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J Thorac Cardiovasc Surg 2000;120:350-358
© 2000 The American Association for Thoracic Surgery

Surgery for acquired cardiovascular disease

Recombinant human complement C5a receptor antagonist reduces infarct size after surgical revascularization

From The Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center of Emory University School of Medicine, Atlanta, Ga; affiliations: Emory University School of Medicine, Atlanta, Ga (Z.-Q.Z., V.H.T., J.E.J., J.V.-J.); Bowman Gray School of Medicine, Winston-Salem, NC (R.D.R; H.S., J.E.J., A.X.F., D.R.H; Jefferson Medical College, Philadelphia, Pa (X.-L.M.); Novartis Institute for Biomedical Research, Summit, NJ (D.F.R., T.C.P, J.P., K.A.B., R.W.L).

Supported by a grant from Novartis Pharmaceuticals.

Address for reprints: Jakob Vinten-Johansen, PhD, Director, Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center of Emory University School of Medicine, 550 Peachtree St, NE, Atlanta, GA 30365.

Objectives: This study tested the hypothesis that a recombinant human C5a antagonist, CGS 32359, attenuates neutrophil activation and reduces infarct size in a porcine model of surgical revascularization.
Methods: CGS 32359 (0.16-16 µmol/L) dose-dependently inhibited superoxide production by human C5a-activated porcine neutrophils (18 ± 3.7 vs 1.6 ± 0.5 nmol/5 min/5 x 10⁶ neutrophils; P < .05) and reduced neutrophil adherence to coronary endothelium from 194 ± 9 to 43 ± 6 neutrophils/mm² (P < .05). The left anterior descending coronary artery was occluded for 50 minutes, after which saline solution (n = 8), mannitol-buffer vehicle (n = 9, 102 mg/kg bolus, 102 mg · kg^–1 · h^–1), or CGS 32359 (CGS, n = 7, 60 mg/kg bolus, 60 mg · kg^–1 · h^–1) was infused. After ischemia, 1-hour arrest was achieved by means of multidose hypothermic (4°C) blood cardioplegia, followed by 2.5 hours of off-bypass reperfusion. The ligature on the left anterior descending artery was released before the second infusion of cardioplegic solution.
Results: Area at risk was similar in all groups (saline solution, 27% ± 2%; mannitol-buffer vehicle, 26% ± 2%; CGS, 26% ± 2% left ventricular mass). Infarct size (area necrosis/area at risk) was significantly reduced by CGS (18% ± 6%, P < .05) versus saline solution (52% ± 3%) and mannitol-buffer vehicle (60% ± 4%). Postischemic systolic shortening (sonomicrometry) in the area at risk was significantly improved with CGS (0.8% ± 0.9%) compared with saline solution (–3.7% ± 1.1%) and mannitol-buffer vehicle (–6.4% ± 1.0%). Myeloperoxidase activity from accumulated neutrophils was less in the ischemic zone of CGS (0.014 ± 0.002 U/100 mg tissue; P < .05) than mannitol-buffer vehicle (0.133 ± 0.012 U/100 mg tissue).
Conclusions: We conclude that the recombinant human C5a receptor antagonist CGS 32359 inhibits surgical ischemia-reperfusion injury after coronary occlusion.

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