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,2
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* Department of Nutrition, Harvard School of Public Health;
Department of Oral Health Policy and Epidemiology, Harvard School of Dental Medicine;
** Departments of Epidemiology and
Biostatistics, Harvard School of Public Health; and
The Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
2To whom correspondence should be addressed. Email: amerchan{at}hsph.harvard.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • dietary fiber • peripheral arterial disease • cereal fiber • prospective study
Peripheral arterial disease (PAD)2 is a major cause of morbidity, and people with PAD are more than four times as likely to die of any cause over 2 y from diagnosis than those without (1). Severe disease often requires surgery, including limb amputation, and operative mortality is high (2). PAD results mainly from atherosclerotic narrowing of the blood vessel lumen and shares some risk factors with coronary heart disease (CHD) and stroke, including diabetes (3), hypertension (4) and cigarette smoking (5). There is little direct evidence, however, for the role of diet. An inverse association between fiber and PAD has been suggested in a cross-sectional study (6), a case-control study (7) and a cohort study conducted among Finnish smokers (8). This is biologically plausible because soluble fiber reduces LDL (9). Cereal fiber intake specifically has been inversely associated with the risk of CHD (10) and diabetes (11), and has been shown to favorably impact total cholesterol, LDL and fasting serum insulin (12). Therefore, we prospectively examined the association of dietary fiber intake with incident PAD in a large cohort of men followed for 12 y.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The Health Professionals Follow-up Study began in 1986 when 51,529 U.S. male health professionals, aged 40 to 75 y, volunteered to participate in the study (29,683 dentists, 4185 pharmacists, 3745 optometrists, 1600 podiatrists and 10,098 veterinarians; 531 African-American and 877 Asian-American) (13). The participants received questionnaires at baseline and biennially to determine lifestyle and medical conditions, and validated food frequency questionnaires (FFQ) every 4 y to determine diet.
We excluded men with a history of PAD, CHD, stroke and diabetes, because they may have changed their diets following disease, and men with inadequate dietary data (reported energy intake <3352 or >17598 kJ, or >70 unanswered of 131 items in the FFQ) (14) resulting in 46,032 men in this analysis. The study was approved by the Human Subjects Committee of the Harvard School of Public Health.
Case ascertainment.
If a participant reported intermittent claudication or surgery for PAD during follow-up, we requested permission to review his medical record to confirm the diagnosis and the date of occurrence of the disease. Cases of PAD were considered definite if the medical record contained either a report of surgery for PAD, ankle systolic blood pressure index (ABPI) < 0.80, a physician diagnosis, or an angiogram or Doppler ultrasound reporting 50% or more obstruction of at least one artery plus symptoms in the ipsilateral limb. Participants who confirmed the diagnosis of PAD by letter or over the telephone, but without available medical records, were considered probable PAD cases.
Diet and exposure information.
Diet was assessed by a validated FFQ every 4 y starting in 1986 (14). For each food the FFQ contains a commonly used unit or portion, e.g., one apple or one cup of cooked spinach. The respondent was requested to estimate how often on average he consumed a unit or portion during the previous year. There were nine possible responses, ranging from never or less than once a month up to six or more times per day. Nutrient (including fiber) intake was estimated by multiplying the mean nutrient content of the specified unit or portion by the number of times it was consumed (14). The nutrient content of foods was estimated from the Harvard University Food Composition Database that is derived from USDA sources, manufacturers’ information and data from peer-reviewed literature. Whole grain foods classified as described by Jacobs et al. (15) and Liu et al. (16), included brown rice, dark breads, whole grain breakfast cereal, cooked cereal, popcorn, wheat germ, bran and other grains. The validity of the FFQ has been described elsewhere (14). When compared with diet records the FFQ was found to be a good measure of breakfast cereal intakes (r = 0.86), dark bread (r = 0.77) (17) and dietary fiber (r = 0.68) (14). Fiber intakes for total energy were adjusted by regression analysis as described elsewhere (18). Briefly, we calculated a residual from a linear regression model with fiber as the dependent variable and total energy as the independent variable. The residual was added to the mean fiber intake for that population. Energy-adjusted intake of cereal fiber, for example, was interpreted as the composition of cereal fiber in the diet independent of the total quantity of food eaten.
