Molecular MRI of Early Thrombus Formation Using a Bimodal α2-Antiplasmin-Based Contrast Agent
Molecular MRI of Early Thrombus Formation Using a Bimodal α2-Antiplasmin-Based Contrast Agent
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DOI：
10.1016/j.jcmg.2009.03.015
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发表时间：
2009-08-01
影响因子：
14
通讯作者：
Kooi, Marianne Eline
中科院分区：
文献类型：
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作者：
Miserus, Robbert-Jan J. H. M.;Herias, M. Veronica;Kooi, Marianne Eline
目的探讨新型双峰α(2)-抗纤溶酶造影剂(CA)在体内磁共振成像(MRI)中能否显示早期血栓的形成。在血栓形成的早期阶段，激活因子XIII(FxiIa)将α(2)-抗纤溶酶与纤维蛋白共价交联，显示了基于α(2)-抗纤溶酶的CA在检测早期血栓形成方面的潜力。对于对照CA，丙氨酸取代了交联所必需的谷氨酰胺残基。将体外生成的血栓同时暴露于CAS中，并通过MRI和双光子激光扫描显微镜进行成像。对人肺血栓栓子切片进行免疫组织化学染色，以确定α(2)-抗纤溶酶和FXIII在不同血栓重塑阶段的存在。结果以α(2)-抗纤溶酶为基础的CA在体外形成的血栓中显示出血栓边缘的高信号。当我们使用基于α(2)-抗纤溶酶的CA与FXIII抑制剂丹西卡维林一起使用时，或当我们使用对照CA时，没有观察到高信号。双光子激光扫描显微镜显示α(2)-抗纤溶酶CA与纤维蛋白结合。免疫组织化学显示新鲜血栓较溶解血栓和机化血栓有大量的α(2)-抗纤溶酶染色。血栓形成后数秒内注射CA后，血栓形成部位的对比噪声比(CNRS2.28+/-0.39，n=6)明显高于对照组(CNRS0.14+/-0.55，p=0.003，n=6)和血栓形成后24~48h注射的α(2)-抗纤溶酶CA(CNR0.11+/-0.23，p=0.006，n=6)。我们的结果表明，这种双峰CA能够实现早期血栓形成的非侵入性体内磁共振可视化。(J Am Coll Hearol IMG 2009；2：987-96)(C)美国心脏病学会基金会2009
OBJECTIVES We aimed to investigate whether early thrombus formation can be visualized with in vivo magnetic resonance imaging (MRI) by the use of a novel bimodal alpha(2)-antiplasmin-based contrast agent (CA).BACKGROUND Thrombus formation plays a central role in several vascular diseases. During the early phases of thrombus formation, activated factor XIII (FXIIIa) covalently cross-links alpha(2)-antiplasmin to fibrin, indicating the potential of alpha(2)-antiplasmin-based CAs in the detection of early thrombus formation.METHODS A bimodal CA was synthesized by coupling gadolinium-diethylene triamine pentaacetic acid and rhodamine to an alpha(2)-antiplasmin-based peptide. For the control CA, a glutamine residue essential for cross-linking was replaced by alanine. In vitro-generated thrombi were exposed to both CAs and imaged by MRI and 2-photon laser-scanning microscopy. Immunohistochemistry was performed on human pulmonary thromboemboli sections to determine the presence of alpha(2)-antiplasmin and FXIII in different thrombus remodeling phases. In vivo feasibility of the CA in detecting early thrombus formation specifically was investigated with MRI.RESULTS In vitro-generated thrombi exposed to the alpha(2)-antiplasmin-based CA showed hyperintense magnetic resonance signal intensities at the thrombus edge. No hyperintense signal was observed when we used the alpha(2)-antiplasmin-based CA in the presence of FXIII inhibitor dansylcadaverine nor when we used the control CA. Two-photon laser-scanning microscopy demonstrated that the alpha(2)-antiplasmin-based CA bound to fibrin. Immunohistochemistry demonstrated substantial alpha(2)-antiplasmin staining in fresh compared with lytic and organized thrombi. The administration of CA in vivo within seconds after inducing thrombus formation increased contrast-to-noise ratios (CNRs 2.28 +/- 0.39, n = 6) at the site of thrombus formation compared with the control CA (CNRs -0.14 +/- 0.55, p = 0.003, n = 6) and alpha(2)-antiplasmin-based CA administration 24 to 48 h after thrombus formation (CNRs 0.11 +/- 0.23, p = 0.006, n = 6).CONCLUSIONS A bimodal CA was developed, characterized, and validated. Our results showed that this bimodal CA enabled noninvasive in vivo magnetic resonance visualization of early thrombus formation. (J Am Coll Cardiol Img 2009;2:987-96) (C) 2009 by the American College of Cardiology Foundation