title: Noninvasive Imaging of Myocardial Inflammation in Myocarditis using68Ga-tagged Mannosylated Human Serum Albumin Positron Emission Tomography.
abstract: The diagnosis of myocarditis traditionally relies on invasive endomyocardial biopsy but none of the imaging studies so far are specific for infiltration of the inflammatory cells itself. We synthesized68Ga-2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) mannosylated human serum albumin (MSA) by conjugating human serum albumin with mannose, followed by conjugation with NOTA and labeling it with68Ga. The efficacy of68Ga-NOTA-MSA positron emission tomography (PET) for imaging myocardial inflammation was tested in a rat myocarditis model. A significant number of mannose receptor-positive inflammatory cells infiltrated the myocardium in both human and rat myocarditis tissue.68Ga-NOTA-MSA uptake was upregulated in organs of macrophage accumulation, such as liver, spleen, bone marrow and myocardium (0.32 (0.31~0.33) for normal versus 1.02 (0.86~1.06) for myocarditis (median (range), SUV); n=4~6 per group, p-value=0.01).68Ga-NOTA-MSA uptake in the left ventricle was upregulated in myocarditis compared with normal rats (2.29 (1.42~3.40) for normal versus 4.18 (3.43~6.15) for myocarditis (median (range), average standard uptake value ratio against paraspinal muscle); n=6 per group, p-value<0.01), which was downregulated in rats with cyclosporine-A treated myocarditis (3.69 (2.59~3.86) for myocarditis versus 2.28 (1.76~2.60) for cyclosporine-A treated myocarditis; n=6 per group, p-value<0.01). The specificity of the tracer was verified by administration of excess non-labeled MSA.68Ga-NOTA-MSA uptake was significantly enhanced earlier in the evolution of myocarditis before any signs of inflammation could be seen on echocardiography. These results demonstrate the potential utility of visualizing infiltration of mannose receptor-positive macrophages with68Ga-NOTA-MSA PET in the early diagnosis of as well as in the monitoring of treatment response of myocarditis.
authors.affiliation: Cardiovascular Center, Seoul National University Hospital;; Department of Internal Medicine, Seoul National University College of Medicine.
authors.forename: Seung-Pyo
authors.initials: SP
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, Seoul National University Hospital and Seoul National University College of Medicine.
authors.forename: Hyung-Jun
authors.initials: HJ
authors.lastname: Im
authors.affiliation: Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Shinae
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Nuclear Medicine, Seoul National University Hospital and Seoul National University College of Medicine.
authors.forename: Seock-Jin
authors.initials: SJ
authors.lastname: Chung
authors.affiliation: Cardiovascular Center, Seoul National University Hospital.
authors.forename: Ye Seul
authors.initials: YS
authors.lastname: Cho
authors.affiliation: Cardiovascular Center, Seoul National University Hospital.
authors.forename: Hyejeong
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Ho Seon
authors.initials: HS
authors.lastname: Park
authors.affiliation: Department of Nuclear Medicine, Seoul National University Hospital and Seoul National University College of Medicine.
authors.forename: Do-Won
authors.initials: DW
authors.lastname: Hwang
authors.affiliation: Cardiovascular Center, Seoul National University Hospital;; Department of Internal Medicine, Seoul National University College of Medicine.
authors.forename: Jun-Bean
authors.initials: JB
authors.lastname: Park
authors.affiliation: Department of Nuclear Medicine, Seoul National University Hospital and Seoul National University College of Medicine.
authors.forename: Jin-Chul
authors.initials: JC
authors.lastname: Paeng
authors.affiliation: Department of Nuclear Medicine, Seoul National University Hospital and Seoul National University College of Medicine.
authors.forename: Gi-Jeong
authors.initials: GJ
authors.lastname: Cheon
authors.affiliation: Department of Nuclear Medicine, Seoul National University Hospital and Seoul National University College of Medicine.
authors.forename: Yun-Sang
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, Seoul National University Hospital and Seoul National University College of Medicine.
authors.forename: Jae Min
authors.initials: JM
authors.lastname: Jeong
authors.affiliation: Cardiovascular Center, Seoul National University Hospital;; Department of Internal Medicine, Seoul National University College of Medicine.
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005710:Gallium Radioisotopes / Q000008:administration & dosage*; D006571:Heterocyclic Compounds / Q000008:administration & dosage*; D006573:Heterocyclic Compounds, 1-Ring; D009205:Myocarditis / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D012680:Sensitivity and Specificity; D012709:Serum Albumin / Q000008:administration & dosage*; D000075462:Serum Albumin, Human
chemical_list: C422455:ALB protein, human; D005710:Gallium Radioisotopes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D012709:Serum Albumin; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid; D000075462:Serum Albumin, Human
keywords: macrophage; mannose receptor; molecular imaging.; myocarditis; positron emission tomography