Ischemic Memory Imaging in Nonhuman Primates with Echocardiographic Molecular Imaging of Selectin Expression

Abstract

Background Selectins are adhesion molecules that are expressed by the vascular endothelium upon activation and may be an imaging target for detecting myocardial ischemia long after resolution. We hypothesized that molecular imaging of selectins with myocardial contrast echocardiography (MCE) molecular imaging could be used to detect recent brief ischemia in closed-chest non-human primates. Methods Myocardial ischemia was produced in anesthetized adult rhesus macaques (n=6) by percutaneous balloon catheter occlusion of the LAD or circumflex coronary artery for 5–10 minutes. Three separate macaques served as non-ischemic controls. MCE perfusion imaging was performed during coronary occlusion to measure risk area (RA) and at 100–110 min to exclude infarction. MCE molecular imaging was performed at 30 and 90 min after reperfusion using a lipid microbubble bearing dimeric recombinant human P-selectin glycoprotein ligand-1 (MB-YSPSL). Collection of blood for a safety data, electrocardiography, and echocardiography were performed at baseline, and before and 10 min after each MB-YSPSL injection. Results Vital signs, O2 saturation, ECG, ventricular systolic function, pulmonary vascular resistance, and serum safety markers were unchanged by intravenous injection of MB-YSPSL. On echocardiography, LV dysfunction in the RA had resolved by 30 min and there was no evidence for infarction on MCE perfusion imaging. On selectin-targeted MCE molecular imaging, signal enhancement was greater (p<0.05) in the RA than remote territory at 30 min (25±11 vs 11±4 IU) and 90 min (13±3 vs 3±2 IU) after ischemia. There was no enhancement (<1 IU) in control non-ischemic subjects. Conclusion In primates, MCE molecular imaging of selectins using a recombinant ligand appropriate for humans is both safe and effective for imaging recent myocardial ischemia. This technique may be useful for detecting recent ischemia in patients with chest pain even in the absence of necrosis.

Ultrasound molecular imaging: Moving toward clinical translation

“…It has been shown that in the post-ischemic myocardium, ultrasound molecular imaging signal substantially increased 3–10 fold using microbubbles targeted to P-selectin in mice [26] and rats [25] after transient myocardial ischemia. Using a non-human primate transient myocardial ischemia model, dual P- and E-selectin-targeted ultrasound of ischemic memory using the same contrast agent described above for IBD imaging has been recently translated from small to large animals with a 240±85% increase in the molecular imaging signal in ischemic myocardium compared to non-ischemic myocardium [27]. Since E-selectin expression is under transcriptional control and cell surface expression can be detected approximately two hours after acute stimulation [27], dual-targeting to both P- and E-selectin is advantageous as imaging signal can be detected from a few minutes up to several hours after the ischemic event.…”

Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy

“…In another recent study on non-human primates with myocardial ischaemia, UMI was shown to be both safe and effective for imaging recent myocardial ischaemia. Lipid-coated MBs functionalised with dimeric recombinant human P-selectin glycoprotein ligand-1, a recombinant ligand appropriate for humans, were used [175]. The study suggests that UMI can be useful for detecting recent ischaemia in patients with chest pain, even in the absence of necrosis [175].…”

Echocardiographic Ischemic Memory Imaging Through Complement-Mediated Vascular Adhesion of Phosphatidylserine-Containing Microbubbles

“…Molecular imaging of resolved ischemia without infarction has been performed with myocardial contrast echocardiography (MCE) in rodent and nonhuman primate models using microbubbles targeted to the selectin family of endothelial cell adhesion molecules that are rapidly expressed in response to ischemia (4)(5)(6)(7). Clinical translation of this approach has been slowed by the arduous regulatory process of testing efficacy and safety of a human-ready microbubble agent bearing a biologically active ligand.…”