摘要:

The hypothesis that body fatness modifies the relation between dietary cholesterol and 25-year coronary mortality was examined in a cohort of 1,792 middle-aged men employed by the Western Electric Company in Chicago. Relative risks of coronary death (and 95% confidence intervals) associated with a 225 mg/day greater intake of dietary cholesterol for men with a subscapular skinfold thickness S14,15-20, and S:21 mm were 1.44 (1.10-1.90), 1.07 (0.84-136), and 0.95 (0.76-1.20), respectively, after adjustment for age; serum total cholesterol level; systolic blood pressure; cigarette smoking; family history of cardiovascular disease; evidence of major organ system disease at baseline; and intake of saturated fatty acids, polyunsaturated fatty acids, energy, and ethanol. Adjusted relative risks associated with a 15-mm greater subscapular skinfold thickness for men with a dietary cholesterol intake £649, 650-799, and 2:800 mg/day were 1.76 (1.04-2.98), 1.64 (1.04-2.57), and 1.00 (0.69-1.55), respectively. Fatter men apparently did not benefit from a diet lower in cholesterol, while men who ate a diet high in cholesterol apparently did not benefit from leanness. These results support the hypothesis that body fatness modifies the relation between dietary cholesterol and coronary mortality, perhaps because leaner men are more responsive than fatter men to the effects of dietary cholesterol on the concentration of low density lipoprotein cholesterol.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

A sample of 200 patients with a clinical diagnosis of heterozygous (189) or homozygous (11) familial hypercholesterolemia (FH) attending lipid clinics in the London area have been screened for the presence of major gene defects in the low density lipoprotein (LDL) receptor gene by Southern blotting of genomic DNA with specific probes. This study Is part of a project to determine the frequency of known mutations in the LDL receptor gene in this population. A new polymorphism for the enzymeBgtII was identified by hybridization with a probe specific for the promoter plus exon 1 of the LDL receptor gene. The observed frequency of the rare allele, characterized by aBgiII fragment of 13 kb compared with 10 kb for the common allele, was 0.08 in this group of FH patients. Several individuals who were heterozygous for the rare allele were also heterozygous for a mutation elsewhere in the LDL receptor gene that is known to cause FH. Eight different mutations, seven deletions and one duplication, were detected in a total of nine patients, accounting for 4.5% of the mutant alleles in this group. Three of the mutations are apparently identical to deletions that have been described previously in FH patients of British or European origin, while the remaining five have not been described. Two of these were in patients of Polish and Asian Indian origin, while the other three were in patients of apparently British ancestry.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Accelerated coronary artery disease has become a major complication to heart transplantation in humans. Therefore, we have developed a surgical model in the rabbit, with transplantation of the thoracic aorta as a bypass graft onto the abdominal aorta of another rabbit The model permits the study of cholesterol metabolism in transplanted arteries. The graft did not accumulate cholesterol for as long as 298 days, provided that the rabbits were normocholesterolemic, i.e., with plasma cholesterol levels of 0.3-0.7 mmol/1. However, after a few weeks of cholesterol feeding resulting in plasma cholesterol levels of 2-5 mmol/1, the homologous graft accumulated cholesterol compared with intact aortic tissue in the rabbits and also compared with autologous aortic grafts. The intimal clearance of plasma cholesteryl ester, mainly high density lipoprotein cholesteryl ester, in the luminal layer of the aortic graft was 60-150 nlxcm2xhr11-2 hours after transplantation. The intimal clearance in the corresponding intact thoracic aorta of the recipient animal was 5-20 nlxcm2xhr"1. The values were 1,500-3,000 nlxcm"2xhr"' 51-298 days after transplantation, while the intimal clearance of the rabbit's own aorta remained unchanged. A pronounced increase in plasma lipoprotein permeability is thus an early event in transplanted arteries. It results in a higher cholesteryl ester influx that leads to cholesterol accumulation in the artery, but only if the rabbits are fed a cholesterol-enriched diet This rabbit model may be useful in the search for interventional measures to prevent or diminish the accelerated coronary artery disease in transplanted hearts in humans.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

In the second World Health Organization MONItoring Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg survey in 1989-1990 (n=4,940), the association between nephelometric plasma fibrinogen level and lifestyle-related potential determinants was assessed in 4,434 subjects aged 25-74 years (89.8% of participants). Irrespective of pregnancy and the use of oral contraceptives, crude fibrinogen values were consistently higher in women than in men of all ages (age-standardized difference, 12.2 mg/dl; 95% confidence interval, 7.0-17.4 mg/dl). Fibrinogen concentrations were positively correlated (psO.0001) with age, body mass index, and waist-to-hip ratio in both sexes and with cigarette smoking In men and were negatively correlated with alcohol consumption in both sexes. In multiple linear regression analyses using categorized determinants as independent variables, a strongly J-shaped relation for body mass index in women and a linear association for waist-to-hip ratio in men were revealed. Smoking had a dose-dependent effect on fibrinogen concentration in men but a lesser effect in women. For alcohol consumption a U-shaped association was found, particularly in men. The curvilinear relations were confirmed in multiple polynomial regression models using continuous determinant variables. The potential epidemiological impact of a determinant was assessed by calculating differences in adjusted fibrinogen concentrations associated with the 10th and 90th percentile values of the determinant distributions actually observed among the study participants. This impact on the population fibrinogen level was most pronounced for age in both sexes, followed by body mass index, cigarette smoking, and alcohol consumption in women and by smoking, waist-to-bip ratio, and alcohol consumption in men. About 29% of the total variance in female and 26% in male fibrinogen values were explained by the three lifestyle factors plus age. Our findings are consistent with the hypothesis that fibrinogen may be an etiologic link between certain lifestyle characteristics and the course of cardiovascular disease.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Previous studies have established the presence of high numbers of activated T lymphocytes and "aberrant" expression of major histocompatibility complex class II antigens by endothellal and smooth muscle cells in human atherosclerotic lesions, implicating the involvement of a local cellular immune response. The identity of the antigen(s) eliciting this immune response, the extent of their effect, and the atherogenic stage at which they occur remain to be determined. In the present studies, 120 normocholesterolemic New Zealand White rabbits were immunized one or more times with various antigens, with or without adjuvants. The antigens and adjuvants included human or rabbit atherosclerotic lesion proteins, ovalbumin, Freund's complete and/or incomplete adjuvants, recombinant mycobacterial heat shock protein 65 (hsp65), and two hsp-free adjuvants, Ribl complete adjuvant and lipopeptide. In addition, some groups received a high-cholesterol diet. Sixteen weeks after the first immunization the animals were killed, and arteriosclerotic lesions in the intima of the aortic arch were found to have developed only in those animals immunized with antigenic preparations containing hsp, either in the form of whole mycobacteria or as purified recombinant hsp65, although their serum cholesterol levels were normal. No arteriosclerotic changes exceeding those of controls were found in the other groups, irrespective of the antigen used. Immunohistopathologic examination revealed that the lesions contained 20% T cells, 10-30% macrophages, and 10-40% smooth muscle cells. Analysis of the peripheral blood T-lymphocyte proliferative responses revealed that the occurrence of lesions was positively correlated with the presence of hsp65-reactive T cells, suggesting that hsp65 is involved in the induction of arteriosclerotic lesions. Furthermore, combined immunization with hsp-containing material and a cholesterol-rich diet provoked development of significantly more severe atherosclerosis and the appearance of characteristic foam cells. We conclude that an (auto)immune response to hsp may initiate the development of atherosclerosis and that a high blood cholesterol level is only one albeit a very important risk factor.