Dietary Folate and the Risk of Nonfatal Myocardial... : Epidemiology (original) (raw)
An accumulating number of studies have shown that elevated plasma levels of homocysteine increase the risk of stroke, peripheral vascular disease and myocardial infarction (MI). 1–4 However, these results do not necessarily imply a causal relation between homocysteine and cardiovascular risk, as homocysteine levels might be just a marker for factors ultimately responsible for the atherothrombogenic process. 4–6 Thus, the potential clinical effectiveness of normalizing homocysteine levels cannot be inferred from the above-mentioned findings alone.
Folate is required for the remethylation of homocysteine to the essential amino acid methionine. 4 Although it has been consistently shown that plasma folate concentrations are inversely related to plasma homocysteine concentrations and that folic acid supplementation can decrease plasma homocysteine, it remains unclear whether folate intake can ameliorate the risk of cardiovascular disease. 2,7,8 Clinical trials designed to clarify this issue are not yet available, and only a few observational studies have suggested that folate supplementation might actually reduce the risk of coronary heart diseases. 9–13 Moreover, in these studies the main sources of this micronutrient were vitamin supplements providing folic acid, which possesses a higher bioavailability than folate from natural dietary sources.
We investigated the association between dietary folate intake and the risk of first nonfatal acute MI in a multicenter case-control study conducted in a Mediterranean population in which plant foods (and not supplements) are the main source of dietary folate.
Materials
Cases
The methods of this study have been reported elsewhere. 14,15 Briefly, cases were defined as women and men less than 80 years of age with a first MI (International Classification of Diseases code 410) admitted to one of the three tertiary hospitals of Pamplona, Spain, within the period October 1999 through June 2000 or October 2000 through February 2001. For inclusion in the study, patients had to fulfill the criteria for definite MI of the MONICA project (two or more electrocardiograms showing definitive changes, electrocardiograms showing probable changes plus abnormal cardiac enzymes, or typical symptoms plus abnormal enzymes). 16 We excluded patients with previous history of angina pectoris, a previous diagnosis of coronary heart disease, or other prior diagnosis of major cardiovascular disease. Institutional Review Board approval was obtained from the Navarre Medical School, and patients provided informed consent before participation. We identified 180 eligible cases; of these, 171 agreed to participate.
Controls
Eligible controls were patients admitted to surgery, trauma or urology wards of the same hospitals for treatment of conditions believed to be unrelated to diet. We applied the same exclusion criteria for controls as for cases. We matched one control to each case by age (within 5 years), sex, calendar time (hospitalized during the same month) and hospital. Eight controls refused to participate; each was replaced by another patient of similar characteristics for matching variables.
Assessment of Exposure
Physicians from the research team approached the patients, invited them to participate, conducted a standardized interview, and provided them with a self-administered questionnaire. We used the same procedures for cases and controls. Most patients were interviewed in the hospital wards; two cases and one control were interviewed at their homes after being discharged from the hospital. The physician who interviewed a case patient also interviewed the respective matched control. Because the physicians had to apply the cardiovascular exclusion criteria, they were not blinded to the participants’ disease status. However, physicians were unaware of the hypothesis currently under investigation. The self-administered questionnaire included a semiquantitative food-frequency questionnaire (118 food items), previously validated in Spain, 17 that was slightly expanded for this study (136 items plus vitamin supplements). For each food item, a commonly used portion size was specified, and participants were asked how often they had consumed that unit on average over the previous year. Emphasis was added to ensure that the answers were related to long-term dietary exposures and not to recent changes in diet. Nine options for frequency of consumption were possible. The type of fat used in frying was specifically assessed. A dietitian updated the nutrient databank using the latest available information included in the food composition tables for Spain. Folate intake was estimated for each individual and included folate from vitamin supplements.
Participants were asked to report their usual time spent practicing the following activities: walking, jogging, running, athletics, cycling, swimming, racquet sports, soccer, team sports other than soccer, dancing, aerobics, hiking, climbing, gardening, skiing, skating, fishing, martial arts and water sports. To quantify the volume and intensity of leisure-time physical activity, we computed an activity metabolic equivalent (MET) index by assigning a multiple of resting metabolic rate (MET score) to each activity. This index was multiplied by the weekly time spent in each activity to produce a value of overall weekly MET-hours. 18,19 Five cases did not personally answer the questionnaire, and we used the answers given by a relative.
The physician clarified any questions the patient might have had in completing the questionnaire and subsequently conducted a face-to-face interview about coronary risk factors (ie, smoking, diabetes, high blood pressure, high blood cholesterol and recent weight changes) and family history of cardiovascular disease. The physician took systolic and fifth-phase diastolic blood pressure readings and measured weight and height according to a standardized protocol, with the subject barefoot and dressed in light clothing. For each participant we calculated the body mass index as the weight (kg) per height squared (m2).
Data Analysis
We defined quartiles of folate intake according to the distribution among controls. Odds ratios and 95% confidence intervals (CIs) were estimated for MI using conditional logistic regression with 171 case-control matched pairs. We assumed that odds ratios from this case-control study provide a valid estimate of the relative risk (RR). 20 Folate intake was evaluated both with and without adjustment for total energy. Total energy-adjusted intakes were computed using the residuals method. 21 We also considered dietary intake of vitamin B6 because this vitamin is an essential cofactor in homocysteine metabolism.
We adjusted relative risks for the following well-established risk factors for MI: body mass index (kg/m2), smoking, physical activity, marital status, education, diabetes, high blood pressure, high blood cholesterol, alcohol use and family history of cardiovascular disease. Quadratic terms for some potential confounders were used to account for nonlinear relations. We considered age, alcohol consumption, smoking, hypertension and diabetes as potential modifiers of the folate-MI association, as suggested in previous studies. 11,12,22
Results
The following analyses included 171 cases with MI and 171 controls. Baseline characteristics of cases and control patients are shown in Table 1. As expected, smoking, hypertension, diabetes and high blood cholesterol were associated with a higher risk of MI.
Characteristics of Case and Control Participants
The average dietary intake of folate among controls was 428 μg per day. The main sources of folate in our population were green leafy vegetables (mainly chard and spinach), green beans, oranges, peppers and lettuce. These five foods explained 80.5% of the variability in folate intake in our sample. Among controls, the mean consumption of vegetables was 583 gm per day and the mean consumption of fruits was 387 gm per day. Very few participants (5.6%) were taking vitamin supplements.
Control participants with folate intake above the first quartile had a generally higher prevalence of high blood cholesterol, diabetes and hypertension, but were less likely to smoke (Table 2). They consumed diets with lower total energy; lower glycemic load; and higher levels of fiber, vitamins B6 and ascorbic acid.
Distribution of Potential Confounding Variables Across Quartiles (Q) of Energy-Adjusted Folic Acid Intake Among Control Subjects (N = 171)
An inverse association between dietary folate and MI was apparent (Table 3). Compared with the lowest quartile of folate intake, the age-, gender- and hospital-matched RR of MI for persons in the second to fourth quartile was 0.57 (CI = 0.35–0.94). Relative risks for each of the three upper quartiles were similar.
Relative Risk of a First Myocardial Infarction According to Energy-Adjusted Folic Acid Intake: Matched Analysis (Age-, Hospital- and Gender-Matched Pairs)
When we adjusted for classical risk factors for MI (smoking, high blood pressure, high blood cholesterol, diabetes, body mass index, physical activity, alcohol use, marital status, education and family history of cardiovascular disease), the RR for quartiles 2–4 compared with quartile 1 was 0.43 (0.22–0.81). Simultaneous adjustment for several other dietary risk factors resulted in a point estimate of similar magnitude for the RR but with a wider confidence interval (RR = 0.51; CI = 0.24–1.06). Of the various dietary risk factors considered independently, adjustment for ascorbic acid had the greatest effect. When we additionally adjusted for intake of long-chain omega-3 fatty acids, the RR was 0.51 (0.26–0.99). The strongest confounders were smoking and diabetes, but they were balanced;ie, adjustment for smoking attenuated the estimation, but adjustment for diabetes strengthened it. When we excluded the 5.6% of vitamin supplement users, the adjusted RR was 0.48 (0.23–1.00).
These findings were similar when we used folate intake without energy adjustment for the comparisons between the first and the other three quartiles, although the magnitude of the association was slightly attenuated (matched crude RR = 0.69 [0.42–1.13]; adjusted RR = 0.59 [0.30–1.18]).
