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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been proposed that elevated levels of tissue iron increase the risk for atherosclerosis, perhaps by favoring the formation of pro-atherogenic oxidized LDL. Working with apoE-deficient (apoE(-/-)) mice, which do not require a high-fat diet to develop atherosclerosis, we compared the effects of standard diet (0.02% iron) or a 2% carbonyl iron diet. After 24 weeks, mice fed the 2% carbonyl iron diet had twice as much iron in their plasma, a ninefold increase in bleomycin-detectable free iron in their plasma, and ten times as much iron in their livers as control mice. Dietary iron overload caused a modest (30%) rise in plasma triglyceride and cholesterol. Nevertheless, this regimen did not exacerbate, but rather reduced the severity of atherosclerosis by 50%, and it failed to elevate hepatic levels of heme oxygenase mRNA, which is induced by many different oxidative insults in vitro. Moreover, hepatic levels of protein-bound dityrosine and ortho-tyrosine, two markers of metal-catalyzed oxidative damage in vitro, failed to rise in iron-overloaded animals. Our observations suggest that elevated serum and tissue levels of iron are not atherogenic in apoE(-/-) mice. Moreover, they call into question the hypothesis that elevated levels of tissue iron promote LDL oxidation and oxidative stress in vivo.
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PMID:Iron overload diminishes atherosclerosis in apoE-deficient mice. 1141 62

Iron is essential for all human cells as well as neoplastic cells and invading microbes. Natural and synthetic iron chelators could affect biological processes involving iron and other metal ions in health and disease states. Iron overload is the most common metal toxicity condition worldwide. There are currently two iron chelating drugs, which are mostly used for the treatment of thalassaemia and other conditions of transfusional iron overload. Deferoxamine was until recently the only approved iron chelating drug, which is effective but very expensive and administered parenterally resulting in low compliance. Deferiprone (L1 or 1,2-dimethyl-3-hydroxypyrid-4-one) is the world's first and only orally active iron chelating drug, which is effective and inexpensive to synthesise thus increasing the prospects of making it available to most thalassaemia patients in third world countries who are not currently receiving any form of chelation therapy. Deferiprone has equivalent iron removal efficacy and comparable toxicity to deferoxamine. There are at least four other known iron chelators, which are currently being developed. Even if successful, these are not expected to become available for clinical use in the next five years and to be as inexpensive as deferiprone. The variation in the chemical, biological, pharmacological, toxicological and other properties of the chelating drugs and experimental chelators provide evidence of the difference in the mode of action of chelators and the need to identify and select molecular structures and substituents based on structure/activity correlations for specific pharmacological activity. Such information may increase the prospects of designing new chelating drugs, which could be targeted and act on different tissues, organs, proteins and iron pools that play important role not only in the treatment of iron overload but also in other diseases of iron and other metal imbalace and toxicity including free radical damage. Chelating drugs could also be designed, which could modify the enzymatic activity of iron and other metal containing enzymes, some of which play a key role in many diseases such as cancer, inflammation and atherosclerosis. Other applications of iron chelating drugs could involve the detoxification of toxic metals with similar metabolic pathways to iron such as Al, Cu, Ga, In, U and Pu.
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PMID:The design and development of deferiprone (L1) and other iron chelators for clinical use: targeting methods and application prospects. 1527 56

Free radicals (FR), highly reactive substances with an unpaired electron in the outer orbital attack lipids, proteins and nucleic acids and alter the structure and function of these macromolecules. Against the negative effects of FR during evolution various defense mechanisms developed described comprehensively as antioxidant defense. Under physiological conditions in the organism equilibrium is established between free radical production and antioxidant defense factors. Extracorporeal renal replacement mechanisms can interfere in a negative way with this equilibrium. They provoke the formation of FR and at the same time they weaken the antioxidant defense e.g. by elimination of substances with antioxidant properties. Impairement of the equilibrium between FR production and antioxidant mechanisms to the disadvantage of antioxidant defense in patients with chronic renal failure was proved and is described as oxidative stress. Oxidative stress threatens dialyzed patients with serious clinical complications e.g. accelerated atherosclerosis, amyloidosis, haemolysis and the development of a state of chronic inflammation. Reduction of oxidative stress can be achieved by reducing FR production by using biocompatible dialyzation membranes, proper correction of acid-base disorders, by preventing an iron overload of the organism. The second approach is to foster the antioxidant defense by supplementation with antioxidants. Final recommendations as regards selection of the optimal dialyzation membrane, type of extracorporeal renal replacement and the amount and composition of antioxidant supplements have not yet been established and the problem is the subject of intense research.
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PMID:[Free radicals and extracorporeal renal replacement therapy]. 1564 Dec 59

Iron is an essential nutrient, but carries potential risks. Iron therapy not only affects the functions of leukocytes, endothelial cells, and cytokine production, but also causes oxidative stress and can support bacterial growth. Intravenous iron therapy may result in nontransferrin-bound iron. This may act as a catalytic agent in the formation of hydroxyl radicals, and thus potentially contribute to cell damage and atherosclerosis. Potential long-term complications of intravenous iron therapy in end-stage renal disease patients include atherosclerosis and infection, particularly in patients with iron overload.
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PMID:Potential risk for infection and atherosclerosis due to iron therapy. 1564 17

Atherosclerosis is a disease of the arterial wall, with increasing wall thickness representing an early event in the progression of the disease. It has been suggested that iron overload, as assessed by increased serum ferritin concentration, may be a risk factor for atherosclerosis. The aim of this study was to investigate the relationship between the influence of intravenous (IV) iron therapy and ferritin levels and carotid intima media thickness (C-IMT) in dialysis patients. Sixty patients (51 +/- 14) years were divided into two groups according to their IMT obtained by ultrasound; group I (high risk) and group II (low risk). The parameters assessed were serum creatinine, urea, calcium, phosphorus, hemoglobin, albumin, uric acid, iron, ferritin, and lipid levels. Thirty-eight patients (88%) in group I and 5 patients (12%) in group II received IV iron therapy while 5 patients (29%) in group I and 12 patients (71%) in group II (P < 0.001) did not receive IV iron therapy. Ferritin levels were higher in group I than in group II (581 +/- 303 and 306 +/- 224) (P < 0.001). C-IMT measurements correlated with serum ferritin and with the intravenous iron dose received during the 24 months preceding the study (r = 0.315, P = 0.015; r = 0.471, P = 0.001). The findings indicate that IV iron therapy and elevated serum ferritin levels may cause an increase in the incidence of atherosclerosis.
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PMID:Intravenous iron therapy as a possible risk factor for atherosclerosis in end-stage renal disease. 1587 9

The anaemia of chronic kidney disease (CKD) is efficiently corrected with a combination of recombinant erythropoietin (rhEPO) and intravenous iron supplementation. Recently, patients with severe cardiac failure and anaemia have also been shown to benefit from this treatment. However, iron excess may lead to the production of free radicals and has been incriminated in the pathogenesis of atherosclerosis and increased risk of infection, the two major causes of death in end-stage renal disease. The exact risk of excess iron supplementation has not been defined and, in the absence of sensitive and specific indicators of iron overload, the risk remains difficult to quantify. There is increasing epidemiological evidence incriminating iron overload as a risk factor in CKD, but direct evidence is still hard to obtain. The precise role of iron is complicated further by the complex inter-relationships between iron metabolism and the inflammatory process characteristic of CKD. The recent discovery of the antimicrobial peptide, hepcidin, may shed light on these inter-relationships. New methods for quantifying non-transferrin-bound (or labile plasma) iron may help in the future to identify patients at risk for toxicity from excess iron supplementation.
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PMID:Intravenous iron supplementation in the anaemia of renal and cardiac failure--a double-edged sword? 1602 27

Nontransferrin-bound iron (NTBI) has been detected in iron overload diseases. This form of iron may exert pro-oxidant effects and modulate cellular function and inflammatory response. The present study has aimed to investigate the effects of serum NTBI on monocyte adherence to endothelium. Measured by a recently developed high-throughput fluorescence-based assay, serum NTBI was found to be higher in both homozygotes of HFE C282Y mutation of hereditary hemochromatosis (7.9+/-0.6 microM, n=9, P<0.001) and heterozygotes (4.0+/-0.5 microM, n=8, P<0.001), compared with controls (1.6+/-0.2 microM, n=21). The effects of these sera on monocyte adhesion and endothelial activation were examined. Adhesion of normal human monocytes to C282Y homozygote- and heterozygote-serum-treated human umbilical vein endothelial cells was higher (25.0+/-0.9 and 22.1+/-0.7%, respectively) compared with controls (17.6+/-0.5%, both P<0.001). For the three groups combined, the expression of adhesion molecules, ICAM-1, VCAM-1, and E-selectin, was positively correlated to NTBI levels but not to the inflammatory marker C-reactive protein. Furthermore, accumulation of intracellular labile iron and oxidative radicals within the cells due to NTBI was evidenced. Finally, counteraction of NTBI-induced endothelial activation was observed using iron chelators. These findings therefore identify a physiological function of NTBI in monocyte-endothelial interactions that may also contribute to the development of atherosclerosis and neurodegenerative diseases.
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PMID:Endothelial activation and induction of monocyte adhesion by nontransferrin-bound iron present in human sera. 1636 18

Iron could promote free radical formation, which may lead to injury of the arterial wall and atherosclerosis. Blood donation may reduce cardiovascular risk by lowering body iron status. We collected data on blood donation history and intima-media thickness of the common carotid artery (CIMT) in 819 subjects (50-70 years), who were recruited from municipal and blood bank registries in The Netherlands. Serum iron parameters were assessed, including non-transferrin bound iron (NTBI) that has recently been found in conditions of iron overload. Serum ferritin was lower in current donors (n=443; 44 microg/L) than in ex-donors (n=120; 114 microg/L) and never-donors (n=256; 124 microg/L, P for trend <0.001). For NTBI, values were 2.33, 2.54, and 2.51 micromol/L, respectively (P<0.05). CIMT was slightly reduced in frequent donors (i.e., > or =49 times during life or > or =2 times per year), although not statistically significant. CIMT was not significantly related to NTBI. Frequent blood donation, resulting in lowered body iron, might give some protection against accelerated atherosclerosis.
Atherosclerosis 2008 Feb
PMID:Blood donation, body iron status and carotid intima-media thickness. 1733 86

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.
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PMID:Iron in arterial plaque: modifiable risk factor for atherosclerosis. 1861 22

Iron-deficiency anaemia (IDA) is a major health problem worldwide, but responds well to iron supplementation. New approaches are leading to more effective management of this condition. Iron deficiency (ID) is usually suspected in at-risk patients with declining haemoglobin (Hb) levels and then confirmed by measuring serum ferritin levels and transferrin saturation. However, regular monitoring of these iron indicators and other laboratory parameters in susceptible individuals may lead to early recognition of falling iron stores and facilitate pre-emptive therapeutic intervention before anaemia develops. Patients with ID are commonly prescribed oral iron preparations because of convenience and low cost. However, the efficacy of these agents is limited by their reduced absorption rate and gastrointestinal side-effects. Alternatively, treatment of IDA in patients requiring erythropoiesis-stimulating agents (ESAs) is more predictably achieved by use of intravenous (i.v.) iron. Unfortunately, the development of serious adverse events (SAEs) from high molecular-weight iron dextran has led to reluctance to use i.v. iron in the treatment of IDA. Similarly, but to a much lesser extent, low molecular-weight iron dextran is associated with a number of SAEs, including allergic or anaphylactic reactions. The introduction of second-generation i.v. iron formulations, including iron sucrose and ferric gluconate, was clearly an improvement over i.v. iron dextran. These formulations proved to be effective in the management of IDA and are not associated with the serious allergic reactions encountered with i.v. iron dextran. For these reasons, use of these preparations became more widespread in the treatment of IDA across a wide range of clinical conditions. An important advantage of i.v. iron over oral iron is that it may bypass hepcidin actions by directly loading transferrin and making iron available to macrophages. Despite a reduction in the short-term risks, there is still concern about the potential for long-term toxicity of i.v. iron use (e. g. atherosclerosis development, infection and increased mortality). The association of atherosclerosis with iron overload remains unclear. Alternatively, the relative risk for mortality or hospitalization from infection in patients undergoing haemodialysis (HD) who received i.v. iron was shown not to be higher than that observed in the overall HD population. Indeed, doses of i.v. iron up to 400 mg/month were associated with improved patient survival. Second-generation i.v. iron formulations are more frequently used for treating IDA than i.v. iron-dextran in patients with various chronic conditions including those with chronic kidney disease. In the latter, IDA should be corrected before initiation of ESA therapy, as iron deficiency can lead to hyporesponsiveness to ESA. However, a major limitation of the second-generation i.v. iron agents is that they cannot be administered in large doses and the typical 1000 mg therapy requires several clinic visits. Thus, there is a need for an i.v. iron agent that can be safely administered in a single dose of 1000 mg of iron and therefore requires less frequent clinic visits. This limitation has now been overcome with the introduction of newer i.v. iron preparations. Ferric carboxymaltose offers effective and rapid correction of IDA by overcoming the limitations observed with previous i.v. iron preparations. This agent has been shown to be effective and well tolerated in a number of randomized controlled trials in a variety of chronic conditions.
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PMID:The efficacy and safety of current intravenous iron preparations for the management of iron-deficiency anaemia: a review. 2064 31


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