title: Combining the hDAF transgene with the GP IIb/IIIa inhibitor tirofiban improves heart performance and reduces myocardial damage following hyperacute rejection in an ex vivo perfusion model.
abstract: Xenograft rejection is associated with vascular injury resulting at least in part from platelet activation, and rejected xenografts invariably demonstrate intravascular thrombosis. Assuming that complement activation is a major determinant of humoral immune reactions bringing about platelet-endothelial cell interactions, we tested the effects of the specific platelet glycoprotein IIb/IIIa inhibitor tirofiban in combination with the human decay accelerating factor (hDAF) transgene on hyperacute rejection of pig hearts. Four groups were studied in a working heart-perfusion model. Pig hearts transgenic for hDAF and nontransgenic pig hearts were perfused with human blood containing tirofiban or with unmodified human blood. Cardiac output, stroke work index, and creatine phosphokinases were measured for the evaluation of the extent of myocardial damage. Consumption of complement components was determined. Endothelial deposition of fibrin and intravascular thrombosis were evaluated. Tirofiban improved cardiac output and stroke work index of nontransgenic pig hearts and was able to further increase hemodynamic function of hDAF transgenic pig hearts. Low levels of creatine phosphokinases also revealed a cardioprotective effect of tirofiban. However, a further extension of the survival of hDAF transgenic pig hearts could not be achieved, although tirofiban prolonged beating time of nontransgenic pig hearts. Tirofiban was able to reduce the consumption of complement components independently of hDAF. Intravascular evidence of fibrin and thrombosis tended to be particularly reduced by the combination of tirofiban and hDAF. Thus, the application of tirofiban together with hDAF improves the performance of pig hearts by reducing myocardial damage and intravascular thrombosis.
authors.affiliation: Department of Cardiac Surgery, Institute for Surgical Research and Institute for Pathology, Ludwig-Maximilians University of Munich, Munich, Germany. ubrandl@icf.med.uni-muenchen.de
authors.forename: U
authors.initials: U
authors.lastname: Brandl
authors.forename: M
authors.initials: M
authors.lastname: Erhardt
authors.forename: H
authors.initials: H
authors.lastname: Joeckle
authors.forename: S
authors.initials: S
authors.lastname: Michel
authors.forename: P
authors.initials: P
authors.lastname: Brenner
authors.forename: I
authors.initials: I
authors.lastname: Bittmann
authors.forename: M
authors.initials: M
authors.lastname: Roessle
authors.forename: V
authors.initials: V
authors.lastname: Mordstein
authors.forename: C
authors.initials: C
authors.lastname: Hammer
authors.forename: M
authors.initials: M
authors.lastname: Schmoeckel
authors.forename: B
authors.initials: B
authors.lastname: Reichart
mesh_terms: D000208:Acute Disease; D000818:Animals; D030801:Animals, Genetically Modified; D018958:CD55 Antigens / Q000235:genetics*; D003402:Creatine Kinase / Q000378:metabolism; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D006801:Humans; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013552:Swine; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D018958:CD55 Antigens; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014443:Tyrosine; D003402:Creatine Kinase; D000077466:Tirofiban