Intimal hyperplasia and restenosis after carotid endarterectomy

Abstract

Endarterectomy of atherosclerotic plaques has long appealed to surgeons. The concept of surgically excising the offending occlusive lesion is simple and straightforward. In the early days of arterial reconstructive surgery, it was the only available technique. However, the patency of endarterectomized arteries is not clinically acceptable, except in a few, select situations. Failure of endarterectomized arteries is more likely when the artery is diffusely diseased or when the flow is limited. Occlusion may be due to acute thrombosis, intimal hyperplasia, or recurrent atherosclerotic plaques. The arteries that are successfully endarterectomized are characterized by high flow-low resistance circulations, with short segments of artery requiring endarterectomy—such as the carotid, mesenteric, and renal arteries. In contrast, long occlusions of the superficial femoral artery, have been resistant to successful reconstruction with surgical endarterectomy or various endovascular techniques such as balloon angioplasty or laser technology. Clinically, an endarterectomy is a major insult to the arterial wall. The trauma induced by the extensive dissection, the long arteriotomy, and the excision of the atherosclerotic plaque results in a significant wound. As in any surgical wound, healing progresses on the luminal surface, within the remaining arterial wall, and on the adventitia. In early clinical experience thrombosis was associated with marked fibrotic reactions both around and within the arterial wall. Subsequent studies in the iliac and carotid arteries have shown a consistent pattern. The surface never fully heals in arteries that remain patent. Endothelialization is rarely observed except with very short endarterectomies. During the first year the luminal surface is lined with a progressive lesion composed of transformed smooth muscle cells and extracellular matrix. Stenotic lesions detected after the first year have many of the characteristics of the original atherosclerotic plaque except the lipid deposition may not penetrate into the original residual media. In addition, neovascularization and calcification of the luminal lesion may occur. If the proliferative lesions of the arterial wall could be controlled, surgical endarterectomy and certain endovascular techniques for plaque ablation might become clinically useful. The vascular smooth muscle cell is responsible for maintaining both structural integrity by cellular proliferation and synthesis of extracellular matrix, and functional control of blood flow by contraction-relaxation. The smooth muscle cell has several potential phenotypes to accomplish these functions. These modulations of cell phenotype occur as a response to environmental changes in adjacent cells, components of the extracellular matrix, and biochemical mediators. The phenotypes range from cells that are primarily contractile to those that are primarily synthetic in character. Smooth muscle cells in adult arteries are predominantly contractile and quiescent. Phenotypic modulation from the contractile to the synthetic state occurs in vivo with mechanical injury. Depending on the chronicity of the forces involved, the phenotype modulation may persist or revert to the contractile, quiescent state. The nature of the injury to the arterial wall must be explored to understand intimal hyperplasia. During surgery the artery, is dissected extensively with concomitant division of vasa vasorum. This devascularization of the media results in myonecrosis of a portion of the outer media. After opening the artery, the endothelial surface, the internal elastic lamina, and a significant portion of the inner medial smooth muscle fibers are removed. There may be associated crushing injury caused by mechanical manipulation or dessication of the surface tissue. The endarterectomized artery has exposed extracellular matrix and partially viable smooth muscle cells on the flow surface, a potentially ischemic media, and raw adventitial surface surrounded by the soft tissue wound. In addition, there are a number of suture holes through the arterial wall creating potential passages for neovascularization, cellular infiltration, and humoral diffusion. These passages might facilitate interaction between the healing exterior soft tissue wound and the vascular media. After flow is restored through the injured artery, an intense interaction between the blood and the flow surface occurs. Platelets adhere to the luminal surface, aggregate, and release a variety of substances including the platelet-derived growth factor. This smooth muscle mitogen stimulates the smooth muscle cells to migrate to the injured flow surface and to proliferate. Additional chemotactic and mitogenic agents that regulate this smooth muscle cell migration and proliferation have been identified and may play a role after endarterectomy. Platelet-derived growth factor can be synthesized by smooth muscle cells and may be responsible for persistent proliferative or secretory activity of adjacent cells. Even if endothelium migrates and covers the flow surface, it may be exposed to repeated injury because of turbulent blood flow and local stasis resulting from slow boundary layer flow. Therefore the endothelium may not inhibit smooth muscle cell growth either by limiting influx of mitogens or by synthesizing inhibitors. Since endothelial cells may be functionally abnormal, they themselves can synthesize mitogens and be responsible for stimulating instead of inhibiting smooth muscle cell growth. The endarterectomized artery sits in the middle of an evolving soft tissue wound. The inflammatory process provides a unique environment that may influence the repair process within the artery. Migration and proliferation of fibroblasts, leucocytes, and macrophages result in local secretion of chemotactic and mitogenic agents. The net effect of multiple chronic mitogenic stimuli may result in progressive intimal hyperplasia, which ultimately narrows the vascular lumen. In addition to the cellular component of intimal hyperplasia, a connective tissue matrix is formed by stimulating the smooth muscle synthesis of collagen, elastic fibers, and proteoglycans. Connective tissue components are important for maintaining the integrity of the arterial wall. However, they also contribute to the progressive nature of intimal hyperplasia, especially in the late phase. In response to injury and with progression of intimal hyperplasia, chondroitin