heart-foundations-evidence-paper-dietary-patterns by Heart Foundation

An evidence-based nutrition statement from the National Heart Foundation of New Zealandâ&#x20AC;&#x2122;s Nutrition Advisory Committee

dietary patterns Authors: J Bremer DipHSc.NZRD A Chisholm DipHSc.MCApSc.PhD.NZRD March 1999

contributors committee members Professor J Mann PhD, MD, FRACP, FRSNZ. Professor of Human Nutrition and Medicine, University of Otago, Dunedin, New Zealand. Dr A Chisholm DipHSc, MCApSc, PhD, NZRD. Research Dietitian, Department of Human Nutrition, University of Otago, Dunedin, New Zealand. Associate Professor L Eyres PhD, MBA. Technical and Developments General Manager, New Zealand Dairy Foods, Auckland, New Zealand. M McKerchar DipSc, PGDipSc (Com Nutr), NZRD. Maori Health Promoter, Southern Public Healt h Services, Invercargill, New Zealand. J Reid BSc (Hons), PGDipDiet, MPH, NZRD. Nutrition Advisor, Ministry of Health, Wellington, New Zealand. D Roberts BPhEd, BSc, PGDipDiet, NZRD. National Dietitian, the National Heart Foundation of New Zealand, Auckland, New Zealand. Associate Professor B Swinburn MB ChB, FRACP, MD. Medical Director, the National Heart Foundation of New Zealand, Auckland, New Zealand. A Tuffin BA, DipTchg. Senior Lecturer Health Education, College of Education, Massey University, Palmerston North, New Zealand. L Young BHSc, PGDipSc (Com Nutr), NZRD. Food Industry Manager, the National Heart Foundation of New Zealand, Auckland, Zealand.

other contributors J Bremer DipHSc, NZRD. Consulting Dietitian, Christchurch, New Zealand. S Mackay BCApSc, PGDipPH, MSc. Nutritionist, Nelson, New Zealand. M Seddon MB ChB, MPH. Public Health Registrar, the National Heart Foundation of New Zealand, Auckland, New Zealand.

reviewing organisations The Ministry of Health, Wellington, New Zealand. The Nutrition and Metabolism Advisory Committee of the National Heart Foundation of Australia, Canberra, Australia.

table of contents section summary Explanatory notes background paper

3 3 14

Examination of the evidence

Introduction

Dietary patterns

Observational studies

Therapeutic dietary patterns

Developing an ideal dietary pattern

abbreviations references

98 100

basic evidence -grading strategy Meta-analyses of, or single, well designed randomized controlled trials

Grade A

Non-randomized and/or controlled studies

Grade B

Historical cohort, population -based

Grade C

Case series

Grade D

Expert opinion

Grade E

section summary A description of those dietary patterns associated with least risk for coronary heart disease is vital to the implementation of dietary recommendations for reducing cardiovascular risk. Dietary patterns recommend for coronary heart disease protection are a synthesis of epidemiological evidence of naturally occurring patterns and randomizedcontrolled trial evidence of specific patterns of eating. The study of dietary patterns attempts to account for the habits of free-living individuals within their particular environment and the interrelationships between nutrients and non-nutrient factors evolving from the many food choices and methods of preparation chosen for their habitual diet. Traditional dietary patterns in certain populations of the Mediterranean and Asia have been associated with low rates of coronary heart disease. Westernisation of these dietary patterns in the past 30 years is associated with increasing rates of coronary heart disease in these populations. The Western diet post-World War Two until the 1960's has been associated with a period of highest recorded coronary heart disease rates in the Western industrialised world. From the 1970's to the 1990's, a change in this dietary pattern compatible with cardiovascular protection has occurred at the same time as a decline in deaths from coronary heart disease, especially in high socioeconomic populations. For the general population A healthy diet is assessed as a whole dietary pattern, rather than having good and bad components. A variety of traditional and modified dietary patterns are associated with reduced risk of coronary heart disease. The relevant proportions of foods and the way they are processed and prepared are the first considerations when choosing a dietary pattern that both protects against coronary heart disease, and provides the essential nutrients to maintain length and quality of life. Protection from coronary heart disease is associated with dietary patterns that have a high content of fruits, vegetables, legumes, and whole grain foods, and which include fish, nuts and low fat dairy products. Dietary patterns that emphasise fat sources from plant oils, nuts, seeds and fish reduce risk for coronary heart disease compared with patterns high in animal fats, hardened plant fats and oils, commercial baked products containing these fats, and deep fried foods. Many individuals have to limit their total intake of all fats and oils, alcohol and low fibre, highly refined foods to avoid excessive energy intakes and subsequent weight gain. Certain individuals may benefit from low fat diets with a high dietary fibre content. For those at high risk of cardiovascular disease Dietary patterns that reduce risk for heart attacks and strokes, include eight or more servings of fruit and vegetables, large servings of whole grains, fish and/or legumes frequently in place of meat and full fat dairy products, nuts and seeds regularly, usually include low fat dairy products daily, and may or may not include small lean meat servings. These dietary patterns use plant oils such as canola, olive, soy, sunflower or other seed or nut oils in cooking and food preparation, and may or may not include soft unsaturated margarines as spreads. Dietary patterns found to reduce heart attacks in people at very high risk are low in saturated fats. When the total fat content of these diets is low, the correspondingly higher carbohydrate con tent is derived mainly from grains, fruits, vegetables and legumes. The dietary intake of refined sugar and flour products is low, and packaged foods have a high fibre and low saturated fat content. Such dietary patterns also promote maintenance of a hea lthy body weight. The response to dietary change is greatest when specific components of diet are adapted to the individual risk profile.

Explanatory notes Dietary factors are associated with cardiovascular risk factors such as dyslipidaemia, blood pressure, obesity, thrombogenesis, impaired glucose tolerance, insulin resistance, and LDL -C oxidation. Traditionally these risk factors have been studied in relation to specific nutrients, components of diet or food groups. However this approach ignores that our diet is composed of a pattern of many different foods leading to a specific combination of nutrients and non-nutrient food factors. Beyond nutritional needs, dietary patterns evolve from a wide range of environmental, traditional, cultural, social and intellectual influences. The study of dietary patterns takes into account the high intercorrelation of nutrients and food factors within a diet due to the choice of foods in which these nutrients occur, or to the consumption of particular foods at the expense of others. It also accounts for components present in foods that are either presently unknown, or not yet identified as beneficial to health. The traditional dietary patterns of certain populations have been associated with either high or low rates of CVD among that population. Furthermore, change in population dietary patterns have been associated with a decrease or an increase in cardiovascular mortality. The most consistent and abundant associations have been observed for CHD. Dietary factors may promote or protect individuals or populations from CHD. Experimental and clinical intervention studies have identified SFAs, dietary cholesterol, trans -unsaturated fat, 3

animal fats and hardened vegetable fats as pathogenic for CHD. Dietary factors that have been identified as protective include PUFAs, including omega-3 PUFAs from fish and plant foods and omega-6 PUFAs from vegetable oils, nuts and seeds, whole plant foods, vegetables, fruit, whole grains, legumes, antioxidants, flavonoids and other phytochemicals such as sterol esters, folate, dietary fibre, and possibly low fat dairy products. A third group of dietary factors are mostly benign at moderate intakes in most circumstances, but may become either pathogenic or protective under certain situations. These factors include refined CHO food products, MUFAs, alcohol, very lean meats and poultry. Six styles of dietary pattern can be identified as associated with risk of CHD.

Dietary patterns associated with promotion of coronary heart disease 1.

The traditional diet of Northern Europe and other “Western” nations, based on animal foods, full fat dairy products and beef, lamb and pork, with small or moderate servings of fruits and vegetables, cereal products (often refined) are associated with high rates of CHD (Level of evidence A).

The modern Western diet rich in processed foods, low in dietary fibre, frequently using fried foods and sugar, low fat to high fat dairy and meat products, with low to moderate fruit and vegetable intakes (Level of evidence B).

Dietary patterns associated with protection against coronary heart disease 3.

Vegetarian diets meeting dietary guidelines are associated with low rates of CHD and reduce cardiovascular risk when practiced in conjunction with a healthy lifestyle (Level of evidence A).

The traditional diet of the Mediterranean coast is high in plant foods: fruits and vegetables, plant and seed oils, beans, nuts and seeds, and includes small amounts of dairy and meat products, and/or fish. This diet is associated with low rates of CHD and reduction of cardiovascular risk (Level of evidence B). Reinfarction rates have been reduced in two quasi-Mediterranean experimental trials of secondary prevention (Level of evidence A).

The traditional diets of Asia, rich in grains, legumes and veget able products, low in animal food content and including fish in coastal regions, are associated with low rates of CHD (Level of evidence B).

Modified Western dietary patterns with a high ratio of plant to animal foods reduce rates of CHD and reduce cardiovascular risk via dietary lipid and fibre changes that influence blood total and LDL-C, blood pressure and potentially other risk factors (Level of evidence A). Dietary patterns where oils rich in unsaturated fats partially replace SFAs reduce rates of CHD and cardiovascular risk (Level of evidence A).

Observational studies Prospective population-based cohort studies: Diet and coronary heart disease mortality

•

Prospective cohort studies consistently demonstrate an inverse association between dietary patterns involving high intakes of dietary fibre (particularly from cereal sources) and CHD -1 -1 mortality. The highest range of intake, associated with least risk is 20 g.d to 35 g.d or more dietary fibre (Level of evidence B). High fibre intakes are associated wit h lower fat intakes, improved micronutrient intakes and people who eat high fibre diets are generally more active, and have a lower BMI (Level of evidence B).

•

Dietary patterns associated with higher risk for CHD mortality are found in populations typically consuming high intakes of SFAs from high intakes of animal fats (Level of evidence

B). High intakes of trans -unsaturated fat from partially hydrogenated (hardened) plant oil products may also contribute to risk (Level of evidence B). •

Components of dietary patterns associated with lower rates of CHD mortality include high dietary fibre intakes, and high intakes of whole plant foods in the form of wholegrain cereal products (wholemeal bread, bran, brown rice, oats), fruits and vegetables, nuts and seeds, fish, soy and legumes, oil and vinegar vinaigrette and use unsaturated plant oils for cooking and food preparation (Level of evidence B). Each of these components is independently associated with less risk (Level of evidence B). Foods associated with increased CHD include hard margarines, cheese, eggs, animal fat, biscuits, cake, white bread, doughnuts, beef, and full fat dairy products, are indicators of higher risk dietary patterns (Level of evidence B).

•

In general, long term epidemiological studies suggest that dietary patterns leading to low intakes of plant foods as indicated by low intakes of flavonoids, dietary fibre and PUFAs, increase risk for CHD (Level of evidence B), and that such dietary patterns are associated with high intakes of animal foods reflected by high intakes of SFAs (Level of evidence B). More recent studies show that intakes of hardened vegetable oils and/or trans -unsaturated fat and refined CHO foods are sources of plant foods that tend to be associated with increased risk.

•

Dietary P UFAs appear protective for CHD mortality but many observational studies show no association (Level of evidence B). This may be due to lack of correction for confounding dietary factors such as other fatty acids and dietary fibre, or due to a narrow range of intake within a population. Unsaturated fat intakes may reflect the benefits of dietary patterns lower in animal or SFA content and/or higher in plant food content. Monounsaturated fats are inversely associated with CHD only after correction for other fatty acids (Level of evidence B).

•

No epidemiological studies have shown low rates of CHD in populations consuming dietary patterns characterised by a high proportion of fats as SFAs, or high rates in populations consuming dietary patterns with high fruit, vegetable and wholegrain cereal intakes (Level of evidence B).

•

Dietary patterns with a high whole plant food content including whole grains, nuts, legumes, and fruits and vegetables, are associated with both reduced intakes of animal foods rich in SFAs and refined CHO foods (that may contribute trans -unsaturated or sucrose intakes). They provide a high intake of vital micronutrients. Individuals consuming high plant food dietary patterns tend to have lower BMI and practice other positive lifestyle attributes (Level of evidence B). Dietary patterns with a low overall GI are associated with a reduced risk of both MI and type 2 diabetes mellitus (Level of evidence B).

Dietary diversity: Dietary patterns and coronary heart disease mortality

•

Individual components of diet do not explain all associations between diets and CHD. For example, fish appears to be protective in two dietary patterns associated with low CHD rates, the classical Mediterranean diet where wine and fish are used in moderation and the Japanese diet where fish plays an important role. However in 1960's Eastern Finland, -1 average daily intakes of 60 g.d of fish did not prevent Finland from having the highest reported CHD mortality rate in the world.

•

Individuals eating dietary patterns close to nutritional recommendations and regularly choosing foods from all of the recommended food groups are 18 -30% less likely to die of heart disease over a given period of time, than those who do not eat as recommended. Individuals consuming diets meeting recommend ations have a risk of CHD death less than half that of those ignoring the recommendations and one third to half that for all -cause mortality (Level of evidence B).

•

Cluster analysis defining the nutritional attributes of diets suggests that dietary patterns where the chief source of added fat is seed oil rich in PUFAs are associated with lowest rates of CHD, followed by diets where the fat is chiefly olive oil rich in MUFAs (Level of evidence B).

•

The total dietary pattern appears to show a consistent associ ation between diet and CHD. Dietary patterns demonstrating reduced risk for CHD have in common: a high fruit, vegetable, legume and wholegrain cereal content, with or without nuts and seeds, a low or absent meat and full fat dairy product content, a high unsaturated to SFA ratio, few processed foods, and often a moderate alcohol content (Level of evidence B).

C a s e -control and cross-sectional studies: Dietary patterns and coronary heart disease risk

•

Large population studies demonstrate that high intakes of total fat, particularly high intakes of SFAs and trans -unsaturated fat, animal fat/animal protein, low P:S ratio, and dietary cholesterol, are associated with higher total and LDL-C levels, while higher CHO and/or dietary fibre intakes, and a high percentage of energy and fat from plant sources are associated with lower blood total cholesterol and LDL-C levels (Level of evidence C).

•

Diagnosis of CHD is associated with low intakes of dietary fibre, fish, vegetables and fruit in men and women, and high intak es of meat, butter and added fat (Level of evidence C).

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Carotid artery wall thickness is positively associated with intakes of animal fat, SFA, Keys score and dietary cholesterol and inversely associated with vegetable fat and PUFA intakes (Level of evidence C).

•

Blood total cholesterol is associated with high intakes of butter and hard margarines and inversely with wholegrain cereals, olive and PUFA oils and soft table margarines (Level of evidence C).

•

Reported changes in dietary pattern favouring macronutrient intakes closer to those recommended have occurred in conjunction with secular changes in blood total cholesterol and LDL-C levels, and blood pressure (Level of evidence C).

•

Higher intakes of CHOs, dietary fibre, low fat animal and dairy products, fruit, vegetables and wholegrain cereals are associated with lower intakes of dietary fat, protein, salt, high fat dairy products, eggs, fried foods, nuts, desserts, white bread. High fat consumers may eat two to three times more fatty foods than low fat consumers but only 60% of their fruit, vegetable and wholegrain intakes (Level of evidence C).

Vegetarian dietary patterns

•

Individuals following a vegetarian dietary pattern tend to enjoy healthier lifestyles with benefits for favourable lipid and lipoprotein profiles, reduced risk for CHD, reduced blood pressure, lower body weight, and increased resistance to in -vitro LDL-C oxidation than non vegetarians (Level of evidence C).

•

Vegetarians participating in research studies follow dietary patterns providing an exemplary intake of micronutrients and a nutrient profile consistent with dietary recommendations, and tend to consume adequate nutrients and have adequate nutritional status (Level of evidence C).

•

Health-interested individuals who eat a vegetarian diet may have around 24% reduced risk of CHD death compared with health interested individuals who eat meat, but risk for all -cause mortality is not different from other health conscious individuals who, together with vegetarians, may have more than 50% reduced risk of CHD than the general population (Level of evidence B).

•

The reduced CHD risk is greatest for vegetarians who eat fish or are lacto-vegetarian (34% less risk than non-vegetarians), occasional meat -eaters have 20% less risk and vegans 26% less risk. Vegans tend to have the same all -cause mortality as non-vegetarians (Level of evidence B).

•

The benefits of a vegetarian eating pattern relate to SFA intake rather than avoidance of meat and poultry. High intakes of fruit, vegetables, raw salad, legumes, wholegrain cereals and nuts are each associated with vegetarian diets, and with reduced risk of CHD in vegetarian and non-vegetarian individuals (Level of evidence B).

•

Consumption of animal fat and meat (and less consistently, eggs and cheese), in the highest level of intake among vegetarians and health interested groups, have each been associated with a two to three fold increased risk for CHD compared with the lowest level of intake -1 -1 (Level of evidence B). Eating 5 srv.d of nuts compared with less than 1 srv. d has been associated with a 40-50% reduced risk of CHD mortality in three studies (Seventh Day Adventists, Nurses' Health Study and Iowa Womens Study) (Level of evidence B).

•

A vegetarian type diet with large servings of vegetables and fruits and wholegrain cereal foods, unhydrogenated fats, and proteins from plant sources, will meet recommendations for a cardioprotective diet, and can be adequate in nutrients (Level of evidence E). An adequate intake of low fat dairy products may be important for achieving nutritional adequacy, and the reduction of blood pressure (Level of evidence E).

Mediterranean or Asian dietary patterns

•

The most widely diverse outcomes for CHD mortality occur between populations with the most widely diverse dietary patterns. In the 1960's the diets of Northern Europe were associated with very high rates of CHD, 20% incidence after 25 years follow-up, and the diets of Japan and Crete with very low rates (4.5% after 25 years) (Level of evidence B).

•

Cross-cultural differences in CHD mortality can be largely explained by differences in intakes of SFAs (73%), flavonoids (8%) and smoking (9%), in the Seven Countries Study (Level of evidence B).

•

Low mortality rates from CHD occur with different dietary patterns. In Japan, traditional dietary patterns led to low intakes of SFAs and total fat (9% of energy), whereas in Crete, low SFA intakes were accompanied by high total fat intakes (36% of energy, greater than 50% as -1 olive oil). In common, these two dietary patterns had high vegetable intakes (250-400 g.d ), -1 -1 high grain intakes (cereal and bread, 400-500 g.d ), low meat intakes (8 -35 g.d ), regular -1 -1 -1 intake of legumes (30-100 g.d ) and alcohol (15-31 ml.d ) and fish (20-200 g.d , with high relative intakes of flavonoids, dietary fibre and nutrient antioxidants, but had variable intakes of fruit and edible oils.

•

Japanese men living in Hawaii and California, shown to have diets different from the traditional Japanese diet (double the percentage energy from total fat, triple the SFA intake and 70% of the percentage energy from CHO) and have significantly higher blood total cholesterol levels (Level of evidence C). Lower all -cause mortality has been associated with a high (compared with low) score for consumption of dietary components character istic of a Greek Mediterranean diet in elderly Greeks, Greek -born and Anglo-Celtic Australians, and in elderly Danish individuals (Level of evidence B).

•

Present day Mediterranean and Japanese diets may be less appropriate models for a cardioprotective diet ary pattern since they are beginning to adopt some aspects of Western diets that promote CHD. Traditionally the people in Mediterranean countries where CHD rates were low tended to lead active lifestyles and/or remain lean throughout life. Other countries and cultures may show these associations but have not been studied. Changing economies have increased fat intakes in many Asian countries, the fats and oils available for consumption in Japan is five times that of the pre-1960's.

•

Not all Mediterranean countries use olive oil exclusively however in Italy an increase in olive oil and reduction in animal fat consumption in recent years has been associated with reduced rates of CHD.

Population trends and cardiovascular disease

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Finland, Norway, the USA, Australia, NZ and other western countries have documented secular changes in dietary patterns, in particular reduced SFA and cholesterol intakes and increased food variety with increased fruits and vegetables and PUFA intakes, and at the same time a decline in CHD mortality. In Northern Europe reductions from high intakes of coffee have also occurred. These changes were observed at the same time that smoking rates declined, improvements in population blood pressure and blood total cholesterol concentrations were re ported, and the treatment of CHD and CHD risk factors had improved.

•

In nations previously consuming very low fat diets the population has increased animal product and total fat intakes over the past 40 years. Increasing rates of CHD mortality have been observed after westernising of dietary patterns in Japan and China. Reductions in cerebral bleeding and cerebrovascular disease in Japan from 1960 to 1985 occurring with reductions in salt intake in particular, but also increased fruit and vegetable consumpti on, may be offset by increasing CHD rates since 1955. During this time, meat and dairy products available for consumption increased nine fold and seven fold respectively, and vegetable fat increased four to five fold. In China, tripling of vegetable oils and animal foods available for consumption has been observed from 1952 to 1991, and a doubling of CHD rates observed from 1975.

•

The NZ diet changed considerably in the 1980's, but apparently changed less in the 1990's. Food availability for consumption data suggest significant increases in PUFA and reductions in SFAs dating from the early 1960's, and from 1968 CHD rates began declining. Dietary surveys demonstrate small dietary changes and reductions in blood total cholesterol and blood pressure, but increas es in BMI (Level of evidence C).

•

New Zealanders intakes of SFAs remain high and fibre intakes low, and small reductions in SFA intakes may have increased sugar intakes in recent years. New Zealanders are likely to benefit from eating more fruits, vegetables, wholegrain cereals and other plant foods and eating less high fat, low fibre foods, and fewer choices of fried and high fat meals away from home.

•

Deliberate changes in dietary pattern have occurred in populations as a result of mass media education programmes. Co-operation of the food industry and agricultural resources have facilitated many of these changes.

Therapeutic dietary patterns Dietary patterns and primary prevention trials

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Dietary trials require large numbers of subjects studied over at leas t five years to demonstrate reduction in disease rates and mortality. The assessment of absolute risk involves multiple risk factors and change of dietary pattern is a multi -component therapy. Primary end-points are essential measurements for dietary trials since outcomes are likely to involve more risk factors than those traditionally measured.

•

Seven primary prevention trials measuring CHD mortality, carried out in the 1960's to the 1980's, achieved mixed results but demonstrated that large numbers of peop le could change their dietary patterns with and without other lifestyle change to subsequently improve risk factors and/or disease incidence and/or CHD mortality (Level of evidence A). Positive results tended to reflect intensity of dietary instruction or supervised intakes, and lack of results were frequently associated with secular trends of dietary change in the control group.

•

There have been two diet -only (LA Veterans Administration and Finnish Mental Hospital Studies) and one diet/no-smoking primary prevention trial of four to eight years duration (Oslo Diet and Smoking Trial). The diets utilised low intakes of SFAs with high PUFA intakes, and achieved significant 14-20% blood total cholesterol reductions, compared to control diet. All achieved significant reduction in CHD or CVD events (Level of evidence A).

•

Primary prevention of CHD has been demonstrated in drug trials achieving a mean 24% reduction in blood LDL-C (Level of evidence A), and although diet can achieve this level of reduction in certain individuals at the upper range of effect, it is unlikely to be achieved as the mean.

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Diet and drug primary prevention trials suggest that if blood total cholesterol-lowering is greater than 12 -20% in populations with elevated mean blood total cholesterol levels of 6.8-7 -1 mmol.L , non-fatal CHD events will be reduced.

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The evidence suggests that cholesterol lowering from comprehensive dietary modification reduces CHD events. Further benefits, involving other risk factors, are likely with more comprehensive changes in the whole dietary pattern and lifestyle.

Dietary patterns and secondary prevention trials

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With the exception of the DART and Lyon Diet Heart Study, dietary trials of secondary prevention have achieved significant lowering of blood total cholest erol and LDL-C (Level of evidence A).

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Dietary patterns with increased LNA and/or EPA content achieve significant reductions in mortality without reduction in blood total cholesterol levels, however other complementary aspects of diet may contribute to thes e effects (Level of evidence A).

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Dietary studies show best effect for reducing rates of sudden death or acute myocardial reinfarction, suggesting they are immediately effective post -MI (Level of evidence A).

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Dietary trials for secondary prevention consistently demonstrate reduced CVD event rates possibly through reduction of thrombosis or arrhythmia risks (Level of evidence A).

•

All secondary prevention trials have reduced SFAs and achieved a P:S ratio 0.65-2.4. No trials have exclusively studied the benefi ts of independently increasing MUFA intakes. There has been no study of secondary prevention directly comparing a low SFA ratio, low fat diet with a moderate to high fat of the same fatty acid ratio.

Therapeutic dietary patterns and risk factor trials Large intervention trials

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Change in dietary patterns and significant (6-14%) reductions in blood total cholesterol can be achieved in large healthy populations when the education is intensive.

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Dietary changes are associated with (8-10%) reductions in blood tot al cholesterol after three to six months, in populations of subjects with at least two risk factors. In the long term these reductions may be less than 5%.

Community intervention trials

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Trials with 200-9,000 participants in healthy or high risk groups, achieve only small reductions in blood total cholesterol, but achieve sufficient blood pressure lowering to reduce mortality after five years.

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Changes in dietary patterns require intensive dietary monitoring in an already changing food environment, and rely on self reporting of food intake. Dietary instruction in trials varies widely in content and intensity. Primary prevention trials need to measure more than one 9

outcome since change of dietary patterns involves simultaneous dietary interventions and multiple risk factor targets. Therapeutic dietary patterns: Lipids and lipoproteins

Randomized controlled trials have tested the following dietary components effective for reducing blood total and LDL-C: •

Low SFA content (Level of evidence A).

•

Partial substitution of SFAs with unsaturated fats (Level of evidence A).

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Very high fibre, or specifically rich in soluble fibre (Level of evidence A).

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Specific modified-fat food products (Level of evidence A).

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Quantified, high fruit and vegetable intake (Level of evidence A).

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Hypocaloric diet/weight loss (Level of evidence A).

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Semi-vegetarian dietary pattern (Level of evidence A).

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Augmented plant food intake, reduced refined and processed foods and animal products (Level of evidence A).

Other components related to the success of these trials: •

Other lifestyle advice is given.

•

Intensive supervision.

Therapeutic dietary patterns: Blood pressure

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Dietary patterns with low animal fat content, high P:S ratio, high intakes of fruit, vegetables and wholegrain products lower blood pressure (Level of evidence A).

•

These effects are independent of dietary sodium and additive to weight reduction (Level of evidence A).

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Dietary fats, fibre, potassium, magnesium, and calcium contents of these diets do not appear to independently account for these effects (Level of evidence A).

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The dietary pattern studied in the DASH trial, a low fat diet with very high content of fruit and vegetables, and enhanced intake of low fat dairy products, but otherwise very low in animal products, has to date demonstrat ed more effective blood pressure reduction than supplementation of diets with minerals, or restriction of salt, and other lifestyle/diet interventions without weight loss, and equals the effect of monotherapy with antihypertensive agents (Level of evidence A).

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Dietary patterns which incorporate a moderately high fish consumption and achieve weight loss produce substantial blood pressure lowering in hypertensive individuals (Level of evidence A).

Specific dietary patterns Trials of Vegetarian dietary patter ns

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Low fat, lacto-vegetarian and ovo -lacto-vegetarian dietary patterns lower blood total cholesterol levels and blood pressure without adversely affecting other risk factors for CHD, when compared with average fat, omnivorous dietary patterns, but do not necessarily offer substantial benefits over similarly healthy low fat dietary patterns, including low animal fat products (Level of evidence A).

•

Ovo-lacto-vegetarian and lacto-vegetarian diets can provide a balance of the nutrients required for health, providing a high content of legumes and pulses, fresh fruits and vegetables and wholegrain products are included (Level of evidence C).

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Semi-vegetarian diets, high in fruits, vegetables, legumes and whole grains, with only small servings of meat, may provide additional LDL-C lowering when required, and prevent relapse after MI compared to traditionally recommended fat modified diets (Table_1) (Level of evidence A).

Trials of Mediterranean dietary patterns

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Traditional dietary patterns from the coastal Mediterranean, have qualities that have each, independently, been shown to influence cardiovascular risk factors and/or CHD mortality-very high intakes of fruits, vegetables, legumes, wholegrain foods, nuts and seeds, small amounts of dairy products and lean meats by western standards and use of unsaturated oils in place of hardened animal and/or vegetable fats (Level of evidence A for each factor).

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When all components of the traditional Mediterranean lifestyle are incorporated into a therapeutic dietary pattern, cardiovascular mortality is reduced in subjects post -MI (Level of evidence A).

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Adoption of these components of Mediterranean-style dietary patterns, as a popular cuisine, may assist dietary changes for the primary prevention of CHD, providing the total oil content remains moderately low and dairy products are low in fat content (Level of evidence E).

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No published studies have tested the efficacy of a 1960's Mediterranean style dietary pattern in individuals living far from the Mediterranean, consuming either a typical western (for example NZ style) diet or a western diet modified along the lines of AHA and NCEP Step I and II diets or the DASH diet.

•

No study has demonstrated that changing to a dietary pattern with a high content of olive oil or other MUFA -rich oil, as the only change, will either improve risk factors or reduce cardiovascular events and mortality outcomes, compared with more PUFA oils, in high risk individuals or those diagnosed with CVD. The strong evidence that thes e individuals benefit from maximal lowering of blood LDL-C levels, suggests that the optimal diet for risk reduction would include substitution of foods rich in SFAs by foods rich in both PUFA and MUFAs.

Table 1. Food guide: Vegetarian dietary pattern (adapted from American Dietetic Association). Food group

Daily servings

Vegetable group

3-5 servings

Fruit group

1-4 servings

Bread/cereal/rice/pasta group

6-11 servings

Milk, yoghurt and cheese group

0-3 servings

Dry beans, nuts, seeds, eggs and meat s ubstitutes group

2-3 servings

Non-randomized population studies •

Mass media, large population, and community group risk factor education programmes have targeted dietary patterns although few report dietary changes. The effects on risk factors suggest that changes are small in the short term and insufficient to expect change in individual risk. The dietary focus has mainly involved dietary SFA changes, and the general population mean blood lipid levels lack sufficient margin for significant change. Studies of lifestyle change for blood pressure reduction have reported reduction of cardiovascular endpoints. In most large population studies, secular trends of improved dietary intakes among the general population or control population were reported during the years of the intervention programme (Level of evidence C).

•

In the successful longer term North Karelia project, greater change in dietary parameters was possible due to very high baseline SFA intakes and blood total cholesterol levels. Dietary education emphasised improving fruit and vegetable intakes as well as dramatic dietary SFA changes. Food industry and government incentives promoted the production of fat modified food products and incentives such as free salads at restaurants, supported by intensive advertising messages. This programme is now credited with contributing to reduced CHD rates in eastern Finland (Level of evidence C).

Conclusions Summary: Dietary patterns

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A variety of food combinations can meet nutritional recommendations within very different ecological or social settings. Beyond nutritional needs, dietary patterns evolve from a wide range of environmental, traditional, cultural, social and intellectual influences. The study of dietary patterns considers the relationships between diet and disease of particular relevance to an individual country or community, rather than evaluating diet in terms of essential nutrients irrespective of the foods supplying them.

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Dietary patterns account for the high interrelation of nutrients and other factors within the diet due to choices of foods in which these nutrients occur; the components in foods that are either presently unknown, or not yet identified as beneficial to health; and the associations between certain dietary behaviours and other lifestyle behaviours.

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Randomized cross -over or placebo-controlled clinical trials that study the individual components of diet may identify the aetiological factors within eating patterns but are limited by the confines of studying individual nutrients, food factors or foods. When a protective nutrient or food is identified, it will cluster with other nutrients and functional non-nutrients within typical foods and diets.

Summary: Dietary patterns associated with coronary heart disease prevention

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The dietary patterns of various cultures, populations and geographical regions around the world have been associated with lower rates of CVD and increased longevity. A large number of longitudinal observations demonstrate consistent inverse associations between incidence of CHD and dietary patterns where the source of fat is predominantly of plant origin (low SFA content), and/or dietary fibre and flavonoid intakes are high. These dietary patterns generally comprise high intakes of fruit, vegetables, and whole grain foods relative to animal source foods and hardened vegetable fats, and/or include low or moderate intakes of refined plant foods.

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Dietary patterns in the modern world are in a constant state of change and even strongly traditional cuisines are changing. Diet -promoted health risks in a new culture may be quickly absorbed by an immigrant population.

•

Vegetarian dietary patterns and certain traditional Mediterranean and Asian dietary patterns practised in certain populations are associated with reduced rates of CHD and have many factors in common. A low or absent meat intake is complemented with a rich content of fruit, vegetables, grains, and cereals or bread, and a moderate content of legumes and/or nuts or seeds, dairy products and/or fish. The evidence for a reduc ed risk associated with Mediterranean or Asian dietary patterns is limited since the only inter-individual comparisons in like populations are of dietary diversity. Vegetarian diets are associated with reduced CHD risk but not all-cause mortality in healt h-interested and religious populations.

•

Protective factors identified within dietary patterns include high intakes of vegetables and fruit, whole grains, inclusion of fish and/or legumes (particularly soy), nuts and seeds, plant oils and potentially low fat dairy products. Intakes of these foods are associated with improved intakes of nutrients and food factors independently identified as having a beneficial role in cardiovascular prevention: folate, vitamin B6, carotenoids, tocopherols, LNA and other omega-3 PUFAs, calcium, magnesium and potassium, dietary fibre, phytochemicals including flavonoids and phytosterols.

•

The epidemiological evidence suggests that known and as yet unknown factors within dietary patterns and lifestyles may be vital to the prevention, delay, and treatment of CHD via pathways other than the three classical risk factors of blood LDL-C, blood pressure and smoking. Mechanisms leading to protection from CHD may include reduction of tHcy concentrations, protection from adverse oxidative changes in blood lipids, and propensity to arrhythmias in addition to improvements for traditional risk factors such as blood pressure, blood lipids, thrombogenesis, and body weight.

•

Dietary trials that modify dietary patterns for primary prevention require at least five years of therapy to influence CHD mortality.

•

The few dietary trials of primary prevention have mostly shown reduced incidence of CHD, however some trial diets only modified the fat content of diet. Successful trials utilised a more comprehensive dietary and lifestyle approach, including increased dietary fibre intake and a moderately reduced total fat content. A number of large scale studies may have fallen short of significant reduction in CHD risk due to the concentration on dietary fats in the dietary protocol, with limited attention to the whole dietary pattern.

•

The monitoring of secular changes in dietary patterns, food intake, prevalence and incidence of associated diseases is necessary to accumulate local data. Many western count ries have experienced large reductions in dietary fat consumption. Changes in total fat consumption in NZ is not confined to SFAs which remain twice that recommended for reducing LDL-C. New Zealand lags behind other countries for PUFA intake and the P:S ratio remains low. Dietary fibre intakes are not increasing with the reduction in fat intakes, and fat appears to have been replaced by an increase in sugar and refined CHO food intake.

Summary: Dietary patterns associated with successful intervention in cor onary heart disease

•

Small studies of one to four years duration trialing multi -component dietary modification, that is change in dietary pattern, with or without lifestyle changes significantly reduce secondary cardiovascular events.

•

A number of large scal e studies may have fallen short of significant reduction in CHD risk due to the dietary protocol concentration on dietary fats, with limited attention to the whole dietary pattern, especially vegetables, fruits, wholegrain cereals and refined CHO intakes.

•

Compared with traditional approaches of dietary fat modification alone, a large number of dietary trials demonstrate greater improvement in blood lipids and lipoproteins with a more comprehensive approach. Optimal lipid lowering requires both reduction of SFAs and an increase in the P:S ratio, even in very low fat diets. Nutrient analysis does not account for potential food factors associated with increased consumption of dietary fibre, plant protein,

and phytochemical -rich foods with a substantial increas e in whole grain, fruit and vegetable intakes, that appear to enhance the lipid modifying potential of diet. •

A similar dietary pattern enhances the reduction of elevated blood pressure levels together with reduction in dietary sodium, alcohol and, energy intake in overweight individuals. Regular intakes of low fat dairy products and/or fatty fish may further enhance these effects.

•

Dietary trials failing to achieve greater than 10% blood total cholesterol reduction, either do not meet dietary targets or the reduction in SFA intake from baseline is very small or the intervention does not report increase of whole grain, fruit and vegetable intake or dietary fibre in the group studied and/or do not mention control of refined sugar or refined starch (high GI) intake or do not increase the P:S ratio.

•

Vegetarian diets, even when compared with low fat, fibre-rich omnivorous diets lower blood total cholesterol and LDL-C levels and blood pressure, although multiple dietary differences between vegetarian and non-vegetarian diets obscure the precise mechanisms of benefit. The precise protective components of traditional coastal Mediterranean-style diets associated with reduced CHD risk have not been determined but are also likely to be associated with their high plant/low animal food content.

•

Epidemiological studies and successful primary or secondary prevention trials reporting lower rates of CHD events and/or CHD mortality typically have in common: a variable -1 -1 absolute fat content and daily intakes up to a maximum of 150 g.d meat, 10 g.d or more of -1 -1 pulses, 400 g.d of breads/cereals/grain/potatoes, 200 g.d or more of vegetables (excluding -1 -1 -1 potato), greater than 100 g.d of fruit, greater than 20 g.d of fish, greater than 15 g.d of -1 -1 plant oil products, milk, us ually less than 30 g.d of cheese, less than one egg, 0-20 g.d of sugar. There is insufficient evidence about the long term effects of change to a very low fat diet in western populations to support a recommendation for a very low fat intake (less than 20% of energy).

background paper Examination of the evidence Introduction Early dietary recommendations for reducing cardiovascular risk were based upon epidemiological observations and trials that demonstrated associations between diet and reduced blood total cholesterol levels and/or cardiovascular mortality. Dietary patterns evolving from these early guidelines differ from the traditional dietary patterns associated with reduced cardiovascular risk in epidemiological studies, but have in common a low level of SFAs. The most frequently measured risk factor in dietary intervention trials for reducing cardiovascular risk, is blood total cholesterol, and the most frequently studied dietary change, reduced total fat and/or SFAs. When other risk factors are included in the assessment of dietary benefit, such as blood pressure, clotting factors, arrhythmias and diabetes, other dietary factors become prominent, 1 giving greater concordance with the results of observational studies . There is now a consensus that dietary fat as a risk factor for chronic disease should not be 2 considered in isolation from the other dietary guidelines .

Patients with higher risk of CHD receive greater benefit from lowering their cholesterol . However, attention to cholesterol alone is insufficient to prevent heart disease in those 2 individuals at risk, or to adequately treat atherosclerosis in most patients with CHD . Clinicians are now advised to make treatment recommendations based on individual overall risk 3 for CHD and not simply on blood total cholesterol level . The benefits of changing dietary patterns needs to be assessed in terms of absolute risk, each dietary treatment category, and each modifiable risk factor. The outcome of changing multiple dietary constituents is the modified dietary pattern, and each dietary change will affect the intake of other foods and subsequently the composition of the remaining diet. Many individual components within dietary patterns exert multiple effects on several risk factors and the end-point outcomes from altering dietary patterns depend upon improvement of risk factors. Recent interpretation of dietary recommendations for reducing CVD has seen a surge in the production of new and modified foods, and new cuisines. No trials have addressed whether diets involving a large proportion of these products will reduce rates of CVD. Dietary recommendations require more than food or nutrient guidelines. They require a comprehensive appreciation of the eating milieu, inducements for choice, and environmental and socio-cultural influences encompassed by dietary patterns. The study of dietary patterns, compared with that of isolated nutrients, ensures that benefits from as yet unknown factors within specific eating and food choice patterns are not lost. The research of dietary patterns, therefore, provides the interface between hypotheses generated from epidemiological observations that demonstrate associations between diet and prevalence of CHD or cardiovascular risk factors, and the outcomes from clinical intervention studies of dietary modification.

Dietary patterns Traditionally the relationship between food intake and cardiovascular risk factors such as blood total cholesterol, blood pressure, thrombotic factors, insulin resistance, and BMI has been studied with respect to single nutrients and/or components of diet or food groups. Such an approach, however, ignores a main feature of diet: it is composed of a pattern of many different foods leading to a specific combination of nutrients and non-nutrient food factors . Beyond nutritional needs, dietary patterns evolve from a wide range of environmental, traditional, cultural, social and intellectual influences . In free-living populations the absolute intakes of major nutrients are positively correlated with total energy intake and with each other. The study of dietary patterns takes into account the high interrelation of nutrients and other factors within the diet due to the choice of foods in which these nutrients occur, or to the consumption of particular 4 foods at the expense others . It also accounts for components in foods that are either presently unknown, or not yet identified as beneficial to health. By investigating the association between dietary patterns and risk factors, possibilities for 5 prevention and target groups emerge, although the aetiology may remain less clear . The study of dietary patterns accounts for, and may demonstrate, associations between certain dietary behaviours and other lifestyle behaviours such as drinking of certain alcoholic beverages, 6 exercising or taking dietary supplements and dietary intake or risk factors . The degree that health risks or benefits are determined by characteristics and habits of individuals rather than specific foods, drinks or dietary patterns raises the question: is it the drink or the drinker, the nuts or the nut-eater? Given the variety of food combinations that can provide a healthful diet, it is impossible to define the potential range of intakes for all foods and all food combinations that might provide a 3 nutritionally adequate diet . Even a large set of food combinations meeting nutritional adequacy,

are unlikely to cover every different ecological or social setting. Recommended nutrient intakes define essential nutrients irrespective of the foods supplying the required nutrients. The study of dietary patterns considers the relationship between diet and disease of particular relevance to an individual country or community, or a specific disease problem. Adherence to a particular food pattern usually associated with a favourable health outcome is one way of evaluating the nutritional soundness of proposed recommendations for dietary 3 changes . For example, the dietary patterns of various cultures, populations and geographical regions around the world have been associated with lower rates of CVD and increased 7 longevity . However, dietary patterns in the modern world are in a constant state of change and even strongly traditional cuisines are changing (Japan, China, Mediterranean). Migration studies measuring the health outcomes of a population moving to another culture, clearly demonstrate that diet -promoted health risks in a new culture may be quickly absorbed by an immigrant 8,9,10 population . The multifactorial nature of dietary patterns, however, precludes the clear identification of specific factors that may be either protective or pathogenic within traditional or altered dietary patterns. Randomized cross -over or placebo-controlled clinical trials study the individual components of diet such as fatty acids, alcohol, antioxidants, garlic, coffee, soy, fruits, vegetables, fibre, CHOs, minerals, other vitamins and other foods. They identify the aetiological factors within eating patterns that reduce risk factors and mortality. Studies have drawn associations between certain characteristics in dietary patterns and reduction of certain risk factors for chronic diseases. Translation of evidence from experimental studies and RCTs into an “ideal” dietary pattern remains problematic. When a single nutrient or food is identified as beneficial, it will cluster with other nutrients and functional non -nutrients within typical foods and diets. Several methods are used to identify dietary patterns, such as 5 cluster analysis and scoring systems such as the “dietary diversity score” . When dietary guidelines recommend dietary change, the outcomes of such changes within the remaining dietary pattern need to be predicted. It is not known whether greater cardiovascular protection and optimal dietary adherence will be better facilitated by traditional dietary patterns and cuisines already existing around the world, or by new diet -styles that manipulate individual dietary components proposed to be of benefit. A traditional dietary pattern tends to be inexpensive, uses available foods and is palatable. Having an existing cuisine and repertoire of recipes, tried, tested and enjoyed for generations, such patterns may be time consuming to prepare. Measurement of whether full or partial change towards dietary recommendations actually prevents disease, is the essential test of efficacy of such change. Dietary recommendations for reducing CVD now universally accepted in Westernised countries, are creating a new dietary pattern in these populations. New foods include certain “ethnic” food-styles and the introduction of manufactured “healthier” alternatives to foods already popular within modernised cultures. The food industry in modernised nations has responded to priorities of convenience and speed, new tastes, and demand for a wide variety of food choices in these populations. Many new products have however, been criticised for their artificial nature and culinary limitations. One manipulated food product may affect the overall dietary pattern in many ways. Marketing claims and clever promotions may also swing food choices in favour of less healthy alternatives that dilute the micronutrient density of the diet.

Dietary patterns and cardiovascular disease Atherosclerosis is the result of complex gene-environment interactions. The most common cardiovascular risk factors can be treated by the least expensive therapies, including lifestyle 2 modification . Among lifestyle habits, only cigarette smoking has been consistently used in CVD prediction equations . The effects of smoking are more clearly independent compared with diet 11 and sedentary activity .

Since the industrialisation of agriculture in the past century, residents of Western countries have 12 disproportionately increased their meat and dairy consumption . Observational studies provide most of the information about health benefits of foods and food groups, however unlike RCTs, they do not control for confounding. On the other hand, RCTs are limited by the confines of studying individual nutrients, food factors or foods. Furthermore, large, long term dietary intervention trials are usually too difficult and expensive to sustain for long enough to achieve the definitive effects on mortality. These problems in detecting associations between dietary factors and a disease process that develops over the course of decades does not mean that failure to observe an association 13 proves that none exists . For example, SFA intakes may not correlate with CHD within populations although metabolic studies and clinical trials provide proof for a causal relation. The Seven Countries Study led to the recognition that dietary patterns of different populations 14 may affect rates of CHD differently . The associations between risk factors and mortality from CHD both at a population level and the individual level were studied in 16 cohorts of men living in 15 seven countries for 25 years . After five years follow-up the investigators had already reported a strong between country correlation between blood total cholesterol and mortality from CHD. No statistically significant differences were observed between the 16 different cohorts with respect to the regression coefficients for within cohort relationships between blood total cholesterol and long term CHD mortality. However the absol ute levels of CHD mortality were strikingly different between countries. Verschuren et al concluded from the 25-year mortality data of the Seven Countries Study that a 15 focus solely on blood total cholesterol for reducing risk of CHD is insufficient . For a blood total -1 cholesterol level of around 5.45 mmol.L they found a three-fold range in mortality rates, varying from 4-5% in Japan and the Mediterranean, to 10% in inland Southern Europe, 12% in the USA and 15% in Northern Europe. Diversity of dietary composition may play an important role in these differences of CHD mortality since dietary patterns differed between cohorts. Compared with Northern Europe and USA diets, the coastal Mediterranean diet at baseline contained less meat but more fish, fruits, vegetables, and alcohol. The fatty acids consumed by the Northern European cohorts were predominantly SFA but in the Mediterranean cohorts were predominantly MUFA. Intake of the antioxidant vitamins, β-carotene and α-tocopherol was highest in Mediterranean Southern Europe. In Southern Europe flavonoid intake was twice that of Northern Europe and the USA, but was highest in Japan. It is unlikely that reductions in blood total cholesterol levels alone will return cultures with high CHD risk, such as the USA and Northern Europe, back to a CHD mortality level characteristic for the traditional Mediterranean or Japanese cultures, unless other risk factors also change. The Mediterranean and Japanese diets, traditi onally low in SFAs and rich in antioxidants, may confer benefits such as altering the propensity of LDL-C to oxidise, reducing tHcy and TG levels, arrthymias and/or processes of thrombogenesis, fibrous plaque formation, arterial injury, insulin resistance, or changing LDL-C composition, in addition to their effects on absolute levels of LDLC and HDL-C and blood pressure. Components of foods selected in these diets are also likely to affect CHO metabolism, blood pressure and body weight. The epidemiological evidence suggests that known and as yet unknown factors within dietary patterns and lifestyles may be vital to the prevention, delay, and treatment of CHD via pathways other than the three classical risk factors of blood LDL-C, blood pressure and smoking. This paper reviews the two major groups of studies that investigate whether dietary patterns contribute to outcomes associated with CVD: •

Epidemiological observations of population cohorts whose diets and outcomes were systematically assessed.

•

Human cli nical dietary intervention trials where therapeutic dietary patterns were tested under randomized, controlled conditions.

The paper will also discuss community or population intervention trials lacking randomisation or a control group, where dietary patterns were modified and outcome data was systematically collected.

Observational studies Prospective population-based cohort studies: Diet and coronary heart disease mortality A number of prospective, observational studies have now been published. Such longitudinal cohort studies can fulfil only some of the criteria needed to confirm cause and effect 3 relationships . Nonetheless the number of large -scale trials demonstrating consistent associations between spec ific eating patterns and cardiovascular risk factors and/or outcomes in different populations, suggest a strong relationship between dietary patterns and rates of CHD. Tracking health risk factors and diet in populations has been the most readily availabl e evidence 3 on which to base food guidelines . However, prospective epidemiological studies observing dietary factors and risk of CHD are subject to bias and inter-country or inter-cultural differences. Causal relationships are difficult to establish in studies of free-living populations due to difficulties in analysis and interpretation of the dietary data. Associations in most studies to date are made between the baseline diet and subsequent incidence of CHD. This method assumes 16,17 that the rank order of dietary variables is the same across time . Repeated measures of dietary intake suggest that null findings would be due to high intra-individual variation. Using the data from the Nursesâ&#x20AC;&#x2122; Health Study, Hu et al have demonstrated that results derived from using only the baseline diet differ from those including the most recent diet or using a cumulative 17 average of repeated dietary measures . Few studies report s ubstantial detail about dietary patterns, but fatty acid and energy intakes have been the most consistently studied dietary variables in relationship with CHD. Since epidemiological studies established blood total cholesterol as an independent, predictive risk factor for CHD, the association between diet and CHD has been investigated and debated. Saturated fats are the nutrients most strongly correlated with CHD deaths, although this finding has not always been consistent among epidemiological studies. Correlations between other fatty acids and CHD have also been inconsistent. Discrepancies may be due to methodological limitations including inadequate dietary assessment methods, inadequate control for confounding, inappropriate accounting for energy intake, lack of control for trans -unsaturated fat, 17 and separate rather than simultaneous analyses of fatty acids . Inconsistent use of risk factors and correlated factors in the regression equations may also produce inconsistent results. The published associations between foods and/or nutrients and CVD and/or mortality, summarised inTable_2 are usually adjusted for age and energy 18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53 intake . Major non-dietary co-variants including risk factors and selected socio-demographics are adjusted for in multivariate analysis. A second model is often included for other foods and/or nutrients related to risk. For example, epidemiological studies reporting risk associations with fatty acids in this decade have controlled for dietary fibre and/or individual fatty acids since these factors change together. Since the accuracy of data collection for fatal events tends to be more accurate and more complete than that for establishing new disease events, the data in Table_2 is confined to CHD mortality. Large scale epidemiological studies beginning in the 1960's, investigating an association between existing dietary patterns and CHD, have now published 10 to 25-year mortality rates, (Table_2). These studies have involved clinical interviews of individuals within cohorts and collection of risk factor data, including measurement of blood pr essure and blood total cholesterol. Dietary analysis has usually been carried out on a sub-sample within each cohort and multivariate regression models were used to incorporate risk factor values. Not all studies have corrected for other potentially correl ated food and/or nutrient factors. The nutrient data

collected in these studies provide an indication of dietary patterns within these populations, but little food intake data are reported. Several large scale prospective studies beginning in the 1970's or later, use similar methodology but information was collected by self-administered food frequency questionnaires, and biochemical or clinical measurements were not performed (Table_2). These studies report associations between specific nutrient and/or foods and CHD mortality, but provide less information about overall dietary patterns. Smaller studies and studies providing selective information about relationships between components in dietary patterns and CHD are also included in Table_2 Reviews of these studies focus on fatty acid, cholesterol and energy intakes since the study 54, 55 reports include little information on overall dietary patterns . In general, CHD mortality has been associated with high animal fat intakes and inversely associated with high plant food intakes, even in the earliest studies. Table_2 separates the evidence for these positive and inverse associations. Intakes of SFAs and dietary cholesterol are nutrient markers of animal food consumption in populations using limited quantities of hydrogenated oils. Trans -unsaturated fat consumption tends to reflect intake of processed foods rich in hydrogenated oils, in more modern cultures. Cis-MUFAs, so far apparent ly neutral in their relationship with CHD compared with SFA, are derived from both plant and animal sources in Western populations. Dietary fibre, PUFAs and flavonoid intakes, measured in many of the studies, represent higher plant food intakes. Remarkably, no studies reporting animal product associations (represented by SFA, Keys score, and dietary cholesterol) report an inverse association with CHD mortality (Table_2) and no studies reporting plant product associations (represented by PUFA, dietary fibre, and flavonoids) report a positive association with CHD mortality. Table_2 also reports associations between CHD mortality and the Keys and Hegsted 56,57,58 scores . These scores provide information about dietary lipid selection within dietary patterns. A high score indicates a high intake of SFAs and dietary cholesterol, and a relatively low intake of PUFAs. Both scores have been used widely in epidemiological studies, not only for predicting the effects of diet on blood total cholesterol, but also as a reference score for evaluating the dietary fat content of different dietary patterns. In the Seven Countries Study, only SFAs, antioxidant flavonoids and cigarette smoking were 59 independently associated with CHD mortality rates . Saturated fats explained 73% of the variance (p= 0.0001), flavonoid intake 8% (p= 0.01) and percentage smoking in each cohort 9% (p=0.03). No associations were found between vitamins E or C, Î˛-carotene or physical activity to 59 explain the differences in CHD mortality between the sixteen cohorts in the seven countries . Trans -unsaturated fats were not included in this analysis, but were correlated with CHD mortality in a later analysis, and were correlated with SFA intakes, confounding an independent 15 association . Although cross-population studies can not be controlled for all cross -cultural differences, this analysis lends strong support to the suggestion that SFAs (perhaps together with trans -unsaturated fat) and flavonoids are markers of dietary patterns associated with risk. They may also be interrelated. In the Male Health Professionals Study, the association of SFAs with CHD death lost statistical significance after correcting for dietary fibre, suggesting that at 18 least some of the effect of SFA -rich diets is due to their low fibre or plant food content . Energy intakes have been negative ly associated with CHD in the Puerto Rico, Zutphen, and Honolulu studies, Bank men, Gotenburg and Caerphilly and no studies have positively associated energy intakes with CHD, indicating a possible association between physical activity 23,26,31,39,40,41 or under -reporting of food intake and CHD . Percentage of energy as total fat was positively associated with CHD mortality in the Puerto Rico, Honolulu, Health Professionals, and Framingham studies and no association was found in the Seven Countries, Nursesâ&#x20AC;&#x2122; and Rancho 23,3 1,40,42,53,54,55 Bernardo studies . A high fat diet may also be correlated with other dietary factors, such as percentage individual fatty acids which were not controlled for in these analyses.

Table 2. Prospective longitudinal epidemiological studies. Nutrients and foods associated with CHD mortality. Observed associations between intakes of nutrients or dietary fibre and CHD mortality+. Positive associations animal products

Trial and year published

Seven Countries Study 1970, 14 15 21 52 59 1995, 12,770 men , , , , Puerto Rico Heart Study 22 23 1980, 8,218 men , Gordon: Three Populations 60 Study 1981, 16,349 men USA Western Electric Study 24 25 1981, 1,900 men , Zutphen Study

Inverse associations plant products

Animal and plant products

Total fat

SFA

Keys score

Dietary cholesterol

Trans

MUFA

PUFA

Fibre

Flavonoids

+ve

NA***

-ve

+ve

-ve

-ve*

-ve

+ve

-ve

+ve

-ve

+ve

-ve

-ve***

-ve

+ve

NAmen -vewomen

-ve

-ve grains

-ve

NA NA 26 27 28 1984, 871 men , , , Ireland-Boston Diet Heart +ve +ve +ve**** 29 Study 1985, 1,001 men Honolulu Heart Study 1985, +ve +ve +ve**** 30 31 7,088 men , Male Health Professionals Study 1996, 435,757 + ve +ve +ve +ve**** 18 3 2 33 men , , ATBC Study 1996, 21,930 NA NA 20 34 smoking men , Nurses Health Study 1997, NA +ve** +ve NA 1 9 35 3 6 37 3 8 68 80,082 women , , , , , British Civil Servants 1977, NA 39 337 men Gotenburg Study 1986, 1,462 NA 40 women Caerphilly Prospective Ischaemic Heart Disease NA 41 42 Study 1987, 2,512 men , Rancho Bernardo Study 1987, NA NA NA 43 859 men and women Belgium Study 1989, 21,500 +ve 51 men and women Framingham Study 1991, 813 +ve +ve NA 53 men Finnish Mobile Clinic Study 1996, 2,748 men 2,385 44 45 women , Iowa Womenâ&#x20AC;&#x2122;s Health Study 1998, 34,492 post 46 47 48 menopausal women , , Zutphen Elderly Study 1996, 49 50 522 men , Scottish Heart Health Study 1999, 11, 629 men and 61 women + After correction for other risk factors, reported from these studies. * Before multivariate analysis. ** Only after multivariate analysis. *** In ratio with SFA. **** Not adjusted for SFA.

