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Nutritional Epidemiology

Dietary Lycopene, Tomato-Based Food Products and Cardiovascular Disease in Women

Howard D. Sesso^*,,**,3, Simin Liu^*,, J. Michael Gaziano^*,** and Julie E. Buring^*,,

^* Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA; Department of Epidemiology, Harvard School of Public Health, Boston, MA; ^** Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA; Department of Nutrition, Harvard School of Public Health, Boston, MA; and Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, MA

³To whom correspondence should be addressed. E-mail: hsesso{at}hsph.harvard.edu.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
In addition to the inverse association of dietary lycopene with various cancers, studies suggest a role for lycopene in cardiovascular disease (CVD) prevention. We determined whether the intake of lycopene or tomato-based foods is associated with the risk of CVD in a prospective cohort of 39,876 middle-aged and older women initially free of CVD and cancer. Participants completed a food-frequency questionnaire and provided self-reports of coronary risk factors. Dietary lycopene levels were divided into quintiles, and primary lycopene food sources (total tomato-based products, including tomatoes, tomato juice, tomato sauce and pizza) were categorized. During 7.2 y of follow-up, 719 CVD cases (including myocardial infarction, stroke, revascularization and CVD death) occurred. Compared with women in the 1st quintile of lycopene, those in increasing quintiles had multivariate relative risks (RR) of CVD of 1.11, 1.14, 1.15 and 0.90 (P for trend = 0.34). For the consumption of tomato-based products, women consuming 1.5 to <4, 4 to <7, 7 to <10 and ≥10 servings/wk had RR (95% CI) of CVD of 1.02 (0.82–1.26), 1.04 (0.82–1.31), 0.68 (0.49–0.96) and 0.71 (0.42–1.17) (P for trend = 0.029) compared with women consuming <1.5 servings/wk. Among lycopene food sources, those in the highest levels of tomato sauce (≥2 servings/wk) and pizza intake (≥2 servings/wk), with multivariate RR of 0.76 (0.55–1.05) and 0.66 (0.37–1.18), respectively, had potential reductions in CVD risk. Dietary lycopene was not strongly associated with the risk of CVD. However, the possible inverse associations noted for higher levels of tomato-based products, particularly tomato sauce and pizza, with CVD suggest that dietary lycopene or other phytochemicals consumed as oil-based tomato products confer cardiovascular benefits.

KEY WORDS: • lycopene • cardiovascular disease • prevention • prospective studies • women

In the United States, >80% of the intake of dietary lycopene, a carotenoid without provitamin A activity, comes from the consumption of tomato products, including tomatoes, tomato juice and tomato sauces (1). Numerous studies have demonstrated an inverse association between dietary lycopene and prostate cancer risk (2). Lycopene cooked and consumed in oil media such as tomato paste, tomato sauce, or pizza appear to be optimal for the efficient absorption of lycopene (3). Only recently has lycopene been suggested to play a role in preventing cardiovascular disease (CVD) (4), perhaps through a mechanism involving LDL cholesterol (5–9). Data limited to adipose or plasma lycopene in smaller studies suggest an inverse association of lycopene with intima-media thickness, atherosclerosis and CVD (10–18). We therefore examined whether dietary lycopene or tomato-based foods were associated with CVD in a large cohort of women.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Study population.

The Women’s Health Study (WHS) is an ongoing clinical trial of low-dose aspirin and vitamin E in the primary prevention of CVD and cancer (19). The ß-carotene component of the WHS was terminated in 1996 on the basis of results from other trials (20). Questionnaires were mailed to >1.7 million women, of whom 65,169 completed questionnaires and were willing and eligible for the trial. After the successful completion of a run-in phase, 39,876 female U.S. health professionals, who were aged ≥ 45 y in 1992, postmenopausal or not intending to become pregnant, and free from prior CVD and cancer (except nonmelanoma skin cancer) were randomized.

At baseline, a 131-item validated semiquantitative food-frequency questionnaire (SFFQ) was completed by 39,310 women, of whom 829 were excluded due to insufficient completion of the SFFQ, or energy intake of either <2510 or ≥14,644 kJ/d (<600 or ≥3500 kcal/d). After additionally excluding prerandomization angina or revascularization, a study population of 38,445 women remained for analysis; the protocol was approved by the hospital Institutional Review Board.

Lycopene and other covariates.

The measurement of lycopene (in mg/d) was based upon food tables maintained by the Harvard School of Public Health, Boston, MA. The validity of lycopene intake measured from the SFFQ was examined in the WHS vs. plasma lycopene levels in a subset of 483 women. The age-adjusted Spearman correlation coefficient was 0.14 for dietary lycopene with plasma lycopene (P = 0.004), and among lycopene food sources only tomato sauce (r = 0.16, P = 0.001) was significant. Other studies indicate high correlations between the SFFQ and dietary records for lycopene food sources (21), suggesting a valid measurement of SFFQ vs. dietary record lycopene (22).

Four major lycopene food sources were also considered, including tomatoes, tomato juice, tomato sauce and pizza, without reference to a quantifiable amount of food, but rather a common unit or portion size for each food. Participants selected from nine responses ranging from "Never or less than once per month" to "6+ per day."

At baseline, women also provided self-reported age (years), weight and height (BMI, in kg/m²), smoking status (never, former, current), alcohol use (rarely/never, 1–3 drinks/mo, 1–6 drinks/wk, ≥1 drink/d), exercise (rarely/never, <1, 1–3, ≥4 times/wk), parental history of myocardial infarction (MI) at <60 y (no, yes), hypertension (no, yes), diabetes (no, yes), and postmenopausal hormone use (never, former or current). Hypercholesterolemia (no, yes) was defined as any history of treatment for high cholesterol, physician diagnosis or self-reported cholesterol levels of ≥240 mg/dL. In addition to fruit and vegetable intake (apart from tomato-based food products; in servings/d), other dietary nutrients were energy-adjusted using the residual method (23) and included the intake of total fiber (g/d), folate (µg/d), nonsupplemental vitamin E (mg/d) and saturated fat (g/d).

Outcome ascertainment.

Follow-up consisted of annual follow-up questionnaires updating health outcomes and risk factors. For each reported CVD endpoint, a consent form was obtained from the participant to request relevant medical records from the hospital or attending physician; nearly all requests were returned. Total CVD included MI, revascularization, stroke and cardiovascular death. Important vascular events, a prespecified endpoint of the WHS, included MI, stroke and cardiovascular death. MI was confirmed using WHO criteria (24). Revascularization procedures were confirmed by hospital records. A stroke was defined as a typical neurological deficit, sudden or rapid in onset, lasting >24 h. CVD death was documented by convincing evidence of a cardiovascular mechanism from death certificates and medical records. All analyses are based on the first confirmed CVD event. After a median follow-up of 7.2 y, morbidity and mortality follow-up was 98.9% and 99.9% complete.

Data analyses.

Lycopene intake was divided into quintiles on the basis of the overall distribution of intake. Participants were first compared according to quintiles of lycopene intake, using mean values or proportions of baseline coronary risk factors. Cox proportional hazards modeled the relative risk (RR) and 95% CI of CVD, important vascular events, MI and stroke with the lowest quintile as the referent. The ≥95th percentile vs. the lowest quintile was also compared. Models were first adjusted for age, total energy intake and randomized treatment assignments, followed by lifestyle and clinical factors, and the final model added dietary factors. Linear trend tests across quintiles of lycopene were tested using the median level for each quintile as an ordinal variable.

Major food sources of lycopene were a priori categorized: tomatoes (one serving comparable to one standard portion size, 1 tomato), none, 1–3 servings/mo, 1–4 servings/wk, ≥5 servings/wk; tomato juice (small glass), none, 1–3 servings/mo, 1 serving/wk, and ≥2 servings/wk; tomato sauce (1/2 cup or 118 mL), none, 1–3 servings/mo, 1 serving/wk, and ≥2 servings/wk; and pizza (2 slices), none, 1–3 servings/mo, 1 serving/wk, and ≥2 servings/wk. We summed the total number of tomato-based products as done by Giovannucci et al. (25) as <1.5, 1.5 to <4, 4 to <7, 7 to <10, and ≥10 servings/wk. These analyses included total energy intake (in kJ/d) in each model. The proportional hazards assumption was verified using a Wald test for the interaction of time with each lycopene indicator variable.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The overall mean energy-adjusted lycopene intake was 9197 ± 6442 µg/d in a population of women aged 53.9 ± 7.0 y. The major contributors to dietary lycopene intake in this population were tomato sauce (40.5%), tomatoes (39.8%), tomato juice (12.3%), pizza (4.7%) and grapefruit (2.7%). The strongest Spearman correlation coefficients for dietary lycopene were with tomatoes (r = 0.67; P < 0.001), tomato sauce (r = 0.56; P < 0.001) and tomato juice (r = 0.35; P < 0.001). Pizza was weakly correlated (r = 0.05; P < 0.001) with dietary lycopene. Dietary lycopene was also significantly correlated (all P < 0.001) with other carotenoids and xanthophylls, including -carotene (Spearman r = 0.18), ß-carotene (r = 0.30), ß-cryptoxanthin (r = 0.13) and lutein + zeaxanthin (r = 0.30).

The baseline characteristics of women were first compared according to quintiles of lycopene intake (Table 1). Women consuming greater amounts of lycopene were slightly younger. In addition, those in higher quintiles of lycopene intake were more likely to exercise more, less likely to be a current smoker and more likely to be a current postmenopausal hormone user. Higher lycopene intake was also associated with a healthier dietary pattern.

On average, women consumed 4.32 ± 3.23 servings of tomato-based products per week, of which 2.20 were from tomatoes, 1.14 from tomato sauce, 0.57 from pizza and 0.46 from tomato juice. Women consuming greater amounts of tomato-based products per week had a lower multivariate risk of total CVD (P for linear trend = 0.029), important vascular events (P for linear trend = 0.008), and MI (P for linear trend = 0.033) (Table 3). Women consuming ≥7 servings/wk of tomato-based products reduced their CVD risk by 30% vs. those consuming <1.5 servings/wk. This risk reduction increased substantially for important vascular events, MI and stroke, particularly among women consuming ≥10 servings/wk.

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
In this large prospective study, we found little evidence for an overall association between dietary lycopene intake with the risk of CVD in women. The nonsignificant CVD risk reductions, except for stroke, noted for women with intake at or above the 95th percentile applied only to women consuming large amounts of lycopene at the high end of its distribution. The lack of significance for dietary lycopene may be due to measurement error in assessing lycopene intake from our questionnaire, which did not correlate strongly with plasma lycopene levels. Despite the largely null findings for dietary lycopene, consuming at least 7 servings/wk of tomato-based products was associated with an 30% reduction in the risk of CVD. This finding, in conjunction with the possible inverse associations for higher levels of tomato sauce and pizza intake, parallels the findings observed for more bioavailable lycopene and prostate cancer (2). Therefore, this study lends support to the notion that either dietary lycopene in bioavailable forms such as tomato sauce or simply tomato-based food products may have a role in CVD prevention.

Previous studies have focused on serum (11,12,17), plasma (13,15,16,18) and adipose tissue (10) levels of lycopene and their associations with atherosclerosis or specific CVD subtypes. Ascherio et al. (26) reported no association between dietary lycopene and stroke in a large cohort of male health professionals. Although most of these studies support an inverse association, given the tremendous interest in other carotenoids often measured in tandem with lycopene, conclusions must be tempered by possible publication bias.

There is an apparent disconnect when comparing blood vs. adipose vs. dietary lycopene, making it difficult to provide mechanistic explanation for previous findings. Data suggest that plasma and adipose carotenoids are not sufficiently correlated to be used interchangeably (27). In our study, there was a low Spearman correlation between either dietary lycopene (r = 0.14) or tomato sauce (r = 0.16) with plasma lycopene levels, raising questions concerning the biologic mechanism by which dietary lycopene may directly or indirectly be related to CVD (4). Other studies have reported higher correlations between dietary and plasma lycopene of 0.30 (2,28). The weaker correlations between dietary and plasma lycopene may instead reflect differences in more recent, short-term dietary patterns.

