Alberto Ascherio

VITAMIN E CONSUMPTION AND THE RISK OF CORONARY HEART DISEASE IN MEN

BACKGROUND The oxidative modification of low-density lipoproteins increases their incorporation into the arterial intima, an essential step in atherogenesis. Although dietary antioxidants, such as vitamin C, carotene, and vitamin E, have been hypothesized to prevent coronary heart disease, prospective epidemiologic data are sparse. METHODS In 1986, 39,910 U.S. male health professionals 40 to 75 years of age who were free of diagnosed coronary heart disease, diabetes, and hypercholesterolemia completed detailed dietary questionnaires that assessed their usual intake of vitamin C, carotene, and vitamin E in addition to other nutrients. During four years of follow-up, we documented 667 cases of coronary disease. RESULTS After controlling for age and several coronary risk factors, we observed a lower risk of coronary disease among men with higher intakes of vitamin E (P for trend = 0.003). For men consuming more than 60 IU per day of vitamin E, the multivariate relative risk was 0.64 (95 percent confidence interval, 0.49 to 0.83) as compared with those consuming less than 7.5 IU per day. As compared with men who did not take vitamin E supplements, men who took at least 100 IU per day for at least two years had a multivariate relative risk of coronary disease of 0.63 (95 percent confidence interval, 0.47 to 0.84). Carotene intake was not associated with a lower risk of coronary disease among those who had never smoked, but it was inversely associated with the risk among current smokers (relative risk, 0.30; 95 percent confidence interval, 0.11 to 0.82) and former smokers (relative risk, 0.60; 95 percent confidence interval, 0.38 to 0.94). In contrast, a high intake of vitamin C was not associated with a lower risk of coronary disease. CONCLUSIONS These data do not prove a causal relation, but they provide evidence of an association between a high intake of vitamin E and a lower risk of coronary heart disease in men. Public policy recommendations with regard to the use of vitamin E supplements should await the results of additional studies.

Dietary Fiber, Glycemic Load, and Risk of NIDDM in Men

OBJECTIVE Intake of carbohydrates that provide a large glycemic response has been hypothesized to increase the risk of NIDDM, whereas dietary fiber is suspected to reduce incidence. These hypotheses have not been evaluated prospectively. RESEARCH DESIGN AND METHODS We examined the relationship between diet and risk of NIDDM in a cohort of 42,759 men without NIDDM or cardiovascular disease, who were 40–75 years of age in 1986. Diet was assessed at baseline by a validated semiquantitative food frequency questionnaire. During 6-years of follow-up, 523 incident cases of NIDDM were documented. RESULTS The dietary glycemic index (an indicator of carbohydrates ability to raise blood glucose levels) was positively associated with risk of NIDDM after adjustment for age, BMI, smoking, physical activity, family history of diabetes, alcohol consumption, cereal fiber, and total energy intake. Comparing the highest and lowest quintiles, the relative risk (RR) of NIDDM was 1.37 (95% CI, 1.02–1.83, P trend = 0.03). Cereal fiber was inversely associated with risk of NIDDM (RR = 0.70; 95% CI, 0.51–0.96, P trend = 0.007; for > 8.1 g/day vs. < 3.2 g/day). The combination of a high glycemic load and a low cereal fiber intake further increased the risk of NIDDM (RR = 2.17, 95% CI, 1.04–4.54) when compared with a low glycemic load and high cereal fiber intake. CONCLUSIONS These findings support the hypothesis that diets with a high glycemic load and a low cereal fiber content increase risk of NIDDM in men. Further, they suggest that grains should be consumed in a minimally refined form to reduce the incidence of NIDDM.

Prospective study of alcohol consumption and risk of coronary disease in men

Although an inverse association between alcohol consumption and risk of coronary artery disease has been consistently found in several types of studies, some have argued that the association is due at least partly to the inclusion in the non-drinking reference group of men who abstain because of pre-existing disease. The association between self-reported alcohol intake and coronary disease was studied prospectively among 51,529 male health professionals. In 1986 the participants completed questionnaires about food and alcohol intake and medical history, heart disease risk factors, and dietary changes in the previous 10 years. Follow-up questionnaires in 1988 sought information about newly diagnosed coronary disease. 350 confirmed cases of coronary disease occurred. After adjustment for coronary risk factors, including dietary intake of cholesterol, fat, and dietary fibre, increasing alcohol intake was inversely related to coronary disease incidence (p for trend less than 0.001). Exclusion of 10,302 current non-drinkers or 16,342 men with disorders potentially related to coronary disease (eg, hypertension, diabetes, and gout) which might have led men to reduce their alcohol intake, did not substantially affect the relative risks. These findings support the hypothesis that the inverse relation between alcohol consumption and risk of coronary disease is causal.

Birth Weight and Adult Hypertension, Diabetes Mellitus, and Obesity in US Men

BACKGROUND Low birth weight has been associated with several chronic diseases in adults, including hypertension, diabetes mellitus, and obesity. Further study of these diseases in a large cohort with information on a wide variety of risk factors is essential to determine more precisely the risks associated with birth weight. METHODS AND RESULTS We examined the relation between birth weight and cumulative incidence of adult hypertension, incidence of non-insulin-dependent diabetes mellitus, and prevalence of obesity in a cohort of 22,846 US men (Health Professionals Follow-up Study). Birth weights, medical histories, family histories, and other factors were collected by biennial mailed questionnaires. Logistic regression was used to examine the association between birth weight and these chronic adult diseases. Low birth weight was associated with an increased risk of hypertension and diabetes; high birth weight was associated with an increased risk of obesity. Compared with men in the referent birth weight category (7.0 to 8.4 lb), men who weighed < 5.5 lb had an age-adjusted odds ratio for hypertension of 1.26 (95% confidence interval [CI], 1.11 to 1.44) and for diabetes mellitus of 1.75 (95% CI, 1.21 to 2.54). There was no material change after controlling for adult body mass index and parental histories of hypertension and diabetes mellitus. Compared with men in the referent group, the age-adjusted odds ratio of being in the highest versus the lowest quintile of adult body mass index for men with birth weight > or = 10.0 lb was 2.08 (95% CI, 1.73 to 2.50). CONCLUSIONS These findings support the hypothesis that early life exposures, for which birth weight is a marker, are associated with several chronic diseases in adulthood.

Environmental risk factors for multiple sclerosis. Part I: the role of infection.

Although genetic susceptibility explains the clustering of multiple sclerosis (MS) cases within families and the sharp decline in risk with increasing genetic distance, it cannot fully explain the geographic variations in MS frequency and the changes in risk that occur with migration. Epidemiological data provide some support for the “hygiene hypothesis,” but with the additional proviso for a key role of Epstein–Barr virus (EBV) in determining MS risk. We show that whereas EBV stands out as the only infectious agent that can explain many of the key features of MS epidemiology, by itself the link between EBV and MS cannot explain the decline in risk among migrants from high to low MS prevalence areas. This decline implies that either EBV strains in low‐risk areas have less propensity to cause MS, or that other infectious or noninfectious factors modify the host response to EBV or otherwise contribute to determine MS risk. The role of infectious factors is discussed here; in a companion article, we will examine the possible role of noninfectious factors and provide evidence that high levels of vitamin D may have a protective role, particularly during adolescence. The primary purpose of these reviews is to identify clues to the causes of MS and to evaluate the possibility of primary prevention. Ann Neurol 2007;61:288–299

Aspirin Use and the Risk for Colorectal Cancer and Adenoma in Male Health Professionals

