Plasma iron is carried in the erythrocytes (1 - 2 g) and circulates in the plasma (5 mg). Daily, 1 - 2 mg of iron is absorbed in the intestine, but the same amount is released by the exfoliation of the mucous membrane. The most significant amount of the iron (20 - 25 mg/day) derives by erythrophagocytosis from the discharge of iron deriving from senescent erythrocytes recycled by Kupffer cells and macrophages from the spleen [1] [2] [3] [4] [5] .

After the reduction of ferric iron to ferrous iron by the duodenal cytochrome B reductase (DCYTB), non-heme iron is absorbed in the duodenum and jejunum, carried by the bivalent metal apical transporter 1 (DMT1) [6] .

Once inside cells, iron is linked to chaperones like poly-(rC)-binding proteins delivering iron itself to ferritin that is the cellular iron store capable of keeping high amounts of iron atoms [1] [6] [7] . Alternatively, iron is exported to plasma from the ferroportin (FPN) by the basolateral membrane according to the needs [6] .

Tissue and circulating iron levels are controlled by several genes such as Hamp, Emojuvelin (HJV) and HFE (Table 1) which are under post-transcriptional regulation according to the systemic iron levels [8] .

During iron deficiency, the transcription of those gene messengers involved in iron absorption (TFR1 and FPN) is stimulated; on the other side, the transcription of those proteins involved in the iron storage (ferritin) is prevented [8] .

The regulation between circulating and stored iron is due to the HAMP gene which encodes for Hepcidin [9] and to FPN1 gene (SLC40A1) which encodes for FPN [7] (Table 1).

Hepcidin is a peptide hormone playing a key role in iron homeostasis [9] - [14] . It is produced mostly by the liver and it is expressed in macrophages, gut, spleen and basically reduces iron cell uptake by inhibiting FPN, which is the main cell iron exporter [9] - [14] .

Mostly, hepcidin level is influenced by two factors: iron level and inflammation [8] [10] [13] . The first acts principally by stimulating the bone morphogenetic proteins (BMPs 2 - 6) which activate iron pathways through SMAD proteins [15] .

BMP6 level is strictly related to iron levels, while BMP2 is constitutively expressed allowing a basal hepcidin synthesis [15] [16] [17] [18] .

BMP6 by binding its receptors BMPR1 and BMPR2 and its co-receptor hemojuvelin allows the activation of SMAD4 which translocates to the nucleus to

HH: Hereditary Hemocromatosis, JH: Juvenile Hemocromatosis; IRIDA; Iron Refractory Iron Deficiency Anemia.

bind specific sequences (BMP-responsive elements, BMP-REs) of the hepcidin promoter [13] [15] (Table 1).

On the contrary, during iron deficiency, BMP-mediated signal is suppressed by a specific hepatic inhibitor, matriptase 2 (TMPRSS6) (Table 1) [19] [20] [21] [22] . Matriptase II is mainly expressed in the liver and reduces BMP-mediated signal on hepcidin transcription by cleaving hemojuvelin (the BMP co-receptor protein) [21] . Mutations affecting matriptase II cause the lack of inhibition of hepcidin and the constitutive activation of hepcidin pathway, leading to a rare form of iron deficiency called “iron refractory deficiency anemia” (IRIDA) [22] [23] (Table 1).

Moreover, inflammation acts on hepcidin pathway mainly by lipopolysaccharides (LPS) and interleukin 6 (IL-6) (through the JAK/STAT pathway) which prevent iron export by inhibiting FPN through its ubiquination and by its internalization in lysosomes [24] - [30] .

The mutation of the FPN ubiquitination leads to a severe iron overload since mutant FPN types fail to be inhibited and they continue to export iron [27] [28] [29] [30] (Table 1).

These insights have suggested pharmacological strategies to manipulate iron pathways. In this regard some compounds are proven to prevent the hepcidin pathway due to inflammation, such as GDF 15, erythroferron and heparin [31] - [36] .

Specifically, GDF15 has been recognized to be a strong hepcidin suppressor, reducing BMP /hepcidin pathways by inhibiting the release of IL-6 and IL-1 by macrophages [31] (Table 2).

IDA: Iron Deficiency Anemia; IRIDA: Iron Refractory Iron Deficiency Anemia; HF: Heart Failure.

Similarly, erythroferron inhibits the hepcidin pathway through the suppression of BMP/SMAD signal [32] [33] [34] (Table 2). Again, heparin has been recently shown to be a strong suppressor of hepcidin, by inhibiting BMP6/SMAD pathways due to blocking hepcidin receptor [35] [36] (Table 2).

Noteworthy, in preclinical models, rapamycin and tacrolimus inhibit hepcidin expression by binding the BMP type I receptor in hepatocytes [37] .

To date, the main effort should be focused on recognizing novel compounds able to influence the major drivers involved in iron pathways such hepcidin, FPN, Matriptase2 and emojuvelin. In this regard, clinical trials are testing agonists and blockers for therapeutic use as shown in Table 3.

Iron is a crucial element for hemoglobin synthesis and for heme and iron-sulfur (Fe/S) clusters production [1] [2] . It takes part in vital biological processes such as breathing, nucleic acid replication, repair, metabolic and host defense reactions [1] [2] . Thus, physiologically it is strictly controlled to avoid both deficiencies and overloads, being an example of balance between inputs and outputs [2] [3] [4] . However, despite its crucial role in many vital functions, it can result toxic if dysregulated [2] [3] . In this regard, recent acquisitions have shown that iron imbalance results critical in several heart conditions [38] - [81] .

Physiologically, cardiac hepcidin values are lower than liver ones, but they increase during ischemia, hypoxia and inflammation, in response to the inflammatory trigger in the early phase of myocardial infarction (MI) according to IL-6 level, BMP6 level [41] and B-type natriuretic release [68] . The increased hepcidin circulating levels in MI were considered as a negative prognostic factor related to endothelial damage and plaque instability [82] . In this regard, a recent study considers the hormone hepcidin as a novel biomarker in HF, showing that circulating hepcidin levels fit with HF stage [69] .

In HF patients, low hepcidin levels due to iron deficiency and low hepatocytes iron depots are predictors of mortality (AFFIRM -AHF trial) [66] .

Some authors recognize that high levels of hepcidin in hemodialysed patients are considered a risk predictor for fatal and non-fatal cardiovascular events [47] . Manlov et al. observed a key role of iron in pathophysiology of atherosclerosis and cardiovascular disease in 63 hemodialysed patients showing that high hepcidin levels were related to plaque instability [47] . On the contrary, due to the lower hepcidin level, patients with hemochromatosis show a lower risk of atherosclerosis, despite the increased risk of iron related cardiomyopathy [48] .

Again, authors show that high circulating hepcidin levels in Kawasaki patients are related to coronary atherosclerosis and lack of clinical response to therapy [49] , while in Friedreich ataxia (FA) they are associated with heart dysfunction and cardiomyopathy due to the increased iron stored in mitochondria [70] [71] .

Recently, increasing evidences have shown the occurrence of iron disorders such as anemia (Hb < 13 g/dl) and iron deficiency (ferritin < 100 ng/mL and transferrin saturation TSAT < 20%) in systolic HF patients [51] - [65] . These conditions affect about 50% of HF patients, increasing the risk of mortality by more than 40% [51] - [65] .

HF is a chronic condition requiring lifestyle changes, an appropriate drug therapy and the possible associated use of cardiac resynchronization therapy [51] - [65] .

Due to the heart’s inability to pump blood effectively and to deliver oxygen to critical organs, such as kidney, brain and muscle, patients suffering from HF show several symptoms, such as dyspnea, cough, asthenia, edema and memory impairment [59] [60] [61] [65] .

Patients who are asymptomatic or who respond to therapy have a long life expectancy before the decline of ventricular function, since compensation mechanisms maintain an adequate cardiac function [56] [57] [58] .

