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American Journal of Clinical Nutrition, Vol. 81, No. 5, 990-997, May 2005
© 2005 American Society for Clinical Nutrition

ORIGINAL RESEARCH COMMUNICATION

Plasma lycopene, other carotenoids, and retinol and the risk of cardiovascular disease in men1,2,3

Howard D Sesso, Julie E Buring, Edward P Norkus and J Michael Gaziano

1 From the Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA (HDS, JEB, and JMG); the Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA (HDS, JEB, and JMG); the Department of Epidemiology, Harvard School of Public Health, Boston, MA (JEB); the Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, MA (JEB); the Departments of Medical Research, Our Lady of Mercy Medical Center and Community and Preventive Medicine, New York Medical College, Bronx, NY (EPN)

2 Supported by grants NIH CA 97193 and BASF AG and a grant from Roche Vitamins Inc. Approximately one-half of the participants in PHS II also participated in PHS I, which was established through grants NIH CA 34944, CA 40360, HL 26490, and HL 34595.

3 Reprints not available. Address correspondence to HD Sesso, Brigham and Women's Hospital, 900 Commonwealth Avenue East, Boston MA 02215-1204. E-mail: hsesso{at}hsph.harvard.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Emerging evidence suggests a possible role of lycopene in the primary prevention of cardiovascular disease (CVD).

Objective: We examined whether plasma lycopene concentrations in the Physicians' Health Study were associated with CVD in a prospective, nested, case-control design.

Design: Baseline blood samples were collected starting in 1996. During a mean follow-up of 2.1 y, we identified 499 cases of CVD (confirmed myocardial infarction, stroke, CVD death, or revascularization procedures) and an equal number of men free of CVD and matched for age (: 69.7 y), follow-up time, and smoking status. We collected self-reported coronary disease risk factors and measured plasma carotenoids, retinol, lipids, and C-reactive protein.

Results: In matched analyses with additional adjustment for plasma total cholesterol and randomized treatment, the relative risks (RRs) of CVD for men in the lowest to highest quartiles of plasma lycopene were 1.00 (reference), 0.92, 1.04, and 0.95 (P for linear trend = 0.93). With multivariate adjustment, the RRs of total CVD were 1.00 (reference), 1.08, 0.94, and 1.03 (P for linear trend = 0.98). For important vascular events (241 cases), excluding revascularization procedures, the multivariate RRs remained nonsignificant (P for linear trend = 0.50). Adding plasma carotenoids, lipids, or C-reactive protein to multivariate models had a minimal effect on the RRs of total CVD for plasma lycopene. Compared with lycopene, higher concentrations of plasma lutein/zeaxanthin and retinol suggested a moderate increase in CVD risk, whereas no association was found for ß-cryptoxanthin, {alpha}-carotene, and ß-carotene.

Conclusions: Higher plasma lycopene concentrations were not associated with the risk of CVD in this study of older men. Further evaluation in diverse populations is necessary.

Key Words: Lycopene • carotenoids • cardiovascular disease • prospective studies • nutrition • epidemiology


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In addition to a well-established inverse association between the intake of lycopene, a carotenoid without provitamin A activity, and prostate cancer (1), evidence also suggests a role of lycopene in the primary prevention of cardiovascular disease (CVD) (2–8). Because lycopene is predominantly found in just a few food sources, as tomato-based foods make up ≥80% of lycopene intake in the American diet (9), any benefits attributed to lycopene may lead to a straightforward intervention to increase intake. This provides an advantage for lycopene over other carotenoids, which are more ubiquitous in fruit and vegetables. Lycopene may enhance LDL degradation (10, 11), although mixed results from 3 dietary intervention studies have yet to verify the biological mechanism (11–13). In addition, lycopene may also be associated with the acute phase response in atherosclerosis (14) and is associated with C-reactive protein concentrations in 2 cross-sectional studies (15, 16).

