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C O N F E R E N C E R E P O RT

DOI: 10.1111/j.1467-3010.2012.01984.x

Food and Health Forum meeting nutritional approaches to cardiovascular health: workshop report
H. L. Mitchell*, J. M. Gibbins, B. A. Grifn, 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 2011

This report summarises the proceedings of a meeting held by the Food and Health Forum at the Royal Society of Medicine, London, on 12 October 2011. The objective of the meeting was to highlight nutritional strategies targeted at cardiovascular health. This included a review of the effects of various foods, nutrients and ingredients on maintenance of healthy cholesterol levels, endothelial function 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 some 37% of deaths. According to the World Health Organization (WHO), up to 80% of these cases could be avoided by improving diets, increasing physical activity and smoking cessation. It is therefore important to identify the types of diet, as well as the contribution of specic foods (including functional foods), that can help to 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
Correspondence: Dr Julian Stowell, DuPont Nutrition & Health, Danisco (UK) Ltd, Reigate Place, 43 London Road, Reigate RH2 9PW, UK. E-mail: julian.stowell@danisco.com

sessions. The rst speaker, Dr Julian Stowell (Danisco Bioactives, UK), set the scene by presenting data showing CVD and diseases of the circulatory system to be the leading cause of death in the UK (ONS 2006) and a major cause of mortality globally (WHO 2004). According to the British Heart Foundation (BHF), CVD caused more than 50 000 premature deaths in the UK in 2008 (BHF 2010). 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 and stopping smoking (WHO 2008). There is convincing evidence that CVD risk increases in association with an increased intake of saturated fatty acids (SFAs) and decreases with an increased intake of sh and sh oils. This has led to recommendations in the UK to reduce SFAs and to consume at least two portions of sh per week, one of which should be oil-rich (SACN 2004). More recently, the Scientic Advisory Committee on Nutrition (SACN) has endorsed 0.45 g/day of longchain n-3 fatty acids for primary prevention and 1 g/day for secondary prevention (DH 1994). Interestingly, however, a single portion of oil-rich sh will not meet this target. Convincing scientic evidence also supports the recommendations to remain active and maintain a healthy bodyweight, to eat less salt and to consume at least 5 portions of a variety of fruit and vegetables throughout the day. The North Karelia Project in Finland has often been cited as a good example of a successful intervention at a population level that has improved public health (Puska 2002). Launched in 1972 as a response to exceptionally high coronary heart disease (CHD) mortality rates in Finland, this project involved a comprehensive approach involving a range of educational programmes focused on improving diet, smoking cessation and

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increasing physical activity. Between 1970 and 1995, mortality from cardiovascular and coronary heart disease decreased by 68% and 73%, respectively. This equated to an increase in life expectancy of 7 years for men and 6 years for women, and paralleled signicant reductions in the prevalence of risk factors, such as smoking, high serum cholesterol and hypertension over the 25-year intervention period. After his presentation, Dr Stowell was asked about the possible causes of the decline in CVD in Europe recently. He suggested that this was attributable primarily to a reduction in the prevalence of smoking and improvements in nutrition throughout life. He pointed out however, that in the North Karelia project, a greater number of women smoked at the end of the intervention period than at the beginning so improvement in other risk factors, besides smoking, had played a role. Concerns were also raised within the audience about the recommendation to eat oil-rich sh in relation to mercury contamination and sustainability. It was pointed out that the recommendations for mercury are currently being revised and that women in Japan, who eat sh more than twice a day, have lower rates of CVD, less cancer and less depression than their counterparts who eat less sh. It was noted by one of the delegates that the North Karelia intervention may have been successful in reducing CVD outcomes because of a reduction in sodium and an increase in potassium in the diet. Dr Stowell suggested that 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 Grifn (University of Surrey, UK) reviewed current biomarkers of cardiovascular health and disease. He explained how the evidence for a relationship between diet and CVD has relied heavily upon observational studies rather than randomised controlled trials (RCTs) and meta-analyses. In practice, the formulation of dietary guidelines and assessment of claims for the benets of foods or nutrients on health requires interpretation of the totality of evidence from all relevant sources. Professor Grifn explained that the Functional Food Science in Europe (FUFOSE) project helped to dene functional foods and the evidence-base required for health claims using either biomarkers (to support claims for enhanced function) or endpoint markers (to support claims of reduced disease risk) (Diplock et al. (1999). When the true endpoint of a claimed benet cannot be measured directly, studies should use markers that are

biologically valid (i.e. they have a known relationship to the outcome) and a known variability within the target population. Building on FUFOSE, the European Commission Concerted Action Process for the Assessment of Scientic Support for Claims on Foods (PASSCLAIM) Project, co-ordinated by the International Life Science Institute Europe, has been a thorough and respected approach to developing a scientic framework of generic criteria for evaluating the amount and quality of evidence to support claims for the benet(s) of food(s) or food components (Mensink et al. 2003a, 2003b). Serum cholesterol is a benchmark biomarker for CVD. However, the Framingham Study (Genest & Cohn 1995) showed serum cholesterol to be a poor determinant of CHD risk within specic countries and there are grey areas of serum cholesterol scores that have no predictive power. Biomarker-based denitions of health and disease are based on a reference range, but subclinical at risk populations are neither healthy nor diseased. This leads to the question as to how we dene the normal population? Enhanced postprandial lipaemia (i.e. impaired ability to remove fat from the bloodstream) is a major CHD risk factor (Grifn & Fielding 2001). The number and quality of circulatory low density lipoprotein (LDL) are more important determinants of LDL atherogenicity than cholesterol content per se. An increased level of small, dense LDL particles has been shown to be a predictor of cardioand cerebrovascular events in subjects with metabolic syndrome (Rizzo et al. 2009). Professor Grifn also explained the anti-atherogenic action of high density lipoprotein (HDL), which protects against the effect of oxidised LDL in the artery wall, promoting cholesterol efux. Low HDL is a powerful biomarker of risk but what is needed is a biomarker of HDL function that relates to its cardio-protective roles, namely antiatherosclerotic, antioxidant, anti-inammatory, antiplatelet/coagulation, vascular dysfunction ageing and senescence. Brachial ow-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 dened according to body mass index (BMI) and waist circumference. However, when using these parameters, it is also important to consider metabolic-obese phenotypes: metabolically benign obesity has been described as fat outside thin inside and the metabolic-obese as thin outside fat inside. Increased intra-hepatocellular fat measured by magnetic resonance spectroscopy is a common nding in those with metabolic syndrome and a

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determinant of cardiometabolic risk (Kotronen & YkiJrvinen 2008). Liver fat may also predict plasma lipid response to dietary extrinsic sugars (Ahmad et al. 2011). Professor Grifn posed the question: how can future processes of diet-CVD risk assessment, such as PASSCLAIM, address cardiometabolic risk? These should accommodate changes in functional biomarkers of HDL and assess biomarkers that characterise metabolic obesity. These markers should include increased visceral and liver fat, inammation, the extent of postprandial lipaemia, lipoprotein subclasses, oxidative damage and vascular dysfunction. The latter includes endothelial dysfunction and arterial dilation, a pragmatic biomarker that can be measured using brachial FMD. Professor Grifn was asked whether fat around the gluteal muscles is protective against CVD. He explained that the ability to store subcutaneous fat below the waist may spare the ectopic and potentially higher risk deposition of fat in internal organs, such as the liver and pancreas. While liver fat can be measured and related to increased cardiometabolic risk, pancreatic fat is amorphous and is very difcult to measure by magnetic resonance imaging. It is important to appreciate that subcutaneous fat can 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 recommendations include an intake of dietary SFAs of less than 10% of total energy. A reduction in dietary SFA has been reported to lower plasma cholesterol concentrations and may lead to improvements in other CVD risk factors. The following question was posed: what is the optimum replacement for SFA unsaturated fats or carbohydrates? Professor Lovegrove discussed how this question has been addressed in a number of RCTs, in which the replacement of SFA with either n-6 polyunsaturated fatty acid (PUFA), cis-monounsaturated fatty acid (MUFA) or complex carbohydrates resulted in benecial reductions in LDL-cholesterol. In contrast, substitution of SFA with rened carbohydrates has been associated with elevated triacylglycerol concentrations (an independent CVD risk marker). Furthermore, when SFAs were replaced with trans fatty acids, elevation of plasma cholesterol has been reported (Kris-Etherton et al. 1999; Mensink et al. 2003a, 2003b; Micha & Mozaffarian 2010). Weight for weight, trans-monounsaturated fats have 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. While these trans fats are considered the bad boys in our diet, the evidence from casecontrol and prospective studies indicates minimal impact on CHD risk at current levels of dietary intake (SACN 2007). Meta-analyses and pooled analysis of observational cohort studies show a signicant reduction in relative CHD risk with an isocaloric (5%) exchange of SFAs for PUFA, but no such benet when SFA is replaced by either carbohydrate or MUFA, although there are limited randomised controlled studies investigating the impact of SFA substitution with MUFA (Micha & Mozaffarian 2010). The addition of a long-chain n-3 PUFA supplement to a low-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 had no inuence on insulin sensitivity, as measured by an intravenous glucose tolerance test, in subjects either at risk of or with metabolic syndrome, respectively. Despite these ndings, these studies demonstrated favourable improvements 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 postprandial lipaemia (now recognised as an independent risk factor 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 PUFA improves vascular function by increasing vasodilation, although more RCTs are required to conrm 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 modication of CVD risk in populations and that the efcacy of dietary recommendations could depend on the cardiometabolic risk of the individual and their specic genetic prole. Differences in the plasma LDLcholesterol response to a dietary supplement of 2.5 g/ day eicosapentaenoic acid and docosahexaenoic acid (DHA) over 6 weeks (Lovegrove & Gitau 2008) demonstrate the enormous variation in dietary response within populations. Two important questions are, whether knowledge of genotype can contribute to a more effective use of diet in a personalised nutrition approach to the prevention of CVD, and whether dietary recommendations and advice place greater emphasis on foods rather than individual nutrients? An example 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 foods such 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 SFA increase CVD risk and what level of intake of dairy products might be protective. She responded that the primary effect of these dietary fatty acids on CVD risk is believed to be mediated through their hypercholesterolaemic effects on plasma LDL, although in addition, trans fats also lower cardio-protective HDL. The cardioprotective effects of dairy foods may be mediated by a reduction in blood pressure through the angiotensin 1-converting enzyme (ACE)-inhibitory effects of bioactive peptides in these foods. Calcium in dairy products may 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 cohort studies rather than RCTs. The former type of study cannot establish cause and effect relationships and can be subject to confounding by many factors. At risk, diseased and non-diseased individuals show variability in their response to dietary interventions and Professor Lovegrove indicated that cluster analysis with mathematical modelling may help optimise dietary strategies for specic groups.

