Introduction

Iron metabolism within the human body presents itself in physiology and pathology with increased interest in current research, aided by recent advancements in the understanding of the finely tuned mechanisms of ferroregulation. Iron (Fe) is a transitional metal, speculated to have been involved in the very formation of life on Earth [1]. The capacity of iron to accept or donate electrons by means of its polyvalent trait [2] catalyzes a plethora of redox reactions throughout biological systems. Being involved in oxygen transport, sequestration, and utilization, comprised in iron-sulfur clusters (ISC) [3], production of reactive oxygen species (ROS), and DNA synthesis, as well as in immunosurveillance [4], it is obvious that tight equilibrium must be maintained in order to avoid detrimental effects spawned by both iron overload and deficiency. Systemic regulation relies mainly on the peptide hormone hepcidin [5] in the hepcidin/ferroportin axis, whereas cellular regulation appears to be more complex. Depending on the iron-responsive protein/iron-responsive elements (IRP/IRE) as a way of iron sensing [6], cellular homeostasis is influenced by the hypoxia-sensing HIF/HRE (hypoxia-induced factor/hypoxia-responsive elements) [7] as well as by the recently discovered tissue-autonomous, cardiac hepcidin/ferroportin axis [8].

In cardiac pathology, iron homeostasis is dysregulated, with both deficiency and overload being cited as culprits [9, 10]. In this review, we examined the metabolic circuits iron participates in and the therapeutic opportunities iron homeostasis present in the treatment of cardiovascular disease.

Ferrokinetics

Iron absorption

The physiologic pathway of iron following ingestion takes part in the milieu of the duodenum. Because the ferrous iron (Fe2+) is readily oxidized in atmospheric conditions to its trivalent, insoluble state, Fe3+ requires reduction by metalloreductases (such as Dcytb [11]) or by reductants within the intestinal lumen (e.g., ascorbic acid), followed by ingress via a non-specific, divalent metal transporter DMT1 (SLC11A2) [12]. With regard to the organic sources of iron, proteolytic enzymes degrade protein-rich foods in order to release heme-abundant hemoglobin/myoglobin. Heme has been proposed to be internalized with the aid of either a low-affinity heme transporter, heme carrier protein 1 (HCP-1) [13], or by the heme-responsive gene 1 protein (HRG-1) [14]. Free Fe2+ from heme is released by catalytic removal of protoporphyrin by heme oxygenase 1 (HO-1) [15]. From here on, Fe can be either lost through shedding of the epithelial cells or be further conveyed at the basolateral membrane of the duodenal enterocyte. Efflux of ferrous iron is mediated by ferroportin (Fpn, SLC40A1 gene) [16]. Re-oxidation of Fe2+ by hephaestin [17] (a ceruloplasmin-like membrane protein), or serum ceruloplasmin itself, occurs to allow binding of Fe3+ to serum apo-transferrin. Serum transferrin (Tf) is a beta-1 globulin synthesized mainly from the liver which attaches two molecules of Fe3+ for transport within the circulatory torrent.

