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(Circulation. 2003;108:218.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Ultrasound Imaging of Acute Cardiac Transplant Rejection With Microbubbles Targeted to Intercellular Adhesion Molecule-1

Gregory E.R. Weller, PhD; Erxiong Lu, MD; Melissa M. Csikari, BS; Alexander L. Klibanov, PhD; David Fischer, BS; William R. Wagner, PhD; Flordeliza S. Villanueva, MD

From the Department of Bioengineering (G.E.R.W., W.R.W.) and McGowan Institute for Regenerative Medicine (G.E.R.W., W.R.W.), University of Pittsburgh, Pa; Cardiovascular Institute (E.L., M.M.C., D.F., F.S.V.), University of Pittsburgh School of Medicine, Pa; and Cardiovascular Imaging Center (A.L.K.), University of Virginia, Charlottesville, Va.

Correspondence to Flordeliza Villanueva, MD, University of Pittsburgh, S-568 Scaife Hall, 200 Lothrop St, Pittsburgh, PA 15213. E-mail villanuevafs{at}msx.upmc.edu

Background— Noninvasive techniques for detecting acute cardiac transplant rejection are limited. We hypothesized that ultrasound contrast microbubbles targeted to the endothelial cell (EC) inflammatory marker intercellular adhesion molecule-1 (ICAM-1) would selectively bind to rejecting versus nonrejecting myocardium and that myocardial contrast echocardiography can therefore detect acute rejection.

Methods and Results— Lipid-based microbubbles were conjugated to anti-rat ICAM-1 (MB_ICAM) or isotype control antibody (MB_Control). In vitro MB_ICAM adhesion to cultured rat ECs, as assessed in a parallel plate flow apparatus, was greater to inflammatory versus normal ECs (11±3 versus 3±2 microbubbles/EC, P<0.005). In vivo abdominal heterotopic heart transplantation was performed in rats (rejection group: Brown Norway to Lewis strain; control group: Lewis to Lewis or Brown Norway to Brown Norway). Triggered myocardial contrast echocardiography was performed during intravenous MB_ICAM or MB_Control (2.5x10⁶) injection on postoperative day 5. Myocardial videointensity from adhered MB_ICAM was significantly higher in rejecting (n=8) versus control (n=7) rats (10±4 versus 1±4 U, P=0.01). Postmortem histology showed normal myocardium in control rats, whereas allograft myocardium demonstrated grade III to IV rejection and strong immunohistochemical ICAM-1 staining.

Conclusions— Preferential adherence of ICAM-1-targeted microbubbles to rejecting versus nonrejecting rat cardiac transplant myocardium can be detected ultrasonically. Targeted microbubbles may thus offer a noninvasive ultrasound imaging technique for the detection of acute cardiac transplant rejection and other processes characterized by endothelial dysfunction.

Key Words: rejection • echocardiography • contrast media • cell adhesion molecules • transplantation

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