Hostname: page-component-7c8c6479df-7qhmt Total loading time: 0 Render date: 2024-03-19T03:37:48.734Z Has data issue: false hasContentIssue false

The assessment of vascular function during dietary intervention trials in human subjects

Published online by Cambridge University Press:  01 July 2011

Damian O. McCall
Affiliation:
Centre for Public Health, Queen's University Belfast, Belfast, UK
Michelle C. McKinley
Affiliation:
Centre for Public Health, Queen's University Belfast, Belfast, UK
Rebecca Noad
Affiliation:
Centre for Public Health, Queen's University Belfast, Belfast, UK
Pascal P. McKeown
Affiliation:
Centre for Public Health, Queen's University Belfast, Belfast, UK
David R. McCance
Affiliation:
Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Grosvenor Road, Belfast, UK
Ian S. Young
Affiliation:
Centre for Public Health, Queen's University Belfast, Belfast, UK
Jayne V. Woodside*
Affiliation:
Centre for Public Health, Queen's University Belfast, Belfast, UK
*
*Corresponding author: Dr Jayne Woodside, fax +44 2890 235900, email j.woodside@qub.ac.uk
Rights & Permissions [Opens in a new window]

Abstract

The potential to reduce cardiovascular morbidity through dietary modification remains an area of intense clinical and scientific interest. Any putatively beneficial intervention should be tested within a randomised controlled trial which records appropriate endpoints, ideally incident CVD and death. However, the large sample sizes required for these endpoints and associated high costs mean that the majority of dietary intervention research is conducted over short periods among either healthy volunteers or those at only slightly increased risk, with investigators using a diverse range of surrogate measures to estimate arterial health in these studies. The present review identifies commonly employed techniques, discusses the relative merits of each and highlights emerging approaches.

Type
Review Article
Copyright
Copyright © The Authors 2011

Observational evidence linking particular dietary factors with a reduced incidence of cardiovascular morbidity and mortality has been used extensively to support various public health promotion strategies(Reference He, Nowson and MacGregor1, Reference Trichopoulou, Costacou and Bamia2). Increasingly, however, investigators are designing randomised controlled trials to confirm whether those diets or food groups may offer vascular protection. While hard clinical endpoints such as myocardial infarction, stroke and death are the ideal in such work, their use would necessitate prohibitively large, prolonged studies. The Dietary Approaches to Stop Hypertension (DASH) trial typifies much of the research in this field in that it recruited mildly hypertensive, but otherwise healthy, volunteers to an 8-week intervention(Reference Appel, Moore and Obarzanek3). While DASH was large enough to successfully employ a clinically relevant endpoint (brachial blood pressure), most dietary intervention studies rely on surrogate measures that will sensitively detect much earlier changes in arterial physiology. To underline this point, a recent meta-analysis considered randomised controlled trials which examined the link between flavonoids/flavonoid-rich foods and cardiovascular risk(Reference Hooper, Kroon and Rimm4). Of the 133 studies included, none had cardiovascular morbidity or mortality as endpoints.

A range of vascular function methodologies is available to clinical researchers, and the choice for any one study is usually governed by local expertise and experience. However, it is vital that nutrition researchers have a clear understanding of the metric which their chosen technique will generate, and how applicable this is to their overall research question.

Here we consider endothelial vasodilator function, pulse wave mechanic analysis and biomarker measurement in the evaluation of arterial health during nutrition intervention studies conducted among human volunteers.

Endothelial dysfunction

All blood vessels are lined by an active cellular monolayer, known as the endothelium, which is responsible for many vital aspects of vascular homeostasis(Reference Félétou and Vanhoutte5). Endothelial cells produce a wide range of paracrine mediators, with multiple beneficial actions including anti-thrombotic, anti-platelet, anti-inflammatory and vasodilatory effects(Reference Davignon and Ganz6). Established cardiovascular risk factors are known to encourage the evolution of an atherosclerotic plaque by unfavourably altering endothelial cell physiology(Reference Hansson7). Thus, assessing the status of endothelial cells in vivo through their ability to produce NO, and thus mediate arterial dilatation, is common in cardiovascular research(Reference Tousoulis, Antoniades and Stefanadis8). Provocation of NO production can be either mechanical (flow-mediated) or pharmacological.

Flow-mediated dilatation

Flow-mediated dilatation (FMD) describes arterial dilatation in response to increased intra-luminal shear stress. In humans, this phenomenon has been described using a forearm technique, in which reactive hyperaemia following release of an arm cuff at suprasystolic pressures mediates increased brachial artery diameter(Reference Celermajer, Sorensen and Gooch9). The vasodilatation can be quantified using B-mode ultrasound, and agreed protocols have been published to guide investigators using this procedure(Reference Corretti, Anderson and Benjamin10, Reference Deanfield, Donald and Ferri11). Since the technique does not involve needles, it has proven popular with researchers and less daunting for potential volunteers.

A growing body of research has not only demonstrated impaired brachial artery FMD among patients with recognised cardiovascular risk factors(Reference Lekakis, Papamichael and Vemmos12Reference Evans, Anderson and Graham14), but also suggests that the measure may serve as an independent prognostic indicator in both high-risk populations(Reference Brevetti, Silvestro and Schiano15Reference Patti, Pasceri and Melfi17) and healthy volunteers(Reference Yeboah, Crouse and Hsu18).

Brachial FMD has been employed by several groups as an endpoint during diet-related intervention trials. The effect of n-3 fatty acids on endothelial function has recently been reviewed(Reference Egert and Stehle19), as has the effect of fruit polyphenols(Reference Chong, Macdonald and Lovegrove20), berries(Reference Basu, Rhone and Lyons21) and green tea(Reference Moore, Jackson and Minihane22, Reference Wolfram23) on vascular health, and these reviews include studies using FMD endpoints. In Table 1 (Reference Balzer, Rassaf and Heiss24Reference Hermann, Spieker and Ruschitzka34), the intervention studies that have examined the effect of chocolate or cocoa on FMD are shown. Consumption of dark chocolate has been shown to improve brachial FMD, both acutely (six out of seven studies), and chronically (five out of six studies).

Table 1 Effect of cocoa or chocolate interventions on flow-mediated dilatation (FMD): evidence from randomised controlled trials

↑ , Significant increase; CAD, coronary artery disease; ↔ , no significant change.

While it provides a minimally invasive option for vascular function assessment, the measurement of brachial FMD does rely on considerable skill in ultrasound image acquisition and concerns about this technique's reproducibility have been expressed(Reference Sanderson, Sattar and Olthof35). De Roos et al. report substantial within-subject variability for FMD among healthy volunteers, with a CV estimated at approximately 50 %(Reference De Roos, Bots and Schouten36). Although much better CV figures (7–10 %) have been published by Deanfield's group(Reference Donald, Charakida and Cole37, Reference Donald, Halcox and Charakida38), there remains a concern that, when employed in smaller, less experienced centres, the technique's inherent variability precludes adequate study power. In addition, the NO dependency of FMD has been questioned(Reference Tschakovsky and Pyke39), such that this response is better considered a consequence of interplay between competing dilator and constrictor influences(Reference Mullen, Kharbanda and Cross40).

Another potential concern is that not all prospective studies have identified brachial FMD as an independent predictor of cardiovascular morbidity. Fathi et al. report no relationship between FMD and the risk of death, acute coronary syndrome or stroke among patients with established risk factors(Reference Fathi, Haluska and Isbel41). Austrian investigators note similar findings among patients undergoing coronary angiography(Reference Frick, Suessenbacher and Alber42) while in almost 3000 older adults, brachial artery diameter and FMD proved equally effective predictors of vascular outcome(Reference Yeboah, Crouse and Hsu18). However, although not always shown to be an independent predictor of cardiovascular events, this does not preclude its use as an endpoint in dietary intervention studies, as long as interpretation of the result is appropriate.

Despite these reservations, brachial FMD is widely regarded as the ‘gold standard’ technique by which to assess conduit vessel function in cardiovascular research(Reference Deanfield, Halcox and Rabelink43). However, before adopting FMD as the endpoint of choice, trial investigators should consider whether conduit vessel function is the best metric with which to detect any intervention-related effect. The response quantified in standard FMD protocols depends upon forearm ischaemia-induced hyperaemic flow, which is itself a function of reduced vascular resistance. The latter is determined largely by endothelium-dependent microvascular tone and thus measures of reactive hyperaemia have been suggested as novel arterial descriptors(Reference Widlansky44). Analysis of brachial ultrasound recordings from over 2000 Framingham volunteers showed that Doppler-derived indices of hyperaemic shear stress correlated better with established cardiovascular risk factors than did FMD(Reference Mitchell, Parise and Vita45). Huang et al. have shown that lower hyperaemic flow velocities in the brachial artery following a standard period of forearm ischaemia independently predicted postoperative morbidity and mortality among patients with peripheral arterial disease undergoing elective vascular surgery(Reference Huang, Silver and Shvenke46).

It has been speculated that the microvascular dysfunction implied by reduced hyperaemic flow responses may be more sensitive to early atherosclerotic change than are disturbances in conduit artery vasomotion as quantified by FMD(Reference Philpott and Anderson47). This has particular relevance for the design of dietary intervention trials which often seek to detect subtle changes in healthy volunteers. It would therefore be considered best practice to record FMD and reactive hyperaemia concurrently, as reactive hyperaemia can be measured simultaneously with FMD, using the same equipment.

Pharmacological provocation of endothelium-dependent vasomotion

Where FMD uses mechanical shear stress to provoke arterial endothelial vasodilator production, the local infusion of appropriate agonists can produce a similar effect. While based on well-established physiological and pharmacological principles, this approach does rely on successful arterial puncture.

