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CONFERENCE REPORT

Food and Health Forum meeting nutritionalapproaches to cardiovascular health:

workshop report

H. L. Mitchell*, J. M. Gibbins, B.A. Griffin, J. A. Lovegrove, J. D. Stowell and E. Foot***The Cot, Acol, Kent, UK;Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, UK;Department of Nutrition and Metabolism, Faculty of Health & Medical Sciences, University of Surrey, UK;Hugh Sinclair Unit of Human Nutrition, Department of Food and Nutritional Sciences, University of Reading, UK;DuPont Nutrition & Health, Danisco (UK) Ltd, Reigate, UK;

**London Genetics Limited, London, UK

Royal Society of Medicine, London, UK, 12

October 2011This report summarises the proceedings of a meetingheld by the Food and Health Forum at the Royal Society

of Medicine, London, on 12 October 2011. The objec-tive of the meeting was to highlight nutritional strategies

targeted at cardiovascular health. This included a reviewof the effects of various foods, nutrients and ingredients

on maintenance of healthy cholesterol levels, endothelialfunction and blood pressure.

Introduction and objectives of the meeting

Despite recent improvements, cardiovascular disease(CVD) remains the leading cause of death worldwide. In

England and Wales, CVD currently accounts for some37% of deaths. According to the World Health Orga-

nization (WHO), up to 80% of these cases could beavoided by improving diets, increasing physical activity

and smoking cessation. It is therefore important to iden-tify the types of diet, as well as the contribution of

specific foods (including functional foods), that can helpto reduce the risk of CVD and its progression.

Summary of presentations

Diseases of the circulatory system

Professor Julie Lovegrove (University of Reading, UK)opened the proceedings and chaired the morning

sessions. The first speaker, Dr Julian Stowell (DaniscoBioactives, UK), set the scene by presenting data showing

CVD and diseases of the circulatory system to be theleading cause of death in the UK (ONS 2006) and a major

cause of mortality globally (WHO 2004). According tothe British Heart Foundation (BHF), CVD caused more

than 50 000 premature deaths in the UK in 2008 (BHF2010). Cardiovascular disease is also responsible for

reduced quality of life in the latter years. However, 80%of cases of CVD could be avoided by lifestyle changes

adopting a healthier diet, increasing physical activity andstopping smoking (WHO 2008).

There is convincing evidence that CVD risk increasesin association with an increased intake of saturated fatty

acids (SFAs) and decreases with an increased intake offish and fish oils. This has led to recommendations in the

UK to reduce SFAs and to consume at least two portionsof fish per week, one of which should be oil-rich (SACN

2004). More recently, the Scientific Advisory Committeeon Nutrition (SACN) has endorsed 0.45 g/day of long-

chain n-3 fatty acids for primary prevention and 1 g/dayfor secondary prevention (DH 1994). Interestingly,

however, a single portion of oil-rich fish will not meetthis target. Convincing scientific evidence also supports

the recommendations to remain active and maintain ahealthy bodyweight, to eat less salt and to consume at

least 5 portions of a variety of fruit and vegetablesthroughout the day.

The North Karelia Project in Finland has often beencited as a good example of a successful intervention at a

population level that has improved public health (Puska2002). Launched in 1972 as a response to exceptionally

high coronary heart disease (CHD) mortality ratesin Finland, this project involved a comprehensive

approach involving a range of educational programmesfocused on improving diet, smoking cessation and

Correspondence: Dr Julian Stowell, DuPont Nutrition & Health,

Danisco (UK) Ltd, Reigate Place, 43 London Road, Reigate

RH2 9PW, UK.

E-mail: [email protected]

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increasing physical activity. Between 1970 and 1995,mortality from cardiovascular and coronary heart

disease decreased by 68% and 73%, respectively. Thisequated to an increase in life expectancy of 7 years for

men and 6 years for women, and paralleled significantreductions in the prevalence of risk factors, such as

smoking, high serum cholesterol and hypertension overthe 25-year intervention period.

After his presentation, Dr Stowell was asked about thepossible causes of the decline in CVD in Europe recently.

He suggested that this was attributable primarily to areduction in the prevalence of smoking and improve-

ments in nutrition throughout life. He pointed outhowever, that in the North Karelia project, a greater

number of women smoked at the end of the interventionperiod than at thebeginning so improvementin other risk

factors, besides smoking, had played a role. Concernswere also raised within the audience about the recom-

mendation to eat oil-rich fish in relation to mercurycontamination and sustainability. It was pointed out that

the recommendations for mercury are currently beingrevised and that women in Japan, who eat fish more than

twice a day, have lower rates of CVD, less cancer and lessdepression than their counterparts who eat less fish. It

was noted by one of the delegates that the North Kareliaintervention may have been successful in reducing CVD

outcomes because of a reduction in sodium and an

increase in potassium in the diet. Dr Stowell suggestedthat while there may have been a change in the ratio of

these minerals, it was probably only part of a number of

dietary and lifestyle improvements.

Biomarkers

Professor Bruce Griffin (University of Surrey, UK)

reviewed current biomarkers of cardiovascular healthand disease. He explained how the evidence for a rela-

tionship between diet and CVD has relied heavily uponobservational studies rather than randomised controlled

trials (RCTs) and meta-analyses. In practice, the formu-lation of dietary guidelines and assessment of claims for

the benefits of foods or nutrients on health requires

interpretation of the totality of evidence from all rel-evant sources.

Professor Griffin explained that the Functional Food

Science in Europe (FUFOSE) project helped to definefunctional foods and the evidence-base required for

health claims using either biomarkers (to support claimsfor enhanced function) or endpoint markers (to support

claims of reduced disease risk) (Diplock et al. (1999).When the true endpoint of a claimed benefit cannot be

measured directly, studies should use markers that are

biologically valid (i.e. they have a known relationship tothe outcome) and a known variability within the target

population.Building on FUFOSE, the European Commission

Concerted Action Process for the Assessment of Scien-tific Support for Claims on Foods (PASSCLAIM)

Project, co-ordinated by the International Life ScienceInstitute Europe, has been a thorough and respected

approach to developing a scientific framework ofgeneric criteria for evaluating the amount and quality of

evidence to support claims for the benefit(s) of food(s)or food components (Mensink et al. 2003a, 2003b).

