Longitudinal 18F-FDG PET imaging in a rat model of autoimmune myocarditis

Werner, Rudolf A.; Wakabayashi, Hiroshi; Bauer, Jochen; Schütz, Claudia; Zechmeister, Christina; Hayakawa, Nobuyuki; Javadi, Mehrbod S.; Lapa, Constantin; Jahns, Roland; Ergün, Süleyman; Jahns, Valérie; Higuchi, Takahiro

doi:10.1093/ehjci/jey119

Cited by 29 publications

(19 citation statements)

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“…Although the exact mechanism underlying myocyte injury in autoimmune myocarditis is not fully understood, the disease process is thought to be initiated by autoreactive T-cells and macrophages (17). We studied rats at 21 days after their first immunization because the peak in inflammation in this model occurs at that time, as shown previously by histology and 18 F-FDG PET imaging (24,25). Focal myocardial inflammatory lesions characterized by myocyte destruction as well as by a high prevalence of macrophages (both M1-and M2polarized) and CD3-positive lymphocytes are typical histological findings in this model (23,24).…”

Section: Discussionmentioning

confidence: 99%

Folate Receptor β–Targeted PET Imaging of Macrophages in Autoimmune Myocarditis

et al. 2020

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Rationale-Currently available imaging techniques have limited specificity for the detection of active myocardial inflammation. Aluminum fluoride-18-labeled 1,4,7-triazacyclononane-N,N′,N″-triacetic acid conjugated folate (18 F-FOL) is a positron emission tomography (PET) tracer targeting folate receptor β (FRβ) that 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 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's adjuvant. Control rats (n = 6) were injected with Freund's adjuvant alone. 18 F-FOL was intravenously injected followed by imaging with a small animal PET/computed tomography (CT) scanner and autoradiography. Contrast-enhanced high-resolution CT or 2-deoxy-2-18 F-fluoro-D-glucose (18 F-FDG) PET images were used for co-registration. Rat tissue sections and myocardial autopsy samples of 6 patients with cardiac sarcoidosis were studied for macrophages and FR-β. Results-The myocardium of 10 out 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 18 F-FOL uptake co-localizing with inflammatory lesions (SUVmean, 2.1 ± 1.1), whereas uptake in the remote myocardium of immunized rats and controls was low (SUVmean, 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 to inflamed myocardium was efficiently blocked by a non-labeled 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, 18 F-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.

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Section: Discussionmentioning

confidence: 99%

Folate Receptor β–Targeted PET Imaging of Macrophages in Autoimmune Myocarditis

et al. 2020

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“…The refinement of current diagnostic tools and imaging modalities could revolutionize our understanding of the pathogenesis of disease. FDG-PET is an important tool to better understand the relationship between cardiac inflammation and the development of DCM 187 and is used in preclinical mouse models of myocarditis to advance the detection of cardiac inflammation 134,188 . Once new imaging markers from animal studies can successfully detect inflammation in patients with myocarditis, they could be refined to detect inflammation in patients with DCM, where inflammatory cells are often scarce.…”

Section: Improved Diagnostic Toolsmentioning

confidence: 99%

Dilated cardiomyopathy

Schultheiss

Fairweather

Caforio

et al. 2019

Nat Rev Dis Primers

474

381

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www.nature.com/nrdp P r i m e r 0123456789(); P r i m e r 0123456789(); 4 | Article citation ID: (2019) 5:32 www.nature.com/nrdp P r i m e r 0123456789(); P r i m e r 0123456789(); P r i m e r 0123456789(); 7 NATURE REVIEwS | DIsEAsE PRIMERs | Article citation ID: (2019) 5:32 P r i m e r 0123456789(); P r i m e r 0123456789(); 9 NATURE REVIEwS | DIsEAsE PRIMERs | Article citation ID: (2019) 5:32 P r i m e r 0123456789(); P r i m e r 0123456789(); P r i m e r 0123456789(); (2019) 5:32 www.nature.com/nrdp P r i m e r 0123456789(); P r i m e r 0123456789();

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“…Two recent studies by Werner et al showed the possibility of longitudinal imaging of macrophages in a rat model of autoimmune myocarditis with fluorodeoxyglucose (FDG) and 11C-Methionin by positron emission tomography (PET) 30,31 . Major limitations of PET imaging are its relatively long scan time and the patients' exposure to radioactivity.…”

Section: Discussionmentioning

confidence: 99%

Molecular magnetic resonance imaging of activated platelets allows noninvasive detection of early myocarditis in mice

Braig

Jakob

Bienert

et al. 2020

Sci Rep

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MRI sensitivity for diagnosis and localization of early myocarditis is limited, although it is of central clinical interest. The aim of this project was to test a contrast agent targeting activated platelets consisting of microparticles of iron oxide (MPIO) conjugated to a single-chain antibody directed against ligand-induced binding sites (LIBS) of activated glycoprotein IIb/IIIa (= LIBS-MPIO). Myocarditis was induced by subcutaneous injection of an emulsion of porcine cardiac myosin and complete Freund's adjuvant in mice. 3D 7 T in-vivo MRI showed focal signal effects in LIBS-MPIO injected mice 2 days after induction of myocarditis, whereas in control-MPIO injected mice no signal was detectable. Histology confirmed CD41-positive staining, indicating platelet involvement in myocarditis in mice as well as in human specimens with significantly higher LIBS-MPIO binding compared to control-MPIO in both species. Quantification of the myocardial MRI signal confirmed a signal decrease after LIBS-MPIO injection and significant less signal in comparison to control-MPIO injection. These data show, that platelets are involved in inflammation during the course of myocarditis in mice and humans. They can be imaged non-invasively with LIBS-MPIO by molecular MRI at an early time point of the inflammation in mice, which is a valuable approach for preclinical models and of interest for both diagnostic and prognostic purposes. Besides myocardial ischemia, myocarditis is one of the most common causes of heart failure. The prevalence among young patients with sudden cardiac death is described within a range of 2-42%, and among patients with non-ischemic dilated cardiomyopathy within a range of 9-16%. The prognosis of progressing myocarditis is poor, symptoms are unspecific and diagnosis is challenging 1. Myocarditis is defined as an inflammatory process of the myocardium established by histological and immunohistochemical criteria associated with cardiac dysfunction. Several pathophysiological causes for myocarditis are known including infectious agents such as viruses, immune-mediated and toxic causes. Clinical symptoms, laboratory values, ECG and echocardiography are very often unspecific or inconclusive 1. To date, the diagnostic gold standard for diagnosis of myocarditis is endomyocardial biopsy (EMB). The Dallas criteria define myocarditis as histological evidence of inflammatory infiltrates within the myocardium associated with myocyte degeneration and necrosis of non-ischemic origin 2. There are also immunohistochemical criteria, namely abnormal inflammatory infiltrate defined as ≥ 14 leucocytes/mm 2 , including up to 4 monocytes/mm 2 with the presence of CD3 positive T-lymphocytes ≥ 7 cells/mm 21 .

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Longitudinal 18F-FDG PET imaging in a rat model of autoimmune myocarditis

Abstract: 18F-FDG PET imaging can provide non-invasive serial monitoring of cardiac inflammation in a rat model of acute myocarditis.

Cited by 29 publications

References 41 publications

Folate Receptor β–Targeted PET Imaging of Macrophages in Autoimmune Myocarditis

Folate Receptor β–Targeted PET Imaging of Macrophages in Autoimmune Myocarditis

Dilated cardiomyopathy

Molecular magnetic resonance imaging of activated platelets allows noninvasive detection of early myocarditis in mice

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