IMAGING INTIMAL HYPERPLASIA, MYOCYTE HYPOXIA, NECROSIS

内膜增生、心肌细胞缺氧、坏死的影像学检查

• 批准号: 2680345
• 负责人: LYNNE L. JOHNSON
• 金额: $ 25.01万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2680345
• 关键词: atherosclerosis; blood vessel prosthesis; blood vessel transplantation; cell proliferation; clinical research; coronary artery; human subject; hyperplasia; miniature swine; myocardial ischemia /hypoxia; necrosis; radiotracer; restenosis; swine; vascular smooth muscle

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.

描述（改编自申请人的摘要）： 该赠款是研究单个光子成像剂 靶向冠状动脉血管新内膜增生或缺氧或 使用动物模型和实验设计的坏死心肌细胞 与临床情况有关。 冠状动脉动脉硬化 是美国的主要健康问题，也是死亡的主要原因。 导管 减少腔窄的技术包括经皮气球 血管成形术和冠状动脉支架。 再狭窄的病理 冠状动脉支架是新的增生，主要包括 平滑肌细胞。 鼠标/人类嵌合Z2D3 F（AB1）2负电荷 用insim-111111 Z2D3靶向蛋白质的修饰抗体放射性标记 在积极增殖平滑肌细胞表面的抗原。 在 初步实验，申请人报告了记录体内摄取的记录 在支架过度曝光再狭窄的猪模型中的In-1111 Z2D3，但那里 在新内膜增殖或腔内之间没有相关性 随着示踪剂吸收的强度而变窄。 申请人提议 因此，要查看另一个变量的效果，平滑速率 示踪剂吸收的肌肉细胞增殖。 另一个疾病过程 由于新内膜增殖而导致的冠状动脉腔是移植 动脉硬化是心脏后患者死亡的主要原因 移植。 In-1111 Z2D3的吸收也将在猪中进行研究 通过移植一段的移植动脉硬化模型 家养猪的冠状动脉进入尤卡坦的颈动脉 Minipig。 最后，两个针对冠状动脉流的后果的示踪剂 还原，缺血（BMS-194796）和坏死（葡萄糖酸），将是 调查。 Glucarate是6个碳原子二羧酸糖，是一个 从血池迅速清除的小分子并显示 急性缺血综合症临床使用的潜力。 进一步的实验 提议确认我们实验室的研究的初步结果 表明葡萄糖摄取可能很早就是敏感的标记 并且非常轻微的心肌细胞坏死发生在起搏和冠状动脉下 狭窄。 BMS-194796，硝基核定细胞，保留在低氧组织中。 据报道，申请人最近记录了对体内的吸收 在需求缺血的猪模型中成像，并建议研究 示踪剂保留和扫描阳性的窗口前后 模仿急性缺血综合征的冠状动脉闭塞。