摘要:

Low density lipoproteins (LDLs) were isolated by ultracentrifugation and radiolabeled with '"In. The in vitro binding of these radiolabels onto platelets of normolipemic volunteers (n = 15) and patients (n=36) with heterozygous familial hypercholesterolemia (FH) was investigated. Binding was saturable and indicated high-affinity binding sites capable of binding 1,757±289 ng protein of '"In-LDL per 10′ platelets (dissociation constant [ATd], 6±3figprotein/mL) in healthy volunteers and significantly (p<0.001) lower amounts in the FH patients (mean, 633±341 ng protein/109platelets;Kd, 10±5figprotein/mL). The capacity of native LDL to displace bound '"In-LDL by half amounted to 10±4figprotein/mL in volunteers and 22±8figprotein/mL in FH patients (p<0.001). Treatment with gemflbrozil alone or in combination with cholestyramine in 10 patients resulted in increased "'In-LDL binding by platelets (470±307 [mean±SD] ng protein/109platelets before therapy, 948±650 ng protein/10 after 2 months of therapy [p<0.01], and l,272±701 ng protein/109platelets after 6 months of therapy [p<0.01]). Significant correlations between nl In-LDL binding capacity and apolipoprotein B (r=−0.83,p<0.001) and LDL cholesterol (r=&#151; 0.80,p<0.000) concentrations were found. Patients with clinically manifested atherosclerosis (p<0.01) and those with diabetes mellitus (p<0.05) had significantly lower platelet LDL binding sites. The findings demonstrate "'In-lipoprotein-specific binding sites on human platelets. Platelets of patients with heterozygous FH express lower numbers of binding sites, which could be upregulated during lipid-lowering intervention. It is concluded that high-affinity LDL binding may involve in vivo processes related to platelet activation in hyperlipemic disorders.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Lipoprotein(a) (Lp[a]) is a newly recognized risk factor for the development of coronary heart disease and stroke in human beings; however, the mechanisms by which Lp(a) increases the risk of coronary heart disease remain unclear. The purpose of this study was to examine the effects of Lp(a) on the occurrence of occlusive arterial thrombosis. Occlusive arterial thrombus formation was examined in 18 cynomolgus monkeys with high plasma Lp(a) concentrations (>35 mg/dL,n=6), intermediate Lp(a) concentrations (20–25 mg/dL, n=6), and low Lp(a) concentrations (<12 mg/dL, n=6). A Goldblatt clamp was positioned around the left common carotid artery to produce a stenotic segment, and the artery was pinch-injured with needle holders. A 20-MHz Doppler velocity crystal, placed distal to the stenosis/injury site, was used to detect cyclic flowreductions (indicative of transient thrombosis) or permanent cessation of velocity (indicative of more stable occlusive thrombosis). All monkeys with high Lp(a) concentrations developed permanent cessation of flow, whereas only one of six arteries from low-Lp(a) monkeys developed permanent cessation of flow (p<0.05). Arteries from monkeys with intermediate Lp(a) concentrations developed pronounced cyclic reductions of flowbut did not progress to permanent cessation of flow.There were no differences in plasma von Willebrand factor activity among the three groups. Immunohistochemical analysis of the damaged arterial segments indicated incorporation of Lp(a) into the adventitia, media, and intima of arteries from monkeys with low and high plasma Lp(a) concentrations, as well as the presence of an occlusive thrombus in arteries that developed permanent cessation of flow.It is concluded that plasma concentrations of Lp(a) may influence the development of occlusive arterial thrombosis of stenotic or injured arteries.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Lower-extremity arterial disease (LEAD) is common in older adults, particularly those with systolic hypertension. In a subgroup of 1,775 participants of the Systolic Hypertension in the Elderly Program, LEAD was assessed noninvasively by the ratio of the ankle to arm blood pressure, the ankle-arm index (AAI). LEAD was defined as an AAI of <0.9 in either leg. The prevalence of was 25% in white men, 38% in black men, 23% white women, and 41% women. About half of those with LEAD had mild disease (AAI, 0.8-0.9), and only 1-3% had a positive Rose questionnaire for intermittent claudication. The prevalence increased with age (p<0.01) and was consistently higher