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Consumption of cocoa, tea and coffee and risk of cardiovascular disease

  • Author Footnotes
    1 Both authors contributed equally to this work.
    Augusto Di Castelnuovo
    Correspondence
    Corresponding author. Tel.: +39 0874312585.
    Footnotes
    1 Both authors contributed equally to this work.
    Affiliations
    Laboratorio di Epidemiologia Genetica ed Ambientale, Laboratori di Ricerca, Fondazione di Ricerca e Cura “Giovanni Paolo II”, Campobasso, Italy
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  • Author Footnotes
    1 Both authors contributed equally to this work.
    Romina di Giuseppe
    Footnotes
    1 Both authors contributed equally to this work.
    Affiliations
    Laboratorio di Epidemiologia Genetica ed Ambientale, Laboratori di Ricerca, Fondazione di Ricerca e Cura “Giovanni Paolo II”, Campobasso, Italy

    Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
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  • Licia Iacoviello
    Affiliations
    Laboratorio di Epidemiologia Genetica ed Ambientale, Laboratori di Ricerca, Fondazione di Ricerca e Cura “Giovanni Paolo II”, Campobasso, Italy
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  • Giovanni de Gaetano
    Affiliations
    Laboratorio di Epidemiologia Genetica ed Ambientale, Laboratori di Ricerca, Fondazione di Ricerca e Cura “Giovanni Paolo II”, Campobasso, Italy
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  • Author Footnotes
    1 Both authors contributed equally to this work.
Published:August 31, 2011DOI:https://doi.org/10.1016/j.ejim.2011.07.014

      Abstract

      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.

      Keywords

      1. Introduction

      Coronary artery disease (CAD) is a leading cause of death worldwide, in men and women [
      • Murray C.J.L.
      • Lopez A.D.
      The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020.
      ]. Smoking, hypertension, hypercholesterolemia, diabetes, obesity, social deprivation, physical activity and dietary habits are recognised risk factors for CAD [
      • Yusuf S.
      • Hawken S.
      • Ounpuu S.
      • Dans T.
      • Avezum A.
      • Lanas F.
      • et al.
      Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
      ]. 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 [
      • Stampfer M.J.
      • Hu F.B.
      • Manson J.E.
      • Rimm E.B.
      • Willett W.C.
      Primary prevention of coronary heart disease in women through diet and lifestyle.
      ]. 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 [
      • de Lorgeril M.
      • Salen P.
      • Martin J.L.
      • Monjaud I.
      • Delaye J.
      • Mamelle N.
      Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study.
      ]. Therefore, most of the efforts for the prevention and treatment of CAD are focused on strategies which promote lifestyle and dietary modifications [
      • de Lorgeril M.
      • Salen P.
      • Martin J.L.
      • Monjaud I.
      • Delaye J.
      • Mamelle N.
      Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study.
      ].
      The traditional Mediterranean diet is characterized by high intake of foods rich in polyphenols and flavonoids [
      • Willett W.C.
      • Sacks F.
      • Trichopoulou A.
      • Drescher G.
      • Ferro-Luzzi A.
      • Helsing E.
      • et al.
      Mediterranean diet pyramid: a cultural model for healthy eating.
      ,
      • Keys A.
      • Menotti A.
      • Karvonen M.J.
      • Aravanis C.
      • Blackburn H.
      • Buzina R.
      • et al.
      The diet and 15-year death rate in the Seven Countries Study.
      ]. 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 [
      • Trichopoulou A.
      • Costacou T.
      • Bamia C.
      • Trichopoulos D.
      Adherence to a Mediterranean diet and survival in a Greek Population.
      ,
      • Sofi F.
      • Abbate R.
      • Gensini G.F.
      • Casini A.
      Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis.
      ]. Mechanisms of action of the Mediterranean diet relate to beneficial effects on lipids as well as antithrombotic, antiatherogenic and antioxidant effects [
      • Dai J.
      • Jones D.P.
      • Goldberg J.
      • Ziegler T.R.
      • Bostick R.M.
      • Wilson P.W.
      • et al.
      Association between adherence to the Mediterranean diet and oxidative stress.
      ,
      • Pitsavos C.
      • Panagiotakos D.B.
      • Tzima N.
      • Chrysohoou C.
      • Economou M.
      • Zampelas A.
      • et al.
      Adherence to the Mediterranean diet is associated with total antioxidant capacity in healthy adults: the ATTICA study.
      ]. 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 [
      • Huxley R.R.
      • Neil H.A.
      The relation between dietary flavonol intake and coronary heart disease mortality: a meta-analysis of prospective cohort studies.
      ,
      • Hooper L.
      • Kroon P.A.
      • Rimm E.B.
      • Cohn J.S.
      • Harvey I.
      • Le Cornu K.A.
      • et al.
      Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials.
      ].
      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 [
      • Huxley R.R.
      • Neil H.A.
      The relation between dietary flavonol intake and coronary heart disease mortality: a meta-analysis of prospective cohort studies.
      ,
      • Hooper L.
      • Kroon P.A.
      • Rimm E.B.
      • Cohn J.S.
      • Harvey I.
      • Le Cornu K.A.
      • et al.
      Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials.
      ,
      • Risner C.H.
      Simultaneous determination of theobromine, (+)-catechin, caffeine, and (−)-epicatechin in standard reference material baking chocolate 2384, cocoa, cocoa beans, and cocoa butter.
      ,
      • McShea A.
      • Ramiro-Puig E.
      • Munro S.B.
      • Casadesus G.
      • Castell M.
      • Smith M.A.
      Clinical benefit and preservation of flavonols in dark chocolate manufacturing.
      ] and methylxanthines [
      • Risner C.H.
      Simultaneous determination of theobromine, (+)-catechin, caffeine, and (−)-epicatechin in standard reference material baking chocolate 2384, cocoa, cocoa beans, and cocoa butter.
      ]. In particular, theobromine, the main methylxanthine in chocolate, is a myocardial stimulant, diuretic, coronary dilator, and smooth muscle relaxant[
      • Risner C.H.
      Simultaneous determination of theobromine, (+)-catechin, caffeine, and (−)-epicatechin in standard reference material baking chocolate 2384, cocoa, cocoa beans, and cocoa butter.
      ,
      • McShea A.
      • Ramiro-Puig E.
      • Munro S.B.
      • Casadesus G.
      • Castell M.
      • Smith M.A.
      Clinical benefit and preservation of flavonols in dark chocolate manufacturing.
      ]. 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. [
      • Lee K.W.
      • Kim Y.J.
      • Lee H.J.
      • Lee C.Y.
      Cocoa has more phenolic phytochemicals and a higher antioxidant capacity than teas and red wine.
      ] 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 [
      • Lee K.W.
      • Kim Y.J.
      • Lee H.J.
      • Lee C.Y.
      Cocoa has more phenolic phytochemicals and a higher antioxidant capacity than teas and red wine.
      ]. However, the biological effects of cocoa flavonoids vary from chocolate to chocolate, since they seem to be greater in dark rather than in milk chocolate [
      • Serafini M.
      • Bugianesi R.
      • Maiani G.
      • Valtuena S.
      • De Santis S.
      • Crozier A.
      Plasma antioxidants from chocolate – dark chocolate may offer its consumers health benefits the milk variety cannot match.
      ]. 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 [
      • Serafini M.
      • Bugianesi R.
      • Maiani G.
      • Valtuena S.
      • De Santis S.
      • Crozier A.
      Plasma antioxidants from chocolate – dark chocolate may offer its consumers health benefits the milk variety cannot match.
      ]. 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 [
      • Engler M.B.
      • Engler M.M.
      • Chen C.Y.
      • Malloy M.J.
      • Browne A.
      • Chiu E.Y.
      • et al.
      Flavonoid-rich dark chocolate improves endothelial function and increases plasma epicatechin concentrations in healthy adults.
      ]. In addition, Wang et al. [
      • Wang J.F.
      • Schramm D.D.
      • Holt R.R.
      • Ensunsa J.L.
      • Fraga C.G.
      • Schmitz H.H.
      • et al.
      A dose–response effect from chocolate consumption on plasma epicatechin and oxidative damage.
      ] further showed that subjects consuming procyanidin-rich chocolate had an increase in plasma antioxidant capacity [
      • Wang J.F.
      • Schramm D.D.
      • Holt R.R.
      • Ensunsa J.L.
      • Fraga C.G.
      • Schmitz H.H.
      • et al.
      A dose–response effect from chocolate consumption on plasma epicatechin and oxidative damage.
      ].
      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.

