Published Online
on September 1, 2009

A more recent version of this article appeared on November 1, 2009

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Original Article

Molecular MRI Detects Low Levels of Cardiomyocyte Apoptosis in a Transgenic Model of Chronic Heart Failure

David E. Sosnovik^1,4; Matthias Nahrendorf¹; Peter Panizzi¹; Takashi Matsui²; Elena Aikawa¹; Guangping Dai¹; Ling Li²; Fred Reynolds¹; Gerald W. Dorn, II³; Ralph Weissleder¹; Lee Josephson¹ and Anthony Rosenzweig²

¹ Massachusetts General Hospital, Harvard Medical School, Boston, MA;
² Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA;
³ Washington University School of Medicine, St. Louis, MO

^* Corresponding author; email: sosnovik{at}nmr.mgh.harvard.edu

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.

Methods and Results—Female mice with over-expression 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 Tesla. 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 (r² = 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 anti-apoptotic therapies in heart failure.

Key Words: apoptosis • heart failure • magnetic resonance imaging • cardiomyocyte • molecular imaging