Despite improvements in HF therapy, most patients still show progressive worsening of ventricular function with an increased risk of potentially fatal cardiac arrhythmias, showing high mortality rates.

In recent years, the management of anemia and iron deficiency are considered critical goals in patients suffering from HF [52] [54] [59] and several randomized controlled trials and meta-analyses have highlighted the beneficial effects of iron therapy in anemic HF patients, in terms of QoL and functional capacity, especially in systolic HF [59] (Table 4).

Despite the iron deficiency is still recognized to be a minor comorbidity in HF, the pathomechanism of this condition could be strictly influenced by anemia through two main mechanisms [53] [54] [55] [60] (Figure 1).

In Table 4 are illustrated interventional phased IV studies (enrolled patients n ≥ 50) which consider as primary endpoints the assessment of the clinical benefits concerning exercise capacity, QoL, recurrence of hospitalization and cardiovascular death during i.v. iron therapy (ferric carbossimaltose, derisomaltose) and/or oral iron therapy (sucrosomial) in patients with iron defects and several cardiovascular diseases (HF, MI and aortic stenosis). ID: IRON DEFICIENCY; IDA: IRON DEFICIENCY ANEMIA; MI: MYOCARDIAL INFARCTION; FCM: FERRICCARBOXYMALTOSE; AS: STENOSIS OF THE AORTA; LVSD: LEFT VENTRICULAR SYSTOLIC DYSFUNCTION; i.v.: intravenous.

Patients with HF may present pre-existing absolute anemia due to blood loss, unbalanced diet, use of anticoagulants or malnutrition [54] . Iron deficiency could affect myocardiocyte metabolism through the imbalance of the production of ATP, leading by itself to cell energetic and mitochondrial imbalance with impairment of ventricular performance and HF with reduced ejection fraction (HFrEF) [56] [62] . Indeed, according to the “iron hypothesis”, iron deficiency can itself trigger HF leading to myocardial and mitochondria energetic failure in HFrEF [56] [61] [62] (Figure 1).

On the other hand, the second “inflammatory” hypothesis assumes that cytokines, released as a result of pre-existing cardiac injury (myocarditis, ischemia, valvulopathy, etc.) or other diseases (diabetes, cancer, obesity), could lead to a functional anemia (with iron sequestration and increased ferritinemia) by stimulating the hepcidin/ferroportin axis and by inducing a fibrotic and adverse myocardial remodeling which predisposes to HF with preserved ejection fraction (HFpEF) [63] [64] [65] . Recent evidences show that inflammatory cytokines could increase nitroxide levels which stimulate IREs and IRP1 that ultimately lead to upregulation of the Hamp gene traduction [8] [13] (Table 1). The consequent overload of the hepcidin level leads to the upregulation of ferritin leading to an iron cytotoxicity dose related due to NBTI (non-binding transferrin iron) [72] [73] [74] [75] . NBTI is a free toxic species of iron which binds to low molecular weight compounds of hepatocytes, pancreatic cells and cardiomyocytes leading to liver fibrosis, chronic HF, diabetes, hypopituitarism and other severe complications [72] [73] [74] [75] .

Moreover, the systemic anemic state sustains a hypoxic condition which triggers a neurohormonal reaction leading to a peripheral vasodilation and systemic hypotension. These phenomena produce the reactive activation of the sympathetic system and the renin angiotensin aldosterone system (RAA) with consequent vasoconstriction which causes decreased blood flow to the peripheral organs and to the kidney with a decreased renal function, decreased glomerular filtration rate (VFG) and decreased Erythropoietin (Epo) release. The consequent lower excretion of sodium and water produces peripheral edema, central and peripheral venous congestion thus stressing the cardiac cavities by producing an altered cardiac hemodynamics and pressure overload leading to a detrimental heart condition and to HFpEF (Figure 1).

We performed a computerized literature search on studies and trials by using the following search terms (also combining them): (anemia, iron, iron deficiency, hepcidin, hepcidin agonist, hepcidin blocker, emojuvelin, matriptase II, ferroportin, heart, heart disease).

This search was achieved in the following databases: PubMed and clinicaltrials.gov. We have selected clinical trials published in the last five years (2018-2023).

Iron is crucial for several biologic functions [1] . Thus, the maintenance of the iron metabolism is strictly controlled at several levels by various genes and encoded proteins. The most important known genes involved in iron regulation, encode for key players of the hepcidin/ferroportin axis (Table 1). Mutations affecting these genes are involved in congenital or acquired iron disorders such as anemia or hemochromatosis (Table 1).

In Table 2 are summarized synthetic and physiologic compounds involved in hepcidin/ferroportin axis modulation. Hepcidin activity is inhibited by several compounds, including GDF-15, heparin and erytroferrone which act through the inhibition of inflammation mediated by BMP and cytokines, as shown in Table 2. Most of these compounds are considered in patients suffered from IDA and anemia of inflammation (Table 2). Furthermore, preclinical studies have evaluated minihepcidins PR73 which are small peptides more effective than hepcidin to inhibit FPN (Table 2). Noteworthy, sodium glucose cotransporter 2 inhibitors largely used in HF patients are considered in patients with IRIDA (Table 2). In Table 3, we have reviewed interventional ongoing studies which have assessed safety profile and efficacy of hepcidin/ferroportin targeted compounds. As shown, most of them are phased I - II ongoing studies. The hepcidin blocker PRS-080 is evaluated in anemic conditions, while hepcidin mimetic, FPN blockers and anti TMPRSS6 are tested in iron overload (Table 3). Specifically, PRS-80 is evaluated in 2 phased I - II ongoing studies conducted in healthy and anemic subjects.

To date, the hepcidin mimetic PTG 300 is tested in 5 phased II - III ongoing studies, while the synthetic human hepcidin LJPC-401 is evaluated in 2 phased II ongoing studies. Moreover, two anti TMPRSS6 molecules (SLN124 and IONIS TMPRSS6-Lrx) are under investigation in phased I - II ongoing studies which are conducted in iron overloaded patients. To date, Vamifeport (VIT 2763) is the only FPN blocker which is considered, and it is under investigation in 4 phased I - II studies.

As reported in Table 3, two clinical trials have enrolled healthy subjects (NCT-02340572-NCT05077436), N. 8 trials have enrolled anemic patients (NCT03388133-NCT04054921-NCT03325621-NCT02754167-NCT03165864-NCT04817670-NCT04364269-NCT04938635). N. 5 clinical trials are conducted on patients with iron overloaded diseases, such as hemochromatosis (NCT03395704) and polycythemia vera (NCT04057040-NCT04767802-NCT06033586-NCT05499013).

Noteworthy, a phased IV study (NCT04707261) on the reduction of the hepcidin pathway by Dapaglifozin has enrolled a large cohort of anemic HF patients (n = 1990).

Preliminary data, supported by clinical evidence, have proven that iron stabilization is effective in improving cardiac failure in patients with anemia and HF (Table 4).

Most of the reviewed interventional phased IV studies are conducted on intravenous (i.v.) iron (Table 4).

Iron administrated was largely ferrocarboxymaltose (FCM), but IRONMAN and IRONMET-HFpEF studies were conducted on ferric derisomaltose. Several clinical interventional phased IV studies conducted on large populations (n ≥ 50) including FAIR-HF(NCT00520780) and CONFIRM-HF (NCT01453608) show that the administration of FCM i.v. improves QoL in patients with HF associated with iron deficiency (Table 4). Noteworthy AFFIRM-HF study proved that that FCM i.v. reduces the hospitalizations by 21% (NCT02937454) (Table 4). As reported in Tab.4, at least n.15 interventional phased IV studies (enrolled patients n. > 50) have assessed the clinical benefits concerning exercise capacity, QoL, recurrence of hospitalization and cardiovascular death after intravenous (i.v.) iron administration (ferric carbossimaltose, derisomaltose) or after oral iron administration (sucrosomial) in patients with iron defects and cardiovascular diseases (HF, MI and aortic stenosis).

As shown in Table 5, ongoing observational studies have recognized hepcidin level as a novel specific biomarker of iron deficiency (NCT02889133-NCT-02637102-NCT04986033-NCT004437866), iron overload (NCT00512564), iron loss (NCT00338234) and acute inflammatory state (NCT01589874) in several conditions.

ICU: Intensive Care Unit; CAD: Coronary Artery Disease.

Iron plays a crucial role in supporting main vital functions and the latest recommendations have recognized that iron check and iron correction are mandatory in patients with HF [71] .

Iron sustains the myocardiocyte metabolism and several pieces of evidences report that iron defects are involved in pathomechanism of several cardiovascular diseases, including HF [61] [71] (Figure 1).

In the light of the main genes taking part in iron regulation (Table 1), we considered those compounds potentially involved in the modulation of hepcidin/ferroportin axis, which is the main pathway for iron signaling (Table 2). In our opinion, these hepcidin targeted compounds should be largely tested in cardiovascular patients. The major goal should be the improvement of iron levels in cardiomyocytes, inducing few changes in systemic iron levels.

The emerging evidence on synthetic hepcidin agonists, hepcidin blockers, anti FPN and anti TMPRSS6 are supplying new insight to modulate iron pathways in iron defected/overloaded patients [82] - [96] (Table 2 and Table 3). To date, the hepcidin agonist PTG300 results in an advanced state of investigation (phased III ongoing studies NCT05210790) in a large cohort of patients suffering from policitemia vera.

Furthermore, sodium glucose co-transport2 (SGLT2) inhibitors have been proven to reduce the risk of cardiovascular death and hospitalization in HF patients with a beneficial effect on hemoglobin level by decreasing the hepcidin pathway [97] [98] [99] . Noteworthy, the hepcidin modulation capability by dapaglifozin is under investigation in ADIDAS study conducted on a large cohort of anemic HF patients (NCT04707261) (Table 3).

HF has long been recognized as an irreversible disease but in recent years this concept has been revised and recent studies show that an early diagnosis associated with an appropriate therapy could improve the clinical scenario of HF [67] . Recent clinical trials (2018-2023) conducted in patient suffering from HF and iron deficiency have proved the beneficial clinical effects of drugging iron regard QoL, hospitalizations and cardiovascular death (Table 4).

Table 5 shows those studies which have evaluated hepcidin as a novel disease specific biomarker of iron imbalance. Actually, authors have proven that circulating hepcidin level could also improve diagnosis of cardiac damage and atherosclerosis achieving an enhanced classification and a more accurate stratification of HF patients effective in clinical practice [43] [47] [49] .

In our opinion, the issue that iron deficiency in cardiovascular patients is underestimated and untreated, represents the major limitation of the reviewed literature. Consequently, novel hepcidin/ferroportin targeted compounds are not tested in cardiovascular patients (Table 3). In addition, the evidence of the critical role of iron administration in cardiovascular setting comes from few studies conducted in heterogeneous populations (Table 4).

We consider crucial to answer to this clinical gap. We advocate that results on novel compounds will provide new skills to modulate hepcidin/ferroportin axis by suggesting a personalized approach with translatable findings in the cardiovascular setting.

We would like to thank Prof. Claudio Napoli for helpful comments and suggestions.

Not applicable.

Ethics approval and consent to participate.

All the authors approved the submission.

The authors have no funding to declare.

The authors declare that they have no competing financial interests or personal relationships that could appear to have influence the content of this paper.

De Pascale, M.R., Rondinelli, M.B., Ascione, F., Maffei, V., Di Lorenzo, C., Scagliarini, S., Faraonio, R. and Faiella, A. (2024) Iron and Heart Failure: Current Concepts and Emerging Pharmacological Paradigms. World Journal of Cardiovascular Diseases, 14, 195-216. https://doi.org/10.4236/wjcd.2024.144016