Furchgott & Zawadzki's description of acetylcholine-mediated endothelium-dependent vasodilatation using isolated arterial segments in vitro was soon extended to in vivo human work(Reference Furchgott and Zawadzki48). Within the coronary circulation, direct intra-arterial injection of acetylcholine mediated vasoconstriction among patients with significant atherosclerotic lesions but dilated angiographically normal vessels(Reference Ludmer, Selwyn and Shook49). Several prospective studies among patients with clinical indications for cardiac catheterisation have established an abnormal coronary response to endothelium-dependent agonists as a powerful independent predictor of cardiovascular morbidity(Reference Al Suwaidi, Higano and Holmes50Reference Targonski, Bonetti and Pumper53). The potential risks associated with invasive cardiac assessment limit this technique's applicability to trials conducted in healthy volunteers. However, the forearm is an accessible and relatively safe vascular bed, in which pharmacological challenges analogous to those described for epicardial vessels can be performed.

While coronary procedures have relied upon quantitative angiography, forearm studies mainly employ venous occlusion plethysmography to measure the efficacy of intra-brachial vasodilators. Concordant, proportionate responses to acetylcholine have been described in synchronously infused coronary and brachial arteries(Reference Hirooka, Imaizumi and Tagawa54, Reference Tagawa, Mohri and Tagawa55). Poor forearm dilator responses to acetylcholine have been shown to predict increased rates of cardiovascular morbidity among hypertensive volunteers(Reference Perticone, Ceravolo and Pujia56) and patients with coronary artery disease(Reference Heitzer, Schlinzig and Krohn57, Reference Fichtlscherer, Breuer and Zeiher58).

It is important to appreciate that, when infused into the brachial artery, vasoactive agents exert their influence on forearm blood flow by modulating small vessel tone and this technique is thus an assessment of microvascular function(Reference Wilkinson and Webb59).

Forearm blood flow response to locally infused endothelium-dependent vasodilators has been used as an endpoint in several dietary intervention trials. Healthy adults who consumed a Mediterranean-style diet for 6 weeks showed significant improvements in endothelium-dependent forearm hyperaemia(Reference Singh, Graves and Taylor60, Reference Ambring, Friberg and Axelsen61); however, Ambring et al. subsequently reported negative findings for a similar 4-week intervention conducted among younger volunteers using the same endpoint(Reference Ambring, Friberg and Axelsen61). Investigators have also employed this technique to document the deleterious effects of increasing salt consumption. It was shown that 5 d of salt loading significantly reduced forearm blood flow responses to intra-brachial acetylcholine(Reference Tzemos, Lim and Wong62). Our group recently reported a significant dose-dependent relationship between increased dietary fruit and vegetable consumption and improved microvascular endothelial function, as quantified using this method(Reference McCall, McGartland and McKinley63).

However, the applicability of forearm blood flow manipulation through local vasodilator infusion to large, multi-centre clinical trials is limited by its reliance on arterial puncture, and the prospect of needle insertion is likely to prove inherently unattractive to many.

The most serious risks of brachial artery cannulation include occlusion of the artery leading to limb ischaemia, and median nerve damage due to direct trauma or compression by haematoma or infection. In reality, complications are rare, and usually involve minor bruising or local discomfort that resolve quickly, without intervention. It is, however, essential that this procedure is performed by an experienced researcher (with a background in vascular access and aseptic techniques) such as an intensivist, cardiologist or surgeon. This therefore restricts the use of this methodology to research centres with access to the aforementioned skilled operators, and also limits its use to smaller studies. The requirement for needle insertion may also deter participants, and those on oral anticoagulation or with significantly increased BMI must be excluded(Reference Wilkinson and Webb59, Reference Benjamin, Calver and Collier64, Reference Kennedy, Grocott and Schwartz65).

An alternative, less invasive, approach to pharmacological manipulation of the microvascular endothelium involves transdermal drug delivery by iontophoresis(Reference Morris and Shore66). A small electrical current is applied to the forearm and mediates movement of polar drugs such as acetylcholine into cutaneous vessels. Changes in skin blood flow are then quantified using laser Doppler flowmetry(Reference Kvandal, Stefanovska and Veber67). In a recent study, a strong correlation between this measure of skin microvasculature and FMD of the brachial artery was reported(Reference Debbabi, Bonnin and Ducluzeau68). Therefore, this may offer an alternative endpoint for future intervention trials, although the clinical relevance is, as yet, less established than for other methods.

A small number of trials have already used this endpoint, including a trial of fruit and vegetable purée-based drinks (a trend towards an effect shown on this endpoint in both acute and chronic settings)(Reference George, Niwat and Waroonphan69), a trial of a green tea polyphenol extract (no effect in the tested chronic setting)(Reference Frank, George and Lodge70), a study of acute fish oil consumption (effect on endpoint demonstrated)(Reference Armah, Jackson and Doman71) and a chronic study of weight reduction and exercise (no effect demonstrated)(Reference Hamdy, Ledbury and Mullooly72). A recent study of orange juice demonstrated an acute postprandial effect of orange juice or hesperidin consumption on microvascular reactivity, but no effect on fasting reactivity after 4 weeks of consumption(Reference Morand, Dubray and Milenkovic73).

Non-invasive assessment using pulse wave mechanics and pulse contour analysis

A range of commercially available devices offers clinical investigators the opportunity to rapidly acquire arterial descriptors, usually by non-invasively recording pulse pressure tracings through a device, which then computes one or more output variables. While user friendly and therefore popular, these techniques rely on important biomechanical assumptions which often complicate their applicability and interpretation.

Translating intermittent ejection of blood from the heart to smooth end-organ perfusion is a complex biomechanical process that relies on optimal ventricular–vascular coupling. A variety of mechanical arterial descriptors has been used to quantify unfavourable disease-related changes in this interaction(Reference Hamilton, Lockhart and Quinn74). Since these parameters are derived largely from non-invasive techniques, they have proved popular surrogate endpoints during intervention trials in cardiovascular medicine(Reference Deanfield, Halcox and Rabelink43). Popular methods include measuring pressure pulse wave velocity (PWV) across a particular arterial segment and calculating indices of vascular compliance by mathematical pulse contour analysis. The effects of dietary and nutrient interventions on these endpoints have recently been systematically reviewed(Reference Pase, Grima and Sarris75).

Pulse wave velocity

The velocity with which pressure pulse waves travel along an arterial segment can be mathematically related to that vessel's mechanical properties, by either the Moens–Kortweg or Bramwell–Hill equations(Reference Oliver and Webb76). These formulae predict that pressure pulse waves will travel faster in less distensible arteries and thus PWV is a commonly cited descriptor of ‘arterial stiffness’(Reference Hughes, Dixon and McVeigh77). A pressure transducer or tonometer is used to detect passage of the pulse wave between two anatomical locations. This can be done sequentially(Reference Schillaci, Pirro and Vaudo78) or simultaneously(Reference Laurent, Katsahian and Fassot79), with gating to a contemporaneously recorded electrocardiogram. The carotid and femoral arteries are commonly chosen tonometry sites, as this allows estimation of aortic PWV.

Prospective data are now available to suggest that carotid-femoral PWV (CFPWV) is an independent predictor of cardiovascular morbidity among healthy individuals(Reference Mattace-Raso, van der Cammen and Hofman80, Reference Willum-Hansen, Staessen and Torp-Pedersen81). While tonometry at the radial site is much more convenient for both volunteer and investigator, carotid-radial PWV did not predict coronary events or strokes among a group of patients with end-stage renal failure in whom CFPWV did have independent prognostic value(Reference Pannier, Guerin and Marchais82). This finding reflects structural distinctions between muscular forearm arteries and larger elastic vessels such as the aorta where medial cells have ectodermal rather than mesodermal origins(Reference Safar and Laurent83).

As the intra-luminal pressure within an artery increases, progressively more collagen fibres are recruited and thus its mechanical characteristics change(Reference Payne and Webb84). An intervention which reduces blood pressure is, therefore, also likely to reduce PWV independent of any pleiotropic effect on the arterial wall(Reference O'Rourke and Nichols85). This is an important caveat to the interpretation of any trial which employs PWV as an endpoint. Several recent trials have reported significant reductions in CFPWV following interventions including weight reduction(Reference Dengo, Dennis and Orr86), DASH(Reference Blumenthal, Babyak and Hinderliter87), low carbohydrate(Reference Keogh, Brinkworth and Noakes88) and low-glycaemic index(Reference Philippou, Bovill-Taylor and Rajkumar89) diets. However, in each case, significant blood pressure reductions are also recorded. Similarly, in a Na-loading study among hypertensive volunteers, changes in CFPWV were positively correlated with changes in brachial blood pressure(Reference Todd, Macginley and Schollum90), whilst 6 months' supplementation with conjugated linoleic acid(Reference Sluijs, Plantinga and de Roos91) or 2 weeks of dietary salt restriction(Reference Dickinson, Keogh and Clifton92) failed to alter either blood pressure or CFPWV. However, an isoflavone intervention over 6 weeks did mediate significantly slower CFPWV in healthy volunteers without 24 h ambulatory blood pressure reduction(Reference Teede, McGrath and DeSilva93).

In summary, if an intervention mediates a significant effect on arterial blood pressure, a concordant effect on PWV will be observed. This does not imply an alteration of vascular structure or function and can be predicted from arterial physiology.

Before choosing it as endpoint, investigators should postulate a mechanism by which their proposed intervention could change CFPWV. Through an in vitro model, impairment of local endothelial NO production has been shown to increase PWV across predefined arterial segments(Reference Wilkinson, MacCallum and Cockcroft94, Reference Schmitt, Avolio and Qasem95). Furthermore, brachial artery FMD has been independently associated with CFPWV in cross-sectional technique comparison studies among healthy volunteers(Reference McEniery, Wallace and Mackenzie96) and patients with isolated systolic hypertension(Reference Wallace, Yasmin and McEniery97). A significant, positive correlation between carotid-radial PWV and microvascular function in the forearm has also been described(Reference McCall, McGartland and Woodside98).

However, during the relatively brief trials that typify much human dietary intervention work it is questionable whether subtle alterations in levels of an endothelium-derived paracrine mediator could significantly change CFPWV which principally reflects aortic medial elastin:collagen ratios. Thus, this parameter is not ideal for use in short-term studies which aim to evaluate the possible endothelial effects of an intervention.

Pulse contour analysis

Palpation and analysis of the radial pulse as a means by which to assess systemic arterial health is a long-established practice in cardiovascular medicine(Reference Oparil and Izzo99). Algorithm-based reconstruction of the aortic pressure pulse from tonometer-derived radial waveforms has fuelled renewed interest in this approach(Reference O'Rourke and Nichols85). A commercially available device has been widely used in cardiovascular research to estimate the aortic augmentation index, a measure of arterial wave reflection(Reference Karamanoglu, O'Rourke and Avolio100, Reference Chen, Nevo and Fetics101). Since it is non-invasive, requires minimal training and generates an easily interpretable numeric output, this technique has proved popular in cardiovascular research.

Among patients undergoing cardiac catheterisation, those in the highest quartile of augmentation index had significantly more coronary disease(Reference Weber, Auer and O'Rourke102). Similarly, patients with end-stage renal failure who had higher augmentation indices were more likely to die during an 8-year follow-up period(Reference London, Blacher and Pannier103). However, a recent review of arterial stiffness by The Framingham Heart Study found that whilst a higher aortic PWV was associated with a 48 % increase in cardiovascular events, the aortic augmentation index, central pulse pressure and pulse pressure amplification showed no such correlation(Reference Mitchell, Hwang and Ramachandran104). Like PWV, the aortic augmentation index is dependent on distending arterial blood pressure(Reference Booth, Wallace and McEniery105, Reference Dart, Gatzka and Cameron106), but additional variables, including height(Reference Yasmin and Brown107) and heart rate(Reference Wilkinson, MacCallum and Flint108), must be factored in to its interpretation.

A number of nutrition intervention studies have used pulse contour analysis as an intermediate measure of vascular function. In an acute feeding study, food and water, but not water alone, reduced the aortic augmentation index 2 h after consumption(Reference Ahuja, Robertson and Ball109). This finding is confounded by concomitant decreases in arterial blood pressure and could be argued to reflect mean blood pressure change and therefore altered vessel haemodynamics, rather than an intrinsic alteration of vascular function. After 8 weeks, both low-fat and low-carbohydrate hypoenergetic diets significantly decreased brachial blood pressure among overweight volunteers, but only the former mediated a significant reduction in aortic augmentation(Reference Bradley, Spence and Courtney110).

Again, investigators should have a clear hypothesis about the mechanism through which their intervention is likely to alter pulse wave morphology before choosing aortic augmentation as the endpoint. It has been shown that pharmacological manipulation of systemic endothelial NO production significantly changes aortic pressure pulse wave morphology and thus the augmentation index(Reference McEniery, Wallace and Mackenzie96). In a situation analogous to the intra-brachial infusion of vasodilators and subsequent forearm blood flow measurement, systemic salbutamol (endothelium-dependent) and nitroglycerine (endothelium-independent) are administered with resulting changes in tonometry-derived aortic augmentation quantified to arrive at a ‘global endothelial function index’(Reference McEniery, Wallace and Mackenzie96). Such an approach may prove more sensitive to altered vascular health than resting measurements of aortic augmentation.

Biomarkers of vascular function

Biomarker measurement remains a popular endpoint in clinical research, as it is minimally invasive and samples can be stored for future analysis. A wide variety of biochemical species has been employed to quantify inflammation, oxidative stress, endothelial activation and arterial injury. Since no single ‘gold standard’ measure has emerged, it is common practice during dietary research trials to employ a panel of such markers.

Biochemical measures

Since atherosclerosis is characterised by ongoing vascular inflammation, the acute-phase reactant C-reactive protein (CRP) has been proposed as a useful tool for improving disease prediction models(Reference Albert and Ridker111). A high-sensitivity assay is used to accurately measure the lower CRP concentrations encountered among healthy individuals. Recent data suggest that statin-mediated reductions in CRP are associated with lower rates of cardiovascular morbidity(Reference Ridker, Danielson and Fonseca112).

The evidence regarding dietary interventions and CRP is equivocal. For example, as summarised in Table 2 (Reference Berry, Mulla and Chowienczyk113Reference Watzl, Kulling and Moseneder128), only five out of sixteen fruit and vegetable randomised controlled trials (including Mediterranean diet and DASH trials, as fruit and vegetables are key components of these diets) have demonstrated a lowering in CRP levels. The duration of these five studies varied from 4 weeks in three studies, to 3 months in one study and 2 years in another. Of the studies, two were juice-based, one was a carotenoid-rich FV intervention and two were Mediterranean diet interventions. We refer the reader to a review by Giugliano et al. (Reference Giugliano, Ceriello and Esposito129) for a broader discussion of the association between diet and inflammation.

Table 2 Effect of fruit and vegetable (FV) interventions on C-reactive protein (CRP): evidence from randomised controlled trials

↔ , No significant change; ↓ , significant decrease; DASH, Dietary Approaches to Stop Hypertension; VBA, vegetables, berries and apples; CAD, coronary artery disease.

* Orange and blackcurrant juice reduced CRP relative to sugar drink.

CRP decreased only after Mediterranean diet with olive oil.

In mediating leucocytic infiltration of the arterial intima, glycoprotein membrane components such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) promote oxidative stress and ongoing arterial inflammation(Reference Ferrario and Strawn130). Activated endothelial cells are thought to shed these molecules into the circulation, allowing levels of their soluble form to be quantified as an estimate of ongoing arterial injury(Reference Hwang, Ballantyne and Sharrett131). Adipocytes also express ICAM-1, and the soluble form of ICAM-1 is elevated in obese patients, being expressed in the stromal-vascular fraction of adipose tissue(Reference Brake, O'Brian Smith and Mersmann132). This is likely to contribute to the link between obesity and inflammatory complications such as atherosclerosis.

Supplementation with isoflavones for 6 weeks has been reported to significantly reduce serum levels of VCAM-1 in healthy subjects(Reference Teede, McGrath and DeSilva93), while additional dietary α-linolenic acid had a similar effect among dyslipidaemic male patients(Reference Rallidis, Paschos and Papaioannou133). Over a 24-month period, daily consumption of the phyto-oestrogen genistein significantly reduced circulating levels of both ICAM-1 and VCAM-1(Reference Atteritano, Marini and Minutoli134). While additional cherry consumption for 4 weeks lowered CRP levels among healthy volunteers, it had no effect on ICAM-1 concentrations(Reference Kelley, Rasooly and Jacob135) and similar negative results have been noted for brief fruit and vegetable interventions(Reference Paterson, Gordon and Niwat125).

Oxidation both contributes to and follows on from the continuous cycle of low-grade vascular inflammation which characterises atherosclerotic arterial degeneration(Reference Chisolm and Steinberg136). Markers of systemic oxidative stress in biological fluids have long been suggested as surrogates for vascular injury, and the isoprostanes, derived from non-enzymic arachidonic acid peroxidation, are commonly measured(Reference Roberts and Morrow137). A dietary intervention study has reported that urinary levels of 8-iso-PGF were significantly reduced among healthy women consuming nine or ten portions of fruit and vegetables daily for 8 weeks(Reference Thompson, Heimendinger and Sedlacek138). However, investigators have largely reported negative findings when this endpoint has been employed to study the effects of black tea(Reference O'Reilly, Mallet and McAnlis139), a Mediterranean diet(Reference Ambring, Friberg and Axelsen61), five or six portions of fruit and vegetables daily(Reference McCall, McGartland and Woodside98, Reference Thompson, Heimendinger and Sedlacek138) and pure dietary flavonoids(Reference Loke, Hodgson and Proudfoot140).

Other potential biomarkers of the atherosclerotic process include the enzyme lipoprotein-associated phospholipase A2(Reference Zalewski and Macphee141, Reference Packard, O'Reilly and Caslake142), tissue plasminogen activator(Reference Thogerson, Jansson and Boman143, Reference Thompson, Kienast and Pyke144) and plasminogen activator inhibitor-1(Reference Hamsten, de Faire and Walldius145).

Novel biochemical approaches

The array of biomarkers available and lack of an agreed ‘gold standard’ often prohibits rational study design. To quantify the biological effects of an ‘anti-inflammatory mix’ dietary supplement among obese volunteers, Bakker et al. employed a novel ‘nutrigenomics’ approach(Reference Bakker, van Erk and Pellis146). This involved measurement and integrated analysis of 120 plasma proteins, 274 plasma metabolites and peripheral blood cell transcriptomes. While such a comprehensive approach is labour intensive and statistically complex, it may represent a valuable means by which to define more subtle intervention-related changes.

More recently, circulating endothelial microparticles (EMP), endothelial progenitor cells and endothelial cells have also been used as indices of vascular health.

Endothelial microparticles

The endothelium is responsible for a diverse range of functions, including regulation of vascular vasomotor activity, coagulation activity, anti-inflammatory status, and therefore a comprehensive assessment of endothelial function or dysfunction is difficult, with available methods usually only providing information on one separate aspect of endothelial function. It has been proposed recently that EMP may fulfil the role of a more universal marker of vascular health(Reference Shantsila147). EMP are small non-nucleated phospholipid vesicles shed from injured endothelial cells in response to pro-inflammatory stimuli and vascular injury. They affect endothelial NO synthesis(Reference Amabile, Guerin and Leroyer148, Reference Boulanger, Scoazec and Ebrahimian149), diminishing acetylcholine-induced vasorelaxation and NO production by endothelial cells in vitro (Reference Brodsky, Malinowski and Golightly150), correlate with markers of inflammation(Reference Shantsila147), and have pro-coagulant potential(Reference Shantsila147, Reference Mallat, Benamer and Hugel151Reference Jimenez, Jy and Mauro153).

A number of studies have examined EMP in relation to vascular damage and CVD risk. A significant increase in EMP has been shown in patients with CHD, the metabolic syndrome, diabetes and heart failure(Reference Mallat, Hugel and Ohan154Reference Garcia, Chirinos and Jiminez158). A recent study by Wang et al. has shown that EMP count is associated with systolic blood pressure, being elevated even in patients with mild hypertension, and was also associated with arterial stiffness(Reference Wang, Su and Wang159). Wang et al. suggest that EMP may be a useful parameter for monitoring the process of vascular repair in hypertensive subjects, whilst the accompanying Editorial calls for further studies to determine whether EMP quantification might be a useful marker of endothelial dysfunction(Reference Shantsila147). Their use in dietary intervention research has been limited to date, but circulating microparticle concentrations are known to increase after ingestion of a fatty meal(Reference Harrison, Murphy and O'Connor160), whilst a recent paper has shown that following a Mediterranean diet for 4 weeks in older subjects significantly decreased total microparticle, EMP and apoptotic EMP concentrations when compared with a SFA-rich diet or a low-fat, high-carbohydrate diet(Reference Marin, Ramirez and Delgado-Lista161). They therefore potentially offer a novel and informative endpoint.

Endothelial progenitor cells

Asahara et al. isolated and characterised a circulating angioblast which had the potential to form endothelial cells in vitro, thus allowing subsequent quantitative flow cytometry in samples of peripheral blood(Reference Asahara, Murohara and Sullivan162). Endothelial progenitor cells (EPC) have a constitutive vasoreparative function, but after acute vascular damage, such as stroke or myocardial infarction, these cells are mobilised into peripheral blood where they participate in endothelial repair, regenerative processes and neovascularisation(Reference Shintani, Murohara and Ikeda163, Reference Wojakowski, Tendera and Michalowska164). It has been proposed that assessment of endothelial progenitor cells offers a dynamic, integrated index of systemic vascular damage and, as such, will offer more insight than any currently available biochemical markers(Reference Werner and Nickenig165). While a wide range of EPC subsets have been identified, most clinical studies have concentrated on CD34+ populations isolated from peripheral blood. An inverse relationship between circulating CD34+ EPC and cardiovascular risk factors has been demonstrated in both healthy subjects and patients with CVD(Reference Vasa, Fichtlscherer and Aicher166, Reference Hill, Zalos and Halcox167), whilst circulating EPC count may also act as a prognostic biomarker, being associated with worse outcome in patients with suspected or confirmed coronary artery disease(Reference Werner, Kosiol and Schiegl168). A recent study has shown that circulating CD34+ cells are inversely associated with obesity, and that weight loss results in an increase in circulating progenitor cells, including EPC(Reference Müller-Ehmsen, Braun and Schneider169).

Among healthy volunteers, short-term dietary interventions with green tea(Reference Kim, Jeong and Cho170), vegetables(Reference Mano, Ishida and Ohya171), red wine(Reference Huang, Chen and Tsai172) and the Mediterranean diet(Reference Marin, Ramirez and Delgado-Lista161) have all been shown to significantly increase circulating concentrations of endothelial progenitor cells. Assessing EPC numbers and function may also be informative, as increasing red wine consumption in healthy volunteers has recently been shown to increase endothelial progenitor cell migration and proliferation and to decrease the extent of apoptosis(Reference Hamed, Alshiek and Aharon173), whilst a high-flavanol intervention has been shown to increase EPC number, but had no effect on their function (measured as ability to survive, differentiate, proliferate and to migrate)(Reference Heiss, Jahn and Taylor33).

Circulating endothelial cells

Circulating endothelial cells are also recognised as markers of endothelial damage, and have been shown to be increased in acute coronary syndromes, heart failure, stroke and diabetes mellitus(Reference Boof, Lip and Blann174). Although no dietary intervention studies have examined effects on numbers of circulating endothelial cells, they may be an informative target in future studies.

Considerations when choosing a method

Investigators should first consider the mechanism through which they propose that the intervention will act, alongside the locally available resources and skills. A decision tree outlining the main considerations and choices is shown in Fig. 1. A panel of approaches, assessing both conduit vessels and the microvasculature, would be most appropriate where possible. Recent studies using different vascular function methodologies, although also with variation in study designs and populations, have demonstrated contrasting results, despite similar interventions(Reference McCall, McGartland and McKinley63, Reference Berry, Mulla and Chowienczyk113), and such a panel of endpoints may well have been informative in explaining these differing results. The choice of method may depend on whether investigators propose and are testing an acute or chronic effect of the dietary intervention. Investigators should also consider whether effects of the intervention are likely to be demonstrated in the fasting or postprandial state, as a recent study of n-3 fatty acids has demonstrated effects on postprandial macro- and microvascular function, but no effect on fasting measures(Reference Stirban, Nandrean and Gotting175).

Fig. 1 Decision tree when considering method of vascular function assessment.

The confounding effects of blood pressure must be considered when interpreting study results. Changes in blood pressure, and therefore blood flow, will also cause changes in the FMD of a conduit artery, and which do not necessarily reflect a change in the endothelial function of that vessel(Reference Corretti, Anderson and Benjamin10). Forearm blood flow and PWV will also be affected by changes in blood pressure. In summary, if an intervention mediates a significant change in arterial blood pressure, a concordant effect on other vascular assessments will be observed. This does not imply an alteration of vascular structure or function and can be predicted from arterial physiology.

Conclusions

A wide variety of techniques are employed to provide surrogate vascular endpoints for short-term dietary trials in human subjects. FMD of the brachial artery and aortic PWV examine conduit and large elastic vessel properties respectively, and therefore do not estimate arterial function at a microvascular level where the bulk of endothelial cells are found.

The mechanism through which an investigator believes their intervention will act, combined with the resources and skill set of the investigating team, will most probably influence the choice of assessment method. At present no single, all-encompassing vascular function test exists, and perhaps a more useful approach would be to combine several methods to comprehensively assess arterial function and mechanics at multiple sites.

Potentially useful emerging techniques include the analysis of post-ischaemic arterial waveforms during FMD determination, quantifying pulse contour changes in response to vasodilator challenges and measuring circulating endothelial progenitor cell and microparticle concentrations.

Acknowledgements

The present study received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

D. O. M. produced the first draft of the review. All other authors contributed substantially in terms of drafting, critical reviewing and editing subsequent versions of the manuscript.

None of the authors has any conflicts of interest to declare.

References

1 He, FJ, Nowson, CA & MacGregor, GA (2006) Fruit and vegetable consumption and stroke: meta-analysis of cohort studies. Lancet 367, 320326.CrossRefGoogle ScholarPubMed
2 Trichopoulou, A, Costacou, T, Bamia, C, et al. (2003) Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 348, 25992608.CrossRefGoogle Scholar
3 Appel, LJ, Moore, TJ, Obarzanek, E, et al. (1997) A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med 336, 11171124.CrossRefGoogle ScholarPubMed
4 Hooper, L, Kroon, PA, Rimm, EB, et al. (2008) Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr 88, 3850.CrossRefGoogle ScholarPubMed
5 Félétou, M & Vanhoutte, PM (2006) Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture). Am J Physiol Heart Circ Physiol 291, H985H1002.CrossRefGoogle ScholarPubMed
6 Davignon, J & Ganz, P (2004) Role of endothelial dysfunction in atherosclerosis. Circulation 109, Suppl. 1, 2732.CrossRefGoogle ScholarPubMed
7 Hansson, GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352, 16851695.CrossRefGoogle ScholarPubMed
8 Tousoulis, D, Antoniades, C & Stefanadis, C (2005) Evaluating endothelial function in humans: a guide to invasive and non-invasive techniques. Heart 91, 553558.CrossRefGoogle ScholarPubMed
9 Celermajer, DS, Sorensen, KE, Gooch, VM, et al. (1992) Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340, 11111115.CrossRefGoogle ScholarPubMed
10 Corretti, MC, Anderson, TJ, Benjamin, EJ, et al. (2002) 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. J Am Coll Cardiol 39, 257265.CrossRefGoogle ScholarPubMed
11 Deanfield, J, Donald, A, Ferri, C, et al. (2005) Endothelial function and dysfunction. Part I: Methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. J Hypertens 23, 717.CrossRefGoogle Scholar
12 Lekakis, J, Papamichael, C, Vemmos, C, et al. (1997) Effect of acute cigarette smoking on endothelium-dependent brachial artery dilatation in healthy individuals. Am J Cardiol 79, 529531.CrossRefGoogle ScholarPubMed
13 Schnell, GB, Robertson, A, Houston, D, et al. (1999) Impaired brachial artery endothelial function is not predicted by elevated triglycerides. J Am Coll Cardiol 33, 20382043.CrossRefGoogle Scholar
14 Evans, M, Anderson, RA, Graham, J, et al. (2000) Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus. Circulation 101, 17731779.CrossRefGoogle ScholarPubMed
15 Brevetti, G, Silvestro, A, Schiano, V, et al. (2003) Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to ankle-brachial pressure index. Circulation 108, 20932098.CrossRefGoogle ScholarPubMed
16 Gokce, N, Keaney, JF Jr, Hunter, LM, et al. (2002) Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. Circulation 105, 15671572.CrossRefGoogle ScholarPubMed
17 Patti, G, Pasceri, V, Melfi, R, et al. (2005) Impaired flow-mediated dilation and risk of restenosis in patients undergoing coronary stent implantation. Circulation 111, 7075.CrossRefGoogle ScholarPubMed
18 Yeboah, J, Crouse, JR, Hsu, FC, et al. (2007) Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study. Circulation 115, 23902397.CrossRefGoogle ScholarPubMed
19 Egert, S & Stehle, P (2011) Impact of n-3 fatty acids on endothelial function: results from human intervention studies. Curr Opin Nutr Metab Care 14, 121131.CrossRefGoogle Scholar
20 Chong, MF, Macdonald, R & Lovegrove, JA (2010) Fruit polyphenols and CVD risk: a review of human intervention studies. Br J Nutr 104, S28S39.CrossRefGoogle Scholar
21 Basu, A, Rhone, M & Lyons, TJ (2010) Berries: emerging impact on cardiovascular health. Nutr Rev 68, 168177.CrossRefGoogle ScholarPubMed
22 Moore, RJ, Jackson, KG & Minihane, AM (2009) Green tea (Camellia sinensis) catechins and vascular function. Br J Nutr 102, 17901802.CrossRefGoogle ScholarPubMed
23 Wolfram, S (2007) Effects of green tea and EGCG on cardiovascular and metabolic health. J Am Coll Nutr 26, 373S388S.CrossRefGoogle ScholarPubMed
24 Balzer, J, Rassaf, T, Heiss, C, et al. (2008) Sustained benefits in vascular function through flavanol-containing cocoa in medicated diabetic patients. J Am Coll Cardiol 51, 21412149.CrossRefGoogle ScholarPubMed
25 Berry, NM, Davison, K, Coates, AM, et al. (2010) Impact of cocoa flavanol consumption on blood pressure responsiveness to exercise. Br J Nutr 103, 14801484.CrossRefGoogle ScholarPubMed
26 Davison, K, Coates, AM, Buckley, JD, et al. (2008) Effect of cocoa flavanols and exercise on cardiometabolic risk factors in overweight and obese subjects. Int J Obes 32, 12891296.CrossRefGoogle ScholarPubMed
27 Engler, MB, Engler, MM, Chen, YV, et al. (2004) Flavonoid-rich dark chocolate improves endothelial function and increases plasma epicatechin concentrations in healthy adults. J Am Coll Nutr 23, 197204.CrossRefGoogle ScholarPubMed
28 Faridi, Z, Njike, VY, Dutta, S, et al. (2008) Acute dark chocolate and cocoa ingestion and endothelial function: a randomised controlled crossover trial. Am J Clin Nutr 88, 5863.CrossRefGoogle Scholar
29 Farouque, HMO, Leung, M, Hope, SA, et al. (2006) Acute and chronic effects of flavanol-rich cocoa on vascular function in subjects with coronary artery disease: a randomised double-blind placebo-controlled study. Clin Sci 111, 7180.CrossRefGoogle Scholar
30 Grassi, D, Necozione, S, Lippi, C, et al. (2005) Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension 46, 398405.CrossRefGoogle ScholarPubMed
31 Heiss, C, Dejam, A, Kleinbongard, P, et al. (2003) Vascular effects of cocoa rich in flavan-3-ols. JAMA 290, 10301031.CrossRefGoogle Scholar
32 Heiss, C, Finis, D, Kleinbongard, P, et al. (2007) Sustained increase in flow-mediated dilation after daily intake of high-flavanol cocoa drink over 1 week. J Cardiovasc Pharmacol 49, 7480.CrossRefGoogle ScholarPubMed
33 Heiss, C, Jahn, S, Taylor, M, et al. (2010) Improvement of endothelial function with dietary flavanols is associated with mobilisation of circulating angiogenic cells in patients with coronary artery disease. J Am Coll Cardiol 56, 218224.CrossRefGoogle ScholarPubMed
34 Hermann, F, Spieker, LE, Ruschitzka, F, et al. (2006) Dark chocolate improves endothelial and platelet function. Heart 92, 119120.CrossRefGoogle ScholarPubMed
35 Sanderson, P, Sattar, N, Olthof, M, et al. (2004) Dietary lipids and vascular function: UK Food Standards Agency workshop report. Br J Nutr 91, 491500.CrossRefGoogle ScholarPubMed
36 De Roos, NM, Bots, ML, Schouten, EG, et al. (2003) Within-subject variability of flow-mediated vasodilation of the brachial artery in healthy men and women: implications for experimental studies. Ultrasound Med Biol 29, 401406.CrossRefGoogle ScholarPubMed
37 Donald, AE, Charakida, M, Cole, TJ, et al. (2006) Non-invasive assessment of endothelial function: which technique? J Am Coll Cardiol 48, 18461850.CrossRefGoogle ScholarPubMed
38 Donald, AE, Halcox, JP, Charakida, M, et al. (2008) Methodological approaches to optimize reproducibility and power in clinical studies of flow-mediated dilation. J Am Coll Cardiol 51, 19591964.CrossRefGoogle ScholarPubMed
39 Tschakovsky, ME & Pyke, KE (2005) Counterpoint: flow-mediated dilation does not reflect nitric oxide-mediated endothelial function. J Appl Physiol 99, 12351237.CrossRefGoogle Scholar
40 Mullen, MJ, Kharbanda, RK, Cross, J, et al. (2001) Heterogenous nature of flow-mediated dilatation in human conduit arteries in vivo: relevance to endothelial dysfunction in hypercholesterolemia. Circ Res 88, 145151.CrossRefGoogle ScholarPubMed
41 Fathi, R, Haluska, B, Isbel, N, et al. (2004) The relative importance of vascular structure and function in predicting cardiovascular events. J Am Coll Cardiol 43, 616623.CrossRefGoogle ScholarPubMed
42 Frick, M, Suessenbacher, A, Alber, HF, et al. (2005) Prognostic value of brachial artery endothelial function and wall thickness. J Am Coll Cardiol 46, 10061010.CrossRefGoogle ScholarPubMed
43 Deanfield, JE, Halcox, JP & Rabelink, TJ (2007) Endothelial function and dysfunction: testing and clinical relevance. Circulation 115, 12851295.CrossRefGoogle ScholarPubMed
44 Widlansky, ME (2009) Shear stress and flow-mediated dilation: all shear responses are not created equally. Am J Physiol Heart Circ Physiol 296, H31H32.CrossRefGoogle Scholar
45 Mitchell, GF, Parise, H, Vita, JA, et al. (2004) Local shear stress and brachial artery flow-mediated dilation: the Framingham Heart Study. Hypertension 44, 134139.CrossRefGoogle ScholarPubMed
46 Huang, AL, Silver, AE, Shvenke, E, et al. (2007) Predictive value of reactive hyperemia for cardiovascular events in patients with peripheral arterial disease undergoing vascular surgery. Arterioscler Thromb Vasc Biol 27, 21132119.CrossRefGoogle ScholarPubMed
47 Philpott, A & Anderson, TJ (2007) Reactive hyperemia and cardiovascular risk. Arterioscler Thromb Vasc Biol 27, 20652067.CrossRefGoogle ScholarPubMed
48 Furchgott, RF & Zawadzki, JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288, 373376.CrossRefGoogle ScholarPubMed
