fajar 125 *Department of Histology, Medical Faculty, Trisakti University Correspondence dr. Fajar Arifin Gunawijaya, MS Department of Histology, Medical Faculty, Trisakti University Jl. Kyai Tapa 260 - Grogol Jakarta 11440 Telp 021-5672731 ext.2701 Univ Med 2008; 27: 125-31 The role of tea in cardiovascular disease July-September, 2008July-September, 2008July-September, 2008July-September, 2008July-September, 2008 Vol.27 - No.3 Vol.27 - No.3 Vol.27 - No.3 Vol.27 - No.3 Vol.27 - No.3 ABSTRACT UNIVERSA MEDICINA Fajar Arifin Gunawijaya* Tea is an infusion of the leaves of the Camellia sinensis plant, which is not to be confused with so-called ‘herbal’ teas. Some biologically active chemicals in tea include flavonoids, caffeine and fluoride. For as long as people have been drinking tea, there have been health benefits associated with it. However, it has only been within the past 20 to 30 years that scientific studies have been conducted to investigate the validity of these claims. Many animal studies, and recently an increasing number of human studies, including epidemiological studies and clinical trials, have examined the relationship between tea drinking and health. Overall, observational studies in humans suggest that daily consumption of at least 3 cups of tea may be associated with a risk reduction of mortality (44%) after myocardial infarction compared with non-tea drinkers. The possibility that tea consumption reduces the risk of cardiovascular events remains open to the need for further clinical trials to clarify the effects of tea polyphenols in humans in order to recommend their use against cardiovascular diseases. Keywords : Tea, coronary heart disease, endothelium INTRODUCTION The Indonesian National Health Survey 2001 showed that the main cause of death a m o n g t h e I n d o n e s i a n p o p u l a t i o n w a s cardiovascular disease (diseases of the heart and great vessels), amounting to 26.3% of all deaths. When compared with the mortality rates due to cardiovascular disease in 1975, 1986 and 1995 of 5.9%, 9.1%, and 19%, respectively, these values indicate an increasing trend in the mortality rate of cardiovascular disease. (1) Epidemiological observations and clinical trials have established an association between regular t e a c o n s u m p t i o n a n d h e a l t h , p a r t i c u l a r l y p r e v e n t i o n o f c a r d i o v a s c u l a r d i s e a s e a n d stroke.(2,3) D i e t a r y f a c t o r s m a y b o t h r e d u c e a n d contribute to risk of cardiovascular disease (CVD) in a number of ways. Antioxidants, such as vitamin C, vitamin E and a range of other plant compounds, such as the flavonoids, are considered beneficial.(4) It is widely known that t h e i n c i d e n c e o f c o r o n a r y e v e n t s ( d e a t h definitely or probably due to coronary heart disease or non-fatal myocardial infarction) is 126 Gunawijaya Tea in cardiovascular substantially lower in the Japanese than in Western populations, although this is still open to question.(5) In Japan, as well as in other Asian countries, tea consumption is very high, and green tea, in particular, is favored by the Japanese. Chemical composition of tea Tea is an infusion of the leaves of the tea plant (Camellia sinensis L.) and its consumption worldwide is second only to that of water. The t e a p l a n t i s f o u n d i n 3 0 c o u n t r i e s , b u t i t originally came from China, where it was cultivated about 4000 years ago. However, recent archeological evidence has revealed that the plant was already utilized about 500,000 years ago.(6) Although the belief in the beneficial qualities of tea had been closely associated with this beverage since its discovery, scientific studies on tea and the substances contained therein were initiated only around 30 years ago. There are three kinds of tea, namely green tea, black tea and oolong tea, which differ in the processing methods used in the curing of the tea leaves. Green tea is prepared from unfermented tea leaves and has been demonstrated to have the highest catechin content. Black tea undergoes a fermentation process, such that most of its catechins are converted into theaflavins and thearubigins. On the other hand, oolong tea is processed by partial fermentation. Black tea is mainly consumed in Europe, North America and North Africa (except Marocco), whereas green tea is consumed in Asia and oolong tea is renowned in China and Taiwan. Most of the tea produced is black tea, amounting to 76-78%, which is consumed throughout the world. Production of green tea is around 20-22% of the global tea production, whereas oolong tea production is only 2%.(7) Tea contains a number of polyphenols, particularly flavonoids. The classification of polyphenols and the origins of the chemical substances contained in the tea plant are listed in Table 1.