Nutrition, Metabolism & Cardiovascular Diseases (2014) xx, 1e7
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REVIEW
Flavonoids and arterial stiffness: Promising perspectives M. Lilamand a,b,*, E. Kelaiditi a, S. Guyonnet a,c, R. Antonelli Incalzi d, A. RaynaudSimon b, B. Vellas a,c,e, M. Cesari a,c,e a
Gérontopôle, Centre Hospitalier Universitaire de Toulouse, France Service de Gériatrie, Centre Hospitalier Universitaire Bichat, Paris, France INSERM UMR 1027, Toulouse, France d Geriatria, Università Campus Bio-Medico, Roma, Italy e Université de Toulouse III Paul Sabatier, Toulouse, France b c
Received 8 November 2013; received in revised form 20 December 2013; accepted 17 January 2014 Available online - - -
KEYWORDS Flavonoids; Arterial stiffness; Wave reflection; Cardiovascular diseases
Abstract Background and aims: Flavonoids are a group of polyphenol compounds, ubiquitously found in plants. Great emphasis has been given to their possible benefits for cardiovascular health. These beneficial effects may be mediated by a specific action on arterial walls. Arterial stiffness is a marker of vascular aging, increasingly used in the clinical setting and assessed by pulse wave velocity. It has shown to be a robust predictor of cardiovascular events and mortality. This review aims at providing a comprehensive evaluation of available intervention and observational studies examining the relationship between flavonoid consumption and arterial stiffness. Data synthesis: A Medline literature search was performed using the keywords “arterial stiffness” and “flavonoids”. As a result, 2 cross-sectional and 16 intervention studies assessing the relationship between flavonoids intake and arterial stiffness were retained. Four intervention trials reported a significant decrease of arterial stiffness after a flavonoid-based intervention, independently from blood pressure changes. The two observational studies reported significant associations between a higher flavonoid consumption and a lower arterial stiffness. In this review, isoflavones, anthocyanins and to a lesser extent cocoa flavan-3-ols appeared to be the more efficient to improve vascular function. Conclusions: Despite their heterogeneity, preliminary data seem to support an improvement of the arterial stiffness related to flavonoid intake. However, further research on absorption and doseeresponse effects of the specific flavonoid subclasses on arterial structure is warranted. ª 2014 Elsevier B.V. All rights reserved.
Introduction The “French paradox” was proposed as an attractive concept to illustrate the contrast between a low rate of coronary heart disease in France, in spite of a high prevalence of cardiovascular risk factors, and an important consumption of saturated fats [1]. One of the features of
* Corresponding author. Institut du Vieillissement, 37 Allées Jules Guesde, 31000 Toulouse, France. Tel.: þ33 (0)5 61145657; fax: þ33 (0)5 61145640. E-mail address: [email protected] (M. Lilamand).
the French diet, is the frequent consumption of red wine, containing high levels of polyphenols. Even though moderate ethanol consumption may explain this cardioprotective role [2], non-ethanol components of wine, and in particular flavonoids, which are a class of polyphenolic compounds, may provide additional health benefits. Flavonoids have especially shown a variety of beneficial actions on cardiovascular health [3,4]. However, their effectiveness on arterial function has not been fully appreciated yet. The aim of this article is to provide a comprehensive evaluation of intervention and observational studies over the last ten years, evaluating the association between
0939-4753/$ - see front matter ª 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.numecd.2014.01.015
Please cite this article in press as: Lilamand M, et al., Flavonoids and arterial stiffness: Promising perspectives, Nutrition, Metabolism & Cardiovascular Diseases (2014), http://dx.doi.org/10.1016/j.numecd.2014.01.015
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flavonoid consumption and arterial stiffness, which is a marker of arterial function and a strong predictor of cardiovascular outcomes and mortality [5]. Firstly, an overview of the flavonoid subclasses and metabolism is presented, as well as their main physiological effects on arteries. Secondly a brief description of arterial stiffness and its potential implications is provided, supplemented by an overview of other vascular assessment methods. Finally, a summary of the current evidence examining the impact of flavonoid consumption on vascular function will be discussed.
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(VEGFRs), fibroblast growth factor and cyclin-dependent kinases (CDKs) which play important roles in both arterial remodeling and cancer pathogenesis [11]. These pharmacological effects have suggested a potential role of flavonoids in clinical trials aiming at improving arterial function and reducing the incidence of cardiovascular events. The effectiveness of flavonoids on predictors of cardiovascular outcomes, has been supported by three meta-analyses of randomized controlled trials [12e14]. Arterial stiffness
Flavonoids Dietary flavonoids constitute a large class of bioactive polyphenolic compounds, commonly consumed in plant foods and beverages [6]. This large family consists of about 7000 molecules, characterized by a phenyl benzopyrone structure. According to the different patterns of this nucleus they are categorized into 6 main subclasses: flavan3-ols (e.g. catechin, epicatechin), flavonols (e.g. quercetin, myricetin, kaempferol), anthocyanidins (e.g. cyanidin, delphinidin), flavones (e.g. apigenin, diosmin), and flavanones (e.g. naringenin, hesperetin). The bioavailability of flavonoids is generally low and may vary drastically among different flavonoid classes as well as individual compounds in a particular class. Isoflavones, flavonols, flavanones and flavan-3-ols, may be absorbed sufficiently to exert possible cardio-protective effects in vivo [7]. Firstly, several biological mechanisms have been indicated to support a beneficial effect of flavonoids on endothelial function. After ingestion, flavonoids are extensively metabolized to various phenolic acids, some of which still possess a radical-scavenging ability. Besides, flavonoids are competitive inhibitors of oxidases (e.g. xanthine oxidase) responsible for superoxide anion production. Therefore, both the absorbed flavonoids and their metabolites may display an anti-inflammatory and antioxidant activity, and the reduced production of reactive oxidant species, may in turn contribute to an enhanced endothelial function [8]. Secondly, flavonoids may reduce LDL-cholesterol oxidation, increase insulin sensitivity and decrease pro-thrombotic and pro-atherosclerotic molecules expression and thus slow down the progression of early atherosclerotic lesions to advanced plaques [9]. Thirdly, polyphenols present antihypertensive effects which can be explained not only by an increase in nitric oxide (NO) production but also by a direct inhibition of angiotensin-converting enzyme. Fourthly, constitutive production of NO by the endothelial cells inhibits the recruitment and adhesion of inflammatory cells, but also reduces ADP/collagen activated platelet-related primary hemostasis [10]. Inhibition of platelet activation combined with inhibition of prothrombotic molecules may be efficient to prevent ischemic diseases (e.g. myocardial infarction or stroke). Finally, anti-angiogenic effects of flavonoids have also been reported, modulating several protein kinases (e.g. protein kinase-C, serineetyrosine kinases), vascular endothelial growth factor receptors
