AJCN North Carolina Research Campus
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rissanen, T. H
Right arrow Articles by Salonen, J. T
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rissanen, T. H
Right arrow Articles by Salonen, J. T
Agricola
Right arrow Articles by Rissanen, T. H
Right arrow Articles by Salonen, J. T
American Journal of Clinical Nutrition, Vol. 77, No. 1, 133-138, January 2003
© 2003 American Society for Clinical Nutrition

Original Research Communication

Serum lycopene concentrations and carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factor Study1,2,3

Tiina H Rissanen, Sari Voutilainen, Kristiina Nyyssönen, Riitta Salonen, George A Kaplan and Jukka T Salonen

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), University of Kuopio, Kuopio, Finland; the School of Public Health, University of Michigan, Ann Arbor (GAK); and the Inner Savo Health Centre, Suonenjoki, Finland (JTS).

2 Supported in part by the Juho Vainio Foundation, the Ida Montin Foundation, the Academy of Finland (KN and JTS), the NHLBI of the United States (GAK), and Oy Jurilab Ltd (Internet: www.jurilab.com).

3 Address reprint requests to JT Salonen, Research Institute of Public Health, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland. E-mail: jukka.salonen{at}uku.fi.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Interest in lycopene is growing rapidly following the recent publication of epidemiologic studies in which high circulating lycopene concentrations were associated with reductions in cardiovascular disease. Lycopene is one of the major carotenoids in the Western diet and is probably one of the protective factors in a vegetable-rich diet.

Objective: We studied the hypothesis that the intima-media thickness of the common carotid artery (CCA-IMT) would be greater in men with low serum lycopene concentrations.

Design: We investigated the relation between serum lycopene concentration and CCA-IMT in 1028 middle-aged men (aged 46–64 y) in eastern Finland who were participants in the Kuopio Ischaemic Heart Disease Risk Factor study and who were examined in 1991–1993. The subjects were classified into quarters according to serum lycopene concentration.

Results: In a covariance analysis with adjustment for covariates, the men in the lowest quarter of serum lycopene concentration had a significantly higher mean CCA-IMT and maximal CCA-IMT (P = 0.005 and P = 0.001 for the difference, respectively) than did the other men. The mean and maximal CCA-IMT increased linearly 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 Finland. This finding suggests that the serum lycopene concentration may play a role in the early stages of atherosclerosis. Increased thickness of the intima-media has been shown to predict coronary events; thus, lycopene intakes and serum concentrations may have clinical and public health relevance.

Key Words: Lycopene • atherosclerosis • carotid arteries • intima-media thickness • carotenoids • Kuopio Ischaemic Heart Disease Risk Factor study • middle-aged men


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Nutrition plays an important role in the development of coronary artery disease (CAD). Diets rich in fruit and vegetables containing carotenoids are of interest because of their potential health benefit against chronic diseases such as CAD and cancer. Increased intakes and tissue or blood concentrations of carotenoids are associated with a reduced risk of cardiovascular disease (1–6). Although ß-carotene has been investigated for many years, lycopene, the acyclic form of ß-carotene, has attracted substantial interest more recently. Lycopene is a red pigment and is one of the major carotenoids in Western diets. In contrast with most other carotenoids, however, which are widely distributed among a great variety of fruit and vegetables, lycopene intake comes predominantly from tomatoes and tomato products. Lycopene has unique structural and chemical features that may contribute to its specific biological properties (7). The antioxidant properties of lycopene are resistant to heat and cooking, and the bioavailability of lycopene in processed tomato products is higher than that in unprocessed, fresh tomatoes.

Lycopene is an antioxidant carotenoid without provitamin A activity and has been shown to be a more potent antioxidant than {alpha}- or ß-carotene (8). The oxidation-protecting effect of lycopene and tomatoes has been shown in both human and animal studies (9, 10). A reduced oxidative modification of LDL may be one of the mechanisms by which lycopene reduces the risk of CAD and atherosclerotic progression (11, 12).

