Abstract

OBJECTIVES:

• To review all prospective studies which provided data about total fruits or vegetables, their subgroups, and specific types of vegetables and fruits, in relation with cardiovascular disease, heart disease, or stroke risk and mortality/survival.
• To define the amount of consumption found to be related with the described effects on CVD.
• To define possible effect modification by confounders.

DATA SOURCE: The Pubmed database was searched (No start date - Nov 27, 2008) for relevant articles using the keywords "prospective, cohort, follow-up, longitudinal" combined with "vegetables, fruit", and a fair amount of other keywords. The exact search term is described in the methods.
Prospective studies published in the English language were included. Reference lists were searched for additional articles.
RESULTS: 67 articles were found which provided information about 36 different cohorts.
Of these, 0 articles needed to be excluded because of language restrictions. And no articles were excluded because of any other reasons.
Results are described when any evidence for an association - as defined in the Methods - was found. In addition, data about total vegetables or fruits is described. Disease incidence and death were considered different end points.

• Total CVD risk.
  -Total vegetables: Data was provided by 4 cohorts, including a total of 5,438 cases. Total vegetables possibly protect against CVD risk among non-users of multivitamins.
  -Total fruit: Data was provided by 5 cohorts, including a total of 5,830 cases. Total fruit possibly protects against CVD risk among women.
  -Green leafy vegetables, and Vitamin-C rich fruits and vegetables possibly protect against CVD risk.
  -Suggestive evidence was found for a protective effect of citrus fruit against CVD risk.
• Heart disease risk.
  -Total vegetables: Data was provided by 7 cohorts, including a total of 3,896 cases. Total vegetables possibly protect against CHD risk. This effect is confined to current smokers, and possibly confined to non-users of multivitamin supplements.
  -Total fruit: Data was provided by 8 cohorts, including a total of 3,914 cases. Total fruit possibly protects against CHD risk.
  -Green leafy vegetables and cruciferous vegetables possibly protect against CHD risk. The effect with cruciferous vegetables is possibly confined to non-users of multivitamin supplements.
  -Citrus fruit: Suggestive evidence was found for a protective effect of citrus fruit against CHD risk.
• Stroke risk.
  -Total vegetables: Data was provided by 7 cohorts, including a total of 2,085 cases. Suggestive evidence was found for a protective effect of total vegetables against stroke risk among men.
  -Total fruit: Data was provided by 7 cohorts, including a total of 2,085 cases. Suggestive evidence was found for a protective effect of total fruit against stroke risk.
  -Green leafy vegetables, citrus fruit, and vitamin-C rich fruits and vegetables possibly protect against ischemic stroke risk.
  -Cruciferous vegetables and citrus fruit juice possibly protect against ischemic stroke risk among non-users of multivitamins.
• Total CVD death.
  -Total vegetables: Data was provided by 3 cohorts, including a total of 1,339 cases. Inconclusive evidence was found for an association between vegetables and CVD death.
  -Total fruit: Data was provided by 4 cohorts, including a total of 2,541 cases. Inconclusive evidence was found for an association between fruit and CVD death.
• Heart disease death.
  -Total vegetables: Data was provided by 7 cohorts, including a total of 2,094 cases. Suggestive evidence was found for a protective effect of vegetables against CHD death among men.
  -Total fruit: Data was provided by 10 cohorts, including a total of 2,983 cases. No evidence was found for an association between total fruit and CHD death.
  -Broccoli possibly protects against CHD death among women.
  -Suggestive evidence was found for a protective effect of apples (/pears) against CHD death among women.
• Stroke death.
  -Total vegetables: Data was provided by 1 cohort, including 83 cases. No evidence was found for an association between total vegetables and stroke death.
  -Total fruit: Data was provided by 3 cohorts, including a total of 2,140 cases. No evidence was found for an association between total fruit and stroke death.

