Abstract
AIMS: Restenosis in drug-eluting stents (DESs) occurs infrequently, however, it remains a pervasive clinical problem. We interrogated our autopsy registry to determine the underlying mechanisms of DES restenosis, and further we investigated the neointimal characteristics of DESs and compared with bare metal stents (BMSs). METHODS AND RESULTS: Coronary lesions from patients with DES implants (n = 82) were categorized into four groups based on cross-sectional area narrowing: patent (<50%), intermediate (50-74%), restenotic (≥ 75% with residual lumen), and total occlusion (organized thrombus within the stent). Restenosis and occlusion were significantly dependent on the total stented length: restenosis (26.7 mm) and occlusion (25.7 mm) compared with patent DESs (17.3 mm). Further, restenotic and occluded lesions were located more distally in the coronary arteries and had greater vessel injury and uneven strut distribution suggesting local drug gradient. Multivariate analysis revealed that normalized maximum inter-strut distance was associated with DES restenosis (OR: 17.4, P = 0.04) while medial tear length was a predictor of DES occlusion (OR: 5.1, P = 0.03). No differences were observed between different DESs (sirolimus-, paclitaxel-, and everolimus-eluting stents) for restenosis and occlusion. Further, neointimal compositions of restenotic DESs demonstrated greater proteoglycan deposition and less smooth muscle cellularity over time, when compared with BMS with greater cell density and collagen deposition. CONCLUSIONS: Our study indicates the impacts of inadequate drug concentration due to wider inter-strut distance and vessel injury as primary mechanisms of DES restenosis and occlusion, respectively. Moreover, the differences in neointimal compositions between DESs and BMSs might serve as a potential target for the suppression of late neointima growth via inhibition of proteoglycans in DESs.