Flavanols and Cardiovascular Disease Prevention

Christian Heiss; Carl L. Keen; Malte Kelm

Disclosures

Eur Heart J. 2010;31(21):2583-2592. 

In This Article

Abstract and Introduction

Abstract

Diet is a major lifestyle factor in the primary and secondary prevention of numerous chronic diseases, including myocardial infarction, stroke, and diabetes. Epidemiological studies suggest that the beneficial cardiovascular health effects of diets rich in fruits and vegetables are in part mediated by their flavonoid content, with particular benefits provided by one member of this family, the flavanols. This concept is supported by findings from small-scale intervention studies with surrogate endpoints including endothelium-dependent vasodilation, blood pressure, platelet function, and glucose tolerance. Mechanistically, short-term effects on endothelium-dependent vasodilation following the consumption of flavanol-rich foods, as well as purified flavanols, have been linked to an increased nitric oxide bioactivity in healthy humans, and those with increased cardiovascular risk. The critical biological target(s) for flavanols have yet to be identified and the extent to which these acute results are important in the context of long-term human health is unknown. While flavanols represent a promising class of food components with respect to their ability to lower cardiovascular risk the flavanol-rich foods used in many trials have been poorly defined with respect to their flavanol content and flavanol-isomer profile; several studies have lacked appropriate controls, and the long-term randomized controlled intervention trials with flavanol-rich foods are missing. Thus, while the literature regarding flavanols and vascular health is encouraging, more in-depth and well-controlled clinical and experimental studies are needed to better define the potential protective vascular effects of these nutrients and their therapeutic value in cardiovascular medicine.

Introduction

Diet is a lifestyle factor that plays a major role in the primary and secondary prevention of several chronic diseases, including certain cancers, coronary artery disease (CAD), stroke, and diabetes.[1] With respect to vascular disease initiation and progression, current dietary recommendations are aimed at optimizing lipid and lipoprotein profiles, blood pressure, blood glucose levels, and body weight. An additional dietary recommendation is to consume more fruits and vegetables.[2] While there is compelling epidemiological evidence that a diet rich in fruits and vegetables lowers the risk of heart disease and stroke,[3,4] the mechanisms by which these diets mediate their beneficial health effects are unclear.[5] It is reasonable to suggest that they are multi-factorial in nature. For example, fruits and vegetables are typically low in calories and fat, high in fibre, have a favourable sodium/potassium ratio and contain numerous bioactive plant molecules, including those from a group of phytochemicals called flavonoids (Figure 1). Flavonoids have generated considerable interest as epidemiological studies have suggested an inverse association between the dietary intake of flavonoids and the risk for vascular disease (refs[6–9] and references therein). Flavonoids share a common basic chemical structure. Important subgroups are flavanols, flavonols, flavones, isoflavones, flavanones, and anthocyanins, which are defined by the chemical residues attached to the basic flavonoid structure (Figure 1A). A complication of the epidemiological observations regarding members of the flavonoid family is that subtle differences in their chemical structures can translate into marked differences in their absorption and metabolism and bioactivities.[8] While it can be speculated that the putative positive vascular effects of flavonoid-rich diets are due to several of the family members, it is equally reasonable to suggest that the vascular effects are likely to be largely driven by a relatively small number of the family. Conceptually, this is an important point, as the profile of flavonoids in different fruits and vegetables, as well as nuts, varies considerably.[8] If the hypothesis that the reported positive vascular effects of plant food-rich diets are due in part to a limited number flavonoids is correct, this has important implications for dietary recommendations, and potentially for the development of new pharmaceuticals. In this context, flavanols, a subgroup of the flavonoid family (Figure 1), are a focus of attention as epidemiological investigations have shown an independent inverse correlation between the dietary intake of flavanol-rich foods and CAD mortality.[10] While the epidemiological findings are provocative, no randomized controlled trials with hard clinical endpoints have been published that corroborate a cause and effect relationship between the intake of flavanols and vascular health.

Figure 1.

(A) Basic structures and examples of the main subclasses of dietary flavonoids. (B) Whereas the majority of flavanols are present as oligomers in food (i.e. cocoa), metabolized flavanol monomers are the dominant flavanols in blood and may be partly responsible for the observed vascular effects.

However, several controlled human dietary intervention studies with flavanol-rich foods and beverages have demonstrated positive effects, including the recovery of endothelial function,[11–15] improvements in insulin sensitivity, decreased blood pressure,[16,17] and reductions in platelet aggregation.[18–20] The pharmacological mechanisms of action of flavanols have yet to be identified, but they likely include an enhancement in nitric oxide (NO) bioactivity, modulation of the immune system, and enhanced endothelial homeostatic vascular repair.[21] While it has been speculated that the intrinsic antioxidant capacity of flavanols, and flavonoids in general, underlies their positive vascular effects (refs[22,23] and references therein), this is as unlikely, although select flavonoids may influence the overall level of oxidative stress through secondary mechanisms.[24,25]

Quantitatively, flavanols represent a major group of flavonoids in the western diet.[26] Major sources include chocolate and cocoa (up to 920–1220 mg/100 g), apples (up to 120 mg/200 g), and tea (up to 300 mg/infusion), however, it must be noted that the profile of flavanols (e.g. (−)-epicatechin, (+)-epicatechin, (−)-catechin, (+)-catechin) in these foods can vary considerably, and it can be changed as a consequence of food processing.[27] Importantly, the methodologies that are typically used to measure flavanols in foods, as well as in biological fluids, do not provide information on the profile of flavanol stereoisomers. The average daily flavanol intake of an adult has been approximated to be in the range of 50–100 mg.[7] However, there is considerable confusion in the literature, as many authors when reporting dietary intakes do not make a distinction between flavanols per se (which are by definition monomers) and procyanidins, which are oligomers of flavanols.[7] Generally, when viewed as a composite, the flavanol monomers ((−)- and (+)-epicatechin, (−)- and (+)-catechin) are approximately 10%[26,28] of the combined monomer and oligomer total. We suggest that the pooling of monomers and procyanidins when presenting dietary intake data is inappropriate, given that while monomers and dimers are absorbed in the small intestine,[29,30] the longer oligomers are not absorbed. Thus, the longer oligomers are unlikely to have direct effects on the vascular endothelium, although we note they may have biological effects within the intestinal track (e.g. they might influence the microbiota, or act as immune modulators). Depending on many factors, peak monomer and dimer plasma concentrations in the nanomolar and low micromolar range are reached at 1–2 h after the ingestion of a flavanol/dimer-rich meal.[30] As a result of phases I and II metabolism during absorption and liver passage, the majority of circulating flavanol monomers are methylated, glucuronidated, and/or sulfated metabolites. Importantly, the metabolite profile that occurs in blood is influenced by the profile of the flavanol isomers that is present in the consumed food/beverage (Figures 1B and 2).[31] In contrast to the monomers, dimers are not thought to be extensively modified subsequent to their absorption.[32] The biological activities of dimers and the extent to which these activities are influenced by dimer type (e.g. A type vs. B type) are a subject of active research.

Figure 2.

Schematic of pharmacokinetically relevant flavanol features pertaining to the composition in foods, absorption, metabolism, distribution, and excretion that are important determinants of flavanol-related effects.

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