Molecular MRI of acute necrosis with a novel dna-binding gadolinium chelate: kinetics of cell death and clearance in inf
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ORAL PRESENTATION
Open Access
Molecular MRI of acute necrosis with a novel dna-binding gadolinium chelate: kinetics of cell death and clearance in infarcted myocardium Shuning Huang1*, Howard H Chen1, Hushan Yuan2, Guangping Dai1, Daniel Schule1, Soeun Ngoy3, Ronglih Liao3, Peter Caravan1, Lee Josephson1, David Sosnovik1 From 2011 SCMR/Euro CMR Joint Scientific Sessions Nice, France. 3-6 February 2011 Objective In the current study, we describe a novel approach to image acute necrotic cell death in vivo through the use of a DNA-binding gadolinium chelate (Gd-TO). Background Detecting cell death in vivo is extremely important in understanding disease pathogenesis, assessing disease progression, and evaluating treatment efficacy. Various MRI techniques have been developed over the years to image cell death. However, most of these techniques are based largely on non-specific pharmacokinetics and accumulation, and usually cannot discriminate acute and chronic injury. Here we present a novel DNA-binding gadolinium chelate (Gd-TO) that binds specifically to the exposed DNA of ruptured/necrotic cells. We show that Gd-TO can be used to selectively detect and image the kinetics of acute necrotic cell death and the subsequent clearance of necrotic debris from injured tissue. Material and methods In vivo imaging was performed in twenty infarcted (permanent ligation of the left coronary artery) C57BL6 mice. The infarcted mice were injected with 0.1 mmol/kg of Gd-TO (15 mice) or Gd-DTPA (5 mice) at varying times post-infarction. MRI was performed 2-3 hours after probe injection on a 9.4T scanner (Biospin, Bruker) with a gradient strength of 150 Gauss/cm. A modified cardiac gated Look-Locker FISP sequence (TR: 3000ms, TE 1.3, MTX: 160x160, FOV: 1 Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA Full list of author information is available at the end of the article
2.5 x 2.5 cm 2 ) was used to detect changes in signal intensity and the longitudinal relaxation rate (R 1 ) in the infarcted myocardium. R1 maps of the myocardium were constructed using Matlab (Mathwork). Statistical analysis (unpaired t-test, ANOVA, and a Tukey’s posttest comparison) of the data was performed with Prism (Graphpad).
Results Cell rupture (Gd-TO uptake) was present within 2 hours of infarction, but peaked 9-18hrs after the onset of injury (Fig 1C). No uptake of Gd-TO was seen 72-96 hours after injury, indicating complete clearance of the necrotic debris at this time. Significant differences were seen between mice injected with Gd-TO less than 48 hours post-infarction and those injected more than 72 hours after infarction. Likewise, while Gd-TO was robustly retained in acute infarcts, complete myocardial washout of Gd-DTPA was seen within 60-90 minutes (Fig 1). Fluorescence microscopy showed that Gd-TO was exclusively bound to DNA in the infarct. Conclusion The uptake of Gd-TO delineates a narrow time window during which acutely necrotic cells are present within an injured tissue. This could have important i
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