T cell and monocyte/macrophage activation markers associate with adverse outcome, but give limited prognostic value in anemic patients with heart failure: results from RED-HF

Background: Activated leukocytes may contribute to the development and progression of heart failure (HF). We investigated the predictive value of circulating levels of stable and readily detectable markers reflecting both monocyte/macrophage and T-cell activity, on clinical outcomes in HF patients with reduced ejection fraction (HFrEF). Methods: The association between baseline plasma levels of soluble CD163 (sCD163), macrophage migration inhibitory factor (MIF), granulysin, soluble interleukin-2 receptor (sIL-2R), and activated leukocyte cell adhesion molecule (ALCAM) and the primary endpoint of death from any cause or first hospitalization for worsening of HF was evaluated using multivariable Cox proportional hazard models in 1541 patients with systolic HF and mild to moderate anemia, enrolled in the Reduction of Events by darbepoetin alfa in Heart Failure (RED-HF) trial. Modifying effects and interaction with darbepoetin alfa treatment were also assessed. Results: All leukocyte markers, except granulysin, were associated with the primary outcome and all-cause death in univariate analysis (all p < 0.01) and remained significantly associated in multivariable analysis adjusting for conventional clinical variables (e.g. age, gender, BMI, NYHA class, creatinine, LVEF, etiology) and CRP. However, after final adjustment for TnT and NT-proBNP no associations were found with outcomes. No interaction with darbepoetin alpha treatment was observed for any marker. Conclusions: Leukocyte activation markers sCD163, MIF, sIL-2R, and ALCAM were associated with adverse outcome in patients with HFrEF, but add little as prognostic markers on top of established biochemical risk markers. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00358215.