Coronary artery disease is the major cause of mortality in the United States. Although many patients come to medical attention because of hemodynamically significant coronary lesions, over one-half who die suddenly from coronary disease have had no pre-existing symptoms. It has been hypothesized that critical abnormalities in the coronary endothelial lining provide a milieu that ultimately promotes acute thrombotic occlusion in the absence of significant prior coronary stenoses. Moreover, in patients with angina due to severe stenoses, endothelial abnormalities likewise promote the development and progression of atherosclerotic plaques that culminate in acute ischemic syndromes. Aberrations in endothelial function in coronary disease involve the microcirculation and occur in other cardiovascular disease states such as heart transplant rejection and ischemia-reperfusion. Endothelial dysfunction is thus a critical mediator of the total burden of atherosclerotic heart disease and a major component of other cardiovascular pathologies, and the identification and treatment of this phenomenon would confer significant health benefits. Unfortunately, methods to identify patients with early endothelial dysfunction are limited. Studies have shown that endothelial overexpression of leukocyte adhesion molecules such as intercellular adhesion mnolecule-1 (ICAM1) promotes the development of the earliest lesions of atherosclerosis, suggesting that ICAM1 can serve as a marker of incipient endothelial disease. Using perfused cultured human coronary artery endothelial cells (ECs), we recently proved the principle that gas-filled microbubbles conjugated to a ligand that binds specifically to ICAM1 adhere to interleukin1?-activated ECs overexpressing ICAM1. Because these bubbles are acoustically active in the presence of ultrasound, we hypothesize that in vivo ultrasound imaging of bubbles targeted to specific cell surface markers of endothelial activation such as ICAM1 will permit non-invasive identification of pre-clinical endothelial dysfunction. To test this hypothesis, in vitro and in vivo models of endothelial activation will be used to address three Specific Aims with respect to bubbles engineered to bind to cell surface markers of endothelial disease: (1) Define shear conditions under which ICAM1-targeted bubbles attach to ECs and optimize bubble characteristics for binding; (2) Identify other EC surface proteins specific for endothelial dysfunction, including selectins, vascular adhesion molecule-1, or vascular endothelial growth factor receptors, evaluate their suitability as imaging targets, and design microbubbles for these targets; and (3) Image and quantify targeted bubble adhesion in vivo under clinically relevant conditions. The ultimate goal of this proposal is to develop targeted ultrasound imaging in order to enhance the early diagnosis of ischemic heart disease or other cardiovascular disease states associated with endothelial dysfunction. Principles gleaned from these studies can be extended to function-specific ultrasound imaging of other targets such as angiogenic markers, and may also provide a basis for targeted therapeutic approaches using microbubble carriers.
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