      2.1 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 [
      • Mao T.K.
      • Van de Water J.
      • Keen C.L.
      • Schmitz H.H.
      • Gershwin M.E.
      Effect of cocoa flavanols and their related oligomers on the secretion of interleukin-5 in peripheral blood mononuclear cells.
      ], tumor necrosis factor-alpha [
      • Kim J.E.
      • Son J.E.
      • Jung S.K.
      • Kang N.J.
      • Lee C.Y.
      • Lee K.W.
      • et al.
      Cocoa polyphenols suppress TNF-α-induced vascular endothelial growth factor expression by inhibiting phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase kinase-1 (MEK1) activities in mouse epidermal cells.
      ] and by influencing the endothelium-derived nitric oxide synthesis and metabolism [
      • Taubert D.
      • Roesen R.
      • Lehmann C.
      • Jung N.
      • Schömig E.
      Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide: a randomized controlled trial.
      ].
      In addition, cocoa flavonoids seem to mediate anti-inflammatory effects related to reductions in platelet and endothelial cell activation [
      • Hermann F.
      • Spieker L.E.
      • Ruschitzka F.
      • Sudano I.
      • Hermann M.
      • Binggeli C.
      • et al.
      Dark chocolate improves endothelial and platelet function.
      ].
      Cocoa consumption led to decreased platelet microparticle formation and inhibited ADP- and epinephrine-stimulated platelet activation [
      • Rein D.
      • Paglieroni T.G.
      • Wun T.
      • Pearson D.A.
      • Schmitz H.H.
      • Gosselin R.
      • et al.
      Cocoa inhibits platelet activation and function.
      ]. More recently, in an in vitro and ex vivo study, Heptinstall and colleagues [
      • Heptinstall S.
      • May J.
      • Fox S.
      • Kwik-Uribe C.
      • Zha L.
      Cocoa flavanols and platelet and leukocyte function: recent in vitro and ex vivo studies in healthy adults.
      ] 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) [
      • Schramm D.D.
      • Wang J.F.
      • Holt R.R.
      • Ensunsa J.L.
      • Gonsalves J.L.
      • Lazarus S.A.
      • et al.
      Chocolate procyanidins decrease the leukotriene-prostacyclin ratio in humans and human aortic endothelial cells.
      ,
      • Steinberg F.M.
      • Bearden M.M.
      • Keen C.L.
      Cocoa and chocolate flavonoids: implications for cardiovascular health.
      ]. 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 1999–2002 flavonoid-rich foods were inversely associated with serum C-reactive protein (CRP) concentrations [
      • Chun O.K.
      • Chung S.J.
      • Claycombe K.J.
      • Song W.O.
      Serum C-reactive protein concentrations are inversely associated with dietary flavonoid intake in US adults.
      ]. In a study conducted by Hamed et al. [
      • Hamed M.S.
      • Gambert S.
      • Bliden K.P.
      • Bailon O.
      • Singla A.
      • Antonino M.J.
      • et al.
      Dark chocolate effect on platelet activity, C-reactive protein and lipid profile: a pilot study.
      ] 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 [
      • di Giuseppe R.
      • Di Castelnuovo A.
      • Centritto F.
      • Zito F.
      • De Curtis A.
      • Costanzo S.
      • et al.
      Regular consumption of dark chocolate is associated with low serum concentrations of C-reactive protein in a healthy Italian population.
      ]. 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 [
      • di Giuseppe R.
      • Di Castelnuovo A.
      • Centritto F.
      • Zito F.
      • De Curtis A.
      • Costanzo S.
      • et al.
      Regular consumption of dark chocolate is associated with low serum concentrations of C-reactive protein in a healthy Italian population.
      ].

      2.2 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 [
      • Manach C.
      • Mazur A.
      • Scalbert A.
      Polyphenols and prevention of cardiovascular diseases.
      ]. In the Zutphen Elderly Study [
      • Buijsse B.
      • Feskens E.J.
      • Kok F.J.
      • Kromhout D.
      Cocoa intake, blood pressure, and cardiovascular mortality: the Zutphen Elderly Study.
      ] 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 [
      • Buijsse B.
      • Weikert C.
      • Drogan D.
      • Bergmann M.
      • Boeing H.
      Chocolate consumption in relation to blood pressure and risk of cardiovascular disease in German adults.
      ], 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) [
      • Buijsse B.
      • Weikert C.
      • Drogan D.
      • Bergmann M.
      • Boeing H.
      Chocolate consumption in relation to blood pressure and risk of cardiovascular disease in German adults.
      ].
      Table 1Summary of studies on chocolate/cocoa and vascular events.
      Chocolate, ReferenceStudyExposureEndpointN. cases/N. totalAdjusted RR or OR (95% CI)Summary
      Buijsse B, 2006
      • Buijsse B.
      • Feskens E.J.
      • Kok F.J.
      • Kromhout D.
      Cocoa intake, blood pressure, and cardiovascular mortality: the Zutphen Elderly Study.
      Zutphen Elderly Study, prospective studyCocoa intake, highest vs lowest tertileCardiovascular mortality152/4700.50 (0.32–0.78)In elderly men, inverse association between cocoa intake and cardiovascular and all-cause mortality
      Cocoa intake, highest vs lowest tertileAll cause mortality162/4700.52 (0.38–0.71)
      Gallus S, 2009
      • Gallus S.
      • Tavani A.
      • La Vecchia C.
      Response to chocolate, well-being, and health among elderly men: chocolate and acute myocardial infarction in a case-control study from Italy.
      Italy, case-control study3 chocolates/day vs <2 chocolates/dayAMI760/14420.23 (0.08–0.65)Eating ≥3 chocolates/day is inversely associated with nonfatal AMI
      Janszky I, 2009
      • Janszky I.
      • Mukamal K.J.
      • Ljung R.
      • Ahnve S.
      • Ahlbom A.
      • Hallqvist J.
      Chocolate consumption and mortality following a first acute myocardial infarction: the Stockholm Heart Epidemiology Program.
      Stockholm Heart Epidemiology Program, population-based inception cohort studyChocolate consumption, 50 g; ≥2/week vs no consumptionCardiac mortality, diabetes free post AMI107/11690.34 (0.17–0.70)
      Total mortality, diabetes-free post AMI210/11690.94 (0.58–1.53)
      Recurrent AMI, diabetes-free post AMI250/11690.86 (0.54–1.37)
      Congestive heart failure, diabetes-free post AMI279/11690.78 (0.52–1.16)Inverse association with cardiac mortality in post-AMI patients
      Stroke, diabetes-free post AMI111/11690.62 (0.33–1.16)
      Any non-fatal event, diabetes-free post AMI471/11690.82 (0.59–1.14)
      Buijsse B, 2010
      • Buijsse B.
      • Weikert C.
      • Drogan D.
      • Bergmann M.
      • Boeing H.
      Chocolate consumption in relation to blood pressure and risk of cardiovascular disease in German adults.
      EPIC-Potsdam Study, prospective studyChocolate intake, highest vs lowest quartileMyocardial infarction166/19,3570.73 (0.47–1.15)Reduced CVD risk according to chocolate consumption partly due to its BP-lowering effect
      Chocolate intake, highest vs lowest quartileStroke136/19,3570.52 (0.30–0.89)
      Interestingly, Grassi et al. [
      • Grassi D.
      • Desideri G.
      • Necozione S.
      • Lippi C.
      • Casale R.
      • Properzi G.
      • et al.
      Blood pressure is reduced and insulin sensitivity increased in glucose-intolerant, hypertensive subjects after 15 days of consuming high-polyphenol dark chocolate.
      ] 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 [
      • Grassi D.
      • Desideri G.
      • Necozione S.
      • Lippi C.
      • Casale R.
      • Properzi G.
      • et al.
      Blood pressure is reduced and insulin sensitivity increased in glucose-intolerant, hypertensive subjects after 15 days of consuming high-polyphenol dark chocolate.
      ].
      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 [
      • Ried K.
      • Sullivan T.
      • Fakler P.
      • Frank O.R.
      • Stocks N.P.
      Does chocolate reduce blood pressure? A meta-analysis.
      ].
      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 [
      • Hooper L.
      • Kroon P.A.
      • Rimm E.B.
      • Cohn J.S.
      • Harvey I.
      • Le Cornu K.A.
      • et al.
      Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials.
      ].
      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 [
      • Hooper L.
      • Kroon P.A.
      • Rimm E.B.
      • Cohn J.S.
      • Harvey I.
      • Le Cornu K.A.
      • et al.
      Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials.
      ].

