Download Chocolate consumption and mortality following a first acute

Original Article
|
doi: 10.1111/j.1365-2796.2009.02088.x
Chocolate consumption and mortality following a first
acute myocardial infarction: the Stockholm Heart
Epidemiology Program
I. Janszky1, K. J. Mukamal2, R. Ljung1,3, S. Ahnve1, A. Ahlbom4 & J. Hallqvist1,5
From the 1Department of Public Health Sciences, Karolinska Institute, Stockholm, Sweden; 2Division of General Medicine and
Primary Care, Beth Israel Deaconess Medical Center, Boston, MA, USA; 3Centre for Epidemiology, The National Board of
Health and Welfare, Stockholm; 4Department of Epidemiology, Institute of Environmental Medicine, Karolinska Institute,
Stockholm; and 5Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden
Abstract. Janszky I, Mukamal KJ, Ljung R, Ahnve S,
Ahlbom A, Hallqvist J (Karolinska Institute, Stockholm, Sweden; Beth Israel Deaconess Medical Center,
Boston, MA, USA; The National Board of Health and
Welfare, Stockholm; Karolinska Institute, Stockholm;
and Uppsala University, Uppsala, Sweden). Chocolate
consumption and mortality following a first acute
myocardial infarction: the Stockholm Heart Epidemiology Program. J Intern Med 2009; 266: 248–257.
Objectives. To assess the long-term effects of chocolate
consumption amongst patients with established coronary heart disease.
Design. In a population-based inception cohort study,
we followed 1169 non-diabetic patients hospitalized
with a confirmed first acute myocardial infarction
(AMI) between 1992 and 1994 in Stockholm County,
Sweden, as part of the Stockholm Heart Epidemiology
Program. Participants self-reported usual chocolate
consumption over the preceding 12 months with a
standardized questionnaire distributed during hospitalization and underwent a health examination 3 months
after discharge. Participants were followed for hospitalizations and mortality with national registries for
8 years.
Introduction
Health effects of chocolate have been of great interest
in recent years. As chocolate is a significant source of
248
ª 2009 Blackwell Publishing Ltd
Results. Chocolate consumption had a strong inverse
association with cardiac mortality. When compared
with those never eating chocolate, the multivariableadjusted hazard ratios were 0.73 (95% confidence
interval, 0.41–1.31), 0.56 (0.32–0.99) and 0.34 (0.17–
0.70) for those consuming chocolate less than once
per month, up to once per week and twice or more
per week respectively. Chocolate consumption generally had an inverse but weak association with total
mortality and nonfatal outcomes. In contrast, intake of
other sweets was not associated with cardiac or total
mortality.
Conclusions. Chocolate consumption was associated
with lower cardiac mortality in a dose dependent
manner in patients free of diabetes surviving their first
AMI. Although our findings support increasing evidence that chocolate is a rich source of beneficial bioactive compounds, confirmation of this strong inverse
relationship from other observational studies or largescale, long-term, controlled randomized trials is
needed.
Keywords: acute myocardial infarction, chocolate,
prognosis.
flavonoid antioxidants [1], several short-term clinical
trials have shown beneficial cardiovascular effects of
chocolate or cocoa consumption, including improvement of endothelial function [2–5], inhibition of
I. Janszky et al.
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Chocolate consumption and post-AMI prognosis
platelet activation [2, 6, 7] and LDL oxidation [8, 9]
and decrease of blood pressure [10, 11].
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 disease
[12] and postmenopausal women [13]. 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 acute myocardial infarction (AMI) has not been explored.
Therefore, we investigated the long-term prospective
relationships between chocolate consumption and total
mortality, cardiac mortality and nonfatal end-points
including recurrent AMI, hospitalization for heart failure and stroke amongst patients surviving their first
AMI in a population-based study of AMI.
Methods
Subjects and design
We followed individuals enrolled as nonfatal AMI
cases in the Stockholm Heart Epidemiology Program
(SHEEP), a population-based case–control study of
incident AMI [14]. The study base comprised all
Swedish citizens living in the Stockholm County, 45–
70 years of age, free of previous clinically diagnosed
AMI. Male cases were identified during a 2-year period (1992–93) and female cases during 3 years
(1992–94). Cases were identified through a special
organization at the 10 emergency hospitals in the
region. Criteria for AMI included (i) symptoms consistent with AMI, (ii) positive blood levels of the
enzymes CK and LD and (iii) specified ECG-changes.