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Mildly oxidized low density lipoprotein (minimally modified low density lipoprotein [MM-LDL]) is capable of inducing gene expression in cells of the artery wall. In this study, we investigated the mechanisms that control the mRNA expression of JE, KC, c-myc, and c-fos in quiescent mouse L-cell fibroblasts stimulated with MM-LDL. The data demonstrate that MM-LDL induces increases 2:20-fold in the levels of transcripts of these genes within 15-60 minutes. Of the four genes examined, JE and KC mRNA showed the greatest response to MM-LDL. The pattern of induction by MM-LDL is distinct from that observed in fibroblasts stimulated with serum, a known inducer of these genes. Treatment with cycloherimide (10/igjml)did not block the MM-LDL-induced increase in the mRNA levels of these genes. The increase of JE and KC mRNA levels in response to MM-LDL could be blocked by treatment with actinomycin D (5 /ig/ml). In nuclear runoff studies, MM-LDL increased the transcription rate ofJEandKCat 4 hours by 13-fold and fivefold, respectively. Small but reproducible stimulations ofc-fosandc-myctranscription by MM-LDL were also observed. In addition, the half-life of JE mRNA was increased after addition of MM-LDL to fibroblasts, suggesting that the MM-LDL-induced accumulation of these mRNAs might be accomplished by both transcriptional and posttranscriptional mechanisms. In protein kinase C-depleted fibroblasts, MM-LDL increased JE and KC mRNA levels, whereas the stimulatory effect of 12-O-tetradecanoyl phorbol-13-acetate on JE and KC expression was blocked under these conditions. Taken together, these data demonstrate that MM-LDL increases transcription of theJEandKCgenes by a mechanism that does not require de novo protein synthesis and is not mediated via a 12-O-tetradecanoyl phorbol-13 -acetate-responsive protein kinase C pathway. These results provide a basis for further investigations of the molecular mechanism of action of MM-LDL.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Sixty-two patients aged 19-64 years with primary hypercholesterolemia (mean level of total cholesterol, 10.8 mmol/1) were treated with 80 mg/day lovastatin (L) alone for 18 weeks and, after randomization to either L+20 g/day guar gum (L+GG) or L+16 g/day cholestyramine (L+C) treatments, for an additional 18 weeks. The total cholesterol level declined from baseline by 34% during L and by 44% and 48% during L+GG and L+C, respectively. In terms of micromoles per miUlmole of cholesterol, serum levels of the cholesterol synthesis precursors cholestenol, desmosterol, and lathosterol were decreased and those of the plant sterols campesterol and sitosterol were increased by treatment with L. The serum contents of cholesterol precursors were increased markedly after the combination of either GG or C with L, but the increase was greater after the addition of C (e.g., the lathosterol to cholesterol ratio was 51% versus 212% for L+GG and L+C, respectively;p< 0.001). Thus, a higher rate of removal of bile acids by C than by GG reduced more effectively the low density lipoprotein cholesterol level but simultaneously stimulated cholesterol synthesis compensatorily to a higher level even under concurrent treatment with L. The serum sitosterol to cholesterol ratio declined by 13% during L+GG but increased by 49% during L+C compared with the value under L alone, suggesting different effects of GG and C on the metabolism of plant sterols.