CONCLUSION: Both, total vegetables and total fruit, possibly protect against both CVD risk, and heart disease risk. The evidence for fruit and CVD was restricted to women, the evidence for vegetables and CHD was restricted to current smokers, and both effects of vegetables were (possibly) confined to non-users of multivitamin supplements. Suggestive evidence for a protective effect was found of total vegetables against stroke risk + heart disease death among men, and of total fruit against stroke risk.
Evidence for possible protective effects was found of green leafy vegetables (CVD risk, CHD risk, ischemic stroke risk); cruciferous vegetables (CHD risk, ischemic stroke risk); vitamin C-rich fruits and vegetables (CVD risk, ischemic stroke risk); citrus fruit (ischemic stroke risk); and citrus fruit juice (ischemic stroke risk). The effects of cruciferous vegetables and citrus fruit juice were (possibly) confined to non-users of multivitamin supplements. Broccoli possibly protects against CHD death among women. Suggestive evidence was found for a protective effect of citrus fruit (CVD risk, CHD risk); and among women of apples (/pears) against CHD death.
No level of consumption for these effects could be defined for any of the outcomes.
PERSPECTIVE: Because few effects were published in servings/grams/cups over a given time period, and in increasing units of consumption, no level of consumption could be calculated where any of the effects were found. This given fact hinders evidence based health recommendations. Most of the evidence was based - to a large extend - on findings from 2 cohorts: "The Nurses' Health Study" & "The Health Professionals' Follow-Up Study". Without these 2 cohorts, all evidence would disappear, except for the suggestive associations between vegetables or apples and CHD death.
A lot of cohorts are currently providing information about diet & various health outcomes. Some cohorts are of very large size (200,000 to 1,000,000 subjects).
In the coming years it can be expected that within each of these large cohorts more than 10,000 to 50,000 subjects will have developed CVD. Since the evidence relating vegetables or fruits to total CVD risk is currently based on a cumulative amount of cases less than 6,000, it is not hard to understand that current evidence could change in any direction in the near future.
AUTHOR'S NOTE: Information was presented about the relation with total CVD, heart disease, and stroke. And information was further stratified into risk, or death. But all information about stroke types was grouped together, regardless if total stroke or ischemic stroke was examined. Also, all information about heart disease types was grouped together, regardless if nonfatal MI or total CHD (nonfatal MI + CHD death) was examined.
The choice could be made to further stratify information, or to group data together (risk & death, or total CVD & CHD & stroke). However, none of these options would result in probable/convincing evidence for an effect of any of the dietary variables according to the methodology used.

Total vegetables and total cardiovascular disease.

6 articles, providing information about 7 different cohorts were found.

CVD risk: Data about CVD risk was provided by 4 cohorts, including a total of 5,438 cases.
A significant trend of a protective effect was found in a pooled analyses of 2 cohorts including 3,634 cases (10). But no associations were found in the other 2 cohorts (20, 34).
Effect modification: Data about effect modification by multivitamin use was provided by a pooled analysis of 2 cohort studies (10). The protective effect of vegetables was confined to non-users of multivitamins. No effect modification was found by smoking status (10, 34)
CVD mortality: Data about CVD mortality was provided by 3 cohorts, including a total of 1,339 cases.
A protective association was found in 1 cohort, but no data is available about the strength or significance of the association (1). A significant trend of a protective effect was found in another cohort among women only (23). But no asociation was found in the third cohort (25).

Conclusion: A significant trend of a protective effect against CVD risk was found in a pooled analysis of 2 cohorts of moderate-large size including 67% of all cases. This effect was confined to non-users of multivitamins. Total vegetables possibly protect against CVD risk among non-users of multivitamins. No level of consumption could be defined for this effect. A significant trend of a protective effect against CVD death was found in one cohort among women only. Other effects were unclear. Inconclusive evidence was found for an association between vegetables and CVD death.

Total vegetables and heart disease.

13 articles, providing information about 12 different cohorts were found.

Heart disease risk: Data about heart disease risk was provided by 7 cohorts, including a total of 3,896 + X cases (no amount of cases was available from one cohort of very small size [3]).
Significant protective effects were found in 3 cohorts (10, 13) including 3,312 cases, but no associatons were found in the remaining 4 cohorts (3, 18, 20, 29).

Note: In 2007, He FJ. published a meta-analysis of 9 cohort studies relating vegetables to CHD risk. This analysis excluded data from "The Shibata Study" (Tanaka H. 1987), and "The Study Of Men Born In 1913" (Strandhagen E. 2000), but it included data from 4 other cohorts which are not added to the following table. Excluded articles & motivations for exclusion are as follows:

• Fraser GE (1992). The Adventist Health Study provided information about salads and legumes, but not total vegetables. Information about these variables is added to the related items in the menu.
• Knekt P (1996). Provided information about CHD death instead of risk. Therefore, information about this variable was added to the table of vegetables in relation to CHD mortality.
• Mann JI (1997). Provided information about green vegetables, but not total vegetables. Therefore, information about this variable is added to the related item in the menu.
• Liu S (2001). Provided information about vegetables rich in carotenoids, but not total vegetables. Therefore, information about this variable is added to the related item in the menu.

Effect modification: Data about effect modification by multivitamin use was provided by a pooled analysis of 2 cohort studies (10). A protective effect of vegetables was confined to non-users of multivitamin supplements.

Heart disease mortality: Data about heart disease mortality was provided by 7 cohorts, including a total of 2,094 cases.
Significant protective effects were found in 3 cohorts (11, 13, 30) including 987 cases, and a nonsignificant protective effect was found in a fourth cohort (2), including 110 cases. Three out of four of these cohorts consisted of men only. No associations were found in 3 other cohorts (7, 18, 31).

Conclusion: Significant protective effects against CHD risk were found in 3 cohorts of moderate-large size, including 85% of all cases. Effects were confined to non-users of multivitamins. Total vegetables possibly protect against CHD risk. This effect is possibly confined to non-users of multivitamin supplements. No level of consumption could be defined for this effect.
Significant protective effects against CHD death were found in 3 cohorts, two of which were of very small size (including 47% of all cases). Most cohorts consisted of men only. No (non)significantly increased risks were found. Suggestive evidence was found for a protective effect of vegetables against CHD death among men. No level of consumption could be defined for this effect.

Total vegetables and stroke.

8 articles, providing information about 8 different cohorts were found.

Stroke risk: Data about stroke risk was provided by 7 cohorts, including a total of 2,085 cases.
Significant protective effects were found in 1 cohort examing men only (13), and in cohort of very small size among men only (3), including a total of 922 cases. No associations were found in the remaining 5 cohorts (6, 8, 10, 25).

Note: In 2006, He FJ. published a meta-analysis of 6 cohort studies relating vegetables to stroke risk. This analysis excluded data from "The Shibata Study" (Tokoyama T. 2000), and "The Framingham Study" (Gillman MW 1995), but it included data from 1 other cohort which was not added to the following table.
The excluded article used data from "The Hiroshima Nagasaki Life Span Study" (Sauvaget C. 2003). This study provided information about stroke mortality instead of stroke risk. In addition, it provided information about green-yellow vegetables, but not total vegetables. Therefore, information about this variable is added to the related item in the menu.
It should be noted that, from this excluded cohort a) the strenght of the association, and b) the amount of cases, accounted to a large extend for the protective effect found in the meta-analysis by He FJ.

Stroke mortality: Data about stroke mortality was provided by cohort of very small size (31). A significant protective effect was found.

Conclusion: Significant protective effects against stroke risk among men were found in 2 cohorts, one of which was of very small size. No other (non)significant associations were found. Suggestive evidence was found for a protective effect of total vegetables against stroke risk among men.
A significant protective effect against stroke death was provided by 1 cohort of very small size. No evidence was found for an association between total vegetables and stroke death.

Total fruit and total cardiovascular disease.

9 articles, providing information about 9 different cohorts were found.

CVD risk: Data about CVD risk was provided by 5 cohorts, including a total of 5,830 cases.
Significant protective associations were found in 2 cohorts (10), and in 2 cohorts among women (19, 34). No other (non)significant associations were found.
CVD mortality: Data about CVD death was provided by 4 cohorts of small size, including a total of 2,541 cases.
A significant protective effect was found in one cohort (25), and a protective association was found in another cohort, but no data is available about the strength or significance of the association (1). No associations were found in the remaining 2 cohorts (12, 23).

Conclusion: Significant protective effects against CVD risk were found in 2 cohorts of moderate-large size, and in 2 additional cohorts among women only. The amount of cases from one cohort (34) was not stratified by gender, but the total amount of cases from these cohorts included well over 50% of all cases. Total fruit possibly protects against CVD risk among women. No level of consumption could be defined for this effect.
A significant protective effect against CVD death was found in one cohort. Other effects were unclear. Inconclusive evidence was found for an association between fruit and CVD death.

Total fruit and heart disease.

18 articles, providing information about 15 different cohorts were found.

Heart disease risk: Data about heart disease risk was provided by 8 cohorts, including a total of 3,914 cases.
Significant protective associations were found in 3 cohorts (10, 29), including 2,323 cases. No associations were found in the remaining 5 cohorts (3, 4, 13, 18, 20).

Note: In 2007, He FJ. publised a meta-analysis of 9 cohort studies relating fruit to CHD risk. This analysis excluded data from "The Shibata Study" (Tanaka H. 1987), and "The Study Of Men Born In 1913" (Strandhagen E. 2000), but it included data from 3 other cohorts which are not added to the following table. Excluded articles & motivations for exclusion are as follows:

• Knekt P (1996). Provided information about CHD mortality instead of risk. In addition, it provided information about fruit other than apples & berries, instead of total fruit. Information about this variable is added to the category "uncategorized" in the menu.
  A protective effect among women, but not men was found of this subgroup of fruits.
• Mann JI (1997). Provided information about CHD mortality instead of risk. Therefore, information about this variable was added to the table of fruit in relation to CHD death.
• Liu S (2001). No information about fruit is published in the article referred to by the meta-analysis. It should be noted that He FJ. probably had access to information about this cohort which is not yet published.

Heart disease mortality: Data about heart disease death was provided by 10 cohorts, including a total of 2,983 cases.
Significant protective effects were found in one cohort (18), and in another cohort among women only (12) including a total of 484 cases. In addition, a nonsignificant trend of a protective effect was found in one cohort among women only (7). No other associations were found (4, 11, 13, 15, 17, 30, 31).

Conclusion: Significant protective associations against CHD risk were found in 2 cohorts of moderate-large size, and one additional cohort including 59% of all cases. Total fruit possibly protects against CHD risk. No level of consumption could be defined for this effect. Significant protective effects agains CHD death were found in one cohort of very small size, and in one cohort of small size among women only. No evidence was found for an association between total fruit and CHD death.

Total fruit and stroke.

11 articles, providing information about 10 different cohorts were found.

Stroke risk: Data about stroke risk was provided by 7 cohorts, including a total of 2,085 cases.
Significant protective effects were found in 3 cohorts (10, 25), and against 1 type of stroke in a fourth cohort (13), including a total of 931 cases. No other associations were found.

Note: In 2006, He FJ. published a meta-analysis of 6 cohort studies relating fruit to stroke risk. This analysis excluded data from "The Shibata Study" (Tokoyama T. 2000), and "The Framingham Study" (Gillman MW. 1995), but it included data from 1 other cohort which was not added to the following table.
The excluded article used data from "The Hiroshima Nagasaki Life Span Study" (Sauvaget C. 2003). This study provided information about stroke mortality instead of stroke risk. Therefore, information about this variable was added to the table about fruit in relation to stroke mortality.
It should be noted that, from this excluded cohort a) the strenght of the association, and b) the amount of cases, accounted to a large extend for the protective effect found in the meta-analysis by He FJ.

Stroke mortality: Data about stroke mortality was provided by 3 cohorts, including a total of 2,140 cases.
A significant protective effect was found in 1 cohort including 1,701 cases (27), but no associations were found in the other 2 cohorts (12, 31).

Conclusion: Significant protective effects against stroke risk were found in 4 cohorts of moderate-large size including 45% of all cases. No other associations were found. Suggestive evidence was found for a protective effect of total fruit against stroke risk. No level of consumption could be defined for this effect.
A significant protective effect against stroke mortality was found in 1 cohort including 79% of all cases. No evidence was found for an association between total fruit and stroke death. When stroke risk and mortality are considered one end point, fruit possibly protects against stroke.

Total fruits & vegetables

Some articles did not provide information about either "total vegetables" or "total fruit", but looked at their combined effect.

Information about this combined effect is only presented if no information about either "total vegetables" or "total fruits" was provided from a cohort.

Total cardiovascular disease: No data about the association with total CVD risk was found.
Data about CVD death was provided by 3 cohorts of (very) small size, including a total of 1,638 cases.
Significant protective associations were found in 2 cohorts (22, 24). A nonsignificant trend of a protective effect among never smokers was found in the third cohort (28).

Coronary heart disease: Data about heart disease risk was provided by 5 small cohorts, including a total of 4,223 + X cases (no data was available from 1 cohort).
A significant protective effect was found in 1 cohort (25). But no associations were found in the remaining cohorts (8, 22, 26, 36).
Data about IHD mortality was provided by 1 cohort of small size (22). A nonsignificant protective trend was found.

Stroke: Data about stroke risk was provided by 2 cohorts of small size. A significant protective effect was found in 1 cohort (22), but no association was found in the other (26).
Data about stroke mortality was provided by 1 cohort of small size (22). A significant trend of a protective effect was found.

Conclusion: Cohort sizes were small, and associations cannot be attributed to either vegetables or fruits. Nonetheless, these findings show little association with disease risk, but strenghten the possibility of a protective association against CVD mortality.