Background: The heterogeneous structure of carotid atherosclerotic plaques may be better understood if it is related to blood flow variations, influencing gene expression and cellular functions. Upstream of the maximum stenosis there is laminar blood flow and high shear stress, downstream there is turbulence and low shear stress. We studied if these variations were associated with differences in plaque morphology and composition between sites located up- and downstream of the maximum stenosis in symptomatic carotid plaques. Methods: Patients with symptomatic carotid stenosis were examined with magnetic resonance angiography to localize the maximum stenosis in-vivo, prior to endarterectomy. In 41 endarterectomized specimens, transverse tissue sections prepared up- and downstream of the maximum stenosis were compared using histopathology and immunohistochemistry. Results: The location of maximum stenosis relative the carotid bifurcation varied considerably between plaques. Compared with the downstream side, the upstream side of the stenosis had higher incidence of severe lesions with cap rupture and intraplaque hemorrhage, more macrophages, less smooth muscle cells and more collagen. Conclusions: The up- and downstream sides of symptomatic carotid plaques differed in plaque morphology and composition. This implies that the intraplaque location of sampling sites may be a confounding factor in studies of atherosclerotic plaques.

1.
Helderman F, Segers D, de Crom R, Hierck BP, Poelmann RE, Evans PC, Krams R: Effect of shear stress on vascular inflammation and plaque development. Curr Opin Lipidol 2007;18:527–533.
2.
Xue YJ, Gao PY, Duan Q, Lin Y, Dai CB: Preliminary study of hemodynamic distribution in patient-specific stenotic carotid bifurcation by image-based computational fluid dynamics. Acta Radiol 2008;49:558–565.
3.
Lovett JK, Rothwell PM: Site of carotid plaque ulceration in relation to direction of blood flow: an angiographic and pathological study. Cerebrovasc Dis 2003;16:369–375.
4.
Dirksen MT, van der Wal AC, van den Berg FM, van der Loos CM, Becker AE: Distribution of inflammatory cells in atherosclerotic plaques relates to the direction of flow. Circulation 1998;98:2000–2003.
5.
Yilmaz A, Lipfert B, Cicha I, Schubert K, Klein M, Raithel D, Daniel WG, Garlichs CD: Accumulation of immune cells and high expression of chemokines/chemokine receptors in the upstream shoulder of atherosclerotic carotid plaques. Exp Mol Pathol 2007;82:245–255.
6.
Smedby O: Do plaques grow upstream or downstream?: an angiographic study in the femoral artery. Arterioscler Thromb Vasc Biol 1997;17:912–918.
7.
Walpola PL, Gotlieb AI, Cybulsky MI, Langille BL: Expression of ICAM-1 and VCAM-1 and monocyte adherence in arteries exposed to altered shear stress. Arterioscler Thromb Vasc Biol 1995;15:2–10.
8.
Segers D, Helderman F, Cheng C, van Damme LC, Tempel D, Boersma E, Serruys PW, de Crom R, van der Steen AF, Holvoet P, Krams R: Gelatinolytic activity in atherosclerotic plaques is highly localized and is associated with both macrophages and smooth muscle cells in vivo. Circulation 2007;115:609–616.
9.
Jander S, Sitzer M, Schumann R, Schroeter M, Siebler M, Steinmetz H, Stoll G: Inflammation in high-grade carotid stenosis: a possible role for macrophages and T cells in plaque destabilization. Stroke 1998;29:1625–1630.
10.
Husain T, Abbott CR, Scott DJ, Gough MJ: Macrophage accumulation within the cap of carotid atherosclerotic plaques is associated with the onset of cerebral ischemic events. J Vasc Surg 1999;30:269–276.
11.
MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis. European Carotid Surgery Trialists’ Collaborative Group. Lancet 1991;337:1235–1243.
12.
Dalager-Pedersen S, Falk E, Ringgaard S, Kristensen IB, Pedersen EM: Effects of temperature and histopathologic preparation on the size and morphology of atherosclerotic carotid arteries as imaged by MRI. J Magn Reson Imaging 1999;10:876–885.
13.
Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW: A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1995;92:1355–1374.
14.
Lovett JK, Gallagher PJ, Hands LJ, Walton J, Rothwell PM: Histological correlates of carotid plaque surface morphology on lumen contrast imaging. Circulation 2004;110:2190–2197.
15.
McElroy DA: Connective Tissue. Washington DC, American Registry of Pathology, 1994.
16.
Svensson PA, Olson FJ, Hagg DA, Ryndel M, Wiklund O, Karlstrom L, Hulthe J, Carlsson LMS, Fagerberg B: Urokinase-type plasminogen activator receptor is associated with macrophages and plaque rupture in symptomatic carotid atherosclerosis. Int J Mol Med 2008;22:459–464.
17.
Redgrave JN, Lovett JK, Gallagher PJ, Rothwell PM: Histological assessment of 526 symptomatic carotid plaques in relation to the nature and timing of ischemic symptoms: the Oxford plaque study. Circulation 2006;113:2320–2328.
18.
Peeters W, Hellings WE, de Kleijn DP, de Vries JP, Moll FL, Vink A, Pasterkamp G: Carotid atherosclerotic plaques stabilize after stroke. Insights into the natural process of atherosclerotic plaque stabilization. Arterioscler Thromb Vasc Biol 2009;29:128–133.
19.
Kwak BR, Mulhaupt F, Mach F: Atherosclerosis: anti-inflammatory and immunomodulatory activities of statins. Autoimmun Rev 2003;2:332–338.
20.
Stroud JS, Berger SA, Saloner D: Numerical analysis of flow through a severely stenotic carotid artery bifurcation. J Biomech Eng 2002;124:9–20.
21.
Cunningham KS, Gotlieb AI: The role of shear stress in the pathogenesis of atherosclerosis. Lab Invest 2005;85:9–23.
22.
Weitkamp B, Cullen P, Plenz G, Robenek H, Rauterberg J: Human macrophages synthesize type VIII collagen in vitro and in the atherosclerotic plaque. Faseb J 1999;13:1445–1457.
23.
Trogan E, Choudhury RP, Dansky HM, Rong JX, Breslow JL, Fisher EA: Laser capture microdissection analysis of gene expression in macrophages from atherosclerotic lesions of apolipoprotein E-deficient mice. Proc Natl Acad Sci USA 2002;99:2234–2239.
24.
Martinet W, Knaapen MW, De Meyer GR, Herman AG, Kockx MM: Overexpression of the anti-apoptotic caspase-2 short isoform in macrophage-derived foam cells of human atherosclerotic plaques. Am J Pathol 2003;162:731–736.
25.
Hagg DA, Jernas M, Wiklund O, Thelle DS, Fagerberg B, Eriksson P, Hamsten A, Olsson B, Carlsson B, Carlsson LM, Svensson PA: Expression profiling of macrophages from subjects with atherosclerosis to identify novel susceptibility genes. Int J Mol Med 2008;21:697–704.
26.
Ijas P, Nuotio K, Saksi J, Soinne L, et al.: Microarray analysis reveals overexpression of CD163 and HO-1 in symptomatic carotid plaques. Arterioscler Thromb Vasc Biol 2007;27:154–160.
27.
Lovett JK, Redgrave JN, Rothwell PM: A critical appraisal of the performance, reporting, and interpretation of studies comparing carotid plaque imaging with histology. Stroke 2005;36:1085–1091.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.