Cellular iron uptake

Cells that exhibit a high transferrin receptor (TfR) count on their surface membrane, such as erythropoietic cells from the bone marrow, are the predominant destination of holo-transferrin [18]. In the recent decades, two types of TfR have been characterized: TfR1 (coding gene TFRC), a transmembrane protein identified to be the same as CD71 antigen [19], and TfR2 (coding gene TFR2)—homologous with TfR1, but with additive function in the regulation of hepcidin, as shown by the development of hemochromatosis type 3 in individuals with TfR2 mutations [20]. The ligand-receptor complex formed is further engulfed within the cell by endocytosis and formation of an endosome. Acidification by vacuolar ATPase within the structure increases the dissociation constant of ferric iron which in turn prompts conformational changes of the Tf molecule with consequent release of Fe molecules. Interestingly enough, the depletion of vacuolar ATPase complexes and ensuing decrease in available intracellular iron are likely involved in the stimulation of hypoxia-inducible factor 1 (HIF1) [21], one of the regulatory pathways in cellular iron equilibrium. Non-transferrin bound iron (NTBI) can also permeate the cell directly by membrane DMT1 and via new metal transporters recently described. ZIP14 and ZIP8 (ZRT/IRT-like protein family) are members of the solute carrier family 39 (SLC39) with function as a zinc and iron membrane transport proteins [22,23,24] that are not regulated by the traditional IRE/IRP axis [25] (detailed below). From here on, the bivalent iron atoms, representing the labile pool of iron, are either chaperoned to different organelles by RNA-binding proteins [26,27,28] or stored within ferritin (Ft). Ft is a protein shell with a ferric hydroxyphosphate core, with two subunits types: H and L [19], owing to their heavy (21–23 kDa) and light (19–21 kDa) molecular weight [29]. Unlike heme, which is found mainly in animal products, Ft appears abundant in whole legumes [30]. Of note, the capacity of Ft to store iron has led to therapeutic use as a genetic iron chelator, with promising results [31]. One of the main sites of iron utilization by the cell is the mitochondrial apparatus [32], which has an array of iron-containing moieties, such as ISC, mitochondrial ferritin (MtFt), reductases, and oxidases, and is the main site of heme production [33].

Systemic ferroregulation

Iron homeostasis must be accomplished by way of uptake regulation, as there is no physiologically known control of excretion; proposed means of iron elimination are intestinal cells sloughing, skin desquamation, and blood loss [34]. Indeed, the pivotal role in iron balance is ascribed to hepcidin (Hep, HAMP gene), a 25 aminoacidic hormone secreted mainly by the liver [35]. Hepcidin downregulates iron uptake via induction of internalization and degradation of Fpn and/or DMT1, particularly acting within the gastrointestinal tract (via DMT1) and the reticuloendothelial system (via Fpn), sites of Fe absorption and recycling, respectively [36]. Studies concerning the mechanism of action of Hep within the enterocytes of the duodenum have suggested that brush border DMT1 is the target of internalization and subsequent degradation in the acute setting, rather than Fpn [37, 38]. It has been proposed that the low influx state driven by inhibition of DMT1 is the factor that decreases Fpn expression in the milieu of sustained Hep stimulation [37, 39]. Hep is transcriptionally upregulated by iron overload, inflammation, and obesity [40], and decreased synthetization is observed with hypoxia (via HIF), hypoferremia, increased erythropoietic drive (e.g., anemia) [41], and cell proliferation [42]. Mechanisms of regulation involve the BMP/SMAD (bone morphogenetic protein (BMP)/s-mother against decapentaplegic) pathway and JAK/STAT pathways [43]. Recently studied processes of regulation have suggested that leptin (an energy balance hormone) causes increased serum hepcidin levels [44]. Leptin disorders are closely associated with obesity and might supply a missing link between inflammation, cardiovascular disease, and metabolism [45].

In the case of increased availability of iron (Fig. 1), Hep synthesis is augmented by the following process: increased concentration of holo-Tf binds to cell membrane TfR1, displacing the human hemochromatosis protein (HFE; high ferrum). HFE then translocates to TfR2, which in turn associates with hemojuvelin (HJV, a BMP co-receptor) which leads to phosphorylation of SMAD and induction of HAMP mRNA [43, 46]. Similarly, with inflammation, cytokines (such as IL-6, IL-1, tumor necrosis factor alpha (TNF-α) [47, 48]) interact with the JAK/STAT3 and activate transcription of Hep [49].

Fig. 1
figure 1

Hepcidin upregulation by iron and inflammation. Transferrin-bound iron becomes attached to the transferrin receptor 1, causing the formation of the HFE-TfR2-HJV-BMP6R complex, with the end result of Hep mRNA synthesis via the SMAD pathway. Inflammation, via cytokine IL-6, causes similar results, either via JAK-STAT pathway or by means of modulation of the BMP-SMAD. RBMP6, bone morphogenetic protein 6 receptor; HAMP, hepcidin antimicrobial peptide gene; HFE, human hemochromatosis protein; HJV, hemojuvelin; IL-6, interleukin 6; JAK, Janus kinases; RE, response elements; SMAD, s-mother against decapentaplegic; STAT, signal transducer and activator of transcription proteins; TfR transferrin receptor

