Low Plasma Lycopene Concentration Is Associated With
Increased Intima-Media Thickness of the
Carotid Artery Wall
Tiina Rissanen, Sari Voutilainen, Kristiina Nyyssönen, Riitta Salonen, Jukka T. Salonen
Downloaded from http://atvb.ahajournals.org/ by guest on June 16, 2017
Abstract—Although a number of epidemiological studies have evaluated the association between ␤-carotene and the risk
of cardiovascular diseases, there has been little research on the role of lycopene, an acyclic form of ␤-carotene, with
regard to the risk of cardiovascular disease. We investigated the relationship between plasma concentrations of lycopene
and intima-media thickness of the common carotid artery wall (CCA-IMT) in 520 middle-aged men and women (aged
45 to 69 years) in eastern Finland. They were examined from 1994 to 1995 at the baseline of the Antioxidant
Supplementation in Atherosclerosis Prevention (ASAP) study, a randomized trial concerning the effect of vitamin E and
C supplementation on atherosclerotic progression. The subjects were classified into 2 categories according to the median
concentration of plasma lycopene (0.12 ␮mol/L in men and 0.15 ␮mol/L in women). Mean CCA-IMT of the right and
left common carotid arteries was 1.18 mm in men and 0.95 mm in women with plasma lycopene levels lower than the
median and 0.97 mm in men (P⬍0.001 for difference) and 0.89 mm in women (P⫽0.027 for difference) with higher
levels of plasma lycopene. In ANCOVA adjusting for cardiovascular risk factors and intake of nutrients, in men, low
levels of plasma lycopene were associated with a 17.8% increment in CCA-IMT (P⫽0.003 for difference). In women,
the difference did not remain significant after the adjustments. We conclude that low plasma lycopene concentrations
are associated with early atherosclerosis, manifested as increased CCA-IMT, in middle-aged men living in eastern
Finland. (Arterioscler Thromb Vasc Biol. 2000;20:2677-2681.)
Key Words: lycopene 䡲 atherosclerosis 䡲 carotid arteries 䡲 nutrition 䡲 carotenoids
L
ow circulating levels of carotenoids have been presumed
to play a role in atherogenesis. There is some supporting
data from studies within populations that have indicated that
high levels of carotenoids in blood1,2 or adipose tissue3,4 are
associated with decreased risk of cardiovascular disease
(CVD). A few studies have evaluated the association between
␤-carotene and the risk of CVD, and the results have been
inconsistent.4,5 Moreover, there has been little interest in the
role of lycopene, an acyclic form of ␤-carotene, with regard
to CVD risk. Like other carotenoids, lycopene is a natural
pigment synthesized by plants and microorganisms but not by
animals.6 Lycopene gives the familiar red color to tomato
products and is one of the major carotenoids in the diet of
Europeans and North Americans. Lycopene, which is an
antioxidant carotenoid without provitamin A activity, has
been shown to be a more potent antioxidant than ␣- or
␤-carotene.7 In the test tube, lycopene in LDL is used before
␤-carotene, lutein, zeaxanthin, or cryptoxanthin in copperinduced LDL oxidation reaction.8 Men who have high titers
of autoantibodies against oxidatively modified LDL and
those with elevated serum 7␤-hydroxycholesterol levels have
accelerated progression of carotid atherosclerosis.9,10 A de-
creased oxidative modification of LDL11 may be one of the
mechanisms by which lycopene could reduce the risk of
coronary heart disease (CHD) and atherosclerotic
progression.
Very few previous studies have dealt with the association
between a low concentration of plasma lycopene and early
atherosclerosis, as manifested by increased intima-media
thickness of the common carotid artery wall (CCA-IMT). The
purpose of the present study was to test the hypothesis that
healthy men and women with decreased levels of serum
lycopene have increased thickness of the CCA-IMT.
Methods
Study Design and Population
The Antioxidant Supplementation in Atherosclerosis Prevention
(ASAP) study is a randomized, double-masked, placebo-controlled,
2⫻2 factorial trial concerning the effect of vitamin E and C
supplementation in the prevention of atherosclerotic progression in
smoking and nonsmoking men and postmenopausal women.12 The
study was approved by the Research Ethics Committee of the
University of Kuopio. All study subjects gave their written informed
consent.
Received March 27, 2000; revision accepted July 4, 2000.
From the Research Institute of Public Health, University of Kuopio (T.R., S.V., K.N., R.S., J.T.S.), Kuopio, Finland, and Inner Savo Health Centre
(J.T.S.), Finland.
Correspondence to Prof J.T. Salonen, Research Institute of Public Health, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland. E-mail
[email protected]
© 2000 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
2677
2678
Arterioscler Thromb Vasc Biol.
December 2000
The subjects were regularly smoking (ⱖ5 cigarettes/d) or nonsmoking men and postmenopausal women aged 45 to 69 years with
a serum cholesterol concentration of ⱖ5.0 mmol/L at a screening
visit. Subjects were not entered into the trial if they had premenopause or regular oral estrogen substitution therapy, regular intake of
antioxidants, acetylsalicylic acid or any other drug with antioxidative
properties, severe obesity (body mass index ⬎32 kg/m2), type 1
diabetes, uncontrolled hypertension (diastolic blood pressure
⬎105 mm Hg), any condition limiting mobility (making study visits
impossible), severe disease that could shorten life expectancy, or
other disease or condition worsening the adherence to the measurements or treatment. The recruitment of the subjects was carried out
in 1993 and the spring of 1994. For the present study, blood for
lycopene and other chemical measurements was drawn before
antioxidant supplementation. Subjects came to the baseline visits at
the Research Institute of Public Health, University of Kuopio,
between October 1994 and October 1995.
Ultrasonographic Assessment of CCA-IMT
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Two identical Biosound Phase 2 systems were used (Biosound)
equipped with a 8- to 10-MHz annular array transducer, with a
measurement precision of 0.03 mm. The scannings were videotaped
with a PAL S-VHS Panasonic AG 7330E VCR. The ultrasonographic examinations were carried out by 3 well-trained ultrasound
technicians. The ultrasonographic scanning of the common carotid
arteries (CCAs), the carotid bulbs, and the proximal internal carotid
artery was performed after a supine rest of 10 minutes, the subject in
the supine position. First, a diagnostic examination of the entire
accessible carotid tree was performed to find the most severe lesions.
Second, the site of the greatest IMT at baseline in the CCA far wall
was located and scanned thoroughly from 3 angles: anterolateral,
lateral, and posterolateral. IMT measurements from videotapes were
made at the same site and angle at all examinations of each subject,
which was the site with the greatest IMT (in any angle) that was
clearly visible at baseline in the far wall of in CCA below the bulb.
At this location, IMT was measured in diastole for a length of 10 mm
(or shorter, if not visible) in 1 angle for the far wall. Most often, this
was the distal centimeter of the CCA.
Computer analysis of ultrasound images to measure IMT was
performed with a reading station equipped with Data Translation DT
2861 video frame grabber interfaced to a Panasonic AG 7355 VCR.
Prosound software, developed by Robert Selzer (University of
Southern California, Los Angeles), with automated boundary detection was used. IMT was determined as the average difference at, on
average, 100 points between the intima-lumen and media-adventitia
interface.13 The “mean IMT” was computed as the mean of ⬇100
IMT measurements in the right CCA and another 100 measurements
in the left CCA.
For measurement variability, 3 technicians scanned 10 subjects
twice during a week in 1995. The videotapes from all scannings were
read by 1 observer. The repeat correlations for the mean CCA-IMT
were 0.988, 0.995, and 0.998, and pairwise interobserver correlations
were 0.975, 0.983, and 0.995. Computer analysis of ultrasound
images to measure IMT was performed by use of a PC with a Data
Translation DT 2861 video frame grabber interfaced to a Panasonic
AG 7355 VCR. The Prosound software developed by Robert Selzer
was used.
Chemical and Dietary Measurements
EDTA blood samples were obtained from subjects between 8:00 and
10:00 AM after an overnight fast. Subjects were instructed to abstain
from alcohol for at least 1 week before the visit. The subjects were
also instructed to avoid strenuous exercise during the previous 24
hours. Plasma and serum was separated within 60 minutes and stored
at ⫺80°C until analyzed. Plasma for lycopene determination was
extracted with ethanol and hexane; the measurements were conducted by reversed-phase high-performance liquid chromatography
(HPLC) with diode-array UV detection in samples that had been kept
at ⫺80°C for 3 to 15 months.14 With this method, the limit of
detection for lycopene was 0.01 to 0.02 ␮mol/L. In the statistical
analysis, values below the limits of detection for the assay batch
were marked as 0.00 ␮mol/L. The coefficients of variation were
determined with a plasma pool analyzed in 14 separate batches. The
coefficient of variation for lycopene was 10.1%.
Dietary intake of foods and nutrients was assessed at baseline by
4-day instructed food recording. Instructions were given, and completed food recordings were checked by a nutritionist. The intake of
nutrients was calculated by use of NUTRICA version 2.5 software.
The data bank of NUTRICA is complied by using mainly Finnish
values of nutrient composition of foods. All nutrients were adjusted
for dietary energy intake by use of the residual method. Energy
adjustment is based on the rationale that a larger, more physically
active person requires a high caloric intake, which is associated with
a higher absolute intake of all nutrients. Therefore, energy adjustment takes into account differences in energy requirements among
individuals. The residuals were standardized by the mean nutrient
intake of a subject consuming 10 MJ/d, the approximate average
total energy intake in the present study population.
Serum cholesterol was determined from fresh samples with an
enzymatic colorimetric method (Konelab). Serum LDL cholesterol
was measured after precipitation with polyvinyl sulfate (Boehringer-Mannheim), and HDL cholesterol was measured from supernatant
after magnesium chloride dextran sulfate precipitation. Serum triglycerides were measured colorimetrically (Boehringer-Mannheim).
Plasma total homocysteine (tHcy) concentration was determined
with HPLC.15 Blood pressure was measured manually with the
subject in a sitting position after a rest of 10 minutes; there were 3
measurements at 3-minute intervals. The body mass index was
computed as the ratio of weight to the square of height (in kilograms
per square meter).
Statistical Analysis
Data were analyzed by using either SPSS statistical software for the
IBM RS/6000 workstation or SPSS 9.01 for Windows 98. Mean age,
ratio of waist-to-hip circumference, systolic blood pressure, diastolic
blood pressure, serum triglycerides, serum HDL cholesterol, LDL
cholesterol, total cholesterol, and intake of nutrients are reported as
mean⫾SD, and cigarette smoking is reported as a percentage.
Subjects were classified into 2 categories according to their concentrations of plasma lycopene and ␤-carotene. We compared the
higher-than-median level with the lower level. The statistical significance of differences between these 2 lycopene groups in the main
characteristics of the subjects was studied by the Student t test.
The association between plasma lycopene and ␤-carotene and
ultrasonographically assessed CCA-IMT was tested for statistical
significance also by using ANCOVA, adjusting for age, smoking,
serum triglycerides, serum HDL and LDL cholesterol, plasma
concentration of tHcy, systolic blood pressure, ultrasound observer,
and intake of 4 nutrients (saturated fatty acids, vitamin C, vitamin E,
and fiber). All tests were 2-tailed, and a value of P⬍0.05 was
considered significant.
Results
The mean⫾SD concentration of plasma lycopene in the study
population was 0.16⫾0.11 ␮mol/L. Mean plasma levels of
lycopene were higher in women (0.17⫾0.11 ␮mol/L) than in
men (0.14⫾0.12 ␮mol/L, P⫽0.007 for difference). The
plasma concentration of lycopene ranged from 0 to 0.62
␮mol/L in men and from 0 to 0.64 ␮mol/L in women.
The main characteristics of the subjects are presented in the
Table. For men, age (P⬍0.001), plasma concentration of
tHcy (P⫽0.004), and dietary vitamin C (P⫽0.010) had a
statistically significant difference between the men who had
plasma levels of lycopene lower than the median (⬍0.12
␮mol/L) and those who had values higher than the median
(ⱖ0.12 ␮mol/L). The women with lower levels of plasma
lycopene (⬍0.15 ␮mol/L) differed significantly with regard
to age (P⬍0.001), HDL cholesterol (P⬍0.001), systolic
blood pressure (P⫽0.016), plasma concentration of tHcy
(P⫽0.010), and dietary vitamin C intake (P⫽0.016) from
women with higher levels of plasma lycopene. Mean IMT of
Rissanen et al
Lycopene and Thickness of Carotid Artery Wall
2679
Main Characteristics of Subjects
Plasma Lycopene, ␮mol/L
Men (n⫽256)
⬍0.12
n
ⱖ0.12
Women (n⫽264)
P for
Difference
⬍0.15
ⱖ0.15
P for
Difference
136
120
144
120
61.6⫾5.0
58.3⫾6.2
⬍0.001
61.1⫾4.6
58.1⫾5.8
⬍0.001
Body mass index, kg/m
26.0⫾3.0
26.1⫾2.8
0.901
26.4⫾3.5
25.8⫾2.9
0.173
Waist-to-hip ratio
0.95⫾0.05
0.95⫾0.05
0.935
0.82⫾0.05
0.82⫾0.04
0.900
Systolic blood pressure, mm Hg
135.3⫾17.7
131.6⫾18.8
0.103
136.1⫾20.8
130.2⫾18.4
0.016
Diastolic blood pressure, mm Hg
79.8⫾8.7
80.9⫾9.0
0.304
78.7⫾9.5
77.8⫾8.3
0.401
Serum total cholesterol, mmol/L
6.30⫾0.92
6.36⫾0.88
0.542
6.44⫾1.00
6.54⫾1.09
0.454
Serum HDL cholesterol, mmol/L
1.11⫾0.27
1.16⫾0.30
0.165
1.31⫾0.34
1.48⫾0.36
⬍0.001
Serum LDL cholesterol, mmol/L
4.56⫾0.96
4.56⫾0.89
0.997
4.53⫾1.00
4.42⫾1.12
0.428
Serum triglycerides, mmol/L
1.65⫾0.76
1.64⫾0.92
0.897
1.58⫾0.90
1.52⫾0.71
0.721
Serum homocysteine, ␮mol/L
11.09⫾2.56
10.10⫾2.51
0.004
9.74⫾2.39
9.02⫾2.08
0.010
16.6⫾4.5
15.7⫾3.7
0.072
15.6⫾3.6
15.3⫾3.5
0.416
Age, y
2
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Dietary saturated fatty acids, E %
Dietary fiber, g/d*
21.9⫾6.7
20.3⫾7.4
0.065
20.6⫾4.6
21.1⫾5.3
0.430
Dietary vitamin C, mg/d*
80.6⫾52.4
100.2⫾66.3
0.010
94.6⫾53.8
113.7⫾73.9
0.016
Dietary vitamin E, mg/d*
9.5⫾4.6
9.6⫾3.6
0.826
9.7⫾2.4
9.8⫾2.3
0.691
53
41
0.053
49
47
0.671
1.18⫾0.39
0.97⫾0.20
0.95⫾0.25
0.89⫾0.19
0.027
Smoking, %†
IMT, mm
⬍0.001
Values are mean⫾SD. E% indicates percentage of energy.
*Adjusted for energy intake.
†Proportion of each group of plasma levels of lycopene.
the right and left CCA was 1.18 mm in men and 0.95 mm in
women with low plasma lycopene levels and 0.97 mm in men
(P⬍0.001 for difference) and 0.89 mm in women (P⫽0.012
for difference) with higher plasma levels of lycopene. In men
in the highest quarter of plasma lycopene level, the CCA-IMT
was 17.5%, and in women, it was 5.6% lower than in men and
women in the lowest quarter of plasma lycopene level
(Figure).
In ANCOVA, adjusting for other cardiovascular risk factors (age, serum triglycerides, serum HDL and LDL choles-
Mean IMT of carotid artery wall in quarters of plasma lycopene
concentration in middle-aged Finnish men and women. Plasma
lycopene concentration quarters for men were ⬍0.06, 0.06 to
0.11, 0.12 to 0.18, and ⬎0.18 ␮mol/L; for women, they were
⬍0.09, 0.09 to 0.15, 0.16 to 0.22, and ⬎0.22 ␮mol/L.
terol, plasma tHcy, and systolic blood pressure), ultrasound
observer, and intake of 4 nutrients (proportion of saturated
fatty acids of total daily energy, vitamin C, vitamin E, and
fiber), low plasma lycopene levels were associated with
17.8% increased IMT in men compared with plasma levels of
lycopene higher than median (P⫽0.003 for difference). In
women, the difference did not remain significant after the
adjustments.
We conducted analyses for ␤-carotene similar to those
presented above for lycopene. In ANCOVA, adjusting for
risk factors, there was no statistically significant association
between plasma concentration of ␤-carotene and IMT.
We also repeated analysis in smokers and nonsmokers. The
association between plasma levels of lycopene and IMT
seems to be stronger among nonsmokers than among smokers. Adjusted IMT was significantly higher (P⫽0.006) in
nonsmokers and nonsignificantly higher (P⫽0.070) in smokers with lower plasma levels of lycopene compared those
with higher plasma lycopene levels. The association between
the plasma level of ␤-carotene and the IMT did not differ in
smokers and nonsmokers.
We also divided subjects into 2 categories according to
IMT (ⱕ1.00 mm and ⬎1.00 mm). The mean level of plasma
lycopene was 0.16 ␮mol/L in men and 0.17 ␮mol/L in
women with lower IMT and 0.12 ␮mol/L in men (P⫽0.003
for difference) and 0.16 in women (P⫽0.225 for difference)
with higher IMT.
Discussion
Our main finding is that in middle-aged men but not in
middle-aged women from eastern Finland, a low concentra-
2680
Arterioscler Thromb Vasc Biol.
December 2000
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tion of plasma lycopene is associated with early atherosclerosis, as manifested by increased thickness of the CCA wall.
Two previous studies have dealt with the concentration of
blood lycopene and the thickness of the artery wall. In the
Atherosclerosis Risk in Communities (ARIC) study,16 there
were 231 age-matched, sex-matched, race-matched, and field
center–matched case-control pairs selected from the larger
study population. Cases exceeded the 90th percentile of IMT
in the cohort, and the control subjects were below the 75th
percentile of IMT for all arterial segments. The cases had
nonsignificantly lower levels of serum lycopene and ␣- and
␤-carotene. The odds ratio of being above the 90 percentile of
IMT, related to low serum levels of lycopene, after adjusting
for risk factors was 0.81 (95% CI 0.60 to 1.08). In the ARIC
study,17 high dietary intake of provitamin A carotenoids was
associated with lower prevalence of carotid plaques, but this
association was not statistically significant. The dietary lycopene intake was not assessed. In the prospective Rotterdam
Study18 on serum carotenoids and atherosclerosis, serum
lycopene was the only carotenoid associated with decreased
risk of aortic atherosclerosis (odds ratio 0.55). However, the
association was nonsignificant. In the Etude sur le Vieillisement Artériel (EVA) Study,19 in the highest quarter of plasma
total carotenoids was associated with lower CCA-IMT in
women (P⫽0.014 for a linear trend between quarters) and
men (P⫽0.02 for a linear trend between quarters), but after
adjustment this association was nonsignificant. Plasma levels
of lycopene were not measured.
Common carotid plaques and increased IMT have been
shown to predict coronary events.20,21 The association between blood or tissue concentration of lycopene and risk of a
CHD has been studied in a cross-sectional study. In a
multicenter European Community Multicenter Study on Antioxidants, Myocardial Infarction, and Breast Cancer (EURAMIC) study,3 subjects who had suffered a myocardial
infarction (MI) had lower concentrations of lycopene in
adipose tissue than did the control subjects. In a nested
case-control study22 that compared subjects who developed
MI with healthy control subjects, the cases had lower serum
concentration of lycopene than did the control subjects, but
the difference was not significant. Only in smokers was a low
serum level of lycopene associated with a significantly
increased risk of subsequent MI.
