Myocardial infarction and ischemic heart disease are among the most common causes of morbidity and mortality in the industrial world. Surgical and percutaneous intravascular approaches are commonly used to treat these diseases. Regrettably, a significant number of patients are either ineligible or demonstrate suboptimal responses to these therapies. In an attempt to provide such patients improved therapeutic options, much effort has been spent developing noninvasive approaches to restore coronary vascular perfusion. One such strategy, termed therapeutic revascularization or angiogenesis, involves administration of proangiogenic factors, which improve coronary perfusion by promoting growth of the coronary vasculature. Thus far, two potential proangiogenic factors have been intensively examined, fibroblast growth factor and vascular endothelial growth factor. Unfortunately, despite their apparent efficacy in animal models, neither factor has performed adequately in the clinic to date. Within the past year a new factor, hedgehog, has been shown to effectively promote the growth of the coronary vasculature and thus has been proposed as a novel candidate for therapeutic revascularization. In this review, we discuss the discovery of the hedgehog pathway as an essential regulator of the development of the coronary vasculature, as an inducer of adult coronary vascular growth, and as a therapeutic in the treatment of ischemic heart disease.
Ischemic Heart DiseaseMyocardial infarction and ischemic heart disease are the leading cause of death in the industrial world. Therapies used for treating these diseases are aimed at restoring and/or improving blood flow to ischemic cardiac tissue. Coronary artery bypass grafting and percutaneous coronary interventions are the mainstays of treatment for these patients and significantly reduce morbidity and mortality (Caines et al. 2004). Unfortunately, roughly 10% of all patients are ineligible for these procedures owing to the presence of diffuse or intractable lesions. Furthermore, significant numbers of diabetic patients that undergo these procedures show insufficient improvement. Without treatment, these patients do poorly, with mortality rates of 8% to 10% per year (Syed et al. 2004).Recently, a noninvasive approach aimed at promoting growth of new coronary blood vessels has been proposed to treat patients who are not eligible for coronary artery bypass grafting and percutaneous coronary interventions. This strategy, termed pharmacological revascularization or angiogenesis, involves either systemic or local administration of proangiogenic agents that promote growth of the established vasculature and/or formation of new coronary blood vessels. The search for molecules that possess this activity is actively underway. Over the past 10 years, it has been realized that expression of a number of known proangiogenic factors can promote coronary vessel growth in animal models. Overexpression of fibroblast growth factor-2 (FGF2), vascular endothelial growth factor-A (VEGF-A), and ...