TY - JOUR
T1 - Folate Receptor β-Targeted PET Imaging of Macrophages in Autoimmune Myocarditis
AU - Jahandideh, Arghavan
AU - Uotila, Sauli
AU - Ståhle, Mia
AU - Virta, Jenni
AU - Li, Xiang Guo
AU - Kytö, Ville
AU - Marjamäki, Päivi
AU - Liljenbäck, Heidi
AU - Taimen, Pekka
AU - Oikonen, Vesa
AU - Lehtonen, Jukka
AU - Mäyränpää, Mikko I.
AU - Chen, Qingshou
AU - Low, Philip S.
AU - Knuuti, Juhani
AU - Roivainen, Anne
AU - Saraste, Antti
N1 - Funding Information:
Kinetic modeling using graphical Patlak analysis supports the concept of irreversible 18F-FOL uptake in inflamed myocardium, as is consistent with a previous study showing internalization of folate conjugates into endosomes (28). However, the Logan plot This study was conducted within the Finnish Centre of Excellence in Cardiovas-cular and Metabolic Diseases supported by the Academy of Finland, University of Turku, Turku University Hospital, and Åbo Akademi University. This study was financially supported by grants from the Academy of Finland, Business Finland, the Jane and Aatos Erkko Foundation, the Finnish Foundation for Cardiovascular Research, and the Sigrid Jusélius Foundation. No other potential conflict of interest relevant to this article was reported.
Publisher Copyright:
COPYRIGHT © 2020 by the Society of Nuclear Medicine and Molecular Imaging.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Currently available imaging techniques have limited specificity for the detection of active myocardial inflammation. Aluminum
18F-labeled 1,4,7-triazacyclononane-
N,N',N″-triacetic acid conjugated folate (
18F-FOL) is a PET tracer targeting folate receptor β (FR-β), which is expressed on activated macrophages at sites of inflammation. We evaluated
18F-FOL PET for the detection of myocardial inflammation in rats with autoimmune myocarditis and studied the expression of FR-β in human cardiac sarcoidosis specimens.
Methods: Myocarditis was induced by immunizing rats (
n = 18) with porcine cardiac myosin in complete Freund adjuvant. Control rats (
n = 6) were injected with Freund adjuvant alone.
18F-FOL was intravenously injected, followed by imaging with a small-animal PET/CT scanner and autoradiography. Contrast-enhanced high-resolution CT or
18F-FDG PET images were used for coregistration. Rat tissue sections and myocardial autopsy samples from 6 patients with cardiac sarcoidosis were studied for macrophages and FR-β.
Results: The myocardium of 10 of 18 immunized rats showed focal macrophage-rich inflammatory lesions, with FR-β expression occurring mainly in M1-polarized macrophages. PET images showed focal myocardial
18F-FOL uptake colocalizing with inflammatory lesions (SUV
mean, 2.1 ± 1.1), whereas uptake in the remote myocardium of immunized rats and controls was low (SUV
mean, 0.4 ± 0.2 and 0.4 ± 0.1, respectively;
P < 0.01). Ex vivo autoradiography of tissue sections confirmed uptake of
18F-FOL in myocardial inflammatory lesions. Uptake of
18F-FOL in inflamed myocardium was efficiently blocked by a nonlabeled FR-β ligand folate glucosamine in vivo. The myocardium of patients with cardiac sarcoidosis showed many FR-β-positive macrophages in inflammatory lesions.
Conclusion: In a rat model of autoimmune myocarditis,
18F-FOL shows specific uptake in inflamed myocardium containing macrophages expressing FR-β, which were also present in human cardiac sarcoid lesions. Imaging of FR-β expression is a potential approach for the detection of active myocardial inflammation.
AB - Currently available imaging techniques have limited specificity for the detection of active myocardial inflammation. Aluminum
18F-labeled 1,4,7-triazacyclononane-
N,N',N″-triacetic acid conjugated folate (
18F-FOL) is a PET tracer targeting folate receptor β (FR-β), which is expressed on activated macrophages at sites of inflammation. We evaluated
18F-FOL PET for the detection of myocardial inflammation in rats with autoimmune myocarditis and studied the expression of FR-β in human cardiac sarcoidosis specimens.
Methods: Myocarditis was induced by immunizing rats (
n = 18) with porcine cardiac myosin in complete Freund adjuvant. Control rats (
n = 6) were injected with Freund adjuvant alone.
18F-FOL was intravenously injected, followed by imaging with a small-animal PET/CT scanner and autoradiography. Contrast-enhanced high-resolution CT or
18F-FDG PET images were used for coregistration. Rat tissue sections and myocardial autopsy samples from 6 patients with cardiac sarcoidosis were studied for macrophages and FR-β.
Results: The myocardium of 10 of 18 immunized rats showed focal macrophage-rich inflammatory lesions, with FR-β expression occurring mainly in M1-polarized macrophages. PET images showed focal myocardial
18F-FOL uptake colocalizing with inflammatory lesions (SUV
mean, 2.1 ± 1.1), whereas uptake in the remote myocardium of immunized rats and controls was low (SUV
mean, 0.4 ± 0.2 and 0.4 ± 0.1, respectively;
P < 0.01). Ex vivo autoradiography of tissue sections confirmed uptake of
18F-FOL in myocardial inflammatory lesions. Uptake of
18F-FOL in inflamed myocardium was efficiently blocked by a nonlabeled FR-β ligand folate glucosamine in vivo. The myocardium of patients with cardiac sarcoidosis showed many FR-β-positive macrophages in inflammatory lesions.
Conclusion: In a rat model of autoimmune myocarditis,
18F-FOL shows specific uptake in inflamed myocardium containing macrophages expressing FR-β, which were also present in human cardiac sarcoid lesions. Imaging of FR-β expression is a potential approach for the detection of active myocardial inflammation.
KW - Experimental autoimmune myocarditis
KW - Folate receptor
KW - Myocarditis
KW - PET
KW - Heterocyclic Compounds, 1-Ring/pharmacokinetics
KW - Humans
KW - Macrophages/metabolism
KW - Rats, Inbred Lew
KW - Rats
KW - Male
KW - Sarcoidosis/metabolism
KW - Animals
KW - Radiopharmaceuticals/pharmacokinetics
KW - Fluorine Radioisotopes/pharmacokinetics
KW - Myocarditis/diagnostic imaging
KW - Positron-Emission Tomography/methods
KW - Autoimmune Diseases/diagnostic imaging
KW - Folate Receptor 2/metabolism
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U2 - 10.2967/jnumed.119.241356
DO - 10.2967/jnumed.119.241356
M3 - Article
C2 - 32284397
AN - SCOPUS:85089400002
SN - 0161-5505
VL - 61
SP - 1643
EP - 1649
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 11
ER -