Serum cholesterol is a benchmark biomarker forCVD. However, the Framingham Study (Genest &

Cohn 1995) showed serum cholesterol to be a poordeterminant of CHD risk within specific countries and

there are grey areas of serum cholesterol scores thathave no predictive power. Biomarker-based definitions

of health and disease are based on a reference range, butsubclinical at risk populations are neither healthy nor

diseased. This leads to the question as to how we definethe normal population?

Enhanced postprandial lipaemia (i.e. impaired abilityto remove fat from the bloodstream) is a major CHD risk

factor (Griffin & Fielding 2001). The number andqualityof circulatory low density lipoprotein (LDL) are more

important determinants of LDL atherogenicity than cho-lesterol content per se. An increased level of small, dense

LDL particles has been shown to be a predictor of cardio-and cerebrovascular events in subjects with metabolic

syndrome (Rizzo et al. 2009). Professor Griffin alsoexplained the anti-atherogenic action of high densitylipoprotein (HDL), which protects against the effect of

oxidised LDL in the artery wall, promoting cholesterolefflux. Low HDL is a powerful biomarker of risk but

what is needed is a biomarker of HDL function thatrelates to its cardio-protective roles, namely anti-

atherosclerotic, antioxidant, anti-inflammatory, anti-platelet/coagulation, vascular dysfunction ageing and

senescence.Brachial flow-mediated dilation (FMD), a biomarker

of endothelial dysfunction, can predict cardiovascular

events in population-based studies (Yeboah et al. 2009).Overweight, obesity and central adiposity can be definedaccording to body mass index (BMI) and waist circum-

ference. However, when using these parameters, it is alsoimportant to consider metabolic-obese phenotypes:

metabolically benign obesity has been described as fatoutside thin inside and the metabolic-obese as thin

outside fat inside. Increased intra-hepatocellular fatmeasured by magnetic resonance spectroscopy is a

common finding in those with metabolic syndrome and a

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determinant of cardiometabolic risk (Kotronen & Yki-Jrvinen 2008). Liver fat may also predict plasma lipid

response to dietary extrinsic sugars (Ahmad et al. 2011).Professor Griffin posed the question: how can future

processes of diet-CVD risk assessment, such as PASS-CLAIM, address cardiometabolic risk? These should

accommodate changes in functional biomarkers of HDLand assess biomarkers that characterise metabolic

obesity. These markers should include increased visceraland liver fat, inflammation, the extent of postprandial

lipaemia, lipoprotein subclasses, oxidative damage andvascular dysfunction. The latter includes endothelial

dysfunction and arterial dilation, a pragmatic biomar-ker that can be measured using brachial FMD.

Professor Griffin was asked whether fat around thegluteal muscles is protective against CVD. He explained

that the ability to store subcutaneous fat below the waistmay spare the ectopic and potentially higher risk depo-

sition of fat in internal organs, such as the liver andpancreas. While liver fat can be measured and related to

increased cardiometabolic risk, pancreatic fat is amor-phous and is very difficult to measure by magnetic reso-

nance imaging. It is important to appreciate thatsubcutaneous fatcan be metabolically active even when it

contributes to increased weight circumference and BMI.

Dietary lipids

Professor Julie Lovegrove (University of Reading, UK)provided an overview of the role of dietary lipids in CVD

risk. She indicated that current dietary recommendationsinclude an intake of dietary SFAs of less than 10% oftotal energy. A reduction in dietary SFA has been

reported to lower plasma cholesterol concentrations andmay lead to improvements in other CVD risk factors.

The following question was posed: what is the optimumreplacement for SFA unsaturated fats or carbohy-

drates? Professor Lovegrove discussed how this questionhas been addressed in a number of RCTs, in which the

replacement of SFA with either n-6 polyunsaturatedfatty acid (PUFA), cis-monounsaturated fatty acid

(MUFA) or complex carbohydrates resulted in beneficial

reductions in LDL-cholesterol. In contrast, substitutionof SFA with refined carbohydrates has been associatedwith elevated triacylglycerol concentrations (an indepen-

dent CVD risk marker). Furthermore, when SFAs werereplaced with trans fatty acids, elevation of plasma cho-

lesterol has been reported (Kris-Etherton et al. 1999;Mensink et al. 2003a, 2003b; Micha & Mozaffarian

2010). Weight for weight, trans-monounsaturated fatshave been shown to promote a greater increase in plasma

LDL-cholesterol than SFA when used to replace carbo-

hydrates in a diet, and to lower HDL-cholesterol. Whilethese trans fats are considered the bad boys in our diet,

the evidence from casecontrol and prospective studiesindicates minimal impact on CHD risk at current levels

of dietary intake (SACN 2007). Meta-analyses andpooled analysis of observational cohort studies show a

significant reduction in relative CHD risk with an isoca-loric (5%) exchange of SFAs for PUFA, but no such

benefit when SFA is replaced by either carbohydrate orMUFA, although there are limited randomised con-

trolled studies investigating the impact of SFA substitu-tion with MUFA (Micha & Mozaffarian 2010). The

addition of a long-chain n-3 PUFA supplement to alow-fat, high-carbohydrate diet has been shown to

reduce the characteristics of metabolic syndrome(Paniagua et al. 2011). However, the multi-centred

RISCK (Jebb et al. 2010) and Lipgene (Tierney et al.2011) studies provided compelling evidence to show that

the replacement of SFA with MUFA or carbohydrate hadno influence on insulin sensitivity, as measured by an

intravenous glucose tolerance test, in subjects either atrisk of or with metabolic syndrome, respectively. Despite

these findings, these studies demonstrated favourableimprovements in the ratio of total to HDL-cholesterol

when SFA was exchanged for MUFA (Jebb et al. 2010).Acute test meal studies show that the extent of postpran-

dial lipaemia (now recognised as an independent riskfactor for CVD) is much greater after meals enriched

with SFA as compared with n-6 PUFA-enriched meals(Jackson et al. 2005). It has also been reported that

replacing SFA with either carbohydrate, MUFA or PUFAimproves vascular function by increasing vasodilation,although more RCTs are required to confirm this effect

