IMAGING INTIMAL HYPERPLASIA, MYOCYTE HYPOXIA, NECROSIS

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DESCRIPTION (Adapted from Applicant's Abstract): The broad objective of this grant is to investigate single photon imaging agents that specifically target either coronary vascular neointimal hyperplasia or hypoxic or necrotic myocardial cells using animal models and experimental designs relevant to clinical situations. Arteriosclerosis of the coronary arteries is a major health problem in the US and a leading cause of death. Catheter techniques to reduce luminal narrowing include percutaneous balloon angioplasty and coronary stenting. The pathology of restenosis following intracoronary stenting is neointimal proliferation comprised largely of smooth muscle cells. The mouse/human chimeric Z2D3 F(ab1)2 negative charge modified antibody radiolabeled with indium-111 Z2D3 targets a protein antigen on the surface of actively proliferating smooth muscle cells. In preliminary experiments, the applicants reported documenting in vivo uptake of In-111 Z2D3 in a swine model of stent overexpansion restenosis, but there was no correlation between the extent of neointimal proliferation or lumenal narrowing with intensity of tracer uptake. The applicants proposed therefore to look at the effect of another variable, the rate of smooth muscle cell proliferation on tracer uptake. Another disease process that compromises the coronary lumen due to neointimal proliferation is transplant arteriosclerosis which is the primary cause of death in patients after heart transplantation. Uptake of In-111 Z2D3 will also be investigated in a swine model of transplant arteriosclerosis produced by transplanting a segment of a coronary artery from a domestic pig into the carotid artery of a Yucatan minipig. Finally, two tracers that target the consequences of coronary flow reduction, ischemia (BMS-194796) and necrosis (glucarate), will be investigated. Glucarate, a 6 carbon atom dicarboxylic acid sugar, is a small molecule that is cleared rapidly from the blood pool and shows potential for clinical use in acute ischemic syndromes. Further experiments are proposed to confirm preliminary results of a study from our lab suggesting that glucarate uptake may be a sensitive marker for very early and very mild myocyte necrosis occurring with pacing and underlying coronary stenosis. BMS-194796, a nitroheterocycle, is retained in hypoxic tissue. The applicants reported to have recently documented uptake on in vivo imaging in a swine model of demand ischemia and propose to investigate the window for tracer retention and scan positivity before and after brief coronary occlusion mimicking an acute ischemic syndrome.