We recently reported a significant association between plasma lycopene and a reduced risk of CVD in a nested case-control study of middle-aged and older women (17). In that study, there was a threshold affect above which plasma lycopene appeared to reduce the risk of CVD. Therefore, we sought to replicate these findings in a nested case-control study of older men from the Physicians' Health Study (PHS). With no widely accepted biological mechanism to explain how lycopene may reduce the risk of CVD, we explored a priori the role of confounding of other carotenoids, lipids, and inflammatory markers with lycopene to explain any effect that may be observed for plasma lycopene (4, 18, 19).


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study population
The Physicians' Health Study (PHS) began as a trial in 1982 of 22 071 men testing aspirin and ß-carotene in the primary prevention of cancer and CVD (20, 21). On its scheduled completion in 1995, the PHS II was initiated as a randomized, double-blind, placebo-controlled, 2 x 2 x 2 x 2 factorial trial testing the benefits and risks of vitamin E, vitamin C, a multivitamin, and ß-carotene in the primary prevention of cancer, CVD, and other chronic diseases in 14 641 male physicians aged ≥50 y (22), including 7641 original physicians from the PHS plus 7000 new physicians recruited into the trial. The ß-carotene component of the trial was terminated in 2003, in part because of the continued lack of effect of ß-carotene on cancer (21, 23) and CVD (21) and because there was no evidence of long-term side effects from >20 y of use. In total, there were 29 071 men randomly assigned into the PHS at either starting point in 1982 or 1995.

Fasting baseline blood samples were collected from PHS participants starting in 1996 and stored in liquid nitrogen until analyzed. For the present analyses, we conducted a prospective nested case-control study identifying 499 cases of CVD and an equal number of controls, all of whom were free of CVD at baseline and provided baseline blood samples starting in 1996 that could be assayed for lycopene. Cases included men who experienced a cardiovascular event after their baseline blood collection, defined as CVD death, nonfatal myocardial infarction (MI), nonfatal stroke, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft. Study physicians conducted blinded reviews of all cases. CVD death was documented by convincing evidence of a cardiovascular mechanism from death certificates and medical records. The diagnosis of MI was confirmed by using World Health Organization criteria (24). A stroke was defined as a typical neurologic deficit, sudden or rapid in onset, lasting >24 h. Revascularization procedures were confirmed by hospital records. During a mean follow-up of 2.1 y, we identified 499 cases of CVD.

Each case of CVD was matched with a control according to age (±1 y), smoking status (never, former, or current smoker), follow-up time from baseline blood collection (±6 mo), and cohort designation (original or new physician in the PHS).

Blood assays
All investigators and laboratory personnel were blinded to the subject's case-control status. Blood samples were handled identically and blindly through all stages of the blood collection, storage, retrieval, and analysis processes. Baseline plasma blood samples from cases and controls were thawed and assayed for total lycopene, other carotenoids, and retinol at Our Lady of Mercy Medical Center, Bronx, NY. All assays were quantified by reversed-phase HPLC after extraction and concentration by conventional methods (25). Internal standards (echinenone for carotenoids and retinyl proprionate for retinol) were used to correct for recoveries of all samples that were analyzed, and the laboratory has participated in the US Quality Assurance Program. We also assayed plasma lipids, including total cholesterol and HDL cholesterol, using commercially available diagnostic kits (Sigma-Aldrich Chemical Co, St Louis, MO) and conventional methods (26, 27). Plasma total cholesterol was assayed because plasma lipoproteins are nonspecific carriers for all the carotenoids in plasma and, to date, total cholesterol appears to be the best way to control for confounding effects due to differences in lipoprotein concentrations between subjects (28). Finally, C-reactive protein was assayed by using a validated, high-sensitivity assay (Denka Seiken Company, Tokyo). On the basis of externally prepared control specimens, the laboratory accuracy is within 7% for each measured carotenoid, whereas the day-to-day and within-day precision (CV) for these assays was 5%.

Baseline covariates
The date of blood collection served as the start of follow-up for this study. Some, but not all, questionnaire information on other self-reported baseline risk factors for CVD was collected with the blood sample. We used the questionnaires that were completed closest to the time of blood collection, always within a few years, to ensure a complete assessment of confounding for our analyses. On these questionnaires, men provided self-reported data on age (in y), weight and height (converted to body mass index; in kg/m2), smoking status (categorized as never, former, or current), alcohol use (categorized as rarely or never, <1 drink/d, or ≥1 drink/d), frequency of exercise (categorized as rarely or never, <3 d/wk, 3–4 d/wk, or ≥5 d/wk), parental history of MI at <60 y of age (yes or no), history of hypertension (yes or no), history of diabetes (yes or no), and history of hypercholesterolemia (yes or no).

Data analyses
Men were first compared according to case-control status by using mean values or proportions of baseline coronary disease risk factors and biochemical markers. Measurements of plasma lycopene concentrations were divided into quartiles based on the overall distribution of plasma lycopene among the 499 controls. Coronary disease risk factors were also compared according to quartiles of plasma lycopene among the control population to assess potential confounding, with the use of ANOVA for continuous variables, Cochran-Armitage trend tests for dichotomous variables, or chi-square tests for categorical variables. Conditional logistic regression analyses generated the RRs and 95% CIs of future CVD for increasing quartiles of plasma lycopene concentrations, with the lowest quartile as the referent. Linear trends across quartiles of plasma lycopene concentrations were tested by using the median concentration for each quartile as an ordinal variable. Power calculations indicated that we had 54% and 98% power to detect a significant linear trend across quartiles, assuming corresponding RRs of 0.70 and 0.50 comparing the highest with the lowest quartile.

Models were first adjusted for randomized treatment assignments and plasma total cholesterol concentration; the next model added body mass index, exercise, alcohol consumption, parental history of MI at <60 y of age, hypertension, diabetes, and hypercholesterolemia. Additional models examined whether other biomarkers—including other carotenoids, HDL cholesterol, or C-reactive protein—added individually to a multivariate model confounded the association between plasma lycopene and CVD, possibly providing mechanistic evidence for any effect attributed to plasma lycopene.

To address a possible threshold effect above which plasma lycopene may be associated with the risk of CVD, as noted in a previous study of women (17), we also considered the association between men with plasma lycopene at or above the 90th percentile and the risk of CVD compared with those in the lowest quartile. Consistent with the previously reported findings for a stronger effect of plasma lycopene and important vascular events (limited to CVD death, MI, and stroke) (17), we repeated the analyses limited to 241 case-control pairs of important vascular events. We compared our results for plasma lycopene with those for other carotenoids and retinol, with each biochemical marker divided into quartiles among the controls and entered into a separate model.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
We first compared baseline characteristics for 499 cases of CVD and an equal number of matched controls who remained free of CVD (Table 1Go). As expected, cases of CVD tended to have a higher body mass index than did controls and were significantly more likely to have a history of hypertension, diabetes, hypercholesterolemia, and early parental history of MI. There were no significant differences in the frequencies of exercise and alcohol consumption between cases and controls (P > 0.05 for all). When matched for age and smoking status, no significant differences were observed between the concentrations of plasma carotenoids in cases and controls, including comparisons when individual concentrations of plasma lutein, zeaxanthin, and the combination of lutein and zeaxanthin were examined. CVD cases had significantly higher total cholesterol concentrations and lower HDL cholesterol concentrations than did controls (P < 0.05 for both). C-reactive protein concentrations were not significantly different (P = 0.66), whether compared as mean (P = 0.66) or log-transformed (P = 0.38) concentrations (data not shown).


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  		TABLE 1. Baseline characteristics of 499 men who subsequently experienced cardiovascular events (cases) and an equal number of men who remained free of cardiovascular disease (controls)

 
Among the 499 controls, plasma lycopene was significantly (P < 0.05 for all) correlated with plasma concentrations of ß-cryptoxanthin (Spearman r = 0.16), lutein/zeaxanthin (r = 0.27), {alpha}-carotene (r = 0.24), and ß-carotene (r = 0.22). There was no significant difference in the Spearman correlation coefficients when plasma lycopene was compared with either lutein alone or zeaxanthin alone (r = 0.27 for both). Plasma lycopene was less strongly correlated with plasma retinol, with a Spearman correlation of 0.11 (P = 0.018). Total cholesterol, a nonspecific carrier of lycopene and other carotenoids, was most strongly and significantly correlated with plasma lycopene (Spearman r = 0.26) compared with values of 0.17 for lutein/zeaxanthin, 0.11 for ß-cryptoxanthin, 0.09 for retinol, and 0.06 for both {alpha}-and ß-carotene. When we calculated total cholesterol–adjusted Spearman correlations between plasma lycopene and other carotenoids, the correlations were only modestly reduced in magnitude and remained significant. Finally, plasma lycopene was negatively correlated with plasma C-reactive protein concentrations (Spearman r = –0.11, P = 0.016).

The plasma lycopene quartile cutoffs were defined as ≤6.4, 6.4–9.3, 9.3–12.7, and >12.7 µg/dL based on the distribution of values in the 499 men who were free of CVD. A comparison of baseline characteristics across these quartiles of plasma lycopene in the 499 controls is shown in Table 2Go. Aside from significant inverse associations between plasma lycopene and both age and history of hypertension, other lifestyle and clinical risk factors did not differ appreciably across quartiles of plasma lycopene. Plasma carotenoids increased significantly (P < 0.05 for all) with increasing plasma lycopene, with the exception of plasma ß-carotene. Total cholesterol concentrations increased, and HDL-cholesterol concentrations decreased with higher concentrations of plasma lycopene (P < 0.001 for both). C-reactive protein decreased with increasing quartiles of plasma lycopene but was not statistically significant as either an untransformed (P = 0.31) or log-transformed (P = 0.17) variable.


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  		TABLE 2. Comparison of baseline characteristics of 499 controls according to quartile of plasma lycopene

 
A series of models calculating the relative risks (RRs) and 95% CIs of either total CVD or important vascular events, based on quartiles of plasma lycopene, are provided in Table 3Go. Neither the crude nor the multivariate models that were further adjusted for lifestyle and clinical factors showed a significant association between plasma lycopene and the risk of total CVD (P for linear trend > 0.05 for both). There was minimal attenuation of the RRs with control for potential confounders. Men with baseline plasma lycopene concentrations at or above the 90th percentile (≥15.9 µg/dL) also had no association with the risk of CVD, as the multivariate RR was 1.25 (95% CI: 0.70, 2.23). When we considered analyses restricted to the 241 case-control pairs of men with important vascular events (MI, stroke, and CVD death), the multivariate RRs for increasing quartiles of plasma lycopene were 1.00 (reference), 1.02 (0.51–2.04), 0.93 (0.47–1.85), and 0.80 (0.39–1.64) (P for linear trend = 0.50). As before, this lack of an association extended to men at or above the 90th percentile of plasma lycopene. For secondary analyses of increasing quartiles of plasma lycopene with the risk of MI (117 case-control pairs), the multivariate RRs were 1.00 (reference), 0.91, 0.84, and 0.68 (P for linear trend = 0.49) with wide 95% CIs. For stroke (71 case-control pairs), the RRs were 1.00 (reference), 2.66, 0.67, and 1.36 (P for linear trend = 0.91), again with extremely wide 95% CIs that limited our ability to dismiss chance.


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  		TABLE 3. Relative risks (RRs) and CIs of total cardiovascular disease (499 case-control pairs) and important vascular events (241 case-control pairs; limited to myocardial infarction, stroke, and cardiovascular disease death) according to quartile of plasma lycopene

 
We also explored whether the additional adjustment for plasma carotenoids, retinol, HDL cholesterol, or C-reactive protein attenuated the association between plasma lycopene and the risk of CVD. In general, there was little indication that any of the aforementioned plasma markers had an effect on any of the reported RRs of CVD (P for linear trend remained > 0.05 for all). Separate, additional control for either plasma lutein or plasma zeaxanthin did not affect the RRs of CVD for plasma lycopene either. Replication of these models for important vascular events resulted in a parallel lack of confounding on the RRs.

For comparison, we then examined the multivariate RRs for plasma lycopene versus other carotenoids and retinol for the risk of CVD based on quartiles of plasma carotenoids in the 499 controls in Table 4Go. Confounding was minimal when crude and multivariate models for each plasma marker were compared (data not shown). Of note, men in higher quartiles of plasma lutein/zeaxanthin had nonsignificant but persistent elevations in the risk of CVD compared with those in the lowest quartile. Separately, the multivariate RRs of CVD for the second through fourth quartiles of plasma lutein were 1.19 (0.76, 1.87), 1.21 (0.75, 1.94), and 1.30 (0.79, 2.14) (P for linear trend = 0.37); for plasma zeaxanthin, the RRs were 1.28 (0.82, 2.00), 1.23 (0.77, 1.97), and 1.40 (0.85, 2.29) (P for linear trend = 0.28). Finally, elevations in plasma retinol were also associated with a borderline significant increased risk of CVD (P for linear trend = 0.06).


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  		TABLE 4. Multivariate relative risks (RRs) and 95% CIs of cardiovascular disease (499 case-control pairs) for a comparison of quartile of plasma lycopene with other plasma carotenoids and retinol in separate models

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We found no overall association between increasing concentrations of plasma lycopene and the risk of CVD in this nested case-control study of older male physicians. This observed lack of association persisted when we also considered concentrations of plasma lycopene of at least the 90th percentile, and when the analyses were limited to only the most important vascular events (MI, stroke, and CVD death). There was no evidence of substantial confounding by major lifestyle and clinical risk factors of CVD. Because we found no overall association between plasma lycopene and CVD, however, our examination of confounding by other carotenoids, lipids, and inflammatory markers could not be reliably addressed.

These results were inconsistent with other findings for plasma lycopene and other carotenoids and the risk of CVD, using different PHS data. Two separate nested case-control studies of MI and ischemic stroke used the earlier 1982 baseline blood samples from the PHS. For plasma lycopene and MI, RRs for increasing quintiles of plasma lycopene were 1.00 (reference), 1.35, 1.41, 1.54, and 1.43 (P for linear trend = 0.13) (29). In contrast, other data based on the earlier 1982 baseline blood samples for a nested case-control study of carotenoids and ischemic stroke showed a potential inverse association for lycopene (30). Specifically, the RRs (95% CIs) of stroke for increasing quintiles of lycopene were 1.00 (reference), 0.66 (0.36, 1.23), 0.54 (0.29, 1.00), 0.55 (0.29, 1.05), and 0.72 (0.38, 1.37). A comparison of the upper 4 with the lowest quintiles showed a 39% risk reduction compared with a nonsignificant increased risk of total stroke in this analysis. Three explanations may account for these differences. First, the PHS subjects were {approx}10 y older in this study. Increasing age was inversely and strongly associated with plasma lycopene concentrations in this and other studies (31, 32). Furthermore, the relevant determinants of plasma lycopene may vary by age (31, 33, 34). Median plasma lycopene concentrations among the PHS controls were considerably lower in these analyses (9.3 µg/dL) in older men compared with the earlier PHS analyses (36.6 or 39.9 µg/dL). Second, the noted differences among studies may have been because 2 different laboratories using different methods conducted the carotenoid assays. Third, although matching schemes were similar across all 3 nested case-control studies, the random nature of selecting cases and controls may also have accounted for the inconsistent findings for plasma lycopene.

