820 Complement inhibition by Compstatin CP40 increases cardiac function in a model for preclinical and clinical xenogeneic transplantations
Wednesday November 18, 2015 from 15:30 to 17:00
Room 109

Jan-Michael Abicht, Germany



Ludwig Maximilian University


Complement inhibition by Compstatin CP40 increases cardiac function in a model for preclinical and clinical xenogeneic transplantations

Jan-Michael Abicht1, Tanja Mayr2, Sofia Koutsogiannaki3, Alexandra Primikyri3, John Lambris3, Sonja Guethoff2, Paolo Brenner2, Bruno Reichart4.

1Department of Anaesthesiology, Ludwig-Maximilians University, Munich, Germany; 2Department of Cardiac Surgery, Ludwig-Maximilians University, Munich, Germany; 3Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States; 4Walter-Brendel-Centre, Ludwig-Maximilians University, Munich, Germany

Background: The complement systems plays a crucial role not only in acute xenogeneic reactions but also in the inflammation induced by foreign materials of any extracorporal circulation techniques. In preclinical cardiac xenotransplantation both mechanisms can be presumed as a cause for the adverse activation of complement. We tested the effect of the Compstatin analog CP40, a potent inhibitor of complement on the level of C3 in an ex-vivo perfusion model.

Methods: Ten wild type pig hearts were perfused ex-vivo in a biventricular working heart model. Hearts were explanted using Bretschneider solution for cardioplegia. After a cold ischemic time of 150 minutes hearts were reperfused with heparinized (5000 IU), diluted (500 ml hydroxyl ethyl starch) freshly drawn human blood (500ml). In the treatment group (n=5) the complement cascade was blocked on the level of C3 using 32mg (18µM) of Compstatin (CP40). After 15 minutes of reperfusion hearts were challenged for 3 hours in a biventricular working heart mode (WM; mean arterial pressure 65mmHg). Cardiac index (CI), heart rate (HR), coronary perfusion index (CPI) and activated C3 were measured. Cardiac weights were obtained before and after perfusion.

Blood was drawn from 5 healthy male individuals. Each person donated twice: for the treatment experiment and after a minimum time of one month for the control experiment.

Results: In all perfusion experiments, the hearts recovered to sinus rhythm after reperfusion. 5/5 hearts of the treatment group and only 4/5 of control were able to be switched to WM. After 180 minutes perfusion CI was larger in the CP40 treated group compared to control (6.5 ± 4.2 ml/min/g vs. 3.48 ±4.8 ml/min/g; p=0.03), as was the HR (129 ±18 vs. 82 ±24; p=0.01). When CP40 was used, there was a trend towards less cardiac weight increase during perfusion (32 ± 29% vs. 1 ± 1%; p=0.09) and towards an improved CPI (3.25 ±0.82 vs. 1.92 ±1.86 ml/min/g). Throughout the perfusion C3 activation was lower in the treated group (mean of all time points: 0.77 ±1.0% vs. 3.42 ±0.35%; p<0.01). Histological examination revealed less hemorrhage and edema.

Conclusions: Blockage of complement on the level of C3 using Compstatin CP40 reduces cell damage and preserves cardiac function, when wild type porcine hearts were xenoperfused  in an ex vivo perfusion circuit. We suggest that Compstatin, that blocks all main pathways of complement activation, could be a beneficial perioperative treatment in preclinical and future clinical xenotransplantations.

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