Molecular MRI of cardiomyocyte apoptosis with simultaneous delayed-enhancement MRI distinguishes apoptotic and necrotic myocytes in vivo: potential for midmyocardial salvage in acute ischemia.
BACKGROUND
A novel dual-contrast molecular MRI technique to image both cardiomyocyte apoptosis and necrosis in vivo within 4 to 6 hours of ischemia is presented. The technique uses the annexin-based nanoparticle AnxCLIO-Cy5.5 (apoptosis) and simultaneous delayed-enhancement imaging with a novel gadolinium chelate, Gd-DTPA-NBD (necrosis).


RESULTS
Mice with transient coronary ligation were injected intravenously at the onset of reperfusion with AnxCLIO-Cy5.5 (n=7) or the control probe Inact_CLIO-Cy5.5 (n=6). T2*-weighted MR images (9.4 T) were acquired within 4 to 6 hours of reperfusion. The contrast-to-noise ratio between injured and uninjured myocardium was measured. The mice were then injected with Gd-DTPA-NBD, and delayed-enhancement imaging was performed within 10 to 30 minutes. Uptake of AnxCLIO-Cy5.5 was most prominent in the midmyocardium and was significantly greater than that of Inact_CLIO-Cy5.5 (contrast-to-noise ratio, 8.82+/-1.5 versus 3.78+/-1.1; P<0.05). Only 21+/-3% of the myocardium with accumulation of AnxCLIO-Cy5.5 showed delayed-enhancement of Gd-DTPA-NBD. Wall thickening was significantly reduced in segments with delayed enhancement and/or transmural accumulation of AnxCLIO-Cy5.5 (P<0.001). Fluorescence microscopy of AnxCLIO-Cy5.5 and immunohistochemistry of Gd-DTPA-NBD confirmed the presence of large numbers of apoptotic but potentially viable cardiomyocytes (AnxCLIO-Cy5.5 positive, Gd-DTPA-NBD negative) in the midmyocardium.


CONCLUSIONS
A novel technique to image cardiomyocyte apoptosis and necrosis in vivo within 4 to 6 hours of injury is presented and reveals large areas of apoptotic but viable myocardium in the midmyocardium. Strategies to salvage the numerous apoptotic but potentially viable cardiomyocytes in the midmyocardium in acute ischemia should be investigated.
Sosnovik
David E
DE
Center for Molecular Imaging Research, the Cardiology Division, Martinos Center for Biomedical Imaging, and the Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston. Mass, USA. sosnovik@nmr.mgh.harvard.edu
Garanger
Elisabeth
E
Aikawa
Elena
E
Nahrendorf
Matthias
M
Figuiredo
Jose-Luiz
JL
Dai
Guangping
G
Reynolds
Fred
F
Rosenzweig
Anthony
A
Weissleder
Ralph
R
Josephson
Lee
L
D009327:4-Chloro-7-nitrobenzofurazan / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000704:Analysis of Variance; D000818:Animals; D017304:Annexin A5 / Q000493:pharmacokinetics*; D017302:Annexins / Q000493:pharmacokinetics*; D017209:Apoptosis; D002232:Carbocyanines / Q000493:pharmacokinetics*; D003287:Contrast Media / Q000493:pharmacokinetics*; D005434:Flow Cytometry; D019786:Gadolinium DTPA / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D007091:Image Processing, Computer-Assisted; D020287:In Situ Nick-End Labeling; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009203:Myocardial Infarction / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology*; D053758:Nanoparticles; D036103:Nanotechnology; D009336:Necrosis / Q000175:diagnosis*; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D018709:Statistics, Nonparametric
D017304:Annexin A5; D017302:Annexins; C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D003287:Contrast Media; D009942:Organometallic Compounds; D004369:Pentetic Acid; D009327:4-Chloro-7-nitrobenzofurazan; D019786:Gadolinium DTPA