Echocardiographic Ischemic Memory Imaging Through Complement-Mediated Vascular Adhesion of Phosphatidylserine-Containing Microbubbles.
This study hypothesized that microvascular retention of phosphatidylserine-containing microbubbles (MB-PS) would allow detection of recent but resolved myocardial ischemia with myocardial contrast echocardiographic (MCE) molecular imaging.



Techniques for ischemic memory imaging which can detect and spatially assess resolved myocardial ischemia are being developed for rapid evaluation of patients with chest pain.



MCE molecular imaging with MB-PS was performed 1.5 h, 3.0 h, and 6.0 h after brief (10 min) myocardial ischemia in mice; data were compared to selectin-targeted microbubbles. MCE molecular imaging with Sonazoid (GE Healthcare, Amersham, United Kingdom), a commercially produced phosphatidylserine (PS) - containing agent, was performed in separate mice at 1.5 h and 3.0 h after ischemia-reperfusion; and in dogs undergoing 135 min of ischemia and 60 min of reflow as well as in closed-chest nonischemic control dogs. The mechanism for MB-PS attachment was assessed by intravital microscopy of post-ischemic muscle and by flow cytometry analysis of cell-MB interactions.



In mice undergoing ischemia-reperfusion without infarction, signal enhancement in the risk area for MB-PS and p-selectin glycoprotein ligand-1-targeted microbubbles was similar at reflow times of 1.5 h (23.3 ± 7.3 IU vs. 30.7 ± 4.1 IU), 3.0 h (42.2 ± 6.2 IU vs. 33.9 ± 7.4 IU), and 6.0 h (24.1 ± 4.3 IU vs. 25.5 ± 4.7 IU). For both agents, signal in the risk area was significantly (p < 0.05) higher than remote region at all reflow times. Sonazoid also produced strong risk area enhancement at 1.5 h (34.7 ± 5.0 IU) and 3.0 h (52.5 ± 4.5 IU) which was approximately 3-fold greater than in the control region, and which correlated spatially with the microsphere-derived risk area. In dogs, Sonazoid signal in the risk area was >5-fold higher than in closed-chest control myocardium (42.2 ± 8.1 IU vs. 7.9 ± 3.3 IU; p < 0.001). Mechanistic studies indicated that MB-PS attached directly to venular endothelium and adherent leukocytes which was dependent on serum complement components C1q and C3.



Ischemic memory imaging with MCE is possible using MB-PS which may obviate the need for ligand-directed targeting.
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon.
Brian
B
Mott
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon.
William
W
Packwood
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon.
Aris
A
Xie
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon.
J Todd
JT
Belcik
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
Ronald P
RP
Taylor
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon.
Yan
Y
Zhao
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon.
Brian P
BP
Davidson
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon. Electronic address: lindnerj@ohsu.edu.
Jonathan R
JR
Lindner
D000818:Animals; D015922:Complement C1q / Q000378:metabolism; D003176:Complement C3 / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism*; D003287:Contrast Media / Q000008:administration & dosage* / Q000378:metabolism; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004285:Dogs; D004452:Echocardiography / Q000379:methods*; D005290:Ferric Compounds / Q000008:administration & dosage* / Q000378:metabolism; D005434:Flow Cytometry; D000069416:Intravital Microscopy; D007501:Iron / Q000008:administration & dosage* / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000378:metabolism; D008810:Mice, Inbred C57BL; D045423:Microbubbles; D057054:Molecular Imaging / Q000379:methods*; D009203:Myocardial Infarction / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D010087:Oxides / Q000008:administration & dosage* / Q000378:metabolism; D010718:Phosphatidylserines / Q000008:administration & dosage* / Q000378:metabolism; D011237:Predictive Value of Tests; D013997:Time Factors
C545610:C3 protein, mouse; D003176:Complement C3; D003287:Contrast Media; D005290:Ferric Compounds; D008562:Membrane Glycoproteins; D010087:Oxides; C084882:P-selectin ligand protein; D010718:Phosphatidylserines; C069727:Sonazoid; D015922:Complement C1q; D003165:Complement System Proteins; D007501:Iron
complement; microbubbles; myocardial contrast echocardiography; myocardial ischemia; phosphatidylserine