Ageyama Naohide, Kurosawa Hiroyuki, Fujimoto Ousuke, Uehara Tomoya, Hiroe Michiaki, Arano Yasushi, Yoshida Toshimichi, Yasutomi Yasuhiro, Imanaka-Yoshida Kyoko
Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Health and Nutrition.
FUJIFILM RI Pharma Co., Ltd.
Int Heart J. 2019 Jan 25;60(1):151-158. doi: 10.1536/ihj.17-734. Epub 2018 Nov 20.
Inflammation after myocardial infarction (MI) may be a major factor influencing ventricular remodeling, leading to congestive heart failure and arrhythmia. Therefore, inflammation in the heart needs to be monitored. Tenascin-C (TNC) is an extracellular matrix molecule not normally expressed, but it is strongly upregulated when associated with active inflammation. Based on this characteristic, we successfully imaged in vivo inflammatory lesions in rat models using Indium (In)-labeled anti-TNC antibodies. The aim of the present study was to further assess the applicability of this molecular imaging probe to detect inflammatory activity in primate hearts.We generated an MI model of cynomolgus monkeys (Macaca fascicularis) by coronary artery ligation and performed dual-isotope single-photon emission computed tomography (SPECT) imaging with an In-labeled anti-TNC antibody Fab' fragment (In-TNC Fab') and technetium methoxy-isobutyl isonitrile (Tc-MIBI). Dual autoradiography was used to compare the uptake of In-TNC Fab' with histology and immunostaining for TNC. Dual-isotope SPECT showed the regional myocardial uptake of In-TNC Fab' complementary to a defect in the perfusion image by Tc-MIBI. The high radioactivity of In-TNC Fab' by autoradiography corresponded to immunostaining for TNC, which was observed in inflammatory lesions at the border zone between the infarcted and non-infarcted areas of the left ventricle and at the epi/pericarditis lesions of the right ventricle. These results demonstrate the potential of In-TNC-Fab' imaging to monitor myocardial injury and inflammation and suggest the feasibility of the non-invasive detection of cardiac inflammation following acute MI in a preclinical stage before testing in humans.
心肌梗死（MI）后的炎症可能是影响心室重塑的主要因素，可导致充血性心力衰竭和心律失常。因此，心脏中的炎症需要进行监测。腱生蛋白-C（TNC）是一种正常情况下不表达的细胞外基质分子，但在与活动性炎症相关时会强烈上调。基于这一特性，我们使用铟（In）标记的抗TNC抗体成功地对大鼠模型中的体内炎症病变进行了成像。本研究的目的是进一步评估这种分子成像探针在检测灵长类动物心脏炎症活性方面的适用性。我们通过冠状动脉结扎建立了食蟹猴（猕猴）的MI模型，并使用In标记的抗TNC抗体Fab'片段（In-TNC Fab'）和甲氧基异丁基异腈锝（Tc-MIBI）进行双同位素单光子发射计算机断层扫描（SPECT）成像。采用双放射自显影法比较In-TNC Fab'的摄取情况与TNC的组织学和免疫染色结果。双同位素SPECT显示In-TNC Fab'在心肌区域的摄取与Tc-MIBI灌注图像中的缺损互补。放射自显影显示In-TNC Fab'的高放射性与TNC的免疫染色相对应，TNC免疫染色在左心室梗死和非梗死区域之间的边界区的炎症病变以及右心室的心外膜/心包炎病变中观察到。这些结果证明了In-TNC-Fab'成像监测心肌损伤和炎症的潜力，并表明在人体试验前的临床前阶段对急性心肌梗死后心脏炎症进行无创检测的可行性。
