Iron Deficiency in Heart Failure: Cellular Mechanisms and Therapeutic Implications

Abstract

Iron deficiency (ID) is a prevalent comorbidity in heart failure (HF), affecting 37-75% of patients and contributing significantly to symptom burden and adverse outcomes independent of anemia status. Current diagnostic criteria for ID in HF include absolute deficiency (ferritin <100 μg/L) and functional deficiency (ferritin 100-299 μg/L with transferrin saturation <20%). Major clinical trials including AFFIRM-AHF, IRONMAN, HEART-FID, and FAIR-HF2 have demonstrated that intravenous iron therapy, particularly ferric carboxymaltose, reduces HF hospitalizations and improves quality of life and exercise capacity. The 2023 European Society of Cardiology guidelines recommend intravenous ferric carboxymaltose for symptomatic iron-deficient patients with heart failure with reduced ejection fraction. Despite these advances, significant knowledge gaps remain regarding optimal diagnostic approaches, the relationship between ID and ferroptosis in cardiac tissue, and the efficacy of newer iron formulations. This review synthesizes current understanding of ID in HF and highlights emerging therapeutic strategies.

Keywords: anemia; heart failure; intravenous ferrum treatment; iron deficiency.

Figure 1

Overview of cardiomyocyte iron metabolism and its regulatory mechanisms. Iron enters cardiomyocytes primarily via transferrin receptor 1 (TfR1)-mediated endocytosis of transferrin-bound iron and through non-transferrin-bound pathways including divalent metal transporter 1 (DMT1), L- and T-type calcium channels, and other metal transport proteins. Intracellular iron is stored within ferritin (FT) and released through NCOA4-mediated ferritinophagy to maintain cytosolic iron availability. Ferroportin (FPN) facilitates iron efflux, and its activity is negatively regulated by hepcidin, which in the heart is also produced locally in an autocrine fashion. Cytosolic iron levels are further balanced by the Iron Regulatory Proteins (IRP1/2), which bind to iron-responsive elements (IREs) on target mRNAs: under iron-depleted conditions, IRP binding stabilizes TfR1 and DMT1 transcripts while repressing ferritin and ferroportin translation; conversely, iron-replete states inactivate IRPs, promoting ferritin synthesis and iron export. Together, these systems preserve myocardial iron homeostasis and prevent both deficiency and overload.