Ironing out heart disease: deplete or not deplete?
William R. Proulx
Recently, there has been increased interest regarding the possible role of iron in the etiology of heart disease. Research reported by Salonen et al. (1992) suggests that stored iron, assessed by serum ferritin, is a risk factor for coronary heart disease (CHD). These results support a theory proposed over a decade ago (Sullivan, 1981) that postulates that the protection from heart disease enjoyed by many premenopausal women is due to low iron stores that result from menstrual blood loss. This theory is believed to provide an explanation for the effects of gender, exercise, oral contraceptives, fish oils, aspirin, and menopausal status on heart disease (Sullivan, 1989). Dr. Sullivan has suggested that if the iron/heart disease theory is valid, then the lowest risk condition would be complete iron depletion (Sullivan, 1992). Therefore, along with other individuals, Dr. Sullivan is promoting the depletion of body iron stores as a prophylactic measure against heart disease for high-risk individuals (Sullivan, 1989; McCord, 1994; Herbert, 1993). However,
William R. Proulx, M.S., R.D., is a doctoral candidate within the Foods and Nutrition Department at Purdue University, where he also received his M.S. degree in the area of mineral metabolism. He received his dietetics degree from Andrews University in Berrien Springs, Michigan. He is currently an assistant professor of nutrition at Andrews University.
Connie M. Weaver, Ph.D., is professor and Head of the Department of Foods and Nutrition at Purdue University. Much of Dr. Weaver’s research has focused on the metabolism of minerals, particularly calcium and iron. these recommendations are opposite to the established policy of encouraging the public to improve their iron status, inasmuch as depleted iron levels have been associated with impaired growth and development, cognitive performance, compromised immune function, and thermoregulation (Li et al., 1994; Pollitt, 1993; Oski, 1993; Lozoff et al., 1991; Beard and Borel, 1988; MacDougall et al., 1975). On the other hand, the recognition that iron storage diseases such as hemochromatosis are much more common than previously thought has raised concern that some individuals may be harmed if the general public is encouraged to increase intake of iron. In fact, hereditary hemochromatosis is presently estimated to be the most common recessive genetic disease afflicting white Americans, with a high frequency also found in northern European countries (Fairbanks, 1994; Rouault, 1993). Heart disease, diabetes mellitus, and cirrhosis of the liver are all clinical manifestations of hemochromatosis. Therefore, when the consequences of both iron depletion and iron overload are considered, it becomes apparent that recommendations to the general public regarding iron status need to be based on clear results obtained from sound scientific investigation and not only on conjecture and hypothesis.
IRON AND LIPID PEROXIDATION
All of the functions that iron performs in biological systems are based on its ability to donate and accept electrons. It is this characteristic that makes iron a highly reactive and potentially toxic nutrient. In fact, iron has been shown to enhance the production of free radicals (Halliwell and Gutteridge, 1989), which are capable of altering molecules and causing cell damage through oxidation reactions. Recently, Steinberg et al. (1989) have proposed that the oxidation of low-density lipoprotein (LDL) results in the modified LDL being taken up more readily by macrophages, which results in the development of the fatty streak, the initial lesion of atherosclerosis. Iron, as well as copper, has been shown to promote the modification of LDL in vitro and is suspected of participating in these reactions in the body.
