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Excerpt
Purpose: We suppose, that ischemia and reperfusion injury after long ischemic time (IT) of xenografts have a marked influence on hyperacute xenograft rejection (HXR). Therefore we investigate the influence of different cold ischemic times on HXR of ex vivo „working pig hearts“ perfused with human blood. Xenoreactive, natural antibodies (XNAb) as a trigger of HXR were eliminated by immunoadsorption (IA) using a Ig-Therasorb® column. Methods: Hearts of Landrace pigs (13-31 kg body weight) were explanted after cardioplegic arrest with Celsior®-solution. Hearts of group G1 (n=6) underwent 4 hours of ischemia prior to start of xenoperfusion. Hearts of control group G2 (n=6) were kept ischemic only for 46.6±15.8 minutes. In group G3 (n=6) with 4 hours of IT and in group G4 (n=6) with 51.2±4.2 min of IT two cycles of IA removed immunoglobulins IgG, IgM and IgA from perfusate. In working heart mode hemodynamic parameters like blood pressure, ECG, Cardiac Output (CO) and Coronary Flow (CF) were measured. Blood samples were collected to determine myocardial enzymes, immunoglobulins, complement and anti pig antibodies. After cardiac arrest tissue samples were taken for histological examination (light/electron microcopy (LM/EM) and immunohistochemistry). Results: IT prolonged the runtime in working heart model (in min: G1 (IT): 356±46.1, G2: 125±31.3*, G3 (IT + IA): 310±44.2, G4 (IA): 335±37.4). IA had no additional impact but was effective alone. Heart weight increased significantly in G2 without IA and IT (in g/h: G1 (IT): 5.67±0.81, G2: 23.9±5.24*, G3 (IT + IA): 8.18±1.59, G4 (IA): 5.69±1.4). CO and CF in G2 was significantly lower compared to the other 3 groups. (CO in ml/min: G1 (IT): 193.3±16.1, G2: 155±86.8, G3 (IT + IA): 198.8±15.4, G4 (IA): 338.5±16.0*). IA only improved CO in G4 (vs. G3, p<0.001). CF tended to be the highest with IT and IA (n.s.)(CF in ml/min: G1 (IT): 157.9±9.15, G2: 59.4±20.1*, G3 (IT + IA): 172.1±11.8, G4 (IA): 151.2±10.9). Histological signs of HXR (LM/EM) could be found in G2 in contrast to the other groups. Serological parameters were best in G4 and the worst in G2. Immediately after starting perfusion anti pig antibody levels in G3 were no more detectable. In G1 XNAb were nearly equally decreasing like in IA group G4. In G2 XNAb decreased within the first hour of organ perfusion during HXR. Conclusion: In contrast to allotransplantation ischemic time showed beneficial effects in this specific xenogeneic heart transplant model. Further evidences are necessary to decide whether these results must be attributed to special effects of the Celsior solution or to changes of the endothelial cell surface (e.g. of glycosylation or loss of α1-3Gal-epitopes). Eventually sudden decrease of XNAb could be caused by a hapten effect of detached α1-3Gal-epitopes. Further studies are necessary to evaluate a possible therapeutic effect of calculated ischemic time for prevention of HXR. Tolerance of longer IT could allow transportation of xenografts over long distances.