The enrollment and follow-up questionnaires requested information on age, smoking, diagnosed or treated hypertension, hypercholesterolemia, angina, supplement use, weight and physical activity. Subjects were asked the average amount of time they spent per week on various physical activities including walking, jogging, running, bicycling, calisthenics, aerobics, machine rowing, swimming, squash, racquetball and tennis. From this information weekly energy expenditure in metabolic equivalent task-hours (MET) were calculated. BMI was computed by dividing weight (kg) by the squared height (m2) for every 2-y follow-up period.
Statistical analysis.
We considered mean intakes of fiber from all dietary assessments before the date of first report of PAD. PAD incidence between each questionnaire cycle was related to the mean dietary intake before that period (19). For example, disease incidence from 1986 to 1988 was related to the intake measured in 1986, and disease incidence from 1990 to 1992 was related to the mean intake from 1986 to 1990. Using this approach long-term diet was assessed and within person error was reduced. Diet update was stopped during follow-up if a person developed heart disease, stroke or had coronary artery by-pass surgery because the diet would change as a result of the condition or procedure. If dietary data were missing for one questionnaire we used the value derived from the preceding questionnaire. Fiber intake was evaluated as a continuous variable and in quintiles. The distribution of potential confounders across categories of fiber intakes was compared.
Person time was calculated for each participant from the return date of the questionnaire in 1986 to the date of report of PAD, death or the end of follow-up, whichever came first. Deaths were reported by family members, the Postal Service or ascertained through state registries or the National Death Index. The ascertainment of death was >98% complete (20). We measured incidence rates of PAD by quintiles of nutrient intakes stratifying by age and smoking using the Mantel-Haenszel method (21). The Cox proportional hazard model with failure time measured in age (mo) in the multivariate analysis was used to estimate the relative risks (RR) and 95% CI of PAD. In the multivariate analysis age was controlled for in months, smoking (never smokers, past smokers who had smoked for <20, 20–30 and >30 y, and current smokers who smoked 1–14, 15–24 or 
25 cigarettes per day), BMI (<21, 21–22.9, 23–24.9, 25–29.9 and 30+ kg/m2), alcohol use (never, 0.1–4.9, 5.0–14.9 15.0–29.9 and 30+ g/d), and physical activity (quintiles of MET), hypertension, hypercholesterolemia, family history of heart disease (dichotomous variables) and total energy (continuous). Diabetics were excluded. The analyses excluding probable cases were repeated. Tests for trend were completed with the Mantel extension test using the median value of the quintiles.
Fiber intake at baseline, mean whole grain intake (main source of cereal fiber in the diet) and soluble and insoluble fiber in relation to PAD risk were also evaluated. To assess possible confounding by other factors in the diet, the associations between cereal fiber and PAD risk for intakes of fruits and vegetables, types of fats, magnesium, vitamins E and C and folic acid (including supplements) were adjusted. Cereal fiber contains magnesium, the intake of which is associated with improved insulin action (22). Men eating more fiber were also more likely to consume more micronutrients associated with PAD risk (23). To detect possible interactions, analyses were conducted stratified by age (<65 and 65 y), supplemental vitamin E use, smoking (never smokers and ever smokers), BMI (<25 and 25 kg/m2), hypertension, hypercholesterolemia, a family history of early myocardial infarction and physical activity. Tests for interaction were conducted by the likelihood ratio method, comparing models with and without the interaction terms. The possibility of a nonlinear association between cumulatively averaged cereal fiber intake and PAD risk, adjusted for confounders, was evaluated using restricted cubic splines (24,25). Splines are regression models evaluating nonlinear associations between exposure and outcome adjusting for confounders and allowing for graphic representation of the results (24).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The median baseline intakes in the lowest and highest quintiles ranged from 13.4 to 29.6 g/d for total fiber and 2.5 to 10.2 g/d for cereal fiber. A bran muffin, for example, contains 
2.8 g of fiber (26). Men in the top quintile of total fiber intake were less likely to smoke, more likely to be nondrinkers, slightly leaner and exercised more than those in the bottom quintile. They were more likely to take vitamin C, E and vitamin supplements, and to eat less monounsaturated, saturated and trans fat. The trends were similar for cereal fiber (Table 1).
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5 g/d intake of cereal fiber and higher intakes did not appear to further reduce risk.
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The test for interaction between cereal fiber intake and PAD was not significant among subgroups of age (<65 and 65 y, P = 0.23), smoking (never smokers and ever smokers, P = 0.46), and BMI (<25 and 25 kg/m2, P = 0.89). The association between cereal fiber intake and PAD risk was stronger in men who took vitamin E supplements (P = 0.02) (Table 3). The relationship between cereal fiber intake and PAD risk did not change when the analysis was restricted to men who were physically inactive, and those without a history of hypertension, hypercholesterolemia or a family history of early myocardial infarction (data not shown).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The associations found between total and cereal fiber and PAD are similar to those found in the same cohort for CHD (10). These results are also consistent with those of a few previous investigations. In a cross-sectional study, Donnan et al. found higher ABPI, indicating less evidence of PAD, in men with higher cereal fiber intake in a randomly selected population, aged 55–74 y, after adjustment for age, sex, height, smoking and total energy (6). Katsoyanni et al. also found an inverse association between dietary fiber and PAD in a case-control study (odds ratio = 0.33, 95% CI 0.17–0.64) after adjusting for age, sex, years of schooling, smoking, alcohol and coffee intake and total energy (7). Finally, Tornwall et al. found an inverse association with PAD comparing the top to bottom quintile of fiber intake in a prospective study (RR = 0.87, 95% CI 0.77–0.97) in Finnish male smokers; separate estimates for cereal, fruit and vegetable fiber were not available (8). The main food source of dietary fiber in that study was rye bread so that the results are also probably due to cereal fiber. Our results demonstrate that it is important to evaluate the different types of fiber in relation to PAD risk because the associations vary considerably.
It has been hypothesized that the apparent protective effect of fiber intake against CHD is mediated by lowered cholesterol especially due to soluble fiber (9), and lowered plaminogen activator inhibitor type 1 and factor VII activity (27). PAD results mainly from atherosclerotic narrowing of the blood vessel lumen. LDL are taken up by monocytes in the intima of the blood vessels, becoming foam cells, and leading to the formation of plaque. Increased cytosolic triglycerides are associated with oxidative stress and can cause endothelial dysfunction (28). Thus, increased serum LDL and triglycerides increase the risk of PAD (29). Other factors that increase PAD risk are hypertension (4), smoking (5) and insulin resistance (29). It has been hypothesized that fiber intake improves insulin sensitivity by slowing the absorption of nutrients from the gut (30), reducing serum glucose levels (31), producing SCFA by gut bacteria and consequently improving glucose metabolism (32).
The inverse association between cereal fiber intake and PAD risk is probably not entirely due to serum cholesterol reduction. Serum cholesterol reduction from cereal fiber intake could not explain the observed 29% reduction in risk for CHD in this cohort (10). Because plasminogen activator inhibitor has not been implicated in the causation of PAD (33), the lower risk of PAD among men with high cereal fiber intake may in part be related to increased insulin sensitivity. Improved glucose metabolism is associated with lower LDL, blood pressure and triglycerides, and higher HDL (9). Each of these factors has been shown to be independently associated with PAD. Foods sources of cereal fiber also contain magnesium and chromium which are associated with improved insulin sensitivity (34,35), and folate which has been inversely associated with PAD risk (23).
Vitamin E has also been shown to prevent LDL oxidation and increase lipoprotein lipase activity (36). Therefore, it is plausible that vitamin E intake would enhance the association between cereal fiber and PAD risk. We observed a slightly stronger association between cereal fiber intake and PAD risk among men who took vitamin E supplements. The association between PAD and cereal fiber intake was not linear, both in the quintile and spline analyses. We observed a threshold of risk reduction at intakes of 5 g/d of cereal fiber. Liu et al. found a similar threshold for the association of whole grain and CHD in the fourth quintile of intake (median cereal fiber of quintile, 5 g/d) among never smokers (16). If the action of cereal fiber were the result of improved insulin-related mechanisms then its effect would be limited by the extent to which impaired glucose metabolism contributes to PAD. Glucose intolerance has been shown to have approximately a two-fold higher risk of PAD in men (4).
In conclusion, we observed that increased dietary cereal fiber intake in a population including smokers and nonsmokers was associated with reduced risk of PAD in men. Increasing cereal fiber in the diet could contribute to the prevention of PAD.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: ABPI, ankle brachial blood pressure index; CHD, coronary heart disease; FFQ, food frequency questionnaire; MET, metabolic equivalents; PAD, peripheral arterial disease; RR, relative risk.
Manuscript received 29 July 2003. Initial review completed 1 September 2003. Revision accepted 8 September 2003.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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