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.     

A study of atherosclerosis regression in Macaca mulatta. V. Changes in abdominal aorta and carotid and coronary arteries from animals with atherosclerosis induced for 38 months and then regressed for 24 or 48 months at plasma cholesterol concentrations of 300 or 200 mg/dl

Young adult male rhesus monkeys (Macaca mulatta) were fed an atherogenic diet for 38 months. After 38 months of atherosclerosis induction, a baseline group was selected and necropsied to determine the extent and severity of atherosclerosis before regression regimens were begun. The remaining animals were fed diets that varied in cholesterol concentration in order to maintain plasma cholesterol concentrations of approximately 200 or 300 mg/dl for either 24 or 48 months. The progression or regression of atherosclerosis in coronary arteries, abdominal aorta, and carotid arteries was determined by comparing them to the baseline group. Coronary artery atherosclerosis regressed in the majority of animals after 4 years but not after 2 years when plasma cholesterol concentrations were about 200 mg/dl. Among the animals maintained at plasma cholesterol concentrations of about 300 mg/dl, about half the animals progressed in the extent of coronary artery atherosclerosis while about half regressed. The majority of the animals that progressed in lesion extent were genetic hyperresponders to dietary cholesterol whereas those that regressed were predominantly hyporesponders, even though their plasma lipid concentrations were equivalent during the regression phase. The changes seen in atherosclerosis extent in the abdominal aorta were quite similar to the changes seen in coronary arteries. Changes at this site were not pronounced after 2 years, but after 4 years animals with plasma cholesterol concentrations of about 300 mg/dl progressed while the animals at 200 mg/dl were mostly unchanged. No evidence for atherosclerosis regression was found in the common carotid arteries or in the carotid bifurcations.     

Comparative primate atherosclerosis: I. Tissue Cholesterol Concentration and Pathologic Anatomy

Stump-tailed macaques (Macaca arctoides), African green monkeys (Cercopithecus aethiops), squirrel monkeys (Saimiri sciureus), and woolly monkeys (Lagothrix lagothricha) were fed control, solid atherogenic (1 mg cholesterol/cal) or liquid diets containing 0, 0.5, or 1 mg cholesterol/cal.Stump-tailed macaques fed the solid atherogenic diet had the highest tissue and serum cholesterol concentration (about 700 mg/dl) and the most extensive atherosclerosis. These monkeys appeared to respond differently to diets containing 1 mg cholesterol/cal. Those animals fed the liquid diet had higher liver cholesterol concentration but lower serum cholesterol concentration than animals fed the solid diet. African green monkeys fed the solid atherogenic diet had serum cholesterol concentrations of about 450 mg/dl. A greater percentage of the abdominal aorta was covered by plaque than the thoracic aorta. Coronary artery atherosclerosis was focal with the largest plaques being found in the left main coronary artery. The microscopic appearance of these plaques was similar to that of plaques from people.Squirrel monkeys fed the atherogenic diet were the most variable group. The average serum cholesterol concentration averaged about 450 mg/dl (range: 291 to 716). The percentage of aorta covered by plaque ranged from 0 to 55% with more thoracic than abdominal aortic atherosclerosis. There were findings consistent with hemorrhage in plaques from two animals. These monkeys, like stump-tailed macaques but unlike African green monkeys had relatively high liver cholesterol concentrations.Woolly monkeys appeared to develop atherosclerosis when fed 1 mg cholesterol/cal but did not have greatly elevated serum cholesterol concentrations.     

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.     

A study of atherosclerosis regression in Macaca mulatta. I. Design of experiment and lesion induction.

