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© 2004 The American Society for Nutritional Sciences J. Nutr. 134:99-103, January 2004

Human Nutrition and Metabolism

Iron Supplementation Does Not Affect the Susceptibility of LDL to Oxidative Modification in Women with Low Iron Status

Amy E. Binkoski, Penny M. Kris-Etherton1 and John L. Beard

Graduate Program in Nutrition, The Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA

1To whom correspondence and reprint requests should be addressed. E-mail: pmk3{at}psu.edu.


   ABSTRACT
TOP
 ABSTRACT
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
Elevated iron stores may or may not promote atherogenesis by increasing free radical formation and oxidative stress, but controlled diet and supplement trials are lacking. We tested the hypothesis that iron supplementation does not increase the susceptibility of LDL to undergo oxidative modification in women with low iron status. A randomized, double-blind, 2-period crossover study design (n = 26) was used to examine the effects of the following diets on measures of LDL oxidation: average American diet (AAD) [36% of energy as fat; 15% saturated fatty acids (SFA)], and a Step 2 diet (26% fat; 7% SFA). In addition, subjects received either a supplement containing 160 mg of ferrous sulfate (50 mg elemental iron) or a placebo twice daily [supplement group received a total of 320 mg ferrous sulfate (100 mg elemental iron) daily]. After supplementation, serum ferritin differed between the supplement and placebo groups (P = 0.008). Measures of LDL oxidation were not affected by supplement intake; however, they were affected by diet. Lag time was shorter after the women consumed the AAD diet than after the Step 2 diet (P < 0.0001). The diets did not affect the rate of oxidation or total dienes. Although iron status was improved by aggressive iron supplementation, LDL oxidative susceptibility was not affected. As expected, lag time was increased after the women consumed the low fat, low SFA diet. Therefore, the results of this study do not support a relationship between iron status and LDL oxidation.

KEY WORDS: • LDL oxidation • lag time • iron • ferritin • dietary fat

Body iron stores were proposed to relate directly to risk of cardiovascular disease (CVD)1 (1). Evidence in support of this hypothesis emerged in 1992 when results published from the Finnish Kuopio Ischemic Heart Disease Risk Factor Study showed a positive linear relationship between risk of heart attack in Finnish men and serum ferritin levels and reported that men with serum ferritin >=200 µg/L had a twofold greater risk of heart attack compared with those with lower serum ferritin values (2). Other prospective studies, however, have not reported a relationship between body iron stores and CVD (3–5), including a meta-analysis of five prospective studies [570 cases of coronary heart disease (CHD)] that obtained a combined risk ratio of 1.0 (95% CI, 0.8–1.3) when using ferritin as a measure of iron status (6).

Oxidative modification of LDL by iron is thought to play an initiating role in the development of atherosclerosis (7–9). Accumulation of oxidized LDL leads to the development of foam cells, resulting in the formation of plaque in the arterial walls. In healthy individuals, "free iron" is not readily measured because iron is either bound to transferrin or stored as ferritin (10). However, the superoxide radical is capable of releasing stored iron from ferritin (11). This released form of iron (Fe+2) initiates the peroxidation of lipids via the Haber-Weiss series of reactions:


Net equation:

The hydroxyl radical affects cardiovascular disease pathologically due the amplified effect that the reduced form of iron has on lipid oxidation (12).

The relationship between iron and heart disease has been reported in epidemiologic studies that provide information regarding associations only and not causal effects. Randomized controlled trials are important for definitively defining a cause and effect relationship. Consequently, it is important to assess the relationship between iron status and heart disease risk experimentally in a controlled clinical trial. A recent retrospective study conducted in subjects that had participated in well-controlled feeding studies (13) did not support a relationship between iron intake, free iron concentration and measures of lipid peroxidation. However, the amount of iron ingested by these subjects (17–21 mg/d) met the RDA for women (18 mg/d) and therefore was not a therapeutic dose. The present study was conducted to examine whether a causal relationship exists between iron status and a potentially important risk factor for cardiovascular disease (LDL oxidation) in response to aggressive iron supplementation, the standard clinical therapy for patients with poor iron status.

Diet modulates the susceptibility of LDL to oxidative modification. Previous work showed decreased susceptibility of LDL to oxidation with a dietary reduction in total and saturated fat (14). When total and saturated fat energy were reduced in a stepwise manner (34, 29 and 25% for total fat and 15, 9 and 6% for saturated fat), the greatest reduction in rate of oxidation as well as formation of total dienes and lipid peroxides occurred when subjects consumed the diet lowest in both total and saturated fat. This is important because the currently recommended blood cholesterol–lowering diets favorably affect potential risk factors beyond lipids and lipoproteins. Of relevance to the present study is that patients with iron deficiency anemia would most likely be following an AAD; if they were taking a therapeutic dose of an iron supplement, a very high prooxidant state could be imposed if iron were, in fact, a catalyst acting as an oxidant. A blood cholesterol–lowering diet might elicit greater protection against oxidative stress in subjects given therapeutic doses of iron, should iron increase oxidative stress. Thus, it may be prudent to recommend a blood cholesterol–lowering diet especially for those treated with supplemental iron for poor iron status to decrease CVD risk.

The aim of the study was to test whether subjects with repleted iron stores due to supplementation would have increased susceptibility of LDL to oxidation as well as to assess whether LDL oxidation was greatest in subjects consuming the AAD and whether a blood cholesterol–lowering diet attenuated the effect. In addition, this study design allowed us to investigate the possible interaction between dietary fat and iron status on measures of LDL oxidation. Therefore, we sought to determine whether iron supplementation in a population most likely to take an iron supplement had adverse consequences related to the susceptibility of LDL cholesterol to oxidative modification, which is a potential marker of CVD risk.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
Subjects

Healthy women (n = 26) ages 19–47 y [mean ± SE (26 ± 1.4 y)] participated in the study. Subjects were recruited by a formal screening process that included a telephone interview, a brief physical examination consisting of height, weight and blood pressure measurements as well as a blood draw for baseline information and chemistries. Study subjects had serum LDL cholesterol between the 50th and 90th percentiles and HDL cholesterol and triglycerides between the 5th and 95th percentiles for age, race and gender as well as low normal baseline hemoglobin (120–140 g/L) and low ferritin (15–40 µg/L) and transferrin saturation levels (15–40%) (Table 1). Subjects were excluded from the study if they had a medical condition or history of chronic disease, used medication that interferes with cholesterol levels, had a BMI > 32 kg/m2, had lost or gained more than 4.54 kg (10 lb) within the past 2 mo, or had any lifestyle issues (i.e., irregular work schedule, frequent travel, extreme physical activity or heavy alcohol consumption) that would make it difficult to comply with the restrictions of the study. The study was conducted in accordance with the guidelines of the Pennsylvania State University Institutional Review Board, and all subjects gave written informed consent.


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  		TABLE 1 Baseline characteristics of the subjects1

 
    Experimental design. Subjects were stratified randomly and assigned to two groups, either treatment (iron supplement) or control. Subjects in the treatment and placebo groups were randomly assigned to a 2-period experimental diet treatment of an AAD or a Step 2 diet. All subjects consumed both test diets. Hence, a two-period crossover study design was employed. Subjects consumed each diet for 3 wk followed by a 2-wk compliance break between diet periods during which time they consumed their habitual diets. The iron treatment group received 320 mg of ferrous sulfate daily administered as a 160 mg ferrous sulfate (50 mg elemental iron) supplement given at both breakfast and dinner; the noniron treatment group received a placebo. Subjects consumed the iron supplement or placebo throughout both diet periods.

Subjects ate breakfast and dinner at the Pennsylvania State University Metabolic Diet Study Center Monday through Friday. Lunches and weekend meals were packed and eaten at a time and place of convenience. Subjects consumed an amount of food consistent with their energy needs and were weighed every day during the week at dinner to ensure that weight was maintained.

    Experimental diets. The target macronutrient composition of the experimental diets was calculated by the Nutritionist IV database (N-Squared Computing, First DataBank Division, San Bruno, CA) (Table 2). The AAD was designed to provide 36% of energy from total fat, 15% from saturated fat and < 300 mg cholesterol/d. The Step 2 diet was designed to provide 26% and <10% of energy for total and saturated fat, respectively and <200 mg cholesterol/d. Both diets contained ~25 g of fiber/d.


