Women's Health Initiative Diet Intervention Did ... - Journal of Nutrition

The Journal of Nutrition Nutrition and Disease

Women’s Health Initiative Diet Intervention Did Not Increase Macular Pigment Optical Density in an Ancillary Study of a Subsample of the Women’s Health Initiative1,2 Suzen M. Moeller,3,7 Rick Voland,3 Gloria E. Sarto,4 Vicki L. Gobel,5 Sharyn L. Streicher,6 and Julie A. Mares3* 3 Department of Ophthalmology and Visual Sciences, 4Department of Obstetrics and Gynecology Medicine, 5Women’s Health Initiative, and 6Center for Women’s Health Research, University of Wisconsin, Madison, WI 53705

Abstract In this study, we examined the impact of long-term (.8 y), low-fat, high-fruit and -vegetable diets on levels of lutein and zeaxanthin in the macula of the retina, as indicated by the OD of macular pigment. Macular pigment OD, measured by heterochromatic flicker photometry, was compared in women aged 60–87 y, who, 7–18 mo earlier (median 12 mo), had been in the dietary modification intervention (n = 158) or comparison (n = 236) groups of the Women’s Health Initiative (WHI) at the Madison, WI site for a mean of 8.5 y. Women in the intervention group ate more fruits and vegetables (mean 6 SEM) (6.1 6 0.2 vs. 4.6 6 0.2 servings/d; P , 0.0001) and had higher intakes of lutein and zeaxanthin from foods and supplements (2.7 6 0.2 vs. 2.1 6 0.1 mg/d; P = 0.0003) than the comparison group. However, macular pigment density did not differ between the intervention (0.36 6 0.02 OD units) and comparison (0.35 6 0.01 OD units) groups. It tended to be higher (11%; P = 0.11) in women consuming lutein and zeaxanthin in the highest compared with the lowest quintile (median 6.4 vs. 1.1 mg/d). The increase in fruit and vegetable intake among dietary modification participants of this WHI subsample was not of sufficient magnitude to alter the mean density of retinal carotenoids, given other existing dietary conditions in this sample. J. Nutr. 139: 1692–1699, 2009.

Introduction The xanthophyll carotenoids lutein and zeaxanthin may protect the eyes against the common age-related visual problems of macular degeneration (1–4) and cataract (5–7). These carotenoids, which comprise macular pigment, could enhance the absorption of blue light that could otherwise be damaging and promote age-related macular degeneration (8). In both the retina and the lens, they could reduce oxidative stress, which contributes to these conditions. Among the hundreds of carotenoids in foods, lutein and zeaxanthin are the only carotenoids that concentrate in the eye (9,10). These plant pigments are most concentrated in the inner retinal layer of the macula (11), but their concentration is high

1

Supported by the Prevent Blindness America Investigator Award, The Karl and Mildred Reeves Foundation, The Retinal Research Foundation, The Research to Prevent Blindness, and a grant from the University of Wisconsin Medical School. This research was an ancillary study of the Women’s Health Initiative (WHI). We thank the National Heart, Lung and Blood Institute of the NIH, U.S. Department of Health and Human Services, which funded the WHI program. 2 Author disclosures: S. M. Moeller, R. Voland, G. E. Sarto, V. L. Gobel, S. L. Streicher, and J. A. Mares, no conflicts of interest. 7 Present address: Department of Medicine and Public Health, American Medical Association, Chicago, IL. * To whom correspondence should be addressed. E-mail: [email protected].

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and variable (9). Levels in the macula, which are easy to measure noninvasively, may reflect levels in other parts of the eye. Lutein and zeaxanthin cannot be synthesized by animals and must be obtained from the diet. Fruits and vegetables are the richest sources. Feeding foods (12–14) or supplements (15–18) containing lutein and zeaxanthin generally increases macular pigment density. However, there is a variable response of retinal carotenoids to supplementation (13,16,18,19) and response may involve other aspects of the diet that influence the uptake of these carotenoids by the intestine and the eye. Thus, it is useful to understand the relationship of particular diet patterns and levels of lutein and zeaxanthin in the eye. This study was designed to examine the effect of a long-term, low-fat, high-fruit and -vegetable diet, as characterized by the Women’s Health Initiative (WHI) Dietary Modification Clinical Trial intervention, on retinal carotenoids. This effect can be estimated, noninvasively, by measuring macular pigment OD (macular pigment density). We hypothesized that macular pigment density would be higher in the group of women who received this intervention than in women in the comparison group. We also explored whether other dietary, lifestyle, physical, or medical characteristics that predicted macular pigment density in previous studies explained, confounded, or modified this comparison.