Cholesterol
Sara Stanner (British Nutrition Foundation, UK) described the importance of LDL-cholesterol as a risk factor for CVD. Every 1 mmol/l decline in LDLcholesterol results in a 21% decrease in cardiovascular events (Yusuf et al. 2009). Dietary changes can have a signicant impact on cholesterol levels if sustained over the long-term and can also help to keep statin doses low, helping to reduce side effects. Evidence related to the inuence of plant phytosterols (including sterols and stanols) on blood cholesterol levels was presented. Major sources of phytosterols in the human diet are oils, fats, nuts and seeds, and there is considerable variation in average intakes between countries and within populations, with levels being highest in those with a relatively high plant food intake (e.g. vegetarians). A typical Western diet contains around 250 mg/ day, which is far below the recommended intake for a signicant cholesterol-lowering effect (2 g/day). Manufactured products with added phytosterols can help to bridge the gap. By interfering with the uptake of

dietary and biliary cholesterol from the intestinal lumen, a 3040% reduction in absorption of cholesterol can be achieved with phytosterols. However, there is some inter-individual variability in absorption, which as yet remains unexplained. Evidence for cholesterol lowering was presented from a number of metaanalyses, the rst of which included 84 RCTs involving 6805 study participants and concluded that, on average, around 2 g of phytosterols lowered LDLcholesterol by 0.34 mmol/l (95% condence interval: -0.36 to -0.31) or 8.8% (-9.4 to -8.3%), with no apparent effect on HDL-cholesterol or triacylglycerol levels (Katan et al. 2003). This and subsequent metaanalyses (Abumweis et al. 2008; Demonty et al. 2009) have considered a range of populations, including healthy adults with normal cholesterol levels, adults with hypercholesterolaemia and familial hypercholesterolaemia, patients with CHD and metabolic syndrome, those with type 1 and 2 diabetes and children with familial hypercholesterolaemia. The degree of cholesterol lowering is clearly inuenced by baseline cholesterol level (i.e. is higher in those with elevated baseline levels), but there remains considerable interindividual variability in the response possibly because of factors including other subject characteristics, the food matrix investigated, the frequency of intake, dietary background, the additive effect of other foods or drugs and genetic factors. The cholesterol-lowering effect has been demonstrated with a range of food matrices, such as margarines, mayonnaise, salad dressings, milk, yogurts and cheese (Katan et al. 2003; Abumweis et al. 2008; Demonty et al. 2009) and the same 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 this dose, while there may be additional cholesterol lowering from higher stanol intakes (though the safety of such intakes remains to be addressed) (Plat et al. 2000). There is good evidence that there is an additive effect of the use of phytosterols with statins in patients with primary hypercholesterolaemia (Simons 2002), and as such, consumption of phytosterols may be recommended to patients on statin therapy to further lower LDL-cholesterol when the LDL-cholesterol goals are not reached by statins alone (Katan et al. 2003) and/or if increasing further the statin dose leads to undesirable side effects. In addition, phytosterols are effective as part of a diet low in SFAs (Cleghorn et al. 2003) and when used within the portfolio diet promoted for its cholesterol-lowering effects (this diet includes plant sterols, soya protein, viscous bre and almonds)

