Flavonoid-Rich Grapeseed Extracts: A New Approach In High Cardiovascular Risk Patients?

P. Kar; D. Laight; K. M. Shaw; M. H. Cummings

Disclosures

Int J Clin Pract. 2006;60(11):1484-1492. 

In This Article

Flavonoids

In 1992, examination of WHO epidemiological data showed an intriguing anomaly in Toulouse, France where subjects, in spite of high saturated fat consumption, comparable cholesterol and similar risk factors showed considerably lower incidence of death from coronary heart disease compared with other countries such as the United States and the United Kingdom. This apparent discrepancy, also known as the 'French Paradox',[34] triggered a specific scrutiny for an explanation of this phenomenon. Review of the epidemiological data suggested that alcohol consumption, especially red wine, may have conferred superior protection compared with other beverages. This suggested that the beneficial effects of red wine were, at least in part, due to components other than alcohol. Although the specific mechanism behind the French paradox has not been identified, further studies, both in vivo and in vitro, showed flavonoid components in red wine to have antioxidant properties possibly contributing to cardiovascular benefits.[35,36,37,38]

While some studies suggest that flavonoid intake was not associated with reduced CHD,[39,40,41] two other prospective trials suggested a lower risk of MIs.[42,43] A total of eight cohort studies found lower CHD mortality with total or specific flavonoid intake[40,44,45,46,47,48,49] but one large cohort study of 38,445 women found a non- significant inverse association between flavonoid intake and CHD mortality.[41] However, a recent meta-analysis indicate a significant protective association between flavonoid intake and risk of CHD mortality, RR = 0.81 (CI 0.71-0.92).[50] One of the authors of the studies[51] that did not show any association described a high background consumption of milk consumption that might have contributed to the null finding, as milk intake can potentially prevent intestinal absorption of flavonoids.[52] Interestingly, most studies, apart from one[53] showed no association for stroke risks,[46,47] although it is likely that these studies did not have sufficient power to study strokes or indeed their various subtypes.

Chemistry of Flavonoids

Revival of interest in traditional medicine coupled with rapid advances in pharmacognosy has led to a greater understanding of the biochemistry and pharmacology of flavonoids.[54,55] Flavonoids are a subgroup of a class of compounds known as polyphenols and are derivatives of 2-phenyl-1-benzopyran-4-one with varied chemical structures present in fruits, vegetables, nuts and seeds. They are polyphenolic compounds possessing 15 carbon atoms; two benzene rings joined by a linear 3-carbon chain (Figure 1).

Figure 1.

Flavonoid structure.

Over 4000 flavonoids have been identified and they are divided into several groups according to their chemical structure. The six major subgroups are: chalcones, flavonols (quercetin and kaempherol), flavanone (the catechins), flavones (apigenin), anthocyanins and isoflavonoids (genistein).

Flavonoids, Oxidative Stress and Inflammation

Flavonoid intake has been inversely related with coronary heart disease in the Zutphen Elderly Study,[42] the Seven Countries Study[45] and a cohort study in Finland[48] (Figure 2). Subsequent research has shown the flavonoid component in wine to inhibit oxidation of human LDL[35] and also inhibit platelet aggregation and adhesion. Cishek et al. showed red wine to cause endothelium-dependent relaxation (EDR).[56] Subsequent experiments indicated that flavonoid monomers failed to show this effect. However, oligomeric procyanidins produced a dose-dependent EDR.

Figure 2.

Pathophysiological factors involved in the metabolic syndrome, atherosclerosis and type 2 diabetes and the potential action of flavonoid-rich grapeseed extracts (GSE).

Quercetin, a flavonoid prominent in onions and apples, has been epidemiologically linked with protection from coronary artery disease and cancer.[42,49] It has also been shown to inhibit monocyte adhesion to endothelial cells,[57] which is believed to be the first step in the process of atherosclerosis.

Chocolate derived from the plant Theobroma cacao, rich in flavonoids, have shown improved endothelium-dependent flow-mediated dilation (FMD).[58] Flavonoids in elderberry have been shown to confer significant protective effects against oxidative insult and thus have important implications upon preserving endothelial cell function and thereby preventing the initiation of endothelial cells associated with vascular disease.[59] In vitro studies have shown flavonoid-rich chocolates to inhibit lipoxygenase pathways, which give rise to proinflammatory leukotrienes.[60,61] In addition to this, some have shown chocolate procyanidins can modulate a variety of other cytokines such as IL-5, tumour necrosis factor-alpha, tumour growth factor-beta - reducing their inflammatory effects.[62,63,64,65] A recent review by Yoon and Back elucidates the anti-inflammatory effects of polyphenols highlighting the potential role for dietary polyphenols to confer health benefits in reducing inflammation.[66]

'Mechanism of Action' of Flavonoids

The mechanism underlying the effects of flavonoids/procyandins on the endothelium has yet to be defined. One of the suggested mechanisms of flavonoid action has been that it creates a 'pseudo-laminar shear stress response', which counters the endothelial dysfunction.[67] Laminar shear stress (LSS) is the frictional force generated by blood flowing over the endothelium and in the context of normal endothelial function, this is one of the important regulatory factors as it induces vasodilation through NO and prostacyclin synthesis while inhibiting vasoconstriction by suppressing endothelin-1 production.[68,69]

