FAP PET identifies earlycardiac molecular changesinduced by doxorubicin chemotherapy
Chul-Hee Lee, Onorina L. Manzo, Luisa Rubinelli, Sebastian E. Carrasco, Sungyun Cho, Thomas M. Jeitner, John Babich, Annarita Di Lorenzo, James M. Kelly
Chul-Hee Lee, Onorina L. Manzo, Luisa Rubinelli, Sebastian E. Carrasco, Sungyun Cho, Thomas M. Jeitner, John Babich, Annarita Di Lorenzo, James M. Kelly
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Research Article Cardiology Therapeutics

FAP PET identifies earlycardiac molecular changesinduced by doxorubicin chemotherapy

Abstract

Anthracycline chemotherapy, widely used in cancer treatment, poses a significant risk of cardiotoxicity that results in functional decline. Current diagnostic methods poorly predict cardiotoxicity because they do not detect early damage that precedes dysfunction. Positron emission tomography (PET) is well suited to address this need when coupled with suitable imaging biomarkers. We used PET to evaluate cardiac molecular changes in male C57BL/6J mice exposed to doxorubicin (DOX). These mice initially developed cardiac atrophy, experienced functional deficits within 10 weeks of treatment, and developed cardiac fibrosis by 16 weeks. Elevated cardiac uptake of [68Ga]Ga-FAPI-04, a PET tracer targeting fibroblast activation protein α (FAP), was evident by 2 weeks and preceded the onset of functional deficits. Cardiac PET signal correlated with FAP expression and activity as well as other canonical indicators of cardiac remodeling. By contrast, cardiac uptake of [18F]DPA-714 and [18F]MFBG, which target translocator protein 18 kDa and the norepinephrine transporter, respectively, did not differ between the DOX animals and their controls. These findings identify FAP as an early imaging biomarker for DOX-induced cardiac remodeling in males and support the use of FAP PET imaging to detect some cancer patients at risk for treatment-related myocardial damage before cardiac function declines.

Authors

Chul-Hee Lee, Onorina L. Manzo, Luisa Rubinelli, Sebastian E. Carrasco, Sungyun Cho, Thomas M. Jeitner, John Babich, Annarita Di Lorenzo, James M. Kelly

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Figure 5

Cardiac [68Ga]Ga-FAPI-04 uptake correlates with FAP expression in cardiomyocytes in mouse tissue.

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Cardiac [68Ga]Ga-FAPI-04 uptake correlates with FAP expression in cardio...
(A) Representative FAP stains. Left: Fap mRNA (punctate red dots) was detected in the cytoplasm and/or nuclei of cardiomyocytes and/or epicardial stromal cells (insets). Scale bar: 20 μm. Right: A quadrupled image of the marked area. (B) Comparison of the H-score from Fap ISH staining between DOX and control groups. Quantitation was performed using QuPath software. (C) The correlation between [68Ga]Ga-FAPI-04 cardiac PET signals and H-score in the corresponding tissues (P = 0.0003). (D) Western blot analysis of cardiac α-SMA and Vimentin expression. Vinculin is used as a reference. ROI quantification of α-SMA and Vimentin protein levels. (E) Representative α-SMA and Vimentin immunostaining in cardiac tissue from control and DOX-treated mice. α-SMA is predominantly expressed in the cytoplasm of smooth muscle cells within cardiac arteries and arterioles. Vimentin immunolabeling is detected in a heterogeneous population of cardiac cells, including pericardial cells, pericytes, endothelial cells, and individual resident macrophages and/or stromal cells. Scale bar: 50 μm. All ROI quantification was performed using ImageJ. Data are presented as the mean ± SD. Statistical comparisons were performed using an unpaired 2-tailed t test (B and D) or a Pearson correlation test (C). *P < 0.05; ****P < 0.0001. ISH, in situ hybridization; α-SMA, α-smooth muscle actin; IHC, immunohistochemistry; ROI, region of interest.