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Over half of all cardiovascular (CV) events could be prevented by improved diet. This is reflected in government targets for fruit/vegetable intake, yet these are variable across the world (UK: 5-a-day; USA: 9-a-day), do not identify specific fruits/vegetables, and prove hard to achieve. Mounting evidence from prospective studies, supported by recent randomised controlled trials suggest that the benefits of fruits/vegetables may be due to bioactive substances called flavonoids. Specifically one sub-class of flavonoids, the anthocyanins, responsible for the red/blue hue, are receiving growing attention. Although promising data is emerging from cohort studies, and cell/animal studies, proof of efficacy from longer-term randomised controlled trials, and an understanding of the importance of differential metabolism in relation to clinical efficacy are distinctly lacking. Diet related ill-health are among the leading priorities of our time and simple dietary change, including incorporating a few portions of anthocyanin-rich fruit into our diet could have a significant impact at a public health level., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Background: Although dietary flavonoid intake has been associated with less weight gain, there are limited data on its impact on fat mass, and to our knowledge, the contribution of genetic factors to this relation has not previously been assessed. Objective: We examined the associations between flavonoid intakes and fat mass. Design: In a study of 2734 healthy, female twins aged 18-83 y from the TwinsUK registry, intakes of total flavonoids and 7 subclasses (flavanones, anthocyanins, flavan-3-ols, flavonols, flavones, polymers, and proanthocyanidins) were calculated with the use of food-frequency questionnaires. Measures of dual-energy X-ray absorptiometry-derived fat mass included the limb-to-trunk fat mass ratio (FMR), fat mass index, and central fat mass index. Results: In cross-sectional multivariable analyses, higher intake of anthocyanins, flavonols, and proanthocyanidins were associated with a lower FMR with mean ± SE differences between extreme quintiles of -0.03 ± 0.02 ( P -trend = 0.02), -0.03 ± 0.02 ( P -trend = 0.03), and -0.05 ± 0.02 ( P -trend < 0.01), respectively. These associations were not markedly changed after further adjustment for fiber and total fruit and vegetable intakes. In monozygotic, intake-discordant twin pairs, twins with higher intakes of flavan-3-ols ( n = 154, P = 0.03), flavonols ( n = 173, P = 0.03), and proanthocyanidins ( n = 172, P < 0.01) had a significantly lower FMR than that of their co-twins with within-pair differences of 3-4%. Furthermore, in confirmatory food-based analyses, twins with higher intakes of flavonol-rich foods (onions, tea, and pears; P = 0.01) and proanthocyanidin-rich foods (apples and cocoa drinks; P = 0.04) and, in younger participants (aged <50 y) only, of anthocyanin-rich foods (berries, pears, grapes, and wine; P = 0.01) had a 3-9% lower FMR than that of their co-twins. Conclusions: These data suggest that higher habitual intake of a number of flavonoids, including anthocyanins, flavan-3-ols, flavonols, and proanthocyanidins, are associated with lower fat mass independent of shared genetic and common environmental factors. Intervention trials are needed to further examine the effect of flavonoid-rich foods on body composition.

At a population level, there is growing evidence of the beneficial effects of dietary flavonoids on health. However, there is extensive heterogeneity in the response to increased intake, which is likely mediated via wide interindividual variability in flavonoid absorption and metabolism. Flavonoids are extensively metabolized by phase I and phase II metabolism (which occur predominantly in the gastrointestinal tract and liver) and colonic microbial metabolism. A number of factors, including age, sex, and genotype, may affect these metabolic processes. In addition, food composition and flavonoid source are likely to affect bioavailability, and emerging data suggest a critical role for the microbiome. This review will focus on the current knowledge for the main subclasses of flavonoids, including anthocyanins, flavonols, flavan-3-ols, and flavanones, for which there is growing evidence from prospective studies of beneficial effects on health. The identification of key factors that govern metabolism and an understanding of how the differential capacity to metabolize these bioactive compounds affect health outcomes will help establish how to optimize intakes of flavonoids for health benefits and in specific subgroups. We identify research areas that need to be addressed to further understand important determinants of flavonoid bioavailability and metabolism and to advance the knowledge base that is required to move toward the development of dietary guidelines and recommendations for flavonoids and flavonoid-rich foods.

