Grape Seed Extract for the Prevention of Cardiac Disease
Grape Seed Extract for the Prevention of Cardiac Disease
September 1999; Volume 2: 91-94
By Dónal P. O’Mathúna
Sales of grape seed extract have recently jumped, making it one of the best-selling herbal remedies. Proponents claim that the extract can treat arthritis and allergic reactions, improve circulation, fight cancer, and protect against heart disease. It is also popular in the treatment of vein and eye problems. All these effects are said to result from the extract’s antioxidant activity.
Recent interest in using antioxidants like vitamin E and selenium to prevent heart disease has fueled clinical and popular interest. Good data suggest that drinking a glass of wine daily may be beneficial. Recommending even moderate consumption of any alcoholic beverage raises concerns about possible negative effects, including the potential for abuse. So would a grape seed extract, without the alcohol from fermented juice, be just as beneficial?
Background
Recent interest in grape seed extracts to prevent cardiovascular disease can be traced to the so-called "French Paradox." Evidence of cholesterol’s role in atherosclerosis was suggested by epidemiological evidence showing that the residents of countries with higher dietary fat intake tended to have higher mortality and morbidity from cardiovascular diseases.1 However, the populations of a number of Mediterranean countries, France in particular, did not fit the pattern. As early as 1979, wine consumption was identified as the factor most significantly associated with lower ischemic heart disease mortality in France.2
A number of studies in the early 1990s confirmed these associations. Further research showed that red wine had beneficial cardiovascular effects not found with ethanol or even white wine.3 Red wine in particular has been shown to reduce platelet aggregation and HDL-cholesterol levels,3 cause endothelium-dependent vasorelaxation,4 raise serum antioxidant capacity,5,6 and inhibit LDL-oxidation.7 The compounds believed to be the source of these properties are called polyphenols. These are found abundantly in red wine, but not white, and are also present in many other fruits and vegetables.
Other grape products, such as grape juice, raisins, and jams, continue to be examined to determine whether they have the same beneficial effects as red wine. Indeed, the search for the chemical origin of wine’s beneficial effects has not always been greeted enthusiastically. Early researchers quipped: "If wine is ever found to contain a constituent protective against ischemic heart disease, then we consider it almost a sacrilege that this constituent should be isolated. The medicine is already in a highly palatable form."2 Regardless, grape seed extract has emerged as the most prominent competitor to a glass of cabernet.
Constituents
Polyphenols, including those found in red wine and grape seed extract, are only made by plants. Tannins, phenolic acids, and flavonoids are all polyphenols.
Some of the flavonoids red wine contains are anthocyanins and procyanidins, the latter of which are compounds made by combining two or more flavonoid molecules. (See Figure 1.) Anthocyanins are the principal flavonoids in grape skins, giving grapes their particular color. Procyanidins are found primarily in grape seeds.8
Other commonly used names for procyanidins include OPCs (oligomeric proanthocyanidin complexes, pycnogenols, and condensed tannins) and the trademarked compound Pycnogenol®. Although Pycnogenol is a U.S. trademark for procyanidins extracted from pine bark by a patented process, pycnogenol is also the name of a specific class of botanical antioxidants.9 Other foods rich in procyanidins also have high antioxidant activity, such as green tea (Camellia sinensis), coffee, chocolate,10 and peanut skins.
Procyanidins, the antioxidants in grape seed extract, are members of which class of chemicals?
a. Peptides
b. Polyphenols
c. Enzymes
d. Vitamins
Mechanism of Action
The proposed cardioprotective mechanism of action for grape seed extract is the same as that for other antioxidants. LDL-cholesterol circulating in the blood can be oxidized by free radicals and peroxides. Oxidized LDL can be removed from the blood by macrophages. These macrophages then form foam cells that deposit significant amounts of cholesterol in the lining of arteries, resulting in atherosclerosis.11 Oxidized LDL is also directly cytotoxic to endothelial cells and promotes vascular smooth muscle proliferation in atherosclerotic lesions.12
Procyanidins from grape seed extract have been shown to be effective scavengers of both superoxide anions and hydroxyl free radicals.13 Measured antioxidant activity is roughly four times that of vitamin C and double that of vitamin E.13 Procyanidins have also been found to inhibit a number of enzymes, including lipooxygenase,14 which oxidizes lipids, and cyclooxygenase, which is involved in platelet aggregation.15 Other mechanisms may contribute cardiac benefits as procyanidins increase nitric oxide synthesis, leading to vasorelaxation and reduced platelet aggregation.16 Other studies have shown that procyanidins inhibit the enzymes which promote oxidative damage of the vascular endothelium.14
Animal Studies
A number of promising animal studies with grape seed extract were recently published.
The hearts of rats whose diet was supplemented with grape seed extract showed greater resistance to experimentally induced myocardial ischemic reperfusion injury, compared with the hearts of rats fed without the extract.17 Similar resistance to ischemic injury was found in another rat study, which also showed a 30-40% increase in plasma total antioxidant capacity.18 Rabbits fed a cholesterol-rich diet showed significantly reduced severe aortic atherosclerosis when grape seed extract was added to their diet compared with those subjects that did not receive the extract.19
Clinical Studies
Three small clinical trials conducted in France in the early 1980s were reviewed by Bombardelli.14 These double-blind trials with patients with chronic peripheral venous insufficiency found that grape seed extract significantly improved venous function compared to a placebo’s effect. In the Netherlands, an epidemiological study of 805 men (aged 65-84 years) followed for five years found that deaths from coronary heart disease were most strongly inversely associated with dietary flavonoid intake.15 The major sources of flavonoids were tea (61%), onions, and apples. These foods contain flavonoids that are similar but not identical to grape seed flavonoids.
A literature search revealed one clinical trial relevant to grape seed extract’s cardioprotective ability (searching MEDLINE, CINAHL, and The Cochrane Library for "grape seed," "procyanidin," "proanthocyanidin," and "pycnogenol"). This single-blind, randomized, crossover study involved 20 healthy subjects (mean age 23 years) given 300 mg/d of grape seed extract.1 Significant increases in serum total antioxidant capacity (TAC) occurred up to three hours after ingestion (P < 0.01); the levels then returned to baseline. No significant differences were found between TAC values on the first and fifth days of treatment. No significant changes in serum vitamin E or C levels were found during the study.
A popular book promoting grape seed extract cited only animal and in vitro studies.20
Adverse Effects
No adverse effects or drug interactions have been noted from use of grape seed extract, although clinical studies have not examined this area. Schultz reports that the calculated LD50 in rats and mice exceeds 4,000 mg/kg.21 Given the harmful effects found with beta-carotene in long-term smokers, caution should be exercised before recommending long-term use of any antioxidant dietary supplement in smokers.12
Formulation/Dosage
Commercial grape seed extract is made by soaking seeds of wine grapes (Vitis vinifera) in warm water and extracting specific, water-soluble antioxidant compounds with hot water.19 The freeze-dried extract contains 75-85% procyanidins, mixed with other flavonoids and organic acids. Tablets or capsules usually contain 150 mg extract, with one or two recommended daily. Red wine contains about 1 g polyphenols per liter.6 One proprietary product is officially approved for use in France for treatment of microcirculation disorders.14
Conclusion
Grape seed extract is a complex mixture of compounds, some of which are powerful antioxidants. Much is known about its biochemistry, and the extract appears to be beneficial in animal models. Results of animal studies and intriguing epidemiological associations, however, do not always translate into clinical benefit. The proposal that antioxidants prevent atherosclerosis remains mired in controversy.11 The American Heart Association remains cautious regarding widespread use of antioxidant supplements.22
Little clinical study of the extract has been undertaken and flavonoids are notorious for chemical modification within plants and during processing.8 The great number of wines and their myriad flavors (even from the same species of grape) is a delicious but confusing tribute to this variability. This variability makes standardization against particular procyanidins extremely difficult, but standardization against antioxidant capacity is possible.
Recommendation
It remains controversial as to whether any one source of antioxidants will provide the same benefit as a diet rich in a variety of antioxidants. Until prospective, randomized clinical trials demonstrate the cardioprotective benefits of grape seed extract, it should be taken as part of a balanced diet that includes antioxidant-rich plant products. Evidence warrants grape seed extract’s inclusion in ongoing research in this area but not supplementation as an isolated compound.
The oxidative damage believed to play a role in atherosclerosis arises from:
a. oxygen in the blood.
b. free radicals produced biochemically.
c. toxins in the diet.
d. ultraviolet light.
Dr. O’Mathúna is a Professor of Bioethics and Chemistry at Mt. Carmel College of Nursing, Columbus, OH.
References
1. Nuttall SL, et al. An evaluation of the antioxidant activity of a standardized grape seed extract, Leucoselect®. J Clin Pharm Ther 1998;23:385-389.
2. St Léger AS, et al. Factors associated with cardiac mortality in developed countries with particular reference to the consumption of wine. Lancet 1979;1: 1017-1020.
3. Seigneur M, et al. Effect of the consumption of alcohol, white wine, and red wine on platelet function and serum lipids. J Appl Cardiol 1990;5:215-222.
4. Fitzpatrick DF, et al. Endothelium-dependent vaso-relaxing activity of wine and other grape products. Am J Physiol 1993;265:H774-H778.
5. Maxwell S, et al. Red wine and antioxidant activity in serum. Lancet 1994;344:193-194.
6. Cao G, et al. Serum antioxidant capacity is increased by consumption of strawberries, spinach, red wine or vitamin C in elderly women. J Nutr 1998;128: 2383-2390.
7. Frankel EN, et al. Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine. Lancet 1993;341:454-457.
8. Brouillard R, et al. Polyphenols produced during red wine ageing. Biofactors 1997;6:403-410.
9. Masquelier J, et al. Flavonoids and pycnogenols. Int J Vitam Nutr Res 1979;49:307-311.
10. Wilkinson SL. Take two cups of coffee and call me tomorrow. Chem Eng News 1999;77:47-50.
11. Futterman LG, Lemberg L. The use of antioxidants in retarding atherosclerosis: Fact or fiction? Am J Crit Care 1999;8:130-133.
12. Lonn EM, Yusuf S. Is there a role for antioxidant vitamins in the prevention of cardiovascular diseases? An update on epidemiological and clinical trials data. Can J Cardiol 1997;13:957-965.
13. Bagchi D, et al. Oxygen free radical scavenging abilities of vitamins C and E, and a grape seed proanthocyanidin extract in vitro. Res Commun Mol Pathol Pharmacol 1997;95:179-189.
14. Bombardelli E, Marazzoni P. Vitis vinifera L. Fitoterapia 1995;66:291-317.
15. Hertog MG, et al. Dietary antioxidant flavonoids and risk of coronary heart disease: The Zutphen Elderly Study. Lancet 1993;342:1007-1011.
16. Fitzpatrick DF, et al. Endothelium-dependent vascular effects of Pycnogenol. J Cardiovasc Pharmacol 1998;32:509-515.
17. Sato M, et al. Cardioprotective effects of grape seed proanthocyanidin against ischemic reperfusion injury. J Mol Cell Cardiol 1999;31:1289-1297.
18. Facino RM, et al. Diet enriched with procyanidins enhances antioxidant activity and reduces myocardial post-ischaemic damage in rats. Life Sci 1999;64: 627-642.
19. Yamakoshi J, et al. Proanthocyanidin-rich extract from grape seeds attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits. Atherosclerosis 1999;142:139-149.
20. Passwater RA, Kandaswami C. Pycnogenol: The Super Protector’ Nutrient. New Canaan, CT: Keats Publishing; 1994.
21. Schulz V, et al, eds. Rational Phytotherapy. Berlin: Springer-Verlag; 1998.
22. Tribble DL. Antioxidant consumption and risk of coronary heart disease: Emphasis on vitamin C, vitamin E, and beta-carotene. Circulation 1999;99:591-595.
September 1999; Volume 2: 91-94
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