scientific paper anastasia dark chocolate and mci
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Dark Chocolate AndCardioprotective Effect
Scientific Paper
Name : Anastasia
NIM : 07120070071
Faculty of Medicine
Universitas Pelita Harapan
2007
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Table Of Content
Chapter 1 : Cardiovascular.......................................................................................3
1.1. Cardiovascular disease.........................................................................................3
1.2. Acute Myocardial Infraction(AMI).....................................................................41.2.1. What causes a heart attack?............................................................................................5
1.3. CVD Marker..........................................................................................................6
1.4. CVD risk factors ...................................................................................................7
Chapter 2 : Chocolate................................................................................................8
2.1. Chocolate in modern life.......................................................................................8
2.2. The content of chocolate.......................................................................................82.2.1. Lipids..............................................................................................................................8
2.2.2. Stearic acid in chocolate...............................................................................................10
2.2.3. Sterols............................................................................................................................12
2.2.4. Fiber..............................................................................................................................13
2.2.5. Minerals........................................................................................................................13
2.2.6. Flavonoids.....................................................................................................................15
2.2.7. Flavonoids in chocolate................................................................................................16
Chapter 3 : Chocolate in relationship with cardiovascular effect.......................21
3.1. Effects of cocoa flavonoids on cardiovascular health.......................................213.1.1. Antioxidant effects........................................................................................................22
3.1.2. Effects on platelet activation.........................................................................................23
3.1.3. Effects on modulation of immune response..................................................................25
3.2. Nitric Oxide and chocolate.................................................................................26
3.3. Dose of chocolate.................................................................................................26
3.4. Chocolate and long term effect for cardiovascular...........................................27
3.5. Aspirin and Cocoa...............................................................................................27
Chapter 4 : Observational Study.............................................................................28
4.1. Stearic Acid Observational Studies....................................................................28
4.2. Flavonoid Observational Studies.......................................................................29
References.................................................................................................................32
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Chapter 1 : Cardiovascular
1.1. Cardiovascular diseaseCardiovascular Disease (CVD) includes dysfunctional conditions of
the heart, arteries, and veins that supply oxygen to vital life-
sustaining areas of the body like the brain, the heart itself, and
other vital organs. If oxygen doesn't arrive the tissue or organ will
die.
Ischemic Heart Disease is the technical term for obstruction ofblood flow to the heart. In general this results because excess fat
or plaque deposits are narrowing the veins that supply oxygenated
blood to the heart. Excess buildup of fat or plaque are respectively
termed arteriosclerosis and atherosclerosis. Equally significant
would be inadequate oxygen flow to the brain, which causes a
stroke.
High Blood Pressure (hypertension) often results from this excess
fat or plaque buildup because of the extra effort it takes to
circulate blood. Even though the heart works harder, blockages
still shortchange the needed blood supply to all areas of the body.
The body's amazing survival systems will mask the subtle damage
that is occurring from this extra wear and tear, but not forever.
High blood pressure is called "The Silent Killer" because the first
warning sign is an angina attack or a deadly heart attack or a
stroke.
Kidney disorders (which leave extra fluids, sodium, and toxins in
the body), obesity, diabetes, birth control pills, pregnancy,
smoking, excess alcohol, stress, and thyroid and adrenal gland
problems can also cause and exacerbate a high blood pressure
condition.
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Damage to the heart tissues from CVD or from heart surgery will
disrupt the natural electrical impulses of the heart and result in
cardiac arrhythmia (an abnormally high or abnormally low heart
rate). Individuals often don't realize the aftermath and side effects
that invasive surgical procedures leave. Sudden fluctuations in
heart rate can cause noticeable palpitations, with an associated
faintness, or dizziness, and if severely abnormal could interfere
with blood flow and even initiate a heart attack.
Proper ranges of cholesterol are also important in the prevention
of heart attack or stroke. Total blood cholesterol above 200 mg/dl,
LDL cholesterol above 130 mg/dl, HDL cholesterol below 35 mg/dl;
and lipoprotein(a) level greater than 30 mg/dl are indicators of
problematic cholesterol. Cholesterol is not actually a damage
mechanism but is more an indicator of compromised liver function,
and increased risk of heart attack.
Infection of the heart, carditis and endocarditis, is an additionalcomplication that can occur as a result of a weak immune system,
liver problems, heart surgery, or from an autoimmune disorder like
rheumatic fever. Endocarditis is quite common in persons with
compromised immune systems from HIV or AIDS. If not
appropriately handled, permanent heart muscle damage can occur
from the infection. Many scientific studies validate the effect diet
and supplements can have for the body to heal damages to the
cardiovascular system. Lifestyle changes can also make a big
difference(1).
1.2. Acute Myocardial Infraction(AMI)
A heart attack (also known as a myocardial infarction) is the death
of heart muscle from the sudden blockage of a coronary artery by
a blood clot. Coronary arteries are blood vessels that supply the
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heart muscle with blood and oxygen. Blockage of a coronary
artery deprives the heart muscle of blood and oxygen,causing
injury to the heart muscle. Injury to the heart muscle causes chest
pain and chest pressure sensation. If blood flow is not restored to
the heart muscle within 20 to 40 minutes, irreversible death of the
heart muscle will begin to occur. Muscle continues to die for six to
eight hours at which time the heart attack usually is "complete."