In a further effort to disentangle the association with folate intake from that of other nutrients, we considered the relation of vitamins other than folate with MI. Vitamin E was not associated with a lower risk of MI (RR = 1.30 [0.64–2.67]) for the highest compared with the lowest quartile of energy-adjusted intake. The RRs for the highest compared with the lowest quartile were 0.71 (0.29–1.74) for dietary vitamin B6 and 0.45 (0.17–1.12) for ascorbic acid. In addition, we examined the risk of MI among participants in the upper quartiles (2 to 4) of both folate and ascorbic acid, as compared with participants in the lowest quartile of both nutrients, which produced an estimated RR of 0.40 (0.19–0.82). The corresponding RR for the upper quartiles (2 to 4) of both folate and vitamin B6, compared with the lowest quartiles of both nutrients, was 0.51 (0.23–1.13). These analyses were adjusted for dietary and nondietary confounders.
In subgroup analyses, the RRs associated with high folate intake were somewhat stronger among individuals 65 years or older, hypertensive patients, or patients with high blood cholesterol than among younger, normotensive individuals and those with normal blood cholesterol. Results were almost identical for diabetic and nondiabetic individuals. Protection afforded by folate was more apparent for nonsmokers or ex-smokers than for current smokers for the first compared with the second to fourth quartiles of dietary intake. However, our sample size was too small for us to properly evaluate these and other potential interactions (eg, folate and alcohol consumption).
Discussion
We found an association between higher dietary intakes of folate and lower risk of MI. Although our sample size limits the ability of our study to address the issue of dose-response patterns, results suggested a lack of dose response for folate intakes above approximately 341 μg per day. This finding is consistent with previous epidemiologic studies on folate intake and the risk of coronary heart disease conducted in the U.S. 9–11,13 and Finland. 12 Moreover, indirect evidence also tends to support a threshold for the upper part of the dose-response curve rather than a linear relation along the whole range of folate with respect to cardiovascular risk. Studies have shown that folate doses higher than approximately 500 μg per day are no more effective at reducing homocysteine levels than doses of 500 μg per day. 2,7,8,23
The information from this study complements that from previous studies because of the dietary peculiarities of our study population and because very few people took multivitamins (5.6%). The average dietary intake of folate in our population (428 μg per day) was higher than what has been reported elsewhere, 11–13 which can be attributed to the very high intake of fresh fruits and vegetables in the Mediterranean diet. In Spain fresh vegetables are especially abundant in the diet, and large amounts of fresh fruit constitute the typical dessert, consumed on a daily basis. It is important to evaluate a wider range of dietary folate, as well as folic acid from multivitamins, because dietary folate is less bioavailable, has a weaker effect on plasma folate/homocysteine levels, 24 and may have different cardiovascular effects. In this context, it is reassuring that the effect was still apparent in our data after excluding the 5.6% of participants who were taking vitamin supplements.
Homocysteine levels increase with age and are higher among patients with hypertension and among heavy smokers. 7,25 Because reductions in plasma homocysteine concentrations with folic acid supplementation are greater at higher baseline homocysteine concentrations, 7,23,25 we hypothesized that folate effect might be stronger among elderly or hypertensive patients or smokers. Results were consistent with a stronger folate effect among elderly or hypertensive individuals. We also found a stronger association among nonsmokers, as did Voutilainen et al. 12 However, our subgroup analyses are based on small samples.
Several lines of evidence support a causal connection among folate intake, homocysteine levels and cardiovascular disease. Folate intake reduces plasma homocysteine levels and increases folate levels. 2,7,8,23 Both lower homocysteine levels and higher plasma folate levels are associated with a lower risk of cardiovascular disease. 1–4,22,26,27 It is hypothesized that homocysteine might damage the vascular system by endothelial cell injury through oxidative stress or through direct toxic effect involving low-density lipoprotein oxidation, proliferation of vascular smooth muscle cells, and impairment of platelet function. 3,4,28 Nonetheless, the homocysteine theory has been criticized 4–6,29 on the basis of the following arguments. First, not all of the prospective studies have reported an increased risk of cardiovascular diseases associated with high plasma homocysteine concentrations, although most found an association. 30 Second, high homocysteine and low folate levels might be consequences, rather than causes, of cardiovascular events or early markers of an arterial inflammatory process. 27 However, experimental studies suggest a direct role of homocysteine because endothelial injuries have been induced in animals infused with homocysteine 1,31,32 and folic acid supplementation has been shown to improve endothelial function and reduce the rate of progression of the atherosclerotic plaque in patients with hyperhomocysteinemia. 33–36 Third, it has been suggested that folate may influence coronary risk through mechanisms other than homocysteine. 27 Neither the current study nor the forthcoming randomized clinical trials can resolve this issue.
