IVUS Detection of Rupture Prone Plaques

描述（由申请人提供）：心血管疾病是美国人的头号杀手，每年夺去50多万人的生命。这些死亡发生在疾病晚期动脉粥样硬化斑块的纤维帽破裂时。目前诊断冠状动脉粥样硬化的筛查试验是有限的。冠状动脉造影是评估有症状患者冠状动脉疾病严重程度的“金标准”，它只能显示管腔狭窄的程度，而不能显示动脉壁。此外，动脉重塑使许多斑块无法通过冠状动脉造影检测到。本建议的总体目标是发展两种实用的超声成像技术（新生血管成像和弹性成像）来识别危及生命的动脉粥样硬化斑块。形成动脉粥样硬化斑块的微血管网络或血管管可能是白细胞和血浆成分迁移到动脉壁或动脉表面内皮的通道。这些炎症细胞，如果允许积累，将削弱纤维帽。血管内超声（IVUS）的分辨率不够高，无法看到斑块新生血管；因此，我们建议开发一种微泡超声造影剂，优先结合新形成的血管。更具体地说，我们建议将微泡造影剂与与CD13结合的ngr归巢序列的肽和与VEGF受体-2结合的单克隆抗体DC101结合。共轭微泡将通过采用二次谐波对比成像模式来可视化，我们建议在商用超声IVUS扫描仪上实现。稳定斑块的力学行为与稳定斑块明显不同。周向应力会积聚在正常内膜和不稳定斑块上覆盖脂质池的纤维帽之间的连接处；而这在稳定斑块中不会发生。为了根据稳定斑块和不稳定斑块的力学行为进行区分，我们建议使用一种新的血管内超声弹性成像原型系统来可视化血管组织内的应力分布。将采用动脉粥样硬化动物模型来评估a)两种成像方法作为独立方法检测危及生命的斑块的敏感性和特异性将相对于微血管-弹性成像联合方法进行评估，b)基于三种成像方法预测斑块破裂倾向的可行性。这项提议的成功结果可能会证明对5000多万不知道自己可能患有晚期冠状动脉粥样硬化的美国人有益，他们应该接受降脂饮食和药物治疗。

DESCRIPTION (provided by applicant): Cardiovascular disease is the number one killer of Americans, claiming over 500,000 lives annually. These deaths occur when the fibrous cap of an atherosclerotic plaque ruptures in the later stages of the disease. Current screening tests for the diagnosis of coronary atherosclerosis is limited. Coronary angiography, the "gold standard" employed to assess the severity of coronary disease in symptomatic patients, reveals only the degree of luminal narrowing, and fails to visualize the arterial wall. Additionally, arterial remodeling prevents many plaques from being detected by coronary angiography. The overall goal of this proposal is to develop two pragmatic ultrasound-imaging techniques (neovascular imaging, and elastography imaging) to identify life threatening atherosclerotic plaques. The microvascular networks or vasa vasorum of developing atherosclerotic plaques may function as a conduit for the migration of leukocytes and plasma components into the arterial wall or into the endothelium on the arterial surface. These inflammatory cells, if allowed to accumulate, will weaken the fibrous cap. The resolution of intravascular ultrasound (IVUS) is not sufficiently high to visualize plaque neovasculature; therefore, we propose to develop a microbubble ultrasound contrast that binds preferentially to newly formed blood vessels. More specifically, we propose to conjugate a microbubble contrast agent to a peptide with the NGR-homing sequence that binds to CD13, and a monoclonal antibody, DC101, that binds to the VEGF receptor-2. The conjugated microbubbles will be visualized by employing the second harmonic contrast imaging mode, which we propose to implement on a commercial ultrasound IVUS scanner. The mechanical behavior of stable plaques is noticeably different from those of stable plaques. Circumferential stress will accumulate at the junction between the normal intima, and the fibrous cap overlaying the lipid pool in unstable plaques; whereas this does not occur in stable plaques. To differentiate between stable and unstable plaques based on their mechanical behavior we propose to visualize the stress distribution within vascular tissue using a novel prototype system for intravascular ultrasonic elastographic imaging. An atherosclerotic animal model will be employed to assess a) the sensitivity and specificity of detecting life-threatening plaques with both imaging approaches as standalone methods will be assessed relative to a combined microvascular-elastography imaging approach, and b) the feasibility of predicting the propensity of plaque to rupture based on the three imaging approaches. A successful out come of the proposed may prove to be beneficial to the over 50 million Americans who are unaware that they may be suffering from advance coronary atherosclerosis and should be placed on a lipid-lowering dietary and pharmacological treatment.