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Nutritional Epidemiology

Some Dietary and Adipose Tissue Carotenoids Are Associated with the Risk of Nonfatal Acute Myocardial Infarction in Costa Rica^1,2

Edmond Kato Kabagambe^*, Jeremy Furtado^*, Ana Baylin^* and Hannia Campos^*,,3

^* Department of Nutrition, Harvard School of Public Health, Boston, MA 02115 and Centro Centroamericano de Población, Universidad de Costa Rica, San Pedro de Montes de Oca, Costa Rica

³To whom correspondence should be addressed. E-mail: hcampos{at}hsph.harvard.edu.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Antioxidants, particularly carotenoids and tocopherols, may protect against cardiovascular disease. The objective of this study was to determine whether dietary and adipose tissue carotenoids and tocopherols are associated with the risk of myocardial infarction (MI). Cases (n = 1456) of a first acute MI were identified and matched by age, sex, and residence to randomly selected population controls (n = 1456) living in Costa Rica. Carotenoids and tocopherols were measured in adipose tissue using HPLC. Dietary intake was assessed using a validated FFQ. Anthropometrical and lifestyle data were collected using an interviewer-administered questionnaire. Subjects were distributed into quintiles of intake or adipose tissue concentration of carotenoids or tocopherols. The lowest quintile was used as the referent in conditional logistic regression analyses. Adipose tissue ß-carotene showed a significant inverse relation with MI risk; the odds ratio (OR) comparing the highest to the lowest quintile was 0.70 (95% CI: 0.51–0.96, P for trend = 0.02). Intake of fruits and vegetables that are rich in ß-carotene was also inversely associated with the risk of MI (OR = 0.74; CI: 0.54–1.01, P for trend = 0.09). In contrast, lutein + zeaxanthin in adipose tissue (OR = 1.46; CI: 1.05–2.05, P for trend = 0.02) and diet (OR = 1.18; CI: 0.88–1.57, P for trend = 0.02) was positively associated with MI risk. MI risk was not associated with any of the other carotenoids or tocopherols in the diet or adipose tissue. Thus, the inverse association between ß-carotene and MI risk suggests that ß-carotene protects against MI or it is a marker of some protective factor in foods containing ß-carotene. The mechanism underlying the positive association between lutein + zeaxanthin and the risk of MI warrants investigation.

KEY WORDS: • biomarkers • antioxidants • carotenoids • tocopherols • myocardial infarction • cardiovascular disease

Carotenoids and tocopherols, as well as other antioxidants, are inversely associated with markers of inflammation such as the intercellular adhesion molecule-1 and C-reactive protein (1–3); they may protect against oxidation of LDL cholesterol and therefore possibly reduce the risk of cardiovascular disease (CVD)⁴ (4–6). Of all the carotenoids and tocopherols, ß-carotene (7) and lycopene (8,9) have shown the most promise for potential protection against CVD, with ß-carotene showing a stronger inverse association among smokers than nonsmokers (7,10). However, results from epidemiologic studies using supplements, diet, or plasma as a biomarker of carotenoids and tocopherols have not been consistent (11,12) with some showing inverse associations for -carotene (13), ß-carotene (7,13), and lycopene (9,14), whereas no association or increased risk was found in others (10,15–17). Within the same study, some carotenoids showed inverse associations with MI risk, whereas others did not show any relation (7,10,13). It is not clear whether the inconsistency is due to measurement error in the diet or the transient nature of plasma concentrations or even the clinical outcome assessed [e.g., carotid intima media thickness, nonfatal acute myocardial infarction (MI) or fatal MI]. Carotenoids and tocopherols are lipid soluble and adipose tissue serves as their major depot. Data utilizing measurements in adipose tissue in which carotenoid and tocopherol concentrations may be relatively stable (18) could be beneficial. Furthermore, cis- and trans-isomers of carotenoids vary in their bioavailability (19) and antioxidant properties (20–23) but data on the relation between different isomers and MI risk are not available. We investigated whether dietary and adipose tissue carotenoids and tocopherols are associated with a reduced risk of incident MI in adult Costa Ricans, a population with a low intake of dietary supplements and a high prevalence and mortality due to CVD. For instance, CVD deaths were 1.3 per 1000 and 6 disability adjusted life years per 1000 were lost due to heart disease in Costa Rica (24,25). The carotenoids and tocopherols analyzed in both diet and adipose tissue were -carotene, ß-carotene, ß-cryptoxanthin, lycopene, lutein + zeaxanthin, -tocopherol, -tocopherol, -tocopherol, and the cis- and trans-isomers of ß-carotene and lycopene. The use of 2 methods in the same study to assess the role of carotenoids and tocopherols in MI may provide insight into the reason for the discrepancies among previous studies.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Study population and design. All subjects were Hispanic Americans of Mestizo background who lived in the central valley of Costa Rica between 1995 and 2004. The details of the study design were published elsewhere (26–28). Briefly, eligible case subjects were men and women who were diagnosed as survivors of a first acute MI by 2 independent cardiologists at any of the 6 recruiting hospitals in the catchment area. To identify 100% of cases, fieldworkers carried out daily visits to the 6 hospitals. All cases met the WHO criteria for MI, which require typical symptoms plus either elevations in cardiac enzyme levels or diagnostic changes in the electrocardiogram (29). Cases were ineligible if 1) they died during hospitalization, 2) they were 75 y old on the day of their first MI, or 3) they were physically or mentally unable to answer the questionnaire. Enrollment was carried out while cases were in the hospital’s step-down-unit. Cases were matched by age (±5 y), sex, and area of residence to population controls who were randomly identified with the aid of data from the National Census and Statistics Bureau of Costa Rica. Because of the comprehensive social services provided in Costa Rica, all persons living in the catchment area had access to medical care without regard to income. Therefore, control subjects came from the source population that gave rise to the cases and were not likely to have been having CVD that was not diagnosed because of poor access to medical care. Control subjects were ineligible if they had ever had an MI or if they were physically or mentally unable to answer the questionnaires. All cases and controls were visited in their homes for the collection of dietary and health information, anthropometric measurements, and biological specimens. Participation was 98% for cases and 88% for controls. All subjects gave informed consent on documents approved by the Human Subjects Committee of the Harvard School of Public Health and the University of Costa Rica.

    Data collection. Trained personnel visited all study participants at their homes. Sociodemographic characteristics, smoking, socioeconomic status, physical activity, and medical history data were collected during an interview using a questionnaire with close-ended questions. Self-reported diabetes and hypertension were validated using the recommended definitions by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (30), and the Third Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNCIII) (31). We computed sensitivities, specificities, and positive and negative predictive values from the questionnaire data and measurements of blood pressure and blood sugar. These parameters showed that self-reported assessments of diabetes and hypertension are reliable in this population (26).

    Dietary assessment. We collected dietary data using an FFQ that had been developed and validated specifically to assess nutrient intake among the Costa Rican population (27,32–34). Intakes were computed by multiplying the consumption frequency of each food by the nutrient content of the specific portion, using food composition values from the USDA database (35,36), food composition data for Costa Rican foods (37), data from manufacturers, and published reports. Carotenoid and tocopherols (including -carotene, ß-carotene, ß-cryptoxanthin, lycopene, lutein + zeaxanthin, -tocopherol, -tocopherol, and -tocopherol) were measured (37) in all commonly consumed Costa Rican foods using the same procedure used to measure them in adipose tissue (32,33). These values were incorporated into the main database used to assess intake.

    Sample collection and biochemical analyses. All biological specimens were collected at the subjects’ homes on the morning after an overnight fast. A subcutaneous adipose tissue biopsy was collected from the upper buttock with a 16-gauge needle and disposable syringe as described (38). In the field, samples were kept in a cooler with ice packs at 4°C and then transported to the fieldwork station within 4 h for storage in liquid nitrogen. Within 6 mo of collection, they were transported over dry ice to the Harvard School of Public Health for analysis. Concentrations of carotenoids and tocopherols in adipose tissue were determined with a dual wavelength Hitachi HPLC system and data station as described previously (32,33). Each subject also provided a blood sample for assessment of plasma lipids. Blood samples were collected into tubes containing 0.1% EDTA. Blood was then centrifuged at 1430 x g for 20 min at 4°C to obtain plasma. Plasma samples were stored at –80°C. Plasma triacylglycerol, total cholesterol, and HDL cholesterol concentrations were measured with enzymatic reagents (Boehringer-Mannheim) and a Roche Cobas Mira Plus autoanalyzer. We used the Friedewald equation to calculate LDL cholesterol concentrations (39). Cholesterol measurements were standardized to guidelines of the CDC and the National Heart, Lung, and Blood Institute (40,41).

