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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<0.003), while C4a was decreased 22.4% in acute and 25.4%
in chronic HF (P<0.004). In contrast, C5a was increased 17.6% in acute HF alone (P<0.002).
Across all cohorts, C3a was found to negatively associate with BMI (P=0.018). Additionally,
LVEF correlated positively with C3a and C4a, but negatively with C5a (P<0.01). Circulating
complement component C3 was found to be decreased 53% in acute HF subjects and 30%
in chronic HF, compared to non-HF (P<0.001). Out of 22 complement-related genes, the
CD59 RNA transcriptome was differentially expressed in DCM patients, with a 10.3%
reduction in RNA transcripts compared to non-failing transcriptomes (P<0.001).
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.
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Copyright
© 2020 Published by Elsevier Inc.
