Cocoa, Blood Pressure, and Vascular Function

Abstract

The consumption of a high amount of fruits and vegetables was found to be associated with a lower risk of coronary heart disease and stroke. Epidemiologically, a similar relationship has been found with cocoa, a naturally polyphenol-rich food. Obviously, double blind randomized studies are difficult to perform with cocoa and chocolate, respectively. However, intervention studies strongly suggest that cocoa has several beneficial effects on cardiovascular health, including the lowering of blood pressure, the improvement of vascular function and glucose metabolism, and the reduction of platelet aggregation and adhesion. Several potential mechanisms through which cocoa might exert its positive effects have been proposed, among them activation of nitric oxide synthase, increased bioavailability of nitric oxide as well as antioxidant, and anti-inflammatory properties. It is the aim of this review to summarize the findings of cocoa and chocolate on blood pressure and vascular function.

Full text

Cocoa, Blood Pressure and Vascular Function 19.4.2012 V1
Cocoa, Blood Pressure
and Vascular Function
Isabella Sudano1, MD; Andreas J Flammer1,2, MD; Susanne Roas1, MD; Frank Enseleit1, MD;
Frank Ruschitzka1,3, MD; Roberto Corti1,3, MD; Georg Noll1,3, MD
1Cardiovascular Center Cardiology, University Hospital Zurich, Switzerland; 2Division of Cardiovascular
Diseases, Department of Internal Medicine, Mayo Clinic and College of Medicine, Rochester, MN, USA;
3Center for Integrative Human Physiology, University Zurich, Switzerland
Correspondence
Prof. Dr. med. Georg Noll
Cardiovascular Center, Cardiology
University Hospital
Raemistrasse 100
CH-8091 Zurich
Tel: +41-44-255 2266
Fax: +41-44-255 4859
eMail: georg.noll@usz.ch

Cocoa, Blood Pressure and Vascular Function 19.4.2012 V1
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ABSTRACT
The consumption of a high amount of fruits and vegetables was found to be associated with a
lower risk of coronary heart disease and stroke. Epidemiologically, a similar relationship has
been found with cocoa, a naturally polyphenol-rich food. Obviously, double blind randomized
studies are difficult to perform with cocoa and chocolate, respectively. However, intervention
studies strongly suggest that cocoa has several beneficial effects on cardiovascular health,
including the lowering of blood pressure, the improvement of vascular function and glucose
metabolism, and the reduction of platelet aggregation and adhesion. Several potential
mechanisms through which cocoa might exert its positive effects have been proposed, among
them activation of nitric oxide synthase, increased bioavailability of nitric oxide as well as
antioxidant, and anti-inflammatory properties. It is the aim of this review to summarize the
findings of cocoa and chocolate on blood pressure and vascular function.
Key words: cocoa, flavanols, polyphenols, antioxidants, endothelial function, blood pressure,
nitric oxide, vascular compliance.

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INTRODUCTION
In epidemiological studies, regular dietary intake of plant-derived foods and beverages
was found to be associated with a reduced risk of coronary heart disease (CAD)[1-4] and
stroke[5], and to be inversely associated with the risk of cardiovascular disease in general.[2, 4]
The Iowa Women's Health Study is a prospective study in 34’489 postmenopausal women
free of cardiovascular disease who were followed for up to 16 years.[6] In this population regular
consumption of food rich in flavonoids was associated with a decreased risk of death due to CAD
and the inverse association between chocolate intake and cardiovascular mortality remained
significant after multivariate adjustment.[6] Moreover, the Zutphen Elderly Study, involving 470
elderly men free of chronic disease, suggest that habitual cocoa intake per se might reduce
cardiovascular risk and is inversely related to cardiovascular and all-cause mortality).[7]
Moreover, a retrospective analysis of the Potsdam arm of the “European Prospective
Investigation into Cancer and Nutrition” recently showed that high consumption of cocoa was
associated with a lower prevalence of stroke and myocardial infarction.[8]
It has been proposed that polyphenols may play an important role in cardiovascular
protection.
Several food sources are exceptionally rich in polyphenols, among them green and black teas,
wine, grape juices, berries and cocoa, the later with particularly high amounts.[9, 10](Table 1)
Several groups of polyphenols are found in fruits, whereas the most important are the flavanols
which can be further subdivided into the monomers epicatechin and catechin,[11, 12] and their
dimers, oligomers and polymers, the so-called procyanidins,[13, 14] responsible for the bitterness
of cacao, through the formation of the complexes with salivary proteins.[15] Although the
flavanols are likely responsible for the beneficial health effects, conventional chocolate

