Original Article
Body Iron Stores and the Risk of Coronary Heart Disease
N Engl J Med 1994; 330:1119-1124April 21, 1994
- Abstract
Background
Recent studies have suggested an association between higher body iron stores and the risk of coronary heart disease. To assess these findings, we examined the association between transferrin saturation and the risk of coronary heart disease, myocardial infarction, overall mortality, and mortality from cardiovascular causes in a large population.
Methods
We studied a total of 4518 men and women from the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study, using a multivariate Cox proportional-hazards model. Base-line data were collected from 1971 to 1974, with follow-up through 1987. Transferrin saturation (serum iron concentration divided by total iron-binding capacity) was used as a measure of the amount of circulating iron available to tissues.
Results
The risk of coronary heart disease was not related to transferrin-saturation levels in white men or women. Estimates of the relative risk of coronary heart disease for the fifth quintile of transferrin saturation as compared with the first quintile were 0.72 (95 percent confidence interval, 0.51 to 1.00) for men and 0.85 (95 percent confidence interval, 0.60 to 1.21) for women. The results were similar for myocardial infarction. A significant inverse association with transferrin saturation was found for overall mortality and for mortality from cardiovascular causes in white men and women. Transferrin saturation was not associated with any of the clinical outcomes in blacks, possibly owing to the small sample.
Conclusions
Higher transferrin-saturation levels were not associated with an increased risk of coronary heart disease or myocardial infarction. On the contrary, the results indicate that there may be an inverse association of iron stores with overall mortality and with mortality from cardiovascular causes. .
Media in This Article
Figure 1
Multivariate Adjusted Risk of Coronary Heart Disease, According to Serum Transferrin Saturation, in White Men and Women 45 to 74 Years of Age at Base Line.Figure 2
Multivariate Adjusted Risk of Myocardial Infarction, According to Serum Transferrin Saturation, in White Men and Women 45 to 74 Years of Age at Base Line.Article Activity
- Article
A possible association between body iron status and the risk of coronary heart disease was bolstered by recent findings from a three-year Finnish study relating increased levels of both serum ferritin and dietary iron to an increased risk of myocardial infarction in men1. Previous support for this hypothesis was less direct and consisted of weak correlations observed between hemoglobin levels or the hematocrit and the risk of coronary heart disease2-4 or observations about differences in iron status and coronary heart disease either between countries5 or in men as compared with women6. Further evaluation of these findings is needed because, coupled with observations suggesting a relation between iron status and the risk of cancer,7-10 these findings could affect decisions about the iron-fortification policies used in many countries to prevent iron deficiency. In addition, a possible association between iron status and death from all causes needs assessment before any changes in iron-fortification policies or dietary recommendations are contemplated. Accordingly, we used data from the first National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study (NHEFS) to examine the putative relation between iron status, as measured by the serum transferrin saturation, and the risk of coronary heart disease and overall mortality among blacks and whites.
Methods
Study Design
The base-line data on the NHEFS cohort were collected from 1971 to 1974 as part of NHANES I11-15. The cohort consisted of 14,407 adults who were 25 to 74 years of age at the time of NHANES I. Follow-up was conducted from 1982 to 1984, again in 1986 (surveying those 55 years of age or older at base line), and again in 1987 (surveying the entire cohort). Subjects who were institutionalized after the data collection at base line continued to be included in NHEFS. At each follow-up, the subjects (or their proxies) were interviewed again, death certificates were obtained for subjects who had died, and hospital and nursing home records were obtained for overnight stays that had occurred since the most recent contact. Informed consent was obtained from the study subjects, and the protocols for NHANES I and NHEFS were reviewed and approved by the appropriate institutional review boards.
Case Definition
Death certificates and hospital-discharge diagnoses were coded with use of the system described in the International Classification of Diseases, 9th Revision (ICD-9): cardiovascular diseases were denoted by codes 390 to 448, coronary heart disease by codes 410 to 414, and myocardial infarction by code 410. Incident cases of coronary heart disease were defined on the basis of the death certificate (indicating the underlying or an associated cause of death) or by the assignment of a diagnosis code from 410 to 414 at hospital discharge. Underlying causes of death were used in the analyses of cause-specific mortality.
