Rutherford: Vascular Surgery, 6th ed

Rutherford: Vascular Surgery, 6th ed., Copyright © 2005 Saunders, An Imprint of Elsevier < Previous Next > Chapter 10 – Artery Wall Pathology in Atherosclerosis CHRISTOPHER K. ZARINS, MD CHENGPEI XU, MD, PhD SEYMOUR GLAGOV, MD Atherosclerosis is the principal pathologic process affecting the large arteries. A degenerative disease, atherosclerosis is characterized by the accumulation of cells, matrix fibers, lipids, and tissue debris in the intima, which may result in narrowing of the lumen and obstruction of blood flow or ulceration, embolization, and thrombosis. Intimal plaque deposition may be accompanied by arterial enlargement and thinning of the underlying artery wall. Such enlargement may compensate for the enlarging intimal plaque and prevent lumen stenosis. It may also, under certain circumstances, lead to aneurysm formation with eventual artery wall rupture. Dissection, arteritis, and other degenerative conditions may also result in similar clinical complications, but they are rare compared with atherosclerosis and are dealt with elsewhere. This chapter discusses the problem of atherosclerosis as it relates to the functional biomechanical properties of the artery wall. Both normal and pathologic responses of the artery wall are considered, as are differences in the evolution of atherosclerotic lesions. Local differences that may account for the propensity of certain areas to form extensive and complex plaques or aneurysms are also discussed. STRUCTURE AND FUNCTION OF THE ARTERY WALL Arteries are not simply a passive system of tubes of uniform and fixed composition that distribute blood to organs. Investigation has revealed that the major arteries are intricate biomechanical structures well suited to carry out their metabolic and mechanical functions under a wide range of conditions.[1] Arteries respond to acute hemodynamic alterations by changing caliber, through either constriction or dilatation.[2] Several mechanisms operate to limit hemorrhage in the event of disruptive injury and to restore wall integrity without long-term sequelae.[3] Arteries also adapt to gradual changes in local hemodynamic stresses and to systemic environmental conditions in order to maintain optimal diameter and mechanical characteristics and to ensure continued adequate blood flow.[4] The following brief review of the functional microanatomy of the artery wall indicates the range and limits of artery wall adaptability. Intima The intima, the innermost layer of the artery wall, extends from the luminal surface to the internal elastic lamina. The luminal surface is lined by the endothelium, a continuous monolayer of flat, polygonal cells. Between the endothelium and the internal elastic lamina, the intima is normally very narrow, with the endothelium lying directly on the internal elastic lamina and containing only a few scattered leukocytes, smooth muscle cells, and connective tissue fibers. It is in this region that atherosclerotic lesions develop. Endothelium The endothelium rests on a basal lamina that provides a continuous, pliable, and compliant substrate. Changes in cell shape and in the extent of junctional overlap among adjacent endothelial cells occur in relation to (1) changes in artery diameter associated with pulsatile wall motion, (2) changes in configuration associated with bending or stretching, and (3) the intimal accumulation of cells and matrix fibers during the development of intimal atherosclerotic plaques.[5] These changes act to prevent the development of discontinuities in the endothelial lining. The endothelium also has numerous focal attachments to the underlying internal elastic lamina.[6] These relatively tight and rigid junctions contribute to stability by preventing slippage, telescoping, or detachment of endothelial cells and disruption or denudation by elevations in shear stress or by other mechanical forces. The endothelium presents a thromboresistant surface as well as a selective interface for diffusion, convection, and active transport of circulating substances into the underlying artery wall. [7] Endothelial cells play a critical role in the physiology and pathophysiology of vascular disorders.[8] They respond to hemodynamic stresses and may transduce an atheroprotective force[9] by regulating the ingress, egress, and metabolism of lipoproteins and other agents that may participate in the initiation and progression of intimal plaques.[3][5] Endothelial Injury The endothelial surface can be injured or disrupted by various means but regenerates rapidly after focal denudation. The healing response, if extensive, may be accompanied by smooth muscle cell proliferation and migration and intimal thickening.[10][11] A series of reactions set into motion by focal endothelial denudation has been proposed as the initiating event in the pathogenesis According to this hypothesis.