Abstract

Purpose

Anthracycline-induced cardiotoxicity (AIC), whose major manifestation is diffuse myocardial fibrosis, is an important clinical problem in cancer therapy. Therefore, early identification and treatment are clinically important. This study aims to explore the feasibility of using ⁶⁸ Ga-labelled fibroblast activation protein (FAP) inhibitor ([⁶⁸ Ga]Ga-FAPI) positron emission tomography/computed tomography (PET/CT) for the early identification of the fibrotic process and guidance of antifibrosis therapy in AIC.

Methods

An AIC rat model was induced by the intravascular administration of doxorubicin (DOX) once per week for 1, 2, 3 and 6 weeks (2.5 mg/kg/injection, groups 1–4), whereas intravascular saline was administered to control rats. Experimental and control groups (n = 4) underwent [⁶⁸ Ga]Ga-FAPI PET/CT following disease induction. Groups 5 and 6 received DOX injections for 3 and 6 weeks, treated with angiotensin-converting enzyme (ACE) inhibitor starting at 3 weeks, treated with enalapril (20 mg/kg, gastric gavage) daily and underwent echocardiography and [⁶⁸ Ga]Ga-FAPI PET/CT at 3 weeks after treatment. Rat hearts were subjected to haematoxylin and eosin staining, FAP immunohistochemistry, Sirius red staining and Masson’s trichrome staining to investigate the pathological changes and deposition of collagen fibres. Rat blood was sampled weekly for the enzyme-linked immunosorbent assay of various markers of myocardial injury, such as plasma cardiac troponin I, B-type natriuretic peptide and angiotensin II.

Results

[⁶⁸ Ga]Ga-FAPI-04 uptake by the heart was significantly higher in the cardiotoxicity group than in the control group at weeks 3 (SUVmax: 1.21 ± 0.23 vs 0.67 ± 0.01, P < 0.05) and 6 (SUVmax: 1.48 ± 0.28 vs 0.67 ± 0.08, P < 0.001), whereas left ventricle ejection fraction (LVEF) did not significantly differ between normal and AIC rats at week 3. FAP⁺ expression began to increase starting at week 3, before irreversible fibrotic changes were detected, until week 6. After 3 weeks of enalapril treatment, [⁶⁸ Ga]Ga-FAPI-04 accumulation decreased in groups 5 and 6 (SUVmax decreased from 1.21 ± 0.23 to 0.77 ± 0.08 and 1.48 ± 0.28 to 1.09 ± 1.06, P < 0.05). Cardiac function was preserved (LVEF was 75.7% ± 7.38% in group 3 vs 74.5% ± 2.45% in group 5, P > 0.05) and improved (LVEF increased from 51.6% ± 9.03% in group 4 to 65.2% ± 4.27% in group 6, P < 0.05), and myocardial fibrosis attenuated (from 6.5% ± 1.2% in group 4 to 4.31% ± 0.37% in group 6, P < 0.01).

Conclusion

[⁶⁸ Ga]Ga-FAPI PET/CT can be used for the early detection of active myocardial fibrosis in AIC and the evaluation of the efficacy of therapeutic interventions. Early treatment guided by [⁶⁸ Ga]Ga-FAPI PET/CT may reduce anthracycline-induced myocardial injury and improve heart function.

中文翻译：

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使用 [68 Ga]Ga-FAPI-04 成像早期检测蒽环类药物引起的心脏毒性

摘要

目的

蒽环类药物引起的心脏毒性（AIC）是癌症治疗中的一个重要临床问题，其主要表现为弥漫性心肌纤维化。因此，早期识别和治疗对于临床具有重要意义。本研究旨在探讨使用⁶⁸  Ga 标记的成纤维细胞激活蛋白（FAP）抑制剂（[ ⁶⁸  Ga]Ga-FAPI）正电子发射断层扫描/计算机断层扫描（PET/CT）用于早期识别纤维化过程并指导的可行性AIC 中的抗纤维化治疗。

方法

通过血管内注射阿霉素 (DOX) 每周一次，持续 1、2、3 和 6 周（2.5 mg/kg/注射，第 1-4 组）来诱导 AIC 大鼠模型，而对照大鼠则注射血管内盐水。实验组和对照组（n = 4） 在疾病诱导后 接受[ ^{68 Ga]Ga-FAPI PET/CT。}第 5 组和第 6 组接受 DOX 注射 3 周和 6 周，从第 3 周开始接受血管紧张素转换酶 (ACE) 抑制剂治疗，每天接受依那普利（20 mg/kg，胃灌胃）治疗，并接受超声心动图和 [ ⁶⁸  Ga]Ga -治疗后 3 周进行 FAPI PET/CT。对大鼠心脏进行苏木精-伊红染色、FAP免疫组化、天狼星红染色和Masson三色染色，观察病理变化和胶原纤维沉积。每周采集大鼠血液样本，用于心肌损伤的各种标记物的酶联免疫吸附测定，例如血浆心肌肌钙蛋白I、B型利尿钠肽和血管紧张素II。

结果

 第 3 周（SUVmax：1.21 ± 0.23 vs 0.67 ± 0.01，P  < 0.05）和第 6 周（SUVmax：^1.48 ± 0.28 vs 0.67 ± 0.08，P  < 0.001），而第 3 周时正常大鼠和 AIC 大鼠的左心室射血分数 (LVEF) 没有显着差异。在检测到不可逆的纤维化变化之前，FAP ⁺表达从第 3 周开始开始增加，直到第6周。依那普利治疗3周后，第5组和第6组的[ ⁶⁸  Ga]Ga-FAPI-04积累减少（SUVmax从1.21±0.23下降至0.77±0.08和1.48±0.28至1.09±1.06，P  <0.05 ）。心功能得到保留（第 3 组的 LVEF 为 75.7% ± 7.38%，第 5 组为 74.5% ± 2.45%，P  > 0.05）并得到改善（LVEF 从第 4 组的 51.6% ± 9.03% 增加到第 5 组的 65.2% ± 4.27%）。第 6 组，P  < 0.05），心肌纤维化减弱（从第 4 组的 6.5% ± 1.2% 降至第 6 组的 4.31% ± 0.37%，P  < 0.01）。

结论

[ ⁶⁸  Ga]Ga-FAPI PET/CT可用于AIC活动性心肌纤维化的早期检测和治疗干预效果的评估。^{[ 68} Ga]Ga-FAPI PET/CT指导下的早期治疗 可减少蒽环类药物引起的心肌损伤，改善心功能。