The Relation between Green Tea Consumption and Cardiovascular Disease as Evidenced by Epidemiological Studies 1,2

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1 The Journal of Nutrition Proceedings of the Fourth International Scientific Symposium on Tea and Human Health The Relation between Green Tea Consumption and Cardiovascular Disease as Evidenced by Epidemiological Studies 1,2 Shinichi Kuriyama* Division of Epidemiology, Department of Public Health and Forensic Medicine, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi , Japan Abstract Although substantial evidence from in vitro and animal studies indicates that green tea preparations inhibit cardiovascular disease processes, the possible protective role of green tea consumption against this disease in humans remains unclear. We conducted a population-based prospective cohort study (the Ohsaki Study) to examine the association between green tea consumption and mortality from cardiovascular disease (CVD), cancer, and all causes with 40,530 persons in Miyagi prefecture, in northern Japan. Previously published work has shown that green tea consumption was inversely associated with mortality from CVD and all causes. The inverse association of mortality from CVD was more pronounced in women (P ¼ 0.08 for interaction with sex). In women, the multivariate hazard ratios (95% confidence intervals) of CVD mortality across increasing green tea consumption categories were 1.00, 0.84 ( ), 0.69 ( ), 0.69 ( ) (P for trend ¼ 0.004). Within CVD mortality, the stronger inverse association was observed for stroke mortality. Because our observational study has found the inverse association, I report here the results of a review of epidemiological evidence from randomized controlled trials (RCT) of the association between green tea or green tea extracts and CVD risk profiles. More than half of the RCT have demonstrated the beneficial effects of green tea on CVD risk profiles. These results from RCT suggest a plausible mechanism for the beneficial effects of green tea and provide substantial support for our observations. J. Nutr. 138: 1548S 1553S, Introduction 1 Published in a supplement to The Journal of Nutrition. Presented at the conference Fourth International Scientific Symposium on Tea and Human Health, held in Washington, DC at the U.S. Department of Agriculture on September 18, The conference was organized by the Tea Council of the U.S.A. and was cosponsored by the American Cancer Society, the American College of Nutrition, the American Medical Women s Association, the American Society for Nutrition, and the Linus Pauling Institute. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Tea Council of the U.S.A. or the cosponsoring organizations. Supplement coordinators for the supplement publication were Lenore Arab, University of California, Los Angeles, CA and Jeffrey Blumberg, Tufts University, Boston, MA. Supplement coordinator disclosure: L. Arab and J. Blumberg received honoraria and travel support from the Tea Council of the U.S.A. for cochairing the Fourth International Scientific Symposium on Tea and Human Health and for editorial services provided for this supplement publication; they also serve as members of the Scientific Advisory Panel of the Tea Council of the U.S.A. 2 Author disclosure: Shinichi Kuriyama received an honorarium and travel support from the Tea Council of the U.S.A. for speaking at the Fourth International Scientific Symposium on Tea and Human Health and for preparing this manuscript for publication. 3 Abbreviations used: CVD, cardiovascular disease; HR, hazard ratio; NHI, national health insurance; RCT, randomized controlled trial. * To whom correspondence should be addressed. kuriyama-thk@ umin.ac.jp. 1548S Green tea polyphenols have been extensively studied as cardiovascular disease (CVD) 3 chemopreventive agents (1,2). Although substantial evidence from in vitro and animal studies indicates that green tea preparations inhibit CVD processes, the possible protective role of green tea consumption against this disease in humans remains unclear. We therefore conducted a population-based prospective cohort study (the Ohsaki Study) to examine the association between green tea consumption and mortality from CVD, cancer, and all causes with 40,530 persons in Miyagi prefecture, in northern Japan, where green tea is widely consumed. In this article, I introduce the results of our cohort study published in 2006 (3), including an overview of the previous prospective cohort studies examining the association between green tea consumption and mortality from CVD (4 6). Furthermore, I report here the results of a review of epidemiological evidence from randomized controlled trials (RCT) of the association between green tea or green tea extracts and CVD risk profiles because clinical trials are ultimately necessary to confirm the protective effect of green tea on diseases. Cohort studies Until 2005, 3 studies have examined the association between green tea consumption and CVD mortality, but their sample sizes were small, and the results were inconsistent (Table 1) (4 6). There was no study regarding the association between green tea consumption and CVD incidence /08 $8.00 ª 2008 American Society for Nutrition.

2 TABLE 1 Summary of the prospective cohort studies examining the association between green tea consumption and mortality from cardiovascular disease Year (ref.) Participants (follow-up) Endpoint (mortality), n Results Green tea consumption/d P-trend 1989 (4) 5,910 women aged $40 y, nondrinking and nonsmoking (4.0 y) 2000 (5) 8,552 subjects aged $40 y (12.0 y) 2002 (6) 2,855 subjects; 1404 men, 1451 women aged y (9.9 y) 2006 (3) 40,530 subjects; 19,060 men, 21,470 women aged y (11.0 y all-cause; 7.0 y cause specific) Stroke, 174 Cerebral hemorrhage, 42 Cardiovascular disease, 274 Mortality rates/1000 population y,5 cups (500 ml) $5 cups (500 ml) Stroke Cerebral hemorrhage $60 y Stroke Cerebral hemorrhage Relative risk in men #3 cups 4 9 cups $10 cups (300 ml) ( ml) (1000 ml) Cardiovascular disease 1.0 (referent) 1.09 ( ) 0.58 ( ) Relative risk in women Cardiovascular disease 1.0 (referent) 0.90 ( ) 0.82 ( ) All causes, 361 Hazard ratio in men,0.5 cup (50 ml) Apoplexy in men, 38 Apoplexy in women, 0 All causes, 4,209 Cardiovascular disease, 892 Coronary heart disease, 209 Stroke, 472 Cerebral infarction, 197 Cerebral hemorrhage, cups ( ml) $4 cups (400 ml) All causes 1 (referent) 0.97 ( ) 0.82 ( ) 0.19 Apoplexy 1 (referent) 0.96 ( ) 0.60 ( ) 0.20 Hazard ratio in women All causes 1 (referent) 0.79 ( ) 0.74 ( ) 0.21 Hazard ratio in men,1 cup (100 ml) 1 2 cups ( ml) 3 4 cups ( ml) $5 cups (500 ml) All causes 1.00 (referent) 0.93 ( ) 0.95 ( ) 0.88 ( ) 0.03 Cardiovascular disease 1.00 (referent) 0.88 ( ) 0.84 ( ) 0.78 ( ) 0.05 Coronary heart disease 1.00 (referent) 1.03 ( ) 0.96 ( ) 0.91 ( ) 0.66 Stroke 1.00 (referent) 0.85 ( ) 0.97 ( ) 0.65 ( ) 0.04 Cerebral infarction 1.00 (referent) 0.78 ( ) 1.16 ( ) 0.58 ( ) 0.15 Cerebral hemorrhage 1.00 (referent) 0.91 ( ) 1.08 ( ) 1.01 ( ) 0.88 Hazard ratio in women All causes 1.00 (referent) 0.98 ( ) 0.82 ( ) 0.77 ( ),0.001 Cardiovascular disease 1.00 (referent) 0.84 ( ) 0.69 ( ) 0.69 ( ) Coronary heart disease 1.00 (referent) 1.04 ( ) 0.79 ( ) 0.77 ( ) 0.31 Stroke 1.00 (referent) 0.79 ( ) 0.61 ( ) 0.58 ( ) Cerebral infarction 1.00 (referent) 0.76 ( ) 0.47 ( ) 0.38 ( ),0.001 Cerebral hemorrhage 1.00 (referent) 1.33 ( ) 1.32 ( ) 0.98 ( ) 0.87 We therefore conducted a population-based prospective cohort study (the Ohsaki Study) to examine the association between green tea consumption and mortality from CVD, cancer, and all causes (Table 1) and reported the results in 2006 (3). Our study population was all national health insurance (NHI) beneficiaries aged y living in the catchment area of Ohsaki Public Health Center, Miyagi Prefecture. The details of the Ohsaki NHI Cohort Study have been described in previous reports (7 9). Of 54,996 eligible individuals, 51,255 persons responded. We started the prospective collection of NHI withdrawal history files from January 1, When a participant was withdrawn from the NHI system because of death, emigration, or employment, the date of withdrawal and its reason were coded on the NHI withdrawal history files. The study protocol was reviewed and approved by the Ethics Committee of Tohoku University School of Medicine. For current analysis, we excluded participants who died before the collection of NHI withdrawal history files (n ¼ 37) and participants with missing data on green tea consumption frequency (n ¼ 6821), as well as those who reported extreme daily energy intake (highest 0.5% or lowest 0.5%; sex-specific cutoff points were used) (n ¼ 444). We also excluded participants who reported a baseline history of cancer (n ¼ 1481), myocardial infarction (n ¼ 1149), or stroke (n ¼ 793) because the presence of these diseases at the baseline could have affected the diet and lifestyle of these responders. Consequently, our ultimate analysis involved 40,530 participants. The questionnaire included a 40-item FFQ, which asked the frequency of recent average consumption of 4 beverages (green tea, oolong tea, black tea, and coffee) and 36 items about food. The frequency of green tea consumption was divided into 5 categories: never, occasional, 1 or 2 cups (200 ml)/d, 3 or 4 cups (300 ml or 400 ml)/d, and $5 cups (500 ml)/d. Within the study region, the volume of a typical cup of green tea is 100 ml. We conducted a validation study of the FFQ in which 113 participants provided 4 separate 3-d food records within the period of 1 y and subsequently responded to the questionnaire. The results showed that Spearman s coefficient for the correlation between the amounts of green tea consumed according to the questionnaire and the amounts consumed according to the food records was 0.71 for men and 0.53 for women; the correlation between consumption measured by the 2 questionnaires administered 1 y apart was 0.63 for men and 0.64 for Green tea and cardiovascular disease 1549S

3 TABLE 2 Summary of the randomized controlled trial examining the association between green tea or green tea extracts consumption and cardiovascular disease profiles 1 Year (ref.) Participants, n, (men/women), age, y Intervention vs.control Duration Primary outcomes Overall results 1996 (13) 10,, 300 ml green tea vs. no drink 30 min Human plasma antioxidant capacity 1998 (14) 43, (22/21), ml green tea/d vs. water 4 wk HDL cholesterol, plasma triglycerides, NSE LDL cholesterol 1999 (15) 20, (20/0), ml green tea vs. water 30 min Systolic blood pressure, diastolic AHE blood pressure 1999, (16) 10, (10/0), mg epigallocatechin gallate vs. placebo 24 h Total 24-h energy expenditure 2000, (17) 21, (10/11), ml green tea vs. water 60 min Plasma antioxidant capacity measured using the ferric-reducing ability of plasma assay 2000, (18) 20, (20/0), ml green tea vs. water 60 min Total antioxidant activity of serum NSE 2000, (19) 30, (14/16), ml green tea/d vs. water 4 wk IL-6, fibrinogen NSE 2002, (20) 13, (10/3), ml green tea/d vs. hot water 7 d Urinary F 2 -isoprostane excretion NSE 2002, (21) 16, (2/2), Basal diet with 18.6 mg catechins/d vs. basal diet 3 wk Plasma antioxidant capacity 2003, (22) 240, (100/140), 375 mg theaflavin-enriched green 12 wk Total cholesterol, LDL cholesterol, tea extract vs. placebo HDL cholesterol, triglycerides 2004, (23) 104, (2/2), Green tea with 573 mg/d catechins vs. placebo 13 wk Body weight regain expressed as NSE percentage of body weight loss 2004, (24) 20, (20/0), ml green tea vs. 400 ml hot water 2 h The response of forearm blood flow to reactive hyperemia, an index of endothelium-dependent vasodilatation 2004, (25) 30, (14/16), Green tea extract supplement vs. black tea 75 min Area under the curve of the antioxidant activity in plasma, determined as trolox equivalents 2005, (26) 24, (0/24), Controlled diet with 400 ml green 42 d Plasma total antioxidant activity tea/d vs. controlled diet (mmol Trolox equivalent/ml) LDL cholesterol 2005, (27) 9, (9/0), mg tea catechins vs. 10 mg tea catechins 6 h Postprandial increase in plasma triglyceride levels measured as the incremental area under the plasma triacylglycerol curves 2005, (28) 76, (2/2), Green tea with 270 mg epigallocatechin 4 wk Body weight change gallate/d vs. placebo 2005, (29) 14, (14/0), mg epigallocatechin gallate with 200 mg 24 h Total 24-h energy expenditure caffeine vs. placebo 2005, (30) 66, (53/13), mg catechins/d vs. no intervention 2 mo Fasting serum glucose, C-reactive protein NSE 2006, (31) 55, (31/24), 900 ml green tea/d vs. 900 ml water/d 4 wk Homeostasis model assessment of NSE insulin resistance, plasma adiponectin, right brachial-ankle pulse wave velocity, hscrp , (32) 46, (0/46), Green tea with mg catechins and mg caffeine/d vs. placebo 87 d Plasma glucose, total cholesterol, LDL cholesterol, HDL cholesterol NSE 2006, (33) 34, (0/34), % Lung Chen tea freeze-dried powder, which contained an equivalent of 540 mg epigallocatechin gallate vs. placebo 2006, (34) 10, (10/0), Extracts of bitter orange, green tea, and guarana, which contained 6 mg of synephrine, 150 mg caffeine, and 150 mg catechin polyphenols vs. placebo 2006, (35) 13, (7/6), g of green tea (Lipton Inc.) added in 450 ml of boiled water for 5 min vs. 125 mg of caffeine (the amount contained in 6 g of green tea) diluted into 450 ml of boiled water 2006, (36) 17, (17/0), 6 portions of 1 g of tea solids dissolved in hot water/d (equivalent to 12 cups of tea/d) vs. daily dose of 360 mg of caffeine supplemented in 6 gelatin capsules 2006, (37) 20, (10/10), Ingested test meals with a preparation containing an extract of black (0.1 g), green (0.1 g), and mulberry (1.0 g) teas vs. ingested test meals with a placebo beverage 3 mo Body weight, fasting cholesterol, fasting triglyceride, fasting glucose 6 h rest and ATP utilization 60 min treadmill walking min Pulse wave velocity, augmentation index 2 d Urinary excretion of intermediates of the citric acid cycle (i.e., citrate, succinate, oxaloacetate, and 2-oxologlutarate) NSE NSE AHE 8 h Carbohydrate malabsorption (Continued) 1550S Supplement

4 TABLE 2 Year (ref.) Continued Participants, n, (men/women), age, y Interventionvs.control Duration Primary outcomes Overall results 2006, (38) 98, (22/77), Active tablets included extracts of asparagus, green tea, 12 wk Body weight, body fat, LDL-cholesterol, black tea, guarana, mate, kidney beans, kidney bean pods, Garcinia cambogia, and chromium yeast vs. placebo fasting glucose 2007, (39) 38, (24/0), A prebiotic antioxidant bread (pre-aox-bread), which additionally 5 wk The 23 investigated immunological contained green tea powder, herbs, and tomato paste/d vs. control bread (placebo) parameters measured in peripheral blood, the ferric-reducing ability of plasma 2007, (40) 31, (15/16), A beverage containing green tea catechins (540 mg), caffeine 3 d 24-h energy expenditure (300 mg), and calcium (633 mg)/d vs. placebo 2007, (41) 270, 2 (156/114), Green tea containing 583 mg of catechins/d vs. green tea 12 wk Body weight, blood pressure, serum containing 96 mg of catechins/d LDL-cholesterol 2007, (42) 49, (21/28), 67.1 (11.1) Tea extract 750 mg/d vs. placebo 3 mo Glycosylated hemoglobin NSE 1 Values are means 1/2 SD or range, y; P, 0.05., significant beneficial effects;. NSE, no significant effects;. AHE; acute harmful effects. 2 A total of 240 persons were analyzed (per protocol analysis). 3 hs CRP, hypersensitive C reactive protein. women (10). Because only 7% of the participants said they never drank green tea and only 19% said they drank it only occasionally, data from these respondents were collapsed into the single category,1 cup (100 ml)/d for the purpose of this analysis. The endpoint was all-cause mortality and cause-specific mortality. To follow up the participants for mortality and migration, we reviewed the NHI withdrawal history files. For decedents identified, we investigated cause of death by reviewing the death certificates filed at Ohsaki Public Health Center. Cox proportional hazards regression analysis was used to calculate the hazard ratio (HR) and 95% CI of all-cause and cause-specific mortality according to green tea consumption categories and to adjust for potentially confounding variables. We considered the following variables as potential confounders a priori: age at baseline in years (continuous variable); job status (employed, unemployed); years of education (,10, 10 12, $13); BMI (,18.5, , , , $30.0) (11,12); engaging in sports or exercise (,1 h/wk, 1 2 h/wk, $3 h/wk); time spent walking (,1 h/d, $1 h/d); history of hypertension (yes, no); history of diabetes mellitus (yes, no); history of gastric ulcer (yes, no); smoking status (never, former, currently smoking 1 19 cigarettes/d, or currently smoking $20 cigarettes/d); alcohol drinking (never, former, current ethanol intakes of,45.6 g/d, current ethanol intakes of $45.6 g/d); daily total energy intake (continuous variable); daily rice consumption (,3 bowls, 3 bowls, 4 bowls, $5 bowls); daily consumption of miso soup (soy bean paste soup) (yes, no); daily consumption of soy bean products, total meat, total fish, dairy products, total fruits, total vegetables (for each food, continuous variable); consumption of oolong tea, black tea, or coffee (never or occasionally, 1 2 cups ( ml)/d, $3 cups(300ml)/d). We found that green tea consumption was inversely associated with mortality from all causes, and the inverse association was more pronounced in women (P ¼ 0.03 for interaction with sex) (Table 1). In men, the multivariate HR (95% CI) of mortality from all causes associated with different green tea consumption frequencies were 1.00 (reference) for,1 cup (100 ml)/d, 0.93 ( ) for 1 2 cups ( ml)/d, 0.95 ( ) for 3 4 cups ( ml)/d, and 0.88 ( ) for $5 cups (500 ml)/d, respectively (P for trend 0.03). The corresponding figures in women were 1.00, 0.98 ( ), 0.82 ( ), 0.77 ( ) (P for trend, ). We also found that green tea consumption was inversely associated with mortality from CVD (Table 1). The inverse association with CVD mortality was