bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperinsulinemia is characterized by jointly disturbed plasma VLDL, LDL, and HDL levels. A population-based study.
Authors: Modan M , Halkin H , Lusky A , Segal P , Fuchs Z , Chetrit A
Published: June 2011

Plasma very low density lipoprotein (VLDL) cholesterol and triglyceride, low density lipoprotein (LDL) cholesterol and triglyceridea, high density lipoprotein (HDL) cholesterol, glucose and insulin response (sums of 1- and 2-hour postload oral glucose levels), body mass index (BMI), and blood pressure were determined in a representative sample (n = 542) of the adult Israeli Jewish population. Persons with diabetes or on antihypertensive medications were excluded. Total VLDL and LDL fractions were estimated from their cholesterol and triglyceride subfraction levels that were standardized relative to the mean of the reference group (participants free of glucose intolerance, obesity, and hypertension--the GOH conditions). Hyperinsulinemia and disturbed levels of VLDL and LDL were defined as levels equal to or greater than the 75th percentile and those of HDL, equal to or less than the 25th percentile of their respective reference group distributions. When VLDL was disturbed jointly with LDL and HDL, the mean insulin response adjusted for age, gender, glucose response, BMI, blood pressure, and smoking was high compared to the reference group (166.0 vs. 122.5, p less than 0.001). With isolated disturbed VLDL, or disturbed LDL and HDL but normal VLDL, the mean insulin response resembled the reference group. The adjusted risk ratio for this jointly disturbed lipoprotein profile among hyperinsulinemic individuals was 3.4 (95% confidence limits 2.6 to 4.4, p less than 0.001) with no further association with the GOH conditions. We conclude that hyperinsulinemia is characterized by an atherogenic lipoprotein profile.
Fibronectin stimulates macrophage uptake of low density lipoprotein-heparin-collagen complexes.
Authors: Falcone D J , Salisbury B G
Published: June 2011

In this study, we investigated whether fibronectin will enhance macrophage uptake of particulate complexes of low density lipoproteins (LDL), heparin, and fibrillar collagen and whether fibronectin's opsonic effect could be modulated by the heparin component in these model matrices. We isolated a heparin fraction (HepFn) based on its affinity to fibronectin. HepFn appeared more charged than unfractionated heparin, as evidenced by enhanced electrophoretic mobility and ability to effect a cathodic shift in the electrophoretic migration of fibronectin. HepFn lacked the smaller molecular weight species present in unfractionated heparin. Macrophage endocytosis of LDL-heparin-collagen complexes, as evidenced by the intracellular accumulation of LDL-derived cholesteryl esters and endogenously synthesized cholesteryl esters, was enhanced by fibronectin. When LDL matrix complexes were prepared with HepFn, fibronectin's opsonic properties were significantly enhanced. F(ab)2 fragments of anti-fibronectin, capable of inhibiting fibronectin's opsonization of gelatin-derivatized latex particles, inhibited the fibronectin-dependent stimulation of cholesteryl ester synthesis by macrophages exposed to LDL-HepFn-collagen complexes. Thus, fibronectin stimulates macrophage endocytosis of LDL matrix complexes. The affinity of the constituent glycosaminoglycan for fibronectin is important in the regulation of this phenomenon.
Decreased coronary vascular reserve in Watanabe heritable hyperlipidemic rabbits.
Authors: Clozel J P , Lengsfeld H , Kuhn H , Baumgartner H R
Published: June 2011

Watanabe heritable hyperlipidemic (WHHL) rabbits have severe hypercholesterolemia due to a genetic defect in their low density lipoprotein receptors. Therefore, they develop severe premature atherosclerosis of the large arteries including the coronary arteries. In the present study, we measured the coronary vascular reserve of these rabbits to evaluate the total cross-sectional coronary surface area. This method allowed us to quantify the functional consequences of the coronary atherosclerotic lesions. To evaluate coronary vascular reserve, we measured coronary blood flow with the radioactive microsphere technique before and after induction of maximal coronary vasodilation by an intravenous dose of 9 mg/kg of carbocromen. A group of pure-bred WHHL rabbits was compared to a group of normal Burgundy rabbits at ages of 100 and 300 days. At 100 days, there was no difference in coronary vascular reserve between the two groups. However, at 300 days, the coronary vascular reserve in WHHL rabbits was 48% smaller than in the normal Burgundy rabbits (p less than 0.001). In addition, by making corrosion casts and morphological studies, we were able to show that at 300 days nearly all the WHHL rabbits had severe coronary atherosclerotic lesions located mainly at the origin of the large coronary arteries. We conclude that WHHL rabbits at 300 days have a severe impairment of their coronary vascular reserve due to proximal atherosclerotic lesions in the coronary arteries.
Lipid composition of aorta of Watanabe heritable hyperlipemic and comparably hypercholesterolemic fat-fed rabbits. Plasma lipid composition determines aortic lipid composition of hypercholesterolemic rabbits.
Authors: Rosenfeld M E , Chait A , Bierman E L , King W , Goodwin P , Walden C E , Ross R
Published: June 2011

