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Differential Associations of Seven Circulating Complement Proteins with Heart Failure: A Single-Center Cross-Sectional Study

Year: 2026

Type: article

Abstract: Background: The complement system is associated with heart failure (HF), but patterns across circulating complement proteins and their sensitivity to covariate adjustment remain unclear. Methods: In this cross-sectional study, 392 participants (164 chronic HF: 128 HFpEF, 14 HFmrEF, 22 HFrEF; 228 non-HF controls) were enrolled, and seven circulating complement proteins were measured. Spearman correlations with NT-proBNP and LVEF, sequential multivariable logistic regression, and restricted cubic splines were assessed for each protein. Benjamini–Hochberg false discovery rate (FDR) correction was applied to fully adjusted models. Subgroup and restricted-sample sensitivity analyses were performed. Exploratory quasi-Bayesian statistical decomposition assessed whether the C8–HF and CD55–HF associations overlapped with CRP, eGFR, and hemoglobin. Results: C7 and CD55 showed the strongest positive correlations with NT-proBNP ( ρ ≈ 0.32) and weak negative correlations with LVEF. After full adjustment, odds ratios for prevalent HF per 1-SD increase were 1.39 (95% CI 1.06– 1.84) for C1r, 1.72 (1.29– 2.29) for C7, and 1.47 (1.13– 1.92) for C9; FDR-adjusted P values were 0.045, 0.0017, and 0.014. C1s and CD46 were not significant; C8 and CD55 associations attenuated after adjustment. No non-linear associations were found. C1r, C7, and C9 remained significant when restricting to eGFR ≥ 60 mL/min/1.73 m 2 or CRP ≤ 10 mg/L, but attenuated to non-significance when HF cases were restricted to LVEF ≥ 50%. Exploratory statistical decomposition suggested that the CD55–HF association partly overlapped with eGFR and hemoglobin, but not CRP; no corresponding overlap was observed for C8. Conclusion: In this cross-sectional sample, C1r, C7, and C9 were associated with prevalent chronic HF after full adjustment and FDR correction, but estimates attenuated in the LVEF-preserved restricted sample. C8 and CD55 associations attenuated after adjustment, while C1s and CD46 were not significant. These associations require prospective validation and should not be interpreted as causal. Keywords: heart failure, complement system, inflammation, cross-sectional study, association analysis

Source: Journal of Inflammation Research

DOI: 10.2147/jir.s638484