C3a, C4a, and C5a Complement Anaphylatoxins Are Paradoxically Decreased in Acute and Chronic Heart Failure

Background Inflammation is a prerequisite for healing after physical insult or microbial invasion. However, sustained and chronic inflammation often leads to deleterious effects. Especially in heart failure (HF), inflammation plays a causative role in adverse cardiac remodeling and functional decline. An important part of the innate immune system, the complement cascade is associated with the initiation and propagation of inflammation for the purpose of clearing bacterial pathogens. Specifically, the anaphylatoxins C3a, C4a, and C5a are integral in the complement cascade, initiating and amplifying inflammation that may exacerbate HF. Hypothesis In light of prior evidence linking innate immune system activation to inflammation and the aggravation of HF, we hypothesize that increased complement activation, evidenced by higher concentrations of circulating anaphylatoxins, are indicative of HF severity and track with traditional HF risk factors. Method Blood and clinical values were obtained from healthy (non-HF), acute HF, and chronic HF subjects. To compare anaphylatoxin levels, serum from non-HF and HF subjects were assayed for circulating C3a, C4a, and C5a concentrations by cytometric bead array, then compared to clinical parameters. C3, the major complement initiating factor for the anaphylatoxins, was measured in serum by ELISA assay. Additionally, data from RNAseq analysis on cardiac tissue isolates from non-HF and dilated cardiomyopathy (DCM) patients were compared for differential expression in 22 complement-related genes. Results Compared to non-HF, Serum C3a was found to be decreased by 24.3% in chronic HF and 20.5% among all HF cohorts (P Conclusions Although inflammation is increased in HF, C3, C3a, and C4a were found to be paradoxically decreased in HF cohorts, while C5a conversely increased in acute HF alone. The significant decreases in anaphylatoxins may be explained by the decreased C3 expression observed in HF subjects. While contrary to our hypothesis, our findings suggest differential complement dynamism, dependent on acute versus chronic HF status.