In the present study, the association between the plasma
level of lycopene and IMT appeared to be stronger among
nonsmokers than among smokers. We found that an association between the plasma level of lycopene and IMT exists in
nonsmokers and is weak in smokers. There are 2 explanations
for this difference. First, mean daily intake of carotenoids
could be lower in smokers than in nonsmokers. An alternative
explanation is that because smoking is such a strong risk
factor itself, smokers do not benefit from lycopene intake as
much as nonsmokers, or they have a greater need of
antioxidants.
The effect of lycopene on IMT was different in women
than in men. There are some possible causes of this difference. Women have a better diet than do men. This is the most
likely explanation for the lack of association with IMT.
Another explanation would be the more effective endogenous
antioxidative system of women.
The oxidative modification of LDL particles may play a
role in the formation of foam cells, atherosclerotic lesions,
and CHD.9,23 Antioxidants can inhibit the oxidative modification of LDL, may retard atherosclerotic progression, and,
consequently, prevent clinical complications of atherosclerosis, such as MI.24,25 Lycopene and other carotenoids have
been shown to act as antioxidants.7,11,26,27 Carotenoids found
in plasma can quench singlet oxygen, a potential initiator of
lipid peroxidation.26 Lycopene, the open-chain isomer of
␤-carotene, exhibits the highest physical quenching rate
constant of all carotenoids with singlet oxygen.7
The mean CCA-IMT in the present subjects was somewhat
higher than that reported in most other studies. In the ARIC
study,16 the mean IMT of the carotid artery was 1.2 mm for
the cases and 0.6 mm for the controls. In the Perth Carotid
Ultrasound Disease Assessment Study (CUDAS),28 the average mean of carotid artery IMT in men was 0.73 mm. In the
EVA study,19 the mean IMT was 0.70 in men and 0.65 in
women. In the Cardiovascular Health Study,21 the mean
CCA-IMT was 1.03 mm in subjects aged ⱖ65 years; thus, the
subjects were ⬎10 years older than in the present study. In
the population in eastern Finland, CCA-IMT seems to be
rather high. This is consistent with the high occurrence of
clinical CHD in eastern Finland. Moreover, the serum LDL
cholesterol in the present study was higher than that in other
studies, and half of the present study subjects smoked
regularly. The mean plasma concentration of lycopene in the
present study was lower than that in other population-based
studies1,16,29; in only 1 earlier study18 was the mean level of
plasma lycopene similar to that in the present study. Evidently, the consumption of tomatoes or tomato products in
Finland may be lower than that in most other European
countries.
It is possible that the plasma level of lycopene could be an
indicator for other favorable dietary factors. However, the
effect of lycopene was significant after an adjustment for 3
other dietary factors, the intakes of saturated fatty acids, fiber,
and vitamin C. Also, smokers had lower plasma levels of
lycopene than did nonsmokers. This could be due to either
dietary differences or a consequence of smoking itself.
However, we adjusted for smoking in our statistical analysis
to shown that the increased CCA-IMT in subjects with low
plasma levels of lycopene was not simply a consequence of a
higher proportion of smokers.
In conclusion, the present study shows that low levels of
plasma lycopene are associated with increased CCA-IMT in
middle-aged men, but not in women, from eastern Finland.
Because increased IMT has been shown to predict coronary
events,20,21 this finding suggests that the plasma level of
lycopene, particularly a biomarker of tomato-rich food intake,
may play a role in the early stages of atherogenesis. Consequently, our results support the previous evidence that plantdominated diet contributes to cardiovascular health.
Acknowledgments
This study was partly funded by the Finnish Academy and the
Juho Vainio Foundation. We are grateful to our staff of almost 30
people and Oy Jurilab Ltd for helping with data collection.
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Low Plasma Lycopene Concentration Is Associated With Increased Intima-Media
Thickness of the Carotid Artery Wall
Tiina Rissanen, Sari Voutilainen, Kristiina Nyyssönen, Riitta Salonen and Jukka T. Salonen
Arterioscler Thromb Vasc Biol. 2000;20:2677-2681
doi: 10.1161/01.ATV.20.12.2677
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