[26] Figure 10-1 . and express surface glycoproteins that promote the adhesion and ingress of neutrophils. These observations suggest that humoral mediators. smooth muscle cell proliferation. Such endothelial desquamation would expose subendothelial tissues to the circulation and stimulate platelet deposition. limit distention and prevent disruption even at very high blood pressures ( Fig. angiotensin II) and vasodilators and inhibitors of platelet aggregation (e. repeated disruptive endothelial injuries and responses to those injuries would account for the localized nature of plaque deposition. and platelets. The thick. The extensive interconnected transmural arrangement of the elastic fibers of the musculoelastic fascicles tends to ensure uniform distribution of tensile mural stresses and prevent the propagation of flaws that develop in the media with age.[13] In addition. with or without platelet adhesion.[25] The elastin fibers are relatively extensible and allow for compliance and recoil of the artery wall in relation to pulse propagation during the cardiac cycle. because of their high elastic modulus. [14] even in the presence of hyperlipidemia. and eventual lipid deposition and plaque formation. Media The media extends from the internal elastic lamina to the adventitia.[12] Focal. Thicker. cellular proliferation. (3) immunologic reactions. endothelial cells become increasingly permeable to low-density lipoprotein. growth factors.of atherosclerosis. In addition. a distinct external elastic lamina may not be present.g. to support the belief that endothelial injury or disruption in the form of desquamation. growth factors. each cellular subgroup or fascicle is encompassed by a system of similarly oriented elastic fibers such that the effective unit of structure is a musculoelastic fascicle. 10–1 ). The outer limit of the media can nevertheless be distinguished in nearly all intact arteries.[21][22] Such factors maintain the smooth muscle cells of the media in a contractile. In such vessels. In relation to the curvature of the artery wall. biologic reactions of the endothelium and artery wall during injury and repair may play important roles in the proliferative and lipid deposition stage of plaque formation. resulting in an appearance on transverse cross-section of elastin lamellae alternating with smooth muscle layers. There is little evidence. and (4) increased exposure to vasoactive agents.g. Platelet-derived growth factor has been isolated from other cellular elements that participate in plaque formation. such as those that characterize hyperlipidemia. prostacyclin and endothelium-derived relaxing factor). The smooth muscle cell layers are composed of groups of similarly oriented cells.[19][20] Under normal circumstances. inducing prostacyclin production. endothelial injury and desquamation may be caused by (1) mechanical forces.[18] and smooth muscle cell proliferation may be an aspect of an overall healing reaction of arteries rather than the underlying primary event in atherosclerosis. particularly in vessels with a thick and fibrous adventitial layer. however.[23] Endothelial cells and monocytes release cytokines. monocytes. On the contrary. the vascular endothelium functions as an antithrombotic surface and contributes to the regulation of vascular tone and artery lumen diameter through the secretion of vasoconstrictors (e. (2) metabolic intermediates. which further promotes monocyte adhesion and diapedesis. Later studies have attempted to define injury in terms of functional alterations that may predispose to the formation of atherosclerotic lesions. because in contrast to the adventitia. each fascicle is oriented in the direction of the imposed tensile stress. extracellular lipid as well as foam cells containing cholesterol esters accumulate in the intima. In response to endothelial cell activation or injury. type I collagen bundles are woven between adjacent large elastic lamellae. and cytokines from altered endothelial cells and from inflammatory cells interacting with other arterial cells are important mediators of macrophage infiltration.[17] their effect on plaque initiation remains questionable. evidence has been advanced that the formation of experimental intimal plaques may require the presence of an endothelial covering. and leukotrienes. crimped. have higher replicative rates. crimped collagen fiber bundles provide much of the tensile strength of the media and. The net effect of cytokine and growth factor production is the stimulation of smooth muscle cell proliferation and migration. this configuration tends to hold the groups of cells together and to prevent excessive stretching or slippage. the release of a platelet-derived growth factor. and lipid deposition. Although physical and mechanical endothelial disruption and denudation may not be reactions that initiate or precipitate events in atherosclerotic plaque formation. the media consists of closely packed layers of smooth muscle cells in close association with elastin and collagen fibers. nonproliferative phenotype with low cholesterol ester content.[24] The aorta and its immediately proximal. develop prothrombotic properties. such as elevated wall shear stress and hypertension. there is no direct evidence that experimentally induced endothelial damage or removal results in eventual sustained lesion formation.