(8) Flavonoids are phenol derivatives that are found in a variety of plants and exhibit an enormous diversity, as more than 40,000 kinds have been recognized.(9) The principal flavonoids present in green tea are the catechins, such as epicatechin (EC), epicatechin-3-gallate (ECG), epigallocatechin (EGC) and epigallocatechin-3- gallate (EGCG). The catechins of black tea undergo polymerization (fermentation/enzymatic oxidation) to form mainly theaflavins and thearubigins. The amount of catechin found in tea depends on the curing process, geographic location and cultivation methods.(8) Epidemiological studies Mukamal KJ, et al. carried out a cohort s t u d y o n p a t i e n t s w i t h a c u t e m y o c a r d i a l infarction, who were asked about their tea drinking habits in the last year before the occurrence of the attack, and subsequently observed for two to four years. Those patients who consumed less than 14 cups per week (moderate tea drinkers) had a hazard ratio of 0.69 (95% CI 0.53 to 0.89), whereas those consuming 14 or more cups per week (heavy tea drinkers), had a hazard ratio of 0.61; 95% CI 0.42 to 0.86). Both groups had a mortality lower risk when compared with persons who did not drink tea.(2) Sesso and colleagues used a case-control design to examine the relation between tea and c o f f e e c o n s u m p t i o n a n d m y c o c a r d i a l infarction.(9) They examined tea and coffee intake by questionnaire in 340 subjects and 340 matched controls from the Boston Health Study and observed a 44% reduction in cardiovascular risk in individuals drinking more than one cup of tea per day. No significant relationship was f o u n d b e t w e e n c o f f e e c o n s u m p t i o n a n d cardiovascular disease. 127 A D u t c h s t u d y d e m o n s t r a t e d t h a t t e a drinking may reduce the risk of fatal heart attacks. The sudy was performed on 4,807 men and women aged 55 years and older, who had suffered no heart attacks during the past five years or more. Persons drinking more than 375 mL of tea daily had a lowered risk of myocardial i n f a r c t i o n , i n c o m p a r i s o n w i t h n o n - t e a drinkers.(10) In contrast, a 7.7 year follow-up on participants of the Scottish Heart Study showed n o r e l a t i o n s h i p b e t w e e n t e a d r i n k i n g a n d cardiovascular disease.(11) Peters et al. have recently pooled data from the USA and Europe into a meta-analysis and reported a protective effect of tea on myocardial infarction (11% per three cups per day).(12) This analysis specifically excluded data from the UK and thus has not clarified t h e i s s u e . M e t a - a n a l y s i s i s a p o w e r f u l s t a t i s t i c a l t o o l , b u t i t c a n n o t a c c o u n t f o r exclusion of major confounding factors, such as dietary intake of other antioxidants (eg. vitamin C and E), or social factors. Cross- culturally this is a major drawback, since the social patterns of tea consumption and its relationship to CVD in the UK are the opposite of those in other countries. Even controlling for a confounding factor, such as social class, Table 1. Classification of polyphenols and origin of chemicals in tea plants(8) Category Classes Major Food Sources Phenolic acids Ferulic acid Caffeic acid: - Chlorogenis acid Condensed tannins Hydrolyzable tannins: - Gallotannins: - Ellagitannins Dietary fibre – hemicelluloses Many fruits and vegetables, coffee Mango fruit Blackberries, raspberries, strawberries, wine, brandy aged in oak barrels Flavonoids Flavones Flavonols: - Quercetin Flavanols: - Catechins : epicatechin (EC) epicatechin-3-gallate (ECG) epigallocatechin (EGC) epigallocatechin-3-gallate (EGCG) Flavanones : - Hesperetin Isoflavones : - Genistein - Daidzein Anthocyanins : - Cyanidin Proanthocyanidins Sweet red pepper, celery Tea, onions, apples, many other fruits and vegetables Tea, especially green tea, chocolate, cocoa Oranges, citrus fruits Soybeans, soy protein-containing foods Red fruits: cherries, plums, strawberries, raspberries, blackberries, grapes, red and black currants Apples, pears, grapes, red wine, tea Lignans Enterodiol Flaxseed, flaxeed oil Stilbenes Resveratrol Red wine Univ Med Vol.27 - No.3 128 Gunawijaya Tea in cardiovascular is often not adequate to remove the whole effect of interest.(13) D r e g e r e t a l . h a v e d e m o n s t r a t e d t h e protective effect of EGCG and theaflavin-3,3’- digallate (TF3) against oxidative stress on rat cardiac muscle, when the substances were administered one hour before induction of oxidative stress by means of hydrogen peroxide. Thus green tea and black tea extracts, containing EGCG and TF3 respectively, may protect the heart muscle against oxidative stress.(14) Several possible mechanisms could explain an association between tea consumption and survival among patients with acute myocardial infarction. A recent randomized trial found that a c u t e a n d c h r o n i c b l a c k t e a c o n s u m p t i o n improved endothelial function in patients with coronary heart disease in an additive fashion.(15) This provides a suggestive mechanism for a beneficial impact of tea intake on survivors of acute myocardial infarction, given the adverse prognosis associated with coronary endothelial dysfunction in patients with coronary heart d i s e a s e . ( 1 6 ) F l a v o n o i d s a l s o i n h i b i t L D L oxidation, perhaps by reducing macrophage superoxide production.(17) Oxidized LDL may promote atheroma formation by increasing macrophage uptake, monocyte recruitment, and direct endothelial cell damage, thus antioxidant use may prevent myocardial infarction, at least in some patients.(2) Platelet aggregation is a precipitating event in cardiovascular disease, and tea contains antioxidant flavonoids that are known to decrease platelet aggregation in vitro. Plasma flavonoids increase with acute and chronic tea consumption, indicating adequate absorption of tea flavonoids. A randomized cross-over design demonstrated that acute and chronic black tea consumption does not affect ex vivo platelet aggregation in patients with coronary artery disease. This finding suggests that an effect of tea flavonoids on platelet aggregation is unlikely to be the explanation for the reduction in risk of cardiovascular events noted in epidemiological studies.(18) Antioxidant capacity of tea Experimentally it has been shown that tea flavonoids may increase the number of gap- junctions, stimulate B cell proliferation, and inhibit cytochrome P430 enzymes in hepatic cells in vitro. ( 19) B y oxy g e n ra d i c a l ab s o r b a n c e capacity (ORAC) assessment it was found that both green and black tea had a higher antioxidant capacity against peroxyl radicals than vegetables such as garlic, kale, spinach and Brussels sprout. Additionally, by determination of ferric reducing antioxidant power (FRAP) it turned out that green tea had a higher antioxidant capacity.(20) The in-vitro antioxidant capacity of tea depends on the test used and does not reflect factors such as bioavailability and metabolism. Thus, for determining the benefits of tea, an in- vivo antioxidant capacity test would be more appropriate. Recently, several clinical trials have shown that drinking tea increases plasma antioxidant levels in adults after 30 to 60 minutes.(21) The statistically significant increase in plasma antioxidant levels (p<0.001) was determined by t h e F R A P a s s a y, a f t e r t h e s u b j e c t s h a d consumed 300 mL of tea infusion (prepared from 20 g tea leaves in 500 mL water) or 2 g of green or black tea extract (equivalent to 3 cups). (21,22) On average, plasma antioxidant levels were raised about one to two hours after d r i n k i n g t e a a n d s u b s e q u e n t l y d e c r e a s e d rapidly.(7) Drinking tea or tea extract repeatedly within one to four weeks appeared to decrease biomarkers of oxidative stress. A study on 40 C h i n e s e m a l e c i g a r e t t e s m o k e r s a n d 2 7 American males and females in the USA, found that drinking 6 cups of green tea daily for one week reduced the levels of DNA oxidation damage, lipid peroxidation, and free radical 129 synthesis.(23) Similarly, among ten patients with type 2 diabetes who consumed high doses of flavonoids for two weeks, including 6 cups of black tea, there was a reduction in oxidative stress against lymphocyte DNA. (24) Plasma malondialdehyde level, another indicator of lipid peroxidation, was reduced in 20 healthy women aged 23 to 50 years, who ingested capsules containing linoleic acid and tea extract (equivalent to 10 cups of green tea). However, administration of placebo did not change the concentration of 8-isoprostaglandin F2α and oxidized glutathione in blood.(25) The results of the latter study are somewhat misleading, b e c a u s e s o m e i n d i v i d u a l s i n b o t h t h e intervention and the control groups had also consumed black tea up to 560 mL per day. Tea and endothelial cell function I t i s n o w g e n e r a l l y a c c e p t e d t h a t endothelial dysfunction plays a role in the early d e v e l o p m e n t o f a t h e r o s c l e r o s i s . ( 1 6 , 2 6) T h e endothelium is made up of squamous cells l i n i n g t h e b l o o d v e s s e l s , a n d p r o d u c e s vasoactive factors, such as nitric oxide (NO) and prostacyclins. These substances are active i n v a s o d i l a t i o n d a n p l a t e l e t i n h i b i t i o n . I m p a i r m e n t o f n i t r i c o x i d e a c t i v i t y o f e n d o t h e l i a l c e l l s m a y c o n t r i b u t e t o t h e pathogenesis of atherosclerosis and disorders of coronary blood flow, which subsequenly may cause coronary heart disease.