Skip to main content
Nutrients logoLink to Nutrients
. 2015 Jun 29;7(7):5177–5216. doi: 10.3390/nu7075177

A Systematic Review of the Efficacy of Bioactive Compounds in Cardiovascular Disease: Phenolic Compounds

Oscar D Rangel-Huerta 1, Belen Pastor-Villaescusa 1, Concepcion M Aguilera 1, Angel Gil 1,*
PMCID: PMC4516993  PMID: 26132993

Abstract

The prevalence of cardiovascular diseases (CVD) is rising and is the prime cause of death in all developed countries. Bioactive compounds (BAC) can have a role in CVD prevention and treatment. The aim of this work was to examine the scientific evidence supporting phenolic BAC efficacy in CVD prevention and treatment by a systematic review. Databases utilized were Medline, LILACS and EMBASE, and all randomized controlled trials (RCTs) with prospective, parallel or crossover designs in humans in which the effects of BAC were compared with that of placebo/control were included. Vascular homeostasis, blood pressure, endothelial function, oxidative stress and inflammatory biomarkers were considered as primary outcomes. Cohort, ecological or case-control studies were not included. We selected 72 articles and verified their quality based on the Scottish Intercollegiate Guidelines Network, establishing diverse quality levels of scientific evidence according to two features: the design and bias risk of a study. Moreover, a grade of recommendation was included, depending on evidence strength of antecedents. Evidence shows that certain polyphenols, such as flavonols can be helpful in decreasing CVD risk factors. However, further rigorous evidence is necessary to support the BAC effect on CVD prevention and treatment.

Keywords: bioactive food compounds, cardiovascular diseases, polyphenols, phenols, flavonols

1. Introduction

The prevalence of cardiovascular disease (CVD) is rising and is the prime cause of death in all developed countries [1], and one of the most important health issues in developing countries [2]. While some risk factors cannot be changed, such as family history, ethnicity and age, detection and control of modifiable factors such as, blood pressure (BP), high cholesterol, obesity, type 2 diabetes (T2D) or unhealthy diets can help to prevent intermediate risk CVD processes like inflammation or oxidative stress. Thus, primary prevention of CVD by identifying and treating at-risk individuals remains a major public-health priority. A healthy life style is the main pre-emptive approach [3,4].

Dietary habits are quite different around world; nevertheless, certain consumption patterns are common worldwide, inclusion of fruits and vegetables or products like cocoa, coffee or condiments is a merging point. Bioactive compounds (BAC) are “extra nutritional” constituents that are present in small quantities in plant products and lipid rich foods [5]. The growing body of scientific evidence indicates that certain BAC play a beneficial role in CVD prevention [6,7,8,9,10,11]. BAC oral supplements along with a usual diet can increase the intake of ingredients reputed to have clinical benefits. These supplements are, usually, an addition to the healthy diet, and not as a conventional food or the sole item of a meal [12].

Putative beneficial biological effects such as antilipidemic, antihypertensive, anti-glycaemic, antithrombotic and anti-atherogenic effects are attributed to BAC. In the present study, the main goal was to examine the scientific evidence of BAC in the prevention and treatment of CVD by a systematic review of randomized clinical trials (RCTs). The BAC considered in this review were all those related to the phenolic compounds.

Phenolic compounds such as stilbenes like the resveratrol (3,5,4′-trihydroxystilbene) can be found principally in the skin of grapes and are produced in other plants, such as peanuts [6]. Red wine is a rich source of resveratrol and is thought to confer the cardio protective effects associated with moderate consumption of wine [13]. Within the catechols family, curcuminoids are multifunctional natural compounds found in native Indonesian plants, with promising cardio protective and anti-inflammatory properties and mainly present in the dried rhizomes of Curcuma longa L. (commonly known as turmeric) [14].

In relation to polyphenols, there are six basic subclasses of flavonoids: flavones, anthocyanins, flavanones, flavonols, isoflavones, and the flavanols, including the flavanol oligomers, the proanthocyanidins that are further subdivided into 16 species including the procyanidins, oligomers of the flavan-3-ols catechin and epicatechin, and the prodelphinidins, oligomers of the gallocatechins [15]. In this review, we utilized equations to divide the results according to the most relevant classes.

Specifically, we examined the effects of BAC on BP, lipid profile [triacylglycerol (TAG), cholesterol, high and low density lipoproteins(HDL and LDL)], carbohydrate (CHO) metabolism (glucose, insulin, and insulin resistance (IR)), oxidative stress, inflammation and endothelial function (EF). Furthermore, we gave a recommendation for consumption based on the evidence grade according to Scottish Intercollegiate Guidelines Network (SIGN) [16].

2. Methodology

We developed a literature search in Medline by PubMed (U.S. National Library of Medicine and the NIH), and in LILACS and EMBASE, including publications in English, Spanish and Portuguese until December 2014. Studies eligible for this review included: randomized controlled trials (RCTs) in healthy and unhealthy adults, with prospective, parallel or crossover designs, with full text, and whose primary outcomes were vascular homeostasis, BP, oxidative stress and/or inflammatory biomarkers; we excluded those studies with cohort, ecological or case-control design, those which analysed a drug, or when BAC were combined with other compounds. However, there was no restriction on publication type or sample size.

2.1. Search Equation

Due to the diversity of the chemical structures of phenol compounds (Figure 1), the type of BAC can present different effects in CVD; consequently, we evaluated the more relevant groups. We included different keywords in the search equation of bioactive compounds, including: Phenols (stilbenes, catechols, flavonoids, anthocyanins, flavanones, isoflavones, polyphenols, phenolic acids, gallic acid and hydroquinones). We combined the MeSH term “cardiovascular diseases” with each bioactive compound as MeSH Major Topic, together with NOT “review” (Publication Type) in PubMed. However, equations in the Spanish language were used when the search was carried out in LILACS i.e., (tw:(polifenoles)) AND (tw:(enfermedad cardiovascular)) AND NOT (tw:(revisión)). When consulting the database EMBASE, the equations were elaborated as “catechols”/mj AND “cardiovascular diseases”/mj “NOT review”. Articles published before 1990 were discarded because they did not comply the inclusion criteria stablished.

Figure 1.

Figure 1

Chemical diversity polyphenols. Simple phenols are represented by (a) catechols and (b) stilbenes, and polyphenols in (c) anthocyanins, (d) flavonols, (e) flavanols and (f) isoflavones.

After the review process by proofreading staff, we included four additional articles. Three of them were not located by our search criteria; the other appeared in our initial search, but its main outcome in relation to exercise did not comply with the requirement for inclusion in the review. Nevertheless, after a second approach by the proofreading staff, we also decided to include it (see footnotes in the Table 1, Table 2 and Table 3).

Table 1.

RCTs of phenolic compounds (catechols, stilbenes and beer/wine) in CVD risk.

Group (Class) Author/Date Jadad Score Design (Follow up) (n) Population Intervention Outcomes Significant Results
Phenols (Stilbenes) Wong et al. (2011) [19] 5 2B, X (1 h) (19) Overweight/obese + ↑ BP men or post-menopausal women 30 mg, 90 mg, 270 mg RSV vs. PCB EF ↑ EF, more with highest dose
Phenols (Stilbenes) Wong et al. (2013) [20] * 5 2B, X (1 h) (28) obese subjects Acute intervention: 75 mg/trans-resveratrol (Resvida) vs. PCB after chronic intervention FMD ↑ FMD
Phenols (Stilbenes) Wong et al. (2013) [20] * 5 2B, X (6 weeks) (28) obese subjects 75 mg/day trans-resveratrol (Resvida) vs. PCB BP, AR, BMI, FMD ↑ FMD
Phenols (Stilbenes) Bo et al. (2013) [21] 5 2B, X (60 days(wash-out 30 days)) (50) Healthy smokers 500 mg RSV/d vs. PCB BP, Anthropometry, lipids profile, CHO metabolism, TAS, hsCRP, ↓ hsCRP, TAG, ↑ TAS
Phenols (Stilbenes) Militaru et al. (2013) [22] 3 2B, Ctrl, PA (60 days) (166) BMI 24–27 kg/m2, stable angina pectoris 20 mg/day RSV, 20 mg/day RSV + 112 mg/day CF, 112 mg/day CF Lipids profile, hsCRP, left ventricular function markers ↓ TC, TAG greater in RSV, hsCRP greater in CF, NT-proBNP more effective RSV+CF
Phenols (Stilbenes) Tomé-Carneiro et al. (2013) [23] 4 3B, PCB (1 year) (75) Stable CAD patients 350 mg/day GE, 350 mg/day GE-RES vs. PCB (6 months); double dose next 6 months PBMCs, inflammatory and fibrinolytic biomarkers ↑ adiponectin, ↓ PAI-1, significantly activated or inhibited 6 key inflammation-related transcription factors in PBMCs
Phenols (Stilbenes) Tomé-Carneiro et al. (2012) [24] 4 3B, PCB (6 months) (75) Primary prevention of CVD 350 mg/day GE, 350 mg/day GE-RES vs. PCB Lipids profile, oxidized LDL ↓ LDLc, ApoB, LDLox and LDLox/ApoB ratio, ↑ nonHDLc/ApoB ratio in GE-RES
Phenols (Stilbenes) Tomé-Carneiro et al. (2013) [25] 5 3B, PCB, dose–response (1 year) (35) T2D, HT with CAD 350 mg/day GE, 350 mg/day GE-RES vs. PCB (6 months); double dose next 6 months PBMCs, inflammatory, fibrinolytic biomarkers ↓ CCL3, IL-1β, TNF-α expression, ↑ transcriptional repressor LRRFIP-1 in PBMCs with GE-RES
Phenols (Stilbenes) Tomé-Carneiro et al. (2012) [26] 4 3B, PCB (1 year) (75) Primary prevention of CVD 350 mg/day GE, 350 mg/day GE-RES vs. PCB (6 months); double dose next 6 months Inflammatory and fibrinolytic biomarkers ↓ CRP, TNF-α, PAI-1, IL-6/IL-10 ratio, sICAM ↑ IL-10, adiponectin in GE-RES
Phenols (Catechols) Alwi et al. (2008) [27] 4 2B, PCB (2 months) (75) ACS patients 45 mg/day, 90 mg/day or 180 mg/day curcumin vs. PCB Lipids profile Not significant effect
Phenols (Catechols) Chuengsamarn et al. (2014) [28] 5 2B, PCB (6 months) (240) T2D patients 750 mg/day curcumin vs. PCB BP, anthropometry, lipids profile, adiponectin, leptin, CHO metabolism, PWV, uric acid ↓ PWV, HOMA, TAG, uric acid, abdominal obesity and leptin, ↑ adiponectin.
Polyphenols (Wine/beer) Botden et al. (2012) [29] 4 2B, PCB, three-period X (4 weeks) (61) HT subjects 280 mg/day red wine polyphenols or 560 mg/day red wine polyphenols vs. PCB BP No significant effect
Polyphenols (Wine/beer) Chiva-Blanch et al. (2014) [30] 4 2B, PCB, X (4 weeks) (36) High risk of CVD males Beer (30 g alcohol/day), the equivalent amount of polyphenols in the form of non-alcoholic beer, or gin (30 g alcohol/day) Circulating endothelial progenitor cells and EPC-mobilizing factors Beer and non-alcoholic beer interventions, ↑-circulating EPC. No significant differences were observed after the gin period
Polyphenols (Wine/beer) Chiva-Blanch et al. (2012) [31] 3 X (4 weeks) (67) High risk of CVD males Red wine (30 g alcohol/day), the equivalent amount of dealcoholized red wine, or gin (30 g alcohol/day) BP and plasma nitric oxide Dealcoholized red wine ↓ DBP and SBP
Polyphenols (Wine/beer) Chiva-Blanch et al. (2012) [32] 3 X (4 weeks) (67) High risk of CVD males Red wine (30 g alcohol/day), the equivalent amount of dealcoholized red wine, or gin (30 g alcohol/day) Inflammatory biomarkers Alcohol ↑ IL-10 and ↓ macrophage-derived chemokine concentrations. Phenolic compounds of Red wine ↓ serum concentrations of ICAM-1, E-selectin, and IL-6

2B, double-blinded, 3B, triple-blinded, ACS, acute coronary syndrome; Apo, apolipoprotein; BMI, body mass index; BP, blood pressure; CAD, chronic artery disease; CHO, carbohydrate; CCL-3, chemokine (C–C motif) ligand 3 CRP, C-reactive protein; hsCRP, high sensitivity c-reactive protein; Ctrl, control, CVD, cardiovascular disease; EF, endothelial function; EPC, endothelial progenitor cells; FMD, flow mediated dilation; GE, grape extract; GE-RES, grape extract containing RSV (8mg); HDLc, high-density lipoprotein cholesterol; HOMA, homeostasis model assessment; HT, hypertension; sICAM, soluble intercellular adhesion molecule; IL, interleukin; LDLc, low-density lipoprotein cholesterol; LDLox, oxidized LDL; LRRFIP-1, leucine rich repeat (in FLII) interacting protein 1; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PAI-1, plasminogen activator inhibitor-1; PCB, placebo, PBMCs, peripheral blood mononuclear cells; PWV, pulse wave velocity; RSV, resveratrol; TAG, triacylglycerols; TC, total cholesterol; TNF-α,tumour necrosis factor alpha; T2D, type 2 diabetes; X, crossover design. * Included after proofreading.

Table 2.

RCTs of polyphenols (anthocyanins, catechins, flavanols and flavonols) in CVD risk.