0022-3166/08 $8.00 ã 2009 American Society for Nutrition. Manuscript received March 24, 2009. Initial review completed April 14, 2009. Revision accepted May 30, 2009. First published online July 8, 2009; doi:10.3945/jn.109.107748.

Methods Study population. The WHI Dietary Modification Clinical Trial was designed to test whether a dietary pattern low in total fat and high in fruits, vegetables, and grains decreased the incidence of breast and colorectal cancer, and secondarily, coronary heart disease in postmenopausal women (20). Participants, aged 50–79 y (21) at enrollment in 1993–1998, were randomly assigned to the intervention group (40%; n = 19,541) or the usual diet comparison group (60%; n = 29,294) at 40 sites around the United States (22). Participants were recruited at each of these sites through regional mass mailings and mass media strategies (23). Exclusion criteria for the dietary modification trial included a history of breast, colorectal, and other cancers except for nonmelanoma skin cancer in the previous 10 y, medical conditions predictive of a survival time of ,3 y, type I diabetes mellitus, or adherence or retention concerns (alcoholism, drug dependency, mental illness, or dementia). Women were also excluded if: 1) they reported consumption of ,2512 kJ/d or .20,934 kJ/d at baseline; 2) their reported total fat intake was ,32% of total energy; or 3) they reported consuming 10 or more main meals per week prepared outside of the home (23). The primary goal of the WHI dietary intervention was to reduce total dietary fat intake to 20% of energy, to increase fruit and vegetable consumption to $5 servings daily, and grain consumption to $6 daily servings, including whole grains (24). To support these goals, women in the intervention group were assigned to groups of 8–15 participants. Within 1 y of their start date, each group was offered 18 sessions designed to promote dietary and behavior change. In subsequent years, group maintenance sessions were conducted quarterly. Intervention group participants were asked to self-monitor dietary intake throughout the trial, which lasted a mean of 8.5 y (21). Comparison group participants were not asked to change their diets but were given a copy of Nutrition and Your Health: Dietary Guidelines for Americans and other health-related materials (25). The present study population consists of women who were enrolled in the dietary modification trial of the WHI at the Madison, WI site and who completed their close-out visit between October 1, 2004 and March 31, 2005. With a goal of recruiting 400 participants, 691 women were sent letters inviting them to participate in the study. Of the 691, 5 were deceased, 2 were ineligible due to poor eye health, and 285 (41%) declined participation. The most common reasons for nonparticipation were: nonresponse to multiple contacts (26%), transportation issues/ moved out of area (27%), or health issues of the participant (8%) or her family (6%, including death of spouse). In 18% of cases, the women refused without stating a reason. Of the 400 (58%) enrolled, 4 were excluded from the analyses because the macular pigment density measurements could not be made. We further excluded 1 woman who could not complete the FFQ and 1 woman missing covariate data. Thus, 394 women comprised the analysis dataset. Of these, 158 had participated in the WHI intervention. All procedures conformed to the Declaration of Helsinki and were approved by the Institutional Review Board at the University of Wisconsin-Madison. Dietary assessment. Diet was assessed using previously validated, semiquantitative FFQ developed by the Nutrition Assessment Shared Resource of Fred Hutchinson Cancer Research Center (26) at WHI baseline (1994–1998) and at the study visit when macular pigment density was measured (October 2005–May 2006). Nutrient and food group estimates at WHI baseline and at the macular pigment density study visit were computed from responses to FFQ at the Fred Hutchinson Cancer Research Center. Lutein and zeaxanthin in the diet at the time of the macular pigment density study visit were assessed by adjusting the values estimated from the FFQ for responses to a question about consumption of dark green leafy vegetables and questions about supplement use. In a separate sample, serum lutein and zeaxanthin and the intake of lutein and zeaxanthin assessed using this questionnaire were correlated (Pearson r = 0.39; P = ,0.001) (27). Use of lutein or zeaxanthin supplements was not questioned at baseline, which was before common availability of these nutrients in retail supplements.

Macular pigment OD. Measurements were made using a standardized protocol by the psychophysical method of heterochromatic flicker photometry during macular pigment density study visits. This protocol was a modified version of the one used in the Carotenoids in Age-Related Eye Disease Study (CAREDS) (28). Briefly, participants viewed a small test field superimposed on a blue background with the right eye, or, in the case of visual problems with the right eye, the left eye was tested in 7 women, because right and left eye macular pigment densities were highly correlated (Pearson r = 0.79; P = ,0.001) (28). The test field alternated between a wavelength (blue or blue-green) that is absorbed by the macular pigment and a reference (green to yellow-green) wavelength that is outside the absorption band of macular pigment. When the frequency of alternation is chosen correctly, the test field appears to flicker. When making measurements, the participant was instructed to adjust the energy of the bluish test light so that the flicker stops. The amount of bluish light that is required to stop this flicker provides a measure of the OD of macular pigment at the retinal location of the test light. Participants were instructed to fixate at the center of the target 0.5 degrees from the foveal center in reference to a target at 7 degrees from the center. This target was previously found to have the lowest within- to between-person variability (28). This protocol was similar to one described previously that was highly repeatable in older women, having a strong test-retest association (r = 0.90; P , 0.001) at the target tested in the present study (28). Unlike the previous protocol, visual acuity was not determined prior to testing and participants were allowed to wear their personal correction lenses, including tinted and progressive lenses (n = 75). Macular pigment density did not differ in women who wore these lenses and those who did not, nor did the percentage of women who wore these lenses differ between intervention groups (data not shown). A validation test [previously described (28)] was performed in the present study (in 386 women) as well. Comparing macular pigment density estimated from this measurement with that used in the present study, the CV of macular pigment density measurements in this study was 8.8%. Covariates. The presence of physician-diagnosed diabetes, cataract, and age-related macular degeneration, family history of cataract (immediate family member before age 65 y) and macular degeneration (immediate family member age $55 y), use of cholesterol-lowering medications, age, and use of nutritional supplements (dose, frequency, duration) were queried in questionnaires submitted at the macular pigment density study visit. Waist circumference was measured 1 inch above the navel in centimeters; the mean of 2 measurements was used in analyses. Additional demographic, lifestyle, and health history data were available from questionnaires completed at WHI study entry (education, smoking, physical activity, height, weight, and hormone replacement therapy and alcohol use). Covariate quantiles were generated from the set of 394 participating women. Statistical analyses. Macular pigment levels in the intervention and comparison groups were compared by unpaired, 2-tailed t test. Although randomization should have equalized the distribution of other determinants of retinal carotenoids that were not part of the dietary intervention (body fat, diabetes, etc.) in the intervention and comparison groups, if differences were detected, the statistical models were adjusted using ANOVA. Wilcoxon’s rank-sum tests and chi-square tests were used to assess the significance of differences in potential covariates between women in the intervention and comparison groups. Relationships between macular pigment density and lifestyle, physical, and medical characteristics were examined by computing mean macular pigment density values across categories using linear regression (Table 2). These relationships were examined in the overall group and in the intervention and comparison groups separately. When there was a marginally significant difference (P # 0.1) in the variables related to macular pigment density in intervention and comparison groups, results were considered separately. Mean macular pigment density was likewise computed across categories of intake of lutein plus zeaxanthin, fruits and vegetables, and other dietary factors (Table 3). Unless noted otherwise, values in the text are means 6 SEM. SAS version 9.1.3 was used throughout (SAS Institute). Diet and macular pigment optical density

