The impact of (poly)phenol-rich foods and extracts on flow-mediated dilation (FMD): a narrative review

Abstract

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, with endothelial dysfunction as a key precursor. Flow-mediated dilation (FMD), the gold-standard measure of endothelial function, is improved by (poly)phenol-rich foods and extracts, with increases of 1% FMD representing 13% reduced cardiovascular risk. This narrative review aims to evaluate the efficacy of various (poly)phenol-rich foods and extracts on endothelial function as measured by flow-mediated dilation (FMD) and assesses the feasibility of a food-first approach. Literature was systematically searched from databases including PubMed and Web of Science, focusing on human clinical trials. While all (poly)phenol-rich food groups demonstrate variable effects, berries (0.9–2.6%), cocoa (0.7–5.9%), and tea (1.2–4.8%) have the most robust evidence, consistently improving FMD, with chronic intake sustaining benefits. A large variance (0.8–8.7%) was observed with grape-derived (poly)phenols, making their effects difficult to substantiate without detailed compositional or metabolomic data; however, a few key studies highlight their potential. Citrus polyphenols also exhibit variable FMD responses (0.2–7.2%). However, strong mechanistic evidence supports their role in vascular health and nitric oxide (NO) bioavailability. Coffee exhibits a variable response, initially impairing FMD, likely due to caffeine, before later improving endothelial function as phenolic metabolites increase. Although estimated (poly)phenol intake in Western populations is high (∼1000–1200 mg day⁻¹), it is primarily derived from tea, coffee, and cocoa, limiting exposure to diverse bioactive compounds. Moreover, the food matrix significantly influences bioavailability, with co-consumed components such as milk or sugar attenuating FMD responses. Interestingly, fortification and enrichment maintain bioactivity and may optimize intake, ensuring consistent and diverse delivery. Future research should refine dietary guidelines, establish intake thresholds, and explore fortification strategies to maximize cardiovascular benefits while considering dose–response relationships and long-term efficacy.

---

1. Introduction

Cardiovascular disease (CVD) remains a leading cause of mortality worldwide, responsible for approximately 17.9 million deaths annually (WHO 2019), with common cardiovascular risk factors such as hypertension, dyslipidaemia, diabetes, obesity, and smoking playing significant roles in its development.^1,2 Increased fruit and vegetable consumption mitigate risk and reduce CVD incidence with consumption of ≥8 portions (>569 g day⁻¹) associated with a reducing risk of cardiovascular mortality by 15% compared to those consuming <3 portions (<240 g day⁻¹).³ Similarly, a meta-analysis by Aune and colleagues highlighted a 28% risk reduction in cardiovascular mortality associated with the consumption of 800 g day⁻¹ of fruits and vegetables.⁴ The effects in part are due to the consumption of (poly)phenol-rich foods such as cocoa, coffee, tea, and berries which contain these bioactive compounds that can modulate endothelial function and the inflammatory processes and reduce oxidative stress.^5,6 The largest (poly)phenol based randomized intervention study to date, COcoa Supplement and Multivitamin Outcomes Study (COSMOS) also supports these population and experimental observations. The COSMOS study intervened with daily supplementation of 500 mg cocoa flavan-3-ols in n = 21 444 people over ∼3.6 years reducing cardiovascular mortality by 27% in the study population.⁷ This narrative review aims to evaluate the efficacy of (poly)phenol-rich foods and extracts on endothelial function as measured by flow-mediated dilation (FMD) and explores dietary guidance considerations based on existing evidence. A systematic search was performed using databases including Medline, Scopus and Web of Science. 4875 manuscripts were screened and 97 were included in the final synthesis (2000–2023). The selection of (poly)phenol-rich foods included in this review was based on their dietary relevance in Western populations, their significant contribution to overall habitual intake, and the availability of robust evidence linking them to improvements in cardiovascular health and endothelial function as measured by FMD.

1.1 Endothelial function and its role in cardiovascular disease

Endothelial function is a critical determinant of cardiovascular health, encompassing impaired functionality of the blood vessel inner lining known as the endothelium.⁸ This layer modulates key vascular processes, including blood flow regulation, vasodilation, vasoconstriction, and the release of signalling molecules.⁹ The pathogenesis of endothelial dysfunction is multifaceted.¹⁰ Albeit, at its core, chronic inflammation and oxidative stress are key mediators,^9,11 negatively impacting endothelial cells and disrupting their normal functions including, misbalancing vasoconstrictors such as endothelin-1 (ET-1) and angiotensin II (AngII), and reducing the production of nitric oxide (NO), a gaseous signalling molecule and potent vasodilator essential for regulating vascular tone.^9,12 Diminished NO availability impairs blood vessel relaxation, leading to vasoconstriction, simultaneously increasing oxidative stress, damaging endothelial cells and further reducing NO bioavailability (the amount of a compound or nutrient that is absorbed, entering systemic circulation where it becomes available to exert a physiological effect), thereby fostering inflammation and stimulating the release of pro-inflammatory cytokines, which contribute to the pathogenesis of atherosclerosis and other cardiovascular conditions.^9,13 NO, produced by endothelial nitric oxide synthase (eNOS), is crucial for vascular health as it promotes vasodilation, inhibits platelet aggregation, and suppresses smooth muscle cell proliferation.¹⁴ Reduced NO bioavailability is a hallmark of endothelial dysfunction and a key contributor to CVD progression.¹⁵

Experimental studies with endothelial cell cultures have provided valuable insights into mechanisms by which various (poly)phenols may mediate endothelial function.^16–18 For instance, resveratrol in human umbilical vein endothelial cells (HUVECs) significantly upregulate eNOS expression, increasing NO production and improving endothelial function.¹⁹ However, phenolic metabolites have been shown to play a more significant role than their parent compounds in modulating endothelial function due to their greater bioavailability and prolonged circulation time. Studies demonstrate direct stimulation of eNOS activity by certain phenolic metabolites including vanillic acid and protocatechuic acid reducing superoxide levels by downregulating NADPH oxidase (NOX) activity, indirectly enhancing NO bioavailability.²⁰ Additionally, they have been shown to enhance nitric oxide (NO) bioavailability by activating the Akt-eNOS signalling pathway in endothelial cells.²¹ Furthermore, protocatechuic acid has been demonstrated to reduce pro-inflammatory markers such as soluble vascular cellular adhesion molecule-1 (sVCAM-1) through modulation of gene expression in HUVECs, highlighting their role in mitigating endothelial inflammation.²² This modulation of endothelial function has also been confirmed in human studies via several mechanisms including upregulation of eNOS activity, and by scavenging reactive oxygen species (ROS), which degrade NO and reduce its bioavailability.^23,24 Additionally, flavan-3-ols such as epicatechin and catechin have been shown to downregulate endothelial dysfunction markers such as EDN1, reducing the production of the potent vasoconstrictor ET-1, and suppress the expression of angiotensin-converting enzyme (ACE), which decreases Angiotensin II levels.^25,26 These mechanisms collectively enhance vascular function, contributing to improved cardiovascular outcomes,²⁷ however a diverse intake of (poly)phenols is required to attain the collective bioactive effects.

1.2 Flow-mediated dilation (FMD): a biomarker of endothelial function

Flow mediated dilation (FMD) is the gold standard and non-invasive assessment of endothelial function, utilising ultrasound to measure arterial dilation in response to shear stress, mediated by the release of NO, with lower FMD values indicating endothelial dysfunction.^28,29 The clinical relevance of FMD has been validated through the establishment of reference values amongst a predominately European population (n = 1579), observing a mean FMD of 6.2% ± 2.0%, with 0.3–0.4% age-related decreases observed per decade. Importantly, values below 3.1% were identified as pathological, while values above 6.5% were considered optimal.³⁰ Moreover, ∼26% of healthy individuals with low cardiovascular risk (SCORE <1%) exhibited low FMD values (<5.4%), highlighting the complexity of endothelial health beyond traditional risk factors.³⁰ Observational meta-analyses further demonstrate that each 1% increase in FMD is associated with a 13% reduction in future cardiovascular events, reinforcing its predictive utility in both diseased and asymptomatic populations.³¹ Furthermore, age- and sex-specific reference values were established from a pooled cohort (n = 5362), confirming that lower FMD values correlate with key cardiovascular risk factors, including hypertension, dyslipidaemia, and diabetes.³² Additionally, FMD values below 3.1% exhibit 95% specificity for identifying individuals at high cardiovascular risk, whereas values above 6.5% demonstrate 95% sensitivity for excluding coronary artery disease.³⁰ However, the accuracy and reliability of FMD measurements are dependent on the use of standardized protocols. Thijssen and colleagues highlight the importance of controlling for factors such as baseline arterial diameter, occlusion time, and ultrasound techniques to ensure reproducibility and comparability across studies.³³ Without such standardization, the variability in FMD results can obscure the true effects of interventions like (poly)phenol supplementation.^33–35

2. Efficacy of (poly)phenol-rich foods and extracts on FMD

Research has increasingly focused on the efficacy of (poly)phenol-rich foods and their extracts in improving FMD and overall endothelial function. Numerous intervention trials (Table 1), meta-analyses and systematic reviews^23,25,36,37 have explored the effects of foods such as berries, grapes, citrus fruits, cocoa, coffee and teas, alongside their respective (poly)phenol extracts, on cardiovascular health. Given the sensitivity of FMD to endothelial changes, it is commonly employed as a primary outcome in studies examining the cardiovascular effects of (poly)phenol-rich foods.^38,39 For instance, (poly)phenols have consistently been shown to improve FMD, reflecting their ability to enhance endothelial function via increased NO bioavailability, modulation of antioxidative pathways, and inflammation reduction, suggesting that these compounds directly enhance endothelial function and reduce CVD risk.^6,40 However, the bioavailability and bioaccessibility (the amount or proportion of a nutrient or compound that is released from the food matrix during digestion which becomes available for absorption in intestine) of (poly)phenols are critical determinants of their efficacy,⁴¹ as ingested (poly)phenols undergo extensive metabolism in the gastrointestinal tract and liver, resulting in a wide range of metabolites with varying biological activity.^5,42,43 Despite this, studies have consistently shown that (poly)phenols from various sources (Tables 1 & 2, and Fig. 1) can improve endothelial function through their action on NO bioavailability and their ability to mitigate oxidative stress and inflammation.^9,12 However, the perceived effect may be impacted by various factors including, class of (poly)phenol, their bioavailability, additional food component or matrix, health status, age and individual variability (Fig. 2).

Fig. 1 Comparison of dose-dependent acute and chronic FMD responses for Whole Foods and Extracts, within each food category. Diamonds represent significant values (p < 0.05) and Straight lines represent non-significant values (p > 0.05). FMD, flow-mediated dilation; TPC, total (poly)phenol content; mg, milligrams.

Fig. 2 Relationship between Age and polyphenol-rich foods and extracts on flow-mediated dilation (ΔFMD%) following chronic and acute interventions. Data presented as the delta change in FMD (%), calculated from relevant studies within each category for acute and chronic interventions.

Table 1 Summary of acute flow-mediated dilation (FMD) responses within different food groups

Food group	Proportion of studies demonstrating a significant effect on FMD	(Poly)phenol dose range (mg)	Acute FMD changes (%)
Acute changes in flow-mediated dilation (FMD) within different food grouped by whole foods (including whole fruits or derived products such as juices, wines etc.) extracts (including freeze-dried food components administered as capsules, reconstituted in water, or used to enrich derived food or a meal) and pure phenolic compounds. FMD, flow-mediated dilation; n, number of studies; mg, milligram; NR, not reported; NA, not applicable.
Whole food
Berry (n = 8)	5/8	200–1910	0.9–2.6
Grape (n = 4)	3/4	NR	0.3–8.6
Citrus fruits (n = 3)	1/1	32–345	1.5–2.1
Cocoa (n = 12)	7/12	185–3282	0.7–5.7
Coffee (n = 8)	5/8	89–900	1.1–3.4
Tea (n = 3)	3/5	398–733	1.4–4.8
Extract
Berry (n = 7)	3/4	116–1791	1.0–2.4
Grape (n = 0)	NA	NA	NA
Citrus fruits (n = 1)	0/0	272–600	1.5
Cocoa (n = 1)	1/1	150–3282	0.7–5.9
Coffee (n = 2)	1/2	355	0.3–2.3
Tea (n = 3)	1/3	330–1817	0.2–3.9
Pure phenolic
Epicatechin (n = 2)	1/2	10–100	1.2–2.9
Resveratrol (n = 2)	1/2	30–270	2.5–3.6
Quercetin (n = 1)	0/1	160	NA
Hesperidin (n = 1)	0/1	450	NA

---

Table 2 Summary of chronic flow-mediated dilation (FMD) responses within different food groups

Food group	Proportion of studies demonstrating a significant effect on FMD	(Poly)phenol dose range (mg)	Chronic FMD changes (%)
Chronic changes in flow-mediated dilation (FMD) within different food grouped by whole foods (including whole fruits or derived products such as juices, wines etc.) extracts (including freeze-dried food components administered as capsules, reconstituted in water, or used to enrich derived food or a meal) and pure phenolic compounds. FMD, flow-mediated dilation; n, number of studies; mg, milligram; NR, not reported; NA, not applicable.
Whole food
Berry (n = 3)	2/3	12–835	0.9–1.1
Grape (n = 3)	2/3	965	0.8–8.7
Citrus fruits (n = 4)	2/4	212–419	0.2–2.2
Cocoa (n = 14)	7/14	185–1113	1.0–5.6
Coffee (n = 2)	1/2	300–780	3.3
Tea (n = 6)	5/6	100–1188	1.2–3.8
Extract
Berry (n = 4)	2/4	116–1910	1.1–1.45
Grape (n = 12)	6/12	1.65 (NR)	0.3–5.5
Citrus fruits (n = 4)	3/4	500–600	2.0–7.2
Cocoa (n = 3)	2/3	523–690	1.2–1.8
Coffee (n = 0)	NA	NA	NA
Tea (n = 1)	1/1	1350	3.5
Pure phenolic
Epicatechin (n = 1)	1/1	10–100	1.1
Quercetin (n = 1)	0/1	160	NA

---

2.1 Berries

Blueberries, cranberries, and blackcurrants are rich in (poly)phenols (200–600 mg per 100 g fresh weight) including anthocyanins, flavan-3-ols, and proanthocyanidins⁴⁴ and significantly contribute to dietary (poly)phenol intake, accounting for approximately 5–20% of total anthocyanin consumption.⁴⁵ Multiple studies (Table 3) have investigated their efficacy in modulating endothelial function as measured by FMD, highlighting both acute and chronic improvements with varying ranges of total (poly)phenol content (TPC), dependant on the timing, dosage, and food matrix.^46–51 Despite this, variability in outcomes—particularly regarding the long-term efficacy of certain berries like cranberries—warrants further analysis.

Table 3 Summary of human intervention trials assessing the effects of (poly)phenol-rich foods and extracts on flow-mediated dilation (FMD)

