title: Dual-contrast molecular imaging allows noninvasive characterization of myocardial ischemia/reperfusion injury after coronary vessel occlusion in mice by magnetic resonance imaging.
abstract: BACKGROUND
  Inflammation and myocardial necrosis play important roles in ischemia/reperfusion injury after coronary artery occlusion and recanalization. The detection of inflammatory activity and the extent of myocardial necrosis itself are of great clinical and prognostic interest. We developed a dual, noninvasive imaging approach using molecular magnetic resonance imaging in an in vivo mouse model of myocardial ischemia and reperfusion.
  
  
  RESULTS
  Ischemia/reperfusion injury was induced in 10-week-old C57BL/6N mice by temporary ligation of the left anterior descending coronary artery. Activated platelets were targeted with a contrast agent consisting of microparticles of iron oxide (MPIOs) conjugated to a single-chain antibody directed against a ligand-induced binding site (LIBS) on activated glycoprotein IIb/IIIa (LIBS-MPIOs). After injection and imaging of LIBS-MPIOs, late gadolinium enhancement was used to depict myocardial necrosis; these imaging experiments were also performed in P2Y12 (-/-) mice. All imaging results were correlated to immunohistochemistry findings. Activated platelets were detectable by magnetic resonance imaging via a significant signal effect caused by LIBS-MPIOs in the area of left anterior descending coronary artery occlusion 2 hours after reperfusion. In parallel, late gadolinium enhancement identified the extent of myocardial necrosis. Immunohistochemistry confirmed that LIBS-MPIOs bound significantly to microthrombi in reperfused myocardium. Only background binding was found in P2Y12 (-/-) mice.
  
  
  CONCLUSIONS
  Dual molecular imaging of myocardial ischemia/reperfusion injury allows characterization of platelet-driven inflammation by LIBS-MPIOs and myocardial necrosis by late gadolinium enhancement. This noninvasive imaging strategy is of clinical interest for both diagnostic and prognostic purposes and highlights the potential of molecular magnetic resonance imaging for characterizing ischemia/reperfusion injury.
authors.affiliation: From the Department of Radiology-Medical Physics (D.v.E., M.B., M. Menza), Department of Pneumology (M.I.), and Institute of Pathology and Comprehensive Cancer Center (P.B.), University Medical Center Freiburg, Freiburg, Germany; Department of Cardiology I, University Heart Center Freiburg, Freiburg, Germany (A.M., D.D., T.W., M. Mauler, I.N., A.Z., T.H., C.B., C.v.z.M.); Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (X.W., K.P.); Faculty of Biology, University Freiburg, Freiburg, Germany (M. Mauler); and Center for Systems Biology, Massachusetts General Hospital, Boston (T.H.).
authors.forename: Dominik
authors.initials: D
authors.lastname: von Elverfeldt
authors.affiliation: From the Department of Radiology-Medical Physics (D.v.E., M.B., M. Menza), Department of Pneumology (M.I.), and Institute of Pathology and Comprehensive Cancer Center (P.B.), University Medical Center Freiburg, Freiburg, Germany; Department of Cardiology I, University Heart Center Freiburg, Freiburg, Germany (A.M., D.D., T.W., M. Mauler, I.N., A.Z., T.H., C.B., C.v.z.M.); Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (X.W., K.P.); Faculty of Biology, University Freiburg, Freiburg, Germany (M. Mauler); and Center for Systems Biology, Massachusetts General Hospital, Boston (T.H.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Maier
authors.affiliation: From the Department of Radiology-Medical Physics (D.v.E., M.B., M. Menza), Department of Pneumology (M.I.), and Institute of Pathology and Comprehensive Cancer Center (P.B.), University Medical Center Freiburg, Freiburg, Germany; Department of Cardiology I, University Heart Center Freiburg, Freiburg, Germany (A.M., D.D., T.W., M. Mauler, I.N., A.Z., T.H., C.B., C.v.z.M.); Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (X.W., K.P.); Faculty of Biology, University Freiburg, Freiburg, Germany (M. Mauler); and Center for Systems Biology, Massachusetts General Hospital, Boston (T.H.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Duerschmied
authors.affiliation: From the Department of Radiology-Medical Physics (D.v.E., M.B., M. Menza), Department of Pneumology (M.I.), and Institute of Pathology and Comprehensive Cancer Center (P.B.), University Medical Center Freiburg, Freiburg, Germany; Department of Cardiology I, University Heart Center Freiburg, Freiburg, Germany (A.M., D.D., T.W., M. Mauler, I.N., A.Z., T.H., C.B., C.v.z.M.); Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (X.W., K.P.); Faculty of Biology, University Freiburg, Freiburg, Germany (M. Mauler); and Center for Systems Biology, Massachusetts General Hospital, Boston (T.H.).