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(Jenkins et al. 2005). Phytosterols have been approved by many regulatory authorities and endorsed by many national and international organisations. In 2008, the European Food Safety Authority (EFSA) issued its rst disease risk reduction claim in the European marketplace, supporting the evidence of plant sterols and stanols to lower cholesterol levels. Studies of the efcacy of phytosterols (i.e. their ability to lower cholesterol in free-living populations) are relatively limited. Compliance must be long-term as cholesterol levels rapidly return to baseline levels when phytosterol intake is ceased. The use of such functional products will, of course, be inuenced by consumer belief in their health benets, ease of use, taste and price and the effects of their consumption on other dietary choices needs to be assessed. Some additional questions remain to be addressed, including the long-term efcacy and safety of higher plant stanol intakes, especially in combination with statins; the identication of genetic polymorphisms inuencing the response to phytosterols; clarication of the best timing of intake and format in relation to glycaemic response and weight control; and most importantly, the effect of phytosterols on CHD risk. Trials with clinical endpoints are lacking and the National Institute for 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 we would 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 cholesterol lowering. A member of the audience asked whether the risk reduction quoted in association with the consumption of phytosterols is a relative or an absolute risk. Ms Stanner conrmed that the risk is relative. Safety concerns 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 suggested that stanols/sterols could accumulate in the brain over 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 has been 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 evidence that 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 as polyphenols, protein, dietary bre, vitamin E and magnesium. The polyphenol content and antioxidant activity of California almonds is dependent on cultivar and harvest year (Bolling et al. 2010). In 2003, the US Food and Drug Administration (FDA) approved a Qualied 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 the evidence 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 The Physicians Health Study (Albert et al. 2002). There is also substantial evidence that almonds may help to mitigate 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 second meal effect studies in adults with impaired glucose tolerance indicate that the inclusion of almonds in the breakfast meal is effective at decreasing blood glucose concentrations and increasing satiety, both acutely and after a second meal. The lipid component of the almond appears to be largely responsible for the post-ingestive response, although the whole nut itself was equally as effective. Overall, day-long insulin sensitivity was increased with whole almond consumption (Josse et al. 2007). Research using pre-diabetic adults on an intervention diet with added almonds showed LDLcholesterol lowering and improved markers of insulin sensitivity (Mori et al. 2011). Almonds have also been found to decrease inammation and oxidative stress in patients with type 2 diabetes and improve glycaemic control and lipid proles (Wien 2010; Chen et al., unpublished data). They have also been shown to decrease postprandial glycaemia, insulinaemia and oxidative damage in healthy individuals (Wien 2010). Dr Lapsley was asked where the almond plant originally came from and if trials had compared the health effects 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 globally but will vary depending on growing conditions. Over-roasting will affect shelf life and nutritional value. Studies have shown most nuts to achieve cholesterol lowering of 510%. When asked about the allergic response to almonds, Dr Lapsley pointed out that about 12% of the population are adversely affected by almonds and the severity of allergic reaction 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 properties of oat b-glucan that inuence its effects on postprandial glucose and LDL-cholesterol, as well as the effective doses required to positively inuence these CVD risk factors (4 and 3 g/day, respectively). The impact of oat b-glucan on postprandial glucose and serum LDL depends on its viscosity and this is controlled by the concentration of bre in solution (C) and its molecular weight (MW). The concentration of the b-glucan is determined by the dose fed and its bioavailability (solubility). Research has suggested that modest doses (34 g/day) of oat b-glucan with a MW 530 000 are effective in lowering LDL-cholesterol, while a MW 210 000 is likely to be ineffective (Wolever et al. 2010). Mr Ruedi Duss (CreaNutritionLtd, Switzerland) described the disease risk reduction claim associated with oat b-glucan in the EU that has been accepted under Article 14 of the EC Regulation on Nutrition and Health Claims (EC 1924/2006). The EFSA concluded that there is sufcient evidence of a cause and effect relationship, that the product is well characterised and that there are sufcient markers of intermediate endpoints to validate a claim. In order to obtain reliable and credible claims, the EC 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 available to be used by the body. For oat b-glucan, there is evidence that the bioactive form is soluble, with a higher viscosity in solution (EFSA 2010, 2011). The Regulation also states that the quantity of the product that can reasonably be expected to be consumed provides a signicant quantity of the nutrient oat beta-glucan. Evidence shows that a signicant quantity is 3 g/day, which can be delivered once a day or 23 times a day via different product formats. The actual disease risk reduction claim endorsed by EFSA is Oat beta-glucan has been shown to lower/reduce blood cholesterol. High cholesterol is a risk factor in the development of coronary heart disease. This claim can be used for foods that provide at least 1 g of oat b-glucan per quantied portion, provided information is given to the consumer that the benecial effect is obtained with a daily intake of 3 g. The EFSA opinion on LDL-cholesterol also includes barley b-glucan (www.efsa.europa.eu/en/efsajournal/ pub/2207.htm). The whole process of approval took approximately 3.5 years from the time of submission to EFSA in June 2008. It was suggested by an audience member that as phytosterols and statins have an additive effect on LDL-

cholesterol lowering, b-glucans may also exhibit a similar additive effect with statins, as the mechanism of effect is owed to reduced cholesterol absorption. It was agreed that this is an area for future research.

