Complement anaphylatoxin C3a as a novel independent prognostic marker in heart failure

The purpose of this study was to evaluate complement activation in a heart failure cohort. Based on their powerful biological activity, we hypothesized that the levels of anaphylatoxin C3a are related to pathological signs and outcomes in heart failure. Complement activation products C3a and SC5b9 were determined in 182 consecutive CHF patients (single centre, prospective cohort study), with a left ventricular ejection fraction < 45%. Mortality and re-hospitalisation due to the progression of CHF were assessed after a median follow-up of 14 months. None. In the univariate analysis, high level of anaphylatoxin C3a was significantly associated with clinical events (p < 0.0001), whereas SC5b9 showed a tendency of association (p = 0.094). In multivariable Cox analysis, adjusted for age, NT-proBNP, diastolic blood pressure, body mass index (BMI), haemoglobin and creatinine levels, C3a was a significant predictor of HF-related re-hospitalization or death (HR 1.189 per 1-SD increase, 95% CI 1.023-1.383), and of cardiovascular events or death (HR 1.302, CI 1.083-1.566). C3a was strongly associated with the presence of peripheral oedema, inflammatory markers (CRP, prealbumin, IL-6, sTNFRI, sTNFRII), heat-shock protein 70 levels and endothelial activation markers (von-Willebrand factor and endothelin-1). Results of the present study showed that complement activation is strongly linked to unfavourable outcomes in heart failure. High levels of anaphylatoxin C3a predicted re-hospitalization, cardiovascular events and mortality in adjusted survival model. Increased C3a levels were associated with biomarkers of acute-phase reaction, inflammation, cellular stress response, endothelial-cell activation and oedematous complications independently from disease severity.