The dead heart muscle is eventually replaced by scar tissue.
Approximately one million Americans suffer a heart attack each
year. Four hundred thousand of them die as a result of their heartattack.
1.2.1. What causes a heart attack?
Atherosclerosis is a gradual process by which plaques (collections)
of cholesterol are deposited in the walls of arteries. Cholesterol
plaques cause hardening of the arterial walls and narrowing of the
inner channel (lumen) of the artery. Arteries that are narrowed byatherosclerosis cannot deliver enough blood to maintain normal
function of the parts of the body they supply. For example,
atherosclerosis of the arteries in the legs causes reduced blood
flow to the legs. Reduced blood flow to the legs can lead to pain in
the legs while walking or exercising, leg ulcers, or a delay in the
healing of wounds to the legs. Atherosclerosis of the arteries that
furnish blood to the brain can lead to vascular dementia (mentaldeterioration due to gradual death of brain tissue over many
years) or stroke (sudden death of brain tissue).
In many people, atherosclerosis can remain silent (causing no
symptoms or health problems) for years or decades.
Atherosclerosis can begin as early as the teenage years, but
symptoms or health problems usually do not arise until later in
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adulthood when the arterial narrowing becomes severe. Smoking
cigarettes, high blood pressure, elevated cholesterol, and diabetes
mellitus can accelerate atherosclerosis and lead to the earlier
onset of symptoms and complications, particularly in those people
who have a family history of early atherosclerosis.
Coronary atherosclerosis (or coronary artery disease) refers to the
atherosclerosis that causes hardening and narrowing of the
coronary arteries. Diseases caused by the reduced blood supply to
the heart muscle from coronary atherosclerosis are called
coronary heart diseases (CHD). Coronary heart diseases includeheart attacks, sudden unexpected death, chest pain (angina),
abnormal heart rhythms, and heart failure due to weakening of the
heart muscle(2).
1.3. CVD Marker
The current study suggests that C-reactive protein, a marker of
systemic inflammation, is a stronger predictor of future
cardiovascular events than LDL cholesterol. In this study, C-
reactive protein was superior to LDL cholesterol in predicting the
risk of all study end points; this advantage persisted in
multivariable analyses in which we adjusted for all traditional
cardiovascularrisk factors and was clear among users as well as
nonusers ofhormone-replacement therapy at base line. However,
C-reactive protein and LDL cholesterol levels were minimally
correlated. Thus, the combined evaluation of both C-reactive
protein andLDL cholesterol proved to be superior as a method of
risk detection to measurement of either biologic marker alone.
Finally, atall levels of estimated 10-year risk for events according
tothe Framingham risk score and at all levels of LDL cholesterol,C-
reactive protein remained a strong predictor of future
cardiovascularrisk(3).
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1.4. CVD risk factors1. Major
Cigarette smoking
Elevated blood pressure
Elevated serum total (and LDL) cholesterol
Low serum HDL cholesterol
Diabetes mellitus
Advancing age
2. Others
Predispositional risk factor
Obesity
Abdominal obesity
Physical inactivity
Family history of premature coronary heart disease
Ethnic characteristics
Psychosocial factors
Conditional risk factors
Elevated serum triglycerides
Small LDL particles
Elevated serum homocysteine
Elevated serum lipoprotein(a)
Prothrombotic factors (eg, fibrinogen)
Inflammatory markers (eg, C-reactive protein) (4)
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Chapter 2 : Chocolate
2.1. Chocolate in modern life
Beneficial effects of eating chocolate:
release of endorphins in the brain, which act as pain-relievers,
boost one's appetite, but does not cause weight gain,
the sugar in chocolate may reduce stress and have a calming
and pain relieving effect
does not give someone acne or other skin eruptions,
does not trigger migraine headaches,
moderate amounts of chocolate makes ones live almost a year
longer,
reduces the risk of heart disease and cancer.
Negative effects of eating chocolate:
People with the highest intake of chocolate either end up with
elevated
VLDL triglycerides (from all that sugar) or with excessive copper
levels. On average, most chocoholic patients test high in both,
and they sooner or later start to exhibit any number of health
problems that area associated with those aspects(5).
2.2. The content of chocolate2.2.1. LipidsCocoa butter accounts for 50% to 57% of the dry weight of cocoa
beans and is responsible for the melting properties of chocolate.
The predominant fatty acids in cocoa butter are saturated (stearic;
18:0, 35% and palmitic; 16:0, 25%) and monounsaturated (oleic;
18:1, 35%), with the remaining fat being primarily polyunsaturated
linoleic (3%). Palmitic and stearic acid are chemically defined as
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saturated fatty acids (SFA). In general, SFA consumption is
correlated with an increased risk of coronary heart disease
because of their propensity to elevate plasma lipids and
lipoproteins and to increase thrombosis. Conversely, unsaturated
fatty acids have been reported to decrease atherogenic factors. As
a consequence of the high SFA content of chocolate and cocoa, it
is often viewed as a negative food with respect to the vascular
system. However, stearic acid is an unusual SFA, in that it does
not elevate blood cholesterol levels to the same extent as other
saturated fatty acid. Possible explanations for this disparity may
include chain length, inefficient absorption, metabolism kinetics,
and hepatic desaturation of stearic into oleic acid.
