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

Xenotransplantation. 2017 Jan;24(1):10.1111/xen.12262. doi: 10.1111/xen.12262. Epub 2016 Sep 27.


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.

Keywords: complement; compstatin; ex vivo; heart; xenotransplantation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Complement Activation / immunology*
  • Complement C3 / metabolism*
  • Graft Rejection / prevention & control
  • Heart
  • Heart Transplantation* / methods
  • Humans
  • Myocardium / immunology
  • Pyridones / metabolism*
  • Swine
  • Transplantation, Heterologous / methods


  • Complement C3
  • Pyridones
  • 1-(ethan-1-ol)-2-methyl-3-hydroxypyridin-4-one