title: Anti-C5a monoclonal antibody reduces cardiopulmonary bypass and cardioplegia-induced coronary endothelial dysfunction.
abstract: OBJECTIVE
  Because C5a induces tissue injury by activating polymorphonuclear leukocytes, the hypothesis was that inhibition of C5a activity would reduce cardioplegia-related injury.
  
  
  METHODS
  Pigs were placed on cardiopulmonary bypass. The hearts were arrested for 1 hour with hyperkalemic cardioplegia. Pigs were then separated from bypass, and the hearts were reperfused for 2 hours. Anti-porcine C5a monoclonal antibody (1.6 mg/kg, intravenously; n = 6) was administered 20 minutes before the onset of cardiopulmonary bypass. Six pigs received saline solution vehicle. Reactivity of coronary arterioles was studied in vitro with videomicroscopy. Microvessels from uninstrumented pigs served as controls for vascular studies.
  
  
  RESULTS
  Endothelium-dependent relaxation to adenosine diphosphate (percent relaxation of precontraction) was reduced after cardioplegic reperfusion (63% +/- 14% vs 77% +/- 10% in control at 10 micromol/L; P =.01). This impairment in endothelium-dependent relaxation was improved with anti-porcine C5a monoclonal antibody (80% +/- 22%; P =.01 vs saline solution), as was the impaired endothelium-dependent relaxation to clonidine (64% +/- 12% control; 26% +/- 17% saline solution; 55% +/- 24% anti-porcine C5a monoclonal antibody at 10 micromol/L; P =.01 saline solution vs control or anti-porcine C5a monoclonal antibody). Myeloperoxidase activity was significantly decreased (0.2 +/- 0.2 units/g protein; P =.04) in the anti-porcine C5a monoclonal antibody group compared with 5.2 +/- 2.7 in the saline solution group. CH50 2 hours after bypass was not statistically different (0.57 +/- 0.41 unit and 0.65 +/- 0.41 unit, respectively) between the anti-porcine C5a monoclonal antibody and saline solution groups. Despite less myocardial polymorphonuclear leukocyte infiltration after C5a inhibition, maximum rate of rise of left ventricular pressure, percent segmental shortening, and blood flow through the left anterior descending coronary artery were similar in the anti-porcine C5a monoclonal antibody and saline solution groups.
  
  
  CONCLUSIONS
  Inhibition of C5a limits neutrophil-mediated impairment of endothelium-dependent relaxation after cardiopulmonary bypass and cardioplegic reperfusion, but it has no effect on short-term myocardial functional preservation.
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Division, Beth Israel-Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tofukuji
authors.forename: G L
authors.initials: GL
authors.lastname: Stahl
authors.forename: A
authors.initials: A
authors.lastname: Agah
authors.forename: C
authors.initials: C
authors.lastname: Metais
authors.forename: M
authors.initials: M
authors.lastname: Simons
authors.forename: F W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015936:Complement C5a / Q000276:immunology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D005260:Female; D006324:Heart Arrest, Induced / Q000009:adverse effects*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D009504:Neutrophils / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009195:Peroxidase / Q000378:metabolism; D013552:Swine
chemical_list: D000911:Antibodies, Monoclonal; D015936:Complement C5a; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse