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 b s t r a c t

a r t i c l e i n f o

Article history:
Received 12 March 2011
Received in revised form 1 July 2011
Accepted 22 July 2011
Available online 30 August 2011

Keywords:
Coronary artery disease prevention
Nutrition
Chocolate
Coffee
Tea

Daily intake of an anti-thrombotic diet may offer a suitable and effective way of coronary artery disease (CAD)
prevention. A diet rich in fruit, vegetables, complex carbohydrates, monounsaturated fat and

fish, moderate

alcohol consumption but poor in salt, saturated fat and simple sugars, plays an important role in protect
against CAD. Chocolate, coffee and tea, unfairly not included in

“traditional healthy food basket”, have

received much attention over the past few years, if for no other reason than they are consumed worldwide
and are important dietary sources of polyphenols (

flavonols and cathechins). Several in vitro and in vivo

studies have tried to elucidate the role of these foods and a large amount of experimental studies clearly
indicated a bene

ficial effect of polyphenols in influencing CAD. However, data from epidemiological studies

are not conclusive.
The blood pressure lowering effects and the anti-in

flammatory 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 bene

ficial 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

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 in

flammation 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 modi

fications

[4]

.

The traditional Mediterranean diet is characterized by high intake

of foods rich in polyphenols and

flavonoids

[5,6]

. Data from a vast

literature clearly demonstrate that adherence to the Mediterranean
diet is associated with a signi

ficant reduction of total as well as CAD

and cancer mortality

[7,8]

. Mechanisms of action of the Mediterranean

diet relate to bene

ficial effects on lipids as well as antithrombotic,

antiatherogenic and antioxidant effects

[9,10]

. Nevertheless, beyond

the traditional Mediterranean dietary components, other polyphenol
and

flavonoid-rich foods (and beverages) such as cocoa, coffee and tea

have been associated with a reduced CAD risk pro

file

[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 bene

ficial effects on CAD

risk pro

file

[11

–14]

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

flavonoids per serving than tea or red wine, which

contribute to its higher antioxidant capacity and, presumably, to its
higher bene

ficial health effects

[15]

. However, the biological effects of

cocoa

flavonoids vary from chocolate to chocolate, since they seem to

European Journal of Internal Medicine 23 (2012) 15

–25

⁎ Corresponding author. Tel.: [phone].

E-mail address:

[e-mail]

(A. Di Castelnuovo).

1

Both authors contributed equally to this work.

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

Contents lists available at

ScienceDirect

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

be greater in dark rather than in milk chocolate

[16]

. Thus, starting

from the hypothesis that cocoa polyphenols bind to milk proteins,
Sera

fini et al. have showed that the increase in total antioxidant

capacity of 100 g dark chocolate was reduced when chocolate was
taken as milk chocolate (200 g) or when dark chocolate (100 g) was
taken with 200 mL full-fat milk

[16]

. Interestingly, results from a

randomized, double-blind, placebo-controlled study on healthy
adults, indicated that consumption of

flavonoid-rich dark chocolate

improved endothelium-dependent vasodilation, via increased plasma
epicatechin concentrations, independent to changes in biomarkers of
antioxidant and oxidative stress

[17]

. In addition, Wang et al.

[18]

further showed that subjects consuming procyanidin-rich chocolate
had an increase in plasma antioxidant capacity

[18]

.

Therefore, based on this evidence it is reasonable to assume that

dark chocolate exerts, at least in part, its bene

ficial effect by increasing

plasma antioxidants.

2.1. Chocolate as an anti-in

flammatory agent

Chocolate

flavonoids possess anti-inflammatory properties since

they are able to inhibit several mediators activated in certain in

flam-

matory conditions. In particular, cocoa products reduce in

flammation

by modulating interleukin-5 in peripheral blood mononuclear cells

[19]

, tumor necrosis factor-alpha

[20]

and by in

fluencing the

endothelium-derived nitric oxide synthesis and metabolism

[21]

.

In addition, cocoa

flavonoids seem to mediate anti-inflammatory

effects related to reductions in platelet and endothelial cell activation

[22]

.

Cocoa consumption led to decreased platelet microparticle 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

flavonols inhibited platelet

aggregation and activation, platelet-monocyte and neutro

fil conjugate

formation with aspirin-like effects. In a study conducted on healthy
volunteers, the authors observed a decrease in leukotrienes and an
increase in prostacyclin after consumption of a

flavonoid-rich dark

chocolate (compared with a

flavonoid poor dark chocolate)

[25,26]

.

Thus, the balance between the inhibitory effect of prostacyclin on
platelet aggregation vs the stimulatory effect of leukotrienes, suggests
the possible effect of chocolate procyanidins on in

flammation 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

[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 signi

ficant 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 bene

ficial effect of cocoa

on cardiovascular risk or cardiovascular risk factors. Several studies
indicate that diets rich in polyphenols are associated with a decrease in
blood pressure (BP) levels

[30]

. In the Zutphen Elderly Study

[31]

men

with a usual consumption of 10 g/day of dark chocolate had a lower
systolic BP as compared with men with no or very low intake (

Table 1

).

Furthermore, in a large cohort (N = 19,357) of middle-aged apparently
health German men and women

[32]

, both systolic and diastolic BP

were lower in the quartile characterized by the highest chocolate
consumption (7.5 g/day) as compared with the low consumption
quartile (

Table 1

)

[32]

.

Interestingly, Grassi et al.

[33]

have shown that a

flavonol-rich

dark chocolate decreases BP, increases

flow-mediated dilation while

improving insulin sensitivity and beta-cell function in hypertensive
patients with impaired glucose tolerance

[33]

.

A recent meta-analysis of 13 trials on the effect of

flavanol-rich

cocoa products on BP in hypertensive and normotensive individuals
revealed a signi

ficant 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

flow-mediated dilation), after acute

(4%; 6 studies) and chronic (1.5%; 2 studies) intake

[12]

.

The effect of cocoa on lipid changes is controversial. After pooling

data from eight trials, cocoa consumption lowered LDL (by 6 mg/dL),
but not HDL cholesterol

[12]

.

2.3. Evidence from epidemiology

Cocoa and chocolate represent the most important source of

flavonoids, but it is not unique. Several studies investigated the asso-
ciation of total

flavonoids with CAD risk

[35

–37]

. The prospective studies

of

flavonoids and risk of CAD published up to 2006 are reviewed in Ding

et al.

[38]

. A meta-analysis of 8 prospective studies, including almost

140,000 subjects, found that intake of

flavonoids from any source

protect against CAD mortality (relative risk equal 0.81; 95% CI: 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

[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

first acute myocardial infarction (

Table 1

)

[40]

. Finally,

in a large U.S. cohort of postmenopausal women followed for 16 years
chocolate consumption, and other

flavonoid-rich foods, has been

inversely associated with CVD death

[36,41]

. However, after multi-

variable adjustment the highly signi

ficant association found in the age

and energy adjusted model (p

b0.001) became borderline (p=0.062)

[41]

.

3. Coffee

Albeit coffee represents, along with tea, the most worldwide

consumed beverage, its potential effect on cardiovascular disease is
still controversial (

Table 2

)

[42

–53]

. Apart from being the main source

of caffeine, coffee contains several other compounds

– in particular

phenols, vitamin B3, magnesium, potassium and

fiber

[54]

– that may

have either bene

ficial or detrimental effects on cardiovascular system.

Cafestol and kahweol are both diterpenoid hypercholesterolemic
compounds present in coffee beans

[55]

; however, the use of a paper

filter during coffee preparation is sufficient to limit their content

[56]

.