Persons with high folate intake might have additional healthy life-style practices that explain their lower risk of MI. For example, participants in the highest quartile of folate intake were less likely to smoke and had diets with more fiber and less fat. Controlling for these factors attenuated the RR. On the other hand, patients with diabetes, hypertension and hypercholesterolemia reported higher folate intakes, probably as a result of a change in their diets after the diagnosis of these conditions. Controlling for these other medical conditions strengthened the association. Accounting for other strong cardiovascular risk factors (eg, body weight or physical activity) gave almost the same estimate.
Fiber, omega-3 fatty acids and ascorbic acid were associated with a lower risk of MI. The inverse association of fiber with MI is widely consistent in the literature, 37 and oxidative stress is thought to be involved in the pathophysiology of MI. 30 Intake of fiber and antioxidants such as ascorbic acid, highly correlated with folate in food, could be at least partially responsible for the risk reduction attributed to folate. Nonetheless, our results suggest a folate effect independent of the protective effect of ascorbic acid and total dietary fiber intake because there was an effect for folate even after adjusting for these nutrients. This same argument also applies regarding intake of marine omega-3 fatty acids. There is a growing body of evidence to suggest that fish intake, especially omega-3 fatty acids, is important for lowering risk of MI, 15,38 but additional adjustment for long-chain omega-3 fatty acids did not suggest that the apparent effect of folate could be explained by confounding for these fatty acids.
A potential weakness of nutritional studies lies in the use of self-reported data of dietary intake. However, information errors are likely to have been minimized by use of a carefully designed and validated food-frequency questionnaire, 17 and by interviews conducted by trained physicians who were unaware of the hypothesis under study. Nondifferential misclassification of folate intake would lead to an underestimation of the true folate effect. On the other hand, if individuals with MI had differential recall of dietary factors related to risk of disease (ie, worse recall of folate sources by cases), this would exaggerate the difference between cases and controls for intake of folate. Finally, use of hospitalized controls would have introduced bias in this study if folate intake were associated with the reason for hospitalization among controls. However, we only included as controls subjects with diseases believed to be unrelated to diet. Furthermore, because the controls include a variety of conditions, the unlikely hypothesis of a previously undocumented adverse effect of folate on any one would have little impact on these findings.
Since 1998, the U.S. Food and Drug Administration has required that all enriched cereal grains be fortified with folic acid by the addition of 0.14 mg per 100 gm of flour. 39 This action was taken to prevent the occurrence of neural tube defects in pregnancies. Fortification of enriched grain products has been associated with an increase in folate levels and a decrease in homocysteine levels in some populations. 40 Besides the prevention of birth defects, current folate fortification might reduce the risk of other pregnancy complications, 41,42 as well as the risk of common chronic diseases such as colon cancer 43 or cardiovascular diseases. In this setting, ongoing interventional studies in the U.S. may be unable to find a benefit associated with additional folic acid supplementation. However, higher-than-recommended levels of folate might be necessary to substantially reduce the effect of hyperhomocysteinemia. 44 A recent cost-effectiveness analysis concluded that, in addition to grain fortification, folic acid supplementation for men over 45 years of age and women over 55 would offer additional benefits if folic acid actually decreases the risk of cardiovascular events. 45
These findings suggest that a high folate intake may represent one of the beneficial constituents of a healthy Mediterranean diet 46 and reinforce the current recommendation of a high intake of fruits and vegetables, the main sources of dietary folate, for the prevention of cardiovascular disease. 37,47
Acknowledgments
We thank Maria Prado and Claudia Brugarolas, who participated in the data collection and interviewed some of the patients; Carmen de la Fuente, the dietitian who updated the food composition databank according to current Spanish food composition tables and helped calculate the nutrients for our analyses; Enrique de los Arcos (Hospital de Navarra), Eugenio Torrano (Hospital Virgen del Camino), and Joaquín Barba (University Clinic of Navarre), the chairmen of the cardiology departments at the three hospitals that participated in this study; and Alberto Ascherio for critically reviewing this manuscript.
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Keywords:
coronary heart disease; folic acid; Mediterranean diet; case-control study
© 2002 Lippincott Williams & Wilkins, Inc.