Dominik von Elverfeldt1, Alexander Maier1, Daniel Duerschmied1, Moritz Braig1, Thilo Witsch1, Xiaowei Wang1, Maximilian Mauler1, Irene Neudorfer1, Marius Menza1, Marco Idzko1, Andreas Zirlik1, Timo Heidt1, Peter Bronsert1, Christoph Bode1, Karlheinz Peter1, Constantin von Zur Muhlen2. 1. 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.). 2. 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.
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. METHODS AND 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.
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. METHODS AND 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.
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