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To examine whether the dietary intake of antioxidants is related to mortality from coronary heart disease in a prospective cohort study of post-menopausal women.

• Valid Iowa driver's license in 1985
• Returned 16-page questionnaire in January, 1986.

 

• Not reached menopause
• Food-frequency questionnaire had 30 or more items left blank
• Reported energy intake was implausibly high or low (less than 600kcal or 5,000kcal or more per day)
• Reported at baseline that a physician had told them they had angina or heart disease or had a heart attack.

Recruitment

The study participants were recruited from a random sample of 99,826 women, 55 to 69 years of age, who had valid Iowa driver's licenses in 1985. These women were sent a 16-page questionnaire in January, 1986; 41,836 women returned it, and they formed the cohort under study.

Design 

The baseline questionnaire included questions concerning factors pertinent to the risk of coronary heart disease. A 127-item food-frequency questionnaire similar to that used in the 1984 survey of the Nurses' Health Study was also included. The list of foods was augmented by questions asking the respondent to specify the type of fat used, the brand names of the multivitamin preparations and breakfast cereals, all of which were potential sources of vitamins. There were also questions about the current use and dosage of supplements of specific vitamins (such as Vitamins A and E). 

Women were followed annually by consulting the State Health Registry of Iowa, which collects information on deaths in Iowa. Deaths were also reported in response to follow-up questionnaires mailed in 1988, 1990 and 1992, and were identified by linking women who did not respond with the National Death Index.

Statistical Analysis

The length of follow-up for each woman was calculated as the number of days from the completion of the baseline questionnaire to the date of death of before or on December 31, 1992, whichever came first.

Because vitamins can be ingested from both foods and supplements, exposure to each vitamin was studied in three ways. First, the total intake of the vitamin from both food and supplements was determined. Second, intake of the vitamin from food alone was determined; this analysis was limited to women who had no supplemental intake of that vitamin. Finally, analyses of supplemental intake were conducted. Because in early 1986 supplemental vitamin A was derived almost exclusively from retinol, the analyses of supplemental vitamin A intake were not partitioned according to whether the vitamin was derived from retinol or carotene.  

The association of vitamins A, E and C with death from coronary heart disease was examined primarily by proportional-hazards regression analysis. Values for vitamin intake were categorized in quintiles or other categories as appropriate, and the mortality rate from coronary heart disease in each category was compared with that in the lowest intake category. The initial analyses examined associations adjusted for age. The analyses were also adjusted for other factors that were significant predictors of death from coronary heart disease or that substantially altered the risk estimates associated with vitamin intake. These included total energy intake, history of hypertension, history of diabetes mellitus, body-mass index (calculated as the weight in kilograms divided by the square of the height in meters), waist-to-hip ratio, history of cigarette smoking, level of physical activity, estrogen-replacement therapy and alcohol intake.

The relative risk associated with a given category of vitamin intake was estimated by calculating the exponent of the proportional-hazards regression coefficient for that level of intake. P values for trend were determined, with each level of exposure weighted according to its median value. 

 

Timing of Measurements

• 1985: Questionnaires were mailed
• January, 1986: Baseline questionnaires were completed
• Women were followed annually by consulting the State Health Registry of Iowa, which collects information on deaths in Iowa
• 1988, 1990 and 1992: Follow-up questionnaires were mailed
• Follow-up ended on December 31, 1992 or at date of death.

Dependent Variables

Mortality from coronary heart disease (State Health Registry of Iowa, the National Death Index: Considered to have died from coronary heart disease if the cause of death was assigned to codes 410 through 414 or 429.2 of the International Classification of Diseases, 9th revision). 

Independent Variables

• Vitamin A intake from food only
• Vitamin A intake from food and supplements
• Vitamin A intake from supplements only
• Vitamin E intake from food only
• Vitamin E intake from food and supplements
• Vitamin E intake from supplements only
• Vitamin C intake from food
• Vitamin C intake from food and supplements
• Vitamin C intake from supplements only.

