This Article Full Text Full Text (PDF) All Versions of this Article: 2/6/460    most recent CIRCIMAGING.109.859678v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Sosnovik, D. E. Articles by Josephson, L. PubMed PubMed Citation Articles by Sosnovik, D. E. Articles by Josephson, L. Related Collections Cardiovascular imaging agents/Techniques Animal models of human disease Apoptosis Imaging Ischemic biology - basic studies CT and MRI Acute myocardial infarction

Original Articles

Molecular MRI of Cardiomyocyte Apoptosis With Simultaneous Delayed-Enhancement MRI Distinguishes Apoptotic and Necrotic Myocytes In Vivo

Potential for Midmyocardial Salvage in Acute Ischemia

David E. Sosnovik, MD; Elisabeth Garanger, PhD; Elena Aikawa, MD, PhD; Matthias Nahrendorf, MD, PhD; Jose-Luiz Figuiredo, MD; Guangping Dai, PhD; Fred Reynolds, PhD; Anthony Rosenzweig, MD; Ralph Weissleder, MD, PhD and Lee Josephson, PhD

From the Center for Molecular Imaging Research (D.E.S., E.G., E.A., M.N., J.L.-F., F.R., R.W., L.J.), the Cardiology Division (D.E.S.), Martinos Center for Biomedical Imaging (D.E.S., G.D.), and the Center for Systems Biology (M.N., R.W.), Massachusetts General Hospital, Harvard Medical School, Boston Mass; and the Cardiovascular Institute (A.R.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass.

Correspondence to David E. Sosnovik, MD, 5416 CMIR, 149 13th St, Charlestown, MA 02129. E-mail sosnovik{at}nmr.mgh.harvard.edu

Received February 19, 2009; accepted September 23, 2009.

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).

Methods and 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.

Key Words: molecular imaging • MRI • apoptosis • myocardium • ischemia

---

 

CLINICAL PERSPECTIVE