Iron and the sex difference in heart disease risk.

Lancet, 12(12):1293-4 1981 Jun 13

Premenopausal women in affluent societies are protected from heart diseases which kill large numbers of men. The basis for this sex difference and the loss of protection with menopause is unknown. The hypothesis offered is that the greater incidence of heart diseases in men and postmenopausal women compared with the incidence in premenopausal women is due to higher levels of stored iron in these two groups. The hypothesis is supported by observations of (1) myocardial failure in iron strong disease, (2) accumulation of stored iron with age in men, and (3) accumulation of stored iron after menopause to levels found in men. In addition, the heart diseases of affluence are rare among impoverished peoples who are often iron deficient. The depletion of iron stores by regular phlebotomy could be the experimental system for testing this hypothesis, and a preventive therapy if the hypothesis is confirmed.




Dietary iron and coronary heart disease risk: a study from Greece.

Am J Epidemiol, 147(2):161-6 1998 Jan 15

The authors investigated the association between dietary iron intake and risk of coronary heart disease by means of a case-control study conducted in Athens, Greece, in January 1990 to April 1991. The case series comprised 329 patients with electrocardiographically confirmed first coronary infarct, or a first positive coronary arteriogram, or both, while the controls were 570 patients from the same study base who presented with minor conditions believed to be unrelated to diet. After adjustment by logistic regression for 14 potentially confounding variables of sociodemographic, life-style and nutritional nature, dietary iron intake was found to be positively associated with risk for coronary disease among men aged 60 years or older (odds ratio (OR) for a monthly increment of 50 mg of iron = 1.47, with 95% confidence interval (CI) 1.02-2.12) and particularly women aged 60 years or older (OR for a similar increment of iron = 3.61, with 95% CI 1.45-9.01). Additional adjustment for blood cholesterol, as well as systolic blood pressure and blood glucose level, reduced the iron regression coefficient among older men from 1.47 to 1.36, and among older women from 3.61 to 3.51; however, it is not clear whether the change reflects control of residual confounding or blocking of an intermediate pathway. These data are compatible with the hypothesis that excess dietary iron intake increases the risk of coronary heart disease, particularly among older women and men.




Body iron stores and the risk of carotid atherosclerosis: prospective results from the Bruneck study [see comments]

Circulation, 96(10):3300-7 1997 Nov 18

BACKGROUND: Fe2+ released from tissue iron stores may accelerate lipid peroxidation by virtue of its pro-oxidant properties and thus promote early atherogenesis. METHODS AND RESULTS: The present prospective survey addresses the potential association between serum ferritin concentrations and the 5-year progression of carotid atherosclerosis as assessed by ultrasonographic follow-up evaluations. The study population comprises a random sample of 826 men and women 40 to 79 years old. Serum ferritin was one of the strongest risk predictors of overall progression of atherosclerosis. The main part of this association appeared to act through modification of the atherogenic potential of LDL cholesterol (OR [95% CI] for a 1-SD unit increase in ferritin at LDL levels of 2.5, 3.6, and 4.9 mmol/L: 1.55 [1.30 to 1.85], 1.77 [1.40 to 2.24], and 2.05 [1.50 to 2.80]; P=.0012 for effect modification). Changes in iron stores during the follow-up period modified atherosclerosis risk, in that a lowering was beneficial and further iron accumulation exerted unfavorable effects. All these findings applied equally to incident atherosclerosis and the extension of preexisting atherosclerotic lesions. The significance of prominent iron stores in the development of carotid stenosis was clearly less pronounced. Finally, ferritin and LDL cholesterol showed a synergistic association with incident cardiovascular disease and death (n=59). CONCLUSIONS: The present study provided strong epidemiological evidence for a role of iron stores in early atherogenesis and suggests promotion of lipid peroxidation as the main underlying pathomechanism. This hypothesis could in part explain the sex difference in atherosclerotic vascular disease.




Systemic iron metabolism and mortality from Parkinson's disease.

Neurology, 50(4):1138-40 1998 Apr

Six measures of systemic iron metabolism were used to predict mortality among 103 patients with Parkinson's disease and 353 controls followed in a longitudinal study. Adjusting for gender, education, ethnicity, presence of dementia, and extrapyramidal signs, transferrin receptor concentration was strongly associated with mortality in patients with PD but not controls. This increase in serum transferrin receptor concentration before death suggests that the previously observed perturbation in iron metabolism continues throughout the disease course.