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Results Characteristics of women. Examination of daily intake estimates from FFQ that were completed at the time of the macular pigment density study visit indicated that women in the intervention group continued to consume significantly more fruits, vegetables, fiber, lutein, and zeaxanthin from foods and less total fat, saturated fat, and polyunsaturated fat at the time of macular pigment density measurement than the comparison group (Table 1). Women in the intervention group were more likely than women in the comparison group to have diabetes at WHI-baseline but not at the time of macular pigment density measurement. Hypertension at WHI-baseline was more common in the intervention group. At WHI-baseline (not shown) and macular pigment density measurement study visits (Table 1), the women in the treatment groups were similar in all other demographic, lifestyle, physical, and medical attributes measured. Despite higher intake of lutein and zeaxanthin among women in the intervention group, macular pigment density did not differ from women in the control group (Table 1). We explored possible sources of bias. The results were unchanged after excluding 16 women with macular degeneration at macular pigment density measurement or after further excluding an additional 11 women with diabetes at WHI-baseline (data not shown). Macular pigment density means also remained constant with adjustment for waist circumference, diabetes at macular pigment density measurement, current use of cholesterol-lowering medication, or intake of lutein or zeaxanthin as supplements (Table 1). To evaluate the potential bias due to lack of participation, we compared characteristics of women in the recruitment dataset who did not enroll in our study (n = 297: declined, deceased, ineligible, or excluded) with those who participated and were included in the analysis dataset (n = 394). The women who did not participate in the present study or were excluded from the analysis dataset were older (mean 63 vs. 60 y), more likely to have a postgraduate education (49 vs. 39%), to use cholesterollowering medications (11 vs. 6%), and to have a BMI .35 kg/m2 (18 vs. 14%), and less likely to report having excellent or very good health (59 vs. 71%) than the women in the analysis dataset (P , 0.05). Nonparticipating or excluded women consumed more of their energy as polyunsaturated fat (7.4 vs. 7.1%), less zinc (12 vs. 13 mg/d), and fewer fruits and vegetables at WHI baseline (3.5 vs. 3.8/d) than the included women (P , 0.05). Otherwise, the percentage in the intervention and treatment groups and demographic, health, and lifestyle characteristics were similar (not shown). Relationship between macular pigment density and nondietary factors. Women with alcohol intakes above the median or cardiovascular disease at WHI baseline had a higher mean macular pigment density than did other women (Table 2). Lower macular pigment density was associated with above-median levels of waist circumference. Women who reported having macular degeneration had similar macular pigment density to women who did not. Waist circumference explained 2.7% of variation in macular pigment density and diabetes (at time of macular pigment density measurement) explained 1.2%. Macular pigment density was not associated with age, use of cholesterol-lowering medication, or hormone replacement therapy or with the history of other chronic diseases (Table 2). Relationship between macular pigment density and dietary factors. Macular pigment density was marginally 1694

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directly related to higher intake of lutein and zeaxanthin, vegetables, and fiber (Table 3). Macular pigment density was not significantly associated with higher intake of total fat, saturated fat, or polyunsaturated fat. However, because fiber and the separate intake of polyunsaturated fat were directly related to macular pigment density in the larger CAREDS study (an ancillary study of the WHI observational study) (28) and there is biologic plausibility to suggest that these aspects of diet promote the absorption or higher blood levels of carotenoids, we explored the joint influence of these diet factors on macular pigment density. Women whose intake was above the median for both dietary fiber and polyunsaturated fat had higher macular pigment density (0.37 6 0.02 OD units) than women whose intake of fiber and polyunsaturated fat was below the median (0.34 6 0.02 OD units). Although this was true across all quintiles of lutein intake (Fig. 1), macular pigment density in these groups, stratified by fiber and PUFA intake, did not differ before (P = 0.23) or after adjusting for waist circumference, diabetes, and lutein intake (P = 0.50).

