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Fruits, vegetables and coronary heart disease

Luc Dauchet, Philippe Amouyel and Jean Dallongeville
Abstract | Diet plays an important part in the maintenance of optimal cardiovascular health. This Review summarizes the evidence for a relationship between fruit and vegetable consumption and the occurrence of coronary heart disease. This evidence is based on observational cohort studies, nutrition prevention trials with fruit and vegetables, and investigations of the effects of fruit and vegetables on cardiovascular risk factors. Most of the evidence supporting a cardioprotective effect comes from observational epidemiological studies; these studies have reported either weak or nonsignificant associations. Controlled nutritional prevention trials are scarce and the existing data do not show any clear protective effects of fruit and vegetables on coronary heart disease. Under rigorously controlled experimental conditions, fruit and vegetable consumption is associated with a decrease in blood pressure, which is an important cardiovascular risk factor. However, the effects of fruit and vegetable consumption on plasma lipid levels, diabetes, and body weight have not yet been thoroughly explored. Finally, the hypothesis that nutrients in fruit and vegetables have a protective role in reducing the formation of atherosclerotic plaques and preventing complications of atherosclerosis has not been tested in prevention trials. Evidence that fruit and vegetable consumption reduces the risk of cardiovascular disease remains scarce thus far.
Dauchet, L. et al. Nat. Rev. Cardiol. 6, 599608 (2009); published online 4 August 2009; doi:10.1038/nrcardio.2009.131

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Introduction

Learning objectives
Upon completion of this activity, participants should be able to: 1 Identify the results and limitations of observational epidemiologic studies of fruit and vegetable consumption and cardiovascular disease. 2 Describe results of prospective trials in regard to fruit and vegetable consumption in the prevention of cardiovascular disease. 3 Specify cardiovascular risk factors most improved with higher intakes of fruit and vegetables. 4 Summarize the results of research on fruit and vegetable nutrients in the prevention of cardiovascular disease.

Interest in the role of diet in maintaining optimal health stems from observations that rates of diseases differ between cultures; dietary variation seems an obvious factor that contributes to such differences. By the end of the 1980s, findings from laboratory, clinical and epidemiological studies indicated that consumption of fruit and vegetables prevents several major diseases, such as cancer and heart disease,18 prompting health authorities to promote consumption of these foods.9,10 This Review summarizes the evidence for a relationship between consumption of fruit and vegetables and the occurrence of coronary heart disease (CHD), through an analysis of observational cohort studies, nutritional prevention trials, and investigations of the effects of fruit and vegetable consumption on cardiovascular risk factors. We focused our analysis on studies that used fruit and vegetables as a nutritional exposure variable, as public health recommendations are usually expressed in terms of fruit and vegetable intake.

Observational epidemiological studies

Competing interests The authors, the Journal Editor B. Mearns and the CME questions author C. P. Vega declare no competing interests.

The proposed relationship between fruit and vegetable consumption and prevention of CHD is based in large part on observational epidemiological studies,28,1113 which can have an ecological, casecontrol, or prospective cohort design. Ecological studies are designed to explore relationships between environmental factors and diseases in human populations. They do not provide precise information about individuals in a population and are subject to many uncontrolled biases. By contrast, in casecontrol studies, individuals diagnosed with CHD

Department of Epidemiology and Public Health, INSERM 744, Institut Pasteur de Lille and University of Lille Nord de France, Lille, France (L. Dauchet, P. Amouyel, J. Dallongeville). Correspondence: J. Dallongeville, Department of Epidemiology and Public Health, INSERM 744, Institut Pasteur de Lille, 1 rue du Pr Calmette, 59019 Lille, France jean.dallongeville@ pasteur-lille.fr

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Key points
Consumption of fruit and vegetables is weakly associated with reduced risk of coronary heart disease in cohort studies Prevention trials have failed to show clear effects of fruit and vegetable consumption on the occurrence of coronary heart disease Consumption of fruit and vegetables is associated with decreases in blood pressure, but effects on other cardiovascular risk factors have not been clearly established Prevention trials have failed to confirm the hypothesis that vitamins and other individual nutrients in fruit and vegetables prevent coronary heart disease Evidence that fruit and vegetable consumption prevents cardiovascular disease remains scarce thus far

are compared with disease-free individuals. Casecontrol nutrition studies rely on retrospective assessment of an individuals diet and are, therefore, particularly subject to selection and recall bias. In prospective cohort studies, the diets of people who are assumed to be healthy are assessed and the group is followed over a period of time. During the follow-up period, some individuals will develop CHD. Because measurements are made before any disease is diagnosed, cohort studies are not subject to recall bias. In this section, we focus on prospective studies because they offer the most useful methodological compromise for studying associations between nutritional factors and CHD. The clinical end points of these studies were fatal and nonfatal CHD, CHD-related mortality (fatal coronary events only) and cardiovascular disease (CVD) events, which include a variety of combined end points associating CHD-related fatal and nonfatal events and other vascular end points, such as stroke, heart failure, and sudden death. Table 1 shows cohort studies from North America, Northern Europe and Japan, published between 1992 and 2009.14,1550 These studies vary considerably in their inclusion criteria, recruitment methods, sample size, duration of follow-up, definition of events and adjustment factors, and presentation of results. Dietary assessment methodssuch as dietary history, 24-h recall, food-frequency questionnaires, and 3-day or 7-day food diariesalso varied between studies. The reliability and accuracy of these methods to assess long-term nutritional habits is limited and was not always properly validated. This heterogeneity complicates the estimation of the magnitude of effects, and the comparison of results between studies.

consumption by one serving a day was associated with a 4% decrease in risk of CHD (relative risk [RR] 0.96, 95% CI 0.930.99). A pooled analysis of the HPFS and the Nurses Health Study (NHS)28 showed a decrease in risk with an additional serving of either fruit (RR 0.94, 95% CI 0.900.98) or vegetables (RR 0.95, 95% CI 0.920.99). Four other studies failed to show a statistically significant inverse relationship between fruit and vegetable consumption and CHD events. 29,35,37,42 Other cohort studies failed to show a statistically significant effect of either fruit 16,29,42 or vegetable29,33,42 intake in reducing risk of ischemic coronary events, although in some of these studies, a trend towards a beneficial effect of fruit and vegetable intake was observed.

CHD-related mortality The relationship between fruit and vegetable consumption and risk of CHD-related mortality has been investigated in ten studies (Table 3). However, only the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study showed a significant inverse relationship between intake of fruits and berries and CHD-related deaths.21 The ATBC Study,21 the Baltimore Longitudinal Study of Aging (BLSA),45 and the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC)50 all reported a significant inverse relationship between vegetable intake and CHD-related deaths. CVD events Twelve studies have shown a relationship between fruit and vegetable consumption and CVD events (Table 4). A significant inverse relationship between fruit and vegetable intake and CVD events was observed in four of seven studies.35,40,44,47 Of the eleven studies24,2931,44,4750 that assessed the protective effects of fruit on CVD, five30,31,44,47,49 showed a significant correlation between fruit consumption and decreased risk of CVD events. Nine studies24,29,30,44,4750 assessed the relationship between cardiovascular protection and vegetable intake but only two24,48 reported a significant correlation. Interpretation of observational studies Epidemiological evidence for causality is controversial.51 Many studies have reported a trend towards an inverse relationship between fruit and vegetable intake and CHD, but few have produced statistically significant results. The risk reduction estimates from cohort studies are, therefore, less impressive than initially observed in ecological or casecontrol studies, both of which can be subject to methodological bias.1 Several factors could explain the limited associations between fruit and vegetable intake and CHD risk. First, these studies cover a period of more than 50 years, during which the ratio of polyunsaturated to saturated fatty acids has improved in the general population; this could affect the outcomes of prospective follow-up. Second, diet was assessed by a variety of methods, some of which did not provide

CHD events Of the eight prospective studies that have evaluated the relationship between fruit and vegetable consumption and CHD, only three recorded more than 1,000 ischemic coronary events,28,35 one recorded 5001,000 events,37 and four recorded fewer than 500 events16,29,33,42 (Table 2). The Health Professionals Follow-up Study (HPFS)28 showed a statistically significant inverse relationship between fruit and vegetable intake and fatal and nonfatal ischemic coronary events. An increase in fruit and vegetable

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Table 1 | Description of cohorts concerning fruit and/or vegetable consumption and the risk of CHD and CVD* Cohort
Adventist Health Study16 MCFSI18 Framingham HFSS25 MCFSI
22 19

Study area
USA (California) Finland USA (Framingham) UK Finland Southwest Finland USA (Massachusetts) UK USA USA UK Southwest Finland USA
30

Population characteristics
Caucasian Adventists Healthy volunteers Framingham residents Vegetarians and HC Healthy volunteers Smokers from a lung cancer prevention trial Volunteers Vegetarians and HC Healthcare professionals Nurses Residents of the UK Smokers from a lung cancer prevention trial Healthcare professionals Men born in 1913 Healthcare professionals Nurses American physicians Vegetarians and HC Population sample Healthy volunteers Population sample Population sample Residents of 4 geographical areas Healthy volunteers Healthy volunteers Healthcare professionals and nurses Children Men 80 years and older Takayama Gifu residents Diabetics Registered inhabitants of 11 public health center areas 45 communities in Japan

Number (men/women)
10,003/16,740 2,748/2,385 832/ 4,336/6,435 2,748/2,385 21,930/ 254/471 4,102/6,700 38,683/ /75,596 1,422/1,826 26,497/ /39,127 730/ 42,148/ /84,251 15,220/ 4,325/6,416 3,684/5,924 27,177/29,876 1,950/ 14,966/23,471 5,171/ 6,669 8,087/ 6,151 37,725/71,910 4,028 501/ 13,355/15,724 4,806/56,042 35,909/41,982 25,206/34,279

Age (years)
>25 3069 4565 >16 3069 5069 60101 1679 4075 3459 3575 50 69 54 (average) 54 4075 3459 40 84 >16 2574 50 64 4260 35103 45 64 5059 30 93 3475 7.5 <80 35 3570 4574 4079

Years of follow-up
6 1216 20 16.8 26 6.1 912 13.3 8 14 7 6.1 5 26 8 14 12 1824 19 3.09 12.8 16 11 5 13 13 37 18 7.33 9 5.9 13

Recruitment dates
1976 19661972 19661969 19731979 19661972 1993 19811984 19801984 1986 1980 19841985 1993 1993 1967 1986 1980 1982 19731979 19711975 19931997 19841989 19781981 19871989 1991 19741989 19841986 19371939 1958 1992 19922000 1990 and 1993 19881990

Dietary assessment
FFQ Dietary history 24-h recall FFQ FFQ FFQ 3-day food diary FFQ FFQ FFQ FFQ Dietary history FFQ FFQ FFQ FFQ FFQ FFQ FFQ Semi-quantitative FFQ 4-day food diary FFQ Semi-quantitative FFQ FFQ FFQ FFQ 7-day inventory 7-day food diary 4 FFQ FFQ and food record FFQ FFQ

ATBC21 BC24 OVS26 HPFS27 NHS

27

BHLS31 ATBC
32

WHS29 MB 1913 HPFS28 NHS28 PHS

33

Sweden (Gteborg) USA USA USA UK USA Denmark Finland (Kupio) Japan USA France and Ulster USA (Washington) USA England, Scotland USA

HFSS34 NHANES35 DDCHS KIHD40 HNLS

41 39

ARIC37 PRIME42 Odyssey43 NHS and HPFS44 Boyd Orr46 BLSA45 Takayama
48

Japan Europe Japan Japan

EPIC diabetic47 JPHC49 JACC50

*For a given cohort, only the most recent results are presented. Abbreviations: CHD, coronary heart disease; CVD, cardiovascular disease; FFQ, food frequency questionnaire; HC, health conscious individuals; IHD, ischemic heart disease; MI, myocardial infarction.

sufficient information or did not adequately assess longterm dietary habits. Thus, the lack of comparability of the assessment instruments combined with inaccurate measurements make it difficult to detect associations or weaken these associations. Third, although metaanalyses report relative risks indicative of a protective effect of fruit and vegetables,6,8 they also show substantial inter-study heterogeneity, which might be explained by

methodological issues or publication bias. Furthermore, meta-analyses of observational nutritional studies (in contrast to meta-analyses of clinical trials) have been criticized because of difficulties in defining exposure variables and because many different nutritional assessment methods are used. Given the extreme variability of nutrition assessment methods and large measurement errors in food intake, trend analyses of doseresponse

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Table 2 | Fruit and vegetable consumption and CHD events Cohort Exposure End points Events Results RR (95% CI)*
0.63 (0.381.17) 0.96 (0.930.99) 0.97 (0.931.00) 1.01 (0.841.21) 0.82 (0.571.17) 0.78 (0.561.07)

Test for trend

0.21 NA NA 0.80 0.29 0.18

Fruit & vegetables WHS29 HPFS28 NHS28 NHANES35 ARIC37 PRIME42 Q5 versus Q1 1 additional serving daily 2 additional servings daily 3 times daily versus <1 daily Q5 versus Q1 T3 versus T1 Fatal or nonfatal MI Fatal or nonfatal MI Fatal or nonfatal MI Fatal or nonfatal MI Fatal or nonfatal MI Fatal or nonfatal MI, angina 126 1,063 1,127 1,786 535 249

appropriately considered in statistical analyses, and their confounding effects in studies of fruit and vegetable consumption might not be fully appreciated. Fruit and vegetable intake might simply be a surrogate for reduced intake of undesirable nutrients, such as saturated fats. Thus, the observation of a favorable association between fruit and vegetable consumption and CHD risk does not necessarily indicate causality. A careful approach to the design and analysis of observational studies, to account for potential confounding factors and reduce or prevent measurement errors, is necessary to accurately estimate the strength of the association.52

Prevention trials

Fruit AHS16 WHS29 HPFS28 NHS28 PRIME42 >2 servings daily versus <1 daily Q5 versus Q1 1 additional serving daily 2 additional servings daily T3 versus T1 Nonfatal MI Fatal or nonfatal MI Fatal or nonfatal MI fatal or nonfatal MI Fatal or nonfatal MI, angina 134 126 1,063 1,127 249 1.07 (0.581.96) 0.66 (0361.22) 0.92 0.95 0.90 (0.661.24) NS 0.26 NA NA 0.13

Vegetables WHS29 HPFS28 NHS28 PHS33 PRIME42 Q5 versus Q1 1 additional serving daily 2 additional servings daily 2.5 servings daily versus <1 daily T3 versus T1 Fatal or nonfatal MI Fatal or nonfatal MI Fatal or nonfatal MI Fatal or nonfatal MI Fatal or nonfatal MI, angina 126 1,063 1,127 387 249 0.88 (0.501.58) 0.97 0.93 0.81 (0.591.31) 1.01 (0.881.15) 0.60 NA NA 0.24 0.93

*RR corresponds to the exposure variables presented in the articles (right column). Abbreviations: CHD, coronary heart disease; MI, myocardial infarction; NA, P value not available; NS, not statistically significant; Q1, 1st quintile; Q5, 5th quintile; RR, relative risk; T1, 1st tertile; T3, 3rd tertile.

relationships do not often reveal statistically significant associations. Thus uncertainty remains about the real magnitude of the relationship between fruit and vegetable intake and the occurrence of CHD. Regardless of methodological issues related to cohort studies, interpretation of the results requires caution. Consumers of fruit and vegetables have specific social, economic, and behavioral characteristics that could influence CVD risk. For example, Joshipura et al.27 found that individuals who consumed large quantities of fruit and vegetables were less likely to smoke and tended to use vitamin supplements. Social and behavioral factors cannot always be measured precisely, or might not be

Randomly assigning individuals to a prescribed diet ensures comparability between groups, and minimizes the effects of confounding factors, which are not always adequately controlled in observational studies. However, although randomized nutritional prevention trials provide the most robust estimate of causal effects, they are difficult to perform and not always feasible. The success of these studies relies on compliance of the participants for the duration of the study, which can be several years. Even with appropriate interventions, changes in fruit and vegetable intake are generally modestbarely one additional portion per day on average according to published trials.53 Strict interventions could potentially be enforced in a medical environment or for individuals with chronic diseases,53 but these conditions might not be feasible or easily extrapolated to public-health settings. Not surprisingly, given these difficulties, few randomized prevention trials have been conducted to evaluate the effect of high fruit and vegetable intake on the incidence or recurrence of CHD.5456 In the Diet And Reinfarction Trial (DART) II,54 recommendations aimed at promoting increased consumption of fruit, vegetables, fiber, and orange juice had no effect on cardiac death in patients with angina pectoris. However, the small difference in fruit and vegetable intake between study and control participants20 g per daycould certainly have contributed to the lack of significance.55,57 In the Womens Health Initiative (WHI) Randomized Controlled Dietary Modification Trial,29 dietary advice was provided for postmenopausal women aged 5070 years, with the goal of reducing their intake of lipids and increasing consumption of fruit, vegetables, and grains. After 6 years, fruit and vegetable intake in the group that received nutritional advice had increased only slightly (by 1.2 servings per day), compared with the control group.56 The two groups did not, however, differ significantly in the rate of major CHD events;56 nutritional advice was associated with a 7% reduction in risk among women with no history of CVD. Post hoc analyses of fruit and vegetable levels showed that women who achieved the highest level of consumption (6.5 servings per day) had an 11% lower risk of CHD than the control group, but this difference was not statistically significant. However, post hoc analyses are subject to residual confounding

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Table 3 | Fruit and/or vegetable consumption and CHD-related mortality Cohort
NHANES35 BLSA45 Fruit AHS16 AHS16 MCFSI18 ATBC21 OVS26 HFSS
34

Exposure
3 daily versus <1 daily 1 additional serving daily

End points
Coronary mortality Fatal MI

Events
639 71

RR (95% CI)*
0.76 (0.561.03) 0.90 (0.761.05)

Test for trend

0.07 NA

Fruit & vegetables

>2 daily versus <1 daily >2 daily versus <1 daily T3 versus T1 Q5 versus Q1 10 per week versus <5 per week 1 daily versus <1 daily 1 additional serving daily Q4 versus Q1 Q4 versus Q1

Coronary mortality (definite) Coronary mortality (death certificate) Coronary mortality Coronary mortality Coronary mortality Coronary mortality Fatal MI Coronary mortality Coronary mortality

260 463 Men: 186 Women: 58 635 64 605 71 298 258

1.08 (0.671.75) 1.18 (0.821.70) Men: 0.77 (0.521.12) Women: 0.66 (0.361.22) 0.78 (0.591.03) 0.89 (0.441.80) 0.89 (0.771.03) 0.97 (0.791.20) 1.19 (0.761.87) 0.79 (0.581.08)

NS NS Men: 0.28 Women: 0.10 0.008 NS NA NA 0.7 0.06

BLSA45 Boyd Orr46 JACC

50

Vegetables MCFSI22 ATBC21 OVS

26

Q4 versus Q1 Q5 versus Q1 5 per week versus <1 per week 1 daily versus <1 daily 1 additional serving daily
46

Coronary mortality Coronary mortality Coronary mortality Coronary mortality Fatal MI Coronary mortality Coronary mortality

Men: 350 Women: 123 635 64 605 71 298 258

Men: 0.89 (0.651.21) Women: 0.77 (0.491.21) 0.60 (0.450.79) 1.34 (0.473.84) 0.94 (0.831.07) 0.73 (0.540.97) 1.01 (0.701.63) 0.77 (0.670.88)

NA <0.001 NS NA NA 0.7 <0.001

HFSS34 BLSA45 Boyd Orr JACC50

Q4 versus Q1 Q4 versus Q1

*RR corresponds to the exposure variables presented in the articles (right column). Abbreviations: CHD, coronary heart disease; MI, myocardial infarction; NA, P value not available; NS, not statistically significant; Q5 and Q1, 5th and 1st quintile; Q4 and Q1, 4th and 1st quartile; RR, relative risk; T1, 1st tertile; T3, 3rd tertile.

factors and are not as strong or robust as randomized controlled trials. The Lyon study 58,59 showed major benefits of a Mediterranean diet but given the complexity of this diet and the use of margarines rich in -linolenic fatty acid, these benefits cannot be attributed to fruit and vegetable consumption alone. Nutritional prevention trials reported thus far have not provided conclusive evidence for a cardioprotective effect of fruit and vegetable consumption. However, the difficulties in modifying long-term fruit and vegetable intake on the basis of nutritional advice alone should be taken into account when interpreting these disappointing results.

always been adequately documented. In this section, we focus on clinical studies that have tested the effects of fruit and vegetable intake on principal cardiovascular risk factors.

Risk factors for CVD

Analysis of the effects of fruit and vegetable intake on established CVD risk factors is an important step in determining the biological plausibility of a causal relationship between fruit and vegetable consumption and CHDrelated events. At present, blood pressure and LDL cholesterol are the only surrogate end points of CHD that are recognized by health authorities. Studies of these end points are, therefore, more relevant than other biological experiments in assessing cause-and-effect relationships. The effect of fruit and vegetable intake per se has not

