Dietary intake of a specific subclass of flavonoids known as flavanols has attracted increasing interest as a result of recent epidemiological,1,2 mechanistic,3,4,5 and human intervention studies suggesting potential beneficial cardiovascular effects.4,5,6 Among the wide variety of dietary flavanol sources, including apples, cranberries, purple grapes, red wine and teas, some cocoas and chocolates can be extraordinarily rich in certain types of flavanols.7,8
This brief review will highlight the growing body of evidence that flavanol-rich cocoa may have a role in improving cardiovascular health. Factors affecting the availability of cocoa flavanols in the diet and limitations that may therefore exist for their application in the public health arena are discussed.
Dietary Flavanol Intake and Coronary Heart Disease
Many population-based studies have used dietary surveys to estimate total flavonoid intake or focused on specific dietary sources, with tea most often being the single largest contributor of measured flavonoids. When these studies were designed, it was not widely recognized that cocoa and chocolate could be significant sources of flavanols, and so potential contributions from these food sources were not included in dietary questionnaires.
The Zutphen study from Hertog et al.12 showed a significant inverse relationship between total flavonoid intake and coronary heart disease (CHD) mortality over a five-year follow-up period in elderly men. Hertog et al.13 also reported beneficial effects of initial high flavonoid intake on CHD mortality over a 25-year period in a total of 16 cohorts drawn from seven countries. However, other studies failed to show a significant relationship between dietary flavonoids and mortality.14,15,16 Studies examining specific foods rich in flavonoids, primarily tea, have suggested a significant relationship between consumption and reduced risk of myocardial infarction.1,11,17 Unfortunately, with regard specifically to flavanols, there is a paucity of epidemiological data regarding any potential cardiovascular benefits.1
Cocoa Flavanols and Mechanisms of Vascular Action
Cocoa flavanols have demonstrated the potential to modulate cardiovascular health in at least two important ways:
- inhibition of platelet activation; and
- improved endothelial function.
Rein et al. demonstrated that flavanol-rich cocoa inhibits platelet activation ex vivo six hours following ingestion, with significant reduction in the expression of the surface proteins glycoprotein IIB/IIIA and P-Selectin.24 Follow-on studies subsequently showed that flavanol-rich chocolate inhibits platelet activation ex vivo in humans25, suggesting that the flavanol content of cocoa-derived products has more influence on platelet function than other components in the products, such as fat or carbohydrate content.
On an acute basis, Pearson et al. directly compared the acute effects of flavanol-rich cocoa and aspirin with respect to inhibition of platelet function.26 The magnitude of the effect induced by flavanol-rich cocoa was less than that of aspirin, but still statistically significant. Existing data suggest that the primary action of flavanol-rich cocoa with respect to platelet function is to increase levels of the anti-aggregatory prostaglandin prostacyclin, decrease the levels of pro-aggregatory leukotrienes, and increase levels of available nitric oxide.4,5,25 More research is needed to determine whether flavanol-rich cocoa can affect other pathways important in the prevention of thrombosis.
During the mid-1990s, Hollenberg et al. validated the observation that the Kuna Indians of Panama do not experience an increase in hypertension as they age.9 This apparent protection was lost in the Kuna when they moved to the urban environment of Panama City. Subsequent dietary research revealed that the Kuna consume large quantities of flavanol-rich cocoa when living in their indigenous environment, but not when they move to the urban environment.2 This observation, coupled with in vitro research demonstrating that specific cocoa flavanols could induce aortic ring relaxation via a nitric oxide dependent mechanism3, suggested that the frequent consumption of flavanol-rich cocoa by the Kuna could be one of the protective factors against age-associated hypertension that this population enjoys.
This speculation gained further support following the report of Heiss et al. that consumption of a single flavanol-rich cocoa beverage could transiently improve forearm brachial artery flow mediated vasodilation.5 Importantly, this observation correlated with increased levels of bioavailable nitric oxide measured in the blood. Neither an increase in flow-mediated vasodilation nor an increase in bioavailable nitric oxide was observed when subjects consumed a low flavanol cocoa beverage.Most recently, Fisher et al. confirmed in vivo in human subjects the hypothesis raised by Karim et al. that at least part of the vascular action of cocoa flavanols is nitric oxide-dependent.6
Cocoa Flavanols in the Diet
Flavanols are a specific class of compounds within the much larger family of polyphenolic compounds known as flavonoids. They occur naturally in a variety of plant-based foods and beverages, including cocoas, chocolates, teas, red wines, fruits, cereals, beans, spices and nuts.7,8 The US Department of Agriculture is developing a database that contains information on the flavanol content in many foods, and this can be accessed via their website (www.usda.gov - see Figure 1).The monomeric flavanols (epicatechin, catechin) and the oligomeric flavanols (procyanidins) are present in cocoas and chocolates to a varying extent depending on the type of cocoa and food processing techniques used to make the finished product.