authors.forename: Moritz
authors.initials: M
authors.lastname: Braig
authors.affiliation: From the Department of Radiology-Medical Physics (D.v.E., M.B., M. Menza), Department of Pneumology (M.I.), and Institute of Pathology and Comprehensive Cancer Center (P.B.), University Medical Center Freiburg, Freiburg, Germany; Department of Cardiology I, University Heart Center Freiburg, Freiburg, Germany (A.M., D.D., T.W., M. Mauler, I.N., A.Z., T.H., C.B., C.v.z.M.); Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (X.W., K.P.); Faculty of Biology, University Freiburg, Freiburg, Germany (M. Mauler); and Center for Systems Biology, Massachusetts General Hospital, Boston (T.H.).
authors.forename: Thilo
authors.initials: T
authors.lastname: Witsch
authors.affiliation: From the Department of Radiology-Medical Physics (D.v.E., M.B., M. Menza), Department of Pneumology (M.I.), and Institute of Pathology and Comprehensive Cancer Center (P.B.), University Medical Center Freiburg, Freiburg, Germany; Department of Cardiology I, University Heart Center Freiburg, Freiburg, Germany (A.M., D.D., T.W., M. Mauler, I.N., A.Z., T.H., C.B., C.v.z.M.); Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (X.W., K.P.); Faculty of Biology, University Freiburg, Freiburg, Germany (M. Mauler); and Center for Systems Biology, Massachusetts General Hospital, Boston (T.H.).
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Department of Radiology-Medical Physics (D.v.E., M.B., M. Menza), Department of Pneumology (M.I.), and Institute of Pathology and Comprehensive Cancer Center (P.B.), University Medical Center Freiburg, Freiburg, Germany; Department of Cardiology I, University Heart Center Freiburg, Freiburg, Germany (A.M., D.D., T.W., M. Mauler, I.N., A.Z., T.H., C.B., C.v.z.M.); Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (X.W., K.P.); Faculty of Biology, University Freiburg, Freiburg, Germany (M. Mauler); and Center for Systems Biology, Massachusetts General Hospital, Boston (T.H.).
authors.forename: Maximilian
authors.initials: M
authors.lastname: Mauler
authors.affiliation: From the Department of Radiology-Medical Physics (D.v.E., M.B., M. Menza), Department of Pneumology (M.I.), and Institute of Pathology and Comprehensive Cancer Center (P.B.), University Medical Center Freiburg, Freiburg, Germany; Department of Cardiology I, University Heart Center Freiburg, Freiburg, Germany (A.M., D.D., T.W., M. Mauler, I.N., A.Z., T.H., C.B., C.v.z.M.); Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (X.W., K.P.); Faculty of Biology, University Freiburg, Freiburg, Germany (M. Mauler); and Center for Systems Biology, Massachusetts General Hospital, Boston (T.H.).
authors.forename: Irene
authors.initials: I
authors.lastname: Neudorfer
authors.affiliation: From the Department of Radiology-Medical Physics (D.v.E., M.B., M. Menza), Department of Pneumology (M.I.), and Institute of Pathology and Comprehensive Cancer Center (P.B.), University Medical Center Freiburg, Freiburg, Germany; Department of Cardiology I, University Heart Center Freiburg, Freiburg, Germany (A.M., D.D., T.W., M. Mauler, I.N., A.Z., T.H., C.B., C.v.z.M.); Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (X.W., K.P.); Faculty of Biology, University Freiburg, Freiburg, Germany (M. Mauler); and Center for Systems Biology, Massachusetts General Hospital, Boston (T.H.).
authors.forename: Marius
authors.initials: M
authors.lastname: Menza
authors.affiliation: From the Department of Radiology-Medical Physics (D.v.E., M.B., M. Menza), Department of Pneumology (M.I.), and Institute of Pathology and Comprehensive Cancer Center (P.B.), University Medical Center Freiburg, Freiburg, Germany; Department of Cardiology I, University Heart Center Freiburg, Freiburg, Germany (A.M., D.D., T.W., M. Mauler, I.N., A.Z., T.H., C.B., C.v.z.M.); Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (X.W., K.P.); Faculty of Biology, University Freiburg, Freiburg, Germany (M. Mauler); and Center for Systems Biology, Massachusetts General Hospital, Boston (T.H.).