Aortic and plasma lipid compositions were compared during a 12-month period in Watanabe heritable hyperlipemic (WHHL), comparably hypercholesterolemic fat-fed, and age-matched control normolipidemic rabbits to determine whether exposure to equivalent degrees of endogenous or exogenous hypercholesterolemia led to differences in the composition and concentration of lipids deposited in the artery wall. Although there were marked differences in the distribution of cholesterol among the lipoproteins in the WHHL versus the fat-fed rabbits, the contents of both free and esterified cholesterol were elevated to an equivalent degree in the aorta and plasma. In contrast, the triglyceride content of both the plasma and aorta were elevated only in the WHHL rabbits. However, aortic total phospholipids were increased in both the WHHL and fat-fed animals as compared to control rabbits. In the control rabbits, there was an age-dependent enrichment in aortic relative to plasma cholesteryl-oleate consistent with low density lipoprotein (LDL) receptor-directed intracellular cholesteryl ester processing. In contrast, enrichment in cholesteryl-oleate in aortae relative to plasma was not detected in either WHHL or fat-fed groups, suggesting that the plasma cholesteryl ester composition was the primary determinant of the aortic cholesterol composition. Thus, during chronic hypercholesterolemia, deposition of lipids in the artery wall appears to be determined by plasma lipoprotein levels and composition if the LDL receptor is either absent on a genetic basis or suppressed due to a high-fat, high-cholesterol diet.
Blood rheology in healthy cigarette smokers. Results from the MONICA project, Augsburg.
Authors: Ernst E , Koenig W , Matrai A , Filipiak B , Stieber J
Published: June 2011

To investigate the relationship between cardiovascular risk factors and the fluidity of blood, a random sample of the population consisting of 4022 persons ages 25 to 64 years was investigated for plasma viscosity, hemoglobin, and total serum protein. A total of 567 healthy nonsmokers and 287 healthy smokers were identified and compared. Plasma viscosity was found to be elevated in male smokers; this was related to both the degree and the duration of cigarette abuse. Plasma viscosity proved to be age-dependent in smokers, but did not change with age in nonsmokers. Total serum protein decreased with age in nonsmokers, while it did not change in smokers. Hemoglobin increased only in female smokers. These findings suggest that blood fluidity is jeopardized in smokers. In men the hemorheological deficit is mostly due to a rise of plasma viscosity, which, in turn, may be caused by an elevation of plasma fibrinogen levels. In women it is predominantly due to an increase in hemoglobin. These alterations in hemorheological variables may be a marker for increased cardiovascular risk in smokers and could reduce blood flow and hinder microcirculatory function.
Individual variation in susceptibility to extracranial carotid atherosclerosis.
Authors: Rubens J , Espeland M A , Ryu J , Harpold G , McKinney W M , Kahl F R , Toole J F , Crouse J R
Published: June 2011

Risk factors for coronary disease were assessed and noninvasive methods were used to quantitate the extent of extracranial carotid atherosclerosis in 382 patients free of cerebrovascular symptoms. The ages of the participants ranged from 27 to 80 years. There were 183 men and 199 women, 30 black and 352 white persons. All patients had heart disease symptoms and were hospitalized for coronary angiography. Correlation of risk factors with extent of extracranial carotid atherosclerosis in this series of patients undergoing coronary angiography uncovered individual variability in relationships between risk factors and carotid atherosclerosis that depended on coronary status. Risk factors for carotid atherosclerosis in patients with and without coronary disease differed. Age and hypertension were independently related to carotid atherosclerosis in patients with, as well as those without, coronary disease. However, other risk factors were related to carotid atherosclerosis in only one group or the other. Risk factors correlated strongly with carotid atherosclerosis in patients with coronary disease (r2 = 0.41) but poorly in those with no coronary disease (r2 = 0.21). Certain risk factors (age, pack years of smoking, left ventricular hypertrophy) related differently to the extent of carotid atherosclerosis in patients with, than in those without, coronary disease. Clarification of the role of coronary status in the carotid atherosclerosis response to risk factors may partly explain the results of certain population-based studies that have related race, gender, and other risk factors to carotid atherosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Apolipoprotein B: the Ag(a1/d) immunogenetic polymorphism coincides with a T-to-C substitution at nucleotide 1981, creating an Alu I restriction site.
Authors: Wang X B , Schlapfer P , Ma Y H , Bütler R , Elovson J , Schumaker V N
Published: June 2011

Short cDNA fragments covering the entire coding region for apolipoprotein (apo) B have been cloned in the pING expression vector. A monoclonal antibody specific for the Ag(d) epitope on apo B has been used, together with the expressed apo B peptides, to locate this epitope to a stretch of 26 amino acids. Sequencing of this region from several genomic DNAs of known Ag(a1/d) genotype showed a single T-to-C substitution at nucleotide 1981, creating an Alu I restriction site and resulting in a val to ala residue change in the corresponding peptide (at position 591 in the mature protein). Southern blots, using the Alu I restriction endonuclease and a short probe for this region of the cDNA, showed perfect correspondence between the restriction fragment length polymorphism and the Ag(a1/d) immunochemical polymorphism in all 17 persons examined.
High density lipoprotein cholesterol and mortality. The Framingham Heart Study.
Authors: Wilson P W , Abbott R D , Castelli W P
Published: June 2011

