Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, United Kingdom; Regional Vascular Unit, St Mary's Hospital, Imperial College Healthcare National Health Service Trust, Imperial College London, London, United Kingdom; The Laboratory of Molecular Imaging, Singapore Bioimaging Consortium, Agency for Science, Technology and Research (ASTAR), Singapore.
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.
J Vasc Surg. 2018 May;67(5):1571-1583.e3. doi: 10.1016/j.jvs.2017.04.046. Epub 2017 Jun 22.
Identification of patients with high-risk asymptomatic carotid plaques remains an elusive but essential step in stroke prevention. Inflammation is a key process in plaque destabilization and a prelude to clinical sequelae. There are currently no clinical imaging tools to assess the inflammatory activity within plaques. This study characterized inflammation in atherosclerosis using dual-targeted microparticles of iron oxide (DT-MPIO) as a magnetic resonance imaging (MRI) probe.
DT-MPIO were used to detect and characterize inflammatory markers, vascular cell adhesion molecule 1 (VCAM-1). and P-selectin on (1) tumor necrosis factor-α-treated cells by immunocytochemistry and (2) aortic root plaques of apolipoprotein-E deficient mice by in vivo MRI. Furthermore, apolipoprotein E-deficient mice with focal carotid plaques of different phenotypes were developed by means of periarterial cuff placement to allow in vivo molecular MRI using these probes. The association between biomarkers and the magnetic resonance signal in different contrast groups was assessed longitudinally in these models.
Immunocytochemistry confirmed specificity and efficacy of DT-MPIO to VCAM-1 and P-selectin. Using this in vivo molecular MRI strategy, we demonstrated (1) the DT-MPIO-induced magnetic resonance signal tracked with VCAM-1 (r = 0.69; P = .014), P-selectin (r = 0.65; P = .022), and macrophage content (r = 0.59; P = .045) within aortic root plaques and (2) high-risk inflamed plaques were distinguished from noninflamed plaques in the murine carotid artery within a practical clinical imaging time frame.
These molecular MRI probes constitute a novel imaging tool for in vivo characterization of plaque vulnerability and inflammatory activity in atherosclerosis. Further development and translation into the clinical arena will facilitate more accurate risk stratification in carotid atherosclerotic disease in the future.
识别具有高危无症状颈动脉斑块的患者仍然是预防中风的一个难以捉摸但必不可少的步骤。炎症是斑块不稳定的关键过程，也是临床后果的前奏。目前没有临床成像工具来评估斑块内的炎症活性。本研究使用双靶向氧化铁微颗粒（DT-MPIO）作为磁共振成像（MRI）探针来描述动脉粥样硬化中的炎症。
DT-MPIO 用于通过免疫细胞化学检测和（2）载脂蛋白 E 缺陷小鼠的主动脉根部斑块来检测和描述炎症标志物血管细胞黏附分子 1（VCAM-1）和 P 选择素。此外，通过放置动脉周围袖套来开发具有不同表型的局灶性颈动脉斑块的载脂蛋白 E 缺陷小鼠，以允许使用这些探针进行体内分子 MRI。在这些模型中，纵向评估不同对比组中生物标志物和磁共振信号之间的相关性。
免疫细胞化学证实了 DT-MPIO 对 VCAM-1 和 P 选择素的特异性和功效。使用这种体内分子 MRI 策略，我们证明了（1）DT-MPIO 诱导的磁共振信号与主动脉根部斑块内的 VCAM-1（r=0.69；P=0.014）、P 选择素（r=0.65；P=0.022）和巨噬细胞含量（r=0.59；P=0.045）相关，（2）在鼠颈动脉中，高危炎症斑块与非炎症斑块在实际临床成像时间范围内得以区分。
这些分子 MRI 探针构成了一种新的成像工具，可用于体内描述动脉粥样硬化斑块的脆弱性和炎症活性。进一步的开发和转化为临床领域将有助于未来更准确地对颈动脉粥样硬化疾病进行风险分层。
