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tween advertisement placement and readership. It may be that
84% of alcohol advertising is seen by readers older than 21 years.
Our analysis suggests that the remaining 16% of alcohol ad-
vertising seen by adolescents is more than what would be ex-
pected by chance if advertisements were placed only as a func-
tion of adult readership.
Paul J. Chung, MD, MS
Department of Pediatrics
David Geffen School of Medicine
University of California
Los Angeles
Craig F. Garfield, MD, MA
Department of Pediatrics
Evanston Northwestern Healthcare Research Institute
Evanston, Ill
Paul Rathouz, PhD
Department of Health Studies
University of Chicago
Chicago, Ill
RESEARCH LETTERS
Chocolate and Blood Pressure in Elderly
Individuals With Isolated Systolic Hypertension
To the Editor: Chocolate may have beneficial cardiovascular
effects, possibly due to cocoa polyphenols.
1
Experiments in ani-
mals suggest that plant polyphenols decrease blood pressure
(BP)
2
; however, evidence from human clinical trials is lack-
ing. We examined whether dark chocolate (polyphenol-rich
chocolate [PRC]) may lower BP in individuals with mild iso-
lated hypertension.
Methods. We conducted a randomized crossover trial in 13
otherwise healthy individuals (6 men and 7 women, aged 55-64
years, with body mass index of 21.9-26.2 [calculated as weight
in kilograms divided by the square of height in meters]) with
recently diagnosed and untreated stage 1 mild isolated systolic
hypertension (mean [SD] systolic BP, 153.2 [3.9] mm Hg; mean
[SD] diastolic BP, 83.8 [3.5] mm Hg). After a cocoa-free run-in
phase of 7 days, participants were randomly assigned to receive
14 consecutive daily doses of either 100-g dark PRC bars con-
taining 500 mg of polyphenols and 480 kcal of energy (Ritter
Sport Halbbitter, Alfred Ritter, Waldenbuch, Germany), or 14
days of 90-g white chocolate (polyphenol-free chocolate [PFC])
bars that also contained 480 kcal and similar amounts of cocoa
butter, macronutrients, fiber, electrolytes, and vitamins (Milka
Weisse Schokolade, Kraft Foods, Bremen, Germany). After a co-
coa-free washout phase of 7 days, participants were crossed over
to the other condition. Participants were asked to substitute the
chocolate bars for foods of similar energy and macronutrient com-
position. Overall diet during the study period was assessed by
reports of daily food intake and by measurement of body weight,
plasma concentrations of lipids and glucose, and urinary excre-
tion of sodium, potassium, and nitrogen at the run-in phase and
after each intervention period.
The BP was recorded daily, in a blinded fashion, with par-
ticipants in a seated position, 12 hours post-dose, in the left
upper arm with a validated oscillometer (Omron HEM 722C,
Omron, Mannheim, Germany). A systolic BP of more than 170
mm Hg or a diastolic BP of more than 100 mm Hg at a single
visit was necessary for referral for antihypertensive pharma-
cological treatment. At the end of the study participants were
referred to their physician for further monitoring and manage-
ment of BP. We received approval for our study from the eth-
ics committee of the Medical Faculty of the University of Co-
logne; all participants gave written informed consent.
Results. Participants had significantly lower systolic and dias-
tolic BPs within 10 days of beginning PRC, but this effect was not
seen during the PFC period (F
IGURE). At the end of the 14-day
PRC intervention, mean (SD) systolic BP had declined by 5.1 (2.4)
mm Hg (P⬍.001; paired 2-tailed t test) and mean (SD) diastolic
BP by 1.8 (2.0) mm Hg (P =.002; paired 2-tailed t test) compared
with PFC. After discontinuation of PRC consumption, BP returned
to preintervention values within 2 days. Heart rate was not affected
by either treatment. There were no sex differences in the effects
of chocolate on BP. None of the participants reached the pre-
Figure. Time Course of Mean Blood Pressure and Heart Rate During
a 14-Day Diet With PRC or PFC and a Subsequent 7-Day Washout
Period
70
Heart Rate
66
67
68
69
65
Treatment
Washout
bpm
160
Systolic Blood Pressure
150
155
145
mm Hg
90
Diastolic Blood Pressure
85
80
0 2 6 8 10 12 14 16 18 20 224
Day
mm Hg
Polyphenol-Rich Chocolate
Polyphenol-Free Chocolate
§
§
‡
‡
‡
‡
∗
∗
††
∗
‡
†
†
*P ⬍.05; †P⬍.001; ‡P =.04; and §P =.03, indicating significant differences in blood
pressure between diets with polyphenol-rich or polyphenol-free chocolate, ad-
justed to a baseline blood pressure difference of zero (paired 2-tailed t tests, in-
dividual P values are adjusted for multiple comparisons by the method of Holm).
All other P values are ⬎.05. Error bars indicate SEM.
LETTERS
©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, August 27, 2003—Vol 290, No. 8 1029
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defined threshold that would have required antihypertensive drug
therapy. Daily energy intake and macronutrient composition
remained stable throughout the study. Body mass index, 24-hour
urinary excretion of sodium, potassium, and total nitrogen, as
well as fasting plasma concentrations of total cholesterol, low-
density lipoprotein cholesterol, high-density lipoprotein choles-
terol, triglycerides, and glucose were not significantly different
between the run-in phase and the postintervention periods.
Comment. A calorie-balanced increase in consumption of
dark chocolate may favorably affect BP in previously un-
treated elderly hypertensive individuals. Control meals using
PFC differed from PRC meals only by the lack of cocoa solids.
Plant polyphenols are major constituents of the cocoa solids,
3
have significant bioavailability,
4
and appear to be responsible
for the reductions in BP. The long-term clinical effects, how-
ever, remain unknown.
Dirk Taubert, MD, PhD
Department of Pharmacology
Reinhard Berkels, PhD
Renate Roesen, PhD
Wolfgang Klaus, MD, PhD
Medical College of the University of Cologne
Cologne, Germany
1. Keen CL. Chocolate: food as medicine/medicine as food. J Am Coll Nutr. 2001;
20(5 suppl):436S-439S, 440S-442S.
2. Diebolt M, Bucher B, Andriantsitohaina R. Wine polyphenols decrease blood
pressure, improve NO vasodilatation, and induce gene expression. Hypertension.
2001;38:159-165.
3. Luna F, Crouzillat D, Cirou L, Bucheli P. Chemical composition and flavor of
Ecuadorian cocoa liquor. J Agric Food Chem. 2002;50:3527-3532.
4. Holt RR, Lazarus SA, Sullards MC, et al. Procyanidin dimer B2 [epicatechin-
(4beta-8)-epicatechin] in human plasma after the consumption of a flavanol-rich
cocoa. Am J Clin Nutr. 2002;76:798-804.
Vascular Effects of Cocoa Rich in Flavan-3-ols
To the Editor: In vitro studies have suggested that flavonoids
may have specific vascular effects, but their mechanism of ac-
tion has not been clarified.
1
A subclass of flavonoids—flavan-
3-ols and their oligomers (procyanidins)—are constituents of
cocoa beans, which can be detected in human plasma after in-
gestion of cocoa.
2
In turn, plant extracts rich in flavan-3-ols
can increase the activity of nitric oxide synthase (NOS) in en-
dothelial cells.
3
Nitric oxide is an essential signaling molecule
in vascular physiology. Nitric oxide bioactivity can be pre-
served in human plasma in a circulating pool via increases in
a number of nitrosated compounds.
4,5
Thus, it is possible that
cocoa rich in flavan-3-ols may lead to improved endothelium-
dependent dilation via an increase of nitric oxide bioactivity.
However, commercially available cocoa drinks contain only
small amounts of flavan-3-ols due to roasting and alkalization
of cocoa beans, which are known to degrade flavan-3-ols. We
tested the hypothesis that ingestion of flavan-3-ol rich cocoa
can increase the circulating pool of nitric oxide in human plasma,
thus increasing endothelium-dependent dilation.
Methods. Participants were 26 outpatients with at least 1 car-
diovascular risk factor, including history of coronary artery dis-
ease, hypertension, hyperlipidemia, diabetes, or current to-
bacco use. Individuals were excluded if they had C-reactive
protein levels greater than 0.5 mg/dL, atrial fibrillation, acute
coronary syndrome, or New York Heart Association class III
or IV heart failure. Individuals were studied in the morning af-
ter a 12-hour fasting period.
In an initial study involving the first 6 participants, we
assessed the time course of flavan-3-ol effects on flow-
mediated dilation (FMD). This was measured at 0, 2, 4, and 6
hours after ingestion of 100 mL of cocoa drink containing
176 mg of flavan-3-ols (70 mg of epicatechin plus catechin,
106 mg of procyanidins [The Positive Food Co, Wokingham,
England]) (n= 6) or control (100 mL cocoa drink with ⬍10
mg of flavan-3-ols [Dovedrink, Mars Inc, Hackettstown, NJ]
or water) (n=3).
We then used these results to guide the timing of a double-
blind crossover study. Twenty participants received 100 mL
of cocoa drinks with high or low levels of flavan-3-ols, in ran-
dom order, on 2 consecutive days. The sum of nitrosylated and
nitrosated species (collectively referred to as RNO) was mea-
sured by reductive chemiluminescence assay 2 hours after in-
gestion on both days.
4
Nitrate and nitrite levels were mea-
sured as previously described.
6
Endothelium-dependent dilation
was assessed by measuring FMD of the brachial artery. In ad-
dition, we measured a number of other vascular parameters that
would not be expected to change as a result of flavan-3-ol, in-
cluding blood pressure, heart rate, and plasma levels of nitrite
and nitrate. Similarly, we measured endothelium-
independent dilation of the brachial artery following sublin-
gual application of 400 µg of glyceroltrinitrate, diameter of the
brachial artery, and forearm blood-flow at rest and during re-
active hyperemia, as assessed by venous occlusion plethys-
mography. (Technical details are available from the authors.)
All variables except endothelium-independent dilation were
measured both before and after ingestion of the cocoa. Endo-
Figure 1. Time Course of Flow-Mediated Dilation After Ingestion of
100 mL of Cocoa Drink Containing High (176 mg mL; n =6) or Low
(⬍10 mg mL; n=3) Amounts of Flavan-3-ols
6
2
1
3
4
5
0
Time, h
Flow-Mediated Dilation, %
Flavan-3-ol Rich Cocoa
Flavan-3-ol Low Cocoa
0 642
∗
Data given as mean (SEM). *Indicates significant difference from baseline (P⬍.001).
LETTERS
1030 JAMA, August 27, 2003—Vol 290, No. 8 (Reprinted) ©2003 American Medical Association. All rights reserved.
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