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European Journal of Nuclear Medicine and Molecular Imaging

Published in:

29-09-2022 | Molecular Imaging | Original Article

Molecular imaging of fibroblast activity in pressure overload heart failure using [⁶⁸ Ga]Ga-FAPI-04 PET/CT

Authors: Guokun Wang, Qinqin Yang, Shengyong Wu, Xudong Xu, Xiao Li, Siyu Liang, Guixia Pan, Changjing Zuo, Xianxian Zhao, Chao Cheng, Suxuan Liu

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 2/2023

Abstract

Purpose

We aimed to evaluate whether [⁶⁸ Ga]Ga-FAPI-04 PET/CT could characterize the early stages of cardiac fibrosis in pressure overload heart failure.

Methods

Sprague–Dawley rats underwent abdominal aortic constriction (AAC) (n = 12) and sham surgery (n = 10). All rats were scanned with [⁶⁸ Ga]Ga-FAPI-04 PET/CT at 2, 4, and 8 weeks after surgery. The expression of fibroblast activation protein (FAP) in the myocardium was detected by immunohistochemistry. [⁶⁸ Ga]Ga-FAPI-04 PET signal and FAP expression were compared between two groups.

Results

Compared with the sham group, the AAC group presented with decreased ejection fraction (EF) and fractional shortening (FS) and increased left ventricular internal dimensions in diastole (LVIDd) and systole (LVIDs) at 4 and 8 weeks (all p < 0.01). The AAC group showed higher [⁶⁸ Ga]Ga-FAPI-04 accumulation in the heart than the sham group at 2, 4, and 8 weeks, and FAPI increased significantly from 2 to 8 weeks (all p < 0.001). Immunohistochemistry confirmed the higher density of the FAP⁺ area in the AAC group. The intensity of the [⁶⁸ Ga]Ga-FAPI-04 correlated with the density of the FAP⁺ area (p < 0.001). The expression of the [⁶⁸ Ga]Ga-FAPI-04 at 4 weeks correlated with the deterioration of cardiac function at 8 weeks (EF: R = − 0.87; FS: R = − 0.72; LVIDd: R = 0.77; LVIDs: R = 0.79; all p < 0.001). The AAC group also showed an increased [⁶⁸ Ga]Ga-FAPI-04 signal in the liver, peaking at 4 weeks and then declining. Cardiac and liver PET signals correlated at 4 weeks in the AAC group (R = 0.69, p = 0.0010), suggesting an early fibrotic link between organs. A combination of the [⁶⁸ Ga]Ga-FAPI-04 intensity in the heart and liver at 4 weeks better predicted the deterioration of cardiac function at 8 weeks.

Conclusions

The activated fibroblasts in the heart and liver after pressure overload can be monitored by [⁶⁸ Ga]Ga-FAPI-04 PET/CT, which reveals an early fibrotic link in cardio-liver interactions and could better predict nonischemic heart failure prognosis.

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Porter KE, Turner NA. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther. 2009;123:255–78. https://doi.org/10.1016/j.pharmthera.2009.05.002.CrossRef

Rai V, Sharma P, Agrawal S, Agrawal DK. Relevance of mouse models of cardiac fibrosis and hypertrophy in cardiac research. Mol Cell Biochem. 2017;424:123–45. https://doi.org/10.1007/s11010-016-2849-0.CrossRef

Ivey MJ, Tallquist MD. Defining the cardiac fibroblast. Circ J. 2016;80:2269–76. https://doi.org/10.1253/circj.CJ-16-1003.CrossRef

Loktev A, Lindner T, Mier W, Debus J, Altmann A, Jager D, et al. A tumor-imaging method targeting cancer-associated fibroblasts. J Nucl Med. 2018;59:1423–9. https://doi.org/10.2967/jnumed.118.210435.CrossRef

Kratochwil C, Flechsig P, Lindner T, Abderrahim L, Altmann A, Mier W, et al. (68)Ga-FAPI PET/CT: tracer uptake in 28 different kinds of cancer. J Nucl Med. 2019;60:801–5. https://doi.org/10.2967/jnumed.119.227967.CrossRef

Varasteh Z, Mohanta S, Robu S, Braeuer M, Li Y, Omidvari N, et al. Molecular Imaging of fibroblast activity after myocardial infarction using a (68)Ga-labeled fibroblast activation protein inhibitor, FAPI-04. J Nucl Med. 2019;60:1743–9. https://doi.org/10.2967/jnumed.119.226993.CrossRef

Notohamiprodjo S, Nekolla SG, Robu S, Villagran Asiares A, Kupatt C, Ibrahim T, et al. Imaging of cardiac fibroblast activation in a patient after acute myocardial infarction using (68)Ga-FAPI-04. J Nucl Cardiol. 2021. https://doi.org/10.1007/s12350-021-02603-z.CrossRef

Aghajanian H, Kimura T, Rurik JG, Hancock AS, Leibowitz MS, Li L, et al. Targeting cardiac fibrosis with engineered T cells. Nature. 2019;573:430–3. https://doi.org/10.1038/s41586-019-1546-z.CrossRef

Lin K, Chen X, Xue Q, Yao S, Miao W. Diffuse uptake of [(68)Ga]Ga-FAPI in the left heart in a patient with hypertensive heart disease by PET/CT. J Nucl Cardiol. 2021. https://doi.org/10.1007/s12350-021-02646-2.CrossRef

10.

