ENHANCED REVASCULARIZATION OF THE ISCHEMIC LIMB BY ANGIOGENIC THERAPY

Background. This study tests the efficacy of an angiogenic growth factor, endothelial cell growth factor, in a rabbit model of persistent hindlimb ischemia. Methods and Results. Ischemia was induced in the left hindlimb of 22 New Zealand White rabbits by ligation of the distal external iliac artery and complete excision of the common and superficial femoral arteries. Two groups of animals were studied: Group 1 consisted of 11 animals who for 10 days received daily intramuscular injections of 4 mg of endothelial cell growth factor beginning on postoperative day 11, and group 2 consisted of 11 animals who underwent the same surgical ischemic procedure but received only injections of saline daily for the same postoperative period. Perfusion of the ischemic left limb was compared with the normal right limb in each animal on postoperative days 10, 20, 30, and 40 using the calf blood pressure ratio, Tc-99m macroaggregate radioisotopic perfusion scans, and serial angiography. Neovascularization in the left thigh at day 40 was quantified from the angiograms. Each technique documented that animals in group 1 had significantly better perfusion than animals in group 2; that is, the calf pressure ratio was higher in group 1 than in group 2 (0.56 versus 0.32 at day 20, 0.64 versus 0.44 at day 30, and 0.70 versus 0.50, P<.0001), and the calf radioisotopic perfusion ratio was also higher in group 1 than in group 2 (0.88 versus 0.74 at day 20, P<.02; 0.93 versus 0.76 at day 30, and 0.96 versus 0.79 at day 40, P<.008). Angiographic studies correlated well with these results demonstrating much earlier distal arterial reconstitution and enhanced neovascularization (23.8 versus 9.0 vessels, P<.007). Conclusions. The data clearly indicate that an angiogenic growth factor, endothelial cell growth factor, promotes revascularization in this experimental ischemic hindlimb model, raising the possibility that in the future such agents might be of value in humans.