Treatment of anemia in heart failure: potential risks and benefits of intravenous iron therapy in cardiovascular disease

Abstract

Iron-deficiency anemia is common in patients with heart failure (HF), but the optimum diagnostic tests to detect iron deficiency and the treatment options to replete iron have not been fully characterized. Recent studies in patients with HF indicate that intravenous iron can rapidly replenish iron stores in patients having iron-deficiency anemia, with resultant increased hemoglobin levels and improved functional capacity. Preliminary data from a subgroup analysis also suggest that supplemental intravenous iron therapy can improve functional capacity even in those subjects without anemia. The mechanisms responsible for this observation are not fully characterized, but may be related to beneficial effects of iron supplementation on mitochondrial respiration in skeletal muscle. The long-term safety of using intravenous iron supplementation in HF populations is not known. Iron is a known pro-oxidant factor that can inhibit nitric oxide signaling and irreversibly injury cells. Increased iron stores are associated with vascular endothelial dysfunction and increased risk of coronary heart disease events. Additional clinical trials are needed to more fully characterize the therapeutic potential and safety of intravenous iron in HF patients.

Figure 1

A schematic illustration of the effects of alterations in iron availability on distribution of body iron stores and clinical manifestations. Shaded areas in the 3 compartments of iron storage (erythropoiesis, other iron containing enzymes, and other tissue iron storage) indicate the relative states of repletion or depletion for each compartment. The distribution of total body iron is highly regulated to provide sufficient quantities for incorporation into hemoglobin during erythropoiesis and synthesis of other iron-containing enzymes. To minimize potentially toxic effects of reactive iron species, almost all iron is bound to hemoglobin, other iron-containing enzymes, or to iron storage proteins ferritin and transferrin. In iron deficient anemia due to nutritional deficiency and/or blood loss, iron loss form all compartments is detected by low serum ferritin values and clinical manifestations of microcytic anemia and associated syndromes. Repletion of iron stores with oral or intravenous iron administration will reverse these clinical manifestations. The iron hypothesis proposes that repletion of iron just above the minimum stores necessary for erythropoiesis may be associated with reduced risk of coronary heart disease events. In functional iron deficiency associated with inflammatory diseases, iron availability for incorporation into hemoglobin and other iron containing enzymes is reduced, but total body iron stores may actually be increased in the storage compartment. Serum ferritin may be elevated, and the anemia is typically not microcytic. Administration of supplemental iron in these disease states can increase erythropoiesis and raise hemoglobin levels, but the full range of biological effects associated with further increases of non-heme iron stores is uncertain. Studies from chronic kidney disease populations indicated that excess iron stores could be associated with increased risk of coronary heart disease events. Iron overload states associated with hemochromatosis or transfusion dependent anemias are associated with end-organ damage. These disease states are characterized by very large amounts of increased storage iron and very high values of serum ferritin, well above those typically observed in response to intravenous iron administration. Data on risk of coronary heart disease have yielded conflicting findings