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Background: Pathogenesis of very late (over 1 year) in-stent restenosis (VL-ISR) might be different from that of usual in-stent restenosis (within 1 year).A couple of pathologic studies have shown that neo-atherosclerosis occur even in the previously implanted stents.Purpose and methods: We performed intravascular ultrasound (IVUS), optical coherence tomography (OCT), angioscopy, and pathological analysis for VL-ISR to clarify its clinical characteristics.A total of 9 patients (1 Cypher, 1 Taxus, 7 bare-metal stents, l emergent case) underwent IVUS and OCT.Angioscopy was available in 2, and pathological analysis could be performed in the other 2 patients (by aspirating detached plaque or retrieved tissue in FiltrapTM).Results: VL-ISR was angiographically focal in 6, diffuse in 2 (both drug-eluting stents), and occlusion in 1.Adequate stent expansion was ascertained by IVUS in all.VL-ISR structure could be analyzed in 7 patients by IVUS.Characteristics of tissue was low echoic and heterogeneous in 4 and homogeneous or layered with low echogenicity near the struts in 3 patients.By OCT, VL-ISR structure was heterogeneous in 7 and layered in 2 patients.Thin-cap fibroatheroma (TCFA) was recognized in 6 (ruptured in 2) and thrombus in 2 patients.Peri-strut low-intensity area was seen in 8 and microvessels in 6 patients.In both angioscopy cases, yellow plaque was partially observed.Fibrous collagenous plaque was adjacent to the lesion where polymorphic smooth muscle cells proliferate with rich proteoglycan at the background with invasion of macrophages as a border in a patient with bare-metal stent indicating the multiple healing process after plaque rupture or erosion even in the VL-ISR.In a case with Cypher, captured material by FiltrapTM was mainly fibrin thrombus.In both cases with pathologic analyses, restenotic tissue was heterogeneous with TCFA by OCT images.Conclusions: Intravascular images and pathologic findings in this study were quite different from those of usual in-stent restenosis reported previously.Vulnerable plaque was frequently observed even in VL-ISR like de novo lesions.Different pathologic feature may be observed in patients with similar OCT patterns in VL-ISR.