Group (Class) Author/ Date Jadad Score Design (Follow up) (n) Population Intervention Outcomes Significant Results
Flavonoids (Anthocyanins) Kuntz (2014) [33] 4 2B, PCB, X (14 days) (30) Healthy females 330 mL/day beverages (PCB, juice or smoothie with 8.9, 983.7 and 840.9 mg/L ACN, respectively) Inflammatory and oxidative stress biomarkers ↑ SOD and CAT after ACN. ↓ MDA after ACN ingestion.
Flavonoids (Anthocyanins) Curtis et al. (2009) [34] 5 PCB, PA (12 weeks) (57) Postmenopausal women 500 mg/day ACN vs. PCB BP, CHO metabolism, lipids profile, inflammatory biomarkers, platelet reactivity No significant effect
Flavonoids (Anthocyanins) Hassellund et al. (2013) [35] 5 2B, PCB, X (4 weeks) (31) Pre-hypertensive males 640 mg/day ACN vs. PCB Lipids profile, CHO metabolism, inflammatory and oxidative stress biomarkers ↑ HDLc and glucose after anthocyanin versus PCB treatment. No effects were observed on inflammation or oxidative stress in vivo, except for vWf
Flavonoids (Anthocyanins) Dohadwala et al. (2011) [36] 4 Open-label, (2 and 4 hour acute study) (15) CAD subjects 835 mg total polyphenols, 94 mg anthocyanins vs. PCB Vascular function No significant effect
Flavonoids (Anthocyanins) Dohadwala et al. (2011) [36] 4 X, 2B, PCB (4 weeks, 2 week washout) (44) CAD subjects 835 mg total polyphenols, 94 mg anthocyanins vs. PCB Vascular function ↓ Carotid femoral pulse wave activity
Flavonoids (Catechins) Miyazaki et al. (2013) [37] 4 2B, PCB (14 weeks) (52) Healthy subjects 630.9 mg/day Green Tea Catechins vs. Ctrl CVD risk markers No significant effect
Flavonoids (Catechins) de Maat et al. (2000) [38] 3 1B, PCB, PA (4 weeks) (64) Healthy subjects Black tea (3 g/day), green tea (3 g/day), green tea polyphenol isolate capsules (3.6 mg/day) and mineral water. Inflammatory and endothelial markers Negative correlation between the levels of the antioxidant β-carotene and the inflammation markers IL6 and fibrinogen
Flavonoids (Catechins) Widmer et al. (2013) [39] 3 2B, Ctrl (4 months) (52) Early atherosclerosis 30 mL/day simple Olive Oil vs. 30 mL/day of EGCG-supplemented Olive Oil EF, inflammation and oxidative stress Only significant when merging data of both groups the EF was improved.
Flavonoids (Catechins) Nagao et al. (2007) [40] 4 2B, PA (12 weeks) (240) Visceral fat-type obesity Green tea containing 583 mg/day catechins (catechin group) vs. 96 mg/day catechins (Ctrl group) Anthropometric measurements, body fat composition and CVD risk ↓ body weight, BMI, body fat ratio, body fat mass, waist circumference, hip circumference, visceral fat area, and subcutaneous fat area, SBP, LDLc
Flavonoids (Flavanols) Farouque et al. (2006) [41] 5 2B, PCB (6 weeks) (40) Healthy males Flavanol-rich chocolate bar and cocoa beverage (total flavanols, 444 mg/day) vs. matching isocaloric PCBs (total flavanols, 19.6 mg/day) EF and adhesion molecules No significant effect
Flavonoids (Flavanols) Berry et al. (2010) [42] * 4 2B, X (2 h, 3–7 days washout) (21) overweight/obese subjects HF, 701 mg or LF, 22 mg cocoa BP, HR, FMD ↑ DBP after exercise were attenuate by HF, improvement of FMD with HF
Flavonoids (Flavanols) Davison et al. 2008 [43] * 4 2B, PCB, PA (12 weeks) (98) overweight/obese subjects 902 mg cocoa flavanols/day vs. 36 mg cocoa flavanols/day With/without exercise protocol BP, HDLc, LDLc, TG, HOMA, FMD ↑ FMD at 6 and 12 weeks with HF vs. LF, ↑ DBP, BP mean, improvement in HOMA (independent of exercise)
Flavonoids (Flavanols) West et al. (2014) [44] 3 2B, PCB, X (4 weeks, 2 weeks washout) (30) Middle-aged overweight 37 g/day of dark chocolate and a sugar-free cocoa beverage (total flavanols = 814 mg/day) vs. low-flavonol chocolate and cocoa free beverage (total flavanols = 3 mg/day) EF, BP ↑ Basal and peak diameter of the brachial artery and basal blood flow volume.
Flavonoids (Flavanols) Faridi et al. (2008) [45] 4 X, Ctrl, 1B (1 days, 7 days washout) (45) Overweight subjects Solid dark chocolate bar (821 mg flavanols) vs. cocoa-free PCB bar (0 mg flavanols) EF, BP Solid dark chocolate improved EF; also ↓ BP
Flavonoids (Flavanols) Faridi et al. (2008) [45] 4 X, Ctrl, 1B (1 days, 7 days washout) (44) Overweight subjects Sugar-free cocoa (805.2 mg flavanols), sugared cocoa (805.2 mg flavanols), vs. PCB (0 mg flavanols). EF, BP Liquid cocoa ingestion improved EF; sugar-free cocoa ↓ BP
Flavonoids (Flavanols) Davison et al. (2010) [46] 3 2B, PA (6 weeks) (52) Men and postmenopausal women with untreated mild HT 33, 372, 712 or 1052 mg/day of cocoa flavanols 24-h BP No significant effect
Flavonoids (Flavanols) Grassi et al. (2008) [47] 3 X, Ctrl, 1B (15 days) (19) HT with Impaired glucose tolerance Flavonol-rich dark chocolate (110.9 mg epicatechin, 36.12 mg catechin, 2.5 mg quercetin, 0.03 mg kaempferol, and 0.2 mg isorhamnetin)/d or flavonol-free white chocolate (0.04 mg/day catechins) EF, IR, β-cell function, BP, CRP, TC ↓ IR, BP, TC, LDLc. ↑ insulin sensitivity, EF
Flavonoids (Flavanols) Flammer et al. (2012) [48] 3 2B, PCB (2 hours) (20) CHF patients 40 g Flavonol rich chocolate (624 mg total flavanols) vs. 28.4 g Ctrl chocolate (0 mg flavanols EF and platelet function in the short term Improvement of vascular function in patients with CHF
Flavonoids (Flavanols) Flammer et al. (2012) [48] 3 2B, PCB (2 and 4 weeks) (20) CHF patients 40 g/day Flavonol rich chocolate (624 mg total flavanols) vs. 28.4 g/day Ctrl chocolate (0 mg flavanols) EF and platelet function in long term by FMD Improvement of vascular function in patients with CHF
Flavonoids (Flavanols) Heiss et al. (2010) [49] 3 Ctrl, 2B, X (30 days) (16) CAD patients High-flavanol intervention (375 mg/day) and a macronutrient- and micronutrient-matched low-flavanol intervention (9 mg/day) twice daily EF and enhancement and function of circulating angiogenic cells ↑ EF, CD34+/KDR+-Circulating angiogenic cells. ↓ SBP
Flavonoids (Flavanols) Horn et al. (2013) [50] 3 2B, X (30 days) (16) CAD patients High-flavanol intervention (375 mg/day) and a macronutrient- and micronutrient-matched low-flavanol intervention (9 mg/day) twice daily Circulating endothelial micro particles, markers of endothelial integrity, EF ↑ Endothelial micro-particles and EF. Improvement of endothelial integrity
Flavonoids (Flavanols) Balzer et al. (2008) [51] 5 2B, PCB, three-period X (2 h) (10) Diabetic subjects Single-dose ingestion of cocoa, containing increasing concentrations of flavanols (75, 371, and 963 mg) EF Single ingestion of flavanol-containing cocoa was dose-dependently acute increases in circulating flavanols and EF
Flavonoids (Flavanols) Balzer et al. (2008) [51] 5 2B, PCB, PA (30 days) (41) Diabetic subjects 963 mg/day Flavanol-rich cocoa vs. nutrient-matched Ctrl (75 mg/day flavanols) EF Flavanol-containing cocoa ↑ baseline EF
Flavonoids (Flavonols) Larson et al. (2012) [52] 3 2B, PCB, X (1 days, 7 days washout) (5) Healthy males 1095 mg quercetin aglycone vs. PCB Angiotensin-converting enzyme, endothelin-1, BP No significant effect
Flavonoids (Flavonols) Conquer et al. (1998) [53] 3 2B (28 days) (27) Healthy subjects 4 capsules (1.0 g quercetin/day) vs. rice flour PCB BP, lipids profile, thrombogenic risk factors No significant effect
Flavonoids (Flavonols) Suomela et al. (2006) [54] 3 2B, PCB, X (4 weeks, 4 weeks washout) (14) Healthy males Oat meal with 78 mg/day flavonol aglycones (sea buckthorn) vs. Ctrl CVD risk markers No significant effect
Flavonoids (Flavonols) Edwards et al. (2007) [55] 3 2B, PCB, X (28 days) (41) Prehypertension and hypertension 730 mg quercetin/day vs. PCB BP, oxidative stress ↓ BP in hypertensive group
Flavonoids (Flavonols) Larson et al. (2012) [52] 3 2B, PCB, X (1 days, 2 days washout) (12) HT stage 1 males 1095 mg quercetin aglycone vs. PCB Angiotensin-converting enzyme, endothelin-1, BP ↓ BP in Hypertensive men

8-iso-PGF2α, 8-iso-prostaglandin F2α; 1B, one-blind, 2B, double-blinded; ACN, anthocyanins; Apo, apolipoprotein; BMI, body mass index; BP, blood pressure; CAD, chronic artery disease; CAT, catalase; CHF, chronic heart failure; CHO, carbohydrate; CRP, C-reactive protein; hsCRP, high sensitivity c-reactive protein; Ctrl, control, CVD, cardiovascular disease; DXA, Dual-energy X-ray absorptiometry; EF, endothelial function; EGCG, epigallocatechin gallate; ESRD, European and North American end-stage renal disease; FM, fat mass; FFM, fat-free mass; FMD, flow mediated dilation; HDLc, high-density lipoprotein cholesterol; HOMA, homeostasis model assessment; HR, heart rate; HT, hypertension; sICAM, soluble intercellular adhesion molecule; IGF-1, insulin-like growth factor-1; IR, insulin resistance; IL, interleukin; LDLc, low-density lipoprotein cholesterol; MDA, malonaldehyde; MPFF, micronized purified flavonoid fraction; MPI, milk protein isolate; NTG, nitro-glycerine-mediated dilation; PA, parallel design, PAI-1, plasminogen activator inhibitor-1; PCB, placebo, PBMCs, peripheral blood mononuclear cells; PS, plant sterols; PWV, pulse wave velocity; QUICKI, quantitative insulin sensitivity check index; SBP, systolic blood pressure; SOD, superoxide dismutase; TC, total cholesterol; TGF, transforming growth factor; T2D, type 2 diabetes; VCAM, soluble vascular cellular adhesion molecule; vWf, von Willebrand factor; X, crossover design. * Included after proofreading.

Table 3.

RCTs of polyphenols (isoflavones and procyanidins) in CVD risk.

Group (Class) Author/Date Jadad Score Design (Follow up) (n) Population Intervention Outcomes Significant Results
Flavonoids (Isoflavones) McVeigh et al. (2006) [56] 3 1B, X (57 days, 4 weeks washout) (35) Healthy males Milk protein isolate (MPI), low-isoflavone soy protein isolate (low-iso SPI; 1.64 ± 0.19 mg aglycone isoflavones/day), and high-isoflavone SPI (high-iso SPI; 61.7 ± 7.4 mg aglycone isoflavones/day) Lipids profile ↓ TC/HDLc, LDLc/HDLc, and Apo B/Apo A-I with both SPI treatments than with MPI treatment
Flavonoids (Isoflavones) Sanders et al. (2002) [57] 3 X (17 days, 25 days washout) (22) Healthy subjects 56 vs. 2 mg isoflavones/day Lipids profile, fibrinogen, and active TGF-β, factor VII coagulant and PAI-1 ↑ HDL and Apo A1 in high-isoflavone
Flavonoids (Isoflavones) Thorp et al. (2008) [58] * 5 2B, PCB, X (6 weeks) (91) Hypercholesterolemia 24 g SP+70–80 mg ISOs (diet S) vs. 12 g SP + 12 g dairy protein (DP) + 70–80 mg ISOs (diet SD) vs. 24 g DP without ISOs (diet D) HDLc, LDLc, TC No significant effect
Flavonoids (Isoflavones) Atkinson et al. (2004) [59] 5 2B, PCB (12 months) (205) Female 43.5 mg red clover-derived isoflavones/day vs. PCB Lipids profile, BP, fibrinogen and PAI-1 No significant effect
Flavonoids (Isoflavones) Marini et al. (2010) [60] 5 2B, PCB (24 months) (138) Females with low bone mass 54 mg/day genistein aglycone vs. PCB Lipids profile, CHO metabolism, HOMA, fibrinogen, osteoprotegerin and homocysteine ↓ fasting glucose and insulin, HOMA, fibrinogen and homocysteine
Flavonoids (Isoflavones) Hodis et al. (2011) [61] 5 2B, PCB (2 years) (350) Postmenopausal women 25 g/day soy protein (91 mg/day aglycone isoflavone equivalents) vs. PCB Atherosclerosis progression No significant effect
Flavonoids (Isoflavones) Atteritano et al. (2007) [62] 5 2B, PCB (24 months) (191) Postmenopausal women 54 mg/day genistein vs. PCB Lipids profile, CHO metabolism, HOMA, fibrinogen, sVCAM-1, sICAM-1, 8-iso-PGF2α, and osteoprotegerin ↓ Fasting glucose and insulin as well as HOMA, fibrinogen, 8-iso-PGF2α, sICAM-1, and sVCAM-1. ↑ Serum osteoprotegerin
Flavonoids (Isoflavones) Garrido et al. (2006) [63] 3 PCB (12 weeks) (29) Postmenopausal women 100 mg/day isoflavones vs. PCB Lipids profile, CHO metabolism and platelet thromboxane A2 receptor density. BP, BMI, subcutaneous fat ↓ Thromboxane A2 after the experimental treatment.
Flavonoids (Isoflavones) Hall et al. (2005) [64] 4 2B, PCB, X (8 weeks, 8 weeks washout) (117) Postmenopausal women Isoflavone-enriched (genistein-to-daidzein ratio of 2:1; 50 mg/day) vs. PCB cereal Inflammatory and vascular homeostasis biomarkers ↓ CRP
Flavonoids (Isoflavones) Rios et al. (2008) [65] 3 2B, PCB (6 months) (47) Postmenopausal women 40 mg/day isoflavone vs. casein PCB Lipids profile No significant effect
Flavonoids (Isoflavones) Villa et al. (2009) [66] 3 PCB (24 weeks) (50) Postmenopausal women 54 mg/day genistein vs. PCB Anthropometric measures, lipid profile, CHO metabolism and C-peptide evaluation, IR and EF HOMA and fasting glucose levels significantly improved
Flavonoids (Isoflavones) Liu et al. (2012) [67] 4 2B, PCB (6 months) (180) Postmenopausal women 15 g/day soy protein and 100 mg/day isoflavone (Soy group), vs. 15 g/day milk protein and 100 mg/day isoflavone (Iso group) vs. 15 g/day milk protein (PCB) Lipids profile, inflammatory markers and composite cardiovascular No significant effect
Flavonoids (Isoflavones) Yang et al. (2012) [68] 3 Open-labelled, prospective (24 week) (130) Healthy Taiwanese postmenopausal women 35 mg/day vs. 70 mg/day soy extractª Lipids profile ↓ TC, LDLc in patients with TC >200 mg/dL
Flavonoids (Isoflavones) Liu et al. (2013) [67] 5 2B, PCB (6 months) (270) Pre-hypertensive women 40 g/day soy flour (whole soy group), 40 g/day low-fat milk powder + 63 mg/day daidzein (daidzein group), vs. 40 g/day low-fat milk powder (PCB) Anthropometric indicators and body composition No significant effect
Flavonoids (Isoflavones) Aubertin-Leheudre et al. (2008) [69] 3 2B, PCB (6 months) (50) Obese postmenopausal women 70 mg/day isoflavones vs. PCB Body composition (DXA), and Lipid profile and CHO metabolism No significant effect
Flavonoids (Isoflavones) Choquette et al. (2011) [70] 4 2B, PCB (6 months) (100) Overweight to obese postmenopausal women PCB or isoflavones (70 mg/day) or exercise + PCB or exercise + isoflavones (70 mg/day). Exercise consisted of three weekly sessions of resistance training and aerobics Body composition, lipids profile, CHO metabolism and HOMA. No significant effect
Flavonoids (Isoflavones) Aubertin-Leheudre M et al. (2007) [71] 3 2B, PCB (12 months) (56) Obese postmenopausal women 70 mg/day isoflavonesb (+weight loss exercise program from the 6 months) vs. PCB Anthropometry, lipids profile, CHO metabolism, CRP ↓ body weight, BMI, total and abdominal FM (kg and %), ↑ FFM/FM ratio with exercise program
Flavonoids (Isoflavones) Hodgson et al. (1999) [72] 3 2B, PCB, PA (8 weeks) (59) High-normal BP 55 mg/day isoflavonoid vs. PCB 8-iso-PGF2α No significant effect
Flavonoids (Isoflavones) Sagara et al. (2004) [73] 3 PCB, 2B, PA (5 weeks) (61) Men with relatively higher BP or TC Diets containing at least 20 g/day soy protein + 80 mg/day isoflavones vs. PCB diets BP and Lipid profile ↓ BP, TC and non-HDLc and ↑ HDLc.
Flavonoids (Isoflavones) Clerici et al. (2007) [74] 4 Ctrl, PA (8 weeks) (62) Hypercholesterolemia 80 g serving/d (33 mg/day isoflavones + negligible soy protein + led to a serum isoflavone concentration of 222 +/- 21 nmol/L) vs. Ctrl group Lipids profile, hsCRP, urinary 8-iso-PGF2α, and EF ↓ LDLc, TC
Flavonoids (Isoflavones) Meyer et al. (2004) [75] 3 PCB, X (5 weeks, without washout) (23) Mildly hypercholesterolemic and/or hypertensive Soy-based milk (30 g/day soy protein + 80 mg/day isoflavones) + yoghurt (treatment) vs. equivalent dairy products (Ctrl) BP, arterial compliance, lipid profile, fatty acids No significant effect
Flavonoids (Isoflavones) Jenkins et al. (2002) [76] 3 1B (1 month, 2 weeks washout) (41) Postmenopausal women with hypercholesterolemia A low-fat dairy food Ctrl diet, high- (50 g soy protein and 73 mg isoflavones/day), low- (52 g soy protein and 10 mg isoflavones/day) isoflavone soy food diets BP, lipids profile, oxidized LDL, calculated CAD risk Soy diets ↓ TC estimated CAD risk, TC/HDLc, LDLc/HDLc, ApoB/A-I. Blood lipid and BP changes, the calculated CAD risk ↓ with the soy diets
Flavonoids (Isoflavones) Blum et al. (2003) [77] 4 2B, PCB, X (6 weeks, 1 month washout) (24) Postmenopausal women with hypercholesterolemia 25 g/day soy protein vs. PCB Vascular inflammation biomarkers No significant effect
Flavonoids (Isoflavones) Teede et al. (2006) [78] 3 Ctrl, X (3 months) (41) Hypertensive postmenopausal Soy cereal (40 g/day soy protein + 118 mg/day isoflavones) vs. gluten PCB cereal BP, arterial function ↑ 24 hour HR, area under curve of 24 h SBP
Flavonoids (Isoflavones) Cicero et al. (2013) [79] 4 Ctrl, 1B prospective study with PA (12 weeks) (40) Mildly dyslipidemic postmenopausal women 60 mg/day soy isoflavones + 500 mg/day berberine vs. PCB (1 tablet/d) BP, HOMA, lipids profile, metalloproteinase Isoflavones-berberine experienced a significant improvement in plasma lipid and metalloproteinase serum levels.
Flavonoids (Isoflavones) Curtis et al. (2013) [80] 5 2B, PCB, PA (1 year) (180) Postmenopausal women with T2D 27 g/day flavonoid-enriched chocolate (containing 850 mg flavan-3-ols [90 mg epicatechin] + 100 mg isoflavones [aglycone equivalents)] /d) vs. PCB. Intima-media thickness of the common carotid artery, pulse wave velocity, augmentation index, BP, and vascular biomarkers Only pulse pressure variability improved
Flavonoids (Isoflavones) Curtis et al. (2013) [80] 5 PA, PCB (1 year) (93) Postmenopausal women with T2D 27 g/day flavonoid-enriched chocolate (containing 850 mg flavan-3-ols [90 mg epicatechin] + 100 mg isoflavones [aglycone equivalents)] /d) vs. PCB. HOMA and QUICKI, lipid profile, BP Estimated 10-year total coronary heart disease risk (derived from UK Prospective Diabetes Study algorithm) was attenuated after flavonoid intervention
Flavonoids (Isoflavones) Chan et al. (2008) [81] 5 2B, PCB (12 weeks) (102) Prior ischemic stroke 80 mg/day isoflavone supplement vs. PCB EF, nitro-glycerine-mediated dilatation, BP, HR, CHO metabolism, haemoglobin A1c, and oxidative stress biomarkers ↓ serum hsCRP and improved brachial EF in patients with clinically manifest atherosclerosis
Flavonoids (Isoflavones) Webb et al. (2008) [82] 4 2B, PA (5 days) (71) Subjects with CAD Isoflavone-intact soy protein (75 mg/day of isoflavones) vs. isoflavone-free PCB Stimulated coronary blood flow, Basal and stimulated coronary artery luminal diameters No significant effect
Flavonoids (Isoflavones) Fanti et al. (2006) [83] 3 2B, Crtl, prospective, pilot study (8 weeks) (32) ESRD patients with systemic inflammation Nutritional supplements (soy groups) containing 26–54 mg isoflavones aglycones vs. isoflavone-free milk-based supplements (Ctrl group) Inflammatory biomarkers Inverse correlation between blood isoflavones levels and CRP, positive correlation between blood isoflavones levels and IGF-1
Flavonoids (Procyanidins) Ras et al. (2013) [84] 5 2B, PCB, PA (8 weeks) (70) Healthy subjects 300 mg/day Grape Seed Extract vs. PCB BP No significant effect
Flavonoids (Procyanidins) Yubero et al. (2013) [85] 3 2B, PCB, X (56 days) (60) Healthy subjects 700 mg/day the Grape Extract (Eminol®) vs. PCB CVD risk and oxidative stress markers ↓TC, LDLc and ↑ TAC and vitamin E.
Flavonoids (Procyanidins) Asher et al. (2012) [86] 5 2B, PCB, four-period X (3.5 days, 4 days washout) (21) Pre-hypertensive or mildly hypertensive adults Hawthorn Extract (1000, 1500, and 2500 mg/day) vs. PCB EF and nitric oxide release No significant effect
Flavonoids (Procyanidins) Liu et al. (2004) [87] 3 PCB, 2B, PA (12 weeks) (58) HT subjects 100 mg/day Pycnogenol vs. PCB Endothelin ↓ Calcium antagonist nifedipine. ↓ endothelin-1 concentration and ↑ of 6-keto prostaglandin F1a.
Flavonoids (Procyanidins) Enseleit et al. (2012) [88] 5 2B, PCB, X (8 weeks, 2 weeks washout) (23) Patients with stable CAD 200 mg/day Pycnogenol vs. PCB EF, oxidation and inflammatory markers, platelet adhesion and 24 h BP EF improvement. ↓ 8-iso-PGF2α
Flavonoids (Procyanidins) Mellen et al. (2010) [89] 3 2B, PCB, X (4 weeks, 4 weeks washout) (50) Patients with CAD 1300 mg/day muscadine grape seed vs. PCB EF, oxidation and inflammatory markers, antioxidant status No significant effect
Flavonoids (Procyanidins) Tauchert et al. (2002) [90] 3 2B, PCB (16 weeks) (209) Chronic stable heart failure patients 1800 mg/day crataegus extract WS 1442 or 900 mg/day crataegus extract WS 1442 vs. PCB Typical heart failure symptoms Typical heart failure symptoms as rated by the patients were ↓ to a greater extent

ªSoy extract contains: contains 17.5 mg soy isoflavones consisting of 5.25 mg glycitin, 8.75 mg daidzein, and 3.5 mg genistein; b 44 mg of daidzein, 16 mg of glycitein, and 10 mg of genistein; c Soy groups in three formats: Protein powder (54mg isoflavones), Cereal-like product (26mg isoflavones), energy bar (26 mg isoflavones).

8-iso-PGF2α, 8-iso-prostaglandin F2α; 1B, one-blind, 2B, double-blinded; ACN, anthocyanins; Apo, apolipoprotein; BMI, body mass index; BP, blood pressure; CAD, chronic artery disease; CAT, catalase; CHF, chronic heart failure; CHO, carbohydrate; CRP, C-reactive protein; hsCRP, high sensitivity c-reactive protein; Ctrl, control, CVD, cardiovascular disease; DXA, Dual-energy X-ray absorptiometry; EF, endothelial function; EGCG, epigallocatechin gallate; ESRD, European and North American end-stage renal disease; FM, fat mass; FFM, fat-free mass; HDLc, high-density lipoprotein cholesterol; HOMA, homeostasis model assessment; HR, heart rate; HT, hypertension; sICAM, soluble intercellular adhesion molecule; IGF-1, insulin-like growth factor-1; IR, insulin resistance; IL, interleukin; LDLc, low-density lipoprotein cholesterol; MDA, malonaldehyde; MPFF, micronized purified flavonoid fraction; MPI, milk protein isolate; NTG, nitro-glycerine-mediated dilation; PA, parallel design, PAI-1, plasminogen activator inhibitor-1; PCB, placebo, PBMCs, peripheral blood mononuclear cells; PS, plant sterols; PWV, pulse wave velocity; QUICKI, quantitative insulin sensitivity check index; SBP, systolic blood pressure; SOD, superoxide dismutase; TC, total cholesterol; TGF, transforming growth factor; T2D, type 2 diabetes; VCAM, soluble vascular cellular adhesion molecule; vWf, von Willebrand factor; X, crossover design. *Included after proofreading.

2.2. Selection and Evaluation

First, both titles and abstracts were identified independently by two reviewers, for exclusion of those articles that did not fit with the language, date, subject matter, design and outcomes established. Then, full-text publications were classified by pathologies according to outcomes analysed in each study.

Moreover, RCTs were finally selected if they obtained a score between 3 and 5 according to the Jadadscale [17]. This method attempts to reduce bias for RCTs, ensuring a certain quality in the evidence; it took into account if they were randomized, blinded and provided detailed information about patients.

Furthermore, we verified the quality of selected articles by the Scottish Intercollegiate Guidelines Network (SIGN) [16]. Diverse quality levels of scientific evidence are established according to two features: the design and bias risk of a study. The levels are from 1++, when the information is considered as high quality, to 4 when the information is considered as very low quality. Signs are used to reporting with reference to compliance degree of key criteria associated with potential bias (1++, 1+, 1-, 2++, 2+, 2-, 3, and 4). Additionally, we included a grade of recommendation, based on the evidence strength of the antecedents, whose levels are A, B, C, D, with “A” being highly recommended and “D” not recommended. These grades of recommendation by SIGN guidelines are equivalent to those designated by the Food and Agriculture Organization of the United Nations/World Health Organization (FAO/WHO), as evidence criteria: convincing, probable, possible and insufficient [18].

3. Results and Discussion

In total, 831 RCT’s were found using the equations proposed in the different databases (EMBASE, LILACS and PubMed). We excluded 717 due to obvious irrelevance, leaving 114 papers in full to read (Figure 2). After papers were read and evaluated using the Jadad scale, 76 articles were selected for the final review, and are included in Table 1, Table 2 and Table 3.

Figure 2.

Figure 2

Review Flow Diagram.

3.1. Simple Phenols

3.1.1. Stilbenes

Eight articles complied with requirements and their score varied from 3–5 and are included in Table 1. The age ranged from 20 until 83 years, with sample sizes of 19–166 participants. Two studies included an acute intervention design and were carried out in overweight/obese men and post-menopausal women with elevated BP [19,20]. Participants consumed three doses of resveratrol (RSV) (30 mg, 90 mg or 270 mg) or 75 mg of trans-resveratrol [20] and one hour after supplementation, they determined possible improvement of EF. Wong et al. [19] observed that EF increased more with the highest dose and later confirmed the increase of flow mediated dilation (FMD) with a 75 mg dose in an acute and a long term study [20]. One study was developed in healthy smoker subjects [21], testing the efficacy of RSV (500 mg/day) on anthropometric parameters and CHO metabolism, apart from lipid profile, markers of inflammation and oxidative stress during 60 days. Thus, after RSV supplementation, hsCRP and decreased, while antioxidant status (TAS) increased. Effects of short-term oral supplementation (60 days) of RSV alone (20 mg/day) or with calcium fructoborate (CF) (20 RSV + 112 CF mg/day) in subjects with stable angina pectoris were recently evaluated by Militaru et al. [22], measuring lipids profile, hsCRP, left ventricular function markers and observed a stronger decreased in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) after RSV+CF administration. Moreover, RSV alone presented the most significant decreases for TC and TAG, although, reduction of high sensitivity C-reactive protein (hsCRP) was greater using CF treatment (112 mg/day). Tomé-Carneiro and colleagues [23,24,25,26] reported four studies with grape extract containing RSV combination (GE-RES), comparing with grape extract alone (GE). In 2012, they developed a clinical trial in primary prevention of CVD patients. After six months with 350 mg/day GE or 350 mg/day GE-RES possible changes in lipid profile and oxidized LDL(oxLDL) were assessed [24] and then, doses were doubled for the next six months. LDLc, apolipoprotein B (ApoB), oxLDL, and oxLDL/ApoB ratio decreased in the GE-RES group, whereas non-HDLc (total atherogenic cholesterol load)/ApoB ratio increased. Moreover, they evaluated the effect in inflammatory and fibrinolytic biomarkers after one year [26]; many improvements were observed: hsCRP, tumour necrosis factor alpha (TNF-α), plasminogen activator inhibitor 1 (PAI-1), interleukin (IL) IL-6/IL-10 ratio, and soluble intercellular adhesion molecule (sICAM) significantly decreased, and IL-10 and adiponectin increased. . In 2013, they evaluated the same doses (350 mg/day GE or 350 mg/day GE-RES), for the first six months and double for the following six months in patients with T2D, HT and stable coronary artery disease (CAD) [25], as well as in patients with stable CAD alone [23]. Peripheral blood mononuclear cells (PBMCs),inflammatory andfibrinolytic biomarkers were assessed in both studies; the pro-inflammatory cytokines CCL3, IL-1β and TNF-α expression levels, were significantly reduced and transcriptional repressor LRRFIP-1 expression increased in PBMCs from T2D, HT and stable CAD patients taking the GE-RES extract [25]. In the other trial, the GE-RES group showed an increase of the anti-inflammatory serum adiponectin and PAI-1 decreased. In addition, six key inflammation-related transcription factors were predicted to be significantly activated or inhibited, with 27 extracellular-space acting genes involved in inflammation, cell migration and T-cell interaction signals presenting down regulation in PBMCs from stable CAD patients [23].

