OBJECTIVES:Collagen synthesis is one of the major mechanisms of primary atherosclerotic plaque growth and is likely to be similarly important in restenosis. The patterns of collagen gene expression in human restenosis and associations with thrombosis/hemorrhage have not been described.METHODS:Using human coronary artery samples obtained via the atherectomy catheter, we compared primary plaques (40 specimens) and restenotic lesions (41 specimens) for type I collagen gene expression using immunocytochemistry (SPI.D8 antibody to type I procollagen, an intracellular precursor of mature collagen) with subsequent computer image analysis.RESULTS:Scattered positive cells were identified in specific, non-random patterns. According to logistic regression analyses, type I procollagen gene expression seems to be more closely associated with certain morphological features (organized thrombus, microvessels, regions enriched with stellate cells) than with belonging to a primary vs. a restenotic sample. However, there may be a tendency for restenotic tissue to have slightly higher numbers of type I procollagen-positive cells than primary lesion tissue.CONCLUSIONS:Symptomatic primary and restenotic lesions exhibit similar patterns of type I collagen gene expression. Plaque microvessels and thrombi/hemorrhages (common features of both kinds of advanced lesions) might stimulate collagen synthesis equally well irrelevant to the nature of the lesion.

Transforming growth factor-beta (TGF-beta) plays an important role in vascular lesion formation and possibly the renarrowing process ("restenosis") that occurs after balloon angioplasty. Secreted in a latent form by most cells, TFG-beta requires enzymatic conversion before it is biologically active. TGF-beta-inducible gene h3 (beta ig-h3) is a novel molecule that is induced when cells are treated with TGF-beta1. This study examined the expression of beta ig-h3 in normal and diseased human vascular tissue. To determine the expression pattern of beta ig-h3 in human arteries, immunocytochemistry was performed on tissue sections from (1) normal internal mammary arteries, (2) the proximal left anterior descending coronary artery (with minimal intimal thickening) of 15 patients aged 18 to 40 years, (3) primary and restenotic coronary lesions from 7 patients, and (4) fresh directional atherectomy tissue from 11 patients. A polyclonal antibody consistently immunodetected beta ig-h3 protein in endothelial cells of all vascular tissue. In normal coronary arteries of young individuals, beta ig-h3 protein was absent from the intima and media but was found in the subendothelial smooth muscle cells of some arteries with modest intimal thickening. In diseased arteries beta ig-h3 protein was more abundant in the intima than the media. Restenotic coronary lesions tended to show higher levels of immunodetectable beta ig-h3 protein, especially in areas of dense fibrous connective tissue. Beta ig-h3 protein was immunodetected in the cytoplasm of plaque macrophages as well as smooth muscle and endothelial cells. By using in situ hybridization on fresh directional atherectomy specimens, we found beta ig-h3 mRNA to be overexpressed by plaque macrophages and smooth muscle cells. Nondiseased human internal mammary arteries also expressed beta ig-h3 mRNA in endothelial cells but not in the smooth muscle cells of the normal intima and media. These results document the expression of beta ig-h3 in diseased human arterial tissue and support the hypothesis that active TGF-beta plays a role in atherogenesis and restenosis.

Neovascularization in the walls of coronary arteries is associated with the presence of atherosclerotic plaque. The mechanisms responsible for the formation of these intraplaque microvessels are not understood. The purpose of this study is to examine the prevalence of endothelial cell replication in plaque microvessels. Two hundred and one primary and restenotic coronary atherectomy specimens were analyzed for the presence of microvessels and proliferation as reflected by positive immunolabeling for Ulex agglutinin and the proliferating cell nuclear antigen, respectively. In primary but not restenotic specimens, proliferation of any cell type was associated with the detection of microvessels on the same slide. However, intraplaque microvessels were more commonly found in restenotic compared to primary specimens (P = 0.004). Twelve highly vascularized specimens with evidence of replication were subjected to detailed histomorphological and quantitative image analyses. At 200 x, the most vascular optical field of each slide was identified and consistently included plaque macrophages. Total slide endothelial cell replication indices for these specimens varied, but in some instances were remarkably elevated (eg, 43.5%). The role of intraplaque angiogenesis may be analogous to that of tumor or wound angiogenesis and be important in development and progression of coronary artery lesions and restenosis.

How an atherosclerotic plaque evolves from minimal diffuse intimal hyperplasia to a critical lesion is not well understood. Cellular proliferation is a relatively infrequent and modest event in both primary and restenotic coronary atherectomy specimens, leading us to believe that other processes, such as the formation of extracellular matrix, cell migration, neovascularization, and calcification might be more important for lesion formation. The investigation of proteins that are overexpressed in plaque compared with the normal vessel wall may provide clues that will help determine which of these processes are key to lesion pathogenesis. One such molecule, osteopontin (OPN), is an arginine-glycine-aspartate-containing acidic phosphoprotein recently shown to be a novel component of human atherosclerotic plaques and selectively expressed in the rat neointima following balloon angioplasty. Using in situ hybridization and immunohistochemical methods, we demonstrate that in addition to macrophages, smooth muscle and endothelial cells synthesize OPN mRNA and protein in human coronary atherosclerotic plaque specimens obtained by directional atherectomy. In contrast, OPN mRNA and protein were not detected in nondiseased vessel walls. Furthermore, extracellular OPN protein collocalized with sites of early calcification in the plaque that were identified with a sensitive modification of the von Kossa staining technique. These findings, combined with studies showing that OPN has adhesive, chemotactic, and calcium-binding properties, suggest that OPN may contribute to cellular accumulations and dystrophic calcification in atherosclerotic plaques.

Directional coronary atherectomy provides a predictable outcome in selected cases; however, DCA may still result in significant complications in a small number of patients. Although many of the complications are similar to those associated with PTCA, some of the complications are unique or more frequently observed with DCA. These complications are often preventable with adequate case selection and appropriate technique. Because of significant differences in the atherectomy procedure compared to PTCA, the operator should recognize and understand the technical differences to prevent potentially serious complications.

Between 1988 and 1990, clinical testing was performed at 12 US institutions using the Simpson Coronary AtheroCath under an Investigational Device Exemption. Data on 1,069 lesions (873 patients) were analyzed and presented to the Food and Drug Administration (FDA) advisory panel in the summer of 1990, forming the basis for approval of this device in September 1990. Analysis of these preapproval data shows a primary success rate of 85% (defined as tissue removal, ≥20% reduction in stenosis, <50% residual stenosis after directional atherectomy, and no major complication), with somewhat higher primary success in prior restenosis and noncalcified lesions. Including the use of conventional angioplasty performed after atherectomy, the overall success rate was 92%. One or more major complications occurred in 4.9% of procedures, and included death (0.5%), nonfatal Q-wave myocardial infarction (0.9%), and emergency bypass surgery (4.0%). These complications were more frequent in right coronary, de novo, and diffuse (>20-mm length) lesions. Six-month angiography results were available in 384 (77%) of 498 lesions eligible for follow-up when the registry closed and showed a restenosis rate (late stenosis > 50%) of 42%. The restenosis rate in both native vessels (30 vs 46%) and bypass grafts (31 vs 68%) was lower in primary (de novo) lesions compared with lesions that had developed restenosis after a prior intervention. Despite the use of prototype atherectomy catheters and still evolving procedural technique, this preapproval experience provided an important initial indication of the situations in which directional coronary atherectomy was most useful and helped set clear standards for performance of this procedure following FDA approval.