Study Variables
The biochemical indicators of iron status used in this study, measured at base line, included the serum transferrin saturation, the serum iron concentration, the serum total iron-binding capacity,16-18 the hemoglobin concentration, and the hematocrit. Hemoglobin, the hematocrit, and the erythrocyte sedimentation rate19 were measured during the base-line examination in a mobile examination center. Assays for the other indicators of iron status and other serum covariables (albumin20 and total cholesterol21-23) were performed by the Centers for Disease Control and Prevention. The details of the procedures used for blood collection and specimen storage, the assays for each indicator, and the procedures for ensuring quality control and obtaining informed consent have been published elsewhere11,24. Transferrin saturation was calculated by dividing the serum iron concentration by the total iron-binding capacity. Serum ferritin levels were not measured in NHANES I.
Blood pressure was measured by a physician at base line with the subject seated25. The blood collection was categorized as occurring before noon or after noon. The determination of diabetes status was based on the responses to questions about the subject's medical history at base line. Smoking status at base line was determined from a questionnaire completed by about half the subjects; for the remaining subjects, this information was obtained retrospectively at the first follow-up visit26,27. Dietary iron intake from food was assessed at base line and was based on the subject's recall of foods eaten during a single 24-hour period. Educational level was based on the number of years of school completed.
Study Subjects
All black and white subjects 45 to 74 years of age for whom there were no missing data were included in this analysis (Table 1Table 1
Events, Persons at Risk in the Cohort, and Selected Base-Line Measurements, According to Race and Sex.). Excluded were 103 subjects lost to follow-up (1.6 percent) and 1097 subjects for whom any data from the base-line examination were missing. Also excluded from the analyses of coronary heart disease were 78 subjects who had no follow-up interview or for whom base-line data on a history of heart disease were missing, and 719 subjects who reported a history of heart disease at base line (i.e., those who had ever been told by a doctor that they had had a heart attack or heart failure or who had used any medicine, drugs, or pills for a weak heart during the six months before base line). In addition, all deaths or incident events within the first five years of follow-up were excluded in order to minimize the effects of preexisting disease on the results. There were 4518 subjects remaining in the study sample.Statistical Analysis
The Cox proportional-hazards model28,29 was used to examine the relation of iron status to the risk of an event according to race and sex in separate age-adjusted and multivariate models. The average follow-up period was 14.6 years. Measures of iron status were expressed in the models as approximate quintiles (for whites) or thirds (for blacks). The lowest group was used as the reference category in all the analyses. Unless otherwise noted, the multivariate models were adjusted for the following base-line variables: age, history of diabetes, systolic blood pressure, smoking status, serum total cholesterol, serum albumin, and level of education. In preliminary analyses (data not shown), further adjustment for the sedimentation rate and the time of blood collection did not affect the results30,31. Tests of the significance of trends across categories of transferrin saturation were conducted in the multivariate models by treating the quintiles as ordered categories scaled to the median for each quintile32.
Failure to use weights in the sample or to account for the complex sampling design in NHANES I may produce biased results33,34. To assess the effect of weighting on the results, the Cox models were calculated both weighted35 and unweighted36. The weighted and unweighted models yielded consistent results. Therefore, only unweighted Cox models, which assume a simple random sampling and tend to have smaller variances, are presented here.
In parallel analyses no association was found between hemoglobin levels, the hematocrit, or dietary iron intake and any of the incidence or mortality outcomes. Only the results for transferrin saturation are shown here.
Results
Descriptive Data
The number of events, the population at risk, and the mean values for age, transferrin saturation, and selected other variables are shown in Table 1 according to race and sex. There were too few cases of myocardial infarction or death from coronary heart disease among blacks to permit examining any association with transferrin saturation. Levels of transferrin saturation, as well as of its component measures, were higher in men than in women and higher in whites than in blacks.
