European Journal of Internal Medicine 23 (2012) 1525

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European Journal of Internal Medicine

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m

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

a r t i c l e i n f o a b s t r a c t

Article history: Daily intake of an anti-thrombotic diet may offer a suitable and effective way of coronary artery disease (CAD)
Received 12 March 2011 prevention. A diet rich in fruit, vegetables, complex carbohydrates, monounsaturated fat and sh, moderate
Received in revised form 1 July 2011 alcohol consumption but poor in salt, saturated fat and simple sugars, plays an important role in protect
Accepted 22 July 2011
against CAD. Chocolate, coffee and tea, unfairly not included in traditional healthy food basket, have
Available online 30 August 2011
received much attention over the past few years, if for no other reason than they are consumed worldwide
Keywords:
and are important dietary sources of polyphenols (avonols and cathechins). Several in vitro and in vivo
Coronary artery disease prevention studies have tried to elucidate the role of these foods and a large amount of experimental studies clearly
Nutrition indicated a benecial effect of polyphenols in inuencing CAD. However, data from epidemiological studies
Chocolate are not conclusive.
Coffee The blood pressure lowering effects and the anti-inammatory activity of dark chocolate suggests its use as
Tea 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 benecial 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.
2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction antiatherogenic and antioxidant effects [9,10]. Nevertheless, beyond

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 inammation are linked, at least in
part, to dietary habits [3]. Changes in nutritional habits of many popu-
lations 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 modications [4].
The traditional Mediterranean diet is characterized by high intake
of foods rich in polyphenols and avonoids [5,6]. Data from a vast
literature clearly demonstrate that adherence to the Mediterranean
diet is associated with a signicant reduction of total as well as CAD
and cancer mortality [7,8]. Mechanisms of action of the Mediterranean
diet relate to benecial effects on lipids as well as antithrombotic,
Corresponding author. Tel.: + 39 0874312585.
E-mail address: dicastel@ngi.it (A. Di Castelnuovo).
1
Both authors contributed equally to this work.
the traditional Mediterranean dietary components, other polyphenol
and avonoid-rich foods (and beverages) such as cocoa, coffee and tea
have been associated with a reduced CAD risk prole [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 benecial effects on CAD
risk prole [1114] and methylxanthines [13]. In particular, theobro-
mine, the main methylxanthine in chocolate, is a myocardial stim-
ulant, 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 avonoids per serving than tea or red wine, which
contribute to its higher antioxidant capacity and, presumably, to its
higher benecial health effects [15]. However, the biological effects of
cocoa avonoids vary from chocolate to chocolate, since they seem to

0953-6205/$ see front matter 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejim.2011.07.014
16 A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) 1525
be greater in dark rather than in milk chocolate [16]. Thus, starting
from the hypothesis that cocoa polyphenols bind to milk proteins,
Serani 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 avonoid-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 benecial effect by increasing
plasma antioxidants.
2.1. Chocolate as an anti-inammatory agent
Chocolate avonoids possess anti-inammatory properties since
they are able to inhibit several mediators activated in certain inam-
matory conditions. In particular, cocoa products reduce inammation
by modulating interleukin-5 in peripheral blood mononuclear cells
[19], tumor necrosis factor-alpha [20] and by inuencing the
endothelium-derived nitric oxide synthesis and metabolism [21].
In addition, cocoa avonoids seem to mediate anti-inammatory
effects related to reductions in platelet and endothelial cell activation
[22].
Cocoa consumption led to decreased platelet microparticle forma-
tion and inhibited ADP- and epinephrine-stimulated platelet activa-
tion [23]. More recently, in an in vitro and ex vivo study, Heptinstall
and colleagues [24] reported that cocoa avonols inhibited platelet
aggregation and activation, platelet-monocyte and neutrol 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 avonoid-rich dark
chocolate (compared with a avonoid 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 inammation through
the modulation of eicosanoid.
In a cross-sectional study based on data from the NHANES 1999
2002 avonoid-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 signicant J-shaped relationship between dark
chocolate consumption and serum CRP was observed [29].
2.2. Cocoa and cardiovascular risk factors
A summary table presents the most relevant studies with
epidemiologic evidence pros and cons the benecial 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 avonol-rich
dark chocolate decreases BP, increases ow-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 avanol-rich
cocoa products on BP in hypertensive and normotensive individuals
revealed a signicant 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 endo-
thelial function (measured as ow-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].
2.3. Evidence from epidemiology
Cocoa and chocolate represent the most important source of
avonoids, but it is not unique. Several studies investigated the asso-
ciation of total avonoids with CAD risk [3537]. The prospective studies
of avonoids 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 avonoids 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 nding from this meta-analysis was conrmed 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 asso-
ciated with cardiac mortality also in a Swedish cohort of 1169 patients
surviving their rst acute myocardial infarction (Table 1) [40]. Finally,
in a large U.S. cohort of postmenopausal women followed for 16 years
chocolate consumption, and other avonoid-rich foods, has been
inversely associated with CVD death [36,41]. However, after multi-
variable adjustment the highly signicant association found in the age
and energy adjusted model (p b 0.001) 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) [4253]. Apart from being the main source
of caffeine, coffee contains several other compounds in particular
phenols, vitamin B3, magnesium, potassium and ber [54] that may
have either benecial 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
lter during coffee preparation is sufcient to limit their content [56].
Nevertheless, many other compounds with antioxidant properties
[57,58] namely chlorogenic acid, avonoids, melanoidins, furans,
pyrroles and maltol have been found in coffee [59]. Denitely, because
of its extensive use, coffee represents one of the major contributors to
the total antioxidant capacity of the diet [60,61].
3.1. 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
 A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) 1525 17