Background: Although increased fruit intake reduces cardiovascular disease (CVD) risk, which fruits are most beneficial and what key constituents are responsible are unclear. Habitual intakes of flavonoids, specifically anthocyanins and flavanones, in which >90% of habitual intake is derived from fruit, are associated with decreased CVD risk in women, but associations in men are largely unknown., Objective: We examined the relation between habitual anthocyanin and flavanone intake and coronary artery disease and stroke in the Health Professionals Follow-Up Study., Design: We followed 43,880 healthy men who had no prior diagnosed CVD or cancer. Flavonoid intake was calculated with the use of validated food-frequency questionnaires., Results: During 24 y of follow-up, 4046 myocardial infarction (MI) and 1572 stroke cases were confirmed by medical records. Although higher anthocyanin intake was not associated with total or fatal MI risk, after multivariate adjustment an inverse association with nonfatal MI was observed (HR: 0.87; 95% CI: 0.75, 1.00; P = 0.04; P-trend = 0.098); this association was stronger in normotensive participants (HR: 0.81; 95% CI: 0.69, 0.96; P-interaction = 0.03). Anthocyanin intake was not associated with stroke risk. Although flavanone intake was not associated with MI or total stroke risk, higher intake was associated with a lower risk of ischemic stroke (HR: 0.78; 95% CI: 0.62, 0.97; P = 0.03, P-trend = 0.059), with the greatest magnitude in participants aged ≥65 y (P-interaction = 0.04)., Conclusions: Higher intakes of fruit-based flavonoids were associated with a lower risk of nonfatal MI and ischemic stroke in men. Mechanistic studies and clinical trials are needed to unravel the differential benefits of anthocyanin- and flavanone-rich foods on cardiovascular health.

Background: There is much speculation with regard to the potential cardioprotective benefits of equol, a microbial-derived metabolite of the isoflavone daidzein, which is produced in the large intestine after soy intake in 30% of Western populations. Although cross-sectional and retrospective data support favorable associations between the equol producer (EP) phenotype and cardiometabolic health, few studies have prospectively recruited EPs to confirm this association., Objective: The aim was to determine whether the acute vascular benefits of isoflavones differ according to EP phenotype and subsequently investigate the effect of providing commercially produced S-(-)equol to non-EPs., Design: We prospectively recruited male EPs and non-EPs (n = 14/group) at moderate cardiovascular risk into a double-blind, placebo-controlled crossover study to examine the acute effects of soy isoflavones (80-mg aglycone equivalents) on arterial stiffness [carotid-femoral pulse-wave velocity (cfPWV)], blood pressure, endothelial function (measured by using the EndoPAT 2000; Itamar Medical), and nitric oxide at baseline (0 h) and 6 and 24 h after intake. In a separate assessment, non-EPs consumed 40 mg S-(-)equol with identical vascular measurements performed 2 h after intake., Results: After soy intake, cfPWV significantly improved in EPs at 24 h (cfPWV change from 0 h: isoflavone, -0.2 ± 0.2 m/s; placebo, 0.6 ± 0.2 m/s; P < 0.01), which was significantly associated with plasma equol concentrations (R = -0.36, P = 0.01). No vascular effects were observed in EPs at 6 h or in non-EPs at any time point. Similarly, no benefit of commercially produced S-(-)equol was observed in non-EPs despite mean plasma equol concentrations reaching 3.2 μmol/L., Conclusions: Acute soy intake improved cfPWV in EPs, equating to an 11-12% reduced risk of cardiovascular disease if sustained. However, a single dose of commercially produced equol had no cardiovascular benefits in non-EPs. These data suggest that the EP phenotype is critical in unlocking the vascular benefits of equol in men, and long-term trials should focus on confirming the implications of EP phenotype on cardiovascular health. This trial was registered at clinicaltrials.gov as NCT01530893.

Background: The predominant etiology for erectile dysfunction (ED) is vascular, but limited data are available on the role of diet. A higher intake of several flavonoids reduces diabetes and cardiovascular disease risk, but no studies have examined associations between flavonoids and erectile function., Objective: This study examined the relation between habitual flavonoid subclass intakes and incidence of ED., Design: We conducted a prospective study among 25,096 men from the Health Professionals Follow-Up Study. Total flavonoid and subclass intakes were calculated from food-frequency questionnaires collected every 4 y. Participants rated their erectile function in 2000 (with historical reporting from 1986) and again in 2004 and 2008., Results: During 10 y of follow-up, 35.6% reported incident ED. After multivariate adjustment, including classic cardiovascular disease risk factors, several subclasses were associated with reduced ED incidence, specifically flavones (RR = 0.91; 95% CI: 0.85, 0.97; P-trend = 0.006), flavanones (RR = 0.89; 95% CI: 0.83, 0.95; P-trend = 0.0009), and anthocyanins (RR = 0.91; 95% CI: 0.85, 0.98; P-trend = 0.002) comparing extreme intakes. The results remained statistically significant after additional adjustment for a composite dietary intake score. In analyses stratified by age, a higher intake of flavanones, anthocyanins, and flavones was significantly associated with a reduction in risk of ED only in men <70 y old and not older men (11-16% reduction in risk; P-interaction = 0.002, 0.03, and 0.007 for flavones, flavanones, and anthocyanins, respectively). In food-based analysis, higher total intake of fruit, a major source of anthocyanins and flavanones, was associated with a 14% reduction in risk of ED (RR = 0.86; 95% CI: 0.79, 0.92; P = 0.002)., Conclusions: These data suggest that a higher habitual intake of specific flavonoid-rich foods is associated with reduced ED incidence. Intervention trials are needed to further examine the impact of increasing intakes of commonly consumed flavonoid-rich foods on men's health.

Background: It is unknown whether habitual intake of dietary flavonoids, known for their antioxidative and anti-inflammatory properties, affects longitudinal change in lung function., Objective: We investigated whether different flavonoid subclasses present in the habitual diet were associated with beneficial changes in lung function over time in the elderly., Design: This longitudinal analysis included 839 participants from the VA (Veterans Affairs) Normative Aging Study whose lung function [forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)] was measured at 2 and up to 5 visits between 1992 and 2008 (n = 2623 measurements). Yearly average intake of major flavonoid subclasses (anthocyanins, flavanones, flavan-3-ols, flavonols, flavones, and polymers) was calculated from food-frequency questionnaires at each visit. We estimated adjusted differences in annual change in lung function associated with each flavonoid subclass, categorized into quartiles, in linear mixed-effects regression models after adjustment for lifestyle and dietary confounders., Results: Strong inverse associations were found between anthocyanin intake and age-related decline in lung function. Independent of dietary and nondietary risk factors, slower rates of FEV1 and FVC decline by 23.6 (95% CI: 16.6, 30.7) and 37.3 (95% CI: 27.8, 46.8) mL/y, respectively, were observed in participants in the fourth quartile of intake compared with participants in the first quartile (P-trend < 0.0001). The protective associations observed for anthocyanin intake were present in both current/former and never smokers. Compared with no or very low intakes, an intake of ≥2 servings of anthocyanin-rich blueberries/wk was associated with slower decline in FEV1 and FVC by 22.5 (95% CI: 10.8, 34.2) and 37.9 (95% CI: 22.1, 53.7) mL/y, respectively. To a lesser extent, higher flavan-3-ol intake was also associated with slower lung function decline., Conclusions: An attenuation of age-related lung function decline was associated with higher dietary anthocyanin intake in this longitudinal sample of predominantly elderly men. Further prospective studies are needed to confirm these novel associations.