Finke D, Heckmann MB, Herpel E, Katus HA, Haberkorn U, Leuschner F, et al. Early detection of checkpoint inhibitor-associated myocarditis using (68)Ga-FAPI PET/CT. Front Cardiovasc Med. 2021;8:614997. https://doi.org/10.3389/fcvm.2021.614997.CrossRef

11.

Wang L, Zhang Z, Zhao Z, Yan C, Fang W. (68)Ga-FAPI right heart uptake in a patient with idiopathic pulmonary arterial hypertension. J Nucl Cardiol. 2020. https://doi.org/10.1007/s12350-020-02407-7.CrossRef

12.

Ku HC, Lee SY, Wu YA, Yang KC, Su MJ. A model of cardiac remodeling through constriction of the abdominal aorta in rats. J Vis Exp. 2016. https://doi.org/10.3791/54818.CrossRef

13.

Lindner T, Loktev A, Altmann A, Giesel F, Kratochwil C, Debus J, et al. Development of quinoline-based theranostic ligands for the targeting of fibroblast activation protein. J Nucl Med. 2018;59:1415–22. https://doi.org/10.2967/jnumed.118.210443.CrossRef

14.

Yang F, Liu S, Gu Y, Yan Y, Ding X, Zou L, et al. MicroRNA-22 promoted osteogenic differentiation of valvular interstitial cells by inhibiting CAB39 expression during aortic valve calcification. Cell Mol Life Sci. 2022;79:146. https://doi.org/10.1007/s00018-022-04177-6.CrossRef

15.

Gonzalez A, Schelbert EB, Diez J, Butler J. Myocardial interstitial fibrosis in heart failure: biological and translational perspectives. J Am Coll Cardiol. 2018;71:1696–706. https://doi.org/10.1016/j.jacc.2018.02.021.CrossRef

16.

Thackeray JT, Bengel FM. Molecular imaging of myocardial inflammation with positron emission tomography post-ischemia: a determinant of subsequent remodeling or recovery. JACC Cardiovasc Imaging. 2018;11:1340–55. https://doi.org/10.1016/j.jcmg.2018.05.026.CrossRef

17.

Glasenapp A, Derlin K, Wang Y, Bankstahl M, Meier M, Wollert KC, et al. Multimodality imaging of inflammation and ventricular remodeling in pressure-overload heart failure. J Nucl Med. 2020;61:590–6. https://doi.org/10.2967/jnumed.119.232488.CrossRef

18.

Dunlay SM, Roger VL, Redfield MM. Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2017;14:591–602. https://doi.org/10.1038/nrcardio.2017.65.CrossRef

19.

Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA Guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;101161CIR0000000000001063. https://doi.org/10.1161/CIR.0000000000001063.

20.

Goto K, Schauer A, Augstein A, Methawasin M, Granzier H, Halle M, et al. Muscular changes in animal models of heart failure with preserved ejection fraction: what comes closest to the patient? ESC Heart Fail. 2021;8:139–50. https://doi.org/10.1002/ehf2.13142.CrossRef

21.

Lopez B, Ravassa S, Gonzalez A, Zubillaga E, Bonavila C, Berges M, et al. Myocardial collagen cross-linking is associated with heart failure hospitalization in patients with hypertensive heart failure. J Am Coll Cardiol. 2016;67:251–60. https://doi.org/10.1016/j.jacc.2015.10.063.CrossRef

22.

Azevedo CF, Nigri M, Higuchi ML, Pomerantzeff PM, Spina GS, Sampaio RO, et al. Prognostic significance of myocardial fibrosis quantification by histopathology and magnetic resonance imaging in patients with severe aortic valve disease. J Am Coll Cardiol. 2010;56:278–87. https://doi.org/10.1016/j.jacc.2009.12.074.CrossRef

23.

Xanthopoulos A, Starling RC, Kitai T, Triposkiadis F. Heart failure and liver disease: cardiohepatic interactions. JACC Heart Fail. 2019;7:87–97. https://doi.org/10.1016/j.jchf.2018.10.007.CrossRef

24.

Pirasteh A, Periyasamy S, Meudt JJ, Liu Y, Lee LM, Schachtschneider KM, et al. Staging liver fibrosis by fibroblast activation protein inhibitor positron emission tomography in a human-sized swine model. J Nucl Med. 2022. https://doi.org/10.2967/jnumed.121.263736.CrossRef

25.

Ostovaneh MR, Ambale-Venkatesh B, Fuji T, Bakhshi H, Shah R, Murthy VL, et al. Association of liver fibrosis with cardiovascular diseases in the general population: the Multi-Ethnic Study of Atherosclerosis (MESA). Circ Cardiovasc Imaging. 2018;11:e007241. https://doi.org/10.1161/CIRCIMAGING.117.007241.CrossRef

Title: Molecular imaging of fibroblast activity in pressure overload heart failure using [68 Ga]Ga-FAPI-04 PET/CT
Authors: Guokun Wang
Qinqin Yang
Shengyong Wu
Xudong Xu
Xiao Li
Siyu Liang
Guixia Pan
Changjing Zuo
Xianxian Zhao
Chao Cheng
Suxuan Liu
Publication date: 29-09-2022
Publisher: Springer Berlin Heidelberg
Keywords: Molecular Imaging
Heart Failure
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 2/2023
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-022-05984-6

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Molecular imaging of fibroblast activity in pressure overload heart failure using [⁶⁸ Ga]Ga-FAPI-04 PET/CT

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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