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Conversely, decreased iron storage (i.e., Ft), hypoxia, and anemia or increased cell proliferation suppress Hep secretion by transcriptional regulation (Fig. 2). Hypoxia inhibits Hep synthesis via hypoxia-inducible factors (HIFs), in order to coordinate the increased requirements of erythropoiesis with iron availability. Erythropoietic signaling by erythropoietin (EPO) indirectly downregulates Hep production by HIFs action, along with growth differentiation factor 15 (GDF15) [50] and twisted gastrulation factor 1 (TWSG1) [41], both released by bone marrow precursors of myeloid lineage. However, little is known on the exact mechanism of action.

Fig. 2
figure 2

Hepcidin downregulation. In the case of decreased iron availability, hypoxia, and anemia, hepcidin synthesis is inhibited by a molecular disruption of the TfR1-transferrin complex formation by competitive binding of the HFE protein. Hypoxia acts via hypoxia-inducible factors, in order to coordinate the increased requirements of erythropoiesis with iron availability. Erythropoietic signaling by erythropoietin indirectly downregulates Hep production by HIFs action, along with growth differentiation factor 15 and twisted gastrulation factor 1, both released by bone marrow precursors of myeloid lineage. However, little is known on the exact mechanism of action. Epo, erythropoietin; ERFO, erythroferrone; GDF15, growth differentiation factor 15; HAMP, hepcidin antimicrobial peptide gene; HFE, human hemochromatosis protein; HIF, hypoxia inducible factor; HJV, hemojuvelin; IL-6, interleukin 6; JAK, Janus kinases; RBMP6, bone morphogenetic protein 6 receptor; RE, response elements; SMAD, s-mother against decapentaplegic; STAT, signal transducer and activator of transcription proteins; TfR, transferrin receptor; TWSG1, twisted gastrulation factor 1

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Cellular ferroregulation

Within the cell, intrinsic levels of iron control the regulation via iron regulatory proteins (IRP) 1/2 and iron-responsive elements (IRE), in a posttranscriptional fashion [6, 41]. Under conditions wherein iron is replete, IRP1 is found within the cytosol where it functions as an aconitase [51], whereas IRP2 undergoes proteasomal degradation [52]. Upon decreased iron availability, the IRPs bind to the untranslated regions (UTR) of target genes. Binding to the upstream 5′-UTR inhibits translation into proteins, while 3′-UTR interaction, located downstream from the protein transcript, will stabilize the mRNA and promote synthesis. Several genes involved in iron homeostasis/metabolism possess IREs either in the 5′-UTR or 3′-UTR of their mRNA transcript (Table 1) [6]. As a result, in low iron conditions, most cells will undergo enhanced iron uptake and modulation of cell development and division, while iron export, storage, and utilization are downregulated. IRP1-HIF2α interaction proves useful in elucidating mechanisms that regulate erythropoiesis in low oxygen and iron conditions in the liver and kidney (reviewed extensively in [52]). It has been proposed that the IRP/IRE pathway is implicated particularly in the iron handling by the mitochondria [53, 54], highlighting the iron-mitochondria connection in health and disease. Notably, the Ft proteins also appear to possess antioxidant properties (particularly subunit H) [55], as shown by the induced synthesis of Ft by inflammatory cytokines and oxidative stress [56, 57]. The molecular mechanism involves antioxidant response elements for the Ft mRNA, in addition to the IRP, connecting and complicating the iron metabolism—inflammation—oxidative stress interplay (Ft regulation reviewed in [58]).

