary lipid may be prophylactic against further progression, while addition of an effective hypolipemic drug may be therapeutically useful.     

The macrophage in atherosclerosis: modulation of cell function by sterols.

Lipid-laden macrophage foam cells are an early and persistent component of atherosclerotic lesions. As such they are likely to play a key role in disease progression, both as scavengers of lipid and as inflammatory mediators. The sterol content of macrophage foam cells is largely native cholesterol together with a small but significant proportion of oxidized cholesterol (oxysterols). Few in vitro investigations of the influence of sterol accumulation on macrophage function have used cells that contain physiologically or even pathologically representative amounts of cholesterol or, more particularly, oxysterols. However, recent studies, using macrophages with a sterol content much closer to that of authentic foam cells, show that the presence of oxysterols causes an impairment in macrophage cholesterol export, suggesting a key role for oxysterols in the maintenance of the foam cell phenotype. The implications of physiologically relevant levels of oxysterols on a wider range of macrophage function remain to be investigated.     

A Study of Atherosclerosis Regression in Macaca mulatta: III. Chemical Changes in Arteries From Animals With Atherosclerosis Induced for 19 Months and Regressed for 48 Months at Plasma Cholesterol Concentrations of 300 or 200 mg/dl

The influence of two levels of plasma cholesterol concentration on the long-term regression of atherosclerotic plaques in rhesus monkeys (Macaca mulatta) was studied. Forty-eight young adult male rhesus monkeys were fed an atherogenic diet for 19 months, then diets designed to maintain plasma cholesterol concentrations at 280-320 mg/dl (actual 316 ± 10 mg/dl; mean ± SEM) of 180-220 mg/dl (actual 204 ± 4 mg/dl). Twelve animals were killed after 19 months to evaluate the atherosclerosis produced. The remaining 36 monkeys were studied after 48 months of atherosclerosis regression. Significantly greater amounts of accumulated nonesterififed and esterified cholesterol were lost from the arteries of monkeys that underwent regression at about 200 mg/dl, in comparison with 300 mg/dl. Regression at both plasma cholesterol concentrations resulted in increased collagen and decreased elastin content in the thoracic aorta but not in the other arteries studied. After regression at 300 mg/dl there was no change (83%) in the frequency of calcification of the thoracic aorta, while at 200 mg/dl the frequency of calcification was reduced to 50%. When compared with monkeys whose athersclerotic lesions were produced in an identical manner but were regressed for only 24 months, after 48 months had increased cholesterol concenrations in the thoracic aorta and carotid artery but not the abdominal aorta of iliaco-femoral artery, regardless of the plasma cholesterol concentration. The lipid composition of the regressed plaque suggested a change in plaque lipid toward the character of extracellular deposits described physically as crystalline in nature. The physical state was influenced by the length of the regression period and the plasma cholesterol concentration during regeression. In the thoracic aorta, principally as a result of changes in elastin content, the collagen-to-elastin ratio increased between 24 and 48 months of regression. It is proposed that the differences in removal of cholesterol from the thoracic and abdominal aorta after 24 and 48 months of regression in animals at 300 mg/dl may be influenced by the rearrangement of connective tissue. On the basis of the lipid and mineral content of uncomplicated atherosclerotic plaques after 4 yers of regression, it appears that the plasma cholesterol concentration during the regression period is a signigicant factor influencing the extent of plaque regression as well as the potential for further progression.     