The evidence that nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, decrease the occurrence of colorectal cancer and possibly other gastrointestinal tumors in humans [1] is not entirely conclusive. Several case reports and small clinical trials show that sulindac causes regression of the polyps in patients with familial polyposis [2-7]. Patients with rheumatoid arthritis, regular users of NSAIDs, appear to have a lower incidence of gastrointestinal tumors, primarily stomach and large-bowel cancers [8-10]. Case-control studies have shown an inverse relation between NSAID use and occurrence of colorectal cancer [11-13] and adenoma [14-16]; an inverse association between aspirin use and mortality from gastrointestinal cancers was observed in a large prospective study [17, 18]. A recent prospective study [19] showed an inverse association between aspirin use and incidence of colon cancer, but another cohort study did not [20]. A randomized trial [21] showed no association between aspirin use and the risk for colorectal cancer, but the dosage may have been too low and the follow-up period too short. A protective influence of NSAIDs on colon cancer has been supported by studies in animals [22-24]. Because the question is unresolved [25], we examined the relation between aspirin and other NSAID use and the risk for colorectal adenoma and cancer incidence and mortality in a large U.S. cohort of male health professionals. Methods Study Population We analyzed data from an ongoing cohort of men, the Health Professionals Follow-up Study. This cohort was initiated in 1986 to study various potential causes of cardiovascular disease and cancer, particularly diet [26]. At baseline, 51 529 U.S. male dentists (58%), optometrists (7%), osteopaths (4%), podiatrists (3%), pharmacists (8%), and veterinarians (20%) who were 40 to 75 years of age responded to mailed questionnaires on aspirin and other NSAID use and on history of cancer and other clinically diagnosed medical conditions. In 1988, 1990, and 1992, we mailed a follow-up questionnaire to update exposure information and ascertain newly diagnosed medical conditions [27]. Current use of aspirin and other NSAIDs was assessed at baseline and at follow-up using a list that included the following categories: 1) aspirin, 2+ times per week (for example, Anacin, Bufferin, Alka-Seltzer); 2) acetaminophen, 2+ times per week (for example, Tylenol); and 3) other anti-inflammatory medications (for example, Motrin, Indocin, Naprosyn, Dolobid). Advil was used as an example rather than Dolobid on the 1988 and 1990 questionnaires. Reasons for use were not assessed at baseline. In 1993, however, a randomly selected sample of 211 participants who reported aspirin use from 1986 to 1990 were mailed a brief supplementary questionnaire. Of the 211 men, 185 (88%) responded and reported one or more of the following reasons: cardiovascular disease, 25.4%; to decrease risk for cardiovascular disease, 58.4%; headaches, 25.4%; joint or musculoskeletal pain, 33.0%; and other reasons, 7.0%. From the supplementary questionnaire, we inferred that the median duration of use during the 1990 to 1992 follow-up period was 9 years. At baseline, we also inquired about age, current and past smoking, weight and height, family history of colorectal cancer, leisure-time physical activity, and dietary and alcohol intake using a semiquantitative food frequency questionnaire [28, 29]. On the follow-up questionnaires, we included questions about the participants history of colonoscopy or sigmoidoscopy before and during the study. We also assessed the indications for endoscopy (bleeding in stool, positive test result for occult fecal blood, abdominal pain, diarrhea or constipation, family history of colon cancer, routine screening [no symptoms], or follow-up). Identification of Patients with Colorectal Cancers The follow-up procedures for this cohort have been described in detail [26]. Briefly, on each of the follow-up questionnaires we asked whether a diagnosis of cancer had been made. The response rate was 95% of total possible person-years through 31 January 1992. Most deaths in the cohort were reported by family members or the postal system in response to the follow-up questionnaires. In addition, we used the National Death Index, a highly sensitive method of identifying deaths among nonrespondents [30]. When a patient (or next of kin for decedents) reported a diagnosis of cancer of the colon or rectum on our follow-up questionnaire, we asked for permission to obtain hospital records and pathology reports. A study physician, blinded to exposure information, reviewed all medical records and extracted data on histologic type, anatomic location, and stage of the cancer. We confirmed 251 new patients with colorectal adenocarcinoma (excluding carcinoma in situ), 225 (90%) by medical records and 26 with corroborating information on diagnosis and treatment from the cohort member. Identification of Patients and Controls with Colorectal Adenomas Because more than 90% of the adenomas were diagnosed in men who had had an endoscopic procedure for routine screening or for unrelated gastrointestinal conditions, we restricted the adenoma analysis to 12 854 men who reported having had a colonoscopy or sigmoidoscopy between 1986 and 1992. Because aspirin-related bleeding could influence the detection of polyps, we limited our major analyses to the 10 521 men who did not have bleeding as an indication for endoscopy. Most procedures were sigmoidoscopies; thus, we studied only patients who had adenomas of the distal colon and rectum. Of the 10 521 men, 1070 reported a diagnosis of polyp of the colon or rectum. Ninety-six percent (1028 of 1070) of the men responded to a follow-up letter; 94 of the 1028 men denied having had a polyp, 3 had died, and all but 35 of the remaining respondents granted us permission to review medical records, 96% of which were available. A diagnosis of adenomatous or hyperplastic polyp was confirmed in 756 men, and, after excluding those with hyperplastic and adenomatous polyps proximal to the descending colon, 472 patients who had distal colorectal adenomas (including carcinoma in situ) remained for analysis. Twenty-eight percent of these adenomas were 1 cm in diameter or larger. In 1993, we surveyed a random sample of 200 men who reported a negative endoscopic result. After one mailing, 140 (70%) men granted permission to review medical records of their endoscopic procedure. No patients with histologically confirmed adenomas were discovered on review, but minute polyps were often destroyed in situ without histologic diagnosis. This practice, along with the dearth of current smokers, who are at considerable risk for small adenomas [31], accounted largely for the relatively high percentage of patients with large adenomas. Data Analysis Before doing the cancer and adenoma analyses, we excluded 3629 men in total, including those whose reported caloric intake was outside the range of 800 to 4200 kcal/d because most of these men probably completed the questionnaire incorrectly, those with 70 or more items left blank on the questionnaire, and those who reported previous cancer (other than nonmelanoma skin cancer), ulcerative colitis, or a familial polyposis syndrome. The remaining 47 900 men contributed follow-up time beginning at the month of return of the initial questionnaire in 1986 and ending at the month of diagnosis of colorectal cancer, month of death from other causes, or at the end of the study period, 31 January 1992. We computed incidence rates for aspirin use by dividing the number of incident cases by the number of person-years in that category and computed the relative risk by dividing this incidence rate by that of nonusers. We used the Mantel-Haenszel summary estimator and proportional hazards modeling to adjust for age (using 5-year categories) and potentially confounding variables [32]. Men diagnosed with adenomas and cancers were included only in the cancer analyses. For the adenoma analyses, we also excluded men who had had a prestudy diagnosis of colorectal polyp. We analyzed patients with separately prevalent adenomas (polyps diagnosed at the time of the first endoscopic procedure), patients with incident adenomas (those discovered in men who had had a negative endoscopic test result before 1986), and patients with a combination of these end points. Multiple logistic regression analysis was used to control for potentially confounding variables [32]. Results Table 1 shows characteristics of cohort members according to aspirin use in 1986. Men who reported regular aspirin use were slightly older, heavier, and less physically active; smoked slightly more; and were more likely to use multivitamin tablets. Dietary patterns were quite similar, but consumption of alcoholic beverages was slightly higher among aspirin users. Intakes of other major nutrients were similar among users and nonusers of aspirin (data not shown), except for vitamins and minerals contained in multivitamin tablets. Table 1. Selected Characteristics of Study Participants by Reported Aspirin Use in 1986* About one third of the men had had an endoscopic procedure before the study period. During the study period, more men who took aspirin had an endoscopic procedure for overt or occult fecal blood (5.9% compared with 4.8%) or for other indications including screening (23.2% compared with 21.8%); both were significant (P < 0.01). Among men having an endoscopy with fecal blood as an indication, an adenoma was found in 5.6% of aspirin users and in 8.1% of nonusers (percentages were age-standardized), suggesting a 31% decrease in risk among aspirin users. We observed a lower risk for colorectal cancer among users of aspirin compared with nonusers (relative risk [RR], 0.70; 95% CI, 0.53 to 0.92; P = 0.008). The decreased risk was noted for the colon (RR, 0.72; CI, 0.53 to 0.97) and rectum (RR, 0.61; CI, 0.31 to 1.20),

