Molecular MRI detects low levels of cardiomyocyte apoptosis in a transgenic model of chronic heart failure.
BACKGROUND
The ability to image cardiomyocyte (CM) apoptosis in heart failure could facilitate more accurate diagnostics and optimize targeted therapeutics. We thus aimed to develop a platform to image CM apoptosis quantitatively and specifically in heart failure in vivo. The myocardium in heart failure, however, is characterized by very low levels of CM apoptosis and normal vascular permeability, factors thought to preclude the use of molecular MRI.


RESULTS
Female mice with overexpression of Gaq were studied. Two weeks postpartum, these mice develop a cardiomyopathy characterized by low levels of CM apoptosis and minimal myocardial necrosis or inflammation. The mice were injected with the annexin-labeled nanoparticle (AnxCLIO-Cy5.5) or a control probe (CLIO-Cy5.5) and imaged in vivo at 9.4 T. Uptake of AnxCLIO-Cy5.5 occurred in isolated clusters, frequently in the subendocardium. Myocardial T2* was significantly lower (7.6+/-1.5 versus 16.8+/-2.7 ms, P<0.05) in the mice injected with AnxCLIO-Cy5.5 versus CLIO-Cy5.5, consistent with the uptake of AnxCLIO-Cy5.5 by apoptotic CMs. A strong correlation (r(2)=0.86, P<0.05) was seen between in vivo T2* (AnxCLIO-Cy5.5 uptake) and myocardial caspase-3 activity.


CONCLUSIONS
The ability of molecular MRI to image sparsely expressed targets in the myocardium is demonstrated in this study. Moreover, a novel platform for high-resolution and specific imaging of CM apoptosis in heart failure is established. In addition to providing novel insights into the pathogenesis of CM apoptosis, the developed platform could facilitate the development of novel antiapoptotic therapies in heart failure.
Sosnovik
David E
DE
Center for Molecular Imaging Research, the Cardiology Division, and Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Masss, USA. osnovik@nmr.mgh.harvard.edu
Nahrendorf
Matthias
M
Panizzi
Peter
P
Matsui
Takashi
T
Aikawa
Elena
E
Dai
Guangping
G
Li
Ling
L
Reynolds
Fred
F
Dorn
Gerald W
GW
Weissleder
Ralph
R
Josephson
Lee
L
Rosenzweig
Anthony
A
D000818:Animals; D017304:Annexin A5 / Q000493:pharmacokinetics*; D017209:Apoptosis; D015153:Blotting, Western; D002232:Carbocyanines / Q000493:pharmacokinetics*; D053148:Caspase 3 / Q000378:metabolism; D003287:Contrast Media / Q000493:pharmacokinetics*; D005260:Female; D006333:Heart Failure / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000473:pathology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D018709:Statistics, Nonparametric
D017304:Annexin A5; C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D003287:Contrast Media; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3