Effects of an Alpha-4 Integrin Inhibitor on Restenosis in a New Porcine Model Combining Endothelial Denudation and Stent Placement

Anne Braun,Serge Rousselle,Alain Stricker-Krongrad,Luis Guerrero,Jane Gunther,Ted Yednock,Lilibeth Dofiles,Elizabeth Messersmith,Christophe Egles

doi:10.1371/journal.pone.0014314

Anne Braun, Serge Rousselle + Show 7 more

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https://doi.org/10.1371/journal.pone.0014314

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Abstract

Restenosis remains the main complication of balloon angioplasty and/or stent implantation. Preclinical testing of new pharmacologic agents preventing restenosis largely rely on porcine models, where restenosis is assessed after endothelial abrasion of the arterial wall or stent implantation. We combined endothelial cell denudation and implantation of stents to develop a new clinically relevant porcine model of restenosis, and used this model to determine the effects of an α4 integrin inhibitor, ELN 457946, on restenosis. Balloon-angioplasty endothelial cell denudation and subsequent implantation of bare metal stents in the left anterior descending coronary, iliac, and left common carotid arteries was performed in domestic pigs, treated with vehicle or ELN 457946, once weekly via subcutaneous injections, for four weeks. After 1 month, histopathology and morphometric analyses of the arteries showed complete healing and robust, consistent restenotic response in stented arteries. Treatment with ELN 457946 resulted in a reduction in the neointimal response, with decreases in area percent stenosis between 12% in coronary arteries and 30% in peripheral vessels. This is the first description of a successful pig model combining endothelial cell denudation and bare metal stent implantation. This new double injury model may prove particularly useful to assess pharmacological effects of drug candidates on restenosis, in coronary and/or peripheral arteries. Furthermore, the ELN 457946 α4 integrin inhibitor, administered subcutaneously, reduced inflammation and restenosis in stented coronary and peripheral arteries in pigs, therefore representing a promising systemic therapeutic approach in reducing restenosis in patients undergoing angioplasty and/or stent implantation.

Highlights

Coronary artery disease (CAD) is the leading cause of death in most developed countries
Drug-eluting stents (DES; e.g. sirolimus- or paclitaxeleluting stents) became the standard of care for the treatment of CAD, due to their strikingly reduced rates of restenosis compared with baremetal stents [2,3]
We investigated the effects of ELN 457946, an a4 integrin inhibitor, on vascular healing and restenosis

Summary

Introduction

Coronary artery disease (CAD) is the leading cause of death in most developed countries. Restenosis (narrowing of the vessel lumen) remains one major complication of coronary angioplasty and stent placement [1] In this context, drug-eluting stents (DES; e.g. sirolimus- or paclitaxeleluting stents) became the standard of care for the treatment of CAD, due to their strikingly reduced rates of restenosis compared with baremetal stents [2,3]. Safety concerns with DES recently arose with reports of increased late in-stent thrombosis, possibly associated with increased mortality and myocardial infarction [4]. These findings have renewed interest for alternative or complementary interventions to reduce restenosis, including systemic pharmacological treatments after bare metal or drug-eluting stent placement

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