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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Limitations The major limitation of the current study is the difficulty to directly use the described MPIOs in patients. MPIOs are covered with polystyrene, which has potential toxicity in humans. Work on the development towards human-compatible contrast-bearing nanoparticles such as liposomes or dendrimers, allowing conjugation with antibodies or peptide-mimetics, is ongoing, and we are optimistic that there will be a compatible formulation in the near future 44, 45 . The anti-LIBS The hypo-intense contrast effect generated by MPIOs necessitated pre- an an n d d po
po p st st st -c c -c on on on tr tr t as a t agent imaging, and therefore a single MRI sequence throughout the experiment. Such an imaging pr r ot ot t oc oc oc ol ol ol h h h as as a t t to pr
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antibody itself is a single-chain antibody with a small molecular weight of around 25kD, which should not cause significant immunoreactivity 46 . Importantly, during all of the experiments performed for this study, no animals died with signs of toxicity or showed symptoms suggesting an allergic reaction. A possible translation into human application also has to take into account the larger size of the examined species, as well as the typically used magnetic field strength in humans, mostly 1.5 or 3T. However, this reduced absolute image resolution should be overcompensated by the increase in object size, resulting in an improved image representation: the larger vessel sizes in humans clearly outweigh the reduced achievable resolution, resulting in more precise scans of the object. In the case of an equal slice thickness, the area of an image pixel would increase roughly by a factor of 100 coming from mouse (in plane 0.1x0.1 mm) to man (1x1mm), whereas the cross section of the coronary artery will increase by a factor of ~300 (diameter mouse ~175μm and man 3mm). In fact, in a previous in vitro MRI study we have demonstrated the general feasibility of detecting LIBS-MPIO at a clinically relevant field strength of 3T 47 .
targeted agents. In particular, a negative contrast agent generated by MPIOs demands a comparison of pre- and post-contrast images and therefore has longer scan times as e.g. PET. However, the “non-invasiveness” of MRI counterweights this limitation and research progress on MRI contrast agent development holds promise of the clinical use of molecular MRI in patients. A restriction to image quality specific to this study was the use of ECG-gated image acquisition. The hence non-constant repetition-time leads to a compromised steady state of longitudinal magnetization. Occasionally resulting image artifacts did not compromise image evaluation. However, a non-clearly defined steady state hinders an optimal flip angle selection he object. In the case of an equal slice thickness, the area of an image pixel woul ul l d d in in i cr cr cr ea a ea se se se
oughly by a factor of 100 coming from mouse (in plane 0.1x0.1 mm) to man (1x1mm), whereas h h e e cr cr cros
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DOI: 10.1161/CIRCULATIONAHA.113.008157 22
and therefore the full optimization of the signal intensity achieved. One possible solution to this is continuous excitation with data acquisition and phase step increment triggered through ECG. This option, allowing for a defined Ernst angle excitation, is part of our current work.
By using a unique dual imaging approach of MRI in mice, we were able to image the extent of myocardial necrosis via gadolinium-induced late enhancement (LGE) as well as platelet accumulation via a contrast agent that selectively targets activated platelets, which contribute to ischemia/reperfusion-associated inflammation as well as potential obstruction of the micro- circulation. Findings in immunohistochemistry and MRI correlated very well, providing a robust basis for noninvasive characterization of these pathologies. Furthermore P2Y 12 knockout in mice confirmed the role of platelets in myocardial ischemia/reperfusion injury and the specificity of our molecular magnetic resonance imaging approach. Overall, this pilot study on magnetic resonance imaging of activated platelets in MI justifies further testing towards establishing the role of platelets in ischemia/reperfusion injury, the assessment of the effect of anti-platelet therapy and its use as indicator of prognosis of ventricular remodeling and adverse cardiovascular events.
Furthermore the authors are grateful to Dr. Pierre Levan and Miss Rebecca Ramb, Dipl. math. for statistical advice.
CvzM), and HE6382/1-1 (TH). DD and DvE were supported by grant number F/09/12 of the German Heart Research Foundation. AM was supported by a grant of the German Heart circulation. Findings in immunohistochemistry and MRI correlated very well, pro ro ovi vi i di ding ng ng a a a r r r ob ob obus
u t basis for noninvasive characterization of these pathologies. Furthermore P2Y 12 knockout in mice co o
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DOI: 10.1161/CIRCULATIONAHA.113.008157 23
Foundation, XW by the National Health and Medical Research Council of Australia and KP by a Future Fellowship of the Australian Research Council. Conflict of Interest Disclosures: None.
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DOI: 10.1161/CIRCULATIONAHA.113.008157 27
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