title: Ultrasound Detection of Myocardial Ischemic Memory Using an E-Selectin Targeting Peptide Amenable to Human Application.
abstract: Vascular endothelial leukocyte adhesion molecules, such as E-selectin, are acutely upregulated in myocardial ischemia/reperfusion and are thus "ischemic memory" biomarkers for recent cardiac ischemia. We sought to develop an ultrasound molecular imaging agent composed of microbubbles (MBs) targeted to E-selectin to enable the differential diagnosis of myocardial ischemia in patients presenting with chest pain of unclear etiology. Biodegradable polymer MBs were prepared bearing a peptide with specific human E-selectin affinity (MBESEL). Control MBs had scrambled peptide (MBCTL) or nonspecific IgG (MBIgG). MBESELadhesion to activated rat endothelial cells (ECs) was confirmed in vitro in a flow system and in vivo with intravital microscopy of rat cremaster microcirculation. Ultrasound molecular imaging of recent myocardial ischemia was performed in rats 4 hours after transient (15 minutes) coronary occlusion. MBESELadhesion was higher to inflamed versus normal ECs in vitro; there was no difference in MBCTLor MBIgGadhesion to inflamed versus normal ECs. There was greater adhesion of MBESELto inflamed versus noninflamed microcirculation and minimal adhesion of MBCTLor MBIgGunder any condition. Ultrasound imaging after injection of MBSELdemonstrated persistent contrast enhancement of the previously ischemic region. Videointensity in postischemic myocardium after MBESELwas higher than that in the nonischemic bed (11.6 ± 2.7 dB vs 3.6 ± 0.8 dB,p< .02) and higher than that after MBCTL(4.0 ± 1.0 dB,p< .03) or MBIgG(1.7 ± 0.1 dB,p< .03). MBs targeted to E-selectin via a short synthetic peptide with human E-selectin binding affinity enables echocardiographic detection of recent ischemia, setting the stage for clinical myocardial ischemic memory imaging to identify acute coronary syndromes.
authors.affiliation: Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Leng
authors.affiliation: Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Carson
authors.affiliation: Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.
authors.forename: Xucai
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.
authors.forename: Huili
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.
authors.forename: Susanne
authors.initials: S
authors.lastname: Ottoboni
authors.affiliation: Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.
authors.forename: William R
authors.initials: WR
authors.lastname: Wagner
authors.affiliation: Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.
authors.forename: Flordeliza S
authors.initials: FS
authors.lastname: Villanueva
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