(Keogh et al. 2005; Vafeiadou et al. 2012).There is increasing evidence to suggest that there may

not be a single, optimum dietary strategy for the modi-fication of CVD risk in populations and that the efficacy

of dietary recommendations could depend on the cardi-ometabolic risk of the individual and their specific

genetic profile. Differences in the plasma LDL-cholesterol response to a dietary supplement of 2.5 g/

day eicosapentaenoic acid and docosahexaenoic acid

(DHA) over 6 weeks (Lovegrove & Gitau 2008) dem-onstrate the enormous variation in dietary responsewithin populations. Two important questions are,

whether knowledge of genotype can contribute to amore effective use of diet in a personalised nutrition

approach to the prevention of CVD, and whetherdietary recommendations and advice place greater

emphasis on foods rather than individual nutrients? Anexample that illustrates the importance of the latter

question is provided by the association between the

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consumption of dairy foods and cardiovascular health.Milk and dairy foods provide between 20% and 40% of

dietary SFA in the UK diet, but higher intakes of foodssuch as milk and cheese are inversely associated with the

incidence of vascular disease and diabetes (Elwood et al.2010).

Professor Lovegrove was asked why trans and SFAincrease CVD risk and what level of intake of dairy

products might be protective. She responded that theprimary effect of these dietary fatty acids on CVD risk is

believed to be mediated through their hypercholestero-laemic effects on plasma LDL, although in addition,

trans fats also lower cardio-protective HDL. The cardio-protective effects of dairy foods may be mediated by a

reduction in blood pressure through the angiotensin1-converting enzyme (ACE)-inhibitory effects of bioac-

tive peptides in these foods. Calcium in dairy productsmay saponify fatty acids, thus promoting their excretion

as insoluble soaps. The associations between dairy food,most notably milk and reduced CVD risk are, in some

cases, impressive, but based on prospective cohortstudies rather than RCTs. The former type of study

cannot establish cause and effect relationships and canbe subject to confounding by many factors. At risk,

diseased and non-diseased individuals show variabilityin their response to dietary interventions and Professor

Lovegrove indicated that cluster analysis with math-

ematical modelling may help optimise dietary strategiesfor specific groups.

Cholesterol

Sara Stanner (British Nutrition Foundation, UK)

described the importance of LDL-cholesterol as a riskfactor for CVD. Every 1 mmol/l decline in LDL-

cholesterol results in a 21% decrease in cardiovascularevents (Yusuf et al. 2009). Dietary changes can have a

significant impact on cholesterol levels if sustained overthe long-term and can also help to keep statin doses

low, helping to reduce side effects. Evidence related tothe influence of plant phytosterols (including sterols

and stanols) on blood cholesterol levels was presented.

Major sources of phytosterols in the human diet areoils, fats, nuts and seeds, and there is considerablevariation in average intakes between countries and

within populations, with levels being highest in thosewith a relatively high plant food intake (e.g. vegetar-

ians). A typical Western diet contains around 250 mg/day, which is far below the recommended intake for a

significant cholesterol-lowering effect (2 g/day). Manu-factured products with added phytosterols can help to

bridge the gap. By interfering with the uptake of

dietary and biliary cholesterol from the intestinallumen, a 3040% reduction in absorption of choles-

terol can be achieved with phytosterols. However, thereis some inter-individual variability in absorption, which

as yet remains unexplained. Evidence for cholesterollowering was presented from a number of meta-

analyses, the first of which included 84 RCTs involving6805 study participants and concluded that, on

average, around 2 g of phytosterols lowered LDL-cholesterol by 0.34 mmol/l (95% confidence interval:

-0.36 to -0.31) or 8.8% (-9.4 to -8.3%), with noapparent effect on HDL-cholesterol or triacylglycerol

levels (Katan et al. 2003). This and subsequent meta-analyses (Abumweis et al. 2008; Demonty et al. 2009)

have considered a range of populations, includinghealthy adults with normal cholesterol levels, adults

with hypercholesterolaemia and familial hypercholes-terolaemia, patients with CHD and metabolic syn-

drome, those with type 1 and 2 diabetes and childrenwith familial hypercholesterolaemia. The degree of

cholesterol lowering is clearly influenced by baselinecholesterol level (i.e. is higher in those with elevated

baseline levels), but there remains considerable inter-individual variability in the response possibly because

of factors including other subject characteristics, thefood matrix investigated, the frequency of intake,

dietary background, the additive effect of other foodsor drugs and genetic factors. The cholesterol-lowering

effect has been demonstrated with a range of foodmatrices, such as margarines, mayonnaise, salad dress-

ings, milk, yogurts and cheese (Katan et al. 2003;Abumweis et al. 2008; Demonty et al. 2009) and thesame dose taken once a day or spread over the day

seems to be equally effective (Musa-Veloso et al. 2011).At intakes of 2 g/day, stanols and sterols are equally

effective, although the effects of sterols plateau at thisdose, while there may be additional cholesterol lower-

ing from higher stanol intakes (though the safety ofsuch intakes remains to be addressed) (Plat et al. 2000).There is good evidence that there is an additive effectof the use of phytosterols with statins in patients with

primary hypercholesterolaemia (Simons 2002), and as

such, consumption of phytosterols may be recom-mended to patients on statin therapy to further lowerLDL-cholesterol when the LDL-cholesterol goals are

not reached by statins alone (Katan et al. 2003) and/orif increasing further the statin dose leads to undesirable

side effects. In addition, phytosterols are effective aspart of a diet low in SFAs (Cleghorn et al. 2003) and

when used within the portfolio diet promoted for itscholesterol-lowering effects (this diet includes plant

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(Jenkins et al. 2005). Phytosterols have been approvedby many regulatory authorities and endorsed by many

national and international organisations. In 2008, theEuropean Food Safety Authority (EFSA) issued its first

disease risk reduction claim in the European market-place, supporting the evidence of plant sterols and

stanols to lower cholesterol levels.Studies of the efficacy of phytosterols (i.e. their ability

to lower cholesterol in free-living populations) are rela-tively limited. Compliance must be long-term as choles-

terol levels rapidly return to baseline levels whenphytosterol intake is ceased. The use of such functional

products will, of course, be influenced by consumerbelief in their health benefits, ease of use, taste and price

and the effects of their consumption on other dietarychoices needs to be assessed.

Some additional questions remain to be addressed,including the long-term efficacy and safety of higher

plant stanol intakes, especially in combination withstatins; the identification of genetic polymorphisms

influencing the response to phytosterols; clarification ofthe best timing of intake and format in relation to gly-

caemic response and weight control; and most impor-tantly, the effect of phytosterols on CHD risk. Trials with

clinical endpoints are lacking and the National Institutefor Health and Clinical Excellence (NICE) has given

advice regarding the need for and design of such trials.

Ms Stanner was asked if in our evolutionary past wewould have ever reached dietary intakes of 2 g/day of

stanols/sterols? She replied that this was highly unlikely

a high plant diet might contain around 400 mg/day,which is well below the 2 g/day required for cholesterollowering. A member of the audience asked whether the

risk reduction quoted in association with the consump-tion of phytosterols is a relative or an absolute risk. Ms

Stanner confirmed that the risk is relative. Safety con-cerns were also raised by a member of the audience

because of the small cohort sample sizes used in studies(approximately 100 people for 6 months). It was sug-

gested that stanols/sterols could accumulate in the brainover time and cause problems within some groups of the

human population. However, this remains speculative

and their use at the recommended intake of 2 g/day hasbeen evaluated as safe by EFSA and other bodies.

Nuts

Dr Karen Lapsley (Almond Board of California, USA)described how epidemiological and clinical studies in

Europe and North America offer compelling evidencethat nuts, eaten as part of a balanced diet, contribute to

the reduction of CHD and related risk factors. Almonds

contain MUFAs, PUFAs and phytosterols, as well aspolyphenols, protein, dietary fibre, vitamin E and mag-

nesium. The polyphenol content and antioxidant activ-ity of California almonds is dependent on cultivar and

harvest year (Bolling et al. 2010). In 2003, the US Foodand Drug Administration (FDA) approved a Qualified

Health Claim for Nuts and Coronary Heart Disease(FDA, Docket No. 02P-0505) 42 g per day of most

nuts may reduce the risk of heart disease. Most of theevidence for this claim has come from large prospective

studies, including The Nurses Health Study (Hu et al.1998), Adventist Health Study (Fraser et al. 1992), Iowa

Womens Health Study (Kushi et al. 1996) and ThePhysicians Health Study (Albert et al. 2002). There is

also substantial evidence that almonds may help to miti-gate weight gain and type 2 diabetes progression in the

context of a healthy, balanced diet (Salas-Salvado et al.2008; Cohen & Johnston 2011; Berryman et al. 2011;

Li et al. 2011; Kamil & Chen 2012). Acute and secondmeal effect studies in adults with impaired glucose tol-

erance indicate that the inclusion of almonds in thebreakfast meal is effective at decreasing blood glucose

concentrations and increasing satiety, both acutely andafter a second meal. The lipid component of the almond

appears to be largely responsible for the post-ingestiveresponse, although the whole nut itself was equally as

effective. Overall, day-long insulin sensitivity wasincreased with whole almond consumption (Josse et al.

2007). Research using pre-diabetic adults on an inter-vention diet with added almonds showed LDL-

cholesterol lowering and improved markers of insulinsensitivity (Mori et al. 2011). Almonds have also beenfound to decrease inflammation and oxidative stress in

patients with type 2 diabetes and improve glycaemiccontrol and lipid profiles (Wien 2010; Chen et al.,

unpublished data). They have also been shown todecrease postprandial glycaemia, insulinaemia and oxi-

dative damage in healthy individuals (Wien 2010).Dr Lapsley was asked where the almond plant origi-

nally came from and if trials had compared the healtheffects of almonds with other nuts or seeds. Originally,

the almond plant was found in Western Asia but is

now found in many locations with hot dry climates.The composition of almonds is fairly standard globallybut will vary depending on growing conditions.

Over-roasting will affect shelf life and nutritionalvalue. Studies have shown most nuts to achieve cho-

lesterol lowering of 510%. When asked about theallergic response to almonds, Dr Lapsley pointed out

that about 12% of the population are adverselyaffected by almonds and the severity of allergic reac-

tion is reduced compared with tree nuts.


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Oat b-glucan

Professor Thomas Wolever (University of Toronto,

Ontario, Canada) explained the physico-chemical prop-erties of oat b-glucan that influence its effects on post-

prandial glucose and LDL-cholesterol, as well as the

effective doses required to positively influence these CVDrisk factors (4 and 3 g/day, respectively). The impact ofoat b-glucan on postprandial glucose and serum LDL

depends on its viscosity and this is controlled by theconcentration of fibre in solution (C) and its molecular

weight (MW). The concentration of theb-glucan is deter-mined by the dose fed and its bioavailability (solubility).

Research has suggested that modest doses (34 g/day) ofoat b-glucan with a MW 530 000 are effective in

lowering LDL-cholesterol, while a MW 210 000 islikely to be ineffective (Wolever et al. 2010).

Mr Ruedi Duss (CreaNutritionLtd, Switzerland)

described the disease risk reduction claim associatedwith oat b-glucan in the EU that has been accepted underArticle 14 of the EC Regulation on Nutrition and Health

Claims (EC 1924/2006). The EFSA concluded that thereis sufficient evidence of a cause and effect relationship,

that the product is well characterised and that there aresufficient markers of intermediate endpoints to validate a

claim. In order to obtain reliable and credible claims, theEC regulation states under Article 5.1 that the use of

health claims shall only be permitted if the substance

for which the claim is made is in a form that is availableto be used by the body. For oat b-glucan, there is

evidence that the bioactive form is soluble, with a higherviscosity in solution (EFSA 2010, 2011). The Regulationalso states that the quantity of the product that canreasonably be expected to be consumed provides a sig-

nificant quantity of the nutrient oat beta-glucan. Evi-

dence shows that a significant quantity is 3 g/day, whichcan be delivered once a day or 23 times a day via

different product formats. The actual disease risk reduc-tion claim endorsed by EFSA is Oat beta-glucan has

been shown to lower/reduce blood cholesterol. Highcholesterol is a risk factor in the development of coro-

nary heart disease. This claim can be used for foods that

provide at least 1 g of oat b-glucan per quantifiedportion, provided information is given to the consumerthat the beneficial effect is obtained with a daily intake of

3 g. The EFSA opinion on LDL-cholesterol also includesbarley b-glucan (www.efsa.europa.eu/en/efsajournal/

pub/2207.htm). The whole process of approval tookapproximately 3.5 years from the time of submission to

EFSA in June 2008.It was suggested by an audience member that as phy-

tosterols and statins have an additive effect on LDL-

cholesterol lowering, b-glucans may also exhibit asimilar additive effect with statins, as the mechanism of

effect is owed to reduced cholesterol absorption. It wasagreed that this is an area for future research.

Docosahexaenoic acid (DHA)Professor Michael Crawford (Imperial College, London,

UK) considered the evidence for the benefits of DHA inmaintaining cardiovascular health. He reminded the

audience that the human brain and vascular endothe-lium is lipid-rich and that PUFAs are responsible for the

elasticity of cells, especially in the vascular and neuralsystems where they also play important functional roles.

Docosahexaenoic acid and arachidonic acid are themost prominent essential fatty acids in the brain endot-

helium and human vascular endothelium. This gives aclear message about their importance in vascular health.

From 1910 to 1970, there was a steep rise in mortalityfrom CHD. As there was no genomic change during that

period, this increase can only be explained by environ-mental factors, such as diet-influencing gene expression

(epigenetics). Professor Crawford explained how mater-nal diets are important in establishing a healthy vascular

system in the fetus and evidence from biomagnificationof DHA across the placenta and in the cord, fetal liver

and fetal brain indicate high proportions of DHAmoving from mother to baby (Crawford et al. 1976).

Six-hundred million years of evolution have shown

the essential role of DHA in photoreception and neural

systems. Docosahexaenoic acid was used to build thefirst visual and neural cell membranes. Fish, amphib-ians, reptiles, birds and mammals, all use DHA for this

purpose. The benefits are in hippocampal and myocytesignalling and the prevention of arrhythmia and sudden

death. The uniqueness of DHA lies in its six methyleneinterrupted double bonds that are electrically active,

alternating with positive and negative areas with thepotential to act as a semiconductor (Crawford et al.

2008). Professor Crawford used Roger Penroses sug-gestion that quantum coherence is probably the expla-

nation for the uniqueness of DHA in the precision of

control in signalling for brain function and heartbeat, aselectrons will only tunnel at a specific energy state.Cardiac electric activity is strongly modulated by its

environment. Deficiency of DHA in the signalling mem-branes will lead to a weak and more frequent signal (i.e.arrhythmia).

A comparison between an African fishing population

and inland vegetarians in the same region showed thosefrom the fishing region to have better cardiovascular

health and lower levels of blood lipids and blood pres-


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sure, as well as less digestive and gastrointestinal (GI)disorders and no protein or iodine malnutrition. Other

evidence supports a positive effect of large amounts ofDHA from fish and improved health (Crawford et al.

2000). Professor Crawford questioned how, when weknow this, CVD is still a leading cause of death world-

wide? According to Professor Crawford, the foodsystem is fundamentally flawed, as the wartime diet,

which improved the nations health, was abandoned infavour of a system focused on production. Professor

Crawford suggested that chicken eaten in 2004 pro-vided three to six times more calories from fat on a

gram-to-gram basis than those eaten in 1976. In thesame time period, the DHA content has reduced phe-

nomenally (Wang et al. 2010) and he also suggested thatwild beef has a higher amount of lean muscle, less fat

and a higher proportion of PUFAs to saturate thanmodern reared beef. In view of the evidence linking SFA

intake with arterial and heart disease, the alteration ofthe nature of meat through domestication and intensi-

fication could be relevant to the rise in mortality fromheart disease. In the wild species, the ratio of non-

essential to essential fatty acids is 3:1; in modern beef,the same ratio is 50:1 (Crawford 1968).

The Global Forum for Health has predicted that thetop three burdens of disease for 2020 will be coronary

heart disease, perinatal conditions and mental ill health

(Global Forum for Health Research 1999). In the UK,mental ill health cost the National Health Service 77

billion in 2007, which is greater than the burden of

heart disease and cancer combined. Latest data suggestthat it is costing around 105 billion.

Professor Crawford emphasised the importance of

health education in schools to empower children withthe knowledge to eat healthily. He also stressed the need

to develop the UK fishing industry. A member of theaudience commented that whenever nutrition and

health are discussed, education seems to be at the heartof the issue and asked what young scientists could do to

improve the situation. Professor Crawford explainedthat there have been several initiatives to encourage the

government to re-introduce compulsory home econom-

ics into schools, but they have not been successful. Heconcluded by saying there has to be political will to turnthe situation around.

Endothelial dysfunction

Professor Roger Corder (Barts and the London School

of Medicine and Dentistry, Queen Mary University ofLondon, UK) highlighted how endothelial dysfunction

and heart disease progress with age. Endothelial dys-

function is prevalent in the elderly but is frequentlyassociated with increased CVD risk in men aged 45+years and women of 55+ years. It is common in smokersand those with dyslipidaemia (high cholesterol) and dia-

betes, and has been linked to hypertension, erectile dys-function and age-related left ventricular dysfunction and

heart failure. It is also implicated in age-related declinein cognitive function.

When assessing endothelial (dys)function, the func-tional measures are FMD with either brachial artery

ultrasound for macrovascular endothelial function orperipheral artery tonometry for microvascular endothe-

lial function. Biomarker signatures are available, butthese are generally unreliable. Currently, the treatment

options for endothelial dysfunction are either medicalvia statins, ACE inhibitors or endothelial antagonists, or

nutraceuticals via flavonoids.

Polyphenols

Professor Corder then went on to describe the dietarysources of polyphenols and their chemical subclasses.

He also explained how high dietary consumption offlavonoids is associated with lower mortality from heart

disease (Mink et al. 2007). Consumption of red winecan have a positive effect on FMD response and coro-

nary microcirculation (Hozumi et al. 2006). Red winecontains high levels of polyphenols. The polyphenols,

quercetin, delphinidin, epicatechin (flavan-3-ol) and res-

veratrol are present in wine as minor components but

have often been investigated. At the amounts present inwine, they have no biological activity. When purifiedprocyanidins were tested for their effects on endothelial

function; findings showed that their potency of action isunrelated to antioxidant properties (Caton et al. 2010).

