Iron deficiency and supplementation in heart failure

Non-anaemic iron deficiency (NAID) is a strategic target in cardiovascular medicine because of its association with a range of adverse effects in various conditions. Endeavours to tackle NAID in heart failure have yielded mixed results, exposing knowledge gaps in how best to define 'iron deficiency' and the handling of iron therapies by the body. To address these gaps, we harness the latest understanding of the mechanisms of iron homeostasis outside the erythron and integrate clinical and preclinical lines of evidence. The emerging picture is that current definitions of iron deficiency do not assimilate the multiple influences at play in patients with heart failure and, consequently, fail to identify those with a truly unmet need for iron. Additionally, current iron supplementation therapies benefit only certain patients with heart failure, reflecting differences in the nature of the unmet need for iron and the modifying effects of anaemia and inflammation on the handling of iron therapies by the body. Building on these insights, we identify untapped opportunities in the management of NAID, including the refinement of current approaches and the development of novel strategies. Lessons learned from NAID in cardiovascular disease could ultimately translate into benefits for patients with other chronic conditions such as chronic kidney disease, chronic obstructive pulmonary disease and cancer. In this Review, Lakhal-Littleton and Cleland use the latest understanding of iron homeostasis to evaluate existing and emerging markers of iron status, describe the reciprocal relationship between iron status and heart failure, and mechanistically examine the benefits of oral and intravenous iron replacement therapies. Non-anaemic iron deficiency (NAID) is a strategic target in cardiovascular medicine because of its high prevalence, adverse effects on a range of outcomes and its role as a precursor to anaemia.In patients with heart failure (HF), variation in iron markers reflects the demographic factors that influence them in the general population as well as the modifying effects of common comorbidities and certain medications.Mechanisms underlying the adverse effects of NAID in HF could include the unmet needs for iron by the myocardium, skeletal muscle or pulmonary vasculature and the role of iron dysregulation in comorbidities.The benefits of oral iron therapies should be re-examined in light of the latest developments in dosing regimens and slow-release formulations.Although intravenous iron therapy benefits some patients with HF, the fate of iron in the body and the long-term safety of repeated dosing remain unknown.Identifying markers of the unmet need for iron by tissues and targeting the iron homeostatic pathways in the body hold the potential to transform the management of NAID.