Cocoa, Blood Pressure and Vascular Function 19.4.2012 V1
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manufacturing processes, such as fermentation and roasting markedly decrease the concentration
of these substances. [10, 16]
In humans, flavanol plasma concentration dose-dependently increases after ingestion,
reaching its peak usually after 2-3h[17, 18] after cocoa ingestion and are still measurable in
plasma 8 hours after cocoa ingestion.[19]
Cocoa and its flavanols might increase nitric oxide (NO) bioavailability, activate nitric
oxide synthase (NOS), and exert antioxidative, anti-inflammatory, and anti-platelet effects, which
in turn might improve vascular function, reduced blood pressure and therefore, explain the
positive impact on clinical outcome proposed by epidemiological studies.[10, 16, 20, 21]
This review will focus on the effect of cocoa on blood pressure and vascular function.

Cocoa, Blood Pressure and Vascular Function 19.4.2012 V1
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Effect of cocoa on blood pressure
Initial findings, which suggested possible antihypertensive effects of cocoa, came from
observations of the Kuna Indians, a native population living on islands off the Panama coast,
which have a very low incidence of hypertension and, remarkably, do not show an age-dependent
increase in blood pressure. These effects are likely environmental because they are lost upon
migration to urban Panama City and are likely linked to the reduction in intake of natural cocoa
drinks rich in flavanols.[22]
A relationship between cocoa consumption and reduced blood pressure was first observed
in a cross sectional analysis of the Zutphen Elderly Study[7] .The association of chocolate
consumption with blood pressure and the incidence of cardiovascular disease was further
evaluated in the population included in a Potsdam arm of the “European Prospective
Investigation into Cancer”.[8] The later study showed over a follow up p to 8 years that a high
consumption of chocolate was associated with a lower cardiovascular risk with a strong inverse
association for stroke (more than for myocardial infarction). The authors emphasized that this
positive effect could be explained at least in part by a reduction in blood pressure, observed in the
group with high as compared to low chocolate-consumption.[8]
Randomized controlled trials have confirmed this epidemiological association mostly in
patients with concurrent arterial hypertension or other cardiovascular risk factors.[23-26]
A meta-analysis of ten such trials[27] found that cocoa consumption was associated with
significant reductions in systolic (-4.5±1.35 mmHg) and diastolic (-2.5±1.36 mmHg) blood
pressures confirming the results of a previous meta-analysis published 2007.[28]
A number of mechanisms have been proposed to explain the cocoa‘s effects on blood pressure.
Because of their importance in blood pressure maintenance, the improvements in nitric oxide
availability and endothelial function associated with cocoa consumption may explain much, of its

Cocoa, Blood Pressure and Vascular Function 19.4.2012 V1
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antihypertensive effects. However, there is some evidence that flavanols and flavanol-rich foods
including cocoa can inhibit angiotensin-converting enzyme (ACE) activity in vitro.[29, 30] ACE
regulates the renin−angiotensin system; it cleaves angiotensin-I into angiotensin-II, which
stimulates the release of vasopressin or aldosterone and antidiuretic hormone, increasing sodium
and water retention. It also inactivates vasodilators bradykinin and kallidin. Whether ACE
inhibition mediates the antihypertensive activity of cocoa flavanols in humans is not yet
completely clear.[31]
One study also looked at the blood pressure responsiveness after exercise showing as an high
flavonols drink reduced the BP response to exercise.[32]

Cocoa, Blood Pressure and Vascular Function 19.4.2012 V1
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Cocoa and vascular function
The vascular endothelium plays a fundamental role in modulating vascular tone and
structure. Physiological production of vascular relaxing factors, including “nitric oxide”,
“prostacyclin” and “hyperpolarizing relaxing factor” protect the vessel wall by antagonizing the
initial pathological steps of atherosclerosis and thrombosis[33].(Figure 1) Cardiovascular risk
factors and disease are associated with endothelial dysfunction or damage.[34, 35] Endothelial
dysfunction in the forearm circulation correlates with the presence of coronary vascular
dysfunction and is predictive of future coronary events.[36-38]
A meta-analysis published in 2008 showed that consumption of polyphenol-rich foods
mostly was associated with an improvement in endothelial function in the short- and long-
term[39] as exemplified with the effect of tea[40] and other flavanoid-rich food such as red wine,
grape juice, dealcoholized red wine extract from grape seeds [41, 42] and orange juice.[43],
As cocoa is particularly rich in polyphenols it is not surprising that cocoa induces NO-
dependent vasodilatation in rat[44] and improve endothelial function in healthy humans and in
patients with cardiovascular risk factors or disease.[10, 16]
Studies evaluating the effect of cocoa/chocolate an endothelial function are summarized in Table
2.
A cocoa drink high in flavanols content enhances the circulating pool of bioactive NO by a third
and in turn improves flow-mediated vasodilation in patients with cardiovascular risk factors.[45,
46] The increase in NO and the improvement of endothelial function induced by cocoa intake
was inhibited by the infusion of L-NMMA, an inhibitor of NO-synthesis.[46] Commercially
available dark chocolate (74% cocoa), but not white chocolate, improves flow-mediated
vasodilatation (FMD) by 80% in young healthy smokers. This effect was seen two hours after
chocolate ingestion and lasted for up to 8 hours. Because plasma antioxidant status, was

Cocoa, Blood Pressure and Vascular Function 19.4.2012 V1
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significantly improved 2 hours after ingestion, it is likely that not only an induction of endothelial
nitric oxide synthase (NOS) and in turn elevated NO levels, but also a reduction in oxidative
stress and in turn a reduced breakdown of NO by reactive oxidant species, contributes to the
enhanced endothelial function, especially under conditions with a high oxidative stress burden,
such as in smokers.[47] Indeed, antioxidants may prevent NO transformation into peroxynitrite
and in turn protect against vasoconstriction and vascular damage.[48] Oxidative stress and
reduced antioxidant defenses play also a crucial role in the pathogenesis of atherosclerosis and in
in transplant vasculopathy. Indeed, we were able to demonstrate that flavonoid-rich dark
chocolate improved epicardial coronary vasomotion in cardiac transplant recipients. [49]
Interestingly 40g dark chocolate induced coronary vasodilatation, improved coronary vascular
function, and decreased platelet adhesion two hours after consumption.
As outlined in Table 2, cocoa consistently improved endothelial function in patients with
atherosclerosis and/or cardiovascular risk factors such as in patients with arterial
hypertension,[24] diabetes mellitus,[50] overweight and obesity,[51] coronary artery disease,[52]
and hart failure.[53] Not only endothelial function improved after consumption of cocoa or
chocolate. Vlachopoulos and colleagues showed that chocolate acutely decrease augmentation
index of the central (aortic) pressure waveform suggesting dilation of small and medium-sized
peripheral arteries and arterioles.[54] Moreover, an observational study in 198 healthy subjects
showed that habitual cocoa consumption is associated with decreased aortic stiffness and wave
reflections and with improved central hemodynamics in healthy subjects.[55]
A possible mechanism explaining the effects of cocoa on the vasculature is the
antioxidative effect of the flavanols and procyanidins contained in cocoa which may reduce the
production of oxygen free-radicals and therefore improve nitric oxide bioavailability and a eNOS
activation.[10, 16](Figure 1) However, the antioxidative effect of cocoa is discussed

Cocoa, Blood Pressure and Vascular Function 19.4.2012 V1
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controversial because in addition to flavanols,[56] macro- and micronutrients, as well as the
increased uric-acid levels resulting from fructose metabolism[57] could affect antioxidative
capacity of plasma.
Ramirez and coauthors showed that epicatechins increase the synthesis of NO via eNOS
activation in human coronary artery endothelial cells.[58] Furthermore, this epicatechin-induced
NO production in human endothelial cells can be obtained through both Ca2+-dependent and
Ca2+-independent eNOS phosphorylation,[59] suggesting that epicatechin may act to retain
vascular function in diseases where NO production is limited.
However, further studies are still needed to clarify the exact mechanisms underlying the
beneficial vascular effects due to cocoa consumption.
CONCLUSION
For many centuries, cocoa has been loved for its good taste and praised for its beneficial effects
on health. In the last ten years many research studies confirmed that cocoa does indeed exert
beneficial effects on vascular and platelet function, probably mainly mediated by its high
polyphenol content, a heterogeneous group of molecules mainly found in fruits and vegetables.
The beneficial effects of cacao are most likely due to a decrease in oxidative stress, induction of
NOS and in turn an increased bioavailability of NO.
ACKNOWLEDGMENTS
Work of the authors was partly supported by the Swiss National Science Foundation (grant Nr.
32000BO-109905/1 to R.C.) The authors received a unrestricted research grant by Nestlé.

Cocoa, Blood Pressure and Vascular Function 19.4.2012 V1
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Table and Figure legend
Table 1 Catechin/Epicatechin Concentrations found in foods. Modified from Manach et al[15]
Table 2 Studies Investigating Cocoa and Endothelial Function. LDL, low density lipoprotein;
NO, nitric oxide; FMD, flow mediated dilatation; CAD, coronary artery disease. Modified
from[10, 16]
Figure 1 Endothelium-dependent effect of cocoa polyphenols. AII indicates angiotensin II; AI,
angiotensin I; PKC, protein kinase C; SOD, superoxide dismutase; PGI2, prostacyclin; ACE,
angiotensin-converting enzyme; ECE, endothelin-converting enzyme; AT1, angiotensin receptor;
ET-1, endothelin 1; bET-1, big endothelin 1; ETa/b, endothelin receptor a and b; cGMP, cyclic
guanosine monophosphate; and ROS, reactive oxygen species. Modified from Corti R et al.[10]

Cocoa, Blood Pressure and Vascular Function 19.4.2012 V1
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Table 1:
Source
Flavanol content
per mg/kg or mg/L
Chocolate
460-610
Beans
350-550
Apricot
100-250
Cherry
50-220
Peach
50-140
Blackberry
130
Apple
20-120
Green tea
100-800
Black tea
60-500
Red wine
80-300
Cider
40

Cocoa, Blood Pressure and Vascular Function 19.4.2012 V1
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Table 2
Author
Year
No
Population
Duration
Intervention
Outcome
Heiss[45]
2003
26
Patients with
at least 1 CV
risk factor
2 hours
(crossover)
Flavanol rich cocoa drink
(100ml)
Improvement of FMD and
increased
levels of nitrosated and
nitrosylated species.
Fisher[60]
2003
27
Healthy
people
5 days
Flavanol rich cocoa
(821mg/d)
Peripheral vasodilatation,
improved vasodilator response to
ischemia assessed by pulse wave
amplitude on the finger
Engler[61]
2004
21
Healthy
subjects
2 weeks
High flavonoid chocolate
(213mg procyanidins,
46mg epicatechin) vs. low
flavonoid chocolate
Improvement of FMD of the
brachial artery, increased
epicatechin concentrations
Grassi[24]
2005
20
Untreated
essential
hypertension
15 days
(crossover)
100 g dark chocolate
(21.91mg catechin, 65,97
mg epicatechins) vs.
flavanol free white
chocolate
Increased FMD of the brachial
artery. Decrease in blood-pressure
and LDL cholesterol, increase of
insulin sensitivity
Heiss[46]
2005
11
Smokers
2 hours
(crossover)
100ml cocoa drink with
high (176-
18mg) or low
(<11mg) flavanol content
Increase of FMD and circulating
NO pool. Increase of flavanol
metabolites
Hermann[47]
2006
20
Healthy
smokers
2 hours
40g commercially
available dark chocolate
vs. white chocolate
Increase in FMD of the brachial
artery. Improvement of antioxidant
status and improvement of platelet
function.
Schroeter[62]
2006
16
Healthy
subjects,
isolated
rabbit rings
2 hours
Drink with high flavonoid
content
Improvement of FMD, paralleled
the appearance of flavanoles in
plasma. Concentrations in plasma
enough to mediate ex vivo
vasodilatation. Pure epicatechins
mimics vascular effects of cocoa.
High flavanol diet is associated
with high urinary excretion of NO
metabolites
Flammer[49]
2007
22
Heart
transplant
patients
2 hours
40g commercially
available dark chocolate
vs. flavonoid free placebo
chocolate
Inducing coronary vasodilation,
improvement in coronary
endothelial function and
improvement of platelet function.
Balzer[50]
2008
41
diabetics
30 days
flavanol-rich cocoa (321
mg flavanolsx3) or a
nutrient-
matched control
(25 mg flavanolsx3)
Improvement in brachial FMD
Shiina[63]
2009
39
Healthy
2 weeks
45g commercially
available dark chocolate
vs. white chocolate
Improvement in coronary
circulation as measured by
coronary velocity flow reserve

Cocoa, Blood Pressure and Vascular Function 19.4.2012 V1
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Davison[51]
2008
Obese and
overweight
patients
12 weeks
Dietary high (902 mg) vs.
low (36 mg) flavanol
intake
Improvement in brachial FMD
Heiss[52]
2010
16
CAD
30 days
Dietary high (375 mgx2)
vs.
low (9 mgx2) flavanol
intake
Improvement in FMD and
mobilization of endothelial
progenitor cells
Njike[64]
2011
44
Healthy BMI
25-35
6 weeks
sugar-free cocoa beverage
or placebo, sugar-
sweetened cocoa beverage
or placebo
Improvement in FMD, n
o change
in weight
Flammer[53]
2011
22
Heart Failure
2 hours and
30 days
40g commercially
available dark chocolate
vs. flavonoid free placebo
chocolate
Inducing brachial vasodilation,
improvement in endothelial
function and acute improvement of
platelet function.

Cocoa, Blood Pressure and Vascular Function 19.4.2012 V1
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Figure 1

Cocoa, Blood Pressure and Vascular Function 19.4.2012 V1
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