Higher longevity for men in south west France andSardinia is localised to areas where the most

procyanidin-rich wines are drunk (Corder et al. 2006).Clinical trials with anthocyanins and procyanidins show

that CVD risk biomarkers and liver and kidney functionare not altered in post-menopausal women after ingest-

ing an elderberry extract rich in anthocyanins for 12

weeks. There was no change in blood pressure or biom-arkers of vascular function (Curtis et al. 2009). A cross-over study showed that there were no significant effects

of cranberry juice on blood pressure or endothelial/vascular function measure when cranberry juice rich in

polyphenols was consumed by patients with coronaryartery disease (Hozumi et al. 2006). Similarly, in a

double-blind crossover study, grape juice consumptionamong pre-hypertensive and stage 1 hypertensive

patients did not lead to a significant reduction in


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24-hour blood pressure or any significant changes invascular function (Dohadwala et al. 2010).

Another rich source of procyanidins is cocoa. In arandomised, double-blind evaluation of the acute effects

of cocoa drinks containing high, medium and low levelsof flavonols in patients with diabetes, the %FMD

increased over time in a dose-related manner (Balzeret al. 2008). Improvement of endothelial function with

cocoa flavonols has also been shown in patients withcoronary artery disease (Heiss et al. 2010).

A meta-analysis of individual data for one millionadults in 61 prospective studies concluded that each

2 mmHg reduction in systolic blood pressure decreasesstroke mortality by 10% and decreases mortality from

CHD by 7% (Lewington et al. 2002). Current medicaltreatments only produce modest improvements in

endothelial function and clinical trials are needed toevaluate the full potential of procyanidin-rich flavonol

products, as well as the need to identify who mightbenefit most from increased flavanol consumption. Iden-

tification of flavanols with the greatest effect on endot-helial function at appropriate purity, bioavailability and

dose should be considered, but evidence of the causeand effect (doseresponse) relationship needs to be

established.

Epicatechin-rich and quercetin-rich foods

Dr Vincent Wilson (University of Nottingham, UK)

described the role of epicatechin-rich and quercetin-richfoods in targeting specific cardiovascular disorders. Cur-rently, no specific dietary advice is given to patients with

stable angina, who are treated according to the NICEguidelines with calcium channel blockers, beta blockers

and long-acting nitrates or with repeated doses of short-acting nitrates. Quercetin and epicatechin are flavonoids

that can form a substantial part of the daily polyphenolintake, being commonly found in red onions, capers,

apples, green tea and cocoa. In free radical studies,epicatechin and quercetin are equipotent antioxidants,

but the antioxidant property does not account for the

cell protective activity of quercetin. In in vitro vascularisometric tension recordings using porcine coronaryartery, it has been shown that quercetin, but not epicat-

echin, possesses vasodilator activity. Quercetin andquercetin sulphate possess vasodilator activity, but quer-

cetin glucuronide is inactive. In vitro models of glyceryltrinitrate (GTN) tolerance indicate that quercetin and

quercetin sulphate reduce the degree of GTN-inducedtolerance (Suri et al. 2010). Quercetin-rich foods should

be evaluated in patients with stable angina.

One-third of chronic kidney disease patients experi-ence a potentially damaging fall in blood pressure

during haemodialysis myocardial stunning. Dietaryadvice is to have a low fluid intake and generally less

than 5 portions of fruit and vegetables per day (toreduce high K+ ion intake). The condition is associated

with an increase in vascular stiffness and high cardio-vascular morbidity. Castilla and colleagues used an

intervention with concentrated grape juice to determinethe antioxidant, hypolipidaemic and anti-inflammatory

effects in both haemodialysis patients and healthy sub-jects (Castilla et al. 2006). The juice was standardised in

terms of quercetin content. The 1-month dietary inter-vention indicated a small, but significant, reduction in

plasma lipids in both healthy subjects and haemodialysispatients. These effects were still evident 1 month after

cessation. The apple variety Evesse EPC has a 100-foldhigher epicatechin content than Evesse OPC, but they

have similar antioxidant activities. However, EvesseOPC possesses vasodilator activity as measured in vitro.

In preliminary human volunteer studies, Evesse EPCapples (3 mg/kg epicatechin) did not cause an overt

change in regional haemodynamics, but did elicit a sig-nificant reduction in vascular stiffness (Wilson et al.,

unpublished observations). Thus, Evesse EPC or OPCmay reduce vascular stiffness in chronic kidney disease

patients and improve the haemodynamic stabilityduring haemodialysis. If evidence from clinical trials

supports their use, then the introduction of dietary

adjuncts for the management of chronic conditions will

lower health costs, improve quality of life and empowerindividuals to manage their own medical problems.

Blood pressure

Dr Daniel Raederstorff (DSM Nutritional Products Ltd,Switzerland) indicated that high blood pressure is one of

the most important and well-known independent riskfactors in the development of cardiovascular conditions.

A small reduction in blood pressure of hypertensivesubjects could significantly reduce the risk of CVDs.

Thus, there is a high interest in nutritional products with

the ability to reduce blood pressure that could contributeto reducing the risk of CVDs. Milk-derived peptideshave been identified as potential antihypertensive agents.

In the last 10 years, over 20 human clinical trials havebeen conducted with lactotripeptides: valine-proline-

proline (VPP) and isolecuine-proline-proline (IPP)demonstrating blood pressure reduction (Pripp 2008;

Xu et al. 2008). Reviews and meta-analyses of con-trolled trials have indicated that products containing

these milk-derived tripeptides have a blood pressure-


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lowering effect, with effective doses in the range of3.0752.5 mg/day. Blood pressure reduction is more

effective in people with raised blood pressure and hasbeen demonstrated with different types of food carriers:

dairy drinks, fruit juice and dietary supplements(Boelsma & Kloek 2009).