      2.3 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 [
      • Rimbach G.
      • Melchin M.
      • Moehring J.
      • Wagner A.E.
      Polyphenols from cocoa and vascular health — a critical review.
      ,
      • Corti R.
      • Flammer A.J.
      • Hollenberg N.K.
      • Lüscher T.F.
      Cocoa and cardiovascular health.
      ,
      • Hollman P.C.H.
      • Geelen A.
      • Kromhout D.
      Dietary flavonol intake may lower stroke risk in men and women.
      ]. The prospective studies of flavonoids and risk of CAD published up to 2006 are reviewed in Ding et al. [
      • Ding E.L.
      • Hutfless S.M.
      • Ding X.
      • Girotra S.
      Chocolate and prevention of cardiovascular disease: a systematic review.
      ]. 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: 0.71–0.92, 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 [
      • Buijsse B.
      • Feskens E.J.
      • Kok F.J.
      • Kromhout D.
      Cocoa intake, blood pressure, and cardiovascular mortality: the Zutphen Elderly Study.
      ] and in an Italian case-control study (Table 1) [
      • Gallus S.
      • Tavani A.
      • La Vecchia C.
      Response to chocolate, well-being, and health among elderly men: chocolate and acute myocardial infarction in a case-control study from Italy.
      ]. 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) [
      • Buijsse B.
      • Weikert C.
      • Drogan D.
      • Bergmann M.
      • Boeing H.
      Chocolate consumption in relation to blood pressure and risk of cardiovascular disease in German adults.
      ]. 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) [
      • Janszky I.
      • Mukamal K.J.
      • Ljung R.
      • Ahnve S.
      • Ahlbom A.
      • Hallqvist J.
      Chocolate consumption and mortality following a first acute myocardial infarction: the Stockholm Heart Epidemiology Program.
      ]. 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 [
      • Corti R.
      • Flammer A.J.
      • Hollenberg N.K.
      • Lüscher T.F.
      Cocoa and cardiovascular health.
      ,
      • Mink P.J.
      • Scrafford C.G.
      • Barraj L.M.
      • Harnack L.
      • Hong C.-P.
      • Nettleton J.A.
      • et al.
      Flavonoid intake and cardiovascular disease mortality: a prospective study.
      ]. However, after multivariable adjustment the highly significant association found in the age and energy adjusted model (p<0.001) became borderline (p=0.062) [
      • Mink P.J.
      • Scrafford C.G.
      • Barraj L.M.
      • Harnack L.
      • Hong C.-P.
      • Nettleton J.A.
      • et al.
      Flavonoid intake and cardiovascular disease mortality: a prospective study.
      ].

      3. Coffee

      Albeit coffee represents, along with tea, the most worldwide consumed beverage, its potential effect on cardiovascular disease is still controversial (Table 2) [
      • Myers M.G.
      • Basinski A.
      Coffee and coronary heart disease.
      ,
      • Lopez-Garcia E.
      • van Dam R.M.
      • Willett W.C.
      • Rimm E.B.
      • Manson J.E.
      • Stampfer M.J.
      • et al.
      Coffee consumption and coronary heart disease in men and women: a prospective cohort study.
      ,
      • Kawachi I.
      • Colditz G.A.
      • Stone C.B.
      Does coffee drinking increase risk of coronary heart disease? Results from a meta-analysis.
      ,
      • Greenland S.
      A meta-analysis of coffee, myocardial infarction, and coronary death.
      ,
      • Reis J.P.
      • Loria C.M.
      • Steffen L.M.
      • Zhou X.
      • van Horn L.
      • Siscovick D.S.
      • et al.
      Decaffeinated coffee, caffeine, and tea consumption in young adulthood and atherosclerosis later in life: the CARDIA study.
      ,
      • Cornelis M.C.
      • El-Sohemy A.
      • Kabagambe E.K.
      • Campos H.
      Coffee, CYP1A2 genotype, and risk of myocardial infarction.
      ,
      • Happonen P.
      • Voutilainen S.
      • Salonen J.T.
      Coffee drinking is dose-dependently related to the risk of acute coronary events in middle-aged men.
      ,
      • Andersen L.F.
      • Jacobs D.R.J.
      • Carlsen M.H.
      • Blomhoff R.
      Consumption of coffee is associated with reduced risk of death attributed to inflammatory and cardiovascular diseases in the Iowa Women's Health Study.
      ,
      • Azevedo A.
      • Barros H.
      Coffee and myocardial infarction: heterogeneity of an association in Portuguese men.
      ,
      • Panagiotakos D.B.
      • Pitsavos C.
      • Chrysohoou C.
      • Kokkinos P.
      • Toutouzas P.
      • Stefanadis C.
      The J-shaped effect of coffee consumption on the risk of developing acute coronary syndromes: the CARDIO2000 case-control study.
      ,
      • Woodward M.
      • Tunstall-Pedoe H.
      Coffee and tea consumption in the Scottish Heart Health Study follow up: conflicting relations with coronary risk factors, coronary disease, and all cause mortality.
      ,
      • Kleemola P.
      • Jousilahti P.
      • Pietinen P.
      • Vartiainen E.
      • Tuomilehto J.
      Coffee consumption and the risk of coronary heart disease and death.
      ]. Apart from being the main source of caffeine, coffee contains several other compounds – in particular phenols, vitamin B3, magnesium, potassium and fiber [
      • Spiller M.A.
      The chemical components of coffee.
      ] – that may have either beneficial or detrimental effects on cardiovascular system. Cafestol and kahweol are both diterpenoid hypercholesterolemic compounds present in coffee beans [
      • Urgert R.
      • Katan M.B.
      The cholesterol-raising factor from coffee beans.
      ]; however, the use of a paper filter during coffee preparation is sufficient to limit their content [
      • van Dusseldorp M.
      • Katan M.B.
      • van Vliet T.
      • Demacker P.N.
      • Stalenhoef A.F.
      Cholesterol-raising factor from boiled coffee does not pass a paper filter.
      ]. Nevertheless, many other compounds with antioxidant properties [
      • Yanagimoto K.
      • Ochi H.
      • Lee K.G.
      • Shibamoto T.
      Antioxidative activities of fractions obtained from brewed coffee.
      ,
      • Daglia M.
      • Papetti A.
      • Gregotti C.
      • Bertè F.
      • Gazzani G.
      In vitro antioxidant and ex vivo protective activities of green and roasted coffee.
      ] namely chlorogenic acid, flavonoids, melanoidins, furans, pyrroles and maltol have been found in coffee [
      • Cornelis M.C.
      • El-Sohemy A.
      Coffee, caffeine, and coronary heart disease.
      ]. Definitely, because of its extensive use, coffee represents one of the major contributors to the total antioxidant capacity of the diet [
      • Svilaas A.
      • Sakhi A.K.
      • Andersen L.F.
      • Svilaas T.
      • Ström E.C.
      • Jacobs Jr., D.R.
      • et al.
      Intakes of antioxidants in coffee, wine, and vegetables are correlated with plasma carotenoids in humans.
      ,
      • Pulido R.
      • Hernandez-Garcia M.
      • Saura-Calixto F.
      Contribution of beverages to the intake of lipophillic and hydrophillic antioxidants in the Spanish diet.
      ].
      Table 2Summary of studies on coffee and vascular events.
      Coffee, ReferenceStudyExposureEndpointN. cases/N. totalAdjusted RR or OR (95% CI)Summary
      Grobbee DE, 1990
      • Grobbee D.E.
      • Rimm E.B.
      • Giovannucci E.
      • Colditz G.
      • Stampfer M.
      • Willett W.
      Coffee, caffeine, and cardiovascular disease in men.
      The Health Professional Follow-up Study, longitudinal studyTotal Coffee consumption ≥4 cups/day vs noneNonfatal MI, CHD death, CABG, PTCA, StrokeBoth caffeine and caffeinated coffee intake do not increase CHD and stroke risk
      Nonfatal MI and CHD death221/45,589; Men1.08 (0.72–1.60)
      CABG and PTCA136/45,589; Men0.95 (0.56–1.61)
      Total CHD357/45,589; Men1.00 (0.73–1.37)
      Fatal and nonfatal stroke54/45,589; Men0.48 (0.18–1.31)
      Total CVD408/45,589; Men0.90 (0.67–1.22)
      Caffeinated coffee consumption ≥4 cups/day vs noneNonfatal MI and CHD death221/45,589; Men1.01 (0.62–1.65)
      CABG and PTCA131/45,589; Men0.66 (0.32–1.34)
      Total CHD342/45,589; Men0.84 (0.56–1.25)
      Fatal and nonfatal stroke52/45,589; Men0.28 (0.06–1.26)
      Total CVD390/45,589; Men0.74 (0.50–1.09)
      Decaffeinated coffee consumption ≥4 cups/day vs noneNonfatal MI and CHD death214/45,589; Men1.55 (0.85–2.81)Decaffeinated coffee moderately increases CHD risk
      CABG and PTCA132/45,589; Men1.74 (0.81–3.73)
      Total CHD346/45,589; Men1.63 (1.02–2.60)
      Fatal and nonfatal stroke51/45,589; Men1.16 (0.26–5.10)
      Total CVD394/45,589; Men1.58 (1.01–2.48)
      Myers MG, 1992
      • Myers M.G.
      • Basinski A.
      Coffee and coronary heart disease.
      11 Prospective Studies (cohorts without history of MI), meta-analysisCoffee intake, ≥6 cups/day vs ≤1 cup/dayCoronary events1.09 (0.97–1.22)No association between coffee consumption and CHD
      Later Cohort1.27 (1.17–1.39)
      Earlier Cohort0.92 (0.80–1.06)
      Pooled cohort1.18 (1.03–1.34)
      Kawachi I, 1994
      • Kawachi I.
      • Colditz G.A.
      • Stone C.B.
      Does coffee drinking increase risk of coronary heart disease? Results from a meta-analysis.
      8 case-control and 15 cohort studies, meta-analysisCoffee drinking, ≥5 cups/day vs noneCHDPooled case-control1.63 (1.50–1.78)Increased CHD risk according to increased coffee drinking
      Pooled cohort1.05 (0.99–1.12)Weak CHD risk in habitual coffee drinkers
      Woodward M, 1999
      • Woodward M.
      • Tunstall-Pedoe H.
      Coffee and tea consumption in the Scottish Heart Health Study follow up: conflicting relations with coronary risk factors, coronary disease, and all cause mortality.
      Scottish Heart Health Study, cohort studyCoffee consumption ≥5 vs noneCHD?/5645; Men0.68 (0.37–1.24)Moderate benefit from coffee consumption
      CHD?/5800; Women0.55 (0.18–1.66)
      Hammar N, 2003
      • Hammar N.
      • Andersson T.
      • Alfredsson L.
      • Reuterwall C.
      • Nilsson T.
      • Hallqvist J.
      • et al.
      Association of boiled and filtered coffee with incidence of first nonfatal myocardial infarction: the SHEEP and the VHEEP study.
      The SHEEP and the VHEEP Study, population-based case-control studyConsumption >9 dL filtered coffee/day vs ≤3 dL/dayFirst nonfatal MI1171/1813; Men1.93 (1.42–2.63)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 >9 dL mixed coffee/day vs ≤3 dL/day2.24 (1.08–4.64)
      Consumption >9 dL boiled coffee/day vs ≤3 dL/day2.20 (1.17–4.15)
      Consumption >9 dL filtered coffee/day vs ≤3 dL/dayFirst nonfatal MI472/854; Women1.43 (0.81–2.54)
      Consumption >9 dL mixed coffee/day vs ≤3 dL/day2.91 (0.28–29.69)
      Consumption >9 dL boiled coffee/day vs ≤3 dL/day4.97 (0.55–44.73)
      Boiled vs filtered coffee1171/1813; Men1.41 (1.07–1.85)Boiled coffee increases the occurrence of first nonfatal MI
      Boiled vs filtered coffee472/854; Women1.63 (1.04–2.56)
      Panagiotakos DB, 2003
      • Panagiotakos D.B.
      • Pitsavos C.
      • Chrysohoou C.
      • Kokkinos P.
      • Toutouzas P.
      • Stefanadis C.
      The J-shaped effect of coffee consumption on the risk of developing acute coronary syndromes: the CARDIO2000 case-control study.
      The CARDIO2000, case-control studyVery heavy coffee drinkers (>600 mL/day) vs noneACS848/10783.10 (1.82–5.26)J-shaped relation between coffee intake and ACS risk
      Happonen P, 2004
      • Happonen P.
      • Voutilainen S.
      • Salonen J.T.
      Coffee drinking is dose-dependently related to the risk of acute coronary events in middle-aged men.
      The Kuopio Ischaemic Heart Disease Risk Factor Study, prospective studyModerate drinkers vs heavy drinkers (≥814 mL/day)Acute coronary events (MI or coronary death)269/1971; Men1.43 (1.06–1.94)Heavy coffee drinking raises the risk of acute MI or coronary death
      Mukamal KJ, 2004
      • Mukamal K.J.
      • Maclure M.
      • Muller J.E.
      • Sherwood J.B.
      • Mittleman M.A.
      Caffeinated coffee consumption and mortality after acute myocardial infarction.
      Determinants of Myocardial Infarction Onset Study, inception cohort studyCoffee consumption >14 cups/week vs noneMortality after AMI315/19021.13 (80–1.60)No association between coffee consumption and post-infarction mortality
      Coffee consumption >14 cups/week vs noneDeaths within 90 days79/19020.38 (0.17–0.86)
      Coffee consumption >14 cups/week vs noneDeaths beyond 90 days236/19021.52 (1.03–2.26)Time variation in coffee effect
      Andersen LF, 2006
      • Andersen L.F.
      • Jacobs D.R.J.
      • Carlsen M.H.
      • Blomhoff R.
      Consumption of coffee is associated with reduced risk of death attributed to inflammatory and cardiovascular diseases in the Iowa Women's Health Study.
      Iowa Women's Health Study, prospective studyRegular coffee ≥6 cups/day vs noneDeath due to CVD, postmenopausal1411/41,8360.92 (0.74–1.14)
      Decaffeinated coffee ≥6 cups/day vs noneDeath due to CVD, postmenopausal1411/41,8360.99 (0.70–1.39)U-shaped associations (death from CVD and total mortality)
      Regular coffee ≥6 cups/day vs noneTotal mortality, postmenopausal4265/41,8360.95 (0.84–1.07)
      Decaffeinated coffee ≥6 cups/day vs noneTotal mortality, postmenopausal4265/41,8360.94 (0.78–1.14)
      Lopez-Garcia E, 2006
      • Lopez-Garcia E.
      • van Dam R.M.
      • Willett W.C.
      • Rimm E.B.
      • Manson J.E.
      • Stampfer M.J.
      • et al.
      Coffee consumption and coronary heart disease in men and women: a prospective cohort study.
      Prospective cohort studyCoffee intake, ≥6 cups/day vs <1 cup/monthCHD
      CHD2173/44,005; Men0.72 (0.49–1.07)
      2254/84,488; Women0.87 (0.68–1.11)No indication that coffee (or caffeine) intake increases CHD
      Caffeine intake, ≥6 cups/day vs <1 cup/monthCHD2173/44,005; Men0.97 (0.84–1.11)
      CHD2254/84,488; Women0.97 (0.85–1.11)
      Azevedo A, 2006
      • Azevedo A.
      • Barros H.
      Coffee and myocardial infarction: heterogeneity of an association in Portuguese men.
      Community-based case-control studyRegular ever coffee drinkersAMI290/364; Men0.5 (0.3–1.1)Significant↓MI in men with no family history of AMI; non significant ↑ MI in men withfamily history of AMI
      Kleemola P, 2006
      • Kleemola P.
      • Jousilahti P.
      • Pietinen P.
      • Vartiainen E.
      • Tuomilehto J.
      Coffee consumption and the risk of coronary heart disease and death.
      Finnish men and women, prospective studyCoffee consumption >7 cups/day vs 1–3 cups/dayNon fatal MI891/10,075; Men0.79 (0.64–0.98)
      Coffee consumption >7 cups/day vs 1–3 cups/dayCHD mortality891/10,075; Men1.22 (0.90–1.65)
      Coffee consumption >7 cups/day vs 1–3 cups/dayAll cause mortality1201/10,075; Men1.01 (0.84–1.22)Coffee drinking is not associated with CHD risk and death
      Coffee consumption >7 cups/day vs 1–3 cups/dayNon fatal MI319/10,3870.93 (0.63–1.36)
      Coffee consumption >7 cups/day vs 1–3 cups/dayCHD mortality99/10,3870.57 (0.28–1.16)
      Coffee consumption >7 cups/day vs 1–3 cups/dayAll cause mortality444/10,3870.62 (0.44–0.87)
      Baylin A, 2006
      • Baylin A.
      • Hernandez-Diaz S.
      • Kabagambe E.K.
      • Siles X.
      • Campos H.
      Transient exposure to coffee as a trigger of a first nonfatal myocardial infarction.
      Costa Rica, case-crossover designHabitual coffee consumptionNonfatal MI, 1 h after coffee drinking
      1 cup/day9/664.14 (2.03–8.42)Coffee intake probably set off MI
      2–3 cups/day44/2801.60 (1.16–2.21)
      4 cups/day27/1201.06 (0.69–1.63)
      Cornelis MC, 2006
      • Cornelis M.C.
      • El-Sohemy A.
      • Kabagambe E.K.
      • Campos H.
      Coffee, CYP1A2 genotype, and risk of myocardial infarction.
      Slow caffeine metabolizerCoffe intake ≥4 cups/day vs <1 cup/dayFirst acute nonfatal MI2014/20141.64 (1.14–2.34)Increased MI risk only in subjects with impaired caffeine metabolism
      Rapid caffeine metabolizer population-based case-control studyCoffe intake ≥4 cups/day vs <1 cup/dayFirst acute nonfatal MI2014/20140.99 (0.66–1.48)
      Silletta MG, 2007
      • Silletta M.G.
      • Marfisi R.
      • Levantesi G.
      • Boccanelli A.
      • Chieffo C.
      • Franzosi M.
      • et al.
      Coffee consumption and risk of cardiovascular events after acute myocardial infarction: results from the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico)-Prevenzione trial.
      GISSI-Prevenzione trial, prospective studyCoffee consumption >4 cups/day vs noneCVD events (CV death, nonfatal MI, nonfatal stroke in post-MI patients1167/11,2130.88 (0.64–1.20)Moderate coffee intake is not associated with CV events post-MI
      Larsson LC, 2008
      • Larsson S.C.
      • Männistö S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Coffee and tea consumption and risk of stroke subtypes in male smokers.
      Alpha-Tocopherol, Beta-CaroteneCoffee consumption ≥8 cups/day vs <2 cups/dayStroke subtypes
      Cancer Prevention Study, prospective studyCerebral infarction2702/26,556; Men0.77 (0.66–0.90)High coffee consumption lowers cerebral infarction risk
      Intracerebral hemorrhages383/26,556; Men0.98 (0.66–1.47)
      Subarachnoid hemorrhages196/26,556; Men1.18 (0.63–2.20)
      Lopez-Garcia E, 2008
      • Lopez-Garcia E.
      • van Dam R.M.
      • Li T.Y.
      • Rodriguez-Artalejo F.
      • Hu F.B.
      The relationship of coffee consumption with mortality.
      Health Professionals Follow-up Study and Nurses' Health Study, prospective cohort studyCoffee consumption ≥6 cups/day vs <1 cup/monthCVD mortality2049/41,736; Men0.56 (0.31–1.03)
      Coffee consumption ≥6 cups/day vs <1 cup/monthCVD mortality2368/86,214; Women0.81 (0.61–1.06)
      Coffee consumption ≥6 cups/day vs <1 cup/monthCancer mortality2491/41,736; Men1.14 (0.79–1.65)
      Coffee consumption ≥6 cups/day vs <1 cup/monthCancer mortality5011/86,214; Women1.05 (0.87–1.28)
      Coffee consumption ≥6 cups/day vs <1 cup/monthOther causes2348/41,736; Men0.65 (0.11–1.04)
      Coffee consumption ≥6 cups/day vs <1 cup/monthOther causes3716/86,214; Women0.60 (0.46–0.77)
      In both men and women the reduced CVD deaths mainly explains the modest inverse association between coffee consumption and all cause mortality
      Coffee consumption ≥6 cups/day vs <1cup/monthAll causes6888/41,736; Men0.80 (0.62–1.04)
      Coffee consumption ≥6 cups/day vs <1cup/monthAll causes11,095/86,214; Women0.83 (0.73–0.95)
      Decaffeinated coffee consumption ≥4 cups/day vs <1cup/monthCVD mortality2049/41,736; Men0.83 (0.52–1.31)
      Decaffeinated coffee consumption ≥4 cups/day vs <1cup/monthCVD mortality2368/86,214; Women0.55 (0.30–1.04)
      Decaffeinated coffee consumption ≥4 cups/day vs <1cup/monthCancer mortality2491/41,736; Men1.20 (0.87–1.66)
      Decaffeinated coffee consumption ≥4 cups/day vs <1cup/monthCancer mortality5011/86,214; Women0.86 (0.60–1.23)
      Decaffeinated coffee consumption ≥4 cups/day vs <1cup/monthAll causes6888/41,736; Men0.81 (0.64–1.03)
      Decaffeinated coffee consumption ≥4 cups/day vs <1cup/monthAll causes11,095/86,214; Women0.78 (0.61–1.00)
      Wu JN, 2009
      • Wu J.N.
      • Ho S.C.
      • Zhou C.
      • Ling W.H.
      • Chen W.Q.
      • Wang C.L.
      • et al.
      Coffee consumption and risk of coronary heart diseases: a meta-analysis of 21 prospective cohort studies.
      21 prospective cohort studies, meta-analysisCoffee consumption <1 cup/day (US) or ≤2 cups/day(Europe) vs ≥6 or ≥7 cups/dayCHD15,599/407,806; pooled1.07 (0.87–1.32)No long-term increased CHD risk
      Moderate coffee consumptionCHDWomen0.82 (0.73–0.92)Lower CHD risk in moderate coffee drinker women
      de Koning Gans JM, 2010
      • de Koning Gans J.M.
      • Uiterwaal C.S.
      • van der Schouw Y.T.
      • Boer J.M.
      • Grobbee D.E.
      • Verschuren W.M.
      • et al.
      Tea and coffee consumption and cardiovascular morbidity and mortality.
      Prospective studyCoffee consumption>6 cups/day vs <1 cup/dayCHD morbidity1387/37,5140.91 (0.74–1.11)U shaped association between coffee consumption and lower CHD morbidity
      Coffee consumption>6 cups/day vs <1 cup/dayStroke morbidity563/37,5141.22 (0.88–1.70)
      Coffee consumption>6 cups/day vs <1 cup/dayCHD mortality1230.73 (0.37–1.42)Non significant slight reduction in CHD mortality according to moderate coffee consumption
      Coffee consumption>6 cups/day vs <1 cup/dayStroke mortality701.34 (0.49–3.64)
      Coffee consumption>6 cups/day vs <1 cup/dayAll causes mortality14050.93 (0.76–1.15)No effect of coffee on stroke or all causes mortality
      Mostofsky E, 2010
      • Mostofsky E.
      • Schlaug G.
      • Mukamal K.J.
      • Rosamond W.D.
      • Mittleman M.A.
      Coffee and acute ischemic stroke onset: the Stroke Onset Study.
      Stroke onset study, multicenter case-crossover studyCoffee drinkers vs non drinkersStroke onset in subjects with acute ischemic stroke
      1 h after 1 serving of coffee35/3902.0 (1.4–2.8)Infrequent coffee drinkers have increased ischemic stroke risk onset
      1 h after 1 serving of caffeinated coffee in subjects drinking ≤1 cup/day↑RR (values not available)

      3.1 Coffe and cardiovascular risk factors: negative aspects

      As extensively reviewed by Cornelis et al. [
      • Cornelis M.C.
      • El-Sohemy A.
      Coffee, caffeine, and coronary heart disease.
      ], and Riksen et al. [
      • Riksen N.P.
      • Rongen G.A.
      • Smits P.
      Acute and long-term cardiovascular effects of coffee: implications for coronary heart disease.
      ], caffeine is involved in the link between coffee and CAD. Intake of caffeine is associated with an increase in blood pressure [
      • Nurminen M.L.
      • Niittynen L.
      • Korpela R.
      • Vapaatalo H.
      Coffee, caffeine and blood pressure: a critical review.
      ,
      • Noordzij M.
      • Uiterwaal C.S.
      • Arends L.R.
      • Kok F.J.
      • Grobbee D.E.
      • Geleijnse J.M.
      Blood pressure response to chronic intake of coffee and caffeine: a meta-analysis of randomized controlled trials.
      ], systemic vascular resistance [
      • Farag N.H.
      • Vincent A.S.
      • McKe B.S.
      • Whitsett T.L.
      • Lovallo W.R.
      Hemodynamic mechanisms underlying the incomplete tolerance to caffeine's pressor effects.
      ], arterial stiffness [
      • Smits P.
      • Thien T.
      • van 't Laar A.
      Circulatory effects of coffee in relation to the pharmacokinetics of caffeine.
      ,
      • Karatzis E.
      • Papaioannou T.G.
      • Aznaouridis K.
      • Karatzi K.
      • Stamatelopoulos K.
      • Zampelas A.
      • et al.
      Acute effects of caffeine on blood pressure and wave reflections in healthy subjects: should we consider monitoring central blood pressure?.
      ], plasma renin activity, epinephrine, and norepinephrine [
      • Robertson D.
      • Frölich J.C.
      • Carr R.K.
      • Watson J.T.
      • Hollifield J.W.
      • Shand D.G.
      • et al.
      Effects of caffeine on plasma renin activity, catecholamines and blood pressure.
      ] and has unfavorable effects on endothelial function in healthy subjects [
      • Papamichael C.M.
      • Aznaouridis K.A.
      • Karatzis E.N.
      • Karatzi K.N.
      • Stamatelopoulos K.S.
      • Vamvakou G.
      • et al.
      Effect of coffee on endothelial function in healthy subjects. The role of caffeine.
      ]. Moreover, in a randomized double-blinded study Riksen et al. [
      • Riksen N.P.
      • Rongen G.A.
      • Smits P.
      Acute and long-term cardiovascular effects of coffee: implications for coronary heart disease.
      ] 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 [
      • Jee S.H.
      • He J.
      • Appe L.J.
      • Whelton P.K.
      • Suh I.
      • Klag M.J.
      Coffee consumption and serum lipids: a meta-analysis of randomized controlled clinical trials.
      ,
      • Rodrigues I.M.
      • Klein L.C.
      Boiled or filtered coffee? Effects of coffee and caffeine on cholesterol, fibrinogen and C-reactive protein.
      ] and homocysteine levels [
      • Verhoef P.
      • Pasman W.J.
      • van Vliet T.
      • Urgert R.
      • Katan M.B.
      Contribution of caffeine to the homocysteine-raising effect of coffee: a randomized controlled trial in humans.
      ].

