Iron and Heart Failure

Figures

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  Figure 1. Systemic Iron Regulation Dietary iron is absorbed in the duodenum and transported across the epithelia where it is delivered to Transferrin (Tf). The majority of iron is then either delivered to the bone marrow where it is used in hematopoiesis, or it is stored in the liver. Hepcidin is a hormone released by the liver that prevents iron absorption and release from macrophages when iron stores reach sufficient levels. Although iron absorbed by the gut and bound to Tf is mostly redox inactive, iron administered intravenously enters systemic circulation as unbound iron and can be toxic to cells and tissues through the production of reactive oxygen species.

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  Figure 2. Cellular Iron Regulation and Systemic Transport (A) A graphic depicting different forms of iron transport through blood vessels. Under normal physiologic conditions, iron is absorbed from the small intestine or recycled through macrophages and released as Tf-bound iron. However, clinical use of intravenous (IV) iron in patients with iron deficiency introduces a large bolus of non–transferrin-bound iron (NTBI) into the vessel. Although the IV iron can be in colloids based on small spheroidal iron-carbohydrate particles, NTBI is redox active and can form reactive oxygen species, damaging endothelial cells. (B) A graphic depicting the import and fate of cellular iron. The uptake of transferrin (Tf)-bound iron is mediated through binding to transferrin receptor 1 (TfR1) and subsequent internalization by endocytosis. The acidic environment of the lysosome liberates iron from the Tf-TfR1 complex, and iron is transported into the cytosol, whereas the Tf-TfR1 complex is recycled to the cell surface. Upon entry into the cytosol, the majority of iron is bound by the storage molecule ferritin, and a small amount remains as labile iron. Non–Tf-mediated iron uptake can also occur through…

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  Figure 3. Free Iron Promotes the Formation of Reactive Oxygen Species and Atherosclerosis A graphic depicting the stepwise production of hydroxyl radicals via the Fenton reaction. Hydroxyl radical is a strong reactive oxygen species that can damage cells and tissues by oxidizing lipid and proteins. Oxidative damage to endothelial cells lining the blood vessels can promote the formation of atherosclerotic lesions.

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  Central Illustration. Absorption and Distribution of Iron Iron infusion introduces large amount of non-transferrin bound iron (NTBI) into the vasculature and bypasses homeostatic mechanisms of the body that meticulously regulate influx of iron into the circulation. Accumulation of NTBI in the serum and labile iron pool (LIP) inside the cells can lead to endothelial cell damage and progression of atherosclerosis. In contrast, absorption of oral iron (PO) is tightly controlled by the function of hepcidin on ferroportin-1 (Fpn1) to minimize the reactive unbound iron pool while ensuring a sufficient supply of iron to the body.