Author (Year) Population	Type of Intervention	Study design	Health Status	Duration	Age (y)	BMI (kg m^−2)	Intervention and (poly)phenol Content (mg)	FMD Outcomes
Age and BMI values are presented as mean ± standard deviation (where not available, the range is provided). Significane compared to control denoted using; *, p < 0.05;**.p < 0.01;***, p < 0.001. Significance compared to baseline denoted using; ^†, p < 0.05; ^††. p < 0.01; ^†††, p < 0.001. BMI, body mass index; CC, caffeinated coffee; CAD, coronary artery disease; CVD, cardiovascular disease; CVR, cardiovascular risk; DC, dark chocolate or decaffeinated coffee (context-dependent); DP1–10, degree of polymerization 1–10; DP2–10, degree of polymerization 2–10; d, day(s); F&V, fruit and vegetables; FMD, flow-mediated dilation; g, grams; GSE, grape seed extract; HCCGA, high CGA coffee; hFCD, high flavan-3-ol cocoa drink; h, hour(s); IFCD, low flavan-3-ol cocoa drink; kg, kilograms; lFCD, low flavan-3-ol cocoa drink; M, males; MC, milk chocolate; MCCGA, medium CGA coffee; mg, milligrams; MGS, muscadine grape seed; MOF, monomeric and oligomeric flavan-3-ols; mth, month(s); n, number of participants; ND, not disclosed; NR, not reported; RGC, red grape concentrate; TPC, total (poly)phenol content; μM, micromolar; WC, white chocolate; wk, week(s); y, years.
Berries
Istas et al. (2018)^52	Whole food	Crossover	Healthy	Acute (2 h)	27 ± 3	23 ± 2	200g Raspberry drink (TPC 201 mg, Anthocyanins 125 mg, Flavonols 5.7 mg, Flavan-3-ols 0.6 mg, Epicatechin 0.6 mg, Catechin 0.01 mg)	Acute (2 h)
n = 10, 100% M				Chronic (24 h)			400g Raspberry drink (TPC 403 mg, Anthocyanins 328 mg, Flavonols 11 mg, Flavan-3-ols 1.2 mg, Epicatechin 1.2 mg, Catechin 0.02 mg)	200 g – **↑1.6% from baseline FMD%
							Control (macro/micronutrient matched drink, with raspberry flavours)	400 g – *↑1.2% from baseline FMD%
								Control – 0.0% from baseline FMD%
								Chronic (24 h)
								200 g – **↑0.9% from baseline FMD%
								400 g – *↑0.5% from baseline FMD%
								Control – 0.1% from baseline FMD%
Alqurashi et al. (2016)^53	Whole food	Crossover	Healthy	Acute (2 h)	46 ± 1.9	27.6 ± 0.4	Açai Smoothie (TPC 694 mg, Anthocyanins 493 mg)	Açai smoothie – **↑1.4% ± 0.6% from baseline FMD%
n = 23, 100% M							Control (macro/micronutrient – matched smoothie)	Control – ↑0.4% ± 0.6% from baseline FMD%
Rodriguez–Mateos et al. (2016)^54	Whole food	Crossover	Healthy	Acute (2 h)	24 ± 2	24 ± 2	Cranberry juice at:	25.1% – *↑0.9% from baseline FMD%
n = 10, 100% M							25.1% (TPC 409 mg, Flavan-3-ols 2.5 mg, Flavonols 14.5 mg, Anthocyanins 6.8 mg)	48.2% – *↑1.55% from baseline FMD%
							48.2% (TPC 787 mg, Flavan-3-ols 5.0 mg, Flavonols 31.3 mg, Anthocyanins 16.2 mg)	75.8% – *↑1.8% from baseline FMD%
							75.8% (TPC 1238 mg, Flavan-3-ols 6.8 mg, Flavonols 48.9 mg, Anthocyanins 23.2 mg)	94% – *↑1.55% from baseline FMD%
							94% (TPC 1534 mg, Flavan-3-ols 10.1 mg, Flavonols 62.8 mg, Anthocyanins 26.3 mg)	117% – *↑1.7% from baseline FMD%
							117% (TPC 1910 mg, Flavan-3-ols 12.3 mg, Flavonols 76.9 mg Anthocyanins 32.3 mg)	Control – ↑0.4% from baseline FMD%
							Control (macro/micronutrient matched drink)
Khan et al. (2014)^51	Whole food	Parallel	Low F&V consumers	Chronic (6 wk)	Low blackcurrant juice: 55 ± 10	Low blackcurrant juice: 28.4 ± 5.4	Low blackcurrant juice (TPC 273 mg, Anthocyanins 40 mg)	Blackcurrant juice
n = 64, 67% M					High blackcurrant juice: 51 ± 11	High blackcurrant juice: 29.2 ± 6.9	High blackcurrant juice (TPC 815 mg, Anthocyanins 143 mg)	Low – ↑0.7% from baseline FMD%
					Placebo: 51 ± 8	Placebo: 28.9 ± 6.5	Control (Flavoured water)	High – *↑1.1% from baseline FMD%
								Control
								1 week – ↓0.9% from baseline FMD%
Dohadwa et al. (2011)^55	Whole food	Crossover	CAD	Acute (2–4 h)	Juice-first: 61 ± 11	Juice-first: 30 ± 5	Cranberry juice (TPC 835 mg, Anthocyanins 94.47 mg, cyn-gal 18.7 mg, cyn-glu 1.58 mg, cyn-ara 16.47 mg, peo-gal 30.83 mg, peo-glu 5.85 mg, and peo-ara 21.03 mg)	Acute (2 h) – ↑0.4% from baseline FMD%
n = 44, 68% M				Chronic (4 wk)	Placebo-first: 63 ± 9	Placebo-first: 29 ± 4		Acute (4 h) – *↑1.0% from baseline FMD%
								Chronic – ↑0.4% from control baseline FMD%
Istas et al. (2019)^49	Whole food/Extract	Parallel	Healthy	Acute (2 h)	24 ± 5.3	23 ± 2.1	Aronia whole fruit – TPC 12 mg (Flavonols 2.6 mg, Anthocyanins 3.6 mg, Proanthocyanidins 3.3 mg, Epicatechin 0 μg, Protocatechuic acid 450 μg)	Acute:
n = 66, 100% M				Chronic (12 wk)			Aronia Extract – TPC 116 mg (Flavonols 35 mg, Anthocyanins 30 mg, Proanthocyanidins 16 mg, Epicatechin 101 μg, Protocatechuic acid 2396 μg)	Whole fruit – ↑0.5% from baseline FMD%
							Control (maltodextrin)	Extract – ↑1.4% from baseline FMD%
								Control – ↑0.3% from baseline FMD%
								Chronic:
								Whole fruit – *0.9% from baseline FMD%
								Extract – *1.0% from baseline FMD%
								Control – ↓0.2% from baseline FMD%
Rodriguez-Mateos et al. (2014)^56	Whole food/Extract	Crossover	Healthy	Acute (24 h)	27 ± 1	25 ± 0.8	Drink containing freeze-dried blueberry 34g (TPC 692 mg, Total anthocyanins 339 mg, Total procyanidins 111 mg, Monomers 29 mg, Dimers 26 mg, Trimers 15 mg, Tetramers 14 mg, Pentamers 9 mg, Hexamers 8 mg, Heptamers 6.5 mg, Octamers 5 mg, Nonamers 4 mg, Decamers 0 mg, Total oligomers 89 mg, Quercetin 24 mg, Chlorogenic acid 179 mg, Caffeic acid 16 mg, Ferulic acid 22 mg)	Blueberry drink:
n = 10, 100% M							Blueberry buns (x3) made with freeze-dried blueberry 34g: (TPC 637 mg, Total anthocyanins 196mg*, Total procyanidins 140 mg, Monomers 29 mg, Dimers 42mg*, Trimers 23mg*, Tetramers 17 mg, Pentamers 11 mg, Hexamers 8 mg, Heptamers 5 mg, Octamers 4 mg, Nonamers 0mg*, Decamers 0 mg, Total oligomers 111 mg, Quercetin 25mg*, Chlorogenic acid 221mg*, Caffeic acid 17 mg, Ferulic acid 38mg*)	1 h: *↑2.4% from baseline FMD%
							Control (Macro/micronutrient matched buns × 3)	2 h: *↑1.55% from baseline FMD%
								4 h: *↑0.15% from baseline FMD%
								6 h: *↑1.3% from baseline FMD%
								Blueberry bun:
								1 h: *↑1.8% from baseline FMD%
								2 h: *↑2.6% from baseline FMD%
								4 h: *↑0.25% from baseline FMD%
								6 h: *↑1.0% from baseline FMD%
								Control
								1 h: ↑0.15% from baseline FMD%
								2 h: ↑0.35% from baseline FMD%
								4 h: ↑0.55% from baseline FMD%
								6 h: ↑0.65% from baseline FMD%
Rodriguez-Mateos et al. (2013)^57	Whole food/Extract	Crossover	Healthy	Acute (6 h)	27 ± 1.3	25 ± 0.8	Drinks containing freeze-dried blueberry:	766mg TPC:
n = 10, 100% M							34 (TPC 766 mg, Anthocyanins 310 mg, Procyanidins 137 mg, Flavan-3-ol monomers 24 mg, Flavan-3-ol oligomers 112 mg, Chlorgenic acid 273 mg, Quercetin 26 mg, Caffeic acid 17 g, p-Coumaric acid 1.4 mg, Ferulic acid 1.4 mg)	1 h: ↑2.4% from baseline FMD%
							57 (TPC 1278 mg, Anthocyanins 517 mg, Procyanidins 228 mg, Flavan-3-ol monomers 40 mg, Flavan-3-ol oligomers 188 mg, Chlorgenic acid 455 mg, Quercetin 43 mg, Caffeic acid 30 mg, p-Coumaric acid 2.4 mg, Ferulic acid 2.4 mg)	2 h: ↑1.5% from baseline FMD%
							80 (TPC 1791 mg, Anthocyanins 724 mg, Procyanidins 320 mg, Flavan-3-ol monomers 56 mg, Flavan-3-ol oligomers 264 mg, Chlorgenic acid 637 mg, Quercetin 61 mg, Caffeic acid 42 g, p-Coumaric acid 3.4 mg, Ferulic acid 3.4 mg)	4 h: ↑0.1% from baseline FMD%
							Control (macro/micronutrient matched drink)	6 h: ↑1.2% from baseline FMD%
								1278mg TPC:
								1 h: ↑2.2% from baseline FMD%
								2 h: ↑1.5% from baseline FMD%
								4 h: ↑0.1% from baseline FMD%
								6 h: ↑0.6% from baseline FMD%
								1791mg TPC:
								1 h: ↑1.8% from baseline FMD%
								2 h: ↑1.0% from baseline FMD%
								4 h: ↑0.1% from baseline FMD%
								6 h: ↑0.4% from baseline FMD%
								Control:
								1 h: ↓0.3% from baseline FMD%
								2 h: ↓0.5% from baseline FMD%
								4 h: ↓0.4% from baseline FMD%
								6 h: ↓0.5% from baseline FMD%
Woolf et al. (2023)^58	Extract	Parallel	Postmenopausal women with elevated BP	Chronic (12 wk)	Blueberry: 60 ± 1	Blueberry: 27.6 ± 1	Freeze-dried Blueberry Powder (TPC 726 mg, Anthocyanins 224 mg)	Freeze-dried Blueberry Powder
n = 43, 0% M					Placebo: 61 ± 1	Placebo: 27.8 ± 1.1	Control (isocaloric and carbohydrate matched)	12 weeks – ↑1.34% from baseline FMD%
							*Added to energy dense meal*	Control 1
								12 weeks – ↓0.4% from baseline FMD%
Heiss et al. (2022)^59	Extract	Parallel	Healthy	Acute (2 h)	Cranberry: 25 ± 3	Cranberry: 23 ± 3	Cranberry powder (TPC 525 mg, Total proanthocyanidins (PACs) 374.2 mg, Epicatechin 0.493 mg, Catechin 0.019 mg, Total flavonols 81 mg, Quercetin-3-rhamnoside eq. 81 mg, Quercetin 0.153 mg, Kaempferol 0.001 mg, Total anthocyanins 54 mg, 3′,4′-Dihydroxycinnamic acid equivalent (caffeic acid) 16 mg, 5-O-Caffeoylquinic acid (chlorogenic acid) 0.720 μg, 3,4-dihydroxybenzoic acid (protocatechuic acid) 0.051 μg, 4′-Hydroxycinnamic acid (p-coumaric acid) 0.034 μg, 4′-Hydroxy-3′,5′-dimethoxycinnamic acid (sinapic acid) 0.010 μg, 4′-Hydroxy-3′-methoxycinnamic acid (ferulic acid) 0.007 μg, 3-Hydroxybenzoic acid 0.006 μg, 3,4-Dihydroxybenzaldehyde 0.004 μg, 2,5-Dihydroxybenzoic acid 0.003 μg, 2-Hydroxybenzoic acid 0.003 μg, 4-Hydroxybenzoic acid 0.001 μg, Dihydrocaffeic acid 0.001 μg, 4-Hydroxy-3′-methoxycinnamic acid (isoferulic acid) 0.000 μg, 4-Hydroxybenzaldehyde 0.000 μg.)	Freeze-dried cranberry Powder:
n = 44, 100% M				Chronic (1 mth)	Control: 25 ± 3	Control: 24 ± 3	Control (Colour matched Maltodextrin)	2 h: ***↑1.5% from baseline FMD%
								1 mth: ***↑1.1% from baseline FMD%
								1 mth, 2 h: ***↑1.5% from baseline FMD%
								Control:
								2 h: ↓0.0% from baseline FMD%
								1 mth: ↓0.0% from baseline FMD%
								1 mth, 2 h: ↓0.1% from baseline FMD%
Curtis et al. (2022)^60	Extract	Crossover	Metabolic syndrome	Acute (24 h)	63.4 ± 7.4	31.4 ± 3.1	Freeze-dried Blueberry Powder (TPC 879 mg, Anthocyanins 364 mg)	Freeze-dried Blueberry Powder:
n = 45, 64% M							Control (isocaloric and carbohydrate matched)	3 h: ↓0.6% from baseline FMD%
							*Added to energy dense meal*	6 h: ↓0.5% from baseline FMD%
								24 h: ↓0.2% from baseline FMD%
								Control:
								3 h: ↓1.1% from baseline FMD%
								6 h: ↓0.6% from baseline FMD%
								24 h: ↓0.2% from baseline FMD%
Huang et al. (2021)^61	Extract	Crossover	Hypercholesterolemia	Acute (1 h)	53 ± 1	31 ± 1	Strawberry powder 50g – TPC 450.7 mg (Flavan-3-ols 99 mg, Flavonols 36.2 mg, Anthocyanins 141.7 mg, Ellagitannins 160.2 mg, Phenolic acids 13.6 mg) – (25 g = 250 g fresh fruit)	Strawberry powder – *↑2.4% from baseline FMD%
n = 46, 46% M								Control – ↑0.7% from baseline FMD%
Curtis et al. (2019)^47	Extract	Parallel	Metabolic syndrome	Chronic (6 mth)	62.8 ± 7.1	31.2 ± 3.0	Freeze-dried Blueberry Powder:	Freeze-dried Blueberry Powder:
n = 115, 68% M							1 cup equivalent (TPC 879 mg, Anthocyanins 364 mg)	1 cup – *↑1.45% from baseline FMD%
							1/2 cup equivalent (TPC 439 mg, Anthocyanins 182 mg)	1/2 cup – ↑0.00% from baseline FMD%
							Control (isocaloric and carbohydrate matched)	Control – ↑0.45% from baseline FMD%
							*Consumed within 8 standardized recipes*
Philip et al. (2019)^62	Extract	Crossover	Healthy	Acute (2 h)	18 – 25	21.3 ± 2.2	Memophenol (TPC 600 mg, Flavonoids 260.4 mg, Flavan-3-ols monomers 123.6 mg, Anthocyanins 0.6 mg, Phenolic acids 3 mg, Oligomers 135 mg, Stillbenes 0.6 mg)	Memophenol – ***↓1.6% from baseline FMD%
n = 30, 47% M								Control ***↓1.5% from baseline FMD%
Grape
Siasos et al. (2014)^63	Whole food	Crossover	Healthy smokers	Chronic (2 wk)	26.34 ± 4.93	23.21 ± 4.10	Concord grape juice 490 ml – (TPC 965 mg, hydroxycinnamates 324 μmol L^−1, flavonols 152 μmol L^−1, flavan-3-ols 868 μmol L^−1, and anthocyanins 592 μmol L^−1)	Concord grape juice
n = 26, 39% M							Control (Grapefruit juice)	7 days – *↑0.8% from baseline FMD%
								14 days – *↑1.14% from baseline FMD%
								Control
								7 days – ↓0.73% from baseline FMD%
								14 days – ↓1.12% from baseline FMD%
Hashemi et al. (2011)^64 n = 20, 54% M	Whole food	Parallel	Metabolic syndrome	Acute (4 h)	13.4 ± 1.1	27.1 ± 1.1	Grape juice – 18 ml kg^−1 day^−1	Grape juice
				Chronic (2 wk)			Pomegranate juice – 200 ml day^−1	4 h – *↑8.55% from baseline FMD%
								1 month – *↑8.66% from baseline FMD%
								Pomegranate juice
								4 h – *↑4.50% from baseline FMD%
								1 month – ↑4.28% from baseline FMD%
Hampton et al. (2010)^65	Whole food	Crossover	Healthy	Acute (30–60 min)	22.2 ± 3.8	23.7 ± 3.15	Meal + Red grape juice – 122.5 ml + water – 52.5 mL	Red grape juice
n = 10, 50% M							Meal + Red grape juice – 122.5 ml + 40% alcohol – 52.5 mL	30 min – ↑1.60% from baseline FMD%
							Meal + Control (water) – 175 ml	60 min – ↑0.35% from baseline FMD%
								Red grape juice + Alcohol
								30 min – ↑2.60% from baseline FMD%
								60 min – ↑0.10% from baseline FMD%
								Control
								30 min – ↓0.00% from baseline FMD%
								60 min – ↓1.05%from baseline FMD%
Coimbra et al. (2005)^66	Whole food	Crossover	Hypercholesterolemia	Chronic (2 wk)	51.6 ± 8.1	24.8 ± 1.5	Grape juice – 500 ml day^−1	Grape juice – ^†↑6.80% from baseline FMD%
n = 16, 50% M							Red wine – 250 ml day^−1	Red wine – ^†↑5.50% from baseline FMD%
Papamichael et al. (2003)^67	Whole food	Crossover	Healthy smokers	Acute (90 min)	28.9 ± 6.5	23.4 ± 3.2	Smoking + Red wine (dealcoholised) – 250 ml (caffeic acid 1.65 mg)	Smoking + Red wine (Dealcoholised)
n = 16, 50% M							Smoking + Red wine (Alcoholised) – 250 ml (caffeic acid 1.63 mg)	15 min – ↓1.15% from baseline FMD%
							Smoking (control)	30 min – ↑0.28% from baseline FMD%
								60 min – ↓0.14% from baseline FMD%
								90 min – ↓0.69% from baseline FMD%
								Smoking + Red wine (Alcoholised)
								15 min – ↓1.67% from baseline FMD%
								30 min – ↓1.74% from baseline FMD%
								60 min – ↓0.92% from baseline FMD%
								90 min – ↓0.74% from baseline FMD%
								Smoking
								15 min – *↓4.61% from baseline FMD%
								30 min – *↓4.25% from baseline FMD%
								60 min – *↓2.42% from baseline FMD%
								90 min – ↓1.30% from baseline FMD%
Chou et al. (2001)^68	Whole food	Parallel	CAD	Chronic (8 wk)	64 ± 10	NR	Purple grape juice (8ml kg^−1 day^−1) – high dose	High dose – ↑ 2.0 ± 4.3% from baseline FMD%
n = 22, 82% M							Purple grape juice (4ml kg^−1 day^−1) – low dose	Low dose – ↑ 2.0 ± 3.6% from baseline FMD%
Hashimoto et al. (2001)^69	Whole food	Crossover	Healthy	Acute (120 min)	34 ± 1	NR	Red wine (0.8 g kg^−1 ethanol) – 500 ml	Red wine (dealcoholised)
n = 11, 100% M							Red wine (dealcoholised) – 500 ml	30 min – **↑4.8% from baseline FMD%
							Japanese vodka (0.8 g kg^−1 ethanol) – 500 ml	120 min – **↑1.8% from baseline FMD%
							Control (water) – 500 ml	Red wine (alcoholised)
								30 min – ↓0.1% from baseline FMD%
								120 min – **↑1.6 from baseline FMD%
								Japanese vodka
								30 min – *↓2.0 from baseline FMD%
								120 min – *↓2.4 from baseline FMD%
								Control
								30 min – ↑0.8% from baseline FMD%
								120 min – ↑0.7%from baseline FMD%
Martelli et al. (2021)^70	Extract	Parallel	Healthy	Chronic (12 wk)	24.46 ± 2.99	22.30 ± 4.87	Taurisolo 400 mg × 2 d^−1 (TPC ND, anthocyanins ND, Epicatechin 1.36 mg, Catechin 1.99 mg, Resveratrol 0.01 mg)	Taurisolo – *↑5.00% from baseline FMD%
n = 30, 100% M							Control – Maltodextrin	Control – ↓0.07% from baseline FMD%
Odai et al. (2019)^71	Extract	Parallel	Prehypertension	Chronic (12 wk)	53.7 ± 7.7	23.4 ± 3.4	Low-dose (200 mg d^−1)	Low dose – ↓0.9% from baseline FMD%
n = 30, 100% M							High-dose (400 mg d^−1)	High dose – ↓1.2% from baseline FMD%
							Control	Placebo – ↑0.1% from baseline FMD%
							∼85% proanthocyanidin and flavan-3-ol monomers
Lee et al. (2019)^72	Extract	Crossover	Postmenopausal women	Chronic (4 wk)	53.6 ± 0.8	22.88	Grape seed extract (TPC 300 mg)	Grape seed extract – ***↑5.5% from baseline FMD%
n = 11, 100% M							Control (NR)	Control – ↓4.6% from baseline FMD%
Greyling et al. (2016)^73	Extract	Crossover	Hypertensive (on diuretic monotherapy)	Chronic (8 wk)	46.8 ± 9.0	26.1 ± 2.1	Grape/Wine extract (TPC 800 mg) (Anthocyanins 140.66 mg, Phenolic acids 9.68 mg, Flavan-3-ols 39.52 mg, Epicatechin 10.64 mg, Catechin 11.25 mg, Flavonols 9.31 mg, Stilbenes 0.92 mg)	Grape/Wine extract – ↑0.2% from baseline FMD%
n = 51, 100% M							Control (microcrystalline cellulose)	Control – ↑0.4% from baseline FMD%
Vaisman & Niv (2015)^74	Extract	Parallel	Pre & stage 1 hypertension	Chronic (12 wk)	57.5	27.46	RGC 200 mg (TPC 11.2 mg, Anthocyanins 1.34 mg, Catechin 2.6 mg, Resveratrol 3 mg)	RGC 200 mg – ↑1.13% from baseline FMD%
n = 50, 100% M							RGC 400 mg (TPC 22.4 mg, Anthocyanins 2.68 mg, Catechin 5.2 mg, Resveratrol 6 mg)	RGC 400 mg – **↑2.1% from baseline FMD%
								Control – ↑0.23% from baseline FMD%
Park et al. (2015)^75	Extract	Parallel	Prehypertension	Chronic (12 wk)	44 ± 10	32.5	Grape seed extract 150mg x 2 day^−1 (TPC 528.24 mg, gallic acid 9.94 mg, Epicatechin 12.78 mg, Catechin 9.94 mg)	Grape seed extract – *↑0.3% from baseline FMD%
n = 36, 42% M							Control ×2 day^−1 (TPC 236 mg, gallic acid 0.5 mg l^−1, Epicatechin ND, Catechin ND)	Control – *↓1.7% from baseline FMD%
Barona et al. (2012)^76	Extract	Crossover	Metabolic syndrome	Chronic (30 d)	30–70	NR	Freeze-dried grape powder 46g d^−1 (TPC 266.8 mg, Flavans 188.6 mg, Anthocyanins 35.4 mg, Flavonols 1.68 mg, Quercetin 1.42 mg, Myricetin 0.12 mg, Kaempferol 0.14 mg, Resveratrol 0.07 mg) *reconstituted*	Freeze-dried grape powder – *↑1.70% from control FMD%
n = 35, 100% M							Control (Macronutrient matched placebo)	Control – 4.00% FMD
Mellen et al. (2010)^77	Extract	Crossover	CVD risk	Chronic (6 wk)	55 ± 10	30 ± 4	Muscadine grape seed supplement (MGS) (TPC 83.98 mg), Proanthocyanidins 92.12 mg, Gallic Acid 1.99 mg, Ellagic Acid 1.33 mg, and Catechins 0.10 mg (Catechin 0.10 mg, Epicatechin 7.03 mg, Catechin Gallate 0.03 mg, Epicatechin Gallate 0.35 mg, Epigallocatechin 0.002 mg, Epigallocatechin Gallate 0.0006 mg, and Resveratrol 0.0039 mg)	MGS – ↓0.65% from baseline FMD%
n = 50, 100% M							Control (methylcellulose USP powder)	Control – ↓0.09% from baseline FMD%
Weseler et al. (2010)^78	Extract	Parallel	Healthy	Chronic (6 wk)	MOF Supplement	MOF Supplement	MOF Supplement 100 mg × 2 (Total Catechins 51.2 mg (including (+)-Catechin 21.8 mg, (−)-Epicatechin 24.4 mg, and (−)-Epicatechin-3-O-gallate 5.0 mg). Total Dimers amount to 55.0 mg, comprising Proanthocyanidin B1 15.4 mg, Proanthocyanidin B2 16.6 mg, Proanthocyanidin B3 5.6 mg, Proanthocyanidin B4 3.2 mg, and Proanthocyanidin B2-gallate 14.2 mg)	MOF Supplement
n = 28, 100% M					46 (30–56)	24 ± 1	Control (microcrystalline cellulose)	4 weeks – ↓0.5% from baseline FMD%
					Control	Control		8 weeks – 0% change from baseline FMD%
					48 (30–60)	25 ± 1
								Control
								4 weeks – ↓0.1% from baseline FMD%
								8 weeks – ↓1.1% from baseline FMD%
van Mierlo et al. (2010)^79	Extract	Crossover	Healthy males	Chronic (2 wk)	31.4 ± 9.0	23.2 ± 2.5	Grape seed solids – 6 × 500mg d^−1 (TPC 800 mg) (Epicatechin 56 mg, Catechin 64 mg, Epicatechingallate 24 mg)	GSE:
n = 35, 100% M							Wine/grape solids – 6 × 500mg d^−1 (TPC 800 mg) (Anthocyanins 137.3 mg, Phenolic acids 9.6 mg, Catechin 4.2 mg, Flavonols 0.9 mg, Stilbenes 0.2 mg)	After low-fat breakfast – ↑0.2 from Control FMD%
							Control (microcrystalline cellulose)	After high-fat lunch – ↓0.2 from Control FMD%
								Wine/grape extract:
								After low-fat breakfast – ↓0.4 from Control FMD%
								After high-fat lunch – ↑0.7 from Control FMD%
								Control
								After low-fat breakfast – 3.9% FMD
								After high-fat lunch – 4.5% FMD
Ward et al. (2005)^80	Extract	Parallel	Treated hypertensive	Chronic (6 wk)	(1) 59.5 ± 5.9	(1) 28.7 ± 3.6	(1) 500 mg day^−1 vitamin C and matched grape-seed (poly)phenol placebo	(1) ↑0.6 from baseline FMD%
n = 69, 70% M					(2) 61.3 ± 6.3	(2) 27.7 ± 3.4	(2) 1000mg day^−1 grape-seed (poly)phenols and matched vitamin C placebo	(2) ↑0.6 from baseline FMD%
					(3) 62.3 ± 7.1	(3) 28.6 ± 2.6	(3) 500 mg day^−1 vitamin C and 1000 mg day^−1 grape-seed (poly)phenols	(3) ↓0.65 from baseline FMD%
					(4) 63.6 ± 8.2	(4) 29.3 ± 4.3	(4) Control (matched placebo tablets for both grape-seed (poly)phenols and vitamin C)
Clifton et al. (2004)^81	Extract	Crossover	High-risk of CVD	Chronic (12 wk)	34–70	28.4	Grape seed extract 2 × 1g (**TPC 592.5 mg g^−1, gallic acid 49 mg g^−1, catechin 41 mg g^−1, epicatechin 66 mg g^−1, proanthocyanidins 436.6 mg Catechin Eq per g**)	GSE – *↑1.1% from baseline FMD%
n = 36, 67% M							Grape seed extract with Quercetin 2 × 1g + 0.5g quercetin	GSE with Quercetin – ↓0.59 from baseline FMD%
							Control (Yogurt (2 × 240 g))	Control – ↓0.33 from baseline FMD%
							*Taken in Yogurt (2 × 240 g)
							**https://www.sciencedirect.com/science/article/pii/S0027510708002571**
Citrus fruit
Li et al. (2020)^82	Whole food	Crossover	Healthy	Acute (7 h)	28.7 ± 6.5	29.8 ± 3.1	Blood orange juice 400 ml d^−1; (Hesperidin 32.08 mg, Narirutin 0.04 mg)	Blood orange juice – **↑2.05% from baseline FMD%
n = 15, 33% M							Control (sugar-matched control drink)	Control – ↓0.34% from baseline FMD%
Constans et al. (2015)^83	Whole food	Crossover	Mild hypercholesterolaemia	Chronic (4 wk)	53.8 ± 10	26 ± 5	Blood orange juice – 3 × 200 ml d^−1 (Hesperidin 266.25 mg, Narirutin 37.43 mg)	Orange juice – **↑0.28% from baseline FMD%
n = 25, 100% M							Control (Matched placebo drink) – 3 × 200 ml day^−1	Control – ↓0.78% from baseline FMD%
Habauzit et al. (2015)^84	Whole food	Crossover	Healthy postmenopausal women	Chronic (6 Mth)	57.8 ± 3.7	25.7 ± 2.3	Grapefruit juice 340 mL d^−1 (Naringenin glycosides 212.9 mg)	Grapefruit juice – ↓0.24% from baseline FMD%
n = 52, 0% M							Control (drink without flavonoids)	Control – ↑0.11% from baseline FMD%
Buscemi et al. (2012)^85	Whole food	Crossover	CVD risk	Chronic (1 wk)	CVR group – 48 ± 13	CVR group – 31.4 ± 2.9	Red orange juice 500 mL d^−1 (TPC 419 mg l^−1), Anthocyanins 71.3 mg L^−1, Narirutin 43 mg L^−1, Hesperidin 319 mg L^−1	CVR Group:
n = 33, 48% M					Control group – 35 ± 8	Control group – 31.4 ± 3.5	Control (blend of water, sugars, and orange & colorants)	Red orange juice – **↑2.2% from baseline FMD%
								Control – ↓0.70% from baseline FMD%
								Healthy:
								Red orange juice – ↑0.1% from baseline FMD%
Valls et al. (2021)^86	Whole food/Extract	Parallel	Pre or stage 1 hypertension	Acute (2–6 h)	Orange juice – 43.3 ± 12.0	Orange juice – 26.4 ± 3.6	Orange juice 500 ml – (Hesperidin 345 mg, Narirutin 64 mg)	Orange juice
n = 159, 67% M				Chronic (12 wk)	Enriched OJ – 43.6 ± 11.8 Control – 45.4 ± 13.0	Enriched OJ – 26.1 ± 3.4	Hesperidin-enriched orange juice 500 ml – (Hesperidin 600 mg, Narirutin 77.5 mg)	2 h – ↑0.45 AU from baseline IRH
						Control – 26.1 ± 3.8	Control (Matched placebo drink) – 500ml	4 h – ↑0.50 AU from baseline IRH
								6 h – ↑0.70 AU from baseline IRH
								Enriched OJ
								2 h – ↑1.00 AU from baseline IRH
								4 h – ↑1.10 AU from baseline IRH
								6 h – *↑1.45 AU from baseline IRH
								Control
								2 h – ↑0.50 AU from baseline IRH
								4 h – ↑0.70 AU from baseline IRH
								6 h – ↑0.65 AU from baseline IRH
Rendeiro et al. (2016)^87	Whole food/Extract	Crossover	Healthy	Acute (7 h)	48 ± 1	28.4 ± 0.4	Orange juice: 128.9 mg d^−1; (Total flavonoids 128.88 mg, Hesperidin 107.30 mg, Narirutin 15.41 mg, Others 6.17 mg)	OJ – *↓0.29% from baseline FMD%
n = 28, 100% M							Flavanone-rich orange juice: 272.1 mg d^−1; (Total flavonoids 272.14 mg, Hesperidin 220.46 mg, Narirutin 34.54 mg, Others 17.14 mg)	FOJ – **↓0.06% from baseline FMD%
							Homogenized whole orange: 452.8 mg d^−1; (Total flavonoids 452.71, Hesperidin 352.80 mg, Narirutin 76.58 mg, Others 23.33 mg)	HWO – **↓0.05% from baseline FMD%
							Control – Isocaloric drink; (Total flavonoids 0.10 mg, Narirutin 0.08 mg, Others 0.02 mg)	Control – ↓3.70% from baseline FMD%
Macarro et al. (2020)^88	Extract	Parallel	Metabolic syndrome	Chronic (8 wk)	NR	NR	Citoven 500 mg twice daily	Citoven – ***↑3.04 from baseline FMD%
n = 114, 84% M								Control – ↑0.54% from baseline
Hashemi et al. (2015)^89	Extract	Parallel	Overweight/Obese	Chronic (1mth)	13.7 ± 7.0	23.38 ± 3.82	Lemon peel – 1000 mg d^−1	Lemon peel – ***↑6.49% from baseline FMD%
n = 30, 43% M							Sour orange peel – 1000 mg d^−1	Sour orange peel – ***↑7.24% from baseline FMD%
							Control (Cornstarch powder) – 1000 mg d^−1	Control – ↓0.05% from baseline FMD%
Rizza et al. (2011)^90	Extract	Crossover	Metabolic syndrome	Chronic (4 wk)	52 ± 2	34.7 ± 1.5	Hesperidin extract – 500 mg d^−1	Hesperidin – *↑2.02% from baseline FMD%
n = 24, 63% M							Control (Cellulose)	Control – ↓0.46% from baseline FMD%
Cocoa/Chocolate
Baynham et al. (2021)^91	Whole food		Healthy	Acute (2 h)	23 ± 4.30	23.66 ± 3.19	hFCD (TPC 1052.5 mg, Flavan-3-ols 681 mg, Procyanidins 495.9 mg, Epicatechin 150 mg, Catechin 35.5 mg), Theobromine 179.8 mg, Caffeine 19.3 mg	hFCD – ***↑0.7% from baseline FMD%
n = 30, 100% M							lFCD (TPC 143 mg, Flavan-3-ols 4.1 mg, Procyanidins ND, Epicatechin <4 mg, Catechin <4 mg), Theobromine 179.8 mg, Caffeine 19.3 mg	lFCD – ***↓1.0% from baseline FMD%
Marsh et al. (2017)^92	Whole food	Crossover	Postmenopausal women	Acute (80 min)	57.6 ± 4.8	24.3 ± 4.1	DC (TPC 394.8 mg, Flavanoids 3600 mg kg^−1, Epicatechin 587.1 μg g^−1, Catechin 1394.2 μg g^−1)	DC – ^††↑2.4% from baseline FMD%
n = 12, 0% M							MC (TPC 200.1 mg, Flavanoids 980 mg kg^−1, Epicatechin 288.4 μg g^−1, Catechin 770.1 μg g^−1)	MC – ↓0.95% from baseline FMD%
							WC (TPC 34.9 mg, Flavanoids 370 mg kg^−1, Epicatechin ND, Catechin 38.4 μg g^−1)	WC – ↑0.25% from baseline FMD%
Dower et al. (2016)^93	Whole food	Crossover	Healthy	Acute (2 h)	61.8 ± 9.3	25.1 ± 2.1	Dark chocolate – 70g and 2 × placebo capsules (Flavan-3-ols (DP1–10) 770 mg, Flavan-3-ols (DP2–10) 578 mg, Epicatechin 150 mg, Catechin 42 mg)	Dark chocolate – **↑0.96% from baseline FMD%
n = 20, 100% M							White chocolate- 75g and 2 × epicatechin capsules (Epicatechin 150 mg)	Epicatechin – ↑0.75% from baseline FMD%
							White chocolate – 75 g and 2 × placebo capsules (microcrystalline cellulose)
Pereira et al. (2014)^94	Whole Food	Parallel	Healthy	Chronic (4 wk)	20.23 ± 2.22	22.92 ± 3.66	10 g dark chocolate (75% cocoa)	Dark Chocolate – ***↑9.31% from baseline FMD%
n = 60 33% M							Control – No intervention	Control – ↑0.38% from baseline FMD%
Loffredo et al. (2014)^95	Whole Food	Crossover	PAD	Chronic (2 wk)	69.9 ± 9	27 ± 3	Dark chocolate (TPC 799 mg, Epicatechin 0.59 mg, Catechin 0.32 mg, Epigallocatechin gallate 1.8 mg)	Dark Chocolate – **↑4.0% from baseline FMD%
n = 20 70% M							Control – Milk chocolate (TPC 296 mg, Epicatechin 0.16 mg, Catechin 0.13 mg, Epigallocatechin gallate 0.28 mg)	Control – ↑1.3% from baseline FMD%
Esser et al. (2013)^96	Whole Food	Crossover	Overweight	Acute (2 h)	Acute – 64 ± 4	Acute – 27.8 ± 2.6	High flavan-3-ol dark chocolate (1078 mg flavan-3-ols, 349 mg epicatechin)	Acute (2 hours)
n = 41, 100% M				Chronic (4 wk)	Chronic – 63 ± 5	Chronic – 27.6 ± 2.3	Normal flavan-3-ol dark chocolate (259 mg flavan-3-ols, 97 mg epicatechin)	HFDC – ↓0.4% from baseline FMD%
								NFDC – ↑0.9% from baseline FMD%
								Chronic (4 weeks)
								HFDC – ↑1.2% from baseline FMD%
								NFDC – ↑0.9% from baseline FMD%
Njike et al. (2011)^97	Whole Food	Crossover	Overweight	Chronic (6 wk)	52.2 ± 11	30.5 ± 3.4	Sugar-free cocoa (Total procyanidins 805 mg, catechin 21 mg, epicatechin 48 mg, procyanidin dimer 92 mg, procyanidin trimer 98 mg, procyanidin tetramer 31 mg, procyanidin pentamer and hexamer 55 mg) – theobromine 436 mg, caffeine 28mg	Sugar-free cocoa – **↑2.4% from baseline FMD%
n = 44, 85% M							Sugar-sweetened cocoa (Total procyanidins 805 mg, catechin 21 mg, epicatechin 48 mg, procyanidin dimer 92 mg, procyanidin trimer 98 mg, procyanidin tetramer 31 mg, procyanidin pentamer and hexamer 55 mg) – theobromine 436 mg, caffeine 28mg	Sugared-sweetned cocoa – **↑1.5% from baseline FMD%