Serum ferritin and heart disease: the effect of moderate exercise on stored iron levels in postmenopausal women.

Can J Cardiol, 12(12):1253-7 1996 Dec

OBJECTIVE: To determine the effect of a moderate exercise regimen on stored iron as measured by serum ferritin in previously sedentary postmenopausal women. DESIGN: Randomized assignment to one of three groups: a five day/week walking group (five-day group, n = 27); a three day/week walking group (three-day group, n = 27) or a sedentary group (control group, n = 25). SETTING: Community-based intervention. PARTICIPANTS: Women who were postmenopausal, over 50 years old, sedentary, not on hormone replacement therapy, nonsmokers, physically capable of exercising, without clinical signs of cardiovascular, pulmonary or metabolic disease, and not on medication that would affect iron metabolism. In addition, they had neither donated blood nor been transfused within the previous 12 months. All participants were screened volunteers who had responded to media advertisements. Seventy-nine participants met these criteria. Results are reported for 56 subjects (five-day group, n = 17; three-day group, n = 19; control group, n = 20) who completed the study. Their mean age was 61.3 +/- 5.8 years. INTERVENTION: The five-day group and the three-day group walked an average of 279 +/- 20 and 171 +/- 7 mins/week, respectively. Participants were counselled not to change their dietary intake. MAIN RESULTS: Following 24 weeks of walking, mean serum ferritin decreased significantly in the five-day group (P < 0.03), but not in the three-day group (P < 0.09) compared with controls. CONCLUSIONS: The extent of physical activity required to elicit a decrease in stored iron in postmenopausal women was determined. This may be clinically significant because stored iron increases significantly following menopause and excess stored iron have been cited as risk factors for coronary artery disease.




Iron metabolism and Parkinson's disease.

Mov Disord, 13 Suppl 1(55):39-45 1998

There are at least three major reasons for thinking that iron participates in the mechanism of nerve cell death in Parkinson's disease (PD): (1) Iron catalyzes the formation of highly toxic hydroxyl radicals through the Fenton reaction. (2) Evidence suggests that oxidative stress participates in the mechanism of nerve cell death in PD. (3) Increased iron concentrations have been observed in the substantia nigra of patients with PD. In this review, we report data suggesting that the vulnerable neurons in PD are particularly sensitive to oxidative stress that may be induced by iron and then discuss the mechanisms by which iron levels may be increased in dopaminergic neurons in PD.




Dietary iron, animal fats, and risk of Parkinson's disease.

Mov Disord, 13 Suppl 1(The Gertrude H. Sergievsky Center, Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.):13-6 1998

BACKGROUND: Recent studies have proposed a role for diet in Parkinson's disease (PD). PD is characterized by a high deposition of iron and a low concentration of ferritin in the substantia nigra. Few data in the literature are available on the possible role of dietary iron in the development of PD. METHODS: In a population-based, case-control study, we addressed the hypothesis that high dietary iron intake was associated with PD. We assessed dietary iron intake with a semiquantitative food-frequency questionnaire in 104 PD patients and 352 control subjects, frequency matched for age and gender. We also studied the association of PD and dietary iron and animal fat intake in the presence of different iron stores measured by transferrin saturation. RESULTS: No significant differences were observed between patients' and control subjects' dietary intake of iron from food or supplements (odds ratio [OR] for the highest quartile of intake, 0.9; 95% confidence interval [95% CI], 0.6, 1.3; p for trend = 0.60). Among those with low transferrin saturation levels (lower 50%), the odds ratio for PD associated with animal fat intake was ninefold higher than the risk of those with low intake (OR, 9.0; 95% CI, 2.7-29.9). Among those with high transferrin saturation, risk of PD was two times higher (relative risk, 1.9; 95% CI, 0.5-7.2) for those who reported high intake of animal fat compared with those who reported low intake. CONCLUSION: Dietary iron intake after caloric adjustment was not associated with an increased risk of PD. However, the previously described association between animal fat intake and PD was modified by iron level stores as measured by transferrin saturation. These observations suggest that dietary fat and a systemic defect in iron metabolism may act synergistically in the process of lipid peroxidation in PD.