New enzyme technology in combination with an invitro ACE assay has produced an IPP-rich milk protein

hydrolysate of casein that has been shown to exert clini-cally relevant blood pressure-lowering effects in subjects

with mild hypertension.High blood pressure is a major cause of death world-

wide. Dietary ingredients only induce a small change inblood pressure, but this can have a major impact on the

development of CVD. Lactopeptides may be included inlifestyle and dietary changes aiming to prevent or reduce

high blood pressure. However, further studies areneeded to confirm the effects and clarify the effective

dose range of lactopeptides.

Wholegrains

Professor Chris Seal (Newcastle University, UK)described the evidence for a beneficial role of wholegrains

in cardiovascular health. Many reports have linked anincreased consumption of wholegrains with a reduction

in the risk of CVD mortality and morbidity. The effectseems to be seen with all forms of CVD. Most of the

evidence has been based on observational studies

showing a significant inverse relationship between

wholegrain intake and CVD risk. The relationships arereduced but (mostly) not removed when statisticalmodels control for confounding lifestyle factors.

However, intervention data have been much more vari-able (Seal & Brownlee 2010). Suggested mechanisms of

action include: lowered inflammatory status; improvedinsulin response; improving vascular function and blood

pressure; modified blood lipidprofiles; facilitating weightcontrol; and delivery of bioactive components such as

fibre, pre-biotics and antioxidants to the gut. ProfessorSeal outlined the evidence for wholegrain intake and

inflammatory status where 7 intervention studies report

an improved status in response to increased wholegrainintake, 5 studies showed no effect on a range of inflam-matory markers and 2 studies showed an inverse rela-

tionship between wholegrain intake and inflammatorystatus (Qi et al. 2006; Katcher et al. 2008; Gaskins et al.

2010; Masters et al. 2010; de Mello et al. 2011). Studiesinvestigating the effect of wholegrains on insulin

response have had inconsistent findings (Keenan et al.2002; Pereira et al. 2002; Lutsey et al. 2007; Andersson

et al. 2007; Alminger & Eklund-Jonsson 2008).

However, studies of the relationship between wholegrainintake and blood pressure indicate a reduced systolic and

diastolic blood pressure after consumption of 48 g ofwholegrain per day (Tighe et al. 2010) and data from the

Health Professionals follow-up study (Flint et al. 2009)indicate a significant difference in the incidence of hyper-

tension between the lowest and highest quintiles ofwholegrain intake. In studies considering wholegrain

intake and vascular function, there has been a trend forsmaller progression in arterial stenosis for the highest

wholegrain consumers compared with lower intakes(Erkkil et al. 2005). Current national recommendations

for bread, cereals and starchy food suggest that thesefoods are best eaten as wholegrain, but the actual

wholegrain intake falls very short of the current recom-mendations. For example, approximately one-third of

the UK population eat no wholegrain (Thane et al. 2007)and in the USA, greater than 95% of the population fail

to meet recommendations set by the USDA in 2010(USDA 2010).

In summary, Professor Seal concluded that evidencefrom meta-analyses supports the beneficial effects of

wholegrain in reducing CVD risk, and according toMellen et al. (2008), in light of this consistent evidence,

policy makers, scientists and clinicians should redoubleefforts to incorporate clear messages on the beneficial

effects of wholegrain into public health and clinicalpractice endeavours. Despite this evidence, however, a

nutritional claim has been refused by EFSA, although

new data will shortly be presented for EFSAs delibera-

tion. Professor Seal suggested that rather than simplyfocus on wholegrain per se, it is important to considerthe effects of specific grains such as rye, wheat, oats or

barley on health as these may vary.Lastly, Professor Seal was asked whether the lectin

found in wheat could damage the endothelium, but didnot think that there was any evidence that this was a

concern.

Blood platelets

Professor Jonathan Gibbins (University of Reading, UK)

explained how platelets perform a pivotal role in theregulation of haemostasis (blood clotting); a physiologi-cal response to injury that prevents excessive bleeding.

Aberrant activation of platelets (e.g. at sites of bloodvessel disease or the rupture of atherosclerotic lesions)

however, triggers thrombosis, resulting in a heart attackor stroke (Ruggeri 2002). The suppression of platelet

function with medication has been demonstrated to beeffective in the prevention of thrombosis, although inci-

dence of thrombotic diseases and the metabolic condi-


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tions from which these develop are ever increasing. Anti-platelet drugs are ineffective in some patients with

complications and side effects such as bleeding (Barrett

et al. 2008). In the past 20 years, substantial progress has

been made in understanding the molecular mechanismsthat regulate platelet function and this is beginning to

impact on the development of new anti-thrombotic strat-egies. This has equipped us with the ability to explore a

long-recognised but perplexing question: how does thediet modulate the risk of thrombotic disease? Professor

Gibbins described how specific dietary components, par-ticularly polyphenols, modulate platelet reactivity and

described on-going work to attribute structurefunctionrelationships for this complex and large family of mol-

ecules and the metabolites of these that are found in vivo(Hubbard et al. 2003, 2004; Wright et al. 2010a,

2010b). The effects of structurally related polyphenolson a range of platelet functions such as aggregation,

secretion and thrombus formation were described. Tounderstand the molecular basis of the effect of these

dietary compounds and their metabolites on plateletfunction, it is necessary to explore their effects on intra-

cellular signal transduction (Hubbard et al. 2003;Wright et al. 2010b). Polyphenols have been shown to

inhibit platelet kinases and protein phosphorylation-dependent signalling in experiments conducted in vitroand in vivo. As kinase cascades form major regulatory

pathways in platelets, this at least, in part, explains theability of selected polyphenols to suppress platelet reac-

tivity. Polyphenols may also inhibit platelet cell surface

receptors by binding to receptor sites (e.g. blockingthomboxane A2 and thereby inhibiting further plateletactivation) (Guerrero et al. 2005). In an attempt to define

inhibitor specificity, molecular modelling and computa-tional docking experiments were presented that support

the ability of quercetin and related molecules to dockinto the Src-family kinases (enzymes that are essential to

platelet function) and thereby modulate their activity.Professor Gibbins indicated that metabolic disorders

dramatically increase the risk of developing CVD.Understanding the links between metabolic disease and

increased risk of thrombosis is clearly a priority. In

recent work from his laboratory, a number of curiouslinks between the regulation of metabolism and theregulation of platelets have been discovered. Surpris-

ingly, these involve intracellular receptors whose role isnormally to regulate gene expression, but in the absence

of a nucleus (platelets do not have one), they appear tocause rapid non-genomic effects. Targeting these

mechanisms was found to result in inhibition of markersof platelet function and a reduction in thrombosis.

