Dual Contrast Molecular Imaging Allows Noninvasive Characterization of Myocardial Ischemia/Reperfusion Injury After Coronary Vessel Occlusion in Mice by mri running title
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DOI: 10.1161/CIRCULATIONAHA.113.008157 1
Myocardial Ischemia/Reperfusion Injury After Coronary Vessel Occlusion in Mice by MRI Running title: von Elverfeldt et al.; Molecular MRI of myocardial injury Dominik von Elverfeldt, PhD 1 *; Alexander Maier, MS 2 *; Daniel Duerschmied, MD 2 *;
Moritz Braig, MS 1 ; Thilo Witsch MD 2 ; Xiaowei Wang, PhD 3 ; Maximilian Mauler, MS 2,4 ;
Irene Neudorfer, MS 2 ; Marius Menza, MS 1 ; Marco Idzko, MD 5 ; Andreas Zirlik, MD 2 ;
Timo Heidt, MD 2,6
; Peter Bronsert, MD 7 ; Christoph Bode, MD 2 ; Karlheinz Peter, MD, PhD 3# ;
2#
1 Dept of Radiology–Medical Physics, University Medical Center Freiburg, Germany; 2 Dept of Cardiology I, University Heart Center Freiburg, Germany; 3 Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia; 4 Faculty of Biology, University Freiburg, Germany; 5 Dept of Pneumology, University Medical Center Freiburg, Germany; 6 Center for Systems Biology, Massachusetts General Hospital, Boston, MA; 7 Institute of Pathology & Comprehensive Cancer Center, University Medical Center Freiburg, Germany * these authors contributed equally; # these authors contributed equally Address for Correspondence: Constantin von zur Muhlen, MD University Heart Center Freiburg Hugstetter Strasse 55 79106 Freiburg, Germany Tel: +49-761-270-37835 Fax: +49-761-270-33884 E-mail: constantin.vonzurmuehlen@universitaets-herzzentrum.de
Irene Neudorfer, MS 2 ; Marius Menza, MS 1 ; Marco Idzko, MD 5 ; Andreas Zi Zi i rl rl rl ik ik ik,
, MD MD MD 2 2 ; ; ; Timo Heidt, MD 2,6 ; Peter Bronsert, MD 7 ; Christoph Bode, MD 2 ; Karlheinz Pete te r r r, M M MD, D D P P PhD hD hD 3# 3# 3# ; ; Constantin von zur Muhlen, MD 2# 1
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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, non-invasive imaging approach using molecular magnetic resonance imaging (MRI) 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“(LAD). Activated platelets were targeted with a contrast agent consisting of microparticles of iron oxide (MPIO) conjugated to a single-chain antibody directed against a ligand-induced binding site (LIBS) on activated glycoprotein (GP)IIb/IIIa (=LIBS-MPIO). After injection and imaging of LIBS-MPIO, late gadolinium enhancement (LGE) was used to depict myocardial necrosis; these imaging experiments were also performed in P2Y 12 -/- mice. All imaging results were correlated to immunohistochemistry findings. Activated platelets were detectable by MRI via a significant signal effect caused by LIBS-MPIO in the area of LAD occlusion two hours after reperfusion. In parallel, LGE identified the extent of myocardial necrosis. Immunohistochemistry confirmed that LIBS-MPIO significantly bound to microthrombi in reperfused myocardium. Only background- binding was found in P2Y 12 -/-
mice. Conclusions—Dual molecular imaging of myocardial ischemia/reperfusion injury allows characterization of platelet-driven inflammation by LIBS-MPIO as well as myocardial necrosis by LGE. This non-invasive imaging strategy is of clinical interest for both diagnostic and prognostic purposes, and highlights the potential of molecular MRI for characterizing ischemia/reperfusion injury.
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DOI: 10.1161/CIRCULATIONAHA.113.008157 3
During cardiac ischemia and after reperfusion, platelets play an important role not only as a mediator of acute macrovessel closure, but also by causing microvascular obstruction (MVO) as well as inflammation in the ischemic/reperfused myocardium, which both have a deleterious effect on myocardial damage 1, 23 . Platelet inhibition is a key factor in acute myocardial infarction management, and increasingly potent antiplatelet drugs targeting the platelet ADP- receptor P2Y 12 have improved patient outcome 4, 5 . Also the amount of platelets in the ischemic/reperfused myocardium has an important prognostic value 6 . Studies have shown that a high degree of MVO that involves platelet microthrombi results in a poor outcome 7, 8
. In addition, the extent of myocardial necrosis is widely accepted to be an important prognostic factor 9, 10
and cardiac magnetic resonance imaging (MRI) can be used to characterize wall motion and myocardial necrosis (late gadolinium enhancement = LGE) after acute myocardial infarction (AMI) 9, 11
. Therefore, it would be highly desirable to noninvasively characterize the extent of platelet involvement in ischemia/reperfusion injury, as well as the extent of myocardial necrosis. LGE specifically detects necrotic myocardial tissue, causing a signal increase in cardiac MRI 12, 13 .
14 . We have previously developed a unique contrast agent, which specifically detects activated platelets by targeting a ligand-induced binding site (LIBS) of the activated glycoprotein (GP)IIb/IIIa-receptor, using a single-chain antibody directed against these sites 15 . This antibody was conjugated to microparticles of iron oxide (MPIO), resulting in the unique activation-specific antiplatelet contrast agent (LIBS-MPIO). These LIBS-MPIOs cause a signal decrease in T 2 * weighted MRI at areas of platelet accumulation with an excellent sensitivity, since the 1 μm-sized MPIOs cause addition, the extent of myocardial necrosis is widely accepted to be an important nt p
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m m m m by guest on December 22, 2017 http://circ.ahajournals.org/ Downloaded from DOI: 10.1161/CIRCULATIONAHA.113.008157 4 a magnetic field disturbance exceeding their own diameter by far. Using this approach, we were able to detect even small amounts of activated platelets in coronary and carotid artery thrombosis, plaque rupture, and cerebral inflammation in mice 16-18 .
ligation of the left anterior descending coronary artery (LAD) and thereafter performed molecular magnetic resonance imaging of activated platelets by LIBS-MPIO to characterize platelet accumulation contributing to MVO and ischemia/reperfusion-associated inflammation. Furthermore, in a dual magnetic resonance imaging approach, myocardial necrosis was directly assessed by LGE in the same animals. The central role of platelets in myocardial ischemia/reperfusion injury as well as the clinical relevance of the respective therapeutic receptor inhibition was confirmed in dual contrast MRI and histology in P2Y 12 knockout mice undergoing temporary LAD ligation. Download 1.2 Mb. Do'stlaringiz bilan baham: 
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