That cocoa butter could have a neutral effect on blood cholesterol
in humans was first reported by Grande and colleagues in 1970.
More recently, Kris-Etherton and colleagues studied subjects who
consumed 10 ounces of chocolate per day incorporated into foods,
supplying 80% of the approximately 37% of total caloriescontributed by fat in a controlled diet. Despite the fact that the
chocolate-enriched diet was high in saturated fat (approximately
20% of calories), subjects experienced a neutral cholesterolemic
response compared with their usual diet that did not include
chocolate and which contained about 14% of calories from
saturated fatty acids. A subsequent study demonstrated that the
daily substitution of a 1.6-ounce milk chocolate bar (a typical
candy bar weighs 1.4 ounces), in place of a high carbohydrate
snack in a National Cholesterol Education Program/American Heart
Association Step One Diet, did not adversely affect LDL-cholesterol
level.
These studies suggest that strategies to reduce dietary fat should
emphasize reduction of the cholesterolemic SFA that are regularly
consumed in relatively larger quantities rather than stearic acid.
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Chocolate consumption in the United States, based on the 1987-
1988 USDA Nationwide Food Consumption Survey, averaged 30 to
90 g/day/person and contributed approximately 1% to 3% of the
total intake of energy and saturated fat intake. A recent analysis
of food sources of dietary SFA and cardiovascular risk in the
Nurse's Health study indicated that chocolate was not a main
contributor to total SFA or stearic acid intake in this large cohort.
Thus, the inclusion of a moderate amount of chocolate containing
stearic acid into the diet is not predicted to have adverse effects
on the lipid and lipoprotein profile of individuals, as long as the
total fat and caloric intake is held constant. Consumption of large
amounts of chocolate, which provides excess fat and calories to
the diet beyond estimated maintenance needs, could contribute to
obesity and negatively impact CVD incidence.
The effects of stearic acid on thrombosis and hemostasis are less
clear and seem to vary among in vitro and in vivo studies. In vitro,
stearic acid is effective in promoting platelet aggregation andfactor VII coagulant activity, whereas, in vivo, preliminary studies
show mixed results. The clinical studies reported on stearic acid to
date are contradictory in that some report neutral effects on
platelet activity and procoagulant factors, whereas others report
negative effects. The long-term effects of stearic acid consumption
on thrombogenic factors are not well elucidated and require
further research.
2.2.2. Stearic acid in chocolateSaturated fat has long been thought to contribute to
atherosclerosis, and thus, adverse for CVD risk. However, stearic
acid has been suggested to be a non-atherogenic type of dietary
saturated fat. Stearic acid is a long-chain 18:0 saturated fatty acid
found commonly in meats and dairy products. Cocoa butter, a fat
derived from cocoa plants and predominantly found in dark
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chocolate, contains an average of 33% oleic acid (cis-18:1
monounsaturated), 25% palmitic acid (16:0 saturated), and 33% of
stearic acid. Thought it is generally considered that saturated fats
overall adversely increase the total cholesterol and LDL levels,
early studies have also suggested stearic acid may be non-
cholesterolemic. This has been confirmed in a series of studies and
a meta-analysis of 60 controlled feeding trials which concludes
stearic acid neither lowers HDL, nor increases LDL or total
cholesterol. The meta-analysis also estimates, that per 1% energy
isocaloric replacement of stearic acid for carbohydrates, stearic
acid intake is predicted to beneficially lower serum triglycerides by
-17.0 nmol/L (p < 0.001). The most recent trial also shows the
effects of stearic acid on lipids is even similar to oleic and linoleic
acids.
Emerging studies have begun to explain how stearic acid in
chocolate may be cholesterol-neutral. One suggested mechanism
is stearic acid's lower absorption, which has been found in severalanimal and human studies though only minimally in others. These
discrepancies may be attributed to the relative position of stearate
on the triglyceride molecule which may affect its relative
absorption rate. This might also explain the suggestion that stearic
acid from plants sources, such as cocoa, may be different from
animal derived sources of stearic acid. Furthermore, some feeding
trials found lower absorption of cocoa buttered compared to corn
oil, though not in others However, heterogeneity may be due to
the dual-presence of calcium in chocolate, in which other trials
found cocoa butter absorption further decreased 13% when
supplemented with calcium (1% by weight), as is done in
chocolate manufacturing. Finally, another strongly supported
protective mechanism relate to the relatively high percent
desaturation of stearic acid to monosaturated oleic acid, a fat
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considered hypocholesterolemic and protective against coronary
heart disease.
Two other pathways suggested for potential benefit are stearicacid's potential anti-platelet and blood pressure reductions
actions(6). Feeding trials have shown that stearic acid reduces
mean platelet volume, an index of platelet activation. However,
mixed findings have been observed regarding the relationship
between stearic acids and factor VIIc coagulation factor, a
predictor of fatal CHD. Though an early study suggested that
stearic acid may increase factor VIIc. no effect on levels of factorVIIc by stearic acid was observed in two other trials. Moreover,
additional trials have refuted the earlier small study and, in fact,
shown that stearic acid lowered the levels of factor VIIc
coagulation factor compared to palmitic and other saturated fatty
acids . As for the relationship between stearic acid and blood
pressure, two feeding trials found stearic acid did not adversely
affect systolic blood pressure. Furthermore, cross-sectionalanalysis within the Multiple Risk Factor Intervention Trial even
found stearic acid levels may be inversely associated with diastolic
blood pressure.
In summary, given the vast majority of studies showing stearic
acid has beneficial or neutral effects on blood pressures and
clotting parameters, it appears unlikely stearic acid intake would
adversely affect CVD risk through these risk factors. Data indicates
stearic acid does not adversely affect established traditional lipid
risk factors, with even favorable lowering of serum triglycerides if
isocalorically replaced for carbohydrates(7)
2.2.3. SterolsPlant sterols and stanols can contribute to improved blood lipid
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profiles by competitive inhibition of dietary cholesterol absorption
in the gut. Very small amounts of plant sterols including sitosterol
and stigmasterol are present in cocoa butter. It is likely that the
minor levels of sterols in finished chocolate have limited impact on
cholesterol absorption; however, this has not been investigated.
2.2.4. FiberThe unprocessed cocoa bean has a seed coat, also termed bran,
which accounts for 15% of the total bean weight. The bran is a
good source of insoluble fiber (44%) and also has some soluble
fiber (11%) that could contribute to lower serum lipids. A novel useof this in a high fiber (25 g total dietary fiber/day) cocoa-bran
cereal was found to increase fecal bulk and resulted in a modest
improvement in serum lipid ratios. In comparison, cocoa powder
contains less than 2% bran, and finished chocolate products have
very little fiber (USDA Nutrient Database, Release 14 July, 2001).
Thus, chocolate consumption does not contribute significantly to
dietary fiber intake.
2.2.5. MineralsThe cocoa bean contains several minerals, some of which are
found in high amounts in processed chocolate.The amount
retained from the cocoa bean depends on the amount of cocoa
bean solids in chocolate; therefore, dark chocolate typically has a
higher amount of minerals than milk chocolate. Although the
cocoa bean itself has a high phytate content, the fermentation and
heat treatments during processing cause hydrolysis of the
phytates; therefore, mineral availability from chocolate and
chocolate products is reasonably good. Chocolate milk has even
been advocated as a potential vehicle for iron fortification. Many
minerals are needed for vascular function, but adequate amounts
of dietary magnesium, copper, potassium, and calcium merit
special attention for their roles in preventing high blood pressure
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and contributing to cardiovascular disease risk reduction.
Magnesium is involved in catalyzing a multitude of biologic
reactions, including protein synthesis, transmission of nerve
impulses, muscle relaxation, energy production, and bone and
teeth adsorption. Although controversial, numerous investigators
have argued that low dietary magnesium intake (
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other biochemical pathways related to cardiovascular health.
Large epidemiologic studies have indicated an inverse association
between potassium intake, blood pressure, and stroke-related
mortality. This association has been reinforced based on results of
clinical trials. The potassium content in a serving of dark and milk
chocolate is very similar (161 and 169 mg, respectively) and is
comparable with the level found in an apple (159 mg; USDA
Nutrient Database, Release 14 July, 2001).
Calcium has also been inversely associated with blood pressure
based on epidemiologic and intervention studies, although lessstrongly than potassium. The calcium content of a serving of milk
chocolate (84 mg) is substantially greater than the level in dark
chocolate (14 mg), and can provide 8% of the USRDA for an adult
woman (USDA Nutrient Database, Release 14 July, 2001). Although
this level is not significant compared with other calcium-rich food
sources, it can make a contribution to the overall ratio of minerals
in the diet. It is becoming clear that consumption of foods in whichminerals exist in combination with other essential nutrients and
phytochemicals in a prudent diet pattern that incorporates a
variety of fruits, vegetables, and whole grains yields the greatest
dietary effects on cardiovascular health.
2.2.6. Flavonoids
The primary flavonoids in cocoa and chocolate are the flavan-3-ols
catechin and epicatechin (monomeric units) and
proanthocyanidins (also termed procyanidins), which are
polymeric compounds comprising catechin and epicatechin
subunits. Procyanidin oligomers make up 12% to 48% of the dry
weight of the cocoa bean. Procyanidins consisting of as many as
10 subunits have been identified in chocolate, and, whereas
apples and chocolate have a similar procyanidin profile, tea and
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wine consist mainly of the monomeric flavonoids. Chocolate
products have a higher total flavan-3-ol concentration on a per
weight basis than is found in most plant-based foods and
beverages that contain flavan-3-ols, yet apples are a very rich
source when expressed on a per kilocalorie basis. Analogous to
many vitamins, time and temperature, in addition to other
manufacturing processes such as alkalization, can be detrimental
to the flavonoid content in chocolate. However, with the proper
processing and manufacturing controls in place, substantial
amounts of these potentially beneficial compounds can be
retained from the cocoa bean. Depending on the methods used in
production, cocoa powder can contain as much as 10% flavonoids
on a dry-weight basis. Dark chocolate is formulated with a higher
percentage of cocoa bean liquor than is milk chocolate, and,
therefore, it often contains greater amounts of flavonoids. This is
an important distinction because not all chocolates are equal
sources of flavonoids. Furthermore, nutrient density of a given
flavonoid-containing food should be considered, along with
enjoyment of the food, when recommending appropriate sources
of dietary phytochemicals. The physiologic effects of flavonoids
present in cocoa and chocolate are described in following sections
of this paper, and the findings are compared briefly with literature
reports of structurally similar flavonoids found in other foods and
beverages(8).
2.2.7. Flavonoids in chocolateA 100 g bar of milk chocolate contains 170 mg of flavonoid
antioxidants, procyanidins and flavanols. It is estimated that
chocolate is a leading source of procyanidin intake in Western
nations (1820%) .Flavonoids belong to a class of antioxidants
called polyphenols from plants. The basic structure of flavonoids is
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a C6-C3-C6 backbone with two armomatic rings and varying
degrees of hydroxylation differentiating one flavonoid type from
another . Flavonoids can be divided into various subclasses,
important of which are flavones, flavonols, flavanones, catechins,
anthocyanidins and isoflavones. Cocoa, is particularly rich in the
flavonoids, epicatechin, catechin, and procyanidins (polymers of
catechins and epicatechins)
Various studies have compared the content of the flavanoids in
cocoa with other food stuffs quantitatively. Cocoa has been shown
to have the highest content of polyphenols (611 mg/serving) and
flavanoids (564 mg/serving of epicatechin), greater than even tea
and wine. Per serving, dark chocolate contains substantially higher
amounts of flavonoids than milk chocolate (951 mg of catechins
per 40 g serving compared to 394 mg in white chocolate) , and
levels of epicatechin in dark chocolate is comparable to red wine
and tea. Also of note, dark chocolate contains significantly greater
amounts of total phenols as well as catechins than milk chocolate
per serving (126+-7.4 mol/g vs. 52.2+-20.2 mol/g). In addition
to dark chocolate having higher flavonoid content, the biologic
effects of flavonoids may also be greater in dark chocolate
because milk in milk chocolate may inhibit the intestinal
absorption of flavanoids. Finally, chocolate is also abundant in
procyanidin flavonoids, comparable with levels in procyanidin-rich
apples . Thus, chocolate is a rich source of flavonoids, particularly
catechins, epicatechins and procyanidins. The earliest
international ecologic study suggested flavonoid intake may be
associated with lower rates of CHD mortality (9).
Mechanisms
Chocolate flavonoids have shown good dose-response
bioavailability in humans. There exists several mechanisms of how
flavonoids may be protective against CVD; these include:
antioxidant, anti-platelet, anti-inflammatory effects, as well as
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possibly increasing HDL, lowering blood pressure, and improving
endothelial function. The body of trials involving chocolate
flavonoid(10).
Central to the pathogenesis of atherosclerosis is the oxidation of
low-density lipoprotein (LDL). The chemical structure of flavonoids
gives the compound free radical scavenging ability, which means
flavonoids may have antioxidant effects.Various studies have
confirmed the role of flavanoids as antioxidants in biological
systems. Flavanoids in chocolate have been shown to exert potent
antioxidant effects in vitro assays under artificial oxidative stressas well increase antioxidant capacity as part of various chocolate
feeding trials. Additionally, because lipid soluble flavonoids may
intercalate into the membranes of lipoprotein particles, studies
have shown flavonoids to decrease lipid peroxidation of biological
membranes . Furthermore, a randomized trial also demonstrated
that flavonoid-rich foods can protect human lymphocytes from
oxidative damage in vivo.
Additionally, aggregation of platelets at the site of plaque rupture
and endothelial dysfunction has been implicated in the
pathogenesis of atherosclerosis. Current research has shown that
a number of components of chocolate, particularly catechin and
epicatechin, have significant antiplatelet effects, quantitatively
similar to that of aspirin. Randomized trials studying platelet
activation markers, microparticle formation and primary platelet
aggregation as end points have found that daily intake of cocoa
beverages produces a significant reduction in all these endpoints
among healthy volunteers. There were also significant correlations
between the reduction in these end points and the plasma
concentrations of catechin and epicatechin. Another study found a
significant reduction in platelet activation in groups consuming
100 g of dark chocolate when compared to those consuming
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similar amounts of white chocolate and milk chocolate. In addition,
randomized trials have also shown that consumption of high-
flavanoid dark chocolate is associated with a significant
improvement of endothelial function, marked by increase in
brachial artery flow mediated dilation, likely mediated by
chocolate flavonoids increasing local production of nitric oxide.
Chocolate may also influence levels of leukotrienes and
prostacyclins. Leukotrienes are potent vasocontrictors,
proinflammatory agents and stimulate platelet aggregation,
whereas prostacyclin is a vasodilator and inhibits plateletaggregation. Consumption of chocolate with high procyanidin
content (147 mg) was shown in a feeding trial to significantly
lower the levels of leukotrienes (29%) and increase the levels of
prostacyclin (32%) when compared to a group consuming a low
procyanidin (3.3 mg) chocolate. In vitro studies have indeed
demonstrated chocolate components to inhibit lipoxygenase
pathways, which gives rise to proinflammatory leukotrienes.Inflammation is now recognized as another independent
mechanism in the pathogenesis of atherosclerosis, with various
inflammatory markers having been shown to predict risk of future
CVD events. In addition to anti-inflammatory effects on the
lipoxygenase pathway, cocoa polyphenols have also been shown
to decrease inflammation via several mechanisms, namely:
inhibition of mitogen induced activation of T cells, polyclonal
activation of B cells, reduced expression of interleukin-2 (IL-2)
messenger RNA, and reduced secretion of IL-2 by T cells Other
have also found chocolate procyanidins can modulate of a variety
of other cytokines (e.g. IL-5, TNF-, TGF-), reducing their
inflammatory effects.
