Published Online
on June 30, 2003

A more recent version of this article appeared on July 15, 2003

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Submitted on January 21, 2003
Revised on March 26, 2003
Accepted on March 31, 2003

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, and 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.

^* To whom correspondence should be addressed. 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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