Cardiomyocyte apoptosis has been implicated in numerous diseases involving the heart including ischemia, reperfusion injury and heart failure. However, despite significant advances in the biochemical characterization of cardiomyocyte apoptosis, the clinical significance of this process remains incompletely understood.
The aim of this proposal is thus to develop the ability to image cardiomyocyte apoptosis in vivo in diseases such as heart failure and reperfusion injury. High-resolution magnetic resonance imaging and a novel magnetic nanoparticle, AnxCLIO-Cy5.5, will be used to accomplish this. The synthesis of AnxCLIO-Cy5.5 has been modified from its originally reported design to significantly improve its biological activity. We now hypothesize that 1) AnxCLIO-Cy5.5 will bind to apoptotic cardiomyocytes with an efficiency similar to that of unmodified Annexin. 2) The sensitivity of the probe will be adequate to detect cardiomyocyte apoptosis in vivo. 3) The degree of AnxCLIO-Cy5.5 uptake in failing myocardium will correlate with the severity of cardiomyocyte apoptosis. 4) The pattern of probe accumulation following reperfusion injury will be of considerable prognostic significance. Preliminary in vitro and in vivo studies with AnxCLIO-Cy5.5 have shown highly encouraging results. We now plan to further investigate the sensitivity of the probe for the detection of cardiomyocyte apoptosis, in vivo, through the use of appropriate surgical and transgenic mouse models. Probe accumulation on the MR images will be correlated with cine MR images of cardiac function and myocardial contractility. Particular attention will be paid to the transmural extent of AnxCLIO-Cy5.5 accumulation after reperfusion injury and the effect this has on segmental contractile function. The proposed research will be conducted as part of an integrated research and training program to facilitate the applicant's transition to research independence. The proposed research also has the potential to facilitate a greater understanding of cardiomyocyte apoptosis and accelerate the development of novel cardioprotective strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL079984-04
Application #
7364548
Study Section
Special Emphasis Panel (ZHL1-CSR-M (F2))
Program Officer
Carlson, Drew E
Project Start
2005-04-15
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
4
Fiscal Year
2008
Total Cost
$132,300
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Chen, Howard H; Josephson, Lee; Sosnovik, David E (2011) Imaging of apoptosis in the heart with nanoparticle technology. Wiley Interdiscip Rev Nanomed Nanobiotechnol 3:86-99
Huang, Shuning; Sosnovik, David E (2010) Molecular and Microstructural Imaging of the Myocardium. Curr Cardiovasc Imaging Rep 3:26-33
Kramer, Christopher M; Sinusas, Albert J; Sosnovik, David E et al. (2010) Multimodality imaging of myocardial injury and remodeling. J Nucl Med 51 Suppl 1:107S-121S
Sosnovik, David E; Wang, Ruopeng; Dai, Guangping et al. (2009) Diffusion MR tractography of the heart. J Cardiovasc Magn Reson 11:47
Sosnovik, David E; Caravan, Peter (2009) Molecular MRI of Atherosclerotic Plaque With Targeted Contrast Agents. Curr Cardiovasc Imaging Rep 2:87-94
Sosnovik, David E; Garanger, Elisabeth; Aikawa, Elena et al. (2009) Molecular MRI of cardiomyocyte apoptosis with simultaneous delayed-enhancement MRI distinguishes apoptotic and necrotic myocytes in vivo: potential for midmyocardial salvage in acute ischemia. Circ Cardiovasc Imaging 2:460-7
Sosnovik, David E (2009) Molecular Imaging of Myocardial Injury: A Magnetofluorescent Approach. Curr Cardiovasc Imaging Rep 2:33-39
Sosnovik, David E; Nahrendorf, Matthias; Panizzi, Peter et al. (2009) Molecular MRI detects low levels of cardiomyocyte apoptosis in a transgenic model of chronic heart failure. Circ Cardiovasc Imaging 2:468-75
Nahrendorf, Matthias; Sosnovik, David E; French, Brent A et al. (2009) Multimodality cardiovascular molecular imaging, Part II. Circ Cardiovasc Imaging 2:56-70
Sosnovik, David E; Wang, Ruopeng; Dai, Guangping et al. (2009) Diffusion spectrum MRI tractography reveals the presence of a complex network of residual myofibers in infarcted myocardium. Circ Cardiovasc Imaging 2:206-12

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