caffeine is associated with an increase in blood pressure [63,64],

cardiovascular and all-cause mortality

Eating 3 chocolates/day is inversely

systemic vascular resistance [65], arterial stiffness [66,67], plasma

In elderly men, inverse association

chocolate consumption partly due

Inverse association with cardiac
renin activity, epinephrine, and norepinephrine [68] and has unfavor-

Reduced CVD risk according to

mortality in post-AMI patients
associated with nonfatal AMI
able effects on endothelial function in healthy subjects [69]. Moreover,

between cocoa intake and

in a randomized double-blinded study Riksen et al. [62] observed that

to its BP-lowering effect

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].
Summary

3.2. Coffe and cardiovascular risk factors: positive aspects

0.50 (0.320.78)

0.52 (0.380.71)
0.23 (0.080.65)

(0.170.70)
(0.581.53)
(0.541.37)
(0.521.16)

0.62 (0.331.16)
0.82 (0.591.14)

0.73 (0.471.15)

0.52 (0.300.89)
The adverse effects of coffee and specically caffeine are in part
Adjusted RR or

counterbalanced by the favorable effect on type 2 diabetes mellitus

OR (95% CI)

[7375] and by the lack of association with incident hypertension in

women [76]. An important contribution to the explanation of the role
0.34
0.94
0.86
0.78

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
N. cases/N. total

capsules containing 200 mg of caffeine) was associated with an

increase in ow-mediated dilation and in a decrease in C-reactive
166/19,357

136/19,357
760/1442

107/1169
210/1169
250/1169
279/1169

111/1169
471/1169
152/470

162/470

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].
Cardiac mortality, diabetes free post AMI

3.3. Evidence from epidemiology

Total mortality, diabetes-free post AMI
Recurrent AMI, diabetes-free post AMI
Congestive heart failure, diabetes-free

Any non-fatal event, diabetes-free

Early [42,44,45] and more recent meta-analyses [79,80] concluded

Stroke, diabetes-free post AMI

that overall coffee consumption was not signicantly associated with an

increased CAD risk, especially when only prospective studies were
Cardiovascular mortality

Myocardial infarction

considered (Table 2). Rather, Wu et al. [80] have shown that drinking 1
All cause mortality

to 4 cups of coffee per day was associated with a lower risk of CAD,
(relative risk of 0.87; 95%CI: 0.800.86 in men and 0.82; 95%CI: 0.73
0.92 in women, Table 2). In a recent prospective cohort study [81], the
Endpoint

post AMI

post AMI

inverse association found in both men and women between regular

Stroke
AMI

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
Chocolate intake, highest vs lowest quartile

Chocolate intake, highest vs lowest quartile

3 chocolates/day vs b 2 chocolates/day

also decaffeinated coffee was inversely associated with all-cause and

Cocoa intake, highest vs lowest tertile

Cocoa intake, highest vs lowest tertile

cardiovascular mortality, albeit the observed effects were relatively

50 g; 2/week vs no consumption

small (Table 2) [81].

Several factors should be taken into account when coffee con-
sumption is investigated in relation to CVD risk factors. One of them is
Chocolate consumption,

how coffee is prepared. Several lines of evidence suggest that boiled

coffee raises cholesterol levels [71]. In agreement with these ndings,
in a Swedish case-control study [82], the incidence of rst nonfatal
myocardial infarction was 1.4 times higher, in men drinking boiled
Exposure

coffee vs men drinking ltered coffee, with an even higher risk for
women (RR: 1.63; 95% CI: 1.042.56, Table 2).
However, Baylin et al. [83] showed that following a transient coffee
Summary of studies on chocolate/cocoa and vascular events.

intake, subjects with a sedentary lifestyle and with three or more risk
Stockholm Heart Epidemiology

factors for CAD have an increased MI risk (Table 2). In addition,

Program, population-based

drinking more than 10 cups of coffee per day was an independent risk
Italy, case-control study
Zutphen Elderly Study,

inception cohort study

factor in a retrospective case-control study for sudden cardiac arrest

EPIC-Potsdam Study,

in patients with CAD [84]. Nevertheless, these ndings stand in

prospective study

prospective study

contrast with others [8587]. In particular, while in one study [85] the
authors observed an inverse association between coffee consumption
and mortality in the rst 90 days after infarction (Table 2), in the post-
Study

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
Chocolate, Reference

Buijsse B, 2006 [31]

Buijsse B, 2010 [32]

Janszky I, 2009 [40]
Gallus S, 2009 [39]

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
Table 1

for CAD by increasing coffee intake the curve reaches a plateau, and
reverts at higher amounts) was also observed in the study of
 18
Table 2
Summary of studies on coffee and vascular events.

Coffee, Study Exposure Endpoint N. cases/N. total Adjusted RR or Summary

Reference OR (95% CI)

Grobbee DE, The Health Professional Total Coffee Nonfatal MI, CHD death, Both caffeine and caffeinated coffee intake do
1990 [88] Follow-up Study, consumption 4 cups/day vs none CABG, PTCA, Stroke not increase CHD and stroke risk
longitudinal study Nonfatal MI and CHD death 221/45,589; Men 1.08 (0.721.60)
CABG and PTCA 136/45,589; Men 0.95 (0.561.61)
Total CHD 357/45,589; Men 1.00 (0.731.37)
Fatal and nonfatal stroke 54/45,589; Men 0.48 (0.181.31)
Total CVD 408/45,589; Men 0.90 (0.671.22)
Caffeinated coffee Nonfatal MI and CHD death 221/45,589; Men 1.01 (0.621.65)
consumption 4 cups/day vs none CABG and PTCA 131/45,589; Men 0.66 (0.321.34)
Total CHD 342/45,589; Men 0.84 (0.561.25)
Fatal and nonfatal stroke 52/45,589; Men 0.28 (0.061.26)
Total CVD 390/45,589; Men 0.74 (0.501.09)

A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) 1525

Decaffeinated coffee Nonfatal MI and CHD death 214/45,589; Men 1.55 (0.852.81) Decaffeinated coffee moderately increases
consumption 4 cups/day vs none CHD risk
CABG and PTCA 132/45,589; Men 1.74 (0.813.73)
Total CHD 346/45,589; Men 1.63 (1.022.60)
Fatal and nonfatal stroke 51/45,589; Men 1.16 (0.265.10)
Total CVD 394/45,589; Men 1.58 (1.012.48)
Myers MG, 11 Prospective Studies Coffee intake, 6 cups/day Coronary events 1.09 (0.971.22) No association between coffee
1992 [42] (cohorts without history vs 1 cup/day consumption and CHD
of MI), meta-analysis Later Cohort 1.27 (1.171.39)
Earlier Cohort 0.92 (0.801.06)
Pooled cohort 1.18 (1.031.34)
Kawachi I, 8 case-control and 15 cohort Coffee drinking, 5 cups/day CHD Pooled case-control 1.63 (1.501.78) Increased CHD risk according to increased
1994 [44] studies, meta-analysis vs none coffee drinking
Pooled cohort 1.05 (0.991.12) Weak CHD risk in habitual coffee drinkers
Woodward M, Scottish Heart Health Study, Coffee consumption 5 vs none CHD ?/5645; Men 0.68 (0.371.24) Moderate benet from coffee consumption
1999 [52] cohort study CHD ?/5800; Women 0.55 (0.181.66)
Hammar N, The SHEEP and the VHEEP Study, Consumption N 9 dL ltered First nonfatal MI 1171/1813; Men 1.93 (1.422.63) Incidence of rst nonfatal MI 1.4 times
2003 [82] population-based case-control study coffee/day vs 3 dL/day higher in men drinking boiled coffee
vs men drinking ltered coffee, with an even
higher risk for women
Consumption N 9 dL mixed 2.24 (1.084.64)
coffee/day vs 3 dL/day
Consumption N 9 dL boiled 2.20 (1.174.15)
coffee/day vs 3 dL/day
Consumption N 9 dL ltered First nonfatal MI 472/854; Women 1.43 (0.812.54)
coffee/day vs 3 dL/day
Consumption N 9 dL mixed 2.91 (0.2829.69)
coffee/day vs 3 dL/day
Consumption N 9 dL boiled 4.97 (0.5544.73)
coffee/day vs 3 dL/day
Boiled vs ltered coffee 1171/1813; Men 1.41 (1.071.85) Boiled coffee increases the occurrence of
rst nonfatal MI
Boiled vs ltered coffee 472/854; Women 1.63 (1.042.56)
Panagiotakos DB, The CARDIO2000, case-control study Very heavy coffee drinkers ACS 848/1078 3.10 (1.825.26) J-shaped relation between coffee intake
2003 [51] (N600 mL/day) vs none and ACS risk
Happonen P, The Kuopio Ischaemic Heart Disease Moderate drinkers vs heavy Acute coronary events 269/1971; Men 1.43 (1.061.94) Heavy coffee drinking raises the risk of
2004 [48] Risk Factor Study, prospective study drinkers ( 814 mL/day) (MI or coronary death) acute MI or coronary death
Mukamal KJ, Determinants of Myocardial Infarction Coffee consumption N 14 Mortality after AMI 315/1902 1.13 (801.60) No association between coffee consumption
2004 [85] Onset Study, inception cohort study cups/week vs none and post-infarction mortality
Coffee consumption N 14 Deaths within 90 days 79/1902 0.38 (0.170.86)
cups/week vs none
Coffee consumption N 14 Deaths beyond 90 days 236/1902 1.52 (1.032.26) Time variation in coffee effect
cups/week vs none
Table 2 (continued)
Coffee, Study Exposure Endpoint N. cases/N. total Adjusted RR or Summary
Reference OR (95% CI)

Andersen LF, Iowa Women's Health Study, Regular coffee 6 cups/day Death due to CVD, 1411/41,836 0.92 (0.741.14)
2006 [49] prospective study vs none postmenopausal
Decaffeinated coffee 6 Death due to CVD, 1411/41,836 0.99 (0.701.39) U-shaped associations (death from CVD
cups/day vs none postmenopausal and total mortality)
Regular coffee 6 cups/day Total mortality, 4265/41,836 0.95 (0.841.07)
vs none postmenopausal
Decaffeinated coffee 6 Total mortality, 4265/41,836 0.94 (0.781.14)
cups/day vs none postmenopausal
Lopez-Garcia E, Prospective cohort study Coffee intake, 6 cups/day CHD
2006 [43] vs b 1 cup/month CHD 2173/44,005; Men 0.72 (0.491.07)
2254/84,488; Women 0.87 (0.681.11) No indication that coffee (or caffeine)
intake increases CHD
Caffeine intake, 6 cups/day CHD 2173/44,005; Men 0.97 (0.841.11)
vs b 1 cup/month CHD 2254/84,488; Women 0.97 (0.851.11)
Azevedo A, Community-based case-control Regular ever coffee drinkers AMI 290/364; Men 0.5 (0.31.1) SignicantMI in men with no family
2006 [50] study history of AMI; non signicant MI in
men withfamily history of AMI