in blacks than whitesp><0.01), although there were no significant differences between men and women. Even in the absence of risk factors such as smoking and diabetes, blacks had a higher prevalence of LEAD than whites. Associations of LEAD with cardiovascular risk factors (high density lipoprotein cholesterol, systolic blood pressure, and smoking) appeared to be similar in blacks and whites, although relations were not always statistically significant in subgroups stratified by race and sex. Independent factors associated with the presence of LEAD included age, black race, smoking, diabetes mellitus, history of myocardial infarction or angina, systolic blood pressure, lower high density lipoprotein cholesterol, and body mass index. LEAD is common in older men and women with systolic hypertension, particularly blacks. However, very few have symptoms of claudication. Black participants with systolic hypertension, even those who are nondiabetic and those who have never smoked, appear to be at increased risk for LEAD.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Inhibitors of cyclic nucleotide phosphodiesterase hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate are known to inhibit platelet aggregation, which plays an important role in acute reocclusion after thrombolysis in acute myocardial infarction. In the present study of a canine preparation of coronary artery thrombosis superimposed on high-grade stenosis, we tested whether the antithrombotic agent cilostazol, an inhibitor of cAMP phosphodiesterase, could prevent acute reocclusion or sustain coronary blood flow after thrombolysis when used with recombinant tissue-type plasminogen activator (rt-PAJ and heparin. Intravenous infusion of rt-PA (0.5 mg/kg body wt for 30 minutes) and heparin (a 150 11)/kg body wt i.v. bolus and then 25 IU/kg body wt per hour i.v.) was combined with cilostazol (0.6 or 1.8 mg/kg body wt for 60 minutes). Without cilostazol, reperfusion was observed in seven of eight dogs, but reocclusion occurred in six of these seven dogs after 9±2 minutes. After administration of 1.8 mg/kg body wt cilostazol (group B-2; a 120-minute observation after the start of rt-PA infusion), reperfusion occurred in all seven dogs (p<0.05 versus control group), and brief cyclic reocclusion was observed in only one dog 63 minutes after reperfusion. At the same dose of cilostazol (group B-2L; a 240-minute observation after the start of rt-PA infusion), reperfusion occurred in all five dogs (p<0.05 versus control group), and coronary blood flow was well maintained except for one short reocclusion in one dog. Cilostazol inhibited cyclic flow reduction in a dose-dependent fashion. We conclude that cilostazol is a new potent antiplatelet agent for preventing reocclusion after coronary thrombolysis, when used in combination with rt-PA and heparin.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The in vivo activity of different 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (vastatins) on neointimal formation induced by insertion of a flexiblecollar around one carotid artery of normocholesterolemic rabbits was investigated. The contralateral carotid artery served as a sham control. Pravastatin, lovastatin, simvastatin, and fluvastatin were given mixed with food at daily doses of 20 ing/kg body wt for 2 weeks starting on the day of collar placement. The treatment with vastatins did not modify rabbit plasma cholesterol concentrations. The neointimal formation was assessed by measuring the cross-sectional thickness of intimal and medial tissues of fixed arteries with light microscopy. Fourteen days after collar placement, intimal hyperplasia (mostly cellular) was pronounced in treated carotid arteries. The intimal/medial (I/M) tissue ratio was 12-fold higher in treated arteries than in arteries without the collar (0.36±0.04 versus 0.03±0.02). Animals treated with lovastatin (R=12), simvastatin (n=12), and fluvastatin (R=12) showed significantly less neointimal formation; I/M tissue ratios were 0.24±0.03, 0.20±0.03, and 0.17±0.03, respectively. The inhibition elicited by pravastatin (n=12, 032 ±0.03) did not reach statistical significance. or-Actin antibody immunofluorescence analysis of serial sections revealed that cells present in the hyperplastic intima were mostly myocytes. Rates of intimal myocyte proliferation were also measured by incorporation of 5-bromo-2′-deoxyuridine, a