Dual-contrast molecular imaging allows noninvasive characterization of myocardial ischemia/reperfusion injury after coronary vessel occlusion in mice by magnetic resonance imaging

Circulation. 2014 Aug 19;130(8):676-87. doi: 10.1161/CIRCULATIONAHA.113.008157. Epub 2014 Jun 20.

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.

Keywords: blood platelets; magnetic resonance imaging; reperfusion; thrombosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal
  • Blood Platelets / metabolism
  • Blood Platelets / pathology*
  • Cardiac Imaging Techniques / methods*
  • Contrast Media
  • Coronary Occlusion / genetics
  • Coronary Occlusion / pathology*
  • Coronary Thrombosis / genetics
  • Coronary Thrombosis / pathology
  • Disease Models, Animal
  • Ferric Compounds
  • Gadolinium
  • Magnetic Resonance Imaging / methods*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Imaging / methods*
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / pathology*
  • Necrosis / pathology
  • Neutrophils / pathology
  • Platelet Activation
  • Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
  • Receptors, Purinergic P2Y12 / genetics

Substances

  • Antibodies, Monoclonal
  • Contrast Media
  • Ferric Compounds
  • P2ry12 protein, mouse
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Receptors, Purinergic P2Y12
  • ferric oxide
  • Gadolinium