Rhesus monkeys were fed an atherogenic diet containing 40% of calories from lard and 1.0 mg/Cal cholesterol for either 19 months (Colony I) or 38 months (Colony II). At the end of the induction period the animals from each colony were divided into three groups (A, B, C) on the basis of total plasma cholesterol concentration during the induction period. Group A animals were killed at the end of the induction period for baseline observation of the extent and severity of atherosclerosis. Group B from each colony was fed a diet which maintained total mean plasma cholesterol concentrations between 280 to 320 mg/dl comparable to human beings with modest hyperlipoproteinemia. Group C from each colony was fed a diet which maintained total mean plasma cholesterol concentrations between 180 to 220 mg/dl, comparable to people who had modest hyperlipoproteinemia but were able to reduce plasma cholesterol concentrations by approximately 100 mg/dl using diet or drugs. Each group was further divided into two subgroups (B₁, B₂, and C₁, C₂). Animals from subgroup 1 were fed these diets for 24 months and animals from subgroup 2 were fed the same diet for 48 months.This report describes the clinical history, chemical analyses of arteries and the morphological extent and severity of atherosclerosis in arteries from animals of both colonies at the end of the induction period.     

Hyperlipoproteinaemia and atherosclerosis in rabbits fed low-level cholesterol and lecithin

Dutch-Belted rabbits were fed for 18 months an atherogenic semipurified gel diet containing 14% hydrogenated coconut oil and 0.06% cholesterol (approximately 0.15 mg/kcal) or a non-atherogenic basal gel diet containing the same ingredients but with no coconut oil or cholesterol. Rabbits fed atherogenic diet developed hypercholesterolaemia (means 733 mg/dl at 16 months) and plasma lipoprotein (LP) distribution shifted from a pattern in which high-density lipoproteins (HDL) predominated to one in which very-low-density lipoproteins (VLDL) were predominant. Total cholesterol/triglyceride ratio in d less than 1.006 LP changed from 0.3 to 1.8. Plasma cholesterol and LP distribution returned to normal in rabbits fed atherogenic diet for 18 months followed by atherogenic diet plus 3% soya lecithin for an additional 4 months. Rabbits fed atherogenic diet for 18 months had extensive, usually full circumference fibromuscular plaques in main branches of coronary arteries and all portions of aorta which compromised lumen area by almost 50%. These lesions were modified in rabbits fed atherogenic diet plus lecithin. The plaques lacked foam cells and cholesterol clefts, were less cellular with a distinct fibrous surface and occupied less space. Animals fed basal diet did not develop hypercholesterolaemia (means 86 mg/dl at 16 months), although distribution of plasma LP shifted slightly in favour of increased low-density lipoproteins (LDL) and decreased HDL compared with rabbits fed standard commercial diet. Basal diet rabbits had no coronary atherosclerosis and only minimal focal foam cell lesions in proximal aorta. Liver injury including fatty change, cholangitis and portal fibrosis occurred in animals fed atherogenic diet. Thus, rabbits fed appropriate diets low in cholesterol accumulate cholesterol-enriched LP in their plasma and develop lesions in abdominal aorta and main branches of coronary arteries which are similar to those in man. Also, in this experimental model, dietary lecithin promotes a return to normal of the LP distribution profile and removal of lipid from established atherosclerotic plaque.     

Hyperlipoproteinaemia and atherosclerosis in rabbits fed low-level cholesterol and lecithin.

Dutch-Belted rabbits were fed for 18 months an atherogenic semipurified gel diet containing 14% hydrogenated coconut oil and 0.06% cholesterol (approximately 0.15 mg/kcal) or a non-atherogenic basal gel diet containing the same ingredients but with no coconut oil or cholesterol. Rabbits fed atherogenic diet developed hypercholesterolaemia (means 733 mg/dl at 16 months) and plasma lipoprotein (LP) distribution shifted from a pattern in which high-density lipoproteins (HDL) predominated to one in which very-low-density lipoproteins (VLDL) were predominant. Total cholesterol/triglyceride ratio in d less than 1.006 LP changed from 0.3 to 1.8. Plasma cholesterol and LP distribution returned to normal in rabbits fed atherogenic diet for 18 months followed by atherogenic diet plus 3% soya lecithin for an additional 4 months. Rabbits fed atherogenic diet for 18 months had extensive, usually full circumference fibromuscular plaques in main branches of coronary arteries and all portions of aorta which compromised lumen area by almost 50%. These lesions were modified in rabbits fed atherogenic diet plus lecithin. The plaques lacked foam cells and cholesterol clefts, were less cellular with a distinct fibrous surface and occupied less space. Animals fed basal diet did not develop hypercholesterolaemia (means 86 mg/dl at 16 months), although distribution of plasma LP shifted slightly in favour of increased low-density lipoproteins (LDL) and decreased HDL compared with rabbits fed standard commercial diet. Basal diet rabbits had no coronary atherosclerosis and only minimal focal foam cell lesions in proximal aorta. Liver injury including fatty change, cholangitis and portal fibrosis occurred in animals fed atherogenic diet. Thus, rabbits fed appropriate diets low in cholesterol accumulate cholesterol-enriched LP in their plasma and develop lesions in abdominal aorta and main branches of coronary arteries which are similar to those in man. Also, in this experimental model, dietary lecithin promotes a return to normal of the LP distribution profile and removal of lipid from established atherosclerotic plaque.     

