Cytokine Networks and Heart Failure Outcomes: CA125 as a Bridge Between Congestion and Inflammation

Inflammation and congestion constitute fundamental mechanisms underlying heart failure (HF). Carbohydrate Antigen 125 (CA125) is a well-established biomarker in HF, primarily associated with congestion, but also it may act as a functional ligand amplifying the inflammatory response in HF. Our aim was to evaluate the potential modulatory effect of CA125 on inflammation, assessed by a set of cytokines (interleukin [IL]-6, IL-10, IL-1β, and tumor necrosis factor [TNF]). We prospectively included 284 patients admitted for acute HF in which cytokines and CA125 were assessed at admission. Study endpoints were all-cause mortality and total HF rehospitalizations. At a median follow-up of 4.2 years (interquartile range: 1.3-7.5), a total of 211 patients (74.3%) died, and 117 patients (41.2%) experienced 249 HF readmissions. In the multivariable analysis, a significant interaction between IL-6 and IL-10 and CA125 was observed for both outcomes (<i>p</i>-value for interactions < 0.05 for all comparisons). Among patients with CA125 > 35 U/mL, both IL-6 and IL-10 showed a positive, linear relationship with the risk of death or HF readmissions. In contrast, we did not find a significant association in patients with CA125 ≤ 35 U/mL. In conclusion, the association between IL-6 and IL-10 with long-term adverse events was significantly modulated by CA125 status, being significantly associated with poor prognosis only when CA125 was upregulated. These findings support a potential modulatory role for CA125 in the inflammatory response in HF.