Flavanols and Cardiovascular Disease Prevention

Christian Heiss; Carl L. Keen; Malte Kelm


Eur Heart J. 2010;31(21):2583-2592. 

In This Article

Epidemiological Evidence

Epidemiological studies suggest that the chronic consumption of a diet rich in plant-based foods is associated with a reduced incidence of CAD, stroke, and myocardial infarction.[3,4,33] The positive health effects of fruits and vegetables are often attributed to their macronutrient profile: they are typically low in fat, high in fiber, have low sodium/potassium ratios, and low-energy densities. Fruits and vegetables can also be important sources of a number of health-promoting micronutrients. These include essential nutrients (e.g. vitamin C, vitamin E, potassium, magnesium), as well as numerous phytochemicals whose bioactivities are poorly defined. Multiple investigators have reported an inverse correlation between the intake of total flavonoids, as well as specific flavonoid classes, and the incidence of cardiovascular mortality.[10] A review of 15 cohort studies examined the relationship between dietary flavonoid intakes and the risk for developing CAD.[10] Thirteen of these prospective studies demonstrated a protective effect of flavanols, procyanidins, flavones, and flavanones in the context of deadly and non-deadly CAD with a reduction of mortality of up to 65%.[10]

Three prospective cohort studies (Zutphen Elderly Study[34–36] and Iowa Women's Health Study,[7,37]European Prospective investigation into Cancer and Nutrition[38]) and one retrospective anthropological study[39] provide evidence for a primary protective effect of flavanols and procyanidins. In the Zutphen Elderly Study, 806 Dutch elderly men were followed over 15 years. The calculated dietary flavonoid intake was inversely associated with a reduction in ischaemic heart disease mortality with a risk ratio of 0.49 in the highest tertile of daily flavanol intake (average intake 124 ± 15 mg/d) as compared with the lowest tertile (average intake of 25 ± 40 mg/d).[36] While the above paper is widely, and appropriately, accepted as a landmark study, a limited number of foods were included in the analysis, thus the flavonoid intakes that were reported in this study are lower than what was actually consumed. The prospective Iowa Women's Health Study followed 34 489 postmenopausal women who were free of cardiovascular disease at inclusion. The results published after 13[37] and 16[7] years of follow-up differed slightly in their food classification and analysis, and as a result provide interesting insights into the types of foods that may be driving the epidemiological results. An inverse association between coronary heart disease mortality and catechin and epicatechin intake, as defined by intake of tea, apples and pears, and chocolate, was initially demonstrated.[37] The analysis at 16 years of follow-up continued to show reduced cardiovascular risk with increased intakes of foods the authors defined as procyanidin-rich (as noted above procyanidins are oligomers of flavanols; foods in this category included chocolate, apples and seeded grapes), however, as a separate class, the dietary intake of flavanols was not associated with a reduced risk. The flavanol-rich foods in their analysis were identified as apples, red wine, and green tea.[7] The seeming discrepancy of the findings between Arts et al.[37] and Mink et al.[7] with respect to flavanols per se is likely due in part to differences in how the data from chocolate and seeded grapes were treated. In the paper by Mink et al.[7] the flavanol intake data from these foods were pooled with the procyanidin intake data from these foods. Importantly, the analysis of the 16 years data continued to show an inverse association between cardiovascular mortality and high chocolate and fruit intake. Recently, Buijsse et al.[38] extended these findings to middle-aged Germans of both sexes in the Potsdam Arm of the European Prospective Investigation into Cancer and Nutrition. The authors reported an inverse relationship between chocolate consumption and cardiovascular disease risk (myocardial infarction, stroke, 8 years follow-up) in a large cohort (n = 19 357) of middle-aged German participants of both sexes, without cardiovascular disease at inclusion. They observed that in the quartile characterized by the lowest chocolate consumption (1.7 g/day) 106 myocardial infarctions and strokes occurred, whereas 61 events occurred (combined relative risk of 0.61) in the quartile with the highest chocolate consumption (7.5 g/day). In the latter group, both systolic and diastolic blood pressures were significantly lower (1 mmHg) than the referent low-chocolate consumption quartile. Baseline blood pressure explained 10–12% of the risk reduction. Counter intuitive to the idea that a high vegetable intake is beneficial, the subgroup with the lowest risk was the group with the lowest vegetable intake while also having the highest chocolate intake. A limitation of this study is that chocolate consumption was only estimated as one item on the food-frequency questionnaire, making a more qualified evaluation of the associated intake of potential bioactive compounds, including flavanols, impossible. In addition, the flavanol/procyanidin content of cocoa/chocolate (as well as other flavanol/procyanidin-rich foods) products can be markedly influenced by food processing, as well as agricultural practices.[40] This is an important issue that must be considered when evaluating data from epidemiological studies.

Evidence in support of the concept that a high intake of dietary flavanols and procyanidins is associated with positive vascular health effects is provided by studies investigating the mortality resulting from cardiovascular events in the Kuna Indians, who live on the San Blas Islands off the coast of Panama. Traditionally, the Kuna, who reside on the islands, consume large volumes of cocoa on a daily basis, and as a group they are characterized by a low incidence of age-related hypertension. When Kuna migrate from the islands to the mainland, they tend to decrease their cocoa intake, and adopt a more westernized diet that is relatively low in flavonoids. Following their movement to the mainland, they typically develop age-related hypertension.[39] That the high cocoa consumption of the Kuna living on the islands can be linked to their reduced risk for hypertension is supported by the observation that urinary nitrite and nitrate excretion, potential NO markers, are higher in Kuna living on the islands than for those living on the mainland.[13] It has been reported that cardiovascular mortality of the Kuna is considerably lower than that of other Pan-American populations (9 vs. 83 age-adjusted deaths/100 000). The determinants of this effect seem to be predominantly environmental rather than genetic, given that this protection is lost on migration of Kuna Indians to Panama City.[39]

Recently, a prospective study (Stockholm Heart Epidemiology Program[41]) was published that reported a secondary preventive effect of chocolate intake in a group of 1169 non-diabetic patients after first acute myocardial infarction with a mean follow-up of 8 years. In this study, a high chocolate intake was associated with a reduction in cardiac mortality in patients that consumed 50 g of chocolate twice or more per week, with a hazard ratio of 0.34. While the above epidemiological studies are promising, epidemiological studies inherently deliver associations. Thus, they are limited with respect to proving cause and effect relationships, or in giving mechanistic insights as the observed associations may be due to strong confounders. An important potential confounder in this context is reporting bias. Subjects with an unhealthy lifestyle may report lower chocolate intake as they may feel guilty about it. In several cases, nutrition intervention studies based on hypotheses generated from epidemiological studies have been disappointing, as exemplified by the report that vitamin E and C supplementation did not reduce major cardiovascular events the Physicians' Health Study II.[42]


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