Docosahexaenoic acid (DHA)

Professor Michael Crawford (Imperial College, London, UK) considered the evidence for the benets of DHA in maintaining cardiovascular health. He reminded the audience that the human brain and vascular endothelium is lipid-rich and that PUFAs are responsible for the elasticity of cells, especially in the vascular and neural systems where they also play important functional roles. Docosahexaenoic acid and arachidonic acid are the most prominent essential fatty acids in the brain endothelium and human vascular endothelium. This gives a clear message about their importance in vascular health. From 1910 to 1970, there was a steep rise in mortality from CHD. As there was no genomic change during that period, this increase can only be explained by environmental factors, such as diet-inuencing gene expression (epigenetics). Professor Crawford explained how maternal diets are important in establishing a healthy vascular system in the fetus and evidence from biomagnication of DHA across the placenta and in the cord, fetal liver and fetal brain indicate high proportions of DHA moving 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 the rst visual and neural cell membranes. Fish, amphibians, reptiles, birds and mammals, all use DHA for this purpose. The benets are in hippocampal and myocyte signalling and the prevention of arrhythmia and sudden death. The uniqueness of DHA lies in its six methylene interrupted double bonds that are electrically active, alternating with positive and negative areas with the potential to act as a semiconductor (Crawford et al. 2008). Professor Crawford used Roger Penroses suggestion that quantum coherence is probably the explanation for the uniqueness of DHA in the precision of control in signalling for brain function and heartbeat, as electrons will only tunnel at a specic energy state. Cardiac electric activity is strongly modulated by its environment. Deciency of DHA in the signalling membranes will lead to a weak and more frequent signal (i.e. arrhythmia). A comparison between an African shing population and inland vegetarians in the same region showed those from the shing 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 of DHA from sh and improved health (Crawford et al. 2000). Professor Crawford questioned how, when we know this, CVD is still a leading cause of death worldwide? According to Professor Crawford, the food system is fundamentally awed, as the wartime diet, which improved the nations health, was abandoned in favour of a system focused on production. Professor Crawford suggested that chicken eaten in 2004 provided three to six times more calories from fat on a gram-to-gram basis than those eaten in 1976. In the same time period, the DHA content has reduced phenomenally (Wang et al. 2010) and he also suggested that wild beef has a higher amount of lean muscle, less fat and a higher proportion of PUFAs to saturate than modern reared beef. In view of the evidence linking SFA intake with arterial and heart disease, the alteration of the nature of meat through domestication and intensication could be relevant to the rise in mortality from heart disease. In the wild species, the ratio of nonessential 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 the top 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 suggest that it is costing around 105 billion. Professor Crawford emphasised the importance of health education in schools to empower children with the knowledge to eat healthily. He also stressed the need to develop the UK shing industry. A member of the audience commented that whenever nutrition and health are discussed, education seems to be at the heart of the issue and asked what young scientists could do to improve the situation. Professor Crawford explained that there have been several initiatives to encourage the government to re-introduce compulsory home economics into schools, but they have not been successful. He concluded by saying there has to be political will to turn the situation around.

function is prevalent in the elderly but is frequently associated with increased CVD risk in men aged 45+ years and women of 55+ years. It is common in smokers and those with dyslipidaemia (high cholesterol) and diabetes, and has been linked to hypertension, erectile dysfunction and age-related left ventricular dysfunction and heart failure. It is also implicated in age-related decline in cognitive function. When assessing endothelial (dys)function, the functional measures are FMD with either brachial artery ultrasound for macrovascular endothelial function or peripheral artery tonometry for microvascular endothelial function. Biomarker signatures are available, but these are generally unreliable. Currently, the treatment options for endothelial dysfunction are either medical via statins, ACE inhibitors or endothelial antagonists, or nutraceuticals via avonoids.