Dietary Induced Atherogenesis in Swine: Morphology of the Intima in Prelesion Stages

Hypercholesterolemia was induced in pigs by feeding a chow diet supplemented with 1.5% cholesterol and 19.5% lard for periods up to 12 weeks. The aortic intima from areas of spontaneously differing permeability to proteins, as demarcated by their uptake of Evans blue dye, was examined using light microscopy and both scanning and transmission electron microscopy to describe the earliest detectable changes in intimal morphology induced by the diet. After 2, 4, and 6 weeks of feeding, cholesterol/lardfed pigs demonstrated monocyte adherence to the endothelium in areas of enhanced permeability (blue areas) in 86% of samples examined, as compared to 52% in areas of lesser permeability (white areas) and 17% in control animals. Similarly, the number of monocytes in the intima was higher in blue areas than in adjacent white areas or blue areas from control animals. After 12 weeks of feeding, all blue areas showed intimal monocytes, with fewer seen in white areas. Aortic endothelial cells in hypercholesterolemic pigs were normal in ultrastructural appearance, except they contained more lysosomes and cytoplasmic filaments than those from control animals. No lesions were observed at 2, 4, and 6 weeks, although plasma cholesterol levels were substantially elevated (200-400 mg/dl) at these times. A marked hyper-β-lipoproteinemia was evident from 4 weeks onward, but no elevation of serum triglycerides was evident at any stage. Plasma phospholipid concentrations increased but not in direct proportion to cholesterol levels. At 12 weeks, foam cell lesions were observed in areas of enhanced permeability but not in adjacent areas of normal permeability. Lesion foam cells appeared to be derived from the monocytes which adhered to and penetrated the endothelium at earlier stages, since no intimal involvement, or lipid engorgement, by medial smooth muscle cells was observed.     

Microscopic findings associated with blood pressure indices in postmortem human aorta samples from young people (ages 15–34)

Standardized postmortem samples of thoracic and abdominal aortas from traumatic death victims (aged 15–34 inclusive) were selected according to renal indices of estimated blood pressure. Half of the males had renal small-artery evidence of elevated blood pressure, and half did not. The group consisted of an approximately equal number of black and white males. All of the individuals were nonsmokers and had similar age, cholesterol, and HDL distribution. Lipid deposition in the thoracic and abdominal aorta sections was determined quantitatively by means of computer micromorphometry in sections stained with Oil Red O. Results showed that there is a marked increase in extracellular lipid deposition in the intima for those arteries studied with elevated renal indices of hypertension. In addition, there is significantly more extracellular lipid in the abdominal aortas in black males than in white males. Also notable was the finding that the thoracic aorta samples exhibited significantly thicker intimas and larger intimal areas in the high blood pressure index groups than in the low blood pressure index groups. These results suggest that the development of atherosclerotic lesions may be due to an increased deposition of extracellular lipid in the matrix of the arterial intima.     

A study of atherosclerosis regression in Macaca mulatta: II. Chemical changes in arteries from animals with atherosclerosis induced for 19 months then regressed for 24 months at plasma cholesterol concentrations of 300 or 200 mg/dl

A clinically important question in people with existing atherosclerosis is whether a low concentration of plasma cholesterol attainable with diet or drug therapy influences preexisting atherosclerotic plaques and at what level of plasma cholesterol do these changes occur. Groups of young adult male rhesus monkeys were fed atherogenic diets for 19 months, then regression diets for 24 months. Regression diets contained sufficient cholesterol to maintain plasma cholesterol concentrations either at 302 ± 8 mg/dl, mean ± SEM (a concentration associated with a high risk for continued progression of atherosclerosis in man) or 194 ± 4 mg/dl (low risk for continued atherosclerosis development). A significantly greater amount of the accumulated arterial cholesterol, esterified cholesterol and phospholipid was removed in monkeys that underwent regression at 200 in comparison to 300 mg/dl. Decreases in arterial cholesterol in animals after 24 months at 200 mg/dl amounted to 100, 100, 93, and 96%, respectively, for carotid artery, thoracic aorta, abdominal aorta and iliaco-femoral artery in sharp contrast to decreases of only 80, 25, 56, and 72% in similar vessels of monkeys at the higher plasma cholesterol concentration. No major difference in arterial collagen or elastin was seen between the two regression groups. The frequency of mineralized plaques as assessed by aortic calcium accumulation was greater in the rhesus monkeys at the higher plasma cholesterol concentration during regression. Translated to human beings, these results suggest that for relatively uncomplicated fatty atherosclerotic lesions the plasma cholesterol concentration influences the degree of plaque regession and that significantly greater regression (as measured by a reduction in arterial lipid content) may be expected to occur at plasma cholesterol concentrations of 200 mg/dl as opposed to 300 mg/dl.     

