Congestive heart failure remains a major public health problem, and is frequently the result of left ventricular remodeling after myocardial infarction. We have recently shown that human adult bone marrow contains endothelial precursors with phenotypic and functional characteristics of embryonic hemangioblasts, and that these can be used to induce infarct bed neovascularization after experimental myocardial infarction. The induction of neovascularization in the peri-infarct period results in protection of cardiomyocytes against apoptosis, induction of cardiomyocyte proliferation and regeneration, long-term salvage and survival of viable myocardium, prevention of left ventricular remodeling and sustained improvement in cardiac function. Our striking observation that neovascularization of acutely ischemic myocardium results in regeneration of endogenous cardiomyocytes suggests that a similar process could be induced in myocardium exposed to chronic ischemia, however no information exists to date regarding whether bone marrow-derived angioblasts could reverse established heart failure and myocardial fibrosis. If similar effects could be achieved by angioblast infusion in an animal model of chronic ischemia and established ventricular remodelling and scarring, this would provide a potential new therapeutic modality for the treatment of established heart failure. In the first aim of this proposal we will specifically establish an animal model of chronic heart failure following ischemia and investigate whether angioblast-dependent neovascularization can result in myocardial regeneration and improvement in cardiac function. In the second aim, we will examine the role of specific CXC chemokines in angioblast migration to chronically ischemic myocardium. We will then seek to develop strategies that enable manipulation of interactions between CXC chemokines and their receptors in order to increase selective angioblast trafficking to chronically ischemic myocardium, promote vasculogenesis, and augment myocardial regeneration and functional improvement. In the final aim we will evaluate whether concomitant use of bone marrowderived angioblasts together with autologous mesenchymal stem cells or pharmacologic agents may provide synergistic, additive benefit in terms of cardiomyocyte regeneration and cardiac function. We believe that gaining an understanding of these issues will prove to be of critical importance in order to be able to rationally design and develop strategies for human clinical trials using autologous bone marrow-derived endothelial progenitors in the treatment of chronic heart disease.
