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platelet function1– 4
Joseph A Vita
292S Am J Clin Nutr 2005;81(suppl):292S–7S. Printed in USA. © 2005 American Society for Clinical Nutrition
cardiovascular risk factors (26). These findings suggest that en- endothelial function. Tea contains an assortment of water-
dothelial function may have utility as a surrogate marker of soluble antioxidant flavonoids, including catechins, quercetin,
cardiovascular risk. Furthermore, endothelial function has kaempferol, and other polyphenols, particularly thearubigins.
evolved into a clinically useful endpoint for studies of potential We examined the short-term and long-term effects of tea con-
interventions for the prevention or treatment of cardiovascular sumption on flow-mediated dilation in the brachial artery among
disease (23). 50 subjects with angiographically proven coronary artery dis-
ease, in a placebo-controlled, crossover study (51). Subjects tak-
ing antioxidant supplements were excluded, and subjects were
STUDIES OF ANTIOXIDANTS AND ENDOTHELIAL asked to refrain from drinking tea and red wine during the study.
DYSFUNCTION All subjects were receiving prescribed medications for coronary
artery disease, and 77% were undergoing lipid-lowering therapy.
With respect to the mechanism of endothelial dysfunction,
Short-term effects of tea were examined by measuring flow-
there has recently been great interest in the importance of oxi-
mediated dilation before and 2 h after the subjects consumed 450
dative stress. These studies fit well with the recognition that
mL of freshly brewed black tea. Long-term effects were exam-
oxidative stress contributes to atherogenesis (39). The impor-
ined by measuring flow-mediated dilation again after the sub-
tance of oxidative stress as a cause of endothelial dysfunction has
jects had consumed 900 mL of black tea per day for 30 d. The
prompted many investigations into the effects of antioxidants on
study used water as a control beverage, and the beverage order
endothelial function. For ascorbic acid in particular, there is
was randomized.
extensive evidence that acute treatment reverses endothelial
Both short-term and long-term tea consumption improved en-
dysfunction in many disease states, including atherosclerosis,
dothelial function, whereas water consumption had no effect.
diabetes mellitus, hypertension, congestive heart failure, renal
There also were no effects of tea consumption on nitroglycerin-
failure, hyperhomocysteinemia, hypercholesterolemia, and
mediated dilation, baseline arterial diameter, or the extent of
others (40).
reactive hyperemia, which confirmed that tea consumption af-
Gokce et al (41) examined the effect of ascorbic acid on bra-
fected endothelial function, rather than the function of vascular
chial artery flow-mediated dilation in a randomized, placebo-
smooth muscle or the stimulus for dilation. Flow-mediated dila-
controlled, double-blind study of patients with coronary artery
tion was not affected by an acute dose of caffeine, which sug-
disease. Flow-mediated dilation reflects shear stress-mediated
gested that the caffeine content of tea did not account for the
nitric oxide production by the endothelium (42). This physiolog-
results. Blood pressure, serum glucose concentrations, and se-
ically relevant response is impaired in the setting of coronary risk
rum lipid concentrations remained stable during tea consump-
factors and is correlated with abnormal responses in the coronary
tion. Although catechins represent a relatively minor component
circulation (43); abnormal responses in the brachial artery pre-
of black tea, they are measurable in plasma. Our study demon-
dict future cardiovascular disease events among high- and low-
strated that total catechin amounts were increased 앑20% after tea
risk patients (34 –36, 38). In the study by Gokce et al (41), bra-
consumption; however, there was no relationship between
chial artery flow-mediated dilation was impaired at baseline.
changes in total catechin amounts and improvements in endo-
Flow-mediated dilation improved 2 h after an acute 2-g dose of
thelial function.
ascorbic acid, and the effect was sustained after 30 d of treatment
Although tea contains flavonoid antioxidants, it remains un-
with 500 mg/d. The responses were unchanged after acute and
clear whether an antioxidant effect explains the observed bene-
chronic treatment with placebo. Mechanistic in vitro studies sug-
fits of tea. Our study demonstrated no effect of tea consumption
gested that the benefit of ascorbic acid may be attributable, in
on plasma antioxidant capacity (51). There also was no effect on
part, to increased activity of nitric oxide synthase resulting from
plasma concentrations of F2-isoprostanes, markers of systemic
stabilization of tetrahydrobiopterin, an essential cofactor for en-
lipid peroxidation, or 8-hydroxydeoxyguanosine, a marker of
zyme activity (44).
DNA oxidation. These findings are consistent with several other
Other water-soluble antioxidant compounds have beneficial
well-conducted studies that failed to demonstrate a reduction in
effects on endothelial function among patients with cardiovas-
markers of oxidative stress after tea consumption (52).
cular disease, including N-acetylcysteine (45, 46), glutathione
Several other studies demonstrated that flavonoid-containing
(47), and the cysteine donor L-2-oxothiazolidine-4-carboxylic
beverages have beneficial effects on endothelial function. For
acid (48). In contrast, the effects of lipid-soluble antioxidants on
example, Hodgson et al (53) examined the effect of tea consump-
endothelium-dependent dilation among human subjects with
tion on brachial artery flow-mediated dilation among a group of
atherosclerosis and cardiovascular risk factors have been rela-
otherwise healthy subjects with modest hypercholesterolemia.
tively disappointing, although benefits have been reported for
Those investigators observed that consumption of 5 cups of black
select, high-risk groups, including patients with type 1 diabetes
tea per day for 5 wk led to improved flow-mediated dilation.
mellitus (49) or multiple risk factors (50).
Interestingly, tea consumption was also associated with an im-
provement in nitroglycerin-mediated dilation, which suggested
that tea improved the bioactivity of endothelium-derived nitric
EFFECTS OF POLYPHENOLS ON ENDOTHELIAL oxide and/or had a beneficial effect on the function of vascular
FUNCTION smooth muscle.
The extensive prior work demonstrating a beneficial effect of Other flavonoid-containing beverages, particularly grape
ascorbic acid on endothelial function prompted us to consider products, have been shown to improve endothelial function.
that other water-soluble antioxidants, such as flavonoids, might Stein et al (54) observed that consumption of grape juice for 14 d
have beneficial effects on endothelial function. To explore this was associated with improved brachial artery flow-mediated di-
possibility, we investigated the effects of tea consumption on lation among 15 adults with angiographically proven coronary
between intake of flavonoids and risk for coronary heart disease in male dysfunction, oxidative stress, and risk of cardiovascular events in pa-
health professionals. Ann Intern Med 1996;125:384 –9. tients with coronary artery disease. Circulation 2001;104:2673– 8.
6. Hertog MG, Sweetnam PM, Fehily AM, Elwood PC, Kromhout D. 34. Gokce N, Keaney JF Jr, Menzoian JO, et al. Risk stratification for
Antioxidant flavonols and ischemic heart disease in a Welsh population postoperative cardiovascular events via noninvasive assessment of en-
of men: the Caerphilly Study. Am J Clin Nutr 1997;65:1489 –94. dothelial function. Circulation 2002;105:1567–72.
7. Yochum L, Kushi LH, Meyer K, Folsom AR. Dietary flavonoid intake 35. Modena MG, Bonetti L, Coppi F, Bursi F, Rossi R. Prognostic role of
and risk of cardiovascular disease in postmenopausal women. Am J reversible endothelial dysfunction in hypertensive postmenopausal
Epidemiol 1999;149:943–9. women. J Am Coll Cardiol 2002;40:505–10.
8. Sesso HD, Gaziano JM, Buring JE, Hennekens CH. Coffee and tea intake 36. Gokce N, Keaney JF Jr, Hunter LM, et al. Predictive value of non-
and the risk of myocardial infarction. Am J Epidemiol 1999;149:162–7. invasively-determined endothelial dysfunction for long-term cardiovas-
9. Geleijnse JM, Launer LJ, Van der Kuip DA, Hofman A, Witteman JC. cular events in patients with peripheral vascular disease. J Am Coll
Inverse association of tea and flavonoid intakes with incident myocardial Cardiol 2003;41:1769 –75.
infarction: the Rotterdam Study. Am J Clin Nutr 2002;75:880 – 6. 37. Schindler TH, Hornig B, Buser PT, et al. Prognostic value of abnormal
10. Mukamal KJ, Maclure M, Muller JE, Sherwood JB, Mittleman MA. Tea vasoreactivity of epicardial coronary arteries to sympathetic stimulation
consumption and mortality after acute myocardial infarction. Circula- in patients with normal coronary angiograms. Arterioscler Thromb Vasc
tion 2002;105:2476 – 81. Biol 2003;23:495–501.
