Angiogenic cytokine therapy for ischemic heart disease

Ischemic heart disease comprises an escalating national and global health challenge. Current therapy consists of pharmacologic optimization and limited revascularization, reconstructive or replacement options. These modalities are highly effective for only a fraction of patients and do not address the significant microvascular deficiencies that persist even when a diseased artery is stented or bypassed. Endogenous machinery to repair injured and ischemic myocardium is inadequate and tremendous resources have been devoted to developing molecular therapies that enhance both the microvascular perfusion and the function of ischemic or infarcted myocardium. A significant portion of this work has focused on angiogenic cytokines, primarily fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), placental growth factor (PGF), and stromal cell-derived factor-1α (SDF). Angiogenic cytokine based therapies act, at least in part, through endothelial progenitor stem cell (EPC) activity, and those cells have the intrinsic ability to mature into the endothelial cells and support network vital for vasculogenesis and functional myocardial vasculature. Phase I and II clinical trials, while not conclusive, have achieved encouraging results using both recombinant protein cytokines and single-agent gene therapies. The data, accumulated over more than a decade, has demonstrated both clinical feasibility and an acceptable safety profile for angiogenic cytokine therapy. In this chapter, we examine both the preclinical and clinical development of angiogenic cytokine therapy for ischemic heart disease and suggest areas for future expansion of this burgeoning field.