Review
Iron in arterial plaque: A modifiable risk factor for atherosclerosis

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Abstract

It has been proposed that iron depletion protects against cardiovascular disease. There is increasing evidence that one mechanism for this protection may involve a reduction in iron levels within atherosclerotic plaque. Large increases in iron concentration are seen in human atherosclerotic lesions in comparison to levels in healthy arterial tissue. In animal models, depletion of lesion iron levels in vivo by phlebotomy, systemic iron chelation treatment or dietary iron restriction reduces lesion size and/or increases plaque stability. A number of factors associated with increased arterial disease or increased cardiovascular events is also associated with increased plaque iron. In rats, infusion of angiotensin II increases ferritin levels and arterial thickness which are reversed by treatment with the iron chelator deferoxamine. In humans, a polymorphism for haptoglobin associated with increased cardiovascular disease is also characterized by increased lesional iron. Heme oxygenase 1 (HO1) is an important component of the system for mobilization of iron from macrophages. Human HO1 promoter polymorphisms causing weaker upregulation of the enzyme are associated with increased cardiovascular disease and increased serum ferritin. Increased cardiovascular disease associated with inflammation may be in part caused by elevated hepcidin levels that promote retention of iron within plaque macrophages. Defective retention of iron within arterial macrophages in genetic hemochromatosis may explain why there is little evidence of increased atherosclerosis in this disorder despite systemic iron overload. The reviewed findings support the concept that arterial plaque iron is a modifiable risk factor for atherogenesis.

Introduction

Nearly three decades ago, it was suggested that a state of sustained iron depletion or mild iron deficiency exert a primary protective action against ischemic heart disease [1], [2], [3], [4], [5], [6], [7], [8]. This “iron hypothesis” was offered as an explanation of the sex difference in coronary disease incidence and the increase in incidence among women after menopause. Despite significant controversy, the idea has achieved standing as a plausible and testable hypothesis [9], [10], [11], [12], [13]. A protective effect of iron depletion that may have multiple beneficial consequences is decreased availability of redox-active iron in vivo [2], [14].

It has been proposed that the amount of free iron available at sites of oxidative or inflammatory injury is a function of the stored iron level and that the availability of redox-active iron in vivo approaches its minimum in the state of iron depletion. There is significant experimental support for this concept [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35]. In particular, it has been shown that removal of stored iron from the body can decrease the amount of iron deposition within atherosclerotic lesions in animal studies. Depletion of lesion iron levels in vivo by phlebotomy, systemic iron chelation treatment or dietary iron restriction reduces lesion size in these studies and increases plaque stability [18], [31], [36], [37], [38]. The original formulation of the iron hypothesis did not specify a mechanism. There may well be multiple mechanisms by which iron depletion protects against heart disease. This animal work as well as a number of more recent studies focuses attention on pathogenic roles for iron within arterial plaque. Iron is present in atherosclerotic plaque at concentrations that appreciably exceed that found in healthy arterial tissue. This iron is not simply an inert component of plaque. Some of the arterial iron is redox active and the ferritin- and hemosiderin-bound iron compartment remains a reservoir of potentially reactive iron within lesions. Does this iron have a role in the production of clinical events? Does it affect plaque stability? Are there any modalities that can decrease the concentration of plaque iron? Would such removal of plaque iron by induced iron deficiency or treatment with iron chelators decrease plaque vulnerability? There have now been a number of studies that provide evidence for one potential mechanism by which iron depletion may protect against atherothrombotic disease. This article will review that work and its relevance to the iron hypothesis.

Section snippets

Presence and modifiability of plaque iron: Early work in animal models and in human studies

In a 1992 study, Smith et al. [39] demonstrated the presence of catalytic iron in material taken from human atherosclerotic lesions, providing important indirect support for the iron hypothesis. Iron deposits in atherosclerotic lesions in the cholesterol-fed rabbit were later confirmed by nuclear microscopy and in human lesions by conventional histologic staining [38], [40].

Matthews et al. [41] observed a large and significant decrease in total aorta cholesterol concentration after iron

Iron in human carotid lesions

Using electron paramagnetic resonance (EPR) spectroscopy and inductively coupled plasma mass spectroscopy (ICPMS) Davies and colleagues [46] quantified iron in ex vivo carotid lesions and in healthy human arteries. They found elevated levels of iron in the intima of lesions compared with healthy controls (0.370 versus 0.022 nmol/mg tissue by EPR, 0.525 versus 0.168 nmol/mg tissue by ICPMS, P p < 0.05 in both cases). Cholesterol levels in lesions correlated positively with iron accumulation. In

Angiotensin II and arterial iron deposition

Ishizaka et al. [57] found that angiotensin II infusion for 7 days in rats caused a > 20-fold increase in ferritin protein expression over control values in aortic endothelial and adventitial cells, including monocytes/macrophages. Stainable iron was seen in the adventitial layer of aorta from angiotensin II infused animals. Iron chelation suppressed aortic induction of ferritin and heme oxygenase-1 (HO1) and suppressed upregulation of mRNA levels of monocyte chemoattractant protein-1 (MCP1). In

Haptoglobin polymorphisms and plaque iron content

Asleh et al. [59] suggested that hemoglobin within plaque derived from microvascular hemorrhage is cleared more slowly from plaques associated with haptoglobin (Hp) 2-2 genotype as compared to Hp 1-1 plaques. The Hp 2-2 genotype is associated with an increased risk of atherosclerotic cardiovascular disease. These investigators then created a type 2 Hp allele in the apoE-deficient mouse and explored the effect of Hp 2-2 genotype on iron, lipid peroxidation and macrophage accumulation in plaque.

Heme oxygenase-1 polymorphisms and plaque iron

A similar pattern may occur with promoter polymorphisms in HO1, an inducible enzyme that catalyzes the rate limiting step in heme catabolism. Heme catabolism is a key function in mobilizing macrophage iron derived from ingested erythrocytes. Alterations in the activity of HO1 influence the rate of clearance of hemoglobin-derived iron from macrophages. In the HO1 deficient mouse (HO1−/−) conspicuous iron loading is seen in Kupffer cells, hepatocytes, hepatic vascular tissue, and renal cortical

Quantitation of carotid plaque iron by MRI based T2⁎ measurement

Raman et al. [68] investigated the role of iron deposition in carotid plaque instability using a novel approach of in vivo plaque characterization by a noninvasive, noncontrast magnetic resonance based T2⁎ measurement. The method was validated using ex vivo plaque analyses of intra-plaque iron composition. Symptomatic patients had significantly shorter plaque T2⁎ values (20.0 ± 1.8 ms) compared with asymptomatic patients (34.4 ± 2.7 ms, p < 0.001), respectively, which is consistent with a shift in

Inflammation, IL-6, hepcidin and iron in arterial plaque

Hepcidin level is a major determinant of the amount of iron retained within macrophages [69], [70], [71], [72]. Production of hepcidin is regulated by a number of interrelated factors. Elevated levels, which favor macrophage iron retention, are encountered with increased iron intake, infection and inflammation. Reduced hepcidin levels are associated with iron deficiency, hypoxia, anemia and homozygous hemochromatosis. Interleukin 6 (IL-6) upregulation as seen in inflammatory states induces

Genetic hemochromatosis and defective iron retention in the macrophage

Genetic hemochromatosis is another factor that could strongly influence the iron concentration of arterial plaque. Because HFE mutations are almost always associated with very low hepcidin concentrations and consequently with decreased retention of iron by the macrophage [71], [72], it appears likely that these mutations may, counter-intuitively, cause more rapid clearance of iron from arterial lesions. The classic finding in inherited hemochromatosis is misplaced hepatic iron. The disease is

The FeAST trial

Findings of a first randomized trial of mild iron reduction therapy in elderly patients with established peripheral vascular disease (the “FeAST” trial) have been recently reported [9], [76], [77]. The trial assessed the potential benefit of mild iron reduction therapy in secondary prevention of cardiovascular disease. It was therefore not a fully valid test of primary prevention as postulated by the iron hypothesis. No overall statistically significant cardiovascular benefit was found.

Iron in arterial plaque: A modifiable risk factor for atherosclerosis

These findings from animal models of atherosclerosis and from studies of human atherosclerotic plaque provide support for the concept that elevated arterial iron levels play a significant role in the pathogenesis of atherosclerosis. Both the animal studies and long clinical experience with the effects of iron deficiency anemia on storage iron show that iron in arterial plaque can be mobilized for erythropoiesis and thereby reduced in concentration. It should be feasible to achieve the normally

Concluding comment: Is stored iron safe?

Suggesting that one disorder, i.e. atherosclerotic plaque, might be treatable by the induction of a second disorder, i.e. iron depletion, may be seen as a controversial proposal largely because there is a deeply held and widely prevalent assumption that iron in storage is inherently safe. The assumption is based ultimately on decades old traditional medical practices rather than on appropriately designed rigorous clinical trials. It has been previously noted [14] that “A benefit of iron

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