Table 1 Cellular iron regulators and their function
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Iron metabolism in the healthy and diseased cardiac myocytes

Previously described mechanisms of iron uptake also apply to cardiomyocytes, with Tf-bound Fe3+ entering the cell via endocytosis. Moreover, there are other pathways for ferrous iron. The cardiomyocytes possess L- and T-type calcium channels (LTCC, TTCC) which in the case of chronic heart failure (CHF) become altered [59]. Murine studies have indicated these channels as points of entry in the cardiac cells during iron overload [60], along with calcium channel blockers (CCB) decreasing iron load [61, 62]. Notably, the aforementioned ZIP14/8 carriers expressions are low in the cardiac tissue [63], suggesting minimal importance in iron trafficking within the cardiomyocyte. Upon being added to the cellular labile iron pool (LIP), Fe can be either deposited in the form of ferritin, used in metabolic cytosolic processes, or enter the mitochondria. In addition, ferritin H chain protein appears downregulated in the failing heart, possibly increasing the LIP and subsequent ROS formation [64]. The ingress of Fe into the mitochondrial apparatus is done by mitoferrin 1 and 2 [65]. Within the mitochondrion, iron contributes to the formation of heme, ISC, and MtFt [66], and oxidative phosphorylation [67]. Indeed, Fe and the cardiac mitochondria are of such paramount importance in the regulation of heart energetics that the regulation of local Hep and Fpn is done by cardiac transcriptional and translational modulation [8]. Lakhal-Littleton et al. [8] have shown that even in the case of physiologic systemic Fe levels, the cardiac iron homeostasis is determined in a paracrine and autocrine manner (via a local Hep/Fpn axis), apart from the systemic control of liver Hep/Fpn axis and the established cellular IRP/IRE system [54], further abetting the complexity of iron interplay in the heart. Seemingly contradictory, the cardiac level of Hep protein is downregulated in the case of systemic iron overload and downregulated during iron deficiency [8]. This is in contrast with the endocrine (systemic) model of Hep/Fpn, where high iron load causes increased Hep secretion as a way to inhibit iron absorption. The reason for this shift most likely relies on the fact that in the case of iron overload, decreased cardiac Hep expression will result in an upregulation of Fpn, therefore increasing iron egress capacity from the cardiomyocyte. Conversely, it can be appraised that in the case of systemic Fe deficiency, protection from organ shortage of the metallic element occurs via the limitation of iron export through cardiac Fpn [8].

Iron disequilibrium in heart diseases

CHF is associated with systemic iron deficiency (ID) in a very high proportion, typically between 10 and 50% of patients presenting some form of anemia or iron deficiency [68]. The etiology is most likely multifactorial, with iron sequestering as a result of malabsorption, gastrointestinal bleeding, and cachexia being the leading causes [9]. Although inflammation has an important role in ferrequilibrium, well-conducted studies [69] have failed to show any correlation between Hep and inflammatory status (i.e., IL-6, TNF-alpha), owing to the anti-inflammatory effects of Hep [70]. Interestingly, it appears that a nutritional iron intake disturbance is of less importance in myocardial ID development. Rather, myocytes dysregulation of iron is brought about by hemodynamic stress that is characteristic of HF [71]. Being cognizant that HF is a syndrome that retains inflammatory characteristics [72] and that iron metabolism is dysfunctional [69], one can surmise that processes within the intricate systemic and cellular meshwork of bioiron are altered, with adverse effects. As such, iron disequilibrium could prove an attractive target for cardiovascular therapies.

At the cellular milieu, HF patients exhibit a plethora of iron-mediated shifts in cell function, independent of systemic iron levels. In the cardiomyocytes of HF patients undergoing transplantation, Melenovsky et al. [73] found decreased iron content compared with controls, associated with decreased mitochondrial enzymatic (respiratory and ROS related) activities. Moreover, patients with the lowest myocardial iron content were most affected by the decrease in function. Congruent with this hypothesis, an in vitro investigation using iron-deficient human cardiomyocytes demonstrated a cellular iron status-dependent decrease of mitochondrial respiration and contractility, along with an increase in the quantitation of storage Ft mRNA [74]. In as much as this upregulation seems paradoxical, it can be appealing to further ascertain its roles (see above section) in the development of cardiac ID. Furthermore, it appears that the IRP/IRE regulation mechanism has a specific role in the development of HF brought about by iron deficiency. A transgenic murine study of cardiac IRP deletion with consequent ID expressed a diminution in respiratory activity of the myocytes mitochondria, especially under stress conditions [53], coupled with a downregulation of the membrane TfR1. Clinically relevant, the studies have shown that the administration of iron at least partially reversed the changes, suggesting an intrinsic role of iron deregulation to the development and changes of CHF patients.

