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© 2008 American Society for Nutrition J. Nutr. 138:1548S-1553S, August 2008

Supplement: 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 Studies1,2

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 980-8575, Japan

* To whom correspondence should be addressed. E-mail: kuriyama-thk{at}umin.ac.jp.


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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 = 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 (0.63–1.12), 0.69 (0.52–0.93), 0.69 (0.53–0.90) (P for trend = 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.


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Introduction
 
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.


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  		TABLE 1 Summary of the prospective cohort studies examining the association between green tea consumption and mortality from cardiovascular disease

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 40–79 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, 1995. 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 = 37) and participants with missing data on green tea consumption frequency (n = 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 = 444). We also excluded participants who reported a baseline history of cancer (n = 1481), myocardial infarction (n = 1149), or stroke (n = 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 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, 18.5–22.9, 23.0–24.9, 25.0–29.9, ≥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 (100–200 mL)/d, ≥3 cups (300 mL)/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 = 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 (0.83–1.05) for 1–2 cups (100–200 mL)/d, 0.95 (0.85–1.06) for 3–4 cups (300–400 mL)/d, and 0.88 (0.79–0.98) for ≥5 cups (500 mL)/d, respectively (P for trend 0.03). The corresponding figures in women were 1.00, 0.98 (0.84–1.15), 0.82 (0.70–0.95), 0.77 (0.67–0.89) (P for trend < 0.0001).

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 = 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, 1966–2007, 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 (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.


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  		TABLE 2 Summary of the randomized controlled trial examining the association between green tea or green tea extracts consumption and cardiovascular disease profiles1

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.


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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).


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FOOTNOTES
 
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, 2007. 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. Back

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. Back

3 Abbreviations used: CVD, cardiovascular disease; HR, hazard ratio; NHI, national health insurance; RCT, randomized controlled trial. Back


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J. Nutr., August 1, 2008; 138(8): 1561S - 1566S.
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I. A. Hakim, H.-H. S. Chow, and R. B. Harris
Green Tea Consumption Is Associated with Decreased DNA Damage among GSTM1-Positive Smokers Regardless of Their hOGG1 Genotype
J. Nutr., August 1, 2008; 138(8): 1567S - 1571S.
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S. P. Kelly, M. Gomez-Ramirez, J. L. Montesi, and J. J. Foxe
L-Theanine and Caffeine in Combination Affect Human Cognition as Evidenced by Oscillatory alpha-Band Activity and Attention Task Performance
J. Nutr., August 1, 2008; 138(8): 1572S - 1577S.
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S. A. Mandel, T. Amit, L. Kalfon, L. Reznichenko, and M. B. H. Youdim
Targeting Multiple Neurodegenerative Diseases Etiologies with Multimodal-Acting Green Tea Catechins
J. Nutr., August 1, 2008; 138(8): 1578S - 1583S.
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K. S. Stote and D. J. Baer
Tea Consumption May Improve Biomarkers of Insulin Sensitivity and Risk Factors for Diabetes
J. Nutr., August 1, 2008; 138(8): 1584S - 1588S.
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