Intimal Plaque Research Articles

Hepatocyte growth factor triggers signaling cascades mediating vascular smooth muscle cell migration

A key event in neointima formation and atherogenesis is the migration of vascular smooth muscle cells (VSMCs) into the intima. This is controlled by cytokines and extracellular matix (ECM) components within the microenvironment of the diseased vessel wall. At present, these signals have only been partially identified. In this study, we demonstrate that Met, the receptor tyrosine kinase for hepatocyte growth factor (HGF), is expressed on VSMCs isolated from the intima of atherosclerotic plaques of carotid arteries. Stimulation with HGF led to activation of Met as well as to activation of PI3-K, PKB/Akt, MEK, and the MAP kinases Erk1 and -2. Moreover, HGF induced lamellipodia formation, a characteristic feature of motile cells, and promoted VSMC migration across fibronectin-coated filters. The HGF-induced cell migration was mediated by β1 integrins and required PI3-K activation. Our results suggest a role for the HGF–Met signaling pathway in the pathogenesis of atherosclerosis and restenosis.

Intimal plaque development and oxidative stress in cholesterol-induced atherosclerosis in New Zealand rabbits.

Although oxidative stress is well known in atherogenesis, the origin, nature and kinetics of free radicals involved have not been well described till now. Here, we correlated parameters of oxidative stress with cellular components during induction and stabilization of aortic intimal lesions which were induced in rabbits by feeding a cholesterol-enriched diet for 6 weeks and a normal diet for further 68 weeks. Plasma lipids, aortic plaque size and composition (macrophages, smooth muscle cells, oxidized LDL by morphometry), as well as aortic radical production (by luminol-enhanced chemiluminescence and TEMPO-9AC fluorescence) were measured after various time points. The parameters of oxidative stress were correlated with the different cellular components of the aortic plaques. The plaques increased until week 21, no significant regression was found until week 74, plasma cholesterol was maximal at week 6. Macrophages, oxidized LDL and generation of different species of free radicals were increased during plaque development, yet with different time kinetics. Whereas chemiluminescence correlated only weakly with the amount of intimal macrophages, strong correlations were found between TEMPO fluorescence and smooth muscle cells (r = 0.4778, P < 0.001) and between macrophages and oxidized LDL (r = 0.5896, P < 0.0001). Different indicators of oxidative stress were increased during plaque progression and stabilization. However, the various correlations show, that distinct types of reactive species secreted probably from macrophages and smooth muscle cells contribute to oxidative stress in the different phases of plaque development.

Cross-reactivity of anti-CagA antibodies with vascular wall antigens: possible pathogenic link between Helicobacter pylori infection and atherosclerosis.

Helicobacter pylori-CagA positive strains have been shown to be associated with atherosclerosis. However, the pathogenesis is still undetermined. The aim of this study was to determine whether anti-CagA antibodies cross-react with antigens of normal and atherosclerotic arteries. Eight umbilical cord sections, 14 atherosclerotic artery sections, and 10 gastrointestinal tract sections were examined by immunohistochemistry using polyclonal anti-CagA antibodies. Five atherosclerotic and 3 normal artery samples were also lysed in ice-cold lysis buffer containing protease inhibitors and were immunoprecipitated using the same antibodies. Anti-CagA antibodies reacted with cytoplasm and nuclei of smooth muscle cells in umbilical cord and atherosclerotic vessel sections, cytoplasm of fibroblasts-like cells in intimal atherosclerotic plaques, and the cell membranes of endothelial cells. Anti-CagA antibodies also specifically immunoprecipitated 2 high molecular weight antigens of 160 and 180 kDa from both normal and atherosclerotic artery lysates. Anti-CagA antibodies cross-react with antigens of both normal and atherosclerotic blood vessels. We speculate that the binding of anti-CagA antibodies to those antigens in injured arteries could influence the progression of atherosclerosis in CagA-positive H pylori-infected patients.

Natriuretic Peptide System Gene Expression in Human Coronary Arteries

The natriuretic peptides (NPs) ANF, BNP, and CNP have potent anti-proliferative and anti-migratory effects on vascular smooth muscle cells (SMCs). These properties make NPs relevant to the study of human coronary atherosclerosis because vascular cell proliferation and migration are central to the pathophysiology of atherosclerosis. However, the existence and cytological distribution of NPs and their receptors in human coronary arteries remain undetermined. This has hampered the development of hypotheses regarding the possible role of NPs in human coronary disease. We determined the pattern of expression of NPs and their receptors (NPRs) in human coronary arteries with atherosclerotic lesions classified by standard histopathological criteria as fatty streak/early atherosclerotic lesions, intermediate plaques, or advanced lesions. The investigation was carried out using a combination of immunocytochemistry (ICC), in situ hybridization (ISH), and semi-quantitative polymerase chain reaction (PCR). Both by ICC and ISH, ANF was found in the intimal and medial layers of all lesions. BNP was highly expressed in advanced lesions where it was particularly evident by a strong ISH signal but weak ICC staining. CNP was demonstrable in all types of lesions, giving a strong signal by ISH and ICC. This peptide was particularly demonstrable in the endothelium, as well as in the SMCs of the intima, media, and vasa vasorum of the adventitia and in macrophages. By ISH, NPR-A was not detectable in any of the lesions but both NPR-B and NPR-C were found in the intimal and the inner medial layers. By RT-PCR, mRNA levels of all NPs tended to be increased in macroscopically diseased arteries, but only the values for BNP were significantly so. No significant changes in NPR mRNA levels were detected by PCR. In general, the signal intensity given by the NPs and their receptors by ICC or ISH appeared dependent on the type of lesion, being strongest in intermediate plaques and decreasing with increasing severity of the lesion. This study constitutes the first demonstration of NPs and NPR mRNAs in human coronary arteries and supports the existence of an autocrine/paracrine NP system that is actively modulated during the progression of atherosclerotic coronary disease. This suggests that the coronary NP system is involved in the pathobiology of intimal plaque formation in humans and may be involved in vascular remodeling.

Percutaneous Retrieval of the Tulip Vena Cava Filter: Feasibility, Short- and Long-Term Changes. An Experimental Study in Dogs

To evaluate experimentally the retrievability of the Tulip inferior vena cava (IVC) filter in an in vivo study. Changes which accompany venous healing after filter retrieval were investigated. In 12 dogs, 23 filters were inserted percutaneously into the lumbar and intrahepatic segments of the IVC. Two weeks (n = 21 filters) or 3 weeks (n = 2 filters) after insertion, filter retrieval was attempted through an 11 Fr coaxial retrieval sheath system placed via the jugular vein. Follow-up studies before and after filter retrieval included cavography, computed tomography and intravascular ultrasound of the IVC. Seven dogs were killed immediately after filter retrieval to confirm short-term changes of the IVC, and 5 dogs were killed 6 months after filter retraction to evaluate long-term changes of the IVC related to filter retrieval. Post-mortem examinations and histologic specimens of the IVC were obtained to evaluate caval wall abnormalities secondary to filter removal. All but one filter were successfully retrieved 2 weeks post-implantation. However, 3 weeks after insertion, filter retrieval was impossible. There were no complications caused by filter extraction. Follow-up studies after filter retrieval revealed no significant changes in the integrity, morphology or composition of the IVC and pericaval tissue. Histologic examination 6 months after filter retrieval revealed only flimsy fibrotic intimal plaques at the sites of former hook insertion. The Tulip filter allows percutaneous insertion and retrieval up to 14 days after insertion, suggesting that it may be useful for either permanent or temporary prophylaxis against pulmonary embolism.

Expression of SR-PSOX, a novel cell-surface scavenger receptor for phosphatidylserine and oxidized LDL in human atherosclerotic lesions.

Receptor-mediated endocytosis of oxidized low density lipoprotein (Ox-LDL) by macrophages and the subsequent foam cell transformation in the arterial intima are key events in early atherogenesis. Recently, we have identified a novel macrophage cell-surface receptor for Ox-LDL by expression cloning from a cDNA library of phorbol 12-myristate 13-acetate-stimulated THP-1 cells, designated as the scavenger receptor for phosphatidylserine and oxidized lipoprotein (SR-PSOX). Here, we examined SR-PSOX expression in human atherosclerotic lesions. Total cellular RNA and fresh frozen sections were prepared from human carotid endarterectomy specimens (from 21 patients) and directional coronary atherectomy specimens (from 11 patients). Fragments of human aortas of 2 patients without visible atherosclerotic lesions served as negative controls. Quantitative reverse transcription-polymerase chain reaction demonstrated that SR-PSOX mRNA expression was prominent in atherosclerotic lesions but undetectable in normal aortas. Immunohistochemistry showed that SR-PSOX was predominantly expressed by lipid-laden macrophages in the intima of atherosclerotic plaques in carotid endarterectomy and directional coronary atherectomy specimens, although its expression was not detectable in normal arterial wall. Double-labeled immunohistochemistry confirmed that SR-PSOX is expressed by intimal macrophages. Taken together, SR-PSOX may be involved in Ox-LDL uptake and subsequent foam cell transformation in macrophages in vivo and thus may play important roles in human atherosclerotic lesion formation.

Formula omitted] -carnitine prevents the progression of atherosclerotic lesions in hypercholesterolaemic rabbits

This study has been initiated to investigate, in hypercholesterolaemic rabbits, whether l -carnitine deficiency could be an additional risk factor in atherosclerosis, and if so, whether l -carnitine supplementation could prevent the progression of atherosclerosis. Hypercholesterolaemia was induced by feeding rabbits 2% cholesterol-enriched diet for 28 days, whereas, carnitine deficiency was induced by daily i.p. administration of 250 mg kg−1of d -carnitine for 28 days. Histopathological examination of aorta and coronaries from hypercholesterolaemic rabbits revealed severe atherosclerotic lesions, intimal plaques and foam cell formation. Also, hypercholesterolaemic diet resulted in a significant 53 and 43% decrease in reduced glutathion (GSH) levels and a significant (1.87-fold) and (14.1-fold) increase in malonedialdhyde (MDA) levels in aorta and cardiac tissues, respectively. Daily administration of l -carnitine (250 mg kg−1) for 28 days, completely prevented the progression of atherosclerotic lesions induced by hpercholesterolaemia in both aorta and coronaries. Conversely, daily administration of d -carnitine (250 mg kg−1) for 28 days increased the progression of atherosclerotic lesions with the appearance of foam cells and apparent intimal plaques which are even larger than that seen in hypercholesterolaemic rabbits. Both l -carnitine and d -carnitine produced similar effects on the lipid profile, GSH and MDA which may point to the conclusion that: (1)l -carnitine prevents the progression of atherosclerotic lesions by another mechanism in addition to its antioxidant and lipid-lowering effects; (2) endogenous carnitine depletion and/or carnitine deficiency should be viewed as an additional risk factor in atherogenesis.

Cholesterol crystal embolization presenting as a colonic pseudotumor: Case report and review

Cholesterol crystal embolization (CCE) syndrome is defined as dislodgement of cholesterol crystals greater than 200 μm in size from atheromatous intimal plaques. Panum1 described the phenomenon of embolization of atheromatous material in 1862. However, Florey is credited with accurately describing the process of occlusion of arterioles by cholesterol crystals.2,3 The syndrome presents as a systemic illness during or immediately after an arterial catheterization, aortic surgery, thrombolytic therapy, or anticoagulation.

Coexpression of endothelin-converting enzyme-1 and endothelin-1 in different stages of human atherosclerosis.

Endothelin-converting enzyme (ECE)-1 activates endothelin-1 (ET-1) and may thus contribute to the regulation of vascular tone and cell growth during atherosclerosis. To evaluate ECE-1 immunoreactivity concerning big ET-1/ET-1, we performed qualitative and quantitative immunohistochemistry in normal internal mammary arteries (n=10), in coronary arteries with adaptive intimal fibrosis (n=10), in aortic fatty streaks (n=10), and in distinct regions of advanced carotid plaques (n=15). Furthermore, we determined ECE-1 activity in the control specimens and in the inflammatory intimal regions of carotid plaques. Double immunolabeling showed that ECE-1 was present in endothelial cells, vascular smooth muscle cells, and macrophages. All ET-1(+) cells were simultaneously ECE-1(+). Most importantly, there were significantly more ET-1(+) cells in the intima and media when atherosclerosis was in an inflammatory stage than when it was in a noninflammatory stage. Moreover, ECE-1 activity was upregulated in the intima of carotid plaques, although immunohistochemically, there were no significant differences between the number of ECE(+) cells in the different compartments of the arterial wall. Together with ET-1, ECE-1 is abundantly present in human arteries and at different stages of atherosclerotic plaque evolution. The upregulation of the ECE-1/ET-1 system is closely linked to the presence of chronic inflammation and is present in very early stages of plaque evolution. Therefore, enhanced production of active ET-1 may substantially contribute to cell growth and the regulation of vascular tone in advanced atherosclerotic lesions and in the very early stages of plaque evolution, when a plaque is still imperceptible clinically.

Regression of early events of atherosclerosis in hypercholesterolemic rabbits by prophylactic treatment with nitroderivative of acetyl salicylic acid

AbstractThe potential of a newly developed compound, nitro‐aspirin (NO‐aspirin, NCX‐4016), on regression of early atherosclerotic events in hypercholesterolemic rabbit (HypR) was examined. Hypercholesterolemia was induced by feeding rabbits 2% cholesterol‐enriched diet for 28 days. During this induction period, HypRs were divided into two groups: one was given an oral single daily dose of 56 mg/kg/day NO‐aspirin in olive oil, whereas the other received olive oil alone and served as a control. A normal group of rabbits fed plain chow diet plus olive oil was also included. At the end of the 28 days, samples from blood, aorta, heart, and coronary arteries were separated for biochemical and histopathological examination. Tissues from HypR aorta and coronaries developed major changes that include formation of large intimal plaques, endothelial gaps with marked accumulation of foam cells. Highly significant increases in serum triglycerides and malondialdehyde and a decrease in reduced glutathione (GSH) in heart and aorta were also observed. Administration of NO‐aspirin markedly improved aortic and coronary architecture to almost normal appearance. NO‐aspirin also improved the antioxidant status in aorta and heart by increasing GSH levels and ameliorating malondialdehyde accumulation. These data support prophylactic use of NO‐aspirin in regression of atherosclerosis. Drug Dev. Res. 53:237–243, 2001. © 2001 Wiley‐Liss, Inc.

The topography of intimal thickening and associated remodeling pattern of early transplant coronary disease: influence of pre-existent donor atherosclerosis

Background: With native coronary disease, intimal plaque initially accumulates at focal areas in the artery, often accompanied by compensatory vessel enlargement. With transplant coronary disease, the topography of intimal thickening and associated remodeling pattern are less studied. Methods: We studied 72 prospectively recruited transplant patients with serial intravascular ultrasound using 4.3F catheters at baseline and at 1-year follow up. We considered 175 ultrasound-recorded segments (mean, 2.4 ± 1.1 segments per patient) exactly matched on the serial studies by both angiographic criteria and ultrasound criteria, using arterial and venous branch points, pericardium, and sinuses as anatomic landmarks. Results: Eighty-eight segments had no donor disease, and 87 had donor disease (80 eccentric and 7 concentric intimal thickening). Progressive intimal thickening occurred in 48 segments without (55%) and 43 segments with donor disease (48%, p = NS). Thickening from segments without donor disease was mainly eccentric (81%). Thickening from segments with donor eccentric plaque was also mainly eccentric (67%, p = NS compared with segments without donor disease), with further thickening superimposed on the original plaque. Concentric intimal thickening was uncommon. Of the 58 patients who had >1 segment matched, intimal changes were discordant in 34 (59%), with progression in some and lack of progression in other segments. Total vessel area change correlated with intimal area change ( r = 0.37 with a slope of 0.79, p < 0.001), including segments with ( r = 0.39; slope, 0.69) and segments without ( r = 0.37; slope, 1.16) donor disease. Conclusion: The intimal thickening of early transplant coronary disease is mainly eccentric and often discordant within each individual patient. Donor eccentric plaque often serves as a nidus for further intimal growth. The topography of intimal thickening in transplant coronary disease resembles that of native coronary disease, but the presence of a pre-existent donor plaque may impede compensatory remodeling as further intimal thickening occurs after transplantation.

