Complement C3 inhibitor Cp40 attenuates xenoreactions in pig hearts perfused with human blood.
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.



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.



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.



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.
Department of Anaesthesiology, Ludwig Maximilian University, Munich, Germany.
Jan-Michael
JM
Abicht
Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
Ioannis
I
Kourtzelis
Walter-Brendel-Centre, Ludwig Maximilian University, Munich, Germany.
Bruno
B
Reichart
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Pennsylvania, PA, USA.
Sophia
S
Koutsogiannaki
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Pennsylvania, PA, USA.
Alexandra
A
Primikyri
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Pennsylvania, PA, USA.
John D
JD
Lambris
Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
Triantafyllos
T
Chavakis
Institute of Laboratory Medicine of Ludwig Maximilian University, Munich, Germany.
Lesca
L
Holdt
Chair of Livestock Biotechnology, School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany.
Alexander
A
Kind
Department of Cardiovascular Surgery, Ludwig Maximilian University, Munich, Germany.
Sonja
S
Guethoff
Department of Anaesthesiology, Ludwig Maximilian University, Munich, Germany.
Tanja
T
Mayr
D000818:Animals; D003167:Complement Activation / Q000276:immunology*; D003176:Complement C3 / Q000378:metabolism*; D006084:Graft Rejection / Q000517:prevention & control; D006321:Heart; D016027:Heart Transplantation / Q000379:methods; D006801:Humans; D009206:Myocardium / Q000276:immunology; D011728:Pyridones / Q000378:metabolism*; D013552:Swine; D014183:Transplantation, Heterologous / Q000379:methods
D003176:Complement C3; D011728:Pyridones; C098211:1-(ethan-1-ol)-2-methyl-3-hydroxypyridin-4-one
complement; compstatin; ex vivo; heart; xenotransplantation
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