Serum lycopene concentrations and carotid atherosclerosis : the Kuopio Ischaemic Heart Disease Risk Factor Study

Serum lycopene concentrations and carotid atherosclerosis: the
Kuopio Ischaemic Heart Disease Risk Factor Study1–3
Tiina H Rissanen, Sari Voutilainen, Kristiina Nyyssönen, Riitta Salonen, George A Kaplan, and Jukka T Salonen
ABSTRACT
one of the major carotenoids in Western diets. In contrast with
Background: Interest in lycopene is growing rapidly following
most other carotenoids, however, which are widely distributed
the recent publication of epidemiologic studies in which high cir-
among a great variety of fruit and vegetables, lycopene intake
culating lycopene concentrations were associated with reductions
comes predominantly from tomatoes and tomato products.
in cardiovascular disease. Lycopene is one of the major
Lycopene has unique structural and chemical features that may
carotenoids in the Western diet and is probably one of the protec-
contribute to its specific biological properties (7). The antioxidant
tive factors in a vegetable-rich diet.
properties of lycopene are resistant to heat and cooking, and the
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Objective: We studied the hypothesis that the intima-media thick-
bioavailability of lycopene in processed tomato products is higher
ness of the common carotid artery (CCA-IMT) would be greater
than that in unprocessed, fresh tomatoes.
in men with low serum lycopene concentrations.
Lycopene is an antioxidant carotenoid without provitamin A
Design: We investigated the relation between serum lycopene con-
activity and has been shown to be a more potent antioxidant than
centration and CCA-IMT in 1028 middle-aged men (aged 46–64 y)
?- or ?-carotene (8). The oxidation-protecting effect of lycopene
in eastern Finland who were participants in the Kuopio Ischaemic
and tomatoes has been shown in both human and animal studies
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Heart Disease Risk Factor study and who were examined in
(9, 10). A reduced oxidative modification of LDL may be one of
1991–1993. The subjects were classified into quarters according
the mechanisms by which lycopene reduces the risk of CAD and
to serum lycopene concentration.
atherosclerotic progression (11, 12).
Results: In a covariance analysis with adjustment for covariates,
Only a few previous studies addressed the association between
by on August 22, 2009
the men in the lowest quarter of serum lycopene concentration had
low concentrations of circulating lycopene and early atheroscle-
a significantly higher mean CCA-IMT and maximal CCA-IMT
rosis. We tested the hypothesis that the intima-media thickness of
(P = 0.005 and P = 0.001 for the difference, respectively) than did
the common carotid artery (CCA-IMT) would be greater in men
the other men. The mean and maximal CCA-IMT increased lin-
with low serum lycopene concentrations.
early across the quarters of serum lycopene concentration.
Conclusions: A low serum lycopene concentration is associated
with a higher CCA-IMT in middle-aged men from eastern Fin-
SUBJECTS AND METHODS
land. This finding suggests that the serum lycopene concentra-
Subjects
tion may play a role in the early stages of atherosclerosis.
Increased thickness of the intima-media has been shown to pre-
The Kuopio Ischaemic Heart Disease Risk Factor (KIHD)
dict coronary events; thus, lycopene intakes and serum concen-
study is an ongoing, population-based study designed to investi-
trations may have clinical and public health relevance.
Am J
gate risk factors for cardiovascular disease, atherosclerosis, and
Clin Nutr 2003;77:133–8.
related outcomes in middle-aged men from eastern Finland, a
population with one of the highest recorded rates of CAD (13).
KEY WORDS
Lycopene, atherosclerosis, carotid arteries,
The study was approved by the Research Ethics Committee of the
intima-media thickness, carotenoids, Kuopio Ischaemic Heart
Disease Risk Factor study, middle-aged men
1 From the Research Institute of Public Health (THR, SV, KN, RS, and JTS)
and the Department of Public Health and General Practice (THR and JTS), Uni-
INTRODUCTION
versity of Kuopio, Kuopio, Finland; the School of Public Health, University of
Nutrition plays an important role in the development of coro-
Michigan, Ann Arbor (GAK); and the Inner Savo Health Centre, Suonenjoki,
nary artery disease (CAD). Diets rich in fruit and vegetables con-
Finland (JTS).
2
taining carotenoids are of interest because of their potential health
Supported in part by the Juho Vainio Foundation, the Ida Montin Founda-
tion, the Academy of Finland (KN and JTS), the NHLBI of the United States
benefit against chronic diseases such as CAD and cancer.
(GAK), and Oy Jurilab Ltd (Internet: www.jurilab.com).
Increased intakes and tissue or blood concentrations of
3 Address reprint requests to JT Salonen, Research Institute of Public
carotenoids are associated with a reduced risk of cardiovascular
Health, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland. E-mail:
disease (1–6). Although ?-carotene has been investigated for many
jukka.salonen@uku.fi.
years, lycopene, the acyclic form of ?-carotene, has attracted sub-
Received June 21, 2001.
stantial interest more recently. Lycopene is a red pigment and is
Accepted for publication February 26, 2002.
Am J Clin Nutr 2003;77:133–8. Printed in USA. © 2003 American Society for Clinical Nutrition
133

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134
RISSANEN ET AL
University of Kuopio, and all study subjects gave their written
were made with the use of a reversed-phase HPLC method in
informed consent.
samples that had been stored at ?80 ?C for 4–36 mo (16). This
A total of 2682 men aged 42, 48, 54, or 60 y were enrolled in
method cannot separate lycopene isomers. The detection limit for
the study between March 1984 and December 1989. Four-year
lycopene with this method was 0.03–0.07 ?mol/L. Values below
reexaminations of those examined in 1987–1989 were conducted
the limit of detection of the assay were marked as 0.00 in the sta-
between March 1991 and December 1993. For the reexaminations,
tistical analysis. The CV was determined with a serum pool ana-
the subjects visited the study site twice, with an interval of 7 d.
lyzed in 25 separate batches. The CVs were 11.0% for lycopene
Blood pressure was measured at the first visit, and CCA-IMT was
and 16.2% for ?-carotene. To evaluate the stability of lycopene,
scanned and blood samples were drawn at the second visit. Of a
we calculated the means of the first 56 samples stored for 36 mo
total of 1229 men eligible for the reexamination, 52 had died, had
(0.113 ?mol/L) and the means of the last 56 samples stored for
severe illness, or had moved away from the region, and 139 could
4 mo (0.110 ?mol/L). Thus, serum lycopene samples were well
not be contacted or refused to participate. High-resolution ultra-
preserved, and the difference in storage times did not attenuate
sound examinations of CCA-IMT and data on serum lycopene
the results.
concentrations were available for 1028 men. These results make
Lipoproteins were separated from fresh serum samples by com-
up the cross-sectional data of the reexamination of the KIHD
bined ultracentrifugation (100 000 ? g, 4 ?C, 23 h) and precipita-
follow-up study.
tion. Concentrations of serum total, LDL, and HDL cholesterol
(Kone Instruments, Espoo, Finland) and of serum triacylglycerols
Ultrasonographic assessment of the intima-media thickness
(Boehringer Mannheim, Mannheim, Germany) were determined
of the common carotid artery
enzymatically with an autoanalyzer (Kone Specific; Kone Instru-
CCA-IMT was assessed by high-resolution B-mode ultra-
ments) (17). Serum folate was determined by radioimmunoassay
sonography of the right and left CCAs at the distal end, proximal
(Bio-Rad, Hercules, CA) (18).
to the carotid bulb. The ultrasound equipment (Biosound Phase 2;
Resting blood pressure was measured in the morning by 2
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Biosound Inc, Indianapolis) was equipped with a high-resolution
trained nurses with a random-zero mercury sphygmomanometer
probe. Images were focused on the posterior wall of the right and
(Hawksley, Lancing, United Kingdom). After the subjects had
left CCAs and were recorded on videotape for image analysis. The
rested in a supine position for 5 min, 6 measurements were taken
ultrasonographic examinations were carried out by well-trained
at 5-min intervals: 3 while the subjects were in a supine position,
ultrasound technicians and were performed after the subjects had
1 while the subjects were standing, and 2 while the subjects were
rested in a supine position for 15 min.
sitting. The mean of all 6 measurements was used as the systolic
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IMT measurements were made through computerized analysis of
and diastolic blood pressure.
the videotaped ultrasound images with PROSOUND software (Uni-
A subject was defined a smoker if he had ever smoked on a reg-
versity of Southern California, Los Angeles). This software uses an
ular basis and had smoked cigarettes, cigars, or a pipe within the
edge-detection algorithm, speci?cally designed for use with ultra-
past 30 d. The number of cigarettes, cigars, and pipefuls of
by on August 22, 2009
sound imaging, that allows automatic detection, tracking, and record-
tobacco currently smoked daily and the duration of regular smok-
ing of the intima-lumen and media-adventitia interfaces, estimated
ing in years were recorded on a self-administered questionnaire
at ?100 points, in both the right and left CCAs in a 1.0–1.5-cm sec-
that was checked by an interviewer.
tion (14). For the present study, 2 measures of IMT were used. Mean
Body weight was measured by using a balance scale. During
IMT was computed as the mean of ?100 IMT measurements in the
the height and weight measurements, the subjects wore light cloth-
right CCA and another 100 measurements in the left CCA. Maxi-
ing and no shoes. Body mass index (BMI) was computed as the
mum IMT was computed as the average of the points of maximum
ratio of weight to the square of height (kg/m2).
thickness from the right and left CCAs, which is indicative of the
depth of intrusion of the IMT into the lumen in this part of the CCA.
Statistical analysis
A separate study concerning the intra- and interobserver vari-
Data were analyzed by using SPSS statistical software (version
ability of IMT measurements was carried out in 10 randomly cho-
10.0 for WINDOWS; SPSS Inc, Chicago). Mean age; BMI; sys-
sen middle-aged men who had participated in the KIHD study.
tolic and diastolic blood pressure; serum triacylglycerols; serum
The between-observer CV was 10.5% for the first assessments by
HDL, LDL, and total cholesterol; and serum folate, ?-carotene,
4 observers for both the right and left CCAs. The correlation coef-
and ?-tocopherol are reported as means ± SDs. Cigarette smok-
ficients ranged from 0.90 to 0.99. The intraobserver variability
ing is reported as a percentage. Subjects were classified into quar-
(reproducibility) was described by the absolute value of difference
ters according to their serum concentration of lycopene: < 0.04,
between the first and the third measurement by each observer. The
0.04–0.12, 0.13–0.22, and > 0.22 ?mol/L). The statistical signifi-
mean absolute difference was 0.087 mm, which is 8.1% of the
cance of the differences between these lycopene groups in the
mean of all measurements (15).
main characteristics of the subjects was studied by using one-way
analysis of variance (ANOVA). The correlations between CCA-
Measurements
IMT and nutritional factors and cardiovascular disease risk fac-
The subjects came to give blood samples between 0800 and
tors were estimated by Spearman’s correlation coefficients.
1000. They were instructed to abstain from ingesting alcohol for
The association between serum concentrations of lycopene and
3 d and from smoking and eating for 12 h before the blood sam-
ultrasonographically assessed CCA-IMT was tested for statistical
pling. After the subjects had rested in a supine position for 30 min,
significance by using covariance analysis. Three different sets of
blood was drawn with Terumo Venoject vacuum tubes (Terumo,
covariates were used: model 1 included age, ultrasound observer,
Tokyo). No tourniquet was used.
