The Case for Going Coo-coo for Cacao
-data, from the dark side-
David L. Katz, MD, MPH, FACPM, FACP
Director, Prevention Research Center
Yale University School of Medicine
Medical Contributor, ABC News
www.davidkatzmd.com
All Candy Expo
June 6, 2006
Heart Disease:
• same as it ever was, and maybe even
worse…
What it is…
Adult Population
100%
Overweight / Obesity
Insulin Resistance
Diabetes Mellitus
Cardiovascular Disease
Time
Children !!
And What it SHALL
be…
100%
Overweight / Obesity
Insulin Resistance
Diabetes Mellitus
Time
Cardiovascular Disease
Obesity, BMI, CVD and Phenols
• CVD leading cause of death in the U.S. for both
men and women and in all racial and ethnic
groups
• Not just a disease of the elderly
• Heart disease accounts for 1 million deaths each
year of these 160,000 were 35-65 years old
Obesity and CVD
• Elevated BMI and obesity have been recognized as major risk factors
for CVD
• Results from NHANES 2003-2004 show that an estimated 66% of
U.S. adults are either overweight or obese
• A retrospective study of individuals who died of CVD showed that the
deceased population had a higher BMI than the general population
(Kern 2004)
• Obesity increases risk of hypertension, diabetes, coronary heart disease
and congestive cardiac failure
Cardiovascular Risk Factors, Old…
•
•
•
•
•
Hyperlipidemia
Hypertension
Diabetes
Obesity
Etc.
…And New
•
•
•
•
•
•
•
•
•
IRS concomitants
CRP/inflammatory markers
Small dense LDL
Lp(a)
Coronary Calcification
Fibrinogen
Hyperhomocysteinemia
Oxidative stress
Vascular Dysfunction
• Wood D. Established and emerging cardiovascular risk factors. Am Heart J.
2001;141(2suppl):S49-S57
• Howard BV et al. Curr Atheroscler Rep. 2000;2:476-81
Incriminating Evidence,
Beyond the Usual Suspects…
• Calcification
• Hecht HS et al. Am J Cardiol. 2001;87:406-412
• CRP/Inflammation
•
•
•
•
Bell DS. Endocrin Pract. 2000;6:272-6
Frohlich M et al. Diabetes Care. 2000;23:1835-9
Pradhan AD et al. JAMA. 2001;286:327-34
Koenig W. Cardiol Rev. 2001;9:31-5
• Small, dense LDL
• Lamarche B et al. Diabetes Metab. 1999;25:199-211
• Fibrinogen/Hypercoagulability
• Bruno G et al. Diabetes Metab Res Rev. 2001;17:124-30
• Endothelial Dysfunction
• Tooke J. Diabetes Obes Metab. 1999;1s1:s17-22
• Tooke JE et al. Diabet Med. 1999;16:710-5
• Shechter M et al. Am J Cardiol. 2000;86:1256-59
Cocoa…
• To the rescue?
Chocolate: bittersweet history
• chocolate, per se, is a product of the seeds of the cacao
tree, indigenous to Central and South America.
• Initially used by meso-American peoples to brew a bitter
drink, chocolate has been in the human diet for over 2000
years.
• The origins of chocolate as a sweet delicacy can be traced
to the 16th century, and conquest of Central America and
Mexico by the Spanish. Cacao was among the spoils of
war, and thus introduced to European epicures.
• The addition of sugar to cacao likely first occurred in
Spain.
Not all chocolate is created equal• And neither is all saturated fat:
• In solid dark chocolate, nearly 80% of the fat is saturated.
• The predominant fatty acid in cocoa butter is stearic acid, an 18carbon molecule.
• Whereas shorter-chain saturated fatty acids such as myristic acid
(14 carbons), and palmitic acid (16 carbons) are associated with
increases in LDL cholesterol and atherogenesis, stearic acid is not
(Sanders TA, Berry SE. Influence of stearic acid on postprandial
lipemia and hemostatic function. Lipids. 2005;40:1221-7).
• Thus, the fat in dark chocolate is at worst neutral with regard to
health effects, if not actually salubrious.
The power of the dark side• Dark chocolate & cocoa are (potentially)
concentrated sources of:
• Flavonoids
• Fiber
• Magnesium
• Arginine
• Caffeine
• Theobromine
Summary of Chocolate And Cocoa Feeding Trials
Author
Year
Subjects
Trial Design
Duration
Intervention
Outcome
Kondo
1996
12
Cross over
1 meal per and
post
Cocoa 35 g vs.
none
Dec LDL
oxidation
Rein
2000
30
Parallel
1 meal 2 & 6
hrs
Cocoa 300 ml
Decreased
platelet activation
Decreased
platelet function
Wang
2000
20
Crossover
I meal 1 week
phase
Procyanidin –
27,35,80 g vs
none
Increased anti
oxidant capacity
Okasabe
2001
20
Parallel
Daily 2 weeks
Cocoa powder
36g/day vs sugar
Decreased LDL
oxidation
Schram
2001
1 meal 1 week
35 g chocolate vs
.09 g procyanidin
Decreased
platelet activation
Holt
2002
18
Crossover
1 meal 2 hrs
25 g semi sweet
Decreased
platelet function
Heiss
2003
20
Crossover
1 meal, 1
day/phase
Cocoa beverage
100 ml
Improved
endothelial
function
Taubert
2003
13
Cross over
Daily 14 days
Dark chcolate 100
g vs white
chocolate 90 gms
Lower systolic BP
Engler
2004
21
Parallel
Daily 2 weeks
High vs low
flavonoid
Improved
endothelial
function
Grassi
2004
15
Crossover
Daily 14 days
Dark vs white
choclate
Lower BP, lower
LDL
Summary of Chocolate And Cocoa Feeding Trials, cont.
Author
Year
Subjects
Trial Design
Duration
Intervention
Outcome
Wiswedel
2004
20
Crossover
1 meal 1 week
washout
High flavanol
vs low flavanol
Lower lipid
peroxidation
Mursu
2004
45
Parallel
Daily 3 weeks
Dark chocolate
vs white
chocolate
Increased HDL
concentration
Zhu
2005
8
Parallel
1 meal
Cocoa beverage
high flavanoid
Reduced
susceptibility to
free radical
hemolysis
Vlachopolus
2005
17
Crossover
1 meal, 1
day/phase
Dark chocolate
vs. none
Improved
endothelial
function
Fraga
2005
28
Parallel
Dail, 14 days
High flavanol
milk chocoalte
vs low flavanol
Lower BP,
lower LDL
Iron fist, velvet glove:
• Dark chocolate ameliorates most cardiac
risk factors.
Blood Pressure
•
Grassi D, Lippi C, Necozione S, Desideri G, Ferri C. Short-term
administration of dark chocolate is followed by a significant increase
in insulin sensitivity and a decrease in blood pressure in healthy
persons. Am J Clin Nutr. 2005;81:611-4
•
Grassi D, Necozione S, Lippi C, Croce G, Valeri L, Pasqualetti P,
Desideri G, Blumberg JB, Ferri C. Cocoa reduces blood pressure and
insulin resistance and improves endothelium-dependent vasodilation
in hypertensives. Hypertension. 2005;46:398-405
Platelet Aggregation
• Innes AJ, Kennedy G, McLaren M, Bancroft AJ, Belch
JJ. Dark chocolate inhibits platelet aggregation in
healthy volunteers. Platelets. 2003;14:325-7
• Pearson DA, Holt RR, Rein D, Paglieroni T, Schmitz
HH, Keen CL. Flavanols and platelet reactivity. Clin
Dev Immunol. 2005;12:1-9
Oxidation / Inflammation
•
Mao TK, Powell J, Van de Water J, Keen CL, Schmitz HH, Hammerstone
JF, Gershwin ME. The effect of cocoa procyanidins on the transcription and
secretion of interleukin 1 beta in peripheral blood mononuclear cells. Life
Sci. 2000;66:1377-86
•
Mursu J, Voutilainen S, Nurmi T, Rissanen TH, Virtanen JK, Kaikkonen J,
Nyyssonen K, Salonen JT. Dark chocolate consumption increases HDL
cholesterol concentration and chocolate fatty acids may inhibit lipid
peroxidation in healthy humans. Free Radic Biol Med. 2004;37:1351-9
•
Wan Y, Vinson JA, Etherton TD, Proch J, Lazarus SA, Kris-Etherton
PM.Effects of cocoa powder and dark chocolate on LDL oxidative
susceptibility and prostaglandin concentrations in humans. Am J Clin Nutr.
2001;74:596-602
Insulin Resistance
• Grassi D, Lippi C, Necozione S, Desideri G,
Ferri C. Short-term administration of dark
chocolate is followed by a significant
increase in insulin sensitivity and a decrease
in blood pressure in healthy persons. Am J
Clin Nutr. 2005;81:611-4
And Endothelial Function
• Improvement in endothelial function has been
seen in healthy adults
– Vlachopoulos C, Aznaouridis K, Alexopoulos N, Economou E,
Andreadou I, Stefanadis C. Effect of dark chocolate on arterial
function in healthy individuals. Am J Hypertens. 2005;18:78591; Fisher ND, Hughes M, Gerhard-Herman M, Hollenberg NK.
Flavanol-rich cocoa induces nitric-oxide-dependent vasodilation
in healthy humans. J Hypertens. 2003;21:2281-6
• and in adults with cardiac risk factors
– Sies H, Schewe T, Heiss C, Kelm M. Cocoa polyphenols and
inflammatory mediators. Am J Clin Nutr. 2005;81(1
Suppl):304S-312S
One risk factor• to rule them all?
Endothelial Dysfunction
ED precedes clinical atherosclerosis,1 is
prominent in the presence of coronary
risk factors, and improves with risk
modification2,3
1. Glasser SP, et al. Am Heart J, 1996
2. Anderson TJ, et al. N Engl N Med, 1995
3. Stroes ES, et al. Lancet, 1995
Role of Nitric Oxide
Endothelial function testing
BP cuff
Inflation
Brachial artery compression
Cuff release: shear stress
NO release
Vasodilatation (Vasoconstriction)
EF Studies at Yale PRC:
•
Katz DL, Evans MA, Nawaz H, Njike VY, Chan W, Comerford BP, Hoxley ML. Egg
consumption and endothelial function: a randomized controlled crossover trial. Int J
Cardiol. 2005;99:65-70
•
Katz DL, Evans MA, Chan W, Nawaz H, Comerford BP, Hoxley ML, Njike VY, Sarrel
PM. Oats, antioxidants and endothelial function in overweight, dyslipidemic adults. J
Am Coll Nutr. 2004;23:397-403
•
Sarrel PM, Nawaz H, Chan W, Fuchs M, Katz DL. Raloxifene and endothelial function
in healthy postmenopausal women. Am J Obstet Gynecol. 2003;188:304-9
•
Katz DL, Nawaz H, Boukhalil J, Chan W, Ahmadi R, Giannamore V, Sarrel PM. Effects
of oat and wheat cereals on endothelial responses. Prev Med. 2001;33:476-84
•
And others in press.
Current Trial-
• Effects of Acute Ingestion of Dark Chocolate on Endothelial
Function in Adults with BMI between 25-35 kg/m2: A
Randomized, Single Blind, Placebo Controlled Trial
With thanks to• Dr. Zubaida Faridi
• Dr. Valentine Njike
Specific Aims
To assess the acute effects of solid, dark chocolate
on endothelial function measured as flow
mediated dilation (FMD) of the brachial artery in
overweight adults
To determine the acute effects of solid, dark
chocolate on blood pressure in overweight
individuals
Study Design
• Randomized, single-blind, placebo controlled
crossover trial
Subjects
Inclusion Criteria
• Ages between 30 -75
• BMI between 25-35 kg/m2
• Waist circumference above 88 cm in women and 102
cm in men
• Non-smoker
• No strenuous exercise at least 8 hours prior to
scanning
Methods
The study consisted of the following phases:
Phase 1: Dose response test
Phase 2: Acute effects of ingestion of solid dark chocolate
vs. placebo on endothelial function [75g (6 blocks of 100g bar provided]
Phase 3: Acute effects of ingestion of sugar free cocoa vs.
