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）： 这项授权是为了研究单光子成像剂， 靶向冠状血管新生内膜增生或缺氧， 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。 冠状动脉的动脉硬化 是美国的一个主要健康问题，也是导致死亡的主要原因。 导管 减少管腔狭窄的技术包括经皮球囊 血管成形术和冠状动脉支架植入术。 术后再狭窄的病理 冠状动脉内支架植入术是新生内膜增生，主要包括 平滑肌细胞 小鼠/人嵌合Z2 D3 F（ab 1）2负电荷 用铟-111 Z2 D3放射性标记的修饰抗体靶向蛋白质 在活跃增殖的平滑肌细胞的表面上的抗原。 在 在初步实验中，申请人报告记录了体内摄取 In-111 Z2 D3在猪支架过度扩张再狭窄模型中的作用，但 新生内膜增生程度或管腔狭窄程度之间无相关性。 随着示踪剂摄取强度的增加而变窄。 申请人建议 因此，我们来看看另一个变量的影响， 肌细胞增殖对示踪剂摄取的影响。 另一种疾病过程， 由于移植的新生内膜增生而危及冠状动脉腔 动脉硬化是心脏病后患者死亡的主要原因 移植 还将在猪中研究In-111 Z2 D3的摄取 移植动脉硬化模型，通过移植一段 一个家猪的冠状动脉进入尤卡坦半岛的颈动脉 迷你猪 最后，两种示踪剂，目标是冠状动脉血流的后果， 减少、缺血（BMS-194796）和坏死（葡萄糖二酸盐）， 研究了 葡糖二酸盐，一种6个碳原子的二羧酸糖，是 一种小分子，从血池中迅速清除， 在急性缺血综合征中的临床应用潜力。 进一步的实验 建议确认我们实验室研究的初步结果 这表明葡萄糖二酸盐摄取可能是非常早期的敏感标志物， 和极轻度的心肌细胞坏死， 狭窄 BMS-194796是一种硝基杂环，保留在缺氧组织中。 申请人报告最近记录了体内摄取 成像在猪模型的需求缺血，并建议调查 短暂治疗前后示踪剂保留和扫描阳性的窗口 冠状动脉闭塞模仿急性缺血综合征。