more remarkable than that with all-cause mortality, and the inverse association was also more pronounced in women (P ¼ 0.08 for interaction with sex). In women, when compared with those who consumed less than 1 cup (100 ml)/d of green tea, those who consumed 5 or more cups (500 ml or more)/d had their risk for CVD death lowered by 31%. In contrast, the association between green tea consumption and cancer mortality was substantially different. We observed a nonsignificant increase in the HR of cancer mortality in all green tea categories compared with the referent category. We further investigated the association between green tea consumption and specific CVD and cancer mortality. We did not find the statistically significant association between green tea consumption and myocardial infarction mortality, although point estimates were all below unity in women. In women, green tea consumption was significantly associated with reduced mortality from stroke, especially cerebral infarction. When compared with women who consumed,1 cup (100 ml)/d of green tea, those who consumed 5 or more cups (500 ml or more)/d had 62% lower risk of death from cerebral infarction. In contrast, we did not find any apparent association between green tea consumption and cerebral hemorrhage. In both men and women, the multivariate HR of gastric, lung, or colorectal cancer mortality were mostly above, but not significantly different from, unity (3). RCT Because most of the observational studies have found the inverse association, I report here the results of a review of epidemiological evidence from RCT of the association between green tea or green tea extracts and CVD risk profiles. Using a combination of the keywords green tea and RCT, I conducted a literature search (MEDLINE, , October 31) that excluded studies not examining CVD or CVD risk profiles. Consequently, 30 studies were found to be eligible (13 42) (Table 2). CVD profiles include body weight (23,28,33,38,41), 24-h energy expenditure (16,29,40), nutrition malabsorption (37), postprandial increase in plasma triglyceride levels (27), plasma lipids (22,26,32,33,38,41), glucose control (30 33,38,42), plasma adiponectin (31), blood pressure (15,41), aortic stiffness (31,35), oxidative status (13,17,18,20,21,25,26,39), oxidative energy metabolism and/or biosynthetic pathways (36), inflammation markers Green tea and cardiovascular disease 1551S

5 (19,30,31), endothelial dysfunction (19,24), ATP utilization (34), and immune system (39). No data on RCT with CVD incidence or mortality outcomes are available. Of the 30 studies, 17 studies (13,16,17,21,22,24 29,36 41) indicated the statistically significant beneficial effects of green tea, and 11 studies (14,18 20,23,30 34,42) showed no such results. Two remaining studies (15,35) of blood pressure or aortic stiffness showed acute harmful effects. Discussion Prospective cohort studies generally indicate the beneficial effects of green tea on CVD mortality. Our study (3) added to a considerable body of knowledge from previous studies (4 6). Our study included a large sample size compared with previous studies; the study included 40,530 persons, whereas the previous studies had included 2855 to 8552 subjects. Furthermore, we considered many confounding factors, including Japanese food items. More than half of the RCT have demonstrated the beneficial effects of green tea on CVD risk profile (13,16,17,21,22,24 29,36 41). These results suggest a plausible mechanism for the beneficial effects of green tea and provide substantial support for our observations (3). In contrast, the remaining trials did not demonstrate these effects (14,18 20,23,30 34,42). The equivocal findings may be explained by the variety of study designs, participant populations, green tea products tested, and study outcomes (Table 2). To draw definite conclusions, long-term RCT are needed. Nevertheless, because of the limitations in feasibility for RCT to address the long-term effects of lifestyle on clinical outcomes (43), continued refinement of prospective cohort studies and well-designed RCT with intermittent endpoints are also essential. Other articles in this supplement include references (44 53). Literature Cited 1. Frei B, Higdon JV. 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