      3.2 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 [
      • van Dam R.M.
      • Hu F.B.
      Coffee consumption and risk of type 2 diabetes: a systematic review.
      ,
      • Ciccarone E.
      • Di Castelnuovo A.
      • Salcuni M.
      • Siani A.
      • Giacco A.
      • Donati M.B.
      • et al.
      Gendiabe Investigators. A high-score Mediterranean dietary pattern is associated with a reduced risk of peripheral arterial disease in Italian patients with Type 2 diabetes.
      ,
      • Loopstra-Masters R.C.
      • Liese A.D.
      • Haffner S.M.
      • Wagenknecht L.E.
      • Hanley A.J.
      Associations between the intake of caffeinated and decaffeinated coffee and measures of insulin sensitivity and beta cell function.
      ] and by the lack of association with incident hypertension in women [
      • Winkelmayer W.C.
      • Stampfer M.
      • Willett W.C.
      • Curhan G.C.
      Habitual caffeine intake and the risk of hypertension in women.
      ]. An important contribution to the explanation of the role of coffee on CAD emerges from the very recent study of Shechter et al. [
      • Shechter M.
      • Shalmon G.
      • Scheinowitz M.
      • Koren-Morag N.
      • Feinberg M.S.
      • Harats D.
      • et al.
      Impact of acute caffeine ingestion on endothelial function in subjects with and without coronary artery disease.
      ]. 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 [
      • Shechter M.
      • Shalmon G.
      • Scheinowitz M.
      • Koren-Morag N.
      • Feinberg M.S.
      • Harats D.
      • et al.
      Impact of acute caffeine ingestion on endothelial function in subjects with and without coronary artery disease.
      ].
      Moreover, caffeine consumption has been shown to inhibit platelet aggregation, possibly by upregulation of adenosine A2A receptors [
      • Nardini M.
      • Natella F.
      • Scaccini C.
      Role of dietary polyphenols in platelet aggregation. A review of the supplementation studies.
      ].

      3.3 Evidence from epidemiology

      Early [
      • Myers M.G.
      • Basinski A.
      Coffee and coronary heart disease.
      ,
      • Kawachi I.
      • Colditz G.A.
      • Stone C.B.
      Does coffee drinking increase risk of coronary heart disease? Results from a meta-analysis.
      ,
      • Greenland S.
      A meta-analysis of coffee, myocardial infarction, and coronary death.
      ] and more recent meta-analyses [
      • Sofi F.
      • Conti A.A.
      • Gori A.M.
      • Eliana Luisi M.L.
      • Casini A.
      • Abbate R.
      • et al.
      Coffee consumption and risk of coronary heart disease: a meta-analysis.
      ,
      • Wu J.N.
      • Ho S.C.
      • Zhou C.
      • Ling W.H.
      • Chen W.Q.
      • Wang C.L.
      • et al.
      Coffee consumption and risk of coronary heart diseases: a meta-analysis of 21 prospective cohort studies.
      ] 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. [
      • Wu J.N.
      • Ho S.C.
      • Zhou C.
      • Ling W.H.
      • Chen W.Q.
      • Wang C.L.
      • et al.
      Coffee consumption and risk of coronary heart diseases: a meta-analysis of 21 prospective cohort studies.
      ] 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: 0.80–0.86 in men and 0.82; 95%CI: 0.73–0.92 in women, Table 2). In a recent prospective cohort study [
      • Lopez-Garcia E.
      • van Dam R.M.
      • Li T.Y.
      • Rodriguez-Artalejo F.
      • Hu F.B.
      The relationship of coffee consumption with mortality.
      ], 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) [
      • Lopez-Garcia E.
      • van Dam R.M.
      • Li T.Y.
      • Rodriguez-Artalejo F.
      • Hu F.B.
      The relationship of coffee consumption with mortality.
      ].
      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 [
      • Rodrigues I.M.
      • Klein L.C.
      Boiled or filtered coffee? Effects of coffee and caffeine on cholesterol, fibrinogen and C-reactive protein.
      ]. In agreement with these findings, in a Swedish case-control study [
      • Hammar N.
      • Andersson T.
      • Alfredsson L.
      • Reuterwall C.
      • Nilsson T.
      • Hallqvist J.
      • et al.
      Association of boiled and filtered coffee with incidence of first nonfatal myocardial infarction: the SHEEP and the VHEEP study.
      ], 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: 1.04–2.56, Table 2).
      However, Baylin et al. [
      • Baylin A.
      • Hernandez-Diaz S.
      • Kabagambe E.K.
      • Siles X.
      • Campos H.
      Transient exposure to coffee as a trigger of a first nonfatal myocardial infarction.
      ] 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 [
      • de Vreede-Swagemakers J.J.
      • Gorgels A.P.
      • Weijenberg M.P.
      • Dubois-Arbouw W.I.
      • Golombeck B.
      • van Ree J.W.
      • et al.
      Risk indicators for out-of-hospital cardiac arrest in patients with coronary artery disease.
      ]. Nevertheless, these findings stand in contrast with others [
      • Mukamal K.J.
      • Maclure M.
      • Muller J.E.
      • Sherwood J.B.
      • Mittleman M.A.
      Caffeinated coffee consumption and mortality after acute myocardial infarction.
      ,
      • Silletta M.G.
      • Marfisi R.
      • Levantesi G.
      • Boccanelli A.
      • Chieffo C.
      • Franzosi M.
      • et al.
      Coffee consumption and risk of cardiovascular events after acute myocardial infarction: results from the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico)-Prevenzione trial.
      ,
      • de Koning Gans J.M.
      • Uiterwaal C.S.
      • van der Schouw Y.T.
      • Boer J.M.
      • Grobbee D.E.
      • Verschuren W.M.
      • et al.
      Tea and coffee consumption and cardiovascular morbidity and mortality.
      ]. In particular, while in one study [
      • Mukamal K.J.
      • Maclure M.
      • Muller J.E.
      • Sherwood J.B.
      • Mittleman M.A.
      Caffeinated coffee consumption and mortality after acute myocardial infarction.
      ] 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 [
      • Silletta M.G.
      • Marfisi R.
      • Levantesi G.
      • Boccanelli A.
      • Chieffo C.
      • Franzosi M.
      • et al.
      Coffee consumption and risk of cardiovascular events after acute myocardial infarction: results from the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico)-Prevenzione trial.
      ] 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) [
      • de Koning Gans J.M.
      • Uiterwaal C.S.
      • van der Schouw Y.T.
      • Boer J.M.
      • Grobbee D.E.
      • Verschuren W.M.
      • et al.
      Tea and coffee consumption and cardiovascular morbidity and mortality.
      ]. 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 Panagiotakos et al. [
      • Panagiotakos D.B.
      • Pitsavos C.
      • Chrysohoou C.
      • Kokkinos P.
      • Toutouzas P.
      • Stefanadis C.
      The J-shaped effect of coffee consumption on the risk of developing acute coronary syndromes: the CARDIO2000 case-control study.
      ]. Finally, the studies aimed at examining the association between coffee consumption and stroke have yielded conflicting results (Table 2) [
      • Silletta M.G.
      • Marfisi R.
      • Levantesi G.
      • Boccanelli A.
      • Chieffo C.
      • Franzosi M.
      • et al.
      Coffee consumption and risk of cardiovascular events after acute myocardial infarction: results from the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico)-Prevenzione trial.
      ,
      • de Koning Gans J.M.
      • Uiterwaal C.S.
      • van der Schouw Y.T.
      • Boer J.M.
      • Grobbee D.E.
      • Verschuren W.M.
      • et al.
      Tea and coffee consumption and cardiovascular morbidity and mortality.
      ,
      • Grobbee D.E.
      • Rimm E.B.
      • Giovannucci E.
      • Colditz G.
      • Stampfer M.
      • Willett W.
      Coffee, caffeine, and cardiovascular disease in men.
      ,
      • Larsson S.C.
      • Männistö S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Coffee and tea consumption and risk of stroke subtypes in male smokers.
      ,
      • Mostofsky E.
      • Schlaug G.
      • Mukamal K.J.
      • Rosamond W.D.
      • Mittleman M.A.
      Coffee and acute ischemic stroke onset: the Stroke Onset Study.
      ].
      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 “J-shaped” relationship between coffee and CVD risk (as in the case of alcohol and CVD [
      • Costanzo S.
      • Di Castelnuovo A.
      • Donati M.B.
      • Iacoviello L.
      • de Gaetano
      Alcohol consumption and mortality in patients with cardiovascular disease: a meta-analysis.
      ]), 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 [
      • Graham H.N.
      Green tea composition, consumption, and polyphenol chemistry.
      ,
      • Cheng T.O.
      All teas are not created equal: the Chinese green tea and cardiovascular health.
      ,
      • McKay D.L.
      • Blumberg J.B.
      The role of tea in human health: an update.
      ]. 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 [
      • Hodgson J.M.
      • Croft K.D.
      Tea flavonoids and cardiovascular health.
      ].
      Flavonoids reduce platelet aggregation and prevent oxidation of low density lipoproteins because of their antioxidant properties [
      • Negre-Salvayre A.
      • Salvayre R.
      Quercetin prevents the cytotoxicity of oxidized LDL on lymphoid cell lines.
      ,
      • Rice-Evans C.A.
      • Miller N.J.
      • Paganga G.
      Structure-antioxidant activity relationships of flavonoids and phenolic acids.
      ,
      • Wu T.W.
      • Fung K.P.
      • Wu J.
      • Yang C.C.
      • Lo J.
      • Weisel R.D.
      Morin hydrate inhibits azoinitiator induced oxidation of human low density lipoprotein.
      ,
      • Gresele P.
      • Cerletti C.
      • Guglielmini G.
      • Pignatelli P.
      • de Gaetano G.
      • Violi F.
      • et al.
      Effects of resveratrol and other wine polyphenols on vascular function: an update.
      ]. In addition, catechins intercede in the process of vascular inflammation and atherosclerosis through several actions (e.g. anti-hypertensive, anti-lipidemic, anti-inflammatory, anti-proliferative and anti-thrombogenic) [
      • Babu P.V.
      • Liu D.
      Green tea catechins and cardiovascular health: an update.
      ,
      • Moore R.J.
      • Jackson K.G.
      • Minihane A.M.
      Green tea (Camellia sinensis) catechins and vascular function.
      ,
      • Naito Y.
      • Yoshikawa T.
      Green tea and heart health.
      ]. Thus, considering that catechins represent 80–90% of total flavonoids in green tea [
      • Babu P.V.
      • Liu D.
      Green tea catechins and cardiovascular health: an update.
      ,
      • Balentine D.A.
      • Wiseman S.A.
      • Bouwens L.C.
      The chemistry of tea flavonoids.
      ], whereas they are only 20–30% in black tea [
      • Babu P.V.
      • Liu D.
      Green tea catechins and cardiovascular health: an update.
      ,
      • Balentine D.A.
      • Wiseman S.A.
      • Bouwens L.C.
      The chemistry of tea flavonoids.
      ], it is reasonable to assume that green tea would exert a more pronounced beneficial effect on cardiovascular system than black tea.

      4.1 Evidence from epidemiology: coronary artery disease

      The results from the Rotterdam study [
      • Geleijnse J.M.
      • Launer L.J.
      • Van der Kuip D.A.
      • Hofman A.
      • Witteman J.C.
      Inverse association of tea and flavonoid intakes with incident myocardial infarction: the Rotterdam Study.
      ], 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) [
      • Geleijnse J.M.
      • Launer L.J.
      • Van der Kuip D.A.
      • Hofman A.
      • Witteman J.C.
      Inverse association of tea and flavonoid intakes with incident myocardial infarction: the Rotterdam Study.
      ]. In the large Dutch cohort of healthy men and women from the European Prospective Investigation into Cancer and Nutrition (EPIC) [
      • de Koning Gans J.M.
      • Uiterwaal C.S.
      • van der Schouw Y.T.
      • Boer J.M.
      • Grobbee D.E.
      • Verschuren W.M.
      • et al.
      Tea and coffee consumption and cardiovascular morbidity and mortality.
      ], 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) [
      • de Koning Gans J.M.
      • Uiterwaal C.S.
      • van der Schouw Y.T.
      • Boer J.M.
      • Grobbee D.E.
      • Verschuren W.M.
      • et al.
      Tea and coffee consumption and cardiovascular morbidity and mortality.
      ]. 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 [
      • Gardner E.J.
      • Ruxton C.H.S.
      • Leeds A.R.
      Black tea – helpful or harmful? A review of the evidence.
      ,
      • Grassi D.
      • Aggio A.
      • Onori L.
      • Croce G.
      • Tiberti S.
      • Ferri C.
      • et al.
      Tea, flavonoids, and nitric oxide-mediated vascular reactivity.
      ], through a mechanism involving the protective effect of tea antioxidants.
      Table 3Summary of studies on tea and vascular events.
      Tea, ReferenceStudyExposureEndpointN. cases/N. totalAdjusted RR or OR (95% CI)Summary
      Woodward M, 1999
      • Woodward M.
      • Tunstall-Pedoe H.
      Coffee and tea consumption in the Scottish Heart Health Study follow up: conflicting relations with coronary risk factors, coronary disease, and all cause mortality.
      Scottish Heart Health Study, cohort studyTea consumptionCHD?/5724; Men1.10 (0.51–2.37)Tendency to increased risk
      CHD?/5843; Women1.06 (0.28–4.05)
      Peters U, 2001
      • Peters U.
      • Poole C.
      • Arab L.
      Does tea affect cardiovascular disease? A meta-analysis.
      10 cohort studies and 7 case-control studies, meta-analysisTea consumption 3 cups/day vs noneStroke, MI and all CHDStroke and CHD too heterogeneous
      MI0.89 (0.70–1.01)Incidence rate of MI decreased by 11% with an increase in tea consumption of 3 cups/day
      Geleijnse JM, 2002
      • Geleijnse J.M.
      • Launer L.J.
      • Van der Kuip D.A.
      • Hofman A.
      • Witteman J.C.
      Inverse association of tea and flavonoid intakes with incident myocardial infarction: the Rotterdam Study.
      The Rotterdam Study, population-based studyTea drinkers >375 mL/day vs nontea drinkersFatal and nonfatal MI
      Incident Mi146/48070.57 (0.33–0.98)Strong reduction of fatal MI according to high green tea consumption
      Nonfatal MI116/48070.68 (0.37–1.26)
      Fatal MI30/48070.30 (0.09–0.94)
      Andersen LF, 2006
      • Andersen L.F.
      • Jacobs D.R.J.
      • Carlsen M.H.
      • Blomhoff R.
      Consumption of coffee is associated with reduced risk of death attributed to inflammatory and cardiovascular diseases in the Iowa Women's Health Study.
      Iowa Women's Health Study, prospective study, postmenopausalTea >3 cups/day vs noneDeath due to CVD1411/41,8360.99 (0.86–1.14)Tea no associations
      Tea >3 cups/day vs noneTotal mortality4265/41,8361.03 (0.95–1.12)
      Kuriyama S, 2006
      • Kuriyama S.
      • Shimazu T.
      • Ohmori K.
      • Kikuchi N.
      • Nakaya N.
      • Nishino Y.
      • et al.
      Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study.
      The Ohsaki National Health Insurance Cohort Study, population based prospective studyGreen tea consumption 3–4 cups/day vs <1 cup/dayCVD, cancer and all causes mortality
      CVD mortality481/40,530; Men0.87 (0.64–1.19)
      All cause mortality2668/40,530; Men0.88 (0.78–1.00)Green tea consumption lowers all causes and CVD mortality
      CVD mortality411/40,530; Women0.61 (0.44–0.85)
      All cause mortality1541/40,530; Women0.80 (0.68–0.94)
      Larsson LC, 2008
      • Larsson S.C.
      • Männistö S.
      • Virtanen M.J.
      • Kontto J.
      • Albanes D.
      • Virtamo J.
      Coffee and tea consumption and risk of stroke subtypes in male smokers.
      Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, prospective studyTea consumption ≥8cups/day vs <2 cups/dayCerebral infarction2702/26,556; Men0.79 (0.68–0.92)High tea consumption reduces Cerebral infarction risk
      Intracerebral hemorrhages383/26,556; Men1.10 (0.77–1.58)
      Subarachnoid hemorrhages196/26,556; Men0.76 (0.42–1.37)
      Arab L, 2009
      • Arab L.
      • Liu W.
      • Elashoff D.
      Green and black tea consumption and risk of stroke: a meta-analysis.
      Meta–analysisGreen or black tea consumption ≥3 cups/day vs <1 cup/dayFatal or nonfatal stroke4378/194,965; pooled0.79 (0.73–0.85)3 cups/day of green or black reduce fatal and nonfatal stroke
      Mostofsky E, 2010
      • Mostofsky E.
      • Schlaug G.
      • Mukamal K.J.
      • Rosamond W.D.
      • Mittleman M.A.
      Coffee and acute ischemic stroke onset: the Stroke Onset Study.
      Stroke onset study, multicenter case-crossover study1 h after 1 serving of caffeinated teaStroke onset in subjects with acute ischemic stroke0.9 (0.4–2.0)
      de Koning Gans JM, 2010
      • de Koning Gans J.M.
      • Uiterwaal C.S.
      • van der Schouw Y.T.
      • Boer J.M.
      • Grobbee D.E.
      • Verschuren W.M.
      • et al.
      Tea and coffee consumption and cardiovascular morbidity and mortality.
      Prospective studyTea consumption>6 cups/day vs <1 cup/dayCHD morbidity1387/37,5140.64 (0.46–0.90)Tea consumption is linearly associated with lower CHD morbidity
      Tea consumption>6 cups/day vs <1 cup/dayStroke morbidity563/37,5141.24 (0.82–1.89)
      Tea consumption>6 cups/day vs <1 cup/dayCHD mortality1230.93 (0.39–2.25)3 to 6 cups of tea/day reduce CHD risk mortality
      Tea consumption>6 cups/day vs <1 cup/dayStroke mortality701.16 (0.38–3.56)No effect of tea on both stroke or all causes mortality
      Tea consumption>6 cups/day vs <1 cup/dayAll causes mortality14051.13 (0.87–1.48)
      In a meta-analysis based on 10 cohort and 7 case-control studies [
      • Peters U.
      • Poole C.
      • Arab L.
      Does tea affect cardiovascular disease? A meta-analysis.
      ], 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 [
      • Wang Z.M.
      • Zhou B.
      • Wang Y.S.
      • Gong Q.Y.
      • Wang Q.M.
      • Yan J.J.
      • et al.
      Black and green tea consumption and the risk of coronary artery disease: a meta-analysis.
      ]. 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: 0.58-0.89) [
      • Wang Z.M.
      • Zhou B.
      • Wang Y.S.
      • Gong Q.Y.
      • Wang Q.M.
      • Yan J.J.
      • et al.
      Black and green tea consumption and the risk of coronary artery disease: a meta-analysis.
      ]. 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 [
      • Wang Z.M.
      • Zhou B.
      • Wang Y.S.
      • Gong Q.Y.
      • Wang Q.M.
      • Yan J.J.
      • et al.
      Black and green tea consumption and the risk of coronary artery disease: a meta-analysis.
      ].
      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 [
      • Hooper L.
      • Kroon P.A.
      • Rimm E.B.
      • Cohn J.S.
      • Harvey I.
      • Le Cornu K.A.
      • et al.
      Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials.
      ,
      • Ostertag L.M.
      • O'Kennedy N.
      • Kroon P.A.
      • Duthie G.G.
      • de Roos B.
      Impact of dietary polyphenols on human platelet function – a critical review of controlled dietary intervention studies.
      ], catechins in green tea [
      • Gardner E.J.
      • Ruxton C.H.S.
      • Leeds A.R.
      Black tea – helpful or harmful? A review of the evidence.
      ] seem to exert a more beneficial effect on CAD [
      • Wang Z.M.
      • Zhou B.
      • Wang Y.S.
      • Gong Q.Y.
      • Wang Q.M.
      • Yan J.J.
      • et al.
      Black and green tea consumption and the risk of coronary artery disease: a meta-analysis.
      ].

      4.2 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) [
      • Kuriyama S.
      • Shimazu T.
      • Ohmori K.
      • Kikuchi N.
      • Nakaya N.
      • Nishino Y.
      • et al.
      Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study.
      ]. Results from a pooled meta-analyses showed that tea drinking, without any confined effect to black or green tea, reduced mortality and morbidity of stroke [
      • Arab L.
      • Liu W.
      • Elashoff D.
      Green and black tea consumption and risk of stroke: a meta-analysis.
      ]. 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) [
      • Arab L.
      • Liu W.
      • Elashoff D.
      Green and black tea consumption and risk of stroke: a meta-analysis.
      ]. 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) [
      • Mostofsky E.
      • Schlaug G.
      • Mukamal K.J.
      • Rosamond W.D.
      • Mittleman M.A.
      Coffee and acute ischemic stroke onset: the Stroke Onset Study.
      ]. On the contrary, in the Dutch EPIC cohort [
      • de Koning Gans J.M.
      • Uiterwaal C.S.
      • van der Schouw Y.T.
      • Boer J.M.
      • Grobbee D.E.
      • Verschuren W.M.
      • et al.
      Tea and coffee consumption and cardiovascular morbidity and mortality.
      ], the consumption of 3 to 6 cups of tea per day was not associated with a reduced risk of stroke (Table 3) [
      • de Koning Gans J.M.
      • Uiterwaal C.S.
      • van der Schouw Y.T.
      • Boer J.M.
      • Grobbee D.E.
      • Verschuren W.M.
      • et al.
      Tea and coffee consumption and cardiovascular morbidity and mortality.
      ].

      4.3 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 [
      • Hooper L.
      • Kroon P.A.
      • Rimm E.B.
      • Cohn J.S.
      • Harvey I.
      • Le Cornu K.A.
      • et al.
      Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials.
      ]. On the contrary, chronic consumption of black tea improved endothelial function (measured as flow-mediated dilation) by 3.4%, whereas the acute effect was modest (1.7%) and not significant [
      • Hooper L.
      • Kroon P.A.
      • Rimm E.B.
      • Cohn J.S.
      • Harvey I.
      • Le Cornu K.A.
      • et al.
      Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials.
      ]. Finally, the intake of 1 L black tea per day reportedly inhibited platelet activation by 4–10% [
      • Ostertag L.M.
      • O'Kennedy N.
      • Kroon P.A.
      • Duthie G.G.
      • de Roos B.
      Impact of dietary polyphenols on human platelet function – a critical review of controlled dietary intervention studies.
      ].
      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 [
      • Stampfer M.J.
      • Hu F.B.
      • Manson J.E.
      • Rimm E.B.
      • Willett W.C.
      Primary prevention of coronary heart disease in women through diet and lifestyle.
      ,
      • de Lorgeril M.
      • Salen P.
      • Martin J.L.
      • Monjaud I.
      • Delaye J.
      • Mamelle N.
      Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study.
      ,
      • Willett W.C.
      • Sacks F.
      • Trichopoulou A.
      • Drescher G.
      • Ferro-Luzzi A.
      • Helsing E.
      • et al.
      Mediterranean diet pyramid: a cultural model for healthy eating.
      ].
      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 [
      • di Giuseppe R.
      • Di Castelnuovo A.
      • Centritto F.
      • Zito F.
      • De Curtis A.
      • Costanzo S.
      • et al.
      Regular consumption of dark chocolate is associated with low serum concentrations of C-reactive protein in a healthy Italian population.
      ].
      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 cups/day) of tea is “possibly” useful for cardiovascular risk reduction [
      • Vogel J.H.K.
      • Bolling S.F.
      • Costello R.B.
      • Guarneri E.M.
      • Krucoff M.W.
      • Longhurst J.C.
      • et al.
      Integrating complementary medicine into cardiovascular medicine: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (Writing Committee to Develop an Expert Consensus Document on Complementary and Integrative Medicine).
      ].
      However, as for other diffused consumption habits, such as those of alcohol [
      • Di Castelnuovo A.
      • Costanzo S.
      • Bagnardi V.
      • Donati M.B.
      • Iacoviello L.
      • de Gaetano G.
      Alcohol dosing and total mortality in males and females: an updated meta-analysis of 34 prospective studies.
      ,
      • Di Castelnuovo A.
      • Costanzo S.
      • Donati M.B.
      • Iacoviello L.
      • de Gaetano
      Prevention of cardiovascular risk by moderate alcohol consumption: epidemiologic evidence and plausible mechanisms.
      ], 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.
      • A large amount of experimental and epidemiological studies clearly indicated a beneficial effect of polyphenols in preventing coronary artery disease.
      • Chocolate, coffee and tea are important dietary sources of polyphenols.
      • The blood pressure lowering effects and the anti-inflammatory activity of dark chocolate suggests its use as potential prophylactic and therapeutic agent.
      • Regular consumption of moderate quantities of coffee and (green) tea seems to be associated with a small protection against coronary artery disease.

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