The diagnosis ‘acute myocardial infarction’ required
two of the criteria (i–iii) to be met. Later comparison
with a population-based register-based incidence register indicated close to complete ascertainment of all
first AMIs [15]. A total of 2246 cases of MI were
identified, of which 1603 were nonfatal defined as
surviving the AMI for at least 28 days. Eighty-six
percent or 1381 of the nonfatal cases participated in
the questionnaires handed out a few days after the
AMI and 1361 provided complete data on chocolate
consumption. To minimize reverse confounding by
patients who may have been counselled to avoid
chocolate or other sweets, we excluded patients with
diabetes mellitus (n = 192), yielding a total of 1169
patients in subsequent analyses.
A health examination measuring blood pressure, height
and weight with a blood sampling was undertaken
3 months after the AMI onset. A total of 1051 non diabetic patients with complete chocolate data participated
in the health examination and hence had information
on measured blood pressure and biomarkers.
Chocolate consumption
The questionnaire distributed a few days after AMI
onset queried the number of usual (50 g) portions of
chocolate that participants usually consumed per day,
per week or per month during the last 12 months.
The original consumption categories included: never,
less than once per month, 1–3 times per month, once
per week, twice per week, 3–4 times per week, 5–6
times per week, once per day, twice per day and 3
times or more per day. Based upon the distribution of
these original categories within the SHEEP population, we categorized usual chocolate consumption as
never, less than once per month, up to once per week
and twice or more per week.
Covariates
Lipids, coagulation, inflammation. As previously
described elsewhere [14], lipids, coagulation factors
[16] and inflammatory markers [17] were measured
from blood samples drawn by venous puncture after
overnight fasting at the health examination.
Glucose, insulin, insulin-like growth factor binding protein-1 (IGFBP-1), insulin resistance. Glucose, insulin and IGFBP-1 levels were determined
from fasting blood samples. An estimate of insulin
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I. Janszky et al.
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resistance was calculated using the homeostasis model
assessment (HOMA-IR) as follows: insulin resistance = fasting glucose · fasting insulin ⁄ 22.5 [18].
Hypertension. Hypertension was defined as (i) being
on antihypertensive drug therapy, for the reason of
hypertension, when included in the study; (ii) a history
of regular antihypertensive drug therapy during the last
5 years (or a part of that time); (iii) a systolic blood
pressure ‡170 mmHg or a diastolic blood pressure
‡95 mmHg. Blood pressure values were the mean of
two measurements in supine position after 5 min rest
at the health examination, i.e. 3 months after AMI.
Obesity. Patients with a measured BMI-value over
30 kg m)2 were classified as being obese.
Physical inactivity. Patients who reported inactive
leisure time, which included occasional walks, during
the last 5–10 years were categorized as physically
inactive.
Smoking. Subjects who had never smoked regularly
(i.e. for at least 1 year) were considered as neversmokers. Subjects, who smoked when included into
the study or had stopped smoking within the last
2 years, were classified as smokers. Subjects, who
had stopped smoking for more than 2 years before
inclusion, were classified as ex-smokers.
Chocolate consumption and post-AMI prognosis
Pharmacological treatment was collected through the
questionnaires and also at the health examination.
Patients were asked to report on current use of pharmacological drugs, all brand names and these were
later assigned generic codes. Both cardiac and non
cardiac medications were recorded. The first one
included calcium channel blockers, b-blockers, ACE
inhibitors, diuretics, digitalis, nitrates and aspirin treatment.
Follow-up
The health care system in Sweden provides virtually
complete follow-up information for all patients by
matching their unique 10 digit person identification
numbers to health care registers. The average followup, from the AMI, was 3158 days (SD = 257 days,
median = 3164 days, interquartile range = 376 days).
All-cause and cardiac mortality were used as primary
end-points as provided by the National Causeof-death Register. The ICD 9 and 10 codes for cardiac mortality included 410–414, 420–429, I20–I25,
I38–I51 respectively. Patients were also followed for
nonfatal AMI using the Swedish Myocardial Infarction Register [22]. Information on hospitalization for
heart failure (ICD-9 and 10 codes were 428, I50
respectively) and stroke (431, 434, I64, I63, I61) was
derived from the Swedish Hospital Discharge Register [23–25]. Follow-up was closed on 1 December
2001.