sulfate proteoglycans increase in the extracellular matrix, presumably synthesized by vascular smooth muscle cells. Platelets, inflammatory cells, and synthetic smooth muscle cells stimulate cellular synthesis of collagen, proteoglycans, fibronectin, and glycoproteins plus the fibrillar components of the matrix. The stimulation and control of synthetic function appears to involve endocrine, paracrine, and autocrine mechanisms. The interrelationships of the extracellular matrix, the biochemical agents bound to it, and the surface receptors of the smooth muscle cells are complex and poorly understood. Healing of an endarterectomy suggests that the remaining arterial wall remodels itself to restore structural and functional components of the injured artery. However, it is not clear from clinical and experimental data whether the intimal hyperplasia that occurs after endarterectomy is a reparative or a pathologic process. In animal models with limited injury, the artery has the ability to repair, adapt, and resume normal structure and function. However, with clinical endarterectomy and animal models with more extensive injury, the proliferative process is progressive and may lead to pathologic structure and function. Numerous factors have been implicated in the initiation and persistence of intimal hyperplasia. These range from abnormal shear forces on the flow surface, to mechanical abnormalities caused by compliance mismatch at the suture line, to surface injury allowing platelet interaction with the media, to chronically altered functional status of vascular cells. A number of therapeutic approaches have been attempted clinically and experimentally. Two general approaches include (1) blocking the interaction of platelets with the arterial wall and (2) modulating the smooth muscle cell response to the arterial injury. Both approaches are based on the predominant assumption that platelet release of a potent smooth muscle cell mitogen plays a pivotal role in intimal hyperplasia. Blocking platelet aggregation and release on the injured flow surface has proved difficult. Numerous clinical and experimental trials of antiplatelet and antithrombotic agents have effectively decreased acute thrombosis but not intimal hyperplasia. The use of selective low dose aspirin or dietary eicosapentaenoic acid provide the optimal biochemical environment to decrease platelet aggregation and release phenomena after endarterectomy. These regimens have only partially blocked intimal hyperplasia. Thrombus formation on the injured flow surface is complex, and the pharmacologic probes currently available will not prevent platelets from aggregating and releasing smooth muscle mitogens. Blocking the response of the smooth muscle cell to the forces of mechanical injury, and numerous mitogens has been equally frustrating. Altering the flow characteristics after endarterectomy by use of patch angioplasty has been advocated. Altering the production of mitogens or the response of the vascular cells to them will be difficult. A biologic approach may have some efficacy. Accelerated healing of the flow surface with endothelium by means of tissue culture and seeding techniques is associated with inhibition of intimal hyperplasia experimentally. This response could be due to the release of prostacyclin and heparin-like glycosaminoglycans, which inhibit the transformation of smooth muscle cells into the synthetic phenotype. The restoration of a balance between growth stimulants and inhibitors plus an intact, functional endothelial interface achieves two major goals of normal healing after endarterectomy. In the past few years, research in vascular biology has been exciting. The normal homeostasis of structure and function of the arterial wall is clearly altered after endarterectomy. An increased awareness is emerging of the multiplicity of factors that contribute to the thrombogenicity of the endarterectomized artery, the proliferative smooth muscle cell response, and the elaboration of extracellular matrix. The tools of molecular biology are revealing the rich heterogeneity of calls making up the arterial wall. Phenotypic modulation of smooth muscle cells has been observed with changes in age, anatomic location, and environment. The functional and structural differences between the contractile and synthetic forms of smooth muscle cells are being recognized and defined. The control mechanisms for phenotypic modulation are being probed. Cell culture techniques are being used extensively to study smooth muscle and endothelial cells. In culture the synthetic state smooth muscle cells immediately respond to mitogens, synthesize increased amounts of extracellular matrix, and accumulate increased amounts of lipid, whereas the contractile state cells are relatively unresponsive. The phenotypic expression of the cells will depend on environmental factors such as the age of the donor tissue, the initial innoculum, and the protein content of the medium. Studies of the interaction of endothelial cells and smooth muscle cells in vivo and in vitro continue in an attempt to define the optimal environment in which to achieve healing of the endarterectomized artery. Control mechanisms for cell growth are being actively investigated. Endocrine, paracrine, and autocrine control mechanisms for control of smooth muscle cell growth are postulated, and early evidence supporting each is available from several laboratories. Future directions for investigation must be diverse and creative. Fundamental questions for study include (1) whether definition of the growth and biologic characteristics of endothelial cells, platelets, macrophages, fibroblasts, and smooth muscle cells will lead to control of the healing process after endarterectomy, (2) how the geometry of the vascular reconstruction alters fluid delivery in a high pressure, pulsatile, non-Newtonian system in straight and branching arteries, (3) how strong is the influence of surgical technique, including periarterial dissection, patch angioplasty, suture technique or composition, and extent of media removed, (4) how the forces that initially led to the development of atherosclerosis in the patient modulate endarterectomy healing, and (5) whether novel antithrombotic and antiplatelet agents and techniques to accelerate the development of thromboresistance by the flow surface should be explored. Advances in endarterectomy and endovascular techniques will be possible only by understanding the biologic process of healing at a cellular level.