Although many studies provide convincing evidence that iron does participate in free radical reactions and the modification of LDL under experimental conditions, it remains unknown what conditions must exist in the body for iron to participate in these reactions. Normally, the body takes great care in keeping iron in a nonreactive state. For example, the potential for free iron to exist in serum is low, because the iron transport protein, transferrin, is only approximately 30% saturated with iron under normal conditions. This allows for a large capacity to deal with changes in iron concentration within the serum pool (Beard, 1993). Only as transferrin saturation approaches 100% does iron become available to participate in free radical generation under normal conditions. However, free iron has been observed in the plasma of hemochromatosis patients whose transferrin saturation was much less than 100% (Aruoma et al., 1988). This may be indicative of an inability of transferrin to bind iron sufficiently in hemochromatosis patients. After delivery of iron to the cell, the transferrin-iron complex enters the cell through receptor-mediated endocytosis. Once in the cell, iron is utilized by iron-dependent systems, and any surplus iron is stored tightly chelated in a nonreactive state in ferritin and hemosiderin McCord, 1991). Ferritin, because of its iron-binding properties, is a strong cytoprotective antioxidant (Balla et al., 1992; Gutteridge and Quinlan, 1993). Moreover, pools of dormant ferritin mRNAs exist in the cytoplasm which can be rapidly translated to yield a large number of ferritin subunits in response to increases in cellular iron (Munro, 1993). This prevents the accumulation of iron within the cytoplasm and the peroxidation of cell lipids, DNA, and various proteins. If the storage capacity of ferritin is exhausted, excess iron is then stored in the form of hemosiderin, which is a more insoluble iron deposit that is not readily available to the organism (Welch, 1992). Therefore, the association of iron with transferrin, ferritin, and hemosiderin prevents iron’s participation in undesirable reactions thought to be involved in the development of atherosclerotic lesions.
Nevertheless, extreme levels of iron in the body can result in myocardial tissue damage as evidenced by the clinical manifestation of heart disease in hemochromatosis and other iron-storage disease patients. Furthermore, the ability of iron chelators to reduce injury to heart tissue immediately after a cardiac arrest demonstrates that iron does contribute to heart damage after a heart attack has occurred (Babbs, 1985; Bernier et al., 1986; Williams et al., 1991). However, it must be recognized that these are extreme conditions that do not implicate normal iron status as a risk factor for atherogenesis in healthy individuals.
Free radicals are generated in the body as part of normal cellular processes. For instance, a major line of defense against bacteria within the body is the event known as the “respiratory burst” (Dallman, 1986). The respiratory burst involves at least two or three iron-dependent steps indicating that under controlled conditions the participation of iron in the production of free radicals in the body is desirable and permitted (Kehrer, 1993). Fortunately, free radical scavenger systems, such as superoxide dismutase and glutathione peroxidase, exist to prevent or terminate the undesirable accumulation of free radicals generated in these situations. Consequently, nutritional status of nutrients known to have antioxidant functions or intregal roles in free radical scavenger systems (i.e. copper, zinc, selenium, carotenoids, and vitamins A, E, and C), is important to consider. It may be a deficiency of these nutrients that creates an opportunistic environment that promotes atherosclerotic lesions and not just the presence of transitional metals such as iron (Ames et al., 1993; Manson, 1993). Therefore, the question that remains is: at what level in the body and under what conditions does iron become available to participate in undesirable free radical production and lipoprotein modification?
THE FINNISH STUDY
Some believe this question was partly answered by Salonen et al. (1992), who found that eastern Finnish men with serum ferritin levels greater than 200 [mu]g/L had a 2.2-fold risk-factor-adjusted risk of acute myocardial infarction (AMI) compared with men with lower serum ferritin levels. This was a prospective 3-year follow-up study of 1931 eastern Finnish men aged 42, 48, 54, and 60 years who had no previous history of heart disease upon entry into the study. During the follow-up period, 51 of these men experienced chest pain that met criteria for either definite or possible AMI. Within this population, serum ferritin ranged from 10 to 2270 [mu]g/L with a mean of 166 [mu]g/L. Four-hundred eighty-two subjects had serum ferritin levels greater than 200 [mu]g/L, and 115 of these subjects had serum ferritin levels greater than 400 [mu]g/L. Only 20 subjects (1%) had serum ferritin levels below the level (16 [mu]g/L), which is considered an indication of iron depletion. Dietary iron was also found to be a significant risk factor for AMI, with a calculated increase of 5% in risk of myocardial infarction (MI) for each milligram increase in dietary iron.
