Implications of the Cardiac Hepcidin/Ferroportin axis for the Management of Iron Deficiency in Heart Failure
Lead Research Organisation:
University of Oxford
Department Name: Physiology Anatomy and Genetics
Abstract
Iron is essential for life. It is required not only for the synthesis of haemoglobin, which carries oxygen around our bodies, but also for the function of the enzymes that generate energy inside our cells. Indeed, iron deficiency reduces exercise capacity, even when haemoglobin levels are normal. At the same time, too much iron within the cells is toxic because it promotes the production of damaging oxidants. Therefore, the control of iron levels is essential for the healthy functioning of our tissues.
Tissues get their iron from the blood. Iron in the blood comes from three different sources; the spleen where iron is recycled from old blood cells, the liver where iron is stored, and the gut where iron is absorbed from the diet. Iron is exported from these organs into the blood by an iron-exporting protein called ferroportin. When iron levels in the blood get too high, the liver produces a hormone called hepcidin that blocks ferroportin so that blood iron levels return to normal. Inflammation also stimulates the production of hepcidin. Because of this, many patients with inflammatory conditions like heart disease and kidney disease have too much hepcidin in their blood. This inhibits the absorption of iron from the gut and causes iron to be locked inside the liver and the spleen. This is why many patients with chronic conditions have low iron levels in the blood and are described as "iron-deficient".
In recent years, studies in these patients have shown that this iron deficiency worsens heart failure and increases mortality. There are now many efforts directed at finding the best way to treat this iron deficiency. Giving these patients oral iron does not work because iron absorption in the gut is blocked by hepcidin. A new treatment involving direct infusion of iron into the blood (by intravenous means) has been developed and rolled out to treat iron deficiency in patients with heart disease.
In the past 5 years, work in my lab has discovered that heart cells use ferroprotin to control the amount of iron inside them. When we made mice that lacked ferroportin just in the heart, but had intact ferroportin in the gut, spleen and liver, these mice developed fatal heart failure because of too much iron being retained in heart cells. Like ferroportin at other sites, ferroportin in the heart can also be blocked by hepcidin. Based on this discovery, we hypothesise that high levels of hepcidin in patients also block ferroportin in heart cells, causing iron to be retained in the heart. When iron availability in the blood is low, this iron retention could protect the heart from becoming iron-depleted. However, when iron availability in the blood is high, especially after intravenous iron infusion, this retention could cause toxic iron accumulation in the heart.
The aim of the research is to test this hypothesis. We will do this using both a mouse model of heart failure and human samples. The research will be conducted at the University of Oxford by my team in collaboration with clinicians who study and treat iron deficiency in heart failure patients.
If our studies show that our hypothesis is true, then they will change how clinicians treat iron deficiency in heart failure patients who have raised hepcidin. One possible change is to give these patients compounds that lower hepcidin first (these are already being tested in clinical trials for other conditions). The advantage of lowering hepcidin is that it corrects iron deficiency in the blood (by unblocking ferroportin in the gut, liver and spleen) and also restores the ability of heart cells to control their iron levels and avoid iron toxicity (by unblocking ferroportin in the heart).
Tissues get their iron from the blood. Iron in the blood comes from three different sources; the spleen where iron is recycled from old blood cells, the liver where iron is stored, and the gut where iron is absorbed from the diet. Iron is exported from these organs into the blood by an iron-exporting protein called ferroportin. When iron levels in the blood get too high, the liver produces a hormone called hepcidin that blocks ferroportin so that blood iron levels return to normal. Inflammation also stimulates the production of hepcidin. Because of this, many patients with inflammatory conditions like heart disease and kidney disease have too much hepcidin in their blood. This inhibits the absorption of iron from the gut and causes iron to be locked inside the liver and the spleen. This is why many patients with chronic conditions have low iron levels in the blood and are described as "iron-deficient".
In recent years, studies in these patients have shown that this iron deficiency worsens heart failure and increases mortality. There are now many efforts directed at finding the best way to treat this iron deficiency. Giving these patients oral iron does not work because iron absorption in the gut is blocked by hepcidin. A new treatment involving direct infusion of iron into the blood (by intravenous means) has been developed and rolled out to treat iron deficiency in patients with heart disease.
In the past 5 years, work in my lab has discovered that heart cells use ferroprotin to control the amount of iron inside them. When we made mice that lacked ferroportin just in the heart, but had intact ferroportin in the gut, spleen and liver, these mice developed fatal heart failure because of too much iron being retained in heart cells. Like ferroportin at other sites, ferroportin in the heart can also be blocked by hepcidin. Based on this discovery, we hypothesise that high levels of hepcidin in patients also block ferroportin in heart cells, causing iron to be retained in the heart. When iron availability in the blood is low, this iron retention could protect the heart from becoming iron-depleted. However, when iron availability in the blood is high, especially after intravenous iron infusion, this retention could cause toxic iron accumulation in the heart.
The aim of the research is to test this hypothesis. We will do this using both a mouse model of heart failure and human samples. The research will be conducted at the University of Oxford by my team in collaboration with clinicians who study and treat iron deficiency in heart failure patients.
