Stored iron and ischemic heart disease. Empirical support for a new paradigm. J L Sullivan Circulation. 1992;86:1036-1037 doi: 10.1161/01.CIR.86.3.1036 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1992 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/86/3/1036.citation
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1036
Editorial Comment Stored Iron and Ischemic Heart Disease Empirical Support for a New Paradigm Jerome L. Sullivan, MD, PhD
In 1981, Hopkins and Williams1 published an exhaustive list of 246 proposed coronary risk factors. It might seem that this would include every plausible coronary risk factor. However, stored iron and serum ferritin were not on the list. They were proposed as risk factors in the same year, after the Hopkins and Williams study was submitted.2 A pathophysiological role for "normal" levels of stored iron in ischemic heart disease (IHD) was first suggested as an explanation for the sex difference in disease expression and for the international variation in disease incidence.2 The idea that normal levels of stored iron promote IHD has considerable explanatory power.34 This hypothesis offers a possible explanation for a wide range of phenomena, including not only the sex difference and the international distribution of IHD but also the protective effects of aspirin, fish oils, and cholestyramine and the disease-promoting effect of oral contraceptives.2-4 Very few of Hopkins and Williams' 246 risk factors' have comparable explanatory power. In particular, there has been no accepted explanation of the sex difference in IHD based on any of the risk factors on their list. See p 803 In addition to these theoretical considerations, there has been a series of investigations beginning in the mid-1980s of the effects of deferoxamine, an iron chelator, on myocardial reperfusion injury in a number of experimental animal systems.5-9 These studies, taken together, overwhelmingly support a major role for iron in myocardial reperfusion injury. They suggest that, in effect, excess iron capable of promoting myocardial injury is present in animals with normal iron status. Other investigators have shown that decreasing levels of stored iron by manipulating iron status in vivo is associated with significant decreases in oxygen radicalinduced injury in several tissues other than heart.10-14 In this issue of Circulation, Salonen and coworkers'5 present a landmark study with the first empirical evidence that serum ferritin is a strong risk factor for acute myocardial infarction. This large prospective study is a confirmation of the prediction that serum ferritin is a strong risk factor for IHD at levels previously regarded The opinions expressed in this editorial comment are not necessarily those of the editors or of the American Heart Association. From the Veterans Affairs Medical Center and the Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston. Address for reprints: Dr. J.L. Sullivan, VAMC (113), 109 Bee Street, Charleston, SC 29401-5799.
as normal.2 4 The study represents the first direct empirical evidence in support of a new IHD paradigm based on the conjecture that stored iron promotes and iron depletion protects against IHD.2-4 The paradigm may give a unifying explanation for a broad range of observations, including most prominently the sex difference in IHD risk. The study also gives new meaning to the emerging body of experimental work on the role of iron in ischemic myocardial injury.5-9 One of the major strengths of the iron paradigm of IHD is that it suggests a common mechanism for promotion of both atherogenesis and postischemic myocardial injury. Iron depletion appears to enhance antioxidant defenses in vivo.10- '4This effect may protect against IHD by inhibiting the oxidative modification of low density lipoprotein (LDL) in vivo16 as well as by directly decreasing postischemic myocardial injury and perhaps arrhythmias.5-9 Mechanisms of myocardial injury are not addressed by the theory that IHD is a function of the plasma cholesterol concentration. One of the original arguments in favor of serum ferritin and stored iron as risk factors for IHD2 was the apparent cardioselective toxicity of iron in massive iron overload. Orthodox thinking does not recognize a relation between the pathophysiology of IHD and the cardiomyopathy of hemochromatosis and transfusional iron overload. However, the research on deferoxamine and ischemic myocardial injury5-9 raises the possibility of an important link between the two. In the aftermath of an ischemic event, pump failure and arrhythmias occur. Pump failure and arrhythmias are also features of iron-overload cardiomyopathy. The deferoxamine experiments suggest that subjects with normal iron status have enough iron present to compromise pump function and cause rhythm disturbances after an ischemic event.5-9 In iron overload cardiomyopathy, the heart may be in a chronic postischemia-like state. At the very high levels of stored iron observed in hemochromatosis, the effect may be a full-blown iron-overload cardiomyopathy. At the much lower levels seen in men and women without the hemochromatosis gene, the effect may be limited to an increased propensity to myocardial infarction. The Finnish findings15 support this proposed link between IHD and iron cardiomyopathy. The study by Salonen et al15 may hold the key to understanding the limited ability of primary prevention trials'7 to reduce coronary mortality. None of the singleor multiple-risk factor interventions attempted to date have a significant effect on stored iron levels. The one possible exception is cholestyramine.1819 Inhibition of iron absorption by cholestyramine1819 could have de-
Downloaded from http://circ.ahajournals.org/ by guest on July 11, 2014
Sullivan
creased iron stores in the experimental group in the Lipid Research Clinics Coronary Primary Prevention Trial (LRCCPPT).20 The effects of cholestyramine on stored iron in the experimental group cannot be determined from the published data. Serum ferritins were not reported, and hemoglobin values are not a sensitive measure of stored iron reductions unless the reductions are large enough to cause anemia. Perhaps the coronary mortality reductions in the LRCCPPT were small and of marginal statistical significance because the cholestyramine dosages were not adequate to lower iron storage levels appreciably. Other interventions17 would not be expected to have a significant impact on stored iron. Dietary changes, even if they include substantial decreases in dietary iron, do not rapidly reduce the level of stored iron in subjects in affluent societies. In the absence of parasitic infections or other medical conditions that cause chronic occult blood loss, iron is very efficiently stored and recycled. A large store of iron would not be readily lost with risk factor interventions of the durations reported to date. Future trials with interventions that cause iron depletion21 may be successful in significantly and substantially reducing coronary mortality. The finding that ferritin is a strong heart disease risk factor is especially relevant to the hypothesis that low iron stores protect young women from heart disease. The finding is pertinent despite the exclusion of women from the Finnish study. A study of ferritin as a risk factor in a group with both men and women would be likely, at the least, to show lower risk and lower ferritin in the women. Such a study might not be a convincing demonstration of the protective effects of low ferritin because the effects of other postulated factors associated with femaleness might be confounded with those of low ferritin. Additional studies including women will of course be necessary to establish that serum ferritin is a risk factor for IHD in women. Studies with young menstruating women are essential to extend the Finnish study to include an adequate population of iron-depleted subjects. Very few of the Finnish men were iron depleted. If decreased iron stores protect against IHD by a mechanism involving decreased reperfusion injury and LDL modification by ferritin-derived iron, then clearly the lowest risk condition should be the absence of ferritin, i.e., complete iron depletion. The extremely low incidence of IHD in young menstruating women may be, in part, an indication of the maximal protection achievable by iron depletion. The greatest relative increment in risk associated with serum ferritin may thus be seen at the lower end of its observed range. The findings of Salonen and coworkers are particularly notable because they show serum ferritin to be a strong risk factor at levels generally much higher than those seen in menstruating women. Further research will be needed to confirm that differences in serum ferritin account not only for some of the relatively small differences in IHD risk among adult men but also for the immense difference in risk between men and menstruating women. The study by Salonen et al'5 marks the beginning of a new era of investigation into the role of iron in the pathophysiology of IHD. It should also inspire a broader debate on the definition of normal iron status. Perhaps iron depletion, defined as the absence of iron stores without anemia, should be regarded as physiolog-
Iron and Ischemic Heart Disease
1037
ically normal iron status. What other benign "condition" eliminates a major injury-promoting substance from the body? Stored iron in the form of ferritin is not essential for life or for preventing anemia, but it can powerfully promote tissue injury.'0-14 A comprehensive debate on the redefinition of normal iron status should address questions on the role of iron not only in IHD, but also in neoplasia,22 infectious disease,23 neonatal disorders,24 brain diseases,14 arthritis,12 and aging.25
References 1. Hopkins PN, Williams RR: A survey of 246 suggested coronary risk factors. Atherosclerosis 1981;40:1-52 2. Sullivan JL: Iron and the sex difference in heart disease risk. Lancet 1981;1:1293-1294 3. Sullivan JL: The iron paradigm of ischemic heart disease. Am Heart J 1989;117:1177-1188 4. Sullivan JL: Stored iron as a risk factor for ischemic heart disease, in Lauffer RB (ed): Iron and Human Disease. Boca Raton, Fla, CRC Press (in press) 5. Babbs CF: Role of iron ions in the genesis of reperfusion injury following successful cardiopulmonary resuscitation: Preliminary data and a biochemical hypothesis. Ann Emerg Med 1985;14:777-783 6. Bernier M, Hearse DJ, Manning AS: Reperfusion-induced arrhythmias and oxygen-derived free radicals: Studies with antifree radical interventions and a free-radical generating system in the isolated perfused rat heart. Circ Res 1986;58:331-340 7. Reddy BR, Kloner RA, Przyklenk K: Early treatment with deferoxamine limits myocardial ischemic/reperfusion injury. Free Radic Biol Med 1989;7:45-52 8. Lesnefsky EJ, Repine JE, Horwitz LD: Deferoxamine pretreatment reduces canine infarct size and oxidative injury. J Pharmacol Exp Ther 1990;253:1103-1108 9. McCord JM: Is iron sufficiency a risk factor in ischemic heart disease? Circulation 1991;83:1112-1114 10. Sullivan JL, Till GO, Ward PA: Iron depletion decreases lung injury after systemic complement activation. (abstract) Fed Proc 1986;45:452 11. Sullivan JL, Till GO, Ward PA, Newton RB: Nutritional iron restriction diminishes acute complement-dependent lung injury. Nutr Res 1989;9:625-634 12. Andrews FJ, Morris CJ, Lewis EJ, Blake DR: Effect of nutritional iron deficiency on acute and chronic inflammation. Ann Rheum Dis 1987;46:859-865 13. Chandler DB, Barton JC, Briggs DD, Butler TW, Kennedy JI, Grizzle WE, Fuimer JD: Effect of iron deficiency on bleomycin-induced lung fibrosis in the hamster. Am Rev Respir Dis 1988;137:85-89 14. Patt A, Horesh IR, Berger EM, Harken AH, Repine JE: Iron depletion or chelation reduces ischemia/reperfusion-induced edema in gerbil brains. J Pediatr Surg 1990;25:224-228 15. 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 16. Heinecke JW, Rosen H, Chait A: Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. J Clin Invest 1984;74:1890-1894 17. McCormick J, Skrabanek P: Coronary heart disease is not preventable by population interventions. Lancet 1988;2:839-841 18. Sullivan JL: Lipid Research Clinics Program. (letter) JAMA 1984; 252:2547 19. Thomas FB, Salsburey D, Greenberger NJ: Inhibition of iron absorption by cholestyramiine: Demonstration of diminished iron stores following prolonged administration. Am J Dig Dis 1972;17:263-269 20. Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial results. JAMA 1984;251:351-374 21. Sullivan JL: Blood donation may be good for the donor: Iron, heart disease, and donor recruitment. Vox Sang 1991;61:161-164 22. Stevens RG, Beasley RP, Blumberg BS: Iron-binding proteins and risk of cancer in Taiwan. J Natl Cancer Inst 1986;76:605-610 23. Weinberg ED: Iron and infection. Microbiol Rev 1978;42:45-66 24. Sullivan JL: Iron, plasma antioxidants, and the 'oxygen radical disease of prematurity.' Am J Dis Child 1988;142:1341-1344 25. Lauffer RB (ed): Iron and Human Disease. Boca Raton, Fla, CRC Press (in press) KEY WoRDs * iron * risk factors * serum ferritin * Editorial Comments
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The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/86/3/1036.citation
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/
Downloaded from http://circ.ahajournals.org/ by guest on July 11, 2014
1036
Editorial Comment Stored Iron and Ischemic Heart Disease Empirical Support for a New Paradigm Jerome L. Sullivan, MD, PhD
In 1981, Hopkins and Williams1 published an exhaustive list of 246 proposed coronary risk factors. It might seem that this would include every plausible coronary risk factor. However, stored iron and serum ferritin were not on the list. They were proposed as risk factors in the same year, after the Hopkins and Williams study was submitted.2 A pathophysiological role for "normal" levels of stored iron in ischemic heart disease (IHD) was first suggested as an explanation for the sex difference in disease expression and for the international variation in disease incidence.2 The idea that normal levels of stored iron promote IHD has considerable explanatory power.34 This hypothesis offers a possible explanation for a wide range of phenomena, including not only the sex difference and the international distribution of IHD but also the protective effects of aspirin, fish oils, and cholestyramine and the disease-promoting effect of oral contraceptives.2-4 Very few of Hopkins and Williams' 246 risk factors' have comparable explanatory power. In particular, there has been no accepted explanation of the sex difference in IHD based on any of the risk factors on their list. See p 803 In addition to these theoretical considerations, there has been a series of investigations beginning in the mid-1980s of the effects of deferoxamine, an iron chelator, on myocardial reperfusion injury in a number of experimental animal systems.5-9 These studies, taken together, overwhelmingly support a major role for iron in myocardial reperfusion injury. They suggest that, in effect, excess iron capable of promoting myocardial injury is present in animals with normal iron status. Other investigators have shown that decreasing levels of stored iron by manipulating iron status in vivo is associated with significant decreases in oxygen radicalinduced injury in several tissues other than heart.10-14 In this issue of Circulation, Salonen and coworkers'5 present a landmark study with the first empirical evidence that serum ferritin is a strong risk factor for acute myocardial infarction. This large prospective study is a confirmation of the prediction that serum ferritin is a strong risk factor for IHD at levels previously regarded The opinions expressed in this editorial comment are not necessarily those of the editors or of the American Heart Association. From the Veterans Affairs Medical Center and the Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston. Address for reprints: Dr. J.L. Sullivan, VAMC (113), 109 Bee Street, Charleston, SC 29401-5799.
as normal.2 4 The study represents the first direct empirical evidence in support of a new IHD paradigm based on the conjecture that stored iron promotes and iron depletion protects against IHD.2-4 The paradigm may give a unifying explanation for a broad range of observations, including most prominently the sex difference in IHD risk. The study also gives new meaning to the emerging body of experimental work on the role of iron in ischemic myocardial injury.5-9 One of the major strengths of the iron paradigm of IHD is that it suggests a common mechanism for promotion of both atherogenesis and postischemic myocardial injury. Iron depletion appears to enhance antioxidant defenses in vivo.10- '4This effect may protect against IHD by inhibiting the oxidative modification of low density lipoprotein (LDL) in vivo16 as well as by directly decreasing postischemic myocardial injury and perhaps arrhythmias.5-9 Mechanisms of myocardial injury are not addressed by the theory that IHD is a function of the plasma cholesterol concentration. One of the original arguments in favor of serum ferritin and stored iron as risk factors for IHD2 was the apparent cardioselective toxicity of iron in massive iron overload. Orthodox thinking does not recognize a relation between the pathophysiology of IHD and the cardiomyopathy of hemochromatosis and transfusional iron overload. However, the research on deferoxamine and ischemic myocardial injury5-9 raises the possibility of an important link between the two. In the aftermath of an ischemic event, pump failure and arrhythmias occur. Pump failure and arrhythmias are also features of iron-overload cardiomyopathy. The deferoxamine experiments suggest that subjects with normal iron status have enough iron present to compromise pump function and cause rhythm disturbances after an ischemic event.5-9 In iron overload cardiomyopathy, the heart may be in a chronic postischemia-like state. At the very high levels of stored iron observed in hemochromatosis, the effect may be a full-blown iron-overload cardiomyopathy. At the much lower levels seen in men and women without the hemochromatosis gene, the effect may be limited to an increased propensity to myocardial infarction. The Finnish findings15 support this proposed link between IHD and iron cardiomyopathy. The study by Salonen et al15 may hold the key to understanding the limited ability of primary prevention trials'7 to reduce coronary mortality. None of the singleor multiple-risk factor interventions attempted to date have a significant effect on stored iron levels. The one possible exception is cholestyramine.1819 Inhibition of iron absorption by cholestyramine1819 could have de-
Downloaded from http://circ.ahajournals.org/ by guest on July 11, 2014
Sullivan
creased iron stores in the experimental group in the Lipid Research Clinics Coronary Primary Prevention Trial (LRCCPPT).20 The effects of cholestyramine on stored iron in the experimental group cannot be determined from the published data. Serum ferritins were not reported, and hemoglobin values are not a sensitive measure of stored iron reductions unless the reductions are large enough to cause anemia. Perhaps the coronary mortality reductions in the LRCCPPT were small and of marginal statistical significance because the cholestyramine dosages were not adequate to lower iron storage levels appreciably. Other interventions17 would not be expected to have a significant impact on stored iron. Dietary changes, even if they include substantial decreases in dietary iron, do not rapidly reduce the level of stored iron in subjects in affluent societies. In the absence of parasitic infections or other medical conditions that cause chronic occult blood loss, iron is very efficiently stored and recycled. A large store of iron would not be readily lost with risk factor interventions of the durations reported to date. Future trials with interventions that cause iron depletion21 may be successful in significantly and substantially reducing coronary mortality. The finding that ferritin is a strong heart disease risk factor is especially relevant to the hypothesis that low iron stores protect young women from heart disease. The finding is pertinent despite the exclusion of women from the Finnish study. A study of ferritin as a risk factor in a group with both men and women would be likely, at the least, to show lower risk and lower ferritin in the women. Such a study might not be a convincing demonstration of the protective effects of low ferritin because the effects of other postulated factors associated with femaleness might be confounded with those of low ferritin. Additional studies including women will of course be necessary to establish that serum ferritin is a risk factor for IHD in women. Studies with young menstruating women are essential to extend the Finnish study to include an adequate population of iron-depleted subjects. Very few of the Finnish men were iron depleted. If decreased iron stores protect against IHD by a mechanism involving decreased reperfusion injury and LDL modification by ferritin-derived iron, then clearly the lowest risk condition should be the absence of ferritin, i.e., complete iron depletion. The extremely low incidence of IHD in young menstruating women may be, in part, an indication of the maximal protection achievable by iron depletion. The greatest relative increment in risk associated with serum ferritin may thus be seen at the lower end of its observed range. The findings of Salonen and coworkers are particularly notable because they show serum ferritin to be a strong risk factor at levels generally much higher than those seen in menstruating women. Further research will be needed to confirm that differences in serum ferritin account not only for some of the relatively small differences in IHD risk among adult men but also for the immense difference in risk between men and menstruating women. The study by Salonen et al'5 marks the beginning of a new era of investigation into the role of iron in the pathophysiology of IHD. It should also inspire a broader debate on the definition of normal iron status. Perhaps iron depletion, defined as the absence of iron stores without anemia, should be regarded as physiolog-
Iron and Ischemic Heart Disease
1037
ically normal iron status. What other benign "condition" eliminates a major injury-promoting substance from the body? Stored iron in the form of ferritin is not essential for life or for preventing anemia, but it can powerfully promote tissue injury.'0-14 A comprehensive debate on the redefinition of normal iron status should address questions on the role of iron not only in IHD, but also in neoplasia,22 infectious disease,23 neonatal disorders,24 brain diseases,14 arthritis,12 and aging.25
References 1. Hopkins PN, Williams RR: A survey of 246 suggested coronary risk factors. Atherosclerosis 1981;40:1-52 2. Sullivan JL: Iron and the sex difference in heart disease risk. Lancet 1981;1:1293-1294 3. Sullivan JL: The iron paradigm of ischemic heart disease. Am Heart J 1989;117:1177-1188 4. Sullivan JL: Stored iron as a risk factor for ischemic heart disease, in Lauffer RB (ed): Iron and Human Disease. Boca Raton, Fla, CRC Press (in press) 5. Babbs CF: Role of iron ions in the genesis of reperfusion injury following successful cardiopulmonary resuscitation: Preliminary data and a biochemical hypothesis. Ann Emerg Med 1985;14:777-783 6. Bernier M, Hearse DJ, Manning AS: Reperfusion-induced arrhythmias and oxygen-derived free radicals: Studies with antifree radical interventions and a free-radical generating system in the isolated perfused rat heart. Circ Res 1986;58:331-340 7. Reddy BR, Kloner RA, Przyklenk K: Early treatment with deferoxamine limits myocardial ischemic/reperfusion injury. Free Radic Biol Med 1989;7:45-52 8. Lesnefsky EJ, Repine JE, Horwitz LD: Deferoxamine pretreatment reduces canine infarct size and oxidative injury. J Pharmacol Exp Ther 1990;253:1103-1108 9. McCord JM: Is iron sufficiency a risk factor in ischemic heart disease? Circulation 1991;83:1112-1114 10. Sullivan JL, Till GO, Ward PA: Iron depletion decreases lung injury after systemic complement activation. (abstract) Fed Proc 1986;45:452 11. Sullivan JL, Till GO, Ward PA, Newton RB: Nutritional iron restriction diminishes acute complement-dependent lung injury. Nutr Res 1989;9:625-634 12. Andrews FJ, Morris CJ, Lewis EJ, Blake DR: Effect of nutritional iron deficiency on acute and chronic inflammation. Ann Rheum Dis 1987;46:859-865 13. Chandler DB, Barton JC, Briggs DD, Butler TW, Kennedy JI, Grizzle WE, Fuimer JD: Effect of iron deficiency on bleomycin-induced lung fibrosis in the hamster. Am Rev Respir Dis 1988;137:85-89 14. Patt A, Horesh IR, Berger EM, Harken AH, Repine JE: Iron depletion or chelation reduces ischemia/reperfusion-induced edema in gerbil brains. J Pediatr Surg 1990;25:224-228 15. 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 16. Heinecke JW, Rosen H, Chait A: Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. J Clin Invest 1984;74:1890-1894 17. McCormick J, Skrabanek P: Coronary heart disease is not preventable by population interventions. Lancet 1988;2:839-841 18. Sullivan JL: Lipid Research Clinics Program. (letter) JAMA 1984; 252:2547 19. Thomas FB, Salsburey D, Greenberger NJ: Inhibition of iron absorption by cholestyramiine: Demonstration of diminished iron stores following prolonged administration. Am J Dig Dis 1972;17:263-269 20. Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial results. JAMA 1984;251:351-374 21. Sullivan JL: Blood donation may be good for the donor: Iron, heart disease, and donor recruitment. Vox Sang 1991;61:161-164 22. Stevens RG, Beasley RP, Blumberg BS: Iron-binding proteins and risk of cancer in Taiwan. J Natl Cancer Inst 1986;76:605-610 23. Weinberg ED: Iron and infection. Microbiol Rev 1978;42:45-66 24. Sullivan JL: Iron, plasma antioxidants, and the 'oxygen radical disease of prematurity.' Am J Dis Child 1988;142:1341-1344 25. Lauffer RB (ed): Iron and Human Disease. Boca Raton, Fla, CRC Press (in press) KEY WoRDs * iron * risk factors * serum ferritin * Editorial Comments
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