Polyphenols
Professor Corder then went on to describe the dietary sources of polyphenols and their chemical subclasses. He also explained how high dietary consumption of avonoids is associated with lower mortality from heart disease (Mink et al. 2007). Consumption of red wine can have a positive effect on FMD response and coronary microcirculation (Hozumi et al. 2006). Red wine contains high levels of polyphenols. The polyphenols, quercetin, delphinidin, epicatechin (avan-3-ol) and resveratrol are present in wine as minor components but have often been investigated. At the amounts present in wine, they have no biological activity. When puried procyanidins were tested for their effects on endothelial function; ndings showed that their potency of action is unrelated to antioxidant properties (Caton et al. 2010). Higher longevity for men in south west France and Sardinia 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 function are not altered in post-menopausal women after ingesting an elderberry extract rich in anthocyanins for 12 weeks. There was no change in blood pressure or biomarkers of vascular function (Curtis et al. 2009). A crossover study showed that there were no signicant effects of cranberry juice on blood pressure or endothelial/ vascular function measure when cranberry juice rich in polyphenols was consumed by patients with coronary artery disease (Hozumi et al. 2006). Similarly, in a double-blind crossover study, grape juice consumption among pre-hypertensive and stage 1 hypertensive patients did not lead to a signicant reduction in

Endothelial dysfunction
Professor Roger Corder (Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK) highlighted how endothelial dysfunction and heart disease progress with age. Endothelial dys-

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24-hour blood pressure or any signicant changes in vascular function (Dohadwala et al. 2010). Another rich source of procyanidins is cocoa. In a randomised, double-blind evaluation of the acute effects of cocoa drinks containing high, medium and low levels of avonols in patients with diabetes, the %FMD increased over time in a dose-related manner (Balzer et al. 2008). Improvement of endothelial function with cocoa avonols has also been shown in patients with coronary artery disease (Heiss et al. 2010). A meta-analysis of individual data for one million adults in 61 prospective studies concluded that each 2 mmHg reduction in systolic blood pressure decreases stroke mortality by 10% and decreases mortality from CHD by 7% (Lewington et al. 2002). Current medical treatments only produce modest improvements in endothelial function and clinical trials are needed to evaluate the full potential of procyanidin-rich avonol products, as well as the need to identify who might benet most from increased avanol consumption. Identication of avanols with the greatest effect on endothelial function at appropriate purity, bioavailability and dose should be considered, but evidence of the cause and 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-rich foods in targeting specic cardiovascular disorders. Currently, no specic dietary advice is given to patients with stable angina, who are treated according to the NICE guidelines with calcium channel blockers, beta blockers and long-acting nitrates or with repeated doses of shortacting nitrates. Quercetin and epicatechin are avonoids that can form a substantial part of the daily polyphenol intake, 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 vascular isometric tension recordings using porcine coronary artery, it has been shown that quercetin, but not epicatechin, possesses vasodilator activity. Quercetin and quercetin sulphate possess vasodilator activity, but quercetin glucuronide is inactive. In vitro models of glyceryl trinitrate (GTN) tolerance indicate that quercetin and quercetin sulphate reduce the degree of GTN-induced tolerance (Suri et al. 2010). Quercetin-rich foods should be evaluated in patients with stable angina.

One-third of chronic kidney disease patients experience a potentially damaging fall in blood pressure during haemodialysis myocardial stunning. Dietary advice is to have a low uid intake and generally less than 5 portions of fruit and vegetables per day (to reduce high K+ ion intake). The condition is associated with an increase in vascular stiffness and high cardiovascular morbidity. Castilla and colleagues used an intervention with concentrated grape juice to determine the antioxidant, hypolipidaemic and anti-inammatory effects in both haemodialysis patients and healthy subjects (Castilla et al. 2006). The juice was standardised in terms of quercetin content. The 1-month dietary intervention indicated a small, but signicant, reduction in plasma lipids in both healthy subjects and haemodialysis patients. These effects were still evident 1 month after cessation. The apple variety Evesse EPC has a 100-fold higher epicatechin content than Evesse OPC, but they have similar antioxidant activities. However, Evesse OPC possesses vasodilator activity as measured in vitro. In preliminary human volunteer studies, Evesse EPC apples (3 mg/kg epicatechin) did not cause an overt change in regional haemodynamics, but did elicit a signicant reduction in vascular stiffness (Wilson et al., unpublished observations). Thus, Evesse EPC or OPC may reduce vascular stiffness in chronic kidney disease patients and improve the haemodynamic stability during 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 empower individuals 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 risk factors in the development of cardiovascular conditions. A small reduction in blood pressure of hypertensive subjects could signicantly reduce the risk of CVDs. Thus, there is a high interest in nutritional products with the ability to reduce blood pressure that could contribute to reducing the risk of CVDs. Milk-derived peptides have been identied as potential antihypertensive agents. In the last 10 years, over 20 human clinical trials have been conducted with lactotripeptides: valine-prolineproline (VPP) and isolecuine-proline-proline (IPP) demonstrating blood pressure reduction (Pripp 2008; Xu et al. 2008). Reviews and meta-analyses of controlled 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 of 3.0752.5 mg/day. Blood pressure reduction is more effective in people with raised blood pressure and has been demonstrated with different types of food carriers: dairy drinks, fruit juice and dietary supplements (Boelsma & Kloek 2009). New enzyme technology in combination with an in vitro ACE assay has produced an IPP-rich milk protein hydrolysate of casein that has been shown to exert clinically relevant blood pressure-lowering effects in subjects with mild hypertension. High blood pressure is a major cause of death worldwide. Dietary ingredients only induce a small change in blood pressure, but this can have a major impact on the development of CVD. Lactopeptides may be included in lifestyle and dietary changes aiming to prevent or reduce high blood pressure. However, further studies are needed to conrm the effects and clarify the effective dose range of lactopeptides.

Wholegrains
Professor Chris Seal (Newcastle University, UK) described the evidence for a benecial role of wholegrains in cardiovascular health. Many reports have linked an increased consumption of wholegrains with a reduction in the risk of CVD mortality and morbidity. The effect seems to be seen with all forms of CVD. Most of the evidence has been based on observational studies showing a signicant inverse relationship between wholegrain intake and CVD risk. The relationships are reduced but (mostly) not removed when statistical models control for confounding lifestyle factors. However, intervention data have been much more variable (Seal & Brownlee 2010). Suggested mechanisms of action include: lowered inammatory status; improved insulin response; improving vascular function and blood pressure; modied blood lipid proles; facilitating weight control; and delivery of bioactive components such as bre, pre-biotics and antioxidants to the gut. Professor Seal outlined the evidence for wholegrain intake and inammatory status where 7 intervention studies report an improved status in response to increased wholegrain intake, 5 studies showed no effect on a range of inammatory markers and 2 studies showed an inverse relationship between wholegrain intake and inammatory status (Qi et al. 2006; Katcher et al. 2008; Gaskins et al. 2010; Masters et al. 2010; de Mello et al. 2011). Studies investigating the effect of wholegrains on insulin response have had inconsistent ndings (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 wholegrain intake and blood pressure indicate a reduced systolic and diastolic blood pressure after consumption of 48 g of wholegrain per day (Tighe et al. 2010) and data from the Health Professionals follow-up study (Flint et al. 2009) indicate a signicant difference in the incidence of hypertension between the lowest and highest quintiles of wholegrain intake. In studies considering wholegrain intake and vascular function, there has been a trend for smaller 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 these foods are best eaten as wholegrain, but the actual wholegrain intake falls very short of the current recommendations. 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 evidence from meta-analyses supports the benecial effects of wholegrain in reducing CVD risk, and according to Mellen et al. (2008), in light of this consistent evidence, policy makers, scientists and clinicians should redouble efforts to incorporate clear messages on the benecial effects of wholegrain into public health and clinical practice endeavours. Despite this evidence, however, a nutritional claim has been refused by EFSA, although new data will shortly be presented for EFSAs deliberation. Professor Seal suggested that rather than simply focus on wholegrain per se, it is important to consider the effects of specic 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 did not 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 the regulation of haemostasis (blood clotting); a physiological response to injury that prevents excessive bleeding. Aberrant activation of platelets (e.g. at sites of blood vessel disease or the rupture of atherosclerotic lesions) however, triggers thrombosis, resulting in a heart attack or stroke (Ruggeri 2002). The suppression of platelet function with medication has been demonstrated to be effective in the prevention of thrombosis, although incidence of thrombotic diseases and the metabolic condi-

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tions from which these develop are ever increasing. Antiplatelet 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 mechanisms that regulate platelet function and this is beginning to impact on the development of new anti-thrombotic strategies. This has equipped us with the ability to explore a long-recognised but perplexing question: how does the diet modulate the risk of thrombotic disease? Professor Gibbins described how specic dietary components, particularly polyphenols, modulate platelet reactivity and described on-going work to attribute structurefunction relationships for this complex and large family of molecules 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 polyphenols on a range of platelet functions such as aggregation, secretion and thrombus formation were described. To understand the molecular basis of the effect of these dietary compounds and their metabolites on platelet function, it is necessary to explore their effects on intracellular signal transduction (Hubbard et al. 2003; Wright et al. 2010b). Polyphenols have been shown to inhibit platelet kinases and protein phosphorylationdependent signalling in experiments conducted in vitro and in vivo. As kinase cascades form major regulatory pathways in platelets, this at least, in part, explains the ability of selected polyphenols to suppress platelet reactivity. Polyphenols may also inhibit platelet cell surface receptors by binding to receptor sites (e.g. blocking thomboxane A2 and thereby inhibiting further platelet activation) (Guerrero et al. 2005). In an attempt to dene inhibitor specicity, molecular modelling and computational docking experiments were presented that support the ability of quercetin and related molecules to dock into 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 curious links between the regulation of metabolism and the regulation of platelets have been discovered. Surprisingly, these involve intracellular receptors whose role is normally to regulate gene expression, but in the absence of a nucleus (platelets do not have one), they appear to cause rapid non-genomic effects. Targeting these mechanisms was found to result in inhibition of markers of platelet function and a reduction in thrombosis. These include PPARg (peroxisome proliferator-activated

receptor), a target for the thiazolidinedione class of antidiabetic 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 function 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) explained how Fruitow, a commercial water soluble tomato concentrate, was the rst functional food ingredient to obtain a new function health claim under Article 13 (5) of EC Regulation 1924/2006 covering the use of nutrition and health claims on foods. Original research by Duttaroy et al. (2001) considered the role of hyperactive platelets in the development of coronary artery thrombosis. As a diet high in fruit and vegetables has cardioprotective 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 have been 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 effect relationship has not been established in the data presented by the applicant. Negative opinions have been given by EFSA because of insufcient evidence that a claimed effect is benecial to human health. This is because there has been insufcient characterisation of the nal product, insufcient human clinical data, inconsistent trial results or unreliable outcome measures or because studies have not been conducted using the nal product form. Adequate product characterisation for FruitowTM included the investigation of 37 compounds identied as contributing towards the antiplatelet activity. By isolating these, IC50 values were generated for each against four different platelet agonists. All compounds were identied and quantied. The importance of each compound to overall bioactivity was assessed and the most important compounds selected as quality controls (OKennedy et al. 2006). Primary aggregation mediators including calcium, brinogen and ADP were measured and secondary aggregation mediators, including epinephrine factor X cascade product eicosanoids, thrombine, collagen serotonin and

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platelet activating factor, were chosen as outcome measures from blood samples recovered and tested in response to the addition of factors promoting platelet aggregation. The EFSA considered that both the selection of subjects and the method used to assess platelet aggregation were appropriate for such studies. Mr Morrison indicated that development of the product and the clinical trials programme for FruitowTM took around 68 years to complete, although this is partly related to the small size of Provexis (Berkshire, UK). Human trial data included 8 pertinent human studies (7 proprietary) and were organised according to the hierarchy: randomised 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 FruitowTM under the proposed conditions of use. As human trial data are central to the substantiation of a claim, the dossiers are expected to contain a written summary of human trial data, with particular illustration of study populations and conditions; magnitude of effect and physiological relevance; sustainability of effects over time; amount of substance needed to achieve the effect; usual intakes in the general population; and whether these amounts could reasonably be obtained as part of a balanced diet. It is the applicants responsibility to present 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 systematic review of anti-platelet therapies and efcacy in prevention of CVD was also supplied. The importance of demonstrating consumer understanding for a potential health claim is a requirement of the EC regulation, although the understanding by the average consumer is not assessed by EFSA, rather by the European Commission, which is responsible for the nal claim. Focus groups were held over a period of 4.5 years across Spain, Poland, Italy and the UK to assess consumer understanding of the claim. Consumers were asked to consider different claims and rate their understanding of them, their relevance and believability. Although it was clear that consumers across Europe have a poor understanding of platelets, the nal claim was considered acceptable FruitowTM helps maintain normal platelet aggregation which contributes to healthy blood ow.

diet and lifestyle factors, it is becoming clear that functional foods can play a useful role in the reduction of CVD risk and may be especially relevant for certain genotypes. Biomarker-based denitions of health and disease used a reference range, but categorising subclinical at risk populations is problematic and can lead to confusion over medicinal vs. nutritional approaches as dened in legislation. There is increasing evidence, particularly from dietary interventions, that the scope to alter CVD risk is dependent on individual cardio-metabolic risk and specic genetic proles. This points to a future for personalised nutrition. While an overall cardio-protective diet is clearly optimal, the positive role of individual foods and ingredients was also highlighted during this meeting. Specic ingredients 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 cause for optimism. The majority of premature death and ill health associated with CVD can be avoided by achieving an appropriate bodyweight and by following a variety of common sense approaches to nutrition. This includes, eating at least 2 portions of sh per week, one of which should be oil-rich, eating at least 5 portions of a variety of fruit and vegetables per day, consuming 48 g of wholegrain per day and cutting down on saturates and salt. While this approach has been promoted for some time, we now have a rm scientic foundation upon which to base these recommendations.

Acknowledgements
The present meeting was supported by DuPont Nutrition and Health.

Conict of interest
There were no conicts of interest disclosed at the meeting or by any of the authors of the report.

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Conclusions
This meeting considered nutritional approaches to improve cardiovascular health. As well as recognised

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