van Dam, Rob M.a,b,c; Naidoo, Nasheena; Landberg, Rikardd
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).
1. Crozier A, Burns J, Aziz AA, et al. Antioxidant flavonols from fruits, vegetables and beverages: measurements and bioavailability. Biol Res 2000; 33:79–88.
2. Neveu V, Perez-Jimenez J, Vos F, et al. Phenol-Explorer: an online comprehensive database on polyphenol contents in foods. Database (Oxford) 2010; 2010:bap024.
3. Amarowicz R, Carle R, Dongowski G, et al. Influence of postharvest processing and storage on the content of phenolic acids and flavonoids in foods. Mol Nutr Food Res 2009; 53 (Suppl. 2):S151–S183.
4. U.S. Department of Agriculture, Agricultural Research Service. USDA Database for the flavonoid content of selected foods, Release 3.0. Nutrient Data Laboratory Home Page: http://www.ars.usda.gov/nutrientdata/flav
7. Gry J, Black L, Eriksen FD, et al. EuroFIR-BASIS – a combined composition and biological activity database for bioactive compounds in plant-based foods. Trends Food Sci Technol 2007; 18:434–444.
8▪. Pérez-Jiménez J, Fezeu L, Touvier M, et al. Dietary intake of 337 polyphenols in French adults. Am J Clin Nutr 2011; 93:1220–1228.
This article provides a comprehensive description of the intake of different classes of polyphenols and their major food sources in a population-based sample based on the new Phenol-Explorer food composition database.
9. Cassidy A, O’Reilly EJ, Kay C, et al. Habitual intake of flavonoid subclasses and incident hypertension in adults. Am J Clin Nutr 2011; 93:338–347.
10▪. Wedick NM, Pan A, Cassidy A, et al. Dietary flavonoid intakes and risk of type 2 diabetes in US men and women. Am J Clin Nutr 2012; 95:925–933.
This article is the first study to report an association between anthocyanidin intake, but not other flavonoid classes, and a lower risk of type 2 diabetes based on data from three US cohort studies. The results also suggest that associations between fruit consumption and risk of type 2 diabetes may depend on the type of fruit consumed with berries and apples being particularly beneficial.
11. Knekt P, Kumpulainen J, Jarvinen R, et al. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr 2002; 76:560–568.
12. Nettleton JA, Harnack LJ, Scrafford CG, et al. Dietary flavonoids and flavonoid-rich foods are not associated with risk of type 2 diabetes in postmenopausal women. J Nutr 2006; 136:3039–3045.
13. Jennings A, Welch AA, Fairweather-Tait SJ, et al. Higher anthocyanin intake is associated with lower arterial stiffness and central blood pressure in women. Am J Clin Nutr 2012; 96:781–788.
14. Mink PJ, Scrafford CG, Barraj LM, et al. Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr 2007; 85:895–909.
15. McCullough ML, Peterson JJ, Patel R, et al. Flavonoid intake and cardiovascular disease mortality in a prospective cohort of US adults. Am J Clin Nutr 2012; 95:454–464.
16▪. Zhu Y, Ling W, Guo H, et al. Anti-inflammatory effect of purified dietary anthocyanin in adults with hypercholesterolemia: a randomized controlled trial. Nutr Metab Cardiovasc Dis 2012 [Epub ahead of print].
Results from this 24-week randomized trial of 150 Chinese individuals are among the first to suggest that intake of anthocyanins may reduce inflammation and improve blood lipid concentrations and endothelial function.
17▪. Morand C, Dubray C, Milenkovic D, et al. Hesperidin contributes to the vascular protective effects of orange juice: a randomized crossover study in healthy volunteers. Am J Clin Nutr 2011; 93:73–80.
This trial tested the effects of the isolated flavonoid hesperidin in addition to orange juice, suggesting that at least some of the health benefits of citrus fruit are mediated by flavonoids.
18▪▪. Hooper L, Kay C, Abdelhamid A, et al. Effects of chocolate, cocoa, and flavan-3-ols on cardiovascular health: a systematic review and meta-analysis of randomized trials. Am J Clin Nutr 2012; 95:740–751.
This is a meta-analysis of a large number of randomized trials on cocoa intake and cardiometabolic biomarkers highlighting the methodological strengths and limitation of the research conducted to date. The results suggest that cocoa intake may improve endothelial function and insulin sensitivity, whereas evidence for effects on blood lipids and blood pressure is weaker.
19. Shrime MG, Bauer SR, McDonald AC, et al. Flavonoid-rich cocoa consumption affects multiple cardiovascular risk factors in a meta-analysis of short-term studies. J Nutr 2011; 141:1982–1988.
20. Desideri G, Kwik-Uribe C, Grassi D, et al. Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment: The Cocoa, Cognition, and Aging (CoCoA) Study. Hypertension 2012; 60:794–801.
21▪. Curtis PJ, Sampson M, Potter J, et al. Chronic ingestion of flavan-3-ols and isoflavones improves insulin sensitivity and lipoprotein status and attenuates estimated 10-year CVD risk in medicated postmenopausal women with type 2 diabetes: a 1-year, double-blind, randomized, controlled trial. Diabetes Care 2012; 35:226–232.
The results from this 12-month trial extends evidence from shorter term trials, suggesting that beneficial effects of flavan-3-ol and isoflavone-rich extracts can lead to long-term improvements in LDL-cholesterol and insulin sensitivity.
22▪. Zheng XX, Xu YL, Li SH, et al. Green tea intake lowers fasting serum total and LDL cholesterol in adults: a meta-analysis of 14 randomized controlled trials. Am J Clin Nutr 2011; 94:601–610.
The results of this meta-analysis of a large number of randomized trials indicate that green tea consumption can lower LDL-cholesterol concentrations.
23. Kim A, Chiu A, Barone MK, et al. Green tea catechins decrease total and low-density lipoprotein cholesterol: a systematic review and meta-analysis. J Am Diet Assoc 2011; 111:1720–1729.
24. Ras RT, Zock PL, Draijer R. Tea consumption enhances endothelial-dependent vasodilation; a meta-analysis. PLoS One 2011; 6:e16974.
25. Suliburska J, Bogdanski P, Szulinska M, et al. Effects of green tea supplementation on elements, total antioxidants, lipids, and glucose values in the serum of obese patients. Biol Trace Elem Res 2012; 149:315–322.
26. Wu AH, Spicer D, Stanczyk FZ, et al. Effect of 2-month controlled green tea intervention on lipoprotein cholesterol, glucose, and hormone levels in healthy postmenopausal women. Cancer Prev Res 2012; 5:393–402.
27. Zhu Y, Xia M, Yang Y, et al. Purified anthocyanin supplementation improves endothelial function via NO-cGMP activation in hypercholesterolemic individuals. Clin Chem 2011; 57:1524–1533.
28. Cassidy A, Rimm EB, O’Reilly ÉJ, et al. Dietary flavonoids and risk of stroke in women. Stroke 2012; 43:946–951.
29. Wang Z-M, Nie Z-L, Zhou B, et al. Flavonols intake and the risk of coronary heart disease: a meta-analysis of cohort studies. Atherosclerosis 2012; 222:270–273.
30. Hollman PCH, Geelen A, Kromhout D. Dietary flavonol intake may lower stroke risk in men and women. J Nutr 2010; 140:600–604.
31. Landberg R, Sun Q, Rimm EB, et al. Selected dietary flavonoids are associated with markers of inflammation and endothelial dysfunction in U.S. women. J Nutr 2011; 141:618–625.
32. Edwards RL, Lyon T, Litwin SE, et al. Quercetin reduces blood pressure in hypertensive subjects. J Nutr 2007; 137:2405–2411.
33. Buijsse B, Weikert C, Drogan D, et al. Chocolate consumption in relation to blood pressure and risk of cardiovascular disease in German adults. Eur Heart J 2010; 31:1616–1623.
34. Khawaja O, Gaziano JM, Djousse L. Chocolate and coronary heart disease: a systematic review. Curr Atheroscler Rep 2011; 13:447–452.
35. Ried K, Sullivan TR, Fakler P, et al. Effect of cocoa on blood pressure. Cochrane Database Syst Rev 2012; 8:CD008893.
36. Schroeter H, Heiss C, Balzer J, et al. (−)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci USA 2006; 103:1024–1029.
37. Wang ZM, Zhou B, Wang YS, et al. Black and green tea consumption and the risk of coronary artery disease: a meta-analysis. Am J Clin Nutr 2011; 93:506–515.
38. Shen L, Song LG, Ma H, et al. Tea consumption and risk of stroke: a dose–response meta-analysis of prospective studies. J Zhejiang Univ Sci B 2012; 13:652–662.
39. InterAct Consortium. Tea consumption and incidence of type 2 diabetes in Europe: the EPIC-InterAct case-cohort study. PLoS One 2012; 7:e36910.
40. Huxley R, Lee CM, Barzi F, et al. Coffee, decaffeinated coffee, and tea consumption in relation to incident type 2 diabetes mellitus: a systematic review with meta-analysis. Arch Intern Med 2009; 169:2053–2063.
41. Iso H, Date C, Wakai K, et al. The relationship between green tea and total caffeine intake and risk for self-reported type 2 diabetes among Japanese adults. Ann Intern Med 2006; 144:554–562.
42. Rebello SA, Chen CH, Naidoo N, et al. Coffee and tea consumption in relation to inflammation and basal glucose metabolism in a multiethnic Asian population: a cross-sectional study. Nutr J 2011; 10:61.
43. Hooper L, Kroon PA, Rimm EB, et al. Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2008; 88:38–50.
44. Halliwell B. Are polyphenols antioxidants or pro-oxidants? What do we learn from cell culture and in vivo studies? Arch Biochem Biophys 2008; 476:107–112.
45. Hollman PC, Cassidy A, Comte B, et al. The biological relevance of direct antioxidant effects of polyphenols for cardiovascular health in humans is not established. J Nutr 2011; 141:989S–1009S.
46. Leiherer A, Mundlein A, Drexel H. Phytochemicals and their impact on adipose tissue inflammation and diabetes. Vascul Pharmacol 2012. doi:pii: S1537-1891(12)00185-1. 10.1016/j.vph.2012.09.002.
47. Chen YK, Cheung C, Reuhl KR, et al. Effects of green tea polyphenol (−)-epigallocatechin-3-gallate on newly developed high-fat/Western-style diet-induced obesity and metabolic syndrome in mice. J Agric Food Chem 2011; 59:11862–11871.
48. Friedrich M, Petzke KJ, Raederstorff D, et al. Acute effects of epigallocatechin gallate from green tea on oxidation and tissue incorporation of dietary lipids in mice fed a high-fat diet. Int J Obes (Lond) 2012; 36:735–743.
49. Ortsater H, Grankvist N, Wolfram S, et al. Diet supplementation with green tea extract epigallocatechin gallate prevents progression to glucose intolerance in db/db mice. Nutr Metab 2012; 9:11.
50▪. Wallace TC. Anthocyanins in cardiovascular disease. Adv Nutr 2011; 2:1–7.
This study reviews the latest findings on the effects of anthocyanins on cardiovascular diseases based on model experiments and the few existing epidemiologic and intervention studies in humans. Potential mechanisms are discussed.
51. Choi JS, Choi YJ, Shin SY, et al. Dietary flavonoids differentially reduce oxidized LDL-induced apoptosis in human endothelial cells: role of MAPK- and JAK/STAT-signaling. J Nutr 2008; 138:983–990.
52. Kay CD. The future of flavonoid research. Br J Nutr 2010; 104 (Suppl. 3):S91–S95.
© 2013 Lippincott Williams & Wilkins, Inc.