Flavanols and Cardiovascular Disease Prevention

Christian Heiss; Carl L. Keen; Malte Kelm


Eur Heart J. 2010;31(21):2583-2592. 

In This Article

Endothelial Function

The endothelium maintains vascular homeostasis through multiple complex interactions with cells in the vessel wall and lumen. It regulates vascular tone by balancing the production of vasodilators, most importantly NO, prostaglandins, and endothelium-derived hyperpolarizing factor, and vasoconstrictors including endothelin-1 (Figure 3). The severity of endothelial dysfunction relates to a patient's risk for experiencing an initial or recurrent cardiovascular event.[43] A number of interventions known to decrease cardiovascular risk, including diets rich in plant foods, exercise, smoking cessation, weight reduction, medication with angiotensin-converting enzyme (ACE) inhibitors, and statin administration are thought to mediate their vascular protective effect in part by restoring endothelial function.[43,44]

Figure 3.

Pharmacodynamics—summary of potential targets for flavanol-mediated vascular effects. (A and B) Cardiovascular risk factors induce endothelial dysfunction and lead to arteriosclerosis and facilitate cardiovascular events by inducing endothelial damage and interaction with platelets,WBCs, and EPCs. (C) Key signaling cascades by which the endothelium modulates its physiological functions and by which flavanols may modulate vascular function and structure. *Clinical human studies, †human ex vivo, #animal studies, ‡ in vitro studies (ADMA, asymmetrical dimethylarginine, A I, angiotensin I; A II, angiotensin II, ACE, angiotensin-converting enzyme; AT1, angiotensin receptor 1, CACs, circulating angiogenic cells; COX, cyclooxygenase; EC, endothelial cells; ECE, endothelin-converting enzyme; EDHF, endothelium derived hyperpolarizing factor; EMPs, endothelial microparticles; EPCs, endothelial progenitor cells; ET-1, endothelin 1; GC, guanylyl cyclase; NO, nitric oxide; NOX, NADPH oxidases; PGL, prostaglandin; SMC, smooth muscle cells; O2 , superoxide anion; WBCs, white blood cells).

Several clinical intervention studies have tested the effect of flavanol-rich foods including cocoa, dark chocolate, tea, grape juice, and red wine on endothelial vasodilator response.[14] In several studies, endothelium-dependent vasodilation was measured as flow-mediated vasodilation of the brachial artery (FMD) using high-resolution ultrasound in a few studies with peripheral artery tonometry (PAT) of the finger tips, and in one study using the cold pressor test during coronary angiography.[45] In general, these studies show that high-flavanol/procyanidin interventions induce an acute and sustained increase or restoration of endothelium-dependent vasodilation in healthy subjects,[46–51] in those with cardiovascular risk factors (smoking, diabetes mellitus, hypertension, hypercholesterolemia),[11,49,52–54] heart transplant recipients,[45] hemodialysis patients,[55] or patients with manifest CAD.[11,15,56–59] (Table 1). A dose dependence of these effects was shown acutely in healthy smokers and non-smokers acutely consuming flavanol-rich cocoa (176–917 mg flavanols) and CAD patients consuming black tea (0–800 mg tea flavonoids) over 1 week.[11–13,15,60,61] Plasma levels of flavanol metabolites were shown to be significant statistical predictors of the FMD increase. Longer term studies with multiple daily dosing regimens for up to 6 weeks have shown that there can be a sustained increase in FMD and PAT, which can be increased by additional application (acute or chronic).[11,56,59] A causal relationship between the intake of flavanols and an improvement of vascular function has been further substantiated in studies where pure flavanols, (−)-epicatechin and epigallocatechin-gallate provided orally, were shown to have acute FMD-enhancing effects.[13,62] In parallel with the FMD and PAT effects, an increase in circulating plasma NO storage forms, RXNO (S- and N-nitros(yl)ated NO species (RX designates that NO is bound to different residues 'R' via different bonds 'X') and nitrite, has been observed in several of these dietary intervention trials including one applying pure (−)-epicatechin.[11,13,63,64] Importantly, these NO species represent both, a marker for endothelial NO synthesis and bioactive NO storage pools, which have intrinsic vasodilator activity.[65,66] The increase in both the FMD and NO species can be abolished by systemic inhibition of NOS using L-NMMA,[12,13] and the PAT response can be blocked by L-NAME.[46] In the context of flavanol-associated cardiovascular effects and their potential mechanisms, these data support the concept that the acute and short-term intake of flavanols can be causally linked to an increase in endothelium-dependent vasodilation in humans. Still, the molecular target(s) of the flavanols have yet to be identified, there is limited information regarding the amount of flavanols that are needed on a chronic basis to elicit the above endothelial effects, and most importantly, it still needs to be shown that intake of flavanols on a chronic basis can prevent the development and progression of vascular disease.


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