11. Sesso HD, Gaziano JM, Liu S, Buring JE. Flavonoid intake and the risk 38. Brevetti G, Silvestro A, Schiano V, Chiariello M. Endothelial dysfunc-
of cardiovascular disease in women. Am J Clin Nutr 2003;77:1400 – 8. tion and cardiovascular risk prediction in peripheral arterial disease:
12. Sesso HD, Paffenbarger RS Jr, Oguma Y, Lee IM. Lack of association additive value of flow-mediated dilation to ankle-brachial pressure in-
between tea and cardiovascular disease in college alumni. Int J Epide- dex. Circulation 2003;108:2093– 8.
miol 2003;32:527–33. 39. Keaney JF Jr, ed. Oxidative stress and vascular disease. Boston: Kluwer
13. Vita JA. Tea consumption and cardiovascular disease: effects on endo- Academic Publishers, 2000.
thelial function. J Nutr 2003;133:3293S–7S. 40. Duffy SJ, Vita JA, Keaney JF Jr. Antioxidants and endothelial function.
14. Duffy SJ, Vita JA. Effects of phenolics on vascular endothelial function. Heart Failure 1999;15:135–52.
Curr Opin Lipidol 2003;14:21–7. 41. Gokce N, Keaney JF Jr, Frei B, Holbrook M, Olesiak M, Zachariah BJ,
15. Higdon JV, Frei B. Tea catechins and polyphenols: health effects, me- Leewenburgh C, Heinecke JW, Vita JA. Long-term ascorbic acid ad-
tabolism, and antioxidant functions. Crit Rev Food Sci Nutr 2003;43: ministration reverses endothelial vasomotor dysfunction in patients with
89 –143. coronary artery disease. Circulation 1999;99:3234 – 40.
16. de Gaetano G, De Curtis A, Di Castelnuovo A, Donati MB, Iacoviello L, 42. Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultra-
Rotondo S. Antithrombotic effect of polyphenols in experimental mod- sound assessment of endothelial-dependent flow-mediated vasodilation
els: a mechanism of reduced vascular risk by moderate wine consump- of the brachial artery: a report of the International Brachial Artery Re-
tion. Ann NY Acad Sci 2002;957:174 – 88. activity Task Force. J Am Coll Cardiol 2002;39:257– 65.
17. Peters U, Poole C, Arab L. Does tea affect cardiovascular disease? A 43. Anderson TJ, Uehata A, Gerhard MD, et al. Close relation of endothelial
meta-analysis. Am J Epidemiol 2001;154:495–503. function in the human coronary and peripheral circulations. J Am Coll
18. Pearson TA. Alcohol and heart disease. Circulation 1996;94:3023–5. Cardiol 1995;26:1235– 41.
19. Klatsky AL, Friedman GD, Armstrong MA, Kipp H. Wine, liquor, beer, 44. Huang A, Vita JA, Venema RC, Keaney JF Jr. Ascorbic acid enhances
and mortality. Am J Epidemiol 2003;158:585–95. endothelial nitric oxide synthase activity by increasing intracellular tet-
20. Di Castelnuovo A, Rotondo S, Iacoviello L, Donati MB, de Gaetano G. rahydrobiopterin. J Biol Chem 2000;275:17399 – 406.
Meta-analysis of wine and beer consumption in relation to vascular risk. 45. Prasad A, Andrews NP, Padder FA, Husain M, Quyyumi AA. Glutathi-
Circulation 2002;105:2836 – 44. one reverses endothelial dysfunction and improves nitric oxide bioavail-
21. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; ability. J Am Coll Cardiol 1999;34:507–14.