Central elastic arteries undergo major age-related modifications and tend to stiffen gradually. In fact, arterial aging may be considered as an integrator of the long-term effects caused by traditional cardiovascular risk factors on the arterial walls [5]. As the arterial tree stiffens, the propagation of the pressure waves speeds up and may overlap with reflected pressure waves, increasing in turn central pulse pressure [15]. These hemodynamic consequences may also damage the microvasculature and lead to end-organ dysfunction. Thus, aortic stiffness has been indicated as a marker of vascular dysfunction and a major predictor of cardiovascular outcomes, including mortality, independently of other cardiovascular risk factors [5,16,17]. Accordingly, growing interest has been given to noninvasive assessment of arterial stiffness in clinical practice. To date, the gold standard to assess aorta stiffness is the measurement of carotid-femoral pulse wave velocity (PWV) usually estimated with applanation tonometry [15]. Briefly, pulse waves are recorded with an applanation tonometer at two arterial sites (carotid and femoral) and the delay in the onset of the wave between these two locations is measured using registration with a simultaneously recorded electrocardiogram. The PWV is calculated by dividing the distance between the two measurement points by the time difference. Various other methods have been validated to estimate regional arterial stiffness noninvasively such as echotracking, magnetic resonance imaging or oscillometric devices. Although arterial stiffness is a consequence of vascular aging, this condition has been shown to be a reversible process. Several pharmacological and non-pharmacological interventions have been proposed, aiming at improving vascular stiffness [15]. Other arterial function measurements In parallel with arterial stiffness assessment, several biological measures of arterial function have been used over the last decades. Although they provide additional information on arterial structure and/or function, they are no substitute for PWV [15]. Aortic pulse pressure also reflects aorta’s stiffness, calculated by subtracting the central diastolic pulse pressure from the central systolic pulse pressure. Its association with cardiovascular outcomes was reported
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Flavonoids and arterial stiffness
to be higher than with conventional (i.e. upper arm) blood pressure [18]. Central blood pressure used to be only measured invasively, with a catheter or a pressure sensor inserted into the aorta. More recently, computer softwares have allowed reliable estimation of the central aortic pressure waveform from those assessed peripherally (e.g. with applanation tonometry) in the radial or in the common carotid arteries. Augmentation index (AIx) is defined as the percentage of central pulse pressure attributed to reflected wave overlap in systole. AIx is also associated with cardiovascular risk factors although its main determinants are thought to be age, systolic blood pressure and heart rate [15]. Therefore, its variations in older individuals should be interpreted with caution. Brachial flow-mediated dilation (FMD) is another noninvasive physiological measure associated with endothelial dysfunction assessed with ultrasonography. Temporary vessel occlusion leads to hyperemia, and measuring the resultant relative augmentation of the arterial diameter indicates FMD. Although FMD has been associated with an increased rate of cardiovascular events, particularly in high risk populations the absence of established gender-specific cut-points distinguishing normal vs pathological values represents a severe limitation of its clinical use [19]. Flavonoids and arterial stiffness: current evidence and future perspectives Despite the growing number of publications reporting the cardiovascular burden related to arterial stiffness, and the effectiveness of pharmacologic and non-pharmacologic interventions targeting vascular function, the limited number of dietary intervention trials focusing on the potential effects of flavonoids on arterial stiffness is still surprising. To our knowledge, there is no comprehensive review of the literature examining the relationship between flavonoids and reliable measures of arterial stiffness, including PWV. Accordingly, a Medline literature search of all articles published over the past 10 years, using the Medical Subject Heading (MeSH) terms “arterial stiffness” and “flavonoids” was conducted (last update: 09/18/13). Twenty-five papers were retrieved. The identified abstracts were evaluated and for those articles that met the search criteria, the full articles were obtained. After identifying the most relevant studies (Fig. 1), 2 cross-sectional and 16 intervention studies assessing the relationship between flavonoids intake and arterial stiffness were retained (Table 1). Observational studies Two cross-sectional studies examined associations between different flavonoid subclasses and measures of arterial stiffness [20,21]. A recent cross-sectional study among women, aged 18e75 years, from the Twins UK registry showed that higher anthocyanin intake was associated with lower PWV (mean SE: 0.4 0.2 m/s, P Z 0.04) and central systolic blood pressure
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(3.0 1.4 mmHg, P Z 0.02) across extreme quintiles of intake [20]. These findings were observed after adjustment for age, smoking, physical activity, body mass index, use of hormone replacement therapy, use of blood pressure or statin medication, use of vitamin supplements, use of oral contraceptives, menopausal status, family history of heart disease or hypertension, and intakes of energy, alcohol, saturated, monounsaturated, polyunsaturated fatty acids, fiber and sodium. This study also showed that higher intake of flavone was associated with lower PWV (mean SE: 0.4 0.2 m/s, P Z 0.04) across extreme quintiles of intake. In the second cross-sectional study among 198 men and women, aged 18e60 years, higher cocoa intake was inversely associated with pulse wave velocity (R2 Z 0.408, P < 0.001), central blood pressure (R2 Z 0.228, P < 0.01), and AIx (R2 Z 0.651, P < 0.05) [21]. The findings were observed after accounting for a number of confounding factors, including age, gender, body mass index, height, mean pressure, heart rate, blood cholesterol and C-reactive protein levels, smoking, coffee and alcohol intake. Common limitations of these studies reside in the self-recall bias, since habitual flavonoid intake was obtained through food frequency questionnaire; measurement errors which are inevitable in epidemiological studies; and residual confounding which cannot be ruled out, although a number of confounding factors were considered. Intervention trials Among the 16 intervention studies retrieved, carotidfemoral PWV, which is the gold standard for arterial stiffness assessment, was defined as an endpoint in only 6 trials (Grassi, Teede x2, Curtis, Nestel, Karatzi). Two other trials utilized carotid-radial PWV (Dohadwala, Turner). Four of them reported a decrease of carotidfemoral PWV after a flavonoid-based intervention, independently from blood pressure changes, highlighting the difference between these two parameters [22e25] Curtis et al. observed a decrease of PWV and central blood pressure after a 1 year intervention (0.07 vs þ0.68 m/s, P Z 0.01), based on isoflavones-enriched chocolate in postmenopausal women with type 2 diabetes [22]. Nestel et al. reported a decrease of PWV (0.98 vs þ0.18 m/s, P < 0.05) and blood pressure after consumption of a flavonoid metabolite (trans-tetrahydrodaidzein) among obese men and postmenopausal women [24]. In the Teede et al. randomized-controlled trial, isoflavones supplementation was associated with a small and significant decrease of PWV in healthy adults (0.3 vs þ0.17, P Z 0.02) [25]. Dohadwala et al. examined the effect of cranberry juice in adults with coronaropathy in a randomized controlled trial with crossover design, and found an improvement of carotid-femoral PWV (0.5 vs þ0.4 m/ s, P Z 0.03) with the intervention [23]. Besides, two intervention studies did not show any brachialeankle PWV improvement after tea consumption [26,27]. Unfortunately, the results of the trials are not directly comparable partially due to the different methods adopted in
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Figure 1
Flow diagram of study selection process.
their design. The flavonoid intervention greatly varied across studies we reviewed, for example in the study of Grassi et al. using flavan-3-ols and isoflavones (100 mg per day) [28], whereas in the study of Teede et al. using isoflavones only at a lower daily dose (80 mg/d) [25], Dohadwala et al. testing anthocyanin intervention [23], and Nestel et al. providing trans-tetrahydrodaidzein [24]. Not only different types and dosages of flavonoids were used, but some uncertainties also exist about the proper measurement of the quantity of flavonoid that was indeed absorbed. Another major weakness affecting the comparison of studies resides in the assessment of study outcomes which was not standardized in its methodology. An additional limitation of current evidence resides in the generally small sample sizes of the trials (usually less than 100 subjects, with some studies recruiting even fewer than 20). The extreme heterogeneity of the studied populations, composed by healthy adults, post-menopausal women, or subjects with cardiovascular risk factors is another drawback. Such heterogeneity is evident by the different values of baseline arterial stiffness across studies. In this perspective, we identified only one study among seven in healthy subjects which showed a significant improvement of arterial stiffness with intervention. In contrast among nine studies in subjects with cardiovascular history, three of them reported a significant effect of flavonoids on arterial function. A potential explanation of this finding may be that substantial variations in arterial stiffness over a short follow-up are unlikely to be observed in healthy individuals with no vascular condition. Nevertheless, it should be acknowledged that the follow-up duration usually ranged from 4 to 12 weeks except for two studies, with a 1-year intervention [22,29]. Although some of the studies we reviewed (Table 1) may support an
improvement of functional and structural arterial walls, the heterogeneous results do not allow us to draw definitive conclusions. Besides, the clinical relevance of a small decrease of aortic stiffness (in our review, less than 10%) is still debated. One reason could be the use of surrogate rather than hard cardiovascular endpoints in the studies that we reviewed, and more generally in intervention studies assessing vascular function changes. To date, most clinical trials have not been designed to fully exploit the potential consequences of a significant improvement in arterial stiffness. On the contrary, peripheral blood pressure improvement in hypertensive subjects is well known to be associated with reduced strong cardiovascular outcomes, for more than a decade [30]. Further research could investigate thoroughly the effects of flavonoids on arterial stiffness improvement and lead to the development of new therapeutic strategies, among which these compounds could play a central role.
Conclusion Recent evidence supports a potential role of flavonoids in the reduction of cardiovascular diseases. In particular, flavonoid-rich food intake has been shown to improve endothelial function and peripheral BP. However, the beneficial effect of flavonoids on arterial stiffness is emerging. In this review, isoflavones (mainly found in soy products), anthocyanins (constituents of red and blue berries) and to a lesser extent cocoa flavan-3-ols have shown to have a positive effect or to be associated with improved measures of vascular function, and in particular with arterial stiffness assessed by PWV. Such interesting findings may have future major clinical and public health
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Flavonoids and arterial stiffness
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Table 1 Studies exploring the relationship between flavonoid consumption and arterial stiffness. Study
Design Flavonoid/Food type
Population
Intervention trials including healthy subjects Wong et al. CR Soy isoflavone vs Normotensive post2012 [31] placebo (80 mg/d) menopausal women 40e60 yo Hoshida et al. CR Black soybean tea Healthy women; 2011 [27] isoflavones smokers þ non(50 mg/d) smokers
Grassi et al. 2009 [28]
CR CO 0, 100, 200, 400 or Healthy men 800 mg/d black tea flavonoids
N
Time Main endpoints Significant (weeks) effects on PWV
24 6
55 8
BP & 24 h-BP; e elasticity index; FMD CAVI; baPWV; No FMD
19 5
FMD; PWV; BP No
Other vascular changes
No
Significant decrease of CAVI among premenopausal women only and increase of FMD among nonsmokers Significant dosedependent augmentation of FMD with black tea; significant decrease of SBP and DBP No
Normotensive postmenopausal women
40 8
AIx
e
Hallund et al. CR 2006 [33]
Soy proteins (112 mg isoflavones) vs placebo Soya isoflavone vs placebo (50 mg/d)
Normotensive postmenopausal women 40e60 yo
30 8
e
Turner et al. 2004 [29]
CR
Garlic powder vs placebo
Healthy 40e60 yo
62 52
Teede et al. 2003 [25]
CR
Isoflavones (80 mg/d) vs placebo
Healthy 45e75 yo
80 6
Systemic arterial compliance; FMD; BP Cholesterol concentration; carotid-radial PWV Systemic arterial compliance; PWV; 24 h-BP; FMD
Significant decrease of PWV with intervention
Significant reduction in central arterial compliance with intervention; no difference on BP and FMD
PWV (subgroup 35 subjects); Aix; CCA-IMT CPP; BP
Significant decrease of PWV with intervention
Significant decrease of CPP with intervention No significant modification of CCAIMT, AIx, BP Early decrease of AIx, central & peripheral SBP at 2 weeks. No significant difference at 8 weeks Significant improvement of FMD, decrease of SBP, DBP and LDL cholesterol with intervention No change of FMD or BP
Törmälä et al. CR 2008 [32]
Intervention trials including subjects with cardiovascular conditions 93 52 Curtis et al. CR Chocolate (850 mg Post-menopausal 2013 [22] flavan-3women with type 2 ols þ 100 mg diabetes mellitus isoflavones) vs placebo Karatzi et al. C Sesame oil vs Hypertensive men 30 8 2012 [34] placebo
Clerici et al. 2011 [35]
CR CO Pasta enriched with Adults with type 2 isoflavones(33 mg/ diabetes mellitus d) vs placebo
Dohadwala CR CO Cranberry juice et al. 2011 (94 mg [23] anthocyanin) vs placebo Clerici et al. CR Pasta enriched with 2007 [36] isoflavones (33 mg/d) vs placebo Teede et al. CR Soy isoflavones 2006 [37] cereal (118 mg/d) vs gluten cereal
Adults with coronaropathy
No Systolic, diastolic central and peripheral BP; PWV
26 8
FMD; BP; LDL cholesterol
47 4
Brachial FMD; BP; PWV
Adults with 62 10 hypercholesterolemia
Adults 30e75 yo with 38 12 hypertension
No
e
Significant decrease of systemic arterial compliance with intervention No
Significant decrease of PWV with intervention Lipid and CRP e Increase of FMD and concentrations; reduction of total and BP; brachial LDL cholesterol in the artery FMD intervention group PWV central No Increase of heart rate and peripheral; and daytime BP in the BP; FMD; heart intervention group. No rate significant difference in PWV, FMD
(continued on next page)
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Table 1 (continued ) Study
Design Flavonoid/Food type
Population
Ryu et al., 2006 [26]
CR CO Green tea (9 g) vs placebo
Adults with type 2 diabetes mellitus
Naissides et al. 2006 [38]
CR
Post-menopausal 45 6 women with hypercholesterolemia
Nestel et al. 2007 [24]
CR CO Metabolite of Obese men and postflavonoids : trans- menopausal women tetrahydrodaidzein (1 g/d) vs placebo
Red wine vs dealcoholized red wine vs placebo
Cross-sectional studies Jennings et al. CS All the flavonoid2012 [20] subclasses
Vlachopoulos CS et al. 2007 [21]
Cocoa
N
Time Main endpoints Significant (weeks) effects on PWV
55 4
25 5
Healthy women 18e75 yo
728 e
Healthy adults 18e60 yo
198 e
baPWV; hsCRP; IL6; blood lipid analysis AIx; Pulse pressure; endothelial nitric oxide levels PWV; BP; isoflavone urinary excretion; blood lipid analysis
No
Other vascular changes No difference after intervention
e
Significant within group decrease of AIx and augmentation pressure in the dealcoholized red wine group Significant Significant decrease of decrease of PWV both SBP&DBP with intervention
PWV; central Lower PWV with PP; CCA-IMT: BP higher intakes of anthocyanin and flavones (P Z 0.04) PWV; AIx; Association central PP between high cocoa consumption and lower PWV (R2 Z 0.408)
Lower SBP (P Z 0.02) and central PP (P Z 0.01) with higher anthocyanin intake Association between high cocoa consumption and lower AIx (R2 Z 0.651) and PP (R2 Z 0.228)
AIx: augmentation index; ba: brachialeankle; BP: blood pressure; C: controlled; CAVI: cardio-ankle vascular index; CCA-IMT: common carotid artery intima media thickness; CO: cross-over; CPP: central pulse pressure; DBP: diastolic blood pressure; FMD: flow-mediated dilation; hsCRP: high sensitivity C-reactive protein; IL6: interleukin 6; PP: pulse pressure; PWV: pulse wave velocity; R: randomized; SBP: systolic blood pressure.
implications in our aging society. Ad hoc designed studies should indeed investigate more in details the causal association between flavonoid consumption and vascular function changes. Nevertheless, further research is also needed to better characterize the effects of the different subclasses of flavonoids, determine the adequate intake to obtain clinically significant modifications, improve the measurement of the real flavonoid absorption and evaluate the potential consequences of flavonoid interventions on cardiovascular outcomes. References [1] Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 1992;339:1523e6. [2] Poli A, Marangoni F, Avogaro A, Barba G, Bellentani S, Bucci M, et al. Moderate alcohol use and health: a consensus document. Nutr Metab Cardiovasc Dis 2013;23:487e504. [3] McCullough ML, Peterson JJ, Patel R, Jacques PF, Shah R, Dwyer JT. Flavonoid intake and cardiovascular disease mortality in a prospective cohort of US adults. Am J Clin Nutr 2012;95:454e64. [4] Mink PJ, Scrafford CG, Barraj LM, et al. Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr 2007;85:895e909. [5] Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 2010;55:1318e27. [6] Erdman JW, Balentine D, Arab L, Beecher G, Dwyer JT, Folts J, et al. Flavonoids and heart health: proceedings of the ILSI North America flavonoids workshop, May 31eJune 1, 2005, Washington, DC. J Nutr 2007;137:718Se37S.
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premenopausal and postmenopausal smokers and nonsmokers: NYMPH Study. Heart Vessels 2011;26:590e5. Grassi D, Mulder TP, Draijer R, Desideri G, Molhuizen HO, Ferri C. Black tea consumption dose-dependently improves flowmediated dilation in healthy males. J Hypertens 2009;27:774e81. Turner B, Molgaard C, Marckmann P. Effect of garlic (Allium sativum) powder tablets on serum lipids, blood pressure and arterial stiffness in normo-lipidaemic volunteers: a randomised, doubleblind, placebo-controlled trial. Br J Nutr 2004;92:701e6. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a metaanalysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903e13. Wong WW, Taylor AA, Smith EO, Barnes S, Hachey DL. Effect of soy isoflavone supplementation on nitric oxide metabolism and blood pressure in menopausal women. Am J Clin Nutr 2012;95:1487e94. Törmälä R, Appt S, Clarkson TB, Groop PH, Rönnback M, Ylikorkala O, et al. Equol production capability is associated with favorable vascular function in postmenopausal women using tibolone; no effect with soy supplementation. Atherosclerosis 2008;198:174e8. Hallund J, Bugel S, Tholstrup T, Ferrari M, Talbot D, Hall WL, et al. Soya isoflavone-enriched cereal bars affect markers of endothelial function in postmenopausal women. Br J Nutr 2006;95:1120e6. Karatzi K, Stamatelopoulos K, Lykka M, Mantzouratou P, Skalidi S, Manios E, et al. Acute and long-term hemodynamic effects of sesame oil consumption in hypertensive men. J Clin Hypertens (Greenwich) 2012;14:630e6. Clerici C, Nardi E, Battezzati PM, Asciutti S, Castellani D, Corazzi N, et al. Novel soy germ pasta improves endothelial function, blood pressure, and oxidative stress in patients with type 2 diabetes. Diabetes Care 2011;34:1946e8. Clerici C, Setchell KD, Battezzati PM, Pirro M, Giuliano V, Asciutti S, et al. Pasta naturally enriched with isoflavone aglycons from soy germ reduces serum lipids and improves markers of cardiovascular risk. J Nutr 2007;137:2270e8. Teede HJ, Giannopoulos D, Dalais FS, Hodgson J, McGrath BP. Randomised, controlled, cross-over trial of soy protein with isoflavones on blood pressure and arterial function in hypertensive subjects. J Am Coll Nutr 2006;25:533e40. Naissides M, Pal S, Mamo JC, James AP, Dhaliwal S. The effect of chronic consumption of red wine polyphenols on vascular function in postmenopausal women. Eur J Clin Nutr 2006;60:740e5.
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Nutrition, Metabolism & Cardiovascular Diseases journal homepage: www.elsevier.com/locate/nmcd
REVIEW
Flavonoids and arterial stiffness: Promising perspectives M. Lilamand a,b,*, E. Kelaiditi a, S. Guyonnet a,c, R. Antonelli Incalzi d, A. RaynaudSimon b, B. Vellas a,c,e, M. Cesari a,c,e a
Gérontopôle, Centre Hospitalier Universitaire de Toulouse, France Service de Gériatrie, Centre Hospitalier Universitaire Bichat, Paris, France INSERM UMR 1027, Toulouse, France d Geriatria, Università Campus Bio-Medico, Roma, Italy e Université de Toulouse III Paul Sabatier, Toulouse, France b c
Received 8 November 2013; received in revised form 20 December 2013; accepted 17 January 2014 Available online - - -
KEYWORDS Flavonoids; Arterial stiffness; Wave reflection; Cardiovascular diseases
Abstract Background and aims: Flavonoids are a group of polyphenol compounds, ubiquitously found in plants. Great emphasis has been given to their possible benefits for cardiovascular health. These beneficial effects may be mediated by a specific action on arterial walls. Arterial stiffness is a marker of vascular aging, increasingly used in the clinical setting and assessed by pulse wave velocity. It has shown to be a robust predictor of cardiovascular events and mortality. This review aims at providing a comprehensive evaluation of available intervention and observational studies examining the relationship between flavonoid consumption and arterial stiffness. Data synthesis: A Medline literature search was performed using the keywords “arterial stiffness” and “flavonoids”. As a result, 2 cross-sectional and 16 intervention studies assessing the relationship between flavonoids intake and arterial stiffness were retained. Four intervention trials reported a significant decrease of arterial stiffness after a flavonoid-based intervention, independently from blood pressure changes. The two observational studies reported significant associations between a higher flavonoid consumption and a lower arterial stiffness. In this review, isoflavones, anthocyanins and to a lesser extent cocoa flavan-3-ols appeared to be the more efficient to improve vascular function. Conclusions: Despite their heterogeneity, preliminary data seem to support an improvement of the arterial stiffness related to flavonoid intake. However, further research on absorption and doseeresponse effects of the specific flavonoid subclasses on arterial structure is warranted. ª 2014 Elsevier B.V. All rights reserved.
Introduction The “French paradox” was proposed as an attractive concept to illustrate the contrast between a low rate of coronary heart disease in France, in spite of a high prevalence of cardiovascular risk factors, and an important consumption of saturated fats [1]. One of the features of
* Corresponding author. Institut du Vieillissement, 37 Allées Jules Guesde, 31000 Toulouse, France. Tel.: þ33 (0)5 61145657; fax: þ33 (0)5 61145640. E-mail address: [email protected] (M. Lilamand).
the French diet, is the frequent consumption of red wine, containing high levels of polyphenols. Even though moderate ethanol consumption may explain this cardioprotective role [2], non-ethanol components of wine, and in particular flavonoids, which are a class of polyphenolic compounds, may provide additional health benefits. Flavonoids have especially shown a variety of beneficial actions on cardiovascular health [3,4]. However, their effectiveness on arterial function has not been fully appreciated yet. The aim of this article is to provide a comprehensive evaluation of intervention and observational studies over the last ten years, evaluating the association between
0939-4753/$ - see front matter ª 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.numecd.2014.01.015
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flavonoid consumption and arterial stiffness, which is a marker of arterial function and a strong predictor of cardiovascular outcomes and mortality [5]. Firstly, an overview of the flavonoid subclasses and metabolism is presented, as well as their main physiological effects on arteries. Secondly a brief description of arterial stiffness and its potential implications is provided, supplemented by an overview of other vascular assessment methods. Finally, a summary of the current evidence examining the impact of flavonoid consumption on vascular function will be discussed.
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(VEGFRs), fibroblast growth factor and cyclin-dependent kinases (CDKs) which play important roles in both arterial remodeling and cancer pathogenesis [11]. These pharmacological effects have suggested a potential role of flavonoids in clinical trials aiming at improving arterial function and reducing the incidence of cardiovascular events. The effectiveness of flavonoids on predictors of cardiovascular outcomes, has been supported by three meta-analyses of randomized controlled trials [12e14]. Arterial stiffness
Flavonoids Dietary flavonoids constitute a large class of bioactive polyphenolic compounds, commonly consumed in plant foods and beverages [6]. This large family consists of about 7000 molecules, characterized by a phenyl benzopyrone structure. According to the different patterns of this nucleus they are categorized into 6 main subclasses: flavan3-ols (e.g. catechin, epicatechin), flavonols (e.g. quercetin, myricetin, kaempferol), anthocyanidins (e.g. cyanidin, delphinidin), flavones (e.g. apigenin, diosmin), and flavanones (e.g. naringenin, hesperetin). The bioavailability of flavonoids is generally low and may vary drastically among different flavonoid classes as well as individual compounds in a particular class. Isoflavones, flavonols, flavanones and flavan-3-ols, may be absorbed sufficiently to exert possible cardio-protective effects in vivo [7]. Firstly, several biological mechanisms have been indicated to support a beneficial effect of flavonoids on endothelial function. After ingestion, flavonoids are extensively metabolized to various phenolic acids, some of which still possess a radical-scavenging ability. Besides, flavonoids are competitive inhibitors of oxidases (e.g. xanthine oxidase) responsible for superoxide anion production. Therefore, both the absorbed flavonoids and their metabolites may display an anti-inflammatory and antioxidant activity, and the reduced production of reactive oxidant species, may in turn contribute to an enhanced endothelial function [8]. Secondly, flavonoids may reduce LDL-cholesterol oxidation, increase insulin sensitivity and decrease pro-thrombotic and pro-atherosclerotic molecules expression and thus slow down the progression of early atherosclerotic lesions to advanced plaques [9]. Thirdly, polyphenols present antihypertensive effects which can be explained not only by an increase in nitric oxide (NO) production but also by a direct inhibition of angiotensin-converting enzyme. Fourthly, constitutive production of NO by the endothelial cells inhibits the recruitment and adhesion of inflammatory cells, but also reduces ADP/collagen activated platelet-related primary hemostasis [10]. Inhibition of platelet activation combined with inhibition of prothrombotic molecules may be efficient to prevent ischemic diseases (e.g. myocardial infarction or stroke). Finally, anti-angiogenic effects of flavonoids have also been reported, modulating several protein kinases (e.g. protein kinase-C, serineetyrosine kinases), vascular endothelial growth factor receptors
Central elastic arteries undergo major age-related modifications and tend to stiffen gradually. In fact, arterial aging may be considered as an integrator of the long-term effects caused by traditional cardiovascular risk factors on the arterial walls [5]. As the arterial tree stiffens, the propagation of the pressure waves speeds up and may overlap with reflected pressure waves, increasing in turn central pulse pressure [15]. These hemodynamic consequences may also damage the microvasculature and lead to end-organ dysfunction. Thus, aortic stiffness has been indicated as a marker of vascular dysfunction and a major predictor of cardiovascular outcomes, including mortality, independently of other cardiovascular risk factors [5,16,17]. Accordingly, growing interest has been given to noninvasive assessment of arterial stiffness in clinical practice. To date, the gold standard to assess aorta stiffness is the measurement of carotid-femoral pulse wave velocity (PWV) usually estimated with applanation tonometry [15]. Briefly, pulse waves are recorded with an applanation tonometer at two arterial sites (carotid and femoral) and the delay in the onset of the wave between these two locations is measured using registration with a simultaneously recorded electrocardiogram. The PWV is calculated by dividing the distance between the two measurement points by the time difference. Various other methods have been validated to estimate regional arterial stiffness noninvasively such as echotracking, magnetic resonance imaging or oscillometric devices. Although arterial stiffness is a consequence of vascular aging, this condition has been shown to be a reversible process. Several pharmacological and non-pharmacological interventions have been proposed, aiming at improving vascular stiffness [15]. Other arterial function measurements In parallel with arterial stiffness assessment, several biological measures of arterial function have been used over the last decades. Although they provide additional information on arterial structure and/or function, they are no substitute for PWV [15]. Aortic pulse pressure also reflects aorta’s stiffness, calculated by subtracting the central diastolic pulse pressure from the central systolic pulse pressure. Its association with cardiovascular outcomes was reported
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Flavonoids and arterial stiffness
to be higher than with conventional (i.e. upper arm) blood pressure [18]. Central blood pressure used to be only measured invasively, with a catheter or a pressure sensor inserted into the aorta. More recently, computer softwares have allowed reliable estimation of the central aortic pressure waveform from those assessed peripherally (e.g. with applanation tonometry) in the radial or in the common carotid arteries. Augmentation index (AIx) is defined as the percentage of central pulse pressure attributed to reflected wave overlap in systole. AIx is also associated with cardiovascular risk factors although its main determinants are thought to be age, systolic blood pressure and heart rate [15]. Therefore, its variations in older individuals should be interpreted with caution. Brachial flow-mediated dilation (FMD) is another noninvasive physiological measure associated with endothelial dysfunction assessed with ultrasonography. Temporary vessel occlusion leads to hyperemia, and measuring the resultant relative augmentation of the arterial diameter indicates FMD. Although FMD has been associated with an increased rate of cardiovascular events, particularly in high risk populations the absence of established gender-specific cut-points distinguishing normal vs pathological values represents a severe limitation of its clinical use [19]. Flavonoids and arterial stiffness: current evidence and future perspectives Despite the growing number of publications reporting the cardiovascular burden related to arterial stiffness, and the effectiveness of pharmacologic and non-pharmacologic interventions targeting vascular function, the limited number of dietary intervention trials focusing on the potential effects of flavonoids on arterial stiffness is still surprising. To our knowledge, there is no comprehensive review of the literature examining the relationship between flavonoids and reliable measures of arterial stiffness, including PWV. Accordingly, a Medline literature search of all articles published over the past 10 years, using the Medical Subject Heading (MeSH) terms “arterial stiffness” and “flavonoids” was conducted (last update: 09/18/13). Twenty-five papers were retrieved. The identified abstracts were evaluated and for those articles that met the search criteria, the full articles were obtained. After identifying the most relevant studies (Fig. 1), 2 cross-sectional and 16 intervention studies assessing the relationship between flavonoids intake and arterial stiffness were retained (Table 1). Observational studies Two cross-sectional studies examined associations between different flavonoid subclasses and measures of arterial stiffness [20,21]. A recent cross-sectional study among women, aged 18e75 years, from the Twins UK registry showed that higher anthocyanin intake was associated with lower PWV (mean SE: 0.4 0.2 m/s, P Z 0.04) and central systolic blood pressure
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(3.0 1.4 mmHg, P Z 0.02) across extreme quintiles of intake [20]. These findings were observed after adjustment for age, smoking, physical activity, body mass index, use of hormone replacement therapy, use of blood pressure or statin medication, use of vitamin supplements, use of oral contraceptives, menopausal status, family history of heart disease or hypertension, and intakes of energy, alcohol, saturated, monounsaturated, polyunsaturated fatty acids, fiber and sodium. This study also showed that higher intake of flavone was associated with lower PWV (mean SE: 0.4 0.2 m/s, P Z 0.04) across extreme quintiles of intake. In the second cross-sectional study among 198 men and women, aged 18e60 years, higher cocoa intake was inversely associated with pulse wave velocity (R2 Z 0.408, P < 0.001), central blood pressure (R2 Z 0.228, P < 0.01), and AIx (R2 Z 0.651, P < 0.05) [21]. The findings were observed after accounting for a number of confounding factors, including age, gender, body mass index, height, mean pressure, heart rate, blood cholesterol and C-reactive protein levels, smoking, coffee and alcohol intake. Common limitations of these studies reside in the self-recall bias, since habitual flavonoid intake was obtained through food frequency questionnaire; measurement errors which are inevitable in epidemiological studies; and residual confounding which cannot be ruled out, although a number of confounding factors were considered. Intervention trials Among the 16 intervention studies retrieved, carotidfemoral PWV, which is the gold standard for arterial stiffness assessment, was defined as an endpoint in only 6 trials (Grassi, Teede x2, Curtis, Nestel, Karatzi). Two other trials utilized carotid-radial PWV (Dohadwala, Turner). Four of them reported a decrease of carotidfemoral PWV after a flavonoid-based intervention, independently from blood pressure changes, highlighting the difference between these two parameters [22e25] Curtis et al. observed a decrease of PWV and central blood pressure after a 1 year intervention (0.07 vs þ0.68 m/s, P Z 0.01), based on isoflavones-enriched chocolate in postmenopausal women with type 2 diabetes [22]. Nestel et al. reported a decrease of PWV (0.98 vs þ0.18 m/s, P < 0.05) and blood pressure after consumption of a flavonoid metabolite (trans-tetrahydrodaidzein) among obese men and postmenopausal women [24]. In the Teede et al. randomized-controlled trial, isoflavones supplementation was associated with a small and significant decrease of PWV in healthy adults (0.3 vs þ0.17, P Z 0.02) [25]. Dohadwala et al. examined the effect of cranberry juice in adults with coronaropathy in a randomized controlled trial with crossover design, and found an improvement of carotid-femoral PWV (0.5 vs þ0.4 m/ s, P Z 0.03) with the intervention [23]. Besides, two intervention studies did not show any brachialeankle PWV improvement after tea consumption [26,27]. Unfortunately, the results of the trials are not directly comparable partially due to the different methods adopted in
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Figure 1
Flow diagram of study selection process.
their design. The flavonoid intervention greatly varied across studies we reviewed, for example in the study of Grassi et al. using flavan-3-ols and isoflavones (100 mg per day) [28], whereas in the study of Teede et al. using isoflavones only at a lower daily dose (80 mg/d) [25], Dohadwala et al. testing anthocyanin intervention [23], and Nestel et al. providing trans-tetrahydrodaidzein [24]. Not only different types and dosages of flavonoids were used, but some uncertainties also exist about the proper measurement of the quantity of flavonoid that was indeed absorbed. Another major weakness affecting the comparison of studies resides in the assessment of study outcomes which was not standardized in its methodology. An additional limitation of current evidence resides in the generally small sample sizes of the trials (usually less than 100 subjects, with some studies recruiting even fewer than 20). The extreme heterogeneity of the studied populations, composed by healthy adults, post-menopausal women, or subjects with cardiovascular risk factors is another drawback. Such heterogeneity is evident by the different values of baseline arterial stiffness across studies. In this perspective, we identified only one study among seven in healthy subjects which showed a significant improvement of arterial stiffness with intervention. In contrast among nine studies in subjects with cardiovascular history, three of them reported a significant effect of flavonoids on arterial function. A potential explanation of this finding may be that substantial variations in arterial stiffness over a short follow-up are unlikely to be observed in healthy individuals with no vascular condition. Nevertheless, it should be acknowledged that the follow-up duration usually ranged from 4 to 12 weeks except for two studies, with a 1-year intervention [22,29]. Although some of the studies we reviewed (Table 1) may support an
improvement of functional and structural arterial walls, the heterogeneous results do not allow us to draw definitive conclusions. Besides, the clinical relevance of a small decrease of aortic stiffness (in our review, less than 10%) is still debated. One reason could be the use of surrogate rather than hard cardiovascular endpoints in the studies that we reviewed, and more generally in intervention studies assessing vascular function changes. To date, most clinical trials have not been designed to fully exploit the potential consequences of a significant improvement in arterial stiffness. On the contrary, peripheral blood pressure improvement in hypertensive subjects is well known to be associated with reduced strong cardiovascular outcomes, for more than a decade [30]. Further research could investigate thoroughly the effects of flavonoids on arterial stiffness improvement and lead to the development of new therapeutic strategies, among which these compounds could play a central role.
Conclusion Recent evidence supports a potential role of flavonoids in the reduction of cardiovascular diseases. In particular, flavonoid-rich food intake has been shown to improve endothelial function and peripheral BP. However, the beneficial effect of flavonoids on arterial stiffness is emerging. In this review, isoflavones (mainly found in soy products), anthocyanins (constituents of red and blue berries) and to a lesser extent cocoa flavan-3-ols have shown to have a positive effect or to be associated with improved measures of vascular function, and in particular with arterial stiffness assessed by PWV. Such interesting findings may have future major clinical and public health
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Table 1 Studies exploring the relationship between flavonoid consumption and arterial stiffness. Study
Design Flavonoid/Food type
Population
Intervention trials including healthy subjects Wong et al. CR Soy isoflavone vs Normotensive post2012 [31] placebo (80 mg/d) menopausal women 40e60 yo Hoshida et al. CR Black soybean tea Healthy women; 2011 [27] isoflavones smokers þ non(50 mg/d) smokers
Grassi et al. 2009 [28]
CR CO 0, 100, 200, 400 or Healthy men 800 mg/d black tea flavonoids
N
Time Main endpoints Significant (weeks) effects on PWV
24 6
55 8
BP & 24 h-BP; e elasticity index; FMD CAVI; baPWV; No FMD
19 5
FMD; PWV; BP No
Other vascular changes
No
Significant decrease of CAVI among premenopausal women only and increase of FMD among nonsmokers Significant dosedependent augmentation of FMD with black tea; significant decrease of SBP and DBP No
Normotensive postmenopausal women
40 8
AIx
e
Hallund et al. CR 2006 [33]
Soy proteins (112 mg isoflavones) vs placebo Soya isoflavone vs placebo (50 mg/d)
Normotensive postmenopausal women 40e60 yo
30 8
e
Turner et al. 2004 [29]
CR
Garlic powder vs placebo
Healthy 40e60 yo
62 52
Teede et al. 2003 [25]
CR
Isoflavones (80 mg/d) vs placebo
Healthy 45e75 yo
80 6
Systemic arterial compliance; FMD; BP Cholesterol concentration; carotid-radial PWV Systemic arterial compliance; PWV; 24 h-BP; FMD
Significant decrease of PWV with intervention
Significant reduction in central arterial compliance with intervention; no difference on BP and FMD
PWV (subgroup 35 subjects); Aix; CCA-IMT CPP; BP
Significant decrease of PWV with intervention
Significant decrease of CPP with intervention No significant modification of CCAIMT, AIx, BP Early decrease of AIx, central & peripheral SBP at 2 weeks. No significant difference at 8 weeks Significant improvement of FMD, decrease of SBP, DBP and LDL cholesterol with intervention No change of FMD or BP
Törmälä et al. CR 2008 [32]
Intervention trials including subjects with cardiovascular conditions 93 52 Curtis et al. CR Chocolate (850 mg Post-menopausal 2013 [22] flavan-3women with type 2 ols þ 100 mg diabetes mellitus isoflavones) vs placebo Karatzi et al. C Sesame oil vs Hypertensive men 30 8 2012 [34] placebo
Clerici et al. 2011 [35]
CR CO Pasta enriched with Adults with type 2 isoflavones(33 mg/ diabetes mellitus d) vs placebo
Dohadwala CR CO Cranberry juice et al. 2011 (94 mg [23] anthocyanin) vs placebo Clerici et al. CR Pasta enriched with 2007 [36] isoflavones (33 mg/d) vs placebo Teede et al. CR Soy isoflavones 2006 [37] cereal (118 mg/d) vs gluten cereal
Adults with coronaropathy
No Systolic, diastolic central and peripheral BP; PWV
26 8
FMD; BP; LDL cholesterol
47 4
Brachial FMD; BP; PWV
Adults with 62 10 hypercholesterolemia
Adults 30e75 yo with 38 12 hypertension
No
e
Significant decrease of systemic arterial compliance with intervention No
Significant decrease of PWV with intervention Lipid and CRP e Increase of FMD and concentrations; reduction of total and BP; brachial LDL cholesterol in the artery FMD intervention group PWV central No Increase of heart rate and peripheral; and daytime BP in the BP; FMD; heart intervention group. No rate significant difference in PWV, FMD
(continued on next page)
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Table 1 (continued ) Study
Design Flavonoid/Food type
Population
Ryu et al., 2006 [26]
CR CO Green tea (9 g) vs placebo
Adults with type 2 diabetes mellitus
Naissides et al. 2006 [38]
CR
Post-menopausal 45 6 women with hypercholesterolemia
Nestel et al. 2007 [24]
CR CO Metabolite of Obese men and postflavonoids : trans- menopausal women tetrahydrodaidzein (1 g/d) vs placebo
Red wine vs dealcoholized red wine vs placebo
Cross-sectional studies Jennings et al. CS All the flavonoid2012 [20] subclasses
Vlachopoulos CS et al. 2007 [21]
Cocoa
N
Time Main endpoints Significant (weeks) effects on PWV
55 4
25 5
Healthy women 18e75 yo
728 e
Healthy adults 18e60 yo
198 e
baPWV; hsCRP; IL6; blood lipid analysis AIx; Pulse pressure; endothelial nitric oxide levels PWV; BP; isoflavone urinary excretion; blood lipid analysis
No
Other vascular changes No difference after intervention
e
Significant within group decrease of AIx and augmentation pressure in the dealcoholized red wine group Significant Significant decrease of decrease of PWV both SBP&DBP with intervention
PWV; central Lower PWV with PP; CCA-IMT: BP higher intakes of anthocyanin and flavones (P Z 0.04) PWV; AIx; Association central PP between high cocoa consumption and lower PWV (R2 Z 0.408)
Lower SBP (P Z 0.02) and central PP (P Z 0.01) with higher anthocyanin intake Association between high cocoa consumption and lower AIx (R2 Z 0.651) and PP (R2 Z 0.228)
AIx: augmentation index; ba: brachialeankle; BP: blood pressure; C: controlled; CAVI: cardio-ankle vascular index; CCA-IMT: common carotid artery intima media thickness; CO: cross-over; CPP: central pulse pressure; DBP: diastolic blood pressure; FMD: flow-mediated dilation; hsCRP: high sensitivity C-reactive protein; IL6: interleukin 6; PP: pulse pressure; PWV: pulse wave velocity; R: randomized; SBP: systolic blood pressure.
implications in our aging society. Ad hoc designed studies should indeed investigate more in details the causal association between flavonoid consumption and vascular function changes. Nevertheless, further research is also needed to better characterize the effects of the different subclasses of flavonoids, determine the adequate intake to obtain clinically significant modifications, improve the measurement of the real flavonoid absorption and evaluate the potential consequences of flavonoid interventions on cardiovascular outcomes. References [1] Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 1992;339:1523e6. [2] Poli A, Marangoni F, Avogaro A, Barba G, Bellentani S, Bucci M, et al. Moderate alcohol use and health: a consensus document. Nutr Metab Cardiovasc Dis 2013;23:487e504. [3] McCullough ML, Peterson JJ, Patel R, Jacques PF, Shah R, Dwyer JT. Flavonoid intake and cardiovascular disease mortality in a prospective cohort of US adults. Am J Clin Nutr 2012;95:454e64. [4] Mink PJ, Scrafford CG, Barraj LM, et al. Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr 2007;85:895e909. [5] Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 2010;55:1318e27. [6] Erdman JW, Balentine D, Arab L, Beecher G, Dwyer JT, Folts J, et al. Flavonoids and heart health: proceedings of the ILSI North America flavonoids workshop, May 31eJune 1, 2005, Washington, DC. J Nutr 2007;137:718Se37S.
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