Do we get too much iron?

Med Hypotheses, 12(12):131-3 1984 Jun

Iron in hemoglobin of 14 gm/100 ml, which is considered normal, may predispose to malignancies and to rheumatoid, heart, bacterial and other infective diseases. Conversely, a mild state of iron-deficiency anemia as presented by hemoglobin of 10 gm/100 ml may be an affordable price for protection from these disease states. The harm due to too much iron is discussed.




The synergistic effects of vitamin E and selenium in iron-overloaded mouse hearts.

Can J Cardiol, 14(7):937-41 1998 Jul

OBJECTIVES: To determine whether supplementation with vitamin E and selenium can improve myocardial antioxidant defenses in iron-overloaded mouse hearts. INTERVENTIONS: Iron-overload state was created in B6D2F1 mice (n = 20) by daily injection of iron dextran (5 mg intraperitoneally/mouse) for four weeks. The mice were also simultaneously randomly assigned to receive vitamin E (alpha-tocopherol acetate, 40 mg intraperitoneally, n = 5), selenium (sodium selenite, 1 part/million orally, n = 5), both (vitamin E + selenium, n = 5) or iron-only treatment (n = 5). The hearts were harvested for determination of selenium concentration and glutathione peroxidase activity. In a subsequent study, 15 B6D2F1 mice were randomly assigned to receive daily injections of iron (n = 5) or iron and combined antioxidant treatment (vitamin E + selenium, n = 5), or to serve as controls (n = 5) for four weeks. The hearts were harvested for determination of total iron concentrations. MAIN RESULTS: Significantly greater concentrations of heart selenium and glutathione peroxidase activity were observed in groups supplemented with both agents, as opposed to iron-only treated or single supplemented mice. Significantly lower concentrations of iron were found in controls and in those receiving combined iron and antioxidant treatment (vitamin E + selenium) than in iron-only treated mice. CONCLUSIONS: Vitamin E and selenium function synergistically in the myocardium to provide important antioxidant defenses in iron-overload states, including increased concentrations of selenium, increased glutathione peroxidase activity and decreased concentrations of iron.




Iron and the sex difference in heart disease risk.

Lancet, 12(12):1293-4 1981 Jun 13

Premenopausal women in affluent societies are protected from heart diseases which kill large numbers of men. The basis for this sex difference and the loss of protection with menopause is unknown. The hypothesis offered is that the greater incidence of heart diseases in men and postmenopausal women compared with the incidence in premenopausal women is due to higher levels of stored iron in these two groups. The hypothesis is supported by observations of (1) myocardial failure in iron strong disease, (2) accumulation of stored iron with age in men, and (3) accumulation of stored iron after menopause to levels found in men. In addition, the heart diseases of affluence are rare among impoverished peoples who are often iron deficient. The depletion of iron stores by regular phlebotomy could be the experimental system for testing this hypothesis, and a preventive therapy if the hypothesis is confirmed.




Dietary iron and coronary heart disease risk: a study from Greece.

Am J Epidemiol, 147(2):161-6 1998 Jan 15

The authors investigated the association between dietary iron intake and risk of coronary heart disease by means of a case-control study conducted in Athens, Greece, in January 1990 to April 1991. The case series comprised 329 patients with electrocardiographically confirmed first coronary infarct, or a first positive coronary arteriogram, or both, while the controls were 570 patients from the same study base who presented with minor conditions believed to be unrelated to diet. After adjustment by logistic regression for 14 potentially confounding variables of sociodemographic, life-style and nutritional nature, dietary iron intake was found to be positively associated with risk for coronary disease among men aged 60 years or older (odds ratio (OR) for a monthly increment of 50 mg of iron = 1.47, with 95% confidence interval (CI) 1.02-2.12) and particularly women aged 60 years or older (OR for a similar increment of iron = 3.61, with 95% CI 1.45-9.01). Additional adjustment for blood cholesterol, as well as systolic blood pressure and blood glucose level, reduced the iron regression coefficient among older men from 1.47 to 1.36, and among older women from 3.61 to 3.51; however, it is not clear whether the change reflects control of residual confounding or blocking of an intermediate pathway. These data are compatible with the hypothesis that excess dietary iron intake increases the risk of coronary heart disease, particularly among older women and men.




