European Journal of Internal Medicine

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1 European Journal of Internal Medicine 23 (2012) Contents lists available at ScienceDirect European Journal of Internal Medicine journal homepage: Review article Consumption of cocoa, tea and coffee and risk of cardiovascular disease Augusto Di Castelnuovo a,,1, Romina di Giuseppe a,b,1, Licia Iacoviello a, Giovanni de Gaetano a a Laboratorio di Epidemiologia Genetica ed Ambientale, Laboratori di Ricerca, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy b Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany article info abstract Article history: Received 12 March 2011 Received in revised form 1 July 2011 Accepted 22 July 2011 Available online 30 August 2011 Keywords: Coronary artery disease prevention Nutrition Chocolate Coffee Tea Daily intake of an anti-thrombotic diet may offer a suitable and effective way of coronary artery disease (CAD) prevention. A diet rich in fruit, vegetables, complex carbohydrates, monounsaturated fat and fish, moderate alcohol consumption but poor in salt, saturated fat and simple sugars, plays an important role in protect against CAD. Chocolate, coffee and tea, unfairly not included in traditional healthy food basket, have received much attention over the past few years, if for no other reason than they are consumed worldwide and are important dietary sources of polyphenols (flavonols and cathechins). Several in vitro and in vivo studies have tried to elucidate the role of these foods and a large amount of experimental studies clearly indicated a beneficial effect of polyphenols in influencing CAD. However, data from epidemiological studies are not conclusive. The blood pressure lowering effects and the anti-inflammatory activity of dark chocolate suggests its use as potential prophylactic and therapeutic agent, in particular considering that epidemiological studies suggest that dark chocolate is inversely associated with CAD. Although regular consumption of moderate quantities of coffee and (green) tea seems to be associated with a small protection against CAD, results from randomized clinical trials about their beneficial effects are less evident. As for other diffuse consumption habits, such as that of alcohol, moderation is the key word. In fact, both for coffee and chocolate, the optimal healthy effects on CAD have been observed to be associated with a moderate intake, while healthy outcomes vanish at heavy consumption European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. 1. Introduction Coronary artery disease (CAD) is a leading cause of death worldwide, in men and women [1]. Smoking, hypertension, hypercholesterolemia, diabetes, obesity, social deprivation, physical activity and dietary habits are recognised risk factors for CAD [2]. Abnormalities in lipoprotein or glucose metabolism, as well as regulation of blood pressure levels, weight, oxidative stress or chronic inflammation are linked, at least in part, to dietary habits [3]. Changes in nutritional habits of many populations have been considered, among others, responsible for increased CAD incidence, whereas adoption of a potentially anti-thrombotic diet may offer a suitable and effective way of CAD prevention [4]. Therefore, most of the efforts for the prevention and treatment of CAD are focused on strategies which promote lifestyle and dietary modifications [4]. The traditional Mediterranean diet is characterized by high intake of foods rich in polyphenols and flavonoids [5,6]. Data from a vast literature clearly demonstrate that adherence to the Mediterranean diet is associated with a significant reduction of total as well as CAD and cancer mortality [7,8]. Mechanisms of action of the Mediterranean diet relate to beneficial effects on lipids as well as antithrombotic, Corresponding author. Tel.: address: dicastel@ngi.it (A. Di Castelnuovo). 1 Both authors contributed equally to this work. antiatherogenic and antioxidant effects [9,10]. Nevertheless, beyond the traditional Mediterranean dietary components, other polyphenol and flavonoid-rich foods (and beverages) such as cocoa, coffee and tea have been associated with a reduced CAD risk profile [11,12]. The aim of this review was to review evidence concerning the association of intake of cocoa, coffee and tea with CAD risk. 2. Cocoa Cocoa research has received much attention over the past years. Cocoa beans and derived products such as chocolate contains different types of physiologically active compounds including, among others, polyphenols, well known components with beneficial effects on CAD risk profile [11 14] and methylxanthines [13]. In particular, theobromine, the main methylxanthine in chocolate, is a myocardial stimulant, diuretic, coronary dilator, and smooth muscle relaxant[13,14]. Furthermore, particular polyphenols, i.e. catechins, epicatechins and procyanidins, typically found in tea and vegetables have also been found in cocoa beans and chocolate. Interestingly, Lee et al. [15] showed that cocoa contains higher concentrations of total phenolic phytochemicals and flavonoids per serving than tea or red wine, which contribute to its higher antioxidant capacity and, presumably, to its higher beneficial health effects [15]. However, the biological effects of cocoa flavonoids vary from chocolate to chocolate, since they seem to /$ see front matter 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi: /j.ejim

2 16 A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) be greater in dark rather than in milk chocolate [16]. Thus, starting from the hypothesis that cocoa polyphenols bind to milk proteins, Serafini et al. have showed that the increase in total antioxidant capacity of 100 g dark chocolate was reduced when chocolate was taken as milk chocolate (200 g) or when dark chocolate (100 g) was taken with 200 ml full-fat milk [16]. Interestingly, results from a randomized, double-blind, placebo-controlled study on healthy adults, indicated that consumption of flavonoid-rich dark chocolate improved endothelium-dependent vasodilation, via increased plasma epicatechin concentrations, independent to changes in biomarkers of antioxidant and oxidative stress [17]. In addition, Wang et al. [18] further showed that subjects consuming procyanidin-rich chocolate had an increase in plasma antioxidant capacity [18]. Therefore, based on this evidence it is reasonable to assume that dark chocolate exerts, at least in part, its beneficial effect by increasing plasma antioxidants Chocolate as an anti-inflammatory agent Chocolate flavonoids possess anti-inflammatory properties since they are able to inhibit several mediators activated in certain inflammatory conditions. In particular, cocoa products reduce inflammation by modulating interleukin-5 in peripheral blood mononuclear cells [19], tumor necrosis factor-alpha [20] and by influencing the endothelium-derived nitric oxide synthesis and metabolism [21]. In addition, cocoa flavonoids seem to mediate anti-inflammatory effects related to reductions in platelet and endothelial cell activation [22]. Cocoa consumption led to decreased platelet microparticle formation and inhibited ADP- and epinephrine-stimulated platelet activation [23]. More recently, in an in vitro and ex vivo study, Heptinstall and colleagues [24] reported that cocoa flavonols inhibited platelet aggregation and activation, platelet-monocyte and neutrofil conjugate formation with aspirin-like effects. In a study conducted on healthy volunteers, the authors observed a decrease in leukotrienes and an increase in prostacyclin after consumption of a flavonoid-rich dark chocolate (compared with a flavonoid poor dark chocolate) [25,26]. Thus, the balance between the inhibitory effect of prostacyclin on platelet aggregation vs the stimulatory effect of leukotrienes, suggests the possible effect of chocolate procyanidins on inflammation through the modulation of eicosanoid. In a cross-sectional study based on data from the NHANES flavonoid-rich foods were inversely associated with serum C- reactive protein (CRP) concentrations [27]. In a study conducted by Hamed et al. [28] in 28 healthy volunteers, the authors observed a 22% reduction of high-sensitive CRP following seven days of regular dark chocolate ingestion, but only in women. The hypothesis that dark chocolate consumption could be inversely related to CRP level had been tested in a large sample of healthy Italian subjects [29]. The levels of CRP were compared between 1317 subjects who denied having eaten any chocolate during the past year and 824 subjects who declared having consumed dark chocolate regularly. After adjustment for lifestyle and other confounders, a significant J-shaped relationship between dark chocolate consumption and serum CRP was observed [29] Cocoa and cardiovascular risk factors A summary table presents the most relevant studies with epidemiologic evidence pros and cons the beneficial effect of cocoa on cardiovascular risk or cardiovascular risk factors. Several studies indicate that diets rich in polyphenols are associated with a decrease in blood pressure (BP) levels [30]. In the Zutphen Elderly Study [31] men with a usual consumption of 10 g/day of dark chocolate had a lower systolic BP as compared with men with no or very low intake (Table 1). Furthermore, in a large cohort (N=19,357) of middle-aged apparently health German men and women [32], both systolic and diastolic BP were lower in the quartile characterized by the highest chocolate consumption (7.5 g/day) as compared with the low consumption quartile (Table 1) [32]. Interestingly, Grassi et al. [33] have shown that a flavonol-rich dark chocolate decreases BP, increases flow-mediated dilation while improving insulin sensitivity and beta-cell function in hypertensive patients with impaired glucose tolerance [33]. A recent meta-analysis of 13 trials on the effect of flavanol-rich cocoa products on BP in hypertensive and normotensive individuals revealed a significant blood pressure-reducing effect of cocoa/chocolate (mean BP change: systolic: 3.2 mmhg; diastolic: 2.0 mmhg), for the hypertensive or pre-hypertensive subgroups only [34]. Another meta-analysis concludes that chocolate increases endothelial function (measured as flow-mediated dilation), after acute (4%; 6 studies) and chronic (1.5%; 2 studies) intake [12]. The effect of cocoa on lipid changes is controversial. After pooling data from eight trials, cocoa consumption lowered LDL (by 6 mg/dl), but not HDL cholesterol [12] Evidence from epidemiology Cocoa and chocolate represent the most important source of flavonoids, but it is not unique. Several studies investigated the association of total flavonoids with CAD risk [35 37]. The prospective studies of flavonoids and risk of CAD published up to 2006 are reviewed in Ding et al. [38]. A meta-analysis of 8 prospective studies, including almost 140,000 subjects, found that intake of flavonoids from any source protect against CAD mortality (relative risk equal 0.81; 95% CI: , comparing highest vs lowest tertiles of intake). On the contrary, evidence is fairly consistent for cardiovascular disease or stroke. The major finding from this meta-analysis was confirmed in the Zutphen Elderly Study [31] and in an Italian case-control study (Table 1) [39]. Another study found that habitual consumption of low amounts of chocolate (6 g/d) was associated with 39% lower incidence of a combined outcome of myocardial infarction and stroke (Table 1) [32]. Chocolate consumption has been shown to be inversely associated with cardiac mortality also in a Swedish cohort of 1169 patients surviving their first acute myocardial infarction (Table 1) [40]. Finally, in a large U.S. cohort of postmenopausal women followed for 16 years chocolate consumption, and other flavonoid-rich foods, has been inversely associated with CVD death [36,41]. However, after multivariable adjustment the highly significant association found in the age and energy adjusted model (pb0.001) became borderline (p=0.062) [41]. 3. Coffee Albeit coffee represents, along with tea, the most worldwide consumed beverage, its potential effect on cardiovascular disease is still controversial (Table 2) [42 53]. Apart from being the main source of caffeine, coffee contains several other compounds in particular phenols, vitamin B3, magnesium, potassium and fiber [54] that may have either beneficial or detrimental effects on cardiovascular system. Cafestol and kahweol are both diterpenoid hypercholesterolemic compounds present in coffee beans [55]; however, the use of a paper filter during coffee preparation is sufficient to limit their content [56]. Nevertheless, many other compounds with antioxidant properties [57,58] namely chlorogenic acid, flavonoids, melanoidins, furans, pyrroles and maltol have been found in coffee [59]. Definitely, because of its extensive use, coffee represents one of the major contributors to the total antioxidant capacity of the diet [60,61] Coffe and cardiovascular risk factors: negative aspects As extensively reviewed by Cornelis et al. [59], and Riksen et al. [62], caffeine is involved in the link between coffee and CAD. Intake of

3 A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) Table 1 Summary of studies on chocolate/cocoa and vascular events. Summary Chocolate, Reference Study Exposure Endpoint N. cases/n. total Adjusted RR or OR (95% CI) Cocoa intake, highest vs lowest tertile Cardiovascular mortality 152/ ( ) In elderly men, inverse association between cocoa intake and cardiovascular and all-cause mortality Cocoa intake, highest vs lowest tertile All cause mortality 162/ ( ) Buijsse B, 2006 [31] Zutphen Elderly Study, Gallus S, 2009 [39] Italy, case-control study 3 chocolates/day vs b2 chocolates/day AMI 760/ ( ) Eating 3 chocolates/day is inversely associated with nonfatal AMI Cardiac mortality, diabetes free post AMI 107/ ( ) Total mortality, diabetes-free post AMI 210/ ( ) Recurrent AMI, diabetes-free post AMI 250/ ( ) Congestive heart failure, diabetes-free 279/ ( ) Inverse association with cardiac post AMI mortality in post-ami patients Stroke, diabetes-free post AMI 111/ ( ) Chocolate consumption, 50 g; 2/week vs no consumption Janszky I, 2009 [40] Stockholm Heart Epidemiology Program, population-based inception cohort study 471/ ( ) Any non-fatal event, diabetes-free post AMI Chocolate intake, highest vs lowest quartile Myocardial infarction 166/19, ( ) Reduced CVD risk according to chocolate consumption partly due to its BP-lowering effect Chocolate intake, highest vs lowest quartile Stroke 136/19, ( ) Buijsse B, 2010 [32] EPIC-Potsdam Study, caffeine is associated with an increase in blood pressure [63,64], systemic vascular resistance [65], arterial stiffness [66,67], plasma renin activity, epinephrine, and norepinephrine [68] and has unfavorable effects on endothelial function in healthy subjects [69]. Moreover, in a randomized double-blinded study Riksen et al. [62] observed that ischemic preconditioning, which exerts a cardioprotective effect, was completely abolished by caffeine. In addition consumption of coffee, especially in the form of boiled coffee, raises serum lipids [70,71] and homocysteine levels [72] Coffe and cardiovascular risk factors: positive aspects The adverse effects of coffee and specifically caffeine are in part counterbalanced by the favorable effect on type 2 diabetes mellitus [73 75] and by the lack of association with incident hypertension in women [76]. An important contribution to the explanation of the role of coffee on CAD emerges from the very recent study of Shechter et al. [77]. The authors found that acute ingestion of caffeine (in the form of capsules containing 200 mg of caffeine) was associated with an increase in flow-mediated dilation and in a decrease in C-reactive protein in subjects with and without CAD [77]. Moreover, caffeine consumption has been shown to inhibit platelet aggregation, possibly by upregulation of adenosine A2A receptors [78] Evidence from epidemiology Early [42,44,45] and more recent meta-analyses [79,80] concluded that overall coffee consumption was not significantly associated with an increased CAD risk, especially when only prospective studies were considered (Table 2). Rather, Wu et al. [80] have shown that drinking 1 to 4 cups of coffee per day was associated with a lower risk of CAD, (relative risk of 0.87; 95%CI: in men and 0.82; 95%CI: in women, Table 2). In a recent prospective cohort study [81], the inverse association found in both men and women between regular coffee consumption and all-cause mortality was independent of caffeine intake and largely explained by a moderate reduction in cardiovascular disease (CVD) risk mortality (Table 2). Furthermore, in the same study also decaffeinated coffee was inversely associated with all-cause and cardiovascular mortality, albeit the observed effects were relatively small (Table 2) [81]. Several factors should be taken into account when coffee consumption is investigated in relation to CVD risk factors. One of them is how coffee is prepared. Several lines of evidence suggest that boiled coffee raises cholesterol levels [71]. In agreement with these findings, in a Swedish case-control study [82], the incidence of first nonfatal myocardial infarction was 1.4 times higher, in men drinking boiled coffee vs men drinking filtered coffee, with an even higher risk for women (RR: 1.63; 95% CI: , Table 2). However, Baylin et al. [83] showed that following a transient coffee intake, subjects with a sedentary lifestyle and with three or more risk factors for CAD have an increased MI risk (Table 2). In addition, drinking more than 10 cups of coffee per day was an independent risk factor in a retrospective case-control study for sudden cardiac arrest in patients with CAD [84]. Nevertheless, these findings stand in contrast with others [85 87]. In particular, while in one study [85] the authors observed an inverse association between coffee consumption and mortality in the first 90 days after infarction (Table 2), in the post- MI patients of the GISSI study [86] moderate coffee consumption was not associated with CVD events (Table 2). Furthermore, in a Dutch cohort of healthy men and women the authors observed a J shaped relationship between incident CAD morbidity and coffee intake with an hazard ratio of 0.55 in subjects drinking from 3 to up 6 cups of coffee per day (Table 2) [87]. The J-shaped relationship between CAD and coffee (meaning that after an initial decrease in relative risk for CAD by increasing coffee intake the curve reaches a plateau, and reverts at higher amounts) was also observed in the study of

4 Table 2 Summary of studies on coffee and vascular events. Coffee, Reference Grobbee DE, 1990 [88] Myers MG, 1992 [42] Kawachi I, 1994 [44] Woodward M, 1999 [52] Hammar N, 2003 [82] Panagiotakos DB, 2003 [51] Happonen P, 2004 [48] Mukamal KJ, 2004 [85] Study Exposure Endpoint N. cases/n. total Adjusted RR or OR (95% CI) The Health Professional Follow-up Study, longitudinal study 11 Prospective Studies (cohorts without history of MI), meta-analysis 8 case-control and 15 cohort studies, meta-analysis Scottish Heart Health Study, cohort study The SHEEP and the VHEEP Study, population-based case-control study The CARDIO2000, case-control study The Kuopio Ischaemic Heart Disease Risk Factor Study, Determinants of Myocardial Infarction Onset Study, inception cohort study Total Coffee vs none Caffeinated coffee vs none vs none Coffee intake, 6 cups/day vs 1 cup/day Coffee drinking, 5 cups/day vs none Summary Nonfatal MI, CHD death, CABG, PTCA, Stroke Both caffeine and caffeinated coffee intake do not increase CHD and stroke risk Nonfatal MI and CHD death 221/45,589; Men 1.08 ( ) CABG and PTCA 136/45,589; Men 0.95 ( ) Total CHD 357/45,589; Men 1.00 ( ) Fatal and nonfatal stroke 54/45,589; Men 0.48 ( ) Total CVD 408/45,589; Men 0.90 ( ) Nonfatal MI and CHD death 221/45,589; Men 1.01 ( ) CABG and PTCA 131/45,589; Men 0.66 ( ) Total CHD 342/45,589; Men 0.84 ( ) Fatal and nonfatal stroke 52/45,589; Men 0.28 ( ) Total CVD 390/45,589; Men 0.74 ( ) Nonfatal MI and CHD death 214/45,589; Men 1.55 ( ) moderately increases CHD risk CABG and PTCA 132/45,589; Men 1.74 ( ) Total CHD 346/45,589; Men 1.63 ( ) Fatal and nonfatal stroke 51/45,589; Men 1.16 ( ) Total CVD 394/45,589; Men 1.58 ( ) Coronary events 1.09 ( ) No association between coffee consumption and CHD Later Cohort 1.27 ( ) Earlier Cohort 0.92 ( ) Pooled cohort 1.18 ( ) CHD Pooled case-control 1.63 ( ) Increased CHD risk according to increased coffee drinking Pooled cohort 1.05 ( ) Weak CHD risk in habitual coffee drinkers Coffee consumption 5 vs none CHD?/5645; Men 0.68 ( ) Moderate benefit from coffee consumption CHD?/5800; Women 0.55 ( ) Consumption N9dLfiltered First nonfatal MI 1171/1813; Men 1.93 ( ) Incidence of first nonfatal MI 1.4 times higher in men drinking boiled coffee vs men drinking filtered coffee, with an even higher risk for women Consumption N9 dl mixed 2.24 ( ) Consumption N9 dl boiled 2.20 ( ) Consumption N9dLfiltered First nonfatal MI 472/854; Women 1.43 ( ) Consumption N9 dl mixed 2.91 ( ) Consumption N9 dl boiled 4.97 ( ) Boiled vs filtered coffee 1171/1813; Men 1.41 ( ) Boiled coffee increases the occurrence of first nonfatal MI Boiled vs filtered coffee 472/854; Women 1.63 ( ) Very heavy coffee drinkers ACS 848/ ( ) J-shaped relation between coffee intake (N600 ml/day) vs none and ACS risk Moderate drinkers vs heavy Acute coronary events 269/1971; Men 1.43 ( ) Heavy coffee drinking raises the risk of drinkers ( 814 ml/day) (MI or coronary death) acute MI or coronary death Coffee consumption N14 Mortality after AMI 315/ ( ) No association between coffee consumption cups/week vs none and post-infarction mortality Coffee consumption N14 Deaths within 90 days 79/ ( ) cups/week vs none Coffee consumption N14 Deaths beyond 90 days 236/ ( ) Time variation in coffee effect cups/week vs none 18 A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) 15 25

5 Table 2 (continued) Coffee, Reference Andersen LF, 2006 [49] Lopez-Garcia E, 2006 [43] Azevedo A, 2006 [50] Kleemola P, 2006 [53] Baylin A, 2006 [83] Cornelis MC, 2006 [47] Silletta MG, 2007 [86] Larsson LC, 2008 [89] Lopez-Garcia E, 2008 [81] Study Exposure Endpoint N. cases/n. total Adjusted RR or OR (95% CI) Iowa Women's Health Study, Prospective cohort study Community-based case-control study Finnish men and women, Summary Regular coffee 6 cups/day Death due to CVD, 1411/41, ( ) vs none postmenopausal 6 cups/day vs none Death due to CVD, postmenopausal 1411/41, ( ) U-shaped associations (death from CVD and total mortality) Regular coffee 6 cups/day Total mortality, 4265/41, ( ) vs none postmenopausal 6 cups/day vs none Total mortality, postmenopausal 4265/41, ( ) Coffee intake, 6 cups/day CHD CHD 2173/44,005; Men 0.72 ( ) 2254/84,488; Women 0.87 ( ) No indication that coffee (or caffeine) intake increases CHD Caffeine intake, 6 cups/day CHD 2173/44,005; Men 0.97 ( ) CHD 2254/84,488; Women 0.97 ( ) Regular ever coffee drinkers AMI 290/364; Men 0.5 ( ) Significant MI in men with no family history of AMI; non significant MI in men withfamily history of AMI Coffee consumption N7 cups/day Non fatal MI 891/10,075; Men 0.79 ( ) Coffee consumption N7 cups/day CHD mortality 891/10,075; Men 1.22 ( ) Coffee consumption N7 cups/day All cause mortality 1201/10,075; Men 1.01 ( ) Coffee drinking is not associated with CHD risk and death Coffee consumption N7 cups/day Non fatal MI 319/10, ( ) Coffee consumption N7 cups/day CHD mortality 99/10, ( ) Coffee consumption N7 cups/day All cause mortality 444/10, ( ) Costa Rica, case-crossover design Habitual coffee consumption Nonfatal MI, 1 h after coffee drinking 1 cup/day 9/ ( ) Coffee intake probably set off MI 2 3 cups/day 44/ ( ) 4 cups/day 27/ ( ) Slow caffeine metabolizer Coffe intake 4 cups/day First acute nonfatal MI 2014/ ( ) Increased MI risk only in subjects with impaired caffeine metabolism Rapid caffeine metabolizer Coffe intake 4 cups/day First acute nonfatal MI 2014/ ( ) population-based case-control study GISSI-Prevenzione trial, prospective study Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, Health Professionals Follow-up Study and Nurses' Health Study, prospective cohort study Coffee consumption N4 cups/day vs none Coffee consumption 8 cups/day vs b2 cups/day CVD events (CV death, nonfatal MI, nonfatal stroke in post-mi patients Stroke subtypes 1167/11, ( ) Moderate coffee intake is not associated with CV events post-mi Cerebral infarction 2702/26,556; Men 0.77 ( ) High coffee consumption lowers cerebral infarction risk Intracerebral hemorrhages 383/26,556; Men 0.98 ( ) Subarachnoid hemorrhages 196/26,556; Men 1.18 ( ) CVD mortality 2049/41,736; Men 0.56 ( ) CVD mortality 2368/86,214; Women 0.81 ( ) Cancer mortality 2491/41,736; Men 1.14 ( ) Cancer mortality 5011/86,214; Women 1.05 ( ) Other causes 2348/41,736; Men 0.65 ( ) Other causes 3716/86,214; Women 0.60 ( ) (continued on next page) A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012)

6 Table 2 (continued) Coffee, Reference Wu JN, 2009 [80] de Koning Gans JM, 2010 [87] Mostofsky E, 2010 [90] Study Exposure Endpoint N. cases/n. total Adjusted RR or OR (95% CI) 21 prospective cohort studies, meta-analysis Prospective study Stroke onset study, multicenter case-crossover study Summary In both men and women the reduced CVD deaths mainly explains the modest inverse association between coffee consumption and all cause mortality All causes 6888/41,736; Men 0.80 ( ) All causes 11,095/86,214; Women 0.83 ( ) CVD mortality 2049/41,736; Men 0.83 ( ) CVD mortality 2368/86,214; Women 0.55 ( ) Cancer mortality 2491/41,736; Men 1.20 ( ) Cancer mortality 5011/86,214; Women 0.86 ( ) All causes 6888/41,736; Men 0.81 ( ) All causes 11,095/86,214; Women 0.78 ( ) Coffee consumption b1 CHD 15,599/407,806; pooled 1.07 ( ) No long-term increased CHD risk cup/day (US) or 2 cups/day(europe) vs 6 or 7 cups/day Moderate coffee consumption CHD Women 0.82 ( ) Lower CHD risk in moderate coffee drinker women Coffee consumptionn6 cups/day CHD morbidity 1387/37, ( ) U shaped association between coffee consumption and lower CHD morbidity Coffee consumptionn6 cups/day Stroke morbidity 563/37, ( ) Coffee consumptionn6 cups/day CHD mortality ( ) Non significant slight reduction in CHD mortality according to moderate coffee consumption Coffee consumptionn6 cups/day Stroke mortality ( ) Coffee consumptionn6 cups/day All causes mortality ( ) No effect of coffee on stroke or all causes mortality Coffee drinkers vs non drinkers Stroke onset in subjects with acute ischemic stroke 1 h after 1 serving of coffee 35/ ( ) Infrequent coffee drinkers have increased ischemic stroke risk onset 1 h after 1 serving of RR (values not available) caffeinated coffee in subjects drinking 1 cup/day 20 A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) 15 25

7 A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) Panagiotakos et al. [51]. Finally, the studies aimed at examining the association between coffee consumption and stroke have yielded conflicting results (Table 2) [86 90]. A non linear dose response relationship between coffee intake and CVD risk may explain the heterogeneity in findings from different studies (which typically investigated the role of coffee at various doses) and, at the least in part, the null findings of meta-analyses. More accurate quantitative review of the literature that consider the Jshaped relationship between coffee and CVD risk (as in the case of alcohol and CVD [91]), are desirable, and can better elucidate the issue. 4. Tea Tea is produced from the leaves of the plant Camellia sinensis. According to the level of fermentation, tea is classified into black (fermented) tea mainly drunk in Europe, North America and North Africa and green tea (unfermented), principally consumed in Asia [92 94]. Because of its high content of catechins (epicatechin, epicatechin gallate, epigallocatechin and epigallocatechin gallate), also known as tea flavonoids, tea consumption seems to protect against the development of CVD [95]. Flavonoids reduce platelet aggregation and prevent oxidation of low density lipoproteins because of their antioxidant properties [96 99]. In addition, catechins intercede in the process of vascular inflammation and atherosclerosis through several actions (e.g. anti-hypertensive, antilipidemic, anti-inflammatory, anti-proliferative and anti-thrombogenic) [ ]. Thus, considering that catechins represent 80 90% of total flavonoids in green tea [100,103], whereas they are only 20 30% in black tea [100,103], it is reasonable to assume that green tea would exert a more pronounced beneficial effect on cardiovascular system than black tea Evidence from epidemiology: coronary artery disease The results from the Rotterdam study [104], in which a lower risk of incident myocardial infarction was observed in tea vs non tea drinkers, suggest an important dual contribution of tea and flavonoids in preventing ischemic heart disease (Table 3) [104]. In the large Dutch cohort of healthy men and women from the European Prospective Investigation into Cancer and Nutrition (EPIC) [87], the consumption of 3 to 6 cups of tea per day (mainly in form of black tea) was associated with a reduced risk of CAD mortality (Table 3) [87]. Regarding black tea, lines of evidence suggest a reduction in the risk of CAD accordingly to a consumption of three or more cups per day [105,106], through a mechanism involving the protective effect of tea antioxidants. In a meta-analysis based on 10 cohort and 7 case-control studies [107], the incidence rate of myocardial infarction decreased by 11% with an increase in tea consumption of 3 cups/day (Table 3). Very recently, the association of black or green tea with CAD has been extensively investigated in a meta-analysis of 13 studies [108]. While after pooling no significant associations were found for black tea, the 5 studies on green tea consumption showed and overall reduced risk of CAD accordingly to highest consumption (summary relative risk: 0.72; 95%CI: ) [108]. Dose response meta-analysis suggested that an increase in green tea consumption of 1 cup/d was associated with a 1% to 18% decrease in the risk of developing CAD [108]. All in all, these studies suggest that whereas the beneficial effects of black tea seem to be confined to heart disease, probably through mechanisms involving the increase in endothelial function and inhibition of platelet activation [12,109], catechins in green tea [105] seem to exert a more beneficial effect on CAD [108] Evidence from epidemiology: cerebrovascular disease A strong inverse association between green tea consumption and stroke mortality, along with a reduced mortality for all causes and cardiovascular disease was observed in the Ohsaki National Health Insurance Cohort Study (Table 3) [110]. Results from a pooled metaanalyses showed that tea drinking, without any confined effect to black or green tea, reduced mortality and morbidity of stroke [111]. Indeed, subjects drinking three or more cups of tea per day had a 21% reduced risk of fatal or non-fatal stroke events (Table 3) [111]. These findings are in line with those from the Alpha-Tocopherol, Beta- Carotene Cancer Prevention Study clearly showing that compared to non drinkers, men drinking 2 or more cups of tea per day had a 21% lower cerebral infarction risk (Table 3) [90]. On the contrary, in the Dutch EPIC cohort [87], the consumption of 3 to 6 cups of tea per day was not associated with a reduced risk of stroke (Table 3) [87] Tea and cardiovascular risk factors With regard to traditional CVD risk factors, a meta-analysis of randomized controlled trials showed that tea intake had no effects on BP, LDL or HDL cholesterol [12]. On the contrary, chronic consumption of black tea improved endothelial function (measured as flowmediated dilation) by 3.4%, whereas the acute effect was modest (1.7%) and not significant [12]. Finally, the intake of 1 L black tea per day reportedly inhibited platelet activation by 4 10% [109]. However, even if the magnitude of the observed associations between tea consumption and CVD is small, it appears to be important from a public health point of view, since tea is a very common beverage largely consumed all over the world. 5. Conclusions Prevention of cardiovascular disease is a crucial part of health care, the two main ways for preventing it being lifestyle changes and medication. In particular, lifestyle changes may have a major impact in preventing the incidence of atherosclerosis, arterial thrombosis and ischemic disease. Regular physical activity combined with a diet rich in fruit, vegetables, complex carbohydrates, monounsaturated fat and fish, moderate and regular alcohol consumption but poor in salt, saturated fat and simple sugars, plays an important role in the reduction of the development of atherosclerosis and other chronic degenerative disease [3 5]. However, chocolate, coffee and tea, unfairly not included in the above mentioned traditional healthy food basket, have received much attention over the past few years. They are consumed worldwide, are important dietary sources of polyphenols (flavonoids) and share antioxidant properties that link the three factors. Several in vitro and in vivo studies have tried to elucidate the role of these foods in development of cardiovascular disease, and despite the fact that a large amount of experimental studies clearly indicated a beneficial effect of polyphenols in regulating CAD risk profile, data from epidemiological studies are not conclusive. The blood pressure lowering effects and the anti-inflammatory activity of dark chocolate suggest its use as potential prophylactic and therapeutic agent, in particular considering that epidemiological studies suggest that dark chocolate is associated with a protection against CAD. However, even if bitter is better, due to its caloric content dark chocolate should be consumed in the context of a balanced and isocaloric diet, limiting its consumption to few squares (50 g) per week [29]. Although regular consumption of moderate quantities of coffee and (green) tea seems to be associated with a small protection against CAD, results from randomized clinical trials about their beneficial effects are less evident. A non linear dose response relationship between coffee intake and CVD risk may explain the heterogeneity in findings. More accurate investigations that consider the J-shaped relationship between coffee and CVD risk are desirable, and can better elucidate the issue. On the other hand, the American College of Cardiology Foundation Task Force suggests that a moderate consumption (1 2

8 Table 3 Summary of studies on tea and vascular events. Tea, Reference Study Exposure Endpoint N. cases/n. total Adjusted RR or OR (95% CI) Woodward M, 1999 [52] Scottish Heart Health Study, cohort study Peters U, 2001 [107] 10 cohort studies and 7 case-control studies, meta-analysis Geleijnse JM, 2002 [104] Andersen LF, 2006 [49] Kuriyama S, 2006 [110] Larsson LC, 2008 [89] The Rotterdam Study, population-based study Iowa Women's Health Study,, postmenopausal The Ohsaki National Health Insurance Cohort Study, population based prospective study Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, Summary Tea consumption CHD?/5724; Men 1.10 ( ) Tendency to increased risk CHD?/5843; Women 1.06 ( ) Tea consumption 3 cups/day vs none Stroke, MI and all CHD Stroke and CHD too heterogeneous MI 0.89 ( ) Incidence rate of MI decreased by 11% with an increase in tea consumption of 3 cups/day Tea drinkers N375 ml/day vs Fatal and nonfatal MI nontea drinkers Incident Mi 146/ ( ) Strong reduction of fatal MI according to high green tea consumption Nonfatal MI 116/ ( ) Fatal MI 30/ ( ) Tea N3 cups/day vs none Death due to CVD 1411/41, ( ) Tea no associations Tea N3 cups/day vs none Total mortality 4265/41, ( ) Green tea consumption 3 4 CVD, cancer and all causes cups/day mortality CVD mortality 481/40,530; Men 0.87 ( ) All cause mortality 2668/40,530; Men 0.88 ( ) Green tea consumption lowers all causes and CVD mortality CVD mortality 411/40,530; Women 0.61 ( ) All cause mortality 1541/40,530; Women 0.80 ( ) Tea consumption 8cups/day vs b2 cups/day Arab L, 2009 [111] Meta analysis Green or black tea consumption 3 cups/day Mostofsky E, 2010 [90] Stroke onset study, multicenter 1 h after 1 serving of caffeinated tea Stroke onset in subjects with case-crossover study de Koning Gans JM, Prospective study Tea consumptionn6 cups/day 2010 [87] Tea consumptionn6 cups/day Tea consumptionn6 cups/day Tea consumptionn6 cups/day Tea consumptionn6 cups/day Cerebral infarction 2702/26,556; Men 0.79 ( ) High tea consumption reduces Cerebral infarction risk Intracerebral hemorrhages 383/26,556; Men 1.10 ( ) Subarachnoid hemorrhages 196/26,556; Men 0.76 ( ) Fatal or nonfatal stroke 4378/194,965; pooled 0.79 ( ) 3 cups/day of green or black reduce fatal and nonfatal stroke 0.9 ( ) acute ischemic stroke CHD morbidity 1387/37, ( ) Tea consumption is linearly associated with lower CHD morbidity Stroke morbidity 563/37, ( ) CHD mortality ( ) 3 to 6 cups of tea/day reduce CHD risk mortality Stroke mortality ( ) No effect of tea on both stroke or all causes mortality All causes mortality ( ) 22 A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) 15 25

9 A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) cups/day) of tea is possibly useful for cardiovascular risk reduction [112]. However, as for other diffused consumption habits, such as those of alcohol [113,114], moderation is the key word. As a matter of fact, coffee, tea and chocolate, seem to exert their optimal favorable effects on cardiovascular risk profile with a regular and moderate consumption, while healthy outcomes vanish at heavy consumption. Conflict of interest statement All authors disclose any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence, their work. Learning points Daily intake of a anti-thrombotic diet may offer a suitable and effective way of coronary artery disease prevention. 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