cocoa with sugar vs. placebo [22g (2 cups (8 oz ) of ~10g cocoa
beverage]
Phase 4: Sustained effects of 6 weeks consumption of
sugar free cocoa vs. cocoa with sugar vs. placebo
-(on-going)
Subjects, Cont
Exclusion Criteria
• Failure to meet inclusion criteria
• Anticipated inability to complete study protocol
for any reason
• Current eating disorder
• Diagnosed coronary artery disease
• Diabetes
• Sleep apnea
• Current or impending pregnancy
• Vasoactive medication use
Methods
• 45 subjects were randomly assigned to one of the treatment
sequences: dark chocolate then placebo or placebo then dark
chocolate
• Participants underwent endothelial function testing using
high frequency ultrasound and blood pressure measurement
pre and post ingestion of 75 gms of solid, dark chocolate or
low flavonoid placebo
• Participants fast overnight for 12 hrs before each test dose
Methods, Cont
• At each visit BARS scans were done
at baseline (before intervention) and
2 hours following intervention
Variables
• Endothelial function was assessed as flow-mediated dilatation, or
FMD; this was calculated as the percent change in diameter postocclusion of brachial artery at 60 seconds relative to the measurement
at baseline before cuff inflation
• To account for variability in the strength of the stimulus that triggered
endothelial reactivity (i.e., hyperemic flow), FMD was divided by
flow at 15 seconds post-cuff deflation to create a stimulus-adjusted
response measure or SARM
• Blood Pressure: Diastolic and Systolic
Outcome Measures
• The difference in the change in FMD between dark
chocolate and placebo (ΔI-ΔP)
• The difference in the change in SARM between dark
chocolate and placebo (ΔI-ΔP)
• The difference in the change in blood pressure between
dark chocolate and placebo (ΔI-ΔP)
Results
Table 1. Baseline Values
Dark Chocolate (n=45)
Placebo (n=45)
Mean ± SD
Mean ± SD
p-value
Age (years)
52.78 ± 11.03
52.78 ± 11.03
1.0000
Weight (lbs)
179.11 ± 22.23
178.84 ± 22.42
0.9549
Body Mass Index (kg/m²)
30.14 ± 3.31
30.09 ± 3.26
0.9396
Room Temperature (ºF)
72.00 ± 0.21
72.04 ± 0.67
0.6744
Diastolic Blood Pressure (mmHg)
68.64 ± 11.77
69.87 ± 11.66
0.6218
Systolic Blood Pressure (mmHg)
124.80 ± 16.95
122.82 ± 15.18
0.5613
Flow Mediated Dilation or FMD (%)*
7.36 ± 3.55
9.10 ± 4.82
0.0553
Stimulus Adjusted Response Measure
or SARM*
0.08 ± 0.08
0.07 ± 0.17
0.6319
Variable
*Occasional missing; SD=Standard deviation; p-values obtained from student ttest
Results, Cont
Table 2. Change in Outcome Measures from Baseline after Treatment Assignment
Dark Chocolate (n=45)
Placebo (n=45)
Between Group
Variable
Mean ± SD
Mean ± SD
p-value
Systolic Blood Pressure (mmHg)
-3.24 ± 5.82
2.68 ± 6.64
<.0001
0.0005
0.0104
----
-1.40 ± 3.91
2.73 ± 6.36
0.0004
0.0206
0.0067
----
4.28 ± 3.43
2.73 ± 6.36
<.0001
<.0001
0.0007
----
0.04 ± 0.10
0.01 ± 0.18
0.3120
0.0129
0.7902
----
Within Group p-value
Diastolic Blood Pressure (mmHg)
Within Group p-value
Flow Mediated Dilation or FMD (%)
Within Group p-value
Stimulus Adjusted Response Measure
Within Group p-value
Results, Cont
Change in Blood Pressure
Change in FMD
Change in SARM
6
5
0.07
4
0.05
0.03
2
SARM
FMD (%)
3
1
0
-1
Dark Chocolate
Placebo
0.01
-0.01
-0.03
-2
-3
-4
Error bars indicate 95% CI
Dark Chocolate
Placebo
Blood Pressure (mmHg)
6
4
2
0
-2
-4
-0.05
-0.07
-6
Dark Chocolate
Placebo
SBP
DBP
Cocoa results-
• Hot off the presses-
Conclusion
In this sample of overweight adults, acute ingestion of
both dark chocolate & cocoa significantly improved
endothelial function and blood pressure
In need of attention:
• The flavanols in chocolate contribute to its bitterness
• Lesschaeve I, Noble AC. Polyphenols: factors influencing their sensory properties and
their effects on food and beverage preferences. Am J Clin Nutr. 2005;81:330S-335S
• Long-term health effects are not known with confidence
• 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
• Kris-Etherton PM, Keen CL. Evidence that the antioxidant flavonoids in tea and
cocoa are beneficial for cardiovascular health. Curr Opin Lipidol. 2002;13:41-9
• Scalbert A, Manach C, Morand C, Remesy C, Jimenez L. Dietary polyphenols and
the prevention of diseases. Crit Rev Food Sci Nutr. 2005;45:287-306
• Dose, diet, substitutions, and calories
• Salutary effects have been seen with between 150mg and 500mg of flavonoids. This
translates into between 1 and 3.5 cups of tea, and from 40 g (1.4 oz) to 125 g (4.4 oz)
of flavonoid-rich chocolate.
If it sounds too good to be true• it’s chicanery, or…
• CHOCOLATE!
• Ariefdjohan MW, Savaiano DA. Chocolate
and
cardiovascular health: is it too good to
be true? Nutr Rev. 2005;63(12 Pt 1):427-30
Thank you.
david.katz@yale.edu
Yale Prevention Research Center
130 Division St.
Derby, CT 06418
www.davidkatzmd.com