Body iron stores and the risk of carotid atherosclerosis: prospective results from the Bruneck study [see comments]

Circulation, 96(10):3300-7 1997 Nov 18

BACKGROUND: Fe2+ released from tissue iron stores may accelerate lipid peroxidation by virtue of its pro-oxidant properties and thus promote early atherogenesis. METHODS AND RESULTS: The present prospective survey addresses the potential association between serum ferritin concentrations and the 5-year progression of carotid atherosclerosis as assessed by ultrasonographic follow-up evaluations. The study population comprises a random sample of 826 men and women 40 to 79 years old. Serum ferritin was one of the strongest risk predictors of overall progression of atherosclerosis. The main part of this association appeared to act through modification of the atherogenic potential of LDL cholesterol (OR [95% CI] for a 1-SD unit increase in ferritin at LDL levels of 2.5, 3.6, and 4.9 mmol/L: 1.55 [1.30 to 1.85], 1.77 [1.40 to 2.24], and 2.05 [1.50 to 2.80]; P=.0012 for effect modification). Changes in iron stores during the follow-up period modified atherosclerosis risk, in that a lowering was beneficial and further iron accumulation exerted unfavorable effects. All these findings applied equally to incident atherosclerosis and the extension of preexisting atherosclerotic lesions. The significance of prominent iron stores in the development of carotid stenosis was clearly less pronounced. Finally, ferritin and LDL cholesterol showed a synergistic association with incident cardiovascular disease and death (n=59). CONCLUSIONS: The present study provided strong epidemiological evidence for a role of iron stores in early atherogenesis and suggests promotion of lipid peroxidation as the main underlying pathomechanism. This hypothesis could in part explain the sex difference in atherosclerotic vascular disease.




Systemic iron metabolism and mortality from Parkinson's disease.

Neurology, 50(4):1138-40 1998 Apr

Six measures of systemic iron metabolism were used to predict mortality among 103 patients with Parkinson's disease and 353 controls followed in a longitudinal study. Adjusting for gender, education, ethnicity, presence of dementia, and extrapyramidal signs, transferrin receptor concentration was strongly associated with mortality in patients with PD but not controls. This increase in serum transferrin receptor concentration before death suggests that the previously observed perturbation in iron metabolism continues throughout the disease course.




Serum ferritin and heart disease: the effect of moderate exercise on stored iron levels in postmenopausal women.

Can J Cardiol, 12(12):1253-7 1996 Dec

OBJECTIVE: To determine the effect of a moderate exercise regimen on stored iron as measured by serum ferritin in previously sedentary postmenopausal women. DESIGN: Randomized assignment to one of three groups: a five day/week walking group (five-day group, n = 27); a three day/week walking group (three-day group, n = 27) or a sedentary group (control group, n = 25). SETTING: Community-based intervention. PARTICIPANTS: Women who were postmenopausal, over 50 years old, sedentary, not on hormone replacement therapy, nonsmokers, physically capable of exercising, without clinical signs of cardiovascular, pulmonary or metabolic disease, and not on medication that would affect iron metabolism. In addition, they had neither donated blood nor been transfused within the previous 12 months. All participants were screened volunteers who had responded to media advertisements. Seventy-nine participants met these criteria. Results are reported for 56 subjects (five-day group, n = 17; three-day group, n = 19; control group, n = 20) who completed the study. Their mean age was 61.3 +/- 5.8 years. INTERVENTION: The five-day group and the three-day group walked an average of 279 +/- 20 and 171 +/- 7 mins/week, respectively. Participants were counselled not to change their dietary intake. MAIN RESULTS: Following 24 weeks of walking, mean serum ferritin decreased significantly in the five-day group (P < 0.03), but not in the three-day group (P < 0.09) compared with controls. CONCLUSIONS: The extent of physical activity required to elicit a decrease in stored iron in postmenopausal women was determined. This may be clinically significant because stored iron increases significantly following menopause and excess stored iron have been cited as risk factors for coronary artery disease.




Iron metabolism and Parkinson's disease.