If our studies show that our hypothesis is true, then they will change how clinicians treat iron deficiency in heart failure patients who have raised hepcidin. One possible change is to give these patients compounds that lower hepcidin first (these are already being tested in clinical trials for other conditions). The advantage of lowering hepcidin is that it corrects iron deficiency in the blood (by unblocking ferroportin in the gut, liver and spleen) and also restores the ability of heart cells to control their iron levels and avoid iron toxicity (by unblocking ferroportin in the heart).
Technical Summary
Iron deficiency (ID) is a recently-recognised co-morbidity in chornic heart failure (CHF), and new guidelines recommend using I.V iron to treat it. These guidelines do not distinguish between different types of ID. One type of ID, most common in chronic conditions, is driven by raised levels of the hormone hepcidin. Hepcidin is raised by inflammation and causes ID by blocking the iron exporter ferroportin FPN in the liver and spleen, respective sites of iron storage and recycling. My lab has recently discovered new functions for hepcidin and FPN in the control of iron export within cardiomyocytes and demonstrated that this control is required for normal heart function. This discovery has important implications. First, raised hepcidin levels affect heart function directly by increasing cardiomyocyte iron retention and maginifying the impact of I.V iron on myocardial iron levels. Second, patients with raised hepcidin levels would benefit from a hepcidin-lowering approach to restore both serum iron levels and normal cardiac iron control.
Aims- 1)To establish the direct effects of raised hepcidin on cardiac iron and function in the setting of heart failure, 2) Identify and target the factors that raise hepcidin in this setting, 3) Determine if serum hepcidin levels modify the outcomes of I.V iron treatment.
Methodology- We will combine mechanistic experiments in an established mouse model of CHF with targeted sub-studies within a relevant patient cohort.
Scientific & medical opportunities- Our studies will generate new mechanistic understanding of the role of raised hepcidin in the pathophysiology of CHF. One clinical application of this understanding is to use hepcidin-lowering drugs to restore both serum iron levels and normal cardiac iron control. FPN is also present in the kidney and lung. The tools and understanding generated by our work will pave the way for studying the role of local iron retention in the chronic conditions that affect these tissues.
Aims- 1)To establish the direct effects of raised hepcidin on cardiac iron and function in the setting of heart failure, 2) Identify and target the factors that raise hepcidin in this setting, 3) Determine if serum hepcidin levels modify the outcomes of I.V iron treatment.
Methodology- We will combine mechanistic experiments in an established mouse model of CHF with targeted sub-studies within a relevant patient cohort.
Scientific & medical opportunities- Our studies will generate new mechanistic understanding of the role of raised hepcidin in the pathophysiology of CHF. One clinical application of this understanding is to use hepcidin-lowering drugs to restore both serum iron levels and normal cardiac iron control. FPN is also present in the kidney and lung. The tools and understanding generated by our work will pave the way for studying the role of local iron retention in the chronic conditions that affect these tissues.
Organisations
- University of Oxford (Fellow, Lead Research Organisation, Project Partner)
- UNIVERSITY OF OXFORD (Collaboration)
- UNIVERSITY OF GLASGOW (Collaboration)
- University of Oslo (Collaboration)
- Erasmus MC (Collaboration)
- University of Hull (Collaboration, Project Partner)
- UNIVERSITY OF LEEDS (Collaboration)
- University of Oslo (Project Partner)
- University of Valencia (Project Partner)
- University of Glasgow (Project Partner)
Publications
Cleland JGF
(2024)
Low Serum Ferritin Might Predict Incident Heart Failure: But Why and Is It Clinically Useful?
in JACC. Heart failure
Lakhal-Littleton S
(2024)
Iron deficiency and supplementation in heart failure.
in Nature reviews. Cardiology
Liu Y
(2022)
Minimal effect of conditional ferroportin KO in the neural retina implicates ferrous iron in retinal iron overload and degeneration.
in Experimental eye research
Loick P
(2023)
Protective Role for Smooth Muscle Cell Hepcidin in Abdominal Aortic Aneurysm
in Arteriosclerosis, Thrombosis, and Vascular Biology
Nair M
(2023)
The complex relationship between iron status and anemia in pregnant and postpartum women in India: Analysis of two Indian study cohorts of uncomplicated pregnancies.
in American journal of hematology
Schwartz AJ
(2021)
Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells.
