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Review
. 2021 Dec 27;11(1):125.
doi: 10.3390/jcm11010125.

Iron Deficiency in Heart Failure: Mechanisms and Pathophysiology

Ridha I S Alnuwaysir  1 , Martijn F Hoes  1 , Dirk J van Veldhuisen  1 , Peter van der Meer  1 , Niels Grote Beverborg  1
Affiliations
Review

Iron Deficiency in Heart Failure: Mechanisms and Pathophysiology

Ridha I S Alnuwaysir et al. J Clin Med. .

Abstract

Iron is an essential micronutrient for a myriad of physiological processes in the body beyond erythropoiesis. Iron deficiency (ID) is a common comorbidity in patients with heart failure (HF), with a prevalence reaching up to 59% even in non-anaemic patients. ID impairs exercise capacity, reduces the quality of life, increases hospitalisation rate and mortality risk regardless of anaemia. Intravenously correcting ID has emerged as a promising treatment in HF as it has been shown to alleviate symptoms, improve quality of life and exercise capacity and reduce hospitalisations. However, the pathophysiology of ID in HF remains poorly characterised. Recognition of ID in HF triggered more research with the aim to explain how correcting ID improves HF status as well as the underlying causes of ID in the first place. In the past few years, significant progress has been made in understanding iron homeostasis by characterising the role of the iron-regulating hormone hepcidin, the effects of ID on skeletal and cardiac myocytes, kidneys and the immune system. In this review, we summarise the current knowledge and recent advances in the pathophysiology of ID in heart failure, the deleterious systemic and cellular consequences of ID.

Keywords: heart failure; iron deficiency; iron metabolism; pathophysiology.

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Conflict of interest statement

The UMCG, which employs several of the authors, has received institutional research support from Vifor Pharma, AstraZeneca, Ionis, Pfizer, Pharma Nord. N.G.B. received consulting fees from Vifor Pharma. P.v.d.M. received consulting fees from Vifor Pharma, Pharmacosmos and Novartis. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. All other authors have no relationships to disclose that could be construed as a conflict of interest.

Figures

Figure 1
Figure 1
Overview of the multifaceted roles of iron in diverse organs and molecular processes. TCA: tricarboxylic acid cycle; miRNA: microRNA, ROS: reactive oxygen species (Created with BioRender.com, accessed on 24 November 2021).
Figure 2
Figure 2
Summary of the current understanding of the mechanisms underlying iron deficiency in heart failure. This step is essential to enable iron uptake by the divalent metal transporter (DMT1). This reduction process is influenced by the pH of the luminal contents, and thus, any factors that influence the pH, such as proton pump inhibitors, can impair non-haeme iron absorption. Within the enterocyte, iron can be stored in ferritin or exported into the bloodstream by the iron exporter ferroportin (FPN), which is controlled by hepcidin. Increased hepcidin levels internalise FPN, leading to sequestration of iron within the enterocytes and thus impairing absorption of iron to the blood. HIF-2 regulates transcription of DCytB, DMT1 and FPN iron transport machinery. Downregulation of HIF-2 can lead to a dysfunctional iron regulating system in HF. Gut microbial metabolites can decrease HIF-2 expression and thus may influence systemic iron homeostasis. The third mechanism that could also result in systemic ID is increased iron loss due to gastrointestinal pathology such as colon cancer. In the heart, neurohormonal activation leads to myocardial ID by downregulating iron-regulatory proteins (IRP1/2). Iron circulation in the heart is controlled by IRP1/2 and hepcidin. In turn, this defective downregulation of IRP1/2 as well as hepcidin leads to increased iron release (as a result of decreased hepcidin levels and thus higher FPN) and decreased iron uptake due to downregulation of transferrin receptor 1 and DMT1. (Created with BioRender.com, accessed on 24 November 2021).
Figure 3
Figure 3
Overview of the biological consequences of iron deficiency. NTproBNP: N-terminal pro-b-type natriuretic peptide; OXPHOS: Oxidative phosphorylation; RNS: reactive nitrogen species; ROS: reactive oxygen species and FGF23: Fibroblast growth factor-23 (Created with BioRender.com, accessed on 24 November 2021).
Figure 4
Figure 4
Summary of current knowledge gaps and future directions regarding iron deficiency in heart failure. ID: iron deficiency; HAMP: hepcidin; IV: intravenous; HF: heart failure; HFmrEF: heart failure with mildly reduced ejection fraction; HFpEF: heart failure with preserved ejection fraction. (Created with BioRender.com, accessed on 24 November 2021).
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