Coronary Heart Disease
The multivariate adjusted estimates of the relative risk of coronary heart disease according to quintile of transferrin saturation are shown in Figure 1Figure 1
Multivariate Adjusted Risk of Coronary Heart Disease, According to Serum Transferrin Saturation, in White Men and Women 45 to 74 Years of Age at Base Line.. The risk of coronary heart disease was not related to the level of transferrin saturation in white men and women. The same was true for the risk of myocardial infarction (Figure 2Figure 2Multivariate Adjusted Risk of Myocardial Infarction, According to Serum Transferrin Saturation, in White Men and Women 45 to 74 Years of Age at Base Line.). The estimates of relative risk above the first quintile tended to be lower than 1, suggesting that higher levels of transferrin saturation may be protective. There was, however, no apparent dose-response relation. Similar results were obtained when the risk of death from myocardial infarction or coronary heart disease was evaluated (data not shown). Nor was there a relation between the risk of incident coronary heart disease and the transferrin saturation among black men and women (Table 2Table 2
Multivariate Adjusted Risk of Coronary Heart Disease and Death Either from Cardiovascular Causes or from All Causes, According to Transferrin Saturation, among Black Men and Women 45 to 74 Years of Age at Base Line.). Because of the relatively small numbers of events, the estimates of relative risk for blacks had wide confidence limits.Death from Cardiovascular Causes
For white women, there was a significant inverse linear trend indicating a decreased risk of death from cardiovascular causes with an increasing level of transferrin saturation (Figure 3Figure 3
Multivariate Adjusted Risk of Death from Cardiovascular Disease, According to Serum Transferrin Saturation, in White Men and Women 45 to 74 Years of Age at Base Line.). The relative-risk estimates in the two highest quintiles were also significantly lower than 1. No association was found between death from cardiovascular causes and transferrin saturation in either white men (Figure 3) or black men and women (Table 2).Mortality from All Causes
Among white women, there was also a significant inverse trend (P = 0.013) between mortality from all causes and the level of transferrin saturation (Figure 4Figure 4
Multivariate Adjusted Risk of Death from All Causes, According to Serum Transferrin Saturation, in White Men and Women 45 to 74 Years of Age at Base Line.). Among white men, all the relative-risk estimates were lower than 1, with no apparent dose-response relation; only the estimate for the fifth quintile was statistically significant (P = 0.008).When deaths during the first five years of follow-up were included, however, all the estimates of relative risk for white men were significantly lower than 1. The estimates themselves were unaffected: for the second through the fifth quintiles, they were 0.81, 0.74, 0.79, and 0.70, respectively (P = 0.12). Similarly, the estimates of relative risk for the fourth and fifth quintiles among white women were now statistically significant, whereas the estimates were unaffected. When all deaths were included, the estimates for white women for quintiles two through five were 1.03, 0.82, 0.63, and 0.72, respectively (P = 0.001).
No association was found between mortality from all causes and transferrin saturation among black men and women (Table 2).
Discussion
Our results do not support the hypothesis that body iron stores, as measured by serum transferrin saturation, are related to the risk of coronary heart disease (including myocardial infarction). Nor do they support a direct association between the level of transferrin saturation and the risk of dying from any cause or from cardiovascular disease. In fact, the results of this study would seem to suggest an inverse association between serum transferrin saturation and the risk of dying from any cause or from cardiovascular disease.
The assessment of whether iron status is related to the risk of disease or death is complicated by several factors: body iron can be divided metabolically into functional iron and storage iron; currently available biochemical indicators of iron status reflect different aspects of these two categories of iron metabolism; and each of these indicators is also affected by non-iron-related factors37-39. Given these circumstances, the strongest evidence for a relation between iron and coronary heart disease would come from a consistent finding of more than one indicator of iron status. To date, this has not been the case. For example, the evidence of an association based on the serum ferritin level, which is a better indicator of iron stores than transferrin saturation,40 has been conflicting. Salonen et al.1 reported an increased risk of acute myocardial infarction among men with a serum ferritin level greater than 200 μg per liter, whereas preliminary results reported by Stampfer et al.41 did not support an increase in this risk. The former study was limited by both a small number of subjects and a short follow-up period.
