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      Iron and thrombosis

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          Abstract

          Although essential for cell physiology, an increase or depletion of body iron has harmful effects on health. Apart from iron deficiency anemia and iron overload-related organ tissue damage, there are increasing evidences that body iron status is implicated in atherosclerotic cardiovascular diseases. The hypothesis formulated in 1981 that iron depletion may protect against cardiovascular events is intriguing and has generated a significant debate in the last two decades. Indeed, to study this phenomenon, several investigators have tried to design appropriate experimental and clinical studies and to identify useful biochemical and genetic markers of iron status. The results of the literature on the effect of iron deficiency and overload on vascular health are critically reviewed in this study from a pathogenic and clinical point of view.

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          Most cited references95

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          High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men.

          Iron can induce lipid peroxidation in vitro and in vivo in humans and has promoted ischemic myocardial injury in experimental animals. We tested the hypothesis that high serum ferritin concentration and high dietary iron intake are associated with an excess risk of acute myocardial infarction. Randomly selected men (n = 1,931), aged 42, 48, 54, or 60 years, who had no symptomatic coronary heart disease at entry, were examined in the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) in Eastern Finland between 1984 and 1989. Fifty-one of these men experienced an acute myocardial infarction during an average follow-up of 3 years. On the basis of a Cox proportional hazards model adjusting for age, examination year, cigarette pack-years, ischemic ECG in exercise test, maximal oxygen uptake, systolic blood pressure, blood glucose, serum copper, blood leukocyte count, and serum high density lipoprotein cholesterol, apolipoprotein B, and triglyceride concentrations, men with serum ferritin greater than or equal to 200 micrograms/l had a 2.2-fold (95% CI, 1.2-4.0; p less than 0.01) risk factor-adjusted risk of acute myocardial infarction compared with men with a lower serum ferritin. An elevated serum ferritin was a strong risk factor for acute myocardial infarction in all multivariate models. This association was stronger in men with serum low density lipoprotein cholesterol concentration of 5.0 mmol/l (193 mg/dl) or more than in others. Also, dietary iron intake had a significant association with the disease risk in a Cox model with the same covariates. Our data suggest that a high stored iron level, as assessed by elevated serum ferritin concentration, is a risk factor for coronary heart disease.
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            Iron and the sex difference in heart disease risk.

            J Sullivan (1981)
            Premenopausal women in affluent societies are protected from heart diseases which kill large numbers of men. The basis for this sex difference and the loss of protection with menopause is unknown. The hypothesis offered is that the greater incidence of heart diseases in men and postmenopausal women compared with the incidence in premenopausal women is due to higher levels of stored iron in these two groups. The hypothesis is supported by observations of (1) myocardial failure in iron strong disease, (2) accumulation of stored iron with age in men, and (3) accumulation of stored iron after menopause to levels found in men. In addition, the heart diseases of affluence are rare among impoverished peoples who are often iron deficient. The depletion of iron stores by regular phlebotomy could be the experimental system for testing this hypothesis, and a preventive therapy if the hypothesis is confirmed.
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              Body iron stores and the risk of carotid atherosclerosis: prospective results from the Bruneck study.

              Fe2+ released from tissue iron stores may accelerate lipid peroxidation by virtue of its pro-oxidant properties and thus promote early atherogenesis. The present prospective survey addresses the potential association between serum ferritin concentrations and the 5-year progression of carotid atherosclerosis as assessed by ultrasonographic follow-up evaluations. The study population comprises a random sample of 826 men and women 40 to 79 years old. Serum ferritin was one of the strongest risk predictors of overall progression of atherosclerosis. The main part of this association appeared to act through modification of the atherogenic potential of LDL cholesterol (OR [95% CI] for a 1-SD unit increase in ferritin at LDL levels of 2.5, 3.6, and 4.9 mmol/L: 1.55 [1.30 to 1.85], 1.77 [1.40 to 2.24], and 2.05 [1.50 to 2.80]; P=.0012 for effect modification). Changes in iron stores during the follow-up period modified atherosclerosis risk, in that a lowering was beneficial and further iron accumulation exerted unfavorable effects. All these findings applied equally to incident atherosclerosis and the extension of preexisting atherosclerotic lesions. The significance of prominent iron stores in the development of carotid stenosis was clearly less pronounced. Finally, ferritin and LDL cholesterol showed a synergistic association with incident cardiovascular disease and death (n=59). The present study provided strong epidemiological evidence for a role of iron stores in early atherogenesis and suggests promotion of lipid peroxidation as the main underlying pathomechanism. This hypothesis could in part explain the sex difference in atherosclerotic vascular disease.
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                Author and article information

                Contributors
                +39-045-8124321 , +39-045-8124626 , mfranchini@univr.it
                Journal
                Ann Hematol
                Annals of Hematology
                Springer-Verlag (Berlin/Heidelberg )
                0939-5555
                1432-0584
                8 December 2007
                March 2008
                : 87
                : 3
                : 167-173
                Affiliations
                [1 ]Servizio di Immunoematologia e Trasfusione, Centro Emofilia, Azienda Ospedaliera di Verona, Verona, Italy
                [2 ]Sezione di Endocrinologia e Malattie del Metabolismo, Dipartimento di Scienze Biomediche e Chirurgiche, Università di Verona, Verona, Italy
                [3 ]Istituto di Chimica e Microscopia Clinica, Dipartimento di Scienze Biomediche e Morfologiche, Università di Verona, Verona, Italy
                [4 ]Servizio di Immunoematologia e Trasfusione, Centro Emofilia, Ospedale Policlinico, Piazzale Ludovico Scuro, 37134 Verona, Italy
                Article
                416
                10.1007/s00277-007-0416-1
                2226003
                18066546
                c4785e62-d3a3-4d0f-9302-e6960378a3d3
                © Springer-Verlag 2007
                History
                : 30 August 2007
                : 11 November 2007
                Categories
                Review Article
                Custom metadata
                © Springer-Verlag 2008

                Hematology
                iron,anemia,thrombosis
                Hematology
                iron, anemia, thrombosis

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