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
authors.affiliation: From the Department of Radiology-Medical Physics (D.v.E., M.B., M. Menza), Department of Pneumology (M.I.), and Institute of Pathology and Comprehensive Cancer Center (P.B.), University Medical Center Freiburg, Freiburg, Germany; Department of Cardiology I, University Heart Center Freiburg, Freiburg, Germany (A.M., D.D., T.W., M. Mauler, I.N., A.Z., T.H., C.B., C.v.z.M.); Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (X.W., K.P.); Faculty of Biology, University Freiburg, Freiburg, Germany (M. Mauler); and Center for Systems Biology, Massachusetts General Hospital, Boston (T.H.).
authors.forename: Andreas
authors.initials: A
authors.lastname: Zirlik
authors.affiliation: From the Department of Radiology-Medical Physics (D.v.E., M.B., M. Menza), Department of Pneumology (M.I.), and Institute of Pathology and Comprehensive Cancer Center (P.B.), University Medical Center Freiburg, Freiburg, Germany; Department of Cardiology I, University Heart Center Freiburg, Freiburg, Germany (A.M., D.D., T.W., M. Mauler, I.N., A.Z., T.H., C.B., C.v.z.M.); Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (X.W., K.P.); Faculty of Biology, University Freiburg, Freiburg, Germany (M. Mauler); and Center for Systems Biology, Massachusetts General Hospital, Boston (T.H.).
authors.forename: Timo
authors.initials: T
authors.lastname: Heidt
authors.affiliation: From the Department of Radiology-Medical Physics (D.v.E., M.B., M. Menza), Department of Pneumology (M.I.), and Institute of Pathology and Comprehensive Cancer Center (P.B.), University Medical Center Freiburg, Freiburg, Germany; Department of Cardiology I, University Heart Center Freiburg, Freiburg, Germany (A.M., D.D., T.W., M. Mauler, I.N., A.Z., T.H., C.B., C.v.z.M.); Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (X.W., K.P.); Faculty of Biology, University Freiburg, Freiburg, Germany (M. Mauler); and Center for Systems Biology, Massachusetts General Hospital, Boston (T.H.).
authors.forename: Peter
authors.initials: P
authors.lastname: Bronsert
authors.affiliation: From the Department of Radiology-Medical Physics (D.v.E., M.B., M. Menza), Department of Pneumology (M.I.), and Institute of Pathology and Comprehensive Cancer Center (P.B.), University Medical Center Freiburg, Freiburg, Germany; Department of Cardiology I, University Heart Center Freiburg, Freiburg, Germany (A.M., D.D., T.W., M. Mauler, I.N., A.Z., T.H., C.B., C.v.z.M.); Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (X.W., K.P.); Faculty of Biology, University Freiburg, Freiburg, Germany (M. Mauler); and Center for Systems Biology, Massachusetts General Hospital, Boston (T.H.).
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.affiliation: From the Department of Radiology-Medical Physics (D.v.E., M.B., M. Menza), Department of Pneumology (M.I.), and Institute of Pathology and Comprehensive Cancer Center (P.B.), University Medical Center Freiburg, Freiburg, Germany; Department of Cardiology I, University Heart Center Freiburg, Freiburg, Germany (A.M., D.D., T.W., M. Mauler, I.N., A.Z., T.H., C.B., C.v.z.M.); Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (X.W., K.P.); Faculty of Biology, University Freiburg, Freiburg, Germany (M. Mauler); and Center for Systems Biology, Massachusetts General Hospital, Boston (T.H.).
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Peter
authors.affiliation: From the Department of Radiology-Medical Physics (D.v.E., M.B., M. Menza), Department of Pneumology (M.I.), and Institute of Pathology and Comprehensive Cancer Center (P.B.), University Medical Center Freiburg, Freiburg, Germany; Department of Cardiology I, University Heart Center Freiburg, Freiburg, Germany (A.M., D.D., T.W., M. Mauler, I.N., A.Z., T.H., C.B., C.v.z.M.); Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia (X.W., K.P.); Faculty of Biology, University Freiburg, Freiburg, Germany (M. Mauler); and Center for Systems Biology, Massachusetts General Hospital, Boston (T.H.). constantin.vonzurmuehlen@universitaets-herzzentrum.de.
authors.forename: Constantin
authors.initials: C
authors.lastname: von Zur Muhlen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology*; D057791:Cardiac Imaging Techniques / Q000379:methods*; D003287:Contrast Media; D054059:Coronary Occlusion / Q000235:genetics / Q000473:pathology*; D003328:Coronary Thrombosis / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005290:Ferric Compounds; D005682:Gadolinium; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057054:Molecular Imaging / Q000379:methods*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000473:pathology*; D009336:Necrosis / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D015539:Platelet Activation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D003287:Contrast Media; D005290:Ferric Compounds; C548577:P2ry12 protein, mouse; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D058925:Receptors, Purinergic P2Y12; C000499:ferric oxide; D005682:Gadolinium
keywords: blood platelets; magnetic resonance imaging; reperfusion; thrombosis