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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-017-0610-9) contains supplementary material, which is available to authorized users.

Dual inhibition of complement factor 5 and leukotriene B4 synergistically suppresses murine pemphigoid disease

“…The efficacy of Coversin in suppressing inflammation in C5-driven conditions has previously been reported for thrombotic microangiopathy, polymicrobial sepsis, antiphospholipid syndrome, myasthenia gravis, and myocardial infarction, among others (19)(20)(21)(22)(23)(24)(25). In contrast, the effect of Coversin on conditions driven by LTB 4 has been investigated only in an acute, 4-hour-long mouse model of immune complex-induced lung injury, where the inhibition of both C5 and LTB 4 by Coversin contributed to the therapeutic effect (15).…”

Prolargin and matrix metalloproteinase‐2 in heart failure after heart transplantation and their association with haemodynamics

“…However, the subsequent APEX‐AMI trial failed to show any beneficial effects . It was later concluded that this inconsistency in the effect of pexelizumab may be ascribed to the use of inadequate concentrations, a late administration that precludes beneficial effects of complement inhibition following myocardial injury or other alternative mechanisms . Thus, complement inhibition needs to be further investigated and may still be a plausible alternative treatment in HF.…”

“…25 It was later concluded that this inconsistency in the effect of pexelizumab may be ascribed to the use of inadequate concentrations, a late administration that precludes beneficial effects of complement inhibition following myocardial injury or other alternative mechanisms. 26,27 Thus, complement inhibition needs to be further investigated and may still be a plausible alternative treatment in HF. Given the important role of inflammation, where the complement system is involved, in cardiac remodelling and progression of HF, 28,29 it is reasonable to assume that treatment with prolargin may be a future alternative to explore in HF studies, as it may have additional or alternative mechanisms of complement inhibition compared with pexelizumab.…”

Anti‐inflammatory therapies in myocardial infarction: failures, hopes and challenges

“…Activation of the complement cascade is a critical part of the innate immune response following MI and has been suggested to extend ischaemic injury (Yasojima et al, ). In experimental studies, complement inhibition strategies have consistently reduced the size of the infarct and improved function in both rodent and large animal models of reperfused MI (Vakeva et al, ; Pischke et al, ). Unfortunately, clinical studies have been disappointing.…”