RSV has been shown to exert its protective effect against cardiovascular disease but it is necessary to reiterate that these data derive from cell culture or small animal model systems, with no reports on long-term health or survival in humans or alternate animal models [91]. It is well known that impaired FMD is recognized as an independent risk factor for the development of CVD [92,93]. Several authors investigated the acute resveratrol supplementation effect in overweight/obese individuals with mildly elevated BP, thus these subjects present cardiovascular risk [94,95]. Wong et al. [19] observed improvements in FMD were correlated with a dose-related increase in plasma RSV concentrations and following up their research, they confirmed the effect of RSV on FMD [20]. However, more long-term interventions are required. The other studies assessed long-term administration, until one year. Generally, trials obtained a decrease in total cholesterol (TC), triglycerides (TAG), C-reactive protein (CRP), CCL3, IL-1β, sICAM, NT-proBNP, TNF-α expression, LDLc, ApoB, LDLox and LDLox/ApoB ratio, as well as adiponectin, non-HDLc/ApoB ratio, IL-10 in different type of subjects [21,22,23,24,25,26].

Reports by Tomé-Carneiro et al. [23,24,25,26] focused on PBMCs, inflammatory andfibrinolytic biomarkers, lipid profile, and oxLDL concentration. Prior studies have shown increased mitochondrial production of ROS in PBMCs, endothelial cells, and other cell types in diabetes, suggesting systemic mitochondrial dysfunction [96,97]. Hartman et al. [98] observed higher basal, maximal, and uncoupled oxygen consumption in the diabetic patients, findings that are consistent with prior work showing increased mitochondrial ROS production in PBMCs. This suggests how serious complications may be in T2D subjects. Results by Tomé-Carneiro et al. [23,24] on transcriptional levels appear interesting; nevertheless, we have not found further similar interventions confirming these results.

3.1.2. Catechols

Two articles about catechols were selected (Table 1). According to the Jadad scale, such studies obtained values from 4–5. In 2008, Alwi et al. [27] assessed effects of curcumin on lipids profile in 75 acute coronary syndrome (ACS) patients (45–73 years). The efficacy was measured using different doses (45 mg/day, 90 mg/day or 180 mg/day) during two months, reporting higher effects in TC, LDL reduction and an increase in HDL with the lower dose, but changes were not significant in respect to placebo. Recently, a study [28] also evaluated the efficacy and safety of curcumin extract (750 mg/day) as an intervention agent for reducing the risks for atherogenesis in 240 T2D patients with a mean age of 61 years, by means of parameters such as BP, anthropometry, lipids profile, adiponectin, leptin, CHO metabolism, uric acid, and pulse wave velocity (PWV). After six months, curcumin treatment significantly reduced PWV, homeostasis model assessment (HOMA), TAG, acid uric, leptin and abdominal obesity, as well as significantly elevated values of adiponectin.

Alwi et al. [27] developed the first study to evaluate the effect of curcumin on the lipid profile of patients with ACS), thus the antecedents are described in in vitro and in vivo animal models. Results did not change significantly when comparing with placebo group. A meta-analysis based on five clinical trials in relation to curcumin on blood lipids concentration, indicated a non-significant effect of curcumin on the lipid profile when considering heterogeneous populations including healthy subjects, obese dyslipidemic patients, elderly subjects with established acute diagnosis of Alzheimer’s disease, ACS and patients with T2D [99]. Chuengsamarn et al. [28] also assessed lipid profiles and did not find significant statistic differences compared with placebo. Ramirez-Boscá et al. [100] observed that a daily treatment with curcumin extract could decrease significantly the LDLc and ApoB concentrations and increase the HDL and ApoAI in healthy subjects. However, due to lack of sufficient data we cannot recommend curcuminoids for improvement lipids profile in healthy and unhealthy subjects until further solid evidence is obtained.

On the other hand, after six months of curcumin intervention [28], PWV, HOMA, TAG, uric acid, abdominal obesity and leptin decreased, in addition to adiponectin increase. In addition, curcumin was well tolerated, with very few adverse effects. Agreeing with that, curcumin administration has been demonstrated, in in vitro and in vivo animal models, to elevate adiponectin and to decrease leptin levels [101,102], and oxidative stress in rabbits [14].

Due to its benefits and safety, Chuengsamarn et al. [28] proposed that curcumin extract might be used as anti-atherosclerotic in T2D populations. We propose however to replicate these results in other populations, since this study was performed in a Thai population and high variabilities of physical activity and diet among populations may exist that affect study results. Moreover, there are not enough studies in humans for recommending curcumin against T2D.

3.1.3. Beer or Wine Polyphenols

Four of the studies were focused on the effects of polyphenols derived from beer or wine; all were in subjects with risk of CVD (55–75 years) (Table 1). They tested 280 mg of red wine polyphenols or 30 g/day of beer or wine (normal and dealcoholized) for four weeks [29,30,31,32]. Botden et al. [29] analysed BP and found no significant effect. Chiva-Blanch et al. [30,31,32] reported that after the beer and non-alcoholic beer interventions the number of circulating endothelial progenitor cells (EPC)-mobilizing factors increased, consumption of dealcoholized red wine decreased BP and alcohol increased IL-10 and decreased macrophage-derived chemokine concentration and that the phenolic compounds of red wine decreased the serum concentrations of ICAM-1, E-selectin and IL-6.

Botden et al. [29] studied the effects of polyphenols from wine on BP and found no effect except that, the use of dealcoholized red wine reduced BP. Moreover, phenolic compounds are related to decreases of inflammatory and vascular homeostasis biomarkers. Nevertheless, there is not strong evidence showing that consumption of beer or wine could help to improve risk of CVD; reports in the literature do not focus on a specific compound, regardless of alcohol content. A review by Rotondo et al. [103] states that wine in low quantities could be beneficial in regard to CVD, but notes possible bias in the publications reviewed. It is necessary to focus research on a specific compound in alcohol-containing products, when assessing for potential benefits in CVD.

3.2. Polyphenols

The different research equations resulted in 59 articles related to different flavonoids and subclasses, such as anthocyanins (ACN), flavonols, flavanols, isoflavones and procyanidins. Eight of the studies were discarded because of lack of information in the abstract or inability to obtain the full-text version. The results are presented in groups according to their class in Table 2 and Table 3.

3.2.1. Anthocyanins

Five publications were related to ACN (Table 2). Quality scores for these studies ranged from 4 to 5 in the Jadad scale. Two of the studies were exclusively in women between 23 and 58 years [33,34] (sample sizes from 31 to 57) and one, in 31 hypertensive men aged between 35 and 51 years [35]. The study developed by Dohadwala and colleagues [36] was in patients with CAD using an acute and a chronic approach.

The doses of ACN provided were from 500 to 640 mg/day [97,98] alone or as juice or blended drink including 94 mg/day [36], 983.7 mg/day and 840.9 mg/day [33], respectively, during periods from 14 days to 4 weeks.

The main outcomes in these studies were related to BP, lipid profile, CHO metabolism, inflammatory and oxidative stress biomarkers, platelet reactivity and vascular function.

One of the studies reported an increase of HDLc and blood glucose after the ACN intake, but no effects on oxidative stress biomarkers [35]. On the other hand, Kuntz et al. [33] reported an increase on superoxide dismutase (SOD) and catalase (CAT) and a decrease of malonaldehyde (MDA) after the ACN ingestion. The other studies did not find any significant effect when analysing BP, CHO metabolism, lipid profile, inflammatory biomarkers, platelet reactivity [34] or vascular function [36].

A recent systematic review has shown the effectiveness of anthocyanins in decreasing CVD risk [104]. Nevertheless, in this review we found that improvement of risk factors related to CVD such as BP, lipids profile, CHO metabolism, inflammatory, oxidative stress biomarkers, and platelet reactivity were not consistent. Hassellund et al. [35] reported modifications in lipid and CHO metabolism, but this result was not supported in the other investigations, as was the case with oxidative stress as well. There is not strong evidence supporting that anthocyanins help to decrease risk of CVD and further studies are required, thus, the grade of recommendation according to the SIGN guidelines is B.

3.2.2. Catechins

Four of the studies were related to catechins (Table 2), and the quality score assigned according to the Jadad scale was around 3–5. Two of the studies were with healthy subjects between 32 and 69 years old [37,38] (sample size 52 and 64 in each one). In regard to the other two studies, one included 52 subjects with early atherosclerosis (mean of 42 years of age) [39], and the other included 240 subjects with visceral fat-type obesity aged around 25–55 years old [40].

In the studies with healthy subjects [37,38] and the one in visceral fat-type obesity [40], catechins were obtained from green and black tea, with doses between 583 mg and 3 g per day during periods between 4 and 14 weeks. The atherosclerotic subjects [39] were supplemented with 30 mL of epigallocatechin gallate (EGCG)-supplemented olive oil during 4 months.

The main outcomes in the healthy subjects [37,38] were related to CVD risk, such as inflammatory and endothelial biomarkers. Subjects with early atherosclerosis [39] were investigated in regards to endothelial function and inflammatory and oxidative stress status. The aims in the subjects with visceral fat-type obesity [40] were anthropometric measurements, body fat composition and CVD risk factors.

There were no significant effects of the use of catechins in healthy subjects when compared with placebo/control; however, there was a negative correlation between beta-carotene and the inflammation biomarkers, IL-6 and fibrinogen [38]. On the other hand, the intervention in visceral fat-type obesity showed significant decreases in body weight, body mass index (BMI), body fat ratio, body fat mass, waist circumference (WC), hip circumference, visceral fat area and subcutaneous fat area, systolic blood pressure (SBP) and LDL cholesterol [40]. Nevertheless, in patients with early atherosclerosis, there was no significant effect, but merging both, the control (olive oil) and the experimental group (olive oil and EGCG)) the endothelial function was improved [39].

Catechins were shown to be effective in reducing LDLc and TC, but there is no robust evidence in reducing CAD risk [105]; a dose of 583 mg of catechins in middle-aged subjects showed a significant effect reducing obesity related makers, such as body weight, BMI, body fat ratio, body fat mass, WC, hip circumference, visceral fat area, and subcutaneous fat area, SBP, LDLc. However, doses of 630 mg or 3 g did not benefit middle and older aged subjects. Furthermore, Widmer et al. [39] investigated the effects of olive oil with EGCG in endothelial function without significant effect; however, they found a significant improvement when they merged both study groups. Nevertheless, this result is attributable to olive oil compounds, independently of the EGCG content. Taking into account the different studies included in this review, we can conclude that there is no robust evidence to suggest a beneficial effect of tea catechins on prevention of CVD; consequently, the grade of recommendation according to the SIGN guidelines is B.

3.2.3. Flavanols

Fourteen investigations studied the effects of flavanols (Table 2); the Jadad quality scores were between 3 and 5. Only one study was in healthy males (mean 68 years, and with a sample size of 40) [41], while four papers were related to overweight adults (with one of them including two designs and thus treated as separated studies [45]), involving subjects from 40 to 64 years (n = 21–98) [42,43]. Furthermore, there were two studies in hypertensive subjects [46,47] with 52 and 19 patients respectively. The study developed by Flammer et al. [48] included 20 chronic heart failure (CHF) patients (58 years mean) with an acute and a long-term intervention. Heiss et al. [49] and Horn et al. [50] studied the effect of flavanol in 16 CAD patients (60 years mean) while Balzer et al. [51] designed a study in diabetic patients with an acute and long-term intervention (10–41 subjects between 50 and 80 years).

Four of the studies [42,45,48,51] used a short-term approach looking for the acute response of flavanols; they tested cocoa or chocolate in amounts from 624 mg to 963 mg/day. Further, the other studies tested the flavanols contained in chocolate in longer interventions, from 4 to 6 weeks in doses from 33 to 1052 mg/day [43,44,46].

The aim of the study in healthy males [41] was to determine the effect on the endothelial function and in the soluble cellular adhesion molecules, without significant effects. In regards the studies with overweight [42,43,45], hypertensive [46,47], CHF [48], CAD [49,50] and diabetic patients [51], the main outcomes were related to EF and BP. Furthermore, Grassi et al. [47] studied the effects on lipids profile and IR.

The results in overweight, HT, CHF, CAD and diabetic patients showed a consistent improvement in EF when comparing different doses of flavanols vs. placebo/control [42,43,44,45,47,48,49,50,51].

When testing flavanols in BP, Faridi et al. [29] found a significant decrease in BP in overweight adults in an acute intervention with two different products using >800 mg/day of flavanols. Additionally, BP decreased significantly in hypertensive subjects using flavanol-rich chocolate during 15 days [47] and in CAD patients [49] with 375 mg twice daily during 30 days. However, this result was not consistent when using doses between 33 and 1052 mg/day of flavanones during six weeks [46] or 814 mg/day during four weeks [44]. Besides, Berry et al. [42] found out that cocoa flavanols could attenuate the increase of BP after exercise. The effects on IR were investigated in two studies, finding a significant improvement [43,47].

Flavanol-rich chocolate and cocoa products have shown a small but statistically significant effect in lowering blood pressure by 2–3 mm Hg in the short term [101], in addition Khawaja et al. [106] suggest that there is ample evidence in support of the beneficial effects of cocoa/dark chocolate on CHD risk. Summary of the evidence showed benefits of cocoa flavanols in BP and EF, in overweight adults [42,43,44,45,46], hypertensive subjects [47], in CHF [48], in CAD [49,50] and in T2D patients [51] utilizing different doses (149–963 mg/day). Additionally, Balzer et al. [51] reported a dose-response in an acute intervention. While the use of cocoa flavanols in BP and EF improvement have shown efficacy, further studies using flavanol-free controls could help to strength the evidence and long-term interventions may clarify the effect on CVD, thus the grade of recommendation according to the SIGN guidelines is B.

3.2.4. Flavonols

Five studies were focused on the effects of flavonols on CVD (Table 2); all of them obtained more than 3 points in the Jadad scale. Three of the publications were focused on healthy males [52,53,54] aged between 24 and 53 years (sample size between 12–27). The other two studies studied the effect on hypertensive subjects [52,55] (24–49 years; including 12 and 41 subjects, each one). Quercetin was the flavonol tested in two of the healthy subject studies at a dose of 1 g/day; Larson et al. [52] used it in an acute study and Conquer et al. [53] used it for 28 days; both of the authors looked for effects in BP and vascular markers without effect. Moreover, Suomela et al. [54] utilized oatmeal with 78 mg of flavonol aglycones from sea buckthorn for four weeks, and likewise did not find any significant effect.

The studies focused on hypertensive subjects looked for effects in BP, oxidative stress, angiotensin-converting enzyme and endothelin. Both, Edwards and Larson [52,55] found a significant reduction in BP in hypertension. Evidence around flavonol has been controversial; previous meta-analyses has associated its consumption with lower rates of CHD [8] or a reduction in risk of stroke [107,108], but reports from other authors do not support the protective role against CHD [10]. In the present review, we have found that doses of 1 g/day of quercetin or an oatmeal with 78 mg of aglycones of quercetin did not shown effects on diverse CVD risk markers, such as endothelin, BP or oxidative stress. Nevertheless, an acute intervention with 1095 mg/of quercetin and a long-term intervention (28 days) with 730 mg/day seems to be effective at reducing BP in hypertensive men [52,55], but not on other oxidative stress or endothelial function markers. We can conclude that there is no effect of flavonols in CHD, thus the grade of recommendation according to the SIGN guidelines is B, but since it seems that flavonols are effective at reducing BP in hypertensive men, further analysis in greater cohorts are needed.

3.2.5. Isoflavones

Thirty papers were related to the consumption of isoflavones (Table 3), the Jadad scores were above three points. Five of the studies were in healthy subjects between 20 and 53 years (sample size 22–205) [56,57,59,60,68]. Most of the studies were developed in postmenopausal women (45–92 years) with normal weight [61,62,63,64,65,66,67], overweight and obese [69,70,71], with BP alterations [78,109], dyslipidaemias [76,77,79] or T2D [80], including from 40 to 350 participants. Other authors also took men in account [58,72,73,74,75]. One study investigated in 102 subjects prior to ischemic stroke [81] (mean 66 years), another in 71 subjects with CAD (mean 58) [82] and Fanti and colleagues studied the effect on patients with systemic inflammation [83].

The doses of isoflavones employed in healthy subjects and postmenopausal women were between 40 and 118 mg/day, with lengths between 17 days to two years. The intervention in postmenopausal women with T2D used 100 mg/day of isoflavones for a one-year period. The subjects with ischemic stroke consumed 80 mg/day of isoflavones for 12 weeks. Patients with CAD included 75 mg/day during five days. Subjects with systemic inflammation included doses between 26–54 mg/day of isoflavones aglycones [56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,109].

The main outcomes established in the articles of healthy, overweight and obese subjects were related to anthropometry [66], body composition [63,70,71,109], lipid profile [56,57,58,59,60,62,63,65,66,67,68,69,70], BP, CHO metabolism [60,62,63,66,70], and inflammatory [57,59,63,64,67], oxidative stress [62] and vascular homeostasis biomarkers [59,62,64] and only one in atherosclerosis progression [61]. Besides, the studies in hypertensive and dyslipidemic patients aimed on lipids profile [73,74,76,79], BP [73,75,76,78,79], oxidative stress [72,74,76], endothelial function [75,78] and just one in vascular inflammation biomarkers [77]. Two articles from Curtis et al. [80,110] in postmenopausal women with T2D looked for effects in HOMA, QUICKI, lipids profile, intima-media thickness of the common carotid artery, pulse wave velocity, augmentation index, BP, and vascular biomarkers.

The results reported in healthy, overweight and obese patients related to anthropometry and body composition were without significant effects of isoflavones. Moreover, in relation with lipids profile, a study reported lower ratios of TC/HDLc, LDLc/HDLc, and ApoB/Apo A-I [56] and another a decrease in TC and LDLc [71]. Besides, Sanders et al. [57] found significant improvements in HDLc and Apo-A; however, seven studies did not find any significant effect in plasma/serum lipids [58,59,60,63,65,66,67,69]. Fasting glucose, insulin, and HOMA were reduced in three studies [59,60,66] but results from other authors were not consistent [63,69,70]. The only author that studied BP [63] did not find any significant change. Atteritano et al. [62] reported significant improvements in isoprostanes (8-iso-PGF2α), sICAM-1 and soluble vascular cell adhesion molecule-1, while Atkinson et al. [59] and Sanders [57] investigated PAI-1 and other authors [72,74] 8-iso-PGF2α without significant results. One study showed a decrease in thromboxane A2 [63] and another in CRP [64]. The study of Liu et al. [67] aimed in inflammatory markers showed no effect. Hodis et al. [61] analysed atherosclerosis progression finding no positive effects. Furthermore, in subjects with BP alterations and dyslipidaemias, there were no significant changes in CHO metabolism [79,80], oxidative stress or inflammatory biomarkers [72,74,76,77]. In relation to BP, Sagara et al. [73] and Teede et al. [78] reported improvements; nevertheless, these results were not consistent with the results obtained by other authors [75,76,79,80]. Moreover, when lipid profile were analysed, a decrease in total cholesterol, LDLc and a decrease was observed [73,76,79] but Meyer et al. [75] and Thorp et al. [58] reported no significant change. Many authors [52,56,57,108] described no significant effects on endothelial function; nonetheless, Jenkins et al. [76] reported a lower calculated risk of CAD. The intervention in subjects’ prior ischemic stroke [81] found a reduction in hsCRP and improved the EF, beside CAD patients [82] showed no effect on EF. Fanti et al. [83] found a significant inverse correlation between isoflavones and CRP.

The use of isoflavones on the prevention of CVD has been associated with the capacity of these compounds to attenuate alterations in lipid profile and inflammatory markers [111,112]. Furthermore, the American Diet Association recommended consumption of soy protein containing isoflavones in high-risk populations with increased total cholesterol and LDLc. Additionally, data from two cohorts [113,114] showed that isoflavones consumption is associated with a lower risk of cardiovascular disease in women. Interestingly, we found that doses above 50 mg/day in healthy subjects improved lipids profiles [56,57,68], but a lower dose for 12 months did not show effect on CVD risk factors [45]. Additionally, normal weight postmenopausal women did not improve the lipid profile in many of the studies in which they included as outcome [60,63,65,66,67,69]. Nevertheless, the response of dyslipidemic postmenopausal women was positive when treated with doses between 60 and 80 mg/day of isoflavones, decreasing TC, HDLc and ratios TC/HDLc, LDLc/HDLc and ApoB/A-I [76,79].

Glucose, insulin and HOMA measurement are important due to its relationship in development of CVD. Although, these indicators were reduced in normal weight subjects [41,43,49], isoflavones in high doses (60–100 mg/day) showed no benefit on overweight/obese postmenopausal women [63,69,70,79].

BP was only measured by Garrido et al. [63] in healthy subjects without significant changes. A different panorama was shown in subjects with BP and dyslipidaemias, while doses above 80 mg improved BP [73,78], doses below did not have any effect [75,76,79,80].

The research focused on inflammatory and oxidative stress biomarkers in healthy subjects gave inconclusive results, markers such as fibrinogen and PAI-1 were not reduced, but only two authors measured them [57,59]. Thromboxane A2, CRP, and 8-iso-PGF2α were markers that also responded effectively to isoflavones intervention, but were not taken in account in all the investigations [57,59,60,62,63,64,67,71]. Moreover, Liu et al. [109] focused his research in measuring inflammatory markers after an intervention with soy or milk protein plus 100 mg of isoflavones without significant effects. This lack of consistent results was already showed by Dong and colleagues [114] in a meta-analysis including 14 trials that analysed soy foods with isoflavones concluded that there is insufficient evidence that soy isoflavones significantly reduce CRP concentrations in postmenopausal women.

Dysfunction of the vascular endothelium has shown to be an early step prior to development of atherosclerosis [115], its prevention is vital for the maintenance of vascular health. Some authors reported no EF improvement [65,74,75,80], indeed, Webb et al. [82] conclude a lack of effect on EF in their intervention; however, the inclusion of more women to perform a specific gender analysis could give different results. Nevertheless, Chang et al. demonstrated that 12-week isoflavone treatment improved brachial FMD in patients with clinically manifest atherosclerosis, thus reversing their endothelial dysfunction status. In this regard, Li et al. [9] developed a meta-analysis measuring isoflavones on vascular endothelial function in postmenopausal women and conclude that oral isoflavone supplementation does not improve endothelial function in postmenopausal women with high baseline FMD levels but leads to significant improvement in women with low baseline FMD levels. Furthermore, Pase et al. [116] determined that soy isoflavone supplementation provides an effective means of reducing arterial stiffness, but this review showed to be biased.

Lastly, the use of isoflavones in body composition and anthropometric measurements showed no effect in most of the interventions that included study of outcomes [63,66,67,69,70]. In summary, the need of further studies with greater population sizes are necessary; the effect of the inflammatory process and endothelial function in postmenopausal women on are possibly the most interesting areas of study. The grade of recommendation according to the SIGN guidelines is B.

3.2.6. Procyanidins

Eight studies from the search were related to procyanidins (Table 3), with a Jadad score above three points. Two interventions were in healthy subjects between 34 and 75 years [84,85], sample size 60 and 70, in each one. Asher et al. [86] and Liu [87] studied the effects of procyanidins in HT and the three other studies were in CAD (18–73 years, sample size of 23 and 50) and the last study included 209 chronic stable New York Heart Association class-III heart failure subjects [90].

The interventions in healthy subjects used 300–700 mg/day of grape extracts with a length of eight weeks in both [84,85]. In HT subjects, the hawthorn extract was investigated in a short tem study of three and a half days in doses of 1 g, 1.5 and 2.5 g [86]. In the other study they used 100 mg/day of Pycnogenol® during 12 weeks [87]; this product was also utilized at a dose of 200 mg/day in stable CAD patients for eight weeks [88]. Besides, muscadine grape seed was used for four weeks in doses of 1300 mg/day [89]. The subjects with stable CHF were treated with 1800 mg of crataegus extract WS 1442 or 900 mg of crataegus extract WS 1442 or with placebo for 16 weeks [90].

In healthy subjects, the outcomes were related to BP, CVD and oxidative stress biomarkers, in hypertensive subjects to endothelial function, in CAD to endothelial function, inflammatory and oxidative stress biomarkers. In patients with stable CHF, the aim was related to typical heart failure symptoms [84,85,86,87,88,90].

There were no significant effects in BP in healthy subjects [84]. However, Yubero et al. [85] reported a significant decrease in TC, LDL and an increase in TAC and vitamin E. Furthermore, in hypertensive subjects, Asher et al. [86] did not find significant effects, while on the contrary Liu et al [87] found a reduction of endothelin-1 concentration and an increase in 6-keto prostaglandin F1a. Moreover, the use of Pycnogenol in CAD also showed an improvement of endothelial function and a reduction of 8-iso-PGF2α [88]. The muscadine grape seed did not show any significant effect [89] and the crataegus extract seemed to reduce the typical heart failure symptoms [90].

Procyanidins are compounds that can stabilize membranes, preventing their disruption by chemical and biological agents, thus mitigating oxidative stress and the activation of proinflammatory signals, factors related to development of CVD. Evidence found in the literature reviewed is not consistent. In healthy subjects, there was no effect on BP [84] using 300 mg/day of grape seed extract. However, Yubero et al. [85] reported improvement on CVD risk and oxidative stress markers with 700 mg/day. Besides, in hypertensive subjects, one study including different doses showed no improvements in EF or NO release, while another with 100 mg of Pycnogenol® reduced the concentration of endothelin and 6-keto prostaglandin F1a. The same compound was utilized in a dose of 200 mg/day in patients with stable CAD with improvements in EF and a decrease in isoprostanes. However, Mellen et al. [89] studied the effect of muscadine grape seed (1300 mg) without further effects. Finally, Tauchert et al. [90] included two different extracts from crataegus in typical heart failure symptoms with a positive decrease as rated by patients. In this regard, there is insufficient evidence to determine if extracts containing procyanidins could improve CVD risk; further investigations are necessary for more homogenous outcomes and greater populations; therefore, the grade of recommendation is C.

4. Limitations and Future Perspectives

Certain limitations need to be considered. Firstly, MeSH terms are not often used by researchers. Such specific terms must be taken into account when articles are drafted and assuring a good indexation and more visibility, facilitating the evidence valuation. Secondly, the application of resources such as CONSORT (Consolidated Standards of Reporting Trials) statement or Jadad scale is highly scarce. Moreover, the existence of checklists helps authors and editors to improve the reporting of RCTs and consequently provides scientific quality in data reports. We consider that a clinical trial is reliable when it is at least randomized and blinded. In addition, the trials included in this review have high levels of heterogeneity, making it more difficult to draw concrete conclusions in relation to types of subjects, form of analysed product or its combination with other compounds.

Future studies must show better designs to avoid the risk of bias usually associated with potential confounding variables such as other dietary or lifestyle factors. In addition, the dosages, polyphenol type, duration and frequency of consumption must be clear, giving the opportunity to assess the possible benefits to a specific compound. Long-term, double-blind, crossover, randomized clinical trials with specific clinical endpoints should be developed to guarantee the possible benefits of phenolic BAC.

In addition, the use of potent new technologies such as omics sciences i.e. transcriptomics, metabolomics, could help to elucidate the different mechanisms in which BAC are involved in CVD and its specific role.

5. Conclusions

The role of BAC as adjuvants in CVD is increasing and validation of its effects is essential. Evidence shows that some polyphenols used as BAC such as flavonols are helpful in decreasing risk factors of CVD. However, it is necessary to develop better quality RCTs (crossover design, double-blinded, long term, placebo/controlled) as well as elaborate rigorous meta-analysis of existing evidence to support the effect of BAC on the prevention and treatment of CVD.

Acknowledgments

The authors are grateful for the support of Mercedes Rodriguez del Castillo Martín who provided technical assistance with the search in databases.

Author Contributions

O.D.R., B.P.V., C.A.G., A.G. contributed to the planning of the search of the literature, designed the analysis and results presentation and created the tool for assessing the quality of the articles. O.D.R., B.P.V. were involved in the analyses of the articles. O.D.R., B.P.V. wrote the draft. All authors discussed and revised all drafts and approved the final manuscript.

Conflicts of Interest

The authors declare no conflict of interest. This paper will be part of the Oscar Daniel Rangel Huerta’s doctorate that it is being carried out within the context of “Biochemistry and Molecular Biology” at the University of Granada.

References

  • 1.Martínez-Augustin O., Aguilera C.M., Gil-campos M., Sánchez de Medina F., Gil A. Bioactive anti-obesity food components. Int. J. Vitam. Nutr. Res. 2012;82:148–156. doi: 10.1024/0300-9831/a000105. [DOI] [PubMed] [Google Scholar]
  • 2.Organization W.H. Obesity and overweight. [(accessed on 14 October 2014)]. Available online: http://www.who.int/mediacentre/factsheets/fs311/en/
  • 3.Perk J., de Backer G., Gohlke H., Graham I., Reiner Ž., Verschuren M., Albus C., Benlian P., Boysen G., Cifkova R., et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012) Eur. Heart J. 2012;33:1635–1701. doi: 10.1093/eurheartj/ehs092. [DOI] [PubMed] [Google Scholar]
  • 4.Stone N.J., Robinson J.G., Lichtenstein A.H., Bairey Merz C.N., Blum C.B., Eckel R.H., Goldberg A.C., Gordon D., Levy D., Lloyd-Jones D.M., et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American college of cardiology/American heart association task force on practice guidelines. J. Am. Coll. Cardiol. 2014;63:2889–2934. doi: 10.1016/j.jacc.2013.11.002. [DOI] [PubMed] [Google Scholar]
  • 5.Kitts D.D. Bioactive substances in food: Identification and potential uses. Can. J. Physiol. Pharmacol. 1994;72:423–434. doi: 10.1139/y94-062. [DOI] [PubMed] [Google Scholar]
  • 6.Kris-Etherton P.M., Hecker K.D., Bonanome A., Coval S.M., Binkoski A.E., Hilpert K.F., Griel A.E., Etherton T.D. Bioactive compounds in foods: Their role in the prevention of cardiovascular disease and cancer. Am. J. Med. 2002;113:71S–88S. doi: 10.1016/S0002-9343(01)00995-0. [DOI] [PubMed] [Google Scholar]
  • 7.Sarriá B., Martínez-López S., Sierra-Cinos J.L., Garcia-Diz L., Goya L., Mateos R., Bravo L. Effects of bioactive constituents in functional cocoa products on cardiovascular health in humans. Food Chem. 2015;174:214–218. doi: 10.1016/j.foodchem.2014.11.004. [DOI] [PubMed] [Google Scholar]
  • 8.Huxley R.R., Neil H.A.W. The relation between dietary flavonol intake and coronary heart disease mortality: A meta-analysis of prospective cohort studies. Eur. J. Clin. Nutr. 2003;57:904–908. doi: 10.1038/sj.ejcn.1601624. [DOI] [PubMed] [Google Scholar]
  • 9.Li S., Liu X., Bai Y., Wang X., Sun K., Chen J., Hui R. Effect of oral isoflavone supplementation on vascular endothelial function in postmenopausal women: A meta-analysis of randomized placebo-controlled trials. Am. J. Clin. Nutr. 2009;91:480–486. doi: 10.3945/ajcn.2009.28203. [DOI] [PubMed] [Google Scholar]
  • 10.Wang Z.-M., Nie Z.-L., Zhou B., Lian X.-Q., Zhao H., Gao W., Wang Y.-S., Jia E.-Z., Wang L.-S., Yang Z.-J. Flavonols intake and the risk of coronary heart disease: A meta-analysis of cohort studies. Atherosclerosis. 2012;222:270–273. doi: 10.1016/j.atherosclerosis.2012.02.026. [DOI] [PubMed] [Google Scholar]
  • 11.Hooper L., Kroon P.A., Rimm E.B., Cohn J.S., Harvey I., Le Cornu K.A., Ryder J.J., Hall W.L., Cassidy A. Flavonoids, flavonoid-rich foods, and cardiovascular risk: A meta-analysis of randomized controlled trials. Am. J. Clin. Nutr. 2008;88:38–50. doi: 10.1093/ajcn/88.1.38. [DOI] [PubMed] [Google Scholar]
  • 12.FDA FDA Basics—Dietary Supplements. [(accessed on 13 Feburbary 2015)]; Available online: http://www.fda.gov/AboutFDA/Transparency/Basics/ucm193949.htm.
  • 13.Lekakis J., Rallidis L.S., Andreadou I., Vamvakou G., Kazantzoglou G., Magiatis P., Skaltsounis A.-L., Kremastinos D.T. Polyphenolic compounds from red grapes acutely improve endothelial function in patients with coronary heart disease. Eur. J. Cardiovasc. Prev. Rehabil. 2005;12:596–600. doi: 10.1097/00149831-200512000-00013. [DOI] [PubMed] [Google Scholar]
  • 14.Quiles J.L., Mesa M.D., Ramírez-Tortosa C.L., Aguilera C.M., Battino M., Gil Á., Ramírez-Tortosa M.C. Curcuma longa extract supplementation reduces oxidative stress and attenuates aortic fatty streak development in rabbits. Arterioscler. Thromb. Vasc. Biol. 2002;22:1225–1231. doi: 10.1161/01.ATV.0000020676.11586.F2. [DOI] [PubMed] [Google Scholar]
  • 15.Corcoran M.P., McKay D.L., Blumberg J.B. Flavonoid Basics: Chemistry, Sources, Mechanisms of Action, and Safety. J. Nutr. Gerontol. Geriatr. 2012;31:176–189. doi: 10.1080/21551197.2012.698219. [DOI] [PubMed] [Google Scholar]
  • 16.Scottish Intercollegiate Guidelines Network . Risk Estimation and the Prevention of Cardiovascular Disease (Guideline 97) Scottish Intercollegiate Guidelines Network; Edinburgh, UK: 2007. [Google Scholar]
  • 17.Jadad A.R., Moore R.A., Carroll D., Jenkinson C., Reynolds D.J., Gavaghan D.J., McQuay H.J. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin. Trials. 1996;17:1–12. doi: 10.1016/0197-2456(95)00134-4. [DOI] [PubMed] [Google Scholar]
  • 18.Uauy R.E.A. Fats and fatty acids in human nutrition, Report of an expert consultation. FAO Food Nutr. Pap. 2008;550:189. [PubMed] [Google Scholar]
  • 19.Wong R.H.X., Howe P.R.C., Buckley J.D., Coates A.M., Kunz I., Berry N.M. Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr. Metab. Cardiovasc. Dis. 2011;21:851–856. doi: 10.1016/j.numecd.2010.03.003. [DOI] [PubMed] [Google Scholar]
  • 20.Wong R.H.X., Berry N.M., Coates A.M., Buckley J.D., Bryan J., Kunz I., Howe P.R.C. Chronic resveratrol consumption improves brachial flow-mediated dilatation in healthy obese adults. J. Hypertens. 2013;31:1819–1827. doi: 10.1097/HJH.0b013e328362b9d6. [DOI] [PubMed] [Google Scholar]
  • 21.Bo S., Ciccone G., Castiglione A., Gambino R., de Michieli F., Villois P., Durazzo M., Cavallo-Perin P., Cassader M. Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial. Curr. Med. Chem. 2013;20:1323–1331. doi: 10.2174/0929867311320100009. [DOI] [PubMed] [Google Scholar]
  • 22.Militaru C., Donoiu I., Craciun A., Scorei I.D., Bulearca A.M., Scorei R.I. Oral resveratrol and calcium fructoborate supplementation in subjects with stable angina pectoris: Effects on lipid profiles, inflammation markers, and quality of life. Nutrition. 2013;29:178–183. doi: 10.1016/j.nut.2012.07.006. [DOI] [PubMed] [Google Scholar]
  • 23.Tomé-Carneiro J., Gonzálvez M., Larrosa M., Yáñez-Gascón M.J., García-Almagro F.J., Ruiz-Ros J.A., Tomás-Barberán F.A., García-Conesa M.T., Espín J.C. Grape resveratrol increases serum adiponectin and downregulates inflammatory genes in peripheral blood mononuclear cells: A triple-blind, placebo-controlled, one-year clinical trial in patients with stable coronary artery disease. Cardiovasc. Drugs Ther. 2013;27:37–48. doi: 10.1007/s10557-012-6427-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Tomé-Carneiro J., Gonzálvez M., Larrosa M., García-Almagro F.J., Avilés-Plaza F., Parra S., Yáñez-Gascón M.J., Ruiz-Ros J.A., García-Conesa M.T., Tomás-Barberán F.A., et al. Consumption of a grape extract supplement containing resveratrol decreases oxidized LDL and ApoB in patients undergoing primary prevention of cardiovascular disease: A triple-blind, 6-month follow-up, placebo-controlled, randomized trial. Mol. Nutr. Food Res. 2012;56:810–821. doi: 10.1002/mnfr.201100673. [DOI] [PubMed] [Google Scholar]
  • 25.Tomé-Carneiro J., Larrosa M., Yáñez-Gascón M.J., Dávalos A., Gil-Zamorano J., Gonzálvez M., García-Almagro F.J., Ruiz Ros J.A., Tomás-Barberán F.A., Espín J.C., et al. One-year supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease. Pharmacol. Res. 2013;72:69–82. doi: 10.1016/j.phrs.2013.03.011. [DOI] [PubMed] [Google Scholar]
  • 26.Tomé-Carneiro J., Gonzálvez M., Larrosa M., Yáñez-Gascón M.J., García-Almagro F.J., Ruiz-Ros J.A., García-Conesa M.T., Tomás-Barberán F.A., Espín J.C. One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. Am. J. Cardiol. 2012;110:356–363. doi: 10.1016/j.amjcard.2012.03.030. [DOI] [PubMed] [Google Scholar]
  • 27.Alwi I., Santoso T., Suyono S., Sutrisna B., Suyatna F.D., Kresno S.B., Ernie S. The effect of curcumin on lipid level in patients with acute coronary syndrome. Acta Med. Indones. 2008;40:201–210. [PubMed] [Google Scholar]
  • 28.Chuengsamarn S., Rattanamongkolgul S., Phonrat B., Tungtrongchitr R., Jirawatnotai S. Reduction of atherogenic risk in patients with type 2 diabetes by curcuminoid extract: A randomized controlled trial. J. Nutr. Biochem. 2014;25:144–150. doi: 10.1016/j.jnutbio.2013.09.013. [DOI] [PubMed] [Google Scholar]
  • 29.Botden I.P.G., Draijer R., Westerhof B.E., Rutten J.H.W., Langendonk J.G., Sijbrands E.J.G., Danser A.H.J., Zock P.L., van den Meiracker A.H. Red wine polyphenols do not lower peripheral or central blood pressure in high normal blood pressure and hypertension. Am. J. Hypertens. 2012;25:718–723. doi: 10.1038/ajh.2012.25. [DOI] [PubMed] [Google Scholar]
  • 30.Chiva-Blanch G., Condines X., Magraner E., Roth I., Valderas-Martínez P., Arranz S., Casas R., Martínez-Huélamo M., Vallverdú-Queralt A., Quifer-Rada P., et al. The non-alcoholic fraction of beer increases stromal cell derived factor 1 and the number of circulating endothelial progenitor cells in high cardiovascular risk subjects: A randomized clinical trial. Atherosclerosis. 2014;233:518–524. doi: 10.1016/j.atherosclerosis.2013.12.048. [DOI] [PubMed] [Google Scholar]
  • 31.Chiva-Blanch G., Urpi-Sarda M., Ros E., Arranz S., Valderas-Martínez P., Casas R., Sacanella E., Llorach R., Lamuela-Raventos R.M., Andres-Lacueva C., et al. Dealcoholized red wine decreases systolic and diastolic blood pressure and increases plasma nitric oxide: Short communication. Circ. Res. 2012;111:1065–1068. doi: 10.1161/CIRCRESAHA.112.275636. [DOI] [PubMed] [Google Scholar]
  • 32.Chiva-Blanch G., Urpi-Sarda M., Llorach R., Rotches-Ribalta M., Guillen M., Casas R., Arranz S., Valderas-Martinez P., Portoles O., Corella D. Differential effects of polyphenols and alcohol of red wine on the expression of adhesion molecules and inflammatory cytokines related to atherosclerosis: A randomized clinical trial (vol 95, pg 326, 2012) Am. J. Clin. Nutr. 2012;95:1506. doi: 10.3945/ajcn.111.022889. [DOI] [PubMed] [Google Scholar]
  • 33.Kuntz S., Kunz C., Herrmann J., Borsch C.H., Abel G., Dietrich H., Rudloff S., Fröhling B., Dietrich H., Rudloff S. Anthocyanins from fruit juices improve the antioxidant status of healthy young female volunteers without affecting anti-inflammatory parameters: Results from the randomised, double-blind, placebo-controlled, cross-over ANTHONIA (ANTHOcyanins in Nutrition Investigation Alliance) study. Br. J. Nutr. 2014;112:925–936. doi: 10.1017/S0007114514001482. [DOI] [PubMed] [Google Scholar]
  • 34.Curtis P.J., Kroon P.A., Hollands W.J., Walls R., Jenkins G., Kay C.D., Cassidy A. Cardiovascular disease risk biomarkers and liver and kidney function are not altered in postmenopausal women after ingesting an elderberry extract rich in anthocyanins for 12 weeks. J. Nutr. 2009;139:2266–2271. doi: 10.3945/jn.109.113126. [DOI] [PubMed] [Google Scholar]
  • 35.Hassellund S.S., Flaa A., Kjeldsen S.E., Seljeflot I., Karlsen A., Erlund I., Rostrup M. Effects of anthocyanins on cardiovascular risk factors and inflammation in pre-hypertensive men: A double-blind randomized placebo-controlled crossover study. J. Hum. Hypertens. 2012;27:100–106. doi: 10.1038/jhh.2012.4. [DOI] [PubMed] [Google Scholar]
  • 36.Dohadwala M.M., Holbrook M., Hamburg N.M., Shenouda S.M., Chung W.B., Titas M., Kluge M.A., Wang N., Palmisano J., Milbury P.E., et al. A Effects of cranberry juice consumption on vascular function in patients with coronary artery disease 1–3. Am. J. Clin. Nutr. 2011;93:934–940. doi: 10.3945/ajcn.110.004242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Miyazaki R., Kotani K., Ayabe M., Tsuzaki K., Shimada J., Sakane N., Takase H., Ichikawa H., Yonei Y., Ishii K. Minor effects of green tea catechin supplementation on cardiovascular risk markers in active older people: A randomized controlled trial. Geriatr. Gerontol. Int. 2013;13:622–629. doi: 10.1111/j.1447-0594.2012.00952.x. [DOI] [PubMed] [Google Scholar]
  • 38.De Maat M.P., Pijl H., Kluft C., Princen H.M. Consumption of black and green tea had no effect on inflammation, haemostasis and endothelial markers in smoking healthy individuals. Eur. J. Clin. Nutr. 2000;54:757–763. doi: 10.1038/sj.ejcn.1601084. [DOI] [PubMed] [Google Scholar]
  • 39.Widmer R.J., Freund M.A., Flammer A.J., Sexton J., Lennon R., Romani A., Mulinacci N., Vinceri F.F., Lerman L.O., Lerman A. Beneficial effects of polyphenol-rich olive oil in patients with early atherosclerosis. Eur. J. Nutr. 2012;52:1223–1231. doi: 10.1007/s00394-012-0433-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Nagao T., Hase T., Tokimitsu I. A green tea extract high in catechins reduces body fat and cardiovascular risks in humans. Obesity (Silver Spring). 2007;15:1473–1483. doi: 10.1038/oby.2007.176. [DOI] [PubMed] [Google Scholar]
  • 41.Farouque H.M.O., Leung M., Hope S.A., Baldi M., Schechter C., Cameron J.D., Meredith I.T. Acute and chronic effects of flavanol-rich cocoa on vascular function in subjects with coronary artery disease: A randomized double-blind placebo-controlled study. Clin. Sci. (Lond). 2006;111:71–80. doi: 10.1042/CS20060048. [DOI] [PubMed] [Google Scholar]
  • 42.Berry N.M., Davison K., Coates A.M., Buckley J.D., Howe P.R.C. Impact of cocoa flavanol consumption on blood pressure responsiveness to exercise. Br. J. Nutr. 2010;103:1480–1484. doi: 10.1017/S0007114509993382. [DOI] [PubMed] [Google Scholar]
  • 43.Davison K., Coates A.M., Buckley J.D., Howe P.R.C. Effect of cocoa flavanols and exercise on cardiometabolic risk factors in overweight and obese subjects. Int. J. Obes. (Lond). 2008;32:1289–1296. doi: 10.1038/ijo.2008.66. [DOI] [PubMed] [Google Scholar]
  • 44.West S.G., McIntyre M.D., Piotrowski M.J., Poupin N., Miller D.L., Preston A.G., Wagner P., Groves L.F., Skulas-Ray A.C. Effects of dark chocolate and cocoa consumption on endothelial function and arterial stiffness in overweight adults. Br. J. Nutr. 2014;111:653–661. doi: 10.1017/S0007114513002912. [DOI] [PubMed] [Google Scholar]
  • 45.Faridi Z., Njike V.Y., Dutta S., Ali A., Katz D.L. Acute dark chocolate and cocoa ingestion and endothelial function: A randomized controlled crossover trial. Am. J. Clin. Nutr. 2008;88:58–63. doi: 10.1093/ajcn/88.1.58. [DOI] [PubMed] [Google Scholar]
  • 46.Davison K., Berry N.M., Misan G., Coates A.M., Buckley J.D., Howe P.R.C. Dose-related effects of flavanol-rich cocoa on blood pressure. J. Hum. Hypertens. 2010;24:568–576. doi: 10.1038/jhh.2009.105. [DOI] [PubMed] [Google Scholar]
  • 47.Grassi D., Desideri G., Necozione S., Lippi C., Casale R., Properzi G., Blumberg J.B., Ferri C. Blood pressure is reduced and insulin sensitivity increased in glucose-intolerant, hypertensive subjects after 15 days of consuming high-polyphenol dark chocolate. J. Nutr. 2008;138:1671–1676. doi: 10.1093/jn/138.9.1671. [DOI] [PubMed] [Google Scholar]
  • 48.Flammer A.J., Sudano I., Wolfrum M., Thomas R., Enseleit F., Périat D., Kaiser P., Hirt A., Hermann M., Serafini M., et al. Cardiovascular effects of flavanol-rich chocolate in patients with heart failure. Eur. Heart J. 2012;33:2172–2180. doi: 10.1093/eurheartj/ehr448. [DOI] [PubMed] [Google Scholar]
  • 49.Heiss C., Jahn S., Taylor M., Real W.M., Angeli F.S., Wong M.L., Amabile N., Prasad M., Rassaf T., Ottaviani J.I., et al. Improvement of endothelial function with dietary flavanols is associated with mobilization of circulating angiogenic cells in patients with coronary artery disease. J. Am. Coll. Cardiol. 2010;56:218–224. doi: 10.1016/j.jacc.2010.03.039. [DOI] [PubMed] [Google Scholar]
  • 50.Horn P., Amabile N., Angeli F.S., Sansone R., Stegemann B., Kelm M., Springer M.L., Yeghiazarians Y., Schroeter H., Heiss C. Dietary flavanol intervention lowers the levels of endothelial microparticles in coronary artery disease patients. Br. J. Nutr. 2013;111:1245–1252. doi: 10.1017/S0007114513003693. [DOI] [PubMed] [Google Scholar]
  • 51.Balzer J., Rassaf T., Heiss C., Kleinbongard P., Lauer T., Merx M., Heussen N., Gross H.B., Keen C.L., Schroeter H., et al. Sustained Benefits in Vascular Function Through Flavanol-Containing Cocoa in Medicated Diabetic Patients. A Double-Masked, Randomized, Controlled Trial. J. Am. Coll. Cardiol. 2008;51:2141–2149. doi: 10.1016/j.jacc.2008.01.059. [DOI] [PubMed] [Google Scholar]
  • 52.Larson A., Witman M.A.H., Guo Y., Ives S., Richardson R.S., Bruno R.S., Jalili T., Symons J.D. Acute, quercetin-induced reductions in blood pressure in hypertensive individuals are not secondary to lower plasma angiotensin-converting enzyme activity or endothelin-1: Nitric oxide. Nutr. Res. 2012;32:557–564. doi: 10.1016/j.nutres.2012.06.018. [DOI] [PubMed] [Google Scholar]
  • 53.Conquer J.A., Maiani G., Azzini E., Raguzzini A., Holub B.J. Supplementation with quercetin markedly increases plasma quercetin concentration without effect on selected risk factors for heart disease in healthy subjects. J. Nutr. 1998;128:593–597. doi: 10.1093/jn/128.3.593. [DOI] [PubMed] [Google Scholar]
  • 54.Suomela J.P., Ahotupa M., Yang B., Vasankari T., Kallio H. Absorption of flavonols derived from sea buckthorn (Hippopha?? rhamnoides L.) and their effect on emerging risk factors for cardiovascular disease in humans. J. Agric. Food Chem. 2006;54:7364–7369. doi: 10.1021/jf061889r. [DOI] [PubMed] [Google Scholar]
  • 55.Edwards R.L., Lyon T., Litwin S.E., Rabovsky A., Symons J.D., Jalili T. Quercetin reduces blood pressure in hypertensive subjects. J. Nutr. 2007;137:2405–2411. doi: 10.1093/jn/137.11.2405. [DOI] [PubMed] [Google Scholar]
  • 56.McVeigh B.L., Dillingham B.L., Lampe J.W., Duncan A.M. Effect of soy protein varying in isoflavone content on serum lipids in healthy young men. Am. J. Clin. Nutr. 2006;83:244–251. doi: 10.1093/ajcn/83.2.244. [DOI] [PubMed] [Google Scholar]
  • 57.Sanders T.A.B., Dean T.S., Grainger D., Miller G.J., Wiseman H. Moderate intakes of intact soy protein rich in isoflavones compared with ethanol-extracted soy protein increase HDL but do not influence transforming growth factor β1 concentrations and hemostatic risk factors for coronary heart disease in healthy subjets. Am. J. Clin. Nutr. 2002;76:373–377. doi: 10.1093/ajcn/76.2.373. [DOI] [PubMed] [Google Scholar]
  • 58.Thorp A.A., Howe P.R.C., Mori T.A., Coates A.M., Buckley J.D., Hodgson J., Mansour J., Meyer B.J. Soy food consumption does not lower LDL cholesterol in either equol or nonequol producers. Am. J. Clin. Nutr. 2008;88:298–304. doi: 10.1093/ajcn/88.2.298. [DOI] [PubMed] [Google Scholar]
  • 59.Atkinson C., Oosthuizen W., Scollen S., Loktionov A., Day N.E., Bingham S. A Modest protective effects of isoflavones from a red clover-derived dietary supplement on cardiovascular disease risk factors in perimenopausal women, and evidence of an interaction with ApoE genotype in 49–65 year-old women. J. Nutr. 2004;134:1759–1764. doi: 10.1093/jn/134.7.1759. [DOI] [PubMed] [Google Scholar]
  • 60.Marini H., Bitto A., Altavilla D., Burnett B.P., Polito F., di Stefano V., Minutoli L., Atteritano M., Levy R.M., Frisina N., et al. Efficacy of genistein aglycone on some cardiovascular risk factors and homocysteine levels: A follow-up study. Nutr. Metab. Cardiovasc. Dis. 2010;20:332–340. doi: 10.1016/j.numecd.2009.04.012. [DOI] [PubMed] [Google Scholar]
  • 61.Hodis H.N., Mack W.J., Kono N., Azen S.P., ShoupeJ D., Hwang-Levine J., Petitti D., Whitfield-Maxwell L., Yan M., Franke A.A., et al. Isoflavone Soy Protein Supplementation and Atherosclerosis in Healthy Postmenopausal Women: A Randomized Controlled Trial. Stroke. 2012;42:3168–3175. doi: 10.1161/STROKEAHA.111.620831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Atteritano M., Marini H., Minutoli L., Polito F., Bitto A., Altavilla D., Mazzaferro S., D’Anna R., Cannata M.L., Gaudio A., et al. Effects of the phytoestrogen genistein on some predictors of cardiovascular risk in osteopenic, postmenopausal women: A two-year randomized, double-blind, placebo-controlled study. J. Clin. Endocrinol. Metab. 2007;92:3068–3075. doi: 10.1210/jc.2006-2295. [DOI] [PubMed] [Google Scholar]
  • 63.Garrido A., de la Maza M.P., Hirsch S., Valladares L. Soy isoflavones affect platelet thromboxane A2 receptor density but not plasma lipids in menopausal women. Maturitas. 2006;54:270–276. doi: 10.1016/j.maturitas.2005.12.002. [DOI] [PubMed] [Google Scholar]
  • 64.Hall W.L., Vafeiadou K., Hallund J., Bügel S., Koebnick C., Reimann M., Ferrari M., Branca F., Talbot D., Dadd T., et al. Soy-isoflavone-enriched foods and inflammatory biomarkers of cardiovascular disease risk in postmenopausal women: Interactions with genotype and equol production. Am. J. Clin. Nutr. 2005;82:1260–1268. doi: 10.1093/ajcn/82.6.1260. [DOI] [PubMed] [Google Scholar]
  • 65.Rios D.R.A., Rodrigues E.T., Cardoso A.P.Z., Montes M.B.A., Franceschini S.A., Toloi M.R.T. Effects of isoflavones on the coagulation and fibrinolytic system of postmenopausal women. Nutrition. 2008;24:120–126. doi: 10.1016/j.nut.2007.10.009. [DOI] [PubMed] [Google Scholar]
  • 66.Villa P., Costantini B., Suriano R., Perri C., Macrì F., Ricciardi L., Panunzi S., Lanzone A. The differential effect of the phytoestrogen genistein on cardiovascular risk factors in postmenopausal women: Relationship with the metabolic status. J. Clin. Endocrinol. Metab. 2009;94:552–558. doi: 10.1210/jc.2008-0735. [DOI] [PubMed] [Google Scholar]
  • 67.Liu Z.M., Ho S.C., Chen Y.M., Ho Y.P. The effects of isoflavones combined with soy protein on lipid profiles, C-reactive protein and cardiovascular risk among postmenopausal Chinese women. Nutr. Metab. Cardiovasc. Dis. 2012;22:712–719. doi: 10.1016/j.numecd.2010.11.002. [DOI] [PubMed] [Google Scholar]
  • 68.Yang T.S., Wang S.Y., Yang Y.C., Su C.H., Lee F.K., Chen S.C., Tseng C.Y., Jou H.J., Huang J.P., Huang K.E. Effects of standardized phytoestrogen on Taiwanese menopausal women. Taiwan J. Obstet. Gynecol. 2012;51:229–235. doi: 10.1016/j.tjog.2012.04.011. [DOI] [PubMed] [Google Scholar]
  • 69.Aubertin-Leheudre M., Lord C., Khalil A., Dionne I.J. Isoflavones and clinical cardiovascular risk factors in obese postmenopausal women: A randomized double-blind placebo-controlled trial. J. Womens Health (Larchmt) 2008;17:1363–1369. doi: 10.1089/jwh.2008.0836. [DOI] [PubMed] [Google Scholar]
  • 70.Choquette S., Riesco É., Cormier É., Dion T., Aubertin-Leheudre M., Dionne I.J. Effects of soya isoflavones and exercise on body composition and clinical risk factors of cardiovascular diseases in overweight postmenopausal women: A 6-month double-blind controlled trial. Br. J. Nutr. 2011;105:1199–1209. doi: 10.1017/S0007114510004897. [DOI] [PubMed] [Google Scholar]
  • 71.Aubertin-Leheudre M., Lord C., Khalil A., Dionne I.J. Effect of 6 months of exercise and isoflavone supplementation on clinical cardiovascular risk factors in obese postmenopausal women: A randomized, double-blind study. Menopause. 2007;14:624–629. doi: 10.1097/gme.0b013e31802e426b. [DOI] [PubMed] [Google Scholar]
  • 72.Hodgson J.M., Puddey I.B., Croft K.D., Mori T.A., Rivera J., Beilin L.J. Isoflavonoids do not inhibit in vivo lipid peroxidation in subjects with high-normal blood pressure. Atherosclerosis. 1999;145:167–172. doi: 10.1016/S0021-9150(99)00029-5. [DOI] [PubMed] [Google Scholar]
  • 73.Sagara M., Kanda T., NJelekera M., Teramoto T., Armitage L., Birt N., Birt C., Yamori Y. Effects of dietary intake of soy protein and isoflavones on cardiovascular disease risk factors in high risk, middle-aged men in Scotland. J. Am. Coll. Nutr. 2004;23:85–91. doi: 10.1080/07315724.2004.10719347. [DOI] [PubMed] [Google Scholar]
  • 74.Clerici C., Setchell K.D.R., Battezzati P.M., Pirro M., Giuliano V., Asciutti S., Castellani D., Nardi E., Sabatino G., Orlandi S., et al. Pasta naturally enriched with isoflavone aglycons from soy germ reduces serum lipids and improves markers of cardiovascular risk. J. Nutr. 2007;137:2270–2278. doi: 10.1093/jn/137.10.2270. [DOI] [PubMed] [Google Scholar]
  • 75.Meyer B.J., Larkin T.A., Owen A.J., Astheimer L.B., Tapsell L.C., Howe P.R.C. Limited lipid-lowering effects of regular consumption of whole soybean foods. Ann. Nutr. Metab. 2004;48:67–78. doi: 10.1159/000075592. [DOI] [PubMed] [Google Scholar]