Objective: To examine whether dietary intake of specific flavonoid subclasses (including flavonols, flavones, flavanones, flavan-3-ols, anthocyanins, and flavonoid polymers) is associated with weight change over time., Design: Three prospective cohort studies., Setting: Health professionals in the United States., Participants: 124,086 men and women participating in the Health Professionals Follow-up Study (HPFS), Nurses' Health Study (NHS), and Nurses' Health Study II (NHS II)., Main Outcome Measure: Self reported change in weight over multiple four year time intervals between 1986 and 2011., Results: Increased consumption of most flavonoid subclasses, including flavonols, flavan-3-ols, anthocyanins, and flavonoid polymers, was inversely associated with weight change over four year time intervals, after adjustment for simultaneous changes in other lifestyle factors including other aspects of diet, smoking status, and physical activity. In the pooled results, the greatest magnitude of association was observed for anthocyanins (-0.23 (95% confidence interval -0.30 to -0.15) lbs per additional standard deviation/day, 10 mg), flavonoid polymers (-0.18 (-0.28 to -0.08) lbs per additional SD/day, 138 mg), and flavonols (-0.16 (-0.26 to -0.06) lbs per additional SD/day, 7 mg). After additional adjustment for fiber intake, associations remained significant for anthocyanins, proanthocyanidins, and total flavonoid polymers but were attenuated and no longer statistically significant for other subclasses., Conclusions: Higher intake of foods rich in flavonols, flavan-3-ols, anthocyanins, and flavonoid polymers may contribute to weight maintenance in adulthood and may help to refine dietary recommendations for the prevention of obesity and its potential consequences., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Flavonoids inhibit the growth of colon cancer cells in vitro. In a secondary analysis of a randomized controlled trial, the Polyp Prevention Trial, a higher intake of one subclass, flavonols, was statistically significantly associated with a reduced risk of recurrent advanced adenoma. Most previous prospective studies on colorectal cancer evaluated only a limited number of flavonoid subclasses and intake ranges, yielding inconsistent results., Objective: In this study, we examined whether higher habitual dietary intakes of flavonoid subclasses (flavonols, flavones, flavanones, flavan-3-ols, and anthocyanins) were associated with a lower risk of colorectal cancer., Design: Using data from validated food-frequency questionnaires administered every 4 y and an updated flavonoid food composition database, we calculated flavonoid intakes for 42,478 male participants from the Health Professionals Follow-Up Study and for 76,364 female participants from the Nurses' Health Study., Results: During up to 26 y of follow-up, 2519 colorectal cancer cases (1061 in men, 1458 in women) were documented. Intakes of flavonoid subclasses were not associated with risk of colorectal cancer in either cohort. Pooled multivariable adjusted RRs (95% CIs) comparing the highest with the lowest quintiles were 1.04 (0.91, 1.18) for flavonols, 1.01 (0.89, 1.15) for flavones, 0.96 (0.84, 1.10) for flavanones, 1.07 (0.95, 1.21) for flavan-3-ols, and 0.98 (0.81, 1.19) for anthocyanins (all P values for heterogeneity by sex >0.19). In subsite analyses, flavonoid intake was also not associated with colon or rectal cancer risk., Conclusion: Our findings do not support the hypothesis that a higher habitual intake of any flavonoid subclass decreases the risk of colorectal cancer.

The most extensively studied class of phytoestrogens, isoflavones, occur in soybeans and other legumes. Six systematic reviews have assessed the effects of soy isoflavones on lipid levels, and suggested that a diet supplemented with soy protein isolate (ISP) containing isoflavones reduces low-density lipoprotein (LDL) cholesterol by around 0.15 mmol/L, but without clear effects on triglycerides or high-density lipoprotein (HDL) cholesterol. However, no review has suggested that purified soy isoflavones or soy protein without isoflavones (where the isoflavones have been removed by an alcohol wash) have statistically significant effects. It remains unclear which are the active components of soy. They may include soy protein which has not been denatured by alcohol wash, interaction of isoflavones within the intact soy matrix, or other compounds removed in the alcohol-extracted fraction. The reduction in total cholesterol may be greater in men than in postmenopausal women. There is little evidence that the effectiveness of soy varies with baseline serum lipid levels, or the amount of isoflavone or soy protein consumed. However, changes in triglycerides may be related to baseline levels. While there is no evidence of beneficial effects of phytoestrogens on blood pressure, arterial compliance or oxidation of LDL cholesterol, there may be beneficial effects on endothelial function in postmenopausal women, and on homocysteine concentrations. There is little suggestion of adverse effects of soy or isoflavones at physiological doses, although those taking soy isoflavone supplements do appear to have higher levels of gastro intestinal and menstrual complaints. There have been no published trials on the effects of phytoestrogens on mortality or cardiovascular events, so studies currently rely on the above bio markers of risk. Most evidence relates to soy isoflavones, but there is some evidence for lignans. Further robust studies assessing the effects of whole soy foods on cardiovascular outcomes are needed.