Nevertheless, many other compounds with antioxidant properties

[57,58]

namely chlorogenic acid,

flavonoids, melanoidins, furans,

pyrroles and maltol have been found in coffee

[59]

. De

finitely, 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

16

A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) 15

–25

caffeine is associated with an increase in blood pressure

[63,64]

,

systemic vascular resistance

[65]

, arterial stiffness

[66,67]

, plasma

renin activity, epinephrine, and norepinephrine

[68]

and has unfavor-

able effects on endothelial function in healthy subjects

[69]

. Moreover,

in a randomized double-blinded study Riksen et al.

[62]

observed that

ischemic preconditioning, which exerts a cardioprotective effect, was
completely abolished by caffeine. In addition consumption of coffee,
especially in the form of boiled coffee, raises serum lipids

[70,71]

and

homocysteine levels

[72]

.

3.2. Coffe and cardiovascular risk factors: positive aspects

The adverse effects of coffee and speci

fically caffeine are in part

counterbalanced by the favorable effect on type 2 diabetes mellitus

[73

–75]

and by the lack of association with incident hypertension in

women

[76]

. An important contribution to the explanation of the role

of coffee on CAD emerges from the very recent study of Shechter et al.

[77]

. The authors found that acute ingestion of caffeine (in the form of

capsules containing 200 mg of caffeine) was associated with an
increase in

flow-mediated dilation and in a decrease in C-reactive

protein in subjects with and without CAD

[77]

.

Moreover, caffeine consumption has been shown to inhibit platelet

aggregation, possibly by upregulation of adenosine A2A receptors

[78]

.

3.3. Evidence from epidemiology

Early

[42,44,45]

and more recent meta-analyses

[79,80]

concluded

that overall coffee consumption was not signi

ficantly associated with an

increased CAD risk, especially when only prospective studies were
considered (

Table 2

). Rather, Wu et al.

[80]

have shown that drinking 1

to 4 cups of coffee per day was associated with a lower risk of CAD,
(relative risk of 0.87; 95%CI: 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

[81]

, the

inverse association found in both men and women between regular
coffee consumption and all-cause mortality was independent of caffeine
intake and largely explained by a moderate reduction in cardiovascular
disease (CVD) risk mortality (

Table 2

). Furthermore, in the same study

also decaffeinated coffee was inversely associated with all-cause and
cardiovascular mortality, albeit the observed effects were relatively
small (

Table 2

)

[81]

.

Several factors should be taken into account when coffee con-

sumption is investigated in relation to CVD risk factors. One of them is
how coffee is prepared. Several lines of evidence suggest that boiled
coffee raises cholesterol levels

[71]

. In agreement with these

findings,

in a Swedish case-control study

[82]

, the incidence of

first nonfatal

myocardial infarction was 1.4 times higher, in men drinking boiled
coffee vs men drinking

filtered coffee, with an even higher risk for

women (RR: 1.63; 95% CI: 1.04

–2.56,

Table 2

).

However, Baylin et al.

[83]

showed that following a transient coffee

intake, subjects with a sedentary lifestyle and with three or more risk
factors for CAD have an increased MI risk (

Table 2

). In addition,

drinking more than 10 cups of coffee per day was an independent risk
factor in a retrospective case-control study for sudden cardiac arrest
in patients with CAD

[84]

. Nevertheless, these

findings stand in

contrast with others

[85

–87]

. In particular, while in one study

[85]

the

authors observed an inverse association between coffee consumption
and mortality in the

first 90 days after infarction (

Table 2

), in the post-

MI patients of the GISSI study

[86]

moderate coffee consumption was

not associated with CVD events (

Table 2

). Furthermore, in a Dutch

cohort of healthy men and women the authors observed a J shaped
relationship between incident CAD morbidity and coffee intake with
an hazard ratio of 0.55 in subjects drinking from 3 to up 6 cups of
coffee per day (

Table 2

)

[87]

. The

“J-shaped” relationship between

CAD and coffee (meaning that after an initial decrease in relative risk
for CAD by increasing coffee intake the curve reaches a plateau, and
reverts at higher amounts) was also observed in the study of

Table

1

Summary

of

studies

on

chocolate/cocoa

and

vascular

events.

Chocolate,

Reference

Study

Exposure

Endpoint

N.

cases/N.

total

Adjusted

RR

or

OR

(95%

CI)

Summary

Buijsse

B,

2006

[31]

Zutphen

Elderly

Study,

prospective

study

Cocoa

intake,

highest

vs

lowest

tertile

Cardiovascular

mortality

152/470

0.50

(0.32

–

0.78)

In

elderly

men,

inverse

association

between

cocoa

intake

and

cardiovascular

and

all-cause

mortality

Cocoa

intake,

highest

vs

lowest

tertile

All

cause

mortality

162/470

0.52

(0.38

–

0.71)

Gallus

S,

2009

[39]

Italy,

case-control

study

≥

3

chocolates/day

vs

b

2

chocolates/day

AMI

760/1442

0.23

(0.08

–

0.65)

Eating

≥

3

chocolates/day

is

inversely

associated

with

nonfatal

AMI

Janszky

I,

2009

[40]

Stockholm

Heart

Epidemiology

Program,

population-based

inception

cohort

study

Chocolate

consumption,

50

g;

≥

2/week

vs

no

consumption

Cardiac

mortality,

diabetes

free

post

AMI

107/1169

0.34

(0.17

–

0.70)

Total

mortality,

diabetes-free

post

AMI

210/1169

0.94

(0.58

–

1.53)

Recurrent

AMI,

diabetes-free

post

AMI

250/1169

0.86

(0.54

–

1.37)

Congestive

heart

failure,

diabetes-free

post

AMI

279/1169

0.78

(0.52

–

1.16)

Inverse

association

with

cardiac

mortality

in

post-AMI

patients

Stroke,

diabetes-free

post

AMI

111/1169

0.62

(0.33

–

1.16)

Any

non-fatal

event,

diabetes-free

post

AMI

471/1169

0.82

(0.59

–

1.14)

Buijsse

B,

2010

[32]

EPIC-Potsdam

Study,

prospective

study

Chocolate

intake,

highest

vs

lowest

quartile

Myocardial

infarction

166/19,357

0.73

(0.47

–

1.15)

Reduced

CVD

risk

according

to

chocolate

consumption

partly

due

to

its

BP-lowering

effect

Chocolate

intake,

highest

vs

lowest

quartile

Stroke

136/19,357

0.52

(0.30

–

0.89)

17

A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) 15

–25

Table 2
Summary of studies on coffee and vascular events.