(27) Recent research findings indicate that black tea may reduce the risk of heart disease b y c o n t r i b u t i n g t o t h e m a i n t e n a n c e o f endothelial cell functions. Presumably there are chemical substances in tea that enhance the dilatory capacity of the arteries. A study by Sudjarwo SA on 30 rabbits has proved that catechin administration may decrease plasma m a l o n d i a l d e h y d e p r o d u c t i o n a n d e n h a n c e acetylcholine-induced endothelium-dependent r e l a x a t i o n o f t h e a o r t a i n r a b b i t s o n a cholesterol-rich diet.(28) In a cross-sectional study by Duffy SJ et al., freshly infused black tea and plain water were randomly assigned to subjects, in whom brachial artery dilation was monitored using Doppler ultrasound. Both short-term (2 hours after drinking 450 mL black tea) and long-term ( 9 0 0 m L b l a c k t e a d a i l y f o r 4 w e e k s ) consumption may enhance vasodilation (p < 0.001). This phenomenon is associated with increased plasma levels of tea polyphenols. On a d m i n i s t r a t i o n o f 2 0 0 m g c a f f e i n e o r n i t r o g l y c e r i n n o v a s o d i l a t o r y e f f e c t w a s found.(15) N a g a y a N e t a l . a l s o r e p o r t e d t h a t administration of 400 mL green tea to cigarette smokers may increase the blood circulation in the arms.(29) It is a well-known fact that free r a d i c a l s i n c i g a r e t t e s m o k e m a y i m p a i r endothelial function. Therefore further research is needed to prove that antioxidants in green tea can lower the risk of cardiovascular events. Vasodilation in patients with coronary heart disease is impaired, in comparison with healthy individuals, thus this study proved that tea can enhance endothelial cell function of the blood vessels. Te a d r i n k i n g i s i n v e r s e l y r e l a t e d t o atherosclerosis formation and progressivity. In the Rotterdam study involving 3,454 adults aged 55 years or older, who were followed-up for two to three years, Geleijnse et al. reported on radiological assessment of aortic atherosclerosis by measuring calcification in the abdominal aorta. The results showed that individuals drinking 1-2 cups of tea per day had an odds ratio of 0.54, which was reduced to 0.31 in those drinking 4 cups or more.(10) Sasazuki et al. a s s e s s e d a t h e r o s c l e r o s i s b y c o r o n a r y arteriography in 512 Japanese over the age of 3 0 y e a r s , a n d r e p o r t e d t h a t t e a p r o v i d e s protection against atherosclerosis.(30) Univ Med Vol.27 - No.3 130 Gunawijaya Tea in cardiovascular Debette S et al. observed 6,597 French men and women aged >65 years, and reported that t h e f r e q u e n c y o f p l a q u e f o r m a t i o n i n t h e common carotid artery was in 44% women who did not drink tea, 42.5% in those drinking 1–2 c u p s o f t e a p e r d a y, a n d 3 3 . 7 % i n t h o s e consuming >3 cups daily. Thus there was a reduction in the frequency of common carotid artery plaque formation when drinking >3 cups of tea daily. (P<0,0001). In this study, tea consumption in men had no effect on common carotid artery plaque formation.(31) Drinking 5-6 cups of green tea daily or 200-300 mg EGCG, as reported by Wolfram S, may maintain cardiac health and metabolic f u n c t i o n i n g o f t h e b o d y. ( 32) T h e s e s t u d i e s indicate that tea antioxidants may help prevent atherosclerosis, particularly coronary heart disease. CONCLUSIONS Te a i s a e x c e l l e n t s o u r c e o f d i e t a r y a n t i o x i d a n t f l a v o n o i d s , w h o s e a c t i o n s o n endothelial function may help explain the cardioprotective effects of tea drinking that has been observed in several countries. Both green and black tea have strong in-vitro and in-vivo antioxidant capacities. Tea plays a role in lowering the risk of cardiovascular disease and stroke. Tea is a drink of global renown, thus f u r t h e r r e s e a r c h s h o u l d b e o f a p p r o p r i a t e design, by measuring total daily consumption of tea and its polyphenol content, with an emphasis on its role in primary and secondary prevention of cardiovascular disease. REFERENCES 1. Department of Health Republic of Indonesia. Laporan studi mortalitas 2001: pola penyakit penyebab kematian di Indonesia. Jakarta: National Institute of Health, Research and Development; 2002. 2. Mukamal KJ, Maclure M, Muller JE, Sherwood JB, Mittleman MA. Tea consumption and mortality after acute myocardial infarct. Circulation 2002; 105: 2474-79. 3. Weisburger JH. Tea and health; the underlying mechanism. Proc Soc Exp Biol 1999; 220: 271-5. 4. Nijveldt RJ, van Nood E, van Hoorn DE, Boelens PG, van Norren K, van Leeuwen PA. Flavonoids: areview o probable mechanismsof action and potential applications. Am J Clin Nutr 2001; 74: 418-25. 5. Egusa G, Yamane K. 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