Molecular MRI of Acute Necrosis With a Novel DNA-Binding Gadolinium Chelate

Abstract

Background— Current techniques to image cell death in the myocardium are largely nonspecific. We report the use of a novel DNA-binding gadolinium chelate (Gd-TO) to specifically detect the exposed DNA in acutely necrotic (ruptured) cells in vivo. Methods and Results— In vivo MRI was performed in 20 mice with myocardial infarction (MI). The mice were injected with Gd-TO or Gd-DTPA at varying time points after MI. MRI was performed 2 hours after probe injection, to avoid nonspecific signal from the late gadolinium enhancement effect. Cell rupture (Gd-TO uptake) was present within 2 hours of infarction but peaked 9 to 18 hours after the onset of injury. A significant increase in the longitudinal relaxation rate (R 1 ) in the infarct was seen in mice injected with Gd-TO within 48 hours of MI, but not in those injected more than 72 hours after MI (R 1 =1.24±0.08 and 0.92±0.03 s −1 , respectively, P <0.001). Gd-DTPA, unlike Gd-TO, washed completely out of acute infarcts within 2 hours of injection ( P <0.001). The binding of Gd-TO to exposed DNA in acute infarcts was confirmed with fluorescence microscopy. Conclusions— Gd-TO specifically binds to acutely necrotic cells and can be used to image the mechanism and chronicity of cell death in injured myocardium. Cell rupture in acute MI begins early but peaks many hours after the onset of injury. The ruptured cells are efficiently cleared by the immune system and are no longer present in the myocardium 72 hours after injury.