These include PPARg(peroxisome proliferator-activated

receptor), a target for the thiazolidinedione class of anti-diabetic drugs; LXR (liver X receptor) responsible for

regulating cholesterol metabolism; and RXRa and b(retinoid X receptor), which play important roles in

development and differentiation (Moraes et al. 2007,2010; Spyridon et al. 2011). An understanding of these

surprising new facets to the regulation of platelet func-tion will provide insight into the connections involving

diet, metabolism, metabolic disease and thrombosis,and may enable integrated preventative and therapeutic

measures (diet and medicines).

Tomato concentrate

Steve Morrison (Provexis, Berkshire, UK) explainedhow Fruitflow, a commercial water soluble tomato

concentrate, was the first functional food ingredient toobtain a new function health claim under Article 13 (5)

of EC Regulation 1924/2006 covering the use of nutri-tion and health claims on foods. Original research by

Duttaroy et al. (2001) considered the role of hyperactiveplatelets in the development of coronary artery throm-

bosis. As a diet high in fruit and vegetables has cardio-protective properties, 17 different fruit extracts were

screened to evaluate their effects on platelet aggregation.Tomato extract was found to be the most effective.

Mr Morrison noted that to date, only 3 claims havebeen approved by EFSA out of 58 submitted under

Article 13.5 where emerging science claims are made

using proprietary data. The EFSA is rejecting claims

most often based on the fact that, a cause and effectrelationship has not been established in the data pre-sented by the applicant. Negative opinions have been

given by EFSA because of insufficient evidence that aclaimed effect is beneficial to human health. This is

because there has been insufficient characterisation ofthe final product, insufficient human clinical data,

inconsistent trial results or unreliable outcome measuresor because studies have not been conducted using the

final product form. Adequate product characterisationfor FruitflowTM included the investigation of 37 com-

pounds identified as contributing towards the anti-

platelet activity. By isolating these, IC50 values weregenerated for each against four different platelet ago-nists. All compounds were identified and quantified. The

importance of each compound to overall bioactivity wasassessed and the most important compounds selected as

quality controls (OKennedy et al. 2006). Primaryaggregation mediators including calcium, fibrinogen

and ADP were measured and secondary aggregationmediators, including epinephrine factor X cascade

product eicosanoids, thrombine, collagen serotonin and


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platelet activating factor, were chosen as outcome mea-sures from blood samples recovered and tested in

response to the addition of factors promoting plateletaggregation. The EFSA considered that both the selec-

tion of subjects and the method used to assess plateletaggregation were appropriate for such studies. Mr Mor-

rison indicated that development of the product and theclinical trials programme for FruitflowTM took around

68 years to complete, although this is partly related tothe small size of Provexis (Berkshire, UK). Human trial

data included 8 pertinent human studies (7 proprietary)and were organised according to the hierarchy: ran-

domised controlled (RCT), randomised non-controlled(RNCT) trials, controlled non-randomised trials and

other studies. Provexis supplied 6 RCTs and 2 RNCTs.The human trials consistently showed a reduction in

platelet aggregation after consumption of FruitflowTM

under the proposed conditions of use. As human trial

data are central to the substantiation of a claim, thedossiers are expected to contain a written summary of

human trial data, with particular illustration of studypopulations and conditions; magnitude of effect and

physiological relevance; sustainability of effects overtime; amount of substance needed to achieve the effect;

usual intakes in the general population; and whetherthese amounts could reasonably be obtained as part of a

balanced diet. It is the applicants responsibility topresent the totality of available evidence. Mr Morrison

explained how Provexis provided acute and duration of

effect data, doseresponse data, chronic effects data and

safety data showing effects of over-consumption. A sys-tematic review of anti-platelet therapies and efficacy inprevention of CVD was also supplied.

The importance of demonstrating consumer under-standing for a potential health claim is a requirement of

the EC regulation, although the understanding by theaverage consumer is not assessed by EFSA, rather by the

European Commission, which is responsible for the finalclaim. Focus groups were held over a period of 4.5 years

across Spain, Poland, Italy andthe UK to assessconsumerunderstanding of the claim. Consumers were asked to

consider different claims and rate their understanding of

them, their relevance and believability. Although it wasclear that consumers across Europe have a poor under-standing of platelets, the final claim was considered

acceptable FruitflowTM helps maintain normal platelet

aggregation which contributes to healthy blood flow.

Conclusions

This meeting considered nutritional approaches to

improve cardiovascular health. As well as recognised

diet and lifestyle factors, it is becoming clear that func-tional foods can play a useful role in the reduction of

CVD risk and may be especially relevant for certaingenotypes. Biomarker-based definitions of health and

disease used a reference range, but categorising sub-clinical at risk populations is problematic and can lead

to confusion over medicinal vs. nutritionalapproaches as defined in legislation. There is increasing

evidence, particularly from dietary interventions, thatthe scope to alter CVD risk is dependent on individual

cardio-metabolic risk and specific genetic profiles. Thispoints to a future for personalised nutrition.

While an overall cardio-protective diet is clearlyoptimal, the positive role of individual foods and ingre-

dients was also highlighted during this meeting. Specificingredients can positively impact on blood pressure and

endothelial function, as well as serum cholesterol status,three key markers of CVD risk. Overall, the data and

ideas shared during this meeting give considerable causefor optimism. The majority of premature death and ill

health associated with CVD can be avoided by achievingan appropriate bodyweight and by following a variety

of common sense approaches to nutrition. This includes,eating at least 2 portions of fish per week, one of which

should be oil-rich, eating at least 5 portions of a varietyof fruit and vegetables per day, consuming 48 g of

wholegrain per day and cutting down on saturates andsalt. While this approach has been promoted for some

time, we now have a firm scientific foundation uponwhich to base these recommendations.

Acknowledgements

The present meeting was supported by DuPont Nutri-tion and Health.

Conflict of interest

There were no conflicts of interest disclosed at the

meeting or by any of the authors of the report.

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