bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency.
Authors: Schaefer E J
Published: June 2011

This review assesses current knowledge of the clinical, genetic, and biochemical features of familial high density lipoprotein (HDL) deficiency syndromes. The focus is on HDL deficiency states occurring in the absence of severe hypertriglyceridemia or lecithin/cholesterol acyltransferase deficiency. Specific entities falling within this category include Tangier disease, familial HDL deficiency with planar xanthomas, familial apolipoprotein A-I and C-III deficiency (formerly known as apolipoprotein A-I absence), familial deficiency of apolipoprotein A-I and C-III, fish-eye disease, familial hypoalphalipoproteinemia, and apolipoprotein A-I variants (apo A-I Milano, apo A-I Marburg, apo A-I Giessen, and apo A-I Munster 1-3). Diffuse corneal opacification and premature coronary artery disease are common features in many of these kindreds. No striking clinical abnormalities have been noted in patients with currently known apolipoprotein A-I variants, possibly because these subjects are heterozygotes for their respective defects. The HDL deficiency in many of these disorders has been associated with abnormalities or deficiencies of apolipoprotein A-I. Further research will undoubtedly define the defects in all the disorders that have been described, uncover new mutations, as well as provide additional insights into the precise relationship between HDL deficiency and atherosclerosis.
Endothelial and smooth muscle cells alter low density lipoprotein in vitro by free radical oxidation.
Authors: Morel D W , DiCorleto P E , Chisolm G M
Published: June 2011

Our purpose was to determine whether the action of oxidative free radicals released by endothelial cells and vascular smooth muscle cells grown in culture could be responsible for certain modifications to low density lipoprotein (LDL). In these experiments we showed that after a 48-hour incubation with human umbilical vein endothelial cells or bovine aortic smooth muscle cells, human LDL: 1) became oxidized, as evidenced by reactivity to thiobarbituric acid; 2) lost variable amounts of sterol relative to protein (up to 20%); 3) had an increased relative electrophoretic mobility (by 30% to 70%); and 4) became toxic to proliferating fibroblasts. None of these changes occurred after a 48-hour incubation with confluent fibroblasts or bovine aortic endothelial cells, and all could be virtually prevented by the presence of butylated hydroxytoluene or other free radical scavengers. The results suggest that cells modifying LDL do so in part by an oxidation of LDL subsequent to cellular generation of free radicals.
George Lyman Duff memorial lecture. Persistent problems in the pathogenesis of atherosclerosis.
Authors: McGill H C
Published: June 2011

In concluding this eclectic review, I believe that we can say with certainty that coronary atherosclerosis has its origins in childhood, at least by age 10 and possibly earlier. Endothelial changes follow lipid accumulation, but, with present methods, there is no evidence that endothelial injury precedes lipid accumulation. Proliferation is a prominent feature of accelerated experimental atherosclerosis, but we do not see evidence that proliferation is a major feature of early naturally occurring human atherosclerosis. The prominence of the monocyte-macrophage in the earliest detectable lesions of atherosclerosis in childhood justifies the current interest in monocyte biology. Hyperlipidemia, in the sense of the average high levels common in our population, seems almost certain to contribute to accelerated atherogenesis in children, but conclusive proof is still lacking. Mild hypertension in children, or even the high range of normal blood pressure, may accelerate the transition of innocuous childhood fatty streaks to more ominous fibrous plaques. The putative relationship of adult coronary heart disease risk factors to the childhood lesions of atherosclerosis is largely based on extrapolation from adult data. Direct evidence bearing on these relationships, however difficult to obtain, would be helpful in designing and promoting effective preventive regimens for children.
Plasma and lipoprotein cholesterol and triglyceride in the Pima Indian population. Comparison of diabetics and nondiabetics.
Authors: Howard B V , Knowler W C , Vasquez B , Kennedy A L , Pettitt D J , Bennett P H
Published: June 2011

Lipoprotein cholesterol and triglyceride concentrations were compared in diabetic and nondiabetic Pima Indians, a homogeneous population with a high occurrence of noninsulin-dependent diabetes mellitus. Data were available on 690 subjects with diabetes or impaired glucose tolerance. Total and very low density lipoprotein (VLDL) triglycerides were approximately 150% of the nondiabetic values, but very few diabetics had pronounced hypertriglyceridemia. Significant elevations in low density lipoprotein (LDL) triglyceride were also observed in diabetic men and women of all ages. Decreases in high density lipoprotein (HDL) cholesterol were similar in diabetic men and women, and the differences in HDL cholesterol were much greater in less obese individuals. Changes in HDL in the diabetics were reflected in all three subfractions, HDL2b, HDL2a, and HDL3. Both total and LDL cholesterol were elevated in diabetic women, but not in diabetic men. Thus, there were greater changes in lipoprotein distribution in diabetic women. When multiple regression analysis was performed to examine the relationships in diabetics between lipoproteins and other variables, plasma glucose appeared to be the variable most closely associated with plasma lipoproteins in diabetics (positive with VLDL and LDL, negative with HDL). In diabetics, obesity was correlated with HDL but not VLDL, whereas alcohol consumption appeared to be associated with VLDL but not HDL.
Exposure to free fatty acid increases the transfer of albumin across cultured endothelial monolayers.
Authors: Hennig B , Shasby D M , Fulton A B , Spector A A
Published: June 2011

An initial exposure to high concentrations of free fatty acid increased the transfer of albumin across cultured endothelial monolayers. The rate and amount of albumin transfer was dependent on the oleic acid concentration to which the cultures were initially exposed, with 300 microM producing the maximum transfer. The albumin transfer also increased with the increasing time of exposure to oleic acid, the maximum effect occurring during the first 24 hours. An exposure to 300 microM linoleic acid produced an even greater increase in albumin transfer than did 300 microM oleic acid. The increased albumin transfer observed when cells were exposed to high concentrations of free fatty acid was largely reversible after reincubation of the cell monolayers in free fatty acid-poor media. In parallel experiments, radioactive oleic acid incorporation into cell triglycerides increased linearly as the fatty acid concentration was raised, with cell triglyceride content increasing up to sevenfold after incubation in a medium containing 300 microM oleic acid. A significant amount of oleic acid was incorporated into phospholipids, and the fatty acid composition of the endothelial triglycerides and phospholipids was modified. All these effects of oleic occurred without altering the incorporation of leucine into the cell protein. These results indicate that exposure to high concentrations of free fatty acid can alter endothelial cell lipid composition, and that this increases the albumin transfer across endothelium. This process might permit more macromolecules to enter the arterial wall.
Atherosclerosis and myocardial ischemic lesions in alloxan-diabetic rabbits fed a low cholesterol diet.
Authors: Miller R A , Wilson R B
Published: June 2011

To reinvestigate the relationship between diabetes and atherosclerosis in rabbits, we fed alloxan-diabetic, alloxan-nondiabetic, and control rabbits a low cholesterol atherogenic diet for up to 40 weeks. Concentrations of plasma total cholesterol, phospholipids, and triglycerides were higher, the percentage of very low density lipoproteins was higher, and the percentage of high density lipoproteins was lower in diabetic than in nondiabetic rabbits. Smooth muscle cell proliferation was prominent, atherosclerosis was more extensive, and a high incidence (29%) of large, sharply demarcated, ischemic myocardial lesions occurred in the diabetic rabbits. These results are in contrast to those of earlier studies where the diabetic state resulted in a partial protection against atherogenesis in alloxan-diabetic rabbits fed larger amounts of cholesterol.
Contribution of the receptor pathway to low density lipoprotein catabolism in humans. New methods for quantitation.
Authors: Slater H R , McKinney L , Packard C J , Shepherd J
Published: June 2011

Receptor-mediated catabolism of low density lipoprotein (LDL) by cultured cells depends on the presence of functionally significant arginine and lysine residues on the lipoprotein apoprotein. When these are blocked, the recognition process is abolished, and catabolism of the modified lipoprotein is restricted to other mechanisms. Accurate discrimination between the activities of the receptor and nonreceptor pathways in vivo depends critically on the metabolic properties of this chemically modified lipoprotein. Here we report our experiences with two lysine-modified LDL tracers, glucosylated LDL (GLC-LDL) and 2-hydroxyacetaldehyde-treated LDL (HOET-LDL). The fractional clearance rate of GLC-LDL (0.25 +/- 0.05 pools/day, n = 5) was 50% of that of control material (0.51 +/- 0.09 pools/day) injected simultaneously into normal subjects. The HOET-LDL was also retarded in its clearance. Here, however, the fractional clearances of the control (0.37 +/- 0.06 pools/day, n = 6) and modified lipoprotein (0.19 +/- 0.03 pools/day) were lower than those obtained by the glucosylation procedure. We suspect that the prolonged incubation required for glucosylation of LDL artifactually accelerated its catabolism. The HOET-LDL does not suffer from this defect and seems to be a better tracer of the receptor-independent pathway. In a group of 10 subjects, HOET-LDL was metabolically indistinguishable from 1,2 cyclohexanedione-treated, arginine-modified LDL.
Control of monocyte recruitment by chemotactic factor(s) in lesion-prone areas of swine aorta.
Authors: Gerrity R G , Goss J A , Soby L
Published: June 2011

Aortic areas predisposed to early atherosclerosis in swine demarcated by Evans blue uptake (blue areas) show preferential intimal penetration by blood monocytes before and during lesion formation. These cells are thought to be the major source of foam cells in these early lesions. To examine mechanisms controlling monocyte migration into these areas, extracts of aortic tissue from both blue and white areas of hypercholesterolemic (H) and normal (N) swine were tested for chemotactic activity against monocytes from N and H swine and neutrophils from H swine. The data indicate that extracts of blue areas from H swine contained at least one, and possibly two, factors chemotactic only for monocytes from H swine, but not N swine. These factors were not present in similar extracts from white areas of H swine, or either blue or white area extracts from N swine. Gel filtration chromatography of crude blue area extracts separated two chemotactically active fractions of molecular weights 68,000 and 5000 that were not present in white area extracts and that elicited a positive chemotactic effect only for H swine monocytes. These findings provide a mechanism explaining our previous findings of preferential monocyte adhesion and intimal penetration in lesion-prone areas, and indicate that control of monocyte recruitment into the artery involves not only alteration of the arterial wall, but also functional changes in the circulating monocyte.
Reversible high affinity uptake of apo E-free high density lipoproteins in cultured pig hepatocytes.
Authors: Bachorik P S , Franklin F A , Virgil D G , Kwiterovich P O
Published: June 2011

We examined the high affinity binding, uptake, and degradation of apo E-free 125I-high density lipoprotein (HDL) in cultured pig hepatocytes. At steady state, the cells degraded 9.4% of cell-associated 125I-HDL/hour, compared with 41.7%/hour for 125I-LDL. Pulse-chase experiments at 4 degrees C revealed that high affinity 125I-HDL binding was reversible. Similar experiments at 37 degrees C revealed that about 70% of the cell-associated 125I-HDL was released as a macromolecule; the remainder was degraded to acid-soluble products. In contrast, over 75% of the 125I-LDL that was released had been degraded to acid soluble products. The amount of macromolecular 125I-HDL released at 37 degrees C was similar to the amount that was bound to the cell surface, as estimated from measurements of trypsin-releasable radioactivity. Density gradient ultracentrifugation and SDS-polyacrylamide gel electrophoretic analysis of macromolecular 125I-HDL released to the medium revealed an increase in density, and the apparent partial proteolysis of apo A-I (Mr 25,000) to products of apparent Mr 12,000-14,000. The findings suggest that high affinity 125I-HDL uptake had a reversible component in which HDL was concentrated temporarily at the cell surface, modified, and then released as a somewhat denser lipoprotein particle. Measurement of 125I-HDL and 125I-LDL degradation in cell homogenates revealed no difference in the inherent susceptibility of the two lipoproteins to proteolysis by lysosomal enzymes. The overall slower rate of degradation of 125I-HDL compared to 125I-LDL was therefore due in part to the smaller fraction of HDL that was committed to irreversible catabolism. The rate of catabolism of this fraction, however, was considerable. Cells pulsed at 4 degrees C and subsequently warmed to 37 degrees C released one-half the acid-soluble products from 125I-HDL within about 4 hours, compared with 2 hours for cells pulsed with 125I-LDL. These findings indicate that HDL was internalized, transported to lysosomes, and degraded at about one-half the rate of LDL.
Comparison of clofibrate and caloric restriction on kinetics of very low density lipoprotein triglycerides.
Authors: Kesaniemi Y A , Beltz W F , Grundy S M
Published: June 2011

This study of 12 patients with mild-to-moderate hypertriglyceridemia compares the mechanisms of triglyceride (TG) lowering by caloric restriction and by clofibrate. Turnover rates of very low density lipoprotein triglycerides (VLDL-TG) were determined by using 3H-glycerol as a precursor. Radioactivity-time curves of VLDL-TG were analyzed with a multicompartmental model. Hypertriglyceridemia in these patients was due mainly to overproduction of VLDL-TG. Clofibrate therapy for 1 month had a variable effect on VLDL-TG levels. A group of relatively poor responders to the drug had a mild increase in the fractional catabolic rate (FCR) of VLDL-TG, but no change in production rates. The remaining patients were relatively good responders; they had increased FCR and modest reductions in synthetic rates of VLDL-TG. However, clofibrate largely failed to correct the primary defect in this group of patients, namely, the overproduction of VLDL-TG. Almost all patients responded to 1 month of caloric restriction (1000 cal/day) with marked reductions in VLDL-TG levels. The major response to reduced caloric intake was a decrease in production of VLDL-TG, although FCR was also increased to some extent. Despite these differences in mechanisms for VLDL-TG lowering, both regimens tended to raise levels of LDL and HDL.
Fenofibrate reduces low density lipoprotein catabolism in hypertriglyceridemic subjects.
Authors: Shepherd J , Caslake M J , Lorimer A R , Vallance B D , Packard C J
Published: June 2011

This study examines the kinetic basis for the increment in plasma low density lipoprotein (LDL) levels that accompanies the fenofibrate treatment of severely hypertriglyceridemic (HTG) patients. Seven HTG men with a mean plasma triglyceride level of 1470 mg/dl were treated for 6 weeks. During treatment, their plasma triglyceride level fell by 77% and their cholesterol level by 41%. The fall in very low density lipoprotein (VLDL) cholesterol level was reciprocated by increments in the cholesterol level in both LDL and high density lipoproteins (HDL); the rise in HDL was confined to HDL3. LDL catabolism was examined before and during therapy using native and chemically modified tracers in an attempt to distinguish receptor-mediated from non-receptor-mediated clearance. In their basal state, the hypertriglyceridemic subjects overcatabolized both the native and the modified lipoprotein, implying that the non-receptor pathways were hyperactive. The mean fractional clearance rate of LDL via the receptor pathway was not significantly different from normal. Fenofibrate therapy corrected the patients' hypercatabolism, reducing the receptor-independent fractional clearance of apo LDL by 50% (from 0.48 to 0.24 pools/day; p less than 0.05). The mean fractional catabolic activity of the receptor route did not change, but when the increment in the plasma apo LDL concentration was taken into account, it was clear that the drug treatment was associated with an increase in the net amount cleared by the receptor pathway and with a reduction of lipoprotein uptake into receptor-independent routes.
Relative contribution of triglyceride-rich lipoprotein particle size and number to plasma triglyceride concentration.
Authors: Poapst M , Reardon M , Steiner G
Published: June 2011

These studies were undertaken to determine whether differences in plasma triglyceride concentrations reflected differences in the number or in the size of the triglyceride-rich lipoprotein particles in the circulation. A population of 122 men and women, composed of normotriglyceridemic individuals and individuals with endogenous hypertriglyceridemia (plasma triglyceride concentration from 60 mg/dl to 1400 mg/dl), was studied by one of four independent experimental procedures. Rates of triglyceride production and particle (as reflected by apolipoprotein B) production were simultaneously determined. The data suggest that 71% of any increase in triglyceride production was due to an increase in the production of particles, and only 29% was due to an increase in the amount of triglyceride carried per particle. Direct measurement of the triglyceride-rich lipoprotein particle size by electron microscopy demonstrated that for a fivefold difference in triglyceride borne by the Sf 12-400 lipoproteins (from 100 mg to 500 mg triglyceride/dl plasma), the mean particle size rose by only 29%. Hence, 71% of this difference was due to an increase in particle number. The same results were obtained when triglyceride levels were related to the number of triglyceride-rich lipoproteins in the plasma. The number of particles for these studies was either estimated from apo B concentration or by calculations based on the chemical composition of ultracentrifugal subfractions. These studies have used four different approaches to show that changes of plasma triglyceride concentration primarily reflected a change in the number, not the size, of triglyceride-rich lipoprotein particles. Our studies also demonstrated that 75% to 80% of the triglyceride-rich lipoproteins in both normotriglyceridemic and hypertriglyceridemic subjects were in the Sf 12-60 or intermediate density lipoprotein subfraction.
Plasma lipoprotein levels in treated and untreated hypertensive men and women. The National Heart Foundation of Australia Risk Factor Prevalence Study.
Authors: MacMahon S W , Macdonald G J , Blacket R B
Published: June 2011

Experimental studies have reported that common antihypertensive drugs such as diuretics, beta-blockers, and methyldopa have adverse effects on plasma lipids and lipoproteins. To investigate whether such effects can be observed in the general population, plasma lipid and lipoprotein levels were compared in subjects receiving antihypertensive treatment, subjects with untreated high blood pressure, and subjects with normal blood pressure in a random sample of 5603 subjects screened in a national study of risk factor prevalence in Australia. In both sexes, high density lipoprotein (HDL) cholesterol was lower in the group receiving treatment than in the others (p less than 0.001). In men, triglycerides (TG) (p less than 0.001) and the ratio of total cholesterol to HDL cholesterol (TC/HDL cholesterol) (p less than 0.05) were higher in the group receiving treatment. In both sexes, the differences in plasma lipids and lipoproteins between treated and untreated hypertensive groups were independent of age, body mass index, alcohol consumption, and smoking. More than 40% of the treated or untreated hypertensive men and women had elevated total cholesterol (TC greater than 252 mg/dl) or an elevated TC/HDL cholesterol ratio (greater than 6.0). In men receiving antihypertensive treatment, the prevalence of an elevated TC/HDL cholesterol ratio was significantly greater than in men with untreated high blood pressure (p less than 0.01). The results of this study suggest that the effects of antihypertensive treatment on plasma lipids and lipoproteins can be observed in population lipid and lipoprotein levels. Even before treatment, a large proportion of high blood pressure patients have a significant plasma cholesterol abnormality, which may be aggravated by conventional antihypertensive therapy.
Serum lipids in the People's Republic of China. Comparison of Western and Eastern populations.
Authors: Kesteloot H , Huang D X , Yang X S , Claes J , Rosseneu M , Geboers J , Joossens J V
Published: June 2011

Serum cholesterol and HDL cholesterol levels were measured in an urban and a rural population of the People's Republic of China and compared with cholesterol values obtained in Belgium and in the Republic of Korea, with use of the same methodology. Total cholesterol levels were markedly lower in the People's Republic of China than in Belgium and generally lower than in Korea, both in male and female subjects. However, the differences in HDL cholesterol levels among the three populations were small in males and only significantly higher in Belgium in the age classes below 34 years. In women of all age groups, HDL cholesterol values were significantly higher in Belgium than in China and Korea. Total cholesterol levels below 100 mg/dl were found in the People's Republic of China in about 2% of the participants. Apolipoprotein B was significantly lower, and the apolipoprotein A1/B ratio was significantly higher, in China and Korea compared to Belgium.
Increase in glycosaminoglycan synthesis in familial hypercholesterolemic fibroblasts.
Authors: Wieczorek A J , Zöllner N
Published: June 2011

The enzymes of biosynthesis are usually bound to membranes and require an undisturbed lipid environment for regulated activity. In familial hypercholesterolemia, this lipid environment is disturbed and there is a low cholesterol ester level in the cellular membranes that results from impaired processing of low density lipoprotein (LDL). Thus, altered activities of various synthesizing enzymes could be expected. In this study, we found that microsomal glucuronyltransferase activity was 3.4-fold higher in homozygous familial hypercholesterolemic skin fibroblasts (n = 5) than in normal fibroblasts (n = 8). The secretion rates of glycosaminoglycans in familial hypercholesterolemia were also higher and the incorporation of radiolabeled precursor into glycosaminoglycans was enhanced. In addition to the differences in total synthesis and secretion, we found an altered pattern of individual glycosaminoglycan species with respect to the carbohydrate backbone and a different degree of sulfation in familial hypercholesterolemia. Heparan sulfate with a high degree of sulfation was secreted at a particularly high rate by hypercholesterolemic fibroblasts. Although the affinity of this glycosaminoglycan for LDL is lower than that of dermatan sulfate, it might cause formation of enhanced LDL-glycosaminoglycan complex and induce the xanthomas and atheromas of familial hypercholesterolemia.
Direct fetal blood examination for prenatal diagnosis of homozygous familial hypercholesterolemia.
Authors: de Gennes J L , Daffos F , Dairou F , Forestier F , Capella-Pavlosky M , Truffert J , Gaschard J C , Darbois Y
Published: June 2011

Prenatal diagnosis of homozygous hypercholesterolemia was achieved at the 24th week of gestation by analysis of lipid values in a fetal blood sample obtained by a needle guided by ultrasound. These abnormal values were compared to values in blood obtained from normal fetuses at the same stage of gestation. After abortion, the diagnosis was confirmed by measuring LDL receptor activity on fibroblast cultures from a skin biopsy. The main advantages of this procedure over measuring LDL receptor activity on cultured amniotic cells are its simplicity and speed.
Quantitative ultrastructural analysis of perifibrous lipid and its association with elastin in nonatherosclerotic human aorta.
Authors: Guyton J R , Bocan T M , Schifani T A
Published: June 2011

Nonatherosclerotic areas in human arteries display an age-related accumulation of cholesteryl ester in the form of small, perifibrous lipid droplets in the deeper intimal layers. We treated human aortic specimens with an osmium-thiocarbohydrazide-osmium sequence en bloc after glutaraldehyde fixation in order to provide electron dense staining of neutral lipid for ultrastructural study. Neutral lipid was quantified in terms of area fractions on thin sections. Extracellular lipid, primarily in the form of small (less than 300 nm) droplets, accounted for 91% of the lipid found in the deep intimal region. Seventy-four percent of extracellular lipid appeared in droplets or aggregates that were demonstrated as adjacent to or within elastic fibers in the plane of section. The fraction of lipid adjacent to elastin in three dimensions is likely to be considerably higher than 74%. The results support the concept that an interaction between elastin or its associated components and lipids or lipoproteins may be important in extracellular lipid deposition in human arteries.
Association of low HDL and HDL2 cholesterol with coronary heart disease in noninsulin-dependent diabetics.
Authors: Laakso M , Voutilainen E , Pyörälä K , Sarlund H
Published: June 2011

Lipids and lipoproteins were measured in 139 men and 145 women who were noninsulin-dependent diabetics (NIDDs) aged 45 to 64 years. Of these, 27 men and 16 women had had a previous definite myocardial infarction (MI). The NIDDs with MI (MI+) showed lower values of HDL and HDL2 cholesterol concentrations than NIDDs without previous MI (MI-) or NIDDS without any symptoms or electrocardiographic signs of coronary heart disease (CHD-). The inverse relationship between HDL, HDL2, and CHD was evident in both sexes, but it was particularly strong among male NIDDs. The difference in HDL and HDL2 cholesterol concentrations between the MI+ and MI- groups or between the MI+ and CHD- groups persisted after adjustment by analysis of covariance for the effect of physical activity, alcohol intake, obesity, duration of diabetes, and glycemic control. It is concluded that in a cross-sectional study, even among NIDDs with generally low HDL and HDL2 cholesterol concentrations, the presence of CHD is associated with a further depression of HDL and HDL2 cholesterol levels. Prospective studies are needed, however, to confirm that the association is predictive and not a consequence of CHD.
Comparative study of density distribution of plasma lipoproteins of normo- and hypercholesterolemic rhesus monkeys and humans.
Authors: Fless G M , Scanu A M
Published: June 2011

Density gradient centrifugation was used to characterize the lipoprotein distribution of rhesus monkeys and human subjects with normal and elevated cholesterol levels. The lipoprotein profile of control monkeys differed from that of normal humans in that their density distribution as a whole was shifted to lower density. The most striking difference was that both rhesus high density lipoprotein (HDL) subspecies had densities lower than human HDL3, with one component having a lower, and the other a higher, density than human HDL2. Rhesus monkeys fed a diet supplemented with 0.5% cholesterol and 15% lard were divided into two groups. Those animals with cholesterol levels less than 435 mg/dl had a high apo A-I concentration and HDL subspecies similar to human HDL2 and HDL3, whereas those with concentrations greater than 435 mg/dl had a low apo A-I concentration and HDL species with a density either similar to, or exceeding that, of human HDL3. Low density lipoprotein (LDL) density decreased in both groups of hypercholesterolemic monkeys and was particularly pronounced in animals with cholesterol levels above 435 mg/dl. When the lipoprotein profiles of normal humans were compared with those having hypercholesterolemia, increases in the density of both HDL2 and HDL3 in hypercholesterolemic men and to a lesser extent in the density of HDL2 in women were detected. The results indicate that the overall density distribution of plasma lipoprotein is different between rhesus monkeys and humans, and may vary within each species as a function of the nutritional status. It follows that it is difficult to define lipoprotein classes of one species by using density intervals determined for another. Furthermore, these intervals can be inadequate in identifying lipoprotein classes within an individual before and after dietary manipulations.
Body fat distribution and hyperinsulinemia as risk factors for diabetes and cardiovascular disease.
Authors: Stern M P , Haffner S M
Published: June 2011

Differences in body fat distribution between diabetics and nondiabetics have been recognized for several decades; diabetics have a more centralized or upper body fat pattern than nondiabetics. Recently, attention has focused on fat patterning and also on hyperinsulinemia as possible risk factors for cardiovascular disease, as well. The case for insulin as a cardiovascular risk factor is bolstered by theoretical considerations related to its possibly atherogenic effects on serum and arterial wall lipids. Empirical evidence for fat patterning and hyperinsulinemia as cardiovascular risk factors rests on six prospective epidemiologic studies, three on fat patterning and three on insulin. Although provocative, none of these studies can be regarded as definitive. In none was a dose-response effect demonstrated, and there are various inconsistencies within and across the studies. Moreover, in none of the studies were hyperinsulinemia and fat patterning evaluated simultaneously. This is of particular importance in view of the well-documented interrelationships between these two variables. For example, insulin resistance and hyperinsulinemia have been found to be greater in women with upper body obesity compared to women with lower body obesity of equivalent degree. Considerable progress has been made recently in understanding the mechanisms of the differential metabolic effects of these two types of obesity. The extent to which fat patterning and hyperinsulinemia are genetic or acquired has received relatively little attention. Further research on this question is warranted since elucidation of any environmental influences on these variables might suggest new clinical and public health control measures.
Biochemical composition of coronary arteries in Finnish children.
Authors: Ylä-Herttuala S , Nikkari T , Hirvonen J , Laaksonen H , Möttönen M , Pesonen E , Raekallio J , Akerblom H K
Published: June 2011

To study the early features of atherosclerosis, we analyzed coronary artery intima medias from 63 boys and 30 girls who were newborn to 15 years old at the time of accidental death. Fatty streaks were found in five boys and one girl and, with one exception, were not present until the second decade of life. From birth there was a continuous increase in esterified cholesterol (EC) and a two- to threefold rise in free cholesterol and phospholipid. DNA, total protein, and collagen tended to rise after the first decade. The content of hyaluronic acid remained fairly constant, but sulphated glycosaminoglycans (GAGs) rose during the second decade; the highest increases were in dermatan and chondroitin sulphates. The content of arterial EC showed significant positive correlations with those of GAGs, but associations with the contents of DNA, total protein, and collagen were not significant. As judged by the observed gradual increase in arterial EC and a change in its fatty acid composition, there is a continuous increase with age in LDL-derived EC in the arterial wall. The mechanism of this accumulation is unknown, but the findings provide circumstantial evidence to support the concept that arterial GAGs may cause retention of plasma-derived lipids, which may subsequently be altered and internalized by the intimal cells.
Decreased arterial elasticity associated with cardiovascular disease risk factors in the young. Bogalusa Heart Study.
Authors: Riley W A , Freedman D S , Higgs N A , Barnes R W , Zinkgraf S A , Berenson G S
Published: June 2011

Noninvasive ultrasonic examinations were performed in 1984 on a biracial sample of 109 10- to 17-year-old adolescents to determine whether elastic properties of the carotid arteries are associated with cardiovascular disease risk factors in the young. The subjects examined were in either the upper (high risk) or lower (low risk) race-, sex-, and age-specific tertile for both serum total cholesterol (TC) and systolic blood pressure (SBP) during a 1981-82 community survey. The pressure-strain elastic modulus (Ep), a measure of stiffness, for the carotid arteries was calculated by dividing the pulse pressure by the fractional diameter increase in the carotid artery during the cardiac cycle, as measured by ultrasonic techniques. Repeat studies on 20 randomly selected subjects demonstrated high reproducibility of the elasticity measurements (intraclass correlation coefficient = 0.84). The mean Ep in the high risk group was 5.1 kPa higher than in the low risk group, after controlling for race, sex, and age (one-sided p value = 0.03). Furthermore, a positive parental history of myocardial infarction was related to increased Ep levels (p less than 0.05), independently of race, sex, age, TC, and SBP. The results indicate that ultrasonic techniques can detect functional differences in the carotid arteries of children and adolescents that are associated with the risk of cardiovascular disease as adults.
Biological and dietary correlates of plasma lipids and lipoproteins among elderly Japanese men in Hawaii.
Authors: Yano K , Reed D M , Curb J D , Hankin J H , Albers J J
Published: June 2011

The relationships of plasma total cholesterol (total-C), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), and triglyceride (TG) to a variety of personal attributes were investigated cross-sectionally in a random sample of approximately 1360 elderly Japanese men, aged 60-81 years, in Hawaii. In multivariate analyses, total-C was positively related to hematocrit (p less than 0.01); LDL-C was positively related to hematocrit (p less than 0.0001), and inversely related to alcohol consumption (p less than 0.0001); HDL-C was positively related to alcohol consumption (p less than 0.0001) and physical activity index (p less than 0.05), and inversely related to body mass index (p less than 0.0001) and antihypertensive medication (p less than 0.05); and LogTG was positively related to body mass index (p less than 0.0001), alcohol consumption (p less than 0.0001), antihypertensive medication (p less than 0.0001), and diastolic blood pressure (p less than 0.01), and inversely related to physical activity index (p less than 0.01). Body mass index and alcohol consumption were the most important correlates of plasma lipids and lipoproteins. Several dietary variables were significantly related to each lipid or lipoprotein fraction after controlling for nondietary variables, but their independent contributions were generally quite modest.
Atherosclerosis in aortocoronary bypass grafts. Morphologic study and risk factor analysis 6 to 12 years after surgery.
Authors: Neitzel G F , Barboriak J J , Pintar K , Qureshi I
Published: June 2011

Segments of aortocoronary vein grafts from a selective group of 42 patients who underwent a second revascularization procedure or came to autopsy 6 to 12 years after coronary bypass surgery were studied. Complex atheromata often associated with an acute thrombus were present in 71% of the grafts. In 14% of the cases, aneurysms of the atherosclerotic type were noted. The medical records of 40 of these patients were reviewed. Special attention was paid to risk factors associated with coronary artery disease. A control population of 535 patients who had undergone coronary artery bypass surgery and had not had recurrence of symptoms requiring reoperation 5 or more years later was drawn from the Milwaukee Cardiovascular Data Registry. Significantly higher triglyceride and cholesterol levels and lower high density lipoprotein levels were noted in the patients undergoing two bypass procedures. In addition more diabetics, cigarette smokers, and patients with abnormal lipoprotein phenotypes were noted in the study group. Hypertension did not appear to be a significant risk factor. Atherosclerosis appears to be an important factor in late graft failure. Vein grafts that develop atherosclerosis appear to be susceptible to aneurysm formation. Risk factors associated with atherosclerosis in coronary arteries also appear to play a role in the development of atherosclerosis in aortocoronary bypass grafts.
Very low density lipoproteins stimulate cholesteryl ester formation in U937 macrophages. Heterogeneity and biologic variation among normal humans.
Authors: Sacks F M , Breslow J L
Published: June 2011

Normolipidemic fasting VLDL stimulated the formation of cholesteryl ester in the human macrophage-like cell line, U937. VLDL from different persons exhibited heterogeneity over a 10-fold range in stimulating cholesterol esterification, and were 7% to 98% as active as human LDL. The effects of VLDL in U937 cells were highly correlated to those in normal human fibroblasts. VLDL did not induce cholesterol esterification in resident mouse peritoneal macrophages, nor in fibroblasts that lacked LDL receptors, suggesting that receptors for LDL, rather than for beta-VLDL, mediate the effects of VLDL. The active VLDL particles were found in the dense VLDL subfraction, Sf20 to 60, but not in Sf60 to 100 or Sf100 to 400. The activity of unfractionated VLDL was correlated directly with % cholesteryl ester in total or Sf20 to 60 VLDL, and inversely with VLDL triglycerides. Biologic variation of fasting VLDL activity in U937 cells was found in 13 normolipidemic ambulatory subjects. As compared to the correlation between the activity of two VLDL samples derived from a single aliquot of blood (r = 0.90), the correlation was lower (r = 0.60) between the activity of samples taken on successive days, and even less (r = 0.05) between VLDL samples obtained 2 weeks apart. Substantial biologic variation also occurred in VLDL composition except for VLDL unesterified cholesterol. These findings suggest an environmental influence on VLDL metabolism by macrophages.
Hereditary hyperlipidemia in the rabbit due to overproduction of lipoproteins. I. Biochemical studies.
Authors: La Ville A , Turner P R , Pittilo R M , Martini S , Marenah C B , Rowles P M , Morris G , Thomson G A , Woolf N , Lewis B
Published: June 2011

An inherited metabolic disorder in a strain of New Zealand White rabbits, characterized by marked hypercholesterolemia (394 +/- 100 mg/dl), with moderately elevated or normal triglyceride levels is described. Low density lipoprotein (LDL), intermediate density lipoprotein (IDL) and very low density lipoprotein (VLDL) cholesterol levels were increased. VLDL and IDL, and to a lesser extent LDL, had increased free cholesterol and esterified cholesterol content, and triglyceride content was reduced. Kinetic studies with 131I and 125I-labelled rabbit lipoproteins showed a marked increase in production rates of VLDL apo B and LDL apo B. LDL cholesterol levels were directly related to LDL apo B production rate (r = 0.938, p less than 0.001). Both in hypercholesterolemic and normal rabbits injected with labelled VLDL, the specific activity-time curves of VLDL apo B and LDL apo B did not intersect, indicating that LDL apo B was in part derived from sources other than VLDL. No defect was demonstrated in receptor-mediated catabolism of LDL by cultured skin fibroblasts from hyperlipidemic animals. The fractional catabolic rate of LDL apo B was subnormal, but increased when the expanded LDL apo B pool size was reduced by exchange transfusion; the low fractional catabolism may therefore be attributable, at least in part, to saturation of LDL receptors consequent upon the increased pool size of LDL. The hyperlipidemia in this strain of rabbits may be unique in that the underlying mechanism appears to be overproduction of VLDL and LDL.
Regression of experimental atherosclerotic lesions in rhesus monkeys consuming a high saturated fat diet.
Authors: Eggen D A , Strong J P , Newman W P , Malcom G T , Restrepo C
Published: June 2011

