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Molecular Imaging of Fibroblast Activation in Rabbit Atherosclerotic Plaques: a Preclinical PET/CT Study

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Abstract

Aim

Atherosclerosis remains the pathological basis of myocardial infarction and ischemic stroke. Early and accurate identification of plauqes is crucial to improve clinical outcomes of atherosclerosis patients. Our study aims to evaluate the potential value of fibroblast activation protein inhibitor (FAPI)-04 PET/CT in identifying plaques via a preclinical rabbit model of atherosclerosis.

Methods

New Zealand white rabbits were fed high-fat diet (HFD), and randomly divided into the model group injured by the balloon, and the sham group only with incisions. Ultrasound was performed to detect plaques, and FAPI-avid was determined through Al18F-NOTA-FAPI-04 PET/CT. Mean standardized uptake values (SUVmean) in lesions were compared, and biodistribution of Al18F-NOTA-FAPI-04 and target-to-background ratios (TBRs) were calculated. Histological staining was performed to display arterial plaques, and autoradiography (ARG) was employed to measure the in vitro intensity of Al18F-NOTA-FAPI-04. At last, the correlation among FAP levels, plaque area, SUVmean values and fibrous cap thickness was assessed.

Results

The rabbit carotid and abdominal atherosclerosis model was established. Al18F-NOTA-FAPI-04 showed a higher uptake in carotid plaques (SUVmean 1.32 ± 0.11) and abdominal plaques (SUVmean 0.73 ± 0.13) compared to corresponding controls (SUVmean 1.07 ± 0.06; 0.46 ± 0.03) (P < 0.05). Biodistribution analysis of Al18F-NOTA-FAPI-04 revealed that the bigger plaques were delineated with higher TBRs. Pathological staining showed the formation of arterial plaques, and ARG staining exhibited a higher intensity of Al18F-NOTA-FAPI-04 in the bigger plaques. Lastly, plaque area was found to be positively correlated to FAP expression and SUVmean, while FAP expression was negatively correlated to fibrous cap thickness of plaques.

Conclusions

We successfully achieve molecular imaging of fibroblast activation in atherosclerotic lesions of rabbits, suggesting Al18F-NOTA-FAPI-04 PET/CT may be a potentially valuable tool to identify plaques.

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Abbreviations

PET:

Positron emission tomography

FAP:

Fibroblast activation protein

FAPI:

Fibroblast activation protein inhibitor

HFD:

High-fat diet

SUVmean:

Mean standardized uptake value

TBR:

Target-to-background ratio

ARG:

Autoradiography

IVUS:

Intravascular ultrasound

CT:

Computed tomography

FDG:

Fluorodeoxyglucose

NaF:

Sodium fluoride

TSPO:

Translocator protein

MMP:

Matrix metalloproteinase

CUS:

Conventional ultrasound

HPLC:

High performance liquid chromatography

ROI:

Region of interest

VOI:

Volume of interest

HE:

Hematoxylin and eosin

DAB:

3,3'-Diaminobenzidine

IMT:

Intima-media thickness

CXCR4:

C-X-C chemokine receptor 4

FM:

Fibrosing mediastinitis

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Funding

This study was funded by grants from the National Natural Science Foundation of China (Grant No. U22A6008, 81971655), the projects for Local Science and Technology Development Guided by the Central Committee of Shanxi Province (Grant No. YDZJSX2021B013), CAMS Innovation Fund for Medical Sciences (Grant No. 2021-I2M-1–008), and Natural Science Foundation for Young Scientists of Shanxi Province (Grant No. 202303021212139).

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Author notes

  1. Tianxiong Ji and Chunfang Zan contributed equally to this work.

Authors and Affiliations

  1. Department of Nuclear Medicine, First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, 030001, China

    Tianxiong Ji, Chunfang Zan, Jianbo Cao, Hongliang Wang, Zhifang Wu & Sijin Li

  2. Shanxi Key Laboratory of Molecular Imaging, Shanxi Medical University, Taiyuan, 030001, China

    Tianxiong Ji, Chunfang Zan, Jianbo Cao, Hongliang Wang, Zhifang Wu & Sijin Li

  3. Collaborative Innovation Center for Molecular Imaging of Precision Medicine, Shanxi Medical University, Taiyuan, 030001, China

    Chunfang Zan, Jianbo Cao, Hongliang Wang, Zhifang Wu, Min-Fu Yang & Sijin Li

  4. College of Medical Imaging, Shanxi Medical University, Taiyuan, 030001, China

    Chunfang Zan

  5. Department of Nuclear Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China

    Lina Li, Yao Su & Min-Fu Yang

  6. State Key Laboratory of Cardiovascular Disease, Beijing, 100037, China

    Kefei Dou

  7. Cardiometabolic Medicine Center, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China

    Kefei Dou

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  1. Tianxiong Ji
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Contributions

T.J., C.Z., L.L., J.C., Y.S., H.W., Z.W., M.Y. K.D. and S.L.: contributed to conceptualization and design of the study. T.J., C.Z. and Y.S.: performed main experiments. T.J. and C.Z.: performed the statistical analysis, and wrote the manuscript. L.L., J.C., Y.S., H.W., Z.W. M.Y. K.D., and S.L.: revised the manuscript and gave constructive suggestions. Z.W., M.Y. K.D. and S.L.: provided the funding. All authors contributed to manuscript revision, read, and approved the submitted version.

Corresponding authors

Correspondence to Zhifang Wu, Min-Fu Yang, Kefei Dou or Sijin Li.

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Ji, T., Zan, C., Li, L. et al. Molecular Imaging of Fibroblast Activation in Rabbit Atherosclerotic Plaques: a Preclinical PET/CT Study. Mol Imaging Biol (2024). https://doi.org/10.1007/s11307-024-01919-9

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