Department of Nuclear Medicine, Klinikum rechts der Isar der TUM, Munich, Germany
Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
J Nucl Med. 2019 Dec;60(12):1743-1749. doi: 10.2967/jnumed.119.226993. Epub 2019 Aug 12.
Heart failure remains a major source of late morbidity and mortality after myocardial infarction (MI). The temporospatial presence of activated fibroblasts in the injured myocardium predicts the quality of cardiac remodeling after MI. Therefore, monitoring of activated fibroblasts is of great interest for studying cardiac remodeling after MI. Fibroblast activation protein (FAP) expression is upregulated in activated fibroblasts. This study investigated the feasibility of imaging activated fibroblasts with a new Ga-labeled FAP inhibitor (Ga-FAPI-04) for PET imaging of fibroblast activation in a preclinical model of MI. MI and sham-operated rats were scanned with Ga-FAPI-04 PET/CT (1, 3, 6, 14, 23, and 30 d after MI) and with F-FDG (3 d after MI). Dynamic Ga-FAPI-04 PET and blocking studies were performed on MI rats 7 d after coronary ligation. After in vivo scans, the animals were euthanized and their hearts harvested for ex vivo analyses. Cryosections were prepared for autoradiography, hematoxylin and eosin (H&E), and immunofluorescence staining. Ga-FAPI-04 uptake in the injured myocardium peaked on day 6 after coronary ligation. The tracer accumulated intensely in the MI territory, as identified by decreased F-FDG uptake and confirmed by PET/MR and H&E staining. Autoradiography and H&E staining of cross-sections revealed that Ga-FAPI-04 accumulated mainly at the border zone of the infarcted myocardium. In contrast, there was only minimal uptake in the infarct of the blocked rats, comparable to the uptake in the remote noninfarcted myocardium (PET image-derived ratio of infarct uptake to remote uptake: 6 ± 2). Immunofluorescence staining confirmed the presence of FAP-positive myofibroblasts in the injured myocardium. Morphometric analysis of the whole-heart sections demonstrated 3- and 8-fold higher FAP-positive fibroblast density in the border zone than in the infarct center and remote area, respectively. Ga-FAPI-04 represents a promising radiotracer for in vivo imaging of post-MI fibroblast activation. Noninvasive imaging of activated fibroblasts may have significant diagnostic and prognostic value, which could aid clinical management of patients after MI.
心肌梗死后心力衰竭仍然是晚期发病率和死亡率的主要原因。在损伤的心肌中活化成纤维细胞的时空存在预测了心肌梗死后心脏重构的质量。因此,监测活化的成纤维细胞对于研究心肌梗死后的心脏重构具有重要意义。成纤维细胞激活蛋白 (FAP) 的表达在活化的成纤维细胞中上调。本研究旨在探讨一种新的 Ga 标记的 FAP 抑制剂 (Ga-FAPI-04) 用于心肌梗死后成纤维细胞活化的 PET 成像的可行性,该抑制剂在心肌梗死后的临床前模型中进行了研究。MI 和假手术大鼠在 MI 后 1、3、6、14、23 和 30 天用 Ga-FAPI-04 PET/CT 进行扫描,并在 MI 后 3 天用 F-FDG 进行扫描。在冠状动脉结扎后 7 天对 MI 大鼠进行动态 Ga-FAPI-04 PET 和阻断研究。在体内扫描后,将动物安乐死并取出心脏进行离体分析。制备冷冻切片进行放射自显影、苏木精和伊红 (H&E) 和免疫荧光染色。Ga-FAPI-04 在冠状动脉结扎后第 6 天在受损心肌中的摄取达到峰值。该示踪剂在 MI 区域强烈积累,这通过 F-FDG 摄取减少来确定,并通过 PET/MR 和 H&E 染色来证实。横截面的放射自显影和 H&E 染色表明,Ga-FAPI-04 主要在梗死心肌的交界区积聚。相比之下,在阻断大鼠的梗死部位仅有最小的摄取,与非梗死的远程心肌的摄取相当(PET 图像衍生的梗死摄取与远程摄取之比:6±2)。免疫荧光染色证实了损伤心肌中存在 FAP 阳性的肌成纤维细胞。全心脏切片的形态计量学分析表明,交界区的 FAP 阳性成纤维细胞密度分别比梗死中心和远程区域高 3 倍和 8 倍。Ga-FAPI-04 是一种很有前途的放射性示踪剂,可用于体内成像心肌梗死后的成纤维细胞激活。活化成纤维细胞的非侵入性成像可能具有重要的诊断和预后价值,这将有助于 MI 后患者的临床管理。