**Iron Status Biomarkers and Cardiovascular Risk**

María Pilar Vaquero, Ángel García-Quismondo, Francisco J. del Cañizo and Francisco J. Sánchez-Muniz

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69040

### **Abstract**

Both iron excess and deficiency may be related to oxidative stress. Serum ferritin, the main marker of iron status, and hepcidin, the key regulator of iron metabolism, are increased in inflammation states and their links with insulin resistance are emerging topics. We have reviewed the role of iron deficiency/overload in cardiovascular risk, including our own results. Most studies deal with the association between iron deposition in tissues and cardiovascular risk, while decreased iron status is predominantly related to protection against atherosclerosis and coronary heart disease. Less information is available on the role of iron status in type 2 diabetes mellitus (T2DM). Serum ferritin is positively correlated with several indicators of cardiovascular risk in healthy adults and diabetics, thus excess body iron is related to cardiometabolic alterations including vascular and heart damage, central obesity, and metabolic syndrome. Our data in an ample sample of T2DM adults suggest that body iron stores, evaluated as ferritin, are clearly related with some key markers of the so-called lipidic triad (high triglyceride and low high-density lipoprotein (HDL) cholesterol) levels together with the presence of small and dense low-density lipoprotein particles which also is in the frame of the dysmetabolic iron overload syndrome.

**Keywords:** iron, cardiovascular diseases, iron overload, iron deficiency, oxidative stress, hepcidin, ferritin, insulin, Type 2 diabetes Mellitus, lipidic triad, biomarker, dysmetabolic iron overload syndrome, human

### **1. Introduction**

### **1.1. Iron metabolism and regulation**

Iron is essential for life as it plays a central role in many biological processes that involve oxygen transport and storage and oxidative metabolism. This essential metal participates in

many enzymatic systems such as those involved in DNA, RNA, and protein syntheses and in the regulation of gene expression, electron transport in the mitochondria, neurotransmitter metabolism, vitamin D activation, and cholesterol catabolism through the 7α-hydroxylase linked to isoenzyme P450 cytochrome (CYP7A1c) that depends on iron and converts cholesterol to colic acid [1, 2].

Most of the functional iron in the body is present in the form of hemoglobin and myoglobin, and minor levels are part of a variety of heme and non-heme enzymes; the remainder is stored and mobilized when physiological demands are increased. The existence of two ionic forms, Fe2+ and Fe3+, means that this nutrient is capable to serve both as an electron donor and as an acceptor, which makes iron essential but also a potential toxic. In order to limit the amount of free ions that can induce free radical formation, iron is transported, bound to proteins, and stored intracellularly within a macro-protein structure, ferritin.

Iron in food is present in two forms, inorganic iron and heme iron. These forms are absorbed by different mechanisms; the heme route is highly efficient but contributes only to about 10–15% of total dietary iron. Non-heme iron bioavailability is enhanced principally by animal tissue and ascorbic acid, whereas phytic acid and polyphenols are the main inhibitors [1, 3–6]. Solubility is an important factor for iron uptake; soluble ferrous iron is transported by the divalent metal transporter (DMT1) located at the luminal side of the duodenal membrane. However, this is not as simple; on the one hand, this carrier is not iron specific and there is competition from other divalent metals, such as calcium [7] and zinc, and on the other hand, ferric ion can be also transported either after reduction to ferrous by the duodenal cytochrome B or by interaction to mucins and subsequent association with β3-integrin and mobilferrin that cross the membrane and internalize iron in the cytosol [8, 9].

It is important to emphasize that iron absorption is tightly controlled, but once absorbed there are no excretion mechanisms. In contrast, iron recycling in the body is highly efficient; senescent erythrocytes are phagocytosed by macrophages in the liver, spleen, and bone marrow. Under normal conditions, only about 10% of the 10–18 mg/day-ingested iron is absorbed. However, during late pregnancy (from 6 to 9 months), in order to cover fetal demands for growth and erythropoiesis, iron absorption increases to 25% [10]. The main serum transporter is transferrin, a protein capable of binding 1 or 2 ferric ions that are released into cells by the transferrin receptor (TfR1). Iron recycling involves 10–20 times greater iron flux than intestinal absorption, that makes approximately 20–25 mg of iron circulating daily, an amount sufficient to ensure erythropoiesis needs. This role is played by macrophages in the spleen, bone marrow, and liver (Küpffer cells) [11]. Iron losses are due to intestinal desquamation and menstruation and should balance absorbed amounts (average 1–2 mg/day). However, hemorrhages, intense menstrual blood loss [12], pregnancy, and intense growth are frequent causes of iron deficiency anemia (IDA).

In iron overload conditions, such as hereditary hemochromatosis, transferrin becomes saturated with iron and the excess occurs as non-transferrin-bound iron (NTBI) that may be toxic [13].

The discovery of the intracellular iron regulatory proteins and that of the key regulator, hepcidin, has triggered a revolution in iron metabolism research. Hepcidin, now accepted as a true hormone, was initially named liver-expressed antimicrobial peptide (LEAP-1) and shortly later renamed as hepcidin because it is expressed in the liver (hep-) and exhibits antimicrobial activity (-cidin) [14, 15].

many enzymatic systems such as those involved in DNA, RNA, and protein syntheses and in the regulation of gene expression, electron transport in the mitochondria, neurotransmitter metabolism, vitamin D activation, and cholesterol catabolism through the 7α-hydroxylase linked to isoenzyme P450 cytochrome (CYP7A1c) that depends on iron and converts choles-

Most of the functional iron in the body is present in the form of hemoglobin and myoglobin, and minor levels are part of a variety of heme and non-heme enzymes; the remainder is stored and mobilized when physiological demands are increased. The existence of two ionic forms, Fe2+ and Fe3+, means that this nutrient is capable to serve both as an electron donor and as an acceptor, which makes iron essential but also a potential toxic. In order to limit the amount of free ions that can induce free radical formation, iron is transported, bound to proteins, and

Iron in food is present in two forms, inorganic iron and heme iron. These forms are absorbed by different mechanisms; the heme route is highly efficient but contributes only to about 10–15% of total dietary iron. Non-heme iron bioavailability is enhanced principally by animal tissue and ascorbic acid, whereas phytic acid and polyphenols are the main inhibitors [1, 3–6]. Solubility is an important factor for iron uptake; soluble ferrous iron is transported by the divalent metal transporter (DMT1) located at the luminal side of the duodenal membrane. However, this is not as simple; on the one hand, this carrier is not iron specific and there is competition from other divalent metals, such as calcium [7] and zinc, and on the other hand, ferric ion can be also transported either after reduction to ferrous by the duodenal cytochrome B or by interaction to mucins and subsequent association with β3-integrin and mobilferrin

It is important to emphasize that iron absorption is tightly controlled, but once absorbed there are no excretion mechanisms. In contrast, iron recycling in the body is highly efficient; senescent erythrocytes are phagocytosed by macrophages in the liver, spleen, and bone marrow. Under normal conditions, only about 10% of the 10–18 mg/day-ingested iron is absorbed. However, during late pregnancy (from 6 to 9 months), in order to cover fetal demands for growth and erythropoiesis, iron absorption increases to 25% [10]. The main serum transporter is transferrin, a protein capable of binding 1 or 2 ferric ions that are released into cells by the transferrin receptor (TfR1). Iron recycling involves 10–20 times greater iron flux than intestinal absorption, that makes approximately 20–25 mg of iron circulating daily, an amount sufficient to ensure erythropoiesis needs. This role is played by macrophages in the spleen, bone marrow, and liver (Küpffer cells) [11]. Iron losses are due to intestinal desquamation and menstruation and should balance absorbed amounts (average 1–2 mg/day). However, hemorrhages, intense menstrual blood loss [12], pregnancy, and intense growth are frequent causes

In iron overload conditions, such as hereditary hemochromatosis, transferrin becomes saturated with iron and the excess occurs as non-transferrin-bound iron (NTBI) that may be toxic [13].

The discovery of the intracellular iron regulatory proteins and that of the key regulator, hepcidin, has triggered a revolution in iron metabolism research. Hepcidin, now accepted as a true

stored intracellularly within a macro-protein structure, ferritin.

that cross the membrane and internalize iron in the cytosol [8, 9].

terol to colic acid [1, 2].

98 Recent Trends in Cardiovascular Risks

of iron deficiency anemia (IDA).

**Figure 1** shows a scheme of the role of hepcidin on systemic iron homeostasis under conditions of high or low iron level. Hepatic hepcidin synthesis is stimulated, secreted into the circulation, and released into tissues when iron levels are high. In different cells but mainly in hepatocytes, enterocytes, and macrophages, hepcidin inhibits iron export, thus decreases absorption, recycling, and circulation of iron. This hormone therefore is a negative regulator of iron status. The mechanism of action is binding to its receptor, the cellular iron exporter ferroportin (FPN), and subsequent internalization and degradation of the hepcidin-ferroportin complex. In contrast, under physiological or pathological situations of low iron levels, hepcidin synthesis is minimized resulting in an enhanced iron flux from liver and macrophages stores and an increased transport through the duodenal basolateral membrane.

The gene-encoding hepcidin, *HAMP*, is expressed primarily in hepatocytes, although there is also evidence of expression in duodenal enterocytes, liver Kupffer cells, splenic macrophages, and placental syncytiotrophoblasts [16]. Sequencing of *HAMP* reveals several mutations that are either not functional [17] or related to a rare form of hemochromatosis [18] indicating low variability and that this gene is highly conserved in humans while the common iron metabolism alterations, either iron deficiency or hemochromatosis, have been associated with polymorphisms in other genes [19–23].

**Figure 1.** Role of hepcidin in systemic iron homeostasis. (A) High iron level conditions. Hepatic hepcidin expression and circulating hepcidin levels are increased; in hepatocytes, enterocytes, and macrophages, hepcidin is bound to the complex ferroportin-hephaestin and ferroportin is internalized and degraded; consequently, iron efflux is inhibited. (B) Low iron level conditions. Hepatic hepcidin synthesis is inhibited and serum hepcidin levels are negligible; consequently, iron crosses the membrane and is delivered into the circulation and transported to tissues by transferrin that is highly saturated (FNP: ferroportin; HP: hephaestin). Modified from Blanco-Rojo R. [24].

On the other hand, hepcidin regulation is a very active field. Many stimuli affect hepcidin transcription; the main factors are iron level, as explained above; inflammation, as hepcidin behaves as an acute phase protein; hypoxia, through the hypoxia inducible factor; and erythropoiesis signals. The details of hepcidin regulation and intracellular iron regulatory proteins involved in transcription are far beyond this revision and have been reviewed by others [16, 19, 24–27].

### **1.2. Role of macrophages in iron recycling**

Hemoglobin in erythrocytes constitutes the major iron pool of the body. Senescent or damaged erythrocytes are phagocytosed by macrophages in the spleen, bone marrow, and liver. This activity is very efficient, as daily 20–25 mg of iron is delivered from macrophages into circulation and recycled, and the amount of iron that has to be absorbed for body functions is only 1–2 mg per day. Moreover, macrophages can work as a reservoir and participate in iron homeostasis [11].

**Figure 2** shows the erythrophagocytic activity of macrophages. Once the macrophage detects an alteration or damage in the erythrocyte, the phagocytosis process is triggered. First, the erythrocyte is incorporated into the phagosome and heme is released. Then, heme is catabolized by hemoxigenase-1, and carbon monoxide, biliverdin, and Fe2+ are released. Fe2+ is transported across the phagosome membrane by DMT1 and natural resistance-associated

**Figure 2.** Erythrophagocytic activity of macrophages. CO: carbon monoxide; HO-1: hemoxygenase-1; Bv: biliverdin; DMT-1: dimetal transporter-1; Nramp1: natural resistance-associated macrophage protein; FTN: ferroportin. Modified from Blanco-Rojo R. [24].

macrophage protein (Nramp1). It seems that the presence of both transporters makes recycling more efficient. If iron is not needed for erythropoiesis, it is stored as ferritin in the form of Fe3+. Finally, iron is released into the circulation via ferroportin and hephaestin (HP), and the iron is donated to transferrin to be reutilized [28].

### **2. Role of iron in oxidative status**

The redox potential of iron, that is the switch between Fe2+ and Fe3+, is essential for many biochemical reactions but is also a potential threat. Iron toxicity is based on the Fenton and Haber-Weiss reaction, which generates •OH (hydroxyl radicals) from H2 O2 (hydrogen peroxide) and superoxide (•O2 − ) in the presence of catalytic amounts of iron. The first step of the catalytic cycle involves reduction of ferric ion to ferrous:

$$\mathrm{Fe^{3+} + \*O\_2 {}^{-} \to Fe^{2+} + O\_2} \tag{1}$$

The second step is:

$$\mathrm{Fe^{2+} + H\_2O\_2 \to Fe^{3+} + OH^- + \bullet OH} \tag{2}$$

Net reaction:

On the other hand, hepcidin regulation is a very active field. Many stimuli affect hepcidin transcription; the main factors are iron level, as explained above; inflammation, as hepcidin behaves as an acute phase protein; hypoxia, through the hypoxia inducible factor; and erythropoiesis signals. The details of hepcidin regulation and intracellular iron regulatory proteins involved in transcription are far beyond this revision and have been reviewed by

Hemoglobin in erythrocytes constitutes the major iron pool of the body. Senescent or damaged erythrocytes are phagocytosed by macrophages in the spleen, bone marrow, and liver. This activity is very efficient, as daily 20–25 mg of iron is delivered from macrophages into circulation and recycled, and the amount of iron that has to be absorbed for body functions is only 1–2 mg per day. Moreover, macrophages can work as a reservoir and participate in iron

**Figure 2** shows the erythrophagocytic activity of macrophages. Once the macrophage detects an alteration or damage in the erythrocyte, the phagocytosis process is triggered. First, the erythrocyte is incorporated into the phagosome and heme is released. Then, heme is catabolized by hemoxigenase-1, and carbon monoxide, biliverdin, and Fe2+ are released. Fe2+ is transported across the phagosome membrane by DMT1 and natural resistance-associated

**Figure 2.** Erythrophagocytic activity of macrophages. CO: carbon monoxide; HO-1: hemoxygenase-1; Bv: biliverdin; DMT-1: dimetal transporter-1; Nramp1: natural resistance-associated macrophage protein; FTN: ferroportin. Modified

others [16, 19, 24–27].

100 Recent Trends in Cardiovascular Risks

homeostasis [11].

from Blanco-Rojo R. [24].

**1.2. Role of macrophages in iron recycling**

$$\bullet \mathrm{O}\_{2}\mathrm{\text{--}} + \mathrm{H}\_{2}\mathrm{O}\_{2} \rightarrow \bullet \mathrm{OH} + \mathrm{OH}^{-} + \mathrm{O}\_{2} \text{(where Fe acts as a catalyst metal)}\tag{3}$$

The catalytic action of iron also leads to the formation of organic reactive oxygen species (ROS), such as peroxyl radicals (ROO•), alkoxyl radicals (RO•), thiyl radicals (RS•), sulfonyl radicals (ROS•), thiyl peroxyl radicals (RSOO•), and disulfides (RSSR). Similarly, heme iron catalyzes the formation of ROS, via the formation of oxoferryl intermediates. In addition, ferrous iron can also contribute as a reactant to free radical generation [29].

It is worth mentioning that ROS are normally produced by the mitochondria aerobic metabolism through the incomplete reduction of molecular oxygen. ROS can also be generated by the membrane-bound NADPH oxidase complex that is an important tool for the antimicrobial defense and is mainly expressed not only in phagocytic macrophages but also in neutrophils and other cell types.

ROS are highly reactive species and promote the oxidation of proteins, nucleic acids, and membrane lipids. Any increase in the ROS levels beyond the antioxidant capacity of the organism causes oxidative stress [29]. In this regard, in primary and secondary iron overload conditions, such as in hereditary hemochromatosis and thalassemia, respectively, oxidative stress is observed as the iron-binding capacity of transferrin gets saturated and high levels of non-transferrin-bound iron reach the cell, are internalized, and induce tissue damage [30, 31].

Excess iron is involved in the pathophysiology of chronic inflammation, Alzheimer disease, diabetes, atherosclerosis, and, generally, cardiovascular diseases (CVD).

### **3. Iron excess and cardiovascular risk**

### **3.1. The iron hypothesis**

Early in the 1980s, Sullivan published in *The Lancet* the hypothesis that higher-stored iron in men and postmenopausal women compared to premenopausal women increase the risk of heart diseases and that iron deficiency is a protective factor [32]. This was supported by epidemiological studies; positive associations between serum ferritin (marker of iron stores), and the cholesterol transported by low-density lipoproteins (LDL-cholesterol) that were reported in men [33]. But other data do not support this hypothesis [34, 35] and the debate still continues. Our research group and others have reported that iron-deficient and anemic women present low lipid levels that increase during pharmacological treatment with iron salts, although final values are in normal range [36, 37]. Other studies coincide in the gender and age differences in iron metabolism and lipoprotein metabolism and the lower cardiovascular risk in women compared to men [38]. However, there may be several interacting factors. In this regard, estrogens are related to higher levels of cholesterol transported by high-density lipoproteins (HDL-cholesterol) and aldosterone that may partly explain lower atherosclerosis and hypertension risk [39]. However, age has been suggested to exert higher influence than hormones as estrogens explain about 25% of the phenotype differences related to cardiovascular risk, and thus menopausal women have higher cardiovascular risk than fertile women mainly due to age [40]. Studies in older men and women do not support the Sullivan's hypothesis and are rather opposite, with a subgroup of individuals who have low iron stores and higher cardiovascular risk [41]. Likewise, our findings in an elderly population consuming a variant of the Mediterranean diet show that prevalence of anemia is higher than that of high ferritin [42].

Therefore, it is likely that iron is only one of the players in the pathophysiological process of cardiovascular diseases.

### **3.2. Iron excess and atherosclerosis**

Atherosclerosis is a chronic inflammatory disease affecting the arterial intima [43, 44]. Endothelial dysfunction induces recruitment of LDL particles and blood monocytes that differentiate into macrophages, phagocyte lipid material, and are transformed into foam cells [45]. The possibility that iron plays an interacting role emerges from its capacity to enhance the formation of ROS and LDL oxidation and its presence in macrophages, where a reservoir of intracellular iron may remain if body iron is high. In this regard, high iron levels hypothetically increase atherosclerosis risk.

However, there are many doubts on this hypothesis. Results from the ARIC study, carried out in the 1990s, did not find an association between ferritin values and LDL oxidation [43] or ferritin and asymptomatic carotid atherosclerosis [44]. Likewise, a recent systematic analysis by Hosseini [46] concludes that iron intake/status is not associated with carotid intima media thickness. In this issue, it could be speculated that the effect of iron is related to the "labile pool" or unbound iron more than to the total amount of iron in the body.

Results from the MONICA study in France [47] show that carotid atherosclerosis was positively associated with serum ferritin in individuals free from subclinical inflammation. In another study [48], atherosclerotic plaque specimens, which were removed from carotids of patients as a stroke reduction strategy, were analyzed. The study compared symptomatic and asymptomatic plaques considering that stroke symptoms occur when carotid bifurcation plaque ruptures and clots move into the cerebral circulation. It has been assumed that iron accumulates in atherosclerosis plaques following plaque rupture and hemorrhage since phagocytosed erythrocytes have been identified in plaque macrophages. It was found that in the symptomatic plaque (causing stenosis and cerebrovascular symptoms), iron is associated with the patient's LDL-cholesterol level. Furthermore, iron is abundant in such unstable plaques within thrombus, in the presence of macrophages, and away from calcium and zinc, elements that co-localize in areas of plaque mineralization. Finally, iron in asymptomatic plaque (causing stenosis but not neurological symptoms) was present as ferritin and was observed in association with CD68-positive macrophages.

**3. Iron excess and cardiovascular risk**

is higher than that of high ferritin [42].

**3.2. Iron excess and atherosclerosis**

cardiovascular diseases.

increase atherosclerosis risk.

Early in the 1980s, Sullivan published in *The Lancet* the hypothesis that higher-stored iron in men and postmenopausal women compared to premenopausal women increase the risk of heart diseases and that iron deficiency is a protective factor [32]. This was supported by epidemiological studies; positive associations between serum ferritin (marker of iron stores), and the cholesterol transported by low-density lipoproteins (LDL-cholesterol) that were reported in men [33]. But other data do not support this hypothesis [34, 35] and the debate still continues. Our research group and others have reported that iron-deficient and anemic women present low lipid levels that increase during pharmacological treatment with iron salts, although final values are in normal range [36, 37]. Other studies coincide in the gender and age differences in iron metabolism and lipoprotein metabolism and the lower cardiovascular risk in women compared to men [38]. However, there may be several interacting factors. In this regard, estrogens are related to higher levels of cholesterol transported by high-density lipoproteins (HDL-cholesterol) and aldosterone that may partly explain lower atherosclerosis and hypertension risk [39]. However, age has been suggested to exert higher influence than hormones as estrogens explain about 25% of the phenotype differences related to cardiovascular risk, and thus menopausal women have higher cardiovascular risk than fertile women mainly due to age [40]. Studies in older men and women do not support the Sullivan's hypothesis and are rather opposite, with a subgroup of individuals who have low iron stores and higher cardiovascular risk [41]. Likewise, our findings in an elderly population consuming a variant of the Mediterranean diet show that prevalence of anemia

Therefore, it is likely that iron is only one of the players in the pathophysiological process of

Atherosclerosis is a chronic inflammatory disease affecting the arterial intima [43, 44]. Endothelial dysfunction induces recruitment of LDL particles and blood monocytes that differentiate into macrophages, phagocyte lipid material, and are transformed into foam cells [45]. The possibility that iron plays an interacting role emerges from its capacity to enhance the formation of ROS and LDL oxidation and its presence in macrophages, where a reservoir of intracellular iron may remain if body iron is high. In this regard, high iron levels hypothetically

However, there are many doubts on this hypothesis. Results from the ARIC study, carried out in the 1990s, did not find an association between ferritin values and LDL oxidation [43] or ferritin and asymptomatic carotid atherosclerosis [44]. Likewise, a recent systematic analysis by Hosseini [46] concludes that iron intake/status is not associated with carotid intima media thickness. In this issue, it could be speculated that the effect of iron is related to the "labile

pool" or unbound iron more than to the total amount of iron in the body.

**3.1. The iron hypothesis**

102 Recent Trends in Cardiovascular Risks

Therefore, iron may be involved both in the initial step of atherosclerosis by activating LDL oxidation and in the final step linked to the vessel lesion within the plaque. Interestingly, increasing the iron levels in circulating macrophages do not increase atherosclerosis [49]. In a mouse model of atherosclerosis (ApoE-/-), mice were fed with a high-fat diet and their tissue iron was increased by parenteral iron administration and a genetic mutation in ferroportin [49]. Iron loading produced an iron level increase in macrophages, liver, and spleen and resulted in the activation of the macrophage antioxidant defenses and in the storage of iron in the form of ferritin. Clearly, this regulation reduced NTBI and toxicity.

With the hypothesis that blood donation reduces cardiovascular risk by lowering body iron status, a study was done in 819 healthy blood donors in the Netherlands [50]. Data included blood donation frequency, body iron status parameters, and a measure of the carotid intimamedia thickness (CIMT). Body iron status was not related to CIMT, but CIMT was slightly and not significantly reduced in frequent donors. Therefore, blood donation might give some protection against atherosclerosis in individuals predisposed to accumulate iron in excess, but the mechanism may be independent of total body iron.

The possibility that heme instead of iron is the inductor of LDL oxidation has also been investigated [51, 52]. Heme oxygenase-1, the heme-catabolizing enzyme, is therefore crucial for heme detoxification (see HO-1 in **Figure 2**). HO-1 induction results in an increase in free iron and ferritin upregulation, which means iron storage and protection of the cell [51]. Interestingly, a child with HO-1 deficiency showed elevated plasma heme levels, extensive LDL oxidation, severe endothelial damage, and accelerated atherosclerosis, and thus the possibility of a HO-1 therapy that mitigates some of the symptoms is a matter of research [52, 53].

### **3.3. Lessons from hemochromatosis and other iron overload disturbances**

Type 1 hereditary hemochromatosis (HH) is a genetic disease defined as homozygous for the C282Y mutation of the *HFE* gene. This gene is located in chromosome 6 and encodes the major histocompatibility complex class I-like protein HFE. The prevalence of HH is approximately 0.1% in the population of Caucasian origin. However, low morbidity has been found in HH and most of the C282Y +/+ have no iron overload phenotype or are asymptomatic until adulthood. Cash et al. [30] compared vascular function, biochemical endothelial markers, and antioxidant status between HH patients (C282Y homozygous and high serum-ferritin levels) and controls. Noninvasive pulse wave analysis and pulse wave velocity were applied to carotid and radial arteries to estimate endothelial dysfunction. They reported that male HH patients had higher pulse wave velocity; however, this effect disappeared after adjusting for hypertension. In both sexes, HH was associated with diminished antioxidant levels but neither increase in lipid peroxidation nor alteration in the systemic inflammation marker (i.e., C-reactive protein) could be demonstrated [30]. Thus, controversy remains on the idea that cardiovascular risk is high in hemochromatosis patients [54].

Iron overload is usually a complication of thalassemia, particularly in patients who require red blood cell transfusions. Among the three types of thalassemia, thalassemia intermedia is characterized by ineffective erythropoiesis, anemia, medullary expansion, and extramedullary hematopoiesis. In contrast to HH, thalassemic patients show a proatherogenic biochemical phenotype which may contribute to enhance cardiovascular risks [31].

There are other iron overload pathological situations, where bone medulla is inefficient and iron overload results from repeated transfusions. In such syndromes, the amount of body iron can reach very high values and myocardial damage is the most frequent collateral effect of the treatment. In these cases, iron chelation therapy may result in higher quality of life and reduction of cardiac events [55].