In 12 years of follow-up for 2748 Framingham Heart Study participants ages 50 to 79, low levels of high density lipoprotein cholesterol (HDL-C) were associated with increased mortality. For men, the relative risk of death in the first HDL-C quintile (less than 35 mg/dl) as compared to the top quintile (greater than 54 mg/dl) was 1.9 for all causes, and 3.6 and 4.1 for death due to cardiovascular and coronary heart disease (CHD), respectively, after adjustment for standard cardiovascular risk factors. In women, corresponding relative risks, comparing the bottom HDL-C quintile (less than 45 mg/dl) to the top quintile (greater than 69 mg/dl), were 1.5, 1.6, and 3.1. With HDL-C considered as a continuous variable, and after adjustment for standard cardiovascular risk factors, highly significant associations were seen with HDL-C and CHD death in both men and women. In addition, a significant HDL-C effect on total mortality and death due to cardiovascular disease was seen in men. In none of the continuous variable analyses was HDL-C associated with cancer death. We conclude that HDL-C is a potent predictor of CHD death in both sexes and has less consistent associations with other types of death.
Cholesterol accumulation in aortic smooth muscle cells exposed to low density lipoproteins. Contribution of free cholesterol transfer.
Authors: Slotte J P , Chait A , Bierman E L
Published: June 2011

Incubation of cultured arterial smooth muscle cells with large concentrations of low density lipoproteins (LDL) resulted in a net increase in cell cholesterol and cholesteryl ester mass that was dependent on LDL concentration and time of incubation. Use of an inhibitor of acyl-CoA:cholesterol acyl-transferase (ACAT) reduced the accumulation of cholesteryl ester mass by 40% (range 25% to 50%), suggesting that a significant proportion of the cholesteryl ester mass that accumulated from LDL did so without being hydrolyzed and re-esterified. Quiescent arterial smooth muscle cells exposed for 48 hours to 0.5 mg/ml of 125I-LDL accumulated 115 nmol total sterol/mg cell protein. However, these cells took up and degraded only 21 micrograms of 125I-LDL protein, which contains 64 nmol total cholesterol. Hence, only about 60% of the increase in cell-associated cholesterol mass was accounted for by LDL particle uptake and degradation. Further, when cells were incubated with 3H cholesteryl linoleyl ether-labeled LDL, the net increase of total cell cholesterol was 81 nmol/mg cell protein. However, only 49 nmol of total cholesterol was taken up by LDL particle uptake, as calculated from the uptake of the 3H cholesteryl linoleyl ether tracer. It thus appears that about 40% of the accumulated cholesterol mass was derived independent of LDL particle uptake, suggesting the possibility of transfer of free cholesterol from the surface of LDL to the cell surface. The occurrence of cholesterol surface transfer was independently verified by the measurement of the uptake and cellular distribution of LDL-derived free 3H-cholesterol. A substantial fraction of the accumulated cell cholesterol mass (approximately 40%) was derived from surface transfer of LDL free cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)
Identification of macrophages in intimal thickening of rat carotid arteries by cytochemical localization of purine nucleoside phosphorylase.
Authors: Verheyen A K , Vlaminckx E M , Lauwers F M , Saint-Guillain M L , Borgers M J
Published: June 2011

Complete desquamation of the endothelium of the rat carotid artery by balloon catheter stripping resulted within 2 weeks in the formation of a large intimal thickening. After an enzyme cytochemical technique was applied to localize cytosolic purine nucleoside phosphorylase (PNP), light microscopical evaluation indicated that this intimal thickening in normocholesterolemic rats was composed of 5.8% to 11.8% (mean 8.8%) PNP-positive cells. At the electron microscopic level, all these PNP-positive cells were identified as macrophages by the absence of a basement membrane and plasmalemmal vesicles and by the occurrence of specific intracytoplasmic granules. The nearly nonreactive intimal cells were classified as modified smooth muscle cells. Additional evidence of the macrophage nature of the PNP-stained intimal cells was obtained by differential immunogold labeling of these cells with a monoclonal antibody against rat macrophages. Moreover, in hypercholesterolemic rats, only the cells stained for PNP transformed into foam cells (between 8.5% and 11.4% of all nucleated intimal cells; mean 9.6%). This study shows that PNP cytochemistry discriminates macrophages from modified smooth muscle cells in the rat carotid intimal thickening. It further suggests that the intimal thickening in normocholesterolemic rats originates not only from migration and proliferation of smooth muscle cells, but also from a considerable number of leukocyte-derived macrophages. Whether the latter cells are actively involved in the establishment of the intimal thickening as has been suggested in dietary hypercholesterolemia, remains to be verified.
Lactosaminated Fab fragments specific for low density lipoproteins/hepatocyte targeting and hypolipoproteinemic activity.
Authors: Bernini F , Via D P , Bocan T M , Gotto A M , Smith L C
Published: June 2011

We have previously reported that Fab fragments of IgGs modified by lactosamination (lac-Fab) can direct macromolecules, including low density lipoproteins (LDL), to the liver. In the present paper we demonstrate that lac-Fab that is specific for LDL is an effective and selective hypolipoprotein agent. A plasma pool of about 60 mg/dl of apoprotein B (apo B) was induced in rats by bolus injection of human LDL (hLDL), which increased the cholesterol value to about 150 mg/dl. Three hours after injection of the highest dose of lac-Fab, the total cholesterol decreased to 80 mg/dl, compared to 120 mg/dl in control animals. Studies conducted with 131I-tyramine-cellobiose-labeled LDL indicated that the liver was the only organ in which lac-Fab increased LDL uptake and degradation. The effect of lac-Fab was dose-dependent. With amounts of lac-Fab between 13 to 42 mg/kg body weight, the amount of hLDL cleared through the lac-Fab mechanism ranged from 30% to 70% of the initial pool. Analysis of the plasma lipoprotein subfractions revealed that high density lipoprotein levels were not affected. Histologic examination of liver sections after sequential injection of fluorescently labeled hLDL and lac-Fab indicated specific uptake in the hepatocytes when compared to control sections obtained from animals injected with Dil-LDL alone. The uptake of fluorescent LDL induced by lac-Fab was completely prevented by a co-injection of an excess of asialofetuin. We conclude that lac-Fab that is specific for LDL is a selective hypolipoproteinemic agent and a specific carrier to the hepatocytes.
Molecular modeling of protein-glycosaminoglycan interactions.
Authors: Cardin A D , Weintraub H J
Published: June 2011

