Abstract 4461: Rho-kinase Pathway Plays an Important Role in the Pathogenesis of Coronary Hyperconstricting Responses Induced by Drug-Eluting Stent

Abstract

It has recently been reported that coronary vasoconstricting responses are enhanced at the edge of coronary segment implanted with drug-eluting stent (DES) as compared with bare-metal stent (BMS) in humans. We have previously demonstrated in animal models and humans that activation of Rho-kinase plays a key role in the molecular mechanism of coronary vasospasm. In this study, we thus examined whether Rho-kinase pathway also is involved in the DES-induced coronary hyperconstriction in vitro and in vivo. In cultured human coronary vascular smooth muscle cells, paclitaxel (10 –1000 nM, comparable tissue concentrations in humans, 24 hours) concentration-dependently up-regulated Rho-kinase expression (n=9) and increased Rho-kinase activity (10 nM, n=6). In a porcine model in vivo, DES (Taxus ™ ) and BMS (Express ™ ) were randomly implanted in the left anterior descending and circumflex coronary arteries (n=5). Four weeks after the implantation, coronary vasoconstricting responses to serotonin (5-HT, 50 and 100 μg/kg, IC) were significantly enhanced at the DES site compared with the BMS site (DES −52±4 vs. BMS −31±5%, P<0.01), and the enhanced responses were prevented by hydroxyfasudil (HF, 90 and 300 μg/kg, IC), a selective Rho-kinase inhibitor ( Figure A ). The same in vivo findings also were noted in another comparison between DES (Cypher ™ ) and BMS (Velocity ™ ) (DES −62±3% vs. BMS −41±3%, n=6, P<0.01) ( Figure B ). Histological analysis showed microthrombus formation only at the DES site. These results suggest that Rho-kinase pathway also plays an important pathogenetic role in the DES-induced coronary hyperconstricting responses.