Association Between Green Tea Intake and Coronary Artery Disease in a Chinese Population

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1 Circulation Journal Official Journal of the Japanese Circulation Society ORIGINAL ARTICLE Epidemiology Association Between Green Tea Intake and Coronary Artery Disease in a Chinese Population Qi-Ming Wang, MD**; Qing-Yue Gong, PhD*, **; Jian-Jun Yan, MD; Jun-Zhu, MD; Jian-Jin Tang, MD; Ming-Wei Wang, MD; Zhi-Jian Yang, MD, PhD; Lian-Sheng Wang, MD, PhD Background: There is still conflicting evidence that green tea may protect against coronary atherosclerosis therefore the present study investigated the association between green tea consumption and arteriographically determined coronary atherosclerosis in a Chinese population. Methods and Results: The study population consisted of 520 consecutive patients (379 men and 141 women) who underwent coronary arteriography for the first time. Patients were divided into 2 groups (Non-coronary artery disease [CAD] and CAD groups) according to the results of coronary arteriography. After adjusting the established and potential confounders, green tea consumption was associated with a reduced risk of CAD in male patients, with an adjusted odds ratio (OR) of 0.62 (95% confidence interval, ) compared with those who did not drink green tea. Compared to non-tea drinkers, the adjusted ORs were 1.09 ( ) in male patients consuming less than 125 g of dried green tea leaves per month, 0.36 ( ) for g per month and 0.36 ( ) for 250 g per month, with a statistically significant test for trend (P<0.001). Similar dose response relationships were also observed for frequency, duration, concentration and starting age of green tea drinking in male patients. In female patients, no inverse association was found between green tea consumption and CAD. Conclusions: Green tea consumption can protect against the development of coronary atherosclerosis in Chinese male patients. (Circ J 2010; 74: ) Key Words: Arteriography; Coronary artery disease; Green tea All tea is derived from the same plant (Camella sinensis), which is grown in approximately 30 countries. Tea is the most widely consumed beverage apart from water with a per capita worldwide consumption of approximately 0.12 L/year. 1 Tea is a rich source of polyphenolic flavonoids, which may possess the bioactivity to affect the pathogenesis of several chronic diseases. Approximately 76 78% of the tea produced and consumed in the world is black, 20 22% is green and <2% is oolong. 2 Black tea is consumed mainly in the USA and Europe, whereas green tea is the main tea beverage consumed in East Asian countries, such as China and Japan. Editorial p 248 Coronary artery disease (CAD) is a major health problem and a major cause of death in most industrialized and developing countries. 3 In the past few years, there has been increasing interest in the relationship between green tea intake and CAD. Green tea consumption has been found to be inversely associated with angiographically proven CAD in 2 studies. 4,5 However, another study has failed to show that green tea has protective effects. 6 The potential protective effect of green tea and tea constituents from CAD may be due to lipid-lowering, 7,8 antioxidative, 9,10 antihypertensive, 11,12 hemorheological abnormality-improving, 13 antithrombogenic 14,15 and vasculoprotective 16,17 activities. To our knowledge, until now there has not been any studies that have evaluated the relationship between green tea consumption and angiographically proven CAD in China. Therefore, the present case-control study aimed to assess whether green tea intake is inversely associated with CAD in Chinese patients undergoing coronary arteriography. Received July 28, 2009; revised manuscript received October 22, 2009; accepted October 27, 2009; released online December 17, 2009 Time for primary review: 15 days Department of Cardiology, First Affiliated Hospital of Nanjing Medical University, *Department of Information Technology, Nanjing University of Chinese Medicine, Nanjing, China **The first two authors contributed equally to this work. Project was supported by grants from the Natural Science Foundation of Jiangsu Province (No BK ), Ministry of Personnel of China for returned student (No DG216D5021) and the National Natural Science Foundation of China (No ). Mailing address: Lian-Sheng Wang, MD, PhD, Department of Cardiology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, , Jiangsu Province, China. drlswang@njmu.edu.cn ISSN doi: /circj.CJ All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 Green Tea and CAD 295 Methods Patients A total of 652 consecutive patients aged years who underwent coronary arteriography at 2 hospitals (First Affiliated Hospital of Nanjing Medical University and Nanjing Chest Hospital) from July 2008 to January 2009 in Nanjing, China, participated in the present study. All patients underwent coronary arteriography because of typical or atypical chest pain, or abnormal ST T changes. The First Affiliated Hospital of Nanjing Medical University is the largest comprehensive hospital in Nanjing and Nanjing Chest Hospital is a hospital that specializes in the treatment of cardiopulmonary disease. They are also appointed hospitals for coronary arteriography under medical insurance and most of the patients who need coronary arteriography in Nanjing attend these 2 hospitals. Seventeen patients declined to participate in the study and 14 patients were severely ill. Patients that previously underwent coronary arteriography (n=11) and patients with valvular disease (n=10), cardiomyopathy (n=8), myocarditis (n=2), or post revascularization of the coronary arteries (n=57) were excluded. There were 13 patients who drank black tea or oolong tea and were also excluded. The final sample consisted of 520 (379 men and 141 women) patients. Of the 520 patients, the CAD cases (n=325) were defined as having significant stenosis in at least 1 major coronary artery and the patients (n=195) who did not have significant stenosis of all arteries were defined as controls. The study was assessed and approved by the institutional Ethics Committees of the First Affiliated Hospital of Nanjing Medical University and Nanjing Chest Hospital. Coronary Angiography Coronary arteriography was carried out in all patients using a standard Judkins technique via the femoral artery or brachial artery. At the 2 hospitals, the percentage of vessel stenosis was assessed by 2 experienced angiographers who were blind to the information of green tea consumption. The severity of coronary obstruction was evaluated in the worst view projection. All of the evaluations were based on the American Heart Association method. 18 CAD was defined as a stenosis 50% in the left main trunk or in the other major coronary arteries (left anterior descending coronary artery, left circumflex coronary artery and right coronary artery). 19 Assessment of Green Tea Consumption We obtained information on tea consumption using a quantitative questionnaire. The participants were classified as nontea drinkers or tea drinkers if they drank tea during the previous 12 months. Participants who were tea drinkers answered the following questions: (1) How often did you drink tea each week?; (2) What kind of tea (green, black or oolong) was usually consumed?; (3) What age did you start this habit?; (4) What was the amount of dried tea leaves you consumed per month?; and (5) What concentration of green tea did you usually consume? Tea concentration was categorized as low (tea leaves were <25% of the volume of the cup), moderate (tea leaves were 25 50% of the volume of the cup) and high (tea leaves were >50% of the volume of the cup). Data Collection All patients were interviewed before coronary arteriography was carried out by trained interviewers who used a structured questionnaire to collect information on demographic data, level of education, family history of coronary heart disease (CHD) (any kind of CHD in first-degree relatives), medical history, physical activity, current medications and environmental exposure history, such as cigarette smoking and alcohol intake. Written informed consent was obtained from all participants before participating in the study. In the present study, non-smokers were defined as having smoked <100 cigarettes in their lifetime. Current smokers were defined as those who smoked during the previous 12 months. Patients who drank alcohol at least once per week during the previous 12 months were classified as current drinkers. Patients were regarded as physically active if they engaged in aerobic activities for more than 30 min (walking, bicycling, running, swimming, etc) at least 3 times per week. Weight and height measurements were taken after the patients removed their shoes and upper garments and put on an examination gown. Height was measured to the nearest 0.1 cm using a wall-mounted stadiometer. Weight was measured to the nearest 0.1 kg using a hospital balance beam scale. Body mass index (BMI) was calculated as weight (kg) divided by the square of height (m 2 ). Biochemical data, including total cholesterol (TC) concentration, triglyceride (TG) concentration and fasting blood glucose concentration, were collected from the patients most recent medical records. Biochemical data were missing for 5 male patients and 1 female patient. Hyperlipidemia was defined as a serum TC concentration >220 mg/dl (5.698 mmol/l) or TG concentration >150 mg/dl (1.695 mmol/l), or the use of lipid-lowering therapy. Patients were considered to have diabetes mellitus if they were under hypo-glucose treatment or if their fasting blood glucose concentration was >110 mg/dl (6.1 mmol/l). Blood pressure was measured in the right arm with the participant seated and the arm bare. Two readings were recorded for each individual and the average was recorded. Hypertension was defined as systolic pressure 140 mmhg or diastolic pressure 90 mmhg, or receiving antihypertensive treatment. Statistical Analysis We analyzed the data in each sex to assess the possible effect-measure modification between sexes. Age and BMI data were treated as continuous variables. Smoking status, alcohol consumption status, family history of CHD, physical activity, locality of residence, hypertension, hyperlipidemia, diabetes mellitus and education level were treated as categorical variables. To facilitate analysis, the green tea consumption variables, except green tea drinking (no vs yes), were categorized into 3 or 4 levels with non-tea drinkers as the reference group. 20 Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to indicate the relationship between green tea consumption and CAD. Multiple logistic regression analysis was used to adjust for age, smoking status, alcohol use, physical activity, hypertension, hyperlipidemia, diabetes mellitus, education level, locality of residence, family history of CAD and BMI. Each quantitative or ordinal measure of green tea consumption was subjected to a linear trend test. A value of P<0.05 was considered statistically significant. All P-values are 2-sided and all statistical computations and analyses were carried out using SPSS version 13.0 (SPSS, Chicago, IL, USA). Results Characteristics of Patients With and Without CAD The characteristics of patients with and without CAD are shown in Table 1 by sex group. Among the 379 male patients, 246 (64.9%) were found to have CAD. The mean

3 296 WANG QM et al. Table 1. Characteristics of Patients With and Without CAD CAD (n=246) Male patients Non-CAD (n=133) CAD (n=79) Female patients Non-CAD (n=62) Age (years) 64.0± ± ± ±8.4 Body mass index 24.6± ± ± ±2.8 Hypertension 162 (65.9) 74 (55.6) 58 (73.4) 42 (67.7) Diabetes mellitus 54 (22.0) 22 (16.5) 22 (27.8) 13 (21.0) Hyperlipidemia 121 (49.2) 63 (47.4) 45 (57.0) 34 (54.8) Family history of CAD 58 (23.6) 27 (20.3) 20 (25.3) 11 (17.7) Physical activity 121 (49.2) 65 (48.9) 24 (30.3) 26 (41.9) Resident in urban area 171 (69.5) 96 (72.2) 52 (65.8) 45 (72.6) Smoking status Never 51 (20.7) 45 (33.8) 71 (89.9) 59 (95.2) Former 66 (26.8) 35 (26.3) 2 (2.5) 2 (3.2) Current 129 (52.4) 53 (39.8) 6 (7.6) 1 (1.6) Alcohol drinking Never 110 (44.7) 52 (39.1) 76 (96.2) 58 (93.5) Former 49 (20.0) 31 (23.3) 1 (1.3) 2 (3.2) Current 87 (35.4) 50 (37.6) 2 (2.5) 2 (3.2) Education Illiteracy 20 (8.1) 5 (3.8) 29 (36.7) 14 (22.6) Primary 40 (16.3) 10 (7.5) 14 (17.7) 12 (19.4) Middle 69 (28.0) 35 (26.3) 13 (16.5) 19 (30.6) High 63 (25.6) 39 (29.3) 16 (20.3) 7 (11.3) College 54 (22.0) 44 (33.1) 7 (8.9) 10 (16.1) Values expressed as mean ± SD or n (%). CAD, coronary artery disease. Table 2. Characteristics of Study Participants Without CAD According to Green Tea Drinking Status Male patients Female patients Green tea drinkers a (n=93) Non-tea drinkers (n=40) Green tea drinkers (n=18) Non-tea drinkers (n=44) Age (years) 60.6± ± ± ±8.7 Body mass index 24.6± ± ± ±3.1 Hypertension 52 (55.9) 22 (55.0) 13 (68.4) 29 (65.9) Diabetes mellitus 14 (15.1) 8 (20.0) 3 (16.7) 10 (22.7) Hyperlipidemia 42 (45.2) 21 (52.5) 12 (66.7) 22 (50.0) Family history of CAD 16 (17.2) 11 (27.5) 3 (16.7) 8 (18.2) Physical activity 45 (48.4) 20 (55.0) 7 (38.9) 19 (43.2) Resident in urban area 70 (75.3) 26 (65.0) 15 (83.3) 30 (68.2) Smoking status Never 26 (28.0) 19 (47.5) 17 (94.4) 42 (95.5) Former 25 (26.9) 10 (25.0) 1 (5.6) 1 (2.3) Current 42 (45.2) 11 (27.5) 0 (0.0) 1 (2.3) Alcohol drinking Never 31 (33.3) 21 (52.5) 17 (94.4) 41 (93.2) Former 22 (23.7) 9 (22.5) 1 (5.6) 1 (2.3) Current 40 (43.0) 10 (25.0) 0 (0.0) 2 (4.5) Education Illiteracy 4 (4.3) 1 (2.5) 3 (16.7) 11 (25.0) Primary 8 (8.6) 2 (5.0) 4 (22.2) 8 (18.2) Middle 23 (24.7) 12 (30.0) 3 (16.7) 16 (36.4) High 25 (26.9) 14 (35.0) 5 (27.8) 2 (4.5) College 33 (35.5) 11 (27.5) 3 (16.7) 7 (15.9) Values expressed as mean ± SD or n (%). a Participants were classified as green tea drinkers if they drank green tea during the previous 12 months. CAD, coronary artery disease.

4 Green Tea and CAD 297 Table 3. Relationship Between Green Tea Consumption and CAD Risk Green tea consumption Non-CAD (n) CAD (n) Crude OR (95%CI) Adjusted OR a (95%CI) Male patients Green tea drinking status b No Yes ( ) 0.62 ( ) Green tea consumption (g/month) < ( ) 1.09 ( ) ( ) 0.36 ( ) > ( ) 0.36 ( ) P for trend <0.001 Frequency of green tea drinking <1 days/week days/week ( ) 0.82 ( ) > 4 days/week ( ) 0.50 ( ) P for trend Years of green tea drinking ( ) 1.11 ( ) ( ) 0.45 ( ) > ( ) 0.46 ( ) P for trend Starting age of green tea drinking > ( ) 1.13 ( ) ( ) 0.60 ( ) ( ) 0.39 ( ) P for trend Green tea concentration c Low ( ) 1.04 ( ) Moderate ( ) 0.36 ( ) High ( ) 0.46 ( ) P for trend Female patients Green tea drinking status No Yes ( ) 0.65 ( ) CAD, coronary artery disease; OR, odds ratio; CI, confidence interval. a Adjustment for age, smoking status, alcohol use, physical activity, hypertension, hyperlipidemia, diabetes mellitus, education, area of residence, family history of CAD, and body mass index in the analysis. b Participants were classified as green tea drinkers if they drank green tea during the previous 12 months. c Tea concentration was categorized as low (tea leaves were <25% of the volume of the cup), moderate (tea leaves were 25 50% of the volume of the cup) and high (tea leaves were >50% of the volume of the cup). ages (SD) of those with and without CAD were 64.0 (10.0) and 61.1 (10.2) years. The proportion of current smokers was 52.4% of patients with CAD and 39.8% of patients without CAD. The prevalence of hypertension was 65.9 and 55.6% in CAD and non-cad patients. A higher proportion of CAD patients were distributed to the lower education class. Among 141 female patients, 79 (56.0%) were found to have CAD. The mean ages (SD) of those with and without CAD were 66.9 (9.1) and 63.2 (8.4) years. A higher proportion of female CAD patients were distributed to the lower education class. Characteristics of Patients Without CAD According to Green Tea Drinking Status The characteristics of patients without CAD according to their green tea drinking status are shown in male and female patients separately (Table 2). Among 133 male patients without CAD, 93 (69.9%) were found to be green tea drinkers. The mean ages (SD) of green tea drinkers and non-tea drinkers were 60.6 (9.9) and 62.3 (10.7) years. The proportion of current smokers was 45.2% in green tea drinkers and 27.5% in non-tea drinkers. The proportion of current alcohol drinkers was 43.0% of green tea drinkers and 25.0% of non-tea drinkers. Among the 62 female patients who did not have CAD, 18 (29.0%) were found to be green tea drinkers. The mean ages (SD) of green tea drinkers and non-tea drinkers were 66.3 (6.8) and 62.0 (8.7) years. The prevalence of hyperlipidemia was 66.7 and 50.0% in green tea drinkers and non-tea drinkers.

5 298 WANG QM et al. Relationship Between Green Tea Consumption and CAD Risk The relationship between green tea consumption and CAD are shown in male and female patients separately (Table 3). In male patients, a decreased tendency was observed between green tea drinking and the risk of CAD, with a crude OR of 0.65 (95%CI, ) and an adjusted OR of 0.62 (95%CI, ) compared with non-tea drinkers. The risk of CAD for male patients tended to decline with an increase in the quantity of green tea consumed, with a statistically significant test for trend (P<0.001). The adjusted ORs for those consuming g and 250 g of dried green tea leaves per month were 0.36 (95%CI, ) and 0.36 (95%CI, ), respectively, compared with non-tea drinkers. Similar dose response relationships were also observed for frequency, concentration and duration of green tea drinking in male patients and the corresponding linear trends were significant. Moreover, the risk for CAD was significantly reduced in male patients who started to drink green tea from the age of 30 or younger. In female patients, no inverse association was found between green tea consumption and CAD. Because green tea drinkers among female patients were few, we categorized green tea consumption into 2 levels (no vs yes). Discussion To our knowledge, the present study is the first to evaluate the association of green tea consumption with angiographically defined coronary atherosclerosis among a Chinese population. In the present study, we found that green tea consumption was inversely associated with the prevalence of CAD, which was defined as at least 1 significant coronary artery stenosis, in male patients. CAD risk for male patients decreased with the increasing frequency, duration, quantity and concentration of green tea consumed. Moreover, the risk for CAD was significantly reduced in male patients who started drinking green tea from the age of 30 or younger. In female patients, there was no inverse association between green tea consumption and CAD. Several previous studies have suggested that tea consumption might protect against atherosclerosis. Miura et al reported that chronic ingestion of tea catechins prevented the development of atherosclerosis in apoe-deficient mice fed an atherogenic diet. 21 Geleijnse et al found an inverse association of tea intake with severe aortic atherosclerosis. 22 The ORs decreased from 0.54 for patients drinking ml/day of tea to 0.31 for patients drinking >500 ml/day compared with those who did not drink tea. 22 In addition, it was reported that atherosclerotic plaques in the carotid arteries were significantly less frequent with increasing tea consumption in women, in particular for a consumption of 3cups/day. 23 The anti-atherosclerosis effects of tea are most commonly attributed to its polyphenolic compounds, mainly flavonoids. In green tea, the major flavonoids are catechins (flavan-2-ols), which include epicatechin (EC), EC-3-gallate, epigallocatechin (EGC) and EGC-3-gallate. 2 Tea catechins have been shown to have lipid-lowering properties in human and animal intervention studies. 7,8 Lipid-lowering therapy could induce significant coronary plaque regression and the percentage of change in the plaque volume showed a positive correlation with the percentage of change in the low-density lipoprotein (LDL)-C level. 24 Underlying mechanisms for the lipid-lowering effects of catechins include reduction of cholesterol absorption, 8 inhibition of cholesterol synthesis 25 and upregulation of the hepatic LDL receptor. 25 The strong antioxidant activity of green tea may be another explanation of its preventive effect on coronary atherosclerosis. Green tea has been found to reduce plasma concentrations of oxidized LDL, 10,26 which may promote atheroma formation by increasing macrophage uptake, 27 monocyte recruitment 28 and direct endothelial cell damage. 29 Apart from the antioxidant and lipid-lowering effects, many other mechanisms may be responsible for the protective effects of green tea in the process of atherogenesis, which include a beneficial effect on hypertension, 11,12 improvement of hemorheological abnormalities, 13 inhibition of platelet aggregation 14,15 and improvement of endothelial function, 16,17 which plays an important role in the first step toward coronary arteriosclerosis. 30 Few studies conducted in Japan have reported the relationship between green tea consumption and angiographically proven CAD. Sano et al reported a strong inverse relationship between green tea intake and CAD. 4 A higher green tea intake lowered the incidence of CAD. Another study by Sasazuki et al showed a protective relationship between green tea consumption and coronary atherosclerosis in men without diabetes mellitus, but not in women. 5 Hirano et al investigated 393 Japanese patients and found no inverse association between green tea intake and CAD. 6 These disparate findings may be explained by the different definitions of CAD. In the study by Hirano et al, CAD was defined as at least 1 coronary artery having >50% luminal diameter stenosis on angiography, 6 whereas, in the studies by Sano et al and Sasazuki et al, CAD was defined as a stenosis >50% in the left main trunk or >75% in the other major coronary arteries. 