Abstract
The 68Gallium-labeled 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid conjugated radiolabelled arginine-glycine-aspartic acid peptide ([68Ga]Ga-NODAGA-RGD) is a positron emission tomography (PET) tracer binding to cell surface receptor αvβ3 integrin that is upregulated during angiogenesis and inflammation. We studied whether αvβ3 targeting PET imaging can detect myocardial inflammation in a rat model of autoimmune myocarditis. To induce myocarditis, rats (n = 8) were immunized with porcine cardiac myosin in complete Freund's adjuvant on days 0 and 7. Control rats (n = 8) received Freund's adjuvant alone. On day 21, in vivo PET/CT imaging with [68Ga]Ga-NODAGA-RGD followed by ex vivo autoradiography and immunohistochemistry were carried out. Inflammatory lesions were detected histologically in the myocardium of 7 out of 8 immunized rats. In vivo PET images showed higher [68Ga]Ga-NODAGA-RGD accumulation in the myocardium of rats with inflammation than the non-inflamed myocardium of control rats (SUVmean 0.4 ± 0.1 vs. 0.1 ± 0.02; P = 0.00006). Ex vivo autoradiography and histology confirmed that [68Ga]Ga-NODAGA-RGD uptake co-localized with inflammatory lesions containing αvβ3 integrin-positive capillary-like structures. A non-specific [68Ga]Ga-DOTA-(RGE)2 tracer showed 76% lower uptake than [68Ga]Ga-NODAGA-RGD in the inflamed myocardium. Our results indicate that αvβ3 integrin-targeting [68Ga]Ga-NODAGA-RGD is a potential PET tracer for the specific detection of active inflammatory lesions in autoimmune myocarditis.
Highlights
Myocarditis is defined as myocardial inflammation characterized by immune cell infiltration and myocyte necrosis, resulting from infectious or non-infectious initiators [1]
Ex vivo autoradiography αvβ3 Integrin Imaging in Myocarditis showed more than six times higher [68Ga]Ga-NODAGARGD uptake in inflammatory lesions of immunized rats as compared with the non-inflamed myocardium
We provided evidence that αvβ3 integrin is expressed in this model at 21 d after first immunization when the peak in acute inflammation in this model occurs [29, 30]. αvβ3 integrin mediates angiogenesis and plays a role in the regulation of macrophage responses during inflammation [21, 22, 32, 33]
Summary
Myocarditis is defined as myocardial inflammation characterized by immune cell infiltration and myocyte necrosis, resulting from infectious or non-infectious initiators [1]. Positron emission tomography (PET)/CT with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is a sensitive non-invasive imaging technique for the detection of myocardial inflammation. While αvβ Integrin Imaging in Myocarditis cardiac [18F]FDG PET has shown good accuracy in the detection of cardiac inflammation, the non-specific physiological uptake of the [18F]FDG in the myocardium may limit its specificity and usefulness in monitoring active disease [2, 3]. Recent studies have provided evidence that more specific identification of myocardial inflammatory lesions could be possible with alternative tracers [4–10]. Studies have shown increased angiogenesis in cancer [12], ischaemic heart disease [13] as well as many inflammatory diseases, such as rheumatoid arthritis [14, 15], diabetic retinopathy [16], psoriasis [17], pulmonary sarcoidosis or fibrosis [18, 19], and atherosclerosis [20, 21]
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