A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) 1525

Kleemola P, Finnish men and women, Coffee consumption N 7 cups/day Non fatal MI 891/10,075; Men 0.79 (0.640.98)
2006 [53] prospective study vs 13 cups/day
Coffee consumption N 7 cups/day CHD mortality 891/10,075; Men 1.22 (0.901.65)
vs 13 cups/day
Coffee consumption N 7 cups/day All cause mortality 1201/10,075; Men 1.01 (0.841.22) Coffee drinking is not associated with
vs 13 cups/day CHD risk and death
Coffee consumption N 7 cups/day Non fatal MI 319/10,387 0.93 (0.631.36)
vs 13 cups/day
Coffee consumption N 7 cups/day CHD mortality 99/10,387 0.57 (0.281.16)
vs 13 cups/day
Coffee consumption N 7 cups/day All cause mortality 444/10,387 0.62 (0.440.87)
vs 13 cups/day
Baylin A, Costa Rica, case-crossover design Habitual coffee consumption Nonfatal MI, 1 h after
2006 [83] coffee drinking
1 cup/day 9/66 4.14 (2.038.42) Coffee intake probably set off MI
23 cups/day 44/280 1.60 (1.162.21)
4 cups/day 27/120 1.06 (0.691.63)
Cornelis MC, Slow caffeine metabolizer Coffe intake 4 cups/day First acute nonfatal MI 2014/2014 1.64 (1.142.34) Increased MI risk only in subjects with
2006 [47] vs b 1 cup/day impaired caffeine metabolism
Rapid caffeine metabolizer Coffe intake 4 cups/day First acute nonfatal MI 2014/2014 0.99 (0.661.48)
population-based case-control study vs b 1 cup/day
Silletta MG, GISSI-Prevenzione trial, prospective Coffee consumption N 4 CVD events (CV death, 1167/11,213 0.88 (0.641.20) Moderate coffee intake is not associated
2007 [86] study cups/day vs none nonfatal MI, nonfatal with CV events post-MI
stroke in post-MI patients
Larsson LC, Alpha-Tocopherol, Beta-Carotene Coffee consumption 8 Stroke subtypes
2008 [89] Cancer Prevention Study, cups/day vs b2 cups/day Cerebral infarction 2702/26,556; Men 0.77 (0.660.90) High coffee consumption lowers cerebral
prospective study infarction risk
Intracerebral hemorrhages 383/26,556; Men 0.98 (0.661.47)
Subarachnoid 196/26,556; Men 1.18 (0.632.20)
hemorrhages
Lopez-Garcia E, Health Professionals Follow-up Coffee consumption 6 cups/day CVD mortality 2049/41,736; Men 0.56 (0.311.03)
2008 [81] Study and Nurses' Health Study, vs b 1 cup/month
prospective cohort study Coffee consumption 6 cups/day CVD mortality 2368/86,214; Women 0.81 (0.611.06)
vs b 1 cup/month
Coffee consumption 6 cups/day Cancer mortality 2491/41,736; Men 1.14 (0.791.65)
vs b 1 cup/month
Coffee consumption 6 cups/day Cancer mortality 5011/86,214; Women 1.05 (0.871.28)
vs b 1 cup/month
Coffee consumption 6 cups/day Other causes 2348/41,736; Men 0.65 (0.111.04)
vs b 1 cup/month
Coffee consumption 6 cups/day Other causes 3716/86,214; Women 0.60 (0.460.77)
vs b 1 cup/month

19
(continued on next page)
 20
Table 2 (continued)
Coffee, Study Exposure Endpoint N. cases/N. total Adjusted RR or Summary
Reference OR (95% CI)

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 All causes 6888/41,736; Men 0.80 (0.621.04)
vs b 1cup/month
Coffee consumption 6 cups/day All causes 11,095/86,214; Women 0.83 (0.730.95)
vs b 1cup/month
Decaffeinated coffee CVD mortality 2049/41,736; Men 0.83 (0.521.31)
consumption 4 cups/day

A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) 1525

vs b 1cup/month
Decaffeinated coffee CVD mortality 2368/86,214; Women 0.55 (0.301.04)
consumption 4 cups/day
vs b 1cup/month
Decaffeinated coffee Cancer mortality 2491/41,736; Men 1.20 (0.871.66)
consumption 4 cups/day
vs b 1cup/month
Decaffeinated coffee Cancer mortality 5011/86,214; Women 0.86 (0.601.23)
consumption 4 cups/day
vs b 1cup/month
Decaffeinated coffee All causes 6888/41,736; Men 0.81 (0.641.03)
consumption 4 cups/day
vs b 1cup/month
Decaffeinated coffee All causes 11,095/86,214; Women 0.78 (0.611.00)
consumption 4 cups/day
vs b 1cup/month
Wu JN, 2009 [80] 21 prospective cohort studies, Coffee consumption b1 CHD 15,599/407,806; pooled 1.07 (0.871.32) No long-term increased CHD risk
meta-analysis cup/day (US) or 2
cups/day(Europe) vs 6
or 7 cups/day
Moderate coffee consumption CHD Women 0.82 (0.730.92) Lower CHD risk in moderate coffee
drinker women
de Koning Gans JM, Prospective study Coffee consumptionN6 cups/day CHD morbidity 1387/37,514 0.91 (0.741.11) U shaped association between coffee
2010 [87] vs b 1 cup/day consumption and lower CHD morbidity
Coffee consumptionN6 cups/day Stroke morbidity 563/37,514 1.22 (0.881.70)
vs b 1 cup/day
Coffee consumptionN6 cups/day CHD mortality 123 0.73 (0.371.42) Non signicant slight reduction in CHD
vs b 1 cup/day mortality according to moderate coffee
consumption
Coffee consumptionN6 cups/day Stroke mortality 70 1.34 (0.493.64)
vs b 1 cup/day
Coffee consumptionN6 cups/day All causes mortality 1405 0.93 (0.761.15) No effect of coffee on stroke or all causes
vs b 1 cup/day mortality
Mostofsky E, Stroke onset study, multicenter Coffee drinkers vs non drinkers Stroke onset in subjects
2010 [90] case-crossover study with acute ischemic stroke
1 h after 1 serving of coffee 35/390 2.0 (1.42.8) 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
 A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) 1525
Panagiotakos et al. [51]. Finally, the studies aimed at examining the
association between coffee consumption and stroke have yielded
conicting results (Table 2) [8690].
A non linear doseresponse relationship between coffee intake and
CVD risk may explain the heterogeneity in ndings from different
studies (which typically investigated the role of coffee at various doses)
and, at the least in part, the null ndings 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 [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 classied into black
(fermented) tea mainly drunk in Europe, North America and North
Africa and green tea (unfermented), principally consumed in Asia
[9294]. Because of its high content of catechins (epicatechin,
epicatechin gallate, epigallocatechin and epigallocatechin gallate), also
known as tea avonoids, 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 [9699]. In
addition, catechins intercede in the process of vascular inammation
and atherosclerosis through several actions (e.g. anti-hypertensive, anti-
lipidemic, anti-inammatory, anti-proliferative and anti-thrombogenic)
[100102]. Thus, considering that catechins represent 8090% of total
avonoids in green tea [100,103], whereas they are only 2030% in black
tea [100,103], it is reasonable to assume that green tea would exert a
more pronounced benecial effect on cardiovascular system than black
tea.
4.1. 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 avonoids 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 signicant 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) [108]. Doseresponse 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 benecial effects of
black tea seem to be conned 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 benecial effect on CAD [108].
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
21
cardiovascular disease was observed in the Ohsaki National Health
Insurance Cohort Study (Table 3) [110]. Results from a pooled meta-
analyses showed that tea drinking, without any conned 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
ndings 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].
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 [12]. On the contrary, chronic consumption
of black tea improved endothelial function (measured as ow-
mediated dilation) by 3.4%, whereas the acute effect was modest
(1.7%) and not signicant [12]. Finally, the intake of 1 L black tea per
day reportedly inhibited platelet activation by 410% [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 sh,
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
[35].
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 (avonoids) 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 benecial effect of
polyphenols in regulating CAD risk prole, data from epidemiological
studies are not conclusive.
The blood pressure lowering effects and the anti-inammatory
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 benecial effects are
less evident. A non linear doseresponse relationship between coffee
intake and CVD risk may explain the heterogeneity in ndings. 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 (12
 22
Table 3
Summary of studies on tea and vascular events.

