A Receptor-Targeted Nanoparticle PET Tracer in Human Carotid Atherosclerosis

项目总结 目前，无症状颈动脉患者的临床治疗指南尚无共识。 狭窄(ACAS)。一些指南建议对ACAS患者行颈动脉内膜切除术(CEA)。 ≥直径的60%。然而，有观点认为，美国95%的ACAS手术干预措施可能 这是不必要的，每年产生20亿美元的不必要的医疗成本。我们在这项提案中的目标是 在分子水平上通过PET成像研究ACAS患者的斑块生物学以帮助识别个体 他们因斑块破裂而患缺血性中风的风险较高，并可能从颈动脉手术干预中受益。 我们提出了一项双中心患者结局研究，该研究扩展了我们早期单项研究的数据和观察 华盛顿大学第一个使用纳米粒子PET放射性示踪剂进行人体研究的中心，该放射性示踪剂针对 利钠肽受体C(NPRC)，以确定它是否可以用于风险分层患者的“高风险” 阿卡斯。我们和其他人已经证明，NPRC在具有特征的复杂斑块中表达水平较高 急性冠脉综合征患者的脆弱性。在我们最新的由NIH R01资助的概念验证研究中， 42例ACAS患者的~(64)Cu-CANF-Comb PET示踪剂摄取率呈线性相关。 CEA中高危斑块的特征及与NPRC存在相关的~(64)Cu-CANF-Comb PET摄取 手术后病人的标本。我们提出以下具体目标：目标1.确定 64Cu-CANF-Comb PET对接受最佳药物治疗的急性冠脉综合征患者进行风险分层的能力 (OMT)仅与患者预后有关。在这项观察性研究中，80名ACAS60%的≥患者将 行64Cu-CANF-Comb PET/MRI检查。患者将接受单独的OMT或接受OMT和CEA 这是由他们的血管外科医生在成像前确定的。OMT将由抗血小板、他汀类药物和 适用时的高血压和糖尿病管理。所有患者将通过电话采访进行评估 每隔3个月至少18个月评估为同侧缺血性脑血管事件。宠物信号 将被评估为事件或进展为CEA的风险的标志，与解剖特征相比较 MRI上的易损斑块，目标是确定提示风险较高的ACAS的PET信号阈值。 目的2：进一步了解NPRC在颈动脉粥样硬化演变中的作用。A.患者 单独接受OMT治疗的患者将在18个月时重复接受PET/MRI检查，如果出现症状，则接受更早的治疗。PET/MRI 18个月期间的变化将被用来进一步了解颈动脉斑块演变的生物学 经OMT治疗后。B.在最初接受CEA的患者中，PET信号将与体外斑块进行比较 脆弱性和NPRC细胞分布，以帮助理解基因表达 免疫组织化学(IHC)和细胞来源通过单细胞RNA/CITE-SEQ转录组学。结果将 提供关于一种新的成像方法--64Cu-CANF-梳状PET对患者进行风险分层的可能性的信息 并揭示有关NPRC在斑块脆弱性和炎症中的作用的机制信息。

PROJECT SUMMARY Currently no consensus exists in clinical guidelines for management of patients with asymptomatic carotid artery stenosis (ACAS). Some guidelines recommend carotid endarterectomy (CEA) surgery for patients with ACAS of ≥ 60% diameter. However, it is argued that 95% of all surgical interventions for ACAS in the United States may be unnecessary, generating needless healthcare costs of >$2 billion annually. Our goal in this proposal is to study plaque biology in ACAS patients through PET imaging at the molecular level to help identify individuals who are at 'higher-risk’ for ischemic stroke from plaque rupture and may benefit from carotid surgical intervention. We propose a 2-center patient outcomes study that expands upon data and observations from our earlier single center first-in-human study at Washington University using a nanoparticle PET radiotracer that targets the natriuretic peptide receptor C (NPRC) to determine if it can be used to risk stratify patients with ‘higher-risk’ ACAS. We and others have shown that NPRC is expressed at higher levels in complex plaques with features of vulnerability in patients with ACAS. In our most recent NIH R01-funded proof-of-concept study in a cohort of 42 patients with ACAS, we have shown linear correlation between 64Cu-CANF-Comb PET radiotracer uptake and features of high-risk plaque and correlative 64Cu-CANF-Comb PET uptake to the presence of NPRC in CEA specimens of patients who underwent surgery. We propose the following Specific Aims: Aim 1. To determine the ability of 64Cu-CANF-Comb PET to risk stratify ACAS patients treated with optimal medical therapy (OMT) alone with respect to patient outcomes. In this observational study, 80 patients with ACAS ≥ 60% will undergo 64Cu-CANF-Comb PET/MRI. Patients will be maintained on either OMT alone or receive OMT and CEA as determined by their treating vascular surgeon prior to imaging. OMT will consist of antiplatelet, statin, and hypertension and diabetes management when applicable. All patients will be evaluated with phone interviews every 3 months for a minimum of 18 months to assess for ipsilateral ischemic cerebrovascular event. PET signal will be assessed as a marker of risk for event or progression to CEA in comparison to anatomic features of vulnerable plaque on MRI, with the goal of determining a PET signal threshold which suggests higher risk ACAS. Aim 2: To further understand the role of NPRC in the evolution of carotid atherosclerosis. A. Patients treated with OMT alone will undergo repeat PET/MRI at 18 months, or earlier if they develop symptoms. PET/MRI changes over the 18-month interval will be used to further understand the biology of carotid plaque evolution after treatment with OMT. B. In patients who initially undergo CEA, PET signal will be compared to ex vivo plaque vulnerability and NPRC cellular distribution to facilitate understanding of gene expression using immunohistochemistry (IHC) and cell origin through single cell RNA/CITE-seq transcriptomics. Results will provide information on the potential of a new imaging approach, 64Cu-CANF-Comb PET, to risk stratify patients with ACAS and reveal mechanistic information about the role of NPRC in plaque vulnerability and inflammation.