Iron and the Genetics of Cardiovascular Disease

Abstract

HomeCirculationVol. 100, No. 12Iron and the Genetics of Cardiovascular Disease Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBIron and the Genetics of Cardiovascular Disease Jerome L. Sullivan Jerome L. SullivanJerome L. Sullivan From the Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Fla. Search for more papers by this author Originally published21 Sep 1999https://doi.org/10.1161/01.CIR.100.12.1260Circulation. 1999;100:1260–1263The hypothesis that iron depletion protects against ischemic heart disease was proposed in 1981 as an explanation for the sex difference in heart disease rates.12345 The “iron hypothesis” has generated significant debate, especially in the 1990s after publication of supportive findings from Finland.6 Confusion has been introduced into the debate by inappropriate study designs in tests of the hypothesis. A recurring weakness is that stored iron is measured by inappropriate methods. In addition, evidence against a particular mechanism may be erroneously taken as evidence against the core hypothesis. For example, in a particular study design, a finding of no association of stored iron with coronary atherosclerosis would not invalidate an association of stored iron with cardiovascular mortality. Recent studies relevant to the iron hypothesis have been reviewed.5789101112In 1994, Ascherio and Willett13 recognized that the iron hypothesis cannot be rejected on the basis of available data, stating that “[s]tronger evidence is needed before the hypothesis is rejected that greater iron stores increase the incidence of coronary heart disease or death from myocardial infarction.” Indeed, nothing in data made available since 1994 excludes the possibility that iron depletion has a large protective effect, large enough to explain the low incidence of myocardial infarction in menstruating women.A 1997 editorial14 on the iron hypothesis suggests that this once-controversial idea has become more acceptable to many scientists. Gillum14 noted that “this important hypothesis and related research fronts have led to many valuable studies like that of Kiechl et al [see Reference 99 ], which will greatly enhance our understanding of atherosclerotic vascular disease and may lead to innovations useful in clinical medicine and public health, perhaps in heretofore unanticipated ways.”Mechanisms of protection have not been completely defined.12345 Iron depletion probably protects by more than 1 mechanism. Unforeseen modes of protection cannot be ruled out. Leading candidates involving the well-known role of iron in free-radical–mediated injury are (1) a decrease in ischemic myocardial injury and/or (2) a decrease in atherogenesis, both effects in association with iron depletion. The relative contribution of these or other mechanisms to protection against clinical events is unknown. Iron depletion may directly protect myocardium against ischemic injury independently of a role in inhibiting atherogenesis. In other words, iron depletion may protect against ischemic events, even in patients with appreciable atherosclerotic disease.12345Cardiovascular Disease in Heterozygous HemochromatosisIn this issue of Circulation, Roest et al15 and Tuomainen et al16 present landmark studies of relevance to the iron hypothesis and to the genetics of cardiovascular disease. Using the newly described genetic polymorphism associated with the majority of patients with hereditary hemochromatosis, Roest et al15 find that heterozygosity for this mutation confers a significant increase in risk of cardiovascular events, including myocardial infarction. The study involved a group of 12 239 women followed up for 16 to 18 years. Incidence-rate ratios of heterozygosity were 1.5 for mortality by myocardial infarction, 2.4 for cerebrovascular mortality, and 1.6 for total cardiovascular mortality. Among hypertensive smokers with the mutation compared with nonsmoking, nonhypertensive normal women, the incidence-rate ratio of heterozygosity was 18.85 for total cardiovascular mortality.In the study by Tuomainen et al,16 hemochromatosis gene (HFE) Cys282Tyr is found to be associated with