Educational attainment. We classified educational
attainment as mandatory school only versus high
school, college or university.
Consumption of sweets and desserts.
Patients
were queried about their usual intake of six types of
sweets – biscuits, cookies, cakes, pastries, confectioneries and ice cream, using the same response options
as for chocolate. Each variable was categorized into
quartiles and a value of 1–4 was assigned to each.
The score values were added up to form a single
sweet score variable ranging from 6–24.
Consumption of alcohol and filtered coffee was
assessed with a semiquantitative food frequency questionnaire, as previously described [19–21].
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Statistical analyses
We used Cox proportional hazard models to examine the association between chocolate consumption
and cardiac and all-cause mortality, new nonfatal
AMI and hospitalization for stroke and heart failure.
The group of never consumers was the reference
category in these models. We tested the proportionality of hazards using log-log curves and formal
tests of interaction with time or log-time. Primary
confounding factors for evaluation of chocolate consumption we included were age (in 5 categories),
gender, smoking (in 3 categories), obesity, physical
inactivity, alcohol consumption (in g day)1), filtered
coffee consumption (in cups per day), educational
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Chocolate consumption and post-AMI prognosis
attainment and sweet score. As blood pressure is a
plausible mediator of the effects of chocolate on
prognosis, we included it only in secondary analyses. In further analyses, we also added additional
clinical characteristics of the index AMI (Killip
class, Q-wave versus non-Q-wave MI and history of
ventricular tachycardia), which were simultaneously
available only in 920 participants. Rothman’s synergy index with 95% confidence intervals was used
to evaluate interaction between chocolate consumption and clinical characteristics [26]. To examine
potential mediators, we calculated adjusted mean
levels of biomarkers according to chocolate consumption and then compared the change in regression coefficients associated with chocolate modelled
as a continuous variable from multivariable proportional hazards models with and without inclusion of
specific biomarkers. For tests of linear trend, we
treated the median value of chocolate intake in
grams within categories as a continuous variable.
Statistical analyses were performed using sas 9 for
Windows (SAS Inc., Cary, NC, USA).
Results
Patient characteristics
Table 1 shows characteristics of SHEEP participants
according to chocolate intake. In general, prevalence
of hypertension, sedentary lifestyle and lower education decreased with increasing chocolate consumption.
Chocolate consumption was strongly correlated with
sweet score (Spearman’s rho = 0.41, P < 0.001).
Chocolate consumption and mortality
Table 2 shows the relationships of chocolate consumption with total and cardiac mortality. There was
an inverse, dose–response relationship between chocolate consumption and cardiac mortality both in ageand gender-adjusted models and after controlling for
other potential confounders. In contrast, sweet score
had no statistically significant relationship to cardiac
or total mortality. The multivariable-adjusted hazard
ratios (HRs) for a single-unit increase in the sweet
Table 1 Characteristics of the patients according to usual chocolate consumption
Never
n
166
Less than once
Up to once
Twice or more
per month
per week
per week
250
453
300
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Age (years)
60.7 (7.5)
59.1 (7.0)
58.6 (7.4)
59.5 (6.7)
n (%)
n (%)
n (%)
n (%)
Male gender
110 (66.3)
188 (75.2)
328 (72.4)
205 (68.3)
Hypertension
71 (43.0)
88 (35.3)
161 (35.7)
101 (34.2)
Sedentary lifestyle
87 (52.7)
120 (48.2)
194 (43.5)
125 (42.0)
Overweight (BMI > 30)
29 (17.5)
39 (15.7)
79 (17.5)
49 (16.3)
Nonsmokers
40 (24.1)
63 (25.2)
106 (23.4)
63 (21.0)
Previous smokers
34 (20.5)
64 (25.6)
120 (26.5)
64 (21.3)
Current smokers
92 (55.4)
123 (49.2)
227 (50.1)
173 (57.7)
48 (29.5)
68 (27.5)
152 (33.6)
104 (34.9)
99 (62.7)
125 (54.6)
241 (57.5)
168 (61.1)
1
95 (67.4)
151 (72.3)
290 (75.1)
162 (66.7)
2+
46 (32.6)
58 (27.8)
96 (24.9)
81 (33.3)
Cigarette smoking
High School ⁄ College or University
Index hospitalization
Q wave infarction
Killip classification
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Table 2 Risk of fatal outcomes following acute myocardial infarction amongst SHEEP participants according to usual chocolate
consumption
Never
Total mortality, n (%)
Age-gender adjusted HR
Age-gender adjusted HR
per week
41 (16.4)
82 (18.1)
52 (17.3)
0.81
0.92
0.85
(0.52–1.28)
(0.62–1.37)
(0.55–1.31)
1.0
0.89
0.96
0.94
(0.56–1.42)
(0.63–1.48)
(0.58–1.53)
24 (14.5)
24 (9.6)
41 (9.1)
18 (6.0)
1.0
0.69
0.67
0.43
(0.39–1.23)
(0.40–1.11)
(0.23–0.80)
0.73
0.56
0.34
(0.41–1.31)
(0.32–0.99)
(0.17–0.70)
95% CI
Multivariable HR
Twice or more
per week
35 (21.1)
95% CI
Cardiac mortality, n (%)
Up to once
per month
1.0
95% CI
Multivariable HR
Less than once
1.0
95% CI
P trend
0.69
0.96
0.02
0.01
Adjusted HR indicated hazard ratio adjusted for age (in 5 categories), gender, smoking (in 3 categories), obesity, physical inactivity, alcohol
consumption (in g day)1), filtered coffee consumption (in cups per day), educational attainment and sweet score, 95% CI indicates 95% confidence interval.
score were 0.98 (0.95–1.02) and 0.98 (0.93–1.04) for
total and cardiac mortality respectively. Additional
adjustment for hypertension and systolic blood pressure did not attenuate the risk associated with chocolate intake with cardiac mortality. In further analyses,
we additionally controlled for markers of infarct
severity (Killip class, maximum CK levels, ventricular
tachycardia and Q-wave MI) with no material change
in the observed HRs. Our results concerning the
strong inverse association between chocolate consumption and cardiac mortality were also robust to
alternative categorizations or using chocolate consumption as a continuous variable.
Chocolate consumers had slightly lower total mortality in all categories when compared to chocolate
abstainers, but the relationship was weaker than that
of with cardiac mortality.
Chocolate consumption and nonfatal outcomes
Table 3 shows the multivariable-adjusted associations
of chocolate consumption with risks of hospitalization
for nonfatal cardiovascular events alone and in combination. In general, chocolate consumers tended to
have slightly lower risk for these events, but there
was no clear evidence of association.
252
We observed a modest variation in the association
between chocolate consumption and stroke over time
(i.e. non proportionality of hazards) restricted to those
consuming chocolate less than once per month compared with chocolate abstainers, but not for any other
categories of intake. Those consuming chocolate less
than once per month had a more substantially lower
risk for stroke after the first 4 years of follow-up (HR
0.48, 95% CI, 0.20–1.18) than during the first half of
follow-up (HR 0.91, 95% CI 0.39–2.08). The proportional hazards assumption was met for all other
outcomes.
Potential mediators
Table 4 presents least squares means of the potential
mediators of the effect of chocolate according to
chocolate intake when adjusted for age, gender,
obesity, physical inactivity, smoking, education, alcohol and filtered coffee consumption and sweet score
(i.e. the same factors we included to the multivariable proportional hazard models). Insulin level
showed a modest inverse relationship with chocolate
intake, but no other significant graded associations
were observed. We also compared the association
of chocolate intake with cardiac mortality before
and after adjustment for potentially mediating
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Chocolate consumption and post-AMI prognosis
Table 3 Risk of nonfatal outcomes following acute myocardial infarction amongst SHEEP participants according to usual chocolate consumption
Recurrent AMI, n (%)
Adjusted HR
Less than once
Up to once
Twice or more
Never
per month
per week
per week
36 (21.7)
51 (20.4)
104 (23.0)
59 (19.7)
1.0
0.95
1.02
0.86
(0.61–1.49)
(0.68–1.55)
(0.54–1.37)
63 (25.2)
91 (20.1)
69 (23.0)
95% CI
Congestive heart failure, n (%)
Adjusted HR
56 (33.7)
1.0
0.82
0.68
0.78
(0.56–1.19)
(0.47–0.97)
(0.52–1.16)
22 (13.3)
24 (9.6)
35 (7.7)
30 (10.0)
1.0
0.67
0.54
0.62
(0.33–1.16)
95% CI
Stroke, n (%)
Adjusted HR
95% CI
Any nonfatal event, n (%)
Adjusted HR
95% CI
(0.36–1.23)
(0.30–0.96)
78 (47.0)
103 (41.2)
177 (39.1)
113 (37.7)
1.0
0.93
0.89
0.82
(0.68–1.26)
(0.67–1.19)
(0.59–1.14)
P trend
0.38
0.78
0.65
0.30
Adjusted HR indicated hazard ratio adjusted for age (in 5 categories), gender, smoking (in 3 categories), obesity, physical inactivity, alcohol
consumption (in g day)1), filtered coffee consumption (in cups per day), educational attainment and sweet score, 95% CI indicates 95% confidence interval.
biomarkers. As expected from the weak associations
of chocolate with these biomarkers, including them
in multivariable analyses attenuated the observed
association of chocolate with cardiac mortality by
no more than 3%.
Stratified analyses
In stratified analyses, we found largely similar associations between chocolate consumption and outcome
across
several
subgroups.
Chocolate
consumption was associated with lower cardiac mortality both amongst men and women, in patients
below or equal to 60 years and in those older than
that, amongst physically active and inactive subjects,
amongst never-, current- and former smokers,
amongst hypertensive patients and patients without
hypertension and amongst patients having high
school ⁄ college degree and lower education. Chocolate consumption was also associated with lower
cardiac mortality for patients with a BMI value
below 30 kg m)2 (HR for the trend variable 0.92;
95% CI 0.82–0.98), but not for those above this
BMI (HR 1.01; 95% CI 0.91–1.11), but the confidence intervals for Rothman’s synergy index for this
interaction included one.
Discussion
In this long-term follow-up study of early survivors
of a first AMI without diabetes, usual chocolate consumption, assessed at the time of hospitalization, had
a strong inverse association with subsequent cardiac
mortality. The corresponding associations with total
mortality and nonfatal cardiovascular events were
considerably weaker. The observed association of
chocolate with lower cardiac mortality was generally
stable across different subgroups and with adjustment
for a variety of confounders. In contrast, intake of
other sweets was not associated with cardiac or total
mortality.
We know of no studies assessing the possible effects
of chocolate consumption on post-AMI prognosis.
Some previous studies have suggested that chocolate
may have protective effects against cardiovascular
events and mortality in the general population. In the
Zutphen Elderly Study, men free of coronary heart disease in the highest tertile of cocoa intake had half of
the cardiovascular mortality of those in the lowest
tertile after adjustment for the potential confounding
factors [12]. In the Harvard Alumni Study, men who
consumed candy had lower all-cause mortality than
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Chocolate consumption and post-AMI prognosis
Table 4 Potential mediatory factors according to usual chocolate consumption
Never
239
n
Less than once
Up to once
Twice or more
P for
per month
per week
per week
homogeneity
307
497
318
LSM* (SE)
LSM (SE)
LSM (SE)
LSM (SE)
133 (1.7)
131 (1.3)
132 (1.0)
130 (1.3)
0.55
Total cholesterol (mmol L)1)
6.22 (0.10)
6.26 (0.08)
6.21 (0.06)
6.15 (0.07)
0.82
LDL
4.21 (0.09)
4.33 (0.07)
4.26 (0.05)
4.19 (0.07)
0.46
HDL
1.09 (0.03)
1.08 (0.02)
1.10 (0.01)
1.08 (0.02)
0.82
ApoB
1.63 (0.03)
1.67 (0.03)
1.63 (0.02
1.64 (0.02)
0.71
ApoA
1.39 (0.02)
1.40 (0.02)
1.40 (0.01)
1.39 (0.02)
0.77
Lp(a)
0.28 (0.03)
0.31 (0.02)
0.30 (0.02)
0.29 (0.02)
0.87
Triglycerides (mmol L)1)
2.24 (0.12)
1.93 (0.09)
1.93 (0.07)
2.02 (0.09)
0.12
0.76
Systolic blood pressure (mmHg)
Serum levels of
Glucose
5.34 (0.10)
5.25 (0.08)
5.35 (0.06)
5.33 (0.07)
Insulin
13.96 (0.95)
13.13 (0.73)
11.65 (0.54)
11.03 (0.69)
0.05
HOMA
3.20 (0.28)
2.99 (0.22)
2.84 (0.16)
2.74 (0.20)
0.59
IGFBP1
29.64 (2.00)
24.22 (1.54)
29.84 (1.15)
27.75 (1.46)
0.02
CRP
4.63 (0.72)
4.07 (0.56)
3.52 (0.42)
4.28 (0.54)
0.50
IL-6
6.70 (3.36)
9.25 (2.61)
8.01 (1.86)
8.90 (2.38)
0.93
TNFalfa
1.83 (0.19)
2.16 (0.15)
2.05 (0.12)
2.13 (0.14)
0.53
PAI-1
20.39 (1.54)
19.01 (1.20)
18.70 (0.89)
21.90 (1.14)
0.13
Fibrinogen
3.83 (0.08)
3.74 (0.06)
3.72 (0.05)
3.66 (0.06)
0.42
tPA-PAI
6.21 (0.38)
5.46 (0.31)
6.09 (0.23)
5.69 (0.29)
0.26
Von Willebrand
1.41 (0.07)
1.55 (0.06)
1.39 (0.04)
1.53 (0.05)
0.07
12.37 (1.09)
11.78 (0.85)
12.99 (0.65)
12.28 (0.80)
0.72
Homocystein
*LSM, least squares means, adjusted for age, gender, obesity, physical inactivity, smoking, education, alcohol, filtered coffee and sweets score;
ApoA, apolipoprotein A; ApoB, apolipoprotein B; Lp (a), lipoprotein (a); HOMA, homeostasis model assessment; IGFBP-1, insulin-like growth
factor binding protein-1; CRP, high sensitivity C-reactive protein; IL-6, interleukin-6; PAI-1, plasminogen activator inhibitor 1; tPA, tissue plasminogen activator; TNF, tumour necrosis factor.
nonconsumers [27], although chocolate and non chocolate candies were not differentiated. Mink et al. [13]
also found an inverse association between chocolate
intake and cardiovascular disease mortality amongst
postmenopausal women. In contrast, in the Nurses’
Health Study, there was no significant association
between moderate chocolate intake and the incidence
of coronary heart disease in multivariate analyses [28].
Two components of chocolate might be particularly relevant to our findings. Fat in chocolate is especially
high in stearic acid (around 30% of all fatty acids)
[29]. The effect of stearic acid on cardiovascular health
remains controversial, but a recent systematic review
concluded that stearic acid has beneficial or neutral
254
effects on blood pressure and clotting parameters and
does not adversely affect traditional lipid risk factors
[30]. Chocolate is also a very rich source of flavonoid
antioxidants [1]. Analysing major American brands,
Gu et al. found that milk chocolate contains 5–
12 mg 100 g)1 of catechin, 18–24 lg 100 g)1 of epicatechin and 0.22–0.31 mg 100 g)1 of procyanidins in
total. For dark chocolate, the corresponding concentrations were 11–33 mg 100 g)1, 52–125 lg 100 g)1 and
0.85–1.99 mg 100 g)1 respectively. In randomized trials, chocolate lowers blood pressure [11] and may
increase bioactive nitric oxide availability [10].
Other potentially bioactive substances in chocolate
include zinc, selenium, magnesium and vitamin E.
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Chocolate consumption and post-AMI prognosis
According to the Swedish National Food Administration [31], the concentrations of these substances in
Swedish chocolates are 1.37 mg 100 g)1 in milk
chocolate and 2.89 mg 100 g)1 in dark chocolate for
zinc, 3.6 lg 100 g)1 and 4.6 lg 100 g)1 for selenium, 63 mg 100 g)1 and 174 mg 100 g)1 for magnesium and 0.74 mg 100 g)1 and 0.66 mg 100 g)1
for vitamin E respectively.
We explored several potentially mediating biomarkers
for the inverse association between chocolate intake
and lower cardiac mortality. Surprisingly, none of the
markers we tested, including lipids, inflammatory
markers, coagulation factors, indicators of glucose
homeostasis or systolic blood pressure, appeared to be
important in linking chocolate to lower cardiac mortality. Based on the results of short-term intervention
trials, improvement in endothelial function [2–5], inhibition of platelet activation [2, 6, 7] and LDL oxidation [8, 9] are other proposed mechanisms that we
could not test in this study.
