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Fibroblast activation protein imaging in reperfused ST-elevation myocardial infarction: comparison with cardiac magnetic resonance imaging

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The aim of this study was to explore the correlation of 18F-labeled fibroblast activation protein inhibitor (FAPI) and cardiovascular magnetic resonance (CMR) parameters in ST-elevation myocardial infarction (STEMI) patients with successful primary percutaneous coronary intervention (PPCI) and to investigate the value of FAPI imaging in predicting cardiac functional recovery, as well as the correlation between FAPI activity and circulating fibroblast activation protein (FAP) and inflammatory biomarkers.

Methods

Fourteen first-time STEMI patients (11 men, mean age: 62 ± 11 years) after PPCI and 14 gender-matched healthy volunteers (10 men, mean age: 50 ± 14 years) who had completed FAPI imaging and blood sample collection were prospectively recruited. All patients underwent baseline FAPI imaging (6 ± 2 days post-MI) and CMR (8 ± 2 days post-MI). Ten patients had follow-up CMR (84 ± 4 days post-MI). Myocardial FAPI activity was analyzed for extent (the percentage of FAPI uptake volume over the left ventricular volume, FAPI%), intensity (target-to-background uptake ratio, TBRmax), and amount (FAPI% × TBRmax). Late gadolinium enhancement (LGE), T2-weighted imaging (T2WI), extracellular volume (ECV), microvascular obstruction (MVO), and cardiac function from CMR imaging were analyzed. Blood samples obtained on the day of FAPI imaging were used to assess circulating FAP, TGF-β1, TNF-α, IL-6, and hsCRP in STEMI patients and controls.

Results

Localized but inhomogeneous FAPI uptake was observed in STEMI patients, which was larger than the edematous and infarcted myocardium, whereas no uptake was detected in controls. The MVO area showed lower FAPI uptake compared with the surrounding myocardium. FAPI activity was associated with the myocardial injury biomarkers T2WI, LGE, and ECV at both per-patient and per-segment levels (all p < 0.05), but was not associated with circulating FAP, TGF-β1, TNF-α, IL-6, or hsCRP. Among the CMR parameters, T2WI had the greatest correlation coefficient with both FAPI% and FAPI% × TBRmax. Baseline TBRmax was inversely correlated with the follow-up left ventricular ejection fraction (LVEF) (r =  − 0.73, p = 0.02).

Conclusion

FAPI imaging detects more involved myocardium than CMR in reperfused STEMI, and is associated with myocardial damage and follow-up LVEF.

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The data underlying this article will be shared on reasonable request to the corresponding author.

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References

  1. Prabhu SD, Frangogiannis NG. The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ Res. 2016;119:91–112. https://doi.org/10.1161/CIRCRESAHA.116.303577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kali A, Cokic I, Tang RL, Yang HJ, Sharif B, Marbán E, et al. Determination of location, size, and transmurality of chronic myocardial infarction without exogenous contrast media by using cardiac magnetic resonance imaging at 3T. Circ Cardiovasc Imag. 2014;7:471–81. https://doi.org/10.1161/CIRCIMAGING.113.001541.

    Article  Google Scholar 

  3. Gupta S, Ge Y, Singh A, Gräni C, Kwong RY. Multimodality imaging assessment of myocardial fibrosis. JACC Cardiovasc Imag. 2021;14:2457–69. https://doi.org/10.1016/j.jcmg.2021.01.027.

    Article  Google Scholar 

  4. Shinde AV, Frangogiannis NG. Mechanisms of fibroblast activation in the remodeling myocardium. Curr Pathobiol Rep. 2017;5:145–52. https://doi.org/10.1007/s40139-017-0132-z.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Nakaya M, Watari K, Tajima M, Nakaya T, Matsuda S, Ohara H, et al. Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction. J Clin Invest. 2017;127:383–401. https://doi.org/10.1172/JCI83822.

