The modulating effect of circulating carbohydrate antigen 125 on ST2 and long-term recurrent morbidity burden

Soluble ST2 (sST2) is released in response to vascular congestion, inflammation, and pro-fibrotic stimuli. In heart failure (HF), elevated levels of sST2 are associated with a higher risk of adverse clinical outcomes. Emerging evidence suggests that carbohydrate antigen 125 (CA125) may act as a ligand that modulates the inflammatory response. We hypothesized that CA125 might be modulating sST2 activity. In a cohort of 160 patients with acute (AHF) and renal dysfunction, we investigated whether the prognostic value of sST2 varies according to CA125 levels. The endpoints were: (a) total cardiovascular and renal hospitalizations and (b) all-cause mortality during follow-up. Cox regression analyses assessed the association between admission sST2 and endpoints across CA125 (≤ 35 vs. > 35 U/ml). This sub-study of the IMPROVE-HF trial shows that sST2 predicted the composite of cardiovascular or renal rehospitalizations when CA125 was elevated (> 35 U/ml) but not when CA125 ≤ 35 U/ml. These results highlight a potential biological interaction between sST2 and CA125, suggesting that CA125 status may refine the prognostic utility of sST2 in AHF. Clinically, these insights could guide personalized risk stratification and management strategies in this high-risk population.