Furthermore, multiple cocoa feeding trials have also found
chocolate to increase HDL cholesterol, and decrease blood
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pressure. Finally, there are also suggestive findings in a few trials
that indicate high-flavonoid chocolate may also lower LDL
cholesterol, and improve insulin sensitivity.
Thus, the large body of evidence from laboratory findings and
randomized trials suggest that high-flavonoid chocolate may
protect against LDL oxidation, inhibit platelet aggregation,
improve endothelial function, increase HDL, lower blood pressure,
and reduce inflammation thereby protective against risk of
CVD(7).
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Chapter 3 : Chocolate inrelationship with cardiovascular
effect
3.1. Effects of cocoa flavonoids oncardiovascular health
The inverse association of high fruit and vegetable intakes with
risk of CVD mortality in numerous epidemiologic studies has led to
many hypotheses regarding the physiologic role of flavonoids.
Cocoa, tea, and wine are increasingly viewed as sources of dietary
components with potentially beneficial functional activities. It
should be noted, however, that there are no epidemiologic studies
specifically evaluating the relationship of chocolate intake and
CVD risk. The chemical structure of flavonoids suggests that they
have antioxidant capacity, with the ability to scavenge free
radicals, and chelate redox active metal ions. It has been
postulated that these bioactive compounds can contribute to the
maintenance of the integrated network of cellular and plasma
oxidant defense mechanisms, to vascular wall tone, and to a
reduction in platelet reactivity with a subsequent reduction in the
risk for clot formation. The key to determining the physiologic
significance of dietary flavonoids will be developing anunderstanding of their metabolism and mechanisms of action(11).
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QuickTime and aTIFF (Uncompressed) decompressor
are needed to see this picture.
3.1.1. Antioxidant effectsThe flavan-3-ols have been identified as the major antioxidant
components of different cocoa ingredients and chocolate
preparations. Oxygen radical absorbance capacity (ORAC) data
show that chocolate, as a whole food, has a potent antioxidant
capacity when compared with other phytochemical-rich foods such
as garlic, blueberries, and strawberries. Furthermore, chocolate
products have higher ORAC values than most other flavanol-containing foods. Purified epicatechin oligomers obtained from
cocoa have been shown to protect LDL and liposomes from
oxidation in several in vitro studies and have also been shown to
protect against peroxynitrite-dependent oxidation reactio. This
suggests that procyanidins can protect against reactive nitrogen
species as well as reactive oxygen species. Commercial chocolate
products were found to decrease lipid oxidation when added toLDL preparations in vitro. That the amount of epicatechin
absorbed from a dose of chocolate can be physiologically
important is suggested by the observation that significant
increases in plasma antioxidant capacity and decreases in plasma
lipid oxidation products correlate with the changes in plasma
epicatechin concentrations. Consistent with the above, ingestion
of flavonoid-rich cocoa products resulted in increased resistance of
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LDL to ex vivo oxidation in three different studies.
For comparison, examination of the literature regarding CVD risk
reduction and plasma antioxidant effects of catechins from dietarysources other than chocolate reveals mixed results, but, overall, a
trend toward beneficial health effects is apparent. A recent
metaanalysis of epidemiologic studies on tea consumption
concluded that 3 cups a day may reduce the population incidence
rate of myocardial infarction. Comparison of individual clinical
trials must take into account variations in design, methods, and
outcome measures of the studies. For example, two studiesreported that consumption of six cups of green or black tea, or a
green tea infusion containing about 400 mg of catechin, resulted
in a significant increase in the total plasma antioxidant capacity in
humans. In contrast to this, consumption of green or black tea was
not shown to increase the resistance of LDL to ex vivo oxidation,
despite observations that tea catechins significantly increased LDL
resistance when added to the assay in vitro. Yet another studyreported a borderline significant increase in the oxidation
resistance of lipoproteins in whole serum in the acute period (90
minutes) following ingestion of tea. Consumption of red wine or
red wine polyphenols was shown to enhance the plasma
antioxidant capacity, and increase the resistance of LDL to ex vivo
oxidation, in five studies, whereas no effect was seen in two
studies, including a recent one(12).
3.1.2. Effects on platelet activationIn addition to the antioxidant effects observed, cocoa flavonoids
may influence cardiovascular health through other mechanisms.
Platelets function to maintain vascular integrity. However,
increased platelet reactivity and aggregation in the presence of
endothelial dysfunction can lead to the development of arterial
thrombosis and the progression of atherosclerosis.
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Rein and colleagues evaluated whether the consumption of a
cocoa beverage modulates human platelet function. Platelet
activation markers, platelet microparticle formation, and primary
aggregation were measured at baseline and at two and six hours
after ingestion of a flavonoid-rich cocoa beverage, a caffeine-
containing control beverage, or water. Diminished expression of
platelet activation markers was present at both two- and six-hour
time points, and decreased platelet aggregation was observed in
response to the cocoa beverage, at six hours. The outcome with
cocoa flavonoids is supported by similar results in a study
demonstrating the ability of flavonoid-rich purple grape juice to
decrease platelet aggregation following its consumption by
healthy subjects. It is important to note that all flavonoid-rich
foods are not equal with regard to their ability to alter platelet
reactivity. Indeed, several types of flavonoids may have only
minimal effects on platelets.
A study by Schramm and colleagues provides evidence that someof the effects of chocolate on platelet activity may be secondary to
changes in eicosanoid metabolism. Eicosanoids are bioactive
metabolites of arachidonic acid that mediate inflammatory
processes. A beneficial change in the ratio of two eicosanoids (a
decrease in leukotriene and an increase in prostacyclin) was
observed after consumption of a flavonoid-rich dark chocolate
compared with a flavonoid-poor dark chocolate (providing 147 mg
and 3.3 mg procyanidins/bar, respectively) in healthy volunteers.
Prostacyclin has been shown to inhibit platelet aggregation and is
also a potent vasodilator, whereas leukotriene stimulates platelet
aggregation, is a vasoconstrictor, and is proinflammatory. The
ratio of these two eicosanoids provides a measure of
proinflammatory vs antiinflammatory balance and thus suggests
that chocolate procyanidins may affect the inflammatory response
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via eicosanoid modulation. Cocoa procyanidins and other
flavanoids are capable of directly inhibiting mammalian 15-
lipoxygenase at low micromolar concentrations. This suggests a
mechanism by which they may modulate eicosanoid metabolism
and thereby contribute to cardiovascular protection.
3.1.3. Effects on modulation of immune responseCacao liquor polyphenols were first described to decrease the
expression of interleukin 2 messenger RNA (mRNA) in human
lymphocytes in 1997. Subsequently, Mao and colleagues have
published several in vitro studies reporting the ability of individualcocoa procyanidin fractions to modulate expression of a variety of
cytokines involved in immune responses. The effects of
procyanidins on cytokines were observed to be at the
transcriptional level and were reflected in the protein level as well.
Findings with cocoa procyanidins are consistent with results from
other cell culture studies of polyphenolics such as quercetin and
transreservatrol, indicating the ability of selected flavonoids to
modulate cytokines involved in acute inflammatory responses.
That cocoa flavonoids may have antiinflammatory properties in
vivo is suggested by the work of Osakabe and colleagues,
reporting that cocoa polyphenols can reduce the severity of
ethanol-induced gastric lesions.
The evidence reviewed in this paper demonstrates that flavonoids
have a multitude of actions in vitro and in vivo. Central to this are
the observations that biologic effects occur at physiologic plasma
concentrations of epicatechin that occur following consumption of
flavonoid-rich chocolates. The exact mechanisms for the actions of
the monomeric flavan-3-ols, oligomeric procyanidins, and their
metabolites in vivo remain to be elucidated. Free radical
scavenging activities and participation in the body's overall
antioxidant defense system could account for some, but not all, of
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the observed effects, and it is likely that the flavonoids also
interact with intracellular signaling mechanisms to elicit a variety
of biologic effects in the vascular and immune systems. Although
recent studies suggest that flavonoid-rich chocolate consumption
may contribute positively to maintaining cardiovascular health by
affecting multiple factors, further clinical investigations are clearly
needed to confirm these promising initial observations. To date,
these studies have all been acute and have provided preliminary
data. Larger chronic studies using appropriate biomarkers are
needed to accurately assess the role of many dietary flavonoids,
including cocoa and chocolate, in maintaining cardiovascular
health(8).
3.2. Nitric Oxide and chocolate
In the first study, researchers gave Boston volunteers cocoa with
either a high or low amount of flavonols. Those who drank cocoawith more flavonols showed more nitric oxide activity.
Nitric oxide plays such an important role in the maintenance of
healthy blood pressure and, in turn, cardiovascular health. Also
one study found that a substance in cocoa helps the body process
nitric oxide (NO), a compound critical for healthy blood flow and
blood pressure(13).
3.3. Dose of chocolateThe best effect is obtained by consuming an average amount of
6.7 grams of chocolate per day, corresponding to a small square of
chocolate twice or three times a week. Beyond these amounts the
beneficial effect tends to disappear. For comparison, a standard-
sized Hershey's Kiss is about 4.5 grams (though the classic Kiss is
not made of dark chocolate) and one Hershey's dark chocolate bar
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is about 41 grams (so a recommendation might be one of those
weekly).
The milk in milk chocolate interferes with polyphenols(13)
3.4. Chocolate and long term effect forcardiovascular
Limited evidence also supports the hypothesis that chocolate
might have long-term protective effects on cardiovascular events.
Population-based studies have found that chocolate or cocoa
consumption is associated with lower cardiovascular mortality
both amongst elderly men free of known coronary heart diseaseand postmenopausal women. The long-term effects of chocolate
consumption amongst patients with established coronary heart
disease is largely unknown and to the best of our knowledge the
prospective association between chocolate consumption and
prognosis in survivors of AMI has not been explored (15).