    Statistical analysis. Data were analyzed using the SAS Software (SAS Institute). Of the 3072 subjects who had adipose tissue measurements, 155 had missing values for major confounders and 5 had missing values on carotenoids and were excluded, leaving 1456 cases and 1456 matched controls for the final analysis. Individual nutrients were correlated with total energy intake and were adjusted for total energy intake as described (27,42). We used the paired t test or Wilcoxon signed rank test for continuous variables, and the McNemar’s test for categorical variables to test differences in means or distributions of lifestyle and dietary variables in the cases and the population-based matched controls. We assessed variables for confounding by distributing them across quintiles of carotenoids or tocopherols in the diet or adipose tissue and by investigating the change in point estimates when a given variable was entered into the conditional logistic regression model. We conducted subgroup analyses to determine whether the associations of carotenoids and tocopherols among smokers differed from those among nonsmokers. Because subgroup analyses cause case-control pairs to split, we used unconditional logistic regression with matching variables and potential confounders in the model. We used the Hosmer-Lemeshow statistic to determine the goodness of fit of the unconditional logistic regression models.

Because cis- and trans-isomers of carotenoids vary in their bioavailability (19) and have functional differences with regard to LDL oxidation and other properties (20–23), we sought to determine whether there were differences in the associations between isomers of carotenoids and MI risk. Data on cis- and trans-isomers of ß-carotene and lycopene and on -tocopherol in adipose tissue were available for 2070 subjects. We thus used unconditional logistic regression as described above to determine whether there were associations among -tocopherol, cis-isomers of ß-carotene and lycopene, and MI risk, and whether these associations would differ from those with trans-isomers. Because we had complete data on cis- and trans-isomers of ß-carotene and lycopene in the diet for all the 1456 case-control pairs, we used conditional logistic regression and adjusted for potential confounders as described above.

To compute the P for trend, we determined the quintile median of each carotenoid or tocopherol and assigned the median to each subject in the respective quintile. The resulting continuous variable was entered into the model and the P for trend was obtained.

We also investigated whether fruits and vegetables rich in a given carotenoid (regardless of frequency of intake) were associated with a reduced risk of MI. We identified 5 fruits and/or vegetables with the highest content of a given carotenoid (37) and calculated the sum of frequencies of their intake. The resulting sum for -carotene (raw carrots, cooked carrots, cooked green plantains, cooked ripe plantain, and cashew-pulp), ß-carotene (raw carrots, cooked carrots, cantaloupe, cooked cilantro, and cooked red sweet pepper), ß-cryptoxanthin (raw cilantro, cooked cilantro, cooked red sweet pepper, tangerine, and canned peaches), lycopene (tomato ketchup, watermelon, raw tomato, papaya, and raw carrot), and lutein + zeaxanthin (cooked cilantro, cooked spinach, cooked mustard greens, cooked red sweet pepper, and raw cilantro) was distributed into quintiles and the highest was compared with the lowest quintile of intake.

We also determined whether fruits and vegetables that are major sources of ß-carotene in the diet were associated with a reduced risk of MI. These foods include carrots, cantaloupes, tangerines, mangoes, watermelon, yellow squash, plantain, and peach-palm.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    General characteristics. Characteristics of nonfatal MI cases and population-based matched controls are shown in Table 1. More cases than controls were current smokers and had a history of diabetes and hypertension (P < 0.05). Compared with controls, cases also had greater waist-to-hip ratios (abdominal obesity); lower incomes; higher intakes of total energy, saturated fat, and lutein + zeaxanthin; and lower intakes of polyunsaturated fat, -tocopherol, and -tocopherol. A lower proportion of cases consumed alcohol at the time of the study compared with controls. Adipose tissue concentrations of most carotenoids were significantly lower in cases than controls.

When adjusted for age, gender, smoking status, and BMI, adipose tissue and diet -carotene (r = 0.13, P < 0.0001), ß-carotene (r = 0.16, P < 0.0001), ß-cryptoxanthin (r = 0.20, P < 0.0001), lycopene (r = 0.20, P < 0.0001) and -tocopherol (r = 0.19, P < 0.0001) showed low correlations. Correlations between the diet and tissue lutein + zeaxanthin (r = –0.06, P = 0.02) and -tocopherol (r = 0.02, P = 0.54) were poor.

    Carotenoids and tocopherols in adipose tissue and the risk of MI. The relation between carotenoids and tocopherols in adipose tissue and nonfatal acute MI risk in adult Costa Ricans is shown in Table 2. Although there were significant inverse associations between -carotene, ß-carotene, ß-cryptoxanthin, and lycopene in adipose tissue and MI risk in basic analyses, only that with ß-carotene persisted after adjusting for smoking and other established cardiovascular risk factors. The adjusted odds ratio (OR; 95% CI) for the fifth compared with the 1st (lowest) quintile of ß-carotene in adipose tissue was 0.70 (95% CI: 0.51–0.96, P for trend = 0.02). In a similar analysis, lutein + zeaxanthin in adipose tissue was associated with an increased risk of nonfatal acute MI (OR = 1.46; 95% CI: 1.05–2.05, P for trend = 0.02). Stratification by smoking status did not alter these associations appreciably.

In analyses adjusted for confounders, the relation between cis-isomers of ß-carotene and lycopene in adipose tissue and MI risk were similar to those with trans-isomers. The adjusted ORs (95% CI) comparing the highest quintile to the lowest quintile of ß-carotene isomers were: 1.00, 0.77 (0.56–1.05), 0.94 (0.68–1.28), 0.68 (0.50–0.94), and 0.67 (0.48–0.94) for the cis-isomer and 1.00, 1.01 (0.74–1.37), 1.01 (0.74–1.38), 0.94 (0.68–1.29), and 0.68 (0.48–0.96) for the trans-isomer. The ORs (95% CI) comparing the highest quintile to the lowest quintile of lycopene isomers were: 1.00, 0.92 (0.67–1.26), 0.91 (0.67–1.25), 0.95 (0.69–1.30), and 0.88 (0.63–1.21) for the cis-isomer and 1.00, 1.08 (0.79–1.47), 1.05 (0.76–1.44), 1.12 (0.81–1.53), and 0.89 (0.64–1.23) for the trans-isomer. The ORs estimated for the cis- and trans-isomers of both ß-carotene and lycopene are similar to those estimated for total ß-carotene and total lycopene, respectively (Table 2).

    Dietary carotenoids and tocopherols and the risk of MI. Basic analyses for dietary intakes of -carotene, ß-carotene, ß-cryptoxanthin, lycopene, lutein + zeaxanthin, -tocopherol, and -tocopherol showed a tendency for these to be protective against MI (Table 3). However, none of these associations remained significant after adjusting for smoking, diet, and other major cardiovascular risk factors (multivariate models 2 and 3). Although the association between dietary lutein + zeaxanthin and MI risk was not significant, there was a significant trend for increased risk (P for trend = 0.02). Both dietary and adipose tissue lutein + zeaxanthin analyses showed a tendency toward increased risk for MI only in the 5th quintile, suggesting that the risk might increase only after a threshold intake or tissue concentration.

    Dietary fruits and vegetables and the risk of MI. Consumption of fruits and vegetables that are major sources of ß-carotene (carrots, cantaloupes, tangerines, mangoes, watermelon, yellow squash, plantain, and peach-palm) in Costa Rica was associated with a decreased risk of MI (OR = 0.74; 95% CI: 0.54–1.01, P for trend = 0.09). No other fruits and vegetables considered to be major sources of other carotenoids were associated with the risk of MI (data not shown). We performed a logistic regression with sources of lutein + zeaxanthin and established cardiovascular risk factors to identify factors that could explain the observed positive association between lutein + zeaxanthin and MI. Surprisingly, cooked spinach (OR = 1.39; 95% CI: 0.97–1.99) and yellow squash (OR = 1.32; 95% CI: 0.98–1.77) were associated with an increased risk of MI.