Although these results indicate that serum ferritin in the uppernormal range was a risk factor for AMI in the population studied, it has been questioned whether the data can be readily extrapolated to other groups (Beard, 1993). The nutritional patterns of a similar group of eastern Finnish men were reported by Ihanainen et al. (1989), who collected nutritional data on 1157 eastern Finnish men aged 54 years. Results of this analysis showed the consumption of vegetables in this population to be low (110 g/day), whereas coffee (586 g/day) and fat intake (40% of energy intake) were high. Intake of saturated fat was four times greater than that of polyunsaturated fat, and dairy product consumption consisted of 70% butter. Meat intake comprised mainly sausage 39%), beef (37%), and pork (21%), and the mean daily intake of cholesterol was 480 mg. The average intake of nutrients known to protect against lipid peroxidation, such as vitamin E, copper, and selenium, was below recommended dietary allowances. The authors of this study indicated their findings were consistent with other studies that have evaluated the diet of the Finnish population (Uusitalo, 1987; Seppanen, 1981).
The enormous range in serum ferritin levels (10-2270 [mu]g/L) in these subjects is a strong indicator that the recessive hemochromatosis gene was present in this cohort and possibly driving the observed association between stored iron and AMI (Beard, 1993). Other explanations for such high serum ferritin levels include the presence of undetected conditions known to elevate ferritin levels, such as liver disease and cancer (Finch et al., 1986). It is these population attributes and the fact that eastern Finnish men have the highest recorded incidence and mortality from CHD (Keys, 1980) that makes extrapolation to other populations difficult. Moreover, although ferritin was found to be a significant risk factor for AMI with a relative risk of 1.03 in this population, several other factors were also found to be statistically significant and have greater relative risks for AMI than serum ferritin. For instance, serum copper, serum apolipoprotein B, and diabetes had approximately 600, 400, and 250 percent greater relative hazards of AMI than ferritin, respectively. The weaker association of ferritin to AMI compared with these other factors may be due to ferritin’s ability to sequester iron in a nonreactive form (Balla et al., 1992; Gutteridge and Quinlan, 1993).
IRON STORES AND AGE
The hypothesis that iron stores are related to the risk of cardiovascular disease (CVD) arose in part from the observation that the incidence of CVD increases with age in men and in postmenopausal women (Kannel et al., 1976; Gordon et al., 1978). Other studies reported that iron stores also accumulated with age in men and in postmenopausal women (Cook et al., 1976). Thus, Sullivan hypothesized that the two observations were related (Sullivan, 1981). However, NHANES II and NHANES III pilot study data appear to indicate that iron may not accumulate with age. Figure 1 represents data of mean serum ferritin values of non-hispanic white (NHW) males and females at various ages from NHANES II and NHANES III pilot data of all persons measured. As can be observed from the graph, ferritin values do not increase appreciably with age in men, but values do increase in women as they pass through menopause. Interestingly, Solonen et al. (1992) reported that serum ferritin concentrations decreased after 48 years of age in the eastern Finnish men they studied.
The recent proposal of a setpoint theory, whereby iron stores regulate iron absorption to maintain an individual’s preset iron stores, challenges the idea that iron stores accumulate with age. Garry et al. (1992) proposed the setpoint theory after assessing iron stores in 27 postmenopausal healthy women who donated 5 units of blood over 1 year compared with 59 controls. Iron stores in the control group did not change over 2 years, despite large differences in baseline iron stores and similar dietary iron intakes. The authors speculated that a setpoint exists for individual iron stores which is under genetic control. If this is so, it would be difficult to increase iron stores through diet or supplementation when iron stores are at or near an individual’s predetermined setpoint. Gavin et al. (1994) further investigated the setpoint theory in 21 individuals selected from the same study population as that used by Garry et al. (1992). Iron absorption changed according to changes in baseline iron stores, and 70% of the variation in iron absorption was explained by the changes in iron stores from baseline, indicating an adaptation to the level of depletion of iron stores below the setpoint. If iron stores are regulated as described by the setpoint theory, iron stores would not be expected to increase with age.
