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Enhanced extracellular matrix accumulation in restenosis of coronary arteries after stent deployment

Ick-M. o Chung, MD^*, Herman K. Gold, MD, Stephen M. Schwartz, MD, PhD^*, Yuji Ikari, MD, Michael A. Reidy, PhD^* and Thomas N. Wight, PhD^*,*

^* Department of Pathology, University of Washington, Seattle, Washington, USA
Hope Heart Institute, Seattle, Washington, USA
Division of Cardiology, Massachusetts General Hospital, Harvard University, Boston, Massachusetts, USA
Division of Cardiology, Mitsui Memorial Hospital, Tokyo, Japan

View larger version (20K): [in a new window]   Figure 1 Bar graph showing the distribution of age of specimens after stent deployment. DCA = directional coronary angioplasty.

View larger version (76K): [in a new window]   Figure 2 Hematoxylin- and eosin-stained tissues retrieved from human coronary stent neointima of three different stent age groups. (A-1) Stent neointima at two months after stenting shows hypercellular myxoid tissue characterized by stellate-shaped smooth muscle cells arranged in a disorganized pattern (high-power field, A-2). Smooth muscle cells were identified by immunostaining for -actin staining of adjacent section (A-3). (B-1) Stent neointima at three months after stenting shows both cell-depleted areas with dense extracellular matrix (ECM) (thick arrow) and a lesion of moderate cellularity with loose ECM (thin arrow). High-power field (B-2) and immunostaining for -actin staining (B-3). (C) Stent neointima at 11 months after stenting shows two kinds of cell-depleted areas: one with dense ECM (thick arrow) and the other with loose ECM (thin arrow). Bar = 100 µm.

View larger version (14K): [in a new window]   Figure 3 Bar graph showing the frequency of specimens containing foci of cell-depleted areas. Note that specimens with foci of cell depleted areas tend to increase over time after stenting. *p < 0.01 for both 3 to 6 months and <6 months vs. <3 months. DCA = directional coronary angioplasty.

View larger version (14K): [in a new window]   Figure 4 Bar graph showing the frequency of specimens containing myxoid tissue. Note that specimens with myxoid tissue tend to decrease over time after stenting. *p < 0.05 for <6 months vs. <3 months. DCA = directional coronary angioplasty.

View larger version (47K): [in a new window]   Figure 5 Immunostaining for Ki-67 shows one positive nucleus (brown color, arrow) in the myxoid tissue of human coronary stent neointima at 2.5 months after stenting (A). In tissue of stent neointima at 23 months after stenting, several Ki-67-positive nuclei were noted (B). Tissue of human tonsil as a positive control shows many positive Ki-67-stained nuclei of lymphocytes in the follicular structure (C). Counterstaining with either hematocylin (A, B) or methylgreen (C). Bar = 100 µm.

View larger version (25K): [in a new window]   Figure 6 Numbers of in-stent restenotic specimens grouped according to various degrees of Ki-67 nuclear antigen labeling. Note that, regardless of stent age, majority of specimens had no Ki-67 labeling. Solid bar = <3 months; hatched bar = 3 to 6 months; diamond bar = >6 months.

View larger version (60K): [in a new window]   Figure 7 Immunohistochemical analysis of extracellular matrix (ECM) of cell-depleted areas in human coronary stent neointimal tissue sections adjacent to the section of Figure 2C. In modified Movat staining, two kinds of cell-depleted areas were characterized. The collagen-rich ECM (pinkish yellow, thick arrow) is colocalized with the dense matrix seen in Figure 2C, and the proteoglycan-rich ECM (blue, thin arrow) with the loose matrix. Fibrin and/or fibrinogen are labeled as red (asterisk). Versican is abundant in the proteoglycan-rich area (brown, thin arrow), but is spared in the collagen-rich ECM (thick arrow). The distribution of hyaluronan is similar to that of versican. The biglycan-stained area is mostly colocalized with the dense collagen-rich matrix (brown, thick arrow). A few fibrin-labeled areas (dark brown) assessed by T2G1 antibodies are shown, counterstaining with methylgreen. Bar = 100 µm.

View larger version (78K): [in a new window]   Figure 8 Immunohistochemical analysis of myxoid tissue in atherectomized human coronary stent neointima at two months after stenting. In modified Movat’s staining, this specimen is composed of two different kinds of tissue: one is the myxoid tissue (labeled as M) enriched in blue-colored proteoglycans, and the other is collagen-rich cell-depleted area (labeled as C). Both versican and hyaluronan are abundant in this myxoid tissue, whereas both molecules are spared in the collagen-rich cell-depleted area. Perlecan staining shows labeling around the stellate-shaped smooth muscle cells. Transforming growth factor-ß1 staining shows cytoplasmic labeling in the stellate cells. Counterstaining with either methylgreen or hematoxylin. Bar = 100 µm.

View larger version (145K): [in a new window]   Figure 9 Transmission electron micrograph of an atherectomized human coronary stent neointima specimen containing the loose proteoglycan-rich matrix. Extracellular matrix contained numerous ruthenuium red positive proteoglycan granules, often linked together by fine filamentous threads, and occasional segments of immature elastin (labeled as E). Bar = 500 nm.