Iron overload cardiomyopathy: Using the latest evidence to inform future applications

Abstract

Iron overload can be the result of either dysregulated iron metabolism in the case of hereditary hemochromatosis or repeated blood transfusions in the case of secondary hemochromatosis (e.g. in β-thalassemia and sickle cell anemia patients). Under iron overload conditions, transferrin (Tf) saturation leads to an increase in non-Tf bound iron which can result in the generation of reactive oxygen species (ROS). These excess ROS can damage cellular components, resulting in the dysfunction of vital organs including iron overload cardiomyopathy (IOC). Multiple studies have demonstrated that L-type and T-type calcium channels are the main routes for iron uptake in the heart, and that calcium channel blockers, given either individually or in combination with standard iron chelators, confer cardioprotective effects under iron overload conditions. Treatment with antioxidants may also provide therapeutic benefits. Interestingly, recent studies have suggested that mitochondrial dynamics and regulated cell death (RCD) pathways are potential targets for pharmacological interventions against iron-induced cardiomyocyte injury. In this review, the potential therapeutic roles of iron chelators, antioxidants, iron uptake/metabolism modulators, mitochondrial dynamics modulators, and inhibitors of RCD pathways in IOC are summarized and discussed.

Keywords: Iron overload cardiomyopathy; iron chelator; mitochondrial dynamics; oxidative stress; regulated cell death.

Figure 1.

Pathophysiological mechanism-based therapeutic approaches for treatment of iron overload cardiomyopathy. Dietary iron uptake through enterocytes into blood circulation via the iron exporter ferroportin which is regulated by hepcidin. Excess iron, both from intestinal absorption and blood transfusion, can potentially be taken up into cardiomyocytes via LTCC, TTCC, and LCN-2 under iron overload conditions. Cytosolic iron can enter the mitochondria via Mfrn and MCU for synthesized protein of heme synthesis and Fe-S proteins for electron transport chain which can regulate by FXN, while iron can be exported via ABCB8. The excess iron in mitochondria can be stored in the mitochondrial ferritin (mtFT). Iron overload causes cardiomyocyte injury via alteration of cardiac mitochondrial dynamics, impairment of cardiac mitochondrial function, and induction of several regulated cell death pathways including apoptosis, ferroptosis, and necroptosis. Several clinical strategies have been proposed including modulation of iron absorption via enhanced hepcidin levels, promotion of iron clearance by iron chelators, blockading against cardiac iron entry by calcium channel blockers, and attenuation of oxidative stress by antioxidants. Evidence from preclinical research indicates several novel potential targets for pharmacological interventions and continues to reveal additional mechanistic insights regarding iron overload cardiomyopathy including the inhibition of Fe³⁺ uptake via LCN-2, the use of mitochondrial dynamics modulators, and the inhibitors of several regulated cell death pathways. (A color version of this figure is available in the online journal.) ABCB: ATP-binding cassette subfamily B member; CCBs: calcium channel blockers; Dcytb: duodenal cytochrome b; DMT1: divalent metal transporter; DRP1: dynamin-related protein 1; Fer-1: ferrostatin-1; Fe-S: iron-sulfur; FPN: ferroportin; FT: ferritin; FXN: frataxin; Hp: hephaestin; LCN2: lipocalin 2; LCN2R: lipocalin 2 receptor; LIP: labile iron pool; LTCC: L-type calcium channel; MCU: mitochondrial calcium uniporter; Mdivi-1: mitochondrial division inhibitor-1; Mfrn: mitoferrin; MLKL: mixed lineage kinase domain-like protein; mtFT: mitochondrial ferritin; Nec-1: necrostatin-1; RIPK1/3: receptor-interacting protein kinase 1/3; ROS: reactive oxygen species; siRNA: silencing RNA; STEAP3: six-transmembrane epithelial antigen of the prostate 3; Tf: transferrin; TfR: transferrin receptor; TNF-α: tumor necrosis factor alpha; TNFR: tumor necrosis factor receptor; TTCC: T-type calcium channel; Z-vad: Z-VAD-FMK.