340:115–26. 46. Andrews NP, Prasad A, Quyyumi AA. N-Acetylcysteine improves cor-
22. Libby P. Molecular basis of the acute coronary syndromes. Circulation onary and peripheral vascular function. J Am Coll Cardiol 2001;37:117–
1995;91:2844 –50. 23.
23. Vita JA, Keaney JF Jr. Endothelial function: a barometer for cardiovas- 47. Kugiyama K, Ohgushi M, Motoyama T, et al. Intracoronary infusion of
cular risk? Circulation 2002;106:640 –2. reduced glutathione improves endothelial vasomotor response to ace-
24. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium- tylcholine in human coronary circulation. Circulation 1998;97:2299 –
derived relaxing factor produced and released from artery and vein is 301.
nitric oxide. Proc Natl Acad Sci USA 1987;84:9265–9. 48. Vita JA, Frei B, Holbrook M, Gokce N, Leaf C, Keaney JF Jr. L-2-
25. Gokce N, Vita JA. Clinical manifestations of endothelial dysfunction. In: Oxothiazolidine-4-carboxylic acid reverses endothelial dysfunction in
Loscalzo J, Schafer AI, eds. Thrombosis and hemorrhage. Philadelphia: patients with coronary artery disease. J Clin Invest 1998;101:1408 –14.
Lippincott Williams & Wilkins, 2002:685–706. 49. Beckman JA, Goldfine AB, Gordon MB, Garrett LA, Keaney JF, Crea-
26. Widlansky ME, Gokce N, Keaney JF Jr, Vita JA. The clinical implica- ger MA. Oral antioxidant therapy improves endothelial function in type
tions of endothelial dysfunction. J Am Coll Cardiol 2003;42:1149 – 60. 1 but not type 2 diabetes mellitus. Am J Physiol Heart Circ Physiol
27. Leeson CPM, Hingorani AD, Mullen MJ, et al. Glu298Asp endothelial 2003;285:H2392– 8.
nitric oxide synthase gene polymorphism interacts with environmental 50. Heitzer T, Yla HS, Wild E, Luoma J, Drexler H. Effect of vitamin E on
and dietary factors to influence endothelial function. Circ Res 2002;90: endothelial vasodilator function in patients with hypercholesterolemia,
1153– 8. chronic smoking or both. J Am Coll Cardiol 1999;33:499 –505.
28. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR, 51. Duffy SJ, Keaney JF Jr, Holbrook M, et al. Short- and long-term black
Lerman A. Long-term follow-up of patients with mild coronary artery tea consumption reverses endothelial dysfunction in patients with cor-
disease and endothelial dysfunction. Circulation 2000;101:948 –54. onary artery disease. Circulation 2001;104:151– 6.
29. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary 52. O’Reilly JD, Mallet AI, McAnlis GT, et al. Consumption of flavonoids
vasodilator dysfunction on adverse long-term outcome of coronary heart in onions and black tea: lack of effect on F2-isoprostanes and autoanti-
disease. Circulation 2000;101:1899 –906. bodies to oxidized LDL in healthy humans. Am J Clin Nutr 2001;73:
30. Halcox JP, Schenke WH, Zalos G, et al. Prognostic value of coronary 1040 – 4.
vascular endothelial dysfunction. Circulation 2002;106:653– 8. 53. Hodgson JM, Puddey IB, Burke V, Watts GF, Beilin LJ. Regular inges-
31. Neunteufl T, Heher S, Katzenschlager R, et al. Late prognostic value of tion of black tea improves brachial artery vasodilator function. Clin Sci
flow-mediated dilation in the brachial artery of patients with chest pain. (Lond) 2002;102:195–201.
Am J Cardiol 2000;86:207–10. 54. Stein JH, Keevil JG, Wiebe DA, Aeschlimann S, Folts JD. Purple grape
32. Perticone F, Ceravolo R, Pujia A, et al. Prognostic significance of en- juice improves endothelial function and reduces the susceptibility of
dothelial dysfunction in hypertensive patients. Circulation 2001;104: LDL cholesterol to oxidation in patients with coronary artery disease.
191– 6. Circulation 1999;100:1050 –5.
33. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial 55. Chou EJ, Keevil JG, Aeschlimann S, Wiebe DA, Folts JD, Stein JH.