Complement activation is associated with poor outcome after out-of-hospital cardiac arrest

Abstract

Background: Cardiopulmonary resuscitation after cardiac arrest initiates a whole-body ischemia-reperfusion injury, which may activate the innate immune system, including the complement system. We hypothesized that complement activation and subsequent release of soluble endothelial activation markers were associated with cerebral outcome including death.Methods: Outcome was assessed at six months and defined by cerebral performance category scale (1À2; good outcome, 3À5; poor outcome including death) in 232 resuscitated out-of-hospital cardiac arrest patients. Plasma samples obtained at admission and day three were analysed for complement activation products C3bc, the soluble terminal complement complex (sC5b-9), and soluble CD14. Endothelial cell activation was measured by soluble markers syndecan-1, sE-selectin, thrombomodulin, and vascular cell adhesion molecule.Results: Forty-nine percent of the patients had good outcome. C3bc and sC5b-9 were significantly higher at admission compared to day three (p < 0.001 for both) and in patients with poor compared to good outcome (p = 0.03 and p < 0.001, respectively). Unadjusted, higher sC5b-9 at admission was associated with poor outcome (odds ratio 1.08 (95% CI 1.01À1.14), p = 0.024). Adjusted, sC5b-9 was still associated with outcome, but the association became non-significant when time to return-of-spontaneous-circulation above 25 min was included as a covariate. Endothelial cell activation markers increased from admission to day three, but only sE-selectin and thrombomodulin were significantly higher in patients with poor versus good outcome (p = 0.004 and p = 0.03, respectively) and correlated to sCD14 and sC5b-9/C3bc, respectively.

Predictive value of soluble CD59 for poor 28-day neurological prognosis and all-cause mortality in patients after cardiopulmonary resuscitation: a prospective observatory study

“…Our findings showed that the above four complement components were all significantly increased in patients after ROSC compared to healthy volunteers. These findings indicated that these three complement pathways were all activated in patients after ROSC, which is in accordance with a recent study [ 7 ]. After complement activation, C3a and C5a, as pro-inflammatory mediators, can contribute to inflammatory cascade, as evidenced by the elevated serum levels of IL-6 and TNF-α after ROSC in this study.…”

“…In addition, the cytolytic sC5b-9, as the common end-product of the classical, lectin, and alternative complement pathways, can directly damage cell membrane. Therefore, the elevated serum complement activation products, including C3a, C5a, and sC5b-9, have been reported to be associated with post-cardiac arrest immunoinflammatory response and poor prognosis [ 7 , 11 , 29 ], which is consistent with our result that the non-survivors had higher concentrations of serum C3a, C5a and sC5b-9 than the survivors.…”

“…The complement system, as an important part of the innate immune system, mainly comprises the classical, lectin and alternative pathways [6]. Previous studies revealed that the activation of complement system was closely associated with ischemia/reperfusion injury [6][7][8][9][10]. Our previous animal study indicated that complement was activated through classical, lectin and alternative pathways after ROSC [11].…”

The Endothelial Glycocalyx: A Possible Therapeutic Target in Cardiovascular Disorders

“…Different animal studies have shown the involvement of the complement system in IRI (137). Deposition of the complement components C3d and C5b-9 was seen in reperfused hearts of myocardial infarction patients (138) and associated with an increase in shedding of syndecan-1, a core protein of the endothelial glycocalyx (139,140). Complement inhibition, by administration of a membrane-targeted molecule derived from complement receptor 1 (141) or by administration of dextran sulfate, was shown to be beneficial in experimental myocardial infarction as well as in cardiac transplantation (142).…”

Non-Invasive Pulsatile Shear Stress Modifies Endothelial Activation; A Narrative Review

“…Postcardiac arrest syndrome (PCAS) is characterized by reperfusion injury from systemic ischemia, myocardial dysfunction, brain, and other vital organ injury, superimposed on underlying diseases, all of which explain the low survival rate of hospital discharge. After CA, a systemic inflammatory response occurs that has been shown to occur in the reperfusion stage, with the release of pro-inflammatory cytokines by leukocytes and endothelial cells through the activation of leukocytes and endothelial cells and the release of secondary cytokines [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ]. EC expresses a wide spectrum of cytokines and chemokines, including pro-inflammatory interleukins; IL-1β, IL-3, IL-5, IL-6, IL-8, IL-11, IL-15, and tumor necrosis factor (TNF-α), as well as anti-inflammatory cytokines such as IL-1 receptor antagonist (IL-1ra), IL-10, IL-13, and transforming growth factor beta (TGF-β) [ 61 , 62 , 63 ].…”