Iron Deficiency in Heart Failure: A Scientific Statement from the Heart Failure Society of America

https://doi.org/10.1016/j.cardfail.2023.03.025Get rights and content

Highlights

  • Iron deficiency is a common co-morbidity in patients with heart failure.

  • The use of intravenous iron therapy has demonstrated improvement in quality of life and reduced readmissions.

  • Further research is needed to determine is needed to determine if this leads to improvement mortality or in all subsets of heart failure, such as preserved ejection fraction.

Abstract

Iron deficiency is present in approximately 50% of patients with symptomatic heart failure and is independently associated with worse functional capacity, lower quality of, life and increased mortality. The purpose of this document is to summarize current knowledge of how iron deficiency is defined in heart failure and its epidemiology and pathophysiology, as well as pharmacological considerations for repletion strategies. This document also summarizes the rapidly expanding array of clinical trial evidence informing when, how, and in whom to consider iron repletion.

Section snippets

Iron Deficiency: A Global Public Health Problem

Although iron is naturally abundant environmentally,1 iron deficiency (ID) is among the most common nutritional deficiencies worldwide.2 Although prehistoric skeletal remains have revealed findings consistent with prevalent ID,3 it was not until 1928 that Helen Mackay observed that infants with limited nutrition given supplemental iron salts experienced less postnatal hypochromic anemia and “looked healthier.”4 Recognition of inadequate dietary iron intake across the spectrum of age and

Operational Definition of ID

Iron exists in aqueous solution as ionized cytotoxic free radicals capable of causing oxidative injury and premature cell death and by necessity must be stored and transported throughout the body as protein–iron complexes.8,9 Most of the iron stored in the body is bound to ferritin, a cytosolic protein, predominantly located in the liver, spleen, skeletal muscles, and bone marrow although small amounts are constitutively released into the bloodstream (Fig. 1).10, 11, 12 Transferrin is a

Epidemiology of ID and Its Overlap With Anemia in HF

Early studies focused primarily on ID as a potentially reversible etiology of anemia, but there is now recognition that ID, independent of anemia, is a clinically relevant comorbidity that independently predicts prognosis in HF.5,31,32 The prevalence of anemia in HF based on World Health Organization criteria (ie, hemoglobin <12.0 g/dL in women and <13.0 g/dL in men) is approximately 30%–40%,33,34 whereas the prevalence of ID has been estimated to be closer to 40%–50%.5,35 Although the presence

Development of ID

Iron homeostasis in normal physiology and in the setting of chronic disease states is subject to a complex and dynamic regulation (Fig. 1). Although contributing factors may include, but are not limited to, reduced nutritional intake, systemic congestion and impaired intestinal absorption, and overt and/or occult blood loss, the pathogenesis of ID in HF is primarily owing to dysregulation of iron metabolism.5,31,32,35 Iron absorption and mobilization are both regulated by hepcidin, a protein

Functional Role of Iron and Clinical Manifestations of ID

Iron is a metabolically active micronutrient and is an important cofactor for enzymes and a key component of structural proteins.49, 50, 51, 52 Iron exists in bodily fluid as an ion in 2 oxidative states, bivalent ferrous (Fe2+) and trivalent ferric (Fe3+) iron, allowing it to serve as a catalyst for enzymatic reactions. However, iron's most pivotal role is in oxygen storage (ie, myoglobin), transport (ie, hemoglobin), and use at the cellular level (ie, oxidative enzymes and the electron

Oral Iron Formulations

Oral iron formulations are used routinely in the management of ID anemia owing to their ease of administration and low cost. However, limitations to oral iron supplementation include poor absorption, adverse effects, nonadherence, and delayed time to complete repletion.20 Formulations differ by their total iron content, excipients, cost, and tolerability. Iron salts are most commonly used and include ferrous fumarate, ferric gluconate, and ferrous sulfate. Polysaccharide iron complex, ferric

Discussion and Future Directions

The rapid evolution supporting the use of intravenous iron in patients with HF has led to raised awareness and need for adoption of its use in treatment in the most recent ACC/AHA/HFSA 2022 guidelines.83 As outlined above, both the 2013 guidelines and the 2016 focused update were void of any recommendation related to measuring iron levels or use of intravenous therapy.99, 100, 101 The 2022 guidelines make specific mention of collection of iron studies, including serum iron, ferritin, Tsat, and

Conclusions

ID is very common in HF, irrespective of the presence of anemia, and is associated with impaired functional capacity and poorer prognosis. Recently conducted clinical trials have shown that patients with HFrEF are relatively refractory to oral iron supplementation but do derive improvement in functional capacity and quality of life in response to intravenous iron repletion. Ongoing clinical trials will further reveal whether intravenous iron repletion improves functional capacity in HFpEF and

Lay Summary

It is not clear to us whether a lay summary is part of HFSA Scientific Statements but we will provide a Lay Summary upon request. Patients who have heart failure are likely to have lower than expected iron levels. This could led to symptoms, such as fatigue, and worsen outcomes. The use of iron replacement through a infusion has demonstrated improvement in symptoms.

Declaration of Competing Interests

None.

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