Atherosclerotic lesions were induced in rhesus monkeys by feeding them a high-fat, high-cholesterol diet for 2 years. Arteries were examined after autopsy of a subgroup of animals (group P) and cholesterol was removed from the diet of the remaining animals. Lesions were examined in other subgroups after 30 weeks (group R1) and after 52 weeks (group R2). A control group (group C) was fed the diet without cholesterol throughout the study. The mean total serum cholesterol concentration before, during, and after lesion induction was 151, 390, and 157 mg/dl, respectively. The mean percent of surface area with fatty streak or fibrous plaque and the free and esterified cholesterol content of the artery increased in all six arterial segments examined in group P. The means for percent of surface with fatty streak and for arterial cholesterol content or concentration (but not for extent of surface with fibrous plaque) were consistently less in groups R1 and R2 than in group P, although they remained greater in groups R1 and R2 than in group C. The mean intimal thickness for coronary arteries was 10-fold greater in group P than in group C and 60 percent less in groups R1 and R2 than in group P; there was, however, much variability among animals and these differences among groups were not statistically significant. By using several measures in several arterial systems, we have shown that there was regression of diet-induced atherosclerotic lesions in rhesus monkeys while they were fed a diet high in saturated fat but without cholesterol for 30 or 52 weeks.
Body fat distribution as a risk factor for coronary artery atherosclerosis in female cynomolgus monkeys.
Authors: Shively C A , Clarkson T B , Miller L C , Weingand K W
Published: June 2011

Central fat deposition is associated with increased risk of coronary heart disease morbidity and mortality in women. Subcutaneous fat distribution was investigated as a potential factor that might exacerbate diet-induced coronary artery atherosclerosis (CAA) in female cynomolgus monkeys (Macaca fascicularis) which share with North American Caucasian women a gender-related protection against CAA. In a retrospective necropsy study (n = 36), the distribution of the antemortem ratio of subscapular/triceps skinfold thickness was divided at the mean and the two resulting groups were designated high and low for this variable. CAA was quantified as the mean cross-sectional intimal area based on nine coronary artery sections. The extent of CAA was significantly greater in the high skinfold ratio group as compared to the low skinfold ratio group. Ponderosity was closely associated with the skinfold ratio but was not a useful predictor of CAA. These findings suggest that female cynomolgus macaques may provide a primate model of the health consequences of regional fat distribution in women.
Increased pulse pressure in patients with arteriosclerosis obliterans of the lower limbs.
Authors: Safar M E , Totomoukouo J J , Asmar R A , Laurent S M
Published: June 2011

Brachial blood pressure, ankle systolic pressure, calf blood flow before and after postocclusive reactive hyperemia, and treadmill exercise results were determined in 16 patients with arteriosclerosis obliterans disease (AOD) of the lower limbs. These values were compared with values from 16 controls matched for age and sex. For the same mean arterial pressure in controls, pulse pressure was significantly higher and resting calf blood flow, slightly lower in patients with AOD. Resting calf blood flow was positively correlated with mean arterial pressure and pulse pressure in patients with AOD but not in controls. In AOD patients, reduced walking distance was strongly and positively correlated with "vascular bed reserve" expressed as the ratio between peak blood flow after postocclusive reactive hyperemia and resting calf blood flow. Correlation studies indicated that the higher the pulse pressure, the more reduced the walking distance and the more altered the vascular bed reserve. The study provided evidence that: increased pulse pressure, rather than increased mean arterial pressure, is a characteristic feature of patients with AOD, and the pulsatile component of blood pressure, which reflects the alteration of the buffering function of large arteries, might influence the reductions in walking distance and vascular bed reserve observed in patients with AOD.
Lack of sex differences in high density lipoproteins in Pima Indians. Studies of obesity, lipase activities, and steroid hormones.
Authors: Howard B V , Pan X R , Harper I , Kuusi T , Taskinen M R
Published: June 2011

To investigate the reasons for the lack of sex differences in high density lipoproteins (HDL) observed in population studies of the Pima Indians, we selected 18 lean (9 men, 9 women, body mass index (BMI) less than 27) and 22 obese (12 men, 10 women, BMI greater than 27) Pima Indians for an inpatient study of HDL composition. We measured lipase activities and steroid hormone concentrations, both of which have previously been implicated in the control of HDL. The lean women had higher concentrations of HDL and HDL2 than did either the obese women or the lean or obese men. Lean women had significantly lower hepatic lipase activities and significantly higher concentrations of estradiol compared to obese women. Lean women also had different HDL2 composition, as indicated by the molar ratio of HDL2 cholesterol/A-I. Significant negative correlations between HDL and obesity measured by either BMI or percent body fat were observed in both sexes, but the slope of the relationship was steeper in women. Significant negative associations were observed between HDL or HDL2 concentrations and hepatic lipase in both sexes, and there were significant positive associations between HDL2 and plasma estradiol in women. The data suggest that obesity in this population has a stronger negative influence on HDL concentrations in women, possibly through changes in estradiol and hepatic lipase activities. Since there are so few lean women in the Pima population, the net result is that HDL levels in women in the population as a whole do not differ from those of men.
Two DNA restriction fragment length polymorphisms associated with Ag(t/z) and Ag(g/c) antigenic sites of human apolipoprotein B.
Authors: Ma Y H , Schumaker V N , Butler R , Sparkes R S
Published: June 2011

Several high frequency restriction fragment length polymorphisms (RFLPs) associated with the human gene for apolipoprotein B have been previously reported by Priestly et al. The EcoRI RFLP here was shown to be very strongly associated with the Ag(t/z) immunochemical polymorphism of human low density lipoproteins, allowing correct Ag(t/z) phenotyping of 17 (out of 17 tested) unrelated individuals. The Xbal RFLP was associated with the Ag(g/c) immunochemical polymorphism, permitting correct phenotyping of 14 (out of 17 tested) unrelated individuals. Its close association with an RFLP permitted localization of the Ag(t/z) polymorphism to the C-terminal end of the apolipoprotein B peptide, and allowed detailed discussion of its probable molecular basis.