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Flavonoid intake and mortality from cardiovascular disease and all causes: A meta-analysis of prospective cohort studies
Clinical Nutrition ESPEN xxx (2017) e1ee10
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Original article
Flavonoid intake and mortality from cardiovascular disease and all causes: A meta-analysis of prospective cohort studies Youngyo Kim, Youjin Je* Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea
a r t i c l e i n f o
s u m m a r y
Article history: Received 5 October 2016 Accepted 22 March 2017
Background and aims: Accumulating studies have suggested that flavonoid intake is associated with a decreased risk of coronary heart disease and cardiovascular disease (CVD). There are many epidemiological studies on flavonoid intake and mortality, but no comprehensive investigation has yet been conducted. To quantitatively assess the association between flavonoid intake and mortality from CVD and all-causes, we performed a meta-analysis of prospective cohort studies. Methods: Eligible studies were identified by searching PubMed and Web of Science databases for all articles published up to May 2016 and via hand searching. Study-specific estimates adjusting for potential confounders were combined to calculate a pooled relative risk (RR) with 95% confidence interval (CI) using a random-effects model. Results: A total of 15 prospective cohort studies that examined the association between flavonoid intake and mortality from CVD and all-causes were identified. The pooled RR of CVD mortality for the highest versus lowest category of flavonoid intake was 0.86 (95% CI: 0.75, 0.98). By subclass of flavonoids, all classes, except flavonols and isoflavones, showed significant inverse associations. A nonlinear association was found between flavonoid intake and CVD mortality in the doseeresponse analysis. For total mortality, a high intake of flavonoids was associated with lower total mortality (pooled RR ¼ 0.86, 95% CI: 0.73, 1.00). Conclusions: Our findings indicate that a high intake of flavonoids is associated with reduced risk of mortality from CVD and all causes in men and women. These results support current recommendations of high fruit and vegetables intake as a part of a healthy diet. © 2017 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
Keywords: Flavonoids Cardiovascular disease Coronary heart disease Mortality Prospective cohort studies
1. Introduction Accumulating scientific evidence has suggested that a high intake of fruit and vegetables is inversely associated with the risk of cardiovascular disease (CVD) incidence [1] and mortality from allcauses and CVD [2]. The beneficial effect of fruit and vegetables may result from potassium [3], magnesium [4] and dietary fiber [5,6], which have been inversely associated with mortality in recent studies. However, flavonoids also may be responsible for the protective association between fruit and vegetables and mortality. Flavonoids are polyphenolic compounds, which are a wide group of
Abbreviations: CVD, cardiovascular disease; CHD, coronary heart disease; RR, relative risk; CI, confidence interval. *Corresponding author. Department of Food and Nutrition, Kyung Hee University, 26 Kyunghee-daero, Dongdaemun-gu, Seoul 02447, South Korea. E-mail address: [email protected] (Y. Je).
secondary metabolites present in plant-based foods [7]. Flavonoids have antioxidant properties and thus may reduce low density lipoproteins, which is considered the main cause of atherosclerotic diseases, by inactivating reactive oxygen species [8]. Furthermore, flavonoids also ameliorate the blood vessel endothelium by reducing the risk of clot formation due to their anti-aggregating properties [9]. Results from recent meta-analyses showed a significant inverse association between total flavonoid intake or intake of subclass of flavonoids and incidence of CVD [10] and coronary heart disease (CHD) [11]. Many prospective cohort studies also have examined the effect of flavonoid intake on risk of mortality from CVD or all-causes to date [12e27]. Some studies have reported significant inverse associations between flavonoid intake and mortality from CVD or all-causes [12,17,23,25], but other studies have found nonsignificant inverse or positive associations [14e16,18e22,24,26,27]. As the results of these studies remained inconsistent, we conducted a
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Please cite this article in press as: Kim Y, Je Y, Flavonoid intake and mortality from cardiovascular disease and all causes: A meta-analysis of prospective cohort studies, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.03.004
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Two investigators (Y.K. and Y.J.) independently performed data extraction based on the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines [30], and any discrepancies were solved via reviewing the original article and discussion. The following information was extracted from each study: first author's last name, year of publication, country name, cohort name, duration of follow-up, number of cases and participants, adjustment factors, and “most fully adjusted” RRs with 95% CIs across each exposure category.
were provided for both total flavonoid intake and subclass of flavonoid intake from the same cohort [12,33], and the RRs for subclass of flavonoid intake [33] were used in the subgroup analysis by flavonoid classes. Likewise, if two individual publications from the same cohort [13,18] reported sex-specific RRs [13] and overall RR [18], respectively, we included the overall RR in the main analysis, and the sex-specific RRs were used in stratified analysis by sex. The summary RRs and study-specific RRs were presented as forest plots where the size of data markers (squares) corresponds to the inverse of the variance of the natural logarithm of RR from each study, and the diamond indicates the pooled RR. The Q-statistic [34] was used to assess statistical heterogeneity among the studies, and inconsistency was quantified by I2 statistic [35]. We performed a doseeresponse meta-analysis using generalized least-squares trend (GLST) estimation method based on the method developed by Greenland and Longnecker [36e38]. When a study did not provide median consumption of the category, we assigned an approximate median by calculating the midpoint of the lower and higher bounds. The highest, open-ended category was considered to have the same interval of intake as the adjacent category. One study that reported flavonoid intake as only two categories [14] was not included in this analysis. Although one article did not report the number of cases in each category [18], another one from the same cohort provided all data, and we thus included the latter in a doseeresponse meta-analysis [13]. We also assessed a potential nonlinear doseeresponse relationship between flavonoid intake and mortality by modeling flavonoid intake levels using restricted cubic splines with 3 knots at fixed percentiles (10th, 50th and 90th) of the distribution. A P value for nonlinearity was computed by testing the null hypothesis that the coefficient of the second spline is equal to zero [39]. To examine whether the present results were affected by a single study, we conducted a sensitivity analysis by excluding one study at a time. We also performed a stratified analysis and metaregression analysis by sex, geographical region, duration of follow-up, median age of baseline, class of flavonoids, and adjustment factors (body mass index [BMI], physical activity, smoking, alcohol consumption, intake of dietary fiber) for evaluation of the variations in pooled risk estimates by study characteristics. Finally, the tests of Begg and Mazumdar [40] and Egger et al. [41] were used to assess publication bias. A two-tailed P value of <0.05 was considered statistically significant. All statistical analyses were conducted using Stata/SE software, version 12.0 (Stata-Corp LP, College Station, Texas).
2.3. Quality assessment for individual studies
3. Results
We assessed the quality of each study using the NewcastleeOttawa quality assessment scale [31]. The following perspectives were considered; representativeness of the exposed cohort; dietary survey methods of flavonoid intake; comparability of cohorts (adjustment for important confounders); assessment of outcome; duration of follow-up; and adequacy of follow-up. A score of 10 or higher (out of 13) indicates as a high-quality study, scores of 7e9 indicate a good-quality study, and a score of 6 or less indicates a low-quality study.
3.1. Study characteristics
systematic review and meta-analysis of prospective cohort studies to quantitatively assess the association between flavonoid intake and mortality from CVD and all-causes in the current study. In addition, we examined whether a doseeresponse relationship was present between flavonoid intake and mortality from CVD and allcauses. 2. Methods 2.1. Literature search and study selection We used the PubMed and Web of Science databases to identify eligible studies published in English and full-paper through May 2016. The following search keywords were used: (“flavonoids” OR “flavonols” OR “flavones” OR “anthocyanidins” OR “flavanones” OR “flavan-3-ols” OR “catechins” OR “proanthocyanidins” OR “quercetin” OR “myricetin” OR “kaempferol” OR “isorhamnetin” OR “apigenin” OR “luteolin”) combined with (“mortality” OR “death” OR “fatal cardiovascular disease” OR “fatal coronary heart disease” OR “fatal ischemic heart disease (IHD)” OR “fatal myocardial infarction (MI)” OR “fatal stroke” OR “fatal CVD” OR “fatal CHD” OR “fatal IHD” OR “fatal MI”). We also identified additional studies by manually searching the reference lists in the selected articles. We included studies in this meta-analysis if they met the following criteria: 1) studies with a prospective cohort design; 2) the exposure of interest was total flavonoids or flavonoid classes; 3) the outcome of interest was the mortality from CVD, CHD, IHD or allcauses; and 4) studies that reported relative risks (RR) with 95% CI. For 3 studies [21,28,29] that provided RRs for the association between flavonoid intake and CHD mortality from the same cohort, Iowa Women's Health Study, we included RRs from more recent and larger study [21]. 2.2. Data extraction
2.4. Statistical analysis We combined a natural logarithm of the RR of each study using the DerSimonian and Laird random-effects models that incorporate both within-and between-study variations [32] to calculate a pooled RR and its 95% CI for the highest versus lowest category of flavonoid intake from original studies. We included the effect estimates of total flavonoid intake in the main analysis [12] when RRs
The detailed process of the literature search is shown in Fig. 1. We identified a total of 15 prospective cohort studies [12e25,27,33] that provided the results for mortality from CVD or all-causes related to flavonoid intake. The main characteristics of the included studies are presented in Table 1. The duration of follow-up ranged from 4.8 to 28 years, and the median follow-up time was 12.0 years for CVD mortality and 12.8 years for total mortality. The study population was all adults (age 29 years) at baseline. With regard to geographical region, nine studies were carried out in Europe [12,15e18,22,24,26,27], four in the USA [14,20,21,23], one in Asia [19] and one in Oceania [25]. By sex, seven studies included both male and female subjects [17e19,23,24,26,27], and eight studies included male [12,14e16,22] or female [20,21,25] subjects only. Seven studies provided RRs by class of flavonoids (flavan-3-ols/flavonols isoflavones/flavones/flavanones/anthocyanidins/proanthocyanidins) [15,19,21e23,26,33]. Most of the studies
Please cite this article in press as: Kim Y, Je Y, Flavonoid intake and mortality from cardiovascular disease and all causes: A meta-analysis of prospective cohort studies, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.03.004
Y. Kim, Y. Je / Clinical Nutrition ESPEN xxx (2017) e1ee10
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Fig. 1. Process used to select prospective cohort studies for meta-analysis of the association between flavonoid intake and CVD and total mortality.
measured flavonoid intake using food frequency questionnaires [14,15,19e21,23,25e27], four studies assessed the intake through interviews [12,17,18,24] and one study used 4-day food records [22]. All of the studies adjusted for age and smoking, and most of the studies provided RRs adjusted for BMI (n ¼ 14) [12,14e24,26,27] and alcohol consumption (n ¼ 11) [12,15,17,19,20,22e27]. Nine studies adjusted for physical activity [16,19e21,23e27]. The assessment of study quality yielded a mean score of 10.4 (range, 8e12). Eleven studies had a score of 10 or above, showing high quality [12,15,17e22,24e26], and the other studies had scores of 8 or 9, indicating good quality [14,16,23,27]. 3.2. Highest flavonoid intake versus lowest 3.2.1. Flavonoid intake and CVD mortality A total of 13 studies including 338,541 participants and 7774 deaths were included in the meta-analysis [12,14e23,25,26]. The pooled RR of CVD mortality was 0.86 (95% CI: 0.75, 0.98), with moderate heterogeneity (I2 ¼ 50.6%, P ¼ 0.02) (Fig. 2). The sensitivity analysis that excluded one study at a time and estimated the pooled RR with the remaining studies showed that the pooled RRs ranged from 0.84 (95% CI: 0.71, 0.98) to 0.88 (95% CI: 0.78, 0.99), which indicated robust results (data not shown). Table 2 shows the results of subgroup analyses. The inverse association between flavonoid intake and risk of CVD mortality was not significantly different by sex (P for difference ¼ 0.72). The differences by geographical region or median age of baseline were not statistically significant, either (P for differences 0.07 in all comparisons). To examine the difference by duration of follow-up, we
chose a median follow-up time of 12.0 years as a cut off. The studies with short follow-up times (<12.0 years) showed a stronger inverse association between flavonoid intake and CVD mortality (RR ¼ 0.66, 95% CI: 0.50, 0.87), as compared to those with long follow-up times (12.0 years) (RR ¼ 0.95, 95% CI: 0.86, 1.05) (P for difference ¼ 0.06). When we limited the analysis to five studies that had all adjusted for smoking, alcohol consumption, BMI and physical activity, the inverse association was stronger (RR ¼ 0.79, 95% CI: 0.63, 0.99), but the difference by adjustment was not significant (P for difference ¼ 0.27). In addition, the results from subgroup analysis by adjustment for intake of dietary fiber were not significantly different (P for difference ¼ 0.32) (data not shown). Regarding the results of subgroup analysis by class of flavonoids, all classes showed significant inverse associations, except two classes (flavonols and isoflavones) that showed nonsignificant inverse associations. 3.2.2. Flavonoid intake and total mortality Eight studies with 97,118 participants and 12,228 deaths were included in the meta-analysis [12,15,18,21,24e27]. The pooled RR of total mortality was 0.86 (95% CI: 0.73, 1.00), with substantial heterogeneity (I2 ¼ 67.6%, P ¼ 0.003) (Fig. 3). When we performed a sensitivity analysis that omitted one study at a time, the pooled RRs ranged from 0.81 (95% CI: 0.65, 1.02) to 0.92 (95% CI: 0.82, 1.03) (data not shown). The results of subgroup analyses by study characteristics are presented in Table 2. The differences by sex, geographical region, follow-up times, median age of baseline, and adjustment factors (smoking/BMI/alcohol/physical activity) were not significant (P for difference >0.06 in all comparisons).
Please cite this article in press as: Kim Y, Je Y, Flavonoid intake and mortality from cardiovascular disease and all causes: A meta-analysis of prospective cohort studies, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.03.004
First author (year)
Hertog (1993) [12]
Country
Netherlands
Cohort name
Zutphen Elderly Study
Follow-up period (years)
Age at baseline (y)
Cause of death
5
65e84
Study size
e4
Sex
Adjustment for covariates
43
Male
805
185
Male
Age, intake of total energy, saturated fatty acids, cholesterol, alcohol, coffee, vitamin C, vitamin E, beta-carotene, dietary fiber, history of myocardial infarction, BMI, smoking, serum total and HDL cholesterol, systolic blood pressure Age, prevalence of chronic disease, intake of total energy, saturated fatty acids, physical activity, BMI, smoking, serum total and HDL cholesterol, blood pressure Age, BMI, smoking, diabetes, profession, hypertension, high cholesterol levels, family history of CHD, intake of vitamin E, alcohol, dietary fiber, carotene and saturated fat Age, smoking (never, exsmoker, or current smoker), baseline evidence of ischemic heart disease, social class, BMI, systolic blood pressure, serum total cholesterol, and intakes of total energy, alcohol, fat, vitamin C, vitamin E, and beta-carotene. Age, smoking (never, exsmoker, or current smoker), social class, BMI, and intakes of total energy, alcohol, fat, vitamin C, vitamin E, and beta-carotene. Age, supplementation group, systolic and diastolic blood pressure, serum total cholesterol, serum high-density lipoprotein cholesterol, BMI, smoking years, number of cigarettes smoked daily, history of diabetes mellitus or coronary heart disease, marital status, educational level, and physical activity Age, sex, geographic area, occupation, blood pressure, smoking, serum cholesterol, BMI, and diabetes, intakes of energy, cholesterol, saturated fatty acids, fiber, vitamin E, vitamin C and carotene Same as above Age, sex, BMI, smoking status, pack-years of cigarette smoking, education level, and daily intakes of alcohol, coffee, polyunsaturated fat, saturated fat, fiber, vitamin E, and total energy Age, energy intake, marital status, education, blood pressure, diabetes, BMI, waist-to-hip ratio, physical activity, smoking, and estrogen use Same as above Age, current smoking, parental history of myocardial infarction before age 60 years, history of hypertension, hypercholesterolemia and diabetes, menopausal status, postmenopausal hormone use, use of aspirin, use of multivitamin and vitamin E supplements, BMI, physical activity, alcohol consumption, and total energy intake
Subjects
No. of deaths
CHD
805
All-causes
Rimm (1996) [14]
USA
Health Professionals follow-up Study
6
40e75
CHD
38,036
140
Male
Hertog (1997) [15]
UK
Caerphilly study
14
45e59
IHD
1900
131
Male
All-causes
1900
338
Male
Hirvonen (2001) [16]
Finland
Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study
6.1
50e69
CHD
25,372
815
Male
Knekt (2002) [18]
Finland
Finnish mobile clinic health examination survey
28
54.0 ± 10.6
IHD
9131
681
Male and Female
Geleijnse (2002) [17]
Netherlands
Rotterdam Study
5.6
53.3 ± 12.8 55
All-causes MI
9131 4807
2085 30
Male and Female Male and Female
Mink (2007) [21]
USA
Iowa Women's Health Study
16
55e69
CVD
34,492
2316
Female
Lin (2007) [20]
USA
Nurses' Health Study
12
30e55
All-causes CHD
34,492 66,360
7091 324
Female Female
Y. Kim, Y. Je / Clinical Nutrition ESPEN xxx (2017) e1ee10
Please cite this article in press as: Kim Y, Je Y, Flavonoid intake and mortality from cardiovascular disease and all causes: A meta-analysis of prospective cohort studies, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.03.004
Table 1 Characteristics of prospective cohort studies included in the meta-analysis of flavonoid consumption and CVD-specific or total mortality.
Japan
Japan Public Health Center-Based Study
12.5
40e59
CVD
27,063
175
Male
Mursu (2008) [22]
Finland
Kuopio Ischemic Heart Disease Risk Factor Study
15.2
42e60
CVD CVD
27,435 1950
57 153
Female Male
McCullough (2012) [23]
USA
Cancer Prevention Study II Nutrition Cohort
7
69.5 (mean)
CVD
98,469
2771
Male and Female
Zamora-Ros (2013) [24]
Spain
EPIC-Spain cohort
13.6
29e70
All-causes
40,622
1915
Male and Female
Tresserra-Rimbau (2014) [27]
Spain
PREDIMED study
4.8y
Male (55e80 y) Female (60-80y)
All-causes
7172
327
Male and Female
Ivey (2015) [25]
Australia
Calcium Intake Fracture Outcome Age Related Extension Study
5
>75
CVD
1063
78
Female
Ponzo (2015) [26]
Italy
Local Health Units of the province of Asti
12
45e64
All-causes CVD
1063 1658
129 60
Female Male and Female
All-causes
1658
158
Male and Female
Age, sex, smoking, alcohol use, BMI, history of hypertension or diabetes mellitus, medication use for Hypercholesterolemia, education level, sports, dietary intake of fruits, vegetables, fish, salt, and energy, center Same as above plus menopausal status Age, examination years, BMI, systolic blood pressure, hypertension medication, serum HDLand LDL-cholesterol, serum TAG, maximal oxygen uptake, smoking, CVD in family, diabetes, alcohol intake, energy-adjusted intake of folate and vitamin E, total fat (percentage of energy) and saturated fat intake (percentage of energy) Age, sex, smoking, beer and liquor intake, history of hypertension, history of cholesterol, family history of myocardial infarction, BMI, physical activity, energy intake, aspirin use, hormone replacement therapy (in women only) Age, sex, BMI, education level, physical activity, tobacco smoking, lifetime alcohol consumption, total energy, vitamin C and fiber intake. Age, smoking, BMI, baseline diabetes, alcohol, total energy intake, physical activity, family history of CVD or cancer, aspirin use, antihypertensive drug use, use of cardiovascular medication, use of oral hypoglycaemic agents, insulin, other medication, intake of protein, saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids and cholesterol Age, prevalent cardiovascular disease and cancer, overweight or obesity, low fruit and vegetable intake, physical inactivity, current cigarette smoking, alcohol consumption. Same as above Age, sex, BMI, education, living in a rural area, METs (hour/week), fiber, and saturated fatty acid intakes, alcohol intake, smoking, values of systolic and diastolic blood pressure, total and HDL cholesterol, fasting glucose, CRP, statin and aspirin use Same as above
Y. Kim, Y. Je / Clinical Nutrition ESPEN xxx (2017) e1ee10
n con Dieta CHD, coronary heart disease; CVD, cardiovascular disease; EPIC, European Prospective Investigation into Cancer and Nutrition; IHD, ischemic heart disease; MI, myocardial infarction; PREDIMED, Prevencio Mediterr anea.
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Please cite this article in press as: Kim Y, Je Y, Flavonoid intake and mortality from cardiovascular disease and all causes: A meta-analysis of prospective cohort studies, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.03.004
Kokubo (2007) [19]
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Y. Kim, Y. Je / Clinical Nutrition ESPEN xxx (2017) e1ee10
Fig. 2. Forest plot of prospective cohort studies of CVD mortality for the highest versus lowest category of flavonoid intake, using a random-effects model.
3.3. Doseeresponse meta-analysis Twelve [12,13,15e17,19e23,25,26] and seven studies [12,13,15, 21,24,26,27] were included for the doseeresponse meta-analysis of CVD mortality and total mortality, respectively. There was evidence of a nonlinear association between flavonoid intake and CVD mortality (P nonlinearity ¼ 0.005, Fig. 4), with a significant risk reduction up to a daily flavonoid intake of 167.5 mg and further increases showed a suggestive inverse association with CVD mortality. There was no evidence of a nonlinear association between flavonoid intake and total mortality (P nonlinearity ¼ 0.06). When we assumed a linear relationship, the pooled RR of CVD mortality for a 50 mg/day increment in flavonoid intake was 0.98 (95% CI: 0.96, 1.00), with moderate heterogeneity (I2 ¼ 59.2%, P ¼ 0.003). For total mortality, the pooled RR for an increase in flavonoid intake of 50 mg/day was 0.99 (95% CI: 0.96, 1.01), with moderate heterogeneity (I2 ¼ 61.4%, P ¼ 0.01). 3.4. Publication bias There was no evidence of publication bias in the meta-analysis of CVD mortality (Begg's P ¼ 0.38; Egger's P ¼ 0.51). For the meta-analysis of total mortality, the Begg's test showed some evidence of bias (P ¼ 0.04); however, evidence of bias was not shown in the Egger regression asymmetry test (P ¼ 0.21). 4. Discussion The current systematic review and meta-analysis of 15 prospective cohort studies including 386,610 individuals and 16,693
deaths examined the association between flavonoid intake and mortality from CVD and all-causes. High flavonoid intake was significantly associated with low mortality from CVD and allcauses. People in the highest category of flavonoid intake had 14% lower risk of mortality from CVD and all-causes compared with those who were in the lowest category. The inverse association did not differ by sex, geographical region and degree of adjustment. The results of subgroup analysis by subclass of flavonoids suggested that flavan-3-ols, flavones, flavanones, anthocyanidins and proanthocyanidins were inversely associated with CVD mortality. A nonlinear inverse relationship was found between flavonoid intake and CVD mortality (P nonlinearity ¼ 0.005), with a significant inverse association up to a daily flavonoid intake of 167.5 mg. We found some evidence of heterogeneity among the studies in the meta-analysis for CVD mortality and total mortality, but the observed heterogeneity disappeared after excluding one study (I2 ¼ 38.1%, P ¼ 0.08 for CVD mortality, I2 ¼ 44.1%, P ¼ 0.10 for total mortality), which was targeted on the elderly population aged 75 years or more in Australia and showed a strong inverse association between flavonoid intake and mortality from CVD and all-causes [25]. Although our analysis by baseline median age (>45 years vs. 45 years for CVD mortality, >50 years vs. 50 years for total mortality) showed no significant difference for the association, additional prospective cohort studies targeting seniors are required to examine the effect of flavonoid intake on mortality in the elderly population. Fruit and vegetables which are sources of flavonoids also contain dietary fiber, and thus it is difficult to be certain that the inverse association between flavonoid intake and mortality from CVD and all-causes is the effect of flavonoids only. However, the
Please cite this article in press as: Kim Y, Je Y, Flavonoid intake and mortality from cardiovascular disease and all causes: A meta-analysis of prospective cohort studies, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.03.004
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Table 2 Pooled relative risks of mortality from CVD and all-causes according to flavonoid intake in a meta-analysis of prospective cohort studies. Study
Number of studies
CVD mortality All studies 13 Sex Male 8 Female 6 Geographical region Europe 7 USA 4 Asia 1 Oceania 1 b Follow-up time <12 years 6 12 years 7 Baseline median age >45 years 6 45 years 7 Adjustment for smoking, BMI, alcohol and physical activity Yes 5 No 8 Class of flavonoids Flavan-3-ols 5 Flavonols 5 Isoflavones 4 Flavones 4 Flavanones 4 Anthocyanidins 4 Proanthocyanidins 3 Total mortality All studies 8 Sex Male 3 Female 3 Geographical region Europe 6 USA 1 Oceania 1 Follow-up timee <12.8 years 4 12.8 years 4 Baseline median age >50 years 4 50 years 4 Adjustment for smoking, BMI, alcohol and physical activity Yes 3 No 5
Relative risk
95% CI
Heterogeneity
P for difference
I2 (%)
P
0.86
0.75, 0.98
50.6
0.02
0.89 0.81
0.73, 1.08 0.68, 0.96
52.2 43.1
0.04 0.12
0.87 0.86 1.15 0.34
0.66, 0.79, 0.66, 0.17,
1.15 0.93 2.01 0.68
61.4 0 0 e
0.02 0.55 0.56 e
0.66 0.95
0.50, 0.87 0.86, 1.05
66.0 0
0.01 0.54
0.06
0.74 0.96
0.60, 0.92 0.82, 1.12
71.7 0
0.003 0.49
0.12
0.79 0.89
0.63, 0.99 0.74, 1.08
35.8 55.9
0.17 0.03
0.27
0.86 0.92 0.97 0.86 0.86 0.89 0.89
0.74, 0.79, 0.89, 0.77, 0.76, 0.83, 0.82,
0.99 1.07 1.07 0.97 0.97 0.95 0.98
42.7 44.1 0 21 31.2 0 0
0.14 0.13 0.51 0.28 0.23 0.65 0.73
0.86
0.73 1.00
67.6
0.003
0.92 0.71
0.63, 1.35 0.47, 1.08
77.1 84.1
0.01 0.002
0.89 0.96 0.38
0.74 1.06 0.89, 1.04 0.22, 0.65
49.5 e e
0.08 e e
0.69 0.96
0.50, 0.93 0.83, 1.10
54.6 59.8
0.09 0.06
0.15
0.74 0.92
0.52, 1.04 0.73, 1.17
77.4 63.9
0.004 0.04
0.41
0.78 0.88
0.63, 0.98 0.72, 1.08
0 78.4
0.74 0.001
0.77
0.72
0.65a 0.56a 0.07a
0.77c 0.13c 0.94c 0.98c 0.75c 0.71c
0.46
0.71d 0.06d
a P value for the difference in RRs (when all regions were included in the meta-regression model simultaneously): USA versus the Europe, P ¼ 0.65; Asia versus Europe, P ¼ 0.56; Oceania versus Europe, P ¼ 0.07. b The median follow-up time for studies included in the analysis of CVD mortality was 12 years. c P value for the difference in RRs (when all types of flavonoids were included in the meta-regression model simultaneously): flavonols versus flavan-3ols, P ¼ 0.77; isoflavones versus flavan-3ols, P ¼ 0.13; flavones versus flavan-3ols, P ¼ 0.94; flavanones versus flavan-3ols, P ¼ 0.98; anthocyanidins versus flavan-3ols, P ¼ 0.75; proanthocyanidins versus flavan-3ols, P ¼ 0.71. d P value for the difference in RRs (when all regions were included in the meta-regression model simultaneously): USA versus the Europe, P ¼ 0.71; Oceania versus Europe, P ¼ 0.06. e The median follow-up time for studies included in the analysis of total mortality was 12.8 years.
