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
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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)