1036
Editorial Comment
Stored Iron and Ischemic Heart Disease
Empirical Support for a New Paradigm
Jerome L. Sullivan, MD, PhD
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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-
Sullivan
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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
Stored iron and ischemic heart disease. Empirical support for a new paradigm.
J L Sullivan
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
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.
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