Cocoa, Flavanols and Cardiovascular Risk

Norman K. Hollenberg; Harold Schmitz; Ian Macdonald; Neil Poulter

Disclosures

Br J Cardiol. 2004;11(5) 

In This Article

Abstract and Introduction

There has been a long-standing interest in the relation between what we eat and cardiovascular risk. Over the years, attention has been given to calories, total fat, saturated fat, cholesterol, omega-3 polyunsaturated fatty acids, trans fatty acids, folic acid, antioxidants and, most recently, flavanols. Flavanol concentrations can be moderately high in a number of foods that have been associated with a reduction in cardiovascular risk including red wine, and black and green tea. Some cocoa and chocolate products are extraordinarily rich in flavanols but, as with other flavanol-containing foods, certain post-harvesting and processing procedures can have a striking influence on the flavanol content of chocolate and cocoa.

Endothelial dysfunction with a consequent reduction in nitric oxide production has achieved a central conceptual role in the pathogenesis of atherosclerosis and coronary artery disease, diabetes mellitus and hypertension. Recent evidence that flavanol-rich cocoa activates vascular nitric oxide synthesis in the intact human raises an interesting possibility of a therapeutic potential.

Interest in the relationship between what we eat and cardiovascular risk continues to grow. Long-standing interest in calories, total fat, saturated fat and cholesterol has been followed more recently by an interest in omega-3 polyunsaturated fatty acids, trans fatty acids, folic acid, fibre, soluble fibre and antioxidants. Among the most recent candidates that have drawn important attention are the flavonoids - polyphenolic compounds found in a variety of foods of vegetable origin, including tea, cocoa, chocolate, red wine, purple grapes, apples, onions and cranberries. In particular, a specific subclass of flavonoids - known as flavanols - has attracted increasing interest as a result of recent epidemiological,[1,2] mechanistic[3,4,5,6,7,8] and human intervention studies.[6,8,9,10,11,12,13] Among the wide variety of dietary flavanol sources, some cocoas and chocolates can be extraordinarily rich in certain flavanols.[14,15,16,17]

A possible confounder in epidemiological studies is a contribution from sources of flavonoids that were not part of the analysis. One striking example in this area is cocoa and chocolate, which can contain flavonoid, specifically flavanol, profiles and concentrations very different from those of other sources.[14,18] Equally important is the fact that foods recognised as being flavonoid-rich vary in their flavonoid content substantially, largely due to common techniques used during post-harvest handling of raw materials and processing during food production.[19]

The biological effects of plant flavonoids are wide-ranging and sometimes substantial. A recent review of the biological effects of flavonoids was 77 pages in length and included over 1,000 references, most of them written in the preceding decade.[20] Subjects covered ranged from general effects on mammalian cells to implications for inflammation, cancer and heart disease. In vitro, flavanols found in cocoas and chocolates have shown specific activities related to vascular health and, in particular, mechanisms associated with endothelial function, endothelium-derived nitric oxide synthesis, platelet function, and cellular processes modified by reactive oxygen and nitrogen species.[3,4,5,6,7,8,13,21]

Epidemiological evidence linking flavonoid consumption to heart disease or mortality in humans is impressive but has often been conflicting.[22,23,24,25,26,27,28,29,30,31,32,33] For example, there has been enormous interest in the 'French paradox' reflecting the interesting finding that the French do not have a myocardial infarction (MI) rate to match their fat intake. Attempts have been made to implicate red wine as a contributor via its flavonoid content. Regarding flavanols consumed as cocoa and chocolate and their potential influence on cardiovascular risk in epidemiological studies, there is a paucity of data. Such studies examining the potential health effects of foods rich in flavonoids have, at times, shown a very large influence on cardiovascular risk. For example, Mukamal et al. reported the findings in a prospective study on the determinants of mortality after acute MI. Patients who consumed an average of 14 or more cups per week of black tea showed a 39% reduction in mortality during a median follow-up of 3.8 years.[33] Perhaps more striking was the fact that the moderate tea drinkers who averaged only two cups of tea per week showed a 31% reduction. Adjustment for the usual risk factors did not alter this association. Why should the results of studies be in conflict given such a robust influence? There are several reasons: indeed, they provide the rationale for this review focusing on the potential cardiovascular health benefits of flavanols in cocoas and chocolates. Sometimes identifying the responsible mechanism(s) can have a substantial influence on the attempt to resolve such issues. This review will focus on the fact that key mechanisms responsible for the potential vascular health benefits of flavanols present in cocoas and chocolates may have been identified.[4,8,9] The clinical processes of interest are characterised by endothelial dysfunction. Studies in vitro, in animal models, and in intact humans have provided growing evidence for an action of this class of natural products on endothelial dysfunction. The final common pathway appears to be activation of nitric oxide synthesis. Figure 1 depicts data from one study in which flavanolrich cocoa activated powerfully vessels of the extremity in healthy intact humans entirely via nitric oxide.[9]

Pulse wave amplitude responses to cocoa and L-NAME (N-nitro-L-arginine methyl ester). a: shows five minutes of baseline pulse wave amplitude recordings from a finger in a volunteer. The baseline demonstrated typical common normal variability in digital pulse wave amplitude. b: shows baseline pulse wave amplitude recordings after four days of ingestion of flavanol-rich cocoa by this volunteer. There was a clear increase in pulse wave amplitude measured in the morning, more than 12 hours after the last dose of cocoa. c: shows that on day 5, exposure to an additional 230 ml dose of cocoa led to a further increase in pulse wave amplitude 90 minutes later. d: shows that after ingestion of flavanol-rich cocoa on day 5, the nitric oxide synthase inhibitor, L-NAME, abolished the increase in pulse wave amplitude (Data from reference 9).

This story has at least one of its beginnings a long way from the issue of phytochemicals in foods. The Kuna Indians in Panama, living in their indigenous island home in the Caribbean, do not show the typical rise in blood pressure with age, and hypertension is very rare.[34] In a study that began with the search for protective genes, the observation that migration to Panama City led to a loss of the protection against hypertension made it clear that an environmental factor was involved. Examination of their diet uncovered the fact that they drank large volumes of a flavanol-rich cocoa.[2] Subsequent in vitro studies suggesting that cocoa extracts can induce endothelium-dependent relaxation[4] led to studies in healthy volunteers,[9] and in patients with vascular risk or disease.[1] In the studies of Heiss et al. ingestion of flavanol-rich cocoa led to an increase in flow-mediated vasodilation of the brachial artery following five minutes of ischaemia, a response that correlated with biochemical evidence of increased nitric oxide bioavailability.[8] In the normal volunteers studied by Fisher et al. flavanol-rich cocoa induced striking dilatation of the vessels of the finger, which was reversed completely by an arginine analogue that blocks nitric oxide synthesis (figure 1).[9]

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