Only a few previous studies addressed the association between low concentrations of circulating lycopene and early atherosclerosis. We tested the hypothesis that the intima-media thickness of the common carotid artery (CCA-IMT) would be greater in men with low serum lycopene concentrations.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
The Kuopio Ischaemic Heart Disease Risk Factor (KIHD) study is an ongoing, population-based study designed to investigate risk factors for cardiovascular disease, atherosclerosis, and related outcomes in middle-aged men from eastern Finland, a population with one of the highest recorded rates of CAD (13). The study was approved by the Research Ethics Committee of the University of Kuopio, and all study subjects gave their written informed consent.

A total of 2682 men aged 42, 48, 54, or 60 y were enrolled in the study between March 1984 and December 1989. Four-year reexaminations of those examined in 1987–1989 were conducted between March 1991 and December 1993. For the reexaminations, the subjects visited the study site twice, with an interval of 7 d. Blood pressure was measured at the first visit, and CCA-IMT was scanned and blood samples were drawn at the second visit. Of a total of 1229 men eligible for the reexamination, 52 had died, had severe illness, or had moved away from the region, and 139 could not be contacted or refused to participate. High-resolution ultrasound examinations of CCA-IMT and data on serum lycopene concentrations were available for 1028 men. These results make up the cross-sectional data of the reexamination of the KIHD follow-up study.

Ultrasonographic assessment of the intima-media thickness of the common carotid artery
CCA-IMT was assessed by high-resolution B-mode ultrasonography of the right and left CCAs at the distal end, proximal to the carotid bulb. The ultrasound equipment (Biosound Phase 2; Biosound Inc, Indianapolis) was equipped with a high-resolution probe. Images were focused on the posterior wall of the right and left CCAs and were recorded on videotape for image analysis. The ultrasonographic examinations were carried out by well-trained ultrasound technicians and were performed after the subjects had rested in a supine position for 15 min.

IMT measurements were made through computerized analysis of the videotaped ultrasound images with PROSOUND software (University of Southern California, Los Angeles). This software uses an edge-detection algorithm, specifically designed for use with ultrasound imaging, that allows automatic detection, tracking, and recording of the intima-lumen and media-adventitia interfaces, estimated at {approx}100 points, in both the right and left CCAs in a 1.0–1.5-cm section (14). For the present study, 2 measures of IMT were used. Mean IMT was computed as the mean of {approx}100 IMT measurements in the right CCA and another 100 measurements in the left CCA. Maximum IMT was computed as the average of the points of maximum 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.

A separate study concerning the intra- and interobserver variability of IMT measurements was carried out in 10 randomly chosen middle-aged men who had participated in the KIHD study. The between-observer CV was 10.5% for the first assessments by 4 observers for both the right and left CCAs. The correlation coefficients ranged from 0.90 to 0.99. The intraobserver variability (reproducibility) was described by the absolute value of difference between the first and the third measurement by each observer. The mean absolute difference was 0.087 mm, which is 8.1% of the mean of all measurements (15).

Measurements
The subjects came to give blood samples between 0800 and 1000. They were instructed to abstain from ingesting alcohol for 3 d and from smoking and eating for 12 h before the blood sampling. After the subjects had rested in a supine position for 30 min, blood was drawn with Terumo Venoject vacuum tubes (Terumo, Tokyo). No tourniquet was used.

Serum for lycopene, ß-carotene, and {alpha}-tocopherol measurements was extracted with ethanol and hexane, and the measurements were made with the use of a reversed-phase HPLC method in samples that had been stored at -80 °C for 4–36 mo (16). This method cannot separate lycopene isomers. The detection limit for lycopene with this method was 0.03–0.07 µmol/L. Values below the limit of detection of the assay were marked as 0.00 in the statistical analysis. The CV was determined with a serum pool analyzed in 25 separate batches. The CVs were 11.0% for lycopene and 16.2% for ß-carotene. To evaluate the stability of lycopene, we calculated the means of the first 56 samples stored for 36 mo (0.113 µmol/L) and the means of the last 56 samples stored for 4 mo (0.110 µmol/L). Thus, serum lycopene samples were well preserved, and the difference in storage times did not attenuate the results.

Lipoproteins were separated from fresh serum samples by combined ultracentrifugation (100 000 x g, 4 °C, 23 h) and precipitation. Concentrations of serum total, LDL, and HDL cholesterol (Kone Instruments, Espoo, Finland) and of serum triacylglycerols (Boehringer Mannheim, Mannheim, Germany) were determined enzymatically with an autoanalyzer (Kone Specific; Kone Instruments) (17). Serum folate was determined by radioimmunoassay (Bio-Rad, Hercules, CA) (18).

Resting blood pressure was measured in the morning by 2 trained nurses with a random-zero mercury sphygmomanometer (Hawksley, Lancing, United Kingdom). After the subjects had rested in a supine position for 5 min, 6 measurements were taken at 5-min intervals: 3 while the subjects were in a supine position, 1 while the subjects were standing, and 2 while the subjects were sitting. The mean of all 6 measurements was used as the systolic and diastolic blood pressure.

A subject was defined a smoker if he had ever smoked on a regular basis and had smoked cigarettes, cigars, or a pipe within the past 30 d. The number of cigarettes, cigars, and pipefuls of tobacco currently smoked daily and the duration of regular smoking in years were recorded on a self-administered questionnaire that was checked by an interviewer.

Body weight was measured by using a balance scale. During the height and weight measurements, the subjects wore light clothing and no shoes. Body mass index (BMI) was computed as the ratio of weight to the square of height (kg/m2).

Statistical analysis
Data were analyzed by using SPSS statistical software (version 10.0 for WINDOWS; SPSS Inc, Chicago). Mean age; BMI; systolic and diastolic blood pressure; serum triacylglycerols; serum HDL, LDL, and total cholesterol; and serum folate, ß-carotene, and {alpha}-tocopherol are reported as means ± SDs. Cigarette smoking is reported as a percentage. Subjects were classified into quarters according to their serum concentration of lycopene: < 0.04, 0.04–0.12, 0.13–0.22, and > 0.22 µmol/L). The statistical significance of the differences between these lycopene groups in the main characteristics of the subjects was studied by using one-way analysis of variance (ANOVA). The correlations between CCA-IMT and nutritional factors and cardiovascular disease risk factors were estimated by Spearman’s correlation coefficients.

The association between serum concentrations of lycopene and ultrasonographically assessed CCA-IMT was tested for statistical significance by using covariance analysis. Three different sets of covariates were used: model 1 included age, ultrasound observer, and examination years; model 2 included model 1 and systolic blood pressure, serum HDL and LDL cholesterol, and smoking; and model 3 included model 2 and serum triacylglycerols, BMI, and 3 nutritional factors (serum folate, ß-carotene, and {alpha}-tocopherol). All tests were two-tailed, and P values < 0.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The mean concentration of serum lycopene was 0.15 ± 0.14 µmol/L, ranging from below the detection limit to 1.02 µmol/L. The main characteristics of the subjects are presented in Table 1Go. Serum ß-carotene, folate, and {alpha}-tocopherol concentrations; age; systolic blood pressure; BMI; and smoking differed significantly between the subjects in different quarters of serum lycopene concentration. Serum lycopene concentrations were higher in the younger (aged 46–55 y) men than in the older (aged > 55 y) men (0.19 and 0.11 µmol/L, respectively, P < 0.001, ANOVA) and were nonsignificantly higher in nonsmokers than in smokers (0.16 and 0.14 µmol/L, respectively, P = 0.07, ANOVA).


View this table:
[in this window]
[in a new window]
  		TABLE 1 Characteristics of the subjects1
 
Serum lycopene concentrations correlated negatively with mean and maximal CCA-IMT (Spearman’s correlation coefficients: r = -0.22, P < 0.001, and r = -0.20, P < 0.001, respectively). The strongest correlations were found between mean CCA-IMT and age, systolic blood pressure, BMI, serum LDL cholesterol, and serum lycopene (Table 2Go). Except for the relation with serum lycopene, all of these relations were positive.


View this table:
[in this window]
[in a new window]
  		TABLE 2 Spearman’s correlation coefficients (r) and statistical significance for the association between mean intima-media thickness of the common carotid artery and nutritional factors and cardiovascular disease risk factors in middle-aged eastern Finnish men
 
In a covariance analysis, we observed a significant inverse association between serum concentrations of lycopene and mean and maximal CCA-IMT. In model 1, men in the lowest quarter of serum lycopene concentration had significantly higher mean (P < 0.001 for the difference) and maximal (P < 0.001 for difference) CCA-IMT than did the other men. Additional adjustment for other covariates (model 2) did not change the observed results (P = 0.001 and P < 0.001 for the difference, respectively). Furthermore, a similar inverse trend remained in model 3 (P = 0.005 and P = 0.001 for the difference, respectively). The increments in the mean and maximal CCA-IMT were linear across the quarters of serum lycopene concentration. The P values for the linear trend for mean and maximal CCA-IMT in model 1 were 0.001 and < 0.001, respectively. In model 2, the corresponding P values were 0.006 and 0.002, respectively, and in model 3 they were 0.039 and 0.013, respectively. In all models, the mean and maximal CCA-IMT decreased linearly across the quarters of serum lycopene concentration (Table 3Go).


View this table:
[in this window]
[in a new window]
  		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
 
The association between serum lycopene concentration and CCA-IMT was stronger in smokers than in nonsmokers. In model 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 quarters = 0.003; maximal CCA-IMT: 1.33, 1.24, 1.15, and 1.21 mm, P for linear trend across the quarters = 0.002). In nonsmokers the association between serum concentrations of lycopene and mean and maximal CCA-IMT was weaker and nonsignificant but linear (mean CCA-IMT: 090, 0.88, 0.88, and 0.85 mm, P for linear trend across the quarters = 0.159; maximal CCA-IMT: 1.25, 1.21, 1.21, and 1.17 mm, P for linear trend across the quarters = 0.098). In the fully adjusted model (model 3), both mean and maximal CCA-IMT were 10% higher (P = 0.002 and P = 0.002 for the difference, respectively) in smokers in the lowest quarter of serum lycopene than in the other smokers. Additional adjustment for smoking years did not significantly change the results.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
High circulating concentrations of carotenoids are presumed to protect against atherosclerosis before its clinical manifestation (19–23). The main finding of the present study is that low serum lycopene concentrations are associated with early atherosclerosis, as manifested as an increased thickness of the CCA in middle-aged men from eastern Finland.

The association between blood concentrations or dietary intakes of lycopene and thickness of the artery wall was studied earlier in very few studies (Table 4Go). In our previous Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study (19), low plasma concentrations of lycopene were associated with CCA-IMT 18% higher than that in men with plasma concentrations of lycopene higher than the median. In women, the difference was nonsignificant after the adjustments. In a subsample of the Atherosclerosis Risk in Communities (ARIC) study (20), there were 231 age-, sex-, race-, and field center–matched case-control pairs. An increased serum concentration of lycopene was associated with nonsignificantly lower odds of being a case after adjustment for risk factors (odds ratio: 0.81). In the same study (21), a high dietary intake of provitamin A carotenoids was associated with a lower prevalence of carotid plaques and a lower thickness of the artery wall, although these associations were not statistically significant. In the ARIC study, the dietary intake of lycopene was not assessed. In the Rotterdam study (22), serum lycopene was the only carotenoid that was associated with a decreased risk of aortic atherosclerosis in current and former smokers.


View this table:
[in this window]
[in a new window]
  		TABLE 4 Studies of the association of circulating and tissue concentrations of lycopene with the risk of cardiovascular disease and atherosclerosis1
 
In the Etude sur le Vieillisement Artériel (23), subjects in the highest quarter of plasma total carotenoids had lower CCA-IMT, but this association became nonsignificant after adjustment for common risk factors. In men, the prevalence of carotid plaques decreased linearly across the quarters of plasma carotenoid concentration (P < 0.016). Plasma concentrations of lycopene were not measured in that study.

The prevalence of carotid plaques and increased thickness of the intima media has been shown to predict coronary events (27, 28). The association between blood or tissue concentrations of lycopene and risk of CAD was studied earlier in several studies. In the multicenter EURAMIC study (6), low adipose tissue concentrations of lycopene were associated with greater risk of a myocardial infarction. In a nested case-control study from Washington County (26), excess risk of myocardial infarction was associated with low serum concentrations of lycopene, but a protective association with higher concentrations of lycopene was suggested in smokers. In the prospective Massachusetts Health Care Panel study (29), a high dietary intake of total carotenoids was associated with a reduced risk of fatal myocardial infarction and cardiovascular disease death. We also found in the KIHD study that men with low serum concentrations of lycopene had a higher risk of an acute coronary event or stroke than did men with higher serum lycopene concentrations (25).

The oxidative modification of LDL particles may play a role in the formation of foam cells, atherosclerotic lesions, and CAD (11, 30). Men who have high titers of autoantibodies against oxidatively modified LDL and those with elevated serum 7ß-hydroxycholesterol concentrations have accelerated progression of carotid atherosclerosis (11, 12). Antioxidants can inhibit the oxidative modification of LDL, may retard atherosclerotic progression, and, consequently, may prevent clinical complications of atherosclerosis such as myocardial infarction (31, 32). Lycopene and other carotenoids have been shown to act as antioxidants (7, 8, 10, 33). This action is probably due to the ability of carotenoids to quench singlet oxygen, a potential initiator of lipid peroxidation (33). Lycopene exhibits the highest physical quenching rate of all carotenoids (8). It has also been shown that serum concentrations of lycopene are inversely correlated with serum thiobarbituric acid–reactive substances (TBARS) (34), an indicator of lipid peroxidation. Both LDL-TBARS and conjugated dienes were lowered significantly by dietary lycopene supplementation (10). Other mechanisms through which lycopene may inhibit atherosclerosis include intercellular gap junction communication and hormonal and immune system modulation (34). In addition, in cell culture, lycopene is the most effective carotenoid at suppressing adhesion molecule and monocyte adhesion to endothelial cells (35).

The mean CCA-IMT in our subjects was somewhat higher than that reported in most other studies (20, 23, 28, 36). This is consistent with the high incidence of clinical CAD in eastern Finland. The mean serum lycopene concentration in our study was much lower than that reported in most other population-based studies from European countries, in which lycopene concentrations were 2–4-fold higher than in our study (2, 24). In an American population, circulating concentrations of lycopene were even 6-fold greater than those in our study (20). In only one earlier study (22) were mean circulating concentrations of lycopene parallel to those in the present study. The most likely explanation for this is the low dietary intake of lycopene in Finland. In the Finnish Mobile Clinic Health Examination Survey (37), the daily intake of lycopene was 0.9 mg for women and 0.7 mg for men, whereas the intake of lycopene is 1.3 mg in Spain (38) and as high as 6.6 mg in the United States (39). Our study subjects had low concentrations of lycopene, and the association was stronger at low concentrations, which may explain the strength of the relation. One explanation for the weak effect found in some studies with high tissue concentrations and more homogeneous concentrations of lycopene may be the lack of low circulating concentrations of lycopene.

It is possible that the serum concentration of lycopene is an indicator for other beneficial dietary factors. However, the effect of lycopene was significant after adjustment for other plant-derived nutrients, serum folate, ß-carotene, and {alpha}-tocopherol. Smokers and older men had lower serum concentrations of lycopene than did nonsmokers and younger men. This could either be due to differences in dietary intake or be a consequence of smoking or aging itself. We adjusted statistical models for age and smoking status to eliminate the effect of these factors. An adjustment for smoking attenuated but did not abolish the association between lycopene and CCA-IMT. However, the association between serum concentrations of lycopene and CCA-IMT seemed to be stronger in smokers than in nonsmokers.

The results of previous studies of the association between blood concentrations of lycopene and atherosclerosis or cardiovascular disease in smokers and nonsmokers are inconsistent. Our results support the findings of the Rotterdam study (22) and the nested case-control study from Washington County (26). In contrast, in the EURAMIC (6) and the ASAP (19) studies, there was a stronger effect of lycopene on myocardial infarction and atherosclerosis among nonsmokers. Smoking is a well-known risk factor for CAD. Smokers have been shown to have lower plasma concentrations of most carotenoids, but results concerning blood concentrations of lycopene according to smoking status are mixed (40). The relation between lycopene and smoking is incompletely understood, and more knowledge is needed to clarify this association.

In conclusion, the results of the present study show that low serum concentrations of lycopene are associated with higher CCA-IMT in middle-aged men from eastern Finland. A higher IMT has been shown to predict coronary events (27, 28); thus, our finding suggests that serum concentrations of lycopene, a biomarker of tomato-rich food intake, may play a role in the early stages of atherogenesis and may have clinical and public health relevance.


   ACKNOWLEDGMENTS
 
We are grateful to our staff of almost 40 persons for helping with data collection.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Price JF, Fowkes FGR. Antioxidant vitamins in the prevention of cardiovascular disease. The epidemiological evidence. Eur Heart J 1997;18:719–27.[Free Full Text]
  2. Kristenson M, Zieden B, Kucinskienë Z, et al. Antioxidant state and mortality from coronary heart disease in Lithuanian and Swedish men: concomitant cross sectional study of men aged 50. BMJ 1997;14:629–33.
  3. van Poppel G. Epidemiological evidence for ß-carotene in prevention of cancer and cardiovascular disease. Eur J Clin Nutr 1996;50:S57–61.
  4. Kardinaal AFM, Kok FJ, Ringstad J, et al. Antioxidants in adipose tissue and risk of myocardial infarction: the EURAMIC study. Lancet 1993;342:1379–84.[Medline]
  5. Knekt P, Reunanen A, Järvinen R, Seppänen R, Heliövaara M, Aromaa A. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol 1994;139:1180–9.[Abstract/Free Full Text]
  6. Kohlmeier L, Kark JD, Gomez-Gracia E, et al. Lycopene and myocardial infarction risk in the EURAMIC Study. Am J Epidemiol 1997;146:618–26.[Abstract/Free Full Text]
  7. Clinton SK. Lycopene: chemistry, biology, and implications for human health and disease. Nutr Rev 1998;56:35–51.[Medline]
  8. DiMascio P, Kaiser S, Sies H. Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch Biochem Biophys 1989;274:532–8.[Medline]
  9. Suganuma H, Inakuma T. Protective effect of dietary tomato against endothelial dysfunction in hypercholesterolemic mice. Biosci Biotechnol Biochem 1999;63:78–82.[Medline]
  10. Agarval S, Rao AV. Tomato lycopene and low density lipoprotein oxidation: a human dietary intervention study. Lipids 1998;33:981–4.[Medline]
  11. Salonen JT, Ylä-Herttuala S, Yamamoto R, et al. Autoantibody against oxidized LDL and progression of carotid atherosclerosis. Lancet 1992;339:883–7.[Medline]
  12. Salonen JT, Nyyssönen K, Salonen R, et al. Lipoprotein oxidation and progression of carotid atherosclerosis. Circulation 1997;95:840–5.[Medline]
  13. Salonen JT. Is there a continuing need for longitudinal epidemiologic research? The Kuopio Ischaemic Risk Factor Study. Ann Clin Res 1988;20:46–50.[Medline]
  14. Salonen JT, Seppänen K, Lakka TA, Salonen R, Kaplan GA. Mercury accumulation and accelerated progression of carotid atherosclerosis: a population-based prospective 4-year follow-up study in men in eastern Finland. Atherosclerosis 2000;148:265–73.[Medline]
  15. Salonen R, Haapanen A, Salonen JT. Measurement of intima-media thickness of common carotid arteries with high-resolution B-mode ultrasonography: inter- and intra-observer variability. Ultrasound Med Biol 1991;17:225–30.[Medline]
  16. Thurnham DI, Smith E, Flora PS. Concurrent liquid-chromatographic assay of retinol, {alpha}-tocopherol, ß-carotene, {alpha}-carotene lycopene, and ß-cryptoxanthin in plasma, with tocopherol acetate as internal standard. Clin Chem 1988;34:377–81.[Abstract/Free Full Text]
  17. Salonen JT, Salonen R, Seppänen K, Rauramaa R, Tuomilehto J. HDL, HDL2, and HDL3 subractions, and the risk of acute myocardial infarction. A prospective population study in eastern Finnish men. Circulation 1991;84:129–39.[Medline]
  18. Voutilainen S, Lakka TA, Porkkala-Sarataho E, Rissanen T, Kaplan GA, Salonen JT. Low serum folate concentrations are associated with an excess incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. Eur J Clin Nutr 2000;54:242–8.
  19. Rissanen T, Voutilainen S, Nyyssönen K, Salonen R, Salonen JT. Low plasma lycopene concentration is associated with increase intima-media thickness of the carotid artery wall. Arterioscler Thromb Vasc Biol 2000;20:2677–81.[Abstract/Free Full Text]