Major types of dietary fat and risk of coronary heart disease: a pooled analysis of 11 cohort studies

BACKGROUND Saturated fatty acid (SFA) intake increases plasma LDL-cholesterol concentrations; therefore, intake should be reduced to prevent coronary heart disease (CHD). Lower habitual intakes of SFAs, however, require substitution of other macronutrients to maintain energy balance. OBJECTIVE We investigated associations between energy intake from monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), and carbohydrates and risk of CHD while assessing the potential effect-modifying role of sex and age. Using substitution models, our aim was to clarify whether energy from unsaturated fatty acids or carbohydrates should replace energy from SFAs to prevent CHD. DESIGN This was a follow-up study in which data from 11 American and European cohort studies were pooled. The outcome measure was incident CHD. RESULTS During 4-10 y of follow-up, 5249 coronary events and 2155 coronary deaths occurred among 344,696 persons. For a 5% lower energy intake from SFAs and a concomitant higher energy intake from PUFAs, there was a significant inverse association between PUFAs and risk of coronary events (hazard ratio: 0.87; 95% CI: 0.77, 0.97); the hazard ratio for coronary deaths was 0.74 (95% CI: 0.61, 0.89). For a 5% lower energy intake from SFAs and a concomitant higher energy intake from carbohydrates, there was a modest significant direct association between carbohydrates and coronary events (hazard ratio: 1.07; 95% CI: 1.01, 1.14); the hazard ratio for coronary deaths was 0.96 (95% CI: 0.82, 1.13). MUFA intake was not associated with CHD. No effect modification by sex or age was found. CONCLUSION The associations suggest that replacing SFAs with PUFAs rather than MUFAs or carbohydrates prevents CHD over a wide range of intakes.

A prospective study of nutritional factors and hypertension among US women.

BackgroundAn effect of diet in determining blood pressure is suggested by epidemiological studies, but the role of specific nutrients is still unsettled. Methods and ResultsThe relation of various nutritional factors with hypertension was examined prospectively among 30,681 predominantly white US male health professionals, 40–75 years old, without diagnosed hypertension. During 4 years of follow-up, 1,248 men reported a diagnosis of hypertension. Age, relative weight, and alcohol consumption were the strongest predictors for the development of hypertension. Dietary fiber, potassium, and magnesium were each significantly associated with lower risk of hypertension when considered individually and after adjustment for age, relative weight, alcohol consumption, and energy intake. When these nutrients were considered simultaneously, only dietary fiber had an independent inverse association with hypertension. For men with a fiber intake of <12 g/day, the relative risk of hypertension was 1.57 (95% confidence interval, 1.20–2.05) compared with an intake of >24 g/day. Calcium was significantly associated with lower risk of hypertension only in lean men. Dietary fiber, potassium, and magnesium were also inversely related to baseline systolic and diastolic blood pressure and to change in blood pressure during the follow-up among men who did not develop hypertension. Calcium was inversely associated with baseline blood pressure but not with change in blood pressure. No significant associations with hypertension were observed for sodium, total fat, or saturated, transunsaturated, and polyunsaturated fatty acids. Fruit fiber but not vegetable or cereal fiber was inversely associated with incidence of hypertension. ConclusionsThese results support hypotheses that an increased intake of fiber and magnesium may contribute to the prevention of hypertension.

Dietary fat and risk of coronary heart disease in men: cohort follow up study in the United States

Abstract Objective: To examine the association between fat intake and the incidence of coronary heart disease in men of middle age and older. Design: Cohort questionnaire study of men followed up for six years from 1986. Setting: The health professionals follow up study in the United States. Subjects: 43 757 health professionals aged 40 to 75 years free of diagnosed cardiovascular disease or diabetes in 1986. Main outcome measure: Incidence of acute myocardial infarction or coronary death. Results: During follow up 734 coronary events were documented, including 505 non-fatal myocardial infarctions and 229 deaths. After age and several coronary risk factors were controlled for significant positive associations were observed between intake of saturated fat and risk of coronary disease. For men in the top versus the lowest fifth of saturated fat intake (median = 14.8% v 5.7% of energy) the multivariate relative risk for myocardial infarction was 1.22 (95% confidence interval 0.96 to 1.56) and for fatal coronary heart disease was 2.21 (1.38 to 3.54). After ajustment for intake of fibre the risks were 0.96 (0.73 to 1.27) and 1.72 (1.01 to 2.90), respectively. Positive associations between intake of cholesterol and risk of coronary heart disease were similarly attenuated after adjustment for fibre intake. Intake of linolenic acid was inversely associated with risk of myocardial infarction; this association became significant only after adjustment for non-dietary risk factors and was strengthened after adjustment for total fat intake (relative risk 0.41 for a 1% increase in energy, P for trend <0.01). Conclusions: These data do not support the strong association between intake of saturated fat and risk of coronary heart disease suggested by international comparisons. They are compatible, however, with the hypotheses that saturated fat and cholesterol intakes affect the risk of coronary heart disease as predicted by their effects on blood cholesterol concentration. They also support a specific preventive effect of linolenic acid intake. Key messages Diets high in saturated fat and cholesterol are associated with an increased risk of coronary disease, but these adverse effects are at least in part explained by their low fibre content and associations with other risk factors Diets high in linolenic acid (N-3 fatty acid from plants) are associated with a reduced risk of coronary heart disease, independently of other dietary and non-dietary risk factors Uncertainty remains on the optimal amount of polyunsaturated fat in the diet for prevention of coronary heart disease Benefits of reducing intakes of saturated fat and cholesterol are likely to be modest unless accompanied by an increased consumption of foods rich in fibre

Relation between Intake of Flavonoids and Risk for Coronary Heart Disease in Male Health Professionals

Recent evidence showing that antioxidants may reduce or prevent disease in humans [1] has led to an expanding body of literature on several classes of natural antioxidants found in foods. Among these natural antioxidants are flavonoids. Flavonoids are polyphenols; subclasses of flavonoids are flavonols and flavones, flavanones, catechins, and anthocyanidins. Flavonols, such as quercetin and kaempferol, are predominantly found in onions, kale, broccoli, apples, cherries, berries, tea, and red wine [2, 3]. Major sources of flavones, such as apigenin, are parsley and thyme (Hollman P. Personal communication). Only a small proportion of flavones and flavonols (<20%) is lost during cooking [4], but data on the absorption of flavonoids by humans are scarce and contradictory. A recent report [5] found that humans absorbed 52% of the quercetin in onions. Because low-density lipoprotein oxidation is thought to be a necessary precursor to atherosclerosis [6], flavonoids that reduce this oxidation [1, 7, 8] may reduce the risk for coronary heart disease. In addition to having antioxidant abilities, flavonoids may have antithrombotic properties [9, 10]. In prospective investigations of intake of flavonoids and coronary heart disease in the Netherlands [11] and Finland [12], persons who had the lowest overall intake of flavonoids had a higher risk for death from coronary heart disease. To test these findings, we investigated the association between intake of flavonols and flavones and coronary heart disease in 34 789 men who were enrolled in the Health Professionals Follow-up Study and were followed prospectively for 6 years. Methods The Health Professionals Follow-up Study is a prospective investigation of 51 529 U.S. men who were 40 to 75 years of age in 1986. Of these men, 29 683 were dentists, 10 098 were veterinarians, 4185 were pharmacists, 3745 were optometrists, 2218 were osteopathic physicians, and 1600 were podiatrists; all were recruited from their professional organizations. The study began in 1986, when each participant completed a detailed questionnaire on his diet and medical history. We mailed biennial follow-up questionnaires to obtain updated information on exposures and to learn about newly diagnosed events related to coronary heart disease [13, 14]. In 1990, participants completed a semi-quantitative food frequency questionnaire. More than 94% of eligible participants were followed in 1988, 1990, and 1992 [15]. The nonresponders were assumed to be alive if they were not listed in the National Death Index, a nationwide registry of deaths in the United States [16]. Because men who receive a diagnosis of cardiovascular disease or related conditions may alter their diets, we excluded men who reported having prevalent cardiovascular disease on the baseline questionnaire in 1986. Dietary Assessment The dietary questionnaires completed in 1986 and 1990 asked about the average frequency of intake of 131 foods during the previous year. Intake of specific nutrients was computed by multiplying the frequency of consumption of an item by its nutrient content, which was derived primarily from U.S. Department of Agriculture sources [17]. We excluded men (about 3% of the sample) whose reported daily energy intake was less than 800 kcal or more than 4200 kcal or those who left 70 or more items blank on their dietary questionnaires. We determined each participants intake of three flavonols and two flavones by using food tables (based on analyses done by Hertog and colleagues [3, 18]) that were supplemented with values for additional U.S. foods (apples, onions, teas, and red wines [three varieties of each]; avocado; cantaloupe; watermelon; blueberries; green beans; corn; sprouts; yellow squash; green pepper; tofu; and apple juice). Foods were analyzed [4, 18] by the same laboratory at the State Institute for Quality Control of Agricultural Products in Wageningen, the Netherlands. Levels of flavones (such as apigenin and luteolin) in foods are very low. Using information about 147 foods and recipes that contain flavonoids, we determined the average intake of quercetin, myricetin, kaempferol, luteolin, and apigenin and summed the totals for these five compounds. Quercetin, kaempferol, and myricetin composed more than 90% of the flavonoids ingested by our study sample. In our baseline 1986 questionnaire, we did not assess intake of onions in sufficient detail. Because much of the flavonols present in the diets of persons in developed countries comes from onions [19, 20], we assumed that the intake of onions reported on the 1990 questionnaire (in response to two separate questions: one about onions as a garnish and one about onions as a vegetable, rings, or soup) had not changed during the previous 4 years and could be added to the dietary information reported in 1986. Because of this limitation, our main analyses were limited to the 34 789 men who responded to both the 1986 and the 1990 dietary questionnaires. To assess the validity of the dietary questionnaire, we compared the intake of nutrients and food as reported on the food frequency questionnaire with that reported in two 1-week dietary records (spaced approximately 6 months apart) kept by a subsample of 127 men [21, 22]. Although we could not directly test the validity of values for intake of flavonoids as derived from the questionnaire, the Pearson correlation coefficients between the questionnaire and the dietary records were high for most nutrients (average, 0.65 [range, 0.30 to 0.92]). We were unable to measure the validity of values for self-reported intake of onions. However, correlations between the questionnaire and the dietary records were good for other main sources of flavonoids: tea (r = 0.77), apples (r = 0.70), and broccoli (r = 0.46) [22]. Case Ascertainment We considered only nonfatal myocardial infarction end points that occurred between the date on which the 1986 questionnaire was returned and 31 January 1992. Because onion consumption as reported on the 1990 questionnaire was needed to calculate total intake of flavonoids, men who had had a fatal myocardial infarction between 1986 and 1990 could not report onion consumption and were not included in this analysis. Participants who reported an incident myocardial infarction on the 1988, 1990, or 1992 questionnaires were sent a letter confirming the report and requesting permission to review medical records. Myocardial infarctions were confirmed using criteria from the World Health Organization [23]: compatible symptoms plus either typical electrocardiographic changes or elevated cardiac enzyme levels. For our secondary analyses of all incident coronary end points between 1990 and 1992, we included nonfatal and fatal myocardial infarction as well as cardiovascular revascularization procedures. Deaths were reported by next-of-kin, coworkers, and postal authorities in addition to being ascertained using the National Death Index. We confirmed fatal infarctions by using medical records or autopsy reports. Further details have been published elsewhere [13, 24]. Statistical Analysis Our primary analyses examined the association between energy-adjusted [25] intake of flavonoids as reported on the 1986 dietary questionnaire (supplemented with intake of onions as reported on the 1990 questionnaire) and nonfatal myocardial infarction. For the secondary analyses, we examined the association between self-reported intake of flavonoids from 1990 and total incident coronary events. For the primary analysis, each participant contributed follow-up time from the date on which he returned his 1986 questionnaire until diagnosis of nonfatal myocardial infarction, death, or 31 January 1992. Relative risks were calculated as the incidence of coronary heart disease among men in a given quintile of intake of flavonoids divided by the incidence among men in the lowest quintile of intake, adjusted for age (in 5-year strata) using the Mantel-Haenszel method [26]. To adjust for other risk factors, we used multiple logistic regression to generate odds ratios as a valid estimate of relative risk. We did the secondary analyses in a similar way, except that intake of flavonoids, disease history, and other variables used in the multivariate model were assessed using the 1990 questionnaire. Results For men in our study, the main sources of flavonols and flavones were tea (25%), onions (25%), apples (10%), and broccoli (7%). The average total intake was 20.1 mg/d; the three primary flavonols ingested were quercetin (15.4 mg/d), kaempferol (3.6 mg/d), and myricetin (0.9 mg/d). Men with a higher intake of flavonoids were slightly older, drank less alcohol, smoked less, ate more dietary fiber, and were more likely to take vitamin E supplements (Table 1). Table 1. Baseline Characteristics of 34 789 Male Health Professionals 40 to 75 Years of Age in 1986 by Quintiles of Energy-Adjusted Total Intake of Flavonols and Flavones* During 6 years of follow-up in 34 789 men who completed the 1986 and 1990 dietary questionnaires, we documented 486 nonfatal myocardial infarctions. Compared with men in the lowest quintile for intake of flavonoids, men in the highest quintile had an age-adjusted relative risk for coronary heart disease of 1.06 (95% CI, 0.81 to 1.40) (Table 2). After multivariate adjustment, the relative risk was essentially unchanged (relative risk, 1.08 [CI, 0.81 to 1.43]). Controlling for intake of dietary fiber, saturated fat, or cholesterol did not substantially alter these results. No individual flavonols or flavones were associated with an appreciable reduction in risk for coronary heart disease. For example, the multivariate relative risk of quercetin (for the highest compared with the lowest quintile of intake) was 1.14 (CI, 0.86 to 1.51). Table 2. Relative Risk for Nonfatal Myocardial Infarction by Quintiles of Energy-Adjusted Intake of Quercetin, Myricetin, Kaempferol, and Total Flavonols and Flavones among 34 789 Men in the