Discussion Our results indicate that general dietary recommendations to consume a low-fat, high-fruit and -vegetable diet for a mean of 8 y did not significantly increase retinal carotenoid concentrations in this sample of postmenopausal women. Approximately 1 y after completing the WHI dietary modification trial, women in the dietary intervention group consumed a mean of approximately 1 extra serving of fruits and vegetables per day and significantly more lutein plus zeaxanthin than did women in the control group. It is possible that the increased intake of fruits and vegetables in the intervention group was of insufficient magnitude to effect macular pigment density levels. We hypothesized a 10% higher macular pigment density among women in the intervention than the comparison group, because we previously observed that macular pigment density increased by 10% for each serving/d increase of total fruits and vegetables (up to 6/d) (27). The present study had 85% power to detect such a difference. The level of dietary or supplemental lutein and zeaxanthin needed to increase macular pigment density has not been systematically studied. Results of previous short-term (3 mo to 1 y) supplementation studies suggest that the response of macular pigment density to intake of lutein and zeaxanthin may be influenced by a variety of conditions. For example, eating 1 egg/d, 6 d/wk contributes only 0.3 mg/d, which is one-half of the mean increase in lutein and zeaxanthin that was associated with being in the WHI diet intervention, but significantly increased macular pigment density in only 3 mo (14). In a different series of studies, doses of lutein and zeaxanthin ranging from 2.4 to 30 mg/d were tested (16). There was a mean increase in macular pigment density of 10% in people supplemented with lutein and zeaxanthin in one study, most of whom received 2.4 mg/d (16). In other studies, supplementing patients with retinal degenerations with much larger doses (20 mg) of lutein and zeaxanthin resulted in significant increases in macular pigment density in only ~50–70% of persons (18,29). In a recent study, a mean 39% increase in macular pigment density was observed after 6 mo of supplementation with 12 mg/d (30). Larger increases were observed after 6 mo than after 1 mo of supplementation and in people with moderate, rather than high or low macular pigment density at baseline. Thus, it appears that a variety of factors, such as duration and amount of

TABLE 1

Characteristics of study participants in the intervention and the comparison groups

Macular pigment OD (OD units) Crude Adjusted1 Daily dietary intake Lutein and zeaxanthin, mg Daily intake from food Supplements Total Fruit + vegetables, servings Fruits Vegetables Fiber, g Fat, % of energy Total fat Polyunsaturated fat Saturated fat Vitamin E, mg Zinc, mg Alcohol, g Demographic Age, y Education,2 % Less than high school College or post-high school Postgraduate Race,2% white Physical Waist circumference, cm BMI, kg/m2, % ,22.5 22.5–25 25–30 30–35 .35 Medical Self-reported history, % Macular degeneration (n = 388) Cataract surgery (n = 392) Glaucoma (n = 392) Diabetes Long-term history,2 % Diabetes Hypertension Overall cardiovascular disease Use of hormone replacement therapy,2 % Never Past Current Use of cholesterol-lowering medication, % General perceived health (n = 384),2 % Excellent Very good Good Fair/poor

Intervention, n = 158

Comparison, n = 236

P for difference

0.36 (0.02) 0.36 (0.02)

0.35 (0.01) 0.35 (0.01)

0.73 0.75

2.5 0.2 2.7 6.1 2.8 3.1 21

2.0 0.1 2.1 4.6 2.1 2.4 18

0.0004 0.20 0.0003 ,0.0001 ,0.0001 ,0.0001 ,0.0001

25 5.7 8.0 7.5 10.8 2.4

33 7.0 11 7.0 9.6 1.6

,0.0001 ,0.0001 ,0.0001 0.37 0.05 0.10

71

70

0.42

23 40 37 99

25 38 37 99

0.86

.0.99

96

96

0.37

17 11 32 25 16

15 11 36 25 13

0.84

5.2 11 1.9 10.8

3.4 7 4.3 9.3

0.44 0.20 0.26 0.73

5.1 34 17

1.3 19 19

0.03 0.002 0.60

32 20 48 39

36 18 45 36

0.70

22 44 32 2

19 53 24 3

0.21

0.60

Values are mean 6 SE or median. Adjusted for waist circumference, diabetes, use of cholesterol-lowering medications, and intake of lutein and zeaxanthin supplements. 2 Values obtained at WHI baseline. All other values were obtained at study visits to measure macular pigment. 1

Diet and macular pigment optical density

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TABLE 2

Macular pigment OD by selected lifestyle, physical, ocular, and medical characteristics in the intervention and comparison groups combined Subgroup, n

Demographic Age, quintile (median y ) 1 (64) 2 (67) 3 (71) 4 (74) 5 (80) Lifestyle Smoking3 Never Past Current Alcohol, quartile (median g/d ) 1 (0.01) 2 (0.5) 3 (3.0) 4 (11.4) Physical Waist circumference quartile (median cm) 1 (82) 2 (92) 3 (101) 4 (116) Medical Self-reported history Macular degeneration: No Yes Cataract surgery: No Yes Glaucoma: No Yes Diabetes: No Yes Long-term history3 Hypertension: No Yes Overall cardiovascular disease: No Yes Hormone replacement therapy3 Never Past Current Use of cholesterol-lowering medication: No Yes General perceived health3 Excellent Very good Good Fair/poor

Unadjusted mean 6 SE, n = 393

Adjusted mean 6 SE, n = 3931

P-linear trend1

0.82 80 78 79 80 76

0.33 0.36 0.37 0.32 0.37

6 0.02 6 0.02 6 0.02 6 0.02 6 0.02

0.33 0.35 0.36 0.31 0.36

6 0.02 6 0.02 6 0.02 6 0.02 6 0.02 0.15

219 163 11

0.38 6 0.06 0.36 6 0.01 0.33 6 0.02

0.35 6 0.06 0.36 6 0.01 0.32 6 0.02 0.042

99 97 99 98

0.32 0.33 0.38 0.38

6 0.02 6 0.02 6 0.02 6 0.02

0.32 0.31 0.37 0.36

6 0.02 6 0.02 6 0.02 6 0.02

98 102 97 96

0.37 0.37 0.34 0.33

6 0.02 6 0.02 6 0.02 6 0.02

0.36 0.36 0.33 0.32

6 0.02 6 0.02 6 0.02 6 0.02

378 15 202 191 366 27 355 38

0.35 0.37 0.34 0.36 0.35 0.34 0.36 0.31

6 0.01 6 0.05 6 0.01 6 0.01 6 0.01 6 0.04 6 0.01 6 0.03

0.34 0.36 0.33 0.35 0.34 0.33 0.34 0.32

6 0.01 6 0.05 6 0.01 6 0.02 6 0.01 6 0.04 6 0.01 6 0.03

295 98 320 73

0.36 0.34 0.34 0.40

6 0.01 6 0.02 6 0.01 6 0.02

0.34 60.01 0.34 6 0.02 0.34 6 0.01 0.40 6 0.02

136 74 183 246 147

0.36 0.37 0.34 0.36 0.33

6 0.02 6 0.02 6 0.01 6 0.01 6 0.02

0.35 0.36 0.32 0.35 0.32

6 0.02 6 0.02 6 0.02 6 0.01 6 0.02

80 193 105 10

0.38 0.33 0.36 0.44

6 0.02 6 0.01 6 0.02 6 0.06

0.37 0.31 0.35 0.43

6 0.02 6 0.02 6 0.02 6 0.06

0.011

0.66 0.46 0.71 0.48

0.85 0.02 0.18

0.15 0.75

1 Means are adjusted for quartile of waist circumference, alcohol intake, history of cardiovascular disease, and total lutein intake at macular pigment density measurement except when expressed by levels of these variables. P-trend values use continuous variables and are adjusted for other risk factors in the model. 2 P-trend for alcohol used log-transformation. 3 Values obtained at WHI baseline. All other values were obtained at study visits to measure macular pigment.