							Control – Placebo drink (no cocoa)	Control – ↓0.8% from baseline FMD%
Westphal & Luley (2010)^98	Whole Food	Crossover	Healthy	Acute (6 h)	25.2 ± 2.5	22.8 ± 2.0	High-Flavan-3-ol Cocoa (Total flavan-3-ols 918.00 mg, monomers 145.96 mg, epicatechin 120.25 mg, catechin 29.37 mg, dimers 113.83 mg, trimers-decamer 383.72 mg) – theobromine 210 mg, caffeine 40 mg	High-Flavan-3-ol Cocoa
n = 18, 11% M							Control – Low-Flavan-3-ol Cocoa (Total flavan-3-ols 14.68 mg, monomers 2.93 mg, epicatechin 0.73 mg, catechin 1.38 mg, dimers 4.77 mg, trimers-decamer 6.97 mg) – theobromine 220 mg, caffeine 40 mg.	2 hours – ***↓1.1% from baseline FMD%
							*Postprandial – Fatty Meal	4 hours – *↓0.5% from baseline FMD%
								6 hours – ↓0.3% from baseline FMD%
								Control
								2 hours – ↓2.0% from baseline FMD%
								4 hours – ↓0.9% from baseline FMD%
								6 hours – ↓0.3% from baseline FMD%
Grassi et al. (2015)^99	Whole Food	Crossover	Healthy	Chronic (1 wk)	53.8 ± 8.9	25.4 ± 2.4	Treatment 1 – Placebo drink (Total flavan-3-ols 0 mg, epicatechin 0 mg) – theobromine 329 mg, caffeine 25 mg.	Treatment 2 – *↑1.07% from control FMD%
n = 20, 85% M							Treatment 2 – Low-flavan-3-ol cocoa (Total flavan-3-ols 80 mg, epicatechin 17 mg) – theobromine 329 mg, caffeine 25 mg.	Treatment 3 – *↑1.44% from control FMD%
							Treatment 3 – Moderate-flavan-3-ol cocoa (Total flavan-3-ols 200 mg, epicatechin 42 mg) – theobromine 329 mg, caffeine 25 mg.	Treatment 4 – *↑1.97% from control FMD%
							Treatment 4 – High-flavan-3-ol cocoa (Total flavan-3-ols 500 mg, epicatechin 105 mg) – theobromine 329 mg, caffeine 25 mg.	Treatment 5 – *↑2.02% from control FMD%
							Treatment 5 – Very high-flavan-3-ol cocoa (Total flavan-3-ols 800 mg, epicatechin 168 mg) – theobromine 329 mg, caffeine 25 mg.
Hammer et al. (2015)^100	Whole Food	Crossover	PAD	Acute (2 hours)	66.9	NR	Dark chocolate (TPC 780 mg, Epicatechin 45 mg, Catechin 13.5 mg)	Dark Chocolate – ↑0.4% from baseline FMD%
n = 21, 71% M							Control – Milk chocolate	Control – ↓2.0% from baseline FMD%
Heiss et al. (2010)^101	Whole Food	Crossover	CAD	Chronic (4 wk)	64 ± 3	27.8 ± 1.8	HiFI (Total Flavan-3-ol 375 mg, Monomers 65 mg, Epicatechin 59 mg, Catechin 6 mg, Dimers 53 mg, Trimers-decamers 258 mg) – theobromine 93 mg, caffeine 11 mg.	HiFI – ***↑3.8% from baseline FMD%
n = 16, 100% M							Control – LoFI (Total Flavan-3-ol 9 mg, Monomers 3 mg, Epicatechin 1 mg, catechin 2 mg, Dimers 2 mg, Trimers-decamers 3 mg) – theobromine 96 mg, caffeine 9 mg.	Control – ↑1.3% from baseline FMD%
Faridi et al. (2008)^97	Whole food	Parallel	Overweight	Acute (2 h)	52.8 ± 11.	30.1 ± 3.3	Placebo chocolate (TPC ND, Flavan-3-ol ND, Epicatechin ND, Catechin ND, Procyanidin dimer ND, Procyanidin trimer ND, Procyanidin tetramer ND, Procyanidin penta/hexamer ND)	Placebo chocolate – ↓1.8% from baseline FMD%
n = 45, 22% M							Solid dark chocolate (TPC 3282 mg, Flavan-3-ol 821 mg, Epicatechin 21.5 mg, Catechin 10.4 mg, Procyanidin dimer 81.4 mg, Procyanidin trimer 67.3 mg, Procyanidin tetramer 37 mg, Procyanidin penta/hexamer 67 mg)	Solid dark chocolate – ***↑4.3% from baseline FMD%
							Sugar-free cocoa (TPC 3282 mg, Flavan-3-ol 805.2 mg, Epicatechin 48.4 mg, Catechin 20.9 mg, Procyanidin dimer 92 mg, Procyanidin trimer 98.1 mg, Procyanidin tetramer 30.6 mg, Procyanidin penta/hexamer 54.8 mg)	Sugar-free cocoa – ***↑5.7% from baseline FMD%
							Sugared cocoa (TPC 3282 mg, Flavan-3-ol 805.2 mg, Epicatechin 48.4 mg, Catechin 20.9 mg, Procyanidin dimer 92 mg, Procyanidin trimer 98.1 mg, Procyanidin tetramer 30.6 mg, Procyanidin penta/hexamer 54.8 mg)	Sugared cocoa – ***↑2.0% from baseline FMD%
							Placebo cocoa (TPC 17.6 mg, Flavan-3-ol 8.8 mg, Epicatechin ND, Catechin ND, Procyanidin dimer ND, Procyanidin trimer 3.3 mg, Procyanidin tetramer ND, Procyanidin penta/hexamer 5.5 mg)	Placebo cocoa – ↓1.5% from baseline FMD%
Davison et al. (2008)^102	Whole Food	Parallel	Healthy	Chronic (12 wk)	HF + Ex – 45.2 ± 4.0	HF + Ex – 33.5 ± 1.1	High-Flavan-3-ol Cocoa Drink (Flavan-3-ols 451 mg) – theobromine 337 mg, caffeine 18 mg.	No exercise
n = 49 37% M					HF + Ex – 45.5 ± 4.0	HF + Ex – 33.2 ± 1.6	Control Cocoa Drink (Flavan-3-ols 18 mg) – theobromine 327 mg, caffeine 21 mg.	HF + Ex – *↑1.8% from baseline FMD%
					LF + Ex – 44.4 ± 4.4	LF + Ex – 34.5 ± 1.8		LF + Ex – ↓0.3% from baseline FMD%
					LF + Ex – 45.3 ± 4.4	LF + Ex – 32.8 ± 1.1		Exercise
								HF + Ex – *↑1.5% from baseline FMD%
								LF + Ex – ↓0.4% from baseline FMD%
Flammer et al. (2008)^103	Whole Food	Parallel	CHF	Acute (2 h)	FRC- 60.3 ± 10.1	FRC – 25.9 ± 5.1	Flavanoid-rich chocolate (TPC 624 mg, Epicatechin 36 mg, Catechin 10.8 mg)	Acute (2 hours)
n = 49 37% M				Chronic (4 wk)	CC – 58.1 ± 11.9	CC – 25.6 ± 3.5	Control chocolate	FRC – *↑1.0% from baseline FMD%
								Control – ↓0.59% from baseline FMD%
								Chronic (4 weeks)
								FRC – **↑1.88% from baseline FMD%
								Control – ↓1.02% from baseline FMD%
Grassi et al. (2008)^104	Whole Food	Parallel	Hypertensive	Chronic (2 wk)	44.8 ± 8.0	26.5 ± 1.9	Dark Chocolate (TPC 1008 mg, Epicatechin 110.9 mg, Catechin 36.12 mg, quercetin 2.5 mg, kaempferol 0.03 mg, isohamnetin 0.2 mg) – theobromine 1.7 mg, caffeine 136 mg.	Dark Chocolate – ***↑1.4% from baseline FMD%
n = 19 58% M							Control – White Chocolate (Epicatechin 0.13 mg, Catechin 0.04 mg)	Control – ↑0.2% from baseline FMD%
Balzer et al. (2008)^105	Whole Food	Crossover (feasability)	T2DM	Acute (6 h)	Feasibility – 64.7 ± 9.9	Feasibility – 27.8 ± 3.6	High-Flavan-3-ol Cocoa Drink (Flavan-3-ols 963 mg, Monomers 253.8 mg, epicatechin 203.0 mg, catechin 50.8 mg, dimers 180.9 mg, trimers-decamer 528.3 mg) – theobromine 586.2 mg, caffeine 31.8 mg.	Acute (2 hours)
n = 41, 29% M		Parallel (efficay)		Chronic (4 wk)	Treatment – 63.1 ± 8.3	Treatment – 32.1 ± 5.1	Medium-Flavan-3-ol Cocoa Drink (Flavan-3-ols 371 mg, Monomers 98.6 mg, epicatechin 78.9 mg, catechin 19.7 mg, dimers 74.3 mg, trimers-decamer 198.1 mg) – theobromine 575.6 mg, caffeine 35.2 mg.	High-Flavan-3-ol – *↑1.8% from baseline FMD%
					Control – 64.4 ± 8.6	Control – 31.1 ± 5.1	Control Cocoa Drink (Flavan-3-ols 371 mg,Monomers 21.0 mg, epicatechin 16.8 mg, catechin 4.2 mg, dimers 21.0 mg, trimers-decamer 30.3 mg) – theobromine 570.3 mg, caffeine 36.9 mg.	Medium-Flavan-3-ol – ↑0.9% from baseline FMD%
								Control – ↑0.2% from baseline FMD%
								Chronic (8 Days)
								Medium-Flavan-3-ol x3 day^−1 – ***↑0.8% from baseline FMD%
								Control – ↓0.4% from baseline FMD%
								Chronic (4 weeks)
								Medium-Flavan-3-ol x3 day^−1 – *↑1.0% from baseline FMD%
								Control – ↑0.1% from baseline FMD%
Heiss et al. (2007)^106	Whole food	Crossover	Healthy smokers	Acute (2 h)	27 ± 1	22 ± 1	hFCD – 100ml (Total Flavan-3-ol 185 mg, Monomers 74 mg, Epicatechin 22 mg, Procyanidins 111 mg)	Acute: (100 ml)
n = 11, 100% M				Chronic (1 wk)			Control – lFCD (Total Flavan-3-ol <11 mg, Monomers <1 mg, Epicatechin <1 mg, Procyanidins <11.4 mg)	Day 1 – ^†↑2.4% from baseline FMD%
								Chronic (300 ml)
								Day 3 – ^†↑2.4% from baseline FMD%
								Day 5 – ^†↑2.7% from baseline FMD%
								Day 8 – ^†↑2.4% from baseline FMD%
Wang-Polagruto et al. (2006)^107	Whole Food	Parallel	Postmenopausal women	Chronic (6 wk)	HCF- 57.7 ± 2.2	HCF – 24.9 ± 1.0	High Cocoa Flavan-3-ol (Total Flavan-3-ols 446 mg)	HFC – **↑2.0% from baseline FMD%
n = 32, 0% M					LCF – 55.4 ± 1.7	LCF – 25.3 ± 0.8	Control – Low Cocoa Flavan-3-ol (Total Flavan-3-ols 43 mg)	Control – ↓1.5% from baseline FMD%
Schroetaler et al. (2006)^108	Whole food	Crossover	Healthy	Acute (2 h)	25–32	19–23	hFCD (Flavan-3-ols 917 mg)	hFCD – *↑∼5.65% from baseline FMD%
n = 10, 100% M							lFCD (Flavan-3-ols 37 mg)	lFCD – ↓0.05% from baseline FMD%
Fisher & Hollenberg (2006)^109	Whole food	Crossover	15 young adults	Chronic (4 wk)	47.9 ± 3.0	Young – 28.4 ± 1.3	hFCD (TPC 910.2 mg, Flavan-3-ol 821 mg, Epicatechin 9.2 mg, Catechin 10.7 mg, and Flavan-3-ol oligomers 69.3 mg)	Younger – **↑3.5% from baseline FMD%
n = 34, 38% M			19 older addults			Older – 28.0 ± 1.9	lFCD (TPC ND, Flavan-3-ol ND, Epicatechin ND, Catechin ND, and Flavan-3-ol oligomers ND)	Older – **↑4.5% from baseline FMD%
Heiss et al. (2005)^110	Whole food	Crossover	Healthy smokers	Acute (2 h)	30 ± 1	21.8 ± 0.7	hFCD (Total Flavan-3-ol 306 mg, Monomers 74 mg, Epicatechin 59 mg, Catechin 15 mg, Dimers 57 mg. Trimer-decamers 175 mg)
n = 11, 55% M							Control – lFCD (Total Flavan-3-ol 312 mg, Monomers 3 mg, Epicatechin 2 mg, Catechin 1 mg, Dimers 2 mg. Trimer-decamers 7 mg)	hFCD- *↑2.7% from baseline FMD%
								lFCD – ↓0.9% from baseline FMD%
Engler et al. (2004)^111	Whole food	Parallel	Healthy	Chronic (2 wk)	Low-flavanoid – 32.5 ± 2.9	Low-flavanoid – 21.9 ± 0.5	HFC (TPC 259 mg, Procyanidins 213 mg, Epicatechin 46 mg)	HFC – **↑1.3% from baseline FMD%
n = 22, 50% M					High-flavanoid – 31.8 ± 3.2	High-flavanoid – 23.2 ± 0.5	LFC (TPC 0 mg, Procyanidins 0 mg, Epicatechin 0 mg)	LFC – ↓0.96% from baseline FMD%
Rodriguez-Mateos et al. (2018)^112	Extract	Parallel	Healthy	Acute (2 h)	DP1–10 – 23 ± 2	DP1–10 – 23.6 ± 0.5	DP1–10 Cocoa flavan-3-ols extract (Total Flavan-3-ol 690 mg, Epicatechin 130 mg, Dimers-decamers 560 mg)
n = 45, 100% M				Chronic (4 wk)	DP2–10 – 25 ± 2	DP2–10 – 24.1 ± 2.2	DP2–10 Cocoa flavan-3-ols extract (Total Flavan-3-ol 560 mg, Epicatechin 20 mg, Dimers-decamers 540 mg)
					Control – 23 ± 2	Control – 23.1 ± 2.4	Control (Matched placebo)	Chronic
								DP1–10 – *↑1.8% from baseline FMD%
								DP2–10 – ↓0.1% from baseline FMD%
								Control – ↑0.4% from baseline FMD%
Sansone et al. (2015)^113	Extract	Crossover	Healthy	Chronic (4 wk)	Flavan-3-ol – 45 ± 8	Flavan-3-ol – 25 ± 3	Intervention (TPC 523 mg, Flavan-3-ol 450 mg, Epicatechin 64 mg, Catechin 9 mg)	Chronic – ↑1.2% from baseline FMD%
n = 100, 52% M					Control – 44 ± 9	Control – 26 ± 3	Control (TPC ND, Flavan-3-ol ND, Epicatechin ND, Catechin ND)	Acute – ↑0.7% from baseline FMD%
								Acute – ↑0.1% from baseline FMD%
Coffee
Kajikawa et al. (2019)^114	Whole Food	Crossover	Pre – or stage 1 hypertension	Acute (2hr)	Study 1 (S1): 53 ± 19	Study 1 (S1): 24.5 ± 4.1	Beverage A (Chlorogenic acids 412 mg, Hydroxyhydroquinone: 0.11 mg)	Study 1:
n = 37, 70% M					Study 2 (S2): 56 ± 15	Study 2 (S2): 23.2 ± 3.2	Beverage B (Chlorogenic acids 373 mg, Hydroxyhydroquinone 0.76 mg)	Beverage A – ^†↑1.5% from baseline FMD%
							Beverage C (Chlorogenic acids: 0 mg, Hydroxyhydroquinone: 0.1 mg)	Beverage B – ↑1.0% from baseline FMD%
								Study 2:
								Beverage A – ^†↑1.5% from baseline FMD%
								Beverage C – ↓0.4% from baseline FMD%
Mills et al. (2017)^115	Whole Food	Crossover	Healthy	Acute (1–5hr)	Study 1: 26.3 ± 1.6	Study 1: 23.5 ± 0.5	LPC (chlorogenic acids 89 mg, 3-caffeoylquinic acid 20 mg, 4-caffeoylqunic acid 22 mg, 3-Feruloylquinic acid 4 mg, 5-Caffeoylqunic acid 29 mg, 4-Feruloylquinic acid 4 mg, 5-Feruloylquinic acid 5 mg, 3,4-Dicaffeoylqunic acid 2 mg, 3,5-Dicaffeoylqunic acid 1 mg, 4,5-Dicaffeoylqunic acid 2 mg)	1 hour
Study 1: n = 15, 100% M					Study 2: 23.8 ± 1.4	Study 2: 23.2 ± 0.4	HPC (Chlorogenic acids 310 mg, 3-Caffeoylquinic acid 43 mg, 4-Caffeoylqunic acid 45 mg, 3-Feruloylquinic acid 10 mg, 5-Caffeoylqunic acid 124 mg, 4-Feruloylquinic acid 6 mg, 5-Feruloylquinic acid 24 mg, 3, 4-Dicaffeoylqunic acid 23 mg, 3, 5-Dicaffeoylqunic acid 17 mg, 4, 5-Dicaffeoylqunic acid 2 mg)	LPC – *↑1.10% from baseline FMD%
Study 2: n = 24, 100% M								HPC – **↑1.34% from baseline FMD%
								Control – ↑0.07% from baseline FMD%
								3 hours
								LPC – ↑0.25% from baseline FMD%
								HPC – ↓0.1% from baseline FMD%
								Control – ↓0.45% from baseline FMD%
								5 hours
								LPC – *↑0.79% from baseline FMD%
								HPC – ***↑1.52% from baseline FMD%
								Control – ↓0.46% from baseline FMD%
Boon et al. (2017)^116	Whole Food	Crossover	Healthy	Acute (2 h)	59.4 ± 6.4	24.7 ± 3.3	Caffeinated (CC) ground coffee – 200 ml × 2 (270 mg caffeine) CC (TPC 300 mg, 5-chlorogenic acid 95 mg)	CC – ↑6.1% from 0% continuous FMD%
n = 12, 58.3% M							Decaffeinated (DC) ground coffee – 200 ml × 2 (ND caffeine) DC (TPC 287 mg, 5-chlorogenic acid 132 mg)	DC – ↑6.0% from 0% continuous FMD%
							Hot water (Control) – 200 ml	Control – ↑4.9% from 0% continuous FMD%
Ward et al. (2016)^117	Whole Food	Crossover	Healthy	Acute (1 h)	59.9 ± 8.2	24.7 ± 3.3	Treatment 1 (5-chlorogenic acid 450 mg)	Treatment 1 – *↑0.6% from baseline FMD%
n = 16, 37.5% M							Treatment 2 (5-chlorogenic acid 900 mg)	Treatment 2 – *↑1.1% from baseline FMD%
							Treatment 3 (Epicatechin 200 mg)	Treatment 3 – ↑0.9% from baseline FMD%
							Control (Maltodextrin)	Control – ↑0.4% from baseline FMD%
Ochiai et al. (2015)^118	Whole Food	Crossover	Healthy	Acute (2hr)	44.9 ± 1.3	21.9 ± 0.5	Coffee bean (poly)phenols (TPC/CGA 600 mg; Caffeoylquinic Acids 349.8 mg (3-CQA, 4-CQA, 5-CQA), Feruloylquinic Acids 119.4 mg (3-FQA, 4-FQA, 5-FQA), Dicaffeoylquinic Acids 130.8 mg (3,4-diCQA, 3,5-diCQA, 4,5-diCQA))	Coffee bean (poly)phenols
n = 13, 100% M							Placebo – no coffee bean (poly)phenols beverage	1 hour – ↓0.50% from baseline FMD%
								2 hours – ↑0.70% from baseline FMD%
								4 hours – ↓0.00% from baseline FMD%
								6 hours – *↓0.20% from baseline FMD%
								Control Beverage
								1 hour – ↑0.40% from baseline FMD%
								2 hours – ↓0.10% from baseline FMD%
								4 hours – ↓0.90% from baseline FMD%
								6 hours – ^†↓1.90% from baseline FMD%
Buscemi et al. (2010)^119	Whole Food	Crossover	Healthy	Acute (1hr)	31 ± 2	23.9 ± 0.7	Caffeinated (CC) Italian espresso coffee – 25 ml (caffeine:130 mg)	CC – *↓1.7% from baseline FMD%
n = 20, 50% M							Decaffeinated (DC) Italian espresso coffee – 25 ml (caffeine: 5 mg)	DC – ↑1.6% from baseline FMD%
Buscemi et al. (2009)^120	Whole Food	Crossover	Healthy	Acute (1hr)	29 ± 3	24.3 ± 0.9	Decaffeinated espresso coffee – 25 ml × 2 (10 mg caffeine)	×1 cups – ↑1.6% from baseline FMD%
n = 15, 53% M							Decaffeinated espresso coffee – 25 ml (5 mg caffeine).	×2 cups – ***↑3.4% from baseline FMD%
Papamichael et al. (2005)^121	Whole Food	Crossover	Healthy	Acute (0.5–2hr)	28.9 ± 3.0	NR	Caffeinated (CC) instant coffee – 200 ml (80 mg caffeine)	CC (30 min) – **↓4.92 from baseline FMD%
n = 17, 53% M							Decaffeinated (DC) instant coffee – 200 ml (<2 mg caffeine)	CC (1hr)- ***↓5.66 from baseline FMD%
								DC (30 min) – ↓0.83 from baseline FMD%
								DC (1hr) – ↓1.86 from baseline FMD%
Agudelo-Ochoa et al. (2016)^122	Whole Food	Parallel	Healthy	Chronic (8 wk)	38.5 ± 9	24.1 ± 2.6	High CGA coffee (Chlorogenic acid 780 mg, Cafesol 0.75 mg, Kahweol 0.92 mg)	HCCGA – ↓0.2% from baseline FMD%
n = 75, 51% M#							Medium CGA coffee (Chlorogenic acid 420 mg, Cafesol 0.75 mg, Kahweol 0.89 mg)	MCCGA – ↑5.9% from baseline FMD%
							Control – No coffee consumption	Control – ↑5.2% from baseline FMD%
Ochiai et al. (2009)^123	Whole Food	Parallel	Healthy	Chronic (8 wk)	30 – 64 years	Active: 24.2 ± 0.9	Hydroxyhydroquinone (HHQ)-reduced coffee (Chlorogenic acid 300 mg, Hydroxyhydroquinone 0.03 mg)	Active (2 weeks) – ^†↑3.3% from baseline FMD%
n = 21 – % M						Placebo: 24.2 ± 1.1	HHQ/CGA-reduced coffee (Chlorogenic acid 0 mg, Hydroxyhydroquinone 0.03 mg)	Placebo (2 weeks) – ↓0.6% from baseline FMD%
							Control – Canned coffee (Chlorogenic acid 134 mg, Hydroxyhydroquinone 0.12 mg)
Naylor et al. (2021)^124	Extract	Crossover	Healthy	Acute (1 – 24 h)	56.2 ± 5.2	27.5 ± 3.7	Decaffeinated green coffee extract (DGCE)	1 Hour
n = 18, 83% M							Dose 1 (TPC/CGA 156.4 mg; 156.4 mg; 3-O-Caffeoylquinic Acid 30.0 mg, 4-O-Caffeoylquinic Acid and 3-O-Feruloylquinic Acid 39.0 mg, 5-O-Caffeoylquinic Acid 38.1 mg, 3,4-O-Dicaffeoylquinic Acid 12.5 mg, 3,5-O-Dicaffeoylquinic Acid 4.6 mg, 4,5-O-Dicaffeoylquinic Acid 9.8 mg, 4-O-Feruloylquinic Acid 9.3 mg, 5-O-Feruloylquinic Acid 12.1 mg, Caffeic Acid 0.6 mg, Ferulic Acid 0.3 mg)	Dose 1 (302 mg) – ↓0.01% from baseline FMD%
							Dose 2 (TPC/CGA 312.8 mg; 3-O-Caffeoylquinic Acid 60.0 mg, 4-O-Caffeoylquinic Acid and 3-O-Feruloylquinic Acid 78.1 mg, 5-O-Caffeoylquinic Acid 76.2 mg, 3,4-O-Dicaffeoylquinic Acid 25.0 mg, 3,5-O-Dicaffeoylquinic Acid 9.2 mg, 4,5-O-Dicaffeoylquinic Acid 19.6 mg, 4-O-Feruloylquinic Acid 18.7 mg, 5-O-Feruloylquinic Acid 24.2 mg, Caffeic Acid 1.3 mg, Ferulic Acid 0.7 mg)	Dose 2 (604 mg) – ↑0.69% from baseline FMD%
							Dose 3 (TPC/CGA 439.9 mg; 3-O-Caffeoylquinic Acid 84.3 mg, 4-O-Caffeoylquinic Acid and 3-O-Feruloylquinic Acid 109.8 mg, 5-O-Caffeoylquinic Acid 107.1 mg, 3,4-O-Dicaffeoylquinic Acid 35.2 mg, 3,5-O-Dicaffeoylquinic Acid 13.0 mg, 4,5-O-Dicaffeoylquinic Acid 27.5 mg, 4-O-Feruloylquinic Acid 26.3 mg, 5-O-Feruloylquinic Acid 34.0 mg, Caffeic Acid 1.8 mg, Ferulic Acid 0.9 mg)	Dose 3 (906 mg) – ↑0.46% from baseline FMD%
							Control – Maltodextrin	Control (Placebo) – ↑0.35% from baseline FMD%
								3 Hours
								Dose 1 (302 mg) – ↑0.45% from baseline FMD%
								Dose 2 (604 mg) – ↑0.47% from baseline FMD%
								Dose 3 (906 mg) – ↑0.69% from baseline FMD%
								Control (Placebo) – ↑0.85% from baseline FMD%
								5 Hours
								Dose 1 (302 mg) – ↑0.75% from baseline FMD%
								Dose 2 (604 mg) – ↑1.09% from baseline FMD%
								Dose 3 (906 mg) – ↑0.99% from baseline FMD%
								Control (Placebo) – ↑0.17% from baseline FMD%
								7 Hours
								Dose 1 (302 mg) – ↑0.90% from baseline FMD%
								Dose 2 (604 mg) – ↑1.17% from baseline FMD%
								Dose 3 (906 mg) – ↑0.75% from baseline FMD%
								Control (Placebo) – ↑1.11% from baseline FMD%
								8.5 Hours
								Dose 1 (302 mg) – *↑1.93% from baseline FMD%
								Dose 2 (604 mg) – ↑1.10% from baseline FMD%
								Dose 3 (906 mg) – ↑1.36% from baseline FMD%
								Control (Placebo) – ↑0.86% from baseline FMD%
								10 Hours
								Dose 1 (302 mg) – ↑1.24% from baseline FMD%
								Dose 2 (604 mg) – ↑1.36% from baseline FMD%
								Dose 3 (906 mg) – ↑1.32% from baseline FMD%
								Control (Placebo) – ↑1.43% from baseline FMD%
								12 Hours
								Dose 1 (302 mg) – *↑1.37% from baseline FMD%
								Dose 2 (604 mg) – ↑1.18% from baseline FMD%
								Dose 3 (906 mg) – ↑1.19% from baseline FMD%
								Control (Placebo) – ↑0.43% from baseline FMD%
								24 Hours
								Dose 1 (302 mg) – *↑0.75% from baseline FMD%
								Dose 2 (604 mg) – ↑0.22% from baseline FMD%
								Dose 3 (906 mg) – ↑0.70% from baseline FMD%
								Control (Placebo) – ↓0.03% from baseline FMD%
Suzuki et al. (2019)^125	Extract	Parallel	Healthy	Chronic (2 wk)	44.6 ± 5.3	21.9 ± 1.7	CGAs-enriched coffee bean extract (cGCE) (Chlorogenic acid 300 mg)	cGCE – *↑0.6% from baseline FMD%
n = 34, 100% M							Water (Control) – 100 ml	Control – ↓1.2% from baseline FMD%
Jokura et al. (2015)^126	Extract	Crossover	Healthy	Acute (4 h)	21.8 ± 2.3	38.1 ± 8.4	Coffee (poly)phenol extract containing beverage (TPC 355 mg; Chlorogenic Acids 256.02 mg (3-CQA, 4-CQA, 5-CQA), Feruloylquinic Acids 68.52 mg (3-FQA, 4-FQA, 5-FQA), Dicaffeoylquinic Acids 29.47 mg (3,4-diCQA, 3,5-diCQA, 4,5-diCQA) and caffeine 54.9 mg)	60 min
n = 19, 100% M							Control (coffee-flavored, Free CGAs and 54.9 mg of caffeine)	Coffee extract – ↓1.85% from baseline FMD%
								Control – ↓3.15% from baseline FMD%
								120 min
								Coffee extract – *↑0.08% from baseline FMD%
								Control – ↓2.35% from baseline FMD%
								180 min
								Coffee extract – *↑0.07% from baseline FMD%
								Control – ↓0.95% from baseline FMD%
								240 min
								Coffee extract – *↑0.1% from baseline FMD%
								Control – ↓0.15% from baseline FMD%
Mubarak et al. (2012)^127	Extract	Crossover	Healthy	Acute (2 h)	52.3 ± 10.6	25.6 ± 4.7	CGA dissolved in water (3-O-caffeoylquinic acid 400 mg)	CGA – ↑0.41% from control FMD%
n = 23, 17% M							Control (water) – 200 ml	Control – 9.60% FMD
Black and Green Tea
Sanguigni et al. (2017)^128	Whole Food/Extract	Crossover	Healthy	Acute (2 h)	38 ± 3	NR	Ice cream + GTE (TPC 1817 mg L^−1 GAE, catechin 1050 mg, epicatechin 910 mg)	Ice cream + GTE – ***↑3.9% from baseline FMD%
n = 14, 50% M							Control – Milk chocolate ice cream (TPC 96 mg L^−1 GAE, catechin 6 mg, epicatechin 3 mg)	Control – ↓0.25% from baseline FMD%
Lorenz et al. (2017)^42	Whole Food/Extract	Crossover	Healthy	Acute (2 h)	33.9 ± 7.6	23.7 ± 2.5	Brewed green tea (Gallic acid 15.65 mg, Gallocatechin 49.95 mg, Catechin 4.77 mg, Gallocatechin gallate 3.45 mg, Epicatechin 22.81 mg, Epicatechin gallate 39.38 mg, Epigallocatechin 62.32 mg, Epigallocatechin gallate 200.00 mg) – Theobromine 6.63 mg, Caffeine 117.13 mg.	Green Tea – **↑1.36% from baseline FMD%
n = 50, 100% M							Green tea extract (Gallic acid 5.36 mg, Gallocatechin 0.00 mg, Catechin 2.64 mg, Gallocatechin gallate 6.70 mg, Epicatechin 28.24 mg, Epicatechin gallate 28.64 mg, Epigallocatechin 58.91 mg, Epigallocatechin gallate 200.02 mg) – Theobromine 0.00 mg, Caffeine 2.88 mg.	Green Tea Extract – ↑0.18% from baseline FMD%
							EGCG supplement (Gallic acid 0.11 mg, Gallocatechin 0.00 mg, Catechin 0.15 mg, Gallocatechin gallate 0.00 mg, Epicatechin 1.07 mg, Epicatechin gallate 8.69 mg, Epigallocatechin 0.00 mg, Epigallocatechin gallate 200.30 mg) – Theobromine 0.00 mg, Caffeine 0.01 mg.	EGCG Supplement – ↓0.23% from baseline FMD%
							Control – Hot water	Control – ↓0.84% from baseline FMD%
Duffy et al. (2001)^129	Whole food/Extract	Crossover	CAD	Acute (2 h)	Water-first: 56 ± 8	Water-first: 30.9 ± 0.9	Brewed (TPC 733.5 mg, Flavanoids 477 mg, Epicatechin 6.3 mg, Catechin 59.85 mg, Epigallocatechin 9 mg, Epicatechin gallate 27 mg, Epigallocatechin gallate 17.55 mg, Theoflavins 27 mg)	Acute
n = 50, 79% M				Chronic (4 wk)	Tea-first: 54 ± 8	Tea-first: 28.4 ± 4.3	Freeze-dried (TPC 1350 mg, Flavanoids 873 mg, Epicatechin 19.8 mg, Catechin 116.1 mg, Epigallocatechin 207 mg, Epicatechin gallate 32.4 mg, Epigallocatechin gallate 27 mg, Theoflavins 22.5 mg)	Brewed- ***↑3.4% from baseline FMD%
					Caffeine: 56 ± 8	Caffeine: 31.5 ± 7.6	Water – 450 ml (Acute) & 900 ml (Chronic)	Water – ↓0.3% from baseline FMD%
							Caffeine (200 mg)	Chronic
								Freeze-dried black tea – ***↑3.5% from baseline FMD%
								Water – ↑0.1% from baseline FMD%
Grassi et al. (2016)^130	Whole food	Crossover	Hypertensive	Chronic (1 wk)	51.3 ± 8.2	27.1 ± 1.2	Black tea (TPC 300 mg, Catechins 24.2 mg, Theaflavins 10 mg, Gallic acid 9 mg)	Chronic – ***↑3.8% from control baseline FMD%
n = 19, 26% M								Acute on Chronic – ***↑1% from baseline FMD%
Ahmad et al. (2018)^131	Whole Food	Crossover	Healthy	Chronic (4 wk)	22.4 ± 3.0	24.1 ± 5.32	Black tea (TPC 1188.24 mg, Gallic acid 197.34 mg, Gallocatechin 186.72 mg, Epigallocatechin 164.16 mg, Catechin 105.42 mg, Epigallocatechin gallate 486.42 mg, Epicatechin 9.06 mg, Gallocatechin gallate 1.50 mg, Epicatechin gallate 37.62 mg) – caffeine 103.92 mg.	Black tea – ***↑1.0% from control continuous FMD%
n = 17, 41% M							Black tea + milk (TPC 1188.24 mg, Gallic acid 197.34 mg, Gallocatechin 186.72 mg, Epigallocatechin 164.16 mg, Catechin 105.42 mg, Epigallocatechin gallate 486.42 mg, Epicatechin 9.06 mg, Gallocatechin gallate 1.50 mg, Epicatechin gallate 37.62 mg, Theobromine 40 mg, Theogallin 136 mg) – caffeine 103.92 mg.	Black tea + milk – ***↓0.64% control continuous FMD%
							Control – Hot water
Grassi et al. (2016)^130	Whole Food	Crossover	Hypertensive	Chronic (1 wk)	51.3 ± 8.2	27.1 ± 1.2	Black tea (TPC 300 mg, Catechins 24.2 mg, Theaflavins 10 mg, Gallic acid 9 mg)	Chronic – ***↑3.8% from control baseline FMD%
n = 19, 26.3% M							Control (Matched placebo) – 100 – 200 ml × 2 d^−1	Acute on Chronic – ***↑1% from baseline FMD%
Schreuder et al. (2014)^132	Whole food	Crossover	Healthy	Acute (1.5 h)	54 ± 8	25.1 ± 2.8	Black tea −150 ml × 3 & 300 ml (TPC 600 mg, Flavanoids 500 mg)	Black Tea – *↑1.4% from baseline FMD%
n = 20, 40% M				Chronic (1 wk)				Hot water – ↑0.1% from baseline FMD%
Bøhn et al. (2014)^133	Whole Food	Parallel	Healthy	Chronic (3–6 months)			Black tea (TPC 429 mg)	Chronic (3 months)
n = 77, 35% M							Control	Tea – ↓0.27% from baseline FMD%
								Control – ↑0.32% from baseline FMD%
								Chronic (6 months)
								Tea – ↓0.13% from baseline FMD%
								Control – ↑0.41% from baseline FMD%
Grassi et al. (2009)^134	Whole food	Crossover	Healthy	Chronic (1 wk)	32.9 ± 10.2	23.9 ± 2.5	Black tea – 150 ml × 2	100 mg – **↑1.2% from control FMD%
n = 19, 100% M							(100, 200, 400, 800 mg flavonoids)	200 mg – **↑1.3% from control FMD%
								400 mg – ***↑1.8% from control FMD%
								800 mg – ***↑2.5% from control FMD%
Jochmann et al. (2008)^135	Whole food	Crossover	Postmenopausal women	Acute (2 h)	58.7 ± 4.5	23.1 ± 1.7	Black tea (Total catechins 560 μM, Epigallocatechin-3-gallate 324 μM, Epicatechin gallate 116 μM, Epigallocatechin 70 μM, Epicatechin 50 μM, Gallocatechin 0 μM, Catechin 0 μM, Gallic acid 91 μM)	Black tea – ***↑4.1% from baseline FMD%
n = 24, 0% M							Green tea (Total catechins 1012 μM, Epigallocatechin-3-gallate 464 μM, Epicatechin gallate 130 μM, Epigallocatechin 257 μM, Epicatechin 79 μM, Gallocatechin 52 μM, Catechin 30 μM, Gallic acid 30 μM)	Green tea – ***↑4.8% from baseline FMD%
								Hot water – ↑0.9% from baseline FMD%
Lorenz et al. (2007)^136	Whole Food	Crossover	Postmenopausal	Acute (2 h)	59.5 ± 5	23 ± 2	Black tea (TPC 505.52 mg, Gallic acid 30.96 mg, Epigallocatechin 42.88 mg, Epigallocatechin gallate 279.02 mg, Epicatechin 29.03 mg, Epicatechin gallate 102.63 mg)	Black tea – **↑4.3% from control continuous FMD%
n = 16, 0% M							Black tea + milk (TPC 1188.24 mg, Gallic acid 197.34 mg, Gallocatechin 186.72 mg, Epigallocatechin 164.16 mg, Catechin 105.42 mg, Epigallocatechin gallate 486.42 mg, Epicatechin 9.06 mg, Gallocatechin gallate 1.50 mg, Epicatechin gallate 37.62 mg)	Black tea + milk – ↑0.8% control continuous FMD%
							Control – Hot water	Control – ↑1.00% control continuous FMD%
Sapper et al. (2016)^137	Extract	Crossover	Normoglycemic	Acute (2 h)	25.3 ± 1.0	22.4 ± 1.8	Starch confection + GTE (Epigallocatechin gallate 489.1 mg, Epigallocatechin 144.5 mg, Epicatechin gallate 65.7 mg, Epicatechin 75.5 mg) – caffeine 7.4 mg.	Starch confection + GTE – ^†↓0.5% from baseline FMD%
n = 15 100% M							Control – Starch confection	Control – ^†↓0.48% from baseline FMD%
Pure phenolic
Alañón et al. (2020)^138	Extract	Crossover	Healthy	Acute (2hr)	23.4 ± 1.30	23.2 ± 1.51	Water-based test drink containing 0.1, 0.5 and 1.0 mg per kg BW of epicatechin	Low dose – ↑0.5% from baseline FMD%
n = 20, 100% M							Control (water)	Medium dose – **↑1.2 ± 0.3% from baseline FMD%
								High dose – ***↑2.9 ± 0.3% from baseline FMD%
								Control – ↓0.05% from baseline FMD%
Made et al. (2017)^139	Extract	Parallel	Overweight/obese	Chronic (4 wk)	61 ± 7	28.4 ± 3.1	trans-resveratrol (trans-resveratrol 150 mg)	trans-resveratrol ↓0.7% from baseline FMD%
n = 45, 55% M							Control (2 × 58 mg day^−1 cellulose)	Control ↑0.2% from baseline FMD%
Salden et al. (2016)^140	Extract	Parallel	Healthy	Acute (2hr)	53 ± 14	29.0 ± 2.6	Hesperidin 2S (450 mg supplied as 500 mg Cordiart)	Acute
n = 68, 68% M				Chronic (6 wk)			Control (Cellulose (500 mg microcrystalline cellulose))	Hesperidin 2S – ↓0.27% from baseline FMD%
								Control – ↓0.49% from baseline FMD%
								Chronic
								Hesperidin 2S – ↓0.21% from baseline FMD%
								Control – ↓0.14% from baseline FMD%
Wong et al. (2013)^141	Extract	Crossover	Overweight/obese	Chronic (6 wk)	61 ± 1.3	33.3 ± 0.6	Resveratrol (75 mg)	30 mg Resveratrol – *↑0.57% from baseline FMD%
n = 28, 43% M							Control (Calcium Hydrogen Phosphate, microcrystalline cellulose)	Control – ↓0.81% from baseline FMD%
Wong et al. (2011)^142	Extract	Crossover	Overweight/obese	Acute (1 h)	56 ± 2	28.7 ± 0.6	Resveratrol (30, 90, 270 mg)	30 mg Resveratrol – *↑2.50% from Control FMD%
n = 19, 74% M							Control (Calcium Hydrogen Phosphate, microcrystalline cellulose)	90 mg Resveratrol – *↑2.40% from Control FMD%
								270 mg Resveratrol – *↑3.60% from Control FMD%
								Control – 4.10% FMD

