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.
Highlights
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
Complete blockade of terminal complement pathway by coversin was revealed by lack of systemic complement activity in plasma and abolished deposition of C5b-9, which was extensive in the area at risk (AAR) in the control group
Targeting the complement system at the terminal stage preventing complement factor 5 (C5) cleavage is a reasonable approach as proximal complement activity is left unaffected and important immunoprotective and immunoregulatory functions exerted by C3 are preserved [12]
Summary
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. 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 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]
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