Biomarkers for congestion assessment and prognosis in acute heart failure: A systematic review

Congestion is the central pathophysiological mechanism and a major determinant of morbidity and mortality in acute heart failure (AHF). Natriuretic peptides (NPs), although guideline-recommended, provide only an indirect assessment of congestion and may have limited accuracy. This systematic review synthesized evidence on four biomarkers, including carbohydrate antigen 125 (CA-125), adrenomedullin (ADM) and its derivatives, soluble suppression of tumorigenicity-2 (sST2), and soluble cluster of differentiation 146 (sCD146), focusing on their associations with congestion and prognosis in AHF. A systematic search of PubMed and Embase was conducted in June 2025. Eligible studies included patients with AHF and evaluated at least one biomarker in relation to clinical, imaging, or laboratory markers of congestion and/or prognostic outcomes. After screening and full-text review, 39 studies met the inclusion criteria. CA-125 consistently correlated with systemic congestion, with higher admission levels predicting increased mortality and rehospitalization. Interventional studies suggested its potential role in guiding decongestive therapy. ADM derivatives were associated with congestion severity and residual congestion at discharge. Bio-adrenomedullin reflected rapid hemodynamic changes due to its short half-life, while mid-regional proadrenomedullin provided prognostic information. sST2, primarily reflecting myocardial stress and inflammation, demonstrated robust prognostic value and dynamic decline during hospitalization. sCD146 emerged as a novel marker strongly associated with systemic congestion, with additional diagnostic value in conditions where NPs underperform. Overall, these biomarkers provide mechanistically complementary information to NPs, improving congestion assessment and risk stratification in AHF. Larger prospective and interventional studies are required to define their role in routine clinical practice and in guiding decongestive strategies.