In addition, the data from the present study in men counter the strong inverse association found when we examined plasma lycopene for the risk of CVD in a nested case-control study among middle-aged and older female health professionals from the Women's Health Study (WHS) (17). Although chance cannot be ruled out as an explanation for the present findings, there were other differences between the PHS and WHS study populations that may explain these discrepant findings. First, the PHS had more limited follow-up time (: 2.1 y) compared with the WHS (: 4.9 y). As a result, the present study may have identified more men with preexisting atherosclerosis that would imminently become manifested as CVD. However, our thorough control for potential confounders should help to minimize such confounding. A second possible explanation for the differences in results from this study compared with the WHS is that the median concentration of plasma lycopene among men in the PHS (9.3 µg/dL) was lower than that among women in the WHS (16.5 µg/dL). This difference may perhaps reflect not only established sex differences in plasma lycopene and carotenoid concentrations but also the fact that these men were on average older (PHS: 69.7 y; WHS: 58.8 y). The broad range of plasma lycopene concentrations observed in the PHS is at the low end of the range of other reported plasma lycopene concentrations (4, 5, 15, 32, 34–40).

As for other studies that have examined plasma lycopene and the risk of CVD, higher adipose tissue concentrations of lycopene are associated with reduced intimal wall thickness (2, 3), although in a Finnish cohort this was found in men but not in women (39). Several other studies report possible inverse associations of serum lycopene concentrations and the risk of MI (4, 40), CVD (6, 7, 40), carotid atherosclerosis (5, 8), and aortic atherosclerosis (41).

Lycopene has garnered promise for a role in the primary prevention of CVD because it is one of the most potent singlet oxygen quenchers, which suggests that it may have comparatively stronger antioxidant properties than its related carotenoids (42). An apparent role in reducing LDL oxidation (10–12) has not necessarily been substantiated with reductions in LDL cholesterol (11), although more studies are needed in this area. The observation that C-reactive protein concentrations were lower among male controls in higher lycopene quartiles is consistent with the findings from other studies (15, 16) for a potential role in mitigating atherogenesis (14).

Among study limitations, we relied on a single baseline measurement of plasma lycopene, raising the possibility of regression to the mean, biasing our RRs toward the null hypothesis and thus underestimating the observed risk reductions. The long-term stability of plasma lycopene has not been tested in our blood samples; however, other studies support the stability of lycopene and other biochemical markers used in the present study (43, 44). We also relied on a composite endpoint for total CVD including CVD death, MI, stroke, and revascularization. Heterogeneity in the results by specific CVD endpoints cannot be ruled out because we had limited power to assess any single outcome. Finally, residual confounding by diet and other risk factors may still be present. However, besides matching for age, smoking, and follow-up time, we believe that we have comprehensively controlled for other coronary risk factors. In addition, in our previous study among women, dietary factors did not strongly attenuate the observed RRs (17).

In conclusion, higher plasma lycopene concentrations were not associated with a reduced risk of CVD in middle-aged and older men. It is critical for additional research not only to carefully examine the association between both plasma and dietary lycopene with the risk of CVD but also to conduct clinical studies that directly test the proposed mechanisms through which lycopene may play a role in the prevention of CVD.


   ACKNOWLEDGMENTS
 
We acknowledge the crucial contributions of the entire staff of the PHS and are indebted to the 29 071 dedicated and committed participants who were randomly assigned into the PHS starting in either 1982 or 1995.

HDS conceived and designed the study, analyzed and interpreted the data, drafted the article, and obtained funding. JEB critically revised the article, collected and assembled the data, and obtained funding. EPN critically revised the article and collected and assembled the data. JMG conceived and designed the study, analyzed and interpreted the data, critically revised the article, and obtained funding. The authors had no personal or financial interest in any company or organization sponsoring the research.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication September 13, 2004. Accepted for publication December 15, 2004.





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