IL-6 and Diuretic Response in Acute Heart Failure

Acute heart failure (AHF) remains a major cause of mortality and rehospitalization, with successful decongestion being the primary therapeutic goal. Plasma interleukin-6 (IL-6) levels are elevated in AHF, are associated with worse outcomes, and may directly affect diuretic response. However, their relationship with natriuresis and diuresis during an AHF hospitalization remains unexplored.

Plasma IL-6 was measured in 273 patients from the PUSH-AHF (Pragmatic Urinary Sodium-based treatment algoritHm in Acute Heart Failure) trial. The association between IL-6 with natriuresis and diuresis at 6, 24, 48, and 72 hours was investigated by using linear mixed-effects models. The 24-hour diuretic response and its association with IL-6, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and bioactive adrenomedullin (bio-ADM) were assessed using linear regression models. A mediation analysis was performed to evaluate whether the 24-hour diuretic response mediated the association between IL-6 and clinical outcomes. Findings were externally validated in a cohort of 1591 patients with AHF from the PROTECT Placebo-controlled Randomized Study of Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function study.

Patients with high IL-6 levels showed higher NT-proBNP levels, higher baseline heart rates, and lower ejection fractions. Patients with high IL-6 levels had significantly lower natriuresis (adjusted-P < 0.001) and lower diuresis over time (adjusted-P = 0.011). Furthermore, IL-6 was independently associated with poorer 24-hour diuretic responses (P = 0.003), unlike NT-proBNP (P = 0.274) and bio-ADM (P = 0.786). The relationship between elevated IL-6 levels and all-cause mortality or rehospitalization due to heart failure was for 44.6% mediated by impaired diuretic response. These findings were broadly similar in the PROTECT study.

Higher IL-6 levels are independently associated with worse diuretic responses and decreased diuresis and natriuresis in AHF, particularly during the initial phase of hospitalization. These results indicate that IL-6 may function as a biomarker of inadequate decongestive response and could represent a potential target for therapeutic intervention.