---

Blueberries have been the focus of several studies,^{46,47,56–58,60,143} indicating their beneficial effects on endothelial function, reporting acute improvements in FMD ranging from 0.9% to 2.4%, typically observed within 1 to 2 hours post-consumption with some studies observing a biphasic response (a second peak) occurring around 6 hours post-ingestion.⁵⁷ Dosages ranging between 300 mg and 1800 mg TPC (Fig. 3) have been tested, but many findings suggest that benefits plateau at moderate doses (∼750 mg), with higher doses failing to offer additional vascular improvements.⁵⁷ This plateau effect underscores the importance of optimal dosing. Curtis and colleagues demonstrated a 1.45% increase in FMD with a daily intake of 1 cup (150 g) equivalent of freeze-dried blueberries (879 mg TPC) over six months in individuals with metabolic syndrome.⁴⁷ However, the study also found that a lower dose (approximately 75 g, which aligns closely with the recommended portion size of 80 g) did not elicit significant FMD improvements. These findings suggest that an above average, but more importantly sustained intake of blueberries can provide long-term benefits without requiring excessive consumption. However, an important consideration which warrants further investigation, is the lack of studies investigating blueberries as a whole food. This highlights questions regarding the efficacy of whole blueberries, as processing, such as freeze-drying, can concentrate (poly)phenols, enhancing their bioaccessibility and bioavailability and thus their impact on FMD.

Fig. 3 Total polyphenol content and composition of dietary polyphenol interventions associated with significant effects. (Left) Mean ± SEM total polyphenol content (TPC) of interventions, expressed in milligrams (mg). (Right) Relative composition of polyphenol subclasses within interventions, displayed as a percentage (%) of total polyphenol content.

Cranberries, like blueberries, have been studied for their vascular effects, albeit results have shown less consistency, particularly in chronic interventions. Although reports indicate a modest and statistically significant 1% increase in FMD (from 7.7 ± 2.9% to 8.7 ± 3.1%, P = 0.01) four hours after acute consumption of cranberry juice (835 mg TPC) in an uncontrolled pilot study involving medicated patients with coronary artery disease (CAD), no significant changes were observed following four weeks of daily intake.⁵⁵ Consistent with the previous findings, Rodriguez-Mateos and colleagues demonstrated that cranberry juice (ranging from 409 mg to 1910 mg TPC) produced acute dose-dependent improvements in FMD increasing up to 2.6%. Notably, a significant effect detected at 787 mg TPC, similar to that of the previous study. Moreover, a plateau effect was again observed at 1200 mg TPC.⁵⁴ Given that acute improvements were observed in both studies, irrespective of health status (healthy vs. CAD patients), the key distinction lies in the chronic response, warranting further investigation. A more recent study⁵⁹ found significant acute (1.5%) vascular improvements aligning with the previous study but, more importantly, significant (p < 0.05) chronic (1.1%) improvements in FMD with a daily intake of cranberry extract (525 mg TPC), confirming the presence of persistence effects of cranberries, although the mode of delivery (extract) and (poly)phenol composition differs (anthocyanins – 94 mg vs. 23 mg vs. 54 mg respectively).

The studies on blueberries and cranberries consistently point to the critical role of the food matrix in modulating the bioavailability and efficacy of (poly)phenols. Whole foods and extracts offer varying degrees of (poly)phenol concentrations and absorption kinetics, which directly influence their vascular effects.^144,145 The absorption of (poly)phenols is also influenced by the interaction between the (poly)phenol compounds and the food matrix itself.^146–148 Complex matrices, such as those found in whole fruits, may impede the release and absorption of (poly)phenols in the digestive tract. In contrast, extracts or purified forms of (poly)phenols, which lack the complex matrix of whole fruits, are absorbed more efficiently, resulting in higher concentrations of (poly)phenols in circulation and potentially more efficacious endothelial improvements. This effect was evident in one study comparing the effects of aronia extract vs. whole fruit, demonstrating a significant (p < 0.01) 1.2% improvement in FMD after 12 weeks of daily extract consumption (TPC 116 mg), whereas whole fruit (TPC 12 mg) consumption resulted in a lesser (0.9%, p < 0.05), yet still significant improvement,⁴⁹ confirming what is highlighted when comparing cranberries composition and resulting effects.^54,59 These studies highlight that the food matrix and mode of delivery significantly affect the absorption and subsequent vascular benefits of (poly)phenols, with extracts delivering more pronounced effects due to their enhanced bioavailability. While some evidence suggests that extracts and processed forms may enhance (poly)phenol bioavailability and, in some cases, yield greater effects than whole fruits, direct comparisons remain limited and warrant further exploring. Moderate doses (100 to 200 g fresh weight or equivalent) appear to provide meaningful improvements in FMD, typically ranging from 0.9% to 2.5%. However, much of the available research focuses on extract/juice-based interventions, warranting further investigation into whether the same bioactivity persists when using whole-berry approaches.

In comparison, other berries, such as raspberries, blackcurrants, and strawberries, have been investigated to a lesser extent. Albeit, available research illustrates promising results regarding their impact on FMD, suggesting potential cardiovascular benefits warranting further exploration. For instance, acute FMD improvements of 1.6% and 1.2% were observed 2 hours post-consumption of raspberry drinks containing 201 mg and 403 mg TPC, respectively, in healthy volunteers. Notably, these improvements persisted at 24 hours post-consumption, correlating with plasma concentrations of urolithin metabolites, highlighting the importance of microbial metabolites in mediating vascular benefits.⁵² Blackcurrants also show promising effects on endothelial function, as evidenced by a Khan and colleagues⁵¹ where healthy subjects with habitually low fruit and vegetable intake showed significant increases in FMD from 5.8% to 6.9% following 6 weeks of daily consumption of blackcurrant juice (250 ml × 4 per day), compared to placebo. This improvement was correlated with increased plasma vitamin C concentrations opposed to circulating phenolics, warranting further investigation. Strawberry interventions also demonstrated a significant acute increase in FMD by 1.5% following strawberry intake (50 g freeze-dried powder equivalent to ∼500 g fresh strawberries), suggesting that strawberries may enhance vascular health independently of broader metabolic changes, potentially mediated by microbial-derived phenolic metabolites such as 3-(4-methoxyphenyl)propanoic acid-3-O-glucuronide.⁶¹ However, this effect was not retained after 4-weeks consumption, raising questions about the persistence of this benefit, although this may be explained by the observed increase in baseline FMD% which may have attenuated the effect size, which arguably, may be indication of endothelial recovery. Collectively, these preliminary findings underscore the potential for raspberries, blackcurrants, and strawberries to positively impact endothelial function, despite fewer studies compared with blueberries and cranberries. Future research should further characterize their efficacy, optimal dosages, and mechanisms of action, including the roles of microbial metabolites, to fully understand their cardiovascular potential.

2.2 Grape

While many studies have reported vascular benefits from grape (poly)phenol consumption, the effects vary depending on factors such as (poly)phenol type, dosage, and delivery method (whole food vs. extract), as well as the population studied. Notably, a range of FMD improvements has been observed across various grape (poly)phenol interventions.^63,75,142 Several studies have examined the impact of grape-derived products, such as grape juice, red wine and grape seed extract (GSE), with results showing FMD increases ranging between 0.8% and 8% over periods of 1 to 8 weeks. However, comparing these findings across studies reveals significant variation, not attributable to a clear dose–response relationship, but rather to differences in intervention duration, food matrix, and population characteristics. For example, moderate grape juice consumption (∼400–600 mL day⁻¹) as calculated for a 70 kg individual, was associated with FMD improvements of 1–2% over 1 to 2 weeks in at-risk populations, such as CAD patients and smokers.^63,68 These modest improvements suggest that even moderate (poly)phenol consumption may exert beneficial effects on endothelial function, though variability between studies remains. For instance, substantial FMD increases of up to 8% in adolescents with metabolic syndrome were observed after a month of consuming a higher dose of grape juice (∼1260 mL day⁻¹).⁶⁴ However, the lack of a control group in this study limits the validity of the findings. Moreover, the absence of specific (poly)phenol composition data in the studies of Hashemi and Chou^64,68 further weakens the ability to draw concrete conclusions about the mechanisms driving FMD enhancements. Siasos and colleagues further elucidate this, noting that consumption of 490 ml concord grape juice (965 mg TPC) over 2 weeks, led to significant improvements in FMD (1.14%, p < 0.05) in addition to mitigating the transient decline post smoking. However, no change in plasma lipids or glucose levels were observed and circulating metabolites were unmeasured, raising questions about the direct impact of (poly)phenols.

Grape-derived products including wine have also demonstrated promising modulation of endothelial function, as measured by FMD.⁴⁰ For instance, acute intake of red wine (0.8 g ethanol per kg body weight) significantly improved brachial artery FMD (1.6%, p < 0.01) in healthy men, 120 minutes post consumption.⁶⁹ Nonetheless, consumption of alcohol-free red wine yielded a similar response at 120 minutes (1.8%, p < 0.01) in addition to substantial improvement at 30 min (4.8%, p < 0.01),⁶⁹ indicating that endothelial benefits are largely independent of alcohol and can be attributed primarily to wine-derived (poly)phenols, although it could be hypothesised that the (poly)phenols present in the alcoholised red wine mitigated the transient decline in FMD% as demonstrated with comparison of alcohol (Japanese vodka) intake (2.0%, p < 0.05) 30 minutes post-intervention.⁶⁹ In support of this, one study⁶⁷ noted that the acute detrimental effects of smoking on FMD were mitigated by consumption of both red wine and dealcoholized red wine (250 mL), maintaining FMD close to baseline levels, with the dealcoholized red wine appearing to have somewhat of a stronger effect,⁶⁷ further supporting a protective role of wine/grape-derived (poly)phenols independent of alcohol. Hampton and colleagues⁶⁵ further explored this alcohol-independent benefit by demonstrating comparable increases in postprandial FMD following consumption of a meal and intake of a grape juice beverage (122.5 mL) with and without alcohol (12% v/v, 21 g alcohol). Both drinks significantly increased FMD compared to water, confirming that the beneficial endothelial response is driven primarily by the grape components opposed to alcohol. Additionally, significant improvements in FMD were demonstrated in hypercholesterolemic individuals after daily consumption of either red wine (250 mL day⁻¹) or grape juice (500 mL day⁻¹) for 14 days, significantly (p < 0.05) increasing FMD by 5.5% and 6.8% respectively. Interestingly, red wine also enhanced endothelium-independent vasodilation significantly (7% p < 0.01), an effect not observed with grape juice, suggesting a possible additional vasodilatory mechanism attributable to red wine's alcohol content. Importantly, neither improvement occurred with significant changes in plasma lipids or platelet function, indicating a different mechanism of action. Nonetheless, the evidence suggests that red wine has potential for improving vascular function as measured by FMD. However, it is important to note the current evidence examining wine and FMD do not provide the (poly)phenol composition of the interventions or the corresponding plasma concentrations of circulating metabolites, limiting the ability to establish an association.