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  		TABLE 2 Nutrient composition of the diets1

 
A 7-d cycle menu was planned using the Nutritionist IV database (N-Squared Computing), incorporating items from Campbell’s Center for Nutrition and Wellness Intelligent Quisine line of products. Previously, in a multicenter clinical trial, patients with hypertension, dyslipidemia and Type 2 diabetes, or any combination of these, achieved significant reductions in key end points over a 10-wk period using the Intelligent Quisine meal program (15). The program, certified by the American Heart Association and supported by the American Diabetes Association, featured fully prepared meals that were nutritionally balanced while incorporating fortification technology. Intelligent Quisine met the American Heart Association guidelines for sodium, cholesterol and saturated fat as well as the National Academy of Sciences/National Research Council guidelines for vitamins and minerals.

Biochemical analyses

Blood samples were collected on two consecutive days at baseline and wk 3 of each diet period to determine serum iron, total iron binding capacity (TIBC), hemoglobin, hematocrit, and ferritin and at the end of each diet period for LDL oxidation susceptibility end points. Experienced phlebotomists collected blood in the morning after subjects had fasted for 12 h. For LDL oxidation measurements, 30 mL of blood was collected into 10 mL Vacutainer tubes (VWR Scientific Products, West Chester, PA) containing an anticoagulant (EDTA). Plasma was separated by low speed centrifugation, and the water-soluble antioxidant TROLOX (Aldrich Chemical, Milwaukee, WI) was added to the plasma to a final concentration of 1 µmol/L. For iron measurements, 15 mL of blood was collected into Vacutainer tubes (VWR Scientific Products) containing SST gel and clot activator. The serum was separated by low speed centrifugation (1500 x g for 30 min), divided into aliquots in 1.5-mL cryovials and stored at -80°C until the completion of the study.

    Oxidation of LDL. LDL was first isolated by density gradient ultracentrifugation (16). A density gradient was formed by adjusting 4 mL of plasma to d = 1.21 kg/L with potassium bromide and then sequentially layering 2.0–2.5 mL of three salt solutions above the plasma (d = 1.063, d = 1.019 and d = 1.006 kg/L). Samples were then centrifuged in a Beckman SW40 or SW41 swinging bucket rotor (Beckman Coulter, Fullerton, CA) at 270,000 x g for 22 h at 10°C. Immediately after centrifugation, the LDL fraction was collected. LDL samples (0.5 mL) were preserved in a 100 g/L sucrose solution to prevent structural and biological changes as a result of freezing. LDL samples were purged with nitrogen and stored at -80°C.

At the completion of the study, LDL samples were grouped and analyzed by subject for the oxidation analyses. LDL was dialyzed for 24 h at 4°C in the dark against a 0.01 mol/L PBS buffer that contained 0.1 g chloramphenicol/L and was also purged with nitrogen. The buffer was changed three times during the 24-h period. Protein analyses were determined upon completion of dialysis (17). Within 24 h of dialysis, total diene formation was monitored as previously described (18). LDL protein (100 µg) was diluted to 1 mL with PBS buffer, and oxidation was initiated by the addition of 1 mmol/L CuCl2 solution to a final concentration of 0.01 mmol/L. Oxidation was measured in a Beckman Coulter Model 50 UV spectrophotometer at an absorbance of 234 nm at 3-min intervals for 3 h at 37°C. From these measurements, lag time, rate of oxidation and total amount of dienes formed were determined for each sample (18). Rate of oxidation and total dienes were determined from the maximum rate of oxidation ({Delta}Abs234/min) and maximum absorbance ({Delta}Abs234) and using the molar extinction coefficient for total lipid hydroperoxides [{epsilon}234 = 29,500 (mol/L)-1 · cm-1].

    Iron measurements. Serum ferritin concentration was determined using IRMA kits (Diagnostics Products Corporation, Los Angeles, CA). Serum total iron and TIBC were determined by colorimetric assays (19). Transferrin saturation was calculated as a percentage of serum total iron divided by TIBC. Quality control samples were analyzed with all samples and within- and between-assay CV were determined. Whole-blood samples were sent to Lab Corp of America (Altoona, PA) for analysis of hemoglobin and hematocrit.