Hemoglobin levels and the hematocrit are measures of the oxygen-carrying capacity of blood and of viscosity. Evidence of a relation between iron status and the risk of coronary heart disease that is based on either measure is not consistent. Many prospective studies,1,42-50 including our own, have not found one or the other to be related to the risk of coronary heart disease, in contrast to a number of other prospective,2,51-55 cross-sectional,56-59 or case-control4 studies, especially among women.
Salonen et al.1 also reported dietary iron intake to be positively associated with an increased risk of myocardial infarction. In contrast, Rimm et al.60 reported no association between dietary iron intake and the risk of coronary heart disease. In another analysis of NHEFS, Cooper and Liao61 found, as we did, no association between dietary iron intake and the risk of coronary heart disease.
In evaluating the relation between iron status and the risk of coronary heart disease, it is also important to rule out non-iron-related factors that can influence biochemical measures of iron status. Two important factors of this type are inflammation and diurnal variation. Both influence indicators of iron status in different ways. For example, all the iron indicators used to relate iron status to coronary heart disease are affected by inflammation, but serum ferritin reacts in the opposite direction from the others -- i.e., it increases in inflammatory states, whereas transferrin saturation, hemoglobin, and hematocrit decrease. This is due to a blocked release of iron from macrophages, so that tissue levels increase while circulating levels decrease62,63. As a result, an association between coronary heart disease and higher serum ferritin levels or the lack of an association between coronary heart disease and higher transferrin-saturation levels, hemoglobin levels, or hematocrit could be confounded by inflammation. In addition, unlike ferritin, transferrin saturation shows substantial diurnal variation37-40. In the present study, however, adjusting for the erythrocyte sedimentation rate, a measure of inflammation, and for the time of drawing blood (before noon vs. after noon) did not affect the results.
Free-radical oxidation is hypothesized to be the basis for the relation between iron status and the risk of coronary heart disease1. In that model, iron is considered to be a catalyst for the formation of tissue-damaging free radicals. Our results do not support the hypothesis that iron status is directly related to the risk of coronary heart disease.
The limitations of the present study include a possible bias arising from loss to follow-up with regard to the incidence of coronary heart disease due to missing hospital data. When Medicare hospitalization data were used as a gold standard, however, it was found that approximately 80 percent of hospital stays for coronary heart disease within the three years before the first period of follow-up that were identified in the Medicare files or NHEFS were also identified by the NHEFS hospital records (unpublished data). A further source of potential bias was misclassification resulting from the inaccuracy of the diagnoses coded on the death certificate or the hospital record. But these biases seem unlikely, given the consistency of the results between the mortality and incidence of coronary heart disease and myocardial infarction, and for mortality from all causes and from cardiovascular disease. It was not possible to control for high-density lipoprotein cholesterol in the multivariate models, since it was not measured at base line.
In summary, in an analysis of a national cohort we found no evidence supporting a direct association between iron status and coronary heart disease. On the contrary, we found a possible inverse association between transferrin saturation and the risk of coronary heart disease and also the risk of death from any cause.
Supported by the National Center for Health Statistics; the National Institute on Aging; the National Cancer Institute; the National Center for Chronic Disease Prevention and Health Promotion; the National Institute of Child Health and Human Development; the National Heart, Lung, and Blood Institute; the National Institute on Alcohol Abuse and Alcoholism; the National Institute of Mental Health; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; and the National Institute of Neurological and Communicative Disorders and Stroke.
We are indebted to Robert Murphy, Jurgen Rehm, Margo Denke, Clifford Johnson, Jennifer Madans, Jacob Feldman, and Manning Feinleib for their critical comments and support; to Sara Adams, Dorothy Blodgett, Shirley Gray, Sandra Payne, and Cuong Vuong for excellent technical assistance; to the sponsoring agencies for assistance in developing the study; and to Westat, Inc., for conducting the field work.
Source Information
From the National Center for Health Statistics, Centers for Disease Control and Prevention, 6525 Belcrest Rd., Rm. 1070, Hyattsville, MD 20782, where reprint requests should be addressed to Dr. Sempos.
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