Ultrasound imaging of acute cardiac transplant rejection with microbubbles targeted to intercellular adhesion molecule-1.
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.


RESULTS
Lipid-based microbubbles were conjugated to anti-rat ICAM-1 (MBICAM) or isotype control antibody (MBControl). In vitro MBICAM 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 MBICAM or MBControl (2.5x10(6)) injection on postoperative day 5. Myocardial videointensity from adhered MBICAM 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.
Weller
Gregory E R
GE
Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pa 15213, USA.
Lu
Erxiong
E
Csikari
Melissa M
MM
Klibanov
Alexander L
AL
Fischer
David
D
Wagner
William R
WR
Villanueva
Flordeliza S
FS
D000208:Acute Disease; D000818:Animals; D000906:Antibodies / Q000737:chemistry; D002478:Cells, Cultured; D003287:Contrast Media / Q000008:administration & dosage* / Q000737:chemistry; D004195:Disease Models, Animal; D004452:Echocardiography / Q000379:methods*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006084:Graft Rejection / Q000000981:diagnostic imaging* / Q000276:immunology / Q000473:pathology; D016027:Heart Transplantation / Q000009:adverse effects* / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D008055:Lipids / Q000737:chemistry; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016042:Transplantation, Heterotopic
D000906:Antibodies; D003287:Contrast Media; D007375:Interleukin-1; D008055:Lipids; D018799:Intercellular Adhesion Molecule-1