Ischemic coronary disease is the leading cause of morbidity and mortality in the Western world. Most available therapeutic approaches aim either at relieving symptoms by reducing myocardial oxygen demand, preventing further disease progression by modifying risk factors, restoring flow to a localized segment of the arterial tree (PTCA or CABG). Therapeutic angiogenesis may restore flow to the ischemic myocardium by creating new venues for blood flow. The purpose of the present investigation will be to examine the therapeutic potential of basic fibroblast growth factor (bFGF) in human ischemic heart disease using percutaneous intrapericardial delivery, define optimal outcome measures for clinical angiogenesis studies using a novel magnetic resonance imaging technique and Biosense electromechanical mapping, and explore novel growth factor deliver methods in animal models of myocardial ischemia, including intramyocardial delivery and gene therapy. We will conduct a clinical trial of therapeutic angiogenesis in patients with ischemic heart disease who are suboptimal candidates for standard revascularization strategies. This trial will examine the angiogenic efficacy of bFGF administered using a novel percutaneous subxyphoid intrapericardial delivery technique. We will investigate the effects of bFGF treatment on clinical parameters, left ventricular function, coronary angiography, and on the size and extent of myocardial ischemia using stress nuclear perfusion scans. Biosense NOGA outcome variables in several ongoing clinical angiogenesis studies and laser myocardial revascularization studies comparing these two treatment strategies. In particular, we will validate two novel outcome measures: magnetic resonance imaging and Biosense NOGA mapping. Finally, we will develop novel delivery strategies in a porcine model of chronic myocardial ischemia and mouse matrigel and infarction models including intramyocardial delivery and gene therapy, and compare protein and gene therapy strategies for growth factor-induced angiogenesis. These novel delivery strategy, if successful, will be investigated clinically. These interrelated projects constitute a cohesive research program aimed at elucidating various aspects of therapeutic angiogenesis. Even though the problem, we wish to address, the techniques involved are necessarily broad, ranging from clinical trials, investigation of novel delivery strategies in animal models, and development of a standardized platforms for the conduction of future trials. This should lead to a novel approach to the treatment of ischemic heart disease and a better understanding of the mechanisms of growth- factor and laser induced """"""""angiogenesis"""""""".
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