Forty-nine regions in 21 proteins were identified as potential heparin-binding sites based on the sequence organizations of their basic and nonbasic residues. Twelve known heparin-binding sequences in vitronectin, apolipoproteins E and B-100, and platelet factor 4 were used to formulate two search strings for identifying potential heparin-binding regions in other proteins. Consensus sequences for glycosaminoglycan recognition were determined as [-X-B-B-X-B-X-] and [-X-B-B-B-X-X-B-X-] where B is the probability of a basic residue and X is a hydropathic residue. Predictions were then made as to the heparin-binding domains in endothelial cell growth factor, purpurin, and antithrombin-III. Many of the natural sequences conforming to these consensus motifs show prominent amphipathic periodicities having both alpha-helical and beta-strand conformations as determined by predictive algorithms and circular dichroism studies. The heparin-binding domain of vitronectin was modeled and formed a hydrophilic pocket that wrapped around and folded over a heparin octasaccharide, yielding a complementary structure. We suggest that these consensus sequence elements form potential nucleation sites for the recognition of polyanions in proteins and may provide a useful guide in identifying heparin-binding regions in other proteins. The possible relevance of protein-glycosaminoglycans interactions in atherosclerosis is discussed.
Dietary fish oil increases conversion of very low density lipoprotein apoprotein B to low density lipoprotein.
Authors: Huff M W , Telford D E
Published: June 2011

Dietary fish oils, which are rich in omega-3 fatty acids, are known to produce a marked lowering of very low density lipoprotein (VLDL) triglyceride concentrations, but they have a less marked effect on low density lipoprotein (LDL) cholesterol. Our previous apolipoprotein (apo) B kinetic studies in miniature pigs demonstrated that conversion of VLDL apo B to LDL apo B accounted for 15% to 20% of total VLDL apo B catabolism. In addition, 75% to 80% of LDL apo B was derived independent of plasma VLDL or intermediate density lipoprotein (IDL) apo B catabolism. The present studies were carried out to determine if fish-oil diets influenced: 1) the conversion of VLDL to LDL, and 2) the pathways of LDL apo B synthesis. Autologous 125I-VLDL and 131I-LDL were injected into four pigs after both a corn-oil (30 g/day for 18 days) and a Maxepa (30 g/day for 18 days) dietary period. Analysis of apo B specific activity curves demonstrated that fish oil reduced the VLDL pool size by 38% (p less than 0.05) due to an increase in fractional catabolic rate (0.83 +/- 0.13 vs. 0.48 +/- 0.03 hr-1), as the synthesis rate was unaffected. However, the proportion of VLDL apo B converted to LDL increased significantly (56 +/- 7% vs. 17 +/- 3%, p less than 0.01) whereas the proportion cleared directly decreased (46 +/- 5% vs. 83 +/- 3%, p less than 0.005). Fish oil reduced total LDL apo B synthesis (0.6 +/- 0.1 vs. 1.1 +/- 0.2 mg/hr/kg, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of porcine aortic smooth muscle cell conditioned medium on endothelial cell replication.
Authors: Hoover G A , McCormick S , Kalant N
Published: June 2011

Previous studies suggested that arterial smooth muscle cells (SMC) may be involved in regulating the growth of capillaries into atherosclerotic plaques. In the present study, we determined the effect of SMC products on porcine aortic endothelial cell (EC) replication in vitro. Quiescent or slowly growing EC in medium without endothelial cell growth factor (ECGF) were stimulated to proliferate in the presence of porcine aortic SMC conditioned medium, while the same conditioned medium inhibited the growth of rapidly dividing EC in high serum concentrations or with ECGF. The magnitude of both activities depended on SMC conditioned medium concentration. The dose-dependent increase in EC number stimulated by ECGF was completely inhibited by SMC conditioned medium. This effect was not due to a direct interaction of conditioned medium with ECGF because SMC conditioned medium inhibited the growth of EC that were rapidly proliferating in 10% serum without ECGF. The inhibitory activity was retained by an ultrafiltration membrane with an exclusion limit of 1000 daltons; the stimulatory activity was recovered in the ultrafiltrate and remained stable after boiling, treatment with acid or base and trypsin, and repeated freezing and thawing, but was removed by activated charcoal. The growth-promoting activity could not be accounted for by release of cell contents from lysed cells or of thymidine into the medium. Conditioned medium from SMC incubated in the presence of serum contained less EC growth-stimulatory activity but more growth-inhibitory activity than that from SMC in serum-free medium.
Relationship of sulfated glycosaminoglycans and cholesterol content in normal and arteriosclerotic human aorta.
Authors: Hollmann J , Schmidt A , von Bassewitz D B , Buddecke E
Published: June 2011

