Author + information
- Received June 26, 2015
- Revision received November 4, 2015
- Accepted November 25, 2015
- Published online August 1, 2016.
- Brian Mott, MDa,
- William Packwood, BSa,
- Aris Xie, MSa,
- J. Todd Belcik, BS, RCS, RDCSa,
- Ronald P. Taylor, PhDb,
- Yan Zhao, MDa,
- Brian P. Davidson, MDa and
- Jonathan R. Lindner, MDa,∗ ()
- aKnight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon
- bDepartment of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia
- ↵∗Reprint requests and correspondence:
Dr. Jonathan R. Lindner, Knight Cardiovascular Institute, UHN-62, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239.
Objectives 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.
Background 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.
Methods 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.
Results 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.
Conclusions Ischemic memory imaging with MCE is possible using MB-PS which may obviate the need for ligand-directed targeting.
Sonazoid was provided for this study by GE Healthcare, Amersham, United Kingdom. Dr. Lindner is supported by grants R01-HL120046, R01-HL078610, and R01-HL111969 from the NIH; and a grant from the Doris Duke Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received June 26, 2015.
- Revision received November 4, 2015.
- Accepted November 25, 2015.
- American College of Cardiology Foundation