results remained significant when we performed the analysis limited to studies that adjusted for intake of dietary fiber, and the differences by adjustment for dietary fiber intake were not significant. Only three studies among all of the studies included in our meta-analysis reported RRs of all-cancer mortality [15,24,25]. One study indicated a strong inverse association between flavonoid intake and all-cancer mortality (RR ¼ 0.25, 95% CI: 0.10, 0.62) [25], but the other two studies showed nonsignificant associations [15,24]. More prospective cohort studies are needed to allow for conducting a meta-analysis of all-cancer mortality in relation to flavonoid intake.
A previous meta-analysis that examined the association between flavonoid intake and CVD risk indicated that flavonols, anthocyanidins, proanthocyanidins, flavones, flavan-3-ols and flavanones were inversely associated with the incidence of CVD [10]. The previous results were consistent with our results of subgroup analysis by subclass of flavonoids which showed that all subclasses except flavonols and isoflavones were inversely associated with CVD mortality. The other meta-analysis also reported that risk of CHD was inversely associated with intakes of total flavonoids [11]. This protective effect of flavonoid intake may be explained by several potential mechanisms. The development of CVD can be prevented by antioxidant, anti-inflammatory and
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Study ID
RR (95% CI)
Hertog (1993)
0.72 (0.50, 1.04)
Hertog (1997)
1.40 (0.99, 1.98)
Knekt (2002)
0.92 (0.81, 1.05)
Mink (2007)
0.96 (0.89, 1.04)
Zamora-Ros (2013)
0.71 (0.49, 1.03)
Tresserra-Rimbau (2014)
0.89 (0.58, 1.36)
Ivey(2015)
0.38 (0.22, 0.65)
Ponzo(2015)
0.78 (0.54, 1.12)
Overall (I-squared = 67.6%, p = 0.003)
0.86 (0.73, 1.00)
NOTE: Weights are from random effects analysis
.2
.5
1
1.5
2
Relative Risk (95% CI) Fig. 3. Forest plot of prospective cohort studies of total mortality for the highest versus lowest category of flavonoid intake, using a random-effects model.
vasodilator functions [10]. Flavonoids can decrease oxidative damage through free radical scavenging activity because they have hydroxyl groups [42]. The antioxidant property of flavonoids can be linked to anti-inflammatory action [43]. High flavonoid intakes were associated with low established biomarkers of inflammation such as NF-kB and C-reactive protein [43]. In addition, flavonoid can induce flow-mediated dilatation [44] through influencing the levels of nitric oxide, which is a potent vasodilator [43]. Accumulating evidence from previous meta-analyses has reported that flavonoid intake is inversely associated with risk of smoking-related cancer [45], breast cancer [46] and type 2 diabetes [47]. High flavonoid intake may help to reduce the risk of total
Fig. 4. Doseeresponse relations between flavonoid intake and CVD mortality.
mortality via decreasing the incidence of these diseases although our analysis suggested a weak inverse association between flavonoid and mortality from all-causes. To the best of our knowledge, this was the first comprehensive meta-analysis to examine the relationship between flavonoid intake and CVD mortality as well as total mortality. In addition, we explored the effect of flavonoid intake on the risk of mortality by carrying out nonlinear doseeresponse analyses. Previous metaanalyses were carried out on the basis of an assumption of a linear trend. We also included prospective cohort studies only in this meta-analysis. The design of prospective study can minimize the possibility of recall or selection bias, which could be of concern in other observational studies. In addition, our results by subclass of flavonoids may give an idea for future research to explore relations between flavonoid intake and mortality. Finally, a large number of populations (338,541 for CVD mortality, 97,118 for total mortality) enhanced the statistical power of this metaanalysis. There are also some limitations that should be acknowledged in the current meta-analysis. First, because most of the studies measured exposure to flavonoids using food frequency questionnaires and flavonoids are present in a wide variety of foods, some misclassification of flavonoid intake is inevitable. However, this misclassification could be nondifferential and biased our results towards the null, and thus the pooled RR of association between flavonoid intake and mortality might have been under-estimated rather than over-estimated. Second, although we pooled the estimate using the RRs that reflected the greatest degree of control for potential confounding variables, we cannot rule out the possibility that unmeasured or residual confounding inherent in original studies might have affected the observed association. When we limited to studies that had adjusted for at least smoking, BMI, alcohol consumption and physical activity for the meta-analysis,
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we found a stronger inverse association between flavonoid intake and mortality from CVD and all-causes. In conclusion, results from this systematic review and metaanalysis of prospective cohort studies suggest that a high flavonoid intake is associated with low mortality from CVD and allcauses. These results are consistent with current recommendations to increase consumption of fruit and vegetables, which contain high flavonoids, as a part of a healthy diet. Further welldesigned prospective cohort studies that adjust for all potential confounders should be conducted in various populations with a wide range of age before recommending flavonoid intake as a public health strategy to prevent the deaths from CVD and allcauses. Funding This work was supported by the Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Science, ICT and Future Planning (NRF2015R1A1A1A05001362). Funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Statement of authorship YJ developed study concept and design and contributed to critical revision of the manuscript for important intellectual content; YK wrote the draft of manuscript and conducted statistical analyses; YK and YJ extracted the data, contributed to discussion and reviewed/edited the manuscript. All authors have read and approved the final version submitted for publication. Conflict of interest There are no conflicts of interest to disclose. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.clnesp.2017.03.004. References [1] Zhan J, Liu YJ, Cai LB, Xu FR, Xie T, He QQ. Fruit and vegetable consumption and risk of cardiovascular disease: a meta-analysis of prospective cohort studies. Crit Rev Food Sci Nutr 2017 May 24;57(8):1650e63. [2] Wang X, Ouyang Y, Liu J, Zhu M, Zhao G, Bao W, et al. Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies. BMJ 2014;349:g4490. [3] Yang Q, Liu T, Kuklina EV, Flanders WD, Hong Y, Gillespie C, et al. Sodium and potassium intake and mortality among US adults: prospective data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 2011;171:1183e91. [4] Guasch-Ferre M, Bullo M, Estruch R, Corella D, Martinez-Gonzalez MA, Ros E, et al. Dietary magnesium intake is inversely associated with mortality in adults at high cardiovascular disease risk. J Nutr 2014;144:55e60. [5] Kim Y, Je Y. Dietary fiber intake and total mortality: a meta-analysis of prospective cohort studies. Am J Epidemiol 2014;180:565e73. [6] Kim Y, Je Y. Dietary fibre intake and mortality from cardiovascular disease and all cancers: a meta-analysis of prospective cohort studies. Arch Cardiovasc Dis 2016;109:39e54. [7] Bravo L. Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr Rev 1998;56:317e33. [8] Kozlowska A, Szostak-Wegierek D. Flavonoidsefood sources and health benefits. Rocz Panstw Zakl Hig 2014;65:79e85. [9] Vita JA. Polyphenols and cardiovascular disease: effects on endothelial and platelet function. Am J Clin Nutr 2005;81:292Se7S.
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Original article
Flavonoid intake and mortality from cardiovascular disease and all causes: A meta-analysis of prospective cohort studies Youngyo Kim, Youjin Je* Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea
a r t i c l e i n f o
s u m m a r y
Article history: Received 5 October 2016 Accepted 22 March 2017
Background and aims: Accumulating studies have suggested that flavonoid intake is associated with a decreased risk of coronary heart disease and cardiovascular disease (CVD). There are many epidemiological studies on flavonoid intake and mortality, but no comprehensive investigation has yet been conducted. To quantitatively assess the association between flavonoid intake and mortality from CVD and all-causes, we performed a meta-analysis of prospective cohort studies. Methods: Eligible studies were identified by searching PubMed and Web of Science databases for all articles published up to May 2016 and via hand searching. Study-specific estimates adjusting for potential confounders were combined to calculate a pooled relative risk (RR) with 95% confidence interval (CI) using a random-effects model. Results: A total of 15 prospective cohort studies that examined the association between flavonoid intake and mortality from CVD and all-causes were identified. The pooled RR of CVD mortality for the highest versus lowest category of flavonoid intake was 0.86 (95% CI: 0.75, 0.98). By subclass of flavonoids, all classes, except flavonols and isoflavones, showed significant inverse associations. A nonlinear association was found between flavonoid intake and CVD mortality in the doseeresponse analysis. For total mortality, a high intake of flavonoids was associated with lower total mortality (pooled RR ¼ 0.86, 95% CI: 0.73, 1.00). Conclusions: Our findings indicate that a high intake of flavonoids is associated with reduced risk of mortality from CVD and all causes in men and women. These results support current recommendations of high fruit and vegetables intake as a part of a healthy diet. © 2017 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
Keywords: Flavonoids Cardiovascular disease Coronary heart disease Mortality Prospective cohort studies
1. Introduction Accumulating scientific evidence has suggested that a high intake of fruit and vegetables is inversely associated with the risk of cardiovascular disease (CVD) incidence [1] and mortality from allcauses and CVD [2]. The beneficial effect of fruit and vegetables may result from potassium [3], magnesium [4] and dietary fiber [5,6], which have been inversely associated with mortality in recent studies. However, flavonoids also may be responsible for the protective association between fruit and vegetables and mortality. Flavonoids are polyphenolic compounds, which are a wide group of
Abbreviations: CVD, cardiovascular disease; CHD, coronary heart disease; RR, relative risk; CI, confidence interval. *Corresponding author. Department of Food and Nutrition, Kyung Hee University, 26 Kyunghee-daero, Dongdaemun-gu, Seoul 02447, South Korea. E-mail address: [email protected] (Y. Je).
secondary metabolites present in plant-based foods [7]. Flavonoids have antioxidant properties and thus may reduce low density lipoproteins, which is considered the main cause of atherosclerotic diseases, by inactivating reactive oxygen species [8]. Furthermore, flavonoids also ameliorate the blood vessel endothelium by reducing the risk of clot formation due to their anti-aggregating properties [9]. Results from recent meta-analyses showed a significant inverse association between total flavonoid intake or intake of subclass of flavonoids and incidence of CVD [10] and coronary heart disease (CHD) [11]. Many prospective cohort studies also have examined the effect of flavonoid intake on risk of mortality from CVD or all-causes to date [12e27]. Some studies have reported significant inverse associations between flavonoid intake and mortality from CVD or all-causes [12,17,23,25], but other studies have found nonsignificant inverse or positive associations [14e16,18e22,24,26,27]. As the results of these studies remained inconsistent, we conducted a
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Two investigators (Y.K. and Y.J.) independently performed data extraction based on the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines [30], and any discrepancies were solved via reviewing the original article and discussion. The following information was extracted from each study: first author's last name, year of publication, country name, cohort name, duration of follow-up, number of cases and participants, adjustment factors, and “most fully adjusted” RRs with 95% CIs across each exposure category.
were provided for both total flavonoid intake and subclass of flavonoid intake from the same cohort [12,33], and the RRs for subclass of flavonoid intake [33] were used in the subgroup analysis by flavonoid classes. Likewise, if two individual publications from the same cohort [13,18] reported sex-specific RRs [13] and overall RR [18], respectively, we included the overall RR in the main analysis, and the sex-specific RRs were used in stratified analysis by sex. The summary RRs and study-specific RRs were presented as forest plots where the size of data markers (squares) corresponds to the inverse of the variance of the natural logarithm of RR from each study, and the diamond indicates the pooled RR. The Q-statistic [34] was used to assess statistical heterogeneity among the studies, and inconsistency was quantified by I2 statistic [35]. We performed a doseeresponse meta-analysis using generalized least-squares trend (GLST) estimation method based on the method developed by Greenland and Longnecker [36e38]. When a study did not provide median consumption of the category, we assigned an approximate median by calculating the midpoint of the lower and higher bounds. The highest, open-ended category was considered to have the same interval of intake as the adjacent category. One study that reported flavonoid intake as only two categories [14] was not included in this analysis. Although one article did not report the number of cases in each category [18], another one from the same cohort provided all data, and we thus included the latter in a doseeresponse meta-analysis [13]. We also assessed a potential nonlinear doseeresponse relationship between flavonoid intake and mortality by modeling flavonoid intake levels using restricted cubic splines with 3 knots at fixed percentiles (10th, 50th and 90th) of the distribution. A P value for nonlinearity was computed by testing the null hypothesis that the coefficient of the second spline is equal to zero [39]. To examine whether the present results were affected by a single study, we conducted a sensitivity analysis by excluding one study at a time. We also performed a stratified analysis and metaregression analysis by sex, geographical region, duration of follow-up, median age of baseline, class of flavonoids, and adjustment factors (body mass index [BMI], physical activity, smoking, alcohol consumption, intake of dietary fiber) for evaluation of the variations in pooled risk estimates by study characteristics. Finally, the tests of Begg and Mazumdar [40] and Egger et al. [41] were used to assess publication bias. A two-tailed P value of <0.05 was considered statistically significant. All statistical analyses were conducted using Stata/SE software, version 12.0 (Stata-Corp LP, College Station, Texas).
2.3. Quality assessment for individual studies
3. Results
We assessed the quality of each study using the NewcastleeOttawa quality assessment scale [31]. The following perspectives were considered; representativeness of the exposed cohort; dietary survey methods of flavonoid intake; comparability of cohorts (adjustment for important confounders); assessment of outcome; duration of follow-up; and adequacy of follow-up. A score of 10 or higher (out of 13) indicates as a high-quality study, scores of 7e9 indicate a good-quality study, and a score of 6 or less indicates a low-quality study.
3.1. Study characteristics
systematic review and meta-analysis of prospective cohort studies to quantitatively assess the association between flavonoid intake and mortality from CVD and all-causes in the current study. In addition, we examined whether a doseeresponse relationship was present between flavonoid intake and mortality from CVD and allcauses. 2. Methods 2.1. Literature search and study selection We used the PubMed and Web of Science databases to identify eligible studies published in English and full-paper through May 2016. The following search keywords were used: (“flavonoids” OR “flavonols” OR “flavones” OR “anthocyanidins” OR “flavanones” OR “flavan-3-ols” OR “catechins” OR “proanthocyanidins” OR “quercetin” OR “myricetin” OR “kaempferol” OR “isorhamnetin” OR “apigenin” OR “luteolin”) combined with (“mortality” OR “death” OR “fatal cardiovascular disease” OR “fatal coronary heart disease” OR “fatal ischemic heart disease (IHD)” OR “fatal myocardial infarction (MI)” OR “fatal stroke” OR “fatal CVD” OR “fatal CHD” OR “fatal IHD” OR “fatal MI”). We also identified additional studies by manually searching the reference lists in the selected articles. We included studies in this meta-analysis if they met the following criteria: 1) studies with a prospective cohort design; 2) the exposure of interest was total flavonoids or flavonoid classes; 3) the outcome of interest was the mortality from CVD, CHD, IHD or allcauses; and 4) studies that reported relative risks (RR) with 95% CI. For 3 studies [21,28,29] that provided RRs for the association between flavonoid intake and CHD mortality from the same cohort, Iowa Women's Health Study, we included RRs from more recent and larger study [21]. 2.2. Data extraction
2.4. Statistical analysis We combined a natural logarithm of the RR of each study using the DerSimonian and Laird random-effects models that incorporate both within-and between-study variations [32] to calculate a pooled RR and its 95% CI for the highest versus lowest category of flavonoid intake from original studies. We included the effect estimates of total flavonoid intake in the main analysis [12] when RRs
The detailed process of the literature search is shown in Fig. 1. We identified a total of 15 prospective cohort studies [12e25,27,33] that provided the results for mortality from CVD or all-causes related to flavonoid intake. The main characteristics of the included studies are presented in Table 1. The duration of follow-up ranged from 4.8 to 28 years, and the median follow-up time was 12.0 years for CVD mortality and 12.8 years for total mortality. The study population was all adults (age 29 years) at baseline. With regard to geographical region, nine studies were carried out in Europe [12,15e18,22,24,26,27], four in the USA [14,20,21,23], one in Asia [19] and one in Oceania [25]. By sex, seven studies included both male and female subjects [17e19,23,24,26,27], and eight studies included male [12,14e16,22] or female [20,21,25] subjects only. Seven studies provided RRs by class of flavonoids (flavan-3-ols/flavonols isoflavones/flavones/flavanones/anthocyanidins/proanthocyanidins) [15,19,21e23,26,33]. Most of the studies
Please cite this article in press as: Kim Y, Je Y, Flavonoid intake and mortality from cardiovascular disease and all causes: A meta-analysis of prospective cohort studies, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.03.004
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Fig. 1. Process used to select prospective cohort studies for meta-analysis of the association between flavonoid intake and CVD and total mortality.
measured flavonoid intake using food frequency questionnaires [14,15,19e21,23,25e27], four studies assessed the intake through interviews [12,17,18,24] and one study used 4-day food records [22]. All of the studies adjusted for age and smoking, and most of the studies provided RRs adjusted for BMI (n ¼ 14) [12,14e24,26,27] and alcohol consumption (n ¼ 11) [12,15,17,19,20,22e27]. Nine studies adjusted for physical activity [16,19e21,23e27]. The assessment of study quality yielded a mean score of 10.4 (range, 8e12). Eleven studies had a score of 10 or above, showing high quality [12,15,17e22,24e26], and the other studies had scores of 8 or 9, indicating good quality [14,16,23,27]. 3.2. Highest flavonoid intake versus lowest 3.2.1. Flavonoid intake and CVD mortality A total of 13 studies including 338,541 participants and 7774 deaths were included in the meta-analysis [12,14e23,25,26]. The pooled RR of CVD mortality was 0.86 (95% CI: 0.75, 0.98), with moderate heterogeneity (I2 ¼ 50.6%, P ¼ 0.02) (Fig. 2). The sensitivity analysis that excluded one study at a time and estimated the pooled RR with the remaining studies showed that the pooled RRs ranged from 0.84 (95% CI: 0.71, 0.98) to 0.88 (95% CI: 0.78, 0.99), which indicated robust results (data not shown). Table 2 shows the results of subgroup analyses. The inverse association between flavonoid intake and risk of CVD mortality was not significantly different by sex (P for difference ¼ 0.72). The differences by geographical region or median age of baseline were not statistically significant, either (P for differences 0.07 in all comparisons). To examine the difference by duration of follow-up, we
chose a median follow-up time of 12.0 years as a cut off. The studies with short follow-up times (<12.0 years) showed a stronger inverse association between flavonoid intake and CVD mortality (RR ¼ 0.66, 95% CI: 0.50, 0.87), as compared to those with long follow-up times (12.0 years) (RR ¼ 0.95, 95% CI: 0.86, 1.05) (P for difference ¼ 0.06). When we limited the analysis to five studies that had all adjusted for smoking, alcohol consumption, BMI and physical activity, the inverse association was stronger (RR ¼ 0.79, 95% CI: 0.63, 0.99), but the difference by adjustment was not significant (P for difference ¼ 0.27). In addition, the results from subgroup analysis by adjustment for intake of dietary fiber were not significantly different (P for difference ¼ 0.32) (data not shown). Regarding the results of subgroup analysis by class of flavonoids, all classes showed significant inverse associations, except two classes (flavonols and isoflavones) that showed nonsignificant inverse associations. 3.2.2. Flavonoid intake and total mortality Eight studies with 97,118 participants and 12,228 deaths were included in the meta-analysis [12,15,18,21,24e27]. The pooled RR of total mortality was 0.86 (95% CI: 0.73, 1.00), with substantial heterogeneity (I2 ¼ 67.6%, P ¼ 0.003) (Fig. 3). When we performed a sensitivity analysis that omitted one study at a time, the pooled RRs ranged from 0.81 (95% CI: 0.65, 1.02) to 0.92 (95% CI: 0.82, 1.03) (data not shown). The results of subgroup analyses by study characteristics are presented in Table 2. The differences by sex, geographical region, follow-up times, median age of baseline, and adjustment factors (smoking/BMI/alcohol/physical activity) were not significant (P for difference >0.06 in all comparisons).
Please cite this article in press as: Kim Y, Je Y, Flavonoid intake and mortality from cardiovascular disease and all causes: A meta-analysis of prospective cohort studies, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.03.004
First author (year)
Hertog (1993) [12]
Country
Netherlands
Cohort name
Zutphen Elderly Study
Follow-up period (years)
Age at baseline (y)
Cause of death
5
65e84
Study size
e4
Sex
Adjustment for covariates
43
Male
805
185
Male
Age, intake of total energy, saturated fatty acids, cholesterol, alcohol, coffee, vitamin C, vitamin E, beta-carotene, dietary fiber, history of myocardial infarction, BMI, smoking, serum total and HDL cholesterol, systolic blood pressure Age, prevalence of chronic disease, intake of total energy, saturated fatty acids, physical activity, BMI, smoking, serum total and HDL cholesterol, blood pressure Age, BMI, smoking, diabetes, profession, hypertension, high cholesterol levels, family history of CHD, intake of vitamin E, alcohol, dietary fiber, carotene and saturated fat Age, smoking (never, exsmoker, or current smoker), baseline evidence of ischemic heart disease, social class, BMI, systolic blood pressure, serum total cholesterol, and intakes of total energy, alcohol, fat, vitamin C, vitamin E, and beta-carotene. Age, smoking (never, exsmoker, or current smoker), social class, BMI, and intakes of total energy, alcohol, fat, vitamin C, vitamin E, and beta-carotene. Age, supplementation group, systolic and diastolic blood pressure, serum total cholesterol, serum high-density lipoprotein cholesterol, BMI, smoking years, number of cigarettes smoked daily, history of diabetes mellitus or coronary heart disease, marital status, educational level, and physical activity Age, sex, geographic area, occupation, blood pressure, smoking, serum cholesterol, BMI, and diabetes, intakes of energy, cholesterol, saturated fatty acids, fiber, vitamin E, vitamin C and carotene Same as above Age, sex, BMI, smoking status, pack-years of cigarette smoking, education level, and daily intakes of alcohol, coffee, polyunsaturated fat, saturated fat, fiber, vitamin E, and total energy Age, energy intake, marital status, education, blood pressure, diabetes, BMI, waist-to-hip ratio, physical activity, smoking, and estrogen use Same as above Age, current smoking, parental history of myocardial infarction before age 60 years, history of hypertension, hypercholesterolemia and diabetes, menopausal status, postmenopausal hormone use, use of aspirin, use of multivitamin and vitamin E supplements, BMI, physical activity, alcohol consumption, and total energy intake
Subjects
No. of deaths
CHD
805
All-causes
Rimm (1996) [14]
USA
Health Professionals follow-up Study
6
40e75
CHD
38,036
140
Male
Hertog (1997) [15]
UK
Caerphilly study
14
45e59
IHD
1900
131
Male
All-causes
1900
338
Male
Hirvonen (2001) [16]
Finland
Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study
6.1
50e69
CHD
25,372
815
Male
Knekt (2002) [18]
Finland
Finnish mobile clinic health examination survey
28
54.0 ± 10.6
IHD
9131
681
Male and Female
Geleijnse (2002) [17]
Netherlands
Rotterdam Study
5.6
53.3 ± 12.8 55
All-causes MI
9131 4807
2085 30
Male and Female Male and Female
Mink (2007) [21]
USA
Iowa Women's Health Study
16
55e69
CVD
34,492
2316
Female
Lin (2007) [20]
USA
Nurses' Health Study
12
30e55
All-causes CHD
34,492 66,360
7091 324
Female Female
Y. Kim, Y. Je / Clinical Nutrition ESPEN xxx (2017) e1ee10
Please cite this article in press as: Kim Y, Je Y, Flavonoid intake and mortality from cardiovascular disease and all causes: A meta-analysis of prospective cohort studies, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.03.004
Table 1 Characteristics of prospective cohort studies included in the meta-analysis of flavonoid consumption and CVD-specific or total mortality.
Japan
Japan Public Health Center-Based Study
12.5
40e59
CVD
27,063
175
Male
Mursu (2008) [22]
Finland
Kuopio Ischemic Heart Disease Risk Factor Study
15.2
42e60
CVD CVD
27,435 1950
57 153
Female Male
McCullough (2012) [23]
USA
Cancer Prevention Study II Nutrition Cohort
7
69.5 (mean)
CVD
98,469
2771
Male and Female
Zamora-Ros (2013) [24]
Spain
EPIC-Spain cohort
13.6
29e70
All-causes
40,622
1915
Male and Female
Tresserra-Rimbau (2014) [27]
Spain
PREDIMED study
4.8y
Male (55e80 y) Female (60-80y)
All-causes
7172
327
Male and Female
Ivey (2015) [25]
Australia
Calcium Intake Fracture Outcome Age Related Extension Study
5
>75
CVD
1063
78
Female
Ponzo (2015) [26]
Italy
Local Health Units of the province of Asti
12
45e64
All-causes CVD
1063 1658
129 60
Female Male and Female
All-causes
1658
158
Male and Female
Age, sex, smoking, alcohol use, BMI, history of hypertension or diabetes mellitus, medication use for Hypercholesterolemia, education level, sports, dietary intake of fruits, vegetables, fish, salt, and energy, center Same as above plus menopausal status Age, examination years, BMI, systolic blood pressure, hypertension medication, serum HDLand LDL-cholesterol, serum TAG, maximal oxygen uptake, smoking, CVD in family, diabetes, alcohol intake, energy-adjusted intake of folate and vitamin E, total fat (percentage of energy) and saturated fat intake (percentage of energy) Age, sex, smoking, beer and liquor intake, history of hypertension, history of cholesterol, family history of myocardial infarction, BMI, physical activity, energy intake, aspirin use, hormone replacement therapy (in women only) Age, sex, BMI, education level, physical activity, tobacco smoking, lifetime alcohol consumption, total energy, vitamin C and fiber intake. Age, smoking, BMI, baseline diabetes, alcohol, total energy intake, physical activity, family history of CVD or cancer, aspirin use, antihypertensive drug use, use of cardiovascular medication, use of oral hypoglycaemic agents, insulin, other medication, intake of protein, saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids and cholesterol Age, prevalent cardiovascular disease and cancer, overweight or obesity, low fruit and vegetable intake, physical inactivity, current cigarette smoking, alcohol consumption. Same as above Age, sex, BMI, education, living in a rural area, METs (hour/week), fiber, and saturated fatty acid intakes, alcohol intake, smoking, values of systolic and diastolic blood pressure, total and HDL cholesterol, fasting glucose, CRP, statin and aspirin use Same as above
Y. Kim, Y. Je / Clinical Nutrition ESPEN xxx (2017) e1ee10
n con Dieta CHD, coronary heart disease; CVD, cardiovascular disease; EPIC, European Prospective Investigation into Cancer and Nutrition; IHD, ischemic heart disease; MI, myocardial infarction; PREDIMED, Prevencio Mediterr anea.
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Please cite this article in press as: Kim Y, Je Y, Flavonoid intake and mortality from cardiovascular disease and all causes: A meta-analysis of prospective cohort studies, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.03.004
Kokubo (2007) [19]
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Y. Kim, Y. Je / Clinical Nutrition ESPEN xxx (2017) e1ee10
Fig. 2. Forest plot of prospective cohort studies of CVD mortality for the highest versus lowest category of flavonoid intake, using a random-effects model.
3.3. Doseeresponse meta-analysis Twelve [12,13,15e17,19e23,25,26] and seven studies [12,13,15, 21,24,26,27] were included for the doseeresponse meta-analysis of CVD mortality and total mortality, respectively. There was evidence of a nonlinear association between flavonoid intake and CVD mortality (P nonlinearity ¼ 0.005, Fig. 4), with a significant risk reduction up to a daily flavonoid intake of 167.5 mg and further increases showed a suggestive inverse association with CVD mortality. There was no evidence of a nonlinear association between flavonoid intake and total mortality (P nonlinearity ¼ 0.06). When we assumed a linear relationship, the pooled RR of CVD mortality for a 50 mg/day increment in flavonoid intake was 0.98 (95% CI: 0.96, 1.00), with moderate heterogeneity (I2 ¼ 59.2%, P ¼ 0.003). For total mortality, the pooled RR for an increase in flavonoid intake of 50 mg/day was 0.99 (95% CI: 0.96, 1.01), with moderate heterogeneity (I2 ¼ 61.4%, P ¼ 0.01). 3.4. Publication bias There was no evidence of publication bias in the meta-analysis of CVD mortality (Begg's P ¼ 0.38; Egger's P ¼ 0.51). For the meta-analysis of total mortality, the Begg's test showed some evidence of bias (P ¼ 0.04); however, evidence of bias was not shown in the Egger regression asymmetry test (P ¼ 0.21). 4. Discussion The current systematic review and meta-analysis of 15 prospective cohort studies including 386,610 individuals and 16,693
deaths examined the association between flavonoid intake and mortality from CVD and all-causes. High flavonoid intake was significantly associated with low mortality from CVD and allcauses. People in the highest category of flavonoid intake had 14% lower risk of mortality from CVD and all-causes compared with those who were in the lowest category. The inverse association did not differ by sex, geographical region and degree of adjustment. The results of subgroup analysis by subclass of flavonoids suggested that flavan-3-ols, flavones, flavanones, anthocyanidins and proanthocyanidins were inversely associated with CVD mortality. A nonlinear inverse relationship was found between flavonoid intake and CVD mortality (P nonlinearity ¼ 0.005), with a significant inverse association up to a daily flavonoid intake of 167.5 mg. We found some evidence of heterogeneity among the studies in the meta-analysis for CVD mortality and total mortality, but the observed heterogeneity disappeared after excluding one study (I2 ¼ 38.1%, P ¼ 0.08 for CVD mortality, I2 ¼ 44.1%, P ¼ 0.10 for total mortality), which was targeted on the elderly population aged 75 years or more in Australia and showed a strong inverse association between flavonoid intake and mortality from CVD and all-causes [25]. Although our analysis by baseline median age (>45 years vs. 45 years for CVD mortality, >50 years vs. 50 years for total mortality) showed no significant difference for the association, additional prospective cohort studies targeting seniors are required to examine the effect of flavonoid intake on mortality in the elderly population. Fruit and vegetables which are sources of flavonoids also contain dietary fiber, and thus it is difficult to be certain that the inverse association between flavonoid intake and mortality from CVD and all-causes is the effect of flavonoids only. However, the
Please cite this article in press as: Kim Y, Je Y, Flavonoid intake and mortality from cardiovascular disease and all causes: A meta-analysis of prospective cohort studies, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.03.004
Y. Kim, Y. Je / Clinical Nutrition ESPEN xxx (2017) e1ee10
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Table 2 Pooled relative risks of mortality from CVD and all-causes according to flavonoid intake in a meta-analysis of prospective cohort studies. Study
Number of studies
CVD mortality All studies 13 Sex Male 8 Female 6 Geographical region Europe 7 USA 4 Asia 1 Oceania 1 b Follow-up time <12 years 6 12 years 7 Baseline median age >45 years 6 45 years 7 Adjustment for smoking, BMI, alcohol and physical activity Yes 5 No 8 Class of flavonoids Flavan-3-ols 5 Flavonols 5 Isoflavones 4 Flavones 4 Flavanones 4 Anthocyanidins 4 Proanthocyanidins 3 Total mortality All studies 8 Sex Male 3 Female 3 Geographical region Europe 6 USA 1 Oceania 1 Follow-up timee <12.8 years 4 12.8 years 4 Baseline median age >50 years 4 50 years 4 Adjustment for smoking, BMI, alcohol and physical activity Yes 3 No 5
Relative risk
95% CI
Heterogeneity
P for difference
I2 (%)
P
0.86
0.75, 0.98
50.6
0.02
0.89 0.81
0.73, 1.08 0.68, 0.96
52.2 43.1
0.04 0.12
0.87 0.86 1.15 0.34
0.66, 0.79, 0.66, 0.17,
1.15 0.93 2.01 0.68
61.4 0 0 e
0.02 0.55 0.56 e
0.66 0.95
0.50, 0.87 0.86, 1.05
66.0 0
0.01 0.54
0.06
0.74 0.96
0.60, 0.92 0.82, 1.12
71.7 0
0.003 0.49
0.12
0.79 0.89
0.63, 0.99 0.74, 1.08
35.8 55.9
0.17 0.03
0.27
0.86 0.92 0.97 0.86 0.86 0.89 0.89
0.74, 0.79, 0.89, 0.77, 0.76, 0.83, 0.82,
0.99 1.07 1.07 0.97 0.97 0.95 0.98
42.7 44.1 0 21 31.2 0 0
0.14 0.13 0.51 0.28 0.23 0.65 0.73
0.86
0.73 1.00
67.6
0.003
0.92 0.71
0.63, 1.35 0.47, 1.08
77.1 84.1
0.01 0.002
0.89 0.96 0.38
0.74 1.06 0.89, 1.04 0.22, 0.65
49.5 e e
0.08 e e
0.69 0.96
0.50, 0.93 0.83, 1.10
54.6 59.8
0.09 0.06
0.15
0.74 0.92
0.52, 1.04 0.73, 1.17
77.4 63.9
0.004 0.04
0.41
0.78 0.88
0.63, 0.98 0.72, 1.08
0 78.4
0.74 0.001
0.77
0.72
0.65a 0.56a 0.07a
0.77c 0.13c 0.94c 0.98c 0.75c 0.71c
0.46
0.71d 0.06d
a P value for the difference in RRs (when all regions were included in the meta-regression model simultaneously): USA versus the Europe, P ¼ 0.65; Asia versus Europe, P ¼ 0.56; Oceania versus Europe, P ¼ 0.07. b The median follow-up time for studies included in the analysis of CVD mortality was 12 years. c P value for the difference in RRs (when all types of flavonoids were included in the meta-regression model simultaneously): flavonols versus flavan-3ols, P ¼ 0.77; isoflavones versus flavan-3ols, P ¼ 0.13; flavones versus flavan-3ols, P ¼ 0.94; flavanones versus flavan-3ols, P ¼ 0.98; anthocyanidins versus flavan-3ols, P ¼ 0.75; proanthocyanidins versus flavan-3ols, P ¼ 0.71. d P value for the difference in RRs (when all regions were included in the meta-regression model simultaneously): USA versus the Europe, P ¼ 0.71; Oceania versus Europe, P ¼ 0.06. e The median follow-up time for studies included in the analysis of total mortality was 12.8 years.
results remained significant when we performed the analysis limited to studies that adjusted for intake of dietary fiber, and the differences by adjustment for dietary fiber intake were not significant. Only three studies among all of the studies included in our meta-analysis reported RRs of all-cancer mortality [15,24,25]. One study indicated a strong inverse association between flavonoid intake and all-cancer mortality (RR ¼ 0.25, 95% CI: 0.10, 0.62) [25], but the other two studies showed nonsignificant associations [15,24]. More prospective cohort studies are needed to allow for conducting a meta-analysis of all-cancer mortality in relation to flavonoid intake.
A previous meta-analysis that examined the association between flavonoid intake and CVD risk indicated that flavonols, anthocyanidins, proanthocyanidins, flavones, flavan-3-ols and flavanones were inversely associated with the incidence of CVD [10]. The previous results were consistent with our results of subgroup analysis by subclass of flavonoids which showed that all subclasses except flavonols and isoflavones were inversely associated with CVD mortality. The other meta-analysis also reported that risk of CHD was inversely associated with intakes of total flavonoids [11]. This protective effect of flavonoid intake may be explained by several potential mechanisms. The development of CVD can be prevented by antioxidant, anti-inflammatory and
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Study ID
RR (95% CI)
Hertog (1993)
0.72 (0.50, 1.04)
Hertog (1997)
1.40 (0.99, 1.98)
Knekt (2002)
0.92 (0.81, 1.05)
Mink (2007)
0.96 (0.89, 1.04)
Zamora-Ros (2013)
0.71 (0.49, 1.03)
Tresserra-Rimbau (2014)
0.89 (0.58, 1.36)
Ivey(2015)
0.38 (0.22, 0.65)
Ponzo(2015)
0.78 (0.54, 1.12)
Overall (I-squared = 67.6%, p = 0.003)
0.86 (0.73, 1.00)
NOTE: Weights are from random effects analysis
.2
.5
1
1.5
2
Relative Risk (95% CI) Fig. 3. Forest plot of prospective cohort studies of total mortality for the highest versus lowest category of flavonoid intake, using a random-effects model.
vasodilator functions [10]. Flavonoids can decrease oxidative damage through free radical scavenging activity because they have hydroxyl groups [42]. The antioxidant property of flavonoids can be linked to anti-inflammatory action [43]. High flavonoid intakes were associated with low established biomarkers of inflammation such as NF-kB and C-reactive protein [43]. In addition, flavonoid can induce flow-mediated dilatation [44] through influencing the levels of nitric oxide, which is a potent vasodilator [43]. Accumulating evidence from previous meta-analyses has reported that flavonoid intake is inversely associated with risk of smoking-related cancer [45], breast cancer [46] and type 2 diabetes [47]. High flavonoid intake may help to reduce the risk of total
Fig. 4. Doseeresponse relations between flavonoid intake and CVD mortality.
mortality via decreasing the incidence of these diseases although our analysis suggested a weak inverse association between flavonoid and mortality from all-causes. To the best of our knowledge, this was the first comprehensive meta-analysis to examine the relationship between flavonoid intake and CVD mortality as well as total mortality. In addition, we explored the effect of flavonoid intake on the risk of mortality by carrying out nonlinear doseeresponse analyses. Previous metaanalyses were carried out on the basis of an assumption of a linear trend. We also included prospective cohort studies only in this meta-analysis. The design of prospective study can minimize the possibility of recall or selection bias, which could be of concern in other observational studies. In addition, our results by subclass of flavonoids may give an idea for future research to explore relations between flavonoid intake and mortality. Finally, a large number of populations (338,541 for CVD mortality, 97,118 for total mortality) enhanced the statistical power of this metaanalysis. There are also some limitations that should be acknowledged in the current meta-analysis. First, because most of the studies measured exposure to flavonoids using food frequency questionnaires and flavonoids are present in a wide variety of foods, some misclassification of flavonoid intake is inevitable. However, this misclassification could be nondifferential and biased our results towards the null, and thus the pooled RR of association between flavonoid intake and mortality might have been under-estimated rather than over-estimated. Second, although we pooled the estimate using the RRs that reflected the greatest degree of control for potential confounding variables, we cannot rule out the possibility that unmeasured or residual confounding inherent in original studies might have affected the observed association. When we limited to studies that had adjusted for at least smoking, BMI, alcohol consumption and physical activity for the meta-analysis,
Please cite this article in press as: Kim Y, Je Y, Flavonoid intake and mortality from cardiovascular disease and all causes: A meta-analysis of prospective cohort studies, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.03.004
Y. Kim, Y. Je / Clinical Nutrition ESPEN xxx (2017) e1ee10
we found a stronger inverse association between flavonoid intake and mortality from CVD and all-causes. In conclusion, results from this systematic review and metaanalysis of prospective cohort studies suggest that a high flavonoid intake is associated with low mortality from CVD and allcauses. These results are consistent with current recommendations to increase consumption of fruit and vegetables, which contain high flavonoids, as a part of a healthy diet. Further welldesigned prospective cohort studies that adjust for all potential confounders should be conducted in various populations with a wide range of age before recommending flavonoid intake as a public health strategy to prevent the deaths from CVD and allcauses. Funding This work was supported by the Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Science, ICT and Future Planning (NRF2015R1A1A1A05001362). Funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Statement of authorship YJ developed study concept and design and contributed to critical revision of the manuscript for important intellectual content; YK wrote the draft of manuscript and conducted statistical analyses; YK and YJ extracted the data, contributed to discussion and reviewed/edited the manuscript. All authors have read and approved the final version submitted for publication. Conflict of interest There are no conflicts of interest to disclose. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.clnesp.2017.03.004. References [1] Zhan J, Liu YJ, Cai LB, Xu FR, Xie T, He QQ. Fruit and vegetable consumption and risk of cardiovascular disease: a meta-analysis of prospective cohort studies. Crit Rev Food Sci Nutr 2017 May 24;57(8):1650e63. [2] Wang X, Ouyang Y, Liu J, Zhu M, Zhao G, Bao W, et al. Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies. BMJ 2014;349:g4490. [3] Yang Q, Liu T, Kuklina EV, Flanders WD, Hong Y, Gillespie C, et al. Sodium and potassium intake and mortality among US adults: prospective data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 2011;171:1183e91. [4] Guasch-Ferre M, Bullo M, Estruch R, Corella D, Martinez-Gonzalez MA, Ros E, et al. Dietary magnesium intake is inversely associated with mortality in adults at high cardiovascular disease risk. J Nutr 2014;144:55e60. [5] Kim Y, Je Y. Dietary fiber intake and total mortality: a meta-analysis of prospective cohort studies. Am J Epidemiol 2014;180:565e73. [6] Kim Y, Je Y. Dietary fibre intake and mortality from cardiovascular disease and all cancers: a meta-analysis of prospective cohort studies. Arch Cardiovasc Dis 2016;109:39e54. [7] Bravo L. Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr Rev 1998;56:317e33. [8] Kozlowska A, Szostak-Wegierek D. Flavonoidsefood sources and health benefits. Rocz Panstw Zakl Hig 2014;65:79e85. [9] Vita JA. Polyphenols and cardiovascular disease: effects on endothelial and platelet function. Am J Clin Nutr 2005;81:292Se7S.
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[10] Wang X, Ouyang YY, Liu J, Zhao G. Flavonoid intake and risk of CVD: a systematic review and meta-analysis of prospective cohort studies. Br J Nutr 2014;111:1e11. [11] Jiang W, Wei H, He B. Dietary flavonoids intake and the risk of coronary heart disease: a dose-response meta-analysis of 15 prospective studies. Thromb Res 2015;135:459e63. [12] Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 1993;342:1007e11. [13] Knekt P, Jarvinen R, Reunanen A, Maatela J. Flavonoid intake and coronary mortality in Finland: a cohort study. BMJ 1996;312:478e81. [14] Rimm EB, Katan MB, Ascherio A, Stampfer MJ, Willett WC. Relation between intake of flavonoids and risk for coronary heart disease in male health professionals. Ann Intern Med 1996;125:384e9. [15] Hertog MG, Sweetnam PM, Fehily AM, Elwood PC, Kromhout D. 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Please cite this article in press as: Kim Y, Je Y, Flavonoid intake and mortality from cardiovascular disease and all causes: A meta-analysis of prospective cohort studies, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.03.004