LAUSR

Iron deficiency (ID), as defined by the Ferric Iron in Heart Failure (FERRIC-HF) criteria,1–3 is now established as an important therapeutic target in patients with heart failure with a reduced ejection fraction (HFrEF). It is evident in ∼50% of these individuals and is associated with worse symptoms, exercise intolerance, and mortality, independently of haemoglobin levels.4–6 More importantly, randomized trials have shown that intravenous (IV) iron repletion improves symptoms and exercise performance in anaemic and non-anaemic subjects,1–3 and that skeletal muscle energetic augmentation might mechanistically underpin these findings.7 However, because the benefits of iron repletion in HFrEF has only been shown with IV iron agents that are ∼20 times more expensive than oral iron tablets, the utility of oral iron supplements in this condition is under investigation. Oral iron tablets are traditionally limited by poor gastrointestinal (GI) absorption and a high burden of GI side effects (∼30–70% of subjects) that decrement compliance.8 Normally, ∼10–20 mg of iron (∼20% as haem and 80% as non-haem) is ingested daily with haem iron better absorbed (∼25–50% absorbed) than non-haem iron (∼1–10%). While the pathway(s) for haem iron absorption are unclear, non-haem (inorganic) iron is imported into enterocytes via divalent metal transporter 1 (DMT1) and exported into the circulation via ferroportin9 (Figure 1). Hepcidin, an acute-phase protein that is up-regulated by inflammation and iron overload, controls systemic iron levels by degrading ferroportin to reduce iron absorption. Thus, the DMT1–ferroportin pathway is susceptible to immune down-regulation, and greater malabsorption leads to a greater expansion of the enterocyte labile iron pool which precipitates greater GI side effects. As HFrEF is a state of diffuse inflammation, it is unsurprisingly that randomized, double-blind,