Human atherosclerosis. I. Cell constitution and characteristics of advanced lesions of the superficial femoral artery

This study represents a systematic analysis of the fine-structural characteristics of atherosclerotic lesions of the superficial femoral artery in man together with the growth characteristics in culture of the smooth muscle cells derived from these lesions. Occlusive fibrous atherosclerotic plaques were obtained from 29 male patients at the time of bypass surgery for occlusion of the superficial femoral artery and were studied by light and transmission electron microscopy. The occluded segment of each artery was obtained immediately after removal from the patient and examined with sterile techniques, and representative segments were fixed for light- and electron-microscopic study. Adjacent segments were used for dissection of the lesion away from the underlying media, and smooth muscle cells were cultured from lesion and nonlesion areas and compared in terms of their growth responses to increasing concentrations of a pool of human whole blood serum. The majority of the lesions were fibroproliferative and contained relatively little lipid. The fibrous cap that covered each lesion consisted of a special form of dense connective tissue that contained flat, pancake-shaped smooth muscle cells in a lacunalike space. This space consisted of concentric layers of basement membrane, collagen fibrils, and proteoglycan. The majority of the cells beneath the fibrous cap were smooth muscle cells mixed with small but varying numbers of macrophages. Most of the lesions were occluded by a thrombus, which had undergone organization and recanalization. A small number of the lesions had deep lipid deposits together with foci of degeneration and calcification. The occluded thrombi contained smooth muscle cells and a larger proportion of macrophages than the lesions themselves. The in vitro growth properties of the smooth muscle cells isolated from the lesion and the underlying media suggested that the lesion cells had senesced, compared with the medial smooth muscle cells derived from the same artery.     

Effect of remote aortic injury and thrombosis on cholesterol atherosclerosis

Recent tissue culture studies indicate that platelet factors enhance lipoproteins to stimulate proliferation of smooth muscle cells, a key event in atherogenesis. It was of interest to determine if continued remote aortic injury and thrombosis can increase the severity of hypercholesterolemia induced atherosclerosis. Four groups of rabbits were studied, two groups fed 0.5 g cholesterol per day, one group with and one group without massive abdominal aortic white mural non-occlusive thrombosis and injury induced with a permanent indwelling catheter, and two groups fed 1 g cholesterol per day, one group with and one group without similar thrombosis and injury. Serum lipids in the four groups were qualitatively and quantitatively not significantly different from each other at 4, 8, and 12 weeks. When they were sacrificed at 12 weeks the percent intimal surface area in the thoracic aorta (48 ± 22) and arch (75 ± 28) of the rabbits with thrombosis and fed 0.5 g cholesterol per day was significantly (p < 0.01) greater than the percent intimal area (20 ± 14) and (24 ± 18) of the rabbits without thrombosis. The percent intimal area with lesions in the rabbits fed 1 g cholesterol per day with thrombosis (59 ± 25) and (84 ± 30) was significantly greater (p < 0.01) than the percent area (24 ± 29) and (32 ± 32) of the rabbits without thrombosis. Since the effects could not be attributed to differing serum lipid levels it is possible that the increased severity of atherosclerosis in the remote arch and thoracic aorta was related to increased permeability, cell proliferation or collagen synthesis possibly stimulated by circulating factors released from the remote massive non-occlusive thrombus or from circulating platelets activated by contact with the injured abdominal aortic wall.     

Increased platelet, but unaltered fibrinogen, accumulation in experimental thrombi in alloxan-induced diabetic rabbits.