[15][16] Although platelets may play a role in the transition of early plaques to more complex and advanced forms. the elastin fiber systems of the musculoelastic fascicles are thick and closely packed. each surrounded by a common basal lamina and a closely associated interlacing basketwork of type III collagen fibrils arranged so as to tighten about the cell groups as the media is brought under tension. larger branches are called elastic arteries because of the prominence of their elastic fibers. As a result of these changes... Focal tight attachment sites between smooth muscle cells and elastic fibers are normally abundant. Although an external elastic lamina demarcates the boundary between the media and adventitia in many vessels. occurs in regions of the vascular tree at highest risk for future lesion development. 10–2 ). Groups of smooth muscle cells (C). 10–1 ) and are organized in groups oriented with their long axes perpendicular to the long axis of the artery. The musculoelastic fascicles. as in elastic arteries. Contraction or . oriented with their long axes perpendicular to the longitudinal axis of the artery (axis of blood flow).[26] Figure 10-2 Transmural organization of a muscular artery. Smooth muscle cells (C) are more numerous and prominent than in elastic arteries (see Fig. 1985. Arteriosclerosis 5:19. because of the preponderance of smooth muscle cells relative to elastin and collagen fibers. Elastin fibers allow for compliance and recoil of the artery during the cardiac cycle. (From Clark JM. which are most clearly evident in elastic arteries. Glagov S: Transmural organization of the arterial wall: The lamellar unit revisited. are generally aligned in the direction of the tensile forces. They are surrounded by a closely associated system of elastic fibers (E) oriented in the same direction as the smooth muscle cells.Transmural organization of the media of large elastic arteries such as the aorta. are also the structural unit of muscular arteries and. they are less prominent and the layering of the media is therefore less distinct ( Fig. However. Wavy bundles or fibers (F) of type I collagen are woven between the adjacent large elastic lamellae and provide much of the tensile strength of the media. are surrounded by a network of fine type III collagen fibrils within a matrix of basal lamina (M).) The smaller-caliber muscular arteries contain relatively less collagen and elastin and more smooth muscle cells than elastic arteries and can therefore alter their diameter rapidly by constricting or dilating. accordingly. whereas each thoracic lamellar unit supports about 2000 dynes/cm. Extension into the plaque of reactive vasa vasorum may help to clear lipid from the intimal lesion but may also induce further proliferation and plaque enlargement. The thickness of the media of the abdominal .relaxation of smooth muscle cells allows for rapid alterations in lumen diameter. Smooth muscle cells are surrounded by a basal lamina matrix containing a meshwork of type III collagen fibrils (M). Arteriosclerosis 5:19.) Medial thickness and the number of musculoelastic layers.[27] Figure 103 Comparison of human thoracic and abdominal aortic segments. Thus. The outer two thirds of the human thoracic aortic wall is supplied with intramural medial vasa vasorum.[27] There are great differences in the media between the thoracic aorta and abdominal aorta ( Fig. Conversely. 10–3 ). are closely related to the lumen radius and to mural tangential tension. allowing greater distensibility and pulse propagation. which contains proportionately more collagen. With increasing species size. lipid accumulation. proportional to the product of pressure and radius (Laplace’s law). Intimal plaque formation would also be expected to increase the diffusion distance across the wall. The average tension per lamellar unit tends to be constant for homologous vessels in mammals. nutrition presumably depends primarily on diffusion from the lumen. (From Clark JM. whereas the actual tensile stress per unit of cross-sectional area is inversely proportional to the wall thickness. even early intimal plaque deposition may augment the barrier to diffusion. or lamellar units. or lamellar units. failure of vasa vasorum ingrowth may result in arterial wall atrophy and promote aneurysm formation. Glagov S: Transmural organization of the arterial wall: The lamellar unit revisited. rendering the abdominal aortic media vulnerable to ischemic degeneration and atrophy. is stiffer and less compliant than the thoracic segment. The thoracic aorta also contains relatively more elastin and less collagen than the abdominal aorta. and further plaque formation.[28] Each abdominal aortic lamellar unit is thought to support approximately 3000 dynes/cm circumferential tension. with corresponding increases in medial thickness and in the number of musculoelastic layers. Because intramural vasa vasorum are largely absent from the abdominal aorta. differences in structure and nutrition would appear to be associated with the different vulnerabilities of the thoracic aorta and abdominal aorta to aneurysmal and occlusive diseases. mammalian adult aortic radius enlarges. Tangential tension on the artery wall is. predisposing to processes that may promote inflammatory cell infiltration. Elastin fibers (E) and type I collagen fibers (F) are present but are less prominent than in elastic arteries. 