Chocolate intake in our study had a considerably
stronger and a more directly inverse association with
fatal cardiac events than nonfatal ones. Although the
HRs for recurrent AMI, stroke and heart failure were
all numerically <1.0 in the top category of chocolate
intake, none of these showed a significant or clear
pattern of a dose-dependent trend. This finding mirrors that seen for n-3 fatty acid supplementation in
secondary prevention trials [32] and could imply an
anti-arrhythmic effect of chocolate intake in this setting. Limited animal and human data support the
hypothesis that antioxidants have anti-arrhythmic
properties in the setting of myocardial ischemia
and ⁄ or reperfusion [33–37]. On the other hand, it is
also likely that nonfatal events, especially stroke and
heart failure were more misclassified as they were
derived from hospital discharge registers [25].
Limitations
Observational studies inherently limit causal inference. Chocolate intake might be associated with
healthier lifestyle characteristics that could themselves
explain the observed inverse association with cardiac
mortality. Although we adjusted for several potential
confounders in our multivariable analyses and found
no attenuation of our results in multivariable models
compared with age- and gender-adjusted models, we
cannot exclude the possibility of uncontrolled confounding. However, any remaining confounder potentially able to influence our results considerably would
need to be strongly associated with both chocolate
intake and cardiovascular mortality following an AMI
and generally unrelated to the factors included in our
models.
It is also possible that some patients ceased chocolate
consumption prior to hospitalization because of poor
health. Diabetes would appear to be the most likely
medical reason that patients would be counselled to
remove chocolate from their diets and hence, we
excluded patients with diabetes from our analyses.
Moreover, we found a weak and statistically nonsignificant association of non chocolate sweet consumption with cardiac mortality, despite the fact that those
patients who stop chocolate consumption due to
health problems would likely also reduce intake of
other sweets. The beneficial effect of chocolate on
cardiac mortality also remained after adjusting for
intake of other sweets.
We queried our patients about chocolate consumption
in general and did not differentiate between dark and
milk chocolate. In the European Union, milk chocolate
has to contain a minimum of 25% of cocoa solids,
dark chocolate 35% [38]. The corresponding proportions in United States are 10% and 15% [39]. According to the main chocolate producer (Marabou owned
by Kraft Foods Sverige AB, Upplands Väsby, Sweden)
in the decade of the 1990s, 90% of the consumption
was milk chocolate in Sweden and Swedish milk
chocolate normally contains 30% cocoa solids.
Milk chocolate contains more fat and sugar than dark
and is less rich in cocoa solids and hence flavonoid
antioxidants [40]. The milk content may also decrease
the absorption of cocoa-related antioxidants in the
gastrointestinal tract [41], although this effect remains
uncertain [42, 43] and Fraga et al. observed lower
oxidative stress in a short-term trial for milk chocolate
ª 2009 Blackwell Publishing Ltd Journal of Internal Medicine 266; 248–257 255
I. Janszky et al.
|
[44]. Thus, our findings may or may not have been
stronger had we queried our patients specifically
about dark chocolate.
Conclusion
Chocolate consumption was associated with lower
cardiac mortality in a dose dependent manner in
patients free of diabetes surviving their first AMI.
Although our findings support increasing evidence
that chocolate is a rich source of beneficial bioactive
compounds and suggest that individuals with coronary
heart disease need not avoid chocolate if consumed in
moderation, confirmation of this strong inverse relationship from other studies is needed.
Conflict of interest statement
No conflict of interest was declared.
Acknowledgements
The SHEEP study was supported by grants from the
Swedish Council for Social Research, the Swedish
Council for Work Life and the County Council of
Stockholm. Dr Janszky was further supported by fellowship grant 2006-1146 of the Swedish Council of
Working Life and Social Research and the Ansgarius
Foundation.
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Correspondence: Dr Imre Janszky, Department of Public Health
Sciences, Karolinska Institute, Norrbacka, 6th floor, Karolinska
University Hospital, SE-171 76 Stockholm, Sweden.
(fax: + 46 8 73 73 888; e-mail: [email protected]).
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