Hypertension Findings of observational population studies6063 and clinical trials 64,65 support the hypothesis that fruit and vegetable consumption can affect blood pressure regu lation. The Dietary Approaches to Stop Hypertension (DASH) study,66 which was conducted under strictly controlled experimental conditions, showed that fruit and vegetable consumption was associated with a significant decrease in blood pressure over an 8 week period (systolic and diastolic blood pressure decreased by 2.8 mmHg and 1.1 mmHg, respectively). The effect was more pronounced in hypertensive patients than in normotensive participants. 6668 In another study, community-dwelling individuals who were encouraged to consume five portions of fruit and vegetables per day for 6 months had lower blood pressure values than the control group (the between group differences for change in systolic and diastolic blood pressure were 3.4 mmHg and 1.4 mmHg, respectively).69 Similarly, increased fruit

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Table 4 | Fruit and/or vegetable consumption and CVD events Cohort
Fruit & vegetables WHS29 NHANES35 KIHD
40

Exposure
Q5 versus Q1 3 daily versus <1 daily Q5 versus <Q1 Q5 versus Q1 5 additional servings daily 80 g daily supplement Q4 versus Q1

End points
Fatal or nonfatal MI, PTCA, CABG Cardiovascular mortality Cardiovascular mortality Cardiovascular mortality Fatal or nonfatal MI and stroke Cardiovascular mortality Fatal or nonfatal MI and stroke Cardiac mortality Cardiovascular mortality or morbidity Cardiovascular mortality or morbidity Fatal or nonfatal MI, PTCA, CABG Cardiovascular mortality Nonfatal MI, angina pectoris, stroke Fatal or nonfatal MI and stroke Cardiovascular mortality Cardiovascular mortality Fatal or nonfatal MI and stroke Cardiovascular mortality Cardiac mortality Fatal or nonfatal MI, PTCA, CABG Cardiovascular mortality Cardiovascular mortality Fatal or nonfatal MI and stroke Cardiovascular mortality Cardiovascular mortality Fatal or nonfatal MI and stroke Cardiovascular mortality

Events
418 1,145 115 378 3,864 517 1,386

RR (95% CI)*
0.85 (0.611.17) 0.73 (0.58-0.92) 0.59 (0.331.06) 0.76 (0.541.06) 0.88 (0.810.95) 0.90 (0.810.99) 0.90 (0.751.07)

Test for trend

0.45 0.008 0.02 0.15 NA NA 0.16

Odyssey43 NHS & HPFS44 EPIC diabetic47 JPHC49 Fruit BC24 BHLS
31

Q3 versus Q1 Daily to never (5 levels), winter fruit Daily to never (5 levels), summer fruit Q5 versus Q1 01 versus 67 intakes per week 01 versus 67 intakes per week 3 additional servings daily Q4 versus Q1 80 g daily supplement Q4 versus Q1 Q4 versus Q1 T3 versus T1
29

101 Men: 205 Women: 187 Men: 205 Women: 187 418 226 209 3,864 Men: 200 Women: 184 517 1,386 1,207 101 418 226 209 3,864 Men: 200 Women: 184 517 1,386 1,207

0.64 (0.341.21) Men: OR = 0.80 Women: OR = 0.63 Men: OR = 0.69 Women: OR = 0.52 0.96 (0.701.33) >26 years of follow-up: 36.7% versus 27.7% Incidence >26 years of follow-up: 32% versus 25.8% 0.87 (0.800.94) Men: 1.20 (0.801.79) Women: 1.01 (0.671.53) 0.88 (0.810.95) 0.81 (0.67-0.97) 0.85 (0.641.14) 0.51 (0.27 0.95) 0.85 (0.611.19) >26 years of follow-up: 35.5% versus 26.9% >26 years of follow-up: 29.8% versus 24.6% 0.93 (0.861.00) Men: 0.91 (0.601.36) Women: 0.68 (0.441.07) 0.85 (0.681.07) 0.97 (0.821.15) 0.96 (0.841.10)

0.48 0.63 0.014 0.70 0.004 0.69 0.042 NS NA 0.49 0.52 NA 0.01 NS 0.04 0.21 NS NS NA 0.93 0.02 NA 0.66 NS

BHLS31 WHS29 MB 191330 MB 191330 NHS & HPFS44 Takayama48 EPIC diabetic47 JPHC49 JACC50 Vegetables BC24 WHS

Q5 versus Q1 01 versus 67 intakes per week 01 versus 67 intakes per week 3 additional servings daily Q4 versus Q1 80 g daily supplement Q4 versus Q1 Q4 versus Q1

MB 191330 MB 191330 NHS & HPFS44 Takayama48 EPIC diabetic47 MB 191349 JACC50

*RR corresponds to the exposure variables presented in the articles (right column). Abbreviations: CVD, cardiovascular disease events; MI, myocardial infarction; NA, P value not available in the paper; NS, not statistically significant; OR, odds ratio; PTCA, percutaneous transluminal coronary angioplasty; Q5 and Q1, 5th and 1st quintile; Q4 and Q1, 4th and 1st quartile; RR, relative risk; T1, 1st tertile; T3, 3rd tertile.

and vegetable consumption combined with reduced fat intake has produced a very modest decrease in blood pressure in some,56 but not all,70 prevention trials despite

large differences in fruit and vegetable intake between the intervention and control groups. Consumption of fruit and vegetables has, therefore, been shown to be

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associated with decreased blood pressure under controlled conditions, particularly in hypertensive individuals. Additional studies are necessary to validate these findings in the long term. could be explained by confounding factors, including education level, social condition, physical activity, and by the possible antagonistic effects of the sugars, fiber, and antioxidants in fruit and vegetables. Randomized prevention trials have demonstrated the effectiveness of complex lifestyle interventions (including promotion of fruit and vegetable intake, physical activity, and body weight reduction) on reducing the risk of diabetes, 96,97 but the contribution of fruit and vegetables per se in these studies is difficult to estimate given the complexity of the interventions. Nutrition trials have not shown that fruit and vegetable intake affects either the risk of diabetes,98 or levels of glycemia and insulin sensitivity.78,99101 Thus, studies published to date do not provide clear evidence that consumption of fruit and vegetables reduces the risk of type II diabetes.

Hypercholesterolemia Several components of fruit and vegetables have cholesterol-lowering properties.71 Dietary fiber promotes elimination of cholesterol through the feces by modifying biliary physiology and the enterohepatic cholesterol cycle.72 Similarly, ingestion of large quantities of phytosterols (>2 g per day) lowers plasma LDL-cholesterol levels.73 Several studies have reported effects of fruit and vegetable consumption on lipid profiles.70,74 Most have shown little or no effect;68,69,7577 however, not all were specifically designed to test the effects of fruit and vegetable consumption in patients with hypercholesterolemia. In cancer prevention trials, interventions aimed at increasing fruit and vegetable intake and reducing lipid intake decreased levels of both LDL cholesterol and HDL cholesterol.56,7880 Thus, the lack of appropriately designed studies has led to a situation where there is little evidence for an effect of fruit and vegetable consumption on LDLcholesterol levels. Obesity Fruit and vegetable are low in fat and have high water and nondigestible fiber content; increasing fruit and vegetable intake, therefore, lowers the energy density of meals. In the generally energy-abundant diets prevalent in western societies, replacing energy-dense foods with fruit and vegetables could help to decrease calorie intake and, therefore, body weight.81,82 Short-term investigations have confirmed this hypothesis, but long-term regulation of satiety seems more complex, particularly for those living in the community (that is, noninstitutionalized individuals).83,84 The effect of fruit and vegetable consumption on weight control has been thoroughly reviewed.8587 In an ambulatory setting, promoting fruit and vegetable consumption has not had a substantial effect on body weight or BMI.76,88 However, these studies did not specifically target overweight or obese individuals. Other studies have shown that decreased fat intake combined with increased fruit and vegetable intake results in greater weight loss when compared with low-fat diets. 78,89,90 Accumulating evidence indicates that the combination of increased fruit and vegetable intake, together with other dietary recommendations, might promote satiety and weight loss in overweight individuals. Diabetes Several cohort studies have reported that components of fruit and vegetablessuch as antioxidants, fiber and magnesiumseem to lower the risk of type II diabetes.9193 The relationship between fruit and vegetable intake and the risk of type II diabetes has not, however, been established and other cohort studies have produced conflicting results.9395 The discrepancies between studies

Biological plausibility

The effects of nutrients on the biological processes leading to atherosclerosis have been tested in animal models and in vitro cell culture systems.102 In chronic pathologies, such as atherosclerosis, that have multiple pathophysiological causes occurring at different time pointsoften with years of latency before clinical manifestationdetermining the contribution of different pathways to the final event is complicated. Thus, identifying the mechanisms of the proposed protective role of fruit and vegetable consumption in multifactorial disease processes is difficult. To further complicate matters, the interactions between the variety of nutrients found in fruit and vegetables are rarely evaluated in biological experiments. Moreover, different varieties of fruit and vegetables, growing techniques, industrial processing, and storage and cooking conditions can strongly affect the composition and properties of the nutrients. Given these variables, determining biological plausibility of the association observed between fruit and vegetable intake and CHD is particularly challenging and beyond the scope of this Review. Nevertheless, in the following section we briefly discuss clinical trials that have investigated the effects of individual components or combinations of components derived from fruit and vegetables on CVD end points. Of the many nutrients in fruit and vegetables, only vitamins have been evaluated in clinical prevention trials. Despite the abundance of biological evidence72 and observational epidemiological data103105 supporting their role in atherosclerosis prevention, meta-analyses of trials with folate, carotenoids, and vitamin C have failed to demonstrate convincingly that these vitamins have a role in preventing CVD and mortality.106112 A meta-analysis evaluating the effects of combinations of multivitamin and mineral supplements on prevention of cardiovascular disease113 found no evidence of a protective effect. Methodological issues, however, require that these trials be interpreted with caution. Factors that might have affected the results include inappropriate dosing or insufficient duration of intake, both of which could influence

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effectiveness.114 Perhaps the most effective combination of vitamins or the optimal biochemical structure for synthetic molecules for CVD prevention was not identified. A further possibility is that CVD prevention trials might have recruited participants not likely to benefit from treatment, such as those with advanced lesions or with satisfactory vitamin status. These limitations should be taken into account in the design of future CVD prevention trials if we are to translate our knowledge of the molecular and cellular mechanisms of atherosclerosis more effectively into clinical benefit. The use of biological and genetic markers as surrogate end points in future studies should help to clarify whether a causal relationship indeed exists between fruit and vegetable intake and CVD preventionso far this relationship has only been inferred. For example, a randomized clinical trial published in 2009 supports epidemiological observations by showing that in hypertensive patients, fruit and vegetable intake resulted in a dose-dependent improvement in endotheliumdependent forearm blood flowan integrated marker of vascular function with known prognostic value.115 Under rigorously controlled experimental conditions, fruit and vegetable consumption is associated with a decrease in blood pressurean important CVD risk factor. The effects of fruit and vegetables on plasma lipid levels, diabetes, and body weight have not yet been thoroughly explored. The hypothesis that components of fruit and vegetables decrease atheroma formation and prevent its complications has been explored in animal models, in vitro cell culture systems and in human studies using integrated end points. In view of the complexity of fruit and vegetable composition and of disease pathophysiology, the relevance of these models to biological plausibility of the association between fruit and vegetable consumption and CHD remains debatable. In conclusion, fruit and vegetables should be eaten as part of a balanced diet, as a source of vitamins, fiber, phytochemicals, and water. Substitution of harmful foods with fruit and vegetables might reduce CVD events and provide a basis for public health recommendations. Confirmation that fruit and vegetables per se have a protective effect against CVD awaits further evidence from nutritional prevention trials and clinical interventions on cardiovascular risk factors. In particular, the quantities of fruit and vegetables necessary for optimal prevention and target population are yet to be defined.
Review criteria
We selected studies that assessed the relationship between coronary heart disease, or risk factors for this condition, and consumption of fruit and vegetables, separately and combined. We focused on CHD (angina and myocardial infarction), but some studies that we examined have looked more broadly at cardiovascular disease (CHD and other vascular events such as stroke and heart failure). We restricted our analysis to cohort studies or trials that used fruit and vegetable intake as a nutritional exposure variable and excluded studies of specific fruits, vegetables, micronutrients or macronutrients. We also excluded studies with complex interventions, such as the Mediterranean diet. MEDLINE and EMBASE publications were searched up to June 2009.

Conclusions

Evidence that fruit and vegetable consumption has a protective effect against CVD comes mainly from observational epidemiological studies. Most of these studies show a decrease in the risk of CHD and CVD with fruit and vegetable consumption. However, as fruit and vegetable intake is associated with particular social, cultural, and lifestyle characteristics that might also confer protection against CVD and, as these confounders are not adequately controlled in observational studies, the conclusion that a causal relationship exists between fruit and vegetable intake and CVD prevention is not justified. Controlled, nutritional prevention trials are still scarce, and the results so far have not shown conclusively that fruit and vegetable intake protects against CVD, in part because the dietary interventions have not been intensive enough to enable optimal analysis of their putative effects.
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