Coffee,
Reference

Study

Exposure

Endpoint

N. cases/N. total

Adjusted RR or
OR (95% CI)

Summary

Grobbee DE,

1990

[88]

The Health Professional
Follow-up Study,
longitudinal study

Total Coffee
consumption

≥4 cups/day vs none

Nonfatal MI, CHD death,
CABG, PTCA, Stroke

Both caffeine and caffeinated coffee intake do
not increase CHD and stroke risk

Nonfatal MI and CHD death

221/45,589; Men

1.08 (0.72

–1.60)

CABG and PTCA

136/45,589; Men

0.95 (0.56

–1.61)

Total CHD

357/45,589; Men

1.00 (0.73

–1.37)

Fatal and nonfatal stroke

54/45,589; Men

0.48 (0.18

–1.31)

Total CVD

408/45,589; Men

0.90 (0.67

–1.22)

Caffeinated coffee
consumption

≥4 cups/day vs none

Nonfatal MI and CHD death

221/45,589; Men

1.01 (0.62

–1.65)

CABG and PTCA

131/45,589; Men

0.66 (0.32

–1.34)

Total CHD

342/45,589; Men

0.84 (0.56

–1.25)

Fatal and nonfatal stroke

52/45,589; Men

0.28 (0.06

–1.26)

Total CVD

390/45,589; Men

0.74 (0.50

–1.09)

Decaffeinated coffee
consumption

≥4 cups/day vs none

Nonfatal MI and CHD death

214/45,589; Men

1.55 (0.85

–2.81)

Decaffeinated coffee moderately increases
CHD risk

CABG and PTCA

132/45,589; Men

1.74 (0.81

–3.73)

Total CHD

346/45,589; Men

1.63 (1.02

–2.60)

Fatal and nonfatal stroke

51/45,589; Men

1.16 (0.26

–5.10)

Total CVD

394/45,589; Men

1.58 (1.01

–2.48)

Myers MG,

1992

[42]

11 Prospective Studies
(cohorts without history
of MI), meta-analysis

Coffee intake,

≥6 cups/day

vs

≤1 cup/day

Coronary events

1.09 (0.97

–1.22)

No association between coffee
consumption and CHD

Later Cohort

1.27 (1.17

–1.39)

Earlier Cohort

0.92 (0.80

–1.06)

Pooled cohort

1.18 (1.03

–1.34)

Kawachi I,

1994

[44]

8 case-control and 15 cohort
studies, meta-analysis

Coffee drinking,

≥5 cups/day

vs none

CHD

Pooled case-control

1.63 (1.50

–1.78)

Increased CHD risk according to increased
coffee drinking

Pooled cohort

1.05 (0.99

–1.12)

Weak CHD risk in habitual coffee drinkers

Woodward M,

1999

[52]

Scottish Heart Health Study,
cohort study

Coffee consumption

≥5 vs none

CHD

?/5645; Men

0.68 (0.37

–1.24)

Moderate bene

fit from coffee consumption

CHD

?/5800; Women

0.55 (0.18

–1.66)

Hammar N,

2003

[82]

The SHEEP and the VHEEP Study,
population-based case-control study

Consumption

N9 dL filtered

coffee/day vs

≤3 dL/day

First nonfatal MI

1171/1813; Men

1.93 (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

N9 dL mixed

coffee/day vs

≤3 dL/day

2.24 (1.08

–4.64)

Consumption

N9 dL boiled

coffee/day vs

≤3 dL/day

2.20 (1.17

–4.15)

Consumption

N9 dL filtered

coffee/day vs

≤3 dL/day

First nonfatal MI

472/854; Women

1.43 (0.81

–2.54)

Consumption

N9 dL mixed

coffee/day vs

≤3 dL/day

2.91 (0.28

–29.69)

Consumption

N9 dL boiled

coffee/day vs

≤3 dL/day

4.97 (0.55

–44.73)

Boiled vs

filtered coffee

1171/1813; Men

1.41 (1.07

–1.85)

Boiled coffee increases the occurrence of
first nonfatal MI

Boiled vs

filtered coffee

472/854; Women

1.63 (1.04

–2.56)

Panagiotakos DB,

2003

[51]

The CARDIO2000, case-control study

Very heavy coffee drinkers
(

N600 mL/day) vs none

ACS

848/1078

3.10 (1.82

–5.26)

J-shaped relation between coffee intake
and ACS risk

Happonen P,

2004

[48]

The Kuopio Ischaemic Heart Disease
Risk Factor Study, prospective study

Moderate drinkers vs heavy
drinkers (

≥814 mL/day)

Acute coronary events
(MI or coronary death)

269/1971; Men

1.43 (1.06

–1.94)

Heavy coffee drinking raises the risk of
acute MI or coronary death

Mukamal KJ,

2004

[85]

Determinants of Myocardial Infarction
Onset Study, inception cohort study

Coffee consumption

N14

cups/week vs none

Mortality after AMI

315/1902

1.13 (80

–1.60)

No association between coffee consumption
and post-infarction mortality

Coffee consumption

N14

cups/week vs none

Deaths within 90 days

79/1902

0.38 (0.17

–0.86)

Coffee consumption

N14

cups/week vs none

Deaths beyond 90 days

236/1902

1.52 (1.03

–2.26)

Time variation in coffee effect

18

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Di
Castelnuovo

et
al.
/

European

Journal

of
Internal

Medicine

23
(2012)

15

–

25

Table 2 (continued)

Coffee,
Reference

Study

Exposure

Endpoint

N. cases/N. total

Adjusted RR or
OR (95% CI)

Summary

Andersen LF,

2006

[49]

Iowa Women's Health Study,
prospective study

Regular coffee

≥6 cups/day

vs none

Death due to CVD,
postmenopausal

1411/41,836

0.92 (0.74

–1.14)

Decaffeinated coffee

≥6

cups/day vs none

Death due to CVD,
postmenopausal

1411/41,836

0.99 (0.70

–1.39)

U-shaped associations (death from CVD
and total mortality)

Regular coffee

≥6 cups/day

vs none

Total mortality,
postmenopausal

4265/41,836

0.95 (0.84

–1.07)

Decaffeinated coffee

≥6

cups/day vs none

Total mortality,
postmenopausal

4265/41,836

0.94 (0.78

–1.14)

Lopez-Garcia E,

2006

[43]

Prospective cohort study

Coffee intake,

≥6 cups/day

vs

b1 cup/month

CHD
CHD

2173/44,005; Men

0.72 (0.49

–1.07)

2254/84,488; Women

0.87 (0.68

–1.11)

No indication that coffee (or caffeine)
intake increases CHD

Caffeine intake,

≥6 cups/day

vs

b1 cup/month

CHD

2173/44,005; Men

0.97 (0.84

–1.11)

CHD

2254/84,488; Women

0.97 (0.85

–1.11)

Azevedo A,

2006

[50]

Community-based case-control
study

Regular ever coffee drinkers

AMI

290/364; Men

0.5 (0.3

–1.1)

Signi

ficant↓MI in men with no family

history of AMI; non signi

ficant ↑ MI in

men withfamily history of AMI

Kleemola P,

2006

[53]

Finnish men and women,
prospective study

Coffee consumption

N7 cups/day

vs 1

–3 cups/day

Non fatal MI

891/10,075; Men

0.79 (0.64

–0.98)

Coffee consumption

N7 cups/day

vs 1

–3 cups/day

CHD mortality

891/10,075; Men

1.22 (0.90

–1.65)

Coffee consumption

N7 cups/day

vs 1

–3 cups/day

All cause mortality

1201/10,075; Men

1.01 (0.84

–1.22)

Coffee drinking is not associated with
CHD risk and death

Coffee consumption

N7 cups/day

vs 1

–3 cups/day

Non fatal MI

319/10,387

0.93 (0.63

–1.36)

Coffee consumption

N7 cups/day

vs 1

–3 cups/day

CHD mortality

99/10,387

0.57 (0.28

–1.16)

Coffee consumption

N7 cups/day

vs 1

–3 cups/day

All cause mortality

444/10,387

0.62 (0.44

–0.87)

Baylin A,

2006

[83]

Costa Rica, case-crossover design

Habitual coffee consumption

Nonfatal MI, 1 h after
coffee drinking

≤1 cup/day

9/66

4.14 (2.03

–8.42)

Coffee intake probably set off MI

2

–3 cups/day

44/280

1.60 (1.16

–2.21)

≥4 cups/day

27/120

1.06 (0.69

–1.63)

Cornelis MC,

2006

[47]

Slow caffeine metabolizer

Coffe intake

≥4 cups/day

vs

b1 cup/day

First acute nonfatal MI

2014/2014

1.64 (1.14

–2.34)

Increased MI risk only in subjects with
impaired caffeine metabolism

Rapid caffeine metabolizer
population-based case-control study

Coffe intake

≥4 cups/day

vs

b1 cup/day

First acute nonfatal MI

2014/2014

0.99 (0.66

–1.48)

Silletta MG,

2007

[86]

GISSI-Prevenzione trial, prospective
study

Coffee consumption

N4

cups/day vs none

CVD events (CV death,
nonfatal MI, nonfatal
stroke in post-MI patients

1167/11,213

0.88 (0.64

–1.20)

Moderate coffee intake is not associated
with CV events post-MI

Larsson LC,

2008

[89]

Alpha-Tocopherol, Beta-Carotene

Coffee consumption

≥8

cups/day vs

b2 cups/day

Stroke subtypes

Cancer Prevention Study,
prospective study

Cerebral infarction

2702/26,556; Men

0.77 (0.66

–0.90)

High coffee consumption lowers cerebral
infarction risk

Intracerebral hemorrhages

383/26,556; Men

0.98 (0.66

–1.47)

Subarachnoid
hemorrhages

196/26,556; Men

1.18 (0.63

–2.20)

Lopez-Garcia E,

2008

[81]

Health Professionals Follow-up
Study and Nurses' Health Study,
prospective cohort study

Coffee consumption

≥6 cups/day

vs

b1 cup/month

CVD mortality

2049/41,736; Men

0.56 (0.31

–1.03)

Coffee consumption

≥6 cups/day

vs

b1 cup/month

CVD mortality

2368/86,214; Women

0.81 (0.61

–1.06)

Coffee consumption

≥6 cups/day

vs

b1 cup/month

Cancer mortality

2491/41,736; Men

1.14 (0.79

–1.65)

Coffee consumption

≥6 cups/day

vs

b1 cup/month

Cancer mortality

5011/86,214; Women

1.05 (0.87

–1.28)

Coffee consumption

≥6 cups/day

vs

b1 cup/month

Other causes

2348/41,736; Men

0.65 (0.11

–1.04)

Coffee consumption

≥6 cups/day

vs

b1 cup/month

Other causes

3716/86,214; Women

0.60 (0.46

–0.77)

(continued on next page)

19

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–

25

Table 2 (continued)

Coffee,
Reference

Study

Exposure

Endpoint

N. cases/N. total

Adjusted RR or
OR (95% CI)

Summary

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

b1cup/month

All causes

6888/41,736; Men

0.80 (0.62

–1.04)

Coffee consumption

≥6 cups/day

vs

b1cup/month

All causes

11,095/86,214; Women

0.83 (0.73

–0.95)

Decaffeinated coffee
consumption

≥4 cups/day

vs

b1cup/month

CVD mortality

2049/41,736; Men

0.83 (0.52

–1.31)

Decaffeinated coffee
consumption

≥4 cups/day

vs

b1cup/month

CVD mortality

2368/86,214; Women

0.55 (0.30

–1.04)

Decaffeinated coffee
consumption

≥4 cups/day

vs

b1cup/month

Cancer mortality

2491/41,736; Men

1.20 (0.87

–1.66)

Decaffeinated coffee
consumption

≥4 cups/day

vs

b1cup/month

Cancer mortality

5011/86,214; Women

0.86 (0.60

–1.23)

Decaffeinated coffee
consumption

≥4 cups/day

vs

b1cup/month

All causes

6888/41,736; Men

0.81 (0.64

–1.03)

Decaffeinated coffee
consumption

≥4 cups/day

vs

b1cup/month

All causes

11,095/86,214; Women

0.78 (0.61

–1.00)

Wu JN, 2009

[80]

21 prospective cohort studies,
meta-analysis

Coffee consumption

b1

cup/day (US) or

≤2

cups/day(Europe) vs

≥6

or

≥7 cups/day

CHD

15,599/407,806; pooled

1.07 (0.87

–1.32)

No long-term increased CHD risk

Moderate coffee consumption

CHD

Women

0.82 (0.73

–0.92)

Lower CHD risk in moderate coffee
drinker women

de Koning Gans JM,

2010

[87]

Prospective study

Coffee consumption

N6 cups/day

vs

b1 cup/day

CHD morbidity

1387/37,514

0.91 (0.74

–1.11)

U shaped association between coffee
consumption and lower CHD morbidity

Coffee consumption

N6 cups/day

vs

b1 cup/day

Stroke morbidity

563/37,514

1.22 (0.88

–1.70)

Coffee consumption

N6 cups/day

vs

b1 cup/day

CHD mortality

123

0.73 (0.37

–1.42)

Non signi

ficant slight reduction in CHD

mortality according to moderate coffee
consumption

Coffee consumption

N6 cups/day

vs

b1 cup/day

Stroke mortality

70

1.34 (0.49

–3.64)

Coffee consumption

N6 cups/day

vs

b1 cup/day

All causes mortality

1405

0.93 (0.76

–1.15)

No effect of coffee on stroke or all causes
mortality

Mostofsky E,

2010

[90]

Stroke onset study, multicenter
case-crossover study

Coffee drinkers vs non drinkers

Stroke onset in subjects
with acute ischemic stroke

1 h after 1 serving of coffee

35/390

2.0 (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)

20

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–

25

Panagiotakos et al.

[51]

. Finally, the studies aimed at examining the

association between coffee consumption and stroke have yielded
con

flicting results (

Table 2

)

[86

–90]

.

A non linear dose

–response relationship between coffee intake and

CVD risk may explain the heterogeneity in

findings from different

studies (which typically investigated the role of coffee at various doses)
and, at the least in part, the null

findings of meta-analyses. More

accurate quantitative review of the literature that consider the

“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 classi

fied into black

(fermented) tea

– mainly drunk in Europe, North America and North

Africa

– and green tea (unfermented), principally consumed in Asia

[92

–94]

. Because of its high content of catechins (epicatechin,

epicatechin gallate, epigallocatechin and epigallocatechin gallate), also
known as tea

flavonoids, tea consumption seems to protect against the

development of CVD

[95]

.

Flavonoids reduce platelet aggregation and prevent oxidation of low

density lipoproteins because of their antioxidant properties

[96

–99]

. In

addition, catechins intercede in the process of vascular in

flammation

and atherosclerosis through several actions (e.g. anti-hypertensive, anti-
lipidemic, anti-in

flammatory, anti-proliferative and anti-thrombogenic)

[100

–102]

. Thus, considering that catechins represent 80

–90% of total

flavonoids in green tea

[100,103]

, whereas they are only 20

–30% in black

tea

[100,103]

, it is reasonable to assume that green tea would exert a

more pronounced bene

ficial 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

flavonoids in

preventing ischemic heart disease (

Table 3

)

[104]

. In the large Dutch

cohort of healthy men and women from the European Prospective
Investigation into Cancer and Nutrition (EPIC)

[87]

, the consumption

of 3 to 6 cups of tea per day (mainly in form of black tea) was associated
with a reduced risk of CAD mortality (

Table 3

)

[87]

. Regarding black

tea, lines of evidence suggest a reduction in the risk of CAD accordingly
to a consumption of three or more cups per day

[105,106]

, through a

mechanism involving the protective effect of tea antioxidants.

In a meta-analysis based on 10 cohort and 7 case-control studies

[107]

, the incidence rate of myocardial infarction decreased by 11%

with an increase in tea consumption of 3 cups/day (

Table 3

). Very

recently, the association of black or green tea with CAD has been
extensively investigated in a meta-analysis of 13 studies

[108]

. While

after pooling no signi

ficant 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]

. Dose

–response meta-analysis suggested that

an increase in green tea consumption of 1 cup/d was associated with a
1% to 18% decrease in the risk of developing CAD

[108]

.

All in all, these studies suggest that whereas the bene

ficial effects of

black tea seem to be con

fined 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 bene

ficial 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

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 con

fined effect to

black or green tea, reduced mortality and morbidity of stroke

[111]

.

Indeed, subjects drinking three or more cups of tea per day had a 21%
reduced risk of fatal or non-fatal stroke events (

Table 3

)

[111]

. These

findings are in line with those from the Alpha-Tocopherol, Beta-
Carotene Cancer Prevention Study clearly showing that compared to
non drinkers, men drinking 2 or more cups of tea per day had a 21%
lower cerebral infarction risk (

Table 3

)

[90]

. On the contrary, in the

Dutch EPIC cohort

[87]

, the consumption of 3 to 6 cups of tea per day

was not associated with a reduced risk of stroke (

Table 3

)

[87]

.

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

flow-

mediated dilation) by 3.4%, whereas the acute effect was modest
(1.7%) and not signi

ficant

[12]

. Finally, the intake of 1 L black tea per

day reportedly inhibited platelet activation by 4

–10%

[109]

.

However, even if the magnitude of the observed associations

between tea consumption and CVD is small, it appears to be important
from a public health point of view, since tea is a very common beverage
largely consumed all over the world.

5. Conclusions

Prevention of cardiovascular disease is a crucial part of health care,

the two main ways for preventing it being lifestyle changes and
medication. In particular, lifestyle changes may have a major impact in
preventing the incidence of atherosclerosis, arterial thrombosis and
ischemic disease. Regular physical activity combined with a diet rich in
fruit, vegetables, complex carbohydrates, monounsaturated fat and

fish,

moderate and regular alcohol consumption but poor in salt, saturated fat
and simple sugars, plays an important role in the reduction of the
development of atherosclerosis and other chronic degenerative disease

[3

–5]

.

However, chocolate, coffee and tea, unfairly not included in the

above mentioned

“traditional healthy food basket”, have received much

attention over the past few years. They are consumed worldwide, are
important dietary sources of polyphenols (

flavonoids) and share

antioxidant properties that link the three factors. Several in vitro and
in vivo studies have tried to elucidate the role of these foods in
development of cardiovascular disease, and despite the fact that a large
amount of experimental studies clearly indicated a bene

ficial effect of

polyphenols in regulating CAD risk pro

file, data from epidemiological

studies are not conclusive.

The blood pressure lowering effects and the anti-in

flammatory

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 bene

ficial 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

21

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–25

Table 3
Summary of studies on tea and vascular events.

Tea, Reference

Study

Exposure

Endpoint

N. cases/N. total

Adjusted RR or
OR (95% CI)

Summary

Woodward M, 1999

[52]

Scottish Heart Health Study,
cohort study

Tea consumption

CHD

?/5724; Men

1.10 (0.51

–2.37)

Tendency to increased risk

CHD

?/5843; Women

1.06 (0.28

–4.05)

Peters U, 2001

[107]

10 cohort studies and 7
case-control studies,
meta-analysis

Tea consumption 3 cups/day vs none

Stroke, MI and all CHD

Stroke and CHD too heterogeneous

MI

–

0.89 (0.70

–1.01)

Incidence rate of MI decreased by
11% with an increase in tea
consumption of 3 cups/day

Geleijnse JM, 2002

[104]

The Rotterdam Study,
population-based study

Tea drinkers

N375 mL/day vs

nontea drinkers

Fatal and nonfatal MI
Incident Mi

146/4807

0.57 (0.33

–0.98)

Strong reduction of fatal MI
according to high green tea
consumption

Nonfatal MI

116/4807

0.68 (0.37

–1.26)

Fatal MI

30/4807

0.30 (0.09

–0.94)

Andersen LF, 2006

[49]

Iowa Women's Health Study,
prospective study, postmenopausal

Tea

N3 cups/day vs none

Death due to CVD

1411/41,836

0.99 (0.86

–1.14)

Tea no associations

Tea

N3 cups/day vs none

Total mortality

4265/41,836

1.03 (0.95

–1.12)

Kuriyama S, 2006

[110]

The Ohsaki National Health
Insurance Cohort Study,
population based prospective
study

Green tea consumption 3

–4

cups/day vs

b1 cup/day

CVD, cancer and all causes
mortality
CVD mortality

481/40,530; Men

0.87 (0.64

–1.19)

All cause mortality

2668/40,530; Men

0.88 (0.78

–1.00)

Green tea consumption lowers all
causes and CVD mortality

CVD mortality

411/40,530; Women

0.61 (0.44

–0.85)

All cause mortality

1541/40,530; Women

0.80 (0.68

–0.94)

Larsson LC, 2008

[89]

Alpha-Tocopherol, Beta-Carotene
Cancer Prevention Study,
prospective study

Tea consumption

≥8cups/day

vs

b2 cups/day

Cerebral infarction

2702/26,556; Men

0.79 (0.68

–0.92)

High tea consumption reduces Cerebral
infarction risk

Intracerebral hemorrhages

383/26,556; Men

1.10 (0.77

–1.58)

Subarachnoid hemorrhages

196/26,556; Men

0.76 (0.42

–1.37)

Arab L, 2009

[111]

Meta

–analysis

Green or black tea consumption

≥3

cups/day vs

b1 cup/day

Fatal or nonfatal stroke

4378/194,965; pooled

0.79 (0.73

–0.85)

≥3 cups/day of green or black reduce
fatal and nonfatal stroke

Mostofsky E, 2010

[90]

Stroke onset study, multicenter
case-crossover study

1 h after 1 serving of caffeinated tea

Stroke onset in subjects with
acute ischemic stroke

0.9 (0.4

–2.0)

de Koning Gans JM,

2010

[87]

Prospective study

Tea consumption

N6 cups/day

vs

b1 cup/day

CHD morbidity

1387/37,514

0.64 (0.46

–0.90)

Tea consumption is linearly
associated with lower CHD
morbidity

Tea consumption

N6 cups/day

vs

b1 cup/day

Stroke morbidity

563/37,514

1.24 (0.82

–1.89)

Tea consumption

N6 cups/day

vs

b1 cup/day

CHD mortality

123

0.93 (0.39

–2.25)

3 to 6 cups of tea/day reduce CHD
risk mortality

Tea consumption

N6 cups/day

vs

b1 cup/day

Stroke mortality

70

1.16 (0.38

–3.56)

No effect of tea on both stroke or all
causes mortality

Tea consumption

N6 cups/day

vs

b1 cup/day

All causes mortality

1405

1.13 (0.87

–1.48)

22

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–

25

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 pro

file with a regular and moderate consump-

tion, while healthy outcomes vanish at heavy consumption.

Con

flict of interest statement

All authors disclose any actual or potential con

flict 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 in

fluence, 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 bene

ficial 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.

References

[1] Murray CJL, Lopez AD. The Global Burden of Disease: A Comprehensive

Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors
in 1990 and Projected to 2020. Boston, Mass: Harvard School of Public Health;
1996.

[2] Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, et al. Effect of

potentially modi

fiable risk factors associated with myocardial infarction in 52

countries (the INTERHEART study): case-control study. Lancet 2004;364:937

–52.

[3] Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of

coronary heart disease in women through diet and lifestyle. N Engl J Med
2000;343:16

–22.

[4] de Lorgeril M, Salen P, Martin JL, 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. Circulation

1999;99:779

–85.

[5] Willett WC, Sacks F, Trichopoulou A, Drescher G, Ferro-Luzzi A, Helsing E, et al.

Mediterranean diet pyramid: a cultural model for healthy eating. Am J Clin Nutr
1995;61:S1402

–6.

[6] Keys A, Menotti A, Karvonen MJ, Aravanis C, Blackburn H, Buzina R, et al. The diet

and 15-year death rate in the Seven Countries Study. Am J Epidemiol 1986;124:
903

–15.

[7] Trichopoulou A, Costacou T, Bamia C, Trichopoulos D. Adherence to a

Mediterranean diet and survival in a Greek Population. N Engl J Med 2003;348:
2599

–608.

[8] So

fi F, Abbate R, Gensini GF, Casini A. Accruing evidence on benefits of adherence

to the Mediterranean diet on health: an updated systematic review and meta-
analysis. Am J Clin Nutr 2010;92:1189

–96.

[9] Dai J, Jones DP, Goldberg J, Ziegler TR, Bostick RM, Wilson PW, et al. Association

between adherence to the Mediterranean diet and oxidative stress. Am J Clin
Nutr 2008;88:1364

–70.

[10] Pitsavos C, Panagiotakos DB, 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. Am J Clin Nutr 2005;82:694

–9.

[11] Huxley RR, Neil HA. The relation between dietary

flavonol intake and coronary

heart disease mortality: a meta-analysis of prospective cohort studies. Eur J Clin
Nutr 2003;57:904

–8.

[12] Hooper L, Kroon PA, Rimm EB, Cohn JS, Harvey I, Le Cornu KA, et al. Flavonoids,

flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized
controlled trials. Am J Clin Nutr 2008;88:38

–50.

[13] Risner CH. Simultaneous determination of theobromine, (+)-catechin, caffeine,

and (

−)-epicatechin in standard reference material baking chocolate 2384,

cocoa, cocoa beans, and cocoa butter. J Chromatogr Sci 2008;46:892

–9.

[14] McShea A, Ramiro-Puig E, Munro SB, Casadesus G, Castell M, Smith MA. Clinical

bene

fit and preservation of flavonols in dark chocolate manufacturing. Nutr Rev

2008;66:630

–41.

[15] Lee KW, Kim YJ, Lee HJ, Lee CY. Cocoa has more phenolic phytochemicals and a

higher antioxidant capacity than teas and red wine. J Agric Food Chem 2003;51:
7292

–5.

[16] Sera

fini M, Bugianesi R, Maiani G, Valtuena S, De Santis S, Crozier A. Plasma

antioxidants from chocolate

– dark chocolate may offer its consumers health

bene

fits the milk variety cannot match. Nature 2003;424:1013.

[17] Engler MB, Engler MM, Chen CY, Malloy MJ, Browne A, Chiu EY, et al. Flavonoid-

rich dark chocolate improves endothelial function and increases plasma
epicatechin concentrations in healthy adults. J Am Coll Nutr 2004;23:197

–204.

[18] Wang JF, Schramm DD, Holt RR, Ensunsa JL, Fraga CG, Schmitz HH, et al. A dose

–

response effect from chocolate consumption on plasma epicatechin and
oxidative damage. J Nutr 2000;130:2115S

–9S.

[19] Mao TK, Van de Water J, Keen CL, Schmitz HH, Gershwin ME. Effect of cocoa

flavanols and their related oligomers on the secretion of interleukin-5 in
peripheral blood mononuclear cells. J Med Food 2002;5:17

–22.

[20] Kim JE, Son JE, Jung SK, Kang NJ, Lee CY, Lee KW, 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. Br J Nutr 2010;104:957

–64.

[21] 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. JAMA 2007;298:49

–60.

[22] Hermann F, Spieker LE, Ruschitzka F, Sudano I, Hermann M, Binggeli C, et al. Dark

chocolate improves endothelial and platelet function. Heart 2006;92:119

–20.

[23] Rein D, Paglieroni TG, Wun T, Pearson DA, Schmitz HH, Gosselin R, et al. Cocoa

inhibits platelet activation and function. Am J Clin Nutr 2000;72:30

–5.

[24] 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. J
Cardiovasc Pharmacol 2006;47:S197

–205 discussion S206-9.

[25] Schramm DD, Wang JF, Holt RR, Ensunsa JL, Gonsalves JL, Lazarus SA, et al.

Chocolate procyanidins decrease the leukotriene-prostacyclin ratio in humans
and human aortic endothelial cells. Am J Clin Nutr 2001;73:36

–40.

[26] Steinberg FM, Bearden MM, Keen CL. Cocoa and chocolate

flavonoids:

implications for cardiovascular health. J Am Diet Assoc 2003;103:215

–23.

[27] Chun OK, Chung SJ, Claycombe KJ, Song WO. Serum C-reactive protein

concentrations are inversely associated with dietary

flavonoid intake in US

adults. J Nutr 2008;138:753

–60.

[28] Hamed MS, Gambert S, Bliden KP, Bailon O, Singla A, Antonino MJ, et al. Dark

chocolate effect on platelet activity, C-reactive protein and lipid pro

file: a pilot

study. South Med J 2009;101:1203

–8 Erratum in: South Med J 2009;102:332.

[29] 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. J Nutr 2008;138:1939

–45.

[30] Manach C, Mazur A, Scalbert A. Polyphenols and prevention of cardiovascular

diseases. Curr Opin Lipidol 2005;16:77

–84.

[31] Buijsse B, Feskens EJ, Kok FJ, Kromhout D. Cocoa intake, blood pressure, and

cardiovascular mortality: the Zutphen Elderly Study. Arch Intern Med 2006;166:
411

–7.

[32] 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.
Eur Heart J 2010;31:1616

–23.

[33] 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. J Nutr
2008;138:1671

–6.

[34] Ried K, Sullivan T, Fakler P, Frank OR, Stocks NP. Does chocolate reduce blood

pressure? A meta-analysis. BMC Med 2010;28:8

–39.

[35] Rimbach G, Melchin M, Moehring J, Wagner AE. Polyphenols from cocoa and

vascular health

— a critical review. Int J Mol Sci 2009;10:4290–309.

[36] Corti R, Flammer AJ, Hollenberg NK, Lüscher TF. Cocoa and cardiovascular health.

Circulation 2009;119:1433

–41.

[37] Hollman PCH, Geelen A, Kromhout D. Dietary

flavonol intake may lower stroke

risk in men and women. J Nutr 2010;140:600

–4.

[38] Ding EL, Hut

fless SM, Ding X, Girotra S. Chocolate and prevention of

cardiovascular disease: a systematic review. Nutr Metab (Lond) 2006;3:2.

[39] 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. Eur J Clin Nutr 2009;63:588

–9.

[40] Janszky I, Mukamal KJ, Ljung R, Ahnve S, Ahlbom A, Hallqvist J. Chocolate

consumption and mortality following a

first acute myocardial infarction: the

Stockholm Heart Epidemiology Program. J Intern Med 2009;266:248

–57.

[41] Mink PJ, Scrafford CG, Barraj LM, Harnack L, Hong C-P, Nettleton JA, et al.

Flavonoid intake and cardiovascular disease mortality: a prospective study. Am J
Clin Nutr 2007;85:895

–909.

[42] Myers MG, Basinski A. Coffee and coronary heart disease. Arch Intern Med

1992;152:1767

–72.

[43] Lopez-Garcia E, van Dam RM, Willett WC, Rimm EB, Manson JE, Stampfer MJ,

et al. Coffee consumption and coronary heart disease in men and women: a
prospective cohort study. Circulation 2006;113:2045

–53.

[44] Kawachi I, Colditz GA, Stone CB. Does coffee drinking increase risk of coronary

heart disease? Results from a meta-analysis. Br Heart J 1994;72:269

–75.

[45] Greenland S. A meta-analysis of coffee, myocardial infarction, and coronary

death. Epidemiology 1993;4:366

–74.

23

A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) 15

–25

[46] Reis JP, Loria CM, Steffen LM, Zhou X, van Horn L, Siscovick DS, et al. Decaffeinated

coffee, caffeine, and tea consumption in young adulthood and atherosclerosis
later in life: the CARDIA study. Arterioscler Thromb Vasc Biol 2010;30:2059

–66.

[47] Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H. Coffee, CYP1A2 genotype,

and risk of myocardial infarction. JAMA 2006;295:1135

–41.

[48] Happonen P, Voutilainen S, Salonen JT. Coffee drinking is dose-dependently

related to the risk of acute coronary events in middle-aged men. J Nutr 2004;134:
2381

–6.

[49] Andersen LF, Jacobs DRJ, Carlsen MH, Blomhoff R. Consumption of coffee is

associated with reduced risk of death attributed to in

flammatory and cardiovascular

diseases in the Iowa Women's Health Study. Am J Clin Nutr 2006;83:1039

–46.

[50] Azevedo A, Barros H. Coffee and myocardial infarction: heterogeneity of an

association in Portuguese men. Cardiovasc Prev Rehabil 2006;13:268

–73.

[51] Panagiotakos DB, 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. J Nutr 2003;133:
3229

–32.

[52] Woodward M, Tunstall-Pedoe H. Coffee and tea consumption in the Scottish

Heart Health Study follow up: con

flicting relations with coronary risk factors,

coronary disease, and all cause mortality. J Epidemiol Community Health
1999;53:481

–7.

[53] Kleemola P, Jousilahti P, Pietinen P, Vartiainen E, Tuomilehto J. Coffee

consumption and the risk of coronary heart disease and death. Arch Intern
Med 2000;160:3393

–400.

[54] Spiller MA. The chemical components of coffee. In: Spiller GA, editor. Caffeine.

Boca Raton: CRC Press; 1998. p. 97

–161.

[55] Urgert R, Katan MB. The cholesterol-raising factor from coffee beans. Annu Rev

Nutr 1997;17:305

–24.

[56] van Dusseldorp M, Katan MB, van Vliet T, Demacker PN, Stalenhoef AF.

Cholesterol-raising factor from boiled coffee does not pass a paper

filter.

Arterioscler Thromb 1991;11:586

–93.

[57] Yanagimoto K, Ochi H, Lee KG, Shibamoto T. Antioxidative activities of fractions

obtained from brewed coffee. J Agric Food Chem 2004;52:592

–6.

[58] Daglia M, Papetti A, Gregotti C, Bertè F, Gazzani G. In vitro antioxidant and ex vivo

protective activities of green and roasted coffee. J Agric Food Chem 2000;48:
1449

–54.

[59] Cornelis MC, El-Sohemy A. Coffee, caffeine, and coronary heart disease. Curr Opin

Clin Nutr Metab Care 2007;10:745

–51.

[60] Svilaas A, Sakhi AK, Andersen LF, Svilaas T, Ström EC, Jacobs Jr DR, et al. Intakes of

antioxidants in coffee, wine, and vegetables are correlated with plasma
carotenoids in humans. J Nutr 2004;134:562

–7.

[61] Pulido R, Hernandez-Garcia M, Saura-Calixto F. Contribution of beverages to the

intake of lipophillic and hydrophillic antioxidants in the Spanish diet. Eur J Clin
Nutr 2003;57:1275

–82.

[62] Riksen NP, Rongen GA, Smits P. Acute and long-term cardiovascular effects of coffee:

implications for coronary heart disease. Pharmacol Ther 2009;121:185

–91.

[63] Nurminen ML, Niittynen L, Korpela R, Vapaatalo H. Coffee, caffeine and blood

pressure: a critical review. Eur J Clin Nutr 1999;53:831

–9.

[64] Noordzij M, Uiterwaal CS, Arends LR, Kok FJ, Grobbee DE, Geleijnse JM. Blood

pressure response to chronic intake of coffee and caffeine: a meta-analysis of
randomized controlled trials. J Hypertens 2005;23:921

–8.

[65] Farag NH, Vincent AS, McKe BS, Whitsett TL, Lovallo WR. Hemodynamic

mechanisms underlying the incomplete tolerance to caffeine's pressor effects.
Am J Cardiol 2005;95:1389

–92.

[66] Smits P, Thien T, van 't Laar A. Circulatory effects of coffee in relation to the

pharmacokinetics of caffeine. Am J Cardiol 1985;56:958

–63.

[67] Karatzis E, Papaioannou TG, Aznaouridis K, Karatzi K, Stamatelopoulos K,

Zampelas A, et al. Acute effects of caffeine on blood pressure and wave re

flections

in healthy subjects: should we consider monitoring central blood pressure? Int J
Cardiol 2005;98:425

–30.

[68] Robertson D, Frölich JC, Carr RK, Watson JT, Holli

field JW, Shand DG, et al. Effects

of caffeine on plasma renin activity, catecholamines and blood pressure. N Engl J
Med 1978;298:181

–6.

[69] Papamichael CM, Aznaouridis KA, Karatzis EN, Karatzi KN, Stamatelopoulos KS,

Vamvakou G, et al. Effect of coffee on endothelial function in healthy subjects.
The role of caffeine. Clin Sci (Lond) 2005;109:55

–60.

[70] Jee SH, He J, Appe LJ, Whelton PK, Suh I, Klag MJ. Coffee consumption and serum

lipids: a meta-analysis of randomized controlled clinical trials. Am J Epidemiol
2001;153:353

–62.

[71] Rodrigues IM, Klein LC. Boiled or

filtered coffee? Effects of coffee and caffeine on

cholesterol,

fibrinogen and C-reactive protein. Toxicol Rev 2006;25:55–69.

[72] Verhoef P, Pasman WJ, van Vliet T, Urgert R, Katan MB. Contribution of caffeine to

the homocysteine-raising effect of coffee: a randomized controlled trial in
humans. Am J Clin Nutr 2002;76:1244

–8.

[73] van Dam RM, Hu FB. Coffee consumption and risk of type 2 diabetes: a systematic

review. JAMA 2005;294:97

–104.

[74] Ciccarone E, Di Castelnuovo A, Salcuni M, Siani A, Giacco A, Donati MB, 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. J Thromb Haemost 2003;1:1744

–52.

[75] Loopstra-Masters RC, Liese AD, Haffner SM, Wagenknecht LE, Hanley AJ.

Associations between the intake of caffeinated and decaffeinated coffee and
measures of insulin sensitivity and beta cell function. Diabetologia 2011;54:
320

–8.

[76] Winkelmayer WC, Stampfer M, Willett WC, Curhan GC. Habitual caffeine intake

and the risk of hypertension in women. JAMA 2005;294:2330

–5.

