Pathology of Carotid Artery Restenosis David Gordon Restenosis at the site of previous atherosclerotic plaque removal or dilatation commonly accompanies mechanical methods to reopen an artery. This often follows balloon angioplasty, atherectomy, endarterectomy, or arterial stenting. In arterial stenting, tissue grows inside the stent, causing a luminal stenosis. In general, the pathologic basis of restenosis appears to be a substantial increase in intimal volume of the affected artery with secondary luminal narrowing. In arteries not stented, some form of artery wall contraction occurs. Both phenomena can result in a vessel that is hemodynamically narrowed. A number of reports on the histopathology of this lesion following a carotid endarterectomy (CEA) or following carotid angioplasty with stenting (CAS) have been published. However, compared with the coronary arteries, there is generally less experience with the carotid lesion, partly because most restenotic cases are asymptomatic, and as such, their surgical removal is usually not indicated. Thus existing pathologic studies are likely to be heavily skewed toward the symptomatic lesions or lesions obtained at autopsy. The estimated rates of restenosis are generally higher for the coronary arteries than for the carotid arteries. In the coronary arteries, with restenosis rates up to 30%, this has become a significant clinical problem. Published rates for restenosis following a CEA are 1% to 4% for symptomatic restenosis. However, if noninvasive methods of serial patient follow-up such as Doppler ultrasound are used, restenosis rates as high as 31% are seen. A significant problem in studying restenosis rates is the lack of a uniform definition of “restenosis,” (e.g., >50% vs. >70% lumenal diameter narrowing, and variable times of study after the surgical intervention). Some restenotic lesions also undergo later regression for unclear reasons. Descriptive Pathology Although several animal model systems have been used to study mechanically induced arterial intimal thickening, the dynamic, human in vivo mechanisms leading to recurrent stenosis remain incompletely understood. In general, some degree of acute mural thrombus formation and acute inflammation can be seen after CEA. Within the first few weeks to months of the arterial manipulation, the restenotic lesion is described as intimal tissue composed of numerous smooth muscle cells, much proteoglycan-rich and collagen-rich extracellular matrix, and a few monocyte/macrophages, and possibly other inflammatory cells. This early-stage lesion thus resembles the diffuse intimal thickening seen in many adult arteries and is best mimicked by animal models of angioplasty-induced arterial injury. After several months to years, the lesion is generally richer in monocyte/macrophages and might contain a necrotic core, with occasional features of thrombosis and hemorrhage. This later lesion thus better resembles the atherosclerotic plaque, which was the type of lesion originally treated. However, there is much variation in the reported histology, and no definite transition time from the former to the latter is evident. Features of both can also coexist in the same primary or restenotic lesion. For example, although some descriptions of regions of restenotic tissue have focused on features such as stellate smooth muscle cells, a proteoglycan-rich matrix, and occasional organizing thrombi, it is important to remember that all of these features can be seen in primary atherosclerotic lesions that have never undergone interventional procedures. Intimal neovascularization can also be seen in both types of lesions. Features of carotid lesions that produce symptoms are also not fully clarified. With the primary atherosclerotic plaque, several studies have suggested that in addition to the degree of stenosis, the presence of plaque complications such as ulceration and thrombus formation are important for producing ipsilateral symptoms. Based on correlations between B-mode ultrasound imaging and pathology, many such complicated lesions are described as heterogeneous on ultrasound imaging, whereas many of the early restenotic lesions are described as both asymptomatic and having a homogeneous ultrasound appearance. This homogeneous character is often correlated with diffuse intimal thickening, which is generally devoid of plaque ulcerations or thrombus formation. One is tempted to speculate therefore that the absence of plaque ulcerations and thrombus formation accounts for the lack of symptoms in most carotid restenosis lesions. Pathogenesis Based on the author’s knowledge of experimental artery wall reactions to injury and results from clinical studies employing ultrasound methods, the presumed