    Statistical procedures. All statistical analyses were performed using SAS version 8.0 (SAS Institute, Cary, NC). Data are expressed as least-squares means ± SE. The mixed model procedure (PROC MIXED) was used to test for main effects and interactions of diet, supplement and order of diets. Tukey-Kramer adjusted P-values were used to test differences between diets as well as supplement status. Pearson correlation analyses tested the relationship between in vitro LDL oxidation potential and iron status (serum iron, TIBC, ferritin, hemoglobin, hematocrit and transferrin saturation). Probability values < 0.05 were considered significant. Stepwise regression analysis was used to examine the relationship between iron status and LDL oxidation. A significant increase in R2 (P < 0.05) with the addition of a variable was considered significant in the regression equation.


   RESULTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
Twenty-six subjects completed the study. All of the subjects maintained their weight during the study. In the supplement group, all of the iron measurements with the exception of hematocrit were significantly different from baseline, whereas in the placebo group, only ferritin concentration and transferrin saturation differed from baseline (Table 3). Only ferritin differed between the supplement and placebo groups (P = 0.008) after supplementation. It was 87.7% higher in the supplement group. The diets (AAD or Step 2) did not affect iron status in either the supplement or placebo group (data not shown).


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  		TABLE 3 Effect of iron supplement or placebo on iron status variables in women with initially low iron status1

 
The diets and supplementation did not affect the rate of LDL oxidation or total dienes (Table 4). However, susceptibility, as indicated by lag time, was affected by the diets (P < 0.0001) but not by the supplement (P = 0.50). Lag time was 49.8% longer after the women consumed the low fat diet compared with the AAD.


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  		TABLE 4 Effect of diets varying in total and saturated fat and iron supplement or placebo on the susceptibility of LDL to oxidation in women with initially low iron status1

 
Stepwise regression analysis was used to examine the relationship between iron status and LDL oxidation. Diet was entered first into the model due to its effect on LDL oxidation. Although stepwise regression of the rate of oxidation did not indicate any significant predictor variables, the percentage change in TIBC from baseline was a significant predictor in addition to diet for both lag time and total dienes (Table 5). The two significant predictor variables for lag time had a combined R2 of 0.40. Diet accounted for 34% of the variance followed by the percentage change in TIBC from baseline (6%). However, for total dienes, the 2% of the variance accounted for by diet was not significant. The model was most influenced by the percentage change in TIBC, which accounted for 16% of the total 18% of variance explained.


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  		TABLE 5 Stepwise regression models relating LDL oxidation susceptibility variables to iron status variables1

 

   DISCUSSION
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
Our results represent a hypothesis-driven study in which the effects of both diet and iron status were examined in a controlled feeding study. The design is unique in that compared with other epidemiologic studies that examined the relationship between iron and cardiovascular disease, we were able to test experimentally the interaction between dietary fat and iron status in a controlled clinical study using LDL oxidation susceptibility as a possible marker of CVD. The results indicate that although diet significantly affected lag time, the addition of a therapeutic dose of iron did not affect measures of oxidative stress despite improved iron status in subjects receiving the supplement as measured by a significant increase in ferritin, transferrin saturation and hemoglobin and a significant decrease in TIBC. Although these results do not support a relationship between iron status and measures of LDL oxidation, the results of the stepwise regression showed that the percentage change in TIBC from baseline was a significant predictor in addition to diet of both lag time and the production of total dienes. However, only a slight change was observed for both lag time (0.24 min) and total dienes (1.52 nmol/mg LDL protein) when the regression equations were implemented. Therefore, although the stepwise regression results were significant, the parameter estimates for the percentage change in TIBC were of such small magnitude for both lag time and total dienes that it is unlikely that the results of these equations are of biological importance. It has been argued that a fourfold increase in lag time may not be adequate to observe a biological effect (20). Therefore, we would expect much larger parameter estimates for the percentage change in TIBC if a clinically relevant relationship existed between iron status and LDL oxidation.

The results of the current study confirm previous work in our laboratory showing that diets lower in total and saturated fat have a more favorable LDL oxidation potential. A study by Yu-Poth et al. (14) showed that a reduction in saturated fat in the diet decreased the susceptibility of LDL to oxidation. Total and saturated fat energy were reduced in a stepwise manner (34, 29 and 25% for total fat and 15, 9 and 6% for saturated fat). The greatest reduction in rate of oxidation as well as formation of total dienes and lipid peroxides occurred when subjects consumed the diet lowest in both total and saturated fat. Hargrove et al. (21) examined the effects of a diet high in monounsaturated fatty acids (MUFA; 34% total fat, 7% saturated fat) as well as an AAD (34% total fat, 16% saturated fat) and a Step 2 diet (25% total fat, 7% saturated fat) on measures of LDL oxidative susceptibility. The MUFA diets included an olive oil diet, a peanut oil diet and a peanuts + peanut butter diet. The lowest rate of oxidation occurred after consumption of the olive oil diet compared with the AAD, peanut oil and peanuts + peanut butter diets (P < 0.05). There were no differences due to diet in the amount of total dienes produced. However, lag time was shorter after the AAD compared with the Step 2 diet, olive oil diet and peanuts + peanut butter diet (P <= 0.1). Thus, that study is consistent with the results of the current study in that only lag time was affected by diet when comparing AAD and Step 2 diets. Therefore, even though supplemental iron (at the dose we used) did not act as an oxidant, on the basis of our end point assays, a blood cholesterol–lowering diet should be recommended for those treated with supplemental iron for poor iron status to decrease CVD risk.

Several studies have examined the possible link between iron and LDL oxidation. In a study by Salonen et al. (22) that included Finnish men (n = 14) who were smokers, a reduction in body iron stores by way of venesection (blood letting) increased resistance of serum LDL to oxidation in vitro. Lag time was increased by 33% and there was a 44% reduction in serum ferritin concentration. In other studies, serum ferritin levels predicted atherosclerosis progression (2,23,24). However, in some studies, no association between body iron stores and measures of LDL oxidation (3–5,25) existed. Consistent with our results, a recent study by Derstine et al. (13) did not support a relationship between iron intake, free iron concentration and measures of lipid peroxidation. That retrospective study examined healthy subjects with normal iron status who had participated in three well-controlled feeding studies in which the diet provided the only iron ingested and thus did not represent a large dose (17–21 mg/d).

In contrast to the results of Salonen et al. (2), which would suggest that persons with iron deficiency should not be treated with supplements due to possible adverse events, the results of the present experimental study showed that measures of oxidative stress were not affected by a therapeutic dose of iron in women with low iron status. In our study, iron status was improved as shown by an increase in ferritin, which is the most reliable marker of iron status. Although we could have used a different model to study the effect of iron supplementation on LDL oxidation that was even more extreme (i.e., subjects with greater iron deficiency, a higher dose of an iron supplement), our study was designed to evaluate the effects of iron supplementation on LDL oxidation in a clinically relevant model. Although measures of LDL oxidation were not affected by supplement intake, lag time was significantly longer after consumption of the low fat diet. In conclusion, the results of this study do not support the hypothesis that LDL susceptibility to oxidation is affected by aggressive supplementation with iron to improve iron status. Iron supplementation, at the dose we used, does not independently affect LDL oxidative susceptibility or interact with either a diet representative of that currently consumed by Americans or a recommended low fat diet. Therefore, if iron does in fact play a role in increasing risk of CVD, it is likely due to a mechanism other than LDL oxidation, or occurs only when there is an excessive intake of iron.


   ACKNOWLEDGMENTS
 
We thank Campbell’s Center for Nutrition and Wellness for their generous donation of Intelligent Quisine products.


   FOOTNOTES
 
2 Abbreviations used: AAD, average American diet; CHD, coronary heart disease; CVD, cardiovascular disease; MUFA, monounsaturated fatty acids; SFA, saturated fatty acids; TIBC, total iron binding capacity. Back

Manuscript received 21 July 2003. Initial review completed 14 August 2003. Revision accepted 1 October 2003.


   LITERATURE CITED
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 

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