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

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

Effects of ELN 457946 on hematology parameters.

<p>Whole blood counts of white blood cells (WBC; top panel), lymphocytes (middle panel) and monocytes (bottom panel), over time after dosing with vehicle (black triangles) or ELN 457946 (grey squares). Dose administrations were done at weekly intervals (black arrows). Blood was collected prior to dose (predose or trough levels), 24 hours after the initial dose, and/or 48 hours post-dose, and prior to necropsy. * p<0.05 and ** p<0.01, when compared to vehicle group using Mann-Whitney. # p<0.05, when compared to baseline data (Day -1) using Mann-Whitney.</p

Histological analysis of the stented vessels.

<p>Representative images of elastin trichrome (A) and hematoxylin and eosin (B–F) stainings of sections in stented arteries. (A) Neointima injury (score 0). Arrows indicate intact elastic lamina in the carotid from a vehicle-treated animal. (B) Complete endothelialization in the LAD from a vehicle-treated animal. Arrows indicate endothelial cells. (C) Full thickness neointima with well-organized smooth muscle cells, in the RI artery from a vehicle-treated animal. (D) Neointima fibrin (score 1), as typically observed around the stent struts, in the LAD from a vehicle-treated animal. Asterisks in Panels C, E and F indicate areas of fibrin deposits. (E, F): Inflammation in the distal region of a right iliac artery from a vehicle-treated animal. (E) Arrowheads/long arrows/short arrows, indicate eosinophils, lymphocytes and macrophages, respectively. (F): Arrow indicates a foreign body giant cell. Bar = 100 µm.</p

Study design.

<p>Study design.</p

Summary of histomorphometric measurements.

<p>Data are means ± SD;</p>†<p><i>P</i>≤0.05;</p><p>*<i>P</i>≤0.01.</p