Abstract 5536: Mechanisms Underlying Coronary Vasopsasm at Distal Arterial Segments of Sirolimus-Eluting Stent Implantation in a Porcine Model
The use of sirolimus-eluting stent (SES) presents serious safety concerns including increased late stent thrombosis and coronary vasospasm that may cause coronary adverse events. Hence we assessed the hypothesis that (1) SES implantation predisposes the coronary arteries to vasospasm in a porcine coronary artery (PCA) stent model; and (2) dysfunction of endothelial and/or smooth muscle cells is involved in the mechanism of SES-associated coronary vasospasm. Bare metal stent (BMS) or SES were deployed in the left anterior descending (LAD) or left circumflex (LCX) PCA. Quantitative coronary angiography and western blotting were performed 28-day postimplantation. As reported clinically in patients after SES implantation, intracoronary administration of serotonin caused vasospasm at distal segments of SES but not BMS (Figure, A⇓). Western blotting of the PCA revealed that SES implantation downregulated eNOS phosphorylation (Ser1177) and myosin phosphatase subunit MYPT1 expression (Figure, B⇓). In cultured human endothelial cells, 24 hr pretreatment with sirolimus (10 ng/ml) inhibited bradykinin (1 μM)-induced phosphorylation of Akt (Ser475) and eNOS. By contrast, in human coronary smooth muscle cells, treatment of sirolimus (0.1 - 10 ng/ml) over 72 hrs did not alter the expression of MYPT1. SES implantation provoked coronary vasospasm to serotonin in PCA in vivo. Direct inhibition of Akt and eNOS phosphorylation in endothelial cells as well as indirect downregulation of myosin phosphatase in vascular smooth muscle cells by sirolimus may play a mechanistic role in the pathogenesis of SES-associated coronary vasospasm.