Values for vitamin intake were categorized in quintiles or other categories as appropriate. Because in early 1986 supplemental vitamin A was derived almost exclusively from retinol, the analyses of supplemental vitamin A intake were not partitioned according to whether the vitamin was derived from retinol or carotene.

Control Variables

The initial analyses were adjusted for age and other factors that were significant predictors of death from coronary heart disease or that substantially altered the risk estimates associated with vitamin intake. These included total energy intake, history of hypertension, history of diabetes mellitus, body-mass index, waist-to-hip ratio, history of cigarette smoking, level of physical activity, estrogen replacement therapy and alcohol intake.

 

Initial N

99,826 women, 55 to 69 years of age, who had valid Iowa driver's license in 1985.

Attrition (Final N)

34,486 [41,836 women returned the baseline questionnaire. Of those, 569 women had not reached menopause; 2,751 women returned a food frequency questionnaire that had 30 or more items left blank; 317 women had a reported energy intake  that was implausibly high or low (less than 600kcal or 5,000kcal or more per day); 3,713 women reported having angina, heart disease, or had had a heart attack.]

Age

55 to 69 years of age in 1985.

Anthropometrics: 

Factor - Body Mass Index	Quintile of Vitamin Intake
	1 (Lowest)	2	3	4	5 (Highest)
Vitamin E
From food and supplements(N=34,486)	27.2	27.1	27.2	26.6	26.6
From food only (N=21,809)	27.2	26.2	27.0	27.2	27.2
Vitamin C
From food and supplements (N=34,486)	26.9	27.1	27.1	26.9	26.6
From food only (N=18,905)	26.9	27.1	27.2	27.4	27.5

Location

Study was conducted by researchers at the University of Minnesota School of Public Health; study participants were residents of Iowa and had Iowa driver's license.

 

 

Women who reported the following risk factors on the base-line questionnaire had higher age-adjusted risks of death from CHD than women without the risk factors: 

• Hypertension (RR, 2.21; 95% CI, 1.70 to 2.86)
• Diabetes mellitus (RR, 4.72; 95% CI, 3.47 to 6.42)
• Current smoking (RR, 3.16; 95% CI, 2.37 to 4.21

Women were at decreased risk if they reported a high degree of physical activity (RR as compared with women with a low degree of physical activity, 0.49; 95% CI, 0.35 to 0.71) or the use of estrogen-replacement therapy (RR as compared with non-users, 0.72; 95% CI, 0.55 to 0.95). Higher body-mass indexes and higher waist-to-hip ratios were also associated with higher age-adjusted risks of death from CHD (P<0.001 for both).

The quintiles with greater overall intake of vitamins were associated with lower mean waist-to-hip ratios, smaller proportions of current smokers and larger proportions of women who were physically active or used estrogen-replacement therapy. Similar patters were seen with regard to the intake of vitamins E and A from food sources alone. With regard to vitamin C derived from food, higher intake was associated with smaller proportions of current smokers and greater physical activity but also with larger proportions of women with hypertension and diabetes mellitus. 

RRs and 95% CIs of Death from CHD According to Category of Antioxidant Intake from Food and Supplements (N=34,486) 

With regard to the intake of Vitamin A, retinol and carotenoids, there were suggestions of inverse associations. In the case of Vitamin A, the association showed an inconsistent dose response, with an elevated risk in the second quintile of intake (RR as compared with the lowest quintile, 1.46) and a decreased risk in the fourth quintile (RR, 0.68). Overall Vitamin E intake also appeared to be inversely associated with the risk of death from CHD; there were significantly decreased risks in the third (RR, 0.53) and fourth (RR, 0.61) quintiles of intake, but the overall trend was not statistically significant. Overall intake of vitamin C was not associated with the risk of death from CHD.

The suggested inverse associations with the intake of vitamins A and E, retinol, and carotenoid were weakened after multivariate adjustment. There was a suggestion of a positive association between overall vitamin C intake and the risk of death from CHD (RR in highest vs. lowest quintile, 1.49; 95% CI, 0.96 to 2.30).

RRs and 95% CIs of Death From CHD According to Category of Antioxidant Intake from Food Alone

Vitamin E intake was inversely associated with the risk of death from CHD among women who did not take vitamin E supplements (RR from lowest to highest quintile of intake, 1.0, 0.68, 0.71, 0.42 and 0.42; P=0.008). In contrast, no association was observed for vitamin A, retinol, carotenoids or vitamin C derived from food. After adjustment for potential confounders, the inverse association with vitamin E derived from food remained (RRs from lowest to highest quintile of intake, 1.0, 0.70, 0.76, 0.32 and 0.38; P=0.004).

RRs and 95% CIs of Death from CHD According to Category of Antioxidant Intake from Supplements Alone (N=34,486)

A relatively low intake (1.0 to 5,000 IU per day) of supplemental vitamin A was associated with a decreased risk of death from CHD (age-adjusted RR, 0.67; 95% CI, 0.47 to 0.95), but higher intake was not. Nor were the data on vitamin E and C supplements consistent with an inverse association. Multivariate analyses also suggested no association of supplemental vitamin intake with the risk of death from CHD.

Results of Analyses Adjusted for other Dietary Factors Associated with CHD

The intake of vitamin E derived from food, but not from supplements, was inversely associated with mortality from CHD, suggesting that vitamin E consumed in food may be a marker for other dietary factors associated with the risk of CHD. We conducted further analyses with adjustment for various factors, including the intake of carotenoids, folic acid, dietary fiber, lineleic acid, linolenic acid, total polyunsaturated fatty acids, meat and other foods and food groups. Adjusting for these factors did not substantially alter the inverse association observed with vitamin E. For example, after the adjustment for linolenucum acid intake, the RRs of death from CHD associated with levels of vitamin E derived from food, from the lowest to the highest quintile of intake, were 1.0, 0.71, 0.79, 0.35 and 0.44 (P=0.019). This was the largest attenuation of the association observed after adjustment for any of the factors examined. 

Multivariate Analysis of the Association of Risk of Death from CHD with the Intake of Specific Foods that are Dietary Sources of Vitamin E

Intake of the following was inversely associated with the risk of death from CHD: Margarine (P=0.048), nuts and seeds (P=0.016) and mayonnaise or creamy salad dressings (P=0.069). Additional adjustment for vitamin E weakened the associations, suggesting that they could be attributed in part to the intake of vitamin E.

The weak positive association of vitamin C with CHD was investigated further by excluding deaths during the first two years of follow-up, since women who were ill early in the study may have taken vitamin C. However, this exclusion did not substantially alter the association (multivariate adjusted RRs from lowest to highest quintile of intake, 1.0, 1.20, 0.95, 1.09 and 1.69; P=0.017). The findings for vitamins A and E were also unaffected by the exclusion of early deaths.

 

Given these caveats, the findings presented here do not constitute definitive evidence of an inverse association between vitamin E intake and mortality from coronary heart disease. Clarification of the effects of supplemental vitamin E in an older population appears warranted, give our findings and those of the Finnish trial. More definitive evidence of an effect of supplemental vitamin E must await the results of clinical trials such as the Women's Health Study, which is testing this association in younger women. However, that study was not designed to test the association of either vitamin E intake from food or dietary changes with the risk of coronary heart disease. Our findings suggest that modifying dietary habits to increase vitamin E intake may also be worthwhile in preventing coronary heart disease. This study of older women provides information that is important in planning intervention trials in the elderly. The observations with regard to vitamins A and C are similarly not definitive, but they suggest that increased intake of these vitamins is not likely to lower the risk of death from coronary heart disease. 

Government:

NIH

Study did take into account the effect of hormone replacement therapy on CHD. Although a significant inverse relationship was found between vitamin E and CHD, the investigators suggest more research is needed.