Flavonoids are a large group of secondary metabolites in plants. Among the flavonoids, several subclasses can be distinguished including flavonols (e.g. tea, onions, and apples), flavones (herbs and celery), flavanones (citrus fruit), flavan-3-ols (green tea, cocoa, and apples), anthocyanidins (colored berries), isoflavones (soy products), and polymeric forms . Until recently, epidemiological research on the relationship between flavonoid intakes and health outcomes was hampered by the limited data on flavonoids in food composition tables. New versions of the US Department of Agriculture (USDA) database and the Phenol-Explorer database include more detailed information on the flavonoid content of foods. As a result of substantial differences in chemical structure, there are large differences in bioavailability and bioactivity between different types of flavonoids. Therefore, distinction between different subclasses of flavonoids is clearly warranted in studies of their health effects. Only recently, a substantial number of epidemiological studies evaluating a wider range of flavonoid subclasses (e.g. anthocyanidins and flavanones) have been published. In addition, the number of randomized trials of flavonoid-rich foods has increased substantially. The aim of this article is to review the recent studies of flavonoids in relation to the development of type 2 diabetes and cardiovascular diseases including epidemiological studies, randomized trials, meta-analyses, and mechanistic studies. This review will focus on flavonoids other than isoflavones as these phytoestrogens may affect cardiovascular disease through different biological pathways.
FLAVONOID INTAKES AND THEIR MAJOR FOOD SOURCES
Assessment of flavonoid intakes is challenged by the large diversity of compounds belonging to this group of polyphenols. Many flavonoid compounds exist as glucosides in foods. To reduce the complexity and to facilitate studies on their effects on human health, flavonoids have typically been divided into subclasses according to the structural similarities and intakes are generally calculated on an aglycone basis. Different individual compounds belonging to the subclasses have been analyzed using a large variety of analytical techniques without much harmonization . Variation in content because of variety, agronomic and environmental conditions, storage, and food processing further adds to the complexity and has made it difficult to assign content values to specific food items .
Recently, several new databases containing a large number of food items and flavonoid compounds have become available. The USDA provides databases on monomeric flavonoids, proanthocyanidins (oligomeric and polymeric flavan-3-ols), and isoflavones. The most recent update was made in 2011 for monomeric flavonoids and it contains the composition of 28 predominant monomeric flavonoid compounds in 500 foods . The USDA databases on the composition of proanthocyanidins and isoflavones were updated in 2004 and 2008, respectively [5,6]. Another recently developed database is Phenol-Explorer (www.phenol-explorer.eu) which contains 502 polyphenols (including 281 flavonoids) in 452 foods . EuroFIR-BASIS is another database developed on bioactive compounds in plant-based foods and it contains some food content data on flavonoids and also on biological effects .
In a population-based study of 4942 French men and women (45–60 years), intake of polyphenols and flavonoids were assessed using the Phenol-Explorer database and repeated 24-h dietary recalls [8▪]. The mean estimated intake was 1.2 g/day for total polyphenols and 506 mg/day for flavonoids. The main contributing food items to total polyphenols were coffee (44%), tea (9%), apples (6%), and red wine (6%), with coffee contributing to intake of phenolic acids rather than flavonoids. In cohorts of US health professionals, intakes of total flavonoids were assessed using the USDA databases and food frequency questionnaires . The mean total flavonoid intakes in the three cohorts ranged from 358 to 414 mg/day. Tea was the main source for total flavonoids followed by apples, orange juice, and strawberries.
EPIDEMIOLOGICAL AND INTERVENTION STUDIES ON FLAVONOIDS AND CARDIOVASCULAR DISEASES
Several recent major studies have explored the roles of anthocyanidins, flavanones, flavonols, flavan-3-ols and cocoa, and green and black tea on cardiovascular disease outcomes. These are discussed in detail below.
Recently, several cohort studies have published data on anthocyanidin intakes (typically ingested as glucosides) in relation to the risk of type 2 diabetes and cardiovascular diseases. In three large US prospective cohorts of health professionals, a higher intake of anthocyanidins, but not other flavonoid subclasses, was consistently associated with a lower risk of type 2 diabetes [10▪]. Consumption of blueberries, the main source of anthocyanidins, was also associated with a lower risk of type 2 diabetes in line with the findings for berry consumption in a Finnish cohort study . In contrast, anthocyanidin intake was not associated with diabetes risk in the Iowa Women's Health Study possibly because important food sources of anthocyanidins were not assessed on the dietary questionnaire . Anthocyanidin intakes were significantly associated with lower systolic blood pressure and pulse wave velocity (a measure of arterial stiffness) in a cross-sectional study of UK women ; with a lower risk of hypertension in cohorts of US male and female health professionals ; and a lower risk of coronary heart disease and cardiovascular disease mortality in two other large US cohorts [14,15]. A randomized double-blind trial of 150 Chinese persons with hyperlipidemia tested the effect of anthocyanin extracts from berries over 24 weeks (Table 1) [16▪]. This intervention resulted in significant improvements in blood lipids and inflammatory markers. In an earlier trial, this research group also reported beneficial acute and longer term (12 weeks) effects of anthocyanin extracts on endothelial function as measured by flow-mediated dilation (FMD) . These promising results warrant further randomized trials on the effects of anthocyanidins on metabolic and cardiovascular health.
In a cohort of female US nurses, higher intake of flavanones (from citrus fruit) was associated with a modestly lower incidence of stroke . This result is consistent with the association between flavanone intakes and incidence of stroke in a Finnish cohort , but at odds with the lack of association with stroke mortality in two other US cohorts [14,15]. In a cross-over study of 24 healthy overweight French men, both orange juice and the flavanone hesperidin reduced diastolic blood pressure over 4 weeks, suggesting that hesperidin may be responsible for this beneficial effect of citrus fruit [17▪]. However, multiple cardiovascular biomarkers were evaluated as an outcome which increases the probability of chance findings. Overall, recent studies have provided some support for the potential benefits of flavanone intake for cardiovascular health, but the evidence is mixed and further studies are clearly needed.
Early epidemiological studies of flavonoids mainly focused on flavonols (sometimes in combination with flavones for which intakes are much lower) and strong inverse associations with coronary heart disease and stroke were reported. However, in a recent meta-analysis of nine cohort studies conducted in Europe and the USA, flavonol intake was not substantially associated with the risk of coronary heart disease [summary relative risk (RR) 0.91; 95% confidence interval (CI) 0.83–1.01 for highest vs. lowest category] . For stroke, a meta-analysis of six cohort studies published up to 2009 supported an inverse association (RR 0.80; 95% CI 0.65–0.98), but results varied substantially between cohorts  and no significant association with stroke mortality was observed in two large cohort studies published after the meta-analysis [15,28]. Thus, the overall epidemiological evidence for a beneficial effect of flavonols is weak for coronary heart disease and inconsistent for stroke. This does not necessarily mean that these dietary components do not provide any benefits for cardiovascular health as measurement error for the assessment of flavonol intakes may have substantially weakened the observed associations. In a recent cross-sectional study, US women with higher flavonol intakes had lower soluble vascular adhesion molecule-1 (sVCAM-1) levels reflecting better endothelial function .
Few intervention studies in humans have evaluated pure flavonol compounds. In a randomized, double-blind, crossover trial, 4 weeks of supplementation with the flavonol quercetin reduced blood pressure in participants with hypertension, but not in those without hypertension . No significant effects were found on the markers of oxidative stress, blood lipids, or fasting glucose concentrations. These results are intriguing but were based on only 22 individuals with hypertension and require confirmation.
Flavan-3-ols and cocoa
Results for total flavan-3-ol intake and risk of cardiovascular diseases in cohort studies have been inconsistent [14,15]. In contrast, most studies of chocolate and cocoa consumption reported an inverse association with the risk of cardiovascular diseases [33,34]. In addition, a large number of trials of the effect of cocoa intake on cardiometabolic biomarkers have been conducted. In a meta-analysis of randomized trials of at least 2 weeks duration, cocoa intake reduced systolic (−2.8 mmHg; 95% CI −4.7 to −0.8; 20 trials) and diastolic blood pressure (−2.2 mmHg; 95% CI −3.5 to −0.9; 19 trials) . However, heterogeneity in the study results was large and tests for publication bias were marginally significant. In subgroup analyses, substantial effects on blood pressure were only found in studies that used a control intervention without any flavanols rather than a low-flavanol control; used an intervention that was not blinded for the participants; or had an intervention duration of only 2 weeks. Because these characteristics largely overlapped between studies, the authors could not distinguish whether the observed effects in these subgroups were a result of a greater contrast in flavanol intakes between the intervention and control group; bias because of a lack of blinding; or an effect that is only short term. In another meta-analysis, the pooled effect of cocoa on lowering LDL-cholesterol and increasing HDL-cholesterol levels was only marginally significant with large heterogeneity and inconsistent results in stratified analyses [18▪▪].
Fewer studies have evaluated the effects of cocoa intake on endothelial function measured by FMD and insulin resistance measured by the HOMA index. However, in meta-analyses the pooled effects for cocoa interventions lasting at least 2 weeks were highly statistically significant and consistent across studies (Table 1) [18▪▪,19]. It should be noted that the trials were small with 181 participants in five trials for insulin resistance and 382 participants in 10 trials for endothelial function. Consistent with the meta-analyses, a subsequently published double-blind, randomized trial in 90 elderly participants found a beneficial effect of cocoa on HOMA-insulin resistance . In addition to the chronic effects, cocoa has also been shown to acutely improve FMD and similar acute effects have been found for the pure flavanol (−)-epicatechin, supporting the hypothesis that flavanols are responsible for the effects of cocoa on endothelial function .
Until recently, trials of the effects of cocoa intake on cardiometabolic biomarkers have been of short duration (maximum of 18 weeks). In a 1-year trial in 93 postmenopausal medicated women with type 2 diabetes, a combination of isoflavones and flavan-3-ols significantly reduced the HOMA index for insulin resistance and LDL-cholesterol [21▪]. These data do not allow distinction between the effects of flavan-3-ols and isoflavone-rich extracts, but suggest that flavonoids can have beneficial long-term effects on cardiovascular health.
Green and black tea
Tea is a source of various flavonoids including flavonols and flavan-3-ols with substantially higher flavan-3-ol concentrations in green tea as compared with black tea. Higher black tea consumption was associated with a lower risk of coronary heart disease in early studies, but not in a recent meta-analysis . In contrast, green tea consumption was associated with a lower risk of coronary heart disease based on five studies in Japan and China, but this finding requires further confirmation as only two prospective studies were available. The association between tea consumption and stroke was also evaluated in a recent meta-analysis of cohort studies . Again, this association was stronger for green tea (summary RR 0.83; 95% CI 0.72–0.96 for 3 cups per day increment; 5 studies) than for black tea (RR 0.91; 95% CI 0.83–0.98; 13 studies). In a large case-cohort study in eight European countries, tea consumption (predominantly black tea) was associated with a modestly lower risk of type 2 diabetes (RR 0.84; 95% CI 0.71–1.00 for ≥4 vs. 0 cups per day)  and consistent with the results from an earlier meta-analysis of cohort studies . Few studies have been published on green tea and the development of type 2 diabetes, and the results have so far been inconsistent [41,42]. Taken together, epidemiological evidence does not support a substantial effect of black tea consumption on risk of coronary heart disease. In most populations, tea consumption is associated with a more health conscious lifestyle. Although the described studies adjusted for potential confounding by lifestyle factors, residual confounding could explain the modest associations between black tea and risk of type 2 diabetes and stroke. The association between green tea and a lower risk of coronary heart disease and stroke was stronger than for black tea, but requires confirmation in further studies.
In a recent meta-analysis of 14 randomized controlled trials, green tea consumption significantly reduced LDL-cholesterol and heterogeneity in study results was limited (Table 1). In contrast, no effect on HDL-cholesterol concentrations was observed. The effect on LDL-cholesterol was found regardless of the type of intervention (beverage or capsule), study quality, or industry funding [22▪]. An independent meta-analysis  and two randomized trials of green tea extracts published subsequently [25,26] confirmed the beneficial effect on LDL-cholesterol. Black tea consumption did not have substantial effects on LDL-cholesterol . In contrast, both green tea and black tea appeared to increase FMD in randomized controlled trials although this mainly reflected acute effects as few studies evaluated effects of longer term consumption .