1985. Thus. The thoracic aorta is larger in diameter than the abdominal aorta and. The abdominal aorta. has a greater number of transmedial lamellar units. in general. whereas the abdominal aorta is largely devoid of medial vasa vasorum. Media total tension of the abdominal aorta is appropriate for its diameter. in addition to synthesizing the collagen and elastin fibers that determine the mechanical properties . is avascular. The media of the proximal aorta and that of the major brachiocephalic elastic arteries contain a larger proportion of elastin and a lower proportion of collagen than the media of the abdominal aorta or of the distal peripheral vessels.[28] In addition. Cir Res 25:677. only 29 lamellar units thick. such as the coronary and renal vessels. lamellar unit. None of the avascular aortic medias or avascular zones of vascular aortic medias of mammals studied are as thick as the media of the human abdominal aorta. Furthermore. 1969. the relative proportions of collagen and elastin differ in muscular and elastic arteries.) For muscular arteries. the abdominal aortic media. (From Wolinsky H.[29] The proximal major vessels are therefore more compliant than the abdominal aorta but are also more fragile and prone to tear when sutured.aorta is appropriate for its diameter. LU. Glagov S: Comparison of abdominal and thoracic aortic medial structure in mammals: Deviation from the usual pattern in man. Other mammals’ aortas that have comparatively elevated tensions per lamellar unit have more than 29 lamellae and vasa vasorum. but tension per lamellar unit is higher than in the thoracic aorta. Medial smooth muscle cells. total tangential tension and the number of transmural layers are also linearly related. but the number of its medial lamellar units is relatively low for the diameter compared with the thoracic aorta. arterioles.[32] In vitro studies have revealed that cyclic stretching of smooth muscle cells grown on elastin membranes results in greater biosynthetic activity.[36] Under these circumstances. and smooth muscle cell metabolism are decreased. pulse pressure. www. All rights reserved.[33] and acute arterial injury experiments have revealed that an intact. medial smooth muscle cell metabolism is higher. and venous channels as well as nerves that mediate smooth muscle tone and contraction. such as exist proximal to an aortic coarctation. a thickened adventitia may contribute to tensile support. however. despite the continued presence of strong atherogenic stimuli such as marked hyperlipidemia. leaving only the adventitia to provide support. removal of the adventitia has little effect on static pressure-volume relationships. and aneurysmal degeneration after endarterectomy is very rare. wall motion. the outer layers of the media are nourished by vasa vasorum that penetrate into the media.of the aortic wall. Adventitia The adventitia is composed of fibrocellular connective tissue and contains a network of vasa vasorum composed of small arteries. metabolically active media may be required for intimal plaque formation. intimal plaque formation is inhibited. when wall motion. Vasa Vasorum The inner layers of the aortic media are nourished by diffusion from the lumen. In thick-walled arteries. as is plaque formation. In these procedures.mdconsult. In the normal aorta. Diffusion of nutrients is apparently sufficient to nourish the inner 0.[34] The composition and microarchitecture of the media are designed to ensure stability. and hypertension may impair vasal flow. increasing intimal plaque thickness may be associated with atrophy of the underlying media. mural stresses and deformations may affect vasa vasorum blood flow. and wall tension.[30] Under conditions of increased pulse pressure.[31] Conversely.[38] Intimal plaque formation increases intimal thickness and may thereby enlarge the diffusion barrier between the lumen and the smooth muscle cells of the media. are actively engaged in metabolic processes that contribute to wall tone and may be related to susceptibility to plaque formation. whereas the metabolic state of the media appears to be an important factor in the pathogenesis of atherosclerotic lesions.5 mm of the adult mammalian aortic media.com Next > . In some arteries. This increase in wall thickness may be accompanied by an ingrowth of vasa vasorum. the adventitia is a layered structure composed of both collagen and elastic fibers and may be thicker than the associated media. as in areas distal to a severe arterial stenosis. such as the proximal renal and mesenteric trunks. the entire intima and most or all of the media are usually removed. Vasa vasorum usually arise from the parent artery at branch junctions and arborize in the adventitia. < Previous About MD Consult Contact Us Terms and Conditions Privacy Policy Registered User Agreement Copyright © 2007 Elsevier Inc. capillaries. and vasa vasorum have been identified in atherosclerotic lesions. The tensile strength and adequacy of the adventitia to provide such support are well demonstrated after carotid or aortoiliac endarterectomy. which corresponds to approximately 30 medial fibrocellular lamellar units. The adventitia varies in thickness and organization.[35] In atherosclerotic arteries.[37] When the aorta is thicker than 30 medial lamellar layers. Both intraplaque hemorrhage and plaque breakdown or disruption may be potentiated by changes in the vascular supply of the artery wall and plaque.