Imaging Apoptosis to Detect Unstable Atheromatous Plaque

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DESCRIPTION (Provided by Applicant): Coronary artery disease is a major national health problem with over 13 million patients in the United States Of these, at least one million people present with acute coronary syndromes annually and 400,000 die of the acute event. The acute coronary event is associated with acute thrombosis of the coronary artery and is likely to result from rupture of the Atherosclerotic plaque. Apoptosis of the neointimal cells has been proposed as one of the important mechanisms responsible for conversion of stable coronary plaque to vulnerable plaque and may continue to lead to plaque rupture. Unlike necrotic cell death, apoptosis is a genetically programmed process and can be potentially prevented. For such a therapeutic strategy to become successful, it is necessary to develop techniques for noninvasive detection of apoptosis in an Atherosclerotic lesion. We have recently demonstrated that radiolabeled annexin V selectively identifies surface alterations of apoptotic cells in various myocardial diseases. We, therefore, reason that annexin V should be able to identify Atherosclerotic lesions rich in apoptotic cells. Our preliminary studies have demonstrated the feasibility of annexin imaging in experimental Atherosclerotic lesions induced in rabbit aorta. The radiotracer uptake was seen only in lesions with abundant apoptotic neointimal cells, predominantly in the apoptotic macrophages. We propose to evaluate the potential role of annexin imaging in the detection of vulnerable plaque. The evaluation will be performed serially in different animal models and finally in a pilot clinical trial. We will first confirm the feasibility of annexin imaging in experimentally induced Atherosclerotic aortic lesions in rabbits and carefully correlate radiolabeled annexin V uptake with the histologic characteristics of the plaque and apoptotic index. In the next step, annexin imaging will be performed in a porcine model for the detection of coronary Atherosclerotic lesions. Subsequently, cellular site of annexin uptake will be precisely characterized in genetically altered rodent models, which demonstrate advanced Atherosclerotic lesions closet to human coronary pathology. Finally, annexin imaging will be performed in a pilot clinical study in patients undergoing carotid endarterectomy. The impending surgical intervention will allow histopathological evaluation of the endarterectomy specimens to define potential utility of annexin imaging.