NEW INSIGHTS INTO THE BIOLOGICAL MECHANISMS
Flavonoids are potent antioxidants in vitro through their scavenging of several types of radicals and their metal ion chelating abilities. However, there is little evidence of antioxidant effects in vivo. This is probably explained by the generally low concentrations in blood because of low bioavailability and extensive metabolism which reduces their antioxidant activity . Recently, research has shifted focus from antioxidant effects to other aspects of bioactivity of flavonoid compounds such as effects on signal transduction and different enzyme systems .
Effects of flavonoids on cardiometabolic biomarkers have been intensively studied in different model systems. For example, results from recent animal studies suggest that catechins (part of the flavan-3-ol subclass) such as epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea, have beneficial effects on the components of the metabolic syndrome. In a high-fat Western diet mouse model, EGCG reduced body fatness, insulin resistance, hyperglycemia, dyslipidemia, hepatic steatosis, and systemic inflammation . Effects appeared to be partly mediated through direct postprandial effects on energy balance and lipid metabolism caused by decreased lipid absorption and increased lipid oxidation . In addition, anti-inflammatory effects mediated through blocking NF-κB activation in endothelial cells may have contributed to the observed beneficial effects. Several catechins may also activate the enzyme AMP-activated protein kinase (AMPK) which plays a central role in the regulation of glucose and lipid metabolism. When activated, AMPK increases cellular energy availability by inhibiting anabolic pathways (e.g. synthesis of glucose and lipids) and stimulating catabolic pathways (e.g. glucose and fat oxidation) . Animal studies also suggest that EGCG may have antidiabetic properties through enhanced pancreatic beta-cell function .
Several flavonoid compounds, particularly among the flavan-3-ols and anthocyanidins, have been shown to improve endothelial function in experimental studies. This improvement is likely to be mediated by a greater availability of the signaling molecule nitric oxide which increases vascular smooth muscle relaxation leading to arterial vasodilation [50▪]. Nitric oxide is synthesized by nitric oxide synthase, and flavan-3-ols and anthocyanidins have been shown to upregulate the expression of this enzyme and its activity. In addition, anthocyanidin compounds have been shown to inhibit endothelial NADPH oxidase which reduces the bioactivity of nitric oxide in the endothelium .
In general, the relevance of in-vitro and animal studies needs to be confirmed for human in-vivo conditions, because many studies tested unrealistic amounts of flavonoid compounds. Moreover, parent compounds rather than metabolites have most often been evaluated, despite the fact that parent compounds typically have low bioavailability and rapid elimination through metabolism and excretion .
Our review of the recent scientific literature on flavonoid intakes and cardiovascular health highlights the substantial advances in the available evidence. In contrast to the results from early studies, the overall data from epidemiological research provides little support for a relationship between higher intakes of flavonols and black tea and a lower risk of coronary heart disease. In contrast, promising results from epidemiological studies and randomized trials are emerging for the beneficial effects of higher intakes of anthocyanidins, green tea, and cocoa on cardiovascular and metabolic health. These findings require confirmation in further prospective cohort studies and larger trials of longer duration. Meta-analyses have highlighted that many of the trials have potential methodological limitations including being underpowered; lack of allocation concealment or adequate reporting thereof; incomplete blinding of participants and researchers; incomplete reporting of dropouts; and industry involvement [18▪▪,22▪]. However, several of the findings, including beneficial effects of green tea on LDL-cholesterol and of cocoa on endothelial function and insulin sensitivity, were robust for exclusions of studies with these limitations. A limitation that remains for almost all published trials is the short duration of the intervention and the use of flavonoid-rich foods or food extracts rather than specific flavonoid compounds. Randomized trials of pure flavonoid compounds are needed to establish that flavonoids are responsible for the health effects of flavonoid-rich foods and what specific flavonoid components and doses are effective. Currently, it seems reasonable to recommend green tea among several healthy beverage choices, berries as part of varied fruit consumption pattern, and dark chocolate in moderate amounts as a preferred alternative to milk or white chocolate. However, establishing what specific compounds in flavonoid-rich foods are responsible for the health benefits is of both scientific and public health interest as consumers may currently receive highly variable health benefits from these foods depending on the concentration of active components.
R.M.v.D. was supported by the Saw Swee Hock School of Public Health, National University of Singapore. R.L. was supported by a Research Grant for Young Investigators from the Swedish Research Council.
Conflicts of interest
R.M.v.D. has received funding for independent research from Nestlé.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 89–90).
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