Research ArticleCardiology

Molecular Imaging of Fibroblast Activity After Myocardial Infarction Using a 68Ga-Labeled Fibroblast Activation Protein Inhibitor, FAPI-04

Zohreh Varasteh, Sarajo Mohanta, Stephanie Robu, Miriam Braeuer, Yuanfang Li, Negar Omidvari, Geoffrey Topping, Ting Sun, Stephan G. Nekolla, Antonia Richter, Christian Weber, Andreas Habenicht, Uwe A. Haberkorn and Wolfgang A. Weber
Journal of Nuclear Medicine December 2019, 60 (12) 1743-1749; DOI: https://doi.org/10.2967/jnumed.119.226993

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    Experimental timeline. OP = operation.

  • FIGURE 2.
    FIGURE 2.

    In vivo dynamic imaging of 68Ga-FAPI-04 uptake. (A) Serial PET/CT images (axial and coronal sections) from 90-min dynamic scan of MI rat at 7 d after coronary ligation. Representative regions of interest (2-dimensional) drawn over infarct border zone and remote myocardium are illustrated as red and black circles, respectively. Regions of interest in infarcts were placed relatively far from surgical wounds. 68Ga-FAPI-04 exhibited elevated uptake in scars from operation (asterisk). (B) Corresponding time–activity curves for infarcted and noninfarcted heart tissue (average and SD, n = 3). (C) Infarct-to-noninfarct ratio over time (average and SD, n = 3). H = heart; Li = liver; p.i. = after injection.

  • FIGURE 3.
    FIGURE 3.

    In vivo imaging of 68Ga-FAPI-04 uptake in longitudinal study. (A) Static PET/CT matched axial slices in same rat subjected to coronary ligation and scanned 1 h after injection of 68Ga-FAPI-04 (1, 3, 6, 14, 23, and 30 d after MI) and 18F-FDG (3 d after MI). Dashed lines separate tracer uptake in myocardium from uptake in surgical wounds. In 6 d after MI image, representative regions of interest (2-dimensional) drawn over infarct border zone and remote myocardium are illustrated as red and black circles, respectively. 68Ga-FAPI-04 uptake in regions of interest of infarcts is demonstrated. (B) Corresponding time–activity curves for infarcted and noninfarcted heart tissue (average and SD, n = 3). 68Ga-FAPI-04 and 18F-FDG exhibited elevated uptake in scars from operation (asterisk).

  • FIGURE 4.
    FIGURE 4.

    Axial sections of in vivo PET/CT imaging with 18F-FDG (day 3 after MI) and 68Ga-FAPI-04 (day 6 after MI) and corresponding ex vivo PET/MRI with 68Ga-FAPI-04 (day 7 after MI). 18F-FDG image was used to identify areas of infarcted myocardium (arrow), where increased uptake of 68Ga-FAPI-04 was apparent (arrowhead). 68Ga-FAPI-04 exhibited elevated uptake in postsurgical scar (asterisk). Dashed line separates 68Ga-FAPI-04 uptake in myocardium from surgical wound. High-resolution MR and PET/MR data confirmed infarcted area, where 68Ga-FAPI-04 uptake was increased.

  • FIGURE 5.
    FIGURE 5.

    Binding specificity test. (A) PET/CT axial views, autoradiographs, and corresponding H&E stainings of 10-μm cross-sections prepared from MI nonblocked, blocked, and sham-operated rats. Autoradiographs and H&E stainings from nonblocked hearts show increased 68Ga-FAPI-04 uptake in infarcted area at 7 d after MI, whereas uptake is negligible after sham operation or injection of nonlabeled FAPI-04 (blocked). Infarcted areas in H&E stainings are identified with arrows. (B) PET image–derived infarct-to-noninfarct uptake ratio (derived from 6 nonblocked and 3 blocked rat hearts subjected to coronary ligation). (C) Autoradiography image–derived infarct-to-noninfarct uptake ratio (derived from 3 nonblocked and 3 blocked MI hearts). QL = quantum level.

  • FIGURE 6.
    FIGURE 6.

    Ex vivo evaluation of 68Ga-FAPI-04 uptake in infarct at 7 d after MI. Representative autoradiograph and corresponding H&E staining from rat heart show elevated and heterogeneous uptake of 68Ga-FAPI-04 in infarct border compared with infarct center.

  • FIGURE 7.
    FIGURE 7.

    (A) Tile scan of entire infarcted heart section showing location of FAP+ fibroblasts. Insets 1, 2, and 3 show higher magnification from infarct border, infarct center, and noninfarcted remote myocardium, respectively. (B) Enumeration of FAP+ fibroblast density in MI hearts (n = 3) showing higher FAP+ fibroblast percentage in border zone than in infarct center or remote zone. (C) H&E-stained parallel section. (D) Photomicrographs of FAP, prolyl-4-hydroxylase β (P4H), α-smooth muscle actin, and vimentin-stained infiltrated fibroblasts in periinfarct border zone. Abundant colocalization of FAP, prolyl-4-hydroxylase β, and vimentin shows that accumulated fibroblasts are activated phenotypes, whereas small portion have differentiated into α-smooth muscle actin–positive mature myofibroblasts.

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