Studies on the progression and regression of coronary and peripheral atherosclerosis in the cynomolgus monkey. I. Effects of dipyridamole and aspirin.

The morphological and biochemical changes in the arteries of the cynomolgus monkey were investigated during the induction and regression of atherosclerosis. During the feeding of an atherogenic diet containing 2% cholesterol and 10% butter for 5 months, the animals developed fibro-fatty plaques which involved the coronary and peripheral arteries and caused significant luminal narrowing of these vessels. The induced aortic lesions contained increased amounts of free and esterified cholesterol, collagen, elastin, and calcium. These changes were associated with an elevation of plasma cholesterol and an increased net influx of plasma cholesterol and LDL into the aorta. Dipyridamole (10 mg/kg) and aspirin (50 mg/kg) had no effect on the arterial uptake of plasma LDL and cholesterol and did not protect against atherosclerosis in any of the vessels examined.During the regression period (low cholesterol diet) of 12 months duration, the induced lesions became more fibrotic and calcified while the cellularity and lipid content of the same lesions decreased. As a result of these changes there were no significant decreases in the atherosclerotic narrowing of the coronary and peripheral vessels. The net influx of plasma LDL and cholesterol into the aorta returned to normal during the regression period. This finding together with the slow rate of aortic cholesterol equilibration suggests that the retention of cholesterol in the regressed aortic lesions is due to a defect in cholesterol transport rather than to an abnormality in intimal permeability. The addition of dipyridamole and aspirin to the regression diet did not alter the course of the atherosclerosis.     

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.     

Atherosclerotic plaque regression in rhesus monkeys induced by bile acid sequestrant.

This study in 10 rhesus monkeys was made to determine whether the bile acid sequestrant, cholestyramine (CST), when added to an atherogenic diet would cause regression of atherosclerotic plaques induced by dietary means. Sequential plaque changes were evaluated by serial angiography, surgical exploration, biopsy, and autopsy. After 23 months on atherogenic diet (Period I) all animals developed fatty fibrous plaques. CST was then added to the diet of eight animals over the following 11 months (Period II) and at the end of this interval seven showed plaque regression. One animal appeared to show regression of atherosclerosis in abdominal aortic branches and progression in the internal carotid artery. Atherosclerotic disease progressed in two control animals which were continued on the atherogenic diet alone during Period II. Overall, CST was effective in lowering cholesterol level sufficiently to induce plaque regression. During Period II, fecal bile acid excretion increased eight fold while average serum cholesterol fell from 400 ± 13 to 237 ± 70 mg/dl. Plaque regression appeared related to level of serum cholesterol during Period II rather than to the magnitude of increase of fecal bile excretion.     

Comparative long-term experience with immunoadsorption and dextran sulfate cellulose adsorption for extracorporeal elimination of low-density lipoproteins

Two low-density lipoprotein (LDL) apheresis methods allowing a specific extracorporeal removal of atherogenic lipoproteins from plasma were compared concerning their efficacy and safety in the long-term therapy of severe familial hypercholesterolemia. Five patients were treated with immunoadsorption (IMA) at weekly intervals over 3 years each, and three patients received weekly therapy with dextran sulfate cellulose adsorption (DSA) for up to 2 years. The mean plasma volume processed per session to decrease total cholesterol to a target level of 100–150 mg/dl at the end of LDL apheresis was significantly lower in DSA than in IMA: 143% vs. 180% of the individual plasma volume. Both LDL apheresis procedures achieved a mean acute reduction of plasma LDL cholesterol by more than 70%. The average interval concentrations of plasma LDL cholesterol obtained without concomitant lipid-lowering medication were 151 ± 26 mg/dl compared to 351 ± 65 mg/dl at baseline in the IMA-treated patients and 139 ± 18 mg/dl compared to 359 ± 48 mg/dl at baseline in the DSA-treated patients. Two patients from the DSA group died after 2 years of study participation due to a stroke and a sudden cardiac death several days after the last plasma therapy. Treatment-related side effects were infrequent. Long-term therapy with IMA and DSA was associated with symptomatic improvement of coronary artery disease and mobilization of tissue cholesterol deposits. Analysis of coronary angiograms after 3 years of weekly LDL apheresis with IMA revealed in five patients nearly identical atherosclerotic lesions without definite regression or progression.Abbreviations LDL low-density lipoprotein - IMA immunoadsorption - DSA dextran sulfate cellulose adsorption - apo apolipoprotein - Lp(a) lipoprotein(a) - HDL high-density lipoprotein - ACE angiotensin-converting enzyme     

Atherosclerosis in Macaca mulatta: Histopathological,morphometric, and histochemical studies in aorta and coronary arteries of spontaneous and induced atherosclerosis

A comparative study of morphology, size, and histochemistry of the intimal lesions in aorta and coronary arteries of spontaneously occurring and cholesterol-induced atherosclerosis in rhesus monkeys has been carried out. A group of 30 normal monkeys was also investigated. Spontaneous atherosclerosis was noted in 10 of 55 adult monkeys autopsied serially; fatty streaks or atheroma in the aorta was noted in seven, fibrous plaque was noted in two, and diffuse intimal thickening was observed on one animal only. The coronary arteries showed fibrous intimal thickening without lipid in 8 of these 10 monkeys. There was fair to heavy deposition of acid mucopolysaccharides in the thickened intima along with proliferation of myointimal cells and collagen fibers. In the seven monkeys which were fed an atherogenic diet for 6 months, the aorta showed fatty streaking and atheroma in all animals. The coronary arteries also showed a variable degree of atherosclerosis but the lipid in the thickened intima was not marked. The atherosclerotic plaque height was not significantly greater than that in the spontaneous disease. These differences between spontaneously occurring and cholesterol-induced atherosclerosis in monkeys tend to indicate that the basic mechanism of lesion formation in the two states may be different.     

Effects of soybean phospholipid,chlorella phospholipid,and clofibrate on collagen and elastin synthesis in the aorta and on the serum and liver lipid contents in rats

The effects of antilipemic agents, soybean polyunsaturated phospholipid (SP), clofibrate, and chlorella phospholipid (CP), on the serum and liver lipid contents and on the synthesis of collagen and elastin in the thoracic aorta in rats were investigated. SP (1%), CP (1%), and clofibrate (0.1%) were added to the basal diet, and the diets were given for 5 weeks to rats from 10 to 15 weeks old. Serum cholesterol and phospholipid contents and liver cholesterol and triglyceride contents were significantly decreased in rats fed CP and clofibrate containing diet compared to the control animals. The contents of collagen and elastin in the thoracic aorta were not changed by CP or clofibrate, although in rats fed the SP-containing diet, incorporation of hydroxyproline from proline into elastin increased. However, the prolin hydroxylase activity in the thoracic aorta was significantly increased (twofold) in CP and clofibrate rats compared to the control and SP animals. In spite of the fact that clofibrate and CP activate the proline hydroxylase activity in the aorta, collagen and elastin content and the incorporation of proline as hydroxyproline into collagen and elastin in the aorta did not increase.     

