Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
Hubei Key Laboratory of Molecular Imaging, Wuhan, Hubei 430022, China.
Mol Pharm. 2022 Nov 7;19(11):4171-4178. doi: 10.1021/acs.molpharmaceut.2c00551. Epub 2022 Aug 15.
Noninvasively monitoring activated fibroblasts is of great value for understanding the dynamic process of myocardial fibrosis after myocardial infarction (MI). This study aimed to evaluate the feasibility of Ga-labeled fibroblast activation protein inhibitor 04 (Ga-FAPI-04) for monitoring reparative fibrosis and reactive fibrosis after MI. MI models were prepared by ligation of the left anterior descending (LAD) coronary artery and validated by electrocardiogram and F-FDG PET/CT 1 day after MI and hematoxylin and eosin (HE) staining. Ga-FAPI-04 PET/CT scans (1, 3, 6, 9, 12, 15, 18, 21, 28, and 35 days after MI) were carried out in MI rats and sham-operated rats without ligation of LAD. Blocking experiments were carried out on MI rats on day 7 after MI with Ga-FAPI-04 and excessive FAPI-04. Autoradiography, HE staining, Masson's trichrome staining, and immunofluorescence staining were carried out for validation. The infarcted area with decreased or defective myocardial metabolic activity in F-FDG PET/CT correspondingly showed high Ga-FAPI-04 uptake in the MI rats. The myocardial tracer uptake was significantly different between MI and sham-operated rats from day 1 to 28 after MI and reached peak value 6 days after MI (0.806 ± 0.257%ID/cc vs 0.199 ± 0.012%ID/cc, < 0.05). Tracer uptake at the infarcted myocardium and normal tissues in MI rats decreased significantly after blocking. Obvious tracer uptake was confirmed by autoradiography, and immunofluorescence staining showed FAP+ cells in the infarcted myocardium and border zone. Masson's trichrome staining of the heart sections of MI rats at different times suggested the presence of myocardial fibrosis. Ga-FAPI-04 uptake was not observed in the distal uninjured myocardium throughout the observation period. In conclusion, Ga-FAPI-04 PET could noninvasively monitor the activated fibroblasts in the early stage post acute MI and may be helpful for evaluating the degree of reparative fibrosis, while reactive fibrosis monitoring still needs further study.
非侵入性监测活化的成纤维细胞对于了解心肌梗死后心肌纤维化的动态过程具有重要价值。本研究旨在评估镓标记的成纤维细胞激活蛋白抑制剂 04（Ga-FAPI-04）监测心肌梗死后修复性纤维化和反应性纤维化的可行性。通过结扎左前降支（LAD）冠状动脉制备心肌梗死模型，并在心肌梗死后 1 天通过心电图和 F-FDG PET/CT 以及苏木精和伊红（HE）染色进行验证。在心肌梗死大鼠和未结扎 LAD 的假手术大鼠中进行 Ga-FAPI-04 PET/CT 扫描（心肌梗死后 1、3、6、9、12、15、18、21、28 和 35 天）。在心肌梗死后 7 天，对心肌梗死大鼠进行 Ga-FAPI-04 和过量 FAPI-04 的阻断实验，并进行放射性自显影、HE 染色、Masson 三色染色和免疫荧光染色验证。F-FDG PET/CT 显示心肌代谢活性降低或缺陷的梗死区在心肌梗死大鼠中显示出高 Ga-FAPI-04 摄取。从心肌梗死后 1 天到 28 天，心肌梗死大鼠与假手术大鼠的心肌示踪剂摄取差异显著，心肌梗死后 6 天达到峰值（0.806±0.257%ID/cc 比 0.199±0.012%ID/cc， <0.05）。在阻断后，梗死心肌和正常组织中的示踪剂摄取明显减少。放射性自显影证实了明显的示踪剂摄取，免疫荧光染色显示梗死心肌和边缘区有 FAP+细胞。不同时间点心肌梗死大鼠心脏切片的 Masson 三色染色显示存在心肌纤维化。在整个观察期间，在远端未受损的心肌中均未观察到 Ga-FAPI-04 摄取。总之，Ga-FAPI-04 PET 可以非侵入性地监测急性心肌梗死后早期的活化成纤维细胞，可能有助于评估修复性纤维化的程度，而反应性纤维化的监测仍需要进一步研究。