Tea, Reference Study Exposure Endpoint N. cases/N. total Adjusted RR or Summary

OR (95% CI)

Woodward M, 1999 [52] Scottish Heart Health Study, Tea consumption CHD ?/5724; Men 1.10 (0.512.37) Tendency to increased risk
cohort study CHD ?/5843; Women 1.06 (0.284.05)
Peters U, 2001 [107] 10 cohort studies and 7 Tea consumption 3 cups/day vs none Stroke, MI and all CHD Stroke and CHD too heterogeneous
case-control studies, MI 0.89 (0.701.01) Incidence rate of MI decreased by

A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) 1525

meta-analysis 11% with an increase in tea
consumption of 3 cups/day
Geleijnse JM, 2002 [104] The Rotterdam Study, Tea drinkers N 375 mL/day vs Fatal and nonfatal MI
population-based study nontea drinkers Incident Mi 146/4807 0.57 (0.330.98) Strong reduction of fatal MI
according to high green tea
consumption
Nonfatal MI 116/4807 0.68 (0.371.26)
Fatal MI 30/4807 0.30 (0.090.94)
Andersen LF, 2006 [49] Iowa Women's Health Study, Tea N 3 cups/day vs none Death due to CVD 1411/41,836 0.99 (0.861.14) Tea no associations
prospective study, postmenopausal
Tea N 3 cups/day vs none Total mortality 4265/41,836 1.03 (0.951.12)
Kuriyama S, 2006 [110] The Ohsaki National Health Green tea consumption 34 CVD, cancer and all causes
Insurance Cohort Study, cups/day vs b 1 cup/day mortality
population based prospective CVD mortality 481/40,530; Men 0.87 (0.641.19)
study All cause mortality 2668/40,530; Men 0.88 (0.781.00) Green tea consumption lowers all
causes and CVD mortality
CVD mortality 411/40,530; Women 0.61 (0.440.85)
All cause mortality 1541/40,530; Women 0.80 (0.680.94)
Larsson LC, 2008 [89] Alpha-Tocopherol, Beta-Carotene Tea consumption 8cups/day Cerebral infarction 2702/26,556; Men 0.79 (0.680.92) High tea consumption reduces Cerebral
Cancer Prevention Study, vs b 2 cups/day infarction risk
prospective study Intracerebral hemorrhages 383/26,556; Men 1.10 (0.771.58)
Subarachnoid hemorrhages 196/26,556; Men 0.76 (0.421.37)
Arab L, 2009 [111] Metaanalysis Green or black tea consumption 3 Fatal or nonfatal stroke 4378/194,965; pooled 0.79 (0.730.85) 3 cups/day of green or black reduce
cups/day vs b 1 cup/day fatal and nonfatal stroke
Mostofsky E, 2010 [90] Stroke onset study, multicenter 1 h after 1 serving of caffeinated tea Stroke onset in subjects with 0.9 (0.42.0)
case-crossover study acute ischemic stroke
de Koning Gans JM, Prospective study Tea consumptionN6 cups/day CHD morbidity 1387/37,514 0.64 (0.460.90) Tea consumption is linearly
2010 [87] vs b 1 cup/day associated with lower CHD
morbidity
Tea consumptionN6 cups/day Stroke morbidity 563/37,514 1.24 (0.821.89)
vs b 1 cup/day
Tea consumptionN6 cups/day CHD mortality 123 0.93 (0.392.25) 3 to 6 cups of tea/day reduce CHD
vs b 1 cup/day risk mortality
Tea consumptionN6 cups/day Stroke mortality 70 1.16 (0.383.56) No effect of tea on both stroke or all
vs b 1 cup/day causes mortality
Tea consumptionN6 cups/day All causes mortality 1405 1.13 (0.871.48)
vs b 1 cup/day
 A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) 1525
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 prole with a regular and moderate consump-
tion, while healthy outcomes vanish at heavy consumption.
Conict of interest statement
All authors disclose any actual or potential conict of interest
including any nancial, personal or other relationships with other
people or organizations within three years of beginning the submitted
work that could inappropriately inuence, or be perceived to inuence,
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 benecial 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-inammatory
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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