and examination years; model 2 included model 1 and systolic
Serum for lycopene, ?-carotene, and ?-tocopherol measure-
blood pressure, serum HDL and LDL cholesterol, and smoking;
ments was extracted with ethanol and hexane, and the measurements
and model 3 included model 2 and serum triacylglycerols, BMI,

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LYCOPENE AND CAROTID ATHEROSCLEROSIS
135
TABLE 1
Characteristics of the subjects1
Quarter of serum lycopene (?mol/L)
P for
< 0.04
0.04–0.13
0.14–0.22
> 0.22
heterogeneity2
Age (y)
58.7 ± 6.03
57.2 ± 6.4
55.5 ± 6.8
53.5 ± 6.2
< 0.001
Systolic blood pressure (mm Hg)
138.1 ± 16.7
136.7 ± 16.8
132.9 ± 17.4
132.0 ± 15.0
0.001
BMI (kg/m2)
27.7 ± 3.9
27.6 ± 4.0
27.5 ± 3.5
26.8 ± 3.1
0.048
Serum lycopene (?mol/L)
0.00 ± 0.00
0.09 ± 0.02
0.17 ± 0.03
0.34 ± 0.12
—
Serum ?-carotene (?mol/L)
0.31 ± 0.18
0.40 ± 0.22
0.40 ± 0.36
0.51 ± 0.36
< 0.001
Serum folate (nmol/L)
9.44 ± 3.81
10.01 ± 3.76
10.53 ± 4.08
11.34 ± 4.64
< 0.001
Serum ?-tocopherol (?mol/L)
27.2 ± 0.2
28.7 ± 0.2
28.5 ± 0.2
30.4 ± 0.2
< 0.001
Serum total cholesterol (mmol/L)
5.57 ± 0.97
5.51 ± 0.92
5.44 ± 0.94
5.58 ± 0.92
0.284
Serum LDL cholesterol (mmol/L)
3.99 ± 0.89
3.87 ± 0.80
3.87 ± 0.85
4.00 ± 0.84
0.128
Serum HDL cholesterol (mmol/L)
1.08 ± 0.29
1.09 ± 0.31
1.10 ± 0.29
1.12 ± 0.26
0.299
Serum triacylglycerols (mmol/L)
1.70 ± 1.18
1.68 ± 1.03
1.59 ± 0.94
1.51 ± 1.00
0.171
Smokers (%)
36
25
24
26
0.011
1 n = 1028.
2 ANOVA.
3 x– ± SD.
and 3 nutritional factors (serum folate, ?-carotene, and ?-toco-
The association between serum lycopene concentration and
pherol). All tests were two-tailed, and P values < 0.05 were con-
CCA-IMT was stronger in smokers than in nonsmokers. In model
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sidered significant.
2, the mean and maximal CCA-IMT decreased nonlinearly across
the quarters of serum lycopene in smokers (mean CCA-IMT:
0.95, 0.88, 0.84, and 0.86 mm, P for linear trend across the quar-
RESULTS
ters = 0.003; maximal CCA-IMT: 1.33, 1.24, 1.15, and 1.21 mm,
The mean concentration of serum lycopene was 0.15 ± 0.14 ?mol/L,
P for linear trend across the quarters = 0.002). In nonsmokers the
ranging from below the detection limit to 1.02 ?mol/L. The main
association between serum concentrations of lycopene and mean
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characteristics of the subjects are presented in Table 1. Serum
and maximal CCA-IMT was weaker and nonsignificant but linear
?-carotene, folate, and ?-tocopherol concentrations; age; systolic
(mean CCA-IMT: 090, 0.88, 0.88, and 0.85 mm, P for linear trend
blood pressure; BMI; and smoking differed significantly between
across the quarters = 0.159; maximal CCA-IMT: 1.25, 1.21, 1.21,
the subjects in different quarters of serum lycopene concentra-
and 1.17 mm, P for linear trend across the quarters = 0.098). In
by on August 22, 2009
tion. Serum lycopene concentrations were higher in the younger
the fully adjusted model (model 3), both mean and maximal CCA-
(aged 46–55 y) men than in the older (aged > 55 y) men (0.19 and
IMT were 10% higher (P = 0.002 and P = 0.002 for the difference,
0.11 ?mol/L, respectively, P < 0.001, ANOVA) and were non-
respectively) in smokers in the lowest quarter of serum lycopene
significantly higher in nonsmokers than in smokers (0.16 and
than in the other smokers. Additional adjustment for smoking
0.14 ?mol/L, respectively, P = 0.07, ANOVA).
years did not significantly change the results.
Serum lycopene concentrations correlated negatively with
mean and maximal CCA-IMT (Spearman’s correlation coeffi-
cients: r = ?0.22, P < 0.001, and r = ?0.20, P < 0.001, respec-
DISCUSSION
tively). The strongest correlations were found between mean
High circulating concentrations of carotenoids are presumed to
CCA-IMT and age, systolic blood pressure, BMI, serum LDL cho-
protect against atherosclerosis before its clinical manifestation
lesterol, and serum lycopene (Table 2). Except for the relation
with serum lycopene, all of these relations were positive.
TABLE 2
In a covariance analysis, we observed a significant inverse asso-
Spearman’s correlation coef?cients (r) and statistical signi?cance for the
ciation between serum concentrations of lycopene and mean and
association between mean intima-media thickness of the common carotid
maximal CCA-IMT. In model 1, men in the lowest quarter of serum
artery and nutritional factors and cardiovascular disease risk factors in
lycopene concentration had significantly higher mean (P < 0.001
middle-aged eastern Finnish men
for the difference) and maximal (P < 0.001 for difference) CCA-
r
P
IMT than did the other men. Additional adjustment for other covari-
Age (y)
0.43
< 0.001
ates (model 2) did not change the observed results (P = 0.001 and
Systolic blood pressure (mm Hg)
0.29
< 0.001
P < 0.001 for the difference, respectively). Furthermore, a similar
BMI (kg/m2)
0.14
< 0.001
inverse trend remained in model 3 (P = 0.005 and P = 0.001 for the
Serum lycopene (?mol/L)
?0.22
< 0.001
difference, respectively). The increments in the mean and maximal
Serum ?-carotene (?mol/L)
?0.07
0.020
CCA-IMT were linear across the quarters of serum lycopene con-
Serum folate (nmol/L)
?0.06
0.051
centration. The P values for the linear trend for mean and maximal
Serum ?-tocopherol (?mol/L)
?0.06
0.046
CCA-IMT in model 1 were 0.001 and < 0.001, respectively. In
Serum total cholesterol (mmol/L)
0.09
0.004
Serum LDL cholesterol (mmol/L)
0.14
< 0.001
model 2, the corresponding P values were 0.006 and 0.002, respec-
Serum HDL cholesterol (mmol/L)
?0.11
< 0.001
tively, and in model 3 they were 0.039 and 0.013, respectively. In
Serum triacylglycerols (mmol/L)
0.11
< 0.001
all models, the mean and maximal CCA-IMT decreased linearly
Smoking (cigarettes/d ? y of smoking)
0.04
0.192
across the quarters of serum lycopene concentration (Table 3).

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136
RISSANEN ET AL
TABLE 3
Adjusted mean and maximal (and 95% CI) intima-media thickness of the common carotid artery (CCA-IMT) by quarter of serum lycopene concentration
in the 3 models1
Quarter of serum lycopene (?mol/L)
< 0.04
0.04–0.13
0.14–0.22
> 0.22
P for linear trend2
mm
Model 1
Mean CCA-IMT
0.92 (0.89, 0.95)
0.88 (0.85, 0,90)
0.87 (0.85, 0.89)
0.85 (0.83, 0.88)
< 0.001
Maximal CCA-IMT
1.28 (1.25, 1.32)
1.21 (1.18, 1.24)
1.20 (1.16, 1.23)
1.18 (1.15, 1.22)
< 0.001
Model 2
Mean CCA-IMT
0.92 (0.89, 0.94)
0.88 (0.85, 0.90)
0.87 (0.85, 0.89)
0.86 (0.83, 0.88)
0.012
Maximal CCA-IMT
1.27 (1.24, 1.31)
1.21 (1.18, 1.25)
1.20 (1.17, 1.23)
1.19 (1.15, 1.22)
0.014
Model 3
Mean CCA-IMT
0.91 (0.89, 0.93)
0.87 (0.85, 0.90)
0.87 (0.85, 0.90)
0.86 (0.84, 0.89)
0.039
Maximal CCA-IMT
1.27 (1.23, 1.30)
1.21 (1.18, 1,24)
1.20 (1.17, 1.23)
1.19 (1.16, 1.23)
0.013
1 Model 1 was adjusted for age, examination years, and ultrasound observer; model 2 was adjusted for model 1 variables plus smoking, systolic blood
pressure, and serum HDL- and LDL-cholesterol concentrations; model 3 was adjusted for model 2 variables plus serum triacylglycerols, body mass index,
and serum ?-tocopherol, folate, and ?-carotene.
2 Covariance analysis.
(19–23). The main finding of the present study is that low serum
association with higher concentrations of lycopene was suggested
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lycopene concentrations are associated with early atherosclerosis,
in smokers. In the prospective Massachusetts Health Care Panel
as manifested as an increased thickness of the CCA in middle-
study (29), a high dietary intake of total carotenoids was associ-
aged men from eastern Finland.
ated with a reduced risk of fatal myocardial infarction and car-
The association between blood concentrations or dietary
diovascular disease death. We also found in the KIHD study that
intakes of lycopene and thickness of the artery wall was studied
men with low serum concentrations of lycopene had a higher risk
earlier in very few studies (Table 4). In our previous Antioxidant
of an acute coronary event or stroke than did men with higher
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Supplementation in Atherosclerosis Prevention (ASAP) study
serum lycopene concentrations (25).
(19), low plasma concentrations of lycopene were associated with
The oxidative modification of LDL particles may play a role in
CCA-IMT 18% higher than that in men with plasma concentra-
the formation of foam cells, atherosclerotic lesions, and CAD (11,
tions of lycopene higher than the median. In women, the differ-
30). Men who have high titers of autoantibodies against oxida-
by on August 22, 2009
ence was nonsignificant after the adjustments. In a subsample of
tively modified LDL and those with elevated serum 7?-hydroxy-
the Atherosclerosis Risk in Communities (ARIC) study (20), there
cholesterol concentrations have accelerated progression of carotid
were 231 age-, sex-, race-, and field center–matched case-control
atherosclerosis (11, 12). Antioxidants can inhibit the oxidative
pairs. An increased serum concentration of lycopene was associ-
modification of LDL, may retard atherosclerotic progression, and,
ated with nonsignificantly lower odds of being a case after adjust-
consequently, may prevent clinical complications of atheroscle-
ment for risk factors (odds ratio: 0.81). In the same study (21), a
rosis such as myocardial infarction (31, 32). Lycopene and other
high dietary intake of provitamin A carotenoids was associated
carotenoids have been shown to act as antioxidants (7, 8, 10, 33).
with a lower prevalence of carotid plaques and a lower thickness
This action is probably due to the ability of carotenoids to quench
of the artery wall, although these associations were not statisti-
singlet oxygen, a potential initiator of lipid peroxidation (33).
cally significant. In the ARIC study, the dietary intake of lycopene
Lycopene exhibits the highest physical quenching rate of all
was not assessed. In the Rotterdam study (22), serum lycopene
carotenoids (8). It has also been shown that serum concentrations
was the only carotenoid that was associated with a decreased risk
of lycopene are inversely correlated with serum thiobarbituric
of aortic atherosclerosis in current and former smokers.
acid–reactive substances (TBARS) (34), an indicator of lipid per-
In the Etude sur le Vieillisement Artériel (23), subjects in the
oxidation. Both LDL-TBARS and conjugated dienes were low-
highest quarter of plasma total carotenoids had lower CCA-IMT,
ered significantly by dietary lycopene supplementation (10). Other
but this association became nonsignificant after adjustment for
mechanisms through which lycopene may inhibit atherosclerosis
common risk factors. In men, the prevalence of carotid plaques
include intercellular gap junction communication and hormonal
decreased linearly across the quarters of plasma carotenoid con-
and immune system modulation (34). In addition, in cell culture,
centration (P < 0.016). Plasma concentrations of lycopene were
lycopene is the most effective carotenoid at suppressing adhesion
not measured in that study.
molecule and monocyte adhesion to endothelial cells (35).
The prevalence of carotid plaques and increased thickness of
The mean CCA-IMT in our subjects was somewhat higher than
the intima media has been shown to predict coronary events (27,
that reported in most other studies (20, 23, 28, 36). This is con-
28). The association between blood or tissue concentrations of
sistent with the high incidence of clinical CAD in eastern Finland.
lycopene and risk of CAD was studied earlier in several studies.
The mean serum lycopene concentration in our study was much
In the multicenter EURAMIC study (6), low adipose tissue con-
lower than that reported in most other population-based studies
centrations of lycopene were associated with greater risk of a
from European countries, in which lycopene concentrations were
myocardial infarction. In a nested case-control study from Wash-
2–4-fold higher than in our study (2, 24). In an American popula-
ington County (26), excess risk of myocardial infarction was asso-
tion, circulating concentrations of lycopene were even 6-fold
ciated with low serum concentrations of lycopene, but a protective
greater than those in our study (20). In only one earlier study (22)

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LYCOPENE AND CAROTID ATHEROSCLEROSIS
137
TABLE 4
Studies of the association of circulating and tissue concentrations of lycopene with the risk of cardiovascular disease and atherosclerosis1
Study, publication year,
Type of
Sex of
Sample of
Mean (±SD)
and nationality of subjects
study
subjects
n
Variables
lycopene
concentration
Findings
ARIC study, Iribarren
Nested
F, M
462
IMT
Serum
Cases: 0.89 ± 0.43;
Nonsigni?cantly lower odds of
et al, 1997 (20):
case-control
controls:
being a case with increases
American
0.91 ± 0.42 ?mol/L
in lycopene
Rotterdam study,
Case-control
F, M
216
Plaques of the
Serum
Cases: 0.12 ± 0.09;
Nonsigni?cantly lower odds
Klipstein-Grobush
abdominal
controls:
ratio in the highest quarter
et al, 2000 (22):
aorta
0.13 ± 0.09 ?mol/L
compared with the lowest.
Dutch
Signi?cant odds ratio in
smokers: 0.35 (0.13–0.94)
Bruneck study, D’Orico
Cross-sectional
F, M
392
Prevalence and
Serum
0.53 ± 0.34 to
Lycopene did not signi?cantly
et al, 2000 (24):
and prospective,
incidence of
0.76 ± 0.49 ?mol/L
predict the risk of
Italian
5-y follow-up
carotid plaques
atherosclerosis
ASAP study, Rissanen
Cross-sectional
F, M
520
IMT
Plasma
Men: 0.14 ± 0.12;
In men, signi?cantly lower
et al, 2000 (19):
women:
adjusted IMT with plasma
Finnish
0.17 ± 0.11 ?mol/L
concentration of lycopene
higher than the median
KIHD study, Rissanen
Prospective,
M
725
Acute coronary
Serum
0.17 ± 0.14 ?mol/L
Adjusted relative risk = 0.30
et al, 2000 (25):
5.3 y follow-up
event and
(0.16?0.59) in 3 highest
Finnish
stroke
quarters compared with the
lowest quarter
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Street et al, 1994 (26):
Nested
F, M
369
MI
Serum
Cases: 39.0 ± 18.6;
Nonsigni?cantly lower serum
American
case-control,
controls:
lycopene concentration in
14 y follow-up
40.2 ± 18.8 ?g/dL
cases than in controls.
Excess risk of MI in
smokers with serum
concentration of lycopene
lower than the median
www.ajcn.org
EURAMIC study
Case-control
M
1379
MI
Adipose
0.21–0.36 ?g/g
Adjusted odds ratio = 0.52
Kohlmeier et al,
tissue
(0.33–0.82) in the 10th
1997 (6): multicenter
compared with the 90th
percentile
Linköping-Vilnius
Cross-sectional
M
210
CAD mortality
Plasma
Linköping: 0.62;
Lower plasma concentration
by on August 22, 2009
Coronary Disease
Vilnius:
of lycopene and higher risk
Risk Assessment
0.33 ?mol/L
of CAD mortality in Vilnius
Study, Kristenson
than in Linköping
et al, 1997 (2):
Swedish and
Lithuanian
1 ARIC, Atherosclerosis Risk in Communities; ASAP, Antioxidant Supplementation in Atherosclerosis Prevention; CAD, coronary artery disease; IMT,
intima-media thickness; KIHD, Kuopio Ischaemic Heart Disease Risk Factor; MI, myocardial infarction.
were mean circulating concentrations of lycopene parallel to those
smoking or aging itself. We adjusted statistical models for age and
in the present study. The most likely explanation for this is the low
smoking status to eliminate the effect of these factors. An adjust-
dietary intake of lycopene in Finland. In the Finnish Mobile Clinic
ment for smoking attenuated but did not abolish the association
Health Examination Survey (37), the daily intake of lycopene was
between lycopene and CCA-IMT. However, the association
0.9 mg for women and 0.7 mg for men, whereas the intake of
between serum concentrations of lycopene and CCA-IMT seemed
lycopene is 1.3 mg in Spain (38) and as high as 6.6 mg in the
to be stronger in smokers than in nonsmokers.
United States (39). Our study subjects had low concentrations of
The results of previous studies of the association between blood
lycopene, and the association was stronger at low concentrations,
concentrations of lycopene and atherosclerosis or cardiovascular
which may explain the strength of the relation. One explanation
disease in smokers and nonsmokers are inconsistent. Our results
for the weak effect found in some studies with high tissue con-
support the findings of the Rotterdam study (22) and the nested
centrations and more homogeneous concentrations of lycopene
case-control study from Washington County (26). In contrast, in
may be the lack of low circulating concentrations of lycopene.
the EURAMIC (6) and the ASAP (19) studies, there was a stronger
It is possible that the serum concentration of lycopene is an
effect of lycopene on myocardial infarction and atherosclerosis
indicator for other beneficial dietary factors. However, the effect
among nonsmokers. Smoking is a well-known risk factor for CAD.
of lycopene was significant after adjustment for other plant-
Smokers have been shown to have lower plasma concentrations of
derived nutrients, serum folate, ?-carotene, and ?-tocopherol.
most carotenoids, but results concerning blood concentrations of
Smokers and older men had lower serum concentrations of
lycopene according to smoking status are mixed (40). The relation
lycopene than did nonsmokers and younger men. This could either
between lycopene and smoking is incompletely understood, and
be due to differences in dietary intake or be a consequence of
more knowledge is needed to clarify this association.

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138
RISSANEN ET AL
In conclusion, the results of the present study show that low
plasma lycopene concentration is associated with increase intima-
serum concentrations of lycopene are associated with higher CCA-
media thickness of the carotid artery wall. Arterioscler Thromb Vasc
IMT in middle-aged men from eastern Finland. A higher IMT has
Biol 2000;20:2677–81.
been shown to predict coronary events (27, 28); thus, our finding
20. Iribarren C, Folsom AR, Jacobs DR, Cross MD, Belcher JD, Eckfeldt JH.
suggests that serum concentrations of lycopene, a biomarker of
Association of serum vitamin levels, LDL susceptibility to oxidation,
and autoantibodies against MDA-LDL with carotid atherosclerosis.
tomato-rich food intake, may play a role in the early stages of athero-
Arterioscler Thromb Vasc Biol 1997;17:1171–7.
genesis and may have clinical and public health relevance.
21. Kritchevsky SB, Tell GS, Shimakawa T, et al. Provitamin A
We are grateful to our staff of almost 40 persons for helping with data collection.
carotenoid intake and carotid artery plaques: the Atherosclerosis Risk
in Communities Study. Am J Clin Nutr 1998;68:726–33.
22. Klipstein-Grobusch K, Launer LJ, Geleijnse JM, Boeing H, Hofman A,
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