Implications of the Cardiac Hepcidin/Ferroportin axis for the Management of Iron Deficiency in Heart Failure

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).

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.