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TABLE 3

Relationships between diet and macular pigment density

Quintile (median values) Lutein+zeaxanthin, diet+supplements, mg/d 1 (1.1) 2 (1.7) 3 (2.3) 4 (3.3) 5 (6.4) Fat, % of energy Total 1 (20) 2 (26) 3 (30) 4 (35) 5 (40) PUFA 1 (4.3) 2 (5.4) 3 (6.5) 4 (7.6) 5 (9.1) Saturated 1 (6.1) 2 (8.2) 3 (9.4) 4 (11.1) 5 (13.5) Fiber, g/d 1 (11) 2 (15) 3 (19) 4 (23) 5 (30) Fruit, servings/d 1 (0.8) 2 (1.5) 3 (2.2) 4 (3.0) 5 (4.2) Vegetables, servings/d 1 (1.3) 2 (2.0) 3 (2.6) 4 (3.7) 5 (5.0) Fruit and vegetables, servings/d 1 (2.4) 2 (3.9) 3 (5.1) 4 (6.6) 5 (8.9) 1

Least square mean (SE)

P-linear trend 0.111

0.34 (0.02) 0.32 (0.02) 0.35 (0.02) 0.36 (0.02) 0.38 (0.03) 0.75 0.36 (0.02) 0.34 (0.02) 0.34 (0.02) 0.35 (0.02) 0.36 (0.02) 0.47 0.37 (0.02) 0.32 (0.02) 0.35 (0.02) 0.34 (0.02) 0.37 (0.02) 0.82 0.36 (0.02) 0.34 (0.02) 0.35 (0.02) 0.36 (0.02) 0.34 (0.02) 0.10 0.35 (0.02) 0.32 (0.02) 0.35 (0.02) 0.36 (0.02) 0.38 (0.02) 0.55 0.34 (0.02) 0.36 (0.02) 0.34 (0.02) 0.34 (0.02) 0.38 (0.02) 0.08 0.37 (0.02) 0.32 (0.02) 0.35 (0.02) 0.35 (0.02) 0.37 (0.02) 0.17 0.38 (0.02) 0.30 (0.02) 0.34 (0.02) 0.34 (0.02) 0.39 (0.02)

P-trend for lutein and zeaxanthin used log-transformed values.

supplementation, the vehicle (food or pill), baseline macular pigment density, and the health of the retina may influence the retinal response to the intake of lutein and zeaxanthin. It is likely that dietary recommendations that target the intake of fruits and vegetables rich in lutein and zeaxanthin would be more effective in enhancing tissue lutein and zeaxanthin than general recommendations to consume any fruits and

FIGURE 1 Macular pigment density in women whose diets were jointly above or below medians for total fat (.30% vs. ,30% energy) and fiber (.19.3 vs. ,19.3 g/d) by quintile of dietary lutein and zeaxanthin. For women with intakes above the median for both fat and fiber, n = 26, 23, 13, 10, and 10 across quintiles 1 through 5 for intake of lutein and zeaxanthin, respectively. For women with intakes below the median for both fat and fiber, n = 4, 7, 27, 24, and 20 across quintiles 1 through 5. Macular pigment density did not differ between above and below the median for fat and fiber intake groups before (0.38 6 0.02 vs. 0.34 6 0.02 OD units; P = 0.23) or after (0.37 6 0.02 vs. 0.35 6 0.02 OD units; P = 0.50) adjusting for waist circumference, diabetes, and lutein and zeaxanthin intake.

vegetables. In CAREDS, green vegetables provided a mean of 50% of the lutein and zeaxanthin in diets (26% from leafy greens and 24% from other green vegetables) (our unpublished data). However, neither the Dietary Guidelines for Americans at the time of the study (31) nor the WHI diet intervention specifically encouraged the intake of green vegetables. However, the more recent 2005 Dietary Guidelines for Americans (32) specifically recommends selecting from all 5 vegetable subgroups (one of which is dark leafy green vegetables, the richest sources of lutein and zeaxanthin) several times per week. Likewise, neither the WHI dietary intervention nor the 1990 US Dietary Guidelines specifically encouraged the intake of fruits and vegetables that are particularly rich in other nutrients or phytochemicals, such as antioxidants, which may spare oxidation of carotenoids. In addition, the dietary intervention did not necessarily specify that women consume whole grains rather than refined grains. Whole grains are richer in dietary antioxidants, which might spare the turnover of carotenoids, in vivo. All of these could have contributed to smaller than expected differences in macular pigment density between women in the intervention and comparison groups. The recommendation to consume less dietary fat may have also adversely affected the bioavailability of carotenoids and other fat-soluble nutrients in the diet. In the present study, women in the intervention group consumed 25% of energy from dietary fat compared with 33% of energy in the comparison group. The intestinal uptake of carotenoids has been found to be enhanced by higher intakes of foods rich in fats at the same meal, such as full-fat vs. low-fat or fat-free salad dressing (33) or the addition of avocados (34) or use of high fat-spreads (35). Consistent with this idea, we previously observed macular pigment density was directly related to PUFA intake (27). Although the adjustment for neither total nor polyunsaturated Diet and macular pigment optical density

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dietary fat in this sample altered the results (data not shown), the differences in levels of intake in fat in usual diets among women in the present study were less than the conditions in the experiments. Moreover, adjusting for total fat intake cannot be expected to model the consumption of eating fruits and vegetables with or without fat at the same time. We speculate that fiber, which we (27) and others (36) have found to be directly related to macular pigment density, is a marker for higher intake of antioxidants from whole grains, fruits, and vegetables. In the present study, the association with fiber intake was only marginally significant. However, when both fiber and fat intake were considered together, women whose intakes were above the median for each had higher macular pigment density at all levels of lutein and zeaxanthin intake (Fig. 1). The trend of lower macular pigment density among women whose diets are low in both fat and fiber was not significant (P = 0.23) and needs to be studied in larger samples. Nonnutritional factors may influence the accumulation of macular pigment density as well. A twin study suggests that 70– 80% of the variability in macular pigment may be related to genetic factors (37). In previous studies, large waist circumference or high levels of body fat (27,38,39) and diabetes (27,40) were also associated with low macular pigment density. The trends in the current study were consistent with these observations (although not significant for diabetes). These associations could reflect the following: 1) the propensity of lutein and zeaxanthin to accumulate in abdominal fat in women: 2) higher levels of oxidative stress and inflammation in obese persons; or 3) that obesity and diabetes could be markers for other metabolic factors that could influence carotenoid distributions, such as lower HDL levels or size. Abdominal obesity is associated with both lower HDL-cholesterol concentrations (41) and smaller HDL particles (42), both of which are related to lower levels of lutein in the blood. Larger LDL and HDL particles carry more lutein (43) and are lower in people with abdominal obesity. Genetic defects in chickens and humans with Tangiers disease (mutations in the ATP-binding cassette transporter A1 that result in low plasma HDL concentrations) also result in low levels of carotenoids in the blood and some tissues (44). Finally, imprecision in the measurement of macular pigment density could have influenced our ability to detect differences between the 2 intervention groups. The test-retest correlation at 0.5 degrees from the foveal center using a similar technique and the same instrument was high (Pearson r = 0.9; P , 0.001) (28). However, if macular pigment density increased at other eccentricities, and/or at the reference point at 7 degrees from the foveal center, in response to the WHI diet intervention, then we might have not detected the increase. Also, at this point in time, it is unclear what densities are clinically relevant or functionally optimal. Recent research suggests that improvements in the ability to see under glare situations and to recover from photostress in young adults are associated with mean increases of macular pigment density of 0.16 OD units (from 0.41 to 0.57 OD units) (30). In summary, this study observed that general dietary recommendations to consume a low-fat, high-fruit and -vegetable diet over a mean of 8.5 y did not significantly increase levels of retinal carotenoids in postmenopausal women. Dietary patterns that have higher levels of lutein and zeaxanthin and/or other dietary factors that facilitate the uptake of lutein and zeaxanthin into the body and retina may be required to enhance retinal carotenoids. A better understanding of the conditions for enhancing retinal carotenoids and the optimal levels of carotenoids in the macula 1698

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and throughout the eye are needed to adequately guide dietary recommendations. Acknowledgment We thank Michael Bodnia for his help in collecting data for this manuscript.

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