Folate Receptor β–Targeted PET Imaging of Macrophages in Autoimmune Myocarditis
Arghavan Jahandideh, Sauli Uotila, Mia Ståhle, Jenni Virta, Xiang‐Guo Li, Ville Kytö, Päivi Marjamäki, Heidi Liljenbäck, Pekka Taimen, Vesa Oikonen, Jukka Lehtonen, Mikko I. Mäyränpää, Qingshou Chen, Philip S. Low, Juhani Knuuti, Anne Roivainen, Antti Saraste
Abstract
Currently available imaging techniques have limited specificity for the detection of active myocardial inflammation. Aluminum 18 F-labeled 1,4,7-triazacyclononane-N,N,N-triacetic acid conjugated folate ( 18 F-FOL) is a PET tracer targeting folate receptor (FR-), which is expressed on activated macrophages at sites of inflammation. We evaluated 18 F-FOL PET for the detection of myocardial inflammation in rats with autoimmune myocarditis and studied the expression of FR- in human cardiac sarcoidosis specimens. Methods: Myocarditis was induced by immunizing rats (n 5 18) with porcine cardiac myosin in complete Freund adjuvant. Control rats (n 5 6) were injected with Freund adjuvant alone. 18 F-FOL was intravenously injected, followed by imaging with a small-animal PET/CT scanner and autoradiography. Contrastenhanced high-resolution CT or 18 F-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. Results: The myocardium of 10 of 18 immunized rats showed focal macrophage-rich inflammatory lesions, with FR- expression occurring mainly in M1-polarized macrophages. PET images showed focal myocardial 18 F-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 18 F-FOL in myocardial inflammatory lesions. Uptake of 18 F-FOL in inflamed myocardium was efficiently blocked by a nonlabeled FR- ligand folate glucosamine in vivo. The myocardium of patients with cardiac sarcoidosis showed many FR--positive macrophages in inflammatory lesions. Conclusion: In a rat model of autoimmune myocarditis, 18 F-FOL shows specific uptake in inflamed myocardium containing macrophages expressing FR-, which were also present in human cardiac sarcoid lesions. Imaging of FR- expression is a potential approach for the detection of active myocardial inflammation.