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Abicht, Jan-Michael; Kourtzelis, Ioannis; Reichart, Bruno; Koutsogiannaki, Sophia; Primikyri, Alexandra; Lambris, John D.; Chavakis, Triantafyllos; Holdt, Lesca; Kind, Alexander; Güthoff, Sonja; Mayr, Tanja (2017): Complement C3 inhibitor Cp40 attenuates xenoreactions in pig hearts perfused with human blood. In: Xenotransplantation, Vol. 24, No. 1, e12262
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Abstract

Background: The complement system plays a crucial role in acute xenogeneic reactions after cardiac transplantation. We used an ex vivo perfusion model to investigate the -effect of Cp40, a compstatin analog and potent inhibitor of complement at the level of C3. Methods: Fifteen wild-type pig hearts were explanted, cardiopleged, and reperfused ex vivo after 150 minutes of cold ischemia. Hearts were challenged in a biventricular working heart mode to evaluate cardiac perfusion and function. In the treatment group (n= 5), the complement cascade was blocked at the level of C3 using Cp40, using diluted human blood. Untreated human and porcine blood was used for controls. Results: Throughout the perfusion, C3 activation was inhibited when Cp40 was used (mean of all time points: 1.11 +/- 0.34% vs 3.12 +/- 0.48% control activation;P<. 01). Compared to xenoperfused controls, the cardiac index improved significantly in the treated group (6.5 +/- 4.2 vs 3.5 +/- 4.8 mL/min/g;P=. 03, 180 minutes perfusion), while the concentration of lactate dehydrogenase as a maker for cell degradation was reduced in the perfusate (583 +/- 187 U/mL vs 2108 +/- 1145 U/mL, P=. 02). Histological examination revealed less hemorrhage and edema, and immunohistochemistry confirmed less complement fragment deposition than in untreated xenoperfused controls. Conclusions: Cp40 efficiently prevents C3 activation of the complement system, resulting in reduced cell damage and preserved function in wild--type porcine hearts xenoperfused ex vivo. We suggest that this compstatin analog, which blocks all main pathways of complement activation, could be a beneficial perioperative treatment in preclinical and in future clinical xenotransplantation.