Myocardial Ischemic Memory Imaging With Molecular Echocardiography

Abstract

Background— Diagnosing acute coronary syndrome in patients presenting with chest discomfort is a challenge. Because acute myocardial ischemia/reperfusion is associated with endothelial upregulation of leukocyte adhesion molecules, which persist even after ischemia has resolved, we hypothesized that microbubbles designed to adhere to endothelial selectins would permit echocardiographic identification of recently ischemic myocardium. Methods and Results— Lipid microbubbles (diameter, 3.3±1.7 μm) were synthesized. The selectin ligand sialyl Lewis x was conjugated to the microbubble surface (MB sLex ). Control bubbles (MB CTL ) bore surface Lewis x or sialyl Lewis c . Intravital microscopy of mouse cremaster muscle was performed after intravenous injection of MB sLex (n=11) or MB CTL (n=9) with or without prior intrascrotal tumor necrosis factor–α. There was greater adhesion of MB sLex to inflamed versus noninflamed endothelium ( P =0.0081). Rats (n=12) underwent 15 minutes of anterior descending coronary artery occlusion. After 30 minutes and 1 hour of reperfusion, high-mechanical-index nonlinear echocardiographic imaging was performed in which single frames were acquired at 3.5 and 4 minutes after intravenous injection of MB sLex or MB CTL . Video intensity at 4 minutes was subtracted from that at 3.5 minutes to derive target-specific acoustic signal. MB sLex caused greater opacification in postischemic versus nonischemic myocardium at both time points ( P ≤0.002). Immunostaining confirmed endothelial P-selectin expression in the ischemic bed. Conclusions— Echocardiographic identification of recently ischemic myocardium is possible using ultrasound contrast agents targeted to selectins. This may offer a new approach to the more timely and precise diagnosis of acute coronary syndrome in patients presenting with chest pain of uncertain cardiac origin.