Therapeutic angiogenesis: the new electrophysiology?

A pproximately 15 million patients suffer from coronary and peripheral atherosclerotic diseases in the United States alone. 1 The evolving development of medical and surgical therapies has significantly improved the physician's ability to manage these patients, yet many continue to suffer debilitating symptoms from their disease and remain at risk for myocardial infarction, limb loss, and death. This clinical imperative, coupled with rapid advances in molecular biology, has led to the exploration of a plethora of therapeutic angiogenesis strategies. A method described in this issue of Circulation 2 offers yet another means by which angiogenesis may be achieved and thus potentially opens a new chapter in the ongoing search for novel approaches for the treatment of ischemia. In placing the novelty of the approach by Kanno et al into perspective, it is worth considering the important advances made during the last decade in the field of therapeutic angiogenesis. The investigators at the forefront of this field have not used a traditional pharmaceutical approach to search for potential angiogenic agents effective against vascular disease. Instead, they have chosen to arm themselves with the fruits of the molecular biology revolution by harnessing the power of endogenous human angiogenic factors. Vascular endothelial growth factor (VEGF) is the most potent and specific endogenous angiogenic factor yet identified, so it makes sense that it would have drawn the attention of cardiologists interested in angiogenic therapies. The demonstration that intra-arterial injection of recombinant VEGF could induce collateral formation in ischemic rabbit hind-limbs 3 suggested that VEGF would be a useful angiogenic agent, and this has subsequently been confirmed by an impressive corpus of preclinical data. Phase I and II clinical trials are now under way to test the effects of VEGF in patients with ischemic vascular disease, and preliminary results from some of these trials have been published. 4,5 Two methods are being used to deliver VEGF: intra-arterial injection of recombinant VEGF protein into an artery supplying ischemic tissue, or delivery of the VEGF cDNA into ischemic zones by plasmid-based or viral vectors. Preliminary data have been quite promising and promote the general concept that VEGF therapy may be beneficial in humans with vascular disease. However, practical and potential obstacles exist when VEGF is delivered either as a protein or through gene-therapy approaches, which may, to a certain extent, temper the enthusiasm generated by these preliminary studies. Intra-arterial injection of VEGF (for instance, into the coronary …