The flap over flavonoids

February 02, 2012

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London, UK - Berries, chocolate, red wine: almost every few weeks, a new study touting the health benefits of foods rich in flavonoids or polyphenols makes news headlines. This month is no exception, with two new studies in the February 2012 issue of the American Journal of Clinical Nutrition, one suggesting a lower rate of cardiovascular death in people consuming a diet high in flavonoid content[1], and the other showing beneficial anti-inflammatory effects of drinking red wine[2].

But there has also been controversy—in particular, the recent reports of fraud surrounding one researcher active in the field. As previously reported by heartwire , Dr Dipak Das (University of Connecticut) has been accused of falsifying data with image-editing software in studies, many of which found that the polyphenol resveratrol (found in red wine; although not a flavonoid) improved cardiovascular health.

heart wire has asked a few experts in the field what effect this controversy might have had and if there is enough information to recommend increased intake of flavonoid-rich food.

Resveratrol in the spotlight

Dr Colin Kay

The universal opinion on the Das saga was that one scientist committing fraud would not have much effect on the area as a whole. Dr Colin Kay (University of East Anglia, Norwich, UK) commented to heart wire :"I wouldn't say the recent controversy over resveratrol has hurt the field tremendously. There is a lot of evidence from many different sources around the world on the benefit of resveratrol. This one researcher shouldn't change things very much. Resveratrol has probably been the compound most studied, and, yes, I would say it has benefits, but probably no more than other polyphenols or flavonoids."

Senior author of the current red-wine study, D r Ramon Estruch (University of Barcelona, Spain), said: "I do think resveratrol is absolutely a beneficial polyphenol, and many people have published hundreds of papers showing this. I don't think questioning the findings of one researcher will make any difference to the whole field."

And lead author of the current cardiovascular mortality study, Dr Marjorie McCullough (American Cancer Society, Atlanta, GA), had a similar view. "These things happen sometimes in most fields. I don't think it will have any lasting damage."

What are polyphenols and flavonoids?

Polyphenols are natural compounds found in plants that are believed to have beneficial health effects. There are thousands of polyphenols, but one has attracted the most attention to date—resveratrol, which is found mainly in red wine and has been suggested to have potential cardiovascular, anticancer, and antiaging benefits.

Flavonoids are a class of polyphenols. They include the following subclasses:

  • Anthocyanidins—In blueberries, red wine, and strawberries.

  • Flavan-3-ols—In apples, black tea, blueberries, chocolate, and red wine.

  • Flavanones—In citrus fruit and juices and herbal tea.

  • Flavones—In celery, garlic, green peppers, and herbal tea.

  • Flavonols—In blueberries, garlic, kale, onions, spinach, tea, broccoli, red wine, and cherry tomatoes.

  • Proanthocyanidins—In apples, black tea, blueberries, chocolate, mixed nuts, peanuts, red wine, strawberries, and walnuts.

  • Isoflavones—In soy products and peanuts.

-SH

Reduction in cardiovascular mortality?

In McCullough's study, which Kay describes as "one of the more convincing pieces of evidence of the benefits of flavonoids to date," the authors examined the association between flavonoid intake and cardiovascular-disease mortality among almost 100 000 participants (average age 70) in the US Cancer Prevention Study II Nutrition Cohort. Participants completed questionnaires on medical history and lifestyle behaviors, including a 152-item food-frequency questionnaire. Flavonoid values for individual foods were derived from three US Department of Agriculture databases.

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During seven years of follow-up, 2741 cardiovascular deaths occurred. Results showed that individuals with total flavonoid intakes in the top (compared with the bottom) quintile had an 18% lower risk of cardiovascular death.

Five flavonoid classes—anthocyanidins, flavan-3-ols, flavones, flavonols, and proanthocyanidins—were individually associated with lower risk of cardiovascular death. In men, total flavonoid intakes were more strongly associated with stroke mortality—showing a 37% reduction—than with ischemic heart disease, which showed a 10% reduction. However, in women, the strongest inverse association was observed with flavones, particularly for fatal ischemic heart disease.

One of the more convincing pieces of evidence of the benefits of flavonoids to date.

Many of the associations observed were nonlinear, with low risks seen at even modest intakes, suggesting that consumption of even relatively small amounts of flavonoid-rich foods may be beneficial for reducing risk of cardiovascular death.

Kay said McCullough's study "definitely backs up the data we already have." He referred to a similar study by Cassidy et al that analyzed data from the Nurses' Health Study, also with around 100 000 participants, and found that flavonoid intake was associated with a reduced risk of incident hypertension[3]. But he noted that McCullough's study was more comprehensive in that it also looked at dose.

Another cohort study conducted in middle-aged Finnish men found an association between high intakes of flavonoids and a reduced risk of ischemic stroke and reduced cardiovascular mortality[4].

Dr Marjorie McCullough

McCullough says her study adds another piece of the puzzle. "Most other studies have looked at a fewer number of flavonoids, and the databases documenting the flavonoid content of foods were less complete. Now these databases are being updated to include a greater number of flavonoids. We looked at the seven best characterized so far, and we saw an inverse association with five of them in terms of cardiovascular death."

She pointed out that of the other classes that were not associated with a reduced risk in this study, one—isoflavones—is present mainly in soy foods, which aren't consumed much in the US. "So maybe it is not that surprising that we didn't show an association here. The studies that have shown inverse associations with isoflavones have been done in Asia, where they eat a lot more soy products."

Yes, I think we can say that we should increase our consumption of these flavonoid-rich foods>.

McCullough says her results support the idea that a diet containing foods with a high flavonoid content could benefit cardiovascular health. "This complements what we already know to some extent in that most of these foods fall under the category of healthy foods already . . . fruits and vegetables. But flavonoids are not just in fruits and vegetables. They are in nuts and seeds, tea, cocoa, and red wine."

"Our take-home message is that more research is needed to confirm our results—but yes, I think we can say that we should increase our consumption of these flavonoid-rich foods."

Supplements not there yet

McCullough does not recommend taking supplements containing these flavonoids, because "we don't know for sure which ones are the best, and we might need some of the other ingredients in the foods, too. It's much better to get these compounds from the diet."

She added: "There's a huge amount of evidence that people who consume a plant-based diet and healthy fats have a reduced risk of cardiovascular disease. We don't ascribe this benefit to one particular component of any one food. Rather, we recommend a mixture of these healthy foods. We recommend that people don't always buy the same fruit but mix it up. If you always eat an apple every day, try berries or other type of fruits instead. Try new vegetables—kale or broccoli—and introduce more nuts into your diet. Little changes in the diet can achieve a wide variety of these compounds."

Little changes in the diet can achieve a wide variety of these compounds.

Kay says the most convincing evidence with flavonoids is on vascular benefits, but there is also some suggestion of positive effects on the brain and cancer and other mechanisms beyond vascular.

He notes that the creation of the flavonoid databases has led to more of these association studies being done. He explained that there are now several databases available that assess the amount of flavonoids in foods. The first ones were produced by the US Department of Agriculture, but now there is a more comprehensive database called Phenol Explorer, which contains more than 35 000 content values for 500 polyphenols in over 400 foods.

Kay points out that these databases are useful, but they will not be 100% accurate. "The trouble is that food is dynamic. The amount of polyphenols and flavonoids will vary with the growing conditions, the amount of sunlight and water, and the country of origin. So these values will be somewhat vague, but the databases are still a useful tool to develop hypotheses."

Anti-inflammatory effects of red wine

Dr Ramon Estruch

Estruch's paper is a much smaller study looking at the specific effects of red wine on various anti-inflammatory markers. Estruch explained to heart wire : "There have been many reports of cardiovascular benefits with red wine; we wanted to look at which components of red wine may be responsible for these effects. Is it the alcohol or is it the polyphenols?"

They conducted a crossover study in 67 high-risk, male volunteers who were given red wine containing 30-g alcohol, the equivalent amount of dealcoholized red wine, or gin (containing 30-g alcohol). Each beverage was given every day for four weeks. Before and after each intervention period, seven cellular and 18 serum inflammatory biomarkers were evaluated.

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Results showed that alcohol alone has some positive effects, as did the dealcoholized red wine, but the most benefit was found with regular red wine. While the polyphenol content of red wine seemed to reduce leukocyte-adhesion molecules, both alcohol and the polyphenols appeared to modulate soluble inflammatory mediators.

Estruch commented: "We recommend that people drink red wine in moderation for anti-inflammatory effects that could be cardioprotective. If individuals do not drink alcohol, they can still get the benefit of polyphenols by drinking dealcoholized red wine."

Drinking red wine will be better than taking a pill.