a 2.3-fold increased risk of acute myocardial infarction in men (P=0.03; n=1150). These findings1516 confirm the earlier corollary hypothesis linking heterozygosity for hemochromatosis with ischemic heart disease.17 The new data1516 are also highly supportive of the hypothesis12345 that iron is an important risk factor for ischemic heart disease in men and in women, as suggested by both groups of authors. The striking increase in incidence among hypertensive women carriers who smoke15 supports the concept that a small burden of stored iron exerts a permissive effect with respect to the impact of other risk factors.It is conceivable that some effect of the Cys282Tyr polymorphism other than increased iron loading could be the actual basis of the observed associations. However, any such mechanism would be entirely speculative. Given the accumulating literature on iron and cardiovascular diseases, as well as the prior prediction of the observed association,17 a mechanism based on elevated iron stores is far more plausible.The findings may substantially underestimate the impact of stored iron on cardiovascular diseases. Most heterozygotes have stored iron loads well within the reference range. In a study involving 1058 obligate heterozygotes, Bulaj et al18 found that only 20% of male and 8% of female heterozygotes had serum ferritin values higher than normal. Few heterozygotes had the very high levels suggestive of homozygosity. For pathologies related specifically to stored iron load, most heterozygotes would be expected to be indistinguishable from normal subjects. It is likely, however, that many heterozygotes with statistically normal iron loads achieve those levels of stored iron earlier in life than normal subjects.18 Heterozygous men and women had significantly higher-than-normal mean serum ferritin levels among the 31- to 60-year-old age group.18 An additional factor tending to obscure the relationship between heterozygosity and disease is the focus of both studies1516 on the Cys282Tyr mutation. A number of subjects without this mutation may nonetheless have higher-than-normal stored iron levels because of other known or unidentified iron-loading mutations.Franco et al19 reported that the HFE genes were not associated with coronary or peripheral atherosclerosis in patients <50 years of age (n=537). Their findings do not invalidate those of Tuomainen et al16 or Roest et al.15 Franco et al19 examined the association of HFE genes with structural lesions, whereas the other studies1516 probed the relationship between carrier status and cardiovascular mortality, ie, a category of cardiovascular events. The role of iron in atherogenesis appears likely to be complex. The new findings151619 suggest that iron could have a clinically more important role in ischemic events than in initiating or promoting vascular structural lesions. Increased events may occur without an increase in atherosclerotic lesions. Failure to demonstrate an increase in atherosclerotic lesions in carriers speaks to mechanism; it does not contradict the independent findings that carriers are at an increased risk of events.A recent study by Nassar et al20 considered the prevalence of HFE genes in 2 groups with cardiovascular disease of early (<50 years of age) or late (>65 years of age) onset (n=300). They found similar prevalences of the HFE genes in the 2 groups; however, the early-onset group had significantly higher serum ferritin levels. The study has limited relevance to this discussion because it does not directly address the question of the association of the carrier state with disease, because all subjects in the study had cardiovascular disease.20Association between carrier status and cardiovascular events counters a frequent criticism of the iron hypothesis. It has been argued that the apparent lack of an increase in coronary atherosclerosis in homozygous hemochromatosis is evidence against the iron hypothesis.2122 Even before the publication of the findings on heterozygotes, there had been no study definitively excluding an increased risk of coronary atherosclerosis in homozygotes. The absence of an increased prevalence of coronary lesions in homozygotes, even if true, would not invalidate the hypothesis that iron depletion protects against cardiovascular events. Evidence against 1 possible mechanism is not evidence against the general hypothesis that iron depletion protects against ischemic heart disease. It has also been noted22 that the “heart lesion of hemochromatosis is relevant to ischemic heart disease precisely because it demonstrates that myocardium can be injured by iron-dependent processes in the absence of coronary occlusion.” Vulnerability of myocardium to ischemic injury appears to be significantly regulated by stored iron level and not exclusively by the degree of coronary atherosclerosis.Homozygotes have iron levels so high that multiple organs are affected. Untreated individuals may tend to die of unrelated causes before clinically significant ischemic myocardial injury occurs. At the extremely high iron levels seen in homozygotes, there is a direct compromise of myocardial function unrelated to coronary artery lesions. At the much lower iron levels associated with heterozygosity, iron-mediated compromise of heart function may arise only after an ischemic event.Predisposition to myocardial infarction and other cardiovascular events may be the principal hazard of heterozygosity for hemochromatosis. Homozygotes have more iron-related disorders, and these occur earlier in life. Recent findings suggest an analogous pattern in cystic fibrosis.23 Patients homozygous for cystic fibrosis have severe lung and pancreatic disease early in life. It now appears that cystic fibrosis heterozygotes do not completely escape the deleterious effects of the mutation. Heterozygotes are at higher-than-normal risk of chronic pancreatitis in adulthood but are free of other, more severe manifestations of the homozygous condition. With the quickening pace of gene identification in inherited disorders, there may well be other recessive conditions that turn out not to be benign in the carrier state. The new findings in hemochromatosis suggest that the heterozygous condition puts the carrier at risk of developing a spectrum of disorders that differ qualitatively and quantitatively from those that beleaguer homozygotes.Iron and the Genetics of Cardiovascular DiseaseA preponderance of evidence supports a familial aggregation of premature myocardial infarction.17242526272829 Roughly 5% to 7% of individuals in the general population fall into the high-risk group.27 Some high-risk families appear to be at increased risk because of familial predisposition to known risk factors such as hyperlipidemia or hypertension. However, in most studies, no aggregation of the known risk factors is seen in a large proportion of the high-risk families.These studies suggest a heritable risk factor (or factors) for myocardial infarction that preferentially affects those younger than 50 years of age and is independent of traditional risk factors. Furthermore, this unknown, heritable factor selectively increases the risk of male family members. Women in the coronary-prone families are relatively protected from the unknown factor(s).These patterns make sense if the mysterious risk factor is a gene favoring iron absorption.17 Stored iron increases with age in normal people. Accumulation is accelerated in hemochromatosis heterozygotes.18 Iron stores in older normal subjects eventually approximate those seen in younger heterozygotes.18 As they age, heterozygotes would be at progressively less relative disadvantage, thus explaining the selective effect of the heritable factor on persons under age 50. Women in high-risk families are spared from the effect of the unknown heritable risk factor. Such a pattern is expected if the unknown factor is the hemochromatosis gene. Iron acquisition in affected women is delayed in comparison with men by continual loss of iron in menstrual blood. The relationship of the mystery factor to known risk factors is unsurprising, because heterozygous hemochromatosis is not known to be associated with increases in the traditional risk factors. The proportion of carriers in the general population is 10% to 13%,18 more than enough to account for the percentage of families with the unknown heritable risk factor given that not all carriers have abnormal levels of stored iron.The findings of Roest et al15 and Tuomainen et al16 provide empirical support for the hypothesis that heterozygosity confers increased risk.17 The findings1516 are significant because they provide strong support for a link between iron and cardiovascular diseases. Roest et al15 and Tuomainen et al16 also give specific support to the corollary hypothesis17 that the much-discussed unknown factor is an inherited predisposition to accumulate iron.ConclusionsAmong the important unresolved questions raised by the iron hypothesis are the following: Does deliberate iron depletion, eg, by regular blood donation, protect against cardiovascular diseases? Does the public need to be informed of the risks of stored iron before a definitive trial is completed?Three studies published in 1997789 are confirmatory of the key prediction12345 that volunteer blood donation is associated with a significant decrease in vascular events and in atherosclerosis. Donors must be in relatively good health before they are permitted to donate and may thus be expected to have lower disease rates than nondonors. However, in the new studies of heart diseases in blood donors,789 donors and nondonors alike were in a similar state of health at entry as defined by subject criteria in the study designs. For this reason, the bias inherent in simple comparisons of disease rates in donors and nondonors is significantly mitigated. The iron hypothesis must ultimately be tested in a randomized, prospective clinical trial of the effects of iron depletion, eg, in blood donors.The practical implications of the risk factor status of stored iron depend on a weighing of the risks and benefits of iron depletion induced under medical supervision. As to the possible risks of iron depletion, a sense of proportion must be maintained. Undeniably, ischemic heart disease is a significantly greater public health problem than iron depletion. There is no epidemic of deaths due to iron depletion or even to iron-deficiency anemia. Iron-deficiency anemia can generally be treated successfully and, unlike ischemic heart disease, is not often in itself an actual cause of death among affluent populations.The investigation of the leading cause of death in the industrialized world imposes a duty to rigorously examine traditional practices. According to conventional wisdom, being a carrier for a hemochromatosis gene confers no risk. However, carriers have only slightly larger loads of storage iron than unaffected individuals. A true estimate of the risk of such nearly “normal” levels of stored iron would require an additional control group: those with no stored iron at all, ie, iron-depleted subjects. Definitive trial data on the safety of maintaining iron in storage are surprisingly absent. Support for the safety of maintaining iron in storage is based on traditional practice, not on scientifically valid data. In the absence of appropriate clinical trial findings on the safety of stored iron, advice to the public must necessarily be based on medical judgment. In my view, the totality of evidence suggests that iron depletion is safer than maintaining iron in storage. A consensus is urgently needed on what specific public health recommendations should be made in light of available data.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Dr Jerome L. Sullivan, PO Box 2661, Winter Park, FL 32790. E-mail [email protected] References 1 Sullivan JL. Iron and the sex difference in heart disease risk. Lancet.1981; 1:1293–1294.CrossrefMedlineGoogle Scholar2 Sullivan JL. The sex difference in ischemic heart disease. Perspect Biol Med.1983; 26:657–671.CrossrefMedlineGoogle Scholar3 Sullivan JL. The iron paradigm of ischemic heart disease. Am Heart J.1989; 177:1177–1188.Google Scholar4 Sullivan JL. Stored iron and ischemic heart disease: empirical support for a new paradigm. Circulation.1992; 86:1036–1037.CrossrefMedlineGoogle Scholar5 Sullivan JL. Iron versus cholesterol: perspectives on the iron and heart disease debate. J Clin Epidemiol.1996; 49:1345–1352.CrossrefMedlineGoogle Scholar6 Salonen JT, Nyyssonen K, Korpela H, Tuomilehto J, Seppanen R, Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation.1992; 86:803–811.CrossrefMedlineGoogle Scholar7 Tuomainen TP, Salonen R, Nyyssonen K, Salonen JT. Cohort study of relation between donating blood and risk of myocardial infarction in 2682 men in eastern Finland. BMJ.1997; 314:793–794.CrossrefMedlineGoogle Scholar8 Meyers DG, Strickland D, Maloley PA, Seburg JK, Wilson JE, McManus BF. Possible association of a reduction in cardiovascular events with blood donation. Heart.1997; 78:188–193.CrossrefMedlineGoogle Scholar9 Kiechl S, Willeit J, Egger G, Poewe W, Oberhollenzer F. Body iron stores and the risk of carotid atherosclerosis: prospective results from the Bruneck study. Circulation.1997; 96:3300–3307.CrossrefMedlineGoogle Scholar10 Tuomainen T-K, Punnonen K, Nyyssönen K, Salonen JT. Association between body iron stores and the risk of acute myocardial infarction in men. Circulation.1998; 97:1461–1466.CrossrefMedlineGoogle Scholar11 Lee T-S, Shiao M-S, Pan C-C, Chau L-Y. Iron-deficient diet reduces atherosclerotic lesions in apoE-deficient mice. Circulation.1999; 99:1222–1229.CrossrefMedlineGoogle Scholar12 Sullivan JL. Iron vs cholesterol: response to dissent. J Clin Epidemiol.1996; 49:1359–1362.CrossrefMedlineGoogle Scholar13 Ascherio A, Willett WC. Are body iron stores related to the risk of coronary heart disease? N Engl J Med.1994; 330:1152–1154.CrossrefMedlineGoogle Scholar14 Gillum RF. Body iron stores and atherosclerosis. Circulation.1997; 96:3261–3263.MedlineGoogle Scholar15 Roest M, van der Schouw YT, de Valk B, Marx JJM, Tempelman MJ, de Groot PG, Sixma JJ, Banga JD. Heterozygosity for a hereditary hemochromatosis gene is associated with cardiovascular mortality in women. Circulation.1999; 100:1268-1273.CrossrefMedlineGoogle Scholar16 Tuomainen T-P, Kontula K, Nyyssönen K, Lakka TA, Heliö T, Salonen JT. Increased risk of acute myocardial infarction in carriers of the hemochromatosis gene Cys282Tyr mutation: a prospective cohort study in men in eastern Finland. Circulation.1999; 100:1274-1279.CrossrefMedlineGoogle Scholar17 Sullivan JL. Heterozygous hemochromatosis as a risk factor for premature myocardial infarction. Med Hypotheses.1990; 31:1–5.CrossrefMedlineGoogle Scholar18 Bulaj ZJ, Griffen LM, Jorde LB, Edwards CQ, Kushner JP. Clinical and biochemical abnormalities in people heterozygous for hemochromatosis. N Engl J Med.1996; 335:1799–1805.CrossrefMedlineGoogle Scholar19 Franco RF, Zago MA, Trip MD, tenCate H, vandenEnde A, Prins MH, Kastelein JJP, Reitsma PH. Prevalence of hereditary haemochromatosis in premature atherosclerotic vascular disease. Br J Haematol.1998; 102:1172–1175.CrossrefMedlineGoogle Scholar20 Nassar BA, Zayed EM, Title LM, O’Neill BJ, Bata IR, Kirkland SA, Dunn J, Dempsey GI, Tan MH, Johnstone DE. Relation of HFE gene mutations, high iron stores and early onset coronary artery disease. Can J Cardiol.1998; 14:215–220.MedlineGoogle Scholar21 Miller M, Hutchins GM. Hemochromatosis, multiorgan hemosiderosis, and coronary artery disease. JAMA.1994; 272:231–233.CrossrefMedlineGoogle Scholar22 Sullivan JL. Hemochromatosis and coronary artery disease. JAMA.1995; 273:25–26.Google Scholar23 Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med.1998; 339:653–658.CrossrefMedlineGoogle Scholar24 Slack J, Evans KA. The increased risk of death from ischaemic heart disease in first degree relatives of 121 men and 96 women with ischaemic heart disease. J Med Genet.1966; 3:239–257.CrossrefMedlineGoogle Scholar25 Sholtz RI, Rosenman RH, Brand RJ. The relationship of reported parental history to the incidence of coronary heart disease in the Western Collaborative Group study. Am J Epidemiol.1975; 102:350–356.CrossrefMedlineGoogle Scholar26 Thelle DS, Forde OH. The cardiovascular study in Finnmark County: coronary risk factors and the occurrence of myocardial infarction in first degree relatives and in subjects of different ethnic origin. Am J Epidemiol.1979; 110:708–715.CrossrefMedlineGoogle Scholar27 Williams RR. Population based perspectives of the genetic epidemiology of early coronary disease in Framingham and Utah. In: Rao DC, Elston RC, Kuller LH, et al, eds. Genetic Epidemiology of Coronary Heart Disease: Past, Present, and Future. New York, NY: Alan R. Liss; 1984:89–91.Google Scholar28 Hamsten A, de Faire U. Risk factors for coronary artery disease in families of young men with myocardial infarction. Am J Cardiol.1987; 59:14–19.CrossrefMedlineGoogle Scholar29 Friedlander Y, Siscovick DS, Weinmann S, Austin MA, Psaty BM, Lemaitre RN, Arbogast P, Raghunathan TE, Cobb LA. Family history as a risk factor for primary cardiac arrest. Circulation.1998; 97:155–160.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Sharifi‐Zahabi E, Abdollahzad H, Mostafa Nachvak S, Moloudi J, Golpayegani M, Asiaei S, Rezavand L, Iraji Z and Jamshidi K (2021) Effects of alpha lipoic acid on iron overload, lipid profile and oxidative stress indices in β‐thalassemia major patients: A cross‐over randomised controlled clinical trial, International Journal of Clinical Practice, 10.1111/ijcp.14062, 75:6, Online publication date: 1-Jun-2021. Wang X, Wu D and Zhong P (2020) Serum bilirubin and ischaemic stroke: a review of literature, Stroke and Vascular Neurology, 10.1136/svn-2019-000289, 5:2, (198-204), Online publication date: 1-Jun-2020. Ploumi C, Kyriakakis E and Tavernarakis N (2019) Dynamics of Iron Homeostasis in Health and Disease: Molecular Mechanisms and Methods for Iron Determination Thermodynamics and Biophysics of Biomedical Nanosystems, 10.1007/978-981-13-0989-2_5, (105-145), . Saed G, Morris R and Fletcher N (2018) New Insights into the Pathogenesis of Ovarian Cancer: Oxidative Stress Ovarian Cancer - From Pathogenesis to Treatment, 10.5772/intechopen.73860 Memon A, Sundquist K, PirouziFard M, Elf J, Strandberg K, Svensson P, Sundquist J and Zöller B (2018) Identification of novel diagnostic biomarkers for deep venous thrombosis, British Journal of Haematology, 10.1111/bjh.15206, 181:3, (378-385), Online publication date: 1-May-2018. Ribeiro Júnior R, Marques V, Nunes D, Stefanon I and dos Santos L (2017) Chronic iron overload induces functional and structural vascular changes in small resistance arteries via NADPH oxidase-dependent O 2 − production, Toxicology Letters, 10.1016/j.toxlet.2017.07.497, 279, (43-52), Online publication date: 1-Sep-2017. Das S, Patel V, Basu R, Wang W, DesAulniers J, Kassiri Z and Oudit G (2017) Females Are Protected From Iron‐Overload Cardiomyopathy Independent of Iron Metabolism: Key Role of Oxidative Stress, Journal of the American Heart Association, 6:1, Online publication date: 11-Jan-2017. Nano J, Muka T, Cepeda M, Voortman T, Dhana K, Brahimaj A, Dehghan A and Franco O (2016) Association of circulating total bilirubin with the metabolic syndrome and type 2 diabetes: A systematic review and meta-analysis of observational evidence, Diabetes & Metabolism, 10.1016/j.diabet.2016.06.002, 42:6, (389-397), Online publication date: 1-Dec-2016. Bečić K, Jandrić Bečić D, Definis-Gojanović M, Zekić Tomaš S, Anterić I and Bašić Ž (2013) Bone porosity and longevity in early medieval Southern Croatia, International Journal of Food Sciences and Nutrition, 10.3109/09637486.2013.854741, 65:2, (172-176), Online publication date: 1-Mar-2014. Merlot A, Kalinowski D and Richardson D (2013) Novel Chelators for Cancer Treatment: Where Are We Now?, Antioxidants & Redox Signaling, 10.1089/ars.2012.4540, 18:8, (973-1006), Online publication date: 10-Mar-2013. Thompson P and Jahanshad N (2014) Ironing out neurodegeneration: is iron intake important during the teenage years?, Expert Review of Neurotherapeutics, 10.1586/ern.12.56, 12:6, (629-631), Online publication date: 1-Jun-2012. Li J, Meng X, Si H, Zhang C, Lv H, Zhao Y, Yang J, Dong M, Zhang K, Liu S, Zhao X, Gao F, Liu X, Cui T and Zhang Y (2012) Hepcidin Destabilizes Atherosclerotic Plaque Via Overactivating Macrophages After Erythrophagocytosis, Arteriosclerosis, Thrombosis, and Vascular Biology, 32:5, (1158-1166), Online publication date: 1-May-2012. Salman I, Ameer O, Sattar M, Abdullah N, Yam M, Abdullah G, Abdulkarim M, Khan M and Johns E (2011) Renal sympathetic nervous system hyperactivity in early streptozotocin-induced diabetic kidney disease, Neurourology and Urodynamics, 10.1002/nau.21007, 30:3, (438-446), Online publication date: 1-Mar-2011. Pardo Silva M, Njajou O, Alizadeh B, Hofman A, Witteman J, van Duijn C and Janssens A (2010) HFE gene mutations increase the risk of coronary heart disease in women, European Journal of Epidemiology, 10.1007/s10654-010-9489-6, 25:9, (643-649), Online publication date: 1-Sep-2010. Franchini M, Targher G, Montagnana M and Lippi G (2007) Iron and thrombosis, Annals of Hematology, 10.1007/s00277-007-0416-1, 87:3, (167-173), Online publication date: 1-Mar-2008. Remacha A, Souto J, Soria J, Buil A, Sardà M, Lathrop M, Blangero J, Almasy L and Fontcuberta J (2005) Genomewide linkage analysis of soluble transferrin receptor plasma levels, Annals of Hematology, 10.1007/s00277-005-1092-7, 85:1, (25-28), Online publication date: 1-Jan-2006. Altés A, Àngels Ruiz M, Remacha Á, Sardá P, Baiget M and Sierra J (2006) Tratamiento de la hemocromatosis hereditaria tipo 1 con magnesio oral, Medicina Clínica, 10.1157/13087717, 126:16, (611-613), Online publication date: 1-Apr-2006. Ndrepepa G, Braun S, Dibra A, Mehilli J, Vogt W, Schömig A and Kastrati A (2005) Iron status and clinical outcome in patients with coronary artery disease after coronary stenting, Nutrition, Metabolism and Cardiovascular Diseases, 10.1016/j.numecd.2005.02.005, 15:6, (418-425), Online publication date: 1-Dec-2005. Nobrega M, Fleming S, Roman R, Shiozawa M, Schlick N, Lazar J and Jacob H (2004) Initial Characterization of a Rat Model of Diabetic Nephropathy, Diabetes, 10.2337/diabetes.53.3.735, 53:3, (735-742), Online publication date: 1-Mar-2004. ROSSI E, KUEK C, BEILBY J, JEFFREY G, DEVINE A and PRINCE R (2004) Expression of the HFE hemochromatosis gene in a community-based population of elderly women, Journal of Gastroenterology and Hepatology, 10.1111/j.1440-1746.2004.03436.x, 19:10, (1150-1154), Online publication date: 1-Oct-2004. Hörl W (2004) Management of anemia in patients with chronic kidney disease Replacement of Renal Function by Dialysis, 10.1007/978-1-4020-2275-3_39, (927-963), . (2004) Opinion of the Scientific Panel on Dietetic products, nutrition and allergies [NDA] related to the Tolerable Upper Intake Level of Iron, EFSA Journal, 10.2903/j.efsa.2004.125, 2:11, (125), Online publication date: 1-Nov-2004. Wilson J, Maher J, Lindquist J, Grambow S and Crook E (2003) Potential Role of Increased Iron Stores in Diabetes, The American Journal of the Medical Sciences, 10.1097/00000441-200306000-00004, 325:6, (332-339), Online publication date: 1-Jun-2003. Chambers V, Sutherland L, Palmer K, Dalton A, Rigby A, Sokol R, Pollitt R, Tanner S and Gleeson D (2003) Haemochromatosis-associated HFE genotypes in English blood donors: age-related frequency and biochemical expression, Journal of Hepatology, 10.1016/S0168-8278(03)00471-9, 39:6, (925-931), Online publication date: 1-Dec-2003. Claeys D, Walting M, Julmy F, Wuillemin W and Meyer B (2002) Haemochromatosis mutations and ferritin in myocardial infarction: a case-control study, European Journal of Clinical Investigation, 10.1046/j.1365-2362.2002.0320s1003.x, 32, (3-8), Online publication date: 1-Mar-2002. POWELL L (2002) Hereditary hemochromatosis and iron overload diseases, Journal of Gastroenterology and Hepatology, 10.1046/j.1440-1746.17.s1.12.x, 17, (S191-S195), Online publication date: 1-Feb-2002. Fox C, Cullen D, Knuiman M, Cumpston G, Divitini M, Rossi E, Gochee P, Powell L and Olynyk J (2002) , Journal of Cardiovascular Risk, 10.1097/00043798-200210000-00010, 9:5, (287-293), Online publication date: 1-Oct-2002. Castellanos M, Puig N, Carbonell T, Castillo J, Martinez J, Rama R and Dávalos A (2002) Iron intake increases infarct volume after permanent middle cerebral artery occlusion in rats, Brain Research, 10.1016/S0006-8993(02)03179-7, 952:1, (1-6), Online publication date: 1-Oct-2002. Bozzini C, Girelli D, Tinazzi E, Olivieri O, Stranieri C, Bassi A, Trabetti E, Faccini G, Pignatti P and Corrocher R (2002) Biochemical and Genetic Markers of Iron Status and the Risk of Coronary Artery Disease: An Angiography-based Study, Clinical Chemistry, 10.1093/clinchem/48.4.622, 48:4, (622-628), Online publication date: 1-Apr-2002. Turner L, Premo D, Gibbs B, Hearthway M, Motsko M, Sappington A, Walker L, Mullendore M and Chew H (2002) Adaptations to iron deficiency: cardiac functional responsiveness to norepinephrine, arterial remodeling, and the effect of beta-blockade on cardiac hypertrophy, BMC Physiology, 10.1186/1472-6793-2-1, 2:1, Online publication date: 1-Dec-2002. Gaenzer H, Marschang P, Sturm W, Neumayr G, Vogel W, Patsch J and Weiss G (2002) Association between increased iron stores and impaired endothelial function in patients with hereditary hemochromatosis, Journal of the American College of Cardiology, 10.1016/S0735-1097(02)02611-6, 40:12, (2189-2194), Online publication date: 1-Dec-2002. Anderson G and Powell L (2002) HFE and Non-HFE Hemochromatosis, International Journal of Hematology, 10.1007/BF02982788, 76:3, (203-207), Online publication date: 1-Oct-2002. Summers K (2001) Iron, infection and the evolutionary ecology of heart disease, Medical Hypotheses, 10.1054/mehy.2000.1236, 56:5, (687-690), Online publication date: 1-May-2001. Hetet G, Elbaz A, Gariepy J, Nicaud V, Arveiler D, Morrison C, Kee F, Evans A, Simon A, Amarenco P, Cambien F and Grandchamp B (2001) Association studies between haemochromatosis gene mutations and the risk of cardiovascular diseases, European Journal of Clinical Investigation, 10.1046/j.1365-2362.2001.00829.x, 31:5, (382-388), Online publication date: 1-May-2001. Rossi E, Bulsara M, Olynyk J, Cullen D, Summerville L and Powell L (2001) Effect of Hemochromatosis Genotype and Lifestyle Factors on Iron and Red Cell Indices in a Community Population, Clinical Chemistry, 10.1093/clinchem/47.2.202, 47:2, (202-208), Online publication date: 1-Feb-2001. Sullivan J (2001) Misconceptions in the debate on the iron hypothesis, The Journal of Nutritional Biochemistry, 10.1016/S0955-2863(00)00142-X, 12:1, (33-37), Online publication date: 1-Jan-2001. Sullivan J and Zacharski L (2001) Hereditary haemochromatosis and the hypothesis that iron depletion protects against ischemic heart disease, European Journal of Clinical Investigation, 10.1046/j.1365-2362.2001.00830.x, 31:5, (375-377), Online publication date: 1-May-2001. Milman N, Byg K, Mulvad G, Pedersen H and Bjerregaard P (2008) Iron status markers in 224 indigenous Greenlanders: influence of age, residence and traditional foods, European Journal of Haematology, 10.1034/j.1600-0609.2001.00312.x, 66:2, (115-125), Online publication date: 1-Feb-2001. Gochee P and Powell L (2001) What’s new in hemochromatosis, Current Opinion in Hematology, 10.1097/00062752-200103000-00007, 8:2, (98-104), Online publication date: 1-Mar-2001. Klevay L (2000) Trace Element and Mineral Nutrition in Ischemic Heart Disease Clinical Nutrition of the Essential Trace Elements and Minerals, 10.1007/978-1-59259-040-7_15, (251-271), . Motulsky A and Beutler E (2000) Population Screening in Hereditary Hemochromatosis, Annual Review of Public Health, 10.1146/annurev.publhealth.21.1.65, 21:1, (65-79), Online publication date: 1-May-2000. De Valk , Addicks , Gosriwatana , Lu , Hider and M. Marx (2001) Non-transferrin-bound iron is present in serum of hereditary haemochromatosis heterozygotes, European Journal of Clinical Investigation, 10.1046/j.1365-2362.2000.00628.x, 30:3, (248-251), Online publication date: 1-Mar-2000. Zacharski L, Ornstein D, Woloshin S and Schwartz L (2000) Association of age, sex, and race with body iron stores in adults: Analysis of NHANES III data, American Heart Journal, 10.1067/mhj.2000.106646, 140:1, (98-104), Online publication date: 1-Jul-2000. Sullivan J (2016) Correspondence, Vascular Medicine, 10.1177/1358836X0000500210, 5:2, (127-128), Online publication date: 1-May-2000. Meyers D (2000) The iron hypothesis:does iron play a role in atherosclerosis?, Transfusion, 10.1046/j.1537-2995.2000.40081023.x, 40:8, (1023-1029), Online publication date: 1-Aug-2000. September 21, 1999Vol 100, Issue 12 Advertisement Article InformationMetrics Copyright © 1999 by American Heart Associationhttps://doi.org/10.1161/01.CIR.100.12.1260 Originally publishedSeptember 21, 1999 KeywordsEditorialsepidemiologycoronary diseaseironmyocardial infarctionPDF download Advertisement