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Silent myocardial ischemia (SI), an asymptomatic manifestation of coronary artery disease (CAD), was identified in 10% of apparently healthy nonsmoking, nondiabetic older (60±7 years, mean±SD) men with normal plasma cholesterol levels. We hypothesized that in the absence of other major risk factors for CAD, the men with SI would have reduced plasma levels of high density lipoprotein (HDL) and HDL2subspecies due to an upper-body fat distribution (waist-to-hip ratio [WHR]), hyperinsulinemia, and abnormal postheparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities. Compared with 47 normal control subjects of similar age, obesity, and maximal aerobic capacity, the 18 men with SI had higher plasma triglyceride (TG) (162±71 versus 102±39 mg/dl,p<0.001) and lower HDL-C (33±6 versus 37±7 mg/dl,p<0.02) levels with no difference in low density lipoprotein cholesterol level. The HDLUand HDL2, subspecies measured by gradient gel electrophoresis were also lower in the men with SI (p<0.01). The plasma glucose and insulin responses during an oral glucose tolerance test were the same in both groups. Postheparin plasma HL activity was significantly higher in 12 men with SI than in 41 control subjects (34±8 versus 27±10 jtmol/ml &#149; hr−1,p<0.03) and was correlated with log insulin area (r=0.36,p<0.05) and WHR (r=032p<0.05) in the control subjects but not in the men with SI. In the control group, the percent HDLttsubspecies was correlated inversely with postheparin plasma HL activity (r=−0.46,p<0.01, n=41) as well as WHR (r=−0.49,p<0.001, n=47) and log insulin area (r=−0.36,p<0.05, n=47) but not in the men with SL Postheparin LPL activity was the same in both groups of men and did not correlate with HDL, WHR, insulin, or plasma TG levels. As the control subjects and men with SI had comparable degrees of abdominal obesity and hyperinsulinemia, these results suggest that the reduced HDL-C levels in men with SI may be related to elevations in HL activity. Thus, abdominal obesity, hyperinsulinemia, elevated TG levels, and low HDL-C and HDLj subspecies levels may predispose these older men to atherosclerosis.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Low density lipoprotein modified by oxidation (Ox-LDL) causes adhesion of leukocytes to the endothelium, a feature common in early atherogenesis. Because leukocyte adhesion under various pathophysiological conditions involves superoxide generation, we explored the possibility that superoxide is likewise involved in leukocyte adhesion in response to Ox-LDL. For our studies, we used the dorsal skin fold chamber model for intravital microscopic observation of leukocyte-endothelium interactions in hamsters. We show here that injection of human LDL (4 mg/kg LDL cholesterol oxidatively modified by incubation in 7.5 μM Cu2+for 18 hours at 37°C) elicited in control hamsters (i»=7) the rolling and adhesion of circulating leukocytes along the endothelium of arterioles and postcapillary venules. This adhesion was significantly attenuated when hamsters were pretreated with bovine copper-zinc-superoxide dismutase (CuZn-SOD, 0.25 ing/kg, n=l) or heparln (2,000 IU/kg,n-1).The CuZn-SOD infusion and the heparin-induced release of extracellular SOD from endothelial cell surfaces to plasma resulted in nearly equal plasma SOD activities. Further inhibition of Ox-LDL-induced leukocyte adhesion could not be achieved by increasing the dose of CuZn-SOD to 5 mg/kg (n=6). Pretreatment of the hamsters with inactivated CuZn-SOD showed no effect These results indicate that Ox-LDL stimulates leukocyte adhesion through a superoxide-dependent step, and they indicate a possible mechanism by which antioxidants might inhibit the onset of experimental and clinical atherosclerosis.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The effects on aortic and platelet fatty acid compositions and on blood levels of prostacyclin and thromboxane A2of lowand high-fat diets containing olive oil or sunflower oil were studied. For 4 weeks, four groups of weanling rats were fed a basal diet containing5%or 25% olive oil or sunflower oil. Rats fed olive oil diets showed higher levels of 18:l(n-9) and polyunsaturated fatty acids of the n-3 series and lower percentages of 18:0 and 18:2(n-6) in aortic and platelet phosphatidylcholine and phosphatidylethanolamine than those fed the sunflower oil diets. Arachidonic acid increased in platelet phosphatldylethanolamine and aortic phosphatidylcholine of rats fed the diet containing 5% sunflower oil compared with those fed 5% olive oil. Plasma 6-ketoprostaglandinFlaincreased in both groups of animals fed olive oil while these rats also showed the lowest levels of serum thromboxane B? and plasma cholesterol. Olive oil feeding leads to changes in lipid metabolism of the vascular compartment that could be favorable in the prevention of thrombosis and atherosclerosis.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID