Imaging Apoptosis to Detect Unstable Atheromatous Plaque

细胞凋亡成像检测不稳定的粥样斑块

• 批准号: 6686786
• 负责人: JAGAT NARULA
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-03 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6686786
• 关键词: angiography; annexins; apoptosis; atherosclerosis; atherosclerotic plaque; bioimaging /biomedical imaging; cardiovascular disorder diagnosis; diagnosis design /evaluation; human subject; laboratory rabbit; laboratory rat; patient oriented research; radiodiagnosis; radiotracer; swine; technetium; vascular endothelium

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.

描述（由申请人提供）：冠状动脉疾病是一种主要的 在美国有超过1300万患者的国家健康问题， 至少有一百万人患有急性冠状动脉综合征 每年有40万人死于急性疾病急性冠脉事件是 与冠状动脉急性血栓形成有关， 动脉粥样硬化斑块破裂新生内膜细胞凋亡 已被提议作为负责转换的重要机制之一， 稳定的冠状动脉斑块的易损斑块，并可能继续导致 斑块破裂与坏死性细胞死亡不同，细胞凋亡是一种遗传学上的 这是一个程序化的过程，可以预防。对于这样的治疗 战略要取得成功，就必须发展技术， 动脉粥样硬化病变中细胞凋亡的非侵入性检测。我们有 最近证明，放射性标记的膜联蛋白V选择性地识别 各种心肌疾病中凋亡细胞的表面改变。我们， 因此，膜联蛋白V应该能够识别动脉粥样硬化， 病变中富含凋亡细胞。我们的初步研究表明， 膜联蛋白成像在实验性动脉粥样硬化病变中的可行性 在兔主动脉。放射性示踪剂摄取仅见于具有丰富 凋亡的新生内膜细胞，主要在凋亡的巨噬细胞中。我们 建议评估膜联蛋白成像在检测 易损斑块评估将在不同的时间连续进行 动物模型，并最终在一个试点临床试验。我们首先要确认 膜联蛋白显像在实验性主动脉粥样硬化中的可行性 并仔细地将放射性标记的膜联蛋白V摄取与 斑块的组织学特征和凋亡指数。未来 步骤，将在猪模型中进行膜联蛋白成像，以检测 冠状动脉粥样硬化病变。随后，膜联蛋白摄取的细胞位点 将在基因改变的啮齿动物模型中得到精确的表征， 显示接近人类冠状动脉的晚期动脉粥样硬化病变 病理最后，膜联蛋白成像将在初步临床研究中进行 在接受颈动脉内膜切除术的患者中。即将进行的外科手术 介入将允许对动脉内膜切除术进行组织病理学评价 标本，以确定膜联蛋白成像的潜在效用。

项目成果

Broad and specific caspase inhibitor-induced acute repression of apoptosis in atherosclerotic lesions evaluated by radiolabeled annexin A5 imaging.

通过放射性标记的膜联蛋白 A5 成像评估广泛且特异性的 caspase 抑制剂诱导的动脉粥样硬化病变细胞凋亡的急性抑制。

• DOI: 10.1016/j.jacc.2007.08.044
• 发表时间: 2007
• 期刊: Journal of the American College of Cardiology
• 影响因子: 24
• 作者: Sarai,Masayoshi;Hartung,Dagmar;Petrov,Artiom;Zhou,Jun;Narula,Navneet;Hofstra,Leo;Kolodgie,Frank;Isobe,Satoshi;Fujimoto,Shinichiro;Vanderheyden,Jean-Luc;Virmani,Renu;Reutelingsperger,Chris;Wong,NathanD;Gupta,Sudhir;Narula,Jaga
• 通讯作者: Narula,Jaga

Noninvasive imaging of atherosclerotic lesions in apolipoprotein E-deficient and low-density-lipoprotein receptor-deficient mice with annexin A5.

使用膜联蛋白 A5 对载脂蛋白 E 缺陷和低密度脂蛋白受体缺陷小鼠的动脉粥样硬化病变进行无创成像。

• 发表时间: 2006
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Isobe,Satoshi;Tsimikas,Sotirios;Zhou,Jun;Fujimoto,Shinichiro;Sarai,Masayoshi;Branks,MichaelJ;Fujimoto,Ai;Hofstra,Leonard;Reutelingsperger,ChrisP;Murohara,Toyoaki;Virmani,Renu;Kolodgie,FrankD;Narula,Navneet;Petrov,Artiom;Naru
• 通讯作者: Naru

How to identify the asymptomatic high-risk patient?

如何识别无症状高危患者？

• DOI: 10.1016/j.cpcardiol.2009.07.001
• 发表时间: 2009
• 期刊: Current problems in cardiology
• 影响因子: 4.2
• 作者: Schuijf,JoanneD;Achenbach,Stephan;Zoghbi,WilliamA;Boersma,Eric;Raggi,Paolo;Weber,Michael;Nagel,Eike;Narula,Jagat;Wackers,FransJTh;Poldermans,Don;Bax,JeroenJ
• 通讯作者: Bax,JeroenJ

99mTc-annexin V imaging for in vivo detection of atherosclerotic lesions in porcine coronary arteries.

99mTc-annexin V 成像用于猪冠状动脉动脉粥样硬化病变的体内检测。

• 发表时间: 2005
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Johnson,LynneL;Schofield,Lorraine;Donahay,Tammy;Narula,Navneet;Narula,Jagat
• 通讯作者: Narula,Jagat

Resolution of apoptosis in atherosclerotic plaque by dietary modification and statin therapy.

通过饮食调整和他汀类药物治疗解决动脉粥样硬化斑块中的细胞凋亡。

• 发表时间: 2005
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Hartung,Dagmar;Sarai,Masayoshi;Petrov,Artiom;Kolodgie,Frank;Narula,Navneet;Verjans,Johan;Virmani,Renu;Reutelingsperger,Chris;Hofstra,Leo;Narula,Jagat
• 通讯作者: Narula,Jagat