Atheromas that cause fatal thrombosis are usually large and frequently accompanied by vessel enlargement

Several lines of clinical evidence show that AMI frequently occurs at sites with mild to moderate degree of coronary stenosis. The degree of luminal stenosis depends on plaque deposition and degree of vessel remodeling, features poorly assessed by coronary angiography. This postmortem study tested the hypothesis that the size of coronary atheroma and the type of remodeling distinguish culprit lesion responsible for fatal AMI from equi-stenotic nonculprit lesion in the same coronary tree. The main coronary branches from 36 consecutive patients with fatal AMI were studied. The culprit lesion (Group 1) and an equi-stenotic nonculprit segment (Group 2) obtained in measurements of another coronary branch from the same patient were compared. Morphometry and plaque composition was assessed in both groups. Compared to Group 2, Group 1 had larger areas of: plaque 9.6 vs. 4.7 mm 2, vessel 12.7 vs. 7.4 mm 2 and lumen 1.7 vs. 1.2 mm 2; ( P<.01). Positive remodeling was more frequent in Group 1 than Group 2: 21/30 (70%) vs. 8/26 (31%). Plaque area correlated positively with lipid core and macrophages and negatively with fibrosis and smooth muscle cells. Atherosclerotic plaques that cause fatal thrombosis are more frequently positively remodeled and tend to be larger than nonculprit plaques with the same degree of cross-sectional stenosis. We tested whether arterial remodeling and plaque size vary between segments containing a fatal thrombosed plaque versus an equi-stenotic nonculprit plaque. Culprit vessel segments had higher cross-sectional areas of intimal plaque and of vessel wall than equi-stenotic nonculprit plaques. The cross-sectional area of the vessel correlated positively with both the lipid core area and CD68 + macrophage content, and negatively with fibrosis area and smooth muscle cell content. These results add elements explaining limitations of angiography in identifying plaques and provide new insights into the role of remodeling in plaque instability.

Experimental study of Yishou Tiaozhi tablet("Equation missing" ) on inhibiting hyperlipemia and atherosclerosis) on inhibiting hyperlipemia and atherosclerosis

Objective: To observe the effect of Yishou Tiaozhi tablet(YSTZT) on lipid metabolism and aortic intimal atherosclerotic plaque coverage in rabbit model of experimental hyperlipemia and atherosclerosis.Methods: Thirty-two rabbits were randomly divided into four groups, Group A, B, C and D, 8 in each group. Forage with cholesterol and lipid plus 1.59 g/kg of YSTZT was fed to Group A every day; for Group B, 22.54 mg/kg gypenoside tablet was added to forage with cholesterol and lipid; for Group C, hyperlipid forage was given and for Group D, only ordinary forage was given. Biochemical parameters were measured and pathomorpho-logical examinations were carried out 6 weeks later.Results: (1) YSTZT obviously lowered the levels of serum total cholesterol(TC), triglyceride(TG), atherosclerotic index(AI), apoprotein(ApoB), lipoprotein [Lp(a)], oxygen-low density lipoprotein cholesterol (ox-LDL), hydroxyproline(HYP), plasma Ca2+, thromboxane B2 (TXB2), and increased the levels of serum high-density lipoprotein cholesterol(HDL-C), apoprotein A1 (Apo A1), ApoA1/ApoB, plasma 6-keto-PGFlα (P < 0.01). (2) Pathomorphological examination showed that in Group A aortic intimal atherosclerotic plaque area and arterial intima thickness were obviously reduced, smooth muscle cell hyperplasia and elastic fibers were not seen.Conclusion: YSTZT can inhibit experimental hyperlipemia and atherogenesis. It is an ideal and effective medicine in preventing and treating hyperlipemia and atherosclerosis.

