摘要:

The effects of angiotensin-converting-enzyme (ACE) inhibition on atherosclerosis-induced changes in arterial function are unknown, as well as whether they are coupled to improvements of structural alterations in the arterial wall. An atherogenic (A) diet and the ACE inhibitor perindopril (P) were given concomitantly for 4 months to seven adult Pitman-Moore minipigs (7 months of age; A+P animals), which were compared with seven A and seven control (C) animals. Perindopril, at a daily dose of 4 mg PO that is commonly used in the clinical setting, induced a continuous 70% inhibition of serum ACE activity. At the end of the study, the atherosclerosis-induced impairment of arterial flow was investigated via the hemodynamics and vascular rheology of hindlimb arteries in non-barbiturate-anesthetized pigs. Structural alterations were evaluated from the histopathology of lesions in the arterial tree (abdominal aorta, left interventricular coronary artery [LIVCA], and brachiocephalic trunk [BCT]), with particular attention given to the analysis of the structure and composition of aortic elastic fibers. Atherosclerosis impaired the function of both capacitance and resistance arteries. Blood pressure (BP) rose significantly because of increased hindlimb peripheral resistance (HPR) and aortic input impedance (Zc), although blood flow was not affected. Altered aortic stress and elastic responses revealed that the stiffness of the aorta was markedly increased because of increased wall tension and reduced viscoelasticity, the viscous component being blunted in the arterial wall. Perindopril significantly opposed these alterations by reducing BP, HPR, and Zc and by returning parietal stiffness values to C values by increasing aortic compliance. ACE inhibition prevented the alteration of both stress and elastic responses. Major fibroproliferative fatty lesions were observed in the aorta and LIVCA, while moderate fibrosclerotic lesions were found in the BCT. Computerized densitometric analysis of orcein-stained elastin showed that elastic laminae fragmentation was prominent in the abdominal aorta, less in the LIVCA, and moderate in the BCT. Furthermore, the elastin content was reduced in the atherosclerotic aorta, although this loss of elastin was not associated with changes in the biochemical nature of alkali-insoluble elastin. Perindopril significantly prevented the development of atherosclerosis in the abdominal aorta, LIVCA, and BCT by decreasing the cross-sectional area of lesions as well as the number of lipid-laden cells in the abdominal aorta and LIVCA. In the abdominal aorta, ACE inhibition significantly prevented the alteration of elastic laminae by specifically preventing elastolytic fragmentation of dense elastic laminae, but it did not modify elastin content. In conclusion, ACE inhibition with perindopril showed a significant preventive action on atherosclerosis-induced deleterious effects on vascular wall function and structure, especially by reducing fragmentation of aortic elastic laminae.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The distributions of plasma lipids, lipoproteins, and apoproteins of 14 524 female and male black and white participants 45 to 64 years old in the Atherosclerosis Risk in Communities (ARIC) Study are presented. All specimens were analyzed at a central laboratory. Mean total cholesterol levels increased with increasing age across all ages from 204 to 229 mg/dL (12%) in women and from 208 to 213 mg/dL (2%) in men. Triglyceride levels increased with age in women, remained stable in men, and were higher in whites than blacks. High-density lipoprotein (HDL) cholesterol levels were higher in black and white women (range, 57 to 59 mg/dL) compared with black men (49 to

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

摘要:

The effect of D-Arg-Gly-Asp-Trp (dRGDW), a synthetic RGD-containing peptide, on platelet adhesion and aggregate formation on various purified adhesive proteins and the extracellular matrix of endothelial cells was investigated with anticoagulated blood recirculating through a parallel-plate perfusion chamber. Aggregate formation on the extracellular matrix of phorbol myristate acetate (PMA)-stimulated endothelial cells and on collagen type I was more strongly inhibited by dRGDW at higher shear rates than at a low shear rate. Platelet adhesion to the extracellular matrix of nonactivated and PMA-stimulated endothelial cells was inhibited by dRGDW, especially at high shear rates, probably as a consequence of the inhibition of platelet spreading. Inhibition by dRGDW of platelet adhesion to von Willebrand factor, fibronectin, and fibrinogen was almost complete, indicating that platelet adhesion to these substrates is mediated through RGD-directed receptors. Platelet adhesion to laminin was not inhibited by the peptide, whereas platelet adhesion to collagen was increased as a consequence of the inhibition of aggregate formation. Our results show that dRGDW is a strong inhibitor of platelet adhesion and aggregate formation, especially at high shear rates.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The possible activity of ticlopidine and its analogue clopidogrel in early atherogenesis was investigated. Incubation of rabbit platelets with the extracellular matrix produced by endothelial cells in culture induced massive platelet adherence in vitro. This phenomenon was strongly reduced when platelets were isolated from rabbits that had been treated with a single dose of clopidogrel (10 mg/kg PO) or three doses of ticlopidine (each 200 mg/kg PO) (94% and 56% inhibition of platelet adhesion, respectively). Three doses of aspirin (each 200 mg/kg PO) were ineffective. Air-drying injury of the rabbit carotid artery resulted in platelet adherence to the underlying subendothelium. This platelet accumulation on the damaged vessel wall was greatly reduced by clopidogrel: 95% (p<.001) inhibition of platelet adhesion after a single oral dose of 25 mg/kg. Ticlopidine (200 mg/kg) was also effective (71% inhibition; ><.001), whereas aspirin (100 mg/kg PO) failed to reduce platelet adhesion to the subendothelium. The effect of clopidogrel on intimal smooth muscle hyperplasia in rabbit carotid arteries subjected to air-drying endothelial injury was then investigated. After a 16-day treatment, clopidogrel (25 mg/kg per day PO) inhibited the development of intimal thickening (48% inhibition;p<.01). This effect was dose dependent and increased with the duration of the treatment. Under the same experimental conditions, ticlopidine (200 mg/kg per day PO) inhibited myointimal thickening (57%;p<.001), whereas aspirin was ineffective. These results show that clopidogrel and ticlopidine, two ADP-selective antiplatelet agents, can reduce myointimal thickening after endothelial injury.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

A new medical image analysis system to quantify atherosclerosis in the lower abdominal aorta using magnetic resonance imaging is described. This medical image analysis and display system permits the quantification of the three-dimensional (3D) properties of the vessel wall and lumen cross-sectional area and volumes. Preliminary results of employing this medical image analysis capability on magnetic resonance images demonstrated a twofold increase in wall volume per unit vessel length, corresponding to intimal thickening, before luminal narrowing was detected. This work demonstrated the feasibility and usefulness of quantitatively evaluating the 3D properties of the vessel lumen and wall by using a combination of magnetic resonance imaging and image analysis. The demonstration that intimal wall thickening is observed in images before observable occlusion of the lumen can be expected to provide an important early indicator of the future development of atherosclerosis. Such capability will permit detailed and quantitative studies to assess the effectiveness of therapies, such as drug, exercise, and dietary regimens.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

To test whether a sex difference in insulin-mediated suppression of nonesterified fatty acids (NEFAs) could account for sex differences in plasma triglyceride levels, we studied 632 normoglycemic men and women of European and South Asian descent aged 40 to 69 years. Mean fasting NEFA levels were 19% higher in women than in men. Between fasting and 2 hours after a 75-g oral glucose load, NEFA levels fell by 69% in women and 55% men, so that mean NEFA levels at 2 hours after loading were 19% lower in women than in men. Plasma triglyceride and apolipoprotein B levels were correlated with 2-hour NEFA levels in each sex and ethnic group, and these associations were independent of glucose, insulin, and central obesity. These results are consistent with experimental studies of the effects of insulin and NEFAs on hepatic production of triglycerides and apolipoprotein B. Suppression of NEFA levels in response to insulin is greater in women than in men, and this may account for some of the sex differences in lipoprotein pattern and coronary heart disease risk.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

This report describes the normalized intimal-medial uptakes [uptake {M, mg • cm~2)-r-serum concentration (c0, mg • cm"3)] of 125I-albumin, l25I-low-density lipoprotein (LDL), and in vivo Evans blue dye (EBD)-albumin complex as functions of pressure (P), time (t), molecular species (i), and location (z) along a ventral longitudinal z axis of the normal, intact, aortic endothelial surface in adult normocholesterolemic Sinclair Research Farm (SRF) minipigs and compares these uptake (A//c0) measurements with atherogenesis in hypercholesterolemic cohorts. Uptakes of porcine serum 125I-albumin (n=21) and 125I-LDL (n=10) were measured in freshly excised, metabolically supported aortas using a recently developed organ-support system. In vivo intimal-medial EBD uptake vs z data were measured photometrically on opened descending aortas from another group (n=6) of normocholesterolemic, adult, SRF minipigs 18 hours after the intravenous administration of EBD. For comparison purposes, the corresponding incidence of atherosclerotic lesions along the aortic z axis was calculated using topographic data from hypercholesterolemic minipig cohorts (n=39). The results showed that uptakes varied greatly with t, z, and macromolecule (i) but not with P. More specifically, the value of Af/c0 at any location (z) rose with t, was insensitive to P, decreased with macromolecular (i) size, and varied with z in a pattern that "peaked" in the upstream region, decreased to a nadir in the downstream region, and then rose again as it approached the abdominal celiac orifice. The spatially z-averaged uptake rates for the three different labeled serum proteins were 0.31 × 10"' cm • IT1 for 12SI-albumin, 0.42 × 10"' cm • h"1 for EBD-albumin, and 0.04 × 10"' cm • h"1 for 12SI-LDL. Nondimensionalized analysis of the individual sets of uptake data indicated that the overall uptake relationship [A/(t,P,z, >)/c,o, cm] could be characterized empirically by the simple product of two separate functions: one, a "scaling function" [m(z,i)], that described the uptake magnitude for a given i and z and appeared to be independent of t or P; the other, a "shape function" O(t,P)], that described the shapes of the uptake vs t and P relationships and appeared to be independent of z or i. The "scaling function" [m(z,i)] vs z contour appeared to correlate well with the corresponding atherosclerotic lesion incidence vs z contour from the group of hypercholesterolemic minipig cohorts. Assuming passive transport, it was shown ("Appendix") that m(z,i) can be interpreted physically in terms of an endothelial diffusive permeability coefficient (9/ cm • s"1). We conclude that (1) transport of albumin and LDL across the intact, normocholesterolemic, aortic endothelial surface is independent of pressure; (2) in vivo intimal-medial uptake of EBD can be used as a reasonable measure of 125I-albumin uptake; and (3) intimal-medial uptake rates of l2:I-albumin, I25I-LDL, and in vivo EBD in the normocholesterolemic state correlate with the local probability of subsequent atherogenesis in the hypercholesterolemic state.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Recent epidemiological evidence indicates that the hemostatic profile is an important predictor of cardiovascular disease, yet its dietary determinants are not well established. An important question is whether dietary fatty acid intake influences blood levels of coagulation proteins. We examined potential dietary determinants of six hemostatic factors &#151;fibrinogen,factor VII, factor VIII, von Willebrand factor (vWF), protein C, and antithrombin III &#151;in four population-based samples totaling over 15 000 participants, blacks and whites, in the Atherosclerosis Risk in Communities (ARIC) Study. Usual dietary intake was assessed by a food frequency questionnaire. Cross-sectional associations were explored using multiple linear regression analysis, adjusting for gender, race, age, body mass index, smoking status, alcohol use, diabetes, and field center. Dietary intake of n-3 polyunsaturated fatty acids (PUFAs) showed negative associations with fibrinogen, factor VIII, and vWF (blacks and whites) and a positive association with protein C (whites only). Fish intake, the major source of dietary n-3 PUFAs, was similarly related to the hemostatic profile: a 1 serving per day greater fish intake was associated with the following predicted differences (95% confidence interval): fibrinogen, -2.9 mg/dL (-6.3, 0.5); factor VIII, -3.3% (-5.4, -1.3); vWF, -2.7% (-5.2, -0.1) (blacks and whites); and protein C, +0.07 $ig/mL (0.03, 0.11) (whites only). Other nutrients or foods were variably associated with the hemostatic factors. These populationbased associations, although cross-sectional, suggest that increases in n-3 PUFA intake from fish may modify the blood levels of several coagulation factors.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Dermatan sulfate (DS), a factor that amplifies plasma heparin cofactor II antithrombin (HCII) activity, has been evaluated in baboons for its relative antithrombotic and antihemostatic effects by use of a model that combines both platelet-rich and fibrin-rich thrombus formation. Thrombus was generated in a two-component thrombogenic device incorporated into exteriorized femoral arteriovenous shunts, in which a proximal segment of collagen-coated tubing induces platelet-rich arterial-type thrombus and distal expanded chambers with disturbed and static flow produce fibrin-rich venous-type thrombus. Thrombus formation was measured as the deposition of autologous '"In-platelets by imaging analysis and by the accumulation of '"I-fibrin. Intravenous infusion of DS at 0.83, 8.3, and 42 mg/kg maintained plasma levels at approximately 7, 70, and 400 ftg/mh, respectively, throughout the period of study. By enhancing HCII-dependent inactivation of soluble thrombin, DS prolonged the coagulation times, reduced plasma fibrinopeptide A levels, and decreased fibrin-rich thrombus formation in the chamber portion of the device in a dose-dependent manner, ie, the intermediate dose reduced fibrin accumulation by approximately 70% (p<.05). By contrast, neither platelet deposition on collagen nor platelet hemostatic function, assessed with bleeding time determinations, was significantly affected by DS at any dose studied (P>.2 and P>.1, respectively, for the high dose), a finding presumably explained by the resistance of immobilized thrombin to inactivation by DS.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID