Dietary flavonoid intakes and CVD incidence in the Framingham Offspring Cohort.

This study examines the relationship between long-term intake of six flavonoid classes and incidence of CVD and CHD, using a comprehensive flavonoid database and repeated measures of intake, while accounting for possible confounding by components of a healthy dietary pattern. Flavonoid intakes were assessed using a FFQ among the Framingham Offspring Cohort at baseline and three times during follow-up. Cox proportional hazards regression was used to characterise prospective associations between the natural logarithms of flavonoid intakes and CVD incidence using a time-dependent approach, in which intake data were updated at each examination to represent average intakes from previous examinations. Mean baseline age was 54 years, and 45 % of the population was male. Over an average 14·9 years of follow-up among 2880 participants, there were 518 CVD events and 261 CHD events. After multivariable adjustment, only flavonol intake was significantly associated with lower risk of CVD incidence (hazard ratios (HR) per 2·5-fold flavonol increase=0·86, P trend=0·05). Additional adjustment for total fruit and vegetable intake and overall diet quality attenuated this observation (HR=0·89, P trend=0·20 and HR=0·92, P trend=0·33, respectively). There were no significant associations between flavonoids and CHD incidence after multivariable adjustment. Our findings suggest that the observed association between flavonol intake and CVD risk may be a consequence of better overall diet. However, the strength of this non-significant association was also consistent with relative risks observed in previous meta-analyses, and therefore a modest benefit of flavonol intake on CVD risk cannot be ruled out.

Improving the estimation of flavonoid intake for study of health outcomes.

Imprecision in estimating intakes of non-nutrient bioactive compounds such as flavonoids is a challenge in epidemiologic studies of health outcomes. The sources of this imprecision, using flavonoids as an example, include the variability of bioactive compounds in foods due to differences in growing conditions and processing, the challenges in laboratory quantification of flavonoids in foods, the incompleteness of flavonoid food composition tables, and the lack of adequate dietary assessment instruments. Steps to improve databases of bioactive compounds and to increase the accuracy and precision of the estimation of bioactive compound intakes in studies of health benefits and outcomes are suggested.

Higher dietary anthocyanin and flavonol intakes are associated with anti-inflammatory effects in a population of US adults.

BACKGROUND: Although growing evidence from trials and population-based studies has supported a protective role for flavonoids in relation to risk of certain chronic diseases, the underlying mechanisms remain unclear. Several previous studies focused on individual inflammatory biomarkers, but because of the limited specificity of any individual marker, an assessment of a combination of biomarkers may be more informative. OBJECTIVE: We used an inflammation score (IS) that integrated 12 individual inflammatory biomarkers for the examination of associations with intakes of different flavonoid classes. DESIGN: The study was a cross-sectional analysis of 2375 Framingham Heart Study Offspring Cohort participants. Intakes of total flavonoids and their classes (anthocyanins, flavonols, flavanones, flavan-3-ols, polymers, and flavones) were calculated from validated food-frequency questionnaires. Individual inflammatory biomarkers were ranked, standardized, and summed to derive an overall IS and subgroup scores of functionally related biomarkers. RESULTS: In multivariate analyses, an inverse association between higher anthocyanin and flavonol intakes and IS was observed with a mean ± SE difference between quintile categories 5 and 1 of -1.48 ± 0.32 (P-trend ≤ 0.001) and -0.72 ± 0.33 (P-trend = 0.01), respectively. Results remained significant after additional adjustment for physical activity and vitamin C and fruit and vegetable intakes. Higher anthocyanin intake was inversely associated with all biomarker subgroups, whereas higher flavonol intake was associated only with lower cytokine and oxidative stress biomarker concentrations. In food-based analyses, higher intakes of apples and pears, red wine, and strawberries were associated with a lower IS with differences between quintiles 5 and 1 of -1.02 ± 0.43 (P = 0.006), -1.73 ± 0.39 (P < 0.001), and -0.44 ± 0.88 (P = 0.02), respectively. Although intakes of other classes were not associated with a reduction in overall IS, higher intakes of flavan-3-ols and their polymers were associated with a significant reduction in oxidative stress biomarkers. CONCLUSION: These findings provide evidence to suggest that an anti-inflammatory effect may be a key component underlying the reduction in risk of certain chronic diseases associated with higher intakes of anthocyanins and flavonols. The Framingham Offspring Study was registered at clinicaltrials.gov as NCT00005121 (Framingham Heart Study).

Evidence for an association of dietary flavonoid intake with breast cancer risk by estrogen receptor status is limited.

BACKGROUND: Results from preclinical studies suggest that flavonoids, which are ubiquitous in plant-based diets, lower breast cancer risk. Epidemiologic studies of flavonoid intake and breast cancer risk, however, are limited, and few investigated associations with the more aggressive estrogen receptor (ER)-negative (ER-) tumors. OBJECTIVE: We examined the associations between 7 subclasses of dietary flavonoids and invasive postmenopausal breast cancer risk overall and by ER status in a U.S. prospective cohort. METHODS: In 1999-2000, 56,630 postmenopausal women completed detailed self-administered questionnaires, among whom 2116 invasive breast cancers were verified during a mean follow-up period of 8.5 y. Cox proportional hazards regression was used to calculate multivariable-adjusted HRs and 95% CIs. RESULTS: Total flavonoid intake was not associated with breast cancer risk. However, there was a modest inverse association between flavone intake and overall breast cancer risk (fifth vs. first quintile HR: 0.88; 95% CI: 0.76, 1.01; P-trend = 0.04) and between flavan-3-ol intake and risk of ER- breast cancer (for an increment of 40 mg/d; HR: 0.81; 95% CI: 0.67, 0.97) but not for ER-positive (ER+) breast cancer risk. CONCLUSION: The inverse association of flavan-3-ol intake with ER- but not ER+ breast cancer is consistent with other studies that suggest a beneficial role of plant-based diets in ER- breast cancer risk.

Dietary flavonoid and proanthocyanidin intakes and prostate cancer risk in a prospective cohort of US men.

Higher dietary intakes of flavonoids and proanthocyanidins have been associated with a lower risk of several cancers. Few prospective epidemiologic studies have examined individual flavonoids and proanthocyanidins in relation to prostate cancer. We examined these associations in a prospective US cohort of 43,268 men with a mean age of 70 years who completed detailed self-administered questionnaires in 1999-2000. During a mean follow-up of 7.8 years, 3,974 total prostate cancers, including 567 high-grade cases and 362 advanced cases, were ascertained. Cox proportional hazards regression models were used to calculate multivariable-adjusted relative risks and 95% confidence intervals. Residual energy-adjusted total flavonoids (for fifth quintile vs. first quintile, relative risk = 1.11, 95% confidence interval: 1.01, 1.23; P for trend = 0.02) and several subclasses were positively associated with overall prostate cancer risk, mostly limited to the top quintile and the first 2 years of follow-up. The associations for total flavonoids, flavan-3-ols, and proanthocyanidins with high-grade prostate cancer risk varied by follow-up time. During follow-up from 2002 to 2009, we observed suggestive inverse trends with higher total flavonoids (P for trend = 0.05) and proanthocyanidins (P for trend = 0.04) with high-grade prostate cancer, but not with advanced prostate cancer. Although evidence is limited, a possible role of total flavonoids and proanthocyanidins in prostate cancer tumor progression deserves further study.

Higher dietary flavonol intake is associated with lower incidence of type 2 diabetes.

Substantial experimental evidence suggests that several flavonoid classes are involved in glucose metabolism, but few clinical or epidemiologic studies exist that provide supporting human evidence for this relationship. The objective of this study was to determine if habitual intakes of specific flavonoid classes are related to incidence of type 2 diabetes (T2D). We followed 2915 members of the Framingham Offspring cohort who were free of T2D at baseline from 1991 to 2008. Diabetes was defined by either elevated fasting glucose (≥7.0 mmol/L) or initiation of hypoglycemic medication during follow-up. Dietary intakes of 6 flavonoid classes and total flavonoids were assessed using a validated, semiquantitative food frequency questionnaire. We observed 308 incident cases of T2D during a mean follow-up period of 11.9 y (range 2.5-16.8 y). After multivariable adjusted, time-dependent analyses, which accounted for long-term flavonoid intake during follow-up, each 2.5-fold increase in flavonol intake was associated with a 26% lower incidence of T2D [HR = 0.74 (95% CI: 0.61, 0.90); P-trend = 0.003] and each 2.5-fold increase in flavan-3-ol intake was marginally associated with an 11% lower incidence of T2D [HR = 0.89 (95% CI: 0.80, 1.00); P-trend = 0.06]. No other associations between flavonoid classes and risk of T2D were observed. Our observations support previous experimental evidence of a possible beneficial relationship between increased flavonol intake and risk of T2D.

Associations between flavonoids and cardiovascular disease incidence or mortality in European and US populations.

Twenty publications from twelve prospective cohorts have evaluated associations between flavonoid intakes and incidence or mortality from cardiovascular disease (CVD) among adults in Europe and the United States. The most common outcome was coronary heart disease mortality, and four of eight cohort studies reported significant inverse associations for at least one flavonoid class (multivariate adjusted p(trend) < 0.05). Three of seven cohorts reported that greater flavonoid intake was associated with lower risk of incident stroke. Comparisons among the studies were difficult because of variability in the flavonoid classes included, demographic characteristics of the populations, outcomes assessed, and length of follow-up. The most commonly examined flavonoid classes were flavonols and flavones combined (11 studies). Only one study examined all seven flavonoid classes. The flavonol and flavone classes were most strongly associated with lower coronary heart disease mortality. Evidence for protection from other flavonoid classes and CVD outcomes was more limited. The hypothesis that flavonoid intakes are associated with lower CVD incidence and mortality requires further study.

Flavonoid intake and cardiovascular disease mortality in a prospective cohort of US adults.

BACKGROUND: Flavonoids are plant-based phytochemicals with cardiovascular protective properties. Few studies have comprehensively examined flavonoid classes in relation to cardiovascular disease mortality. OBJECTIVE: We examined the association between flavonoid intake and cardiovascular disease (CVD) mortality among participants in a large, prospective US cohort. DESIGN: In 1999, a total of 38,180 men and 60,289 women in the Cancer Prevention Study II Nutrition Cohort with a mean age of 70 and 69 y, respectively, completed questionnaires on medical history and lifestyle behaviors, including a 152-item food-frequency questionnaire. Cox proportional hazards modeling was used to calculate multivariate-adjusted hazard RRs and 95% CIs for associations between total flavonoids, 7 flavonoid classes, and CVD mortality. RESULTS: During 7 y of follow-up, 1589 CVD deaths in men and 1182 CVD deaths in women occurred. Men and women with total flavonoid intakes in the top (compared with the bottom) quintile had a lower risk of fatal CVD (RR: 0.82; 95% CI: 0.73, 0.92; P-trend = 0.01). Five flavonoid classes-anthocyanidins, flavan-3-ols, flavones, flavonols, and proanthocyanidins-were individually associated with lower risk of fatal CVD (all P-trend < 0.05). In men, total flavonoid intakes were more strongly associated with stroke mortality (RR: 0.63; 95% CI: 0.44, 0.89; P-trend = 0.04) than with ischemic heart disease (RR: 0.90; 95% CI: 0.72, 1.13). Many associations appeared to be nonlinear, with lower risk at intakes above the referent category. CONCLUSIONS: Flavonoid consumption was associated with lower risk of death from CVD. Most inverse associations appeared with intermediate intakes, suggesting that even relatively small amounts of flavonoid-rich foods may be beneficial.

Flavonoid consumption and esophageal cancer among black and white men in the United States.

Flavonoids and proanthocyanidins are bioactive polyphenolic components of fruits and vegetables that may account for part of the protective effect of raw fruit and vegetable consumption in esophageal cancer. We studied the relationship between esophageal cancer and dietary proanthocyanidins, flavonoids and flavonoid subclasses (anthocyanidins, flavan-3-ols, flavanones, flavones, flavonols and isoflavonoids) using recently developed USDA and Tufts flavonoid and proanthocyanidin databases. The study was a population-based, case-control analysis of 161 white men with esophageal adenocarcinoma (EAC), 114 white and 218 black men with esophageal squamous cell carcinoma (ESCC) and 678 white and 557 black male controls who lived in 3 areas of the United States. Neither total flavonoid nor proanthocyanidin intake was associated with EAC and ESCC in either white or black men. In white men, inverse associations were observed between anthocyanidin intake and EAC (4th vs. 1st quartile odds ratio [OR], 0.47, 95% confidence interval [CI], 0.24-0.91; p(trend) = 0.04) and between isoflavonoid intake and ESCC (4th vs. 1st quartile OR, 0.43, 95% CI, 0.20-0.93; p(trend) = 0.01). None of the associations remained significant after adjusting for dietary fiber, which is strongly correlated with flavonoid consumption. We conclude that total flavonoids and proanthocyanidins do not have strong protective effects in either EAC or ESCC. Some protective effects were evident in flavonoid subclasses and population subgroups. In white men, foods rich in anthocyanidins may have chemopreventive effects in EAC and those rich in isoflavonoids may do so in ESCC.

Measuring flavonoid intake: need for advanced tools.

OBJECTIVE: Flavonoids are phytochemicals with potentially beneficial biological effects that are poorly characterised in existing tables of food composition. DESIGN: To describe new techniques for analysis, absorption, informatics and dietary assessment that are important in measuring the flavonoid content in foods and in developing a flavonoid food composition database. SETTING: Data on chemical analyses of the major flavonoid compounds that exist in the food science literature are being located, collated and compiled into a preliminary flavonoid food composition database. RESULTS: The analytical process begins with preparation of the food for flavonoid analysis using techniques to disrupt the food matrix, alcoholic extraction, and enzymatic or acidic hydrolysis to remove sugars. Separation is usually accomplished using high-performance liquid chromatography. Flavonoids are identified by diode array spectrometry, mass spectrometry or nuclear magnetic resonance spectroscopy. Quantification usually employs comparison of the sample with standards, if available, using the area under the curve of the chromatogram to estimate quantity. Absorption studies are useful since flavonoids vary in their absorption. Finally, information management technologies (informatics) are used to translate flavonoid data information into food composition databases. This process involves identification of foods containing the compounds of interest, collection and organisation of sources of existing analytical data, assignment of quality scores or aggregation of acceptable data for each component and food, calculation of appropriate statistics, assignment of food codes and verification, and finalization. The resulting food flavonoid database can be used with state-of-the-art dietary assessment methods to develop estimates of flavonoid intakes in foods and to correlate these with estimates of disease risk. CONCLUSIONS: A provisional flavonoid database, including at least two components from each of six classes of flavonoids, should be completed in 2002.