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

Effect of Cardiac Stem Cells on Left-Ventricular Remodeling in a Canine Model of Chronic Myocardial Infarction

Background-Regenerative medicine, including cell therapy, is a promising strategy for recovery of the damaged myocardium. C-kit-positive cardiac stem cells (CSCs) have been shown to improve myocardial function after ischemic injury in animal models and in early clinical experience. We used a chronic large animal model of myocardial infarction with substantial reductions in left-ventricular (LV) ejection fraction and adverse remodeling to examine the effect of late autologous CSC intramyocardial injection on long-term cardiac structure and function. Methods and Results-Thoracotomy and ligation of the proximal left anterior descending artery, additional diagonal branches, and atrial biopsy for CSC culture were performed in canines. Baseline cardiac MRI was performed at 6 weeks postinfarct followed by repeat thoracotomy for randomization to intramyocardial injection of CSCs (n=13) or vehicle alone (n=6). At 30 weeks postmyocardial infarction, repeat MRI was performed. Data were analyzed using nonparametric tests (Wilcoxon signed-rank and rank-sum tests). In control animals, LV end-systolic volume and end-diastolic volume increased from 6 to 30 weeks (median and interquartile range, 51.3 mL [43.3-57.4] to 76.1 mL [72.0-82.4]; P=0.03 and 78.5 mL [69.7-86.1] to 99.2 mL [97.1-100.4]; P=0.03). Left-ventricular ejection fraction declined further (35.2% [27.9-38.7] to 26.4% [22.0-31.0]; P=0.12). In the cell-treated animals, this late adverse LV remodeling was attenuated (LV end-systolic volume, 42.6 mL [38.5-50.5] to 56.1 mL [50.3-63.0]; P=0.01 versus control). There was a nonsignificant attenuation in the increase in LV end-diastolic volume (64.8 mL [60.7-71.3] to 83.5 mL [74.7-90.8]; P=0.14 versus control) and LV ejection fraction change over time differed (30.5% [28.4-33.4] to 32.9% [28.6-36.9]; P=0.04 versus control). Conclusions-Intramyocardial injection of autologous CSCs in a late phase model of chronic infarction resulted in less increase in LV end-systolic volume and preservation of LV ejection fraction

Effect of Cardiac Stem Cells on Left-Ventricular Remodeling in a Canine Model of Chronic Myocardial Infarction

Background-Regenerative medicine, including cell therapy, is a promising strategy for recovery of the damaged myocardium. C-kit-positive cardiac stem cells (CSCs) have been shown to improve myocardial function after ischemic injury in animal models and in early clinical experience. We used a chronic large animal model of myocardial infarction with substantial reductions in left-ventricular (LV) ejection fraction and adverse remodeling to examine the effect of late autologous CSC intramyocardial injection on long-term cardiac structure and function. Methods and Results-Thoracotomy and ligation of the proximal left anterior descending artery, additional diagonal branches, and atrial biopsy for CSC culture were performed in canines. Baseline cardiac MRI was performed at 6 weeks postinfarct followed by repeat thoracotomy for randomization to intramyocardial injection of CSCs (n=13) or vehicle alone (n=6). At 30 weeks postmyocardial infarction, repeat MRI was performed. Data were analyzed using nonparametric tests (Wilcoxon signed-rank and rank-sum tests). In control animals, LV end-systolic volume and end-diastolic volume increased from 6 to 30 weeks (median and interquartile range, 51.3 mL [43.3-57.4] to 76.1 mL [72.0-82.4]; P=0.03 and 78.5 mL [69.7-86.1] to 99.2 mL [97.1-100.4]; P=0.03). Left-ventricular ejection fraction declined further (35.2% [27.9-38.7] to 26.4% [22.0-31.0]; P=0.12). In the cell-treated animals, this late adverse LV remodeling was attenuated (LV end-systolic volume, 42.6 mL [38.5-50.5] to 56.1 mL [50.3-63.0]; P=0.01 versus control). There was a nonsignificant attenuation in the increase in LV end-diastolic volume (64.8 mL [60.7-71.3] to 83.5 mL [74.7-90.8]; P=0.14 versus control) and LV ejection fraction change over time differed (30.5% [28.4-33.4] to 32.9% [28.6-36.9]; P=0.04 versus control). Conclusions-Intramyocardial injection of autologous CSCs in a late phase model of chronic infarction resulted in less increase in LV end-systolic volume and preservation of LV ejection fraction.6199+NIH [P20 HL101866-01]NIH [P20 HL101866-01