Coronary artery disease (GAD) remains the leading cause of morbidity and mortality in the western world. Chronic, progressive worsening of an arterial stenosis can lead to complete occlusion of the coronary artery resulting in adverse clinical outcomes. In many patients with chronic ischemic heart disease (IHD), however, compensatory mechanisms that limit myocardial ischemia and preserve cardiac function (even in the presence of a complete arterial occlusion) can occur: patients in whom the robust formation of new capillaries (angiogenesis) and/or the formation of collateral arterial supply (arteriogenesis) occurs have markedly better cardiac function and clinical outcomes when compared to patients where the angiogenesis/arteriogenesis is limited or nonexistent. A striking, but mechanistically unexplained, clinical observation is that patients with similar degrees of coronary stenosis and myocardial ischemia have markedly heterogenous extent of myocardial neovascularization. Chemokines, a superfamily of cytokines originally described for their role in mediating leukocyte recruitment to sites of inflammation, have been established as important mediators of angiogenesis and arteriogenesis in diverse disease settings. A unique feature of chemokines is that while some are potent promoters of neovascularization, others are potent inhibitors. To date, very little is known regarding the role of chemokines in chronic IHD. Our overall hypothesis is that the relative balance of angiogenic and angiostatic chemokines contributes to neovascularization of the myocardium in patients with chronic IHD. We propose to test this hypothesis in a highly characterized population of chronic IHD patients undergoing coronary angiography under the following Spiecific Aims: (1) To correlate the presence and extent of myocardial neovascularization in patients with chronic IHD undergoing coronary angiography with their circulating levels of angiogenic and angiostatic chemokines;(2) To determine the frequency of genetic polymorphisms in angiogenic and angiostatic chemokines associated with myocardial neovascularization in a highly characterized population of chronic IHD patients undergoing coronary angiography;and (3) To assess the predictive value of angiogenic and angiostatic chemokines as biomarkers of future adverse cardiac events in patients with chronic IHD.
The relevance of this proposal is that it will elucidate the mechanism(s) of the clinically important but incompletely understood problem of neovascularization of the ischemic myocardium. Its innovation is that it has the potential to link the well-characterized mechanism of chemokine- mediated vascular remodeling to ischemic heart disease, and ultimately result in novel diagnostic and therapeutic applications.
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