in Nature metabolism
Description | Chemitry in Cells- Imaging labile iron in-vivo |
Amount | £30,000 (GBP) |
Funding ID | http://chemistry-in-cells.chem.ox.ac.uk/ |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 05/2022 |
End | 04/2024 |
Description | High-throughput imaging platform for probing acute hypoxic sensing in a physiologically-relevant model of pulmonary vascular smooth muscle |
Amount | £9,885 (GBP) |
Funding ID | 0011384 |
Organisation | University of Oxford |
Sector | Academic/University |
Country | United Kingdom |
Start | 02/2022 |
End | 02/2023 |
Description | Magnetic Resonance Imaging to establish the kinetics of iron uptake into the heart following intravenous iron replacement therapy: A feasibility study |
Amount | £36,368 (GBP) |
Funding ID | HSR00031 |
Organisation | University of Oxford |
Sector | Academic/University |
Country | United Kingdom |
Start | 11/2021 |
End | 07/2023 |
Description | Research Excellence (round 3) |
Amount | £6,000,000 (GBP) |
Funding ID | RE/18/3/34214 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2019 |
End | 03/2024 |
Description | Characterisation of iron-associated cardiac dysfunction at the subcellular level |
Organisation | University of Oxford |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have provided cardiac tissues from genetically altered animals, that harbour mutations in iron-regulatory genes. |
Collaborator Contribution | Our collaborator has characterised the site of iron deposition within the cardiac tisssue. |
Impact | The collaboration has produced a number of research outcomes, some of which have been included in the recent PNAS paper, and presented at the European Iron Club Meeting in September 2014. |
Start Year | 2014 |
Description | EFFECT OF IL-6 ANTAGONISM ON HEPCIDIN IN ACUTE HEART FAILURE-ASSAIL-LI trial |
Organisation | University of Oslo |
Country | Norway |
Sector | Academic/University |
PI Contribution | Our team will investigate whether Tocilizumab (an IL-6 receptor antagonist) prevents the rise in hepcidin following heart failure, and the extend to which this contributes to observed benefits. |
Collaborator Contribution | Our collaborators will provide access to plasma samples and relevant clinical data from the ASSAIL-MI trial. |
Impact | This collaboration is at the data collection stage |
Start Year | 2022 |
Description | HEPCIDIN AND IRON HOMEOSTASIS IN ACUTE HEART FAILURE- OXFORD ACUTE MYOCARDIAL INFARCTION OXAMI |
Organisation | University of Oxford |
Department | Nuffield Department of Clinical Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Our team will investigate changes in hepcidin and other iron homeostatic markers in the acute and chronic stages of heart failure, in order to gain greater understanding of the mechanisms that drive iron deficiency in patients, and the contribution thereof to clinical outcomes. |
Collaborator Contribution | Collaboration with OxAMI investigators has given us access to a large cohort of blood samples from the acute and chronic stages of heart failure, and associated clinical data, including MRI data on heart function. |
Impact | Data are currently in analysis stage. |
Start Year | 2021 |
Description | IMPACT OF HEPCIDIN ON RESPONSE TO INTRAVENOUS IRON SUPPLEMENTATION IN CHRONIC HEART FAILURE PATIENTS- IRONMAN TRIAL |
Organisation | University of Glasgow |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Our team will investigate the modifying effect of baseline hepcidin on the clinical outcomes of intravenous iron treatment in patients with heart failure. |
Collaborator Contribution | Our collaborators are providing access to samples from IRONMAN trial. |
Impact | This collaboration is to enter the data collection stage. |
Start Year | 2022 |
Description | Imaging Intravenous Iron PID16038 |
Organisation | University of Oxford |
Department | Oxford Centre for Magnetic Resonance |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are running a clinical study using MRI to investigate iron uptake into tissues in the hours and days post intravenous iron replacement therapies. The study's target enrollment is 12 . So far, 9 participants have completed the study. We are measuring tissue uptake into the liver, heart, kidneys, spleen and skeletal muscle. |
Collaborator Contribution | MRI expertise, particularly T2* relaxometry for estimating tissue iron |
Impact | Results are currently being collected |
Start Year | 2022 |
Description | Investigating hepcidin in procine model of ischemia reperfusion injury |
Organisation | Erasmus MC |
Country | Netherlands |
Sector | Hospitals |
PI Contribution | The collaborations seeks to explore changes in iron-regulated gene expression in the hours and days post cardiac ischemia reperfusion inury using a porcine model. |
Collaborator Contribution | porcine model |
Impact | results currently being collected |
Start Year | 2023 |
Description | MECHANISMS OF IRON DEFICIENCY IN CHRONIC HEART FAILURE- HULL-LIFE COHORT |
Organisation | University of Hull |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Our team's aim is to identify the factors that drive iron deficiency anaemia in patients over the course of heart failure. |
Collaborator Contribution | Our collaborators have provided access to longitudinal samples from 700 heart failure patients. |
Impact | We are currently at the data acquisition stage |
Start Year | 2022 |
Description | Skeletal muscle iron homeostasis in heart failure with reduced ejection fraction |
Organisation | University of Leeds |
Department | stage@leeds |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | The collaboration seeks to investigate how iron homeostasis is altered in muscle of patients with HFrEF, in order to explore the potential role of iron in skeletal muscle impairment. |
Collaborator Contribution | Muscle samples |
Impact | Results currently being collected |
Start Year | 2022 |
Description | European Iron Club meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I gave a talk on the importance of iron homeostasis in cardiovscaular health |
Year(s) Of Engagement Activity | 2022 |
URL | https://web.cvent.com/event/6d7f8f9b-8a91-41df-a30d-1537efe26a32/summary |
Description | Invited talk at the meeting of the European Hematology Association |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I gave a talk on the role of iron deficiency in heart failure |
Year(s) Of Engagement Activity | 2022 |
URL | https://ehaweb.org/congress/previous-congresses/eha2022-hybrid/eha2022-congress/ |