Generation of C-Reactive Protein and Complement Components in Atherosclerotic Plaques

C-reactive protein (CRP) and complement are hypothesized to be major mediators of inflammation in atherosclerotic plaques. We used the reverse transcriptase-polymerase chain reaction technique to detect the mRNAs for CRP and the classical complement components C1 to C9 in both normal arterial and plaque tissue, establishing that they can be endogenously generated by arteries. When the CRP mRNA levels of plaque tissue, normal artery, and liver were compared in the same cases, plaque levels were 10.2-fold higher than normal artery and 7.2-fold higher than liver. By Western blotting, we showed that the protein levels of CRP and complement proteins were also up-regulated in plaque tissue and that there was full activation of the classical complement pathway. By in situ hybridization, we detected intense signals for CRP and C4 mRNAs in smooth muscle-like cells and macrophages in the thickened intima of plaques. By immunohistochemistry we showed co-localization of CRP and the membrane attack complex of complement. We also detected up-regulation in plaque tissue of the mRNAs for the macrophage markers CD11b and HLA-DR, as well as their protein products. We showed by immunohistochemistry macrophage infiltration of plaque tissue. Because CRP is a complement activator, and activated complement attacks cells in plaque tissue, these data provide evidence of a self-sustaining autotoxic mechanism operating within the plaques as a precursor to thrombotic events.

Atherosclerotic enlargement of the human abdominal aorta

Aortic aneurysms usually develop in the atherosclerosis prone infrarenal abdominal aorta. To assess the role of atherosclerosis in aortic enlargement, we studied the relation between plaque formation and aortic size in 30 pressure-fixed male cadaver aortas (age 40–95 years, mean age 67 years). Morphometric analysis of transverse sections of the mid-thoracic and the mid-abdominal aortas included measurement of intimal plaque area, lumen area, plaque and media thicknesses. The area encompassed by the internal elastic lamina area (IEL area) was taken to be an index of aortic size. IEL area increased with age at both the thoracic ( r=0.77, P<0.01) and abdominal ( r=0.54, P<0.01) aortic levels. The aorta also enlarged with increasing plaque area at the thoracic ( r=0.73, P<0.01) and abdominal ( r=0.79, P<0.01) levels. Regression analysis of IEL area on age, body weight, height and plaque area revealed that the primary predictor of thoracic aortic size was age, whereas the primary predictor of abdominal aortic size was plaque area. Plaque thickness in the abdominal aorta was greater than in the thoracic aorta ( P<0.01). Increased plaque area was associated with a significant decrease in media thickness in the abdominal aorta ( r=−0.75, P<0.01) but not in the thoracic aorta. Aortas with relatively enlarged abdominal segments, i.e. those with a thoracic to abdominal ratio of <1.2 ( n=13), were compared to those with a normal ratio (≥1.2, n=17). Relatively large abdominal aortas had twofold greater plaque area ( P<0.001), reduced medial thickness ( P<0.05), fewer medial elastic lamellae ( P<0.01) and greater mural tensile stress ( P<0.05) than relatively normal abdominal aortas. We conclude that plaque formation in the infrarenal abdominal aorta in humans is associated with aortic enlargement and decreased media thickness. These changes may be predisposing factors for the preferential development of subsequent aneurysmal dilation in the abdominal aorta.

Aneurysmal and occlusive atherosclerosis of the human abdominal aorta

Purpose: The purpose of this study was to assess atherosclerotic plaque deposition and aortic wall responses in the abdominal aorta in relation to the development of aneurysmal and occlusive disease in the infrarenal aorta. Methods: Morphologic differences at five standardized locations in the infrarenal aorta in 67 pressure perfusion–fixed male cadaver aortas (aged, 41-98 years; mean, 66 years) were studied and compared with the supraceliac segment. Quantitative computer-assisted morphometry of histologic sections included measurement of plaque area, lumen area, lumen diameter, media thickness, number of medial elastic lamellae, and the area encompassed by the internal elastic lamina that best represents the artery size of each segment. The ratio of the supraceliac segment to the midabdominal segment (normally greater than 1.3) was used to define three groups: Group I (normal): ratio greater than or equal to 1.30 (n = 31); Group II (intermediate): ratio greater than or equal to 1.20 but less than 1.30 (n = 20); and Group III: ratio less than 1.20 (n = 16), which represented dilated midabdominal aortas. There was no significant difference in age among the groups. Results: Group I had minimal intimal plaque and little gross evidence of atherosclerosis. Group II had increased intimal plaque compared with Group I (P <.01) and gross evidence of atherosclerosis, which was maximally localized in the distal aorta; there was no aortic enlargement or thinning of the media underneath the plaque. Group III had more intimal plaque than Group I (P <.01) and Group II (P <.01) and was associated with localized aortic enlargement and media thinning compared with Group I (P <.05) and Group II (P <.01). Increasing intimal plaque in Group III correlated with an increase in lumen diameter (r = 0.61, P <.05), but this relationship was not significant in Group I and Group II. The aortic media in Group III had a reduced number of medial elastic lamellae, was reduced in thickness, and was more exposed to increased wall stress than the aortas in Groups I and II. Conclusion: These results suggest that there may be different local responses to atherosclerosis in the abdominal aorta in human beings. Plaque deposition associated with localized dilation, thinning of the media, and loss of medial elastic lamellae may predispose that segment of aorta to subsequent aneurysm formation. Plaque deposits without media thinning, without loss of elastic lamellae, and without artery wall dilation may predispose the aorta, in the event of continuing plaque accumulation, to the development of lumen stenosis. (J Vasc Surg 2001;33:91-6.)

