Suppression of Erythroid Cell Development in Patients with Chronic Heart Failure and Anemia of Unknown Origin: Evidence of an Immune Basis

Background: Anemia is a prevalent and adverse comorbidity in chronic heart failure (CHF) but its origins are frequently elusive. Diffuse inflammation is also a feature of CHF and a potent trigger of impaired erythropoiesis. Hypothesis: We hypothesized that unexplained anemia in CHF may mimic the anemia of chronic disease in being subsequent to diminished erythropoiesis as a result of immune-mediated suppression of erythroid colony formation. Methods: We studied 61 CHF patients (age 66 ± 1yrs, LVEF 30 ± 1%, 82% male) and 20 healthy controls (63 ± 2yrs, 77% male). Absolute reticulocyte counts were enumerated and the reticulocyte production index (RPI) derived. Circulating primitive hematopoietic and erythroid precursor cells were quantified by flow cytometry. Peripheral blood erythroid progenitors (BFU-E) were scored in methylcellulose cultures in the absence and presence of monocytes and sera, and with anti-tumor necrosis factor (TNF) neutralizing antibody. Results: Anemic patients (n = 21) had significantly higher TNF and interleukin-6 concentrations than non-anemic patients (n = 40) and healthy controls (n = 20). Despite lower hemoglobin (Hb) and higher EPO levels (p<0.05), anemic subjects did not mount a reticulocytosis as evidenced by their lower absolute reticulocyte counts (p = 0.01) and RPIs (p<0.001). Diminished erythropoiesis was paralleled by attenuated circulating primitive hematopoietic, erythroid progenitor and precursor cells in anemic patients (all p<0.01). Depletion from cultures of monocytes derived only from anemic patients enhanced BFU-E growth by 35 ± 8% (n = 8, p<0.05). Only monocytes and sera from anemic patients suppressed BFU-E colony formation when co-cultured with autologous anemic or allogeneic control T-cell depleted BFU-E (n = 8, p<0.01). Higher TNF levels related to lower colony yields (r = -0.30, p<0.05). Anti-TNF neutralizing antibody abrogated the inhibitory effects of anemic sera on erythroid colony growth (n = 6, p<0.05). Conclusion: Anemia of unknown origin in patients with CHF results largely from suppressed erythropoiesis and monocytes, via a direct effect of TNF on erythroid cells, orchestrate a significant degree of this suppression. Recombinant EPO with adjuvant iron therapy is a rational strategy in this cohort.