Purpose: Intimal hyperplasia is known to promote in-stent restenosis after vascular stent implantation. Although previous studies have presented a variety of evidence that suggests the mechanisms of intimal lesion formation, it is still controversial which factor(s) predominantly contribute to the development of in-stent restenosis. In this study, we hypothesized that heterogeneous mechanisms coexist in the same lesion and then assessed the validity with resected whole arteries with in-stent lesions.
Methods: Whole arterial specimens with in-stent lesions were surgically resected from five patients who had undergone implantation of a Palmaz-Schatz stent 7 to 19 months previously and were histologically analyzed. For assessment of the pathogenetic heterogeneity of in-stent lesions, we divided each cross section into three parts: the inner intima within 250 microm from the luminal surface (zone A), the area surrounding the stent struts within 250 microm from the strut hole (zone B), and the remaining part of the intimal layer (zone C). We then evaluated cell density, cell replication, and cellular composition in each zone. Cell replication and cellular composition were analyzed with immunohistologic staining with antibodies against proliferating cell nuclear antigen and cell-specific antibodies. Each section was also stained with Alcian blue or Elastica van Gieson method for detection of matrix components.
Results: In all samples, the cell density of zone A was significantly higher than that of zone B (P <.05). Proliferating cell nuclear antigen staining results showed significantly higher cell replication in zone A as compared with that in other zones (P <.05). To the contrary, cell-specific immunostaining results revealed marked accumulation of leukocytes, macrophages, and T lymphocytes in zone B (P <.05). Regarding matrix components, proteoglycan was predominantly stained around stent struts and in the inner intima.
Conclusion: The data of this study showed that two different pathogenetic processes in different zones possibly contributed to in-stent lesion formation at the same time. One process was an increase of cell number in the inner intima, which was the result of a prolonged increase of cell replication. The other process was accumulation of matrix around stent struts, which was suggested to be linked to infiltration of inflammatory cells in the same zone.