Effects of lipids and lipoproteins on thrombosis and rheology

Atherosclerotic plaque rupture and erosions precipitate thrombus formation and may lead to an acute ischemic syndrome. Lipids and lipoproteins modulate the expression and/or function of thrombotic, fibrinolytic and rheologic factors, and thereby influence hemostasis and potential tissue damage resulting from vascular injury. Triglyceride-enriched lipoproteins are accompanied by elevations in factor VII clotting activity, plasminogen activator inhibitor (PAI-1) and viscosity of blood and plasma. Low density lipoprotein (LDL) promotes platelet activation and tissue factor expression and LDL levels correlate with levels of vitamin K dependent coagulation factors and fibrinogen. Conversely, LDL inhibits tissue factor pathway inhibitor (TFPI) which limits activation of the extrinsic coagulation pathway. High density lipoprotein (HDL) has anti-atherothrombotic properties that result from inhibition of platelet and erythrocyte aggregation, reduced blood viscosity and suppression of tissue factor activity and PAI-1 activity and antigen levels. The effects of lipids and lipoproteins on hemostasis and rheology may have important implications for the clinical sequelae following plaque disruption and erosion.     

Vitamin C, high density lipoproteins and heart disease in elderly subjects.

Plasma vitamin C, total and high density lipoprotein (HDL) cholesterol and cortisol levels were measured in a random sample of 337 elderly subjects living at home in S. Wales; measurements of relative body weight and information about fruit intake, smoking habits and symptoms of cardiovascular disease were also collected. There was a sex difference, over all age groups, in plasma vitamin C and in total HDL cholesterol levels. Plasma vitamin C was strongly correlated with fruit intake in both sexes. Both HDL cholesterol and low and very density lipoprotein (LDL + VLDL) cholesterol levels tended to increase with increasing plasma vitamin C but this reached significance only for the LDL + VLDL fraction. In addition, HDL cholesterol was negatively correlated with Quetelet's index in the women. Symptoms and medication for heart disease did not correlate significantly with plasma vitamin C or with HDL cholesterol levels, but reported angina showed a weak positive association with total cholesterol in the men, and there was some evidence of increased cortisol levels in subjects with heart disease.     

Population correlates of plasma fibrinogen and factor VII, putative cardiovascular risk factors.

Recent prospective investigations have reported that higher plasma fibrinogen concentrations and higher factor VII coagulant activity are associated with greater risk of cardiovascular disease. To discover what characteristics may influence fibrinogen and factor VII, we analyzed data from the Atherosclerosis Risk in Communities Study obtained from over 12,000 men and women, aged 45-64 years, from four communities in December 1986 to June 1989. Fibrinogen was higher in blacks than whites and in women than men; in general, it increased with age, smoking, body size, diabetes, fasting serum insulin, LDL cholesterol, lipoprotein(a), leukocyte count, and menopause, and it decreased with ethanol intake, physical activity, HDL cholesterol, and female hormone use. Factor VII was higher in women than men and, in women, increased with age; in both sexes, it increased with body size, triglycerides, LDL cholesterol, and HDL cholesterol, and it decreased with ethanol intake. These findings indicate that elevations in fibrinogen and factor VII may be modifiable through appropriate lifestyle changes.     

Evidence that plasma lipoproteins inhibit the factor VIIa-tissue factor complex by a different mechanism that extrinsic pathway inhibitor

Factor VIIa participates in blood clotting by activating factor X and/or factor IX by limited proteolysis. The proteolytic activity of factor VIIa is absolutely dependent on a lipoprotein cofactor designated tissue factor. We have examined the ability of purified preparations of human plasma high density, low density and very low density lipoproteins, as well as apolipoproteins A-I and A-II, to inhibit the factor VIIa-tissue factor mediated activation of either factor X or factor IX before and after treatment of the lipoprotein preparation with polyclonal antibody directed against partially- purified human plasma extrinsic pathway inhibitor (EPI). In the absence of anti-EPI IgG, HDL, LDL, VLDL, and apolipoprotein A-II noncompetitively inhibited factor X activation by factor VIIa-tissue factor with apparent Ki values of 3.39 mumol/L, 124 nmol/L, 33 nmol/L, and 10.5 mumol/L, respectively. Apolipoprotein A-I had no effect on this reaction. The inhibitory activity of HDL, LDL, VLDL, and apolipoprotein A-II in this reaction was unaffected by the presence of high levels of anti-EPI IgG. In the absence of exogenous factor Xa, none of the lipoproteins studied inhibited the activation of factor IX using the tritiated peptide release assay. In the presence of added factor Xa (1 nmol/L), LDL and VLDL, but not HDL and apolipoprotein A- II, inhibited the activation of factor IX by factor VIIa-tissue factor. This inhibition was completely blocked by prior incubation of the lipoprotein with anti-EPI IgG indicating association of EPI with these particles. Taken collectively, our data indicate that HDL, LDL, and VLDL, at or below their plasma concentration, each selectively inhibits the factor VIIa-tissue factor mediated activation of factor X by a mechanism that appears to be distinct from extrinsic pathway inhibitor. These lipoproteins may not only play a role in the regulation of extrinsic blood coagulation, but may also selectively promote the activation of factor IX by factor VIIa-tissue factor in vivo at low tissue factor concentrations.     

Lipoprotein sub-fraction levels and composition in obese subjects before and after gastroplasty.

Obesity is frequently associated with several alterations of plasma lipid levels and lipoprotein metabolism. To evaluate the effects of severe obesity and weight loss on plasma lipoprotein sub-class levels and composition 11 grossly obese patients were examined before and six and 12 months after gastroplasty. Plasma lipoproteins were isolated by ultracentrifugation in a zonal rotor under rate flotation conditions. Mean body weight was 121.9 kg before gastroplasty, 97.6 kg after six months, and 90.7 kg after 12 months. Total plasma cholesterol was not affected by the weight reduction. Obese patients were characterized by increased levels of IDL and small dense LDL (LDL3). LDL levels, but not LDL3, were reduced following weight reduction. Plasma apo B levels of obese patients were always higher than in controls and were not affected by the weight reduction. After 12 month's weight loss total HDL cholesterol increased without modification of HDL sub-class cholesterol distribution, which was similar to that of normal controls. Plasma apo AI in obese patients was not affected by changes in body weight, and remained below normal. The percentage protein-lipid composition of LDL2 and HDL3 in obese patients was characterized by a decreased cholesterol ester content before gastroplasty which was normalized 12 months after gastroplasty. The presence of IDL and LDL3 in increased concentrations in severely obese patients may represent a vascular risk factor since similar abnormalities were recently observed in non-obese patients affected with vascular diseases.     

Plasma lipoproteins and apolipoproteins in insulin-dependent and young non-insulin-dependent Arab women

Summary Plasma lipids, lipoproteins and apolipoproteins (apo) were analysed in 30 young Arab IDDM and 50 young insulin-requiring NIDDM women. The mean age of IDDM and NIDDM groups was 20.2 and 34.5 years, and mean duration of diabetes was 5.7 and 4.6 years, respectively. Two groups of 40 and 60 healthy women (matched for age and BMI) provided corresponding control groups. In comparison with control subjects, diabetics showed marked increases in the following parameters: total cholesterol (TC), low density lipoprotein (LDL) cholesterol, total triglycerides (TG), very low density lipoprotein (VLDL) triglycerides, phospholipids, apoB, LDL apoB, glucose and glycosylated hemoglobin (HbA_1c) as well as the ratios of total cholesterol/high density lipoprotein (HDL) cholesterol, LDL-cholesterol/HDL-cholesterol, LDL cholesterol/high density lipoprotein 2 (HDL₂) cholesterol and apoB/apoAI. Plasma LCAT activity, concentrations of HDL₃ apoAI and apoAII in plasma and lipoprotein fractions were normal in both the diabetic groups. Levels of C-peptide, HDL, HDL₂ and HDL₃ cholesterol, plasma apoAI, HDL apoAI and HDL₂ apoAI were markedly decreased in the diabetic groups as compared to their corresponding controls. There was no significant correlation between fasting glucose or HbA_1c and any of the above parameters. Despite insulin therapy in both the diabetic groups studied, abnormalities in lipids, apoB and apoAI still persisted. Our data suggest a possible higher risk of atherosclerosis in these patients.     

Dietary fish lipids do not diminish platelet adhesion to subendothelium

There is a discrepancy in the results of reported studies of levels of vitamin K dependent coagulation factors in patients on warfarin therapy. This may have arisen partly because of the problem of assuring compliance with therapy in outpatients. The plasma concentrations of the vitamin K dependent clotting factors II, VII, IX and X were studied in 23 outpatients whose adherence to prescribed warfarin therapy was determined using a pharmacological indicator of compliance. In these patients, who were shown to have consistently good compliance and stable anticoagulant control over a period of 3-6 months, the activities in plasma of the four coagulation factors were not equally suppressed. Factor IX levels were significantly greater than those of factor VII (P less than 0.0001) which in turn were significantly greater than the levels of factor II (P less than 0.0001) or factor X (P less than 0.0001). There was no significant difference between the levels of factors II and X which were depressed to a similar extent. The proportion of variability of the International Normalized Ratio (INR) explained by linear regression was 51-77% and a model was derived to predict the INR from the mean of the levels of the four clotting factors. The concentrations of the coagulation factors II, VII, IX and X are likely to be highly dependent on the degree of compliance with warfarin therapy which should be taken into account when investigating the behaviour of these factors.     

Plasma high density lipoprotein is increased in man when low density lipoprotein (LDL) is lowered by LDL-pheresis.

Plasma high density lipoprotein (HDL) concentrations were increased in five hypercholesterolemic normoglyceridemic patients after removal of plasma low density lipoprotein (LDL) by LDL-pheresis. In each patient up to 80% of circulating LDL was removed by passing plasma through immunoadsorption columns containing antibody to apolipoprotein B immobilized to Sepharose. Rebound of LDL was slow after the procedure: 5-7 days in four non-familial hypercholesterolemic patients and greater than 14 days in one patient with homozygous familial hypercholesterolemia. Plasma HDL rose above the pretreatment baseline during the interval between treatments in four of the five patients. When treatments were repeated weekly, time-averaged plasma LDL was lowered by 40-70%, while plasma HDL cholesterol and apolipoprotein AI were increased up to 2-fold, depending on the degree of LDL lowering. Plasma HDL concentrations fell back to their baseline values when LDL-pheresis was stopped and rose again when treatment was restarted. Thus, LDL-pheresis may augment the therapeutic effectiveness of LDL lowering by raising plasma HDL levels and the concentration of HDL relative to LDL.     

Changes in plasma lipoproteins in acute malaria

Plasma lipid and lipoprotein concentrations were monitored in 16 patients with acute malaria. Plasma high density lipoprotein (HDL) levels decreased dramatically during the first 3 d after diagnosis to around 0.2 mmol l-1 (reference range 0.8-1.6 mmol l-1). The low HDL levels were related to parasitaemia, and rapidly recovered after successful therapy. Plasma triglyceride concentrations were moderately increased and plasma low density lipoprotein (LDL) cholesterol concentrations decreased during the course of infection. The mechanisms underlying the selective and pronounced decline in HDL cholesterol concentration remain obscure, but the reproducible phenomenon may be useful as an additional diagnostic tool in suspected malaria infection.     

Effect of probucol on cholesterol synthesis, plasma lipoproteins and the activities of lipoprotein and hepatic lipase in the rat

The postheparin plasma lipoprotein lipase (LPL) activity and plasma HDL and LDL cholesterol concentrations, decreases significantly during probucol treatment of the rat. The reduction of the LPL activity obviously took place in adipose tissue. The activity of hepatic lipase and the in vitro synthesis of cholesterol in the liver or isolated jejunal villous cells were unaffected by the probucol treatment. Plasma triglyceride and VLDL cholesterol concentrations remained similar in the control and probucol groups despite the difference in the LPL activity, whereas the esterified VLDL cholesterol level was significantly reduced in the probucol group. The results suggest that the HDL lowering action of probucol is contributed by the reduced LPL activity probably via impaired VLDL metabolism.     

Influence of plasma triglycerides on lipoprotein patterns in normal subjects and in patients with coronary artery disease

This study examined the correlation of plasma triglyceride levels with concentrations of intermediate, low and high density lipoproteins (IDL, LDL, and HDL, respectively) and to particle sizes of LDL in 93 normal men and 106 men with coronary artery disease. Plasma triglyceride concentrations were in the normal range for all persons in both groups. Analysis of lipoproteins of density less than 1.063 g/ml was carried out by analytical ultracentrifugation. The analytical pattern gave the peak Sf for LDL as well as an indication of heterogeneity of particle sizes in the density range of LDL. In both normal subjects and patients with coronary artery disease, a positive correlation was found between peak Sf for LDL and concentrations of plasma triglycerides. Plasma triglyceride levels also were correlated positively with concentrations of Sf 20 to 60 lipoproteins and total IDL mass, and inversely with HDL cholesterol levels. Furthermore, the value for peak Sf for LDL correlated inversely with the IDL mass concentration and IDL/LDL mass ratio, and positively with the HDL cholesterol levels. The results indicate that the lipoprotein pattern, including lipoprotein concentrations and particle sizes, is sensitive to concentrations of plasma triglycerides even when the latter are within the normal range.     

内源性高甘油三酯血症患者血浆极低密度脂蛋白、低密度脂蛋白及高密度脂蛋白对血凝及纤维蛋白溶解的影响

研究内源性高甘油三酯血症患者血浆极低密度脂蛋白、低密度脂蛋白及高密度脂蛋白是否发生了氧化修饰及其对凝血及纤维蛋白溶解活性的影响。对 2 1例内源性高甘油三酯血症患者与 2 1例年龄性别相近的正常人的血脂、脂质过氧化物进行了分析。用一次性密度梯度超速离心法分离血浆极低密度脂蛋白、低密度脂蛋白及高密度脂蛋白。测定这 3种脂蛋白的 2 34nm吸光度、相对电泳迁移率和硫代巴比妥酸反应物质含量。分别将这 3种脂蛋白加入由正常人新鲜混合血浆构成的反应系统中 ,按试剂盒分别测定凝血酶原时间、活化部分凝血酶原时间、组织型纤溶酶原激活物活性及纤溶酶原激活物抑制剂 1活性。内源性高甘油三酯血症患者血浆甘油三酯含量平均升高 2 .73倍 ,高密度脂蛋白胆固醇下降 1.71倍 ,同时硫代巴比妥酸反应物质含量升高 1.2 2倍 ;内源性高甘油三酯血症组极低密度脂蛋白、低密度脂蛋白及高密度脂蛋白的 2 34nm吸光度、相对电泳迁移率和硫代巴比妥酸反应物质含量均较对照组显著增加 (P <0 .0 1) ,表明内源性高甘油三酯血症患者血浆极低密度脂蛋白、低密度脂蛋白及高密度脂蛋白均发生了氧化修饰 ,生成了氧化极低密度脂蛋白、氧化低密度脂蛋白及氧化高密度脂蛋白。凝血酶原时间及活化部分凝血酶原时间在分别加入内     

Effect of large-dose progesterone on plasma levels of lipids, lipoproteins and apolipoproteins in males

Eleven men with sexual deviation syndrome were hospitalized for treatment with medroxyprogesterone acetate (Depo-provera). Plasma total cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, apo A-I and LDL apo B were measured before and during Depo-provera treatment. Ten normolipidemic and one mildly hypertriglyceridemic patient with 117 +/- 17% ideal body weight were maintained on a regular hospital diet before and during the study. They received an average total dose of 1273 +/- 467 mg Depo-provera by im injections over a mean period of 17 +/- 6 days. In the whole group, Depo-provera significantly reduced the plasma total cholesterol by 12% (p less than 0.0005), triglycerides by 24% (p less than 0.005), LDL cholesterol by 13% (p less than 0.01), LDL apo B by 15% (p less than 0.05), and apo A-I by 7% (p less than 0.05). Total HDL cholesterol, HDL2 cholesterol and HDL3 cholesterol did not change significantly. Excluding from the data analysis a normolipidemic patient who had a significant weight loss during the study and the hypertriglyceridemic patient, the fall in apo A-I during Depo-provera treatment was no longer statistically significant. We conclude that short-term, pharmacological doses of progesterone significantly reduce plasma concentrations of cholesterol, triglycerides, LDL cholesterol, and LDL apo B in men.     

Cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase activities in hispanic and anglo postmenopausal women: associations with total and regional body fat

Reverse cholesterol transport is one process by which high-density lipoprotein (HDL) cholesterol has been hypothesized to play a role in reducing the risk of coronary heart disease. This study was designed to examine cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT) activities, 2 modulators of reverse cholesterol transport, in Hispanic and Anglo postmenopausal women. The associations between plasma CETP and LCAT activities and body composition were also examined. Of the 199 subjects, 33% were of Hispanic origin and 47% were undergoing hormone replacement therapy (HRT). Body composition was measured by dual-energy x-ray absorptiometry (DXA) and anthropometry. Plasma CETP activity was higher in Hispanic compared to Anglo women, although the difference was eliminated when data were adjusted for abdominal fat. Hispanic women had lower plasma HDL cholesterol concentrations, higher total cholesterol:HDL cholesterol ratios and triglyceride concentrations, and greater susceptibility of low-density lipoprotein (LDL) particles to oxidation. Hispanic women also had a significantly greater relative deposition of body fat on the trunk and intra-abdominally than did Anglo women, even after adjusting for total body fat. There were no significant ethnic differences in LCAT activity. Plasma CETP and LCAT activities were negatively correlated with HDL cholesterol and positively correlated with total cholesterol, LDL cholesterol, and triglycerides, as well as total and regional body composition variables. In conclusion, results suggest a greater risk for coronary heart disease in Hispanic women compared to Anglo women.     

Serum Lipoproteins in Children with Anaemia

Plasma and erythrocyte lipids were estimated in 9 children with different types of anaemia and in 9 healthy control children. The anaemic children had rather high plasma triglycerides, but low total cholesterol and phospholipids. The levels of high density lipoprotein (HDL) cholesterol were particularly low, with a mean of only 70% of the controls. A positive correlation was found for haematocrit with HDL cholesterol, but not with low density lipoprotein (LDL) cholesterol. Plasma albumin was at the same level in both groups of children, however, suggesting that the diluting effect of increase in plasma volume could only partly explain the lowering of HDL cholesterol. A striking, inverse correlation between HDL cholesterol and very low density lipoprotein (VLDL) triglycerides was present in the anaemic children. Anaemia in children adds to previously recognized pathophysiological conditions which induce inversely interrelated changes in HDL and VLDL.     

Serum lipoproteins in children with anaemia.

Plasma and erythrocyte lipids were estimated in 9 children with different types of anaemia and in 9 healthy control children. The anaemic children had rather high plasma triglcerides, but low total cholesterol and phospholipids. The levels of high density lipoprotein (HDL) cholesterol were particularly low, with a mean of only 70% of the controls. A positive correlation was found for haematocrit with HDL cholesterol, but not with low density lipoprotein (LDL) cholesterol. Plasma albumin was at the same level in both groups of children, however, suggesting that the diluting effect of increase in plasma volume could only partly explain the lowering of HDL cholesterol. A striking, inverse correlation between HDL cholesterol and very low density lipoprotein (VLDL) triglycerides was present in the anaemic children. Anaemia in children adds to previously recognized pathophysiological condditions which induce inversely interrelated changes in HDL and VLDL.     

Changes in plasma lipoprotein concentrations and compositions upon feeding cholesterol in high- and low-responding rhesus monkeys

When fed cholesterol, the high-responding rhesus monkeys develop severe hypercholesterolemia, whereas low-responding rhesus monkeys show only slight increases in plasma cholesterol levels. We report changes in plasma lipoprotein concentrations and compositions along with changes in plasma lipid concentrations in high- and low-responding rhesus monkeys fed a high-cholesterol diet. On low-cholesterol diet, the concentrations and compositions of plasma lipoprotein fractions were similar in the two groups. Upon feeding cholesterol, plasma very-low-density (VLDL), intermediate-density (IDL) and low-density (LDL)-lipoprotein concentrations increased in both groups, but the increases were significantly (p less than 0.01) higher in high-responders than in low-responders. Plasma HDL concentration decreased significantly (p less than 0.01) in high responders but not in low responders. In high responders, percent cholesterol increased in both VLDL and IDL fractions but in low responders, it decreased in VLDL and increased in IDL. Percent triglycerides decreased in VLDL, IDL and LDL fractions in high responders, while in low responders it tended to increase in VLDL, remained unchanged in IDL and decreased in LDL. The composition of HDL did not change in the two groups upon feeding cholesterol. Thus, when fed cholesterol, the high- and the low-responding monkeys respond distinctly differently in plasma lipoprotein concentrations and compositions. The responses occurred simultaneously, suggesting metabolic interrelationships between various lipoproteins.     

Plasma lipoprotein cholesterol in India in healthy persons and those with coronary heart disease

The plasma total cholesterol and lipoprotein cholesterol levels are presented for 186 healthy Indian subjects and 213 patients with coronary heart disease (CHD). Plasma lipid and lipoprotein concentrations vary with age. Higher total cholesterol and LDL cholesterol were noted in men compared with women. HDL cholesterol is highest in women in the age group 20-49 years. HDL cholesterol levels (negatively associated with CHD) are significantly higher in India compared with western countries. It is suggested that the high level of HDL cholesterol may be responsible for the relatively low incidence of CHD in India.     

Lipoprotein distribution and composition in the human nephrotic syndrome

Plasma lipoprotein profiles were quantitated in 9 patients with the nephrotic syndrome. Six subjects were studied both during an active proteinuric phase and during a remission phase without proteinuria. During the proteinuric phase, the plasma triglyceride, cholesterol and apo B levels were markedly increased, whereas the HDL cholesterol, apo A-I, and apo A-II concentrations were normal. Analysis of the distribution and composition of the lipoprotein subclasses, separated by isopycnic ultracentrifugation, showed typical patterns characterized by: (1) elevated apo B-rich VLDL and LDL fractions, (2) the presence of a denser LDL subfraction, floating at d 1.053 g/ml, which contained about 35% of LDL cholesterol and apo B and (3) a redistribution among HDL subclasses. The HDL2b (d 1.063-1.100 g/ml) fraction was markedly decreased, while the HDL2a + 3a (d 1.100-1.150 g/ml) and HDL3b + 3c (d 1.150-1.210 g/ml) subclasses were moderately elevated. The decreased cholesterol and apo A-I contents of HDL2b therefore counterbalanced their increase in HDL2a + 3a and HDL3b + 3c, resulting in normal plasma HDL cholesterol and apo A-I concentrations. When reinvestigated during a remission phase without proteinuria, the nephrotic patient's overall lipoprotein distribution and composition were similar to those in healthy controls. The combination of several factors such as the presence of elevated apo B-rich VLDL, IDL and LDL, together with decreased HDL2 cholesterol and HDL2 apo A-I suggests that nephrotic patients are at increased risk for atherosclerosis.     

Increased low-density lipoprotein levels after splenectomy: a role for the spleen in cholesterol metabolism in myeloproliferative disorders

Patients with myeloproliferative disorders demonstrate decreased plasma cholesterol and apolipoprotein B concentrations, and this has been related to the presence of a large spleen. Patients that underwent splenectomy in the past demonstrated normal plasma cholesterol levels. Plasma high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I were also reduced in these patients, but were normal after splenectomy. To study the immediate effect of splenectomy on the plasma lipid pattern, three patients with myeloproliferative disease and a large spleen who were undergoing splenectomy were compared with two control groups, one undergoing orthopedic operations and the second, cholecystectomy. In the control groups, plasma lipids tended to decrease for the first 2 days after surgery and then returned to preoperative levels. After splenectomy, however, plasma cholesterol, low-density lipoprotein (LDL), and apolipoprotein B significantly increased, reaching maximum levels after 4 days. Plasma HDL as well as apolipoprotein A-I decreased 1 day after splenectomy, but then increased over and above their preoperative concentrations. These results suggest an important role for the spleen in cholesterol metabolism in these patients. The spleen appears to be an important site for LDL catabolism in these patients.