Flavanols and Cardiovascular Disease Prevention

Christian Heiss; Carl L. Keen; Malte Kelm


Eur Heart J. 2010;31(21):2583-2592. 

In This Article

Clinical Intervention Studies

While the data from epidemiological studies can be directional, randomized controlled clinical intervention studies are the preferred method for generating the evidence that is needed to causally link increased dietary flavanol consumption with effective cardiovascular disease prevention. Key questions that should be considered when conducting such trials include, what are the meaningful endpoints that need to be studied and what populations should be used? Ideally, flavanol-rich foods should be given to large groups of subjects in a randomized placebo-controlled study. Study populations should include subjects with (secondary prevention) or without (primary prevention) cardiovascular disease, and clinical hard endpoints including death, myocardial infarction, stroke, but also hospitalization or clinical symptoms, should be studied over a long-time frame. The study populations should be large enough to address age and sex considerations and to ensure that the results are applicable to the public. To our knowledge, no such trials have been conducted with any member of the flavonoid family. However, several small-scale and short-term clinical studies have been performed with cardiovascular surrogate endpoints thought to reflect key pathophysiologically relevant entities. These studies are useful as they can help to elucidate the mechanisms by which flavanols mediate their pleiotropic effects, as these surrogate parameters reflect key pathophysiological entities implied in cardiovascular disease development and progression. These endpoints include, but are limited to, endothelial vasomotor function, blood pressure, blood lipids, glucose tolerance, and activity of platelets, inflammatory and circulating progenitor cells.

Independent of the endpoint studied, certain limitations apply to many of the flavonoid feeding studies that have been conducted to date. For example, many of the papers in this area describe studies that lack proper food/beverage controls; they often provide minimal compositional analysis of the foods that are being tested; the studies are often of limited duration; and in many cases there is a lack of relevant study populations. Ideally, the control food/beverage should be indistinguishable from the intervention by means of taste and appearance to assure proper blinding and exclude bias. The controls should be matched for micro- and macronutrient composition, including other potential bioactive compounds, such as theobromine and caffeine in the case of cocoa or chocolate. Illustrative of the above, in several studies where the putative positive health effects of a flavonoid-rich chocolate was being studied, a white or milk chocolate was used as a control for a 'high flavanol' dark chocolate. The use of this type of 'control' clearly prohibits blinding, and these food products, in addition to having differences in their flavonoid content, vary in their content of numerous other nutrients and bioactive compounds such as methylxanthines. Similar to the above example, in many tea studies, water has been used as a 'control'. The lack of appropriate food/beverage controls in studies evaluating the putative vascular effects of specific flavonoids is a significant issue that needs to be addressed in a systematic manner. Until this is done, progress in the field will be hampered. Another difficulty with the interpretation of the collection of studies done to date is that when evaluating the information on the flavanol content of the test foods used, it is evident that the amounts vary considerably across studies, a fact that complicates the comparison of the results from the investigations. Another impediment to a comprehensive interpretation of the studies reported to date is that in several cases, plasma concentrations of flavanols and flavanol metabolites are not reported. In the cases where values are reported, there is minimal standardization as to when the blood samples were collected. This is an issue in the case of flavanols, as the metabolic turnover of these nutrients is very fast with a half-life of approximately 1–2 h. We suggest that one reason the importance of dietary flavanols with respect to vascular health has received minimal attention is the common use of fasted samples in clinical settings, as well as in many epidemiological studies. With the caveats noted above, below we review some of surrogate endpoints that have been studied in short-term flavanol studies. We primarily cite literature from the cocoa/chocolate field, as the test foods used in many of these studies have been better characterized than what is typically reported in studies with tea or grape products.


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