title: Activated protein C in the cardioplegic solution on a porcine model of coronary ischemia-reperfusion has deleterious hemodynamic effects.
abstract: OBJECTIVE
  In reperfusion injury activation of coagulation and inflammation contribute to organ dysfunction. Activated protein C (APC) exhibits anticoagulant and anti-inflammatory properties in models of reperfusion injury. We hypothesized that APC could be cardioprotective after ischemia and cardiopulmonary bypass (CPB).
  
  
  METHODS
  20 pigs, undergoing 120 min of CPB and aortic cross-clamping, were randomized to receive 1 mg of human APC or placebo to the last cardioplegic solution given 15 min before declamping to the systemic circulation. After aortic declamping the heart was supported by continuing CPB for 30 min followed by 30 min surveillance. Thrombin-antithrombin complexes, neutrophil L-selectin expression in blood and myeloperoxidase activity (MPO) of myocardial biopsies were measured.
  
  
  RESULTS
  There was no indication of APC-induced increased bleeding. Thrombin levels were significantly lower in the APC group than in the placebo group and so were the rates of thrombin formation during the first 3 min of reperfusion and between 10 and 30 min after declamping. There were no differences in MPO or in the proportion of L-selectin (+) to L-selectin (-) neutrophils between groups. Significant systolic hypotension in the APC group was observed at 30 and 45 min compared with the placebo group which associated with the increased mortality observed in the APC group (p = 0.019).
  
  
  CONCLUSIONS
  Human APC in cardioplegic solution during CPB in pigs, decreased reperfusion induced thrombin formation with no associated bleeding. No anti-inflammatory effects of human APC were seen. However, in this setting, APC caused hemodynamic deterioration. The observed phenomenon could be explained by systolic hypotension potentially produced by the release of vasoactive substances generated by the APC activation of PARs in the endothelium.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA. jfernand@scripps.edu
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández
authors.forename: Antti E
authors.initials: AE
authors.lastname: Vento
authors.forename: Mikko
authors.initials: M
authors.lastname: Jormalainen
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
authors.forename: Ero
authors.initials: E
authors.lastname: Pesonen
authors.forename: Martti
authors.initials: M
authors.lastname: Syrjälä
authors.forename: Heikki
authors.initials: H
authors.lastname: Repo
authors.forename: Sten-Erik
authors.initials: SE
authors.lastname: Jansson
authors.forename: O Juhan
authors.initials: OJ
authors.lastname: Rämö
authors.forename: Jari
authors.initials: J
authors.lastname: Petäjä
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000037:antagonists & inhibitors / Q000378:metabolism; D002314:Cardioplegic Solutions / Q000627:therapeutic use / Q000633:toxicity*; D002315:Cardiopulmonary Bypass / Q000379:methods; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology; D019041:L-Selectin / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011486:Protein C / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D011897:Random Allocation; D044462:Receptors, Proteinase-Activated / Q000378:metabolism; D015427:Reperfusion Injury / Q000503:physiopathology*; D013552:Swine; D013997:Time Factors
chemical_list: D002314:Cardioplegic Solutions; D011486:Protein C; D044462:Receptors, Proteinase-Activated; C046193:antithrombin III-protease complex; D019041:L-Selectin; D000990:Antithrombin III; D009195:Peroxidase; D010447:Peptide Hydrolases