HISTOPATHOLOGY OF IN-STENT RESTENOSIS IN PATIENTS WITH PERIPHERAL ARTERY DISEASE

Background Clinical studies have suggested that smooth muscle cell (SM C) hyperplasia is the most likely cause of in-stent restenosis. Howeve r, pathological data regarding this issue are limited. Specifically, d irect evidence of proliferative activity in tissues excised from steno tic stents has not been previously reported. Methods and Results Tissu e specimens were retrieved by directional atherectomy from 10 patients in whom in-stent restenosis complicated percutaneous revascularizatio n of peripheral artery disease. Analysis of cellular composition was p erformed quantitatively after cell-specific immunostaining. For specim ens preserved in methanol (7 of 10), cellular proliferation was evalua ted by use of antibodies to proliferating cell nuclear antigen (PCNA), cyclin E, and cdk2. TUNEL staining for apoptosis was performed on 8 p araformaldehyde-preserved specimens. Each of the 10 specimens containe d extensive foci of hypercellularity composed predominantly of SMCs (m ean+/-SEM, 59.3+/-3.0%). Evidence of ongoing proliferative activity wa s documented in all 7 methanol-preserved specimens: 24.6+/-2.3% of SMC s were PCNA-positive, 24.8+/-3.1% were cyclin E-positive, and 22.5+/-2 .2% were cdk2-positive. Apoptotic cells were detected in all 8 specime ns that had been appropriately preserved to permit DNA nick-end labeli ng. Macrophages and leukocytes were identified in each of the 10 speci mens but accounted for a proportionately smaller number of cells (14.5 +/-1.9% and 9.5+/-1.4%, respectively). Organized thrombus was observed in 6 of the 10 specimens. Conclusions These findings support the noti on that in-stent restenosis results from SMC hyperplasia and suggest t hat adjunctive therapies designed to inhibit SMC proliferation may fur ther enhance the utility of endovascular stents.