Mov Disord, 13 Suppl 1(55):39-45 1998

There are at least three major reasons for thinking that iron participates in the mechanism of nerve cell death in Parkinson's disease (PD): (1) Iron catalyzes the formation of highly toxic hydroxyl radicals through the Fenton reaction. (2) Evidence suggests that oxidative stress participates in the mechanism of nerve cell death in PD. (3) Increased iron concentrations have been observed in the substantia nigra of patients with PD. In this review, we report data suggesting that the vulnerable neurons in PD are particularly sensitive to oxidative stress that may be induced by iron and then discuss the mechanisms by which iron levels may be increased in dopaminergic neurons in PD.




Dietary iron, animal fats, and risk of Parkinson's disease.

Mov Disord, 13 Suppl 1(The Gertrude H. Sergievsky Center, Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.):13-6 1998

BACKGROUND: Recent studies have proposed a role for diet in Parkinson's disease (PD). PD is characterized by a high deposition of iron and a low concentration of ferritin in the substantia nigra. Few data in the literature are available on the possible role of dietary iron in the development of PD. METHODS: In a population-based, case-control study, we addressed the hypothesis that high dietary iron intake was associated with PD. We assessed dietary iron intake with a semiquantitative food-frequency questionnaire in 104 PD patients and 352 control subjects, frequency matched for age and gender. We also studied the association of PD and dietary iron and animal fat intake in the presence of different iron stores measured by transferrin saturation. RESULTS: No significant differences were observed between patients' and control subjects' dietary intake of iron from food or supplements (odds ratio [OR] for the highest quartile of intake, 0.9; 95% confidence interval [95% CI], 0.6, 1.3; p for trend = 0.60). Among those with low transferrin saturation levels (lower 50%), the odds ratio for PD associated with animal fat intake was ninefold higher than the risk of those with low intake (OR, 9.0; 95% CI, 2.7-29.9). Among those with high transferrin saturation, risk of PD was two times higher (relative risk, 1.9; 95% CI, 0.5-7.2) for those who reported high intake of animal fat compared with those who reported low intake. CONCLUSION: Dietary iron intake after caloric adjustment was not associated with an increased risk of PD. However, the previously described association between animal fat intake and PD was modified by iron level stores as measured by transferrin saturation. These observations suggest that dietary fat and a systemic defect in iron metabolism may act synergistically in the process of lipid peroxidation in PD.




Do we get too much iron?

Med Hypotheses, 12(12):131-3 1984 Jun

Iron in hemoglobin of 14 gm/100 ml, which is considered normal, may predispose to malignancies and to rheumatoid, heart, bacterial and other infective diseases. Conversely, a mild state of iron-deficiency anemia as presented by hemoglobin of 10 gm/100 ml may be an affordable price for protection from these disease states. The harm due to too much iron is discussed.




The synergistic effects of vitamin E and selenium in iron-overloaded mouse hearts.

Can J Cardiol, 14(7):937-41 1998 Jul

OBJECTIVES: To determine whether supplementation with vitamin E and selenium can improve myocardial antioxidant defenses in iron-overloaded mouse hearts. INTERVENTIONS: Iron-overload state was created in B6D2F1 mice (n = 20) by daily injection of iron dextran (5 mg intraperitoneally/mouse) for four weeks. The mice were also simultaneously randomly assigned to receive vitamin E (alpha-tocopherol acetate, 40 mg intraperitoneally, n = 5), selenium (sodium selenite, 1 part/million orally, n = 5), both (vitamin E + selenium, n = 5) or iron-only treatment (n = 5). The hearts were harvested for determination of selenium concentration and glutathione peroxidase activity. In a subsequent study, 15 B6D2F1 mice were randomly assigned to receive daily injections of iron (n = 5) or iron and combined antioxidant treatment (vitamin E + selenium, n = 5), or to serve as controls (n = 5) for four weeks. The hearts were harvested for determination of total iron concentrations. MAIN RESULTS: Significantly greater concentrations of heart selenium and glutathione peroxidase activity were observed in groups supplemented with both agents, as opposed to iron-only treated or single supplemented mice. Significantly lower concentrations of iron were found in controls and in those receiving combined iron and antioxidant treatment (vitamin E + selenium) than in iron-only treated mice. CONCLUSIONS: Vitamin E and selenium function synergistically in the myocardium to provide important antioxidant defenses in iron-overload states, including increased concentrations of selenium, increased glutathione peroxidase activity and decreased concentrations of iron.