Studies investigating (poly)phenol extracts and FMD, generally report more consistent findings with increases typically ranging from 2–5%. For example, a 1.1% (p < 0.05) improvement in FMD was found after 4 weeks of supplementation with 2 g day⁻¹ of GSE (1 g of polyphenols) in subjects with elevated vascular risk.⁸¹ Additionally, Barona and colleagues reported significant improvements in FMD (approximately 1.7%) following daily supplementation (1 month) with 46 g grape powder extract (266 mg TPC) in subjects with metabolic syndrome. Additionally, a decreased systolic blood pressure correlated with a reduction in inflammatory markers (sVCAM-1) and increased plasma NO metabolites was observed, highlighting anti-inflammatory effects and increased NO bioavailability as potential mechanisms.⁷⁶ Supporting this, significant improvements in FMD (2.14%, p < 0.01) were observed following daily intake of 400 mg red grape cell powder over 12 weeks in prehypertensive and mildly hypertensive subjects. Moreover, the researchers noted improvement of plasma lipids although these did not reach significance.⁷⁴ In contrast, Greyling and colleagues reported no statistically significant differences in blood pressure or FMD following eight weeks of high-dose grape and wine polyphenol supplementation (800 mg total polyphenols daily) in hypertensive patients already on antihypertensive medication.⁷³ This suggests that the vascular efficacy of grape-derived polyphenols may be attenuated or masked by pharmacological intervention, emphasizing the necessity for further investigation into interactions between dietary polyphenols and existing medication regimens. Additional reports, also founds no significant improvement in brachial artery FMD with a muscadine grape seed supplement (83.98 mg TPC) in individuals at high cardiovascular risk, although a significant increase in resting brachial artery diameter was observed suggesting some level of vascular improvement.⁷⁷

Although the consumption of grape-derived (poly)phenols consistently improves FMD across multiple studies, whole foods, such as grape juice, appear to have quite a high degree of variability in response, although this appears to more prevalent in grape juice studies as studies on wine show some degree of endothelial improvement across all studies, whether it is improving FMD or mitigating a transient decline. However, it must be noted that the removal of alcohol from these interventions, appears to offer more pronounced effect size likely mediated by the phenolics. In contrast, extracts appear to provide more consistent results, partly because of lack of interacting food components but also the length of the studies allowing sufficient exposure time for the phenolics and their metabolites to have an effect. However, the optimal (poly)phenol dosage to maximize FMD improvements without eliciting a plateau effect remains an area that requires further investigation. Additionally, it is important to note that GSE has a distinct (poly)phenol composition compared to whole grapes or grape juice. While GSE is primarily composed of proanthocyanidins, whole grapes particularly red or purple varieties which contain anthocyanins alongside a broader range of (poly)phenols. These compositional differences may influence their respective vascular effects and mechanisms of action. Moreover, the lack of detailed data on circulating (poly)phenol metabolites presents a significant limitation in our understanding of how these compounds exert their cardiovascular benefits. Therefore, future research should focus on optimizing (poly)phenol bioavailability, understanding long-term effects, and refining dosage recommendations to ensure maximum cardiovascular benefits.

2.3 Citrus fruits

Citrus fruits contain significant levels of (poly)phenols, primarily flavanones such as hesperidin and narirutin. Although research in this area is limited, several studies have reported potential benefits with respect to endothelial function including effects on FMD.^82–90 For instance, daily consumption (500 ml) of red orange juice (ROJ) over one week significantly improved FMD from 5.7% ± 1.2% to 7.9% ± 1.4% (p < 0.001) in subjects at risk for CVD. This improvement was accompanied by reductions in inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6).⁸⁵ Similarly, two weeks of blood orange juice (BOJ) consumption led to significant FMD improvements in overweight and obese individuals, with an increase from 8.15% ± 2.92% to 10.2% ± 3.31%.⁸² Interestingly, flavanone-rich citrus (orange) beverages were found to mitigate (3.6%) the postprandial decline in endothelial function following a high-fat meal.⁸⁷ Collectively these results suggest a strong mechanistic role of citrus (poly)phenols including hesperidin and narirutin in modulating endothelial function by increasing NO bioavailability and reducing inflammation.^82,85,87 However, a null effect observed by Constans and colleagues following a longer 4-week intervention of BOJ in subjects with mild hypercholesterolaemia raises questions about sustained benefits.⁸³ This contrast may be owed to differences in the health status of the study population. However, the baseline FMD was lower in the aforementioned study (1.1% vs. 5.7% and 8.15%) thus a comparable effect would be expected as the composition and dosages of interventions were somewhat comparable,^82,83,85,87 warranting further longer-term studies to elucidate these findings.

Interestingly, daily supplementation (1000 mg day⁻¹) of lemon and sour orange peel extracts, found notable FMD improvements (5.50 ± 2.12 to 11.99 ± 4.05 and 5.55 ± 2.17 to 12.79 ± 5.47 respectively) after four weeks.⁸⁹ The substantially higher FMD increases observed in this study, compared to juice-based interventions, suggest that peel extracts may provide enhanced vascular benefits however the lack of (poly)phenol composition or metabolomics make it difficult to substantiate. Additionally, daily hesperidin (500 mg) consumption across 3 weeks, was also found to significantly increase FMD in individuals with metabolic syndrome, from 7.78% ± 0.76% to 10.26% ± 1.19% (p = 0.02). The study also reported significant reductions in inflammatory biomarkers, such as CRP and serum amyloid A (SAA), which supports the earlier hypothesis that hesperidin's cardiovascular benefits are mediated by both enhanced NO bioavailability and anti-inflammatory effects.⁹⁰ Moreover, in vitro studies demonstrate that hesperitin—a metabolite of hesperidin—stimulates NO production through endothelial nitric oxide synthase (eNOS) activation, further highlighting the mechanistic pathway by which hesperidin enhances vasodilation and improves endothelial function. These results are significant as they provide both in vivo and mechanistic evidence of the role that hesperidin and its metabolites play in vascular health. While these studies strongly support the vascular benefits of citrus (poly)phenols, some research highlights the importance of the food matrix and dosage in determining their efficacy. Purified compounds or peel extracts, as previously mentioned may provide a more concentrated and bioavailable source of (poly)phenols than juices, leading to greater improvements in FMD. This distinction between different food matrices raises important questions about how best to deliver citrus (poly)phenols for optimal cardiovascular benefits.

2.4 Cocoa/dark chocolate

The cardiovascular benefits of cocoa (poly)phenols, particularly flavan-3-ols such as epicatechin and catechin, are known to improve NO bioavailability, mitigate oxidative stress, and reduce inflammation; all of which contribute to improved vascular health. Increasing studies have emphasized the potential and limitations of cocoa interventions in various populations. Heiss and colleagues provided early evidence¹¹⁰ of these effects in healthy smokers, reporting a significant increase (2.7%, p < 0.05) in FMD following acute consumption of a high-flavan-3-ol cocoa drink (306 mg total flavan-3-ols), compared to a 0.9% decrease in the low-flavan-3-ol control. This is further supported by a follow-up study¹⁰⁶ involving an acute intervention of 100 ml high-flavan-3-ol cocoa (185 mg total flavan-3-ols) which improved FMD by 2.4%, thus confirming previous findings. Furthermore, sustained improvements were observed following daily supplementation of 300 ml for one week, with a plateau (2.7%, p < 0.05) observed on the fifth day. These findings reinforce the role of both acute and chronic cocoa flavan-3-ol intake in modulating vascular function, particularly in individuals with elevated endothelial dysfunction risk, though the transient nature of peak effects suggests potential adaptation over time (Fig. 5). Interestingly, research has indicated that cocoa flavan-3-ols may offer greater effects in individuals with pre-existing endothelial dysfunction (Fig. 6). For instance, daily consumption of flavan-3-ol-rich dark chocolate (∼800 mg total (poly)phenols) in patients with peripheral artery disease significantly improved FMD by 4.0% (p < 0.001). This improvement was accompanied by reductions in oxidative stress markers, including a 37% decrease in sNOX2-dp, a key marker of NADPH oxidase activity. Concurrently, NO bioavailability increased by 57%, as indicated by elevated serum nitrite/nitrate (NOx) levels. These biochemical changes correlated with endothelial function improvements, as evidenced by reductions in vascular adhesion molecule-1 and sE-selectin levels. Notably, the in vitro findings align with these results, showing that human umbilical vein endothelial cells (HUVEC) treated with cocoa-derived (poly)phenols (including epicatechin, catechin and epigallocatechin-3-gallate) exhibited increased NO production and reduced expression of adhesion molecules, including E-selectin and VCAM-1. These findings reinforce the role of cocoa flavan-3-ols in modulating endothelial function through oxidative stress reduction and enhanced NO signalling.⁹⁵

Fig. 4 Acute and chronic changes in flow-mediated dilation (ΔFMD%) among in response to various controls. Data presented as Mean ± SD.

Fig. 5 Acute and chronic time-dependent changes in flow-mediated dilation (ΔFMD%) in response to extracts (left panels) and whole foods (right panels).

Fig. 6 Effect of polyphenol-rich foods and extracts on flow-mediated dilation (ΔFMD%) following chronic and acute interventions across different health statuses and polyphenol-rich food groups. (Left panels) Mean ± SEM change in FMD (%) following acute and chronic polyphenol intervention across different health statuses. (Right panels) Mean ΔFMD% for each polyphenol-rich food group, calculated from relevant studies within each category for acute and chronic interventions.

In contrast, the Flaviola Health Study¹¹³ further explored the vascular impact of cocoa flavan-3-ol supplementation in healthy adults, reporting a modest acute FMD improvement of 0.7% after a single dose of a cocoa flavan-3-ol-rich drink (450 mg total flavan-3-ols, 64 mg epicatechin). This is likely attributable to the cohorts’ lack of endothelial dysfunction or potential variations in dosage. Nonetheless, chronic supplementation over four weeks induced a 1.2% increase in FMD (p < 0.05), aligning with earlier reports,^105,111 which observed between 1.0–1.3% increases in FMD following consumption of high-flavan-3-ol chocolate and cocoa supplementation for 2–4 weeks respectively. Faridi and colleagues⁹⁷ expanded on these findings by evaluating cocoa-based interventions in overweight individuals, revealing that solid dark chocolate (3282 mg total (poly)phenols) increased FMD by 4.3%, while sugar-free cocoa resulted in a 5.7% improvement. The addition of sugar mitigated the response to 2.0%. Moreover, Rodriguez-Mateos's research group highlighted the importance of the degree of polymerisation (DP) of cocoa flavan-3-ols, demonstrating that lower-degree polymerized flavan-3-ols (DP1–10) yielded a more substantial endothelial function improvement (1.7% vs. −0.2%), in contrast to higher polymerized fractions (DP2–10).¹¹² Together, these observations emphasize the importance of flavan-3-ol composition and formulation, as well as dietary context, in optimizing cocoa's vascular benefits, indicating that both whole-food products and refined cocoa extracts can serve as effective interventions for enhancing vascular health.

Additionally, cocoa (poly)phenols, particularly their metabolites, have been shown to modulate the production of reactive oxygen species (ROS) through activation of AKT/AMPK/eNOS pathways.³⁸ This activation may mitigate NO loss from oxidative stress and protect endothelial cells from damage contributing to the long-term improvement of vascular function. Moreover, the anti-inflammatory effects of cocoa (poly)phenols, demonstrated by their ability to lower CRP and IL-6 levels, further support their role in preventing the progression of endothelial dysfunction and atherosclerosis.¹⁴⁹ These mechanisms, combined with theobromine potential to enhance NO production and inhibit phosphodiesterase activity, suggest that the cardiovascular benefits og cocoa are multifactorial and extend beyond the simple enhancement of NO bioavailability.¹⁵⁰ Notably, evidence from Sansone and colleagues demonstrated that co-administration of cocoa flavan-3-ols with methylxanthines significantly enhanced FMD responses compared to flavan-3-ols alone (2.5% vs. 1.4%, p < 0.05). This effect was associated with an increased plasma concentration of epicatechin metabolites, suggesting that methylxanthines enhance flavan-3-ol bioavailability, leading to greater improvements in endothelial function. These findings underscore the complex interactions between cocoa flavan-3-ols and methylxanthines, highlighting the importance of considering the full cocoa matrix when evaluating its vascular effects.¹⁵¹

To summarise, cocoa (poly)phenols, particularly flavan-3-ols such as epicatechin, offer significant potential for improving endothelial function, as evidenced by the robust increases in FMD observed across multiple studies. The dose-dependent nature of these effects, as well as the influence of food matrices and the correlation between circulating metabolites and FMD, underscores the complexity of cocoa's impact on vascular health. While NO bioavailability remains a central mechanism, the antioxidant and anti-inflammatory properties of cocoa (poly)phenols are equally important in contributing to their cardiovascular benefits. Future research should focus on optimizing the delivery and establishing dosages and dietary recommendation of cocoa (poly)phenols to maximize their therapeutic potential, particularly in populations at high-risk for endothelial dysfunction.

2.5 Caffeinated and decaffeinated coffee

Coffee, one of the most widely consumed beverages globally, contains bioactive compounds such as caffeine, and chlorogenic acids (CGAs), all of which have been linked to effects on cardiometabolic health. The impact of coffee consumption on endothelial function, has been extensively investigated, though the findings remain ambiguous. The variability in results likely arises from factors such as coffee type (ground, instant, espresso), caffeine content, (poly)phenol concentration, and individual tolerances. In particular, studies comparing caffeinated coffee (CC) and decaffeinated coffee (DC) have revealed conflicting results. While some studies suggest that DC yields a more favourable response in terms of FMD, CC has been associated with detrimental or static effects, likely due to caffeine's influence on endothelial function.

Early reports examined the acute effects of caffeinated and decaffeinated instant coffee on FMD in healthy subjects, finding CC (80 mg caffeine) significantly reduced FMD from 7.78% to 2.12% at 60 minutes post-ingestion (p < 0.001), indicating acute endothelial impairment.¹²¹ Similarly, a study investigating the acute consumption of caffeinated espresso (130 mg caffeine) reported a reduction in FMD from 7.7% to 6.0% (p < 0.001).¹¹⁹ Interestingly, in both studies, DC had a more favourable outcome. Caffeine increases sympathetic nervous system activity, elevating circulating adrenaline and noradrenaline levels,^152–155 leading to increased vascular tone and peripheral vasoconstriction.^154–157 This acute vasoconstriction reduces arterial responsiveness, reflected as impaired FMD. Thus, the initial endothelial dysfunction observed following caffeinated coffee intake is potentially driven by caffeine-induced vasoconstrictive effects rather than (poly)phenol content. In the study by Papamichael and colleagues, the reduction in FMD for DC was smaller (7.07% to 5.20%) and non-significant, while Buscemi's research group noted a modest improvement in FMD (6.9% to 8.5%) with DC, though this did not reach statistical significance. However, when investigating dose-dependent effects in earlier research, they found that FMD improved significantly following the consumption of 1 cup (6.9% to 8.5%) and 2 cups (7.4% to 10.8%, p < 0.001) of DC, likely due to its higher (poly)phenol and lower caffeine content compared to instant coffee.¹²⁰ These findings suggest that caffeine may acutely impair endothelial function (Fig. 5), while DC, with its lower caffeine content and higher (poly)phenol concentration, may offer protective benefits. Decaffeinated coffee's (poly)phenol profile and the potential endothelial improvements may be impacted by the decaffeination method used.¹⁵⁸ Processes such as the Swiss Water Process, solvent-based chemical decaffeination, and carbon dioxide extraction differ substantially in their efficiency at retaining chlorogenic acids and other bioactive (poly)phenols^158,159 potentially altering decaffeinated coffee's vascular benefits. Consequently, the specific decaffeination method may critically influence the cardiovascular outcomes associated with decaffeinated coffee consumption. However, as highlighted by Boon and colleagues the variability in responses may be influenced by other factors such as brewing method, frequency of consumption/individual tolerances, and baseline endothelial health.¹¹⁶ Additives commonly consumed with coffee, such as milk and sugar, significantly modulate its cardiovascular effects. For instance, the inclusion of sugars can negatively impact endothelial function through increased oxidative stress and impaired glycaemic control, potentially counteracting the benefits of coffee (poly)phenols.¹⁶⁰ Milk proteins can form complexes with various (poly)phenols including chlorogenic acids, potentially reducing their bioavailability and subsequent endothelial benefits.^161,162 Evidence suggests milk protein-(poly)phenol complexes may decrease antioxidant capacity, thus attenuating (poly)phenol-driven improvements in FMD.^163–165 Moreover, the type of coffee was also found to influence FMD in a study investigating the consumption of boiled Greek coffee in comparison other types of coffee, noting a linear increase in FMD (4.33% to 6.47%, p = 0.032) with increased coffee consumption but interestingly a higher FMD (5.26% vs. 3.65%, p = 0.035) was found with higher intake of boiled Greek coffee compared to other coffees respectively.¹⁶⁶ Therefore, both the choice of coffee type and consumption patterns regarding additives are crucial considerations when evaluating coffee's overall vascular impact (Fig. 4).

Further research explored the time-dependent FMD response to high-(poly)phenol coffee (HPC) and low-(poly)phenol coffee (LPC) finding a significant biphasic FMD increase at 1 hour for both LPC (1.10%, p < 0.05) and HPC (1.34%, p < 0.05). At 5 hours, only HPC showed sustained improvement (1.52%, p < 0.0001),¹¹⁵ highlighting the importance of (poly)phenol content in maintaining persistent vascular improvements. The researchers further explored the acute effects of varying doses of CGA metabolites, specifically 5-caffeoylquinic acid (5-CQA) on FMD, finding that a 450 mg dose of 5-CQA increased FMD from 6.02% to 6.77% at 1-hour post-ingestion, nearing statistical significance (p = 0.06).¹¹⁵ These results suggest that while caffeine may induce short-term reductions in FMD, the (poly)phenol content, particularly CGAs, can mitigate these effects and even improve endothelial function over time. This is supported by earlier research which demonstrated improvements in continuous FMD response following doses of 450 mg (0.47%, p = 0.016) and 900 mg (0.65%, p < 0.001) of 5-CGA, with the higher dose showing sustained benefits up to 4 hours post-ingestion.¹¹⁷ Furthermore, consumption of 600 mg of CGAs before a high-calorie meal was found to mitigate the postprandial decline in FMD, preserving endothelial function at 6 hours (5.6% vs. 4.0%, p < 0.05) compared to placebo.¹¹⁸ However, not all studies align with these findings. In fact, caffeinated coffee (270 mg caffeine, 95 mg 5-CGA) was found to have significantly higher continuous FMD response (4.081%, p < 0.001) compared to DC (132 mg 5-CGA) and control,¹¹⁶ emphasizing the need to consider individual variation and other external factors that may affect FMD response to coffee consumption. Individual differences in response to coffee consumption, especially concerning caffeine, are influenced by genetic variability, notably polymorphisms in genes encoding cytochrome P450 enzymes such as CYP1A2.^167–170 Individuals with fast caffeine metabolism (homozygous CYP1A21A alleles) generally experience fewer negative cardiovascular effects from caffeine,¹⁷¹ whereas those with slow metabolism (carrying the CYP1A21F allele) may show heightened sensitivity to caffeine-induced vasoconstriction and endothelial impairment.^171,172 These genetic variations highlight the complexity of assessing coffee's cardiovascular effects across populations, underscoring the necessity of personalized nutritional recommendations. These findings underscore the potential of CGA extracts to improve endothelial function through their antioxidant and NO-mediated mechanisms, offering more predictable benefits than whole coffee (Fig. 2).

2.6 Black and Green tea

Tea is another commonly consumed beverage globally and represents approximately 35–40% of dietary (poly)phenol intake in certain populations, contributing significantly to the reduction of cardiovascular disease risk and improvements in vascular health through its bioactive compounds.^39,173,174 For instance, daily consumption of black tea (450 ml) significantly improved FMD in patients with CAD, increasing from 5.2% ± 0.7% to 9.4% ± 1.0% immediately after consumption (p < 0.001), with further gains to 10.7% ± 1.2% after four weeks.¹²⁹ These sustained benefits were attributed to enhanced NO bioavailability, mediated in part by the catechins in black tea, which upregulate antioxidative pathways, reducing reactive oxygen species (ROS) and protecting NO from degradation. In comparison, studies investigating green tea have shown more variable effects, ranging from significant improvements in FMD (2.3% ± 0.4%, p < 0.01), concurrent with reductions in oxidative stress among hypertensive patients consuming five cups of green tea daily for eight weeks,¹³⁰ to no significant change in FMD following short-term green tea consumption in healthy participants.¹³⁵ Black tea and green tea differ substantially in their (poly)phenolic composition, notably regarding catechins. Green tea predominantly contains unoxidised catechins such as epigallocatechin gallate (EGCG), epicatechin gallate, epigallocatechin, and epicatechin.^175,176 Conversely, black tea undergoes enzymatic oxidation, converting catechins into polymerized forms like theaflavins and thearubigins, significantly altering their bioavailability and their putative bioactivity.^177–180 Interestingly, one study that demonstrated beneficial improvements in FMD (4% ± 1%, p < 0.05) following consumption of black tea, also noted that the addition of milk nullified this benefit, likely due to milk proteins binding to tea catechins and reducing their bioavailability.¹³¹ This suggests that black tea, consumed without milk, may be more effective in promoting endothelial health. The importance of bioavailability was further highlighted in a study observing that higher plasma concentrations of catechins were associated with greater FMD improvements.⁴² Participants consuming five cups of green tea daily for one week had plasma levels of 90 nmol L⁻¹ for epicatechin and 180 nmol L⁻¹ for catechin, correlating with an increase in FMD from 6.3% ± 0.7% to 7.9% ± 0.9% (p < 0.05),⁴² underscoring the importance of catechin absorption and individual metabolic differences in determining vascular outcomes.

Studies comparing populations with compromised versus healthy endothelial function highlight notable differences in FMD responses to tea (poly)phenols.¹⁸¹ showed that black tea consumption significantly increased FMD from 8.3% ± 1.5% to 14.0% ± 2.0% (p < 0.05) in renal transplant recipients, a population with compromised endothelial function, suggesting that tea (poly)phenols may provide greater benefits to individuals with existing cardiovascular or endothelial impairments. Similarly, Grassi and colleagues found significant improvements in hypertensive patients,¹³⁰ while studies on healthy individuals,^{131–133,135} have often reported less pronounced or transient effects, and may arise due to a potential ‘ceiling effect’, limiting the magnitude of measurable FMD improvements following (poly)phenol consumption. This may indicate that (poly)phenols beneficial vascular effects are more pronounced in individuals with baseline endothelial impairment, however a recent meta-analysis comparing n = 26 studies investigating flavan-3-ols found a linear increase in chronic ΔFMD% response with increasing baseline FMD, indicating that those with a lower baseline FMD may have a diminished effect, which may be resultant of a compromised endothelial cellular function.¹⁸²

In summary, both black and green tea have demonstrated their capacity to improve endothelial function.^174,183,184 However, the bioavailability of catechins, influenced by factors such as milk addition and individual metabolic differences, plays a crucial role in determining the efficacy of tea (poly)phenols. Populations with compromised endothelial function appear to experience greater benefits from tea consumption, suggesting that regular intake may be effective in reducing cardiovascular risk among individuals with existing vascular impairments. However, the recent evidence from Lagou and colleagues suggests that it may be the opposite of this and warrants further investigation.

3. Relationship between circulating metabolites and FMD

(Poly)phenols exert their beneficial effects on cardiovascular health primarily through the action of their circulating metabolites, which modulate endothelial function and FMD.^185,186 These metabolites, including phase II conjugates such as ferulic acid, vanillic acid, homovanillic acid, play a critical role by reducing oxidative stress, modulating inflammation, and enhancing NO bioavailability.^187–189 One of the key mechanisms by which these metabolites function is through their modulation of redox-sensitive cell signalling pathways, particularly those regulating endothelial NO production.^12,15,190 This action prevents the degradation of NO, ensuring its availability for cell signalling and vasodilation.^9,191,192 Moreover, these metabolites have also been shown to upregulate eNOS through activation of the PI3K/Akt and AMPK/SIRT1 signalling pathways, which enhance eNOS phosphorylation, transcription, and enzymatic stability,^190,193,194 further increasing NO bioavailability.

Cranberries, blueberries, and other berries are particularly rich in anthocyanins and ellagitannins. However, their cardiovascular benefits are primarily mediated through the action of their metabolites. Cranberry-derived metabolites, such as cinnamic acid-4′-glucuronide and 3′-hydroxycinnamic acid, have been identified as predictors of FMD improvements, suggesting that the vascular benefits of (poly)phenol-rich foods are closely tied to bioavailability and metabolite profiles. These metabolites support NO bioavailability and reduce oxidative stress, contributing to improvements in FMD within the range of 1% to 3%. Similarly, after consuming blueberries, phenolic metabolites such as vanillic acid (30–40 nmol L⁻¹) and homovanillic acid (40–50 nmol L⁻¹) have been linked to FMD improvements ranging from 2% to 4%.^46,57,195 Additionally, microbial-derived metabolites including urolithins, also play a significant role. Urolithins are produced from the breakdown of ellagitannins by the gut microbiota and have been shown to enhance FMD by regulating the Nrf2 pathway.¹⁹⁶ This pathway activates antioxidant genes such as heme-oxygenase-1 (HO-1), which reduces endothelial oxidative stress. Although urolithins do not directly impact NO bioavailability, their strong antioxidant properties contribute to improvements in vascular function.⁵² The extent of these benefits can vary due to differences in gut microbiota composition among individuals, affecting the metabolism and circulation of (poly)phenol-derived metabolites.^186,196 Together, the metabolites from berries and the microbial-derived urolithins highlight the complexity of (poly)phenol metabolism and its role in sustaining vascular health.

Cocoa and tea, rich in flavan-3-ols such as epicatechin and catechins, have also been shown to improve FMD through similar mechanisms.^91,197 Cocoa-derived epicatechin, reaches concentrations of 600–800 nmol L⁻¹ approximately 1–2 hours post consumption, and is associated with FMD improvements in the range of 3% to 5%.^150,182,198 Epicatechin and catechin metabolites enhance NO bioavailability by upregulating endothelial nitric oxide synthase (eNOS) and mitigating oxidative stress through the inhibition of nuclear factor kappa B (NF-κB), a key regulator of inflammation.¹⁸³ These effects are sustained for several hours post-consumption, with cocoa metabolites remaining in the bloodstream reaching peak concentration between 4–6 hours and remaining in the circulation up to 48 h hours post-consumption, contributing to prolonged vascular benefits.^199,200 In tea, catechin metabolites present at 90–180 nmol L⁻¹ after consumption have been associated with FMD improvements of 1.5% to 4%, further supporting the hypothesis that (poly)phenol metabolites from both tea and cocoa enhance NO bioavailability and promote endothelial health.

