Detection of antecedent myocardial ischemia with multiselectin molecular imaging

Abstract

Objectives: Our aim was to develop an echocardiographic molecular imaging approach for detecting recent myocardial ischemia by using recombinant P-selectin glycoprotein ligand (PSGL)-1 as a targeting ligand, which is a feasible approach for human use.

Background: Ischemic memory imaging using human PSGL-1 as a targeting moiety may extend the time window for postischemic detection by targeting the early (P-selectin) and late (E-selectin) endothelial ischemic response.

Methods: Lipid microbubbles bearing recombinant human PSGL-1 (MB(YSPSL)) or P-selectin antibody (MB(Ab)) were prepared. Targeted attachment was evaluated by using flow chamber and intravital microscopy. In vivo ultrasound molecular imaging was first performed in the hindlimb in wild-type and P-selectin-deficient (P(-/-)) mice 45 to 360 min after brief ischemia-reperfusion injury. Myocardial contrast echocardiography molecular imaging was performed 1.5, 3, 6, and 18 h after brief left anterior descending coronary artery ischemia-reperfusion.

Results: Microbubble attachment to P-selectin-immunoglobulin G fusion protein in flow chamber experiments (shear stress 0.5 to 8.0 dyne/cm(2)) and to activated venular endothelium on intravital microscopy were similar for MB(Ab) and MB(YSPSL). Intense enhancement was seen for MB(Ab) and MB(YSPSL) in postischemic muscle and was more stable over time for MB(YSPSL). On myocardial contrast echocardiography, both MB(YSPSL) and MB(Ab) produced similar signal enhancement at 90 min and 3 h after ischemia, which spatially correlated with the postischemic risk area. Signal significantly decreased but was still present at 6 to 18 h.

Conclusions: Echocardiographic molecular imaging with a human multi-selectin-targeted contrast agent bearing recombinant human PSGL-1 can detect myocardial ischemia hours after resolution. This approach may potentially be used for rapid bedside evaluation of patients with recent chest pain.