Taken together, the pathophysiology of HF in respect to ID can be viewed as an effect of reduced myocardial iron content, which in turn causes the deficient activity of key enzymes of oxidative phosphorylation and impaired contractility. Thus, the energetical demands of the cardiac muscle cell cannot be met by dysfunctional mitochondria, which leads to the poor survival rates found in patients with ID and HF [69]. The etiological connection between HF and myocardial iron deficiency remains elusive, although the reduced expression of iron uptake via TfR1 [53], ZIP14, DMT1 [73, 75], a Ft mediated diminished availability of NTBI [74], and pleiotropic influence of the HIF/IRP/Hep regulation mechanisms [52, 76] could prove useful starting points in future endeavors.

In contrast, supplementary investigations have revealed that a state of iron disequilibrium (that is an imbalance rather than purely deficit of iron) could better explain the intracellular and extracellular metabolism of iron. To this end, multiple studies [10, 77,78,79,80,81] have concluded that an increase of iron content in the myocardial mitochondria of subjects with heart disease may be one of the reasons behind pathological disequilibrium, even though there have been little studies concerning intraorganellar iron quantitation and its effects in HF. It appears that even though decreased systemic iron availability is present in half of HF patients [82], at the cellular and mitochondrial level there might be an increase in Fe concentrations [78, 83], leading to ROS generation and oxidative damage. Additionally, in the acute and ischemic setting of heart diseases (i.e., myocardial infarction), both human and animal model researches have shown increased iron deposition in the cardiac cells [79, 84, 85], as well as increased Hep synthesis [86] associated with adverse cardiac effects.

Augmented iron levels in the HF patients were referred to as the probable cause of increased ROS via heme and non-heme bound iron in the mitochondrial compartment [83]. Likewise, it seems that in the iron-deficient setting, cardiac myocytes respond by an increase of Hep protein synthesis, followed by a Fpn-mediated decrease of iron egress [10, 87]. It also seems plausible that an increase of LTCC mediated iron absorption in the failing hearts may have a role, aside from the canonical Tf-bound iron [88]. Concurrently, ischemia/reperfusion models of HF have also been linked with decreased cellular viability and function, owing to ferroptosis by increased heme and non-heme iron contents within the mitochondria and augmented iron release by increased levels of HO-1, with chelators amending the degree of cardiomyocyte dysfunction [89]. Interestingly, the subcellular iron fraction was increased, while cytosolic levels were not significantly different from controls, suggesting mitochondrial iron deposition at the expense of the LIP and consequent dysfunction of the iron-dependent elements in the heart.

Indeed, one could hypothesize that the disparate relationship between systemic and cardiac intracellular iron levels, with diverging results regarding regulation of iron, transferrin, hepcidin, ferroportin [8, 74, 88], suggests a rather intimate relation between cardiac iron and development of HF, with both decrease of systemic and increase of intraorganellar iron as cause. Amplified heme and HO-1 levels in the cardiac mitochondria leading to increased unbound iron and production of ROS could prove a suitable theoretical model to explain such divergence between studies.

Therapeutic approaches

Defining iron deficiency and overload

In the most prominent randomized controlled trials (RCT) conducted to establish the potential benefits of iron supplementation in iron-deficient patients with CHF [90, 91], ID was defined based on Ft serum levels and/or serum saturation of Tf (TSAT) by way of a dichotomous cutoff: either a Ft < 100 ng/mL or Ft 100–300 ng/mL with a TSAT < 20% would serve as diagnostic criteria. The former is used to define absolute deficiency, while the latter suggests functional ID. Although arbitrarily chosen, the definitions were incorporated in an international consensus regarding ID in inflammatory diseases [92], signifying valid targets for treatment initiation and disease outcome monitoring. However, additional inquiries into the subject by Beverborg et al. [93] have steered to different propositions. Based on a number of 42 CHF patients undergoing coronary artery bypass grafting and bone marrow aspiration compared with 387 outpatients, the study found that the most reliable predictors of all-cause mortality were TSAT < 19.8% and serum iron levels < 13 μmol/L. While not an unequivocal research, it raises questions pertaining to the right treatment to the right patients. Similarly, another study [94] pinpointed low levels of iron and hemoglobin, but high values of Ft and vitamin B12 as culprits in total mortality of CHF patients, with only serum iron being attributed to cardiovascular-related mortality.

In the case of iron overload, the diagnosis issue is intertwined with multiple etiologies and even further complicated by the need of biochemical (TSAT, Ft, Tf), genetic, and imaging (MRI) tests. Detailed algorithms for defining hemochromatosis are beyond the scope of this paper and have been reviewed in depth elsewhere [95]. With regard to cardiac siderosis, the majority of investigations make extensive use of organ-level magnetic resonance imaging [96].

Supplementing iron

Due to the increased side effects and little clinical improvement of oral iron therapy [97], clinical trials have shifted towards intravenous supplementation in HF. Ferric carboxymaltose is the preferred preparation as opposed to other formulations, as it appears that it produces a more potent and precipitous increase in hematinic parameters [98]. Currently, there are clinical trials for a number of other forms of iron, such as iron protein succinylate (ClinicalTrials.gov Identifier: NCT03344523), ferric maltol (NCT03774615), and iron maltoside (NCT02642562).

A great focus has been put on evaluating and treating iron deficiency (ID) and the resulting iron-deficient anemia (IDA), as it appears that low iron availability correlates with deleterious effects, such as increased mortality and hospitalization and decreased quality of life [99]. The causative relation between heart failure and ID or IDA is likely multifactorial. Decreased dietary iron intake [100], multiple drug interactions and drug-induced bleeding [101], IL-6- and TNF-α-mediated inflammation [102], blunted erythropoietin production [103], and hemodilution [104] are the most frequently cited means of iron metabolism disruption.

Current guidelines in Europe and the USA suggest seeking and treating ID in patients with HF [105]. Multiple RCTs have shown that intravenous administration of carbohydrate-bound Fe results in improved quality of life and effort capacity and decreased hospitalization and symptoms [90]. Additionally, other organs such as the skeletal muscles seem to account for beneficial effects [106] of iron replenishment via an increase in cellular energy generation, as shown by current studies concerning HF patients [107, 108], again emphasizing the mitochondrial importance in iron metabolism. It is important to highlight that the decision to administer iron formulations is based on systemic (i.e., serum) iron parameters, using the Ganzoni formula [91]. Even though these trials were not powered for primary cardiovascular endpoints and survival duration, post-hoc analyses were able to infer that there is a potential benefit from IV iron replenishment regimens [99], with other RCTs currently underway to clarify such a vital issue [99]. However, another meta-analysis [90], which studied the effects of intravenous iron to patients with systolic heart failure, has failed to show any correlation between mortality and iron treatment.

Decreasing iron

Current treatment of hemochromatosis consists mainly of venesection, despite a lack of RCT to confirm the benefit. The European Association for the Study of the Liver recommends a target of serum Ft below 50 μg/L reached by regular phlebotomies started when the aforesaid parameter is above normal range [109]. However, in certain pathologies, such as hemoglobinopathies, this practice proves unfeasible. Chelation therapy has been made available in the last decades, and as such, three compounds are approved for therapy: deferoxamine, deferiprone (DFP), and deferasirox [110]. In patients with cardiac siderosis and β-thalassemia, DFP proved significantly superior to deferoxamine in regard to iron quantitation by T2* MRI and ventricular ejection fraction, while deferasirox compared with deferoxamine demonstrated non-inferiority [111]. Due to its lipophilic nature, DFP seems to be the only approved agent that is a mitochondria permeant chelator, ferrying intracellular and intramitochondrial iron [112]. In more recent studies, other xenobiotic chelators have shown increased efficacy. Eltrombopag, a thrombopoietin receptor agonist exhibited more potent chelation activity of cardiomyocytes in vitro than the licensed alternatives, along with reduced ROS formation [113]. Similarly, dexrazoxane, a drug approved for treatment of anthracycline cardiotoxicity, decreased cellular and organellar levels of iron [89, 114], as it seems reasonable that anthracyclines mediate cardiac dysfunction through increased mitochondrial iron deposition [115].

Effective iron release can occur, from a teleological point of view, in two ways: blocking the influx and removal of iron (i.e., chelation) from the labile iron pool. As it appears plausible in iron overload diseases (hemochromatosis, β-thalassemia) to inhibit cellular Fe ingress, blockers of iron transport (such as calcium channel blockers) [61, 62, 116] and of mitochondrial iron ingress (mitoferrin inhibitors) [89, 117] have been used in these pathologies with improvement in cardiac function, reduction of ROS, and cardioprotective effects. A series of studies have been employed to determine the efficiency of iron exclusion in managing iron disequilibrium present in cardiovascular disease (Table 2). The rationale behind iron removal is based on the increased formation of ROS (i.e., hydroxyl radicals), radical effects of iron itself, increased calcium uptake via LTCC [27, 60], and ferroptosis [24], facilitated by increased levels of iron within the mitochondria [119, 124,125,126]. Additionally, the low Fe export capacity of the mitochondria makes them more susceptible to the toxic effects of iron accumulation. The only known Fe2+/3+ transporter protein, the ATP-binding cassette B8 (ABCB8), is essential in mitochondrial ferrequilibrium, as indicated by the development of cardiomyopathy in the case of ABCB8 deletion [125]. Oxidative phosphorylation in the mitochondrion is the main site of ROS production [127]. With increased iron load, the consequent lipid peroxidation and organelle damage seem to be mediated by the augmentation of combined oxidative stress and unbound Fe [128].

Table 2 Iron chelation effects in cardiovascular disease
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ABCB8, ATP-binding cassette B8; Ang II, angiotensin II; EDTA, ethylenediaminetetraacetic acid; EF, ejection fraction; Ft, ferritin; HF, heart failure; HO-1, heme-oxygenase 1; I/R, ischemia/reperfusion; ROS, reactive oxygen species; Tf, transferrin

Conclusion

The iron metabolism issue in chronic inflammatory conditions is emerging as an important therapeutic and research subject, with a particular interest in the field of cardiovascular disease, cancer [129], and neurodegenerative disorders. As advancements in the understanding of ferrequilibrium unveil, theories regarding a compelling explanation in regard to contrasting findings of iron balance must accommodate both an increase and a decrease of iron availability (Fig. 3). Given the paucity of intramitochondrial iron levels quantifications and its effects in HF cardiomyocytes and an encouraging clinical response in patients receiving IV iron supplementation, it can be difficult to ascertain the magnitude of each end of the spectrum. Of note, the majority of the beneficial effects of iron chelation come from the use of DFP. Given the ability of shuttling iron between cellular compartments rather than simply eliminating the metal, it could prove one of the links of the high-low iron conundrum.

Fig. 3
figure 3

Iron disequilibrium model in heart disease. As compared with the physiologic modulation of iron metabolism, the pathologic shift and loss of bound and unbound iron from the circulatory system into the subcellular compartments cause increased formation of reactive oxygen species and even ferroptosis

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Certainly, a few questions arise in view of the recent discrepancies that require addressing in future research endeavors: (1) What is the role of ferritins in HF? (2) Is the canonical transferrin-bound iron or other iron transport mechanisms that best explain the altered ferrequilibrium in the heart? (3) Are the current systemic markers for ID reliable and beneficial to direct iron replenishment therapies in HF patients? (4) What is the weighted effect of iron supplementation with respect to the heart versus other iron-deficient organs? and (5) Is iron treatment beneficial to ischemia/reperfusion caused HF?

It appears that even though a consistent proportion of patients with HF have a decreased systemic iron balance, recent developments have raised the issue of coexistent increased intracellular and intraorganellar iron levels, challenging the status quo of hypoferremia currently used in the clinical setting. While the systemic deficit is the main rationale behind IV iron supplementation in HF with proven symptomatic improvements, it may be that the increased mitochondrial and cardiomyocyte Fe deposits will benefit from chelation, removing the ROS generation substrate and alleviating the cells` oxidative stress and overall bioenergetic profile.