processes leading to arterial restenosis can be categorized as follows, although this is likely not a complete listing: smooth muscle cell proliferation, extracellular matrix synthesis, thrombus organization, and artery wall remodeling. These processes can occur to varying degrees in the affected arteries. Cell Proliferation The initial major focus in this disease was on cell proliferation after either the mechanical balloon dilatation or endarterectomy of the atherosclerotic artery. In the case of endarterectomy, the artery is opened longitudinally from the adventitia, usually through to the lumen. The atherosclerotic intima is removed in the segment, and variable amounts of the underlying media are removed as well. The artery thus has mechanical injury to all layers of the artery wall, resulting with media and the cut ends of the proximal and distal intima exposed to the blood elements. Such exposure of collagen and possibly tissue factor promotes platelet adhesion to this injured surface, as well as variable amounts of fibrin deposition. Platelet deposition and release of growth factors, smooth muscle necrosis, and fibrin deposition as a scaffold for subsequent mesenchymal cell migration all result from the initial injury. These factors act to induce smooth muscle proliferation, migration, and extracellular matrix synthesis, which in turn are all visible aspects of the restenotic lesion. Speculation about subsequent arterial wall repair has been heavily influenced by detailed studies of the reactions of normal arteries to balloon dilatation injury. They are best described in the rat carotid artery model. Here endothelial denudation is accompanied by variable degrees of medial smooth muscle cell injury and death, followed in 1 to 3 days by a brisk smooth muscle proliferative response, reaching proliferative indices of about 30% to 50% and higher. Modulated smooth muscle–derived cells that have lost most of their smooth muscle–distinguishing features eventually repopulate the media, migrate into the intima, and continue their proliferation and intimal expansion for weeks thereafter, albeit with a gradually decreasing proliferative index. These smooth muscle–derived cells also synthesize much extracellular matrix, proteoglycans and collagen in particular, and thereby greatly expand the volume of the intima further. This general sequence of events is presumed to occur in human atherosclerotic arteries as well, and somewhat similar sequences of events have been described in some animal models of angioplasty injury to preexisting atherosclerotic arteries. Such proliferative indices tend to peak at later times after injury, with somewhat decreased proliferative indices when compared with the rat carotid model. However, this sequence of events for human restenosis was originally called into question based on measurements of actual proliferative indices in human restenotic tissue obtained by atherectomy catheter. The authors’ laboratory first studied human coronary arterial samples obtained from the atherectomy catheter in both primary atherosclerotic plaques and restenoses after previous angioplasty/atherectomy resection. Using proliferating cell nuclear antigen (PCNA), the authors found proliferative indices in the 0% to 2% range for both classes of lesions, with no significant differences between the two. This has been confirmed by others using PCNA and the Ki-67 proliferation marker. Other studies using PCNA immunolabeling on human iliac and femoral arterial plaques and restenosis lesions have reported average PCNA labeling indices on the order of 3.6% in primary atherosclerotic lesions and 15.2% in restenosis lesions. The reason for these reportedly higher labeling indices is not clear. It is possible that restenosis biology differs in the iliac, femoral, and possibly carotid arteries compared with coronary lesions. The larger lower extremity arteries, when they have restenoses, might allow an enrichment of actual restenotic tissue samples, whereas the smaller coronary arteries are more likely to yield a mixture of primary lesion and restenotic tissue. Most of these studies have looked at restenotic tissue several weeks after the initial surgical intervention, a time at which animal models indicate that the cell proliferation rate has returned to low levels. Only gold members can continue reading. 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Pathology of Carotid Artery Restenosis David Gordon Restenosis at the site of previous atherosclerotic plaque removal or dilatation commonly accompanies mechanical methods to reopen an artery. This often follows balloon angioplasty, atherectomy, endarterectomy, or arterial stenting. In arterial stenting, tissue grows inside the stent, causing a luminal stenosis. In general, the pathologic basis of restenosis appears to be a substantial increase in intimal volume of the affected artery with secondary luminal narrowing. In arteries not stented, some form of artery wall contraction occurs. Both phenomena can result in a vessel that is hemodynamically narrowed. A number of reports on the histopathology of this lesion following a carotid endarterectomy (CEA) or following carotid angioplasty with stenting (CAS) have been published. However, compared with the coronary arteries, there is generally less experience with the carotid lesion, partly because most restenotic cases are asymptomatic, and as such, their surgical removal is usually not indicated. Thus existing pathologic studies are likely to be heavily skewed toward the symptomatic lesions or lesions obtained at autopsy. The estimated rates of restenosis are generally higher for the coronary arteries than for the carotid arteries. In the coronary arteries, with restenosis rates up to 30%, this has become a significant clinical problem. Published rates for restenosis following a CEA are 1% to 4% for symptomatic restenosis. However, if noninvasive methods of serial patient follow-up such as Doppler ultrasound are used, restenosis rates as high as 31% are seen. A significant problem in studying restenosis rates is the lack of a uniform definition of “restenosis,” (e.g., >50% vs. >70% lumenal diameter narrowing, and variable times of study after the surgical intervention). Some restenotic lesions also undergo later regression for unclear reasons. Descriptive Pathology Although several animal model systems have been used to study mechanically induced arterial intimal thickening, the dynamic, human in vivo mechanisms leading to recurrent stenosis remain incompletely understood. In general, some degree of acute mural thrombus formation and acute inflammation can be seen after CEA. Within the first few weeks to months of the arterial manipulation, the restenotic lesion is described as intimal tissue composed of numerous smooth muscle cells, much proteoglycan-rich and collagen-rich extracellular matrix, and a few monocyte/macrophages, and possibly other inflammatory cells. This early-stage lesion thus resembles the diffuse intimal thickening seen in many adult arteries and is best mimicked by animal models of angioplasty-induced arterial injury. After several months to years, the lesion is generally richer in monocyte/macrophages and might contain a necrotic core, with occasional features of thrombosis and hemorrhage. This later lesion thus better resembles the atherosclerotic plaque, which was the type of lesion originally treated. However, there is much variation in the reported histology, and no definite transition time from the former to the latter is evident. Features of both can also coexist in the same primary or restenotic lesion. For example, although some descriptions of regions of restenotic tissue have focused on features such as stellate smooth muscle cells, a proteoglycan-rich matrix, and occasional organizing thrombi, it is important to remember that all of these features can be seen in primary atherosclerotic lesions that have never undergone interventional procedures. Intimal neovascularization can also be seen in both types of lesions. Features of carotid lesions that produce symptoms are also not fully clarified. With the primary atherosclerotic plaque, several studies have suggested that in addition to the degree of stenosis, the presence of plaque complications such as ulceration and thrombus formation are important for producing ipsilateral symptoms. Based on correlations between B-mode ultrasound imaging and pathology, many such complicated lesions are described as heterogeneous on ultrasound imaging, whereas many of the early restenotic lesions are described as both asymptomatic and having a homogeneous ultrasound appearance. This homogeneous character is often correlated with diffuse intimal thickening, which is generally devoid of plaque ulcerations or thrombus formation. One is tempted to speculate therefore that the absence of plaque ulcerations and thrombus formation accounts for the lack of symptoms in most carotid restenosis lesions. Pathogenesis Based on the author’s knowledge of experimental artery wall reactions to injury and results from clinical studies employing ultrasound methods, the presumed processes leading to arterial restenosis can be categorized as follows, although this is likely not a complete listing: smooth muscle cell proliferation, extracellular matrix synthesis, thrombus organization, and artery wall remodeling. These processes can occur to varying degrees in the affected arteries. Cell Proliferation The initial major focus in this disease was on cell proliferation after either the mechanical balloon dilatation or endarterectomy of the atherosclerotic artery. In the case of endarterectomy, the artery is opened longitudinally from the adventitia, usually through to the lumen. The atherosclerotic intima is removed in the segment, and variable amounts of the underlying media are removed as well. The artery thus has mechanical injury to all layers of the artery wall, resulting with media and the cut ends of the proximal and distal intima exposed to the blood elements. Such exposure of collagen and possibly tissue factor promotes platelet adhesion to this injured surface, as well as variable amounts of fibrin deposition. Platelet deposition and release of growth factors, smooth muscle necrosis, and fibrin deposition as a scaffold for subsequent mesenchymal cell migration all result from the initial injury. These factors act to induce smooth muscle proliferation, migration, and extracellular matrix synthesis, which in turn are all visible aspects of the restenotic lesion. Speculation about subsequent arterial wall repair has been heavily influenced by detailed studies of the reactions of normal arteries to balloon dilatation injury. They are best described in the rat carotid artery model. Here endothelial denudation is accompanied by variable degrees of medial smooth muscle cell injury and death, followed in 1 to 3 days by a brisk smooth muscle proliferative response, reaching proliferative indices of about 30% to 50% and higher. Modulated smooth muscle–derived cells that have lost most of their smooth muscle–distinguishing features eventually repopulate the media, migrate into the intima, and continue their proliferation and intimal expansion for weeks thereafter, albeit with a gradually decreasing proliferative index. These smooth muscle–derived cells also synthesize much extracellular matrix, proteoglycans and collagen in particular, and thereby greatly expand the volume of the intima further. This general sequence of events is presumed to occur in human atherosclerotic arteries as well, and somewhat similar sequences of events have been described in some animal models of angioplasty injury to preexisting atherosclerotic arteries. Such proliferative indices tend to peak at later times after injury, with somewhat decreased proliferative indices when compared with the rat carotid model. However, this sequence of events for human restenosis was originally called into question based on measurements of actual proliferative indices in human restenotic tissue obtained by atherectomy catheter. The authors’ laboratory first studied human coronary arterial samples obtained from the atherectomy catheter in both primary atherosclerotic plaques and restenoses after previous angioplasty/atherectomy resection. Using proliferating cell nuclear antigen (PCNA), the authors found proliferative indices in the 0% to 2% range for both classes of lesions, with no significant differences between the two. This has been confirmed by others using PCNA and the Ki-67 proliferation marker. Other studies using PCNA immunolabeling on human iliac and femoral arterial plaques and restenosis lesions have reported average PCNA labeling indices on the order of 3.6% in primary atherosclerotic lesions and 15.2% in restenosis lesions. The reason for these reportedly higher labeling indices is not clear. It is possible that restenosis biology differs in the iliac, femoral, and possibly carotid arteries compared with coronary lesions. The larger lower extremity arteries, when they have restenoses, might allow an enrichment of actual restenotic tissue samples, whereas the smaller coronary arteries are more likely to yield a mixture of primary lesion and restenotic tissue. Most of these studies have looked at restenotic tissue several weeks after the initial surgical intervention, a time at which animal models indicate that the cell proliferation rate has returned to low levels. Only gold members can continue reading. Log In or Register to continue Share this:Click to share on Twitter (Opens in new window)Click to share on Facebook (Opens in new window) Related Related posts: Embolic Protection Devices to Prevent Stroke during Percutaneous Angioplasty and Stenting Transaortic Renal Artery Endarterectomy for Renal Artery Atherosclerosis Percutaneous Arterial Dilation for Fibrodysplastic Renovascular Hypertension Intraoperative Assessment of the Technical Adequacy of Carotid Endarterectomy Stay updated, free articles. Join our Telegram channel Join Tags: Current Therapy in Vascular and Endovascular Surgery Aug 25, 2016 | Posted by admin in CARDIOLOGY | Comments Off on Pathology of Carotid Artery Restenosis Full access? Get Clinical Tree