4,5 The definition of CAD used in the present study was the same as that used in the study by Hirano et al. However, we found an inverse relationship between green tea intake and the prevalence of CAD in male patients. Furthermore, higher green tea consumption measured in dry weight has been associated with reduced risks for CAD. This inconsistency may be due to different ways of brewing green tea in different populations and variable contents in different brands of green tea. Hot black tea consumption was associated with a significantly lower risk of skin cancer but was this was not the case for iced black tea, 31 suggesting that the protective effects of tea can be influenced by the method of preparation. Furthermore, the production of Japanese green tea involves a steaming process at a high temperature to keep the green color of the tea. This process may lead to changes in the chemical composition and concentration of the bioactive constituents in green tea. 20 In female patients, we found no preventive effect of green tea consumption for coronary atherosclerosis. It is widely accepted that menopause may confer an increased risk of CAD. A study by Sullivan et al indicates that estrogen replacement therapy in postmenopausal women can protect against CAD. 32 In the present study, women who consumed green tea were older compared with those who did not drink green tea. It is possible that green tea drinkers had experienced a longer postmenopausal status. Although adjustment for age was carried out, it may not have been sufficient to eliminate the potential confounding effect of postmenopausal duration. Furthermore, a study by Wu suggests that regular green tea consumption could lead to a significant decrease in plasma estrogen levels. 33 This might attenuate the protective effect of green tea. The relatively small sample of female patients in the present study may be another explanation for the lack of association.

6 Green Tea and CAD 299 Study Limitations Although we found an inverse association between green tea consumption and coronary atherosclerosis in male patients, several limitations of the present study should be considered. First, CAD and control patients all underwent coronary arteriography. Thus, the study patients may not be representative of the general population. Although recruitment was conducted carefully, the inherent selection bias cannot be ruled out completely. This kind of selection bias should be avoided in further studies. Second, a potential recall bias should be considered. However, we excluded the patients who had previously undergone coronary interventions and assessed green tea consumption before coronary arteriography to minimize the recall bias. Moreover, it is unlikely that such differences in recall would have been conscious, as the study patients were not aware of the possible relationship between drinking green tea and coronary atherosclerosis. Third, we did not obtain detailed dietary information on these patients, and we cannot rule out the possibility that dietary factors confounded the association between green tea and coronary atherosclerosis. However, adjustment for alcohol consumption, cigarette smoking and other lifestyle and clinical characteristics made little difference to the present study. Therefore, we speculate that dietary factors may not greatly influence the present results. Finally, although a number of confounding factors were controlled in the present study, it is nevertheless possible that some unidentified lifestyle factors, such as sleep duration 34 and job stress, 35 might not have been accounted for. In conclusion, this case-control study provides evidence that green tea consumption is inversely associated with coronary atherosclerosis in Chinese male patients, but not in Chinese female patients. The findings are consistent with data from in vitro and in vivo experiments, indicating that green tea may serve as an effective bioactive agent for coronary atherosclerosis. However, further studies are needed to fortify our preliminary inference about the link between green tea consumption and coronary atherosclerosis. Acknowledgments This project was supported by grants from the Natural Science Foundation of Jiangsu Province (No. BK ), Ministry of Personnel of China for returned students (No. DG216D5021) and the National Natural Science Foundation of China (No ). References 1. Graham HN. Green tea composition, consumption, and polyphenols chemistry. Prev Med 1992; 21: McKay DL, Blumberg JB. The role of tea in human health: An update. J Am Coll Nutr 2002; 21: Rao GH, White JC. Coronary artery disease: An overview of risk factors. Indian Heart J 1993; 45: Sano J, Inami S, Seimiya K, Ohba T, Sakai S, Takano T, et al. 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