title: Ultrasound imaging of acute cardiac transplant rejection with microbubbles targeted to intercellular adhesion molecule-1.
abstract: 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.
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pa 15213, USA.
authors.forename: Gregory E R
authors.initials: GE
authors.lastname: Weller
authors.forename: Erxiong
authors.initials: E
authors.lastname: Lu
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Csikari
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Klibanov
authors.forename: David
authors.initials: D
authors.lastname: Fischer
authors.forename: William R
authors.initials: WR
authors.lastname: Wagner
authors.forename: Flordeliza S
authors.initials: FS
authors.lastname: Villanueva
mesh_terms: 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
chemical_list: D000906:Antibodies; D003287:Contrast Media; D007375:Interleukin-1; D008055:Lipids; D018799:Intercellular Adhesion Molecule-1