TRANSFERRIN SATURATION AND HEART DISEASE
Within the iron/heart disease paradigm, it would be predicted that other indicators of iron deficiency, such as a low transferrin saturation (serum iron divided by total iron binding capacity X 100), would indicate protection against heart disease, because a low transferrin saturation would possess potent antioxidant activity. As indicated by Beard (1993), determination of transferrin saturation could provide a better understanding of the association of iron and heart disease. Magnusson et al. (1994) studied 2036 men and women between the ages of 25 and 74 years who were participating in a large epidemiological study. It was found that increased total iron binding capacity (TIBC) was protective against MI, whereas serum ferritin had no significant association. It was also observed that transferrin saturation had less predictive power for MI than did TIBC. Another study was recently completed on 46,932 subjects whose serum iron and TIBC were measured and who were followed for a 14-year period (Baer et al., 1994). During the followup period, 969 men and 871 women had an Ami-related hospital stay. Results did not show iron deficiency, as indicated by low transferrin saturation, to be protective against heart disease. Liao et al. (1994) examined data from the 4237 respondents of NHANES I aged 40-74 years (1827 men and 2410 women). Hemoglobin, serum iron, and the total iron-binding capacity of transferrin (TIBC) were determined. During the 13-year followup, 489 persons had an AMI, and 1151 developed CHD. Hemoglobin, hematocrit, and TIBC were not associated with the incidence of MI or CHD. Transferrin saturations in both men and women who developed CHD were lower than in those who did not, and each 10% increase in transferrin saturation was associated with a 9% decrease in risk of CHD among men and a 12% decrease among women. The authors caution that these results are only suggestive, because the influence of diurnal variation and other factors such as inflammation and malignancy were not monitored or controlled. Sempos et al. (1994) also assessed the association between the risk of MI and serum transferrin saturation in 4518 men and women who were part of NHANES I. The risk of CHD was not related to transferrin saturation levels, and results indicated there may even be an inverse relationship.
OTHER RESEARCH OF IRON AND CARDIOVASCULAR DISEASE
Since the publication of the Finnish study by Salonen et al. (1992), many other studies that have investigated the association of iron and heart disease have been completed. Researchers from the Karolinska Institute in Stockholm, Sweden, conducted a case-control study to investigate the effect of iron on the risk of AMI at a young age (Regnstrom et al., 1994). Ninety-four men who experienced an MI before the age of 45 years were compared with 100 age-matched population controls. There was no association between the measure of iron status and severity of coronary atherosclerosis, suggesting that iron stores were not a risk factor for premature coronary atherosclerosis. In another investigation, 252 patients between the ages of 29 and 84 who were admitted for cardiac catheterization to Duke University Medical Center also had their blood analyzed for serum ferritin, total iron, TIBC, and transferrin with lipoprotein profiles (Lin et al., 1994). When coronary artery disease (CAD) risk factors (age, sex, body mass index, lipid-lowering drugs, smoking, and special diet) were controlled for, no relationship between indicators of iron status and extent of CAD was found. A prospective study of plasma ferritin and risk of MI in 238 men with MI and 238 controls matched for age and smoking found that, after adjustment for other coronary risk factors, men with serum ferritin levels greater than 200 [mu]g/L had a relative risk of 1.1 (Stampfer et al., 1993). This suggests little or no increased risk associated with normal ferritin levels. Aronow (1993) evaluated the association between serum ferritin levels and CAD in 171 men and 406 women. The mean age of men (n = 74) and women (n = 172) with CAD was 82 years; that of men and women without CAD was 81 years. The mean serum ferritin concentration was not significantly different between men and women with and without CAD, indicating ferritin was not a risk factor for CAD in these elderly men and women. Miller and Hutchins (1993) selected 130 adult patients from 48,000 autopsy records performed from 1889 to 1993 at Johns Hopkins University. These patients were carefully matched for age, sex, and time of death. Sixty-five of these had iron overload and 65 did not. The researchers concluded that people with iron overload did not appear to have significant amounts of CAD. Only 3 of the 65 patients with iron overload had one coronary artery with 90% or more blockage.