The lack of an association between lycopene and CVD in the present study appears to be contradicted by an inverse association found for higher levels of tomato-based products. First, tomato products may lower the risk of CVD through unidentified nutrients other than lycopene. Second, the consumption of tomato products, predominantly as tomatoes and tomato sauce, may be a surrogate for a Mediterranean dietary pattern suggested to have greater cardiovascular benefits (29). The consumption of tomato-based food sources along with fruit, fresh vegetables and olive oil are common in a Mediterranean dietary pattern and provide a variety of nutrients with potential cardiovascular benefits. Third, there may be both risks and benefits from lycopene food sources resulting in no overall effect with CVD. Pizza may combine both detrimental and beneficial foods, yet it contributed a nominal proportion of lycopene intake, indicating a need for caution in suggesting its consumption for its lycopene content.

Lycopene has strong antioxidant properties relative to other carotenoids (30) and may play a role in the regulation of cholesterol metabolism (6). Lycopene, as with some other carotenoids, has also been inversely associated with C-reactive protein (31). Short-term supplementation studies have provided dietary lycopene in various forms to investigate its effects on LPL cholesterol, with mixed results (5–9). More short-term intervention studies are warranted to explore specific mechanisms through which dietary lycopene or readily absorbable lycopene food sources may increase plasma lycopene or induce changes in other relevant biochemical markers affecting subsequent CVD risk. Yet, recent null results from major clinical trials investigating various vitamins and antioxidants (32,33) reinforce the importance of building a solid foundation of research on dietary lycopene and tomato-based food products.

Several important methodological considerations must be considered. There is considerable variation in lycopene intake and its food sources across studies, largely due to cultural and temporal patterns in dietary habits. We lacked information on prescribed diets that subjects may have followed; however, lycopene and tomato-based food products would not be expected to be primary target of dietary interventions in women. Inherent misclassification in the single baseline measurement of dietary factors may also have biased our results toward the null, whereas multiple dietary assessments have revealed a stronger magnitude of effect (2). Misclassification of tomato intake may have also arisen from participants attempting to convert their intake of tomato slices or wedges into the standard portion size of one tomato. Another limitation of epidemiologic studies is that higher lycopene intake may be only a surrogate for other uncontrolled or unidentified lifestyle factors or dietary constituents that are associated with CVD. However, additional control for such measured factors had a nominal effect on the RR. In our analyses of dietary lycopene, the multicolinearity of lycopene with other carotenoids, xanthophylls, and other nutrients and foods may provide alternative explanations to our findings, yet we observed little confounding by diet in this study. Next, these results apply to healthy, middle-aged and older women free of major morbidity and willing to participate in the WHS. More studies should examine dietary lycopene and tomato-based food products in other study populations to ensure consistency. Finally, only 71 of the women died from cardiovascular causes, a small sample for examining the association between lycopene intake and CVD death.

Although we found no association between total dietary lycopene intake and the risk of CVD in women, there was evidence that overall tomato-based product intake may be associated with a reduced risk of CVD. Whether these findings parallel the more thorough epidemiologic evidence for lycopene in prostate cancer prevention, however, remains to be seen.

	ACKNOWLEDGMENTS

 
The authors acknowledge the crucial contributions of the entire WHS staff, under the leadership of David Gordon, as well as Susan Burt, Mary Breen, Marilyn Chown, Lisa Fields-Johnson, Georgina Friedenberg, Inge Judge, Jean MacFadyen, Geneva McNair, David Potter, Claire Ridge and Harriet Samuelson. We are also indebted to the 39,876 dedicated and committed participants of the WHS.

	FOOTNOTES

 
¹ Presented in abstract form at the Society of Epidemiologic Research conference [Sesso, H. D., Liu, S., Buring, J. E. & Gaziano, J. M. (2002) Dietary lycopene and the risk of cardiovascular disease in women. Am. J. Epidemiol. 155: S56 (abs.)].

² Supported by research grants AG-15933, CA-47988, HL-43851, HL-65727, and NS-34108 from the National Institutes of Health, Bethesda, MD and a grant from Roche Vitamins, Inc.

⁴ Abbreviations: CVD, cardiovascular disease; MI, myocardial infarction; RR, relative risk; SFFQ, semiquantitative food-frequency questionnaire; WHS, Women’s Health Study.

Manuscript received 13 January 2003. Initial review completed 17 February 2003. Revision accepted 28 March 2003.

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