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).