It is critical to note that the amount and type of flavanols in any food, including cocoa and chocolate products, can vary widely. This point must be considered when evaluating the potential bioactivity of cocoa flavanols regarding cardiovascular health.The flavanols present in a finished food product, including cocoa and chocolate, largely depends on the cultivar type, geographical origin, agricultural practices, post-harvest handling, and processing of the flavanol-containing ingredient.10 For example, post-harvest handling techniques such as prolonged fermentation and alkalization will greatly reduce or eliminate the flavanol level remaining in a finished cocoa or chocolate product. Figure 2 provides an example of how flavanol content can vary in cocoa-based products due to use of different processing techniques. Other flavanol-containing ingredients widely used in the food industry have similar issues related to content remaining in the finished products. Thus, caution must be used when interpreting flavanol levels likely to be present in specific finished food products based on information derived from raw ingredients or generic food composition tables.
Clinical investigators wishing to ascertain the vascular actions of flavanols in chocolate or cocoa should use only specific products that are well characterized for their flavanol content.
Notes on Chocolate Specifically
One of the primary uses of cocoa is the manufacture of chocolate. Chocolate is an energy-dense food, and individuals must keep caloric intake and expenditure in mind when including it in their diet, as any food when eaten in excess will cause an increase in weight. Physical activity, diet, and other lifestyle factors must be balanced carefully to avoid detrimental weight gain over time.
In the context of nutrition, one must also consider that the cardiovascular benefits of flavanol-rich foods, including those chocolates that are flavanol-rich, could be offset if they were to simultaneously contribute significant levels of unhealthy fats such as certain saturated fatty acids that are known to raise blood cholesterol levels. Chocolate is rich in oleic and stearic acids, in addition to palmitic acid, and several studies have demonstrated a neutral effect on blood lipids in humans following short-term consumption of cocoa butter and/or chocolate.21
Potential Cardiovascular Health Applications of Flavanol-rich Cocoa
The mechanisms of vascular action described above following the feeding of flavanol-rich cocoa suggest potential for use in a variety of applications related to cardiovasular health.18,20 Recent studies by Taubert et al. and Fisher et al. provide tantilizing hints for what this potential could be.6,22 Taubert et al. utilized a cross-over design to study the effects of polyphenol-rich and polyphenol-free chocolate on blood pressure in 13 individuals aged between 55 and 64 years with untreated isolated systolic hypertension over a period of 14 consecutive days.A significant reduction in blood pressure was noted 10 days after polyphenol-rich chocolate ingestion and after 14 days a mean blood pressure reduction of 5/2mm Hg (SD 2.4/2.0) was seen. There was no change in the control group. Blood pressure returned to pre-intervention levels within two days of stopping the polyphenol-rich chocolate. Unfortunately, the flavanol composition of the chocolate products used in this study was not reported. The blood pressure reduction in this study was not observed by Fisher et al. in a shorter duration study of 27 healthy volunteers who drank a flavanol-rich cocoa (821mg per day) split into four doses per day.6
After four days of flavanol-rich cocoa supplementation blood pressure was measured and then measured again 90 minutes later following consumption of a single dose, with no significant change in blood pressure observed. In addition, low-dose L-NAME, a nitric oxide synthase inhibitor,was infused on days 1 and 5. Before cocoa administration, L-NAME caused a modest increase in systolic blood pressure from 117 ┬▒ 2.3mm Hg to 122 ┬▒ 2.3mm Hg at 60 minutes (p = 0.03) and a non-significant increase in diastolic blood pressure, from 68 ┬▒ 2.1mm Hg to 71 ┬▒ 1.7mm Hg. Interestingly, L-NAME caused a larger increase in systemic blood pressure following four days of flavanol-rich cocoa ingestion. Systolic blood pressure rose from 117 ┬▒ 2.1mm Hg to 128 ┬▒ 4.0mm Hg (p = 0.005), and diastolic blood pressure rose from 66 ┬▒ 1.8mm Hg to 71 ┬▒ 1.9mm Hg (p = 0.004). Presumably, in these healthy volunteers, baroreceptor adjustments were sufficient to minimize the influence of vasodilation induced by flavanol-rich cocoa on blood pressure.
Conclusive evidence in the form of large-scale randomized clinical trials is still lacking with respect to the ability of flavanol-rich cocoa to confer cardiovascular health benefits. However, the scientific data that cocoa flavanols may make an important contribution to cardiovascular health continues to grow at a rapid pace. Currently, one important pathway in vascular biology that cocoa flavanols can influence has been identified, i.e. nitric oxide synthesis, and possibly more, e.g. prostaglandin and eicosanoid synthesis. Human experiments demonstrate that flavanol-rich cocoa can at least transiently influence platelet function and endothelial function in a positive way. Unfortunately, as with other flavanol sources, e.g. grapes, tea, and apples, flavanols in cocoa are generally reduced or eliminated during post-harvest handling and production of finished food and beverage products, indicating that further investment in food technology is required to translate their potential cardiovascular health benefit into products that can have real public health impact. This research should be pursued in parallel with further investigation of the potential clinical health benefits for the simple reason that compliance is the ultimate key to public health impact, and cocoa-based products offer an extraordinary opportunity to successfully overcome often observed compliance issues.