Inhibition of lipid deposition in the hypercholesterolemic rat by clentiazem, a calcium channel blocker.

We studied the effects of clentiazem, a calcium channel blocker (1) on the accumulation of lipid in the aorta, (2) on the level of plasma lipids, and (3) on the number of adherent intimal monocytes and foam cells. Seventy Wistar rats were assigned to one of the following groups: (1) regular diet, (2) an atherogenic diet consisting of regular chow with 2% cholesterol, 1% cholic acid, and 0.5% thiouracil (CCT), (3) CCT supplemented with 5 mg/kg/day clentiazem, and (4) CCT with 25 mg/kg/day clentiazem. Animals were sacrificed after 6 or 12 weeks of diet. Aortas were studied by light microscopy after staining with oil red O (ORO) and/or hematoxylin. ORO staining was quantified in both abdominal and thoracic regions of the aorta. The aortas of the clentiazem groups demonstrated significantly less ORO staining than CCT diet controls in thoracic aorta after 6 weeks and abdominal aorta after 12 weeks. There was no significant difference in the plasma lipid concentrations. The clentiazem-treated groups had fewer numbers of adherent monocytes and foam cells. We conclude that clentiazem inhibits lipid deposition in cholesterol-fed rats without lowering plasma lipid concentrations and that the number of intimal monocytes and foam cells is decreased in the presence of this calcium antagonist.     

Dietary fish oil enhances monocyte adhesion and fatty streak formation in the hypercholesterolemic rat.

Using the rat model of atherosclerosis, the influence of dietary fish oil on early stages of atherosclerotic lesion formation was studied. Normocholesterolemic rats (serum cholesterol less than 100 mg/dl), moderately hypercholesterolemic rats fed cholesterol and cholic acid (serum cholesterol less than 400 mg/dl), and severely hypercholesterolemic rats fed cholesterol, cholic acid, and 2-thiouracil (serum cholesterol greater than 900 mg/dl) had their diets supplemented with 5% (w/w) "MaxEPA" fish oil for a period of 2 weeks. In each diet group safflower oil was used as a control for fish oil. Monocyte adhesion to the thoracic aorta and intimal foam cell formation were used to measure the extent of atherosclerotic lesion formation in each rat. Cholesterol and triglyceride levels were measured in both plasma and lipoprotein fractions. In normocholesterolemic rats, fish oil did not influence the morphology of the vessel wall. In moderately hypercholesterolemic rats, monocyte adhesion was the same irrespective of dietary oil, however, intimal foam cell formation was 2-fold higher in the fish oil-fed animals despite a reduction in serum cholesterol levels when compared to the safflower oil-fed animals. In severely hypercholesterolemic rats, monocyte adhesion to the vessel wall and intimal foam cell formation were both 4-fold higher in the fish oil compared with the safflower oil fed animals. These observations could not be attributed to differences in the plasma or lipoprotein profiles of safflower oil vs. fish oil fed rats. The results of this study suggest that dietary fish oil, when fed to hypercholesterolemic rats for a period of 2 weeks, enhances the rate of monocyte adhesion and fatty streak formation in the thoracic aorta.     

Considerations of aortic elastin chemistry in the genesis of the intimal plaque (broad-breasted white turkey)

Fragmentation of internal and external elastic membranes occurs in the abdominal but not in the thoracic aorta of the Broad-Breasted White turkey during the early developmental period. In this early period, isolated elastin from the abdominal aorta contains more polar amino acid residues than elastin of the thoracic aorta. Additionally, the relative amount of a chemically unstable elastin cross-link, dehydrolysinonorleucine, is greater in the abdominal as compared to the thoracic aorta during the early developmental and adult periods. Cells of the abdominal aorta exposed to a higher arterial pressure and a greater rate of arterial pressure rise ($\text{dp}\text{dt}$) and in a region with a higher collagen:elastin ratio (reduced compliance to pulse-pressure-volume deformations) may synthesize a chemically unstable elastin which breaks down in regions of accentuated wall stress. Though these breaks of the internal elastic membranes, modified smooth muscle cells may migrate, proliferate and ultimately synthesize new elastin in forming the intimal plaque.     

The assessment of arteriolosclerosis by serum lipids data, and carotid ultrasonography and pulse wave velocity, and its evaluation as a tool for preventive medicine: II. Carotid ultrasonography and pulse wave velocity for hyperlipemia and diabetes mellitus

We studied the test results of carotid ultrasonography and pulse wave velocity against a sample of hyperlipemia and diabetes mellitus. Sixty four hyperlipemia samples (HL), 85 diabetes mellitus samples (DS), and 27 complicated samples (CS) were compared with 56 healthy samples (HS). Hyperlipemia samples were selected from cholesterol under 300 mg/dl, and neutral fat under 300 mg/dl. Diabetes mellitus samples were selected from fasting plasma glucose (FBS) under 200 mg/dl. Samples from severe conditions with various disease were excluded. Ratio over 1.1 mm intima-media thickness (IMT) was 0% in HS, 48% in HL, 40% in DS and 33% in CS. PWV value was max 1896cm/s in CS. There was no significant correlation within IMT, serum lipid(Total Cholesterol, Neutral Fat, HDL-Cholesterol, LDL-Cholesterol) and FBS. For early treatment or accurate diagnosis of arteriosclerosis in hyperlipemia or diabetes mellitus patients, who are at high risk of developing arteriosclerosis, to vital function tests (carotid ultrasonography and pulse wave velocity) should be performed, in addition to normal blood tests.     

Influence of apolipoprotein B signal peptide insertion/deletion polymorphism on serum lipids and apolipoproteins in a Chinese population

Insertion/deletion polymorphism of the apo B gene encoding signal peptide and its influence on serum lipids and apolipoproteins was studied in 269 Chinese of both sexes in Singapore. The frequency of the Del allele was found to be 0.20, which is significantly lower than that in Caucasians (France) (0.34). The distribution of genotypes of ins/del polymorphism was at Hardy-Weinberg equilibrium in this population. There was an excess of individuals with the deletion allele in hypercholesterolemic subjects compared to those with normal cholesterol levels (P less than 0.05). All the lipid and apolipoprotein values were regressed for age, sex and BMI by multiple regression analysis. Individuals with one or two del alleles had significantly higher levels of serum total cholesterol (248.8 +/- 13.0 and 255.4 +/- 20.4 mg/dl, respectively) compared to those in individuals with only the Ins allele (218.4 +/- 7.8 mg/dl) (P less than 0.05). Serum LDL cholesterol level was also significantly higher in individuals with del allele (173.4 +/- 11.7 mg/dl) compared to that in those without the del allele (141.1 +/- 7.4 mg/dl) (P = 0.02). The percentages of sample variance of different lipid traits explained by apo B signal peptide polymorphism were estimated by analysis of variance (ANOVA) with sex, age and BMI as covariates. 2.3% of variability of serum total cholesterol (F = 3.27, P = 0.040) and 2.8% of LDL cholesterol (F = 3.87, P = 0.023) could be explained by the ins/del polymorphism of the apo B signal peptide gene.     

Lipid lowering treatment with bezafibrate in patients on chronic haemodialysis: Pharmacokinetics and effects