    Article  PubMed  Google Scholar 

  6. Ubil E, Duan J, Pillai IC, Rosa-Garrido M, Wu Y, Bargiacchi F, et al. Mesenchymal-endothelial transition contributes to cardiac neovascularization. Nature. 2014;514:585–90. https://doi.org/10.1038/nature13839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Toms J, Kogler J, Maschauer S, Daniel C, Schmidkonz C, Kuwert T, et al. Targeting fibroblast activation protein: radiosynthesis and preclinical evaluation of an 18F-labeled FAP inhibitor. J Nucl Med. 2020;61:1806–13. https://doi.org/10.2967/jnumed.120.242958.

    Article  CAS  PubMed  Google Scholar 

  8. Altmann A, Haberkorn U, Siveke J. The latest developments in imaging of fibroblast activation protein. J Nucl Med. 2021;62:160–7. https://doi.org/10.2967/jnumed.120.244806.

    Article  CAS  PubMed  Google Scholar 

  9. Tillmanns J, Hoffmann D, Habbaba Y, Schmitto JD, Sedding D, Fraccarollo D, et al. Fibroblast activation protein alpha expression identifies activated fibroblasts after myocardial infarction. J Mol Cell Cardiol. 2015;87:194–203. https://doi.org/10.1016/j.yjmcc.2015.08.016.

    Article  CAS  PubMed  Google Scholar 

  10. Tallquist MD, Molkentin JD. Redefining the identity of cardiac fibroblasts. Nat Rev Cardiol. 2017;14:484–91. https://doi.org/10.1038/nrcardio.2017.57.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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 68Ga-FAPI-04. J Nucl Cardiol. 2021. https://doi.org/10.1007/s12350-021-02603-z.

    Article  PubMed  Google Scholar 

  13. Kessler L, Kupusovic J, Ferdinandus J, Hirmas N, Umutlu L, Zarrad F, et al. Visualization of fibroblast activation after myocardial infarction using 68Ga-FAPI PET. Clin Nucl Med. 2021;46:807–13. https://doi.org/10.1097/RLU.0000000000003745.

    Article  PubMed  Google Scholar 

  14. Diekmann J, Koenig T, Zwadlo C, Derlin T, Neuser J, Thackeray JT, et al. Molecular imaging identifies fibroblast activation beyond the infarct region after acute myocardial infarction. J Am Coll Cardiol. 2021;77:1835–7. https://doi.org/10.1016/j.jacc.2021.02.019.

    Article  CAS  PubMed  Google Scholar 

  15. Tillmanns J, Fraccarollo D, Galuppo P, Wollert KC, Bauersachs J. Changes in concentrations of circulating fibroblast activation protein alpha are associated with myocardial damage in patients with acute ST-elevation MI. Int J Cardiol. 2017;232:155–9. https://doi.org/10.1016/j.ijcard.2017.01.037.

    Article  PubMed  Google Scholar 

  16. Raposeiras-Roubín S, Barreiro Pardal C, Rodiño Janeiro B, Abu-Assi E, García-Acuña JM, González-Juanatey JR. High-sensitivity C-reactive protein is a predictor of in-hospital cardiac events in acute myocardial infarction independently of GRACE risk score. Angiology. 2012;63:30–4. https://doi.org/10.1177/0003319711406502.

    Article  CAS  PubMed  Google Scholar 

  17. Oemrawsingh RM, Cheng JM, Akkerhuis KM, Kardys I, Degertekin M, van Geuns RJ, et al. High-sensitivity C-reactive protein predicts 10-year cardiovascular outcome after percutaneous coronary intervention. EuroIntervention. 2016;12:345–51. https://doi.org/10.4244/EIJY15M07_04.

    Article  PubMed  Google Scholar 

  18. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, et al. 2015 ACC/AHA/SCAI focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv. 2016;87:1001–19. https://doi.org/10.1002/ccd.26325.

    Article  PubMed  Google Scholar 

  19. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39:119–77. https://doi.org/10.1093/eurheartj/ehx393.

    Article  PubMed  Google Scholar 

  20. Fu X, Khalil H, Kanisicak O, Boyer JG, Vagnozzi RJ, Maliken BD, et al. Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart. J Clin Invest. 2018;128:2127–43. https://doi.org/10.1172/JCI98215.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Wang S, Zhou X, Xu X, Ding J, Liu S, Hou X, et al. Clinical translational evaluation of Al18F-NOTA-FAPI for fibroblast activation protein-targeted tumour imaging. Eur J Nucl Med Mol Imag. 2021;48:4259–71. https://doi.org/10.1007/s00259-021-05470-5.

    Article  CAS  Google Scholar 

  22. Flett AS, Hayward MP, Ashworth MT, Hansen MS, Taylor AM, Elliott PM, et al. Equilibrium contrast cardiovascular magnetic resonance for the measurement of diffuse myocardial fibrosis: preliminary validation in humans. Circulation. 2010;122:138–44. https://doi.org/10.1161/CIRCULATIONAHA.109.930636.

    Article  PubMed  Google Scholar 

  23. Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, et al. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation. 2011;123:594–604. https://doi.org/10.1161/CIRCULATIONAHA.110.982777.

    Article  CAS  PubMed  Google Scholar 

  24. Siwik DA, Chang DL, Colucci WS. Interleukin-1beta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. Circ Res. 2000;86:1259–65. https://doi.org/10.1161/01.res.86.12.1259.

    Article  CAS  PubMed  Google Scholar 

  25. Nagaraju CK, Dries E, Popovic N, Singh AA, Haemers P, Roderick HL, et al. Global fibroblast activation throughout the left ventricle but localized fibrosis after myocardial infarction. Sci Rep. 2017;7:10801. https://doi.org/10.1038/s41598-017-09790-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Saxena A, Chen W, Su Y, Rai V, Uche OU, Li N, et al. IL-1 induces proinflammatory leukocyte infiltration and regulates fibroblast phenotype in the infarcted myocardium. J Immunol. 2013;191:4838–48. https://doi.org/10.4049/jimmunol.1300725.

    Article  CAS  PubMed  Google Scholar 

  27. Kempf K, Haltern G, Füth R, Herder C, Müller-Scholze S, Gülker H, et al. Increased TNF-alpha and decreased TGF-beta expression in peripheral blood leukocytes after acute myocardial infarction. Horm Metab Res. 2006;38:346–51. https://doi.org/10.1055/s-2006-925403.

    Article  CAS  PubMed  Google Scholar 

  28. Kehmeier ES, Lepper W, Kropp M, Heiss C, Hendgen-Cotta U, Balzer J, et al. TNF-α, myocardial perfusion and function in patients with ST-segment elevation myocardial infarction and primary percutaneous coronary intervention. Clin Res Cardiol. 2012;101:815–27. https://doi.org/10.1007/s00392-012-0465-x.

    Article  CAS  PubMed  Google Scholar 

  29. Di Stefano R, Di Bello V, Barsotti MC, Grigoratos C, Armani C, Dell’Omodarme M, et al. Inflammatory markers and cardiac function in acute coronary syndrome: difference in ST-segment elevation myocardial infarction (STEMI) and in non-STEMI models. Biomed Pharmacother. 2009;63:773–80. https://doi.org/10.1016/j.biopha.2009.06.004.

    Article  CAS  PubMed  Google Scholar 

  30. Navarro SL, Brasky TM, Schwarz Y, Song X, Wang CY, Kristal AR, et al. Reliability of serum biomarkers of inflammation from repeated measures in healthy individuals. Cancer Epidemiol Biomarkers Prev. 2012;21:1167–70. https://doi.org/10.1158/1055-9965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Judd RM, Lugo-Olivieri CH, Arai M, Kondo T, Croisille P, Lima JA, et al. Physiological basis of myocardial contrast enhancement in fast magnetic resonance images of 2-day-old reperfused canine infarcts. Circulation. 1995;92:1902–10. https://doi.org/10.1161/01.cir.92.7.1902.