Estrogens and women's health: interrelation of coronary heart disease, breast cancer and osteoporosis

The determinants of blood levels of estrogen, estrogen metabolites, and relation to receptors and post-transitional effects are the likely primary cause of breast cancer. Very high risk women for breast cancer can now be identified by measuring bone mineral density and hormone levels. These high risk women have rates of breast cancer similar to risk of myocardial infarction. They are candidates for SERM therapies to reduce risk of breast cancer. The completion of the Women's Health Initiative and other such trials will likely provide a definite association of risk and benefit of both estrogen alone and estrogen-progesterone therapy, coronary heart disease, osteoporotic fracture, and breast cancer. The potential intervention of hormone replacement therapy, obesity, or weight gain and increased atherogenic lipoproteinemia may be of concern and confound the results of clinical trials. Estrogens, clearly, are important in the risk of bone loss and osteoporotic fracture. Obesity is the primary determinant of postmenopausal estrogen levels and reduced risk of fracture. Weight reduction may increase rates of bone loss and fracture. Clinical trials that evaluate weight loss should monitor effects on bone. The beneficial addition of increased physical activity, higher dose of calcium or vitamin D, or use of bone reabsorption drugs in coordination with weight loss should be evaluated. Any therapy that raises blood estrogen or metabolite activity and decreases bone loss may increase risk of breast cancer. Future clinical trials must evaluate multiple endpoints such as CHD, osteoporosis, and breast cancer within the study. The use of surrogate markers such as bone mineral density, coronary calcium, carotid intimal medial thickness and plaque, endothelial function, breast density, hormone levels and metabolites could enhance the evaluation of risk factors, genetic-environmental intervention, and new therapies.

Reduction of aortic wall motion inhibits hypertension-mediated experimental atherosclerosis.

Hypertension is a well-known risk factor for coronary artery disease and carotid and lower extremity occlusive disease. Surgically induced hypertension in hypercholesterolemic animals results in increased aortic wall motion and increased plaque formation. We tested the hypothesis that reduction in aortic wall motion, despite continued hypertension, could reduce plaque formation. New Zealand White rabbits (n=26) underwent thoracic aortic banding to induce hypertension and were fed an atherogenic diet for 3 weeks. In 13 rabbits, a segment of aorta proximal to an aortic band was externally wrapped to reduce wall motion. All animals were fed an atherogenic diet for 3 weeks. Four groups were studied: 1, coarctation control (no wrap, n=7); 2, coarctation with loose wrap (n=6); 3, coarctation with firm wrap (n=7); and 4, control (noncoarcted, n=6). Wall motion, blood pressure, and pulse pressure were measured at standard reference sites proximal and distal to the coarctation by use of intravascular ultrasound. Quantitative morphometry was used to measure intimal plaque. Mean arterial pressure and cyclic aortic wall motion were equally increased proximal to the aortic coarctation in all 3 coarcted rabbit groups compared with the control group (P:<0.001). Wall motion in the segment of aorta under the loose and firm wraps was no different from the control value. The external wrap significantly reduced intimal thickening in the 4 groups by the following amounts: group 1, 0.30+/-0.03 mm(2); group 2, 0.06+/-0.02 mm(2); group 3, 0. 04+/-0.02 mm(2); and group 4, 0.01+/-0.01 mm(2) (P:<0.001). Localized inhibition of aortic wall motion in the lesion-prone hypertensive aorta resulted in significant reduction in intimal plaque formation. These data suggest that arterial wall cyclic motion may stimulate cellular proliferation and lipid uptake in experimental atherosclerosis.