Sulfated glycosaminoglycans were extracted from arteriosclerotic and adjacent nonarteriosclerotic areas of human aortas from persons ages 28 to 83 years; the glycosaminoglycans were compared with the cholesterol and triglyceride content of the tissues. Sulfated glycosaminoglycans were isolated after proteolytic digestion of defatted arterial tissue and were quantified after reductive labeling with NaB3H4. The amount of glycosaminoglycans in the aorta increased with the age of the person and the cholesterol content (degree of arteriosclerosis) of the aorta. The proportion of chondroitin sulfate/dermatan sulfate increased significantly with age and cholesterol content, whereas the corresponding amounts of heparan sulfate decreased.
Profiles of velocity in coronary arteries of dogs indicate lower shear rate along inner arterial curvature.
Authors: Bell D R , Sabbah H N , Stein P D
Published: June 2011

Multiple-range, gate-pulsed Doppler velocimetry was used to examine the velocity profile within the lumen of the left circumflex and left anterior descending coronary arteries of 10 anesthetized, open-chest dogs at rest and after administration of propranolol and intracoronary adenosine. The peak diastolic and mean profiles of velocity were skewed away from the inner walls of the vessels (p less than 0.01). The extent of skewness was not affected by propranolol or adenosine. The shear rates were significantly lower along the inner wall in comparison to the outer wall under all conditions in both the left circumflex and the left anterior descending coronary arteries (p less than 0.017). Irrespective of the levels of flow, therefore, the velocity profiles were skewed away from the inner wall of the coronary arteries. Consequently, the shear rates were lower along the inner walls of the coronary arteries.
Augmented vasoconstrictor responses to serotonin precede development of atherosclerosis in aorta of WHHL rabbit.
Authors: Wines P A , Schmitz J M , Pfister S L , Clubb F J , Buja L M , Willerson J T , Campbell W B
Published: June 2011

Watanabe heritable hyperlipidemic (WHHL) rabbits have elevated concentrations of plasma cholesterol and develop progressive atherosclerosis. The present investigation was undertaken to evaluate the vascular responses to vasoactive compounds of aorta from WHHL rabbits and normal New Zealand White (NZW) rabbits at 1 and 6 months of age. Rings of distal thoracic aorta were suspended under isometric tension in oxygenated Krebs buffer. Developed tension was measured in response to graded concentrations of agonists. Maximal responses to KCl (40 mM) were the same in aortas from the 1-month-old and 6-month-old WHHL and NZW rabbits. Aortas from 1-month-old animals were more sensitive to serotonin than aortas from 6-month-old animals. Aortas from WHHL rabbits exhibited an increased maximal response to serotonin when compared with NZW controls. In contrast, the constrictor responses to norepinephrine were reduced in WHHL rabbits compared with NZW rabbits at both age groups. Methacholine decreased tension development in serotonin-contracted vessels. This relaxation was greatest in aortas from NZW rabbits. In 1-month-old NZW rabbits fed a high cholesterol diet, the constrictor responses to serotonin and the relaxation responses to methacholine did not differ from NZW rabbits ingesting a normal diet. However, the responses to norepinephrine were markedly attenuated in the hypercholesterolemic NZW rabbits. Microscopic evaluation of the aortas revealed occasional adherent leukocytes and irregularities in the vascular endothelium in 1-month-old WHHL animals. These changes were greater in aortas from 6-month-old WHHL animals, with more adherent leukocytes, adherent platelets, and severe irregularities in the endothelial surface.(ABSTRACT TRUNCATED AT 250 WORDS)
Homozygous familial hypercholesterolemia among French Canadians in Québec Province.
Authors: Moorjani S , Roy M , Gagné C , Davignon J , Brun D , Toussaint M , Lambert M , Campeau L , Blaichman S , Lupien P
Published: June 2011

Nineteen patients with homozygous familial hypercholesterolemia (FH) living at the time of the 1981 Canada census are the subject of this report. Their mean age at that time was 15, with a range of 1 to 26 years. All patients had extensive xanthomatosis but showed variable clinical manifestations of coronary heart disease (CHD); five (mean age, 21; range, 11 to 27 years) died from sudden death due to CHD. Plasma cholesterol levels varied more than twofold (557 to 1532 mg/dl). Variation in the concentrations of both plasma and low density lipoprotein cholesterol, as well as apolipoprotein B, were related neither to age at death from CHD nor to the clinical course of CHD. The mean high density lipoprotein cholesterol concentration (37 mg/dl) was lower than the mean value (49 mg/dl) in the control population (p less than 0.001). Both the clinical and biochemical features of this cohort are typical of homozygous FH. The prevalence of homozygotes among French Canadians in Québec was approximately 1:275,000, and the minimum estimated frequency of heterozygotes was 1:270. In northeastern Québec, the frequency of homozygotes was approximately 1:100,000, and the minimum estimated frequency of heterozygotes was 1:154. Only Afrikaaners in South Africa have correspondingly higher frequencies.
Hyperlipemic response of young trained and untrained men after a high fat meal.
Authors: Merrill J R , Holly R G , Anderson R L , Rifai N , King M E , DeMeersman R
Published: June 2011