We further examined whether there was a relation between plasma lipids and adipose tissue carotenoids among control subjects. It was surprising to find a strong inverse association between plasma triacylglycerol and adipose tissue ß-carotene, but a strong positive association of triacylglycerol with lutein + zeaxanthin. For instance, the adjusted mean plasma triacylglycerol concentrations were 2.21, 2.22, 1.89, 1.62, and 1.47 mmol/L for the 1st, 2nd, 3rd, 4th, and 5th quintile of adipose tissue ß-carotene, respectively. Corresponding mean concentrations across quintiles of lutein + zeaxanthin were 1.77, 1.73, 1.83, 1.89, and 2.19 mmol/L, respectively. Plasma HDL cholesterol concentration increased with increased adipose tissue ß-carotene (1.19, 1.23, 1.28, 1.36, and 1.37 mmol/L for the 1st through 5th quintile), whereas it decreased with increased adipose tissue lutein + zeaxanthin (1.34, 1.36, 1.30, 1.24, and 1.18 mmol/L for the 1st through 5th quintile, respectively). These means were adjusted for smoking, area of residence, age, gender, history of diabetes, history of hypertension, abdominal obesity, physical activity, and intake of alcohol, saturated fat, polyunsaturated fat, trans fat, total energy, fiber, and coffee.

In all analyses, adjusting for other potential confounders such as vitamin E, vitamin C, and calcium or -linolenic acid instead of total polyunsaturated fat did not change the results appreciably.

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
In this study we found that ß-carotene in adipose tissue but not that in the diet is associated with a decreased risk of nonfatal acute MI and that both cis- and trans-isomers of adipose tissue ß-carotene are inversely associated with the risk of MI. Major fruit and vegetable sources of ß-carotene were also inversely associated with the risk of MI. Lutein + zeaxanthin was positively associated with risk of MI, whereas -carotene, ß-cryptoxanthin, lycopene, -tocopherol, -tocopherol, and -tocopherol in diet or adipose tissue were not associated with the risk of nonfatal acute MI in this study, although high concentrations of tocopherols in adipose tissue tended to increase the risk of MI.

These results are from a large study with 1456 newly identified cases of MI and 1456 randomly selected population-based matched controls with exposure measured using 2 methods, namely, a validated FFQ (27) and adipose tissue (34), which is a relatively stable biomarker of intake (18). Thus, the results are less susceptible to recall bias or changes in diet that could be associated with a diagnosis of MI. Also, carotenoids and tocopherols in the diet were measured using food composition data for commonly consumed fruits and vegetables in Costa Rica (37), a factor that would enhance the quality of the intake data.

Our finding of an inverse association between adipose tissue ß-carotene and risk of MI are consistent with those of Kardinaal in adipose tissue (7) and those of Osganiaan et al. in diet (13) but differ from those of Hak et al. (10) who reported an inverse but nonsignificant association for ß-carotene in plasma. The finding of a null association between dietary ß-carotene and the risk of MI in our study compared with that of Osganian et al. (13) may be due to the higher level of ß-carotene intake in the Costa Rican population compared with the female nurses in the United States. For instance, the median intakes in the lowest and highest quintiles in our study were 2425 and 7910 µg/d compared with 1720 and 7639 µg/d in the nurses’ study, respectively. The high intake of ß-carotene in the reference group in our study could partly explain this lack of association. The other possible explanation is potential measurement error in the assessment of ß-carotene intake compared with adipose tissue measurements. Both cis- and trans-isomers of ß-carotene in adipose tissue were inversely associated with the risk of MI. A comparison of cis- and trans-isomers of ß-carotene with regard to the risk of MI has not been reported previously and will have to be investigated in other studies. Our findings on the inverse association between consumption of fruits and vegetables that are major sources of ß-carotene and the risk of MI are consistent with previous findings and support the observed association between ß-carotene and MI risk (43,44). Because of null results from clinical trials of ß-carotene and our finding of a positive association between ß-carotene and HDL cholesterol, it is not clear whether the observed inverse association between ß-carotene in adipose tissue and the risk of MI is causal or whether ß-carotene is simply a marker for a protective factor that may also increase HDL cholesterol and lower triacylglycerol. In rats, foods that are rich in ß-carotene, e.g., carrots, lower total cholesterol and triacylglycerol in plasma and the liver (45), a relation similar to that of ß-carotene and lipids in the current study. Thus, the inverse association between ß-carotene and MI risk suggests that ß-carotene protects against MI or it is a marker of some protective factor in foods containing ß-carotene.