Asked which particular polyphenols in red wine may be producing the benefits, Estruch said: "We believe it is all the polyphenols together that have the effect. It is not just one. There are maybe 1000 different ones in red wine that seem to have synergistic effect when taken together." He added that while resveratrol has attracted the most attention, it may not be any more important than many others. "A lot of people have focused on this one polyphenol, but I believe you need all of them together, not just one compound. So drinking red wine will be better than taking a pill, as you can't reproduce exactly what is in the wine."

Kay agrees with this view. "It is very difficult to draw conclusions about just one class of flavonoid or polyphenol, as no food has just one such compound in it. In nutrition, we tend not to promote one single compound. Rather we promote a food for its all-round benefit."

Can chocolate really be good for you?

Another area that has had great publicity is dark chocolate, but Kay points out that many of the studies showing beneficial effects have used products enriched with flavonoids. "It is not the chocolate you buy in the shops. Normal chocolate is more like the chocolate they use as placebo in these studies. I wouldn't recommend that people buy a Snickers bar to get their polyphenols. Normal chocolate is too full of fat and calories and doesn't contain high levels of polyphenols. But there are definitely groups pushing chocolate as a source of these compounds, and chocolate companies are starting to bring out flavonoid-enriched cocoa powders and chocolate bars. I think that is the way to go with the healthy-chocolate message."

I wouldn't recommend that people buy a Snickers bar to get their polyphenols.

Kay says there is not much information on the effects of individual polyphenols or flavonoids yet, with the main one that has captured attention being resveratrol. And he points out that studies that have suggested a benefit of a particular compound have generally used very high concentrations in animal or cell models. "You can't get those levels from your diet. You would have to take supplements. But for the time being, we are better off pushing for people to eat higher daily amounts of flavonoid-containing foods. That's a better public-health message."

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He notes that there have been many small randomized trials of individual foods where people take a measured dose of the specific food every day, like Estruch's red-wine study. He points out that such studies are hard to control, as people's diet varies, and they can't be done on a large scale. "But we can look at such things like vascular reactivity, blood pressure, [and other] biomarkers in these sorts of studies."

He says that outcome studies require many more people, and really the only way to do these is to look across people's entire diet and analyze particular trends, as in McCullough's current study.

A recent meta-analysis of the randomized controlled trials of flavonoids conducted to date[5] found a significant amount of evidence to support the activity of cocoa catechins on systolic blood pressure and flow-mediated dilatation; however, there were not enough data to reach conclusions on most other compounds.

The best things to eat and drink

Kay comments: "If you distill the literature, it may appear that the best things to eat and drink are chocolate and red wine, but this is only because this is what has been studied most. I would say there is also significant evidence of benefits with tea, berries, and orange juice."

He has written a paper highlighting the problems of proving the benefits of flavonoids[6]. These include their great diversity in foods, the limited data available regarding their content in foods, and a limited understanding of what happens to them in the body. "We need to be able to characterize the structural forms of flavonoids as they occur in the body, so they may be applied in appropriate levels and forms to experimental models of biological activity. This will provide insight into the understanding of how flavonoids contribute to a healthy diet and how they may be utilized in the prevention or treatment of disease," he concludes in his paper.

What is the mechanism?

On the mechanism of action of these compounds, a lot again seems uncertain. McCullough said the flavonoids are thought to have multiple mechanisms, including antioxidant and anti-inflammatory properties, reduction of LDL oxidation, and weak estrogenic activity. In their current paper, McCullough et al report that cocoa induces nitric-oxide synthase, which is important in the vasodilator response, and other flavonoid-rich foods (green tea, soy products, and cocoa or chocolate) have been associated with increased flow-mediated dilatation, reduced LDL cholesterol, and reduced blood pressure.

And a new paper published this week in Cell suggests that resveratrol inhibits certain phosphodiesterases, which then triggers a series of events in a cell, one of which indirectly activates sirtuin 1, a protein associated with aging[7].

Kay says that in the future there may well be individual flavonoids or polyphenols developed as dietary supplements or medicines, but this will require much more research addressing all the issues discussed above. "The field is still quite young but is growing fast. There are so many compounds, so much to study. It has come into its own in the past 10 years. It is now known in the mainstream. It has captured people's attention. For now, the best advice is to eat more of these flavonoid-containing foods. Everyone knows they should eat healthily. News stories about a food that has shown benefits on health are always of interest. It applies to everyone. Everyone has to eat. Why not eat things that are said to be good for you?"

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