LSS also has been shown to alter expression of a spectrum of genes. Gene array studies have demonstrated that physiological levels of LSS suppress the mRNA levels of genes associated with vascular dysfunction and increase the expression of protective genes.[70,71]

Grapes and Grapeseed Extract

The medicinal and nutritional value of grapes (Vitis vinifera) has been heralded for thousands of years. Egyptians consumed this fruit at least 6000 years ago, and several ancient Greek philosophers praised the healing power of grapes - usually in the form of wine. European folk healers developed an ointment from the sap of grapevines to cure skin and eye diseases. Unripe grapes were used to treat sore throats and dried grapes (raisins) were used to heal consumption, constipation, and thirst. The ripe, sweet grapes were used to treat a range of health problems including cancer, cholera, smallpox, nausea, eye infections, and skin, kidney, and liver diseases.

A general composition of the grape ( Table 1 ) consists of 2-6% stems, 5-12% skins, 80-90% juice and 0-5% seeds. Chemically, one of the important constituents are phenolic substances (frequently called polyphenols) which embrace many classes of compounds ranging from phenolic acids to simple and complex flavonoids. Grapeseeds, although they make up a small percentage of the weight of grapes, contain two-thirds of the extractable phenols.[72] The seeds are highest in phenol content and may contain up to 5-8% phenols by weight[73] and are essentially all flavonoids. They are also referred to as monomeric flavan-3-ols, which when joined together is known as oligomeric procyanidins. The procyanidins have been the subject of intensive research - mostly looking at its antioxidant role and its effect on the vascular endothelium.

The rich presence of flavonoid components in grape juice/grapeseed extract (GSE) further prompted research in cardiovascular disease ( Table 2 ). Initially, reduced platelet aggregation was noted with GSE in canine coronary arteries.[33] Suppression of lipid peroxidation has also been shown in neonatal rats. Rejuvenation of antioxidant system in central nervous system of rats, by GSE, has also been shown.

Further research showed reduced LDL oxidation in human high cardiovascular risk patients[35,38,74] reduced human platelet aggregation,[37,75,76] enhanced NO release[36] and improved human endothelial function.[39] Post-prandial oxidative stress was also seen to be reduced in models of oxidative stress (smoking).[77] Flow-mediated vasodilation has also seen to be improved after GSE administration.[78] In this context, it is important to remember that although there is no existing data relating impaired FMD to cardiac events in subjects without coronary disease, those patients with coronary disease who have very impaired FMD have more events.[79] Subjects with impaired FMD are also more likely to have coronary disease on angiography.[80] Statins improve mortality and one mechanism may be via their improvement of FMD.[81]

The University of California demonstrated that constituents present in GSE relaxed isolated blood vessels from rabbits by a pathway in which NO production is implicated,[82] while flavonoid-rich extract from GSE showed attenuation of development of aortic atherosclerosis in cholesterol-fed rabbits.[83]

Endothelium-dependent vasorelaxing activity in an aortic ring model is increased by incubation with grape products and these changes appear to be mediated by the NO-cGMP pathway.[84] Interestingly, in vitro tests using a cupric-ion-mediated LDL + VLDL oxidation model showed a synergistic effect of GSE with both Vitamin C and Vitamin E. Research by Peng et al. also indicated a decrease in arterial pressure in spontaneously hypertensive rats - probably via an antioxidant mechanism.[85]

Grapeseed extract has also been shown to be a more potent scavenger of oxygen-free radicals (an oxidative stressor) than other common antioxidants such as Vitamin C and E.[86,87] Uses of grapeseed-derived procyanidins (flavonoids with oligomeric structure) have also been shown to have an anti-hyperglycaemic effect on streptozotocin-induced diabetic rats. This was significantly increased if accompanied by a low insulin dose, which may partially have been due to the insulinomimetic activity of procyanidins on insulin-sensitive cell lines.[88] Research from Vinson et al. in 2001 used GSE in 17 subjects (nine normal and eight hypercholesterolaemic). Lipid profile and plasma antioxidant capacity were seen to be improved in the high-cholesterol subjects without a concomitant improvement in the healthy individuals.[89] Recent experimental trials have also suggested that proanthocyanidin-rich extract has protective effects against ischaemia-reperfusion-induced renal damage associated with oxidative stress.[90]

Other potential benefits of GSE have been centred on its effect on neoplasia and there have been several encouraging trials undertaken suggesting a beneficial effect.[90,91,92,93,94] Tebib et al.[95] reported an interesting finding in 1994 whereby faecal excretion of cholesterol by rats fed GSE was approximately twofold higher compared with the control group and could be attributed to a reduction or inhibition of intestinal cholesterol absorption.

Side-effects and Safety Profile of Grapeseed Extract

It is important to keep in mind with any potential treatment the possible side effects it brings with it. Fortunately, in vivo studies have not reported any major side effects and there are no known scientific reports of interactions between grapeseed and conventional medications either.

Grapeseed extract has been used as a dietary supplement for a number of years - both in Europe and the USA, and at present holds GRAS (Generally regarded as safe) status - as assessed by the FDA. 'Recommended dosage' has varied from 100 to 300 mg/day while pregnant and breast-feeding women are advised to avoid GSE.

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