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Ultrasound Molecular Imaging of Transient Acute Myocardial Ischemia With a Clinically Translatable P- and E-Selectin Targeted Contrast Agent: Correlation With the Expression of Selectins

Hyvelin, Jean-Marc PhD; Tardy, Isabelle PhD; Bettinger, Thierry PhD; von Wronski, Mathew PhD; Costa, Maria MSc; Emmel, Patricia MSc; Colevret, Delphine MSc; Bussat, Philippe BSc; Lassus, Anne MSc; Botteron, Catherine DECVP, DVM, PhD; Nunn, Adrian PhD; Frinking, Peter PhD; Tranquart, François MD, PhD

doi: 10.1097/RLI.0000000000000018
Original Articles

Objective The diagnosis of acute coronary syndrome remains challenging especially in patients without clear symptoms or electrocardiographic and/or biomarker features. A hallmark of ischemia/reperfusion is activation of endothelial cells leading to altered expression of molecular markers, including selectins. In this context, we aimed to validate the value of ultrasound molecular imaging for detecting transient myocardial ischemia by using a clinically translatable dual P- and E-selectin–targeted ultrasound contrast agent (UCA) and microbubble (MBselectin).

Material and Methods Transient (20 minutes) myocardial ischemia of rat heart was produced by ligation of the left anterior descending coronary artery ligation followed by 2-, 5-, or 24-hour reperfusion. Imaging of the transient ischemic event was achieved by the use of MBselectin. Performance of this clinically translatable targeted UCA was compared with that of antibody-targeted streptavidin MBs. Finally, immunohistochemistry staining of rat myocardial ischemic tissue was performed to assess expression of selectins accessible to targeted UCA.

Results In rats subjected to myocardial ischemia (20 minutes) followed by reperfusion (2 hours), injection of MBselectin produced high late phase (ie, 10-minute postinjection) ultrasound molecular imaging enhancement in the myocardium, which colocalized with the ischemic area. Late phase enhancement persisted 5 and 24 hours after reperfusion. Similarly, the use of MBP and MBE, comprising antibodies specific for P- and E-selectin, respectively, showed high late-phase enhancement within the ischemic area compared with remote myocardial tissue. Two and 5 hours after ischemia has resolved, a persistent expression of these 2 selectins was detected. After 24 hours of reperfusion, only MBE produced late phase enhancement within the ischemic myocardium. Immunohistochemical findings revealed that both P- and E-selectin were expressed and accessible on the surface of the activated endothelium 2 and 5 hours after the acute ischemic event, whereas only E-selectin remained accessible after 24 hours.

Conclusions Ultrasound molecular imaging of transient myocardial ischemia using dual selectin-targeted UCA is able to monitor the time course of expression of selectins after resolution of the ischemic event, paving the way for a large clinical diagnostic window.

From the Bracco Suisse SA, Geneva, Switzerland.

Received for publication July 18, 2013; and accepted for publication, after revision, October 24, 2013.

Conflicts of interest and sources of funding: All authors are employees of Bracco Suisse Geneva, part of Bracco Group.

Reprints: Jean-Marc Hyvelin, PhD, Bracco Suisse SA, 31 route de la Galaise, CH-1228 Plan-Les-Ouates, Geneva, Switzerland. E-mail:

© 2014 by Lippincott Williams & Wilkins