Effective decongestion remains a central therapeutic goal in acute heart failure (AHF), yet diuretic response varies substantially during hospitalization. A biomarker analysis from the PUSH-AHF trial, published in the Journal of Cardiac Failure, assessed whether plasma interleukin-6 (IL-6) levels were associated with natriuresis, diuresis, and diuretic response in patients hospitalized with AHF. 

The study included 273 patients with AHF, with IL-6 measured at baseline. Associations between IL-6 and natriuresis and diuresis were evaluated at 6, 24, 48, and 72 hours using linear mixed-effects models. Additionally, 24-hour diuretic response was analyzed using linear regression models alongside N-terminal pro–B-type natriuretic peptide (NT-proBNP) and bio-adrenomedullin (bio-ADM). Mediation analysis assessed whether diuretic response statistically mediated the association between IL-6 and clinical outcomes. External validation was performed in an independent cohort of 1,591 patients from the PROTECT study.

Patients with elevated IL-6 levels had higher NT-proBNP levels, higher baseline heart rate, and lower left ventricular ejection fraction. Higher IL-6 levels were associated with reduced natriuresis (adjusted p<0.001) and lower diuresis over time (adjusted p=0.011). IL-6 was independently associated with poorer 24-hour diuretic response (p=0.003), whereas NT-proBNP (p=0.274) and bio-ADM (p=0.786) were not associated with diuretic response.

Mediation analysis showed that 44.6% of the association between elevated IL-6 and the composite outcome of all-cause mortality or heart failure rehospitalization was statistically mediated by reduced diuretic response. Similar findings were observed in the external validation cohort.

Higher IL-6 levels were associated with poorer decongestive response in AHF. Reduced diuretic response statistically mediated part of the association between elevated IL-6 and adverse outcomes.