急性心肌梗死后趋化因子受体 CXCR4 的分子成像。
Molecular Imaging of the Chemokine Receptor CXCR4 After Acute Myocardial Infarction.
机构信息
Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany.
Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
出版信息
JACC Cardiovasc Imaging. 2015 Dec;8(12):1417-1426. doi: 10.1016/j.jcmg.2015.09.008. Epub 2015 Nov 11.
OBJECTIVES
An assay for molecular imaging of myocardial CXCR4 expression was evaluated, in order to obtain mechanistic insights noninvasively based on quantitative positron emission tomography (PET).
BACKGROUND
The chemokine receptor CXCR4 has emerged as a therapeutic target after acute myocardial infarction (AMI), because of its role in inflammatory and progenitor cell recruitment.
METHODS
PET with the specific CXCR4 ligand, gallium-68 ((68)Ga)-pentixafor, was performed in mice (n = 53) and compared with ex vivo autoradiography, immunohistochemistry, and left ventricular flow cytometry. In addition, 12 patients were imaged at 2 to 8 days after AMI.
RESULTS
In mice, (68)Ga-pentixafor identified regional CXCR4 upregulation in the infarct region, peaking at 3 days (infarct/remote [I/R] ratio 1.5 ± 0.2 at 3 days vs. 1.2 ± 0.3 at 7 days; p = 0.03), corresponding to a flow cytometry-based peak of CD45+ leukocytes and immunohistochemical detection of CD68+ macrophages and Ly6G+ granulocytes. Blockade with the CXCR4 antagonist AMD3100 abolished the signal. No specific uptake was found in sham-operated or control animals. Long-term treatment with oral enalapril attenuated the CXCR4 signal (I/R 1.2 ± 0.2 at 3 days and 1.0 ± 0.0.1 at 7 days; p = 0.01 vs. untreated). Patients showed variable degrees of CXCR4 upregulation in the infarct region. No single clinical parameter allowed for prediction of CXCR4 signal strength. At multivariate analysis, a combination of infarct size and time after reperfusion predicted the CXCR4 infarct signal (rmultiple = 0.73; p = 0.03). Infarct signal in the myocardium was paralleled by elevated pentixafor uptake in bone marrow (r = 0.61; p = 0.04), which highlighted systemic interactions.
CONCLUSIONS
Targeted PET imaging with (68)Ga-pentixafor identifies the global and regional CXCR4 expression pattern in myocardium and systemic organs. CXCR4 upregulation after AMI coincides with inflammatory cell infiltration, but shows interindividual variability in patients. This may have implications for the response to CXCR4- or other inflammation-targeted therapy, and for subsequent ventricular remodeling.
目的
评估一种用于检测心肌 CXCR4 表达的分子成像分析方法，以便能够基于定量正电子发射断层扫描（PET）进行无创性的机制研究。
背景
趋化因子受体 CXCR4 已成为急性心肌梗死（AMI）后的治疗靶点，因为它在炎症和祖细胞募集中发挥作用。
方法
对 53 只小鼠进行了特定 CXCR4 配体镓-68（68）Ga-戊环佛司可林的 PET 检测，并与离体放射性自显影、免疫组化和左心室流式细胞术进行了比较。此外，对 12 例 AMI 后 2-8 天的患者进行了成像。
结果
在小鼠中，68Ga-戊环佛司可林识别出梗死区的 CXCR4 上调，在第 3 天达到峰值（梗死/远隔区 [I/R] 比值为 1.5 ± 0.2，第 3 天比第 7 天的 1.2 ± 0.3高；p = 0.03），这与基于流式细胞术的 CD45+白细胞峰值和 CD68+巨噬细胞和 Ly6G+粒细胞的免疫组化检测相对应。用 CXCR4 拮抗剂 AMD3100 阻断信号可消除该信号。在假手术或对照动物中未发现特异性摄取。口服依那普利的长期治疗可减弱 CXCR4 信号（第 3 天的 I/R 比值为 1.2 ± 0.2，第 7 天为 1.0 ± 0.0.1；与未治疗组相比，p = 0.01）。患者在梗死区表现出不同程度的 CXCR4 上调。没有单一的临床参数可以预测 CXCR4 信号强度。多变量分析显示，梗死面积和再灌注后时间的组合可以预测 CXCR4 梗死信号（rmultiple = 0.73；p = 0.03）。心肌中的梗死信号与骨髓中 pentixafor 摄取的升高相平行（r = 0.61；p = 0.04），这突出了系统间的相互作用。
结论
用 68Ga-戊环佛司可林进行靶向 PET 成像可识别心肌和全身器官中 CXCR4 的整体和局部表达模式。AMI 后 CXCR4 的上调与炎症细胞浸润同时发生，但在患者中存在个体间的差异。这可能对 CXCR4 或其他炎症靶向治疗的反应以及随后的心室重构产生影响。
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