title: Complement factor 5 blockade reduces porcine myocardial infarction size and improves immediate cardiac function.
abstract: Inhibition of complement factor 5 (C5) reduced myocardial infarction in animal studies, while no benefit was found in clinical studies. Due to lack of cross-reactivity of clinically used C5 antibodies, different inhibitors were used in animal and clinical studies. Coversin (Ornithodoros moubata complement inhibitor, OmCI) blocks C5 cleavage and binds leukotriene B4 in humans and pigs. We hypothesized that inhibition of C5 before reperfusion will decrease infarct size and improve ventricular function in a porcine model of myocardial infarction. In pigs (Sus scrofa), the left anterior descending coronary artery was occluded (40 min) and reperfused (240 min). Coversin or placebo was infused 20 min after occlusion and throughout reperfusion in 16 blindly randomized pigs. Coversin significantly reduced myocardial infarction in the area at risk by 39% (p = 0.03, triphenyl tetrazolium chloride staining) and by 19% (p = 0.02) using magnetic resonance imaging. The methods correlated significantly (R = 0.92, p < 0.01). Tissue Doppler echocardiography showed increased systolic displacement (31%, p < 0.01) and increased systolic velocity (29%, p = 0.01) in coversin treated pigs. Interleukin-1β in myocardial microdialysis fluid was significantly reduced (31%, p < 0.05) and tissue E-selectin expression was significantly reduced (p = 0.01) in the non-infarcted area at risk by coversin treatment. Coversin ablated plasma C5 activation throughout the reperfusion period and decreased myocardial C5b-9 deposition, while neither plasma nor myocardial LTB4 were significantly reduced. Coversin substantially reduced the size of infarction, improved ventricular function, and attenuated interleukin-1β and E-selectin in this porcine model by inhibiting C5. We conclude that inhibition of C5 in myocardial infarction should be reconsidered.
authors.affiliation: Department of Immunology, Oslo University Hospital, Rikshospitalet, P.b. 4950 Nydalen, 0424, Oslo, Norway. s.e.pischke@medisin.uio.no.|K.G. Jebsen IRC, University of Oslo, Oslo, Norway. s.e.pischke@medisin.uio.no.|Intervention Centre, Oslo University Hospital, Oslo, Norway. s.e.pischke@medisin.uio.no.|Division of Emergencies and Critical Care, Department of Anaesthesiology, Oslo University Hospital, Oslo, Norway. s.e.pischke@medisin.uio.no.
authors.forename: Soeren E
authors.identifier: 0000-0003-2543-3251
authors.initials: SE
authors.lastname: Pischke
authors.affiliation: Department of Immunology, Oslo University Hospital, Rikshospitalet, P.b. 4950 Nydalen, 0424, Oslo, Norway.|K.G. Jebsen IRC, University of Oslo, Oslo, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Gustavsen
authors.affiliation: Department of Immunology, Oslo University Hospital, Rikshospitalet, P.b. 4950 Nydalen, 0424, Oslo, Norway.|K.G. Jebsen IRC, University of Oslo, Oslo, Norway.|Division of Emergencies and Critical Care, Department of Anaesthesiology, Oslo University Hospital, Oslo, Norway.
authors.forename: H L
authors.initials: HL
authors.lastname: Orrem
authors.affiliation: Department of Immunology, Oslo University Hospital, Rikshospitalet, P.b. 4950 Nydalen, 0424, Oslo, Norway.|K.G. Jebsen IRC, University of Oslo, Oslo, Norway.
authors.forename: K H
authors.initials: KH
authors.lastname: Egge
authors.affiliation: Intervention Centre, Oslo University Hospital, Oslo, Norway.
authors.forename: F
authors.initials: F
authors.lastname: Courivaud
authors.affiliation: Intervention Centre, Oslo University Hospital, Oslo, Norway.
authors.forename: H
authors.initials: H
authors.lastname: Fontenelle
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Despont
authors.affiliation: Immunology Research Centre, St. Vincent's Hospital, Melbourne, VIC, Australia.|Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: A K
authors.initials: AK
authors.lastname: Bongoni
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Rieben
authors.affiliation: Division of Emergencies and Critical Care, Department of Anaesthesiology, Oslo University Hospital, Oslo, Norway.
authors.forename: T I
authors.initials: TI
authors.lastname: Tønnessen
authors.affiliation: Akari Therapeutics Plc, London, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Nunn
authors.affiliation: Department of Pathology, Oslo University Hospital, University of Oslo, Oslo, Norway.
authors.forename: H
authors.initials: H
authors.lastname: Scott
authors.affiliation: Department of Cardiology, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo, Norway.
authors.forename: H
authors.initials: H
authors.lastname: Skulstad
authors.affiliation: Department of Immunology, Oslo University Hospital, Rikshospitalet, P.b. 4950 Nydalen, 0424, Oslo, Norway.|K.G. Jebsen IRC, University of Oslo, Oslo, Norway.|Division of Emergencies and Critical Care, Department of Anaesthesiology, Oslo University Hospital, Oslo, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Barratt-Due
authors.affiliation: Department of Immunology, Oslo University Hospital, Rikshospitalet, P.b. 4950 Nydalen, 0424, Oslo, Norway.|K.G. Jebsen IRC, University of Oslo, Oslo, Norway.|Research Laboratory, Nordland Hospital, Bodø, Norway.|Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway.|Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: T E
authors.initials: TE
authors.lastname: Mollnes
mesh_terms: D000818:Animals; D060829:Arthropod Proteins / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology; D003182:Complement C5 / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004452:Echocardiography; D005455:Fluorescent Antibody Technique; D008279:Magnetic Resonance Imaging; D009203:Myocardial Infarction / Q000473:pathology*; D011897:Random Allocation; D034421:Sus scrofa
chemical_list: D060829:Arthropod Proteins; D002352:Carrier Proteins; D003182:Complement C5; C521053:OmCI protein, tick
keywords: C5; Complement; Contractility; Ischemia/reperfusion; LTB4; Myocardial infarction