To test the hypothesis that endurance training is associated with a decreased lipemia after a high fat meal, 16 young men [22 to 34 years old, nine of whom were trained (T) and seven of whom were untrained (UT)] were recruited. T ran greater than 30 or biked greater than 100 miles a week, while UT had been sedentary for at least the preceding 3 months. Daily caloric intake and daily caloric expenditure during exercise were 35% and 704% greater, respectively, in T than in UT. VO2max was 31% greater, while percent body fat was 36% lower in T than in UT. Dietary composition and body height and weight were similar. After a fasting blood sample was taken, the men ate a high fat meal (approximately 56% of total calories as fat in 1100 kcal adjusted to body weight), and additional blood samples were taken hourly for 8 hours. Fasting lipids were similar. Postprandial peak triglyceride (TGmax), percent TG increase (%TGI), and total lipemic response (TLR, the area under the lipemia curve in excess of fasting TG) were 42%, 54%, and 75% greater, respectively, in UT vs. T. Stepwise regression analysis showed that the same three-variable model (training status, fasting TG, and VO2max) described the variation in TGmax (R2 = 0.97), %TGI (R2 = 0.75), and TLR (R2 = 0.92). Furthermore, this same analysis showed that after adjustment for fasting TG and VO2max, the UT group had a significantly greater postprandial lipemia whether expressed as TGmax (p less than 0.0001), %TGI (p = 0.0002), or TLR (p = 0.0002).(ABSTRACT TRUNCATED AT 250 WORDS)
Apoprotein E polymorphism and coronary artery disease. Increased prevalence of apolipoprotein E-4 in angiographically verified coronary patients.
Authors: Kuusi T , Nieminen M S , Ehnholm C , Yki-Järvinen H , Valle M , Nikkilä E A , Taskinen M R
Published: June 2011

Several studies have indicated that genetic polymorphism of apolipoprotein (apo) E is related to coronary artery disease (CAD). We therefore determined the apo E phenotype in 91 consecutive Finnish men with angiographically confirmed CAD. The apo E phenotype distribution differed significantly from that observed in the Finnish population (p less than 0.05). In the patient group, the frequency of the epsilon 4 allele was 0.324, which is 1.4-fold higher than in the normal Finnish population and twice as high as in other Caucasian populations. Serum lipoproteins and postheparin plasma lipase activities did not display any significant variation according to apo E phenotype. These studies confirm and extend, in a population with high epsilon 4 allele frequency, the previous data on the impact of the epsilon 4 allele on the risk of CAD and suggest that the high epsilon 4 allele frequency in the Finnish population may be one factor contributing to Finns' increased susceptibility to CAD.
Regional variability of prostacyclin biosynthesis.
Authors: Fann J I , Cahill P D , Mitchell R S , Miller D C
Published: June 2011

To investigate the regional variability in arterial and venous endothelial prostacyclin (PGI2) biosynthesis, we obtained 1-cm segments of carotid arteries, external jugular veins, femoral arteries and veins, iliac arteries and veins, inferior venae cavae (IVC), and aortas from 17 dogs. Vessel luminal PGI2 production was measured in the basal state by radioimmunoassay of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). A total of 90 arterial specimens (57, 19, and 14 segments, respectively, of femoral/carotid arteries, iliac arteries, and aorta) and 41 venous specimens (15, 10, and 16 segments, respectively, of femoral/jugular veins, iliac veins, and IVC) were analyzed. Overall, arterial endothelial 6-keto-PGF1 alpha was higher than venous (8.1 +/- 0.5 ng/ml vs. 4.9 +/- 0.7 ng/ml, p less than 0.0004); 6-keto-PGF1 alpha levels were greater in the arteries than in their corresponding veins [femoral/carotid arteries (6.3 +/- 0.4 ng/ml) vs. femoral/jugular vein (2.1 +/- 0.4 ng/ml), p less than 0.0002; iliac arteries (9.3 +/- 1.0 ng/ml) vs. iliac veins (4.8 +/- 0.9 ng/ml), p less than 0.005; aorta (14.0 +/- 1.6 ng/ml) vs. IVC (7.5 +/- 1.4 ng/ml), p less than 0.006].(ABSTRACT TRUNCATED AT 250 WORDS)
Probucol does not affect lipoprotein metabolism in macrophages of Watanabe heritable hyperlipidemic rabbits.
Authors: Nagano Y , Kita T , Yokode M , Ishii K , Kume N , Otani H , Arai H , Kawai C
Published: June 2011

We recently reported that the antioxidant action of probucol inhibited the progression of atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. In this study, we investigated another possible action of probucol: its action as an antiatherogenic agent on macrophages. When WHHL rabbit peritoneal macrophages were pre-incubated in vitro with probucol and then incubated with several atherogenic lipoproteins, the incorporation of the lipoproteins was not significantly prevented. In the case of mouse peritoneal macrophages, pre-incubation with probucol showed slight, although not statistically significant, changes in the amount of lipoprotein incorporations. We also used macrophages obtained from mice and WHHL rabbits fed with probucol, but the amount of uptake of lipoproteins by these cells was not less than that by control macrophages. Furthermore, to investigate the incorporation of atherogenic lipoproteins into these cells, we prepared probucol-containing macrophages; however, probucol in macrophages failed to prevent the uptake of such lipoproteins. In conclusion, probucol did not prevent foam cell transformation of macrophages of WHHL rabbit or mice directly, and the effect of probucol against atherogenesis in WHHL rabbits was due mainly to its inhibitory effect on the oxidative modification of low density lipoprotein, as previously reported.
Mechanisms of HDL reduction after probucol. Changes in HDL subfractions and increased reverse cholesteryl ester transfer.
Authors: Franceschini G , Sirtori M , Vaccarino V , Gianfranceschi G , Rezzonico L , Chiesa G , Sirtori C R
Published: June 2011