49 Ludmer, PL, Selwyn, AP, Shook, TL, et al. (1986) Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 315, 10461051.CrossRefGoogle ScholarPubMed
50 Al Suwaidi, J, Higano, ST, Holmes, DR Jr, et al. (2001) Obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries. J Am Coll Cardiol 37, 15231528.CrossRefGoogle ScholarPubMed
51 Schachinger, V, Britten, MB & Zeiher, AM (2000) Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101, 18991906.CrossRefGoogle ScholarPubMed
52 Halcox, JP, Schenke, WH, Zalos, G, et al. (2002) Prognostic value of coronary vascular endothelial dysfunction. Circulation 106, 653658.CrossRefGoogle ScholarPubMed
53 Targonski, PV, Bonetti, PO, Pumper, GM, et al. (2003) Coronary endothelial dysfunction is associated with an increased risk of cerebrovascular events. Circulation 107, 28052809.CrossRefGoogle ScholarPubMed
54 Hirooka, Y, Imaizumi, T, Tagawa, T, et al. (1994) Effects of l-arginine on impaired acetylcholine-induced and ischemic vasodilation of the forearm in patients with heart failure. Circulation 90, 658668.CrossRefGoogle ScholarPubMed
55 Tagawa, T, Mohri, M, Tagawa, H, et al. (1997) Role of nitric oxide in substance P-induced vasodilation differs between the coronary and forearm circulation in humans. J Cardiovasc Pharmacol 29, 546553.CrossRefGoogle ScholarPubMed
56 Perticone, F, Ceravolo, R, Pujia, A, et al. (2001) Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation 104, 191196.CrossRefGoogle ScholarPubMed
57 Heitzer, T, Schlinzig, T, Krohn, K, et al. (2001) Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 104, 26732678.CrossRefGoogle ScholarPubMed
58 Fichtlscherer, S, Breuer, S & Zeiher, AM (2004) Prognostic value of systemic endothelial dysfunction in patients with acute coronary syndromes: further evidence for the existence of the “vulnerable” patient. Circulation 110, 19261932.CrossRefGoogle ScholarPubMed
59 Wilkinson, IB & Webb, DJ (2001) Venous occlusion plethysmography in cardiovascular research: methodology and clinical applications. Br J Clin Pharmacol 52, 631646.CrossRefGoogle ScholarPubMed
60 Singh, N, Graves, J, Taylor, PD, et al. (2002) Effects of a ‘healthy’ diet and of acute and long-term vitamin C on vascular function in healthy older subjects. Cardiovasc Res 56, 118125.CrossRefGoogle ScholarPubMed
61 Ambring, A, Friberg, P, Axelsen, M, et al. (2004) Effects of a Mediterranean-inspired diet on blood lipids, vascular function and oxidative stress in healthy subjects. Clin Sci 106, 519525.CrossRefGoogle ScholarPubMed
62 Tzemos, N, Lim, PO, Wong, S, et al. (2008) Adverse cardiovascular effects of acute salt loading in young normotensive individuals. Hypertension 51, 15251530.CrossRefGoogle ScholarPubMed
63 McCall, DO, McGartland, CP, McKinley, MC, et al. (2009) Dietary intake of fruits and vegetables improves microvascular function in hypertensive subjects in a dose-dependent manner. Circulation 119, 21532160.CrossRefGoogle ScholarPubMed
64 Benjamin, N, Calver, A, Collier, J, et al. (1995) Measuring forearm blood flow and interpreting the responses to drugs and mediators. Hypertension 25, 918923.CrossRefGoogle ScholarPubMed
65 Kennedy, AM, Grocott, M, Schwartz, MS, et al. (1997) Median nerve injury: an underrecognised complication of brachial artery cardiac catheterisation? J Neurol Neurosurg Psychiatry 63, 542546.CrossRefGoogle ScholarPubMed
66 Morris, SJ & Shore, AC (1996) Skin blood flow responses to the iontophoresis of acetylcholine and sodium nitroprusside in man: possible mechanisms. J Physiol (Lond) 496, 531542.CrossRefGoogle Scholar
67 Kvandal, P, Stefanovska, A, Veber, M, et al. (2003) Regulation of human cutaneous circulation evaluated by laser Doppler flowmetry, iontophoresis, and spectral analysis: importance of nitric oxide and prostaglandines. Microvasc Res 65, 160171.CrossRefGoogle ScholarPubMed
68 Debbabi, H, Bonnin, P, Ducluzeau, PH, et al. (2010) Noninvasive assessment of endothelial function in the skin microcirculation. Am J Hypertens 23, 541546.CrossRefGoogle ScholarPubMed
69 George, TW, Niwat, C, Waroonphan, S, et al. (2009) Effects of chronic and acute consumption of fruit- and vegetable-puree-based drinks on vasodilation, risk factors for CVD and the response as a result of the eNOS G298T polymorphism. Proc Nutr Soc 68, 148161.CrossRefGoogle ScholarPubMed
70 Frank, J, George, TW, Lodge, JK, et al. (2009) Daily consumption of an aqueous green tea extract supplement does not impair liver function or alter cardiovascular disease risk biomarkers in healthy men. J Nutr 139, 5862.CrossRefGoogle ScholarPubMed
71 Armah, CK, Jackson, KG, Doman, I, et al. (2008) Fish oil fatty acids improve postprandial vascular reactivity in healthy men. Clin Sci 114, 679686.CrossRefGoogle ScholarPubMed
72 Hamdy, O, Ledbury, S, Mullooly, C, et al. (2003) Lifestyle modification improves endothelial function in obese subjects with the insulin resistance syndrome. Diabetes Care 26, 21192125.CrossRefGoogle ScholarPubMed
73 Morand, C, Dubray, C, Milenkovic, D, et al. (2011) Hesperidin contributes to the vascular protective effects of orange juice: a randomised crossover study in healthy volunteers. Am J Clin Nutr 93, 7380.CrossRefGoogle Scholar
74 Hamilton, PK, Lockhart, CJ, Quinn, CE, et al. (2007) Arterial stiffness: clinical relevance, measurement and treatment. Clin Sci 113, 157170.CrossRefGoogle ScholarPubMed
75 Pase, MP, Grima, NA & Sarris, J (2011) The effects of dietary and nutrient interventions on arterial stiffness: a systematic review. Am J Clin Nutr 93, 446454.CrossRefGoogle ScholarPubMed
76 Oliver, JJ & Webb, DJ (2003) Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol 23, 554566.CrossRefGoogle ScholarPubMed
77 Hughes, SM, Dixon, LJ & McVeigh, GE (2004) Arterial stiffness and pulse wave velocity: problems with terminology. Circulation 109, e3.CrossRefGoogle ScholarPubMed
78 Schillaci, G, Pirro, M, Vaudo, G, et al. (2005) Metabolic syndrome is associated with aortic stiffness in untreated essential hypertension. Hypertension 45, 10781082.CrossRefGoogle ScholarPubMed
79 Laurent, S, Katsahian, S, Fassot, C, et al. (2003) Aortic stiffness is an independent predictor of fatal stroke in essential hypertension. Stroke 34, 12031206.CrossRefGoogle ScholarPubMed
80 Mattace-Raso, FU, van der Cammen, TJ, Hofman, A, et al. (2006) Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation 113, 657663.CrossRefGoogle ScholarPubMed
81 Willum-Hansen, T, Staessen, JA, Torp-Pedersen, C, et al. (2006) Prognostic value of aortic pulse wave velocity as index of arterial stiffness in the general population. Circulation 113, 664670.CrossRefGoogle ScholarPubMed
82 Pannier, B, Guerin, AP, Marchais, SJ, et al. (2005) Stiffness of capacitive and conduit arteries: prognostic significance for end-stage renal disease patients. Hypertension 45, 592596.CrossRefGoogle ScholarPubMed
83 Safar, ME & Laurent, P (2003) Pulse pressure and arterial stiffness in rats: comparison with humans. Am J Physiol Heart Circ Physiol 285, H1363H1369.CrossRefGoogle ScholarPubMed
84 Payne, RA & Webb, DJ (2006) Arterial blood pressure and stiffness in hypertension: is arterial structure important? Hypertension 48, 366367.CrossRefGoogle ScholarPubMed
85 O'Rourke, MF & Nichols, WW (2005) Aortic diameter, aortic stiffness, and wave reflection increase with age and isolated systolic hypertension. Hypertension 45, 652658.CrossRefGoogle ScholarPubMed
86 Dengo, AL, Dennis, EA, Orr, JS, et al. (2010) Arterial destiffening with weight loss in overweight and obese middle-aged and older adults. Hypertension 55, 855861.CrossRefGoogle ScholarPubMed
87 Blumenthal, JA, Babyak, MA, Hinderliter, A, et al. (2010) Effects of the DASH diet alone and in combination with exercise and weight loss on blood pressure and cardiovascular biomarkers in men and women with high blood pressure: the ENCORE study. Arch Intern Med 170, 126135.CrossRefGoogle ScholarPubMed
88 Keogh, JB, Brinkworth, GD, Noakes, M, et al. (2008) Effects of weight loss from a very-low-carbohydrate diet on endothelial function and markers of cardiovascular disease risk in subjects with abdominal obesity. Am J Clin Nutr 87, 567576.CrossRefGoogle ScholarPubMed
89 Philippou, E, Bovill-Taylor, C, Rajkumar, C, et al. (2009) Preliminary report: the effect of a 6-month dietary glycemic index manipulation in addition to healthy eating advice and weight loss on arterial compliance and 24-hour ambulatory blood pressure in men: a pilot study. Metabolism 58, 17031708.CrossRefGoogle ScholarPubMed
90 Todd, AS, Macginley, RJ, Schollum, JB, et al. (2010) Dietary salt loading impairs arterial vascular reactivity. Am J Clin Nutr 91, 557564.CrossRefGoogle ScholarPubMed
91 Sluijs, I, Plantinga, Y, de Roos, B, et al. (2010) Dietary supplementation with cis-9, trans-11 conjugated linoleic acid and aortic stiffness in overweight and obese adults. Am J Clin Nutr 91, 175183.CrossRefGoogle ScholarPubMed
92 Dickinson, KM, Keogh, JB & Clifton, PM (2009) Effects of a low-salt diet on flow-mediated dilatation in humans. Am J Clin Nutr 89, 485490.CrossRefGoogle ScholarPubMed
93 Teede, HJ, McGrath, BP, DeSilva, L, et al. (2003) Isoflavones reduce arterial stiffness: a placebo-controlled study in men and postmenopausal women. Arterioscler Thromb Vasc Biol 23, 10661071.CrossRefGoogle ScholarPubMed
94 Wilkinson, IB, MacCallum, H, Cockcroft, JR, et al. (2002) Inhibition of basal nitric oxide synthesis increases aortic augmentation index and pulse wave velocity in vivo. Br J Clin Pharmacol 53, 189192.CrossRefGoogle ScholarPubMed
95 Schmitt, M, Avolio, A, Qasem, A, et al. (2005) Basal NO locally modulates human iliac artery function in vivo. Hypertension 46, 227231.CrossRefGoogle ScholarPubMed
96 McEniery, CM, Wallace, S, Mackenzie, IS, et al. (2006) Endothelial function is associated with pulse pressure, pulse wave velocity, and augmentation index in healthy humans. Hypertension 48, 602608.CrossRefGoogle ScholarPubMed
97 Wallace, SM, Yasmin, , McEniery, CM, et al. (2007) Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension 50, 228233.CrossRefGoogle ScholarPubMed
98 McCall, DO, McGartland, CP, Woodside, JV, et al. (2010) The relationship between microvascular endothelial function and carotid-radial pulse wave velocity in patients with mild hypertension. Clin Exp Hypertens 32, 474479.CrossRefGoogle ScholarPubMed
99 Oparil, S & Izzo, JL Jr (2006) Pulsology rediscovered: commentary on the Conduit Artery Function Evaluation (CAFE) study. Circulation 113, 11621163.CrossRefGoogle ScholarPubMed
100 Karamanoglu, M, O'Rourke, MF, Avolio, AP, et al. (1993) An analysis of the relationship between central aortic and peripheral upper limb pressure waves in man. Eur Heart J 14, 160167.CrossRefGoogle ScholarPubMed
101 Chen, CH, Nevo, E, Fetics, B, et al. (1997) Estimation of central aortic pressure waveform by mathematical transformation of radial tonometry pressure. Validation of generalized transfer function. Circulation 95, 18271836.CrossRefGoogle ScholarPubMed
102 Weber, T, Auer, J, O'Rourke, MF, et al. (2004) Arterial stiffness, wave reflections, and the risk of coronary artery disease. Circulation 109, 184189.CrossRefGoogle ScholarPubMed
103 London, GM, Blacher, J, Pannier, B, et al. (2001) Arterial wave reflections and survival in end-stage renal failure. Hypertension 38, 434438.CrossRefGoogle ScholarPubMed
104 Mitchell, GF, Hwang, S-J, Ramachandran, RS, et al. (2010) Arterial stiffness and cardiovascular events – The Framingham Heart Study. Circulation 121, 505511.CrossRefGoogle ScholarPubMed
105 Booth, AD, Wallace, S, McEniery, CM, et al. (2004) Inflammation and arterial stiffness in systemic vasculitis: a model of vascular inflammation. Arthritis Rheum 50, 581588.CrossRefGoogle Scholar
106 Dart, AM, Gatzka, CD, Cameron, JD, et al. (2004) Large artery stiffness is not related to plasma cholesterol in older subjects with hypertension. Arterioscler Thromb Vasc Biol 24, 962968.CrossRefGoogle Scholar
107 Yasmin, & Brown, MJ (1999) Similarities and differences between augmentation index and pulse wave velocity in the assessment of arterial stiffness. QJM 92, 595600.CrossRefGoogle ScholarPubMed
108 Wilkinson, IB, MacCallum, H, Flint, L, et al. (2000) The influence of heart rate on augmentation index and central arterial pressure in humans. J Physiol (Lond) 525, 263270.CrossRefGoogle ScholarPubMed
109 Ahuja, KD, Robertson, IK & Ball, MJ (2009) Acute effects of food on postprandial blood pressure and measures of arterial stiffness in healthy humans. Am J Clin Nutr 90, 298303.CrossRefGoogle ScholarPubMed
110 Bradley, U, Spence, M, Courtney, CH, et al. (2009) Low-fat versus low-carbohydrate weight reduction diets: effects on weight loss, insulin resistance, and cardiovascular risk: a randomized control trial. Diabetes 58, 27412748.CrossRefGoogle ScholarPubMed
111 Albert, MA & Ridker, PM (2006) C-reactive protein as a risk predictor: do race/ethnicity and gender make a difference? Circulation 114, e67e74.CrossRefGoogle Scholar
112 Ridker, PM, Danielson, E, Fonseca, FA, et al. (2008) Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 359, 21952207.CrossRefGoogle ScholarPubMed
113 Berry, SE, Mulla, UZ, Chowienczyk, PJ, et al. (2010) Increased potassium intake from fruit and vegetables or supplements does not lower blood pressure or improve vascular function in UK men and women with early hypertension: a randomised controlled trial. Br J Nutr 104, 18391847.CrossRefGoogle ScholarPubMed
114 Blum, A, Monir, M, Khazim, K, et al. (2007) Tomato-rich (Mediterranean) diet does not modify inflammatory markers. Clin Invest Med 30, E70E74.CrossRefGoogle Scholar
115 Dalgard, C, Nielsen, F, Morrow, JD, et al. (2009) Supplementation with orange and blackcurrant juice, but not vitamin E, improves inflammatory markers in patients with peripheral arterial disease. Br J Nutr 101, 263269.CrossRefGoogle Scholar
116 Erlinger, TP, Miller, ER, Charleston, J, et al. (2003) Inflammation modifies the effects of a reduced-fat low-cholesterol diet on lipids. Results from the DASH-sodium trial. Circulation 108, 150154.CrossRefGoogle ScholarPubMed
117 Esposito, K, Marfella, R, Ciotola, M, et al. (2004) Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 292, 14401446.CrossRefGoogle ScholarPubMed
118 Freese, R, Vaarala, O, Turpeinen, AM, et al. (2004) No difference in platelet activation or inflammation markers after diets rich or poor in vegetables, berries and apples in healthy subjects. Eur J Nutr 43, 175182.CrossRefGoogle ScholarPubMed
119 Jin, Y, Cui, X, Singh, UP, et al. (2010) Systemic inflammatory load in humans is suppressed by consumption of two formulations of dried, encapsulated juice concentrate. Mol Nutr Food Res 54, 15061514.CrossRefGoogle ScholarPubMed
120 Karlsen, A, Paur, I, Bohn, SK, et al. (2010) Bilberry juice modulates plasma concentration of NF-κB related inflammatory markers in subjects at increased risk of CVD. Eur J Nutr 49, 345355.CrossRefGoogle ScholarPubMed
121 Lehtonen, H-M, Suomela, J-P, Tahvonen, R, et al. (2010) Berry meals and risk factors associated with metabolic syndrome. Eur J Clin Nutr 64, 614621.CrossRefGoogle ScholarPubMed
122 McCall, DO, McGartland, CP, McKinley, MC, et al. (2010) The effect of increased dietary fruit and vegetable consumption on endothelial activation, inflammation and oxidative stress in hypertensive volunteers. Nutr Metab Cardiovasc Dis (Epublication ahead of print version 12 April 2010).Google ScholarPubMed
123 Mena, M-P, Sacanella, E, Vazquez-Agell, M, et al. (2009) Inhibition of circulating immune cell activation: a molecular anti-inflammatory effect of the Mediterranean diet. Am J Clin Nutr 89, 248256.CrossRefGoogle Scholar
124 Michalsen, A, Lehmann, N, Pithan, C, et al. (2006) Mediterranean diet has no effect on markers of inflammation and metabolic risk factors in patients with coronary artery disease. Eur J Clin Nutr 60, 478485.CrossRefGoogle Scholar
125 Paterson, E, Gordon, MH, Niwat, C, et al. (2006) Supplementation with fruit and vegetable soups and beverages increases plasma concentrations but does not alter markers of oxidative stress or cardiovascular risk factors. J Nutr 136, 28492855.CrossRefGoogle ScholarPubMed
126 Rallidis, LS, Lekakis, J, Kolomvotsou, A, et al. (2009) Close adherence to a Mediterranean diet improves endothelial function in subjects with abdominal obesity. Am J Clin Nutr 90, 263268.CrossRefGoogle ScholarPubMed
127 Stull, AJ, Cash, KC, Johnson, WD, et al. (2010) Bioactives in blueberries improve insulin sensitivity in obese, insulin-resistant men and women. J Nutr 140, 17641768.CrossRefGoogle ScholarPubMed
128 Watzl, B, Kulling, SE, Moseneder, J, et al. (2005) A 4-wk intervention with high intake of carotenoid-rich vegetables and fruit reduces plasma C-reactive protein in healthy, nonsmoking men. Am J Clin Nutr 82, 10521058.CrossRefGoogle ScholarPubMed
129 Giugliano, D, Ceriello, A & Esposito, K. (2006) The effect of diet on inflammation: emphasis on the metabolic syndrome. J Am Coll Cardiol 48, 677685.CrossRefGoogle ScholarPubMed
130 Ferrario, CM & Strawn, WB (2006) Role of the renin–angiotensin–aldosterone system and proinflammatory mediators in cardiovascular disease. Am J Cardiol 98, 121128.CrossRefGoogle ScholarPubMed
131 Hwang, SJ, Ballantyne, CM, Sharrett, AR, et al. (1997) Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study. Circulation 96, 42194225.CrossRefGoogle ScholarPubMed
132 Brake, DK, O'Brian Smith, E, Mersmann, H, et al. (2006) ICAM-1 expression in adipose tissue: effects of diet-induced obesity in mice. Am J Physiol 291, C1232C1239.CrossRefGoogle ScholarPubMed
133 Rallidis, LS, Paschos, G, Papaioannou, ML, et al. (2004) The effect of diet enriched with α-linolenic acid on soluble cellular adhesion molecules in dyslipidaemic patients. Atherosclerosis 174, 127132.CrossRefGoogle ScholarPubMed
134 Atteritano, M, Marini, H, Minutoli, L, et al. (2007) Effects of the phytoestrogen genistein on some predictors of cardiovascular risk in osteopenic, postmenopausal women: a two-year randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 92, 30683075.CrossRefGoogle ScholarPubMed
135 Kelley, DS, Rasooly, R, Jacob, RA, et al. (2006) Consumption of Bing sweet cherries lowers circulating concentrations of inflammation markers in healthy men and women. J Nutr 136, 981986.CrossRefGoogle Scholar
136 Chisolm, GM & Steinberg, D (2000) The oxidative modification hypothesis of atherogenesis: an overview. Free Radic Biol Med 28, 18151826.CrossRefGoogle ScholarPubMed
137 Roberts, LJ & Morrow, JD (2000) Measurement of F-isoprostanes as an index of oxidative stress in vivo. Free Radic Biol Med 28, 505513.CrossRefGoogle Scholar
138 Thompson, HJ, Heimendinger, J, Sedlacek, S, et al. (2005) 8-Isoprostane F2α excretion is reduced in women by increased vegetable and fruit intake. Am J Clin Nutr 82, 768776.CrossRefGoogle ScholarPubMed
139 O'Reilly, JD, Mallet, AI, McAnlis, GT, et al. (2001) Consumption of flavonoids in onions and black tea: lack of effect on F2-isoprostanes and autoantibodies to oxidized LDL in healthy humans. Am J Clin Nutr 73, 10401044.CrossRefGoogle ScholarPubMed
140 Loke, WM, Hodgson, JM, Proudfoot, JM, et al. (2008) Pure dietary flavonoids quercetin and ( − )-epicatechin augment nitric oxide products and reduce endothelin-1 acutely in healthy men. Am J Clin Nutr 88, 10181025.CrossRefGoogle ScholarPubMed
141 Zalewski, A & Macphee, C (2005) Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology and possible therapeutic target. Arterioscler Thromb Vasc Biol 25, 923931.CrossRefGoogle ScholarPubMed
142 Packard, CJ, O'Reilly, DSJ, Caslake, MJ, et al. (2000) Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. N Engl J Med 343, 11481155.CrossRefGoogle ScholarPubMed
143 Thogerson, AM, Jansson, J, Boman, K, et al. (1998) High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation 98, 22412247.CrossRefGoogle Scholar
144 Thompson, SG, Kienast, J, Pyke, SD, et al. (1995) Haemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 332, 635641.CrossRefGoogle ScholarPubMed
145 Hamsten, A, de Faire, U, Walldius, G, et al. (1987) Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet ii, 39.CrossRefGoogle Scholar
146 Bakker, GC, van Erk, MJ, Pellis, L, et al. (2010) An antiinflammatory dietary mix modulates inflammation and oxidative and metabolic stress in overweight men: a nutrigenomics approach. Am J Clin Nutr 91, 10441059.CrossRefGoogle Scholar
147 Shantsila, E (2009) Endothelial microparticles: a universal marker of vascular health? J Hum Hypertens 23, 359361.CrossRefGoogle ScholarPubMed
148 Amabile, N, Guerin, AP, Leroyer, A, et al. (2005) Circulating endothelial microparticles are associated with vascular dysfunction in patients with end-stage renal failure. J Am Soc Nephrol 16, 33813388.CrossRefGoogle ScholarPubMed
149 Boulanger, CM, Scoazec, A, Ebrahimian, T, et al. (2001) Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction. Circulation 104, 26492652.CrossRefGoogle ScholarPubMed
150 Brodsky, SV, Malinowski, K, Golightly, M, et al. (2002) Plasminogen activator inhibitor-1 promotes formation of endothelial microparticles with procoagulant potential. Circulation 106, 23722378.CrossRefGoogle ScholarPubMed
151 Mallat, Z, Benamer, H, Hugel, B, et al. (2000) Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation 101, 841843.CrossRefGoogle ScholarPubMed
152 Heloire, F, Weill, B, Weber, S, et al. (2003) Aggregates of endothelial microparticles and platelets circulate in peripheral blood. Variations during stable coronary disease and acute myocardial infarction. Thromb Res 110, 173180.CrossRefGoogle ScholarPubMed
153 Jimenez, JJ, Jy, W, Mauro, LM, et al. (2003) Endothelial cells release phenotypically and quantitatively distinct microparticles in activation and apoptosis. Thromb Res 109, 175180.CrossRefGoogle ScholarPubMed
154 Mallat, Z, Hugel, B, Ohan, J, et al. (1999) Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation 99, 348353.CrossRefGoogle ScholarPubMed
155 Bernal-Mizrachi, L, Jy, W, Fierro, C, et al. (2004) Endothelial microparticles correlate with high-risk angiographic lesions in acute coronary syndromes. Int J Cardiol 97, 439446.CrossRefGoogle ScholarPubMed
156 Koga, H, Sugiyama, S, Kugiyama, K, et al. (2005) Elevated levels of VE-cadherin-positive endothelial microparticles in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 45, 16221630.CrossRefGoogle ScholarPubMed
157 Arteaga, RB, Chirinos, JA, Soriano, AO, et al. (2006) Endothelial microparticles and platelet and leukocyte activation in patients with the metabolic syndrome. Am J Cardiol 98, 7074.CrossRefGoogle ScholarPubMed
158 Garcia, S, Chirinos, J, Jiminez, J, et al. (2005) Phenotypic assessment of endothelial microparticles in patients with heart failure and after heart transplantation: switch from cell activation to apoptosis. J Heart Lung Transplant 24, 21842189.CrossRefGoogle ScholarPubMed
159 Wang, JM, Su, C, Wang, YJ, et al. (2009) Elevated circulating endothelial microparticles and brachial-ankle pulse wave velocity in well-controlled hypertensive patients. J Hum Hypertens 23, 307315.CrossRefGoogle ScholarPubMed
160 Harrison, M, Murphy, RP, O'Connor, PL, et al. (2009) The endothelial microparticle response to a high fat meal is not attenuated by prior exercise. Eur J Appl Physiol 106, 555562.CrossRefGoogle Scholar
161 Marin, C, Ramirez, R, Delgado-Lista, J, et al. (2011) Mediterranean diet reduces endothelial damage and improves the regenerative capacity of the endothelium. Am J Clin Nutr 93, 267274.CrossRefGoogle Scholar
162 Asahara, T, Murohara, T, Sullivan, A, et al. (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964967.CrossRefGoogle ScholarPubMed
163 Shintani, S, Murohara, T, Ikeda, H, et al. (2001) Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 103, 27762779.CrossRefGoogle ScholarPubMed
164 Wojakowski, W, Tendera, M, Michalowska, A, et al. (2004) Mobilization of CD34/CXCR4+, CD34/CD117+, c-met+ stem cells, and mononuclear cells expressing early cardiac, muscle, and endothelial markers into peripheral blood in patients with acute myocardial infarction. Circulation 110, 32133220.CrossRefGoogle ScholarPubMed
165 Werner, N & Nickenig, G (2006) Influence of cardiovascular risk factors on endothelial progenitor cells: limitations for therapy? Arterioscler Thromb Vasc Biol 26, 257266.CrossRefGoogle ScholarPubMed
166 Vasa, M, Fichtlscherer, S, Aicher, A, et al. (2001) Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 89, 17.CrossRefGoogle ScholarPubMed
167 Hill, JM, Zalos, G, Halcox, JP, et al. (2003) Circulating endothelial progenitor cells, vascular function, cardiovascular risk. N Engl J Med 348, 593600.CrossRefGoogle ScholarPubMed
168 Werner, N, Kosiol, S, Schiegl, T, et al. (2005) Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 353, 9991007.CrossRefGoogle ScholarPubMed
169 Müller-Ehmsen, J, Braun, D, Schneider, T, et al. (2008) Decreased number of circulating progenitor cells in obesity: beneficial effects of weight reduction. Eur Heart J 29, 15601568.CrossRefGoogle ScholarPubMed
170 Kim, W, Jeong, MH, Cho, SH, et al. (2006) Effect of green tea consumption on endothelial function and circulating endothelial progenitor cells in chronic smokers. Circ J 70, 10521057.CrossRefGoogle ScholarPubMed
171 Mano, R, Ishida, A, Ohya, Y, et al. (2009) Dietary intervention with Okinawan vegetables increased circulating endothelial progenitor cells in healthy young women. Atherosclerosis 204, 544548.CrossRefGoogle ScholarPubMed
172 Huang, PH, Chen, YH, Tsai, HY, et al. (2010) Intake of red wine increases the number and functional capacity of circulating endothelial progenitor cells by enhancing nitric oxide bioavailability. Arterioscler Thromb Vasc Biol 30, 869877.CrossRefGoogle ScholarPubMed
173 Hamed, S, Alshiek, J, Aharon, A, et al. (2010) Red wine consumption improves in vitro migration of endothelial progenitor cells in young, healthy individuals. Am J Clin Nutr 92, 161169.CrossRefGoogle ScholarPubMed
174 Boof, CJ, Lip, GYH & Blann, AD (2006) Circulating endothelial cells in cardiovascular disease. J Am Coll Cardiol 48, 15381547.Google Scholar
175 Stirban, A, Nandrean, S, Gotting, C, et al. (2010) Effects of n-3 fatty acids on macro- and microvascular function in subjects with type 2 diabetes mellitus. Am J Clin Nutr 91, 808813.CrossRefGoogle ScholarPubMed
Figure 0

Table 1 Effect of cocoa or chocolate interventions on flow-mediated dilatation (FMD): evidence from randomised controlled trials

Figure 1

Table 2 Effect of fruit and vegetable (FV) interventions on C-reactive protein (CRP): evidence from randomised controlled trials

Figure 2

Fig. 1 Decision tree when considering method of vascular function assessment.