(Circulation. 1999;100:446-449.)
© 1999 American Heart Association, Inc.
Correspondence |
Body Iron Stores, Infection, and Risk of Acute Myocardial Infarction
UCLA Neuropsychiatric Institute and Hospital Los Angeles, Calif
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To the Editor:
Tuomainen et al1 have noted an association between increased iron stores, as measured by a reduced ratio of serum transferrin receptor concentration to serum ferritin concentration, and excess risk of acute myocardial infarction (AMI).
It has been suggested that iron can catalyze toxic redox reactions, which may lead to an increased risk for coronary heart disease and AMI. Another mechanism by which iron might increase the risk of AMI involves a possible role for iron in facilitating some infections.
Vertebrates have a hypoferremic response during infection that lowers the presence of iron as serum transferrin, temporarily storing the metal as ferritin. Intestinal absorption of iron also declines during infection. Bacterial mechanisms to obtain iron from a host include direct uptake of iron from the labile iron pool, siderophore-mediated iron uptake, and iron uptake by direct interaction with transferrin, lactoferrin, or heme-containing proteins.
Various mechanisms by which infectious processes might induce atherogenesis have been proposed, including cytopathic effects of infection on endothelial and smooth muscle cells, formation of circulating toxins or immune complexes that deposit on vessel walls, elicitation of an inflammatory response, induction of alterations of serum prostaglandin and lipid metabolism, or elicitation of a hypercoagulable state that increases the risk of thrombosis.
Recent research has suggested that numerous organisms may be associated with an increased risk of AMI. These include Helicobacter pylori, Chlamydia pneumoniae, herpes simplex virus, and cytomegalovirus.2
Several investigators have noted the importance of iron acquisition for H pylori growth.3 No studies have reported on the iron requirements of C pneumoniae. However, Raulston4 noted that iron restriction caused a significant reduction in infectivity of C trachomatous elementary bodies. The smaller subunit (R2) of herpes simplex virus ribonucleotide reductase, which catalyzes the reduction of ribonucleotides to deoxyribonucleotides, contains binuclear ferric iron centers; ferrous iron is necessary to generate the binuclear ferric iron centers and to ensure full enzymatic activity. Gumbel et al5 noted that desferrioxamine, an iron chelator with antiherpetic activity, can inhibit cytomegalovirus infection in vitro and in vivo. It had been proposed that 1 mechanism of action by which desferrioxamine and other iron chelators inhibit various infections might involve ribonucleotide reductase inhibition.
Further studies are needed to investigate the possible role of infections in the etiology of AMI and of iron in promoting those infections.
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1. Tuomainen T-P, 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.
2.
Ridker PM. Inflammation, infection, and
cardiovascular risk: how good is the clinical evidence?
Circulation. 1998;97:1671–1674.
3.
Husson MO, Legrand D, Spik G, Leclerc H. Iron
acquisition by Helicobacter pylori: importance of human
lactoferrin. Infect Immun. 1993;61:2694–2697.
4. Raulston JE. Response of Chlamydia trachomatis serovar E to iron restriction in vitro and evidence for iron-regulated chlamydial proteins. Infect Immun. 1997;65:4539–4547.[Abstract]
5. Gumbel H, Cinatl J, Rabenau H, Vogel JU, Doerr HW, Ohrloff C. Selective inhibition of replication of cytomegalovirus by desferrioxamine in vitro and in vivo. Ophthalmologe. 1995;92:840–843.[Medline] [Order article via Infotrieve]
Response
Research Institute of Public Health, University of Kuopio, Kuopio, Finland
Department of Clinical Chemistry Kuopio University Hospital, Kuopio, Finland
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We thank Dr Rabinoff for his interesting comments on our study of body iron and the risk of first acute myocardial infarction.1 We agree that iron is an essential nutrient and enzyme cofactor in different infectious agents as well as in humans. The role of some infectious agents, especially of Helicobacter pylori, Chlamydia pneumoniae, herpes simplex virus, and cytomegalovirus, in the etiology of cardiovascular disease has been studied by several study groups, but no solid conclusions can yet be drawn.2 Most of the studies that support this association have been small, and positive publication bias seems very likely. Although we acknowledge that high body iron may predispose to some potentially cardiovascular disease–related infections, we would emphasize the inflammation itself. Plenty of evidence links inflammation and both central and peripheral atherosclerosis.3 If atherosclerosis is taken as a chronic inflammatory disease, it is likely that any factor that enhances inflammation accelerates the process of atherogenesis.
However, the direct effect of elevated body iron in driving different free radical–generating reactions that propagate lipid peroxidation and cause untargeted direct and indirect oxidative damage in arterial wall and in myocytes is probably far more important.1 4 5 Whether high iron predisposes to coronary heart disease or low iron protects against it remains to be ascertained. Currently, high (elevated) body iron appears to be a risk-increasing factor in cardiovascular disease, independent of infections.1
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References |
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TopIntroductionReferencesIntroduction References |
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1. Tuomainen T-P, 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.
2.
Ridker PM, Hennekens CH, Stampfer MJ, Wang F.
Prospective study of herpes simplex virus, cytomegalovirus, and the
risk of future myocardial infarction and stroke.
Circulation. 1998;98:2796–2799.
3.
Ross R. Mechanisms of disease:
atherosclerosis: an inflammatory disease. N
Engl J Med.. 1999;340:115–126.
4. Stohs SJ, Bagchi D. Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med.. 1995;18:321–336.[Medline] [Order article via Infotrieve]
5. Salonen JT. Excessive intake of iron and mercury in cardiovascular disease. Bibl Nutr Dieta. 1998;(54):112–126.
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