Abstract 8768: Involvement of Rho-Kinase Activation in the Pathogenesis of Coronary Hyperconstricting Responses Induced by Drug-Eluting Stents in Patients with Coronary Artery Disease

Abstract

Background: We have previously demonstrated that activation of Rho-kinase, the effector of the small GTP-binding protein Rho, plays a central role in the pathogenesis of coronary vasospasm in pigs and humans and coronary hyperconstricting responses following drug-eluting stent (DES) implantation in pigs. In this study, we further examined whether Rho-kinase activation is also involved in the DES-induced coronary hyperconstricting responses in humans. Methods: We examined 25 patients with coronary artery disease who underwent coronary intervention with either DES (n=16, sirolimus/paclitaxel 15/1, M/F 10/6, 69 ± 11[SD] years) or bare-metal stents (BMS, n=9, M/F 7/2, 70 ± 8 years). We examined coronary vasoconstricting responses to intracoronary (IC) acetylcholoine (ACh) before and after the intracoronary treatment with a Rho-kinase inhibitor, fasudil (300 μ g/min for 15 min). We evaluated coronary vasomotor responses by quantitative coronary angiography (QCA) and coronary vascular structure by optical coherence tomography (OCT). Results: QCA showed that the coronary vasoconstricing responses to ACh were significantly enhanced in the DES group compared with the BMS group at both the proximal (BMS -13.0 ± 10.7% vs. DES -24.7 ± 14.2[SD] %, P<0.05) and the distal segments (BMS -24.4 ± 12.2%, DES -42.8 ± 14.8%, P<0.01). Importantly, fasudil markedly attenuated the enhanced vasoconstricting responses to ACh in the DES group (proximal -10.2 ± 11.3%, distal -14.2 ± 10.2% vs. before fasudil, both P<0.01). In contrast, coronary vasodilator responses to intracoronary isosorbide dinitrate were comparable between the 2 groups. Although OCT showed a variable degree of intimal thickening at the segments adjacent to DES, there was no significant correlation between intimal thickness and coronary vasoconstriction to ACh. Conclusion: These results indicate that Rho-kinase activation is substantially involved in the pathogenesis of the DES-induced coronary hyperconstricting responses in patients with CAD as well, suggesting the therapeutic importance of Rho-kinase pathway.