Figure 2.

Mechanisms of functional iron deficiency in patients with heart failure. Red arrows indicate the shifts in iron homeostasis in patients with heart failure. Heart failure is often accompanied by increased systemic inflammation, which activates hepcidin, thus impairing the absorption of iron from the duodenum and the release of iron from macrophages and hepatocytes and leading to a decline in iron levels in circulating blood. Inflammation and oxidative stress also promote the synthesis of ferritin and suppress ferritinophagy, thus impairing the release of intracellular iron stores into the cytosol and leading to the depletion of bioreactive cytosolic Fe²⁺. Transferrin receptor protein 1 may be down‐regulated in the failing heart, but it is upregulated when cytosolic levels of Fe²⁺ are threatened. GPX4, glutathione peroxidase 4; IRP1 and IRP2, iron regulatory proteins 1 and 2; NCOA4, nuclear receptor coactivator 4.