    Article  CAS  PubMed  Google Scholar 

  32. Nijveldt R, Hofman MB, Hirsch A, Beek AM, Umans VA, Algra PR, et al. Assessment of microvascular obstruction and prediction of short-term remodeling after acute myocardial infarction: cardiac MR imaging study. Radiology. 2009;250:363–70. https://doi.org/10.1148/radiol.2502080739.

    Article  PubMed  Google Scholar 

  33. van der Bijl P, Abou R, Goedemans L, Gersh BJ, Holmes DR Jr, Ajmone Marsan N, et al. Left ventricular post-infarct remodeling: implications for systolic function improvement and outcomes in the modern era. JACC Heart Fail. 2020;8:131–40. https://doi.org/10.1016/j.jchf.2019.08.014.

    Article  PubMed  Google Scholar 

  34. Lustosa RP, van der Bijl P, El Mahdiui M, Montero-Cabezas JM, Kostyukevich MV, Ajmone Marsan N, et al. Noninvasive myocardial work indices 3 months after ST-segment elevation myocardial infarction: prevalence and characteristics of patients with postinfarction cardiac remodeling. J Am Soc Echocardiogr. 2020;33:1172–9. https://doi.org/10.1016/j.echo.2020.05.001.

    Article  PubMed  Google Scholar 

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Funding

This work was supported by Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support (ZYLX202105).

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Author notes

  1. Boqia Xie, Jiaxin Wang, and Xiao-Ying Xi are contributed equally to this work and co-first authors.

Authors and Affiliations

  1. Cardiac Center, Beijing Chaoyang Hospital, Capital Medical University, 8th Gongtinanlu Rd, Chaoyang District, Beijing, 100020, China

    Boqia Xie, Cuncun Hua, Pixiong Su & Mulei Chen

  2. MR Center, Fuwai Hospital, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases of China, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China

    Jiaxin Wang & Shihua Zhao

  3. Department of Nuclear Medicine, Beijing Chaoyang Hospital, Capital Medical University, 8th Gongtinanlu Rd, Chaoyang District, Beijing, 100020, China

    Xiao-Ying Xi, Bi-Xi Chen, Lina Li & Min-Fu Yang

  4. Department of Radiology, Beijing Chaoyang Hospital, Capital Medical University, 8th Gongtinanlu Rd, Chaoyang District, Beijing, 100020, China

    Xiaojuan Guo

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Contributions

Boqia Xie, Jiaxin Wang, Xiao-Ying Xi, Mulei Chen, and Min-Fu Yang wrote the draft of the manuscript; Boqia Xie, Jiaxin Wang, Xiao-Ying Xi, Xiaojuan Guo, Bi-Xi Chen, Cuncun Hua, and Pixiong Su collected and analyzed the clinical data; Jiaxin Wang, Xiaojuan Guo, and Shihua Zhao analyzed the CMR data; Xiao-Ying Xi, Bi-Xi Chen, and Min-Fu Yang analyzed the PET/CT data; Lina Li collected and analyzed the blood samples and drafted the related discussion; Boqia Xie, Pixiong Su, Mulei Chen, and Min-Fu Yang conceived the study and interpreted the results. All authors contributed to the article’s revision, agreed to its submission, and had full access to original data.

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Correspondence to Mulei Chen or Min-Fu Yang.

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All procedures involving human participants were carried out in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Xie, B., Wang, J., Xi, XY. et al. Fibroblast activation protein imaging in reperfused ST-elevation myocardial infarction: comparison with cardiac magnetic resonance imaging. Eur J Nucl Med Mol Imaging 49, 2786–2797 (2022). https://doi.org/10.1007/s00259-021-05674-9

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