thymidine analogue, into replicating DNA. Immunofluorescence analysis showed that 5-bromo-2′-deoxyuridine was actively incorporated into intimal myocytes after insertion of the collar, with a labeling index (percent of labeled myocytes) of 2.15 after 14 days. Labeling indexes for pravastatin-, lovastatin-, simvastatin-, and fluvastatin-treated carotid arteries were 2.01, 1.32,1.23, and 1.20, respectively, suggesting a direct effect of vastatins on arterial myocyte proliferation. The different responsiveness shown by the vastatins tested may be attributed to the differences in their capacity to penetrate cell membranes and their potency in inhibiting the HMG CoA reductase enzyme. We conclude that the inhibition of carotid intimal myocyte proliferation by these vastatins is independent of their effect on plasma cholesterol concentrations.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The objective of this study was to determine whether normotriglyceridemic patients with low levels of high density lipoprotein (HDL) cholesterol have concomitant defects in the metabolism of low density lipoproteins (LDLs). To address this question, measurements of turnover rates of apolipoprotein A-I (apo A-I) and LDL apolipoprotein B (apo B) were made in 36 middle-aged men with low HDL cholesterol (<40 mg/dL), normal triglyceride (<2S0 mg/dL), and normal total cholesterol (<90th percentile) levels. Similar measurements were made in eight hypertriglyceridemic men having low HDL levels. For control, turnover rates of LDL apo B were measured in 24 healthy, normolipidemic men, and apo A-I kinetics were determined in 20 other healthy men with normal HDL cholesterol levels. In all patients with low HDL levels, fractional catabolic rates (FCRs) for apo A-I were increased compared with control subjects; in contrast, input rates for apo A-I in low-HDL patients were similar to control. Hypertriglyceridemic patients had significantly higher FCRs for LDL (0.463±0.040 pool/day, [mean±SEM]) than control subjects (0.328±0.008 pool/day,p<0.001). In normolipidemic patients having low HDL, a bimodal pattern of LDL-apo B kinetics was observed. For 23 low-HDL patients, FCRs for LDL apo B averaged 0.450±0.017 pool/day and were significantly higher than control values. Additionally, in these patients, levels of very low density lipoprotein plus intermediate density lipoprotein (VLDL+IDL) cholesterol and VLDL+IDL apo B were higher than in control subjects (54±3 versus 32±3 mg/dL and 25±2 versus 18±1 mg/dL, respectively). The remaining 13 low-HDL patients had lower and essentially normal FCRs for LDL (0.300±0.009 pool/day); these patients also had relatively low levels of cholesterol and apo B in VLDL+IDL. Thus, two patterns of LDL kinetics were present in normotriglyceridemic patients with low HDL levels. One pattern was indistinguishable from that typically present in patients with hypertriglyceridemia, whereas the other was similar to normal control subjects. These two patterns of LDL-apo B kinetics may reflect different mechanisms for the causation of low HDL cholesterol concentrations.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Experimental and epidemiological evidence supports the hypothesis that oxidation of low density lipoprotein (LDL) appears to be important in mediating the atherogenicity of LDL. To test this hypothesis in humans, it will be necessary to perform intervention studies in large populations. We performed two studies to assess the effectiveness of supplementation with β-carotene and vitamin E, used alone in combination with each other, and with vitamin C, to protect LDL from oxidation. In phase 1, after a placebo period, eight subjects were given β-carotene (60 mg/day) for 3 months, then β-carotene plus vitamin E (1,600 mg/day) for another 3 months, and then β-carotene plus vitamin plus vitamin C (2 g/day) for 3 months. During phase 2, β-carotene and vitamin C were discontinued, subjects took only vitamin E for 5 months. During each period, LDL samples were isolated, and measurements of susceptibility to oxidation were performed. β-Carotene levels in LDL increased nearly 20-fold, but LDL susceptibility to oxidation did not change. Addition of vitamin E increased LDL vitamin levels nearly 2.5-fold, and this decreased LDL oxidation 30-40%. During the vitamin C supplementation period, plasma levels of β-carotene and vitamin E rose, but only β-carotene increased in LDL. However, the susceptibility of LDL to oxidation in this period was not decreased further. During phase 2, when subjects took only vitamin E, LDL susceptibility to oxidation was decreased by 50% as measured by thiobarbituric acid-reactive substances, conjugated dienes, and lipid peroxide formation as well by macrophage degradation. Thus, long-term supplementation with large doses of vitamin E alone, but not $-carotene, conferred increased protection to LDL in in vitro assays of oxidation. These data should be useful in planning therapeutic strategies to test the antioxidant hypothesis in humans.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

It has been suggested that or-tocopherol, a safe and effective antioxidant, be used in clinical trials to evaluate the ability of antioxidant therapy to inhibit atherosclerosis. Recent reports, however, have raised the possibility that there may be greater enrichment of plasma low density lipoprotein (LDL) in a-tocopherol resulting from the use of the naturally occurringRRR-a-tocophero]isomer compared with the other isomers present in the synthetic racemic form of or-tocopherol. Therefore, we fed equal dosages (1,600 mg/day) of the two forms of vitamin E to 16 men and women for 8 weeks and compared the effects of this supplementation on the susceptibility of isolated lipoproteins to oxidation. Neither form of vitamin E had appreciable effects on lipid or lipoprotein levels. or-Tocopherol levels in LDL increased at a similar rate in both groups and were nearly twofold higher than baseline levels by the end of the study. The susceptibility of LDL to oxidation was measured by formation of conjugated dienes, lipid peroxides, and thiobarbituric acid-reactive substances, as well as by macrophage degradation of LDL exposed to oxidizing conditions in vitro. The susceptibility of LDL to oxidation was decreased in both vitamin E groups compared with the baseline value, and this reduction occurred to a similar extent in both vitamin E-supplemented groups. or-Tocopherol levels in LDL also strongly correlated with all measures of LDL oxidation. This study demonstrates that, at this dosage, supplementation with either the natural or synthetic form of ar-tocopherol provided equal antioxidant protection to LDL.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The long-term patency of arteriovenous (AV) fistulas created for hemodialysis of renal-failure patients is usually measured in months, particularly when polytetrafluoroethylene (PTFE) material is interposed between the artery and vein. This is due to the rapid development of intimal hyperplastic lesions in the anastomosis region of the PTFE graft material with the vein. We studied the proliferative patterns in seven human AV fistulas removed at the time of fistula revision. Cell proliferation was determined by using an antibody to the proliferating cell nuclear antigen (PCNA), and specific cell types were identified by immunochemical reagents for smooth muscle cells, monocytes/macrophages, monocytes, lymphocytes, and endothelial cells. All venous segments exhibited a markedly hyperplastic intima. Vascularization of the intima and media by capillary-sized vessels was found. The main intimal cellular component was smooth muscle. Macrophages were usually seen around microvessels, and many also populated the perigraft region of the adventitia. In contrast to human atherosclerotic lesions, high rates of cell proliferation were observed in these fistulas. PCNA indices (percentage of cells that were PCNA positive [mean±SD]) were as follows: intima 17.7±11.3%, media 24±11.2%, and adventitia 20±11.6%. However, the distribution of PCNA-positive cells was not uniform. Instead, the PCNA index in microvesselcontaining intimal fields was five to six times that of avascular fields (28.9 ±10.6% versus 4.9 ±4.5%, respectively,p< 0.001). Double immunolabeling revealed a large proportion of PCNA-positive microvascular endothelial cells and surrounding pericyte-like smooth muscle cells, a few proliferating macrophages, luminal endothelial cells, and subendothelial smooth muscle cells, as well as smooth muscle cells without visual connection to either microvessels or the lumen. Thus, cell proliferation associated with neovascularization seems to be one of the major mechanisms of human AVfistulafailure.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID