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      Local Delivery of 17-Beta-Estradiol Modulates Collagen Content in Coronary Porcine Arteries after PTCA and Stent Implantation

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          Background: Percutaneous transluminal coronary angioplasty (PTCA) and stent implantation are associated with intimal hyperplasia and extracellular matrix (ECM) accumulation, resulting in restenosis. We showed that local delivery of 17-beta-estradiol (17βE) reduced restenosis following PTCA and stent implantation by 47 and 23%, respectively. Because estrogens decreased type I and type III collagen synthesis in vitro, we hypothesized that local delivery of 17βE may influence intimal hyperplasia formation by modulating ECM expression. Methods: Porcine coronary arteries underwent PTCA or stenting and were randomly assigned to 17βE or placebo. After 28 days, animals were sacrificed for histology and collagen type I and III content analysis. Results: Both collagen subtypes increased in the media by 1.7 to 2.6-fold after PTCA and by 15.7 to 16.1-fold after stenting, as compared to PTCA segments. In the neointima, the ratio of collagen type III to type I was 2.7 in stented arteries and only 0.3 in PTCA arteries. In the neointima of 17βE-treated animals, collagen type I (but not type III) content upregulation was limited by 53% after PTCA and by 74% after stenting. Conclusion: Local delivery of 17βE reduces restenosis, in part by decreasing the density of collagen type I in the neointima in PTCA and stented arteries.

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          Most cited references 23

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          Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery.

          Preliminary reports of studies involving simple coronary lesions indicate that a sirolimus-eluting stent significantly reduces the risk of restenosis after percutaneous coronary revascularization. We conducted a randomized, double-blind trial comparing a sirolimus-eluting stent with a standard stent in 1058 patients at 53 centers in the United States who had a newly diagnosed lesion in a native coronary artery. The coronary disease in these patients was complex because of the frequent presence of diabetes (in 26 percent of patients), the high percentage of patients with longer lesions (mean, 14.4 mm), and small vessels (mean, 2.80 mm). The primary end point was failure of the target vessel (a composite of death from cardiac causes, myocardial infarction, and repeated percutaneous or surgical revascularization of the target vessel) within 270 days. The rate of failure of the target vessel was reduced from 21.0 percent with a standard stent to 8.6 percent with a sirolimus-eluting stent (P<0.001)--a reduction that was driven largely by a decrease in the frequency of the need for revascularization of the target lesion (16.6 percent in the standard-stent group vs. 4.1 percent in the sirolimus-stent group, P<0.001). The frequency of neointimal hyperplasia within the stent was also decreased in the group that received sirolimus-eluting stents, as assessed by both angiography and intravascular ultrasonography. Subgroup analyses revealed a reduction in the rates of angiographic restenosis and target-lesion revascularization in all subgroups examined. In this randomized clinical trial involving patients with complex coronary lesions, the use of a sirolimus-eluting stent had a consistent treatment effect, reducing the rates of restenosis and associated clinical events in all subgroups analyzed. Copyright 2003 Massachusetts Medical Society
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            Cardiac interstitium in health and disease: the fibrillar collagen network.

             Karl T Weber (1989)
            Composed of type I and III collagens, the valve leaflets, chordae tendineae and collagen matrix of the myocardium form a structural continuum. Synthesized by cardiac fibroblasts, these fibrillar collagens support and tether myocytes to maintain their alignment, whereas their respective tensile strength and resilience resist the deformation, maintain the shape and thickness, prevent the rupture and contribute to the passive and active stiffness of the myocardium. An acquired or congenital defect in this collagen network can lead to abnormalities in myocardial architecture, mechanics or valve function. In the hypertrophic process that accompanies a pressure overload, for example, increased collagen synthesis, fibroblast proliferation and a structural and biochemical remodeling of the matrix are seen. This includes distinctive patterns of reparative and reactive myocardial fibrosis, each of which alters diastolic and systolic myocardial stiffness and may lead to pathologic hypertrophy. Alternatively, a loss of collagen tethers or decline in matrix tensile strength can be responsible for regional or global transformations in myocardial architecture and function seen in the reperfused ("stunned") myocardium and in dilated (idiopathic) cardiopathy. Inherited disorders in the transcriptional and posttranslational processing of collagen can also alter the biophysical properties of the network. Future studies into collagen gene regulation, gene switching events and the control of collagen synthesis and degradation are needed to develop a more complete understanding of the relation between the collagen network and acquired and inherited forms of heart disease and to utilize therapeutics that will prevent, retard or regress abnormal collagen matrix remodeling.
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              Fibrous cap formation or destruction--the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation.

               S Newby,  A Zaltsman (1999)
              Endothelial activation and infiltration of monocyte macrophages are essential prerequisites for fibrous cap formation, which comprises proliferation and migration of smooth muscle cells and net matrix deposition. Macrophage foam cells and endothelium act as a source of growth factors and chemoattractants for smooth muscle cells. However, growth factors alone do not stimulate smooth muscle cell proliferation or migration. This requires, in addition, the remodelling of the extracellular matrix, at least partly mediated by metalloproteinases. In particular, loss of basement membrane components and contact with the interstitial matrix appears to be required to release a brake on proliferation and migration exerted by the basement membrane. Unless there is a change in the phenotype of macrophages in advanced lesions, it is not clear why fibrous cap destruction rather than formation should take place in macrophage-rich shoulder regions of plaques. Impaired cap formation caused by smooth muscle senescence, mummification and propensity to apoptosis may be as important as increased cap destruction in promoting plaque rupture.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                October 2008
                02 May 2008
                : 45
                : 6
                : 503-511
                aResearch Center, Montreal Heart Institute, and Departments of bBiomedical Sciences, cMedicine and dPharmacology, Université de Montréal, Montréal, Qué., Canada
                128603 J Vasc Res 2008;45:503–511
                © 2008 S. Karger AG, Basel

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                Page count
                Figures: 5, Tables: 1, References: 34, Pages: 9
                Research Paper


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