title: Treatment with the C5a receptor antagonist ADC-1004 reduces myocardial infarction in a porcine ischemia-reperfusion model.
abstract: BACKGROUND
  Polymorphonuclear neutrophils, stimulated by the activated complement factor C5a, have been implicated in cardiac ischemia/reperfusion injury. ADC-1004 is a competitive C5a receptor antagonist that has been shown to inhibit complement related neutrophil activation. ADC-1004 shields the neutrophils from C5a activation before they enter the reperfused area, which could be a mechanistic advantage compared to previous C5a directed reperfusion therapies. We investigated if treatment with ADC-1004, according to a clinically applicable protocol, would reduce infarct size and microvascular obstruction in a large animal myocardial infarct model.
  
  
  METHODS
  In anesthetized pigs (42-53 kg), a percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 minutes, followed by 4 hours of reperfusion. Twenty minutes after balloon inflation the pigs were randomized to an intravenous bolus administration of ADC-1004 (175 mg, n = 8) or saline (9 mg/ml, n = 8). Area at risk (AAR) was evaluated by ex vivo SPECT. Infarct size and microvascular obstruction were evaluated by ex vivo MRI. The observers were blinded to the treatment at randomization and analysis.
  
  
  RESULTS
  ADC-1004 treatment reduced infarct size by 21% (ADC-1004: 58.3 ± 3.4 vs control: 74.1 ± 2.9%AAR, p = 0.007). Microvascular obstruction was similar between the groups (ADC-1004: 2.2 ± 1.2 vs control: 5.3 ± 2.5%AAR, p = 0.23). The mean plasma concentration of ADC-1004 was 83 ± 8 nM at sacrifice. There were no significant differences between the groups with respect to heart rate, mean arterial pressure, cardiac output and blood-gas data.
  
  
  CONCLUSIONS
  ADC-1004 treatment reduces myocardial ischemia-reperfusion injury and represents a novel treatment strategy of myocardial infarct with potential clinical applicability.
authors.affiliation: Department of Cardiology, Skåne University Hospital, Lund, Sweden.
authors.forename: Jesper
authors.initials: J
authors.lastname: van der Pals
authors.forename: Sasha
authors.initials: S
authors.lastname: Koul
authors.forename: Patrik
authors.initials: P
authors.lastname: Andersson
authors.forename: Matthias
authors.initials: M
authors.lastname: Götberg
authors.forename: Joey F A
authors.initials: JF
authors.lastname: Ubachs
authors.forename: Mikael
authors.initials: M
authors.lastname: Kanski
authors.forename: Håkan
authors.initials: H
authors.lastname: Arheden
authors.forename: Göran K
authors.initials: GK
authors.lastname: Olivecrona
authors.forename: Bengt
authors.initials: B
authors.lastname: Larsson
authors.forename: David
authors.initials: D
authors.lastname: Erlinge
mesh_terms: D017130:Angioplasty; D000818:Animals; D001426:Bacterial Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000494:pharmacology; D002985:Clinical Protocols; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D007275:Injections, Intravenous; D050505:Mutant Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000494:pharmacology; D009203:Myocardial Infarction / Q000188:drug therapy*; D009206:Myocardium / Q000473:pathology*; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013552:Swine
chemical_list: D001426:Bacterial Proteins; D050505:Mutant Proteins; D044087:Receptor, Anaphylatoxin C5a; C493134:chemotaxis inhibitory protein, Staphylococcus aureus