[77] Shechter M, Shalmon G, Scheinowitz M, Koren-Morag N, Feinberg MS, Harats D,

et al. Impact of acute caffeine ingestion on endothelial function in subjects with
and without coronary artery disease. Am J Cardiol 2011;107(9):1255

–61.

[78] Nardini M, Natella F, Scaccini C. Role of dietary polyphenols in platelet

aggregation. A review of the supplementation studies. Platelets 2007;18:
224

–43.

[79] So

fi F, Conti AA, Gori AM, Eliana Luisi ML, Casini A, Abbate R, et al. Coffee

consumption and risk of coronary heart disease: a meta-analysis. Nutr Metab
Cardiovasc Dis 2007;17:209

–23.

[80] Wu JN, Ho SC, Zhou C, Ling WH, Chen WQ, Wang CL, et al. Coffee consumption

and risk of coronary heart diseases: a meta-analysis of 21 prospective cohort
studies. Int J Cardiol 2009;137:216

–25.

[81] Lopez-Garcia E, van Dam RM, Li TY, Rodriguez-Artalejo F, Hu FB. The relationship

of coffee consumption with mortality. Ann Intern Med 2008;148:904

–14.

[82] 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. J Intern Med 2003;253:653

–9.

[83] Baylin A, Hernandez-Diaz S, Kabagambe EK, Siles X, Campos H. Transient

exposure to coffee as a trigger of a

first nonfatal myocardial infarction.

Epidemiology 2006;17:506

–11.

[84] de Vreede-Swagemakers JJ, Gorgels AP, Weijenberg MP, Dubois-Arbouw WI,

Golombeck B, van Ree JW, et al. Risk indicators for out-of-hospital cardiac arrest
in patients with coronary artery disease. J Clin Epidemiol 1999;52:601

–7.

[85] Mukamal KJ, Maclure M, Muller JE, Sherwood JB, Mittleman MA. Caffeinated

coffee consumption and mortality after acute myocardial infarction. Am Heart J
2004;147:999

–1004.

[86] Silletta MG, Mar

fisi 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. Circulation 2007;116:2944

–51.

[87] de Koning Gans JM, Uiterwaal CS, van der Schouw YT, Boer JM, Grobbee DE,

Verschuren WM, et al. Tea and coffee consumption and cardiovascular morbidity
and mortality. Arterioscler Thromb Vasc Biol 2010;30:1665

–71.

[88] Grobbee DE, Rimm EB, Giovannucci E, Colditz G, Stampfer M, Willett W. Coffee,

caffeine, and cardiovascular disease in men. N Engl J Med 1990;323:1026

–32.

[89] Larsson SC, Männistö S, Virtanen MJ, Kontto J, Albanes D, Virtamo J. Coffee and tea

consumption and risk of stroke subtypes in male smokers. Stroke 2008;39:
1681

–7.

[90] Mostofsky E, Schlaug G, Mukamal KJ, Rosamond WD, Mittleman MA. Coffee and

acute ischemic stroke onset: the Stroke Onset Study. Neurology 2010;75:1583

–8.

[91] Costanzo S, Di Castelnuovo A, Donati MB, Iacoviello L, de Gaetano. Alcohol

consumption and mortality in patients with cardiovascular disease: a meta-
analysis. J Am Coll Cardiol 2010;55:1339

–47.

[92] Graham HN. Green tea composition, consumption, and polyphenol chemistry.

Prev Med 1992;21:334

–50.

[93] Cheng TO. All teas are not created equal: the Chinese green tea and

cardiovascular health. Int J Cardiol 2006;108:301

–8.

[94] McKay DL, Blumberg JB. The role of tea in human health: an update. J Am Coll

Nutr 2002;21:1

–13.

[95] Hodgson JM, Croft KD. Tea

flavonoids and cardiovascular health. Mol Aspects

Med 2010;31:495

–502.

[96] Negre-Salvayre A, Salvayre R. Quercetin prevents the cytotoxicity of oxidized LDL

on lymphoid cell lines. Free Radic Biol Med 1992;12:101

–6.

[97] Rice-Evans CA, Miller NJ, Paganga G. Structure-antioxidant activity relationships

of

flavonoids and phenolic acids. Free Radic Biol Med 1996;20:933–56.

[98] Wu TW, Fung KP, Wu J, Yang CC, Lo J, Weisel RD. Morin hydrate inhibits azoinitiator

induced oxidation of human low density lipoprotein. Life Sci 1996;58:17

–22.

[99] 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. J Nutr
Biochem 2011;22:201

–11.

[100] Babu PV, Liu D. Green tea catechins and cardiovascular health: an update. Curr

Med Chem 2008;15:1840

–50.

[101] Moore RJ, Jackson KG, Minihane AM. Green tea (Camellia sinensis) catechins and

vascular function. Br J Nutr 2009;102:1790

–802.

[102] Naito Y, Yoshikawa T. Green tea and heart health. J Cardiovasc Pharmacol

2009;54:385

–90.

[103] Balentine DA, Wiseman SA, Bouwens LC. The chemistry of tea

flavonoids. Crit Rev

Food Sci Nutr 1997;37:693

–704.

[104] Geleijnse JM, Launer LJ, Van der Kuip DA, Hofman A, Witteman JC. Inverse

association of tea and

flavonoid intakes with incident myocardial infarction: the

Rotterdam Study. Am J Clin Nutr 2002;75:880

–6.

[105] Gardner EJ, Ruxton CHS, Leeds AR. Black tea

– helpful or harmful? A review of the

evidence. Eur J Clin Nutr 2007;61:3

–18.

[106] Grassi D, Aggio A, Onori L, Croce G, Tiberti S, Ferri C, et al. Tea,

flavonoids, and

nitric oxide-mediated vascular reactivity. J Nutr 2008;138:1554S

–60S.

[107] Peters U, Poole C, Arab L. Does tea affect cardiovascular disease? A meta-analysis.

Am J Epidemiol 2001;154:495

–503.

[108] Wang ZM, Zhou B, Wang YS, Gong QY, Wang QM, Yan JJ, et al. Black and green tea

consumption and the risk of coronary artery disease: a meta-analysis. Am J Clin
Nutr 2011;93:506

–15.

[109] Ostertag LM, O'Kennedy N, Kroon PA, Duthie GG, de Roos B. Impact of dietary

polyphenols on human platelet function

– a critical review of controlled dietary

intervention studies. Mol Nutr Food Res 2010;54:60

–81.

[110] 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. JAMA 2006;13:1255

–65.

24

A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) 15

–25

[111] Arab L, Liu W, Elashoff D. Green and black tea consumption and risk of stroke: a

meta-analysis. Stroke 2009;40:1786

–92.

[112] Vogel JHK, Bolling SF, Costello RB, Guarneri EM, Krucoff MW, Longhurst JC, 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). J Am Coll Cardiol
2005;46:184

–221.

[113] Di Castelnuovo A, Costanzo S, Bagnardi V, Donati MB, Iacoviello L, de Gaetano G.

Alcohol dosing and total mortality in males and females: an updated meta-
analysis of 34 prospective studies. Arch Intern Med 2006;166:2437

–45.

[114] Di Castelnuovo A, Costanzo S, Donati MB, Iacoviello L, de Gaetano. Prevention of

cardiovascular risk by moderate alcohol consumption: epidemiologic evidence
and plausible mechanisms. G Intern Emerg Med 2010;5(4):291

–7.

25

A. Di Castelnuovo et al. / European Journal of Internal Medicine 23 (2012) 15

–25