Platelets from diabetic humans and animals have been found previously to be hypersensitive to agonists, including thrombin, in vitro but it is unclear if this hypersensitivity also occurs in vivo and leads to a greater thrombotic tendency. In the present study, the effect of diabetes was examined on thrombus formation and vessel wall responses which result from continuous intimal injury induced by indwelling aortic catheters in rabbits. Platelet and fibrin(ogen) associated with the thrombus and damaged aortae were examined. Control or alloxan-induced diabetic rabbits (9-12 months after initial treatment) were injected with 51Cr-labeled autologous platelets and 125I-labeled fibrinogen (prepared from control rabbits) before insertion of indwelling aortic catheters. The anesthetized rabbits were perfused-fixed after 20 hr or 4 days. The dry weight of thrombus that formed was determined and platelet and fibrin(ogen) accumulation in thrombi and on injured aortae were calculated from the associated 51Cr and 125I, respectively. In diabetic rabbits, more platelets accumulated in the thrombi which formed after either 20 hr or 4 days, although the weight of thrombus and net fibrin(ogen) incorporation into the thrombus were not different from corresponding control rabbits. Net platelet and fibrin(ogen) association with the injured aortae were not different between control and diabetic rabbits. It is likely that the increased platelet accumulation in arterial thrombi in diabetic rabbits which results from continuous injury to aortae is a consequence of hypersensitivity of these platelets to thrombin generated in the thrombus and at the sites of vessel injury.     

Experimental canine atherosclerosis and its prevention. The dietary induction of severe coronary, cerebral, aortic, and iliac atherosclerosis and its prevention by safflower oil.

Severe atherosclerotic lesions were produced without thyroid suppression in seven out of eight dogs by feeding semisynthetic diets containing 5 per cent cholesterol and 16 per cent hydrogenated coconut oil for 12 to 14 months. Occlusive plaques were located in the coronary arteries and major cerebral arteries as well as in the aorta and iliac vessels. The lesions were characterized by an intense sclerotic reaction to areas of lipid deposition and foam cell accumulation in the intima. The diet induced a rapid elevation of plasma-free and esterfied cholesterol, triglyceride, and phospholipid, and the extent of aortic atherosclerosis was shown to be partially dependent on mean plasma cholesterol concentration. A second group of eight dogs were fed a diet identical with the first except for the replacement of 4 per cent hydrogenated coconut oil by 4 per cent safflower oil. Despite receiving the same amounts of dietary cholesterol and fat, this second group of dogs was completely protected from the atherogenic process. Plasma lipids became only slightly elevated and no induced atherosclerotic lesions were found at autopsy. Circulating thyroid hormone concentrations were similar between the two groups of dogs and the thyroid glands had a normal morphology in both groups.     

Combined streptokinase and taurochenodeoxycholate action on experimentally induced atherothromboemboli. Chandler Tube Study

Atheroembolic lesions consist of both thrombus and atheroma, including cholesterol crystals; therefore, dissolution requires both a thrombotic agent and a lipid emulsifier. In vitro tests were performed in a Chandler tube apparatus to assess the effectiveness of predetermined dose and concentration levels for such agents. Between 0.065 and 0.1 mL of human atheroma, concentrated at 125 mg/mL, was added to 1 mL of recalcified rabbit whole blood in a Chandler tube to produce an atherothromboembolus. Specified amounts of streptokinase (SK) and/or taurochenodeoxycholate (TCDC) were introduced into the tube, either SK first, followed 30 minutes later by TCDC, or in the reverse order. The experimental thrombi were measured for length and weight, and samples from representative thrombi were processed and examined with both light and transmission electron microscopy. The combined SK/TCDC treatment appears to work best of all the treatments in reducing the size of the experimental thrombi and their cholesterol crystal components; and better than the TCDC/SK treatment. It is suggested that this combined treatment might be useful in the treatment of atherothromboembolism.