Abstract 2564: Hepcidin and TNFα-Mediated Dysregulation of Monocyte Iron Transport Proteins as the Molecular Basis of Defective Iron Homeostasis in Chronic Heart Failure
Background: Defective iron homeostasis is a major cause of anemia in patients (pts) with chronic heart failure (CHF) but its origins are unknown.
Hypothesis: We hypothesized that diminished circulating iron in the presence of adequate iron stores in CHF may be due to the adverse modulation of cellular iron export (ferroportin) and import (divalent metal transporter [DMT]-1) proteins by the inflammatory mediators, hepcidin and tumor necrosis factor (TNF) α.
Methods: We studied 45 CHF pts (age 68±10yrs, 75% NYHA class 3, 78% male) and 13 healthy controls (66±11yrs, 77% male). Serum pro-hepcidin and cytokine levels were measured by ELISA. Healthy peripheral blood mononuclear cells were incubated with or without CHF serum ± anti-TNFα neutralizing antibody. Monocyte ferroportin and DMT-1 expression were quantified by flow cytometry.
Results: Compared to controls and CHF pts with normal circulating iron (transferrin saturation [TSAT] >20%; n=29), CHF pts with reduced circulating iron (TSAT ≤20%; n=16) had lower haemoglobin (P<0.0001) and higher pro-hepcidin (controls: 120±45 mg/mL; TSAT >20%: 132±74 mg/mL; TSAT ≤20%: 192±122 mg/mL; P=0.046), TNFα (P=0.17), soluble TNF receptor-1 (P=0.048), IL-6 (P=0.008) and IL-1β (P=0.09) levels. Ferritin levels did not differ (P=0.29). Sera from pts with TSAT ≤20% (n=8) induced a greater reduction in ferroportin (−218% vs. −29±20%, P=0.03) and a greater escalation in DMT-1 (−4±22% vs. 23±48%, P=0.046) expression from baseline than sera from pts with TSAT ≤20% (n=16). Changes in ferroportin related only to log TNFα (r = − 0.72, P=0.004), log pro-hepcidin (r = − 0.58, P=0.03), and TSAT (r = 0.64, P=0.01). Anti-TNFα antibody completely abolished the effects of sera from pts with TSAT ≤20% on ferroportin and DMT-1 expression (all P<0.05).
Conclusion: Defective iron homeostasis in CHF is associated with downregulated ferroportin and upregulated DMT-1 expression, a pattern that facilitates monocyte iron retention in vivo. Hepcidin levels relate to such aberrant patterns and TNF-α directly dysregulates monocyte iron transporters in CHF. Unrestricted monocyte iron sequestration may hamper the full utility of iron supplements in this cohort and may be reversed by the targeted ablation of enhanced hepcidin and TNF-α activity.