Treatment with probucol, a widely used lipid-lowering agent, is associated with a significant reduction of high density lipoprotein (HDL) cholesterol levels, but with an apparently improved removal of cholesteryl esters from tissues (e.g., from tendon xanthomas). The effects of probucol (500 mg twice daily) on HDL subfraction distribution and cholesteryl ester transfer activity were tested in 12 patients with stable type II hyperlipidemia [low density lipoprotein (LDL) cholesterol greater than 180 mg/dl] after a placebo-controlled cross-over trial. Probucol significantly lowered total cholesterol (-13.8%), LDL cholesterol (-9.1%), and HDL cholesterol (-30%). By rate zonal ultracentrifugation, a marked reduction of HDL2 cholesterol (-68%) was shown, whereas changes in HDL3 were less significant (-21%). These findings were confirmed by polyacrylamide gradient gel electrophoresis, typically showing a reduction or disappearance of HDL2b particles and the prevalence of particles in the HDL3a range. Cholesteryl ester transfer from HDL to lower density lipoproteins was significantly increased (30%) in all patients. These findings suggest that, in addition to the well-documented in vitro changes (prevention of LDL peroxidation and macrophage uptake), probucol characteristically modifies HDL particle distribution in vivo, and is associated with a significant increase of cholesteryl ester transfer activity.
Role of hepatic-triglyceride lipase activity in the association between intra-abdominal fat and plasma HDL cholesterol in obese women.
Authors: Després J P , Ferland M , Moorjani S , Nadeau A , Tremblay A , Lupien P J , Thériault G , Bouchard C
Published: June 2011

Intra-abdominal fat content is an important variable in the association between regional body fat distribution and plasma high density lipoprotein (HDL) cholesterol levels. In the present study, we report on the role of plasma postheparin lipases as well as abdominal and femoral adipose tissue lipoprotein lipase activities in the association between body fat distribution and plasma lipoprotein levels. Postheparin plasma lipoprotein lipase (LPL), hepatic-triglyceride lipase (H-TGL), abdominal and femoral adipose tissue (AT)-LPL activities and plasma lipoprotein levels were measured after an overnight fast in a sample of 16 obese women (ages 36.0 +/- 6.1 years [mean +/- SD], percent body fat 46% +/- 6%). Computed axial tomography was used to assess body fat distribution. Plasma postheparin LPL activity was neither correlated with total adiposity nor with the level of intra-abdominal fat. Intra-abdominal fat deposition was, however, positively correlated with H-TGL activity (r = 0.66, p less than 0.005). Furthermore, covariance analysis showed that the association between intra-abdominal fat and H-TGL was independent from total adiposity. Plasma postheparin LPL and abdominal AT-LPL activities showed no significant correlation with plasma lipoprotein levels, whereas femoral AT-LPL activity was positively correlated with the HDL2 cholesterol/HDL3 cholesterol ratio (r = 0.51, p less than 0.05). H-TGL activity was, however, negatively correlated with HDL2 cholesterol (r = -0.60, p less than 0.05), but not with HDL3 cholesterol (r = -0.28, NS). These results suggest that the high H-TGL activity in obese women with excess deep abdominal fat could be responsible for the reduction in plasma HDL2 cholesterol levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Beta-very low density lipoprotein uptake in cultured fibroblasts and smooth muscle cells from Watanabe heritable hyperlipidemic rabbits.
Authors: Wernette-Hammond M E , Garcia Z , Arnold K S , Innerarity T L
Published: June 2011

Watanabe Heritable Hyperlipidemic (WHHL) rabbits are an important animal model used to study the effects of defective low density lipoprotein (LDL) receptors on lipoprotein metabolism. In the present study, the receptor-mediated catabolism of apolipoprotein (apo) E-containing lipoproteins was investigated in fibroblasts and smooth muscle cells cultured from WHHL rabbits. Fibroblasts from WHHL rabbits bound little, if any, human LDL, an apo B-containing lipoprotein, in 4 degrees C equilibrium binding experiments. In contrast, canine beta-very low density lipoproteins (beta-VLDL), which contain apo E, bound to these cells with an affinity similar to that for fibroblasts of normal New Zealand White rabbits (Kd approximately 0.6 micrograms/ml), although the maximal binding was only approximately 9% of that of New Zealand White cells. At 37 degrees C, beta-VLDL were degraded efficiently by WHHL fibroblasts, that is, at rates approximately half of that for New Zealand White fibroblasts. The degradation of beta-VLDL by WHHL fibroblasts was blocked by reductive methylation of the lipoproteins and was inhibited by the anti-apo E monoclonal antibody, 1D7. Unlike human LDL, canine beta-VLDL induced 14C-oleate incorporation into cholesteryl esters in WHHL fibroblasts and smooth muscle cells. The uptake of beta-VLDL by WHHL cells was mediated by the LDL receptor, since preincubation of the fibroblasts with cholesterol plus 25-hydroxycholesterol inhibited beta-VLDL degradation, and specific antibodies to rabbit LDL receptors abolished the degradation of beta-VLDL in WHHL fibroblasts. These results indicate that the altered LDL receptors expressed on cultured WHHL rabbit cells are sufficient for apo E-dependent, receptor-mediated uptake of lipoproteins. Thus, the altered LDL receptors could contribute to in vivo metabolism of apo E-containing lipoproteins despite their lack of LDL binding activity.
A role for intracellular histamine in ultrastructural changes induced in platelets by phorbol esters.
Authors: McNicol A , Saxena S P , Brandes L J , Gerrard J M
Published: June 2011

In human platelets, phorbol esters, such as phorbol-12-myristate-13-acetate (PMA), induce morphological changes, including pseudopod formation and the swelling and fusion of intracellular granule membranes with those of the surface-connected canalicular system, effects which have been attributed to activation of protein kinase C. However, a novel intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethanamine. HCl (DPPE), previously has been shown to block PMA-induced aggregation independently of protein kinase C interaction, an effect reversible in permeabilized platelets by the addition of histamine. We now demonstrate that DPPE inhibits, in a concentration-dependent manner, the effects of PMA on human platelet ultrastructure. In permeabilized platelets, histamine reverses this inhibition, although it alone induces minimal effects on morphology. The results support a role for this amine to promote the labilization of platelet granules and pseudopod formation induced by PMA, presumably by acting in concert with additional PMA-activated pathways.
Identification of LDL receptor gene marker associated with altered levels of LDL cholesterol and apolipoprotein B in baboons.
Authors: Hixson J E , Kammerer C M , Cox L A , Mott G E
Published: June 2011

We are studying the genetic factors underlying the common forms of heart disease by identifying genes that affect normal variations in plasma lipid, lipoprotein, and apolipoprotein concentrations in baboons. For these studies we are using cloned human gene probes to identify restriction fragment length polymorphisms (RFLPs) at loci encoding the proteins of cholesterol metabolism. In this report we present the identification and mapping of a polymorphic Ava II cleavage site in intron 17 of the baboon low density lipoprotein (LDL) receptor gene. We determined genotypes for this RFLP on a population of 253 pedigreed baboons and assessed the effect of LDL receptor RFLP genotypes on serum concentrations of LDL cholesterol (LDL-C) and apolipoprotein B (apo B). These measures were obtained for each baboon on each of two diets: a low cholesterol, low fat (basal) diet and a high cholesterol, high saturated fat (atherogenic) diet. Statistical analysis detected a significant association between LDL receptor genotype and serum LDL-C and apo B concentrations on both diets. Homozygotes for the rarer allele had lower serum concentrations of LDL-C and apo B than did homozygotes for the common allele, and with the exception of apo B levels on the basal diet, intermediate levels were observed in heterozygotes. The LDL receptor RFLP accounted for approximately 3% to 7% of the variation in serum LDL-C and apo B concentrations on both diets.
Initiation of atherosclerotic lesions in cholesterol-fed rabbits. II. Selective retention of LDL vs. selective increases in LDL permeability in susceptible sites of arteries.
Authors: Schwenke D C , Carew T E
Published: June 2011

We asked if the arterial sites most prone to early lesions in cholesterol-fed rabbits have higher permeabilities to low density lipoprotein (LDL) in normolipidemic rabbits or if these sites become more permeable shortly after the onset of cholesterol feeding. We also considered whether the focal increases in the concentration of LDL within the arterial wall in lesion-susceptible sites before fatty streak formation can be explained by increased arterial permeability to LDL or by other mechanisms such as decreased rates of LDL efflux or degradation. 125I-tyramine cellobiose-labeled LDL was injected 1 hour before death to determine the initial rate of LDL entry into lesion-prone and lesion-resistant sites of aorta as a measure of permeability. This was studied in normal rabbits and in rabbits fed cholesterol for 4, 8, or 16 days. Combining this permeability data with the tracer data described in the accompanying article, we fit a kinetic model to calculate the mass and mean residence time of intact LDL within the artery and the fractional rates of LDL degradation and efflux from the artery. In normal rabbits, the permeability of lesion-susceptible branch sites of the abdominal aorta was about four times that of the lesion-resistant, nonbranched areas. However, the permeability of the aortic arch, a susceptible site, was similar to that of the lesion-resistant descending thoracic aorta. Permeability to LDL did not increase in any aortic site during the 16 days of cholesterol feeding, even in sites with the largest increases in arterial LDL concentrations. Plasma LDL cholesterol concentration increased substantially and total LDL cholesterol delivery into the artery increased many fold. Since there was no differential change in permeability between susceptible and resistant sites, the increased entry of LDL did not explain the selective increases in arterial LDL concentration in susceptible sites. Kinetic analysis indicated that the fractional rate of degradation of the arterial LDL pool was lower in lesion-prone sites than in lesion-resistant sites in all animals. Fractional rates of efflux of arterial LDL decreased in lesion-susceptible branch sites of the abdominal aorta and were low in the lesion-susceptible aortic arch. These results suggest that the focal increases in LDL concentration observed in all lesion-susceptible sites of cholesterol-fed rabbits before fatty streak formation are due to localized differences in LDL retention and diminished fractional rates of LDL degradation, not to selectively increased permeability.(ABSTRACT TRUNCATED AT 400 WORDS)
Effects of atropine on diastolic time.
Authors: Conrad K A
Published: June 2011

Atropine was given intravenously to 10 normal volunteers in increments of 0.01 mg/kg to a total dose of 0.04 mg/kg. This produced an increase in heart rate from 65 +/- 11 to 112 +/- 14 beats/min, a decrease in diastolic time from 534 +/- 131 to 180 +/- 65 msec, and a decrease in percent diastole from 55.6 +/- 5.3% to 32.4 +/- 7.2% (p < 0.001). Administration of isoproterenol in doses that increased heart rate from 69 +/- 9 to 99 +/- 12 beats/min produced a decrease in diastolic time from 485 +/- 98 to 312 +/- 47 msec and only a slight decrease in percent diastole, from 54.2 +/- 4.3% to 50.6 +/- 3.9%. Atropine, in doses commonly used clinically, may significantly reduce diastolic time and the percent diastole. Because diastolic time is an important determinant of coronary perfusion, administration of atropine to patients with coronary artery disease may increase myocardial ischemia.