  20. Iribarren C, Folsom AR, Jacobs DR, Cross MD, Belcher JD, Eckfeldt JH. Association of serum vitamin levels, LDL susceptibility to oxidation, and autoantibodies against MDA-LDL with carotid atherosclerosis. Arterioscler Thromb Vasc Biol 1997;17:1171–7.[Abstract/Free Full Text]
  21. Kritchevsky SB, Tell GS, Shimakawa T, et al. Provitamin A carotenoid intake and carotid artery plaques: the Atherosclerosis Risk in Communities Study. Am J Clin Nutr 1998;68:726–33.[Abstract]
  22. Klipstein-Grobusch K, Launer LJ, Geleijnse JM, Boeing H, Hofman A, Wittemen JCM. Serum carotenoids and atherosclerosis: The Rotterdam Study. Atherosclerosis 2000;148:49–56.[Medline]
  23. Bonithon-Kopp C, Coudray C, Berr C, et al. Combined effects of lipid peroxidation and antioxidant status on carotid atherosclerosis in a population aged 59–71 y: the EVA Study. Am J Clin Nutr 1997;65:121–7.[Abstract/Free Full Text]
  24. D’Orico, Martines D, Kiechl S, et al. High plasma levels of {alpha}- and ß-carotene are associated with a lower risk of atherosclerosis. Results from the Bruneck study. Atherosclerosis 2000;153:231–9.[Medline]
  25. Rissanen TH, Voutilainen S, Nyyssönen K, et al. Low serum lycopene concentration is associated with an excess incidence of acute coronary events and stroke: the Kuopio Ischaemic Heart Disease Risk Factor study. Br J Nutr 2001;85:749–54.[Medline]
  26. Street DA, Comstock GW, Salkeld RM, Schüep W, Klag MJ. Serum antioxidants and myocardial infarction. Are low levels of carotenoids and {alpha}-tocopherol risk factors for myocardial infarction? Circulation 1994;90:1154–61.[Medline]
  27. Salonen JT, Salonen R. Ultrasound B-mode imaging in observational studies of atherosclerotic progression. Circulation 1993;87:1156–65.
  28. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999;340:14–22.[Abstract/Free Full Text]
  29. Gaziano JM, Manson JE, Branch LG, Colditz GA, Willett WC, Buring JE. A prospective study of consumption of carotenoids in fruits and vegetables and decreased cardiovascular mortality in the elderly. Ann Epidemiol 1995;5:255–60.[Medline]
  30. Witztum JL, Hörkkö S. The role of oxidized LDL in atherogenesis: immunological response and anti-phospholipid antibodies. Ann N Y Acad Sci 1997;811:88–96.[Free Full Text]
  31. Salonen JT. Epidemiological studies on antioxidant, lipid peroxidation and atherosclerosis. Arch Toxicol Suppl 1998;20:249–67.[Medline]
  32. Diaz MN, Frei B, Vita JA, Keaney JF Jr. Antioxidants and atherosclerotic heart disease. N Engl J Med 1997;337:408–16.[Free Full Text]
  33. Stahl W, Sies H. Perspectives in biochemistry and biophysics. Lycopene: a biologically important carotenoid for humans? Arch Biochem Biophys 1996;336:1–9.[Medline]
  34. Rao AV, Agarval S. Effect of diet and smoking on serum lycopene and lipid peroxidation. Nutr Res 1998;18:713–21.
  35. Martin KR, Wu D, Meydani M. The effect of carotenoids on the expression of cell surface adhesion molecules and binding of monocytes to human aortic endothelial cells. Atherosclerosis 2000;150:265–74.[Medline]
  36. McQuillan BM, Peilby JP, Nidorf M, Thompson PL, Hung J. Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening. The Perth Carotid Ultrasound Disease Assessment Study (CUDAS). Circulation 1999;99:2383–8.[Medline]
  37. Järvinen R. Carotenoids, retinoids, tocopherols and tocotrienols in the diet; the Finnish Mobile Clinic Health Examination Survey. Int J Vitam Nutr Res 1995;65:24–30.[Medline]
  38. Granado F, Olmedilla B, Blanco I, Rojas-Hidalgo E. Major and vegetable contributors to the main serum carotenoids in the Spanish diet. Eur J Clin Nutr 1996;50:246–50.[Medline]
  39. Slattery ML, Benson J, Curtin K, Ma K-N, Schaeffer D, Potter JD. Carotenoids and colon cancer. Am J Clin Nutr 2000;71:575–82.[Abstract/Free Full Text]
  40. Arab L, Steck S. Lycopene and cardiovascular disease. Am J Clin Nutr 2000;71(suppl):1691S–5S.[Abstract/Free Full Text]
Received for publication June 21, 2001. Accepted for publication February 26, 2002.




