Yu-Xiang Ye1, Claudia Calcagno1, Tina Binderup1, Gabriel Courties1, Edmund J Keliher1, Gregory R Wojtkiewicz1, Yoshiko Iwamoto1, Jun Tang1, Carlos Pérez-Medina1, Venkatesh Mani1, Seigo Ishino1, Camilla Bardram Johnbeck1, Ulrich Knigge1, Zahi A Fayad1, Peter Libby1, Ralph Weissleder1, Ahmed Tawakol1, Shipra Dubey1, Anthony P Belanger1, Marcelo F Di Carli1, Filip K Swirski1, Andreas Kjaer1, Willem J M Mulder1, Matthias Nahrendorf2. 1. From the Center for Systems Biology, Department of Radiology (Y.-X.Y., G.C., E.J.K., G.R.W., Y.I., R.W., F.K.S., M.N.) and Division of Cardiology (A.T.), Massachusetts General Hospital and Harvard Medical School, Boston; Translational and Molecular Imaging Institute, Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (C.C., J.T., C.P.-M., V.M., S.I., Z.A.F., W.J.M.M.); Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging (T.B., C.B.J., A.K.) and Departments of Clinical Endocrinology PE and Surgery C (U.K.), Rigshospitalet, National University Hospital & University of Copenhagen, Copenhagen, Denmark; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L., M.F.D.C.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.D., A.P.B., M.F.D.C.); and Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands (W.J.M.M.). 2. From the Center for Systems Biology, Department of Radiology (Y.-X.Y., G.C., E.J.K., G.R.W., Y.I., R.W., F.K.S., M.N.) and Division of Cardiology (A.T.), Massachusetts General Hospital and Harvard Medical School, Boston; Translational and Molecular Imaging Institute, Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (C.C., J.T., C.P.-M., V.M., S.I., Z.A.F., W.J.M.M.); Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging (T.B., C.B.J., A.K.) and Departments of Clinical Endocrinology PE and Surgery C (U.K.), Rigshospitalet, National University Hospital & University of Copenhagen, Copenhagen, Denmark; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L., M.F.D.C.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.D., A.P.B., M.F.D.C.); and Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands (W.J.M.M.). mnahrendorf@mgh.harvard.edu.
Abstract
RATIONALE: Local plaque macrophage proliferation and monocyte production in hematopoietic organs promote progression of atherosclerosis. Therefore, noninvasive imaging of proliferation could serve as a biomarker and monitor therapeutic intervention. OBJECTIVE: To explore (18)F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis. METHODS AND RESULTS: (18)F-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased (18)F-FLT signal was observed in atherosclerotic lesions, spleen, and bone marrow (standardized uptake values wild-type versus apolipoprotein E knock out mice, 0.05 ± 0.01 versus 0.17 ± 0.01, P<0.05 in aorta; 0.13 ± 0.01 versus 0.28 ± 0.02, P<0.05 in bone marrow; 0.06 ± 0.01 versus 0.22 ± 0.01, P<0.05 in spleen), corroborated by ex vivo scintillation counting and autoradiography. Flow cytometry confirmed significantly higher proliferation of macrophages in aortic lesions and hematopoietic stem and progenitor cells in the spleen and bone marrow in these mice. In addition, (18)F-FLT plaque signal correlated with the duration of high cholesterol diet (r(2)=0.33, P<0.05). Aortic (18)F-FLT uptake was reduced when cell proliferation was suppressed with fluorouracil in apolipoprotein E knock out mice (P<0.05). In rabbits, inflamed atherosclerotic vasculature with the highest (18)F-fluorodeoxyglucose uptake enriched (18)F-FLT. In patients with atherosclerosis, (18)F-FLT signal significantly increased in the inflamed carotid artery and in the aorta. CONCLUSIONS: (18)F-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis.
RATIONALE: Local plaque macrophage proliferation and monocyte production in hematopoietic organs promote progression of atherosclerosis. Therefore, noninvasive imaging of proliferation could serve as a biomarker and monitor therapeutic intervention. OBJECTIVE: To explore (18)F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis. METHODS AND RESULTS: (18)F-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased (18)F-FLT signal was observed in atherosclerotic lesions, spleen, and bone marrow (standardized uptake values wild-type versus apolipoprotein E knock out mice, 0.05 ± 0.01 versus 0.17 ± 0.01, P<0.05 in aorta; 0.13 ± 0.01 versus 0.28 ± 0.02, P<0.05 in bone marrow; 0.06 ± 0.01 versus 0.22 ± 0.01, P<0.05 in spleen), corroborated by ex vivo scintillation counting and autoradiography. Flow cytometry confirmed significantly higher proliferation of macrophages in aortic lesions and hematopoietic stem and progenitor cells in the spleen and bone marrow in these mice. In addition, (18)F-FLT plaque signal correlated with the duration of high cholesterol diet (r(2)=0.33, P<0.05). Aortic (18)F-FLT uptake was reduced when cell proliferation was suppressed with fluorouracil in apolipoprotein E knock out mice (P<0.05). In rabbits, inflamed atherosclerotic vasculature with the highest (18)F-fluorodeoxyglucose uptake enriched (18)F-FLT. In patients with atherosclerosis, (18)F-FLT signal significantly increased in the inflamed carotid artery and in the aorta. CONCLUSIONS: (18)F-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis.
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