Summary Hyperlipidaemia may contribute to the high rate of cardiovascular complications in patients on chronic haemodialysis (CHD). However, possibilities of lipid lowering therapy in CHD are still limited. The applicability of bezafibrate (BF), a recently developed clofibrate analogue, was investigated in patients on CHD with triglyceride and/or total cholesterol levels above 300 mg/dl.The lipid lowering effect was studied in a placebo-controlled trial over 6 months in 19 patients. Long-term effect was followed in six patients over a mean period of 29 months.Elimination half-life and mean therapeutic serum concentration were calculated by 72-h BF serum profiles, obtained after the first drug administration of a single 200-mg dose and during steady state after 12 weeks of treatment. Elimination half-lives were 17 h at start and 22 h after 12 weeks compared with 2 h in subjects with normal renal function. Dose reduction to 200 mg every 3rd day was necessary and resulted in a mean therapeutic serum concentration of 3.4 mg/l, which was similar to 3.0 mg/l of normal subjects, who received the dose optimal for lowering of lipids (200 mg 3 × /day). The protein-bound serum fraction of BF was decreased to 8% in CHD patients, compared with 95% found in normal subjects.BF therapy resulted in a marked reduction of serum triglycerides from 478 mg/dl by 31% and total cholesterol levels from 311 mg/dl by 19% as well as -Lp-cholesterol from 178 mg/dl by 17%, whereas the initially low -Lp-cholesterol increased significantly from 18,3 mg/dl by 58%. Under long-term therapy not only continuously low triglyceride and cholesterol levels could be maintained, moreover a further decline (–20% and –7%) could be achieved.Safety laboratory controls, comprising haemoglobin, bilirubin, liver enzymes, CK and albumin, showed no significant changes apart from a slight reversible increase in CK and a decrease in gamma-GT and alkaline phosphatase. Subjective side effects were not reported. Under this dosage schedule, BF therapy was thus effective and safe, improving potentially atherogenic disturbances of lipid metabolism.Abbreviations BF bezafibrate - CHD chronic haemodialysis - HDL high density lipoproteins - IDL intermediate density lipoproteins - LDL low density lipoproteins - VLDL very low density lipoproteins     

Differing patterns of altered glucocorticoid secretion in experimental malignant and benign hypertension. Influences upon the lymphoid system and on arterial connective tissue metabolism

Alterations in plasma glucocorticoid levels and in the evolution of the thymus gland were studied in groups of malignant (MHY) and benign (BHY) hypertensive rats sacrificed at 6, 9, 12 and 24 days after aortic ligation between the renal arteries. Although the degree of blood pressure elevation was similar in MHY and BHY animals, MHYs were characterised by severe weight loss, increased plasma renin activity and elevated blood urea nitrogen. MHY animals sacrificed at day 6 showed markedly increased plasma corticosterone (PC) levels (PC: 604 ± 3·9 μg/dl) accompanied by severe thymus atrophy (123 ± 19 mg). In 6-day BHY animals elevated plasma corticosterone and thymus atrophy were also present but were not as marked as in MHY (BHY: PC: 38·8 ± 4·6 μg/dl, thymus wt: 244 ± 33 mg). Values from BHYs were, however, significantly different from sham-operated (Sham-op) controls (Sham-op: PC: 22·6 ± 1·4 μg/dl; thymus wt: 631 ± 32 mg). In BHY animals sacrificed at day 9, plasma corticosterone had returned to baseline levels. From this time period onward, in BHY animals normal plasma corticosterone was accompanied by a steady recovery of the thymus gland, generalised lymphoid proliferation, and by the proliferation of collagen and elastin (measured by the in-vitro incorporation of ¹⁴C-l-proline into both proteins) in the intima-media and adventitia of the thoracic aorta. Contrary to the normalisation of plasma corticosterone and thymus recovery observed in BHYs, corticosterone remained chronically elevated in MHYs and thymus atrophy was present throughout the entire evolution oif the disease. In MHYs, the arterial connective tissue proliferation was repressed and the synthesis of collagen and elastin was similar to normotensive controls. A. Statistically significant decrease in collagen concentration was present in both intima-media and adventitia of MHYs when compared to either BHMs or normotensive controls. Impaired vascular hypertrophy in MHYs coexisted with marked alterations in the lymphoid system. In the thymus severe atrophy, thymocyte depletion and a reverse corticomedullary pattern were observed. When the thymocytes remaining in the organ were challenged with the T cell mitogen concanavalin A they showed an impaired proliferative response. In the blood a significant reduction in circulating lymphocytes and marked neutrophilia were observed. These findings suggest that increased glucocrticoid secretion marks important modifications in cells and tissues involved in the production of necrotising arterial lesions during the evolution of malignant hypertension.