P198Chronic, atherosclerosis-like ischemia model in hypercholesterolemic rabbits reveals a challenge for angiogenic gene therapy

Abstract

Introduction: Angiogenic gene therapy has shown potential for treatment of peripheral ischemic diseases in animal models but unfortunately clinical trials have failed to show consistent improvements in patients. We hypothesized that the differential outcomes of animal and clinical trials could be explained by pathological differences between animal models and human disease. Methods: Chronic ischemia was developed by causing endothelial denutation via balloon catheters to limb arteries of New Zealand White rabbits (n=89) on a 1% cholesterol diet. Development of arterial narrowing and signs of ischemia were monitored weekly after the operation using ultrasound imaging, angiography and muscle force measurements. Adenoviral vascular endothelial growth factor (VEGF) or beeta-galactosidase control gene therapy was applied intramuscularly with the total dose of 3x10e11vp in 3ml of saline once muscles started showing signs of ischemia (at 2-6 weeks). The effects of gene therapy were followed 1, 2 and 4 weeks after gene transfers. Results: Atherosclerosis-resembling narrowing of the femoral artery was detected starting 2 weeks after denutation leading to chronically decreasing muscle function even in the presence of collateral formation and at least partial restoration of muscle blood flow. VEGF gene transfer induced capillary enlargement and improved muscle blood flow but at the same time increased muscle necrosis and worsened muscle function. Conclusions: Angiogenic gene therapy may not be the optimal treatment in chronic ischemia if muscle blood flow has already been restored by collateral circulation. The analysis of muscle capillary flow may help identify patients with chronic ischemia that could benefit from angiogenic therapies.