Complement factor 5 blockade reduces porcine myocardial infarction size and improves immediate cardiac function

Basic Research in Cardiology, Mar 2017

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.

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Complement factor 5 blockade reduces porcine myocardial infarction size and improves immediate cardiac function

Basic Res Cardiol Complement factor 5 blockade reduces porcine myocardial infarction size and improves immediate cardiac function Soeren E. Pischke 0 1 3 4 5 6 7 9 11 A. Gustavsen 0 1 3 4 5 6 7 9 11 H. L. Orrem 0 1 3 4 5 6 7 9 11 K. H. Egge 0 1 3 4 5 6 7 9 11 F. Courivaud 0 1 3 4 5 6 7 9 11 H. Fontenelle 0 1 3 4 5 6 7 9 11 A. Despont 0 1 3 4 5 6 7 9 11 A. K. Bongoni 0 1 3 4 5 6 7 9 11 R. Rieben 0 1 3 4 5 6 7 9 11 T. I. Tønnessen 0 1 3 4 5 6 7 9 11 M. A. Nunn 0 1 3 4 5 6 7 9 11 H. Scott 0 1 3 4 5 6 7 9 11 H. Skulstad 0 1 3 4 5 6 7 9 11 A. Barratt-Due 0 1 3 4 5 6 7 9 11 T. E. Molln 0 1 3 4 5 6 7 9 11 s 0 1 2 3 4 5 6 7 8 9 10 11 Soeren E. Pischke 0 1 3 4 5 6 7 9 11 0 Intervention Centre, Oslo University Hospital , Oslo , Norway 1 K.G. Jebsen IRC, University of Oslo , Oslo , Norway 2 Research Laboratory, Nordland Hospital , Bodø , Norway 3 Department of Immunology, Oslo University Hospital , Rikshospitalet, P.b. 4950 Nydalen, 0424 Oslo , Norway 4 Department of Cardiology, Oslo University Hospital , Rikshospitalet , University of Oslo , Oslo , Norway 5 Department of Pathology, Oslo University Hospital, University of Oslo , Oslo , Norway 6 Akari Therapeutics Plc , London , UK 7 Department of Clinical Research, University of Bern , Bern , Switzerland 8 Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø , Tromsø , Norway 9 Immunology Research Centre, St. Vincent's Hospital , Melbourne, VIC , Australia 10 Centre of Molecular Inflammation Research, Norwegian University of Science and Technology , Trondheim , Norway 11 Division of Emergencies and Critical Care, Department of Anaesthesiology, Oslo University Hospital , Oslo , Norway 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). Ischemia/reperfusion; Complement; C5; Contractility; Myocardial infarction; LTB4 - The introduction of early reperfusion therapy of acute myocardial infarction (MI) in the clinical setting has decreased morbidity and mortality and improved post-MI cardiac function. However, a considerable part of the ischemic myocardium is still lost upon reperfusion. Ischemia and reperfusion cause liberation of damage associated molecular patterns (DAMP) from ischemic or injured cells, activating innate immune responses, a prerequisite for the healing process, currently reviewed in [19]. However, overactivation causes detrimental effects by injuring the myocardium, an effect termed ischemia/ reperfusion injury (IRI) [22], leading to aggravated infarct size and pump failure. Complement is an upstream sensor and effector system of innate immunity, a key system for immune surveillance and homeostasis, but also implicated to play a critical role in the pathophysiology of myocardial IRI [4, 35]. Complement as a danger sensing alarm system relies on soluble pattern recognition receptors of three different activation pathways, the classical, the lectin and the alternative pathway [35]. They all converge at the central component C3, which is cleaved into C3a and C3b and subsequently leads to cleavage of C5, which generates the potent anaphylatoxin C5a and the terminal C5b-9 complement complex, both exerting proinflammatory effector functions [35]. Complement inhibition in myocardial infarction was first shown to reduce infarction size in rodents already in 1990 [47]. Experimental studies investigating complement inhibition in a clinically relevant context are rare, i.e. the inhibitor was given after onset of ischemia, but confirmed the protective potential of C5 inhibition [44]. Pigs are highly recognized for the translational value of results obtained [20], however C5 inhibition has not been tested as no inhibitors for pig C5 have been available. Inhibition of various other parts of the complement cascade by inhibition of complement factor 1 [21], treatment with soluble complement receptor 1 [2], protecting the endothelium with dextran sulfate [3] and tyrosine-O-sulfate [4] clearly showed the potential of complement inhibition in pigs. Clinical studies with the C5-antibody pexelizumab (...truncated)


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Soeren E. Pischke, A. Gustavsen, H. L. Orrem, K. H. Egge, F. Courivaud, H. Fontenelle, A. Despont, A. K. Bongoni, R. Rieben, T. I. Tønnessen, M. A. Nunn, H. Scott, H. Skulstad, A. Barratt-Due, T. E. Mollnes. Complement factor 5 blockade reduces porcine myocardial infarction size and improves immediate cardiac function, Basic Research in Cardiology, 2017, pp. 20, Volume 112, Issue 3, DOI: 10.1007/s00395-017-0610-9