Coffee, rich in chlorogenic acids, follows a similar pathway. Ferulic acid, a metabolite of chlorogenic acid, reaches concentrations of 0.1–0.15μmol L⁻¹ after consuming chlorogenic acid-enriched coffee. This metabolite is linked to modest FMD improvements in the range of 1% to 3%, attributed to enhanced antioxidant enzyme activity, such as superoxide dismutase (SOD), which reduces oxidative stress and preserves NO bioavailability.¹¹⁵ Similar to other (poly)phenol-rich foods, the impact of coffee on FMD is strongly linked to the bioavailability of its circulating metabolites and the duration of their presence in the bloodstream. The duration and extent of metabolite presence in the bloodstream are critical for optimizing vascular benefits, however, the bioavailability and metabolism of (poly)phenols vary between individuals due to differences in gut microbiota composition, genetic factors, and health status, which can affect circulating levels of active metabolites and the extent of endothelial improvements.^200–203

4. Potential for dietary guidance

(Poly)phenol dietary recommendations for cardiovascular health have gained considerable attention due to their potential role in various metabolic pathways.^{36,147,204,205} However, translating these recommendations into practical dietary guidelines remains challenging due to the natural variability of (poly)phenol content in foods. Factors such as climate, soil conditions, and harvest timing can significantly affect (poly)phenol levels in the same food type.^144,206,207 For instance, wild blueberries contain approximately 487 mg anthocyanins per 100 g in contrast to highbush blueberries (∼130 mg per 100 g). Consequently, consuming 80 g wild blueberries would meet an efficacious dose (∼390 mg anthocyanins), while nearly 200 g of highbush blueberries would be required to achieve similar bioactivity.⁴⁶ Similarly, cocoa (poly)phenol content varies markedly due to cultivation and processing methods, ranging from 50 to 150 mg flavan-3-ols per 100 g in commercial dark chocolate.^150,208 This variability underscores the importance of standardized (poly)phenol measurements to inform accurate dietary guidance. This variability complicates efforts to establish reliable guidelines based on total (poly)phenol content (TPC). Typically, dietary recommendations focus on portion sizes rather than precise nutrient quantities, which complicates ensuring optimal intake for cardiometabolic health.

Interestingly, habitual background (poly)phenol intake may influence the magnitude of cardiovascular benefits observed with supplementation or dietary interventions. Data from the EPIC study²⁰⁹ indicate that individuals in lowest percentile of flavan-3-ol consumption (<100–150 mg day⁻¹), were at higher risk for high BP and CVD Risk. Complimenting this, evidence from the COSMOS study,⁷ suggests that individuals with lower baseline flavanol intake or poorer-quality habitual diets may experience more pronounced improvements in cardiovascular outcomes and biomarkers such as FMD when supplemented with cocoa flavanols. In line with this evidence, the Academy of Nutrition and Dietetics recently recommended a daily flavan-3-ol intake of 400–600 mg,³⁶ which not only aligns with typical dietary flavan-3-ol intakes (200–500 mg day⁻¹)^3,45,210,211 but also with tested dosages of cocoa and tea which elicited responses in FMD studies (Tables 1 & 2). This recommendation is sufficient to attain the associative benefits while remaining below the plateau range (500–100 mg day⁻¹). However dietary guidance for cocoa in particular is complicated, as the typical interventions used in clinical studies such as the COSMOS trial have more highly concentrated (poly)phenol compositions than that of commercially available cocoa and dark chocolate.⁷ In contrast, anthocyanins, and chlorogenic acids, found in foods like berries and coffee respectively, have daily consumption levels generally below the dosages used in clinical intervention studies. For instance, average daily intake of anthocyanins ranges from 10 mg to 50 mg day⁻¹, which is considerably lower than the quantities used in FMD studies (20–400 mg), equivalent 100 g to 300 g which also falls outside the general recommendations for a portion (60–80 g) of berries. Similarly, daily intake levels of hydroxycinnamic acids (up to 231.8 mg day⁻¹), including (poly)phenols such as chlorogenic acids are lower than the typically tested ranges (>300 mg), this is further complicated with variations in coffee consumption patterns, types of coffee used and preparation methods.^3,45,210,211

Fortification or enrichment may provide a practical solution to the variability in (poly)phenol content across natural sources.^147,212 Enriching foods with (poly)phenols can ensure more consistent intake by controlling TPC levels and more importantly specific bioactive phenolics, making it easier to meet the dosages shown to be effective in clinical research.^145,213 Importantly, (poly)phenols have been shown to remain stable during food processing preserving their bioactive properties and health benefits. For example, cereal products enriched with cranberry (poly)phenols maintained their anthocyanin content even after high-temperature processing, ensuring the bioactive compounds remain intact post-manufacture.²¹⁴ Albeit stability does not guarantee that (poly)phenols will maintain their bioavailability as the food matrix may be altered, introducing other food components which may inhibit absorption, such as sugar, fat and proteins thus mitigating any potential benefits. For instance, blueberry buns fortified with (poly)phenols did not impact TPC although did alter the polyphenol composition, decreasing anthocyanins by ∼42% and increasing chlorogenic acid content. This compositional change also impacted the Cmax and AUC of various metabolites. Nonetheless, significant improvements in endothelial function were observed in comparison to non-enriched bun and comparable to the blueberry drink positive control, demonstrating that bioactivity was preserved following processing.⁵⁶ Other studies also confirm (poly)phenol stability during food processing, for instance orange juice enriched with hesperidin, provided greater improvements in endothelial function than regular juice, showing the potential of enrichment in widely consumed beverages.⁸⁶ While coffee fortified with cocoa²¹⁵ and enriched with chlorogenic acid¹¹⁷ were demonstrated to be stable, yielding favourable endothelial modulation. However, implementation of (poly)phenol fortification in public health contexts is constrained by both regulatory and practical considerations.^36,216,217 Regulatory frameworks for functional foods and nutraceuticals vary internationally, often requiring extensive safety and efficacy evaluations before approval.^216,217 Additionally, practical barriers such as the cost of high-purity extracts and consumer acceptability/tolerance of fortified products must be considered to ensure safe and effective applications.^216–219 Addressing these challenges is critical if fortification strategies are to complement dietary diversification as a means of maximising the cardiometabolic benefits of (poly)phenols.

In conclusion, dietary (poly)phenols and (poly)phenol-rich foods beneficially modulate endothelial function as measured by FMD. While the development of dietary recommendations for cardiometabolic health is essential, their implementation is hindered by the lack of confirmed (poly)phenol content of various foods and the intrinsic variability in (poly)phenol content across food sources, making it challenging to establish precise intake guidelines. Whilst the estimated daily intake of (poly)phenols in Western populations can reach approximately 1000–1200 mg day⁻¹,^45,210 exceeding efficacious dosages used in many clinical trial, this intake is largely derived from a limited range of sources, primarily tea, coffee, and cocoa providing specific subclasses such as flavan-3-ols and chlorogenic acids which may also be impaired by other food matrix components such as sugar and milk. Albeit, these compounds have well-established health benefits, yet the lack of diversity restricts exposure to other beneficial compounds including anthocyanins, flavanones etc. which limits potential complementary and/or distinct bioactive effects. Furthermore, these intake estimations rely on dietary self-reporting, which is subject to inaccuracies, and do not account for inter-individual differences in metabolism, absorption, or the influence of other dietary components on (poly)phenol bioavailability or the resulting bioactivity. Critically, evidence consistently suggests that greater (poly)phenol consumption is associated with enhanced health benefits, indicating that current dietary patterns may still be suboptimal. Moreover, if typical dietary sources were sufficient to maximize (poly)phenol-mediated health effects, higher intakes would not correspond with additional benefits. Given this, strategies to enhance (poly)phenol intake through fortification and enrichment technologies warrant further exploration. These approaches may offer a means of increasing overall intake and ensure the consistent delivery of bioactive compounds, however compositional changes present a challenge as the associated bioactivity may be altered or diminished dependant on the degree of the compositional and/or food matrix change and may warrant revaluation if potential nutrition or health claims are to be utilised by industry.

Nonetheless, the establishment of dietary recommendations remains a critical area of research, as it will define effective daily intakes while accounting for the plateau effects observed in many clinical trials. Understanding the thresholds beyond which additional intake does not confer further benefits will aid in optimizing recommendations, ensuring that individuals achieve sufficient (poly)phenol exposure without unnecessary overconsumption. Future research should focus on refining both dietary guidelines and fortification strategies, assessing their long-term efficacy in improving cardiovascular health outcomes.

Author contributions

B. Ó. M and C. I. R. G., were involved in review design. The manuscript was prepared by B. Ó. M., H. R. N., N. M., E. J. R., L. K. P., P. R., C. P., D. G., S. R., L. B., D. D. R., A. R. M., A. C. and C. I. R. G with contributions from all the authors.

Conflicts of interest

The authors report no conflicts of interest.

Data availability

No new data were generated or analysed in this narrative review. All data discussed in this article are derived from previously published studies, which are appropriately cited in the manuscript. As this is a secondary analysis of existing literature, no primary research results, datasets, software, or code have been included.

Acknowledgements

C. I. R. G., B. Ó. M and A. R. M acknowledge the Nutrition Society and the Phytochemicals and Health Special Interest Group (SIG) for supporting research in this field. We also acknowledge colleagues and collaborators for their valuable insights.

References

1. K. Kurakula, V. F. E. D. Smolders, O. Tura-Ceide, J. Wouter Jukema, P. H. A. Quax and M. J. Goumans, Endothelial dysfunction in pulmonary hypertension: Cause or consequence?, MDPI AG, 2021, preprint,  DOI:10.3390/biomedicines9010057.
2. T. Maruhashi, J. Soga, N. Fujimura, N. Idei, S. Mikami, Y. Iwamoto, M. Kajikawa, T. Matsumoto, T. Hidaka, Y. Kihara, K. Chayama, K. Noma, A. Nakashima, C. Goto and Y. Higashi, Nitroglycerine-induced vasodilation for assessment of vascular function: A comparison with flow-mediated vasodilation, Arterioscler., Thromb., Vasc. Biol., 2013, 33, 1401–1408.
3. M. Leenders, H. C. Boshuizen, P. Ferrari, P. D. Siersema, K. Overvad, A. Tjønneland, A. Olsen, M.-C. Boutron-Ruault, L. Dossus, L. Dartois, R. Kaaks, K. Li, H. Boeing, M. M. Bergmann, A. Trichopoulou, P. Lagiou, D. Trichopoulos, D. Palli, V. Krogh, S. Panico, R. Tumino, P. Vineis, P. H. M. Peeters, E. Weiderpass, D. Engeset, T. Braaten, M. L. Redondo, A. Agudo, M.-J. Sánchez, P. Amiano, J.-M. Huerta, E. Ardanaz, I. Drake, E. Sonestedt, I. Johansson, A. Winkvist, K.-T. Khaw, N. J. Wareham, T. J. Key, K. E. Bradbury, M. Johansson, I. Licaj, M. J. Gunter, N. Murphy, E. Riboli and H. B. Bueno-De-Mesquita, Fruit and vegetable intake and cause-specific mortality in the EPIC study, Eur. J. Epidemiol., 2014, 29, 639–652.
4. D. Aune, E. Giovannucci, P. Boffetta, L. T. Fadnes, N. N. Keum, T. Norat, D. C. Greenwood, E. Riboli, L. J. Vatten and S. Tonstad, Fruit and vegetable intake and the risk of cardiovascular disease, total cancer and all-cause mortality-a systematic review and dose-response meta-analysis of prospective studies, Int. J. Epidemiol., 2017, 46, 1029–1056.
5. D. Del Rio, A. Rodriguez-Mateos, J. P. E. Spencer, M. Tognolini, G. Borges and A. Crozier, Dietary (poly)phenolics in human health: Structures, bioavailability, and evidence of protective effects against chronic diseases, 2013, preprint,  DOI:10.1089/ars.2012.4581.
6. A. Micek, J. Godos, D. Del Rio, F. Galvano and G. Grosso, Dietary Flavonoids and Cardiovascular Disease: A Comprehensive Dose-Response Meta-Analysis, Mol. Nutr. Food Res., 2021, 65, e2001019.
7. H. D. Sesso, J. E. Manson, A. K. Aragaki, P. M. Rist, L. G. Johnson, G. Friedenberg, T. Copeland, A. Clar, S. Mora, M. V. Moorthy, A. Sarkissian, W. R. Carrick and G. L. Anderson, Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial, Am. J. Clin. Nutr., 2022, 115, 1490–1500.
8. R. P. Brandes, Endothelial dysfunction and hypertension, Hypertension, 2014, 64, 924–928.
9. D. J. Medina-Leyte, O. Zepeda-García, M. Domínguez-Pérez, A. González-Garrido, T. Villarreal-Molina and L. Jacobo-Albavera, Endothelial dysfunction, inflammation and coronary artery disease: Potential biomarkers and promising therapeutical approaches, MDPI AG, 2021, preprint,  DOI:10.3390/ijms22083850.
10. J. Loader, C. Khouri, F. Taylor, S. Stewart, C. Lorenzen, J. L. Cracowski, G. Walther and M. Roustit, The continuums of impairment in vascular reactivity across the spectrum of cardiometabolic health: A systematic review and network meta-analysis, Blackwell Publishing Ltd, 2019, preprint,  DOI:10.1111/obr.12831.
11. C. C. Tangney and H. E. Rasmussen, Polyphenols, inflammation, and cardiovascular disease, Curr. Atheroscler. Rep., 2013, 15, 324.
12. C. Andreas Daiber or T. Münzel, A. Daiber, S. Steven, A. Weber, V. V. Shuvaev, V. R. Muzykantov, I. Laher, H. Li, S. Lamas and T. Münzel, Themed Section: Redox Biology and Oxidative Stress in Health and Disease,  DOI:10.1111/bph.v174.12/issuetoc.
13. D. Miricescu, A. Totan, C. Stefani, I. I. Stanescu, M. Imre, A. M. A. Stanescu, R. Radulescu, D. Balan, A. E. Balcangiu-Stroescu and M. Greabu, Hyperuricemia, endothelial dysfunction and hypertension, Rom. J. Med. Pract., 2020, 15, 178–182.
14. R. P. Brandes, Endothelial dysfunction and hypertension, Hypertension, 2014, 64, 924–928.
15. C. Heiss, A. Rodriguez-Mateos and M. Kelm, Central Role of eNOS in the Maintenance of Endothelial Homeostasis, Mary Ann Liebert Inc., 2015, preprint,  DOI:10.1089/ars.2014.6158.
16. G. Serreli and M. Deiana, Role of Dietary Polyphenols in the Activity and Expression of Nitric Oxide Synthases: A Review, MDPI, 2023, preprint,  DOI:10.3390/antiox12010147.
17. M. Otręba, L. Kośmider, J. Stojko and A. Rzepecka-Stojko, Cardioprotective activity of selected polyphenols based on epithelial and aortic cell lines. A review, MDPI, 2020, preprint,  DOI:10.3390/molecules25225343.
18. I. Mozos, C. Flangea, D. C. Vlad, C. Gug, C. Mozos, D. Stoian, C. T. Luca, J. O. Horbańczuk, O. K. Horbańczuk and A. G. Atanasov, Effects of anthocyanins on vascular health, MDPI AG, 2021, preprint,  DOI:10.3390/biom11060811.
19. Z. Ungvari, Z. Bagi, A. Feher, F. A. Recchia, W. E. Sonntag, K. Pearson, R. De Cabo and A. Csiszar, Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2, Am. J. Physiol.: Heart Circ. Physiol., 2010, 299, H18–H24.
20. M. Edwards, C. Czank, G. M. Woodward, A. Cassidy and C. D. Kay, Phenolic metabolites of anthocyanins modulate mechanisms of endothelial function, J. Agric. Food Chem., 2015, 63, 2423–2431.
21. J. Festa, A. Hussain, Z. Al-Hareth, S. J. Bailey, H. Singh and M. Da Boit, Phenolic Metabolites Protocatechuic Acid and Vanillic Acid Improve Nitric Oxide Bioavailability via the Akt-eNOS Pathway in Response to TNF-α Induced Oxidative Stress and Inflammation in Endothelial Cells, Metabolites, 2024, 14, 613.
22. E. F. Warner, Q. Zhang, K. Saki Raheem, D. O. Hagan, M. A. O'Connell and C. D. Kay, Common phenolic metabolites of flavonoids, but not their unmetabolized precursors, reduce the secretion of vascular cellular adhesion molecules by human endothelial cells, J. Nutr., 2016, 146, 465–473.
23. T. Behl, S. Bungau, K. Kumar, G. Zengin, F. Khan, A. Kumar, R. Kaur, T. Venkatachalam, D. M. Tit, C. M. Vesa, G. Barsan and D. E. Mosteanu, Pleotropic Effects of Polyphenols in Cardiovascular System, Elsevier Masson s.r.l., 2020. preprint,  DOI:10.1016/j.biopha.2020.110714.
24. A. Tanghe, E. Heyman, E. Lespagnol, J. Stautemas, B. Celie, J. O. ‘t Roodt, E. Rietzschel, D. D. Soares, N. Hermans, E. Tuenter, S. Shadid and P. Calders, Acute Effects of Cocoa Flavanols on Blood Pressure and Peripheral Vascular Reactivity in Type 2 Diabetes Mellitus and Essential Hypertension, Nutrients, 2022, 14, 2692.
25. M. H. Oak, C. Auger, E. Belcastro, S. H. Park, H. H. Lee and V. B. Schini-Kerth, Potential mechanisms underlying cardiovascular protection by polyphenols: Role of the endothelium, Elsevier Inc., 2018. preprint,  DOI:10.1016/j.freeradbiomed.2018.03.018.
26. T. Schewe, Y. Steffen and H. Sies, How do dietary flavanols improve vascular function? A position paper, 2008, preprint,  DOI:10.1016/j.abb.2008.03.004.
27. C. Di Lorenzo, F. Colombo, S. Biella, C. Stockley and P. Restani, Polyphenols and Human Health: The Role of Bioavailability, Nutrients, 2021, 13, 273.
28. M. C. Corretti, T. J. Anderson, E. J. Benjamin, D. Celermajer, F. Charbonneau, M. A. Creager, J. Deanfield, H. Drexler, M. Gerhard-Herman, D. Herrington, P. Vallance, J. Vita and R. Vogel, Guidelines for the Ultrasound Assessment of Endothelial-Dependent Flow-Mediated Vasodilation of the Brachial Artery A Report of the International Brachial Artery Reactivity Task Force, 2002.
29. T. Maruhashi, J. Soga, N. Fujimura, N. Idei, S. Mikami, Y. Iwamoto, M. Kajikawa, T. Matsumoto, T. Hidaka, Y. Kihara, K. Chayama, K. Noma, A. Nakashima, C. Goto, H. Tomiyama, B. Takase, A. Yamashina and Y. Higashi, Relationship between flow-mediated vasodilation and cardiovascular risk factors in a large community-based study, Heart, 2013, 99, 1837–1842.
30. C. Heiss, A. Rodriguez-Mateos, M. Bapir, S. S. Skene, H. Sies and M. Kelm, Flow-mediated dilation reference values for evaluation of endothelial function and cardiovascular health, Cardiovasc. Res., 2023, 119, 283–293.
31. R. T. Ras, M. T. Streppel, R. Draijer and P. L. Zock, Flow-mediated dilation and cardiovascular risk prediction: A systematic review with meta-analysis, Int. J. Cardiol., 2013, 168, 344–351.
32. S. M. Holder, R. M. Bruno, D. A. Shkredova, E. A. Dawson, H. Jones, N. D. Hopkins, M. T. E. Hopman, T. G. Bailey, J. S. Coombes, C. D. Askew, L. Naylor, A. Maiorana, L. Ghiadoni, A. Thompson, D. J. Green and Di. H. J. Thijssen, Reference Intervals for Brachial Artery Flow-Mediated Dilation and the Relation with Cardiovascular Risk Factors, Hypertension, 2021, 77, 1469–1480.
33. D. H. J. Thijssen, R. M. Bruno, A. C. C. M. Van Mil, S. M. Holder, F. Faita, A. Greyling, P. L. Zock, S. Taddei, J. E. Deanfield, T. Luscher, D. J. Green and L. Ghiadoni, Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans, Eur. Heart J., 2019, 40, 2534–2547.
34. T. Maruhashi, M. Kajikawa, S. Kishimoto, H. Hashimoto, Y. Takaeko, T. Yamaji, T. Harada, Y. Han, Y. Aibara, F. M. Yusoff, T. Hidaka, Y. Kihara, K. Chayama, A. Nakashima, C. Goto, H. Tomiyama, B. Takase, T. Kohro, T. Suzuki, T. Ishizu, S. Ueda, T. Yamazaki, T. Furumoto, K. Kario, T. Inoue, S. Koba, K. Watanabe, Y. Takemoto, T. Hano, M. Sata, Y. Ishibashi, K. Node, K. Maemura, Y. Ohya, T. Furukawa, H. Ito, H. Ikeda, A. Yamashina and Y. Higashi, Diagnostic Criteria of Flow-Mediated Vasodilation for Normal Endothelial Function and Nitroglycerin-Induced Vasodilation for Normal Vascular Smooth Muscle Function of the Brachial Artery, J. Am. Heart Assoc., 2020, 9, e013915.
35. M. L. Bots, J. Westerink, T. J. Rabelink and E. J. P. De Koning, Assessment of flow-mediated vasodilatation (FMD) of the brachial artery: Effects of technical aspects of the FMD measurement on the FMD response, Eur. Heart J., 2005, 26, 363–368.
36. K. M. Crowe-White, L. W. Evans, G. G. C. Kuhnle, D. Milenkovic, K. Stote, T. Wallace, D. Handu and K. E. Senkus, Flavan-3-ols and Cardiometabolic Health: First Ever Dietary Bioactive Guideline, Adv. Nutr., 2022, 13, 2070–2083.
37. R. R. Huxley and H. a. W. Neil, 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.
38. Y. Xie, H. Wang and Z. He, Recent advances in polyphenols improving vascular endothelial dysfunction induced by endogenous toxicity, John Wiley and Sons Ltd, 2021, preprint,  DOI:10.1002/jat.4123.
39. Y. Kishimoto, M. Tani and K. Kondo, Pleiotropic preventive effects of dietary polyphenols in cardiovascular diseases, 2013, preprint,  DOI:10.1038/ejcn.2013.29.
40. S. R. Weaver, C. Rendeiro, H. M. McGettrick, A. Philp and S. J. E. Lucas, Fine wine or sour grapes? A systematic review and meta-analysis of the impact of red wine polyphenols on vascular health, Springer Science and Business Media Deutschland GmbH, 2021, preprint,  DOI:10.1007/s00394-020-02247-8.
41. A. Rodriguez-Mateos, D. Vauzour, C. G. Krueger, D. Shanmuganayagam, J. Reed, L. Calani, P. Mena, D. Del Rio and A. Crozier, Bioavailability, bioactivity and impact on health of dietary flavonoids and related compounds: an update, Springer Verlag, 2014, preprint,  DOI:10.1007/s00204-014-1330-7.
42. M. Lorenz, F. Rauhut, A. Rubió-Codina, J. Schrörs, M. Gillen, F. Männle, C. Hofmann, T. Schmid, S. Jochem, T. Ansari, H. Engelke, A. Revel, J. Hocherl, L. Bertram, T. Ziemssen, T. Löwel, R. Maerz, A. Neuhäuser-Bernt, G. Kasper, V. Schaarschmidt, U. Wittenbecher, J. van der Auwera, M. Dirnagl, T. Krüger, J. Zegers, M. Dreno, K. Gericke, S. Schulz-Bernhard, P. Häring, A. Matschke, D. Böttcher, V. Heesen, E. Teichert, S. Allinie, K. Sudhoff, L. v. Kriesheim, S. Küchl, E. Deckert, N. Vindhya, P. Gholkar, T. Kalra, S. Matthes, J. Gwan and M. Wetz, et al., Tea-induced improvement of endothelial function in humans: No role for epigallocatechin gallate (EGCG), Sci. Rep., 2017, 7, 2279.
43. E. Eran Nagar, Z. Okun and A. Shpigelman, Digestive fate of polyphenols: updated view of the influence of chemical structure and the presence of cell wall material, Elsevier Ltd, 2020, preprint,  DOI:10.1016/j.cofs.2019.10.009.
44. V. Neveu, J. Perez-Jiménez, F. Vos, V. Crespy, L. du Chaffaut, L. Mennen, C. Knox, R. Eisner, J. Cruz, D. Wishart and A. Scalbert, Phenol-Explorer: an online comprehensive database on polyphenol contents in foods, Database, 2010, bap024.
45. R. Zamora-Ros, V. Knaze, J. A. Rothwell, B. Hémon, A. Moskal, K. Overvad, A. Tjønneland, C. Kyrø, G. Fagherazzi, M. C. Boutron-Ruault, M. Touillaud, V. Katzke, T. Kühn, H. Boeing, J. Förster, A. Trichopoulou, E. Valanou, E. Peppa, D. Palli, C. Agnoli, F. Ricceri, R. Tumino, M. S. de Magistris, P. H. M. Peeters, H. Bas Bueno-De-Mesquita, D. Engeset, G. Skeie, A. Hjartåker, V. Menéndez, A. Agudo, E. Molina-Montes, J. M. Huerta, A. Barricarte, P. Amiano, E. Sonestedt, L. M. Nilsson, R. Landberg, T. J. Key, K. T. Khaw, N. J. Wareham, Y. Lu, N. Slimani, I. Romieu, E. Riboli and A. Scalbert, Dietary polyphenol intake in europe: The european prospective investigation into cancer and nutrition (EPIC) study, Eur. J. Nutr., 2016, 55, 1359–1375.
46. A. Rodriguez-Mateos, G. Istas, L. Boschek, R. P. Feliciano, C. E. Mills, C. Boby, S. Gomez-Alonso, D. Milenkovic and C. Heiss, Circulating Anthocyanin Metabolites Mediate Vascular Benefits of Blueberries: Insights from Randomized Controlled Trials, Metabolomics, and Nutrigenomics, J. Gerontol., Ser. A –, 2019, 74, 967–976.
47. P. J. Curtis, V. Van Der Velpen, L. Berends, A. Jennings, M. Feelisch, A. M. Umpleby, M. Evans, B. O. Fernandez, M. S. Meiss, M. Minnion, J. Potter, A. M. Minihane, C. D. Kay, E. B. Rimm and A. Cassidy, Blueberries improve biomarkers of cardiometabolic function in participants with metabolic syndrome-results from a 6-month, double-blind, randomized controlled trial, Am. J. Clin. Nutr., 2019, 109, 1535–1545.
48. E. Wood, S. Hein, C. Heiss, C. Williams and A. Rodriguez-Mateos, Blueberries and cardiovascular disease prevention, Food Funct., 2019, 10, 7621–7633.
49. G. Istas, E. Wood, M. Le Sayec, C. Rawlings, J. Yoon, V. Dandavate, D. Cera, S. Rampelli, A. Costabile, E. Fromentin and A. Rodriguez-Mateos, Effects of aronia berry (poly)phenols on vascular function and gut microbiota: A double-blind randomized controlled trial in adult men, Am. J. Clin. Nutr., 2019, 110, 316–329.
50. Y. Jin, D. Alimbetov, T. George, M. H. Gordon and J. A. Lovegrove, A randomised trial to investigate the effects of acute consumption of a blackcurrant juice drink on markers of vascular reactivity and bioavailability of anthocyanins in human subjects, Eur. J. Clin. Nutr., 2011, 65, 849–856.
51. F. Khan, S. Ray, A. M. Craigie, G. Kennedy, A. Hill, K. L. Barton, J. Broughton and J. J. F. Belch, Lowering of oxidative stress improves endothelial function in healthy subjects with habitually low intake of fruit and vegetables: A randomized controlled trial of antioxidant- and polyphenol-rich blackcurrant juice, Free Radicals Biol. Med., 2014, 72, 232–237.
52. G. Istas, R. P. Feliciano, T. Weber, R. Garcia-Villalba, F. Tomas-Barberan, C. Heiss and A. Rodriguez-Mateos, Plasma urolithin metabolites correlate with improvements in endothelial function after red raspberry consumption: A double-blind randomized controlled trial, Arch. Biochem. Biophys., 2018, 651, 43–51.
53. R. M. Alqurashi, L. A. Galante, I. R. Rowland, J. P. E. Spencer and D. M. Commane, Consumption of a flavonoid-rich acai meal is associated with acute improvements in vascular function and a reduction in total oxidative status in healthy overweight men, Am. J. Clin. Nutr., 2016, 104, 1227–1235.
54. A. Rodriguez-Mateos, R. P. Feliciano, A. Boeres, T. Weber, C. N. Dos Santos, M. R. Ventura and C. Heiss, Cranberry (poly)phenol metabolites correlate with improvements in vascular function: A double-blind, randomized, controlled, dose-response, crossover study, Mol. Nutr. Food Res., 2016, 60, 2130–2140.
55. M. M. Dohadwala, M. Holbrook, N. M. Hamburg, S. M. Shenouda, W. B. Chung, M. Titas, M. A. Kluge, N. Wang, J. Palmisano, P. E. Milbury, J. B. Blumberg and J. A. Vita, Effects of cranberry juice consumption on vascular function in patients with coronary artery disease, Am. J. Clin. Nutr., 2011, 93, 934–940.
56. A. Rodriguez-Mateos, R. del Pino-García, T. W. George, A. Vidal-Diez, C. Heiss and J. P. E. Spencer, Impact of processing on the bioavailability and vascular effects of blueberry (poly)phenols, Mol. Nutr. Food Res., 2014, 58, 1952–1961.
57. A. Rodriguez-Mateos, C. Rendeiro, T. Bergillos-Meca, S. Tabatabaee, T. W. George, C. Heiss and J. P. Spencer, Intake and time dependence of blueberry flavonoid–induced improvements in vascular function: a randomized, controlled, double-blind, crossover intervention study with mechanistic insights into biological activity, Am. J. Clin. Nutr., 2013, 98, 1179–1191.
58. E. K. Woolf, J. D. Terwoord, N. S. Litwin, A. R. Vazquez, S. Y. Lee, N. Ghanem, K. A. Michell, B. T. Smith, L. E. Grabos, N. B. Ketelhut, N. P. Bachman, M. E. Smith, M. Le Sayec, S. Rao, C. L. Gentile, T. L. Weir, A. Rodriguez-Mateos, D. R. Seals, F. A. Dinenno and S. A. Johnson, Daily blueberry consumption for 12 weeks improves endothelial function in postmenopausal women with above-normal blood pressure through reductions in oxidative stress: a randomized controlled trial, Food Funct., 2023, 14, 2621–2641.
59. C. Heiss, G. Istas, R. P. Feliciano, T. Weber, B. Wang, C. Favari, P. Mena, D. Del Rio and A. Rodriguez-Mateos, Daily consumption of cranberry improves endothelial function in healthy adults: a double blind randomized controlled trial, Food Funct., 2022, 13, 3812–3824.
60. P. J. Curtis, L. Berends, V. van der Velpen, A. Jennings, L. Haag, P. Chandra, C. D. Kay, E. B. Rimm and A. Cassidy, Blueberry anthocyanin intake attenuates the postprandial cardiometabolic effect of an energy-dense food challenge: Results from a double blind, randomized controlled trial in metabolic syndrome participants, Clin. Nutr., 2022, 41, 165–176.
61. L. Huang, D. Xiao, X. Zhang, A. K. Sandhu, P. Chandra, C. Kay, I. Edirisinghe and B. Burton-Freeman, Strawberry Consumption, Cardiometabolic Risk Factors, and Vascular Function: A Randomized Controlled Trial in Adults with Moderate Hypercholesterolemia, J. Nutr., 2021, 151, 1517–1526.
62. P. Philip, P. Sagaspe, J. Taillard, C. Mandon, J. Constans, L. Pourtau, C. Pouchieu, D. Angelino, P. Mena, D. Martini, D. Del Rio and D. Vauzour, Acute intake of a grape and blueberry polyphenol-rich extract ameliorates cognitive performance in healthy young adults during a sustained cognitive effort, Antioxidants, 2019, 8, 650.
63. G. Siasos, D. Tousoulis, E. Kokkou, E. Oikonomou, M.-E. Kollia, A. Verveniotis, N. Gouliopoulos, K. Zisimos, A. Plastiras, K. Maniatis and C. Stefanadis, Favorable Effects of Concord Grape Juice on Endothelial Function and Arterial Stiffness in Healthy Smokers, Am. J. Hypertens., 2014, 27, 38–45.
64. M. Hashemi, R. Kelishadi, M. Hashemipour, A. Zakerameli, N. Khavarian, S. Ghatrehsamani and P. Poursafa, Acute and long-term effects of grape and pomegranate juice consumption on vascular reactivity in paediatric metabolic syndrome, Cardiol. Young, 2010, 20, 73–77.
65. S. M. Hampton, C. Isherwood, V. J. E. Kirkpatrick, A. C. Lynne-Smith and B. A. Griffin, The influence of alcohol consumed with a meal on endothelial function in healthy individuals, J. Hum. Nutr. Diet., 2010, 23, 120–125.
66. S. R. Coimbra, S. H. Lage, L. Brandizzi, V. Yoshida and P. L. Da Luz, The action of red wine and purple grape juice on vascular reactivity is independent of plasma lipids in hypercholesterolemic patients, 2005, vol. 38.
67. C. Papamichael, E. Karatzis, K. Karatzi, K. Aznaouridis, T. Papaioannou, A. Protogerou, K. Stamatelopoulos, A. Zampelas, J. Lekakis and M. Mavrikakis, Red wine’s antioxidants counteract acute endothelial dysfunction caused by cigarette smoking in healthy nonsmokers, Am. Heart J., 2010, 23, 120–125.
68. E. J. Chou, J. G. Keevil, S. Aeschlimann, D. A. Wiebe, J. D. Folts and J. H. Stein, Effect of Ingestion of Purple Grape Juice on Endothelial Function in Patients With Coronary Heart Disease, 2001, vol. 88.
69. M. Hashimoto, S. Kim, M. Eto, K. Iijima, J. Ako, M. Yoshizumi, M. Akishita, K. Kondo, H. Itakura, K. Hosoda, K. Toba and Y. Ouchi, Effect of acute intake of red wine on flow-mediated vasodilatation of the brachial artery, Am. J. Cardiol., 2001, 88, 1457–1460.
70. A. Martelli, L. Flori, E. Gorica, E. Piragine, A. Saviano, G. Annunziata, M. N. D. Di Minno, R. Ciampaglia, I. Calcaterra, F. Maione, G. C. Tenore, E. Novellino and V. Calderone, Vascular effects of the polyphenolic nutraceutical supplement taurisolo®: Focus on the protection of the endothelial function, Nutrients, 2021, 13, 1540.
71. T. Odai, M. Terauchi, K. Kato, A. Hirose and N. Miyasaka, Effects of grape seed proanthocyanidin extract on vascular endothelial function in participants with prehypertension: A randomized, double-blind, placebo-controlled study, Nutrients, 2019, 11, 2844.
72. D.-S. Lee and J. Kim, Letter to the Editor Effects of Grape Seed Extract Supplementation on Hemodynam-ic Response and Vascular Endothelial Function in Postmenopausal Women Dear Editor-in-Chief, 2019, vol. 48.
73. A. Greyling, R. M. Bruno, R. Draijer, T. Mulder, D. H. J. Thijssen, S. Taddei, A. Virdis and L. Ghiadoni, Effects of wine and grape polyphenols on blood pressure, endothelial function and sympathetic nervous system activity in treated hypertensive subjects, J. Funct. Foods, 2016, 27, 448–460.
74. N. Vaisman and E. Niv, Daily consumption of red grape cell powder in a dietary dose improves cardiovascular parameters: A double blind, placebo-controlled, randomized study, Int. J. Food Sci. Nutr., 2015, 66, 342–349.
75. E. Park, I. Edirisinghe, Y. Y. Choy, A. Waterhouse and B. Burton-Freeman, Effects of grape seed extract beverage on blood pressure and metabolic indices in individuals with pre-hypertension: A randomised, double-blinded, two-arm, parallel, placebo-controlled trial, Br. J. Nutr., 2016, 115, 226–238.
76. J. Barona, J. C. Aristizabal, C. N. Blesso, J. S. Volek and M. L. Fernandez, Grape polyphenols reduce blood pressure and increase flow-mediated vasodilation in men with metabolic syndrome, J. Nutr., 2012, 142, 1626–1632.
77. P. B. Mellen, K. R. Daniel, K. B. Brosnihan, K. J. Hansen and D. M. Herrington, 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.
78. A. R. Weseler, E. J. B. Ruijters, M. J. Drittij-Reijnders, K. D. Reesink, G. R. M. M. Haenen and A. Bast, Pleiotropic benefit of monomeric and oligomeric flavanols on vascular health – A randomized controlled clinical pilot study, PLoS One, 2011, 6, e28460.
79. L. A. J. van Mierlo, P. L. Zock, H. C. M. van der Knaap and R. Draijer, Grape Polyphenols Do Not Affect Vascular Function in Healthy Men, J. Nutr., 2010, 140, 1769–1773.
80. N. C. Ward, J. M. Hodgson, K. D. Croft, V. Burke, L. J. Beilin and I. B. Puddey, The combination of vitamin C and grape-seed polyphenols increases blood pressure: a randomized, double-blind, placebo-controlled trial, Lippincott Williams & Wilkins, 2005, vol. 23.
81. P. M. Clifton, Effect of grape seed extract and quercetin on cardiovascular and endothelial parameters in high-risk subjects, J. Biomed. Biotechnol., 2004, 2004, 272–278.
82. L. Li, G. K. Lyall, J. Alberto Martinez-Blazquez, F. Vallejo, F. A. Tomas-Barberan, K. M. Birch and C. Boesch, Blood orange juice consumption increases flow-mediated dilation in adults with overweight and obesity: A randomized controlled trial, J. Nutr., 2020, 150, 2287–2294.
83. J. Constans, C. Bennetau-Pelissero, J. F. Martin, E. Rock, A. Mazur, A. Bedel, C. Morand and A. M. Bérard, Marked antioxidant effect of orange juice intake and its phytomicronutrients in a preliminary randomized cross-over trial on mild hypercholesterolemic men, Clin. Nutr., 2015, 34, 1093–1100.
84. V. Habauzit, M. A. Verny, D. Milenkovic, N. Barber-Chamoux, A. Mazur, C. Dubray and C. Morand, Flavanones protect from arterial stiffness in postmenopausal women consuming grapefruit juice for 6 mo: A randomized, controlled, crossover trial, Am. J. Clin. Nutr., 2015, 102, 66–74.
85. S. Buscemi, G. Rosafio, G. Arcoleo, A. Mattina, B. Canino, M. Montana, S. Verga and G. Rini, Effects of red orange juice intake on endothelial function and inflammatory markers in adult subjects with increased cardiovascular risk, Am. J. Clin. Nutr., 2012, 95, 1089–1095.
86. R. M. Valls, A. Pedret, L. Calderón-Pérez, E. Llauradó, L. Pla-Pagà, J. Companys, A. Moragas, F. Martín-Luján, Y. Ortega, M. Giralt, L. Rubió, N. Canela, F. Puiggrós, A. Caimari, J. M. Del Bas, L. Arola and R. Solà, Hesperidin in orange juice improves human endothelial function in subjects with elevated blood pressure and stage 1 hypertension: A randomized, controlled trial (Citrus study), J. Funct. Foods, 2021, 85, 104646.
87. C. Rendeiro, H. Dong, C. Saunders, L. Harkness, M. Blaze, Y. Hou, R. L. Belanger, G. Corona, J. A. Lovegrove and J. P. E. Spencer, Flavanone-rich citrus beverages counteract the transient decline in postprandial endothelial function in humans: A randomised, controlled, double-masked, cross-over intervention study, Br. J. Nutr., 2016, 116, 1999–2010.
88. M. S. Macarro, J. P. M. Rodríguez, E. B. Morell, S. Pérez-Piñero, D. Victoria-Montesinos, A. M. García-Muñoz, F. C. García, J. C. Sánchez and F. J. López-Román, Effect of a combination of citrus flavones and flavanones and olive polyphenols for the reduction of cardiovascular disease risk: An exploratory randomized, double-blind, placebo-controlled study in healthy subjects, Nutrients, 2016, 116, 1999–2010.
89. M. Hashemi, E. Khosravi, A. Ghannadi, M. Hashemipour and R. Kelishadi, Effect of the peels of two Citrus fruits on endothelium function in adolescents with excess weight: A triple-masked randomized trial, J. Res. Med. Sci., 2015, 20, 721–726.
90. S. Rizza, R. Muniyappa, M. Iantorno, J. Kim, H. Chen, P. Pullikotil, N. Senese, M. Tesauro, D. Lauro, C. Cardillo and M. J. Quon, Citrus Polyphenol Hesperidin Stimulates Production of Nitric Oxide in Endothelial Cells while Improving Endothelial Function and Reducing Inflammatory Markers in Patients with Metabolic Syndrome, J. Clin. Endocrinol. Metab., 2011, 96, E782–E792.
91. R. Baynham, J. J. C. S. V. van Zanten, P. W. Johns, Q. S. Pham and C. Rendeiro, Cocoa flavanols improve vascular responses to acute mental stress in young healthy adults, Nutrients, 2021, 13, 1103.
92. C. E. Marsh, H. H. Carter, K. J. Guelfi, K. J. Smith, K. E. Pike, L. H. Naylor and D. J. Green, Brachial and Cerebrovascular Functions Are Enhanced in Postmenopausal Women after Ingestion of Chocolate with a High Concentration of Cocoa, J. Nutr., 2017, 147, 1686–1692.
93. J. I. Dower, J. M. Geleijnse, L. Gijsbers, P. L. Zock, D. Kromhout and P. C. Hollman, Effects of the pure flavonoids epicatechin and quercetin on vascular function and cardiometabolic health: a randomized, double-blind, placebo-controlled, crossover trial, Am. J. Clin. Nutr., 2015, 101, 914–921.
94. T. Pereira, J. Maldonado, M. Laranjeiro, R. Coutinho, E. Cardoso, I. Andrade and J. Conde, Central arterial hemodynamic effects of dark chocolate ingestion in young healthy people: A randomized and controlled trial, Cardiol. Res. Pract., 2014, 2014, 945951.
95. L. Loffredo, L. Perri, E. Catasca, P. Pignatelli, M. Brancorsini, C. Nocella, E. De Falco, S. Bartimoccia, G. Frati, R. Carnevale and F. Violi, Dark chocolate acutely improves walking autonomy in patients with peripheral artery disease, J. Am. Heart Assoc., 2014, 3, e001072.
96. D. Esser, M. Mars, E. Oosterink, A. Stalmach, M. Müller and L. A. Afman, Dark chocolate consumption improves leukocyte adhesion factors and vascular function in overweight men, FASEB J., 2014, 28, 1464–1473.
97. Z. Faridi, V. Y. Njike, S. Dutta, A. Ali and D. L. Katz, Acute dark chocolate and cocoa ingestion and endothelial function: a randomized controlled crossover trial 1–4, 2008.
98. S. Westphal and C. Luley, Flavanol-rich cocoa ameliorates lipemia-induced endothelial dysfunction, Heart Vessels, 2011, 26, 511–515.
99. D. Grassi, G. Desideri, S. Necozione, P. Di Giosia, R. Barnabei, L. Allegaert, H. Bernaert and C. Ferri, Cocoa consumption dose-dependently improves flow-mediated dilation and arterial stiffness decreasing blood pressure in healthy individuals, J. Hypertens., 2015, 33, 294–303.
100. A. Hammer, R. Koppensteiner, S. Steiner, A. Niessner, G. Goliasch, M. Gschwandtner and M. Hoke, Dark chocolate and vascular function in patients with peripheral artery disease: A randomized, controlled cross-over trial, Clin. Hemorheol. Microcirc., 2015, 59, 145–153.
101. C. Heiss, S. Jahn, M. Taylor, W. M. Real, F. S. Angeli, M. L. Wong, N. Amabile, M. Prasad, T. Rassaf, J. I. Ottaviani, S. Mihardja, C. L. Keen, M. L. Springer, A. Boyle, W. Grossman, S. A. Glantz, H. Schroeter and Y. Yeghiazarians, 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.
102. K. Davison, A. M. Coates, J. D. Buckley and P. R. C. Howe, Effect of cocoa flavanols and exercise on cardiometabolic risk factors in overweight and obese subjects, Int. J. Obes., 2008, 32, 1289–1296.
103. A. J. Flammer, I. Sudano, M. Wolfrum, R. Thomas, F. Enseleit, D. Périat, P. Kaiser, A. Hirt, M. Hermann, M. Serafini, A. Lévêques, T. F. Lüscher, F. Ruschitzka, G. Noll and R. Corti, Cardiovascular effects of flavanol-rich chocolate in patients with heart failure, Eur. Heart J., 2012, 33, 2172–2180.
