The Case for Going Coo-coo for Cacao-data, from the dark side-

David L. Katz, MD, MPH, FACPM, FACPDirector, Prevention Research CenterYale University School of Medicine

Medical Contributor, ABC Newswww.davidkatzmd.com

All Candy ExpoJune 6, 2006

Heart Disease:

• same as it ever was, and maybe even worse…

What it is…Adult PopulationAdult Population

100%100%

TimeTime

Overweight / Obesity

Insulin Resistance

Diabetes Mellitus

Cardiovascular Disease

And What it SHALL be…Children !!Children !!

100%100%

TimeTime

Overweight / Obesity

Insulin Resistance

Diabetes Mellitus 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 18-

carbon 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;18:785-91; 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, 19962. Anderson TJ, et al. N Engl N Med, 19953. Stroes ES, et al. Lancet, 1995

Role of Nitric Oxide

Endothelial function testing

Brachial artery compression

Cuff release: shear stress

NO release

Vasodilatation (Vasoconstriction)

BP cuffInflation

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

SubjectsInclusion 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 post-occlusion 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)

ResultsTable 1. Baseline Values

Variable

Dark Chocolate (n=45) Placebo (n=45)p-value

Mean ± SDMean ± SD

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

*Occasional missing; SD=Standard deviation; p-values obtained from student ttest

Results, ContTable 2. Change in Outcome Measures from Baseline after Treatment Assignment

Variable

Dark Chocolate (n=45) Placebo (n=45) Between Group

Mean ± SD Mean ± SD p-value

Systolic Blood Pressure (mmHg) -3.24 ± 5.82 2.68 ± 6.64 <.0001

Within Group p-value 0.0005 0.0104 ----

Diastolic Blood Pressure (mmHg) -1.40 ± 3.91 2.73 ± 6.36 0.0004

Within Group p-value 0.0206 0.0067 ----

Flow Mediated Dilation or FMD (%) 4.28 ± 3.43 2.73 ± 6.36 <.0001

Within Group p-value <.0001 0.0007 ----

Stimulus Adjusted Response Measure 0.04 ± 0.10 0.01 ± 0.18 0.3120

Within Group p-value 0.0129 0.7902 ----

Results, Cont

Change in FMD

-4

-3

-2

-1

0

1

2

3

4

5

6

Dark Chocolate Placebo

FMD

(%)

Change in SARM

-0.07

-0.05

-0.03

-0.01

0.01

0.03

0.05

0.07

Dark Chocolate PlaceboSARM

Error bars indicate 95% CI

Change in Blood Pressure

-6

-4

-2

0

2

4

6

Dark Chocolate Placebo

Blood

Press

ure (m

mHg) SBP

DBP

Cocoa results-

• Hot off the presses-

In this sample of overweight adults, acute ingestion of both dark chocolate & cocoa significantly improved endothelial function and blood pressure

Conclusion

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.eduYale Prevention Research Center

130 Division St.Derby, CT 06418

www.davidkatzmd.com