Wall shear stress and early atherosclerosis: a review.

therosclerosis remains the leading cause of morbidity and mortality in the Western world [1, 2]. It is usually regarded as a systemic disease and several well-identified risk factors (i.e., hypertension, hyperlipidemia, diabetes mellitus, and cigarette smoking) have been implicated in its pathogenesis. Noninvasive imaging of atherosclerosis, such as intimal wall thickening and plaque formation, is routinely available using a variety of imaging techniques. The causes of atherosclerosis are multifactorial and knowing them could allow earlier prevention and detection of the disease. The frequent occurrence of atherosclerotic plaques in well-recognized arterial districts, together with the focal distribution of these plaques in regions of curvature, bifurcation, and branching of the vessels, suggests that fluid dynamics and vessel geometry may play a localizing role in the cause of plaque formation [3]. In vitro and in vivo models have been used to study the flow patterns in a variety of arterial territories and to look for an association between areas of preferential atherosclerotic plaque formation and blood flow hemodynamics [4‐7]. The magnitude and rate of change of blood flow close to a vessel wall, which can be expressed using the concept of wall shear stress, have been linked to the pathogenesis of atherosclerosis. Vessel segments with low wall shear stress or highly oscillatory wall shear stress appear to be at the highest risk for development of atherosclerosis. The purpose of this review is to familiarize the imager with the concepts and principles underlying wall shear stress measurements. Wall shear stress mapping may someday become part of the multifactorial, multidisciplinary approach to early atherosclerosis detection. We first review this hypothesized association between atherosclerosis and wall shear stress. We then review the use of phase-contrast velocity-encoded MR imaging and Doppler sonography to map velocity profiles in vascular structures. These hemodynamic parameters can be used to calculate how quickly the blood velocity increases when moving from the vessel wall to the center of the vessel. Estimation of wall shear stress is now possible with noninvasive imaging techniques such as MR imaging and Doppler sonography. MR imaging can be used to confirm, in vivo, what is known from in vitro hemodynamic studies and observations made at autopsy and in experimental models. Someday, this may help us better understand the importance of flow hemodynamics in the multifactorial etiology of atherosclerosis. Wall Shear Stress

Inhibition of transplant vasculopathy in a rat aortic allograft model after infusion of anti-inflammatory viral serpin.

Transplant vasculopathy remains a difficult therapeutic problem, resulting in the majority of late cardiac graft losses. This chronic vascular disease is thought to be triggered by alloantigen-dependent and alloantigen-independent inflammatory factors. Despite improved 1-year survival, the incidence of transplant vasculopathy has not improved with current immunosuppressive protocols. Highly effective strategies have evolved in the large DNA viruses that shield infecting viruses from host inflammatory responses. Serp-1 is a secreted myxoma virus anti-inflammatory serine proteinase inhibitor. Serp-1 inhibits plasminogen activators in a manner similar to plasminogen activator inhibitor (PAI-1), a vascular protein that plays a pivotal regulatory role in vascular wound healing. In this study, we tested the ability of purified Serp-1 protein to ameliorate posttransplant vasculopathy after rat aortic allograft surgery. Serp-1 protein or controls were infused into 98 rats immediately after segmental aortic allograft transplantation. After either late (28 days, 64 rats) or early (12 to 48 hours, 24 rats) follow-up, transplanted aortic segments were harvested for morphological and immunohistochemical analysis. Significant reductions in intimal plaque growth (P<0.002) and mononuclear cell invasion (P<0.033) were detected after Serp-1 infusion at nanogram doses. Serp-1 reduced early macrophage (P<0.0016) and nonspecific lymphocyte (P<0.0179) invasion into medial and adventitial layers and inhibited associated depletion of medial smooth muscle cells (P<0.0006). Infusion of a viral anti-inflammatory serpin, Serp-1, significantly reduces early inflammatory responses and later luminal occlusion in a rat aortic allograft model.