Salonen et al. (1992) also reported that the intake of dietary iron was strongly associated with the risk of AMI in eastern Finnish men. However, Rimm et al. (1993) measured dietary iron intake through a food frequency questionnaire during a 4-year followup of 45,720 men aged 40-75 years with no previous history of heart disease. Eight-hundred eighty cases of coronary disease were documented, and, after adjusting for other risk factors, men with the highest intake of iron had an insignificant relative risk of heart disease compared with men with the lowest intake of iron. The relative risk of CHD for each milligram increase in dietary iron was 1.0, indicating no increased risk. Ascherio and Willet (1994) studied iron intake and its association with coronary disease in 44,933 men aged 40-75 years and found that higher intakes of heme iron were associated with greater risks for MI but not dietary iron in general.
ORAL CONTRACEPTIVE USE AND CHD
Based on the iron/heart disease theory, premenopausal women are thought to have increased protection against heart disease due to iron loss as a result of menstruation. It has been shown that oral contraceptives-dermase menstrual blood flow and significant differences in iron stores have been found between users and nonusers (Frassinelli-Gunderson et al., 1985). Moreover, earlier studies found that current and discontinued use of oral contraceptives was associated with an increased risk of heart disease (Slone et al., 1981). Dr. Sullivan hypothesized that the increased risk for CHD among oral contraceptive users was due to the accumulation of iron (Sullivan, 1981). A recent study on the effects of low-dose oral contraception on menstrual blood loss and iron status found that menstrual blood loss was reduced by approximately 44% in women taking low-dose oral contraceptives (Larsson, 1992). However, serum ferritin concentrations in these subjects remained unchanged over the 6-month period of the study. Stampfer et al. (1988) studied 119,000 women who were 30 to 55 years of age and found that the use of oral contraceptive agents in the past did not raise a woman’s risk of heart disease. Because oral contraceptives decrease menstrual blood loss and increase iron stores, it would be expected that longer usage of oral contraceptives would be associated with an increased risk. However, Stampfer et al. (1988) noted that women who had previously used oral contraceptives for more than 10 years had no increased risk. On the other hand, current users of oral contraceptives did have an increased risk of CHD of 2.5, but this excess risk was observed predominately in smokers. Porter et al. (1985) studied more than 65,000 women, 15 to 44 years of age, who were healthy nonsmokers and found that no use occurred in users of oral contraceptives. The 11 deaths due to CVD in the 6-year period occurred in the women who were not using oral contraceptives (Porter et al., 1987). The increased incidence of MI in older users of oral contraceptives appears to be due to higher doses of estrogen in the formulations taken by these women. Stampfer et al. (1991) observed less benefit among women taking more than 1.25 mg of estrogen daily. In another study, an increased incidence of heart disease was found only among older users who had other known risk factors for heart disease (Mann et al., 1976). Mant et al. (1987) analyzed results from a large cohort study in Britain and found the risk ratio for MI in current users of oral contraceptives was not increased, and no MI were found in women who used formulations with less than 50 [mu]g of estrogen. Therefore, the increased risk of heart disease that has been observed in women who use oral contraceptives, past and present, appears to be strongly associated with the dose of estrogen and smoking habits rather than iron stores.
HEART DISEASE AND MENOPAUSE
The iron/heart disease paradigm also has been used to explain the remarkable increase in CHD experienced by women after menopause, because there is an increase in levels of stored iron due to postmenopausal amenorrhea. However, this theory ignores the observed role of estrogen in the decreased incidence of heart disease among women (Colditz et al., 1987; Stampfer et al., 1991; Wolf et al., 1991). Several investigations have found that women who have had a hysterectomy (cessation of menses) without removal of the ovaries (retained estrogen) have an increased coronary risk (Gordon, 1978; Palmer, 1992). Nevertheless, estrogen-replacement therapy has been shown to have favorable effects upon lipoprotein profiles in postmenopausal women with as much as a 40% reduction in CVD being reported (Green and Bain, 1993). Stampfer et al. (1991) have reviewed the issue of estrogen-replacement therapy and heart disease and found that, of 15 prospective studies, 14 found no increased of heart disease among estrogen users. Colditz et al. (1987) also investigated the association of estrogen and heart disease in a prospective cohort of 121,700 U.S. female nurses. In this study, 14,000 women experienced natural menopause, and another 8061 reported hysterectomy alone. After controlling for age and cigarette smoking, women who experienced natural menopause and who had not received hormone-replacement therapy had no appreciable increased risk of CHD when compared with premenopausal women. However, women who had undergone bilateral oophorectomy (loss of estrogen) and who had never taken estrogen after menopause had an increased risk. This risk appeared to be eliminated in women who used estrogen in the postmenopausal period. Mathews et al. (1989) found that natural menopause had negative effects on lipid metabolism, indicated by decreases in high-density lipoprotein (HDL) and increases in low-density lipoprotein (LDL) cholesterol, but women who had received horinonereplacement therapy (estrogen) did not experience any changes in HDL or LDL cholesterol. Estrogen has been found to exhibit antioxidant activity by protecting against the cytotoxicity of oxidized LDL by inhibiting LDL oxidation outside the cell and by enhancing cellular resistance against oxidized LDL in the cell (Negre-Salvayre et al., 1993). Estrogen-replacement therapy, either past or present, was strongly associated with lower LDL-cholesterol, glucose, insulin, fibrinogen, obesity, and age and higher HDL-cholesterol (Manolio et al., 1993). Physiological levels of estrogen cause vasodilation of endothelium in the forearm of postmenopausal women, which may be partly responsible for the observed long-term effects of estrogen replacement therapy on cardiovascular incidents in postmenopausal women Gilligan et al., 1994). Estrogen’s apparent ability to improve blood cholesterol profiles as well as act as an antioxidant and vasodilator make it effective in lowering risk of heart disease in premenopausal women and women using postmenopausal hormone replacement.
Although the iron and heart disease hypothesis offers an intriguing explanation for many of the factors associated with heart disease, subsequent research has not been supportive of the paradigm. Confounding variables inherent in the study of eastern Finnish men (i.e., the presence of serum ferritin levels of 2200 [mu]g/L, the known high level of CAD, high concentration of LDL, and the potentially atherogenic diet in this population) make definitive conclusions and extrapolations to other population groups difficult. However, other factors analyzed in this investigation that were found to have more substantial relative risks for AMI than ferritin may be worthy of further investigation. Manttari et al. (1993) found that there was a linear trend in CHD risk with increasing ceruloplasmin, the copper transport protein, in dyslipidemic men. In the Finnish study, serum copper had the highest relative risk of all factors analyzed. Numerous studies investigating the relationship between iron and heart disease largely have been unable to support the findings of the Finnish study and the iron/heart disease paradigm. On the other hand, research supporting estrogen as the main factor explaining the difference in rates of heart disease between men and premenopausal women is convincing. Nevertheless, when the negative consequences of iron deficiency are considered along with the prevalence of iron-overload disease, prudent but timely action on this issue is imperative. Universal screening for iron storage diseases as recommended by Herbert (1992) seems to be an efficacious and reasonable approach to the public health problem of iron overload, because measurements of iron status are relatively inexpensive and effective treatment is available. Those found to have levels of iron that would put them at risk for toxicity should be advised to reduce their iron levels and avoid iron supplements. Otherwise, until sound scientific evidence indicates differently, the rest of the general public should be encouraged to consume as near the RDA for iron for their age and gender as possible.
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