This article has been cited by other articles:


Home page
 Am. J. Clin. Nutr.Home page
N. O'Kennedy, L. Crosbie, M. van Lieshout, J. I Broom, D. J Webb, and A. K Duttaroy
Effects of antiplatelet components of tomato extract on platelet function in vitro and ex vivo: a time-course cannulation study in healthy humans.
Am. J. Clinical Nutrition, September 1, 2006; 84(3): 570 - 579.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
S. Voutilainen, T. Nurmi, J. Mursu, and T. H Rissanen
Carotenoids and cardiovascular health
Am. J. Clinical Nutrition, June 1, 2006; 83(6): 1265 - 1271.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
M. Gajic, S. Zaripheh, F. Sun, and J. W. Erdman Jr.
Apo-8'-Lycopenal and Apo-12'-Lycopenal Are Metabolic Products of Lycopene in Rat Liver
J. Nutr., June 1, 2006; 136(6): 1552 - 1557.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
O. I. Bermudez, J. D. Ribaya-Mercado, S. A. Talegawkar, and K. L. Tucker
Hispanic and Non-Hispanic White Elders from Massachusetts Have Different Patterns of Carotenoid Intake and Plasma Concentrations
J. Nutr., June 1, 2005; 135(6): 1496 - 1502.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
H. D Sesso, J. E Buring, E. P Norkus, and J M. Gaziano
Plasma lycopene, other carotenoids, and retinol and the risk of cardiovascular disease in men
Am. J. Clinical Nutrition, May 1, 2005; 81(5): 990 - 997.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
K. Canene-Adams, J. K. Campbell, S. Zaripheh, E. H. Jeffery, and J. W. Erdman Jr
The Tomato As a Functional Food
J. Nutr., May 1, 2005; 135(5): 1226 - 1230.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
P. J. Pussinen, K. Nyyssonen, G. Alfthan, R. Salonen, J. A. Laukkanen, and J. T. Salonen
Serum Antibody Levels to Actinobacillus actinomycetemcomitans Predict the Risk for Coronary Heart Disease
Arterioscler. Thromb. Vasc. Biol., April 1, 2005; 25(4): 833 - 838.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Coll. Nutr.Home page
S. T. Mayne, B. Cartmel, H. Lin, T. Zheng, and W. J. Goodwin Jr
Low Plasma Lycopene Concentration is Associated with Increased Mortality in a Cohort of Patients with Prior Oral, Pharynx or Larynx Cancers
J. Am. Coll. Nutr., February 1, 2004; 23(1): 34 - 42.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
H. D Sesso, J. E Buring, E. P Norkus, and J M. Gaziano
Plasma lycopene, other carotenoids, and retinol and the risk of cardiovascular disease in women
Am. J. Clinical Nutrition, January 1, 2004; 79(1): 47 - 53.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
B.-L. Lee, A.-L. New, and C.-N. Ong
Simultaneous Determination of Tocotrienols, Tocopherols, Retinol, and Major Carotenoids in Human Plasma
Clin. Chem., December 1, 2003; 49(12): 2056 - 2066.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rissanen, T. H
Right arrow Articles by Salonen, J. T
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rissanen, T. H
Right arrow Articles by Salonen, J. T
Agricola
Right arrow Articles by Rissanen, T. H
Right arrow Articles by Salonen, J. T

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS