Non-Invasive Methods for Imaging Myocardial Angiogenesis

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The goal of this project is to develop non-invasive imaging strategies for identifying the hypoxic stimulus for angiogenesis, and to use targeted imaging to non-invasively track the angiogenic process over time in ischemic models in relationship to changes in regional myocardial perfusion, and hypoxia. Myocardial hypoxia is known to stimulate angiogenesis in the heart, thereby providing a potential marker for the initiation of angiogenesis. We hypothesize that effective angiogenesis should result in an improvement in resting myocardial perfusion and a reduction in regional myocardial hypoxia. We hypothesize that myocardial hypoxia can be identified non-invasively with 99mTc-nitroimidazole single photon emission computed tomography (SPECT) imaging. The angiogenic response is also controlled by modulation of the composition of the extracellular matrix and intercellular adhesions. We also hypothesize that the angiogenic process can be directly tracked non-invasively by SPECT imaging of radiolabeled ligands targeted to markers of angiogenesis, like the alphavbeta3 integrin. These hypotheses will be addressed in 4 specific aims. Aim 1 will investigate the relationship between level of hypoxia and retention of a 99mTc-labeled nitroimidazole using in vitro, and in vivo preparations. The degree of hypoxia will also be related to the up-regulation of acute markers of hypoxia and angiogenesis. Aim 2 will investigate the selectivity of a labeled quinolone alphavbeta3 antagonist for identification of angiogenesis. Localization of a fluorescent-labeled analog of the radiolabeled antagonist will be compared with a highly specific alphavbeta3 antibody (LM609), using in vitro endothelial cell cultures. Aim 3 will investigate the temporal changes in regional hypoxia and perfusion in relationship to changes in regional myocardial uptake of the radiolabeled aphavbeta3 antagonist, using established experimental rodent models of angiogenesis. Alterations in regional hypoxia, perfusion and integrin expression will be related to immuno-histochemical and immuno-fluorescent markers of angiogenesis. To extend the findings from the rat models towards clinically applicable non- invasive imaging stategies, Aim 4 will evaluate the ability of SPECT imaging to directly track the angiogenic process in chronic canine models of catheter induced reperfused infarction. We will compare SPECT imaging strategies employing the 111In-labeled alphavbeta3 antagonist and 99mTc-labeled nitroimidazole, with radiolabeled microsphere measures of regional myocardial flow, 201T1 perfusion, and immuno-histological analysis of angiogenesis. To accomplish this final aim, additional cardiac phantoms studies will be performed to develop and validate approaches for quantitative analysis of dual isotope perfusion and 99mTc-or 111 In-labeled "hot spot" SPECT images of angiogenesis. The proposed nuclear imaging approaches are designed to exploit the specific biology of angiogenesis to provide critically important non-invasive methods of evaluating angiogenesis in patients. The development of more sensitive and specific imaging strategies for evaluation of methods of evaluating angiogenesis in patients. The development of more sensitive and specific imaging strategies for evaluation of myocardial angiogenesis and tracking this process non-invasively are critical in evaluation of new angiogenic therapy for the heart.