3.5. Aspirin and CocoaThe other study compared how blood platelets responded to aflavonol-rich cocoa drink with 25 grams of semi-sweet chocolate
pieces and a blood-thinning, 81-milligram aspirin dose. The
research found similar reactions to the two from a group of 20- to
40-year-olds: both the drink and the aspirin prevented platelets
from sticking together or clotting, which can impede blood flow. In
other words, flavonol-rich cocoa and chocolate act similarly to low-
dose aspirin in promoting healthy blood flow. Reducing the blood's
ability to clot also reduces the risk of stroke and heart attacks but
the effects you see in aspirin are longer-lasting than the effects
you see in flavonols(16)
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Chapter 4 : Observational
Study
4.1. Stearic Acid Observational StudiesHowever, the observational studies of stearic acid's association
with CVD are inconclusive. Among retrospective studies, a
Japanese case-control study of serum levels reported no
association for stenosis, a Norwegian study found lower odds of MI
, while a Costa Rican study of dietary intake found higher risk of MI
with higher intake of stearic acid. However, the results from the
Costa Rican study should not be given much weight since
retrospective self-report of dietary intakes are notoriously
inaccurate and susceptible to reporting bias. Nevertheless, higher
rates of CHD and CAD progression was found in several
prospective studies, while stroke was not increased in another
study.
On the other hand, several limitations exist for observational
studies of stearic acid. First, researchers have cautioned that
analyses of dietary stearic acid are very difficult due to high
correlations of stearic acid intake with other fatty acids (often r =
0.7 to 0.9), thus impeding optimal study of associations.
Additionally, the larger prospective study that found higher risk ofCHD also noted chocolate was a very small contributor (5%) of
total stearic acid intake, with red meats as primary sources of
stearic acid. Finally, since there exists high interconversion of
stearic acid to unsaturated fatty acids studies involving serum
levels of stearic acid do not answer the relevant causal question of
dietary intake of stearic acid and risk of disease. The associations
of long-term serum stearic acid levels represent the effects of
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post-conversion stearic acid levels after a large proportion of the
original dietary stearic acid has already been converted away to
monounsaturated fat, which is well-established to exert protective
effects against CVD.
Thus, relatively little information can be inferred from
observational studies of the association of stearic acid and CHD,
and no epidemiologic study has, thus far, appropriately and
optimally answered the causal question of the association of
dietary stearic acid intake and risk of CVD. However, a sufficient
body of strong evidence from short term randomized trialssuggests stearic acid components in chocolate may be beneficial
for cardiovascular health. However, further research in this area is
warranted.
4.2. Flavonoid Observational StudiesMechanistic studies involving stearic acid and flavonoids have only
assessed effects on intermediate cardiovascular endpoints.
However, one cannot always assume effects from short term trials
effects will necessarily translate into long term effects on CVD
outcomes. Therefore, one needs to examine observational studies
followed to CVD events. While one small study found moderate
consumption of candy and chocolate was associated with lower
all-cause mortality, this analysis neither isolates chocolate nor
CVD events. Thus, in absence of specific studies of chocolate
flavonoids and risk of CVD, studies of all flavonoids are the best
available evidence to infer risk.
The prospective studies of flavonoids and risk of CVD are
summarized. The earliest international ecologic study suggested
flavonoid intake may be associated with lower rates of CHD
mortality. While some studies report flavonoid intake is not
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associated with CHD incidence, two other prospective studies
suggested flavonoids may lower risk of MI. For stroke, the
evidence is fairly consistent. Other than one small early study
which found a significantly lower risk of stroke with higher total
flavonoid intake, most studies indicated no association for risk of
stroke. However, most of these studies had insufficient power to
adequately study stroke, nor enough power to stratify on various
subtypes of stroke with different etiologies.
However, the most extensively consistent finding is the
association between flavonoid intake and CHD mortality. A total ofeight cohort studies found risk of lower CHD mortality with total or
specific flavonoid intake, with one study finding marginally
protective association among men with prior CVD conditions. Only
one study reported absolutely no association between flavonoid
intake and CHD mortality. However, as noted by the authors of
one of the studies, a high background consumption of milk with
tea intake may have led to the null finding, since milk intake hasbeen shown to prevent the intestinal absorption of flavonoids.
A meta-analysis of the 7 prospective studies prior to September
2001 found that, overall, flavonoids may be protective against
CHD mortality. However, this meta-analysis did not include a large
subsequent cohort study of 38,445 women, which found a non-
significant inverse association between flavonoid intake and CHD
mortality. However, results from our updated meta-analysis still
indicate a significant protective association exists between
flavonoid intake and risk of CHD mortality, RR = 0.81 (95% CI:
0.710.92), comparing highest vs. lowest tertiles.
However, a limitation of inference exists in that flavonoids consists
of a wide variety of polyphenol compounds, the variety of which
may differ between studies due to varying sources of dietary
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flavonoids. Nonetheless, dark chocolate does contain substantially
more flavanols than tea, apple, onions, and red wine. Additionally,
chocolate has all the flavonoids of tea, has 4 times the catechins
of tea, has many flavonoids not found in tea, and substantially
contributes to the total flavonoid intake in the diet of many
countries. However, inference from observational studies on the
protective effect of flavonoids in chocolate on CVD risk is
somewhat indirect and may need to be examined by further
studies.
Overall, these epidemiologic findings, combined with the largebody of evidence from short term randomized chocolate feeding
trials, suggests flavonoid intake from chocolate is likely protective
against CVD, particularly CHD mortality. Additionally, given that
dark chocolate has substantially higher levels of flavonoids than
milk chocolate, and that milk may inhibit absorption of flavonoids
it would be more prudent to consume high flavonoid dark
chocolate rather than milk chocolate(7).
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