Data from some observational, animal, and in vitro studies suggest that lutein + zeaxanthin may protect against early atherosclerosis (46,47). The finding of a positive association between lutein + zeaxanthin and MI risk in this study is thus surprising because the major food sources of lutein + zeaxanthin in Costa Rica (celery, eggs, broccoli, salsa, peppers, spinach, oranges, yellow squash, avocado, and cilantro) are considered desirable components of the diet. Surprisingly, cooked spinach and yellow squash were associated with increased risk of MI. Because lutein and zeaxanthin have been tested and classified as generally safe (48,49), the explanation for this observation is complex. One possible explanation is that these foods could be associated with undesirable chemical substances such as agricultural pesticides. Hazardous pesticides such as acephate, dicloran, chlorpyriphos, dichlorodiphenyltrichloroethane, and dieldrin have been detected in spinach, yellow squash, sweet potatoes, and other vegetables in the United States (50) and Costa Rica (51) but why this is not the case with other carotenoids is difficult to explain. However, it is notable that although there is an overlap in the sources of lutein + zeaxanthin and ß-carotene or other carotenoids, spinach and yellow squash, the major sources of lutein + zeaxanthin, are not the major sources of ß-carotene or other carotenoids in the Costa Rican population. This could explain in part why lutein + zeaxanthin are associated with increased risk but not ß-carotene. The residual levels and potential effects of these pesticides on MI risk warrant further studies. Another possible explanation could be that high intake of lutein + zeaxanthin and the adipose tissue concentrations are markers of low HDL cholesterol and high triacylglycerol, which are risk factors for MI. Unfortunately, we could not adjust the current analyses for plasma lipids because blood collection in cases occurred after MI. Our study is not the first to report a positive association between lutein + zeaxanthin and MI. A similar observation was reported (10) in analyses using plasma as a biomarker but not with diet (13). It is apparent that a high intake is necessary for the risk of MI to be elevated. This is because increased risk was observed only in the highest quintile in this study and was not observed in the study by Osganian (13) in which the intake in the highest quintile corresponded to that in our 4th quintile.

Our results of null associations with ß-cryptoxanthin, lycopene, -tocopherol, and -tocopherol are similar to those of others (7,10,13) but differ from those of Rissanen et al. (9) who reported an inverse association between serum lycopene and carotid intima-media thickness, a marker of atherosclerosis and future risk of CVD. The lack of association with lycopene in this study could be due to the low intake of lycopene in the Costa Rican population compared with others (13). Although no significant trend was detected for the relation between tocopherols and risk of MI, the tendency toward increased risk for MI among subjects with high adipose tissue concentrations of tocopherols is of interest, especially given the recent reports of increased risk of MI among subjects administered long-term vitamin E supplements in clinical trials (52). Most of the tocopherols in Costa Rica come from vegetable oils, particularly soybean oil, which is also a major source of trans fat. However, trans fat is not likely to be the reason for the tendency toward increased risk because intake of trans fat was poorly correlated with adipose tissue concentrations of tocopherols (r = 0.07, P = 0.01 for -tocopherol and r = 0.22, P < 0.0001 for -tocopherol). Furthermore, we adjusted all analyses for the intake of trans fatty acids.

The inverse associations between antioxidants and intermediate cardiovascular end points (e.g., carotid intima-media thickness) and markers of inflammation (e.g., soluble E-selectin, intercellular adhesion molecule-1, and C-reactive protein) (1–3,9) may indicate that if carotenoids and tocopherols are protective, their effect is small and probably more important at the beginning of the disease process. Although there are known differences in the bioavailability and biochemical properties of cis- and trans-isomers of carotenoids (20–22), we did not detect differences in the relation between isomers of ß-carotene or lycopene and MI risk in diet or adipose tissue. The mechanism underlying the positive association between lutein + zeaxanthin and MI warrants further investigation. Other carotenoids and tocopherols did not show associations with a risk of nonfatal acute MI, although higher adipose tissue concentrations of tocopherols tended to be associated with an increased risk of MI.

	ACKNOWLEDGMENTS

 
We are grateful to Ms. Xinia Siles of Proyecto Salud Coronaria, San José, Costa Rica for her help in data collection.

	FOOTNOTES

 
¹ Supported by grants HL071888 and HL60692 from the National Institutes of Health.

² Supplemental Table 1 is available as Online Supporting Material with the online posting of this paper at www.nutrition.org.

⁴ Abbreviations used: CVD, cardiovascular disease; MI, myocardial infarction; OR, odds ratio.

Manuscript received 22 February 2005. Initial review completed 19 March 2005. Revision accepted 18 April 2005.

	LITERATURE CITED

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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