  • 76.Jenkins D.J.A., Kendall C.W.C., Jackson C.J.C., Connelly P.W., Parker T., Faulkner D., Vidgen E., Cunnane S.C., Leiter L.A., Josse R.G. Effects of high- and low-isoflavone soyfoods on blood lipids, oxidized LDL, homocysteine, and blood pressure in hyperlipidemic men and women. Am. J. Clin. Nutr. 2002;76:365–372. doi: 10.1093/ajcn/76.2.365. [DOI] [PubMed] [Google Scholar]
  • 77.Blum A., Lang N., Peleg A., Vigder F., Israeli P., Gumanovsky M., Lupovitz S., Elgazi A., Ben-Ami M. Effects of oral soy protein on markers of inflammation in postmenopausal women with mild hypercholesterolemia. Am. Heart J. 2003;145:e7. doi: 10.1067/mhj.2003.115. [DOI] [PubMed] [Google Scholar]
  • 78.Teede H.J., Giannopoulos D., Dalais F.S., Hodgson J., McGrath B.P. Randomised, controlled, cross-over trial of soy protein with isoflavones on blood pressure and arterial function in hypertensive subjects. J. Am. Coll. Nutr. 2006;25:533–540. doi: 10.1080/07315724.2006.10719569. [DOI] [PubMed] [Google Scholar]
  • 79.Cicero A.F.G., Tartagni E., Ferroni A., de Sando V., Grandi E., Borghi C. Combined nutraceutical approach to postmenopausal syndrome and vascular remodeling biomarkers. J. Altern. Complement. Med. 2013;19:582–587. doi: 10.1089/acm.2011.0624. [DOI] [PubMed] [Google Scholar]
  • 80.Curtis P.J., Potter J., Kroon P.A., Wilson P., Dhatariya K., Sampson M., Cassidy A. Vascular function and atherosclerosis progression after 1 y of flavonoid intake in statin-treated postmenopausal women with type 2 diabetes: A double-blind randomized controlled trial. Am. J. Clin. Nutr. 2013;97:936–942. doi: 10.3945/ajcn.112.043745. [DOI] [PubMed] [Google Scholar]
  • 81.Chan Y.H., Lau K.K., Yiu K.H., Li S.W., Chan H.T., Fong D.Y.T., Tam S., Lau C.P., Tse H.F. Reduction of C-reactive protein with isoflavone supplement reverses endothelial dysfunction in patients with ischaemic stroke. Eur. Heart J. 2008;29:2800–2807. doi: 10.1093/eurheartj/ehn409. [DOI] [PubMed] [Google Scholar]
  • 82.Webb C.M., Hayward C.S., Mason M.J., Ilsley C.D., Collins P. Coronary vasomotor and blood flow responses to isoflavone-intact soya protein in subjects with coronary heart disease or risk factors for coronary heart disease. Clin. Sci. 2008;115:353. doi: 10.1042/CS20070443. [DOI] [PubMed] [Google Scholar]
  • 83.Fanti P., Asmis R., Stephenson T.J., Sawaya B.P., Franke A.A. Positive effect of dietary soy in ESRD patients with systemic inflammation—Correlation between blood levels of the soy isoflavones and the acute-phase reactants. Nephrol. Dial. Transplant. 2006;21:2239–2246. doi: 10.1093/ndt/gfl169. [DOI] [PubMed] [Google Scholar]
  • 84.Ras R.T., Zock P.L., Zebregs Y.E.M.P., Johnston N.R., Webb D.J., Draijer R. Effect of polyphenol-rich grape seed extract on ambulatory blood pressure in subjects with pre- and stage I hypertension. Br. J. Nutr. 2013;110:2234–2241. doi: 10.1017/S000711451300161X. [DOI] [PubMed] [Google Scholar]
  • 85.Yubero N., Sanz-Buenhombre M., Guadarrama A., Villanueva S., Carrión J.M., Larrarte E., Moro C. LDL cholesterol-lowering effects of grape extract used as a dietary supplement on healthy volunteers. Int. J. Food Sci. Nutr. 2013;64:400–406. doi: 10.3109/09637486.2012.753040. [DOI] [PubMed] [Google Scholar]
  • 86.Asher G.N., Viera A.J., Weaver M.A., Dominik R., Caughey M., Hinderliter A.L. Effect of hawthorn standardized extract on flow mediated dilation in prehypertensive and mildly hypertensive adults: A randomized, controlled cross-over trial. BMC Complement. Altern. Med. 2012;12:26. doi: 10.1186/1472-6882-12-26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Liu X., Wei J., Tan F., Zhou S., Würthwein G., Rohdewald P. Antidiabetic effect of Pycnogenol® French maritime pine bark extract in patients with diabetes type II. Life Sci. 2004;75:2505–2513. doi: 10.1016/j.lfs.2003.10.043. [DOI] [PubMed] [Google Scholar]
  • 88.Enseleit F., Sudano I., Périat D., Winnik S., Wolfrum M., Flammer A.J., Fröhlich G.M., Kaiser P., Hirt A., Haile S.R., et al. Effects of Pycnogenol on endothelial function in patients with stable coronary artery disease: A double-blind, randomized, placebo-controlled, cross-over study. Eur. Heart J. 2012;33:1589–1597. doi: 10.1093/eurheartj/ehr482. [DOI] [PubMed] [Google Scholar]
  • 89.Mellen P.B., Daniel K.R., Brosnihan K.B., Hansen K.J., Herrington D.M. Effect of muscadine grape seed supplementation on vascular function in subjects with or at risk for cardiovascular disease: A randomized crossover trial. J. Am. Coll. Nutr. 2010;29:469–475. doi: 10.1080/07315724.2010.10719883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Tauchert M. Efficacy and safety of crataegus extract WS 1442 in comparison with placebo in patients with chronic stable New York Heart Association class-III heart failure. Am. Heart J. 2002;143:910–915. doi: 10.1067/mhj.2002.121463. [DOI] [PubMed] [Google Scholar]
  • 91.Tang P.C.-T., Ng Y.-F., Ho S., Gyda M., Chan S.-W. Resveratrol and cardiovascular health—Promising therapeutic or hopeless illusion? Pharmacol. Res. 2014;90:88–115. doi: 10.1016/j.phrs.2014.08.001. [DOI] [PubMed] [Google Scholar]
  • 92.Shechter M., Issachar A., Marai I., Koren-Morag N., Freinark D., Shahar Y., Shechter A., Feinberg M.S. Long-term association of brachial artery flow-mediated vasodilation and cardiovascular events in middle-aged subjects with no apparent heart disease. Int. J. Cardiol. 2009;134:52–58. doi: 10.1016/j.ijcard.2008.01.021. [DOI] [PubMed] [Google Scholar]
  • 93.Yeboah J., Crouse J.R., Hsu F.C., Burke G.L., Herrington D.M. Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: The cardiovascular health study. Circulation. 2007;115:2390–2397. doi: 10.1161/CIRCULATIONAHA.106.678276. [DOI] [PubMed] [Google Scholar]
  • 94.Rossi R., Nuzzo A., Origliani G., Modena M.G. Prognostic Role of Flow-Mediated Dilation and Cardiac Risk Factors in Post-Menopausal Women. J. Am. Coll. Cardiol. 2008;51:997–1002. doi: 10.1016/j.jacc.2007.11.044. [DOI] [PubMed] [Google Scholar]
  • 95.Williams I.L., Chowienczyk P.J., Wheatcroft S.B., Patel A.G., Sherwood R.A., Momin A., Shah A.M., Kearney M.T. Endothelial function and weight loss in obese humans. Obes. Surg. 2005;15:1055–1060. doi: 10.1381/0960892054621134. [DOI] [PubMed] [Google Scholar]
  • 96.Widlansky M.E., Duffy S.J., Hamburg N.M., Gokce N., Warden B.A., Wiseman S., Keaney J.F., Frei B., Vita J.A. Effects of black tea consumption on plasma catechins and markers of oxidative stress and inflammation in patients with coronary artery disease. Free Radic. Biol. Med. 2005;38:499–506. doi: 10.1016/j.freeradbiomed.2004.11.013. [DOI] [PubMed] [Google Scholar]
  • 97.Shenouda S.M., Widlansky M.E., Chen K., Xu G., Holbrook M., Tabit C.E., Hamburg N.M., Frame A.A., Caiano T.L., Kluge M.A., et al. Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus. Circulation. 2011;124:444–453. doi: 10.1161/CIRCULATIONAHA.110.014506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Hartman M.-L., Shirihai O.S., Holbrook M., Xu G., Kocherla M., Shah A., Fetterman J.L., Kluge M.A., Frame A.A., Hamburg N.M., et al. A Relation of mitochondrial oxygen consumption in peripheral blood mononuclear cells to vascular function in type 2 diabetes mellitus. Vasc. Med. 2014;19:67–74. doi: 10.1177/1358863X14521315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.Sahebkar A. A systematic review and meta-analysis of randomized controlled trials investigating the effects of curcumin on blood lipid levels. Clin. Nutr. 2013;33:406–414. doi: 10.1016/j.clnu.2013.09.012. [DOI] [PubMed] [Google Scholar]
  • 100.Ramírez-Boscá A., Soler A., Carrión M.A., Díaz-Alperi J., Bernd A., Quintanilla C., Quintanilla Almagro E., Miquel J. An hydroalcoholic extract of Curcuma longa lowers the apo B/apo A ratio. Implications for atherogenesis prevention. Mech. Ageing Dev. 2000;119:41–47. doi: 10.1016/S0047-6374(00)00169-X. [DOI] [PubMed] [Google Scholar]
  • 101.Weisberg S.P., Leibel R., Tortoriello D.V. Dietary curcumin significantly improves obesity-associated inflammation and diabetes in mouse models of diabesity. Endocrinology. 2008;149:3549–3558. doi: 10.1210/en.2008-0262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Tang Y., Zheng S., Chen A. Curcumin eliminates leptin’s effects on hepatic stellate cell activation via interrupting leptin signaling. Endocrinology. 2009;150:3011–3020. doi: 10.1210/en.2008-1601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Rotondo S., di Castelnuovo A., de Gaetano G. The relationship between wine consumption and cardiovascular risk: From epidemiological evidence to biological plausibility. Ital. Heart J. 2001;2:1–8. [PubMed] [Google Scholar]
  • 104.Wang X., Ouyang Y.Y., Liu J., Zhao G. Flavonoid intake and risk of CVD: A systematic review and meta-analysis of prospective cohort studies. Br. J. Nutr. 2013;111:1–11. doi: 10.1017/S000711451300278X. [DOI] [PubMed] [Google Scholar]
  • 105.Johnson R., Bryant S., Huntley A.L. Green tea and green tea catechin extracts: An overview of the clinical evidence. Maturitas. 2012;73:280–287. doi: 10.1016/j.maturitas.2012.08.008. [DOI] [PubMed] [Google Scholar]
  • 106.Khawaja O., Gaziano J.M., Djoussé L. Chocolate and coronary heart disease: A systematic review. Curr. Atheroscler. Rep. 2011;13:447–452. doi: 10.1007/s11883-011-0203-2. [DOI] [PubMed] [Google Scholar]
  • 107.Wang Z.M., Zhao D., Nie Z.L., Zhao H., Zhou B., Gao W., Wang L.S., Yang Z.J. Flavonol intake and stroke risk: A meta-analysis of cohort studies. Nutrition. 2014;30:518–523. doi: 10.1016/j.nut.2013.10.009. [DOI] [PubMed] [Google Scholar]
  • 108.Hollman P.C.H., Geelen A., Kromhout D. Dietary flavonol intake may lower stroke risk in men and women. J. Nutr. 2010;140:600–604. doi: 10.3945/jn.109.116632. [DOI] [PubMed] [Google Scholar]
  • 109.Liu Z.M., Ho S.C., Chen Y.M., Woo J. A six-month randomized controlled trial of whole soy and isoflavones daidzein on body composition in equol-producing postmenopausal women with prehypertension. J. Obes. 2013;2013 doi: 10.1155/2013/359763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 110.Curtis P.J., Sampson M., Potter J., Dhatariya K., Kroon P.A., Cassidy A. Chronic Ingestion of Flavan-3-ols and and Lipoprotein Status and Attenuates With Type 2 Diabetes. Diabetes Care. 2012;35:226–232. doi: 10.2337/dc11-1443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111.Azadbakht L., Atabak S., Esmaillzadeh A. Soy protein intake, cardiorenal indices, and C-reactive protein in type 2 diabetes with nephropathy: A longitudinal randomized clinical trial. Diabetes Care. 2008;31:648–654. doi: 10.2337/dc07-2065. [DOI] [PubMed] [Google Scholar]
  • 112.Li Z., Hong K., Saltsman P., DeShields S., Bellman M., Thames G., Liu Y., Wang H.-J., Elashoff R., Heber D. Long-term efficacy of soy-based meal replacements vs an individualized diet plan in obese type II DM patients: Relative effects on weight loss, metabolic parameters, and C-reactive protein. Eur. J. Clin. Nutr. 2005;59:411–418. doi: 10.1038/sj.ejcn.1602089. [DOI] [PubMed] [Google Scholar]
  • 113.Kokubo Y., Iso H., Ishihara J., Okada K., Inoue M., Tsugane S. Association of dietary intake of soy, beans, and isoflavones with risk of cerebral and myocardial infarctions in Japanese populations: The Japan Public Health Center-based (JPHC) study cohort I. Circulation. 2007;116:2553–2562. doi: 10.1161/CIRCULATIONAHA.106.683755. [DOI] [PubMed] [Google Scholar]
  • 114.Dong J.-Y., Wang P., He K., Qin L.-Q. Effect of soy isoflavones on circulating C-reactive protein in postmenopausal women: Meta-analysis of randomized controlled trials. Menopause. 2011;18:1256–1262. doi: 10.1097/gme.0b013e31821bfa24. [DOI] [PubMed] [Google Scholar]
  • 115.Vanhoutte P.M., Shimokawa H., Tang E.H.C., Feletou M. Endothelial dysfunction and vascular disease. Acta Physiol. (Oxf). 2009;196:193–222. doi: 10.1111/j.1748-1716.2009.01964.x. [DOI] [PubMed] [Google Scholar]
  • 116.Pase M.P., Grima N.A., Sarris J. The effects of dietary and nutrient interventions on arterial stiffness: A systematic review. Am. J. Clin. Nutr. 2011;93:446–454. doi: 10.3945/ajcn.110.002725. [DOI] [PubMed] [Google Scholar]

Articles from Nutrients are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

RESOURCES