Focal Angiogenic Therapy for Myocardial Ischemia

Background: Therapeutic angiogenesis, which involves the administration of angiogenic cytokines to stimulate collateral formation and improve myocardial perfusion, is being tested as an alternative treatment for patients with medically intractable angina who are no longer candidates for conventional revascularization techniques. Methods: Administration of recombinant protein formulations for these growth factors and transfection of the DNA itself have proven effective in animal models. At present, transfection of the DNA (gene therapy) appears preferable in that a single administration achieves a prolonged but transient, localized exposure of the ischemic tissues to the angiogen. The important technical aspects of surgical gene therapy via a mini thoracotomy incision are described. Results: Four Phase I clinical trials of angiogenic therapy recently have been reported, two involving administration of the recombinant protein combined with coronary bypass and two involving gene therapy alone. These studies have shown that this approach is relatively safe; the early evidence of efficacy is encouraging. The largest study reported six-month follow-up on 30 patients who received plasmid DNA for vascular endothelial growth factor-165 (VEGF165) and documented improvement in angina, treadmill exercise tolerance, and myocardial perfusion in the majority of patients studied. Conclusions: These preliminary results will need to be supported by randomized clinical trials in which angiogenic therapy alone is compared to standard medical therapy or a placebo. Catheter-based intramyocardial gene transfer and combined coronary arterial bypass grafting or transmyocardial laser revascularization plus gene therapy trials are also underway. If proven effective, angiogenic therapy may provide a relatively noninvasive modality for revascularization of ischemic myocardium not amenable to current techniques.