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Specific Coronary Drug-Eluting Stents Interfere With Distal Microvascular Function After Single Stent Implantation in Pigs

Mieke van den Heuvel, MD, MSc^_*,, Oana Sorop, PhD^_*, Wendy W. Batenburg, PhD, Charlotte L. Bakker, BSc^_*, René de Vries, BSc, Sietse Jan Koopmans, PhD, Heleen M.M. van Beusekom, PhD^_*, Dirk J. Duncker, MD, PhD^_*, A.H. Jan Danser, PhD, Willem J. van der Giessen, MD, PhD^_*,,_*

^_* Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands
Department of Internal Medicine, Sector of Pharmacology and Metabolic Diseases, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, the Netherlands
BioMedical Research, Wageningen University and Research Center, Lelystad, the Netherlands
Interuniversity Cardiology Institute, ICIN/KNAW, Utrecht, the Netherlands

^_* Reprint requests and correspondence: Dr. Willem J. van der Giessen, Erasmus University Medical Center, Thoraxcenter, Room Ee2393, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands (Email: w.j.vandergiessen{at}erasmusmc.nl).

Objectives: The aim of this study was to compare the effects of single drug-eluting stents (DES) on porcine coronary function distal to the stent in vivo and in vitro.

Background: The mechanism of endothelial dysfunction occurring in human coronary conduit arteries up to 9 months after DES implantation is unknown.

Methods: A sirolimus-eluting stent (SES), paclitaxel-eluting stent (PES), and a bare-metal stent (BMS) were implanted in the 3 coronary arteries of 11 pigs. After 5 weeks, in vivo responses in distal coronary flow to different doses of bradykinin (BK) and nitrates were measured. In vitro, vasodilation to BK and nitrates, as well as vasoconstriction to endothelin (ET)-1 were assessed in both distal coronary conduit and small arteries. In addition, contributions of nitric oxide (NO) and endothelium-derived hyperpolarizing factors (EDHFs) and cyclic guanosine monophosphate (cGMP) responses to BK-stimulation were determined in vitro.

Results: Both DES did not alter in vivo distal vasomotion. In vitro distal conduit and small arterial responses to BK were also unaltered; DES did not alter the BK-induced increase in cGMP. However, after NO synthase blockade, PES showed a reduced BK-response in distal small arteries as compared with BMS and SES (p < 0.05). The ET-1–induced vasoconstriction and vascular smooth muscle cell function were unaltered.

Conclusions: In this study of single stenting in healthy porcine coronaries for 5 weeks, SES did not affect distal coronary vascular function, whereas PES altered distal endothelial function of small arteries under conditions of reduced NO bioavailability. Therefore, specifically the EDH-component of microvascular function seems affected by PES.

Key Words: coronary • drug-eluting stent • endothelial function • endothelium derived hyperpolarizing factors • microcirculation

Abbreviations and Acronyms   BK = bradykinin   BMS = bare-metal stent(s)   cGMP = cyclic guanosine monophosphate   CRC = concentration-response curve   DES = drug-eluting stent(s)   EDHF = endothelium-derived hyperpolarizing factor   ET = endothelin   L-NAME = N-nitro-L-arginine methyl ester   NO = nitric oxide   pEC50 = concentration necessary to produce 50% of the maximal response   PES = paclitaxel-eluting stent(s)   SES = sirolimus-eluting stent(s)   SNAP = S-nitroso-N-acetylpenicillamine