104. D. Grassi, G. Desideri, S. Necozione, C. Lippi, R. Casale, G. Properzi, J. B. Blumberg and C. Ferri, Blood Pressure Is Reduced and Insulin Sensitivity Increased in Glucose-Intolerant, Hypertensive Subjects after 15 Days of Consuming High-Polyphenol Dark Chocolate13, J. Nutr., 2008, 138, 1671–1676.
105. J. Balzer, T. Rassaf, C. Heiss, P. Kleinbongard, T. Lauer, M. Merx, N. Heussen, H. B. Gross, C. L. Keen, H. Schroeter and M. Kelm, 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.
106. C. Heiss, D. Finis, P. Kleinbongard, A. Hoffmann, T. Rassaf, M. Kelm and H. Sies, Sustained Increase in Flow-Mediated Dilation After Daily Intake of High-Flavanol Cocoa Drink Over 1 Week.
107. J. F. Wang-Polagruto, A. C. Villablanca, J. A. Polagruto, L. Lee, R. R. Holt, H. R. Schrader, J. L. Ensunsa, F. M. Steinberg, H. H. Schmitz and C. L. Keen, Chronic Consumption of Flavanol-rich Cocoa Improves Endothelial Function and Decreases Vascular Cell Adhesion Molecule in Hypercholesterolemic Postmenopausal Women, 2006.
108. H. Schroeter, C. Heiss, J. Balzer, P. Kleinbongard, C. L. Keen, N. K. Hollenberg, H. Sies, C. Kwik-Uribe, H. H. Schmitz and M. Kelm, ( )-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans, 2006.
109. N. D. L. Fisher and N. K. Hollenberg, Aging and vascular responses to flavanol-rich cocoa.
110. C. Heiss, P. Kleinbongard, A. Dejam, S. Perré, H. Schroeter, H. Sies and M. Kelm, Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers, J. Am. Coll. Cardiol., 2005, 46, 1276–1283.
111. M. B. Engler, M. M. Engler, A. Browne, E. Y. Chiu, M. L. Mietus-Snyder, S. M. Paul, M. J. Malloy, C. Y. Chen, H. K. Kwak, P. Milbury and J. Blumberg, Flavonoid-Rich Dark Chocolate Improves Endothelial Function and Increases Plasma Epicatechin Concentrations in Healthy Adults, J. Am. Coll. Nutr., 2004, 23, 197–204.
112. A. Rodriguez-Mateos, T. Weber, S. S. Skene, J. I. Ottaviani, A. Crozier, M. Kelm, H. Schroeter and C. Heiss, Assessing the respective contributions of dietary flavanol monomers and procyanidins in mediating cardiovascular effects in humans: randomized, controlled, double-masked intervention trial, Am. J. Clin. Nutr., 2018, 108, 1229–1237.
113. R. Sansone, A. Rodriguez-Mateos, J. Heuel, D. Falk, D. Schuler, R. Wagstaff, G. G. C. Kuhnle, J. P. E. Spencer, H. Schroeter, M. W. Merx, M. Kelm and C. Heiss, Cocoa flavanol intake improves endothelial function and Framingham Risk Score in healthy men and women: a randomised, controlled, double-masked trial: the Flaviola Health Study, Br. J. Nutr., 2015, 114, 1246–1255.
114. M. Kajikawa, T. Maruhashi, T. Hidaka, Y. Nakano, S. Kurisu, T. Matsumoto, Y. Iwamoto, S. Kishimoto, S. Matsui, Y. Aibara, F. M. Yusoff, Y. Kihara, K. Chayama, C. Goto, K. Noma, A. Nakashima, T. Watanabe, H. Tone, M. Hibi, N. Osaki, Y. Katsuragi and Y. Higashi, Coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone improves postprandial endothelial dysfunction in patients with borderline and stage 1 hypertension, Eur. J. Nutr., 2019, 58, 989–996.
115. C. E. Mills, A. Flury, C. Marmet, L. Poquet, S. F. Rimoldi, C. Sartori, E. Rexhaj, R. Brenner, Y. Allemann, D. Zimmermann, G. R. Gibson, D. S. Mottram, M. J. Oruna-Concha, L. Actis-Goretta and J. P. E. Spencer, Mediation of coffee-induced improvements in human vascular function by chlorogenic acids and its metabolites: Two randomized, controlled, crossover intervention trials, Clin. Nutr., 2017, 36, 1520–1529.
116. E. A. J. Boon, K. D. Croft, S. Shinde, J. M. Hodgson and N. C. Ward, The acute effect of coffee on endothelial function and glucose metabolism following a glucose load in healthy human volunteers, Food Funct., 2017, 8, 3366–3373.
117. N. C. Ward, J. M. Hodgson, R. J. Woodman, D. Zimmermann, L. Poquet, A. Leveques, L. Actis-Goretta, I. B. Puddey and K. D. Croft, Acute effects of chlorogenic acids on endothelial function and blood pressure in healthy men and women, Food Funct., 2016, 7, 2197–2203.
118. R. Ochiai, Y. Sugiura, K. Otsuka, Y. Katsuragi and T. Hashiguchi, Coffee bean polyphenols ameliorate postprandial endothelial dysfunction in healthy male adults, Int. J. Food Sci. Nutr., 2015, 66, 350–354.
119. S. Buscemi, S. Verga, J. A. Batsis, M. Donatelli, M. R. Tranchina, S. Belmonte, A. Mattina, A. Re and G. Cerasola, Acute effects of coffee on endothelial function in healthy subjects, Eur. J. Clin. Nutr., 2010, 64, 483–489.
120. S. Buscemi, S. Verga, J. A. Batsis, M. R. Tranchina, S. Belmonte, A. Mattina, A. Re, R. Rizzo and G. Cerasola, Dose-dependent effects of decaffeinated coffee on endothelial function in healthy subjects, Eur. J. Clin. Nutr., 2009, 63, 1200–1205.
121. C. M. Papamichael, K. A. Aznaouridis, E. N. Karatzis, K. N. Karatzi, K. S. Stamatelopoulos, G. Vamvakou, J. P. Lekakis and M. E. Mavrikakis, Effect of coffee on endothelial function in healthy subjects: the role of caffeine, 2005, vol. 109.
122. G. M. Agudelo-Ochoa, I. C. Pulgarín-Zapata, C. M. Velásquez-Rodriguez, M. Duque-Ramírez, M. Naranjo-Cano, M. M. Quintero-Ortiz, O. J. Lara-Guzmán and K. Muñoz-Durango, Coffee consumption increases the antioxidant capacity of plasma and has no effect on the lipid profile or vascular function in healthy adults in a randomized controlled trial, J. Nutr., 2016, 146, 524–531.
123. R. Ochiai, A. Chikama, K. Kataoka, I. Tokimitsu, Y. Maekawa, M. Ohishi, H. Rakugi and H. Mikami, Effects of hydroxyhydroquinone-reduced coffee on vasoreactivity and blood pressure, Hypertens. Res., 2009, 32, 969–974.
124. L. H. Naylor, D. Zimmermann, M. Guitard-Uldry, L. Poquet, A. Leveques, B. Eriksen, R. Bel Rhlid, N. Galaffu, C. D′urzo, A. De Castro, E. Van Schaick, D. J. Green and L. Actis-Goretta, Acute dose-response effect of coffee-derived chlorogenic acids on the human vasculature in healthy volunteers: A randomized controlled trial, Am. J. Clin. Nutr., 2021, 113, 370–379.
125. A. Suzuki, T. Nomura, H. Jokura, N. Kitamura, A. Saiki and A. Fujii, Chlorogenic acid-enriched green coffee bean extract affects arterial stiffness assessed by the cardio-ankle vascular index in healthy men: a pilot study, Int. J. Food Sci. Nutr., 2019, 70, 901–908.
126. H. Jokura, I. Watanabe, M. Umeda, T. Hase and A. Shimotoyodome, Coffee polyphenol consumption improves postprandial hyperglycemia associated with impaired vascular endothelial function in healthy male adults, Nutr. Res., 2015, 35, 873–881.
127. A. Mubarak, C. P. Bondonno, A. H. Liu, M. J. Considine, L. Rich, E. Mas, K. D. Croft and J. M. Hodgson, Acute effects of chlorogenic acid on nitric oxide status, endothelial function, and blood pressure in healthy volunteers: A randomized trial, J. Agric. Food Chem., 2012, 60, 9130–9136.
128. V. Sanguigni, M. Manco, R. Sorge, L. Gnessi and D. Francomano, Natural antioxidant ice cream acutely reduces oxidative stress and improves vascular function and physical performance in healthy individuals, Nutrition, 2017, 33, 225–233.
129. S. J. Duffy, J. F. Keaney, M. Holbrook, N. Gokce, P. L. Swerdloff, B. Frei and J. A. Vita, Short-and Long-Term Black Tea Consumption Reverses Endothelial Dysfunction in Patients With Coronary Artery Disease, 2001.
130. D. Grassi, R. Draijer, C. Schalkwijk, G. Desideri, A. D’Angeli, S. Francavilla, T. Mulder and C. Ferri, Black tea increases circulating endothelial progenitor cells and improves flow mediated dilatation counteracting deleterious effects from a fat load in hypertensive patients: A randomized controlled study, Nutrients, 2016, 8, 727.
131. A. F. Ahmad, L. Rich, H. Koch, K. D. Croft, M. G. Ferruzzi, C. D. Kay, J. M. Hodgson and N. C. Ward, Effect of adding milk to black tea on vascular function in healthy men and women: A randomised controlled crossover trial, Food Funct., 2018, 9, 6307–6314.
132. T. H. A. Schreuder, T. M. H. Eijsvogels, A. Greyling, R. Draijer, M. T. E. Hopman and D. H. J. Thijssen, Effect of black tea consumption on brachial artery flow-mediated dilation and ischaemia–reperfusion in humans, Appl. Physiol., Nutr., Metab., 2014, 39, 145–151.
133. S. K. Bøhn, K. D. Croft, S. Burrows, I. B. Puddey, T. P. J. Mulder, D. Fuchs, R. J. Woodman and J. M. Hodgson, Effects of black tea on body composition and metabolic outcomes related to cardiovascular disease risk: A randomized controlled trial, Food Funct., 2014, 5, 1613–1620.
134. D. Grassia, T. P. J. Mulder, R. Draijer, G. Desideri, H. O. F. Molhuizen and C. Ferri, Black tea consumption dose-dependently improves flow-mediated dilation in healthy males, J. Hypertens., 2009, 27, 774–781.
135. N. Jochmann, M. Lorenz, A. von Krosigk, P. Martus, V. Böhm, G. Baumann, K. Stangl and V. Stangl, The efficacy of black tea in ameliorating endothelial function is equivalent to that of green tea, Br. J. Nutr., 2008, 99, 863–868.
136. M. Lorenz, N. Jochmann, A. Von Krosigk, P. Martus, G. Baumann, K. Stangl and V. Stangl, Addition of milk prevents vascular protective effects of tea, Eur. Heart J., 2007, 28, 219–223.
137. T. N. Sapper, E. Mah, J. Ahn-Jarvis, J. D. McDonald, C. Chitchumroonchokchai, E. J. Reverri, Y. Vodovotz and R. S. Bruno, A green tea-containing starch confection increases plasma catechins without protecting against postprandial impairments in vascular function in normoglycemic adults, Food Funct., 2016, 7, 3843–3853.
138. M. E. Alañón, S. M. Castle, G. Serra, A. Lévèques, L. Poquet, L. Actis-Goretta and J. P. E. Spencer, Acute study of dose-dependent effects of (−)-epicatechin on vascular function in healthy male volunteers: A randomized controlled trial, Clin. Nutr., 2020, 39, 746–754.
139. S. M. v. d. Made, J. Plat and R. P. Mensink, Trans-Resveratrol Supplementation and Endothelial Function during the Fasting and Postprandial Phase: A Randomized Placebo-Controlled Trial in Overweight and Slightly Obese Participants, Nutrients, 2017, 9, 596.
140. B. N. Salden, F. J. Troost, E. De Groot, Y. R. Stevens, M. Garcés-Rimón, S. Possemiers, B. Winkens and A. A. Masclee, Randomized clinical trial on the efficacy of hesperidin 2S on validated cardiovascular biomarkers in healthy overweight individuals1,2, Am. J. Clin. Nutr., 2016, 104, 1523–1533.
141. R. H. X. Wong, N. M. Berry, A. M. Coates, J. D. Buckley, J. Bryan, I. Kunz and P. R. C. Howe, Chronic resveratrol consumption improves brachial flow-mediated dilatation in healthy obese adults, J. Hypertens., 2013, 31, 1819–1827.
142. R. H. X. Wong, P. R. C. Howe, J. D. Buckley, A. M. Coates, I. Kunz and N. M. Berry, Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure, Nutr., Metab. Cardiovasc. Dis., 2011, 21, 851–856.
143. E. Wood, S. Hein, R. Mesnage, F. Fernandes, N. Abhayaratne, Y. Xu, Z. Zhang, L. Bell, C. Williams and A. Rodriguez-Mateos, Wild blueberry (poly)phenols can improve vascular function and cognitive performance in healthy older individuals: a double-blind randomized controlled trial, Am. J. Clin. Nutr., 2023, 117, 1306–1319.
144. I. Eseberri, J. Trepiana, A. Léniz, I. Gómez-García, H. Carr-Ugarte, M. González and M. P. Portillo, Variability in the Beneficial Effects of Phenolic Compounds: A Review, MDPI, 2022, preprint,  DOI:10.3390/nu14091925.
145. L. Arfaoui, Dietary plant polyphenols: Effects of food processing on their content and bioavailability, MDPI AG, 2021, preprint,  DOI:10.3390/molecules26102959.
146. L. Arfaoui, Dietary plant polyphenols: Effects of food processing on their content and bioavailability, MDPI AG, 2021, preprint,  DOI:10.3390/molecules26102959.
147. A. Tresserra-Rimbau, R. M. Lamuela-Raventos and J. J. Moreno, Polyphenols, food and pharma. Current knowledge and directions for future research, Biochem. Pharmacol., 2018, 156, 186–195.
148. H. Li, R. Tsao and Z. Deng, Factors affecting the antioxidant potential and health benefits of plant foods, 2012, preprint,  DOI:10.4141/CJPS2011-239.
149. D. Grassi, G. Desideri, S. Necozione, C. Lippi, R. Casale, G. Properzi, J. B. Blumberg and C. Ferri, Blood Pressure Is Reduced and Insulin Sensitivity Increased in Glucose-Intolerant, Hypertensive Subjects after 15 Days of Consuming High-Polyphenol Dark Chocolate13, J. Nutr., 2008, 138, 1671–1676.
150. A. Kerimi and G. Williamson, The cardiovascular benefits of dark chocolate, Vasc. Pharmacol., 2015, 71, 11–15.
151. R. Sansone, J. I. Ottaviani, A. Rodriguez-Mateos, Y. Heinen, D. Noske, J. P. Spencer, A. Crozier, M. W. Merx, M. Kelm, H. Schroeter and C. Heiss, Methylxanthines enhance the effects of cocoa flavanols on cardiovascular function: randomized, double-masked controlled studies, Am. J. Clin. Nutr., 2017, 105, 352–360.
152. J. M. Butler, C. M. Frampton, G. Moore, M. L. Barclay and D. L. Jardine, Immediate effect of caffeine on sympathetic nerve activity: why coffee is safe? A single-centre crossover study, Clin. Auton. Res., 2023, 33, 623–633.
153. V. K. Sharma, A. Sharma, K. K. Verma, P. K. Gaur, R. Kaushik and B. Abdali, A COMPREHENSIVE REVIEW ON PHARMACOLOGICAL POTENTIALS OF CAFFEINE, J. Appl. Pharm. Sci. Res., 2023, 6, 16–26.
154. C. Papadelis, C. Kourtidou-Papadeli, E. Vlachogiannis, P. Skepastianos, P. Bamidis, N. Maglaveras and K. Pappas, Effects of mental workload and caffeine on catecholamines and blood pressure compared to performance variations, Brain Cogn, 2003, 51, 143–154.
155. J. L. Flueck, F. Schaufelberger, M. Lienert, D. S. Olstad, M. Wilhelm and C. Perret, Acute Effects of Caffeine on Heart Rate Variability, Blood Pressure and Tidal Volume in Paraplegic and Tetraplegic Compared to Able-Bodied Individuals: A Randomized, Blinded Trial, PLoS One, 2016, 11, e0165034.
156. D. Echeverri, F. R. Montes, M. Cabrera, A. Galán and A. Prieto, Caffeine's Vascular Mechanisms of Action, Int. J. Vasc. Med., 2010, 2010, 834060.
157. R. Islam, M. Ahmed, W. Ullah, Y. B. Tahir, S. Gul, N. Hussain, H. Islam and M. U. Anjum, Effect of Caffeine in Hypertension, Curr. Probl. Cardiol., 2023, 48, 101892.
158. D. Shofinita, D. Lestari, R. Purwadi, G. A. Sumampouw, K. C. Gunawan, S. A. Ambarwati, A. B. Achmadi and J. T. Tjahjadi, Effects of different decaffeination methods on caffeine contents, physicochemical, and sensory properties of coffee, Int. J. Food Eng., 2024, 20, 561–581.
159. A. Farah, T. De Paulis, D. P. Moreira, L. C. Trugo and P. R. Martin, Chlorogenic acids and lactones in regular and water-decaffeinated arabica coffees, J. Agric. Food Chem., 2006, 54, 374–381.
160. G. Mammadov, E. Şimşek, I. Y. Şimşir, B. Yağmur, C. S. Çınar, G. Mammadov, E. Şimşek, I. Y. Şimşir, B. Yağmur and C. S. Çınar, Acute Effects of Blood Sugar Regulation on Endothelial Functions in Patients with Diabetes, J. Updates Cardiovasc. Med., 2022, 10, 130–136.
161. A. Rashidinejad, O. Tarhan, A. Rezaei, E. Capanoglu, S. Boostani, S. Khoshnoudi-Nia, K. Samborska, F. Garavand, R. Shaddel, S. Akbari-Alavijeh and S. M. Jafari, Addition of milk to coffee beverages; the effect on functional, nutritional, and sensorial properties, Crit. Rev. Food Sci. Nutr., 2022, 62, 6132–6152.
162. T. M. El-Messery, E. A. Mwafy, A. M. Mostafa, H. M. F. El-Din, A. Mwafy, R. Amarowicz and B. Ozçelik, Spectroscopic studies of the interaction between isolated polyphenols from coffee and the milk proteins, Surf. Interfaces, 2020, 20, 100558.
163. A. R. Bhagat, A. M. Delgado, M. Issaoui, N. Chammem, M. Fiorino, A. Pellerito and S. Natalello, Review of the Role of Fluid Dairy in Delivery of Polyphenolic Compounds in the Diet: Chocolate Milk, Coffee Beverages, Matcha Green Tea, and Beyond, J. AOAC Int., 2019, 102, 1365–1372.
164. K. Horita, T. Kameda, H. Suga and A. Hirano, Molecular mechanism of the interactions between coffee polyphenols and milk proteins, Food Res. Int., 2025, 202, 115573.
165. B. J. Azad, J. Heshmati, E. Daneshzad and A. Palmowski, Effects of coffee consumption on arterial stiffness and endothelial function: a systematic review and meta-analysis of randomized clinical trials, Bellwether Publishing, Ltd., 2021, preprint,  DOI:10.1080/10408398.2020.1750343.
166. G. Siasos, E. Oikonomou, C. Chrysohoou, D. Tousoulis, D. Panagiotakos, M. Zaromitidou, K. Zisimos, E. Kokkou, G. Marinos, A. G. Papavassiliou, C. Pitsavos and C. Stefanadis, Consumption of a boiled Greek type of coffee is associated with improved endothelial function: The Ikaria Study, Vasc. Med., 2013, 18, 55–62.
167. J. J. L. Low, B. J. W. Tan, L. X. Yi, Z. D. Zhou and E. K. Tan, Genetic susceptibility to caffeine intake and metabolism: a systematic review, J. Transl. Med., 2024, 22, 1–28.
168. R. R. Kocatürk, İ. Karagöz, E. Yanik, Ö. Ö. Özcan, T. T. Ergüzel, M. Karahan and N. Tarhan, The effects of CYP1A2 and ADORA2A genotypes association with acute caffeine intake on physiological effects and performance: A systematic review, Balt. J. Health Phys. Act, 2022, 14, 8.
169. A. Zhou and E. Hyppönen, Long-term coffee consumption, caffeine metabolism genetics, and risk of cardiovascular disease: a prospective analysis of up to 347,077 individuals and 8368 cases, Am. J. Clin. Nutr., 2019, 109, 509–516.
170. J. L. Fulton, P. C. Dinas, A. E. Carrillo, J. R. Edsall, E. J. Ryan and E. J. Ryan, Impact of Genetic Variability on Physiological Responses to Caffeine in Humans: A Systematic Review, Nutrients, 2018, 10, 1373.
171. C. C. Hou, D. M. Tantoh, C. C. Lin, P. H. Chen, H. J. Yang and Y. P. Liaw, Association between hypertension and coffee drinking based on CYP1A2 rs762551 single nucleotide polymorphism in Taiwanese, Nutr. Metab., 2021, 18, 78.
172. M. C. Cornelis, A. El-Sohemy, E. K. Kabagambe and H. Campos, Coffee, CYP1A2 Genotype, and Risk of Myocardial Infarction, J. Am. Med. Assoc., 2006, 295, 1135–1141.
173. G. Williamson, The role of polyphenols in modern nutrition,  DOI:10.1111/nbu.12278.
174. D. Grassi, G. Desideri, P. D. Giosia, M. D. Feo, E. Fellini, P. Cheli, L. Ferri and C. Ferri, Tea, flavonoids, and cardiovascular health: Endothelial protection, Am. J. Clin. Nutr., 2013, 98, 1660S–1666S.
175. N. Khan and H. Mukhtar, Tea Polyphenols in Promotion of Human Health, Nutrients, 2018, 11, 39.
176. Z. Y. Cai, X. M. Li, J. P. Liang, L. P. Xiang, K. R. Wang, Y. L. Shi, R. Yang, M. Shi, J. H. Ye, J. L. Lu, X. Q. Zheng and Y. R. Liang, Bioavailability of Tea Catechins and Its Improvement, Molecules, 2018, 23, 2346.
177. B. Abudureheman, X. Yu, D. Fang and H. Zhang, Enzymatic Oxidation of Tea Catechins and Its Mechanism, Molecules, 2022, 27, 942.
178. D. R. Faustina, R. Gunadi, A. Fitriani and S. Supriyadi, Alteration of Phenolic and Volatile Compounds of Tea Leaf Extract by Tyrosinase and β-Glucosidase during Preparation of Ready-to-Drink Tea on Farm, Int. J. Food Sci., 2022, 2022, 1977762.
179. T. Zhao, X. Huang, J. Zhao, C. S. Yang, S. Zhang, J. Huang, K. Wang, Z. Liu and M. Zhu, Theaflavins: An underexploited functional compound in black tea, Trends Food Sci. Technol., 2024, 154, 104755.
180. L. Chen, H. Wang, Y. Ye, Y. Wang and P. Xu, Structural insight into polyphenol oxidation during black tea fermentation, Food Chem.:X, 2023, 17, 100615.
181. M. R. Ardalan, M. K. Tarzamni, M. M. Shoja, R. S. Tubbs, B. Rahimi-Ardabili, K. Ghabili and H. T. Khosroshahi, Black Tea Improves Endothelial Function in Renal Transplant Recipients, Transplant Proc., 2007, 39, 1139–1142.
182. V. Lagou, A. Greyling, M. G. Ferruzzi, S. S. Skene, J. Dubost, A. Demirkan, I. Prokopenko, J. Shlisky, A. Rodriguez-Mateos and C. Heiss, Impact of flavan-3-ols on blood pressure and endothelial function in diverse populations: a systematic review and meta-analysis of randomized controlled trials, Eur. J. Prev. Cardiol., 2025, 1–13.
183. J. M. Hodgson and K. D. Croft, Tea flavonoids and cardiovascular health, Mol. Aspects Med., 2010, 31, 495–502.
184. P. V. Dludla, B. B. Nkambule, S. E. Mazibuko-Mbeje, T. M. Nyambuya, P. Orlando, S. Silvestri, F. Marcheggiani, I. Cirilli, K. Ziqubu, F. Ndevahoma, V. Mxinwa, K. Mokgalaboni, J. Sabbatinelli, J. Louw and L. Tiano, Tea consumption and its effects on primary and secondary prevention of coronary artery disease: Qualitative synthesis of evidence from randomized controlled trials, Clin. Nutr. ESPEN, 2021, 41, 77–87.
185. S. Mithul Aravind, S. Wichienchot, R. Tsao, S. Ramakrishnan and S. Chakkaravarthi, Role of dietary polyphenols on gut microbiota, their metabolites and health benefits, Food Res. Int., 2021, 142, 110189.
186. F. Cardona, C. Andrés-Lacueva, S. Tulipani, F. J. Tinahones and M. I. Queipo-Ortuño, Benefits of polyphenols on gut microbiota and implications in human health, J. Nutr. Biochem., 2013, 24, 1415–1422.
187. P. Mena, R. Domínguez-Perles, A. Gironés-Vilaplana, N. Baenas, C. García-Viguera and D. Villaño, Flavan-3-ols, anthocyanins, and inflammation, Blackwell Publishing Ltd, 2014, preprint,  DOI:10.1002/iub.1332.
188. H. Schroeter, C. Heiss, J. Balzer, P. Kleinbongard, C. L. Keen, N. K. Hollenberg, H. Sies, C. Kwik-Uribe, H. H. Schmitz and M. Kelm, ()-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans, 2006.
189. D. Martini, M. Marino, S. Venturi, M. Tucci, D. Klimis-Zacas, P. Riso, M. Porrini and C. Del Bo, Blueberries and their bioactives in the modulation of oxidative stress, inflammation and cardio/vascular function markers: a systematic review of human intervention studies, Elsevier Inc., 2023, preprint,  DOI:10.1016/j.jnutbio.2022.109154.
190. G. Grosso, J. Godos, W. Currenti, A. Micek, L. Falzone, M. Libra, F. Giampieri, T. Y. Forbes-Hernández, J. L. Quiles, M. Battino, S. La Vignera and F. Galvano, The Effect of Dietary Polyphenols on Vascular Health and Hypertension: Current Evidence and Mechanisms of Action, Nutrients, 2022, 14, 545.
191. M. T. García-Conesa, K. Chambers, E. Combet, P. Pinto, M. Garcia-Aloy, C. Andrés-Lacueva, S. De Pascual-Teresa, P. Mena, A. K. Ristic, W. J. Hollands, P. A. Kroon, A. Rodríguez-Mateos, G. Istas, C. A. Kontogiorgis, D. K. Rai, E. R. Gibney, C. Morand, J. C. Espín and A. González-Sarrías, Meta-analysis of the effects of foods and derived products containing ellagitannins and anthocyanins on cardiometabolic biomarkers: Analysis of factors influencing variability of the individual responses, MDPI AG, 2018, preprint,  DOI:10.3390/ijms19030694.
192. C. Manach, A. Scalbert, C. Morand, C. Rémésy and L. Jiménez, Polyphenols: food sources and bioavailability, Am. J. Clin. Nutr., 2004, 79, 727–747.
193. G. Serreli and M. Deiana, Role of Dietary Polyphenols in the Activity and Expression of Nitric Oxide Synthases: A Review, Antioxidants, 2023, 12, 147.
194. M. Das, K. P. Devi, T. Belwal, H. P. Devkota, D. Tewari, A. Sahebnasagh, S. F. Nabavi, H. R. Khayat Kashani, M. Rasekhian, S. Xu, M. Amirizadeh, K. Amini, M. Banach, J. Xiao, S. Aghaabdollahian and S. M. Nabavi, Harnessing polyphenol power by targeting eNOS for vascular diseases, Crit. Rev. Food Sci. Nutr., 2023, 63, 2093–2118.
195. A. Rodriguez-Mateos, C. Heiss, G. Borges and A. Crozier, Berry (poly)phenols and cardiovascular health, American Chemical Society, 2014, preprint,  DOI:10.1021/jf403757g.
196. J. C. Espín, M. Larrosa, M. T. García-Conesa and F. Tomás-Barberán, Biological Significance of Urolithins, the Gut Microbial Ellagic Acid-Derived Metabolites: The Evidence So Far, Evidence-Based Complementary Altern. Med., 2013, 2013, 270418.
197. M. Gröne, R. Sansone, P. Höffken, P. Horn, A. Rodriguez-Mateos, H. Schroeter, M. Kelm and C. Heiss, Cocoa Flavanols Improve Endothelial Functional Integrity in Healthy Young and Elderly Subjects, J. Agric. Food Chem., 2020, 68, 1871–1876.
198. C. Heiss, A. Dejam, P. Kleinbongard, T. Schewe, H. Sies and M. Kelm, Vascular Effects of Cocoa Rich in Flavan-3-ols, J. Am. Med. Assoc., 2003, 290, 1030–1031.
199. M. Gómez-Juaristi, B. Sarria, S. Martínez-López, L. B. Clemente and R. Mateos, Flavanol bioavailability in two cocoa products with different phenolic content. A comparative study in humans, Nutrients, 2019, 11, 1441.
200. P. Mena, L. Bresciani, N. Brindani, I. A. Ludwig, G. Pereira-Caro, D. Angelino, R. Llorach, L. Calani, F. Brighenti, M. N. Clifford, C. I. R. Gill, A. Crozier, C. Curti and D. Del Rio, Phenyl-γ-valerolactones and phenylvaleric acids, the main colonic metabolites of flavan-3-ols: Synthesis, analysis, bioavailability, and bioactivity, Royal Society of Chemistry, 2019, preprint,  10.1039/c8np00062j.
201. H. M. Latif, S. R. Richardson and J. M. Marshall, Beneficial Effects of Cocoa Flavanols on Microvascular Responses in Young Men May Be Dependent on Ethnicity and Lifestyle, Nutrients, 2024, 16, 2911.
202. P. Mena, C. Favari, A. Acharjee, S. Chernbumroong, L. Bresciani, C. Curti, F. Brighenti, C. Heiss, A. Rodriguez-Mateos and D. Del Rio, Metabotypes of flavan-3-ol colonic metabolites after cranberry intake: elucidation and statistical approaches, Eur. J. Nutr., 2022, 61, 1299–1317.
203. C. Favari, J. F. R. de Alvarenga, L. Sánchez-Martínez, N. Tosi, C. Mignogna, E. Cremonini, C. Manach, L. Bresciani, D. Del Rio and P. Mena, Factors driving the inter-individual variability in the metabolism and bioavailability of (poly)phenolic metabolites: A systematic review of human studies, Elsevier B.V., 2024, preprint,  DOI:10.1016/j.redox.2024.103095.
204. G. Williamson and B. Holst, Dietary reference intake (DRI) value for dietary polyphenols: Are we heading in the right direction?, Br. J. Nutr., 2008, 99, S55–S58.
205. M. L. Castro-Acosta, T. A. B. Sanders, D. P. Reidlinger, J. Darzi and W. L. Hall, Adherence to UK dietary guidelines is associated with higher dietary intake of total and specific polyphenols compared with a traditional UK diet: Further analysis of data from the Cardiovascular risk REduction Study: Supported by an Integrated Dietary Approach (CRESSIDA) randomised controlled trial, Cambridge University Press, 2019, preprint,  DOI:10.1017/S0007114518003409.
206. D. Heimler, A. Romani and F. Ieri, Plant polyphenol content, soil fertilization and agricultural management: a review, Springer Verlag, 2017, preprint,  DOI:10.1007/s00217-016-2826-6.
207. L. Di Vittori, L. Mazzoni, M. Battino and B. Mezzetti, Pre-harvest factors influencing the quality of berries, Sci. Hortic., 2018, 233, 310–322.
208. A. M. M. Jalil and A. Ismail, Polyphenols in Cocoa and Cocoa Products: Is There a Link between Antioxidant Properties and Health?, Molecules, 2008, 13, 2190–2219.
209. J. I. Ottaviani, A. Britten, D. Lucarelli, R. Luben, A. A. Mulligan, M. A. Lentjes, R. Fong, N. Gray, P. B. Grace, D. H. Mawson, A. Tym, A. Wierzbicki, N. G. Forouhi, K. T. Khaw, H. Schroeter and G. G. C. Kuhnle, Biomarker-estimated flavan-3-ol intake is associated with lower blood pressure in cross-sectional analysis in EPIC Norfolk, Sci. Rep., 2020, 10, 1–14.
210. N. Ziauddeen, A. Rosi, D. Del Rio, B. Amoutzopoulos, S. Nicholson, P. Page, F. Scazzina, F. Brighenti, S. Ray and P. Mena, Dietary intake of (poly)phenols in children and adults: cross-sectional analysis of UK National Diet and Nutrition Survey Rolling Programme (2008–2014), Eur. J. Nutr., 2019, 58, 3183–3198.
211. N. P. Bondonno, B. H. Parmenter, A. S. Thompson, A. Jennings, K. Murray, D. B. Rasmussen, A. Tresserra-Rimbau, T. Kühn and A. Cassidy, Flavonoid intakes, chronic obstructive pulmonary disease, adult asthma, and lung function: a cohort study in the UK Biobank, Am. J. Clin. Nutr., 2024, 120, 1195–1206.
212. M. K. Khan, K. Ahmad, S. Hassan, M. Imran, N. Ahmad and C. Xu, Effect of novel technologies on polyphenols during food processing, Elsevier Ltd, 2018, preprint,  DOI:10.1016/j.ifset.2017.12.006.
213. N. P. Kelly, A. L. Kelly and J. A. O'Mahony, Strategies for enrichment and purification of polyphenols from fruit-based materials, Elsevier Ltd, 2019, preprint,  DOI:10.1016/j.tifs.2018.11.010.
214. A. Demangeat, H. Hornero-Ramirez, A. Meynier, P. Sanoner, F. S. Atkinson, J. A. Nazare and S. Vinoy, Complementary Nutritional Improvements of Cereal-Based Products to Reduce Postprandial Glycemic Response, Nutrients, 2023, 15, 4401.
215. P. Mena, L. Bresciani, M. Tassotti, A. Rosi, D. Martini, M. Antonini, A. D. Cas, R. Bonadonna, F. Brighenti and D. Del Rio, Effect of different patterns of consumption of coffee and a cocoa-based product containing coffee on the nutrikinetics and urinary excretion of phenolic compounds, Am. J. Clin. Nutr., 2021, 114, 2107–2118.
216. H. Cory, S. Passarelli, J. Szeto, M. Tamez and J. Mattei, The Role of Polyphenols in Human Health and Food Systems: A Mini-Review, Front. Nutr., 2018, 5, 370438.
217. P. Patanè, P. Laganà, P. Devi, A. Vig, M. A. Haddad, S. Natalello, M. A. Cava, S. M. Ameen and H. A. Hashim, Polyphenols and Functional Foods from the Regulatory Viewpoint, J. AOAC Int., 2019, 102, 1373–1377.
218. D. Arráez-Román, T. Leszczy'nska, L. Leszczy'nska, B. Borczak, J. Kapusta-Duch, N. C. Coşkun, S. S. Sarıtaş, M. Bechelany and S. Karav, Polyphenols in Foods and Their Use in the Food Industry: Enhancing the Quality and Nutritional Value of Functional Foods, Int. J. Mol. Sci., 2025, 26, 5803.
219. S. Olaitan Balogun, E. Lucas, D. Santos and M. El Oirdi, Harnessing the Power of Polyphenols: A New Frontier in Disease Prevention and Therapy, Pharmaceuticals, 2024, 17, 692.

---