+ve -ve NA

Positive association. Negative association. No Association.

Dietary fats and dietary patterns (Table_2) The inconsistent associations between fatty acids and CHD mortality in epidemiological 55 observations have been reviewed by Caggiula and Mustad . Of particular relevance to dietary patterns in free -living populations is that intakes of the different fatty acids are highly inter correlated. Since fatty acids coexist in all fats in foods, when fatty acids are adjusted for simultaneously, the relationships with CHD risk predicted from the results of metabolic ward and intervention studies become strengthened. This has been shown in cross -population studies 62,63 using food disappearance statistics (in 40 countries, and in 18 countries ) and in large within 18,19 population cohort studies . In the analysis of epidemiological data from 40 countries or 18 countries, a positive association between MUFA intakes and CHD became inverse after adjustment for SFAs and dietary 62,62 cholesterol, and an inverse association with PUFA intakes became evident . In the Nursesâ&#x20AC;&#x2122; Health Study MUFAs became inversely associated with CHD risk after adjustment for other fatty acids. Dietary cholesterol is generally correlated with SFA intake. The respective positive and negative associations with CHD for SFA and PUFA intakes are supported by adipose tissue fatty acid concentrations studied in four populations of varying 64 55 risk . Adipose tissue fatty acid concentrations are believed to reflect dietary fatty acid intakes . Three of the large within -population cohort studies, two of health professionals in the USA, the Male Health Professionals Follow-up Study and the Nursesâ&#x20AC;&#x2122; Health Study, and a study of male smokers in Norway, have extensively analysed a number of dietary factors demonstrating the 18,19,20 complexities that arise from the changing modern dietary patterns within a population . These extended analyses of the associations between dietary fatty acids and disease risk within a population are among the few st udies reporting the results of changing dietary patterns over time. Although the reports are confined to individual nutrients and foods, the data supports a dietary pattern rich in plant foods, and reduced in animal products. The Nursesâ&#x20AC;&#x2122; Health Study, cond ucted from Boston, USA, was established in 1976, when 121,700 female nurses aged 30-55 years completed a mailed questionnaire. A final cohort of 8,082 were sent biennial follow-up questionnaires to up-date information on risk factors and diagnosed diseases. In 1980, 1984, 1986 and 1990 food frequency questionnaires were included to assess dietary intakes of specific fats and other nutrients. Reports on the association between independent nutrients and CHD have been published at various points along the foll ow-up 17,19,3 5,36,37,38,,65,66,67 period . Importantly this study has accounted for dietary change or foods occurring during the observation period. In the Nurses Study, mean intakes of self-reported total fat intakes as a percentage of energy 17 had declined by about 19% from 1980 to 1990 . The relationship between dietary intakes of specific types of fatty acids and risk of CHD (non-fatal MI or coronary death) compared highest 19 versus lowest quintiles of intake and was reported after 14 years follow -up . Relative risk (95% CI) of CHD after multivariate analysis, including risk factors and dietary confounders (not including dietary fibre) with adjustment for other fats or fatty acids were: Vegetable fat 0.67 (0.51 to 0.88) (mean intake 17.2% of energy vs. 5.4%); Polyunsaturated fat 0.68 (0.53 to 0.88) (mean intake 6.4% vs. 2.9%); Trans -unsaturated fat 1.53 (1.16 to 2.02) (mean intake 2.95% vs. 1.3%); Keys score 1.27 (1.02 to 1.60); Monounsaturated fat 0.95 (0.64 to 1.39) (mean intake 19.3% vs. 11% ) The trend across quintiles was significant for all but MUFAs. After multivariate analysis before adjustment for other nutrients, highes t versus lowest quintiles of animal fat (36.4% of energy vs. 17.4) and SFAs (18.8 vs. 10.7) showed trends for association with increased CHD risk (p for trend=0.05 and 0.04 respectively). Monounsaturated fats in this population are derived mainly from beef, dairy fats and hydrogenated vegetable oils and quintiles of intake were not associated with CHD risk. When trans -unsaturated and PUFAs were examined in combination, risk was lowest in the group with the lowest quintile of trans -unsaturated fat intake and highest quintile of PUFA representing a relative risk of 0.31 (95% CI, 0.11 to 0.88, p for trend=0.01) compared with the highest trans 21

unsaturated fat and lowest PUFA quintiles. This comparison in general represented consumption of unhydrogenated oils compared with hard margarines and products made from these products. This study, perhaps for the first time addresses the consequences of modern food technology on long term disease patterns within a rapidly changing dietary environment in an affluent culture. For each increase in 5% of energy as fats when compared with equivalent energy from CHO, relative risk for CHD increased with SFAs (relative risk 1.17, 95% CI, 0.97 to 1.41, NS) and decreased with PUFAs (relative risk 0.62, 0.46 to 0.85, p for trend=0.003) and MUFAs (relative risk 0.81, 95% CI 0.65 to 1.00, p for trend=0.05), and increased for each increment of 2% energy from trans -unsaturated fat (relative risk 1.93, 95% CI 1.43 to 2.61, p for trend<0.001). There was no association found with total fat. The Nursesâ&#x20AC;&#x2122; Health Study found an inverse association between LNA intake and fatal CHD after 10 years of follow-up (multivariate relative risk, 0.55; 95% CI, 0.32 to 0.94, p for trend=0.01) but 37 not with non-fatal MI (multivariate risk, 0.85; 95% CI, 0.61 to 1.19) . Intakes in the highest -1 -1 quintile of intake were 1.36 g.d versus 0.7 g.d in the lowest quintile. Consumption of oil -based mayonnaise and oil and vinegar dressings were an important determinant of higher intakes (19% of intake), and 70% of intakes were from plant sources. A sub-group of women with prior MI had even greater reduction of risk. The ratio of linoleic relative to LNA was less strongly related to risk than LNA acid alone since both fatty acids were inversely related to risk. This study, suggests that diets incorporating added fats with a higher proportion of PUFAs are associated with least risk for CHD, and that MUFAs are associated with reduced risk only after adjustment for other fatty acids and only when compared with total (undefined) CHO. Further study has demonstrated that highest versus lowest quintile intakes of 12:0 and 14:0, 16:0, and 18:0 fatty acids were each associated with increased risk of CHD. Age adjusted risk was 1.5 (95% CI, 1.23 to 1.83, p for trend=0.0001), 1.71 (95% CI, 1.40 to 2.08, p for 67 trend=0.0001), and 1.97 (95% CI, 1.61 to 2.42, p for trend=0.0001) respectively . These trends remained through multivariate adjustment but were not significant when adjusted for other fatty acids since SFAs are found in the same foods. This study suggests that a distinction between the various SFAs is not important. The Nurses' Health Study also found a strong association between t he P:S ratio and reduced risk of CHD. The multivariate adjusted relative risk for the highest versus the lowest quintile of PUFA to SFA (0.72 vs. 0.23) was 0.58 (95% CI 0.41 to 0.83, p for trend<0.0001) and the multivariate risk simultaneously adjusted for relevant nutrients was 67 0.79 (0.70 to 0.89) for every 0.2 unit increase . The Male Health Professionals Follow-up Study, begun in 1986 when 43,757 men aged 40 to 75 years completed a food frequency questionnaire, reported cardiovascular death after 6 years of 18 follow-up . This study has shown that although age-adjusted analysis shows expected associations of total fat, SFAs and trans -unsaturated fat with MI and CHD deaths, multivariate analysis correcting for risk factors and then further correcting for dietary interrelationships changes the significance of these associations. This study highlights the complexities of dietary interactions within dietary patterns. Daily intakes of grams total fat, SFAs and trans -unsaturated fat, and Keys score, were each associated with increased risk for MI and fatal CHD after adjustment for non -dietary risk factors, 18 however these associations weakened when dietary fibre intake was introduced into the model . Relative risk of CHD mortality for the highest versus lowest quintile of intake for total fat was 1.59 (95% CI, 1.01 to 2.51, p for trend<0.02), when adjusted for fibre relat ive risk was 1.22 (0.75 to 2.00, NS). For SFAs relative risk was 2.21 (1.38 to 3.54, p for trend =0.0016), when adjusted for fibre 1.72 (1.01 to 2.0, p for trend =0.09), for trans -unsaturated fat 1.78 (1.11 to 3.35, p for trend=0.003) and with fibre 1.41 (0.86 to 2.32, p for trend=0.42), for Keys score 2.1 (1.32 to 3.35, p for trend =0.003), with fibre 1.59 (0.094 to 2.68, p for trend =0.14). Absolute intakes of linoleic and LNA fatty acids were not significantly associated with risk of CHD, and milligrams of cholesterol was not significantly related after multivariate analysis. When nutrients were assessed as a percentage of energy, linoleic acid was inversely related with fatal CHD, but was significant only after control for total fat (relative risk 0.58; 95% CI, 0.34

to 0.99 for every 5% increase of percentage fatty acid intake, p for trend<0.05), but was not significant for all MI. Significance was attenuated after adjustment for dietary fibre. Linolenic acid was inversely associated with all MI in multivariate analysis for risk factors and when controlled for both total fat and fibre (relative risk 0.41; 95% CI, 0.21 to 0.80, for every 1% increase of percentage fatty acid intake, p<0.01), but not with fatal CHD. The association between an increase of 5% in SFA intake as a percentage of energy remained significant in multivariate analysis for CHD deaths (relative risk 1.49; 95% CI, 1.22 to 1.89, p for trend<0.001), but not for all MI, and this association remained significant with adjustment for total fat (relative risk 1.52; 95% CI, 1.00 to 2.31, p for trend<0.05) but not when fibre was added to the model (relative risk 1.34; 95% CI, 0.86 to 2.08 ). Trans -unsaturated fat as percentage of energy were associated with all MI (but not CHD death) after multivariate analysis, but this was not significant when total -1 fat or fibre were adjusted for. Dietary cholesterol as 100 mg.4 MJ was not associated with CHD after multivariate analysis. The authors suggest that benefits of reducing SFAs and dietary cholesterol are likely to be modest unless accompanied by an increase of foods rich in fibre and that the effects of diets high in SFAs and cholesterol are at least in part due to their low fibre content and associations with other risk factors. The ATBC Study was a RCT with daily supplementation of α-tocopherol and β-carotene, 2 0,34 conducted in Finland and followed for 6.1 years . The dietary study conducted as part of this trial was in effect a prospective observational study. The subjects, 21,930 middle-aged men who smoked but were free of diagnosed CVD, completed a dietary questionnaire at baseline. The group had high intakes of SFAs and cholesterol. There were no associations between SFA, cis -MUFA or linoleic fatty acids or dietary cholesterol and risk of CHD death, when dietary fibre and other fatty acids were included in the multivariate 18 analysis, as in the Male Health Professionals Study . After multivariate and adjustment for trans and cis-MUFAs and SFAs, linolenic acid intakes were inversely associated with CHD death (relative risk 0.75, 95% CI, 0.52 to 1.10, p= 0.05), highest versus lowest quintiles of intake. Trans -1 unsaturated fat intakes (median daily intake for top quintile, 6.2 g.d vs. lowest quintile, median -1 daily intake 1.3 g.d ) were associated with CHD mortality (relative risk, 1.39; 95% CI, 1.09 to 1.78, p for trend=0.004), after multivariate analysis. Lin oleic acid and omega-3 PUFA intakes from fish did not demonstrate predicted associations suggesting that different populations of subjects may have different outcomes from certain dietary patterns.

Dietary fibre and dietary patterns (Table_2) In the Male Health Professionals’ Study, after 6 years, dietary fibre intake was inversely related -1 with CHD death, highest quintile (median, 28.9 g.d ) versus lowest quintile of intake (median, -1 12.4 g.d ) age-adjusted relative risk was 0.45 (95% CI, 0.28 to 0.72), and for total MI was 0.59 32 -1 (95% CI, 0.46 to 0.76) and after multivariate adjustment 0.64 (95% CI, 0.47 to 0.87) . A 10 g.d increase in dietary fibre intake corresponded with a relative risk of t otal MI of 0.81(95% CI, 0.70 to 0.93). Cereal fibre was most strongly associated 0.73 (95% CI, 0.56 to 0.94). After simultaneous adjustment for other sources of fibre, only cereal fibre remained significant, and remained so even after further adjustment for β-carotene, folate and vitamin B 6, relative risk 0.73 -1 (95% CI, 0.57 to 0.94) for each 10 g.d increase. The 12% and 17% reduced risk for vegetable and fruit fibre intakes respectively, lost significance. Grams per day of the various sources of dietary fibre are shown in Table_3 In the Nurses’ Health Study after 10 years, dietary fibre intake was inversely related with CHD 68 -1 (non-fatal MI and CHD death) . Highest quintile (median, 22.2 g.d ) versus lowest quintile of -1 intake (median, 11.5 g.d ) age-adjusted relative risk was 0.53 (95% CI, 0.40 to 0.69, p for trend<0.001), and multivariate relative risk was 0.77 (95% CI, 0.57 to 1.04, p for trend=0.07). Age-adjusted relative risk for nonfatal MI was 0.57 (95% CI, 0.42 to 0.77, p for trend<0.001), and -1 for fatal CHD 0.41 (95% CI, 0.23 to 0.70, p for trend=0.002). A 10 g.d increase in dietary fibre intake corresponded with a multivariate relative risk of CHD of 0.81(95% CI, 0.66 to 0.99), further adjustment for nutrients widened the confidence interval slightly (relative risk, 0.79; 95% CI, 0.59 23

to 1.07). Only cereal fibre was independently associated with reduced risk. Multivariate risk, after simultaneous adjustment for other sources of fibre and other nutrients, for the highest versus -1 lowest quintiles, was 0.66 (95% CI, 0.49 to 0.88, p for trend<0.001). For each 5 g.d increase in cereal fibre, the multivariate relative risk was 0.63 (95% CI, 0.49 to 0.81). No risk association was found for vegetable or fruit fibre intakes. Mean fibre intakes were relatively low. For lowest -1 versus highest quintiles of intake respectively, total dietary fibre intake was 10.6 g.d and 23.7 -1 -1 -1 -1 -1 g.d , cereal fibre 2.8 g.d and 6.0 g.d ; vegetable fibre 4.0 g.d and 9.2 g.d , and fruit fibre 1.6 -1 -1 -1 -1 -1 g.d and 6.0 g.d . Soluble fibre intakes were 3.2 g.d and 6.8 g.d and insoluble fibre 7.4 g.d -1 and 16.9 g.d , respectively. -1

For men in the ATBC Study and in the highest quintile of fibre intake (median, 34.8 g.d ), the relative risk of CHD death after six years follow-up was 0.69 (95% CI, 0.54 to 0.88, p for -1 34 trend<0.001) compared with men in the lowest quintile of intake (median, 16.1 g.d ) . Adjustment for risk factors, SFAs and antioxidant vitamin intakes did not s ubstantially change the -1 association. A 10 g.d greater daily intake of fibre was associated with reduced risk of CHD, relative risk, 0.83 (95% CI, 0.56 to 0.95). The results were similar between placebo and supplemented groups. In the ATBC Study a low dietary fibre intake appeared to have a more significant association with CHD than ratio of dietary fatty acids. In the Male Health Professionals’ Study, researchers concluded that low dietary fibre intakes in high fat consumers could explain most of the association between SFAs and CHD in this population, supporting an increase in plant food intake relative to animal food intake. In the Male Health Professionals’ Study, the Nurses’ Health Study and the ATBC Study, the 3 2,34,68 highest quintile of fibre intake was ass ociated with lower SFA and cholesterol intakes . In the ATBC Study alcohol intake reduced, and β-carot ene , vitamin C and vitamin E, increased, with each quintile of fibre intake. Subjects in the higher quintile of fibre intake were also more active. Male Health Professionals in the highest quintile of fibre intake were older, leaner, less likely to smoke, and more likely to take α-tocopherol supplements. In the Nurses' Health Study, the highest quintile of fibre intake was associated with increased dietary supplement use, vigorous exercise, less alcohol and higher CHO, vitamin C, vitamin B6, E, folate, β-carotene and magnesium intakes. Morris et al followed male British Civil Servants in London for 10 -20 years and reported a 39 reduction in CHD mortality but only age, smoking and occupation were adjusted in the analysis . In British Civil Servants as for the Male Health Professionals’ and Nurses’ Health Study, cereal fibre was most strongly associated with least risk whereas in the ATBC Study vegetable fibre was more strongly associated with least CHD risk. In the Rancho Bernardo Study, inverse risk for fibre intakes of men and women was attenuated -1 after correcting for energy intake but mean fibre intakes were only 6.4 g.4.2 MJ and 7.1 g.4.2 -1 43 MJ respectively, for those who died from CHD compared with those who survived . A 6 g unadjusted higher fibre intake was associated with a 25% lower CHD mortality (relative risk 0.74; 95% CI, 0.58 to 0.94, p for trend=0.01). In the Zutphen Study after 10 years of follow-up, there was a four-fold lower 20 year CHD 27 mortality rate between highest versus lowest quintiles of dietary fibre intake . Absolute mean -1 -1 intakes of dietary fibre (mean fibre intake 27 g.d (SD 8.1) and 31 g.d (SD 9.7) for cases versus survivors respectively (p<0.06). Polysaccharide and vegetable protein intakes were significantly higher in survivors than in those who died from CHD. This population had high mean fibre -1 intakes (30 g.d ) and the differenc e in intakes was small. The fibre association was no longer significant after accounting for polysaccharides and vegetable protein intakes and energy intake by stepwise regression analysis, but remained significant for all -cause mortality.

Table 3. Food sources of dietary fibre in quintiles of fibre, lowest to highest intakes in g.d-1 per quintile of fibre intake, lowest to highest (mean energy intakes 8.2-8.4 MJ.d-1), Male Health Professionals Study. Quintiles

Dietary fibre sources (median values) Cereal

Wheat

Oat

Fruit

Vegetable

Cruciferous

Total

3.4

2.8

0.2

1.9

4.2

0.7

12.4

4.6

3.8

0.3

3.1

5.6

0.9

16.6

5.6

4.6

0.4

4.0

6.6

1.1

19.6

6.6

5.3

0.5

5.1

7.8

1.3

23.0

8.9

6.7

0.7

7.4

10.3

1.7

28.9

In the Nurses' Health Study and the Male Healt h Professionals studies, after six years follow-up, dietary GI has been associated with risk of type 2 diabetes, the highest versus lowest quintile relative risk was 1.37 (95% CI, 1.09 to 1.71, p for trend=0.005) and 1.37 (95% CI, 1.02 to 1.83, p 69,70 for trend=0.03), for the two studies respectively . Cereal fibre was inversely associated with risk in both studies and the combined glycaemic load and cereal fibre relative risk 2.5 (95% CI, 1.14 to 5.51) and 2.17 (95% CI, 1.04 to 4.54) respectively for the two studies (highest GI and lowest cereal fibre vs. lowest GI and highest cereal fibre). In the Iowa Older Women's Study total grain and grain fibre and total fibre were associated inversely with type 2 diabetes, the multivariate adjusted relative risks for whole grain and fibre respectively were 0.79 (p for trend 71 0.009), and 0.78 (p for trend=0.005) . Dietary glycaemic load has also been associated with risk of MI in the Nurses' Health Study, relative risk 1.98 (95% CI, 1.41 to 2.77; p for trend<0.0001), 72 for highest versus lowest quintile of glycaemic load .

Flavonoid intakes and dietary patterns (Table_2 and Table_4) In the cross -population Seven Countries Study, average flavonoid intake was inversely relat ed 59 with CHD mortality . The six cohort studies reporting associations between flavonoid intake and CHD are listed in Table_4. Flavonoid intakes in the top quintile of reported studies were 30-40 -1 -1 mg.d , excepting for the Finnish Mobile Clinic Study with 4.5-5.5 mg.d . Lowest quintile intakes -1 -1 ranged from 18-19 mg.d to less than 3 m g.d . Outcome data are reported in Table_2. The percentage of flavonoid intake derived from tea drinking was 61% in Zutphen elderly, 70% in the 28 Zutphen cohort of the Seven Countries Study , 25% in Male Health Professionals, 82% in Caerphilly, 80% in the Japanese cohort of the S even Countries Study and in Finland, and 35% in Iowa women. Red wine was the major source of flavonoids in Italy, 40% of intake. Most of the remaining measured flavonoid intakes was from apples and onions, however the flavonoid content of many foods were not known for these analyses and other constituents that provide protection may not have been measured. These results are at best preliminary. All studies were corrected for most antioxidant vitamin intakes. Of the two studies showing no risk reduction with flavonoid intake, in Caerphilly most of the flavonoid intake was from tea with milk in the background of a high fat diet, and in the Male Health Professionalsâ&#x20AC;&#x2122; Study there was a trend for an inverse association in men with prevalent CHD, relative risk 0. 63 (95% CI, 0.33 to 1.2). In the Zutphen Study highest versus lowest flavonoid intakes were inversely associated with fatal and non-fatal stroke [relative risk 0.27 (95% CI 0.11 to 0.70)] but in the Iowa Women'sâ&#x20AC;&#x2122; Health 28,47 Study no association with stroke was found .

Table 4. Prospective studies of flavonoid intake and cardiovascular disease. Study Percentile cut-off 28

Zutphen Study Quartiles Zutphen Elderly 49 50 Study , Tertiles Iowa Women's 47 Health Quintiles Finnish Mobile 44 Clinic Quartiles 41

15 yr

Highest vs. Lowest intake (m g.d-1) 33.3 vs. 14.2

10 yr

>34 vs. <19*

CHD mortality

0.46 (0.23 to 0.92)

0.025

10 yr

28.6 vs. 4.0

CHD mortality

0.20 (0.44 to 0.87)

0.11**

26 yr

>5.5 vs. <2.4* >4.8 vs. <2.1*

CHD mortality women men

0.73 (0.41 to 1.32) 0.67 (0.44 to 1.00)

0.21**

14 yr

43 vs. 13.5

CHD mortality

1.60 (0.90 to 2.90)

0.119

Follow-up

Outcome Stroke

Relative risk, (95% CI) High vs. low intake 0.27 (0.11 to 0.70)

p for trend

Caerphilly Quartiles Male Health 6 yr 40 vs. 7.1 Non-fatal MI 1.08 (0.81 to 1.43) 33 Professionals Quintiles * Percentile cut-off, mean intake not reported. ** In these studies the trend was significant before multivariate analysis included antioxidant nutrients.

0.004

0.12

In general, epidemiological observations report an inverse association between dietary flavonoid intakes and risk of CHD adding support to dietary patterns with high plant food content. Current findings are limited by incomplete food composition data for flavonoid content of foods.

Foods associated with coronary heart disease risk (Table_2) In the Seven Countries Study the opposing effects risk of animal and vegetable foods were apparent; combined vegetable foods (excluding alcohol) were inversely correlated (r= -0.519), whereas combined animal foods (excluding fish) were directly correlated (r=0.798) with CHD 62 death rates . Univariate analysis showed significant positive correlation coefficients for butter (r=0.887), meat (r=0.645), pastries (r=0.752), and milk (r=0.600) and negative correlation coefficients for legumes (r= -0.822), oils (r=-0.571), and alcohol (r= -0.609). Individual foods found associated with CHD, may be indicators of specific food constituents that influence CHD risk or, they may reflect the lifestyle habits of individuals who habitually consume 6 these foods . The Nursesâ&#x20AC;&#x2122; Health Study has demonstrated a relationship between the ratio of red meat consumed relative to white meat, and higher risk of CHD (multivariate relative risk 1.32, p for trend=0.001), and ratio of high fat to low fat dairy products (multivariate relative risk 1.27, p for 67 trend=0.0004) . After 14 years follow-up the age-adjusted risk for highest versus lowest quintiles -1 -1 of red meat intake (1.78 srv.d vs. 0.42 srv.d of meat) was 1.61 (p for trend<0.001) and 1 srv.d 1 corresponded with a relative risk of 1.43 (95% CI, 1.35 to 1.65), the significance for both was -1 attenuated after multivariate adjustment. Poultry and fish intakes of 0.88 srv.d versus 0.21 -1 srv.d , were associated with lower age adjusted relative risk (0.62, p for trend<0.001) and multivariate adjusted relative risk (0.85, p for trend=0.06) and the simultaneously adjusted -1 multivariate relative risk for 1 srv.d was 0.76 (95% CI, 0.56 to 1.02). High fat dairy products (3 -1 -1 srv.d vs. 0.3 srv.d ) were associated with an age adjusted relative risk of 1.22 (p for -1 trend=0.001), and low fat dairy products (2.28 vs. 0.05 srv.d ) with 0.56 (p for trend<0.0001). Significance was attenuated after simultaneous multivariate adjustment including the comparison foods. The Nursesâ&#x20AC;&#x2122; Health Study has shown lower CHD mortality in the highest quintile of nut -1 -1 consumption (>150 g.wk ) compared with the lowest quintile (<30 g.mth ) relative risk 0.61 66 (95% CI 0.35 to 1.05 p for trend=0.007) . This magnitude of risk reduction was similar and significant for non-fatal MI. In another report from the study, intakes of foods high in trans isomers -margarine, cookies, cake and white bread were each significantly associated with higher 35 risks of CHD . In another report, oil and vinegar dressing in the highest quintile of intake greater

than five to six times per week compared with the lowest quintile of intake (less than once per month) was associated with reduced risk of fatal CHD (multivariate adjusted relative risk, 0.46; 37 95% CI, 0.27 to 0.76) . A 15% reduced risk ass ociated with creamy dressings and mayonnaise was not significant. In the USA, these dressings are commonly made from soybean oil which 37 contain 7% LNA . Intakes of wholegrain foods have been reported from t he Nurses’ Health Study and the Iowa 73,74 Womens' Health Study . In the Nurses’ Health Study, the multivariate adjusted relative risk for fatal and non-fatal CHD between highest and lowest quintiles of intake was 0.74 (95% CI, 0.58 to 0.94, p for trend =0.01) and was little affected by further adjustment for fats, dietary fibre, folate, vitamin B 6 and vitamin E, relative risk 0.79 (95% CI, 0.62 to 1.01, p for trend =0.07). Median -1 intakes for the five quintiles of intake 0.13, 0.43, 0.85, 1.31 and 2.7 srv.d of wholegrain foods in -1 -1 1984 (median intakes for the group were 1.12 srv.d in 1984 and 1.43 srv.d in 1990) had -1 -1 increased slightly by 1990. Dietary fibre intakes were 20 g.d and 14 g.d respectively for highest and lowest quintiles. For a sub-group of never smokers the inverse relationship between wholegrain intake and CHD was even stronger (relative risk after multivariate and additional adjustment for relevant nutrients, 0.47 (97% CI, 0.27 to 0.79, p for trend=0.006). An association found between refi ned grain and CHD was attenuated after adjustment for risk factors and wholegrain intake. -1

Relative risk of CHD (fatal and non-fatal MI) for extreme quartiles of intake, 1 srv.d of bran versus almost never having bran, was 0.63 (95% CI, 0.42 to 0.95, p for trend =0.001); for 1 srv.d 1 versus almost never having wheat -germ relative risk was 0.41 (95% CI, 0.15 to 1.10, p for -1 trend=0.01); and for 0.8 srv.d brown rice versus almost none was 0.45 (95% CI, 0.06 to 3.20, p -1 for trend =0.04). For extreme intake quintiles of wholegrain breakfast cereal, 0.93 srv.d versus almost no servings per day the relative risk was 0.76 (95% CI, 0.57 to 1.0, p for trend =0.007). No association was found with popcorn or oatmeal intakes. Higher intakes of wholegrain were associ ated with lower intakes of fat, cholesterol and alcohol and increased intakes of fruit and vegetables, CHO, protein and folate. Women in the higher range of intake smoked less, exercised more and were more likely to take supplemental vitamins or hormone replacement. In the Iowa Women's’ Health Studies the top quintile of wholegrain servings (median 22 servings per week) was inversely associated with CHD death relative to the lowest quintile of intake (1.5 -1 48,73 srv.wk ), relative risk 0.70 (95% CI, 0.50 to 0.98, p for trend=0.018) . Women in the highest -1 quintile of intake ate less total energy, meat and sucrose, less refined grain (11 srv.wk vs. 20 -1 -1 -1 srv.wk com pared with lowest quintile), more dietary fibre (22.3 g.d vs. 16.3 g.d in lowest -1 -1 quintile) and fruit and vegetables (40 srv.wk vs. 34 srv.wk respectively) and had lower Keys -1 -1 scores. Highest intakes of dark bread (17.5 srv.wk to 42 srv.wk ) compared with lowest intakes -1 (0.05 srv.wk ) were associated with reduced risk of CHD death, relative risk, 0.67 (95% CI, 0.49 to 0.91, p for trend=0.023), after multivariate adjustment. Higher grain intakes were associated with more education, lower BMI, increased activity, and greater use of vitamin supplements and hormone replacement. -1

-1

Servings per week of refined grain (30 srv.wk vs. 4 srv.wk for extreme quintiles), white bread, refined breakfast cereal, sweets or desserts or other refined grains or crac ker biscuits were not associated with CHD risk after proportional hazards regression analysis for individual risk factors -1 -1 and other dietary factors. White bread intake (7 srv.wk to 42 srv.wk vs. zero per week for extreme quartiles of intake) was associ ated with CHD death after adjustment only for age and energy intake, relative risk 1.43 (95% CI 1.07 to 1.81, p for trend=0.002) while desserts and other refined grains were associated with reduced risk. Higher refined grain intakes were associated with less physical activity, less vitamin and hormone replacement use, lower fruit and -1 -1 -1 vegetable intakes (28.6 srv.wk vs. 45.5 srv.wk ) and higher sucrose intakes (47 g.d vs. 38 g.d 1 -1 -1 ) and lower fibre intakes (17 g.d vs. 22 g.d ), for extreme quintiles. 47

In the Iowa Women's’ Flavonoid Study , broccoli intake (highest vs. lowest intakes, 4-42 times per month vs. virtually none) was associated with reduced risk of CHD death, relative risk 0.52 (0.37 to 0.74, p for trend =0.0001).

In the British Civil Servants Study the high range of cereal fibre intake associated with lower -1 -1 risk of CHD included average intakes of 113 g.d of breakfast cereal, 162 g.d of porridge, 900 -1 -1 -1 g.d of baked goods, 315 g.d of brown or wholemeal bread and 1 kg.wk of white bread. In the Male Health Professionalsâ&#x20AC;&#x2122; Study, mean servings per day of several foods were reported for quintiles of SFA intakes. Compared with the lowest quintil e, the group in the highest quintile of intake consumed 1.5 times more sweets, 3.5 times more red meat, 5 times more high fat dairy 18 products and 0.78 of cereal, 0.60 of vegetable, and 0.46 of fruit intakes . In a separate analysis for selected foods, men had significantly reduced relative risk of MI if they ate the following (compared with eating little of these foods): Cold breakfast cereal 2-4 times a week relative risk, 0.83 (95% CI, 0.69 to 0.99); a serving of carrots 2-4 times a week relative risk, 0.59 (95% CI, 0.4 to 0.88); an apple a day relative risk, 0.82 (95% CI, 0.58 to 1.17); and a daily serving of peas relative risk, 0.52 (95% CI, 0.31 to 0.88). The ATBC Study median daily intakes in the highest versus lowest quintiles of dietary fibre -1 -1 -1 -1 intake were 172 g.d and 16 g.d for rye products respectively, 214 g.d versus 47 g.d of other -1 -1 -1 -1 cereals, 154 g.d versus 25 g.d of vegetables, and 246 g.d versus 25 g.d of fruit and 34 berries . Intakes of rye products, potatoes, vegetables, and fruit were all significantly and independently inversely associated with CHD deaths, but not coronary events (relative risk, 0.75, 95% CI, 0.58 to 0.98, p for trend= 0.2; 0.74, 95% CI, 0.57 to 0.97, p for trend=0.02; 0.60, 95% CI, -1 0.45 to 0.79, p<0.001; and 0.78, 95% CI, 0.59 to 1.03, p =0.008, respectively). A 100 g.d higher intake of vegetables was associated with a 26% lower risk of coronary death. Rye was eaten as 34 the major whole grain in this population . Only vegetable intake was inversely associated with all coronary events. Relative risk in higher versus lower quintiles of intake, 0.73 (95% CI, 0.60 to 0.88). In the Finnish Mobile Clinic Study, male cases of CHD death consumed significantly more dairy products (p<0.001), and less vegetables p<0.001), fruits (p= 0.04) and (p= 0.06) margarine (mixed 45 varieties not all PUFA) than survivors . The female survivors consumed more cereals (p= 0.03) and margarine (p<0.05). Margarine types may have varied between the sexes. In the Ireland-Boston Diet -Heart Study, researchers used an animal -foods score and a 29 vegetable-foods score to rate diets . Vegetable-foods score and fibre intake were significantly lower among survivors but only of borderline significance when adjusted for risk factors associated with CHD. A Keys score in the highest tertile of lipid intake, carried an increased relative risk of 1.60 compared with the lowest tertile. A fibre intake in the highest tertile carried a decreased relative risk of 0.57 (95% CI, 0.33 to 0.97) compared with intakes in the lowest 32 tertile . In two studies not reporting dietary fibre intake, CHO data may have reflected plant food intake. Total CHO and non-starch CHO intakes were inversely associated with CHD in the Honolulu 31 Heart Study (p< 0.05) . Before correction for other risk factors, vegetable protein intake and percentage of energy from CHO was also higher in survivors. After multivariate analysis, an independent inverse relationship was found between CHO as legumes and CHD incidence in the Puerto Rico Heart Study, and before multivariate analysis percentage energy from PUFAs was 23 inversely related to MI and CHD death in the urban cohort .

Summary Within the dietary patterns of free-living individuals, differences of dietary fatty acid composition create differences in associated food constituents and nutrients with potentially confounding influences. In general, epidemiological observations support a positive association between SFA intakes and CHD and an inverse association with PUFA intakes. No studies report the converse of these associations. Although many studies report no associations between CHD and these fatty acids, most have not adjusted for fatty acid intakes after multivariate analysis for confounding risk factors. Few studies have reported associations between MUFAs and CHD and these remain unclear. Since MUFAs occur with SFAs in foods, after adjustment for all fats and

dietary cholesterol, MUFAs may became inversely associated with CHD. These associations support a reduced intake of animal foods relative to plant foods. Population studies of dietary fibre and flavonoid intakes support the suggestion that low intakes increase risk for CHD. From the large cohort studies, the macronutrient intake data, in particular the food sources of fatty acids and dietary fibre, support a recommendation that a cardioprotective/ anti -cardiovascular dietary pattern involves an increase in whole plant food intakes. Despite the limitations of epidemiological studies, that even strong associations do not ensure causal relations, the large number of studies involving thousands of participants show very consistent associations between higher rates of CHD and dietary patterns where the source of fat is predominantly of animal origin, and/or dietary fibre, or vegetable intakes are low. Intra-population cohort observations and case-control studies unanimously find an association -1 between dietary fibre in the highest range of intake (20-35 g.d ) and reduced risk for CHD. In general, epidemiological observations favour cereal fibre as the major influence when comprising -1 at least one third of higher dietary fibre intake. Intakes of dietary fibre of less than 16 g.d are associated with increased risk for CHD. Inconsistent associations found between refined foods and CHD might be explained by type of food and low fibre intakes of the study populations as a whole. Higher fibre intakes are associated with reduced SFA intakes, improved micronutrient intakes and other lifestyle attributes. Prospective population -based studies therefore support a recommendation for dietary patterns comprising high intakes of fruit, vegetables and wholegrain foods relative to animal s ource foods and reduced intakes of hardened vegetable fats, and moderation in refined plant food intake.

Dietary diversity: Studies of dietary patterns. Prospective cohort studies and total or coronary heart disease mortality Studying dietary patterns in relation to total or CHD mortality provides a practical way to evaluate 75 the health effects of adherence to dietary guidelines . Food variety as a predictor of health outcome gives information about dietary patterns. Whilst not providing data on specific protective or pathogenic factors within a dietary pattern, sufficient evidence for reduced mortality and morbidity justifies use of this method to promote food variety through food-based dietary 3 guidelines . Study of dietary patterns also raises confounders often not controlled for in single nutrient or single food assessments. For example, differences in 25 -year mortality rates from CHD for the 16 cohorts of the Seven Countries Study could not be explained by differences in alcohol, fish, 76 fibre or antioxidant vitamin intake . Alcohol and fish intakes were inversely associated with 25year CHD mortality in univariate analysis but these associations became insignificant when multivariate analysis corrected for di fferences in SFA, flavonoids and smoking. This was due to a significant inverse association between alcohol and SFA intakes, and a significant positive association between fish intakes and flavonoid intakes. These data come after individual associations had been demonstrated in independent cohorts for 27,50,77 fish, fibre, and flavonoids and rates of CHD . These studies highlight the importance of the full dietary pattern, and that independent components may affect one population, or the dietary pattern of that population, and not another. For example when fish intake was separated from the 1960 dietary analysis i n the Zutphen cohort (852 men 40-59 years of age) and related to mortality 20 years later, quintiles of fish -1 77 intake ranged from 0 to greater than 45 g.d . The risk factor adjusted risk ratio of 20-year CHD mortality was 0.36 (95% CI, 0.14 to 0.93) and 0.39 (95% CI, 0.13 to 1.15) for average intakes of -1 -1 -1 30 g.d to 44 g.d and more than 44 g.d of fish respectively, compared with lowest intakes but SFA, fibre, and alcohol were not included in the logistic -regression model. Investigators of indices of fo od variety have used a “dietary diversity score” which counts number of food groups consumed daily; cluster analysis of food groups or nutrients; a diet or food score or “healthy diet indicator” where a score is given for inclusion, quantity or frequency of certain

foods, food groups and/or nutrients . Measures of food frequency in tertiles, quartiles or quintiles of intake, in the large cohort studies, further contribute the independent relationships of individual foods within dietary patterns associated with increased or decreased CHD mortality.

Prospective cohort studies and cardiovascular mortality Seven Countries Study

Since 1984, Finland, Italy and the Netherlands cohorts of the Seven Countries Study continued the examination of their cohorts. The dietary pattern and 20-year mortality in elderly men in 79 Finland, Italy and the Netherlands was reported in 1997 . A healthy diet indicator was calculated for the dietary pattern using the WHO guidelines for the prevention of chronic diseases. The criteria for the healthy diet indicator included awarding a dichotomous value of “1” when SFAs were 0-10% of energy, PUFAs 3-7% of energy, protein 10-15%, complex CHO 50-70% of -1 -1 energy, dietary fibre 27-40 g.d , fruits and vegetables greater than 400 g.d , pulses, nuts and -1 seeds greater than 30 g.d , monosaccharides and disaccharides 0-10% of energy, and -1 cholesterol 0-300 m g.d . The healthy diet indicator was the sum of those variables scoring “1”. A score of “0” was given for values outside the above ranges for PUFAs, protein, complex CHOs, dietary fibre, and values less than the value given for fruit and vegetables, and pulses, seeds and nuts, and greater than the value given for SFAs, monosaccharides and disaccharides, and dietary cholesterol. After adjustment for age, alcohol intake and cigarette smoking, men with the highest healthy diet indicator (mean score 4.0, n=129) had 13% lower risk of all -cause death than men with the lowest healthy diet indicator (mean score 0.9, n=785), 18% lower cardiovascular mortality and 15% lower risk of death from cancer. Those with a medium healthy diet indicator had a mean score of 2.0 and numbered 969. The group with the healthiest diet indicator were clearly the minority. The workers also concluded that the dietary pattern as a whole, rather than individual components of the healthy diet indicator, was responsible for these associations. In this analysis it was assumed that the diet in 1990 was similar to that in 1970 when the dietary analysis was carried out. The differences between cultures have, however, become smaller as assessed by separate analysis. The Finnish and Dutch cohorts have changed slightly in the direction of 80 healthier diets but remain high in SFA (animal foods) . Italian Studies

Farchi et al have studied the relationships between the individual diets of 1,535 men, measured in 1965 on the two Italian rural cohorts of the Seven Countries Study on CVD, and subsequent 81 20-year mortality (Table_5) . Rather than setting pre-defined sub-divisions, subgroups of subjects were grouped according to similar habits. Clusters were determined by nutrient analysis but this paper provided food information about each cluster. •

Cluster 1 was characterised by a high alcohol intake (30% or more of energy i ntake)

•

Cluster 2 had highest intakes of PUFAs (about three times the value of other groups)

•

Cluster 3 had highest intakes of MUFA and SFAs

•

Cluster 4 had highest intakes of CHOs (about 50% of energy intake).

Mortality rates from CHD for cluster 2 and 3 were lower than for cluster 1 and 4 especially at the 10 and 15 year anniversaries. Cluster 2 had the lowest rates of CHD death and highest consumption of PUFAs. The main difference between clusters 2 and 3 were intakes of oils: 45 -1 -1 g.d of seed oils daily versus 43 g.d of olive oil daily, respectively, and cluster 2 had higher alcohol intakes. These clusters, 2 and 3, had higher SFA intakes despite less CHD, compared with clusters 1 and 4 but their P:S ratios were 1.6 and 1.2 (clusters 2 and 3 respectively) relative to 0.4 for clusters 3 and 4. The diets of these Italian subjects were characterised by low vegetable intakes in all groups. 30

Stroke rates were statistically higher in cluster 1 and 3, lower in cluster 2 and lowest in cluster 4, especially at the 15 year anniversary. Coronary heart disease and stroke deaths together were lowest in cluster 2, 5.4 deaths per 100 in 15 years versus 14.4, 10.1 and 10.1 in clusters 1, 3 and 4 respectively. Presence of CVD was an exclusion criterion at entry to the study . Cancer rates were lowest in cluster 4. All cause mortality was similar between clusters 2, 3 and 4 but significantly greater in cluster 1 (high alcohol group) and most evident at 10 years when cluster 1 mortality was twice that of the other groups. The different clusters do not easily fit into commonly identifiable dietary patterns excepting that cluster 4 may represent one interpretation of the â&#x20AC;&#x153;prudent dietâ&#x20AC;?. Diets change over the intervening years between assessment and events and these data were lacki ng. In another study, Farchi et al studied the relationships of eating patterns and conformity to dietary recommendations with subsequent 20 -year rates of total mortality and mortality from 82 specific causes in the same two rural Italian cohorts . Defining dietary pattern in terms of nutrients, the researchers compared macronutrient intakes with the WHO recommendations as the reference. In these recommendations CHOs constitute 55-75% of energy, and are calculated as total and complex CHO without reference to fibre, non-starch polysaccharides or whole plant foods and were associated with lower total and cancer mortality. Lowest CHD mortality was associated with CHO intakes of 45-55% of energy. Alcohol was excluded from the energy analysis. Although relationships with all-cause mortality were found dietary intakes meeting recommendations for total CHO, protein (10-15% of energy) and fat (15-30% of energy), relationships with CHD mortality were the only trends observed in the subjects conforming with the individu al fatty acid recommendations (energy from SFAs <10% vs. >10%, relative risk 0.88; 95% CI, 0.59 to 1.31; from PUFAs <7% vs. >7%, relative risk 0.74; 95% CI, 0.53 to 1.14), although these confidence intervals are too wide for significance. Intakes meeting all of the macronutrient recommendations compared with those meeting none were associated with reduced total mortality -relative risk 0.59 (95% CI, 0.41 to 0.84), and reduced CHD mortality, relative risk 0.45 (95% CI, 0.23 to 0.89) but both lost significance when corrected for age, smoking and physical activity-relative risk 0.81 (95% CI, 0.56 to 1.17) and 0.66 (95% CI, 0.31 to 1.33) respectively. The same group have further reported the relationship between diet and mortality over 20 years 83 in the same cohort . In this study dietary intakes of nutrients were divided into quartiles of intake, each quartile being given a score. Survival varied little between quartiles of SFA intake perhaps explaining the lack of clear relationships in the previous study. The dietary pattern -1 corresponding to lowest mortality rate (27% over 20 years) had provided more than 11.7 MJ.d , >41% of energy from CHOs, >9% from protein, 16-23% from unsaturated lipids, and 13-19% from alcohol. As the number of decrements away from these numbers increased, the CHD mortality rate increased to reach a maximum 69% in 20 years in the worst case. In the proportional hazards model, the relative risk for subjects with a diet score of five was 2.32 (95% CI, 1.15 to 3.84) compared with subjects with a score of 0. The crude death rate was reported for CHD - 4.8% for the group with the lowest dietary score and 21.6% for the highest score. -1

Alcohol intakes were very high in this population (mean intakes 86.3 ml.d ) and when excluded from the analysis mortality continued to correlate with the dietary score, 31.6% incidence of CHD mortality over 20 years with the optimal dietary pattern and 66.1% in the worst case.

Table 5. Reported daily food consumption (g.d-1) . Food

Cluster 1

Cluster 2

Cluster 3

Cluster 4

Meat

77.0

101.0

105.0

93.0

Sausage

25.0

17.0

27.0

21.0

Fish

21.0

18.0

22.0

21.0

Pulses Vegetables Fruit

6.0

5.0

6.0

51.0

42.0

55.0

155.0

212.0

198.0

196.0

Cheese

10.0

13.0

19.0

12.0

Oils

31.0

36.0

50.0

45.0

Seed oil

6.0

45.0

2.0

5.0

Olive oil

30.0

5.0

43.0

26.0

Other fats

22.0

21.0

26.0

17.0

Eggs

18.0

15.0

18.0

16.0

Cakes, biscuits etc

17.0

34.0

31.0

29.0

Starchy food-bread, rice, potato

455.0

434.0

401.0

590.0

Alcohol

150.0

67.0

55.0

62.0

7.3

10.1

11.7

7.6

% Energy

SFA PUFA

2.9

8.1

3.3

2.8

MUFA

13.8

14.2

20.8

13.6

CHO

34.0

40.0

38.6

49.6

Protein

8.7

10.7

11.5

Alcohol

33.0

16.8

14.1

15.0

Prospective cohort studies and all-cause mortality Other studies of dietary patterns or a combination of several nutrients have reported overall 7 5,78,84 mortality within a single population, without separating out cardiovascular mortality . However these studies have been carried out on middle-aged or elderly groups for whom cardiovascular mortality is a major cause of death, but add to the findings of the above two studies. Nube and co-workers investigated the effect of a dietary score on longevity among 2,820 middleaged Dutch civil servants. Using the recall of the frequency of intake of ten particular foods rather than extensive dietary history, they found a significant linear trend for 25-year survival 75 from highest (healthiest) to lowest scores in men but not in women . Higher intakes of brown bread, porridge and/or yoghurt, vegetables, fish and fruit were independently associated with a slightly better survival and in separate analysis a significant inverse relationship between survival and coffee consumption was found. This study was limited by dietary collection procedures and foods available 45 years ago. Kant et al examined dietary diversity and all -cause mortality in the USA NHANES I 78 Epidemiological Follow-up Study . A food diversity score based on number of food groups consumed daily, had predictive power for mortality and allowed sex differences in this prediction to be recognised. Age-adjusted relative risk for all -cause mortality was 1.9 (95% CI, 1.6 to 2.4) for men consuming zero to two food groups per day compared with the group consuming 5 food groups per day. For women the mortality was 1.5 (95% CI, 1.2 to 1.8) under the same conditions. Mortality for subjects consuming three to four food groups daily was intermediate between these values. In those reporting consuming less than five food groups on the survey day, less than 5% of respondents reported omitting the meat or grain groups, but 46% of respondents reported no fruit, 25% no dairy and 17% no vegetable foods.

Greek Diet Studies

Trichopoulou et al used an approach similar to the healthy diet indicator in the International Union of Nutritional Sciences (IUNS) food habits in later life programme and survey in Europe 85,86 studying nutrition and the elderly (Euronut Study) . They assessed the influence of the traditional Greek food pattern on overall survival (cause of death not identified) among 182 elderly residents of three rural Greek villages. Follow-up was for four to five years in which time 53 subjects died. These subjects were all consuming a Mediterranean diet (only 19% of subjects were consuming two or less of the desirable dietary components) and being in their 70's represented â&#x20AC;&#x153;survivorsâ&#x20AC;&#x2122; already. A diet score was calculated on the basis of eight component characteristics of the traditional Mediterranean region. The diet score cut -off points were the median intake in grams for each sex. For men and women respective ly, median daily consumption in grams adjusted for energy intakes of 10.5 MJ and 8.4 MJ were: vegetables 303 -1 -1 -1 -1 -1 -1 g.d and 248 g.d , legumes 60 g.d and 49 g.d , fruits and nuts 249 g.d and 216 g.d , dairy -1 -1 -1 -1 products 201 g.d and 194 g.d , cereals 291 g. d and 248 g.d , meat and meat products 109 -1 -1 -1 -1 g.d and 91 g.d , alcohol 10 ml.d and 0 ml.d and the MUFA to SFA ratio was 1.6 and 1.6. A one unit increase in the diet score was associated with a 17% reduction in overall mortality (95% CI, 1% to 31%), an increase in four units was associated with a 50% reduction in mortality. Dairy product intake was the only dietary variable independently associated with mortality (4% -1 increase in the hazard of death for every 20 g.d increase in consumption adjusted for energy, rate ratio 1.04; 95% CI, 1.01 to 1.07) suggesting that the overall pattern is more important than individual dietary components. In another cohort of the Euronut Study, Osler and Schroll studied diet and nutritional status among 202 men and women born 1914 to 1918 living in a Danish Municipality in 1988, and 84 followed them for 6 years . The diet score identifying seven dietary characteristics of the Mediterranean (Greek) diet, as in the Greek study, was associated with a significant reduction in mortality. A one unit rise in the diet score predicted a 21% reduction in mortality (rate ratio 0.79; 95% CI, 0.64 to 0.98). In this study only the relationship of the cereal food group with mortality was statistically significant. This again suggests that total dietary pattern may be more important than individual components of diet. Subjects with high scores had significantly higher plasma carotene levels and plasma carotene was inversely associated with mortality. A high score was represented by high MUFA to SFA ratio, moderate alcohol consumption, high consumption of fruits, cereals, vegetables and legumes, low consumption of meat, low consumption of milk and dairy products. In the Australian IUNS Study of Greek Australians living in Melbourne, using the same dietary score, increases in fruit and cereal intakes and increases in the MUFA to SFA ratios decreased 85 -1 the hazard for death . For every 20 g.d inc rease in fruit or cereal consumption there was a 5% to 8% reduction in the hazard of death after adjusting for energy intake. The rate ratios were 0.95 (95% CI, 0.91 to 1.00) for fruit and 0.92 (95% CI, 0.85 to 0.99) for cereals. In this study also, other individual components of diet were not significantly associated with survival and the overall dietary pattern score appeared a better descriptor of survival. In both Greek born and AngloCeltic Australians the predicted reduction in mortality per unit increase in the traditional Greek food pattern score was 17%, however unlike the Danish and Greek cohorts, did not quite reach significance. These results suggest that the traditional Greek food pattern may be protective regardless of ethnic origin.

Summary Measurement of food variety as a predictor of health outcomes has demonstrated that dietary patterns conforming to recommendations to reduce intakes of SFA -rich foods and increase intakes of fruits, vegetables and other plant foods, are associated with reduc ed CHD and allcause mortality compared to dietary patterns not conforming to these qualities. There is suggestive evidence that the further from the recommendations a dietary pattern is scored, the greater the risk. These studies test the overall dietary pattern as an integrated sum of all individual dietary constituents, thus diminishing confounding from independent variables while 33

testing the strengths of both protective and pathogenic components consumed together in varying proportions.

Studies of specific dietary patterns Vegetarian dietary patterns

Vegetarianism as practiced in developed nations is an identifiable dietary pattern in action, although not all vegetarians subscribe to healthy eating habits. Those volunteering for study are more likely to maintain healthy habits and to practice other healthy lifestyle behaviours. Dietary factors that favourably influence CHD mortality, are exemplified in vegetarian dietary patterns typically low in total fat, SFAs and dietary cholesterol and rich in dietary fibre, flavonoids and PUFAs. Vegetarian diets are commonly associated with an active or simple lifestyle and low rates of CHD such as in New Guinea highlanders, or with conservative religious lifestyles such 87 as Seventh Day Adventist (SDA) . Despite similar rates of blood pressure elevation, and higher levels of blood TG levels, Papua New Guinea highlanders have lower blood total cholesterol and 88 lower rates of CHD than other Australians . Vegetarian diets have long been associated with lower blood lipid le vels, reduced risk of CHD, reduced blood pressure and lower body weight compared with non -vegetarian 87, 89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106 diets . People who eat fish but not meat have similar 92 blood total cholesterol and LDL -C as lactovegetarians . Vegan diets exclude all dairy and egg products in addition to flesh meats, and may require specific guidelines to ensure adequate 106, 107 vitamin B 12, calcium and vitamin D intakes . Vegan diets are associated with lower blood 91,92,99,106, 108 total cholesterol and LDL-C concentrations than lacto-vegetarian diets . Full fat dairy product consumption may differentiate vegans from lacto-vegetarians in terms of blood total cholesterol levels since blood total cholesterol concentrations correlate with SFA intake and 108 inversely correlates with P:S ratio in groups of vegetarians . 109,110

Vegetable protein, in particular soy protein lowers blood total cholesterol . Soybeans exert other actions consistent with their fatty acid (especially linolenic acid), dietary fibre, protein, mineral, oligosaccharide and phytochemical (especially isoflavone) content, including suppression of in vitro oxidation of LDL-C, amino acid efficiency and reduced postprandial 98,110 glucose excursions . They may be critical for the nutritional efficiency of vegan diets. Vegetarianism has been associated with lower plasma apolipoprotein A -1, B, and E concentrations. Apolipoprotein B synthesis was lower in a population with habitual low 111 cholesterol diet that was higher in omega-3 PUFAs than in individuals on typical western diet . Low density lipoprotein cholesterol production has been shown to be lower in vegetarians than in 112,113 omnivores . Vegans and lacto-vegetarians have higher linoleic acid concentrations and 100, 114 lower arachidonic acid concentrations in platelets than omnivores . Meat and fish uniquely supply retinol, iodine, iron, zinc, vitamin B12, taurine and DHA but these nutrients can be s upplied by vegetarian diets in a readily utilised form. Adequate intakes of essential nutrients can be achieved with a vegetarian diet with the exception of vitamin B12 in 106,107,115,116 vegan diets . Vegetarians have absolute iron intakes similar to or higher than moderate meat -eaters, may or may not have lower blood ferritin concentrations, but usually have normal haemoglobin concentrations, that may be slightly lower or similar to those of 106,115, 117 omnivores . Vegetarians do not necessarily suffer from higher rates of iron deficiency 106,107,115 anaemia than omnivores . Iron deficiency anaemia is highest among vegetarians relying on rice as a staple and iron intakes are relatively high in vegetarians and vegans whose staple food is wholemeal bread. Similar numbers of omnivorous and vegetarian women in mixed eating 106 populations, have low blood ferritin concentrations . Vegetarian zinc intakes are usually 106,115 adequate and similar to those of omnivores . In NZ vegetarian SDAs, the dietary intake of key micronutrients is lower only for vitamin B 12 compared with non-vegetarian SDAs, however biochemical indicators of iron and vitamin B 12 status, and blood lipid levels, did not differ between vegetarians and non-vegetarians. Vegetarian 34

total fat intakes vary widely from 15-40% of energy and lacto-vegetarian intakes may or may not differ from intakes of moderate meat -eaters in similar populations, however vegans have the 9 2,97,99,106,115, 118 lowest fat intakes . Saturated fat intakes as a percentage of energy are generally 92,9 7,99,115,118 lower in vegetarians and always lower in vegans . Vegetarian intakes of CHO are higher, choles terol intakes lower, dietary fibre intakes and the P:S ratio higher, than the intakes 9 2,97,99,106,115,118 of meat -eaters. Fibre intakes are highest in vegans . The odds of regularly consuming whole grains is lower in non-vegetarians compared with vegetarians, odds ratio 0.15 119 (95% CI, 0.13 to 0.17) with semi vegetarians between, odds ratio 0.57 (95%CI, 0.49 to 0.67) . Other micronutrients, including dietary antioxidants may be more concentrated in vegetarian 97,106,115 diets . Possible mechanisms for longevity in vegetarians have recently been explored including dietary effects on LDL-C oxidation, treatment of diabetes, and reduction of tHcy levels, but a decrease in 120,121,122 thrombosis tendency compared with meat -eaters has not been established . Korpela et al found resistance of LDL-C to oxidation in vitro was greater in established vegetarians compared 120 with meat and fish eaters . Vegetarians had the lowest proportion of uns aturated long chain fatty acids in their LDL-C, while fish eaters had the highest levels and least resistance to LDL-C 120 oxidation . An early report from the SDA studies in California found that after 6 years of follow-up (n=24,000), CHD mortality rates for ages 35 -65 and greater than 65 years of age were 28% and 87 50% respectively, of rates for the total population of California at the time . Several large prospective cohort studies observing individuals following vegetarian diets have been carried out since. The Adventist Mortality Study , a prospective cohort investigation, recruited 25,153 SDAs from 123 198 congregations in California in 1960 when dietary information was collected . Questionnaires were repeated in 1976. Deaths were identified up to 1980. This study showed an association between meat eating and CHD death. Male non-vegetarian compared with vegetarian (combined use of meat or poultry less than one day per week and 97.5% of whom also did not eat fish), relative risk of CHD death was 1.49 (95% CI, 1.3 to 1.8), and for females 1.37 (95% CI, 1.2 to 1.6) for subjects with no history of CHD in 1960. The relative risk was slightly lower for subjects who had CHD in 1960. The relative risk was increased in the younger men, but not in younger women. The relative risk for fatal CHD in non -vegetarian versus vegetarian males, 45-54 years of age, was 4.02 (95% CI, 1.6 to 9.9) and in older men, 75-84 years, the relative risk was 1.51 (95% CI, 1.3 to 1.7). This trend was also apparent in risk for increasing meat intakes, the worst scenario being young men consuming meat greater than 6 -1 -1 d.wk , compared with less than 1 d.wk relative risk 5.89 (95% CI, 2.1 to 16.7). Age-adjusted -1 relative risk of fatal CHD for all men consuming meat less than 6 d.wk versus men consuming -1 meat less than 1 d.wk was 1.62 (95% CI, 1.2 to 2.1, p for trend<0.001) and for women, 1.58 (95% CI, 1.3 to 2.0, p for trend<0.001). Women under 65 years did not have increased CHD risk for eating meat. The Adventist Health Study was a prospective cohort investigation of 26,473 non -Hispanic white 124 California SDAs who were followed up for six years . Dietary information was collected at baseline in 1976, alo ng with reported cardiovascular risk factors, which did not include blood total cholesterol level. This population was well educated (33% of men and 22% of women were college graduates), were interested in diet and health, were virtually all non-smoking, had a low consumption of alcohol, and many frequently adhered to a lacto-vegetarian diet. Dietary information was collected using a semi -quantitative questionnaire of current use of 65 items. The vegetarian SDAs consumed more tomatoes, legumes, nuts and fruit and much less coffee, -1 doughnuts, and eggs than non-vegetarians, who ate meat, on average, 4.25 wk , mostly beef. Semi-vegetarians preferred wholemeal bread less than vegetarians odds ratio 0.57 (95% CI, 0.49 to 0.67), and non-vegetarians even less, odds ratio 0.15 (95% CI, 0.13 to 0.17). The odds of consuming alcohol were 22 times greater for non-vegetarians versus vegetarians, and two to 119 three times greater for semi -vegetarians .

The only tested foods associated inversely with CHD (fatal or non-fatal MI or coronary death) were nuts and whole wheat bread. Lack of energy and nutrient data (although a sub-set did gave 24-hour recall data to validate the frequency questionnaire) and primary risk factor variables, mean that at best these foods are only indicators of reduced risk. After adjusting for non-dietary risk factors and consumption of other related foods, consumption of nuts more than five times per week (highest tertile), compared with eating nuts less than once per week (lowest tertile), was associated with a relative risk for CHD death of 0.52 (95% CI, 0.36 to 0.76, p<0.0001). The relative risk for nonfatal MI was similar. Whole wheat bread consumption was associated with a relative risk for fatal CHD of 0.89 (95% CI, 0.60 to 1.33, p<0.01), compared with those who usually ate white bread. The association was stronger for non-fatal MI (relative risk, 0.56; 95% CI, 0.35 to 0.89, p<0.01). No important associations were found between risk for CHD and cons umption of eggs, fruit, cheese, fish, poultry, coffee, or legumes. There were increased CHD deaths with higher meat intakes (at least three times weekly), in men only (relative risk, 2.31; 95% CI, 1.11 to 4.78). Previous studies in vegetarians would suggest this was a low risk group with usually low SFA intakes. Sixty -nine percent of men and 54% of women exercised moderately or at a high level. In an extension of this study, Fraser et al have looked at the most elderly of this group. Foods associated with reduced CHD risk were nuts, relative risk 0.62 (95% CI, 0.45 to 0.83, p<0.001), and increased relative risk of CHD risk with eating, compared with not eating, donuts was 2.10 (95% CI, 1.15 to 3.81) and beef four times weekly, 1.97 (95% CI, 0.97 to 4), after multivariate 125 analysis and in men only . In the Health Shoppers Study , health food shoppers and members of vegetarian societies were 126 recruited in the UK in 1973-79 and followed up for mortality data after seven years . Specific information, collected from the 10,943 participants, included wholemeal bread intake to assess the effects of dietary fibre in the diets of vegetarians and other health conscious individuals. A subset of 71 subjects kept a seven day weighed dietary intake record for dietary analysis, which demonstrated 50% higher dietary fibre intakes in the vegetarian men (p<0.01) and 41% higher in 127 vegetarian women (p<0.001) compared with non -vegetarians . Wholemeal bread consumption was associated with higher fibre intakes. Observed deaths were about 50% of the expected standard mortality ratio (SMR) for England and Wales, for the whole cohort whether or not they were vegetarian or consumers of wholemeal bread. CHD mortality however, was 35.6% and 51.5% lower than the SMR for vegetarians and non-vegetarians respectively (p<0.05 for the difference). Exclusion of the first year of study results attenuated the significance. The major difference occurred in men. The second report of this study of 10,771 men and women after a mean period of 16.8 years from 1973 to 1979 found that the SMR (observed vs. expected in England and Wales) for CHD in the whole of this health-oriented cohort was 0.53 (95% CI, 0.46 to 0.60) for men and 0.46 (95% 128 CI, 0.38 to 0.55) for women . CHD mortality ratio for vegetarians compared with nonvegetarians in this cohort was 0.85 (95% CI, 0.68 to 1.06). Dietary data collected at baseline involved a simple questionnaire including frequency of consumption of wholemeal bread, bran cereals, nuts or dried fruit, fresh fruit and raw vegetable salads. A subset, reassessed 1.5 to 6 years after recruitment demonstrated that dietary habits did change during the study. After adjustment only for age, smoking and sex, daily consumption of fresh fruit was associated with significantly reduced CHD m ortality compared with less than daily consumption (mortality ratio, 0.76; 95% CI, 0.60 to 0.97), and reduced all -cause mortality (mortality ratio, 0.79; 95% CI, 0.70 to 0.90). Daily consumption of raw salad had a similarly significant reduced CHD mortality (mortality ratio, 0.74; 95% CI, 0.59 to 0.92) compared with less than daily consumption. Trends for reduced relative risk of CHD mortality for daily consumption of wholemeal bread and nuts or dried fruit did not reach significance. The Oxford Vegetarian Study was a prospective cohort study of 10,802 vegetarians, semi vegetarians and meat -eaters in the UK who were followed for a mean duration of 13.3 years, 113, 129 from 1980 to 1994 . The non-vegetarian controls were friends and family of the subjects. All subjects were not only relatively diet -interested, but they were mostly lean, non-smoking and of 36

high social class. A semi-quantitative food frequency questionnaire was completed at baseline along with informatio n about smoking, exercise, social class and self-reported height and weight. Standardised mortality ratios for CHD were 0.44 (95% CI, 0.35 to 0.56) for men and 0.46 (95% CI, 0.35 to 0.61) for women, for the entire cohort. All -cause and cancer mortality rates were also lower. In subjects with no evidence of pre-existing disease at recruitment, CHD mortality in vegetarians and vegans (eat no meat or fish) compared with meat -eaters; death risk ratio was 0.83 (95% CI, 0.48 to 1.43), and all-cause death risk ratio 1.02 (95% CI, 0.82 to 1.27). A third group, semi -vegetarians demonstrated a mortality rate similar to meat -eaters. Prior to exclusion of subjects with pre-existing CHD, the death risk ratio for CHD was 0.63, 95% CI, (0.42 to 0.93), demonstrating there is less benefit for non-CHD subjects. In an earlier analysis, when the cohort was divided into two groups, non-meat-eatersâ&#x20AC;&#x2122; (23% ate meat or fish but not more than once per week) 12-year SMR for all -cause deaths was 0.41 (95% CI, 0.35 to 0.46, p<0.01) and 0.54 (95% CI, 0.47 to 0.62) for meat -eaters (ate meat at least once per week. The SMR for CHD was 0.28 (95% CI, 0.20 to 0.28, p<0.01) for non-meat -eaters and 0.51 (95% CI, 0.38 to 0.66) for meat -eaters. The adjusted death ratio for non-meat -eaters versus meat -eaters was 0.72 (95% CI, 0.47 to 1.10) and for all-cause mortality, 0.80 (95% CI, 0.65 to 113 0.99) . The protective effects of a non -meat diet, including a 39% significant reduction in cancer deaths after 12 years follow-up, were predicted to lie in the qualities of the vegetarian diet such as high fruit, vegetable, cereal, pulses and nut intakes, rather than meat exclusion. In the 13.3 year study, the whole cohort consumption levels of the tested dietary va riables, meat, eggs, milk, cheese, animal fat, saturated animal fat, dietary cholesterol, fish, green vegetables, carrots, fresh or dried fruit, nuts, dietary fibre and alcohol, showed no associations with all-cause 129 mortality . However CHD mortality was associated with higher intakes of eggs (mean intake â&#x2030;Ľ6 -1 -1 wk or more eggs vs. <1 wk - relative risk 2.68; 95% CI, 1.19 to 6.02, p<0.01), cheese (mean -1 -1 intake â&#x2030;Ľ5 wk vs. <1 wk - relative risk 2.47; 95% CI, 0.97 to 6.26, p for trend p<0.01), total -1 -1 animal fat (highest vs. lowest tertile, mean intakes 74.8 g.d and 25.5 g.d respectively - relative risk 3.29; 95% CI, 1.5 to 7.21, p for trend p<0.01), SFA (highest vs. lowest tertile, mean intakes -1 -1 41 g.d and 14.6 g.d - relative risk, 2.77; 95% CI, 1.25 to 6.13, p for trend p<0.01), and dietary -1 -1 cholesterol (highest vs. lowest tertile, mean intakes 431 m g.d and 155.6 m g.d - relative risk, 3.53; 95% CI, 1.57 to 7.96, p for trend p<0.001). Trends for lower CHD mortality with nut and carrot intake were not statistically significant, and there was no association with other tested variables; fish, green vegetables, dietary fibre or alcohol. Although the only significant associations between CHD and foods were with eggs and animal fats, there was a trend for an association with cheese intake. The authors point out that the study group represented a wide range of fat intake which may have highlighted the significance of differences in intake on CHD -1 -1 -1 mortality. For example mean intakes for tertiles of SFA were 14.6 g.d , 27.4 g.d , 41 g.d in men in this study, whereas in the USA (male) Health Professional Follow-up Study, mean daily -1 -1 -1 -1 -1 intakes for quintiles of total SFAs were 16 g.d , 21.5 g.d , 24.6 g.d , 27.7 g.d , and 32.4 g.d 18 . In the latter study SFAs were less significantly associated with CHD than linolenic acid intakes were inversely associated. Conversely, the absence of an effect of dietary fibre or othe r potentially protective foods may be due to their less important role in populations already consuming a diet rich in cereals, fruit and -1 vegetables. In this study, median dietary fibre intake for men was 39.6 g.d in the highest tertile -1 of intake and 17. 9 g.d in the lowest. Median dietary fibre intakes in the highest and lowest -1 -1 6 quintiles were 28.9 g.d and 12.4 g.d , respectively, in the male Health Professionals Study . Studies in Norway and Germany have also demonstrated lower SMRs for individuals eating vegetarian style. In Norwegian SDAs (7,173 in number) followed from 1962 to 1986, men had a 130,132 SMR of 82 (p<0.001) . Lower SMR in vegetarian women was not statistically significant from the usual Norwegian. Since the time in life that lifestyle is most important in determining future risk remains unclear, this study looked at age of change of dietary pattern, defined as age entering the church of SDA. When subjects were stratified for less than 19, 19-34 and greater than 35 years of age on entering the church, the SMR for all CVD increased from 44 and 76 to

87 (p for trend<0.05), respectively, with mortality in the latter group being no different from the 130 general population . In the German cohort of 1,904 moderate and strict vegetarians, the observed deaths for all CVD were significantly lower than the national mortality rates, in the Federal Republic of Ger many. The SMR for men was 39, and for women 46, both significant. All cause SMRs were 44 and 53 respectively. This study suggested that lifestyle attributes of vegetarians may be as important, or more important than nutritional aspects. Duration of vegetar ianism was associated with a tendency for lower total mortality; relative risk 0.71 (95 % CI 0.49 to 1.02, p for trend =0.07), for 132 more than 20 years duration compared with less than 20 years . The five large prospective studies reported here have been meta-analysed, excluding the subjects from the Health Shoppers Study who were involved in the Oxford Vegetarian 113,123,128,131,132,133 Study . The data on 76,172 men and women included 27,808 vegetarians, defined as those who did not eat any meat or fish, was collected over 5.6 to 18.4 years. In the four studies reporting overall standardised mortality ratios for men and women combined, they were 49% in the Adventist Mortality Study, 56% in the Food Shoppers Study, 48% in the 113,123,128,132 Heidelberg Study and 46% in the Oxford Study . For all studies all-cause death rate ratio was 0.95 (95% CI, 0.82 to 1.11). Mortality from CHD was 24% lower in vegetarians than in non-vegetarians (death ratio: 0.76, 95% CI, 0.62 to 0.94; p<0.01), and were lower in men 0.69 (95% CI, 0.56 to 0.84) then women 0.80 (95% CI, 0.67 to 0.95). The lower mortality from CHD among vegetarians was greater at younger ages and was restricted to those who had followed t heir current diet for more than five years. Further categorisation of diets showed that in comparison with regular meat-eaters, mortality from CHD was 20% lower in occasional meat -eaters, less than once per week (death rate ratio, 0.80, 95% CI, 0.69 to 0.93), 34% lower in people who ate fish but not meat, 0.66 (95% CI, 0.48 to 0.90), 34% lower in lacto-ovo-vegetarians, 0.66 (95% CI, 0.52 to 0.83) and 26% lower in vegans, 0.74 (95% CI, 0.46 to 1.21). In occasional meat -eaters, fish eaters and lacto-ovo- veget arians, allcause mortality was 15% lower than for meat -eaters whereas vegans were no different from meat -eaters. Cerebrovascular mortality was not higher in vegetarians, death rate ratio, 1.06 (95% CI, 0.50 to 1.24). Since the control and comparison groups in these studies were like health-oriented individuals, they demonstrate not only that vegetarians and occasional meat -eaters have lower CHD rates than the general population, but health-interested populations, also have lower rates. Mediterranean and Asian dietary patterns

The Seven Countries Study a cross -population study, is descriptive in terms of dietary patterns 134 and researched several cultures using relatively consistent methodology . Providing the most extensive information on dietary patterns among the epidemiological studies, the Seven Countries Study has the advantage of studying differences between cohorts in different cultures and countries at one time. This was a prospective study involving 16 cohorts of men aged 40-59 years who lived in seven different countries - USA, Japan, Finland, the Netherlands, Italy, former Yugoslavia, and Greece. Dietary analysis for most of the cohorts was estimated from randomly selected sub -samples of 30-50 men in each cohort. The comprehensive dietary analysis involved seven day food records in 14 of the 16 cohorts, duplicate intake analysis and re-sampling for each season. The USA cohort was assessed with a 24 -hour recall and a food frequency questionnaire, and one of the Japanese cohorts used a four day record. The Seven Countries Study can be credited with â&#x20AC;&#x153;discoveringâ&#x20AC;? the association between the Mediterranean dietary pattern and lower incidence of CHD, and possibly cancer. The Japanese dietary pattern was also associated with low rates of CHD. The study involved five rural Mediterranean cohorts and two Japanese cohorts. One of the most important findings was that in the two cohorts with lowest 25-year mortality from CHD, Crete in Greece and Tanushimaru in Japan, SFA intakes were among the lowest, 7.7 and 2.9% of energy respectively, but whilst total fat intakes in the Japanese cohort were 9.0% of energy, in the Cretan cohort they contributed 38

14,135

36% of energy . Both dietary patterns were rich plant foods relative to animal products, when compared with Western diets. The Seven Countries Study provided information about dietary patterns because it was quickly recognised that death rates from CHD varied markedly between the 16 cohorts. After 15 years, approximately 20% of the original 11,570, apparently healthy subjects in 15 of the cohorts had 14 135 died . After 25 years, 47% of the full 12,763 men from the 16 cohorts had died . Only 56 men were lost to follow-up. Death rates at 25 years ranged from 28.8% in Finland to 4.5% in Tanushimaru, Japan and 4.6% in Crete. The different death rates between Northern Europe and USA, and Japan and Mediterranean Europe were remarkable and were correlated with blood total cholesterol. Nine cohorts were made up of rural Europeans, five of these cohorts were Mediterranean (“Med Europe”-Dalmatia, Montegiorgio, Crevalcore, Crete and Corfu) and alike in that olive oil provided from 15% to 30% of total ene rgy, animal fat intakes were low, and wine was an important part of 14 main meals supplying from 8% to 20% of energy . In contrast, four cohorts in rural Finland and former Yugoslavia (“Non-Med Europe”-East and W est Finland, Slavonia, Velika Krsna), consumed milk and meat fats as the main dietary fats and beer and distilled spirits were the alcoholic beverages, often taken outside meal times. The striking difference between these two areas in all-cause mortality (for Non-Mediterranean Europe: 2,077.6; 95% CI, 2,230.6 to 1,924.6 deaths per 10,000 healthy men at entry and for Mediterranean Europe: 1,611.5; 95% CI,1,733.2 to 1,489.8) was primarily a reflection of great contrast in the death rates from CHD (655.1; 95% CI, 748.4 to 561.1 and 284.0; 95% CI, 339.0 to 229.0 respectively). The investigators have pointed out a major limitation of this study is that the diets of some cohorts may change over the course of the study, thus diluting the differences among cohorts and importance of the different dietary factors. Repeated dietary surveys were carried out in only 136 seven of the cohorts . The rural Italian cohorts showed an increase in percent energy from animal fats, the Finnish cohort showed a trend toward a decrease i n SFAs, and the Dutch cohort showed no change. Whilst the results are not claimed as causal, the association between death from CHD and mean blood pressure, mean blood total cholesterol and percentage of dietary SFAs has been consistent from the earliest reports. In the 15-year mortality report, other fatty acids were 14 considered, highlighting differences between the dietary patterns . The MUFA to SFA ratio accounted for 44% of the variance in CHD and together with age, blood pressure, blood total cholesterol and smoking accounted for 85% of the variance. Use of the MUFA to SFA ratio separates the sources of MUFAs -animal origin relative to plant origin since MUFAs exist in lesser proportion than SFAs in anima l fats. Saturated fat intakes were lowest in the same cohorts as those cohorts experiencing lowest CHD deaths (Japanese, Greek and two of the former Yugoslavia cohorts) and were associated with death rates when the MUFA to SFA ratio was included with other risk factors in the multiple regression analysis. Oleic acid accounted for almost all of the differences in monounsaturates among cohorts and death rates were low in countries with olive oil as the main fat. There was no association found between total fat intakes and CHD deaths. Hu et al have suggested that an association between total fat and CHD is not expected when the opposing 17 associations of specific types of fat are considered . When percentage ener gy from total fat is plotted against CHD mortality, Zutphen, Eastern Finland and the USA cohort clearly have the 14 highest intakes and the highest percentage mortality . The percentage of total fat from SFAs, 135 was also highest in these three cohorts . During the 1960's food consumption data were collected from random samples of the cohorts using a food record method. In Finland the intake of milk, potatoes, edi ble fats, and sugar products was very high. A similar pattern but lower intake pattern was observed in the Netherlands. Fruit, meat and pastry consumption was high in the USA; cereal, and alcoholic drink consumption was high in Italy, bread consumption was high in former Yugoslavian cohorts except Belgrade. In Greece the intake of olive oil and fruit was high and the Japanese cohorts

were characterised by a high consumption of fish (fish and seaweed products were 27% of total food consumption), rice, and soy products. This diversity of these food consumption patterns 135 were reported to have narrowed during 25 years of follow-up . 136

Comprehensive data about 15 food groups have been published . The diversity of dietary patterns, using this information, (Table_6) demonstrates intakes in the four cohorts with lowest CHD mortality -the two Japanese cohorts and two Greek cohorts; and the cohorts with highest CHD mortality -the USA cohort, two Finnish cohorts and the Netherlands, Zutphen cohort; and a range for the Italian and former Yugoslavian cohorts (“other Med”), the cohorts with intermediate CHD mortality. Of the “other Mediterranean” cohorts, Dalmatia had rates of CHD mortality similar to Corfu. Compared to other cohorts in the “other Mediterranean” group, intakes in Dalmatia were considerably higher for fish, milk, edible fats and alcohol, while cheese was lowest for the group. Olive oil was the major source of fat in this group of cohorts. From Table_6 it can be seen that countries with lowest CHD mortality (Ushibuka, Tanushimaru, Crete, and Corfu), have high cereal/bread intakes, consistently high vegetable int akes, significant legume and alcohol intakes but variable intakes of fruit, fish and edible fats. It is difficult to assess which combination of foods might be optimal as they clearly interact. For example do fish and legumes make up for lack of fruit in Japan, or fruit make up for a high olive oil diet, or olive oil counteract a high milk intake in Crete? Or do olive oil and alcohol simply provide harmless energy? The source of edible fats is clearly important, and in Northern European cohorts this was lar gely dairy fat. The type, refining and GI of cereals and bread may 137 also be important since CHO is a large proportion of food intake . Highest grain intakes occurred in poorer regions. Fish intakes in Eastern Finland were not protective but may have 20 contributed excess mercury or been counteracted by high dairy fat intakes . In Crete, intakes of fish were less, and milk and olive oil intakes greater, than in Corfu, although CHD mortality was lower. Not all Mediterranean countries use olive oil exclusively. France uses 7,138 little olive oil, using mainly seed-oils while in Spain less than 50% of the oil supply is olive oil . Household budget surveys show that in Spai n consumption of olive oil declined 23% while other oils and fats increased by 21% from 1981-82, to 1990-91, and since 1976 a decline on CHD 139 mortality has been observed, although other factors are contributory . Olive oil consumption increased by 41% in Italy from 1981-82, to 1990-91, while butter and animal fats declined 81% and CHD mortality has had an accelerated decline since the 1980's.

Summary Prospective cohort studies clearly demonstrate a relationship between reduced CHD mortality and eating fish or lacto-vegetarian diets among population groups who voluntarily choose to exclude meat and poultry from their diets. Vegan and semi -vegetarian diet consumers tend to experience a risk between that of lacto-vegetarians and meat -eaters. Cross -sectional studies indicate that individuals who consume vegetarian diets also demonstrate more favourable blood lipid and lipoprotein profiles, lower blood pressure, body weight and their blood LDL-C appears less susceptible to in vitro oxidation, and that their nutrient intakes and parameters of nutritional status are as adequate as those of meat -eaters. Their diets may be improved in essential micronutrients and plant food constituents compared with diets of meat -eaters, and are typically low in SFA, rich in dietary fi bre, oligosaccharides, phytochemicals, folate and unsaturated fats. Traditional Mediterranean and Asian dietary patterns practised in certain populations have been associated with reduced rates of CHD mortality and have many factors in common with vegetari an diets. Together with a low meat content they are rich in fruit, vegetables, grains, and cereals or bread, with a moderate content of legumes and/or nuts or seeds, dairy products and/or fish. The evidence for reduced risk associated with Mediterranean and Asian dietary patterns is weaker than that for vegetarian diets and is so far confined to inter-population, and inter-country comparisons. The only inter -individual comparisons are nutrient -based, single food studies or comparisons of dietary diversity.

Table 6. Comparison of food intake patterns in the Seven Countries cohorts*. Food intake of population cohorts (g.d-1)**

Food group Ushibuka

Tanu

Crete

Corfu

Other Med

USA

EFin

WFin

Zutphen

Bread

380

450

244-790

380

356

252

Cereals

449

497

29-170

Bread and cereals

459

502

410

495

294-823

451

455

269

Potatoes

190

150

30-214

124

273

296

252

Legumes

103

7-49

Vegetables

222

174

191

115-260

171

108

104

227

Fruits

464

462

1-200

233

All fruits and veg

317

398

875

833

166-580

529

422

442

563

Leg/fruits/veg

283

303

685

683

138-445

405

149

146

311

Meat

70-226

273

105

107

138

Fish

207

0-96

Eggs

19-51

Cheese

4-203

Milk

235

8-434

231

1192

1090

447

Edible fats

28-88

Sugar products

1-54

101

Pastries

0-12

100% alcohol

5-79

Adapted from Kromhout et al136 .

Cohorts: Ushibuka and Tanushimaru: Japan, Crete and Corfu :Greece, Other Med : includes three Italian and six former Yugoslav cohorts, USA: United States railroad, EFin :Eastern Finland, WFin : Western Finland, Zutphen : The Netherlands.

leg

Legumes.

veg

Vegetables.

Case-control or cross-sectional studies of dietary patterns and coronary heart disease risk Case-control and cross-sectional studies have specific problems when the tested exposure is dietary. In free-living populations absolute intakes of nutrients are positively correlated with total 4 energy intake and with each other and other non-nutrient constituents in food . Dietary variables may represent non-dietary variables such as physical activity, socio-cultural issues and environmental factors which are not easily controlled for. A further confounding factor is that a single dietary survey may measure recently altered dietary patterns due to diagnosis, treatment 24 140 or risk prevention . Change in diet confounds the cross -sectional association . Such studies lack the accuracy of prospective cohort studies when dietary exposure is assessed prior to onset of disease outcome. They do, however, represent the free-living population without significant entry -t o-study effects, but largely rely on self-reported dietary intake.

Cross-sectional studies, risk and risk factors A number of cross -sectional studies have studied the relati onships between dietary factors and risk factors of CHD. Studies in general have observed nutrient associations rather than other aspects of diet. Caggiula and Mustad have reviewed epidemiological studies of the effects of 55 dietary fat and fatty acids on CHD risk . Studies finding nutrients positively or inversely associated with CHD risk factors are summarised in Table_7.

In general the associations have been weak and inconsistent. Cross -population studies are more likely to show associations than intra -population studies. Dietary differences within a population can be quite small compared with cross -cultural differences between populations. The small differences in effect between all fatty acids, for example in demonstrating an association between PUFAs and blood total cholesterol, may be due to the narrow range of intake, or result from confounding because all high fat foods are likely to have a high content of all fatty acids or 62 SFAs may dominate . The established association between SFAs and dietary cholesterol in RCTs is found in cross 141 sectional analysis of cross -population studies . In the Seven Countries Study individual dietary 134 patterns and genetic backgrounds were highly variant . In the Japan-Honolulu -San Francisco Study subjects were genetically similar but dietary intakes were diverse, and in the cross -cultural comparison between Taipei Chinese and Framingham Americans, both genetics and diet were 142,143 diverse . In four regions of the UK very small differences in genetics and nutrient intake were 144 insufficient to explain differences in CHD risk factors . The combined data for the Seven Countries Study found positive associations between total and SFA intakes and blood total cholesterol concentrations. The Japan-Honolulu-San Francisco Study found that men in the lowest quintile of blood total cholesterol had lower mean intakes of animal protein, S FAs and 142 dietary cholesterol and higher intakes of complex CHOs . In the Taipei-Framingham Study, the 1990 age-standardised CHD mortality rate in newly industrialised Taiwan remained low at 70 per 100,000 while the USA CHD mortality rate was 156 143 per 100,000 . Twenty -four hour recall assessments demonstrated that Taipei urban workers consumed 8% more CHO and 9% less fat as a percentage of energy than Framingham subjects and SFA to MUFA to PUFA intakes (percentage of energy) were 9:13:13 and 16:15:8 respectively. These are substantial differences in P:S ratio, 1.4 and 0.5 respectively. After adjustment for body size, these nutrient intake differences were associated with significantly -1 -1 lower mean blood total cholesterol levels, 5.1 mmol.L and 4.99 mmol.L for men and women -1 -1 respectively in the Taipei workers and 5.38 mmol.L and 5.25 mmol.L in Framingham subjects -1 -1 -1 -1 and lower LDL-C levels: 3.18 mmol.L and 2.95 mmol.L , and 3.57 mmol.L and 3.26 mmol.L respectively. The Taipei diet was characterised by rice and rice products, together providing the highest contribution to total energy (29%) and 47% of CHO intakes. Pork products contributed the most animal fat and were the s econd highest contributor to PUFA intakes after soybean oil used for cooking. Soybean oil contributed 11% of energy. Fruits and vegetables provided the highest source of fibre. Plant sources provided 67% of energy, 46% of protein and 51% of fat intakes. In abstracting case-control data from a cross -sectional study, researchers reporting the Scottish Heart Study have separated subjects who were previously diagnosed or not diagnosed with CHD at recruitment, to explain why studies may give results converse to those expected as a result of 145,146,147 diagnosis . Undiagnosed subjects comprised 6% and diagnosed subjects 14.5%, in this population of 10,359 subjects. Differences between extreme quintile odds ratios showed that men in the diagnosed CHD group had significant ly lower energy, protein and SFA intakes and increased PUFA intakes and P:S ratios than the undiagnosed CHD group (all p<0.01) who had higher energy and alcohol intakes. These results suggest that diagnosed men had better diets. For women the differences between quintile odds ratios were significant only for reduced alcohol and increased P:S ratio in the diagnosed group. Contrary to expectation dietary fats including SFA and trans -unsaturated fats intakes were not 146,147 associated with CHD in the undiagnosed sub jects . However the chance of being an undiagnosed CHD subject was significantly lower in the highest versus lowest quintiles of Î˛carotene, dietary fibre and vitamins C, E and A intake in men, but in undiagnosed women the risk was lower only with higher fibre intakes. Higher nutrient densities for vitamins C and E, and dietary fibre (opposite trends) were observed in the odds ratios for having a previous CHD 146 diagnosis in men, but not women, further supporting that the men had improved their diets . The Atherosclerosis Risk in Communities (AIRC) Study found that in 9,750 white American and 3,400 African American men and women, carotid artery wall thickness was associated positively

with intakes of animal fat (p<0.0001 and p=0.009 for white women and white men respectively), SFA (p=0.006, p=0.66) and Keys score (p<0.0001, p= 0.083) and cholesterol (p<0.0001, p= 0.076) while intakes of vegetable fat (p=0.004, p=0.001) and PUFAs (p=0.095, p=0.056) were 148 inversely associated. These associations persisted for both sexes and both races . Erkkila and Sarkinen et al analysed correlations between dietary variables and blood lipid concentrations in 49 men with coronary bypass, 46 with balloon angioplasty, and 79 with acute 149 MI and 79 with acute myocardial ischaemia who were not using lipid lowering medications . Fatty acid composition of blood cholesteryl esters was used as a bio-marker of dietary fat quality. Blood lipids were not associated with reported intakes of total, SFA, PUFA or MUFA intakes. Use of soft margarines (not hard margarines) on bread , high intakes of fibre, cereal products and wholegrain products were associated with lower blood total cholesterol (p<0.05, p<0.05 and p<0.01 respectively for lowest versus highest quartile of intake). Cholesteryl ester content of linoleic acid was inversely associated with blood total cholesterol (correlation coefficient, r= 0.144, p= 0.026) and TG (r= -0.189, p= 0.004) levels, the EPA proportion was inversely associated with TGs levels (r= -0.209, p= 0.001) and positively with HDL-C levels r=0.175, p= 0.007), and low oleic acid was associated with lower TG levels (r=0.259, p<0.001). This may be the first study to address the question of whether use or no use of fat spreads on bread has benefits for blood lipid levels. Blood total cholesterol concentrations were higher in -1 -1 non-users (mean 6.79 SD 1.13 mmol.L ) and butter users (mean 6.51 SD 1.31 mmol.L ) than in -1 margarine users (mean 6.18 SD 1.06 mmol.L ), p=0.0005 ANCOVA and LDL-C tended to be higher, p= 0.074 ANCOVA, but no information was given about total fatty acid intakes or the percentage of total fat as spreads. Comparison of quartiles of intake demonstrated that blood total cholesterol and HDL-C were -1 higher in individuals consuming less than 69 g.d of wholegrain cereals compared with greater -1 than 147 g.d (p<0.01, p<0.01 respectively), and blood total cholesterol and LDL-C were higher -1 -1 in consumers of less than 153 g.d of cereal products vs. greater than 254 g.d p<0.01, p<0.05). -1 Higher vegetable intakes were associated with lower TG levels less than 183 g.d versus greater -1 than 239 g.d (p<0.05). In the Italian Nine Communities Study (4,903 men and women) increased intakes of butter and margarine were associated with significantly higher blood pressure, blood total cholesterol and 150 blood glucose levels in men but only with blood glucose in women (all p<0.001) . In both sexes use of olive or PUFA oils was inversely associated with blood total cholesterol, SBP and blood glucose levels (p<0.001 except for SBP in women p<0.01). Levels of fat intake were not reported, and butter and margarine use was not separated in the analysis. Margarine was apparently similar in SFA content to butter, (â&#x20AC;&#x2DC;stickâ&#x20AC;&#x2122; or hardened margarine) and only 50% of the study population were users. Olive oil was used by a large percent but not for cooking, whereas PUFA oils were used mostly for cooking. Migrant populations either adopting the dietary patterns of their new environment or continuing their traditional patterns have been studied. Japanese men living in Hawaii, shown to have diets different from the traditional Japanese diet, consumed double the percentage energy from total 142 fat and triple the SFA intake and 70% of the percentage energy from CHO . Fat and SFA intakes were positively and CHO inversely, associated with blood total cholesterol levels (simple correlation coefficients were significant at 0.01 for each of these associations).

Table 7. Cross-sectional Studies. Nutrients and foods associated with risk factors. Trial, year published, subjects

Total fat and TC

SFA and TC

SFA and LDL-C

APRO and TC

Fibre CHO and TC

CHO and HDL-C

VPRO and TC

Unsat fat and TC

-ve

Caerphilly Study, 1988, 653 151 men Japan/Honolulu, San Francisco Study,1973 in Japan, 1,717 men

+ve

-ve

Hawaii, 7,949 men

+ve

-ve

+ve

California, 178 men

+ve

-ve

Scottish Heart Health Study, +ve 1991, 5,123 men, 5236 145 146 147 152 women Framingham Nutrition +ve +ve Studies 3 rd exam,1996, 153 1,422 women Framingham original cohort, +ve 154 1962, 413 men +ve Positive association. -ve Negative association. NA Tested but no association found. APRO Protein from animal food sources. VPRO Protein from plant food sources.

-ve

+ve

-ve

Other case-control/cross-sectional studies relating foods with risk factors Gramenzi et al, in an Italian hospital case-control study have compared the dietary habits of 287 women who had a MI with those of 649 controls who had acute traumatic disorders unrelated to CHD, using a food frequency questionnaire to measure weekly consumption of ten specific 155 foods . The age-adjusted risk of acute MI was significantly associated with frequency of consumption of meat (odds ratio 1.5 for upper vs. lower tertile of intake), ham and salami (1.4), butter (2.3), added fat (1.6) and coffee 2.8, and significantly inversely associated with fish (0.6), carrots (0.4), green vegetables (0.6), and fresh fruit (0.4) (no confidence interval reported). Adjustment for risk factors changed the relative risk for coffee to 1.8, and reduced the significance of meat. Adjustment for key nutrients reduced the significance of all associations excepting for carrots, ham and salami, and added fat however the multiple logistic regression 156 used for collinearly between several factors is known to be difficult to interpret . Huijebregts et al have used cluster analysis to aggregate 518 elderly men in the Zutphen Study into four groups, characterised either by high alcohol intake, high meat consumption, healthy diet 5 pattern, or high intake of refined sugars . The healthy diet pattern was identified as higher intake of bread, cereals, potatoes, legumes, vegetables, and fruit and lower intakes of meat, fish, eggs, cheese, milk products, edible fats, and sugar. The healthy diet was associated with more favourable levels of cardiovascular risk factors at old age but these were not statistically significant. The alcohol cluster had significantly higher HDL-C levels but a trend to more hypertension. Cross-sectional analysis of secular trends has shown that expected reductions in blood total cholesterol due to observed reductions in total fat intake and Keys score, were consistent with observed reductions in blood total cholesterol concentrations in the Framingham Study, between 157,158 1966-69 and 1984-88, and in the Minnesota Heart Study, between 1980-82 and 1985-87 . In the Framingham Study the two periods of data were collected from the original Framingham Heart Study cohort and the Framingham Off-spring -Spouse Study. The latter group were asked about changes to their diets in the previous 10 years. A change in eating habits â&#x20AC;&#x153;to be healthierâ&#x20AC;? was reported by 63% of women and 56% of men. Forty to 50% of men and 45% to 60% of 44

women, had reduced red meat, eggs, whole milk, butter, and salt over the 10 years; 50% had increased fish and poultry intakes and around 40% of men and 50% of women had increased vegetable and low fat milk consumption. Sixty -five percent of men and women had not changed cheese intakes, 45% had not changed stick (hard) margarine consumption and 25-30% had not changed soft margarine consumption (around 40% did not use soft margarines, 29% did not use stick margarine), 50-60% did not change fruit or vegetable intake, and 40 -50% did not change whole grain or baked goods intakes. Less than 6% of men and women had increased red meat, whole milk, eggs, butter, commercial or home-baked goods, or salt. Framingham subjects who reported modifying their dietary pattern were more likely to achieve -1 the NCEP criteria for dietary lipids and blood total cholesterol concentrations (<6.2 mmol.L ). From 1966-69, through to 1984-88, dietary intakes of cholesterol had declined 30-50%, but reductions in macronutrient and fatty acid intakes, although statistically significant were very small (1-2% of energy) despite reductions in blood total cholesterol and LDL-C, SBP and DBP and cigarette smoking, although prevalence rates of overweight and hypertension had increased. Recommendations for dietary total fat were achieved by 20% of subjects and for SFAs 25%. A further survey from the Offspring Study, between 1991 and 1995 reported that 70% or more of participants now conform to dietary guidelines for protein, MUFA and PUFAs, cholesterol, 159 alcohol and vitamin C and vitamin B12 . Fifty percent or fewer conformed to guidelines for CHO, total (37%) and SFA (43%), fibre (28%), Î˛-carotene , vitamins A, vitamin E and vitamin B6, calcium and sodium with some gender differences. Comparison of median values with the mean values of the previous report suggest substantial changes in dietary patterns, as evidenced by fat and CHO intakes, toward those recommended. Since dietary recommendations for more than 40 years (AHA 1950's) have included reducing fat intakes, dietary patterns associated with a low-fat diet have been investigated in the USA 160 National Health Examination Follow-up Study . This study of 10,306 individuals in the general population used a food frequency questionnaire, nutrient analysis and division of percentage of energy from fat into quartiles. The cut -points for each quartile were 29.7%, 33.5% and 37% of -1 -1 -1 energy from fat, representing approximate mean intakes of 40 g.d , 50 g.d , 60 g.d and 70 g.d 1 of fat from lowest to highest quartiles. The associations between fat and nutrient and food group intakes were evaluated. The researchers found it was important to divide food groups, such as dairy products into low fat and high fat sections. The lowest quartile of percentage energy from fat was associated with greater intakes of vitamin C, percentage of energy from CHO, dietary fibre, poultry, low-fat dairy products, fruits, vegetables, cereals, and whole grains and lower intakes of protein, total fat, SFA, oleic and linoleic acid, cholesterol, sodium, all red meats, high-fat dairy products, eggs, nuts, white breads, fried potatoes, desserts, fats and oils. Median intakes of all red meats, high fat dairy products, nuts, white bread, fried potatoes, desserts, and fats and oils were approximately 100-300% higher in the high-fat quartile, while intakes of low-fat milk, poultry, proportion of white meat, fruit, yellow-red vegetables, cereals and whole grain were approximately 40-100% lower in the high fat quartile.

Summary Cross-sectional and case-control studies further support the associations found between components of dietary patterns and CHD in prospective cohort studies. Blood lip id concentrations are adversely associated with intakes of animal products, SFAs, cholesterol and Keys score and beneficially associated with dietary fibre, unsaturated fatty acid products and plant food intakes. Blood pressure and TG levels have been studied less, but in general are inversely associated with dietary patterns conforming with dietary guidelines. Altering dietary patterns can improve risk factors and the micronutrient density of energy intake.

Population trends and cardiovascular disease Die tary patterns, national food consumption patterns, disease and risk factors

Since changes in dietary lipids have been shown to precede increases and decreases in mortality from CHD, the observation of changes in dietary patterns within countries and subsequent change in CHD mortality, may identify positive or detrimental changes in dietary patterns associated with rates of CHD. The results of observations generated from statistical information collected within communities or countries may initiate valid hypotheses for testing in that particular population. Population differences

Recognition that France and Finland have had widely disparate CHD mortality rates, yet similar SFA and cholesterol intakes has been known since the 1950's and led to the concept of t he 161 â&#x20AC;&#x153;French Paradoxâ&#x20AC;? . Another apparent paradox, the low CHD rates in the Inuit groups of the Arctic despite high total fat and dietary cholesterol intakes, can be explained by a high P:S ratio in their largely marine origin diets. In attempting to explain the French Paradox, Artaud-Wild, Connor, Sexton and Connor have studied the relationships between CHD mortality and forty dietary variables in middle-aged men 62, 162 from forty countries that could supply CHD mortality rates and food supply data . After univariate analyses 20 dietary variables had significant positive associations, nine had inverse and 11 no association with CHD mortality. The associations were expected: negative correlations occurred with energy from plant foods or nutrients predominating in plant foods (CHO, starch, fibre, folic acid, vitamin E) and iron; and positive associations were from animal foods (r=0.79, p<0.001) and total fat or nutrients associated with animal foods (mainly milk and meat, calcium, MUFA and SFAs, cholesterol SFA index, and alcohol and sodium). No association was found for PUFAs, sucrose, fish, wine, vitamins C and A, niacin, magnesium, potassium or cheese but when France and Finland were excluded, cheese was positively correlated with CHD. The association of the cholesterol SFA index was significant for the forty countries (r=0.78, p >0.001) but France and Finland were significant outliers. The associations with milk, milk protein and milk calcium were strongest (r= 0.76, 0.77 and 0.83 respectively, all p<0.001) and France and Finland conformed with the correlation. The strongest inverse correlation was with calories from vegetable foods (r= -0.80, p<0.001). After adjustment for cholesterol and dietary fat, milk and butterfat remained correlated with CHD mortality, percentage energy from total, MUFA and PUFAs emerged as negatively correlated, and alcohol became unrelated. These factors were suggested as explanation for the five -fold CHD mortality difference between France and Finland. In Finland, intakes of milk were 3.4 times that of France, butterfat 1.5 times, and intakes of olive and peanut products 0.03, liquid vegetable oils 0.13, and vegetable intakes 0.23 those of France. Further analysis of the 18 countries with high cholesterol and SFA intakes demonstrated a possible inverse association with alcohol and wine but in the 22 countries with lower cholesterol and SFA intakes, alcohol, wine, total fat, and PUFA and MUFAs lost their association with CHD mortality but omega-3 PUFAs became inversely associated (r= -0.55, p<0.01), while other associations, particularly those with dairy foods, remained unchanged. Law and Wald propose that there is a lag effect, between exposure and evidence of disease that explains some of thes e 162 differences . These observations associating dairy products with CHD are supported by inter-population observations by Turpeinen in 22 countries, in two regions of Belgium, but not in one of three regions of France where butter intake was lower, and plant food and oil intakes higher in the 163,164,165 higher cheese consumption area . These population differences highlight that the atherogenicity of dietary patterns cannot be defined by dietary SFA and cholesterol content alone. 46

Secular trends Finland 166

In the early 1970's, Finland reported the highest rates of CHD in the world . Between 1972 and 1992, CHD mortality has declined by 55% in men and 68% among women. About three quarters of this change has been explained by changes in the main risk factors, in particular changes in blood total cholesterol. From 1972 to 1992, cardiovascular risk factors were surveyed in several 167,168 areas of Finland and from 1982 to 1992 dietary information was also collected . Earlier 169 diet ary information is available from a dietary survey carried out in 1969-72 . The province of North Karelia had reported the highest rates of CHD, and in 1972 a community based programme for the prevention of CVD was launched. This programme is believed to have had influence over greater Finland. Health campaigns throughout the country utilised the North Karelia experience, and health and catering personnel, and the food industry were heavily involved. The total fat content of the Finnish diet changed from 38% of energy to 34% of energy, SFAs from 21% to 16%, and PUFAs from 3% to 5% and intakes of dietary cholesterol decreased by 16%, from 1972 to 1992. A shift from boiled to filtered coffee has also occurred. The authors calculated that these changes could be predicted to have caused the 13% decrease in blood total cholesterol levels of men, and 17.6% in women, from 1972 to 1992. Fruit and vegetable intakes have increased two to three fold at the same time and supplementation of fertilisers with selenium has tripled selenium intakes since 1985. Dietary questions were mainly qualitative or frequency questions, but consumption of milk, coffee, tea, bread and amount of spread used on bread were assessed quantitatively. Substantial changes have occurred in use of high-fat milk (75% of men and women in 1972), and 15-25% of most population groups were consuming skim milk (0.05% fat) by 1992. Type of fat used on bread changed from more than 80% of men and women using butter on bread in Eastern Finland in 1972, to only 22% of men and 14% of women using butter in North Karelia in 1992 and only 9% of men and 8% of women in Helsinki. There has been increased use of soft vegetable margarines and butter -oil mixtures but by 1992, 22% of men and 27% of women in North Karelia were using new low fat spreads (40% fat), and 25% of men and 27% women in -1 -1 Helsinki. Amount of fat used on a slice of bread also decreased, from 9 g.sl to less than 5 g.sl in North Karelia from 1972 to 1992. In Helsinki, 9% to 13% of men and 14% of wom en used no 168 spread on bread by 1992 . National food balance sheets show that consumption of butter in 1992 was one third that of 1970 -1 -1 -1 -1 -1 -1 (15 kg.capita .yr to 5 kg.capita .yr ). Cheese consumption has increased (5 kg.cap ita .yr to -1 -1 around 13 kg.capita .yr ) and total table margarines have remained stable for the 22 years although their composition has changed. Meat consumption increased until the mid-1980's and has been declining since, the major meat consumed is lean pork. -1

-1

One of the major changes has been the increasing consumption of vegetables (20 kg.capita .yr -1 -1 -1 -1 -1 -1 to over 50 kg.capita .yr ) and fruit (45 kg.capita .yr to nearly 90 kg.capita .yr ) - almost 400 -1 -1 g.capita .yr of fruit and vegetables. Sugar reduced in the 1970's and has remained stable.

Over 90% of the population drink coffee, traditionally boiled coffee, but by 1992 only 15% drank -1 boiled coffee. Finland has moved from being a country of high salt intake (14 -15 g.d ) to one of -1 -1 average salt i ntake (men 12 g.d and women 8-9 g.d ), and there are now legislative limits on salt content for many processed foods, including breads, and even categories of â&#x20AC;&#x153;heavily saltedâ&#x20AC;?. The food industry has been pro-active in producing low fat products. Price reduction of fruits and vegetables and introduction of a free salad have aided increases in fruit and vegetable consumption. The authors concluded that dietary changes appear to explain the changes in blood total cholesterol and that together with a decline in smoking among males, and a decline in blood pressure, have contributed to the dramatic decline in CHD mortality in Finland. In Finland, 47

mortality rates and SFA consumption remain high relative to other countries and the food and 168 nutrition policy continues its efforts to improve the dietary pattern . United States of America

In the USA, from the mid-1980's, nutrition education and health promotion programmes have focused on chronic disease prevention, and by the 1990's firm national guidelines for the dietary 170 prevention of cardiovascular risk factors were in place (NCEP, USDA, Surgeon General ), with 171 quantitative guidelines for total and SFA and cholesterol intakes . These federal level guidelines converged with messages sounded for several decades by the AHA and American Cancer Society. Together with a change in Federal Trade Commission Policy in the 1980's allowing “health messages” in advertising of food products and in 1994 the implementation of the Nutrition Labellin g and Education Act these guidelines may have contributed to population dietary changes. Reported total fat and SFA intakes as a percentage of total energy have been declining over the 172 past 30 years according to the USDA Surveys of individuals for selected sex and age groups . On a relative basis, however, SFA has declined less than has total fat intake. Whilst household and individual surveys of the USDA have changed their methodology over time, a 24 -hour recall method has remained a consistent technique for assessment of individual dietary intake throughout these surveys. From 1965 to 1995, fat as a percentage of energy dropped from 41% to 43% of energy for males and females to 41.5% and 37% for males and females respectively in 1985, to 32% to 34% of energy for both sexes in 1995. Saturated fat intake data available only from 1985, was reported as 13.5% of energy and dropped to around 11% by 1995. Lichtenstein et al conducted additional analyses to ascertain how the underlying food patterns in the Americ an population have contributed to these changes using the 1995 USDA’s Continuing 172 Survey of Food Intake by Individuals (CSII) . The authors used “low fat” to describe individuals meeting the 1995 USDA/HHS dietary guidelines for less than 30% of energy from fat, and “high fat” for those consuming diets providing greater than 30% energy from fat. Reported -1 consumption was 59 versus 116 g.d of fat consumption for the two groups respectively for men -1 -1 -1 -1 and 27 g.d and 41 g.d for women. Daily SFA intakes were 19 g.d and 40 g.d for low and -1 -1 high fat consuming men and 14 g.d and 27 g.d , respectively, for women. Individuals of all ages consuming less than 30% of energy from fat reported consistently lower energy intakes. Lower dietary fat intakes occurred in parallel with lower SFA intakes. Fat modified foods play a more important role in the diets of individuals reporting less than 30% energy from total fat and less than 10% energy from SFAs. Fruit intake was dramatically hi gher in individuals consuming low fat diets and grain intake was higher. Milk product consumption is only slightly higher in the low fat consumers but low fat dairy consumption contributes more to dairy intake than for the high fat consumers. The data suggested that some dietary patterns appear key to effective fat reduction, fruit, grains and low fat milk being three food items found routinely in low-fat diets in this Western population. The authors conclude that it would be a mistake to equate all low fat diets with nutritionally optimal diets and that the type of fat reduction strategy followed by any individual has implications for the ultimate quality of the diet. Since the early 1960's the periodic health examinations surveys of the USA population, conducted by the National Centre for Health Statistics, have included monitoring trends in blood total cholesterol. In the National Health and Nutrition Examination Survey in 1971 to 1974 (NHANES I), continuing through to NHANES III, 1988 to 1994, dietary intake data have been collected by 24-hour recall. National Health and Nutrition Examination Surveys are a series of cross -sectional health 171 examination surveys . Since 1972 all dietary lipids as a proportion of energy have moved in a favourable direction. From 1972 to 1990 respectively, age -adjusted intakes of total fat as percentage of energy dropped from 36.4% to 34.1%, and SFAs as percentage of energy, from 13.2 to 11.7% (a 1.5% decrease), most of the changes occurring between 1978 and 1990

(intakes were 40% of intake in the 1960's). Polyunsaturated fats increased 1972 through to 1990 from 4.3% to 7.1% of total energy (a 2.8% increase). -1

-1

Blood total cholesterol levels dropped 0.23 mmol.L from 1972 to 1990, 0.21 mmol.L occurring -1 from 1978 to 1990, final value 5.3 mmol.L . Prediction equations using Keys and Hegsted equations, and the dietary changes for all persons were similar in magnitude and direction as the observed blood total cholesterol changes. Information collected from NHANES II and NHANES III 171 indicate that this decline was entirely due to changes in LDL-C . Between 1960 and 1990, age adjusted mean blood total cholesterol concentrations for USA adults fell from 5.69 to 5.30 -1 173 mmol.L . Ernst et al also compared per capita supply of foods in three food categories that have been major sources of fat and cholesterol in the national food supply, with the reported national intake 171 data . Between 1970 and 1990, there was a significant and steady substitution of low-fat milk and skim milk for whole milk, an increase in yoghurts most of which is low fat, while cheese, half and half, light cream, sour cream and dips increased. There was a trend to more poultry and fish consumption with no increase in meat consumption. The major change in fat available in the food supply was in type of fat, primarily due to increases in MUFA and PUFAs from vegetable sources. These reports are consistent with an extraordi nary improvement in cardiovascular mortality during this time, to which dietary changes may have contributed. Progress in heart disease research has been credited with a 32% decline in age-adjusted death rates for CHD and 27% for 171 stroke over the past decade . Between 1973 and 1993 the combined death rates for all CVDs 174,175 declined by 45% . These data have not reported trans -unsaturated fatty acid intakes although during the time of this reduction in CHD mortality, there has been considerable substitution of hardened vegetable fats for SFAs. Norway

Coronary heart disease mortality in Norway increased dramatically between 1945 and 1970, and has since declined. Johanssen et al have compared national food supply data, household budget 176 surveys and trends for CHD mortality for the past century . The food pattern data was translated into nutrients by use of a food composition table adjusted for changes in the food supply such as changes in the fatty acid composition of margarines and the leanness of pork. From 1890 to 1975 the energy percentage of fat in the national food supply increased from 20% to 40% and then decreased to 34% by 1992. Household consumption data showed a similar trend, however dietary fat increased more in urban areas compared with rural areas. The peak in dietary fat consumption may have occurred intermittently between 1950 and 1975, but the two methods vary. The dietary fatty acid pattern, however has changed considerably. Polyunsaturated fats accounted for 15% of total fat in 1900, decreasing to 10% in 1950 and increasing after this to 17% by the 1960's. Hydrogenation of oils for margarines started in 1913 when trans -unsaturated fat intakes would be very low. Estimated trans -unsaturated fat intakes increased to 4% of energy in 1958 and decreased to 3% of energy by 1990. Changes in consumption and composition of margarines had a marked influence on the fatty acid pattern of the diet over the past century. Today margarine contributes 20% of SFA, 40% of PUFA and 80% of trans -unsaturated fat intakes of Norwegians. Other dietary factors identified as improving recently in the Norwegian diet include, increased fruit, juice and vegetable intakes as evidenced by improved vitamin C intakes over the past 40 years, reduced c onsumption of boiled coffee since the 1950's, and improvement in selenium status with importation of wheat for 50 years, consumption of fish oils and intermittently high -1 -1 consumption of fish. Current fish consumption is reported as 40 g.person . d . The peak mortality from CHD in Norway occurred in the 1970's, and the peak in estimated blood total cholesterol levels in the 1950's, even earlier in urban areas. During 1971 to 1993 mortality

of CHD dropped by 43% in men and 29% in women aged 50-59 years. Cholesterol levels have now decreased to levels similar to those reported early in the century. The changes were reportedly consistent with theories of a five to 10 year time lag between changes in diet and blood total cholesterol and effects on CHD mortality. This Norwegian data suggests that despite CHD being of multifactorial causation, changes in dietary lipids can explain a great deal of the change in CHD mortality during this century. Other aspects of the dietary pattern such as those contributing to increased intakes of antioxidants and reduced boiled coffee intakes, may also contribute to reduced CHD mortality over the past 20 176 years . Japan

Thirty years ago, the Seven Countries Study documented the outstandingly low concentration of fat in the average Japanese diet in relation to the diet of the Western industrialised nations at that time. Other studies compared individuals of Japanese descent in Tokyo, Hawaii and San Francisco to emphasise the unfavourable role of diet ary fats on CHD and cancer in populations 177 with minimal genetic variance . Japan went through a period of accelerated growth from 1950 to 1970. The Japanese diet has 8 increased in fats and sugars but has also become more diverse . The dietary pattern in Japan, is apparently becoming more like that of the USA, the Japanese living in Japan becoming migrants of time with changed patterns of macronutrient consumption and resultant health 177 consequences . Whilst the reversal of CHD rates seen in Finland, Norway and the USA may be due to many factors, medical research and improved health care included, in Japan the increases in CHD and other chronic diseases cannot be attributed to genetics or poorer health care. The changing dietary patterns in Japan provide valuable insights into outcomes of differences in lifestyle. Already Japan has seen dramatic reductions in cerebral bleeding and cerebrovascular disease from 216 and 283 deaths respectively, per 100,000 population in 1960 to 31 and 112 per 177 100,000 in 1985, after a nationwide effort to reduce the very high average salt intakes . Coronary heart disease rates have increased from 36 to 41 deaths per 100,000 population in that time. -1

-1

In 1910 the daily per capita macronutrient intake in Japan consisted of 430 g.person . d of CHO -1 -1 -1 -1 (rice and beans), 13 g.person . d of fat, and only 3 g.person . d of animal protein. By 1989 -1 -1 -1 - 1 daily intake of CHOs had dropped to 190 g.person . d , fat intake rose to 59 g.person . d , and -1 -1 animal protein rose to 42 g.person . d , while salt intake dropped from an estimated 30 g.person 1 -1 -1 - 1 .d to 12 g.person . d . The traditional dietary patt ern, described as â&#x20AC;&#x153;rice (with salt) accompanied by soybean soup and pickled vegetables with some fish and shellfishâ&#x20AC;? has been replaced by a new Japanese eating style (described by the Ministry of Agriculture, Forestry and Fisheries), of â&#x20AC;&#x153;small servings of boiled rice, with addition of meat, fish, vegetables and milk. The Japanese diet now includes milk and dairy products, red meat, poultry, eggs, fruit and fresh 8 vegetables . -1

-1

As recently as 1955, the Japanese diet was based on cereals, 156 kg.capita .yr (66% of -1 -1 energy), predominantly rice, which has now declined to 101 kg.capita .yr (36% of energy). -1 -1 -1 -1 From 1955 to 1994, meat consumption increased from 3.3 kg.capita .yr to 30.6 kg.capita .yr , -1 -1 chicken consumption increased 35 fold, milk and dairy products from 12 kg.capita .yr to 89 -1 -1 -1 -1 -1 -1 kg.capita .yr , eggs from 3.4 kg.capita .yr to 18 kg.capita .yr , vegetable fats and oils from -1 -1 -1 -1 -1 -1 2.7 kg.capita .yr to 14 kg.capita .yr . Fruit and vegetables i ncreased from 12.3 kg.capita .yr -1 -1 -1 -1 and 83 kg.capita .yr respectively to 1970 but have remained stable at 42.8 kg.capita .yr and -1 -1 -1 -1 103 kg.capita .yr from 1970 to 1994. Fish consumption is high, 36 kg.capita .yr , but there has been a move from cheap tinned fish to more expensive tuna, salmon, shrimp and lobster.

China

Over the past four decades, Chinaâ&#x20AC;&#x2122;s gross national product increased from 104 Yuan per capita per year in 1952 to 1401 Yuan per capita per year in 1991, and the real household purchasing power increased more than four -fold in conjunction with vast improvements in living conditions 178 and health status for Chinese inhabitants . Affluent diseases are now emerging as a public health problem in urban populations, while undernutrition is being alleviated in the poor areas. The sheer size of the population means that this nation could have a significant growth in the burden of CVD. Over the last decade, food production in China increased remarkably. From 1980 to 1990, the Statistical Yearbook of China reports that fruit production increased from 6.79 to 21.76 million tons, grains from 320 to 435, vegetable oils from 7.69 to 16.4 and meat products from 12 to 27 178 million tons . The average per capita food consumption has also increased significantly from 1952 to 1991. From 1952 to 1991 the kilogram per capita per year increases in food consumption -1 -1 -1 -1 were consistently linear: grains from 197 kg.capita .yr to 234 kg.capita .yr , total animal -1 -1 -1 -1 -1 -1 products 11 kg.capita .yr to 35 kg.capita .yr , meat products 6.84 kg.capita .yr to 19.23 -1 -1 -1 -1 -1 -1 -1 -1 kg.capita .yr , poultry 0.43 kg.capita .yr to 1.98 kg.capita .yr , eggs 1.02 kg.capita .yr to -1 -1 -1 -1 -1 -1 7.10 kg.capita .yr , seafood 2.67 kg.capita .yr to 6.79 kg.capita .yr , vegetable oils 2.10 -1 -1 -1 -1 -1 -1 -1 -1 kg.capita .yr to 5.89 kg.capita .yr , sugar 0.91 kg.capita .yr to 4.98 kg.capita .yr , and wine -1 -1 -1 -1178,179 1.14 kg.capita .yr to 11.93 kg.capita .yr . With the increase in food consumption, a change of dietary pattern and nutritional status of the Chinese people has been observed. The first nationwide nutrition survey was conducted in 1959, -1 -1 involving 1.5 million subjects. Average energy intakes were 8,611 kJ.capit a .yr and protein -1 -1 intake 57 g.capita .yr and food from plant sources contributed 89% of the dietary protein. The -1 -1 second survey, reported in 1982, demonstrated higher energy intakes, 10,387 kJ.capita .yr and -1 -1 67 g.capita .yr protein. In general, undernutrition was reported to have been solved. Since the mid-1980's the changes in dietary pattern have become more apparent than total amounts of food. Data from the State Statistical Bureau showed urban household energy intakes -1 -1 stabilised at 9,163 kJ.capita .yr in 1983, and rural intakes stabilised around 1984 at 10,814 -1 180 kJ.d . However, considerable differences between rural and urban fat intakes were evident. - 1 -1 From 1981 to 1989, fat intakes increased from 61 (26% of energy) to 71 g.capita .d for urban -1 -1 -1 -1 Chinese (30% of energy), and 35 g.capita . d to 44 g.capita . d (13 and 15% of energy 180 respectively) for rural Chinese . Reported rates for CHD increased from 27.35 per 100,000 in 1975 to 51.29 in 1992 joining cerebrovascular disease and cancer as one of the three leading causes of death (rates for cerebrovascular disease declined from 135.2 per 100,000 in 1980 to 122.6 in 1992, cancer increased to 125.76 by 1992). China is not equally developed geographically due to the vastness of the territory and differences in circumstances. A comprehensive survey conducted in 2,000 people in selected urban, rural, pastoral and fishing areas in 1986 to 1990 showed that the dietary pattern in different areas was diverse. In pastoral areas consumption of meat and milk was highest but soybean was almost not eaten. The herdsmen consumed 80% of their fat as animal fat. Prevalence of hypertension 178 and CHD was highest in herdsmen and lowest in fishermen . New Zealand

As in other Western countries, CHD death rates in NZ increased in the post second World War period, reaching a peak in the late 1960's. Since the mid 1960's CHD death rates have fallen 181,182 dramatically . From 1968 to 1996, CHD deaths in men aged 45 to 64 declined 63%, and in women 67%. In the age group over 65 years, CHD deaths fell 43% in men and 29% in women. 183 Jackson and Beaglehole , suggest it is unlikely that improved medical management is the major reas on for this decline since it began before widespread use of pre -hospital resuscitation, coronary care units, coronary bypass surgery or widespread antihypertensive therapy. In 1988 they estimated that diet was responsible for a minimum of 22% to 39% of the CHD mortality in 51

184

NZ each year . From 1970 to 1996, cerebrovascular disease deaths have also fallen, by 56% 181 and 60% in men and women . Apart from sociocultural factors, dietary patterns in a country are profoundly influenced by the food supply or deficiency in supply. The NZ Department of Statistics compiles annual Food Balance Sheets calculated on international guidelines developed by the Food and Agriculture Organisation of the United Nations (FAO) and more recently by the Organisation for Economic 185,186 Co-operation and Development (OECD) . The Food Balance Sheet shows estimates of total amounts of foodstuffs available in NZ and the amounts available for human consumption, or â&#x20AC;&#x153;net foodâ&#x20AC;?. Net food (apparent consumption) = total production + estimated home production (where applicable) + imports + opening stocks (where available)-exports-non food usage wastage -usage for manufacture of another food balance commodity-closing stocks (where available). No allowance is made for distribution and household wastage of food, such as occurs in oversupply, feeding to pets, foods used as a cooking medium, parts normally removed before consumption, preparation and plate waste. Using the Food Balance Sheet data, Laugesen and Swinburn, have reported the NZ per capita consumption of key foods from 1961 to 1995, and compared these figures with other OECD 185 countries . In 1995, NZ continued to have the highest figure for butter and meat fat available for -1 - 1 -1 - 1 consumption among OECD countries. Dairy fats dropped from 62 g.capita . d to 39 g.capita . d from 1965 to 1995, mostly due to a halving of butter available for consumption in the 20 years of -1 - 1 -1 - 1 study. Meat fat supply increased from 59 g.capita . d to 75 g.capita . d , from 1961 to 1995. In -1 - 1 1995 edible meat and meat fat supply was 271 g.capita . d . Despite an increase in oil supply -1 -1 -1 -1 nd from 3 g.capita .yr to 24 g.capita . d in the 20 years (Table_8), NZ ranks 22 among OECD count ries. The percentage of energy from animal sources only fell from 47% to 42% from 1961 to 1995, when NZ ranked second highest consumers of energy from animal products among OECD countries. In 1995 dairy fats were providing 36% of SFA supply and meats 48%, and total SFA -1 -1 available for consumption was estimated as 65.3 g.capita . d . The total fat supply remained relatively unchanged but SFA supply was down slightly (Table_9). Increases in barley, maize, rice, and sugar supply have offset reductions in wheat and oats - 1 -1 supplies. In 1995, NZ sugar supply (140 g.capita .d , excluding alcoholic beverages) ranked third after the USA and Iceland among OECD countries. Fruit supply increased from 127 -1 -1 -1 -1 g.capita . d in 1961 to 235 g.capit a . d in 1995, while vegetables increased only slightly th (Table_9), but OECD ranking's remained moderate at 11 for both fruit and vegetables. As might be expected from these changes, the estimated dietary fibre intake increased only slightly from th 185 1961 to 1995, and NZ was moderately ranked at 13 among the 24 OECD countries . In terms of nutrient intake, an estimated increase in NZ total energy supply of 13% from 1961 to 1995, was significant ly correlated with dietary fat but not with carbohydrate. Saturated fat supply declined little from 1961 to 1995. Monounsaturated fats hardly increased despite the increased -1 -1 oil supply, due to the 81% animal fat contribution to the MUFA supply (57 g.capita . d in 1995). -1 -1 The contribution of PUFA increased slightly (24 g.capita . d in 1995) but NZ ranks low among st OECD at 21 of the 24 countries. The supply of seafood fats and oils in NZ remains only onetenth that of high consuming countries such as Japan. Although pointing out the limitations of methodology in the collection of food for consumption data over the two decades, particularly in terms of meat fat supply, Laugesen and Swinburn, 185 conclude that NZ is possibly one of the least vegetarian countries in the world . These statistics support the results of dietary surveys, suggesting that reduction of milk, butter and animal fat available for consumption is consistent with reduced SFA intakes and changes in dietary pattern. Increases in fruits and vegetables available for consumption, together with unsaturated oils suggest that NZers have continued increasing their plant food intakes,

particularly obvious in the added fats categories. Nevertheless SFA intakes remain too high and plant oil and fibre intakes remain lower than lower risk populations. Jackson and Beaglehole studied per capita consumption of fats from 1965 to 1981 and concluded that NZ SFA intakes peaked in 1963, and have gradually declined since, except for 183 transient increases in the early and late 1970's . They estimated there was a 12% fall in SFA intakes from 1968 to 1980, and a reciprocal 73% increase in PUFA intakes, the P:S ratio increasing from 0.11 to 0.22. Dietary surveys in New Zealand

In 1971, the National Heart Foundation of NZ published a report: Coronary Heart Disease: a NZ Report and another document five years later, Coronary Heart Disease: A progress report. These reports raised questions about the contribution of the NZ diet to the high national rates of CHD 187,188 relative to other countries, and led to the initiation of the first national diet survey in NZ . Until this time, no large scale study of individual nutrient intakes for the different population age groups had been undertaken. There have now been three national diet surveys, the National Diet Survey 1977 (NDS), the Life In NZ Survey 1991 (LINZ) (data collected 1989) and the 1997 189,190,191 National Nutrition Survey (NNS) (published 1999) . The findings from these surveys, summarised in Table_10, Table_11, Table_12 suggest that the NZ dietary pattern is changing, as demonstrated by reduced consumption of animal fats and increased consumption of plant foods. These results concur with food available for consumption data, demonstrating a change in fat sources from animal to vegetable origin. Interpretation of these trends requires caution since the methodologies employed are not entirely comparable.

Table 8. Selected foods available for consumption in g.capita-1 .d-1 for the New Zealand population. (Adapted 185 from Laugesen and Swinburn ). Food item

Year 1961

1970

1980

1990

1995

Total dairy fat

Total meat fat

Oils

Fruit

127

146

168

205

235

Vegetables

163

158

185

172

193

Seafood

Table 9. Estimates of selected nutrient intakes derived from food available for consumption data in New 185 Zealand (Adapted from Laugesen and Swinburn ). Nutrient item

Year 1961

1970

1980

1990

1995

13,398.0

13,587.0

14,053.0

14,608.0

15,196.0

47.0

48.0

46.0

44.0

42.0

Total

35.0

35.9

36.6

37.3

36.4

SFA

18.6

18.8

18.0

17.2

16.2

MUFA

13.2

13.9

14.0

14.3

14.2

-1

Total energy (kJ.d ) Animal product (% energy) Fat

(% energy)

PUFA Dietary fibre (g.d-1)

3.2

4.6

5.8

5.9

30.0

27.0

29.0

30.0

34.0

From the 1997 survey results, t otal fat and SFA intakes as percentage of energy are apparently declining relative to those of the 1991 survey (Table_10 ). The concomitant increase in percentage of energy from CHO, however, was accompanied by an increase in suc rose intake (and increase in mean energy intakes) while fibre intakes did not increase (Table_12 ). Absolute fat intakes actually increased (Table_10 ), and it appears that major changes in NZ dietary fat patterns may have been greater in the previous decade. These differences however may be explained by more accurate collection of data in the latest study. Processed and pre-prepared foods appear to contribute more to fat and energy intakes as convenienc e becomes an increasingly important influence in dietary patterns. In the 1997 survey, dairy products and meats, fish and poultry contributed 34-35% of total fat; spreads, fats and oils 20-21%; while pastries, baked goods, bread items, and potatoes and kumara (cooked in fat or oil) together contributed 31-33%. The residual 10-15% was from sweets, grains and pasta, nuts, seeds, snack foods, sauces and egg dishes and also includes some highly processed foods. In 1977 dairy products, meat, fish and poultry contributed 47-55% of total fat intakes and spreads, fats and oils contributed greater than 22% (Table_11). Dietary changes between the 1989 and 1997 surveys have been accompanied by reductions in mean blood total cholesterol levels, and blood pressure, but an increase in body weight. In men -1 and women the mean blood total cholesterol level was 5.7 mmol.L in the 1997 survey, and 5.8 -1 and 6.0 mmol.L for men and women respectively, reported in the 1989 survey (p<0.05 for all -1 and for women). High-density lipoprotein cholesterol levels were 1.2 mmol.L in men and 1.4 in -1 -1 women in the 1997 survey (1.3 mmol.L and 1.5 mmol.L respectively in 1989), and 23.2% of -1 men and 23.7% of women had blood total cholesterol levels greater than 6.5 mmol.L (26.6% and 33.7% respectively in 1989 survey). In 1997, mean blood pressures were 137 mm Hg SBP and 80 mm Hg DBP for men and 127 mm Hg and 76 mm Hg for women; 61% of men and 73.5% of women in the adult population were normotensive. In the NZ Maori population representing approximately 15% of the study population (12% of the NZ population), mean blood total -1 -1 cholesterol concentrations in men were 5.6 mmol.L in the 1989 survey and 6 mmol.L in 1997 -1 -1 (NSD) and in women were 5.7 mmol.L in 1989 and 5.3 mmol.L (p<0.01). Mean body weight for NZ Maori men was 82.3 kg in 1989 and 87.3 kg in 1997 (NSD) and for women 72.2 kg in 1989 and 75.2 kg in 1997. Of NZ Maori men, 63.1% were normotensive and 76% of NZ Maori women were normotensive. Other regional studies in NZ support these results, suggesting that the NZ diet and dietary patterns are changing with an influence on cardiovascular risk factors. Jackson et al described trends from three cross -sectional surveys in Auckland, from 1982 to 192 1994 . From 1986 to 1994 there were significant falls in mean blood total cholesterol levels, by 6% and 9% respectively in men and women aged 35 -64 years. These changes were greater between the national surveys of 1989 and 1997; changes from 1982 to 1994 were approx 7% and 10% reduction in blood total cholesterol for men and women respectively. Over the 12 years there was a fall in blood pressure (4 mm Hg to 7 mm Hg) and in HDL-C, while mean BMI increased from 25.6 to 26.4 in men and 24.5 to 25.1 in women. A study of the Auc kland diet, reported mean intakes of percentage energy from fat and SFAs were 32% and 16% in men, and 193 34% and 15% respectively in women . These SFA figures are similar to the Life in NZ Survey results of the 1989 national diet. Ninety -four percent of New Zealanders are omnivorous, and one third are currently trying to make dietary changes, especially to increase fruit intakes (14%) and to reduce consumption of 189 high fat foods (22%) . Sixty -seven percent rep ort eating three or more servings of vegetables daily, and 46% have two or more servings of fruit daily. Thirty -seven percent of men and 43% of women consume less than 33% of energy from fat. Some groups in the NZ population appear to have dietary patterns that may be more atherogenic than those average population. Maori men and women have around double the CHD mortality 194 rates of Europeans . Coronary heart disease mortality rates for Pacific Islands people are 194 intermediate between European and Maori . The 1997 NNS found that Maori men and women consumed 37% and 36% of energy from fat compared with European intakes of 35% and 34% 54

respectively, but the reported percentage of energy from SFAs was very similar between the groups. Both Maori and European are experiencing declines in CHD rates and reduction in percentage energy fat intakes. A cross -sectional study of 10,021 subjects participating in two surveys in Auckland, a multinational workforce study and a stratified random sample of the electoral roll, has assessed dietary fat and SFA intakes by a dietary fat habits score and a short food frequency 195 questionnaire . Among men, younger age, Maori ethnicity, and lower socioeconomic status were associated with higher fat habits scores, high intakes of takeaway foods and pies, and a low intake of fruit and fish. Current smoking and heavy drinking were associated with higher fat habits scores. Women had lower fat habits scores but associations with other factors were weaker. Summary

The monitoring of secular changes in dietary patterns, food intake and incidence of associated diseases is necessary to accumulate local data. The diversity of the changes occurring in other populations and countries further expands the understanding of risks or benefits derived from dietary change. The USA and Finland have experienced massive reductions in dietary fat consumption largely in response to calls for attention to reducing individual risk of CHD. Similar changes have occurred in NZ with a drop from 43% of energy in 1977 to 35% in 1997, but the change has not been confined to SFAs which remain twice that recommended for LDL -C reduction. New Zealand lags behind other countries in PUFA intake and the P:S ratio was only 0.33 in 1997. New Zealand dietary fibre intakes are not changing as fast as fat intakes, and fat appears to have been replaced by increased sugar intake. On the other hand Japan and China represent countries where in certain regions, fat intakes have moved just as quickly in the reverse direction from Western countries, and although it may yet be too early to estimate the disease outcomes of changes in the past decade, a trend to increasing CHD rates in these populations is already evident.

Table 10. Macronutrient and dietary fibre intakes: Three national surveys. Survey (year of data collection) -1

Total energy intakes (MJ.d )

NDS (1977)*

LINZ (1989)**

NNS (1997)**

14.0

11.2

11.9

8.5

7.2

8.0

39.0

42.0 (265)

45.0 (305)

40.0

45.0 (183)

47.0 (214)

42.0

38.0 (103)

35.0 (110)

43.5

30.7 (65)

35.0 (72)

19.0

16.0 (44)

15.0 (47)

20.0

16.0 (28)

15.0 (30)

19.0

17.0

12.0 (37)

19.5

17.0

11.0 (24)

3.9

4.8 (13)

5.0 (15)

3.9

4.5 (8)

5.0 (10)

0.2

0.30

0.33

0.2

23.0

24.0

18.0

69.0

42.0

69.0

47.0

27.0

49.0

-1

Percentage energy (g.d )*** CHO Total fat SFA MUFA PUFA P:S ratio Dietary fibre (g.d-1) -1

Sucrose (g.d )

0.29

0.33

Approximate derived from median values.

Mean values.

***

50th percentile figures for comparison, mean values in 1997 were slightly higher than these figures.

Table 11. Principal food sources of total fat: Three national surveys. Food sources, % of fat intake

Survey (year of data collection) NDS (1977)

LINZ (1989)

NNS (1997)

Dairy Milk

6.7

7.0

5.7

5.5

3.4

3.5

Beef, pork, lamb, and sausage

37.2

28.5

Poultry

1.2

<3*

1.2

<3*

1.1

<3*

1.2-4

<3*

Cheese Other dairy Flesh meats

Fish and shellfish Added fats Butter

16.0

17.0

3.4

3.5

Butter and margarine

19.4

16**

20.5

Oil

1.1

1.8

Baked goods, breads, cereals

11.8

11.2

Bread-based items

Margarine

Fats and oils Pastries and pies

Potatoes and kumara * **

16**

6 5

Items less than 3% of fat intake were not reported. Fat portion attributed to spreads is under-represented since â&#x20AC;&#x153;bread-based itemsâ&#x20AC;? include items containing spreads.

Table 12. Principal food sources of CHO (and dietary fibre*) : Three national surveys. Food sources, % of intake Bread Potatoes Grain/pastas Cereals Total for group Sugars/sweets Cakes and biscuits Pastries Total for group Milk Vegetables Fruit

Survey (year of data collection) NDS (1977)

LINZ (1989)

NNS (1997)

8-14

24 (29)

20 (22)

10-17

24 (30)

21 (22)

6-14

9 (6)

11 (13)

10-12

7 **

9 (10)

4 (4)

5 (4)

5 (6)

5 (4)

5-6

5 (7)

5 (12)

4-5

4 (5)

5 (12)

42 (46)

41 (51)

40 (41+)

40 (48)

10-17

10-13

15-18

9 (5)

14-17

10 (6)

Incl

4 (>7)

2 (2)

Incl

5 (>4)

1 (1)

5-6

6.6

3 (24)

3 (16)

6.7

4 (22)

4 (18)

8.4

7 (11)

7 (10)

10-13

11 (16)

10 (16)

Range of values across age groups.

Dietary fibre in bracket, only reported for 1991 and 1997.

Not reported.

â&#x20AC;&#x153;Inclâ&#x20AC;&#x153;

Included in the item listed directly above this one.

Therapeutic dietary patterns Introduction Changes in dietary lipids precede the increase or decrease in CHD mortality and establish dietary interventions as useful for assessing the outcomes from change in dietary patterns. Thousands of humans have now participated in dietary trials where habitual dietary patterns have been deliberately altered to test the effects on risk factors for CVD. These trials have involved single foods, dietary supplements, multiple dietary modifications, or combined diet/lifestyle interventions, with or without drug intervention. Typically, drug trials for cardiovascular intervention, in particular the lipid-lowering trials, have involved dietary intervention in both drug and placebo arms. Together these trials have provided a considerable literature addressing the effects of dietary modification on the course of CVD. Drug trials now dominate secondary prevention trials, and provide earlier results for primary prevention than 1, 196 dietary trials do . Although the literat ure provides an insight into probable factors that may identify an “ideal” diet or dietary pattern, the perfect controlled dietary trial for the prevention of CVD has not been 197,198 published and possibly cannot ever be done . Prospective, controlled clinical trials are required to assess the strong links between dietary components and CHD but they are difficult to perform since it is almost impossible to provide control foods to ensure blinding of both investigators and volunteers. When blinding is feasible, such as in an institutional setting, the test of free -living populations is lost, randomisation may be less satisfactory, and contamination of the control group is difficult to avoid. Studies involving the complex nature of diet and dietary patterns, are not as simple to interpret as studies of drug therapies or life-style interventions such as not -smoking or exercising three times per week. Reviews and meta-analyses of dietary intervention trials are problematic and have been criticised for combining studi es with different dietary methodologies, combining diet and diet/lifestyle studies, combining metabolic ward and free -living trial studies, and combining diet and drug studies. The study of dietary patterns requires larger scale and longer term clinical t rials than those investigating a specific food or nutrient. The outcome measures are not single risk factors such as blood total cholesterol or LDL -C, but are a cluster of risk factors, cardiovascular events and/or cardiovascular and all -cause mortality. Dietary intervention studies can be divided into primary and secondary prevention studies. In prevention studies, the measurement of isolated risk factors such as blood total cholesterol, does 199 not represent absolute risk . The assessment of absolute risk i nvolves multiple risk factors. Interventions targeting multiple risk factors are complex. Each risk factor may be influenced by multiple dietary components. The most clearly identifiable end -point of prevention is no-death. Non-fatal cardiac events are less accurately assessed in large scale studies but do provide an indicator of incidence and measure improved morbidity. Other end points are angiographic measurement of changes in the coronary arteries or evidence of symptoms. Rationale for evaluating dietary intervention trials to assess therapeutic dietary patterns: •

Epidemiological study of the associations between traditional dietary patterns and disease patterns identify potential dietary patterns for testing in intervention trials.

•

Intervention trials t hat measure disease end -points provide the most definitive evidence of the benefits or risk from an intervention.

•

Trials that assess dietary patterns or multiple dietary modifications are unable to identify cause and effect for isolated dietary factors. 59

•

New dietary patterns for trial as multiple risk factor interventions, are generated from multiple randomized and controlled dietary trials, that test cause and effect for single dietary components.

•

The most definitive trials test has only one outcome variable, for example the DASH Study investigated only the effects of diet on hypertension.

Dietary information from dietary intervention trials produce the prototype for dietary patterns likely to reduce risk for CVD and a variety of other disorders. The relat ionship between a specific nutrient and a specific risk factor is defined by a metabolic diet study where a limited number of subjects are fed a precisely defined diet, whereas the efficacy of dietary modification on CHD 196 and CHD risk factors remains a test of a specific dietary pattern in free-living populations . Meta-analysis of studies where habitual dietary patterns are altered in individuals known to be at risk for disease demonstrate evidence for effect. These same trials may apply to the general population but there are limitations to consider when extrapolating conclusions outside metabolic ward conditions. External regulation of intake, compliance variables, and the complex and changing mixtures of foods whose elements create behavioural and/or biological interactions are just some factors altering the outcomes that occur when single dietary components are 200 manipulated . In the absence of any large scale, long term trials testing a dietary pattern defined by all known protective elements with disease end-points as the major outcome variable, one method to identify an optimal dietary pattern is to observe components common to those trials with most efficacious outcomes. Whether the general population should undertake dietary modification, will depend upon whether primary prevention generates benefit, or all-cause mortality when the whole population is involved. Primary prevention trials have included healthy and moderately 1 high risk subjects. Drug trials of primary prevention have been reviewed . Although only one trial has achieved reduction in CHD mortality, none have as yet achieved reductions in all-cause 201 mortality .

Randomized controlled trials There have only been three diet -only trials of primary prevention. These three trials are old and may not represent either an achievable or a desirable diet for free-living individuals. Metaanalyses of primary prevention trials involving diet have not been pos itive, leading some reviewers to support individual risk factor interventions rather than mass primary prevention.

Dietary patterns and primary prevention: Diet trials •

Los Angeles Veterans Administration Study

•

Finnish Mental Hospital Study

•

Minnesota Co ronary Survey

202

203

204

Dietary patterns and primary prevention: Multiple risk factor trials including diet (excluding trials using lipid lowering agents) 205,206

•

Oslo Diet and Anti-smoking Trial -diet, anti -smoking, stress reduction

•

The MRFIT-diet and anti-hypertensive s

•

Gotenburg, Sweden, Trial -diet, anti-hypertensives, small number on lipid lowering agents 208 (not statins)

•

WHO European Collaborative Trial -diet and anti -hypertensives, stress reduction, exercise, no 209 smoking, 1986 .

207

Dietary and lifestyle modification rema in the cornerstone of trials for the primary prevention of CVD. Cholesterol reduction has been the focus of major trials, those trials reporting end-points including mortality are listed in Table_13. Primary prevention trials us ually comprise less than 25% of subjects with diagnosed previous MI to test the effect of an intervention to prevent coronary events and deaths. Among primary prevention trials involving lipid lowering drugs that report significant reductions of 20% to 35% in non-fatal coronary events, the WHO Clo-fibrate Study, Helsinki Heart Study, LRC-CPPT and the 201, 210,211,212 WOSCOPS Study Group . Only the latter reports reductions in either all -cause or coronary deaths of statistical significance. Another study included 30% of subjects with established CHD, achieved a 56% reduction in non-fatal events and a 46% reduction in CHD 213 deaths reaching significance in men but not in women, and not significant for all-cause deaths . In the WOSCOP trial, the maximum benefit of a 45% risk reduction was associated with a mean 24% fall in LDL-C. In the Air Force/Texas Coronary Atherosclerosis Prevention Study, first acute major coronary events were reduced by 37% (p<0.001) and coronary events by 25% (p= 0.006) 214 and LDL-C decreased by 25% . In lipid-lowering drug trials dietary instruction is usually given to the control group, the drug effect representing the difference above the diet effect. In bile-acid sequestering resin and fibrate studies the blood total cholesterol lowering above the control diet was 8.5-9.4% and in the two 201,210,211,213,214 statin trials was 18-20% . Subjects in these trials are also exposed to media “guidance” and especially to “entry to study” effects so that there is likely to be considerable variance in dietary patterns both within and between studies. The WOSCOPS Study confirmed that event rates are low in hypercholesterolaemic men with no 215 other risk factors or family history of coronary disease . Benefits were independent of the baseline LDL-C level, there was no risk reduction without cholesterol reduction, but the effects of 201 the study drug pravastatin could not be fully explained by the reduction in LDL -C . The absolute benefit of therapy was greatest in subjects with highest total baseline risk when sex, smoking, family history, diabetes, symptoms, blood pressure, total and HDL-C were entered into the risk 215 score model . The top quartile of risk distribution accounted for 45% of primary end points and 64% of coronary deaths, the 55% and 36% remaining accounted for the other three quartiles. Since the number of individuals needing to be treated to prevent one coronary event in lower risk groups is considerable, the authors suggest a strong case exists for aggressive lifestyle 215 intervention before consideration of drug therapy in primary prevention . Projected mechanisms beyond lipid lowering for improved coronary risk, possibly via endothelial function, include endothelial normalisation, anti -inflammatory effects, strengthening of the fibrous cap, inhibition of platelet thrombus formation and deposition and reduction of thrombogenic 216 responses . On the other hand lipid and risk parameters other than blood total cholesterol or LDL-C may explain why CHD event reduction is not even greater with the most powerful drugs. These include HDL-C, TG, lipoprotein (a), other thrombogenic factors, LDL-C particle size and susceptibility to oxidise, all potentially modifiable to some extent with dietary intervention. These studies suggest that if absolute blood total cholesterol -lowering is greater than 12-20% in -1 populations with elevated mean blood total cholesterol levels of 6.8-7 mmol.L , non-fatal CHD events will be reduced. To date primary intervention trials have not greatly influenced mortality, but since secondary prevention significantly reduces mortality, the separation of higher risk individuals into secondary treatment with drug therapy would allow further assessment of 216,217 whether lower risk individuals will continue to derive benefits for CHD events . The first question when developing an ideal dietary pattern for primary prevention is whether cholesterol lowering from dietary modification will achieve reduction in CHD events similar to drug trials. Even further benefits, involving other risk factors, are likely to be derived from more comprehensive changes in the whole dietary pattern and lifestyle. Drug trials have therefore facilitated the development of lipid-lowering targets for projected and recommended changes in dietary pattern.

Table 13. Dietary prevention trials. Diet vs. Control

Baseline TC

â&#x2C6;&#x2020; TC from baseline

(mmol.L-1)

424/422 300/309

Subjects

CHD deaths

CHD events

(%â&#x2C6;&#x2020; vs. control)

(RR 95% CI)

(%)

6.06

-20.0

-12.7

0.82 (0.55 to 1.21)

24 (p<0.05)

7.1

-15.0

-6.0

43 (p<0.05)

M 2,197/2,196 F 2,344/2,320

5.4

-14.5

-13.8

1.12 (0.78 to 1.61)

6,428/6,438

6.5

-2.0

0.93 (0.72 to 1.19)

0(47at16yrs) 39

(% less)

Primary prevention diet trials 202

LA Veterans 8 yr

203

Finnish Mental Hospital 4 yr 204

Minnesota 1 yr

Primary prevention multiple risk factor trials 205

MRFIT 6.5 yr

206

Oslo Diet and Smoking 6.5 yr 207

Gotenburg 10 yr

208

WHO Collaborative 5.5 yr Secondary prevention diet trials (Low fat diets) Low fat Diet Trial 3 yr Soy bean 3.2 yr

218

219

220

8.4

-19.6

-10.0

0.47 (0.19 to 1.17)

6.5

-7.0

1.00 (0.90 to 1.12)

24,615/25,169

5.5

-7.0 (4 yrs)

-1.0

0.95 (0.83 to 1.09)

123/129

6.8

-17.0

-6.6

0.89 (0.50 to 1.61)

199/194

7.0

-17.0

-14.3

0.98 (0.58 to 1.63)

28/52

6.7

0/-9.0

-3.6

2.78 (0.52 to 14.83)

221/237

7.3

+4.0

-4.0

1.44 (0.90 to 2.30)

206/206

7.7

-29.0

-14.4

0.75 (0.53 to 1.06)

204/202

5.9

-12.7

-9.0

0.55 (0.36 to 0.87)

1,015/1,018

6.5

4.0

0.67 (0.51 to 0.89)

16 (fish)

302/303

6.5

-9.0

+2.0

0.21 (0.07 to 0.67)

188/187

6.0

-12

0.64 (0.44 to 0.92)

26/28

7.2

-14.0

-11.1

0.43 (0.07 to 2.72)

28/20

6.1

-24.3

-25.8

Only 1 death

232

39/-

6.9

-10.1

233

56/57

6.05

-10

Angiographic only

Rose 2 yr

Woodhill 5 yr Oslo 5 yr

221

222

Singh 2 yr

223,224

DART 2 yr shift

225,226

Lyon Heart Study 2.3 yr 228

227

Kallio 3 yr Angiographic trials STARS 3 yr Ornish 1 yr Leiden

604/628 10,004/20,028

Schuler

229,230

231

-10

Primary prevention: Diet only trials The three diet -only primary prevention trials were all institutional studies, involving significant 202,203,204 dietary changes . The Helsinki Mental Hospital achi eved a reduction of 43% (p<0.05) in , coronary events and the LA Veterans trial a 24% reduction in coronary events and cerebral infarction (p<0.05), but trends for reduction in all -cause mortality were not significant in either 202,234,235,236,237,238,239 trial . Men in the Finnish Mental Hospital Study had significantly reduced CHD mortality (p<0.002). Women had significantly reduced CHD mortality in one of the two hospitals but not in the pooled sample, and CHD incidence for women was not significant when analysed separately from men. The LA Veterans Study reported 18% reduction in CHD mortality with the experimental diet, and 32% reduction in all fatal atherosclerotic events (p= 0.01). In the Minnesota Coronary Survey, a RCT, there were no significant reductions in CHD events, 204 CHD or all-cause deaths . Mean duration on the diets was only 384 days, changing therapies in mental hospitals during the trial period meant earlier than expected discharges of trial participants, and high turnover of residents. Subjects missing less than 5% of meals in the dining room had mean blood total cholesterol reductions of 15.4% and those missing greater than 50% of meals, mean 6.2% reduction.

The Mental Hospital, LA Veterans and Minnesota studies all achieved significant reductions of blood total cholesterol of 15%, approximately 20%, and 14.5% respectively, from baseline levels in the intervention group. The Finnish Mental Hospital Study, a non-randomized, crossover trial, was very large for an institutional diet study was conducted over 12 years, six years on each the experimental and control diets. The Veterans Administration Study was an eight year RCT in an institutional setting in men. This study tested adherence as the percentage of all supplied meals consumed and was approximately 50% overall. A small number of subjects were taking medications but none were lipid lowering. Blood total cholesterol had dropped 11% by year two but then dropped to about 20% for the remainder of the study. Dietary adherence was tested by adipose tissue biopsy in both the Finnish Hospital and LA Veterans studies. The LA Veterans and Minnesota studies showed that younger participants and those with higher cholesterol levels showed favourable trends for reduced cardiovascular end -points. These two studies are remarkable in their attempts in applying a randomized, double-blind trial. The experimental diets were devised to replicate the control (usual) diet as far as practicable. However in order to achieve similar looking diets, the enormous efforts to provide a large number of “replica” sweet items such as cakes and desserts, did not encourage improvement in other aspects of diet such as increasing fruits and vegetables and wholegrain intakes. These were strictly studies of fat modification, rather than of dietary pattern. The three studies used similar diets (with that achieved in Minnesota in bracket ), reflecting the questions of the time. They were high fat, 35-40% of energy from fat, but low in SFAs, 8(9)% of total energy in Minnesota and 7.4% in the Finnish Mental Hospital Study. The P:S ratio in Minnesota was 2.5(1.6), in the Finnish Mental Hospital 1.4 to 1.78, and in LA Veterans 1.7, with 20(15)%, 18-20% and 15% of energy from PUFAs respectively. In the LA Veterans Study, 25% of fat was animal and hardened vegetable fats, 46% was added oil (mostly soybean, but some safflower, corn and cottonseed) and 28% was unsaturated corn oil -1 margarine. Sitosterol and unidentified sterol intakes were 190 m g.d . Foods in all three studies included replacement of animal fats and hydrogenated shortening with vegetable oils and PUFA margarines, filled milks, ice cream, toppings and cheeses, special filled sausage and ground beef products and liberal use of oil in cooking and baking. Large vegetable -1 -1 intakes (350-500 g.d potatoes, approximately 220 g.d of other vegetables) were reported in -1 the Finnish Mental Hospital, 2 srv.d were prescribed in the LA Veterans trial, and in Minnesota moderate vitamin C intakes suggest moderate intakes of fruit and vegetables. These trials were conducted at the time of a major shift in thinking in western cultures away from dietary patterns rich in SFAs. These diets were not low in total fat but low in SFAs. Soy oil was a major fat source in the studies, increasing linolenic as well as linoleic acid fatty acids. In the -1 Finnish Mental Hospital Diet linolenic acid intake was 5.6 g.d , 1.8% of energy. Other -1 -1 characteristics of the dietary patterns were mean daily intakes of 60 g.d of fish and 60-200 g.d of sugar in the Finnish Mental Hospital diet. These trials clearly demonstrated reduction in risk factors and coronary events, and a trend to reduced coronary mortality, similar to that achi eved in drug trials other than those using statins, when only the “pathogenic” potential of diet was altered. This was achieved despite the short duration of trials and limited adherence in trials where subjects were (blinded) to their change in intake. They leave unanswered the full potential of changing the whole dietary pattern, using simultaneous improvements in protective factors other than PUFAs and plant sterols, and with the full appreciation of self-motivation and adherence-enhancing techniques.

Table 14. Daily fat intake from various sources in two studies (g.d-1). Study

% energy as fat

Finnish Hospital LA Veterans

204

237

Total fat

Vegetable oil

Added unsaturated margarine

Meat and hard margarine

Other fats

110

44.6

29.7

22.4

112

52.0

32.0

28.0

Primary prevention: Multiple risk factor trials including diet Four multiple risk factor trials, with a dominant dietary component, have measured mortality 205,206,207,208,209 outcomes (Table_13) . They all addressed smoking, weight control and blood pressure, utilising antihypertensive agents where necessary. The Oslo and WHO Collaborative 205,209 studies also addressed stress as a risk factor . The Oslo Diet and Antismoking Trial involved 1,232 men and their wives in individualised and 205,206,240 group counselling for dietary change and smoking cessation (80% smoked) . It has been argued that the success of this study was due to the subjects being younger men with higher baseline cholesterol levels than in other trials. Although tested 35 years ago, the Oslo diet represents a dietary pattern well suited to modern Western culture and current evidence for an anti-CHD prescription. Mean intakes of macronutrient energy were 28% from total fat, 8% from each SFA and PUFAs (P:S ratio 1.0), 52% from CHO and 8.3% from sucrose. Fibre was measured as crude fibre and increased 36% from baseline during the intervention. Adherence to dietary assessments after five years of study demonstrated that the best responders (quintile of most cholest erol reduction) ate more fish and vegetables, more skimmed rather than whole milk, less hard margarines, and more PUFA margarine and oils than those in the lower quintiles. Dietary changes in this Norwegian population, habitual consumers of very high intakes of SFA diets as dairy products, involved increased intakes of dark rye bread, fruits and vegetables, fish, low fat dairy products, PUFA margarines and oils (see later). Dietary analysis was performed on a subset of conscientious dieters. Mean blood tot al cholesterol reduction in this group was 19.6% 206 after four years and HDL-C rose 76% (Table_13) . In 1985, the 6.5-year report indicated that the net difference of 10% in blood total cholesterol between groups was the main cause for the significant reduction in incidence of first major CHD event, and that smoking cessation made a lesser contribution. At the 102 month follow-up, 3.5 years post intervention (and after the control group were told they may benefit from reducing their fat intake), although net differences in risk factors between the two groups had narrowed, significant reductions in CHD events (45% less, p= 0.022) and sudden coronary death (70% less, p= 0.034) were evident in the diet group. CHD mortality was 59% lower and all -cause mortality 40% lower in the intervention group, neither reaching significance (Table_13). The MRFIT recruited men at high risk for CHD who were intensively counselled to make dietary 207 changes according to blood total cholesterol responses . This trial produced a huge volume of papers about the dietary patterns of subjects. The basic food pattern aimed for less than 35% of -1 total energy from fat, 10% from SFAs, about 10% from PUFA and less than 300 mg.d cholesterol. When baseline recordings revealed relatively low fat intakes, the SFA allowance was reduced to 8% of energy. Later in the trial, a phase two pattern was introduced with 5% of energy 241 from SFAs, particularly to assist with weight loss . The basic food pattern represented a modified fat western diet, similar in direction to the -1 changing American diet of the time: less than 180 g.d meat/fish/chicken, some meat less meals, two serves of low fat dairy products, 2-4 tablespoons of specified spreads and oils, greater than four servings of bread, cereal, and grains, greater than four servings fruits and vegetables. There were further limitations if weight reduction was required. Increases of fish, poultry, skim milk, PUFA margarines and oils, fruits, breads and cereals, and reduction in egg intakes were made 64

with relative ease while difficult changes included reducing high fat meats and cheeses, high fat 242 crackers, snacks and desserts or increasing vegetarian meat alternatives . Reductions in the three targeted risk factors, blood total cholesterol, blood pressure and smoking were substantial, but at six years CHD deaths and mortality from all -causes were not significantly less than the usual care group. To investigate this lack of effect on CHD risk, follow-up after completion of the intervention, at 10 and 16 years from baseline, tested for a potential lag before 243 benefit . An 11% reduction in CHD and all -cause mortality in the intervention group remained not significant, but sudden coronary death was 20.4% lower in the intervention group (p= 0.02). Total coronary events and total cardiovascular events were 47% (p= 0.028) and 44% (p= 0.038) lower in the intervention group, compared with control. The MRFIT and Gotenburg trials were both affected by improvements in the control group during the course of the study. Nevertheless the results of the MRFIT Study represent a disappointing outcome for a huge dietary effort lending support to the inefficacy of fat -focussed recommendations. Dietary analysis demonstrated that from baseline to intervention total fat intakes dropped from 38.4% to 34% of total energy, SFAs from 14.2% to 10.4%, MUFA decreased from 15.1% to 12.7% and PUFA i ncreased from 6.4 to 8.4% of energy. Despite â&#x20AC;&#x153;encouragementâ&#x20AC;? to eat more grains, vegetables and fruits in their dietary patterns, mean dietary -1 -1 fibre intakes of the subjects had only increased from 13.6 g.d to 14.9 g.d (7.9 g insoluble, 4.6 g soluble, 5.12 g from vegetables and legumes, 2.96 g from fruit, 3.38 g from bread, 3.38 g from 244 cereals and grains) . 208

The Gotenburg Study carried out in Sweden involved 30,000 men . The 2,769 men in the intervention group of 10,000, who smoked greater than 25 cigarettes per day, or had -1 hypertension or blood total cholesterol greater than 6.7 mmol.L were given specific lifestyle counselling whereas the remainder received written dietary advice. Subjects not controll ed by dietary counselling received drug therapy (26% vs. 19.6% for intervention and control groups respectively, for blood pressure, less than 7% of the intervention group received nicotinic acid or clofibrate (the latter was withdrawn during the trial). The trial results reflected mixed intensity of counselling and a variety of treatments. After 10 years blood total cholesterol reductions were 7% in both control and treatment groups while SBP was slightly improved in the intervention group. Weight increased and smoking rates decreased similarly in both groups and there were no differences in disease end-points. The WHO European Collaborative Trial of Multi-factorial Prevention of Coronary Artery Disease involved 63,732 men employed in 88 factories in Belgium, Italy, the UK and Poland randomized to receive advice for risk factor reduction (by written material, group discussions and mass 209, 245,246,247 media methods) or no advice . Dietary advice was focussed on blood total cholesterol 209 reduction and weight reduction (if overweight) and mainly concerned dietary lipid modification . Like the Gothenburg trial, participants with high risk were given individual counselling. Lipid lowering agents were not employed. Initial cholesterol reductions of 7% by four years of the study had virtually returned to baseline levels after 10 years, four years after the intervention was completed. The average of four follow-up assessments for the whole group demonstrated 1.2% reduction of blood total cholesterol, 2% reduction of blood pressure and 8.5% reduction of daily 246 cigarettes . The estimated combined reduction in risk was 11%. Those participants receiving more intensive counselling achieved greater blood total cholesterol reductions and a 19% reduction in combined risk. Certain sites had very little research staff or contact with participants and numbers of staff correlated with reducti on in risk. In Italy with six full-time staff for 3,131 men combined CHD risk fell 28% whereas in the UK with two full-time staff for 9,734 men, overall 246 CHD risk fell only 4% by the end of the intervention period . The Belgian sector of this trial involving 15 factories used most personnel and achieved risk 248 reduction second only to the Italian factories . It was the only country to report significant reductions in total mortality and CHD incidence (p<0.05), suggesting that more aggressive intervention achieves results. Although the intervention group combined risk of CHD mortality or incidence was 26% and 16% lower at years two and four respectively, than in the control group, by the study closure at six years, the difference was 4%. This was attributed to reduced

248

intervention effect in the intervention group and to secular improvements in the control group . The intervention efforts were more intense during the first two years of the study and there was no strong maintenance programme in the second half of the trial. The WHO Study concluded that the degree of benefit depended on the degree of risk factor control and that the relationship between adherence with the intervention, and subsequent CHD 248 incidence confirmed that the advice was effective to the extent that it was accepted . The Finnish Businessmen Study also is in this category of trials but greater drug interventions 249 preclude clear assessment of effect of dietary changes . Summary

Trials that have tested the effects of modifying dietary patterns on the primary prevention of CHD have largely addressed the hypothesis that high intakes of SFAs lead to elevated blood lipid and lipoprotein levels, which in turn lead to increased risk of CHD. The content of diets was generally directed to alteration in the lipid content, although some trials increased the fruit and vegetable component of diets. Trials carried out in institutions have provided the most definitive evidence that dietary modification alone, can prevent CHD, however since the trials were possibly too short to establish significant reductions on mortality, the evidence is limited to reduction of incidence. The trial among free -living individuals that utilised a more comprehensive dietary approach, including increased dietary fibre intake and a moderately reduced total fat content (Oslo Diet and Antismoking trial) achieved the most significant reduction in event rate, however follow-up to 16 years post-intervention has demonstrated the significance of lesser changes in diet (MRFIT).

Dietary patterns and secondary prevention: Diet trials Early low fat diets/oil supplemented diets 218

•

Low Fat Diet Trial-Medical Research Council, London

•

Soybean Trial-oil supplemented diet, Medical Research Council, London

•

Rose et al-oil supplemented diets

•

Woodhill et al-the Sydney Heart Trial

219

220 221

Diets increased in polyunsaturated fats 222

•

Oslo Diet Heart Study -PUFA equal to 20% of energy, P:S ratio 2.4

•

Indian Heart Study -PUFA equal to 11% of energy, P:S ratio 2.09

•

DART-fat advice diet P:S ratio 0.85, fish advice diet 2.4 g.wk

•

Lyon Diet Heart Study-PUFA equal to 4.48% of energy, 0.81 g.d linolenic content, P:S ratio 227 0.65

•

Kallio et al-Reduced SFAs and increased PUFAs

-1

223,224

EPA

225,226

-1

228

Angiographic trials 229,230

•

STARS -PUFA 7.5% of energy, low SFAs, high fibre

•

The Lifestyle Heart Trial -very low fat, vegetarian diet

•

Leiden Intervention Trial -PUFA 16.8% of energy, vegetarian diet

•

Schuler-low fat diet, less than 20% of energy

231 232

233

The study of dietary effects in secondary prevention began with the trial of Morrison who treated 250 every second patient presenting with MI with a low cholesterol, low fat diet . After 12 years all 50 of the control group had died, whereas 19 of the 50 treated with diet were still alive. Several other dietary trials were completed before it was considered unethical to continue a control group with untreated lipids. Several trials have compared diet in secondary prevention with a traditional lipid-lowering 223,227,231 diet . Dietary trials have generally yielded more significant outcomes for secondary prevention since individuals already have CHD. Differences in mortality and/or angiography between intervention and control groups can be shown within one year, particularly if the 223,227,231 intervention is begun very soon after MI . Several trials have shown significantly reduced all-cause and CHD deaths (Table_13), despite these trials being relatively short in contrast with 222,226,227,228 the duration of ather ogenesis . The interpretation of the effects of diet in trials of secondary prevention may be confounded by the effects of the many drugs usually prescribed post -MI, however none of the studies reported here used lipid-lowering agents. Early low fat diets/oil supplemented diets 218,219

The Medical Research Council in London, trialed two diets in the 1960's in men post -MI . In -1 -1 one trial, men were randomized to a 40 g.d fat diet, reduced in SFAs plus an 80 g.d 219 supplement of unhydrogenated soybean oil (46% energy from fat, P:S ratio 2:1), or usual care . -1 -1 In the other trial, men were assigned to a very low fat diet, 40 g.d (mean daily intake 45 g.d , -1 218 20% of energy) or a control diet (mean intake 118 g.d , >50% of energy) . Dietary instruction was intensive, mean blood total cholesterol reduction in the soybean trial was 22% in the first six months, and 16.9% at three years (the mean duration of the trial), and in the low fat trial 16.9% at the end of the three to four year trial. Control groups in both trials decreased blood total cholesterol levels. By the end of each trial there was a trend toward lower recurrence rates of CHD in the treatment groups but not reaching statistical significance (Table_13) possibly due to small numbers of subjects. The advice was mainly restrictive about SFAs, sugar intakes were relatively high in the test groups and nutrient density is likely to have been affected. In both trials men requiring weight loss were instructed for reduced energy intake. The similarity of outcomes in these two trials, and that treatment groups did better than controls, suggests that low fat diets and low fat diets supplemented with predominantly unsaturated fatty acid oils, within similar dietary patterns, may be safe and equally effective for cholesterol lowering. In two studies dietary change was not effective, and perhaps detrimental for reducing CHD. In -1 the study of Rose et al, 43 men post-MI were randomized to a diet containing 80 g.d of corn oil 220,220 or olive oil or to a control group . Subjects in the oil groups were instructed to avoid high fat -1 foods. Fifty to 75 g.d of oil were consumed daily by subjects in both groups during different sections of the trial, and total fat comprised around 50% of energy. Despite significant mean blood total cholesterol reductions on the corn oil diet only, the proportion of participants surviving and free of reinfarction after two years was highest in the control group-75%, then the olive oil group 57%, and least in the corn oil group 52%. The sample size was very small but the trial raises the safety of some oils at this extraordinary intake, but is an impractical contributor to meta-analysis. The oils in the corn oil and soybean oil diets respectively, contributed greater than 14% and -1 -1 greater than 18% of energy from total PUFAs and 0.99 g.d and 6.32 g.d of LNA. 221

The Sydney Diet -Heart Study began in 1965 . Four-hundred and fifty-eight men with CHD were randomly allocated to either a diet where 9.8% of energy was from SFAs and 15% from PUFAs or to a control group where the only instruction was to aid weight loss if necessary, and PUFAs margarines could be used (dietary analysis :13.5% of energy from SFA and 8.9% from PUFAs). The diets were very similar in other respects. Prognosis over five years was determined by the extent of the coronary and myocardial disease as judged by clinical parameters. Multivariate 67

analysis showed that none of the dietary factors were significantly related to survival. Overall five year survival was better in the control group and reductions in mean total blood cholesterol were 7% for the test diet and 11% in the control. It was concluded that other confounders may have influenced the results, however it lends no support to diets containing 10% of SFAs and 15% of energy from PUFAs. Ten dietary trials of secondary prevention have achieved significant reductions in CHD, although 222,223,226,227,228,230,231,232,233, 251 all are of short duration and have small numbers of subjects . Four are angiographic studies and six studies provide information about the dietary patterns used in the trial. Diets increased in polyunsaturated fats

In the DART, 2, 033 men recovering from MI were randomized to receive or not receive dietary advice on three factors : to reduce fat to 30% of energy, with P:S ratio of 1.0; or to increase fatty -1 -1 -1 fish intakes to 200 g.wk to 400 g.wk ; or to increase grain fibre intake t o 18 g.d and total fibre -1 225,226 to 30 g.d . The relevant nutrient intakes in these groups relative to controls were: for the “fat advice” group, fat intak e was 32% of energy, SFAs 11% and the P:S ratio 0.78 versus 35%, 15% and 0.44 respectively in the “no fat advice” group; for the “fish advice” group EPA intake -1 -1 -1 was 2.4 g.wk versus 0.60 g.wk for “no-fish advice” group; grain fibre intake was 17 g.d in the -1 -1 “fibre advice” group versus 9 g.d in the “no fibre advice” group, and total fibre intake 26 g.d -1 and 20 g.d respectively. In this study simultaneous changes were made for more than one dietary instruction, and after two years, those 251 subjects who received advice to modify all three dietary components had the second lowest all -cause mortality rate (8%), compared with the 252 subjects with no advice. The 257 participants receiving fish advice only had the lowest rate (7%) and relative risk of CHD events 0.84 (95% CI, 0.66 to 1.07) and for all -cause mortality, 0.71 (95% CI, 0.54 to 0.93, p<0.05). The fat and fibre advice had no independent effects on mortality or CHD, however neither group met the dietary targets, blood total cholesterol reduction was minimal, differences between groups for fat and fibre intakes were relatively small, and neither instruction is known to influence MI relapse in such a short time. There are many aspects of dietary change unaccounted for when individuals respond to advice for change of a single dietary component, rather than a composite change in the full dietary pattern. Singh et al utilised traditional Indian foods implicated in the modulation of blood concentrations of lipids and glucose, and fibrinolytic activity to devise their “cardiovasoprotective (CP) diet” for 223,224 participants who were immediately post -MI . These foods included onion, garlic, guava, stargooseberries, fenugreek seeds, mushrooms, black, red and bangal, trichosanthes, bitter gourd, soy beans, oils of ground nut, soy bean and sunflower, almonds and walnuts. The control group of post -MI patients was instructed on a prudent diet reflecting the recommendations of the AHA and had usual care follow-up (and a small degree of deterioration of adherence). The Diet CP group had regular reinforcement one to twelve weekly depending on severity of the infarction (and continued adherence). Both groups received other advice for smoking cessation, reducing alcohol intake, managing stress and improving physical activity. Patients on Diet CP were recommended to eat tasty fruits and vegetables before major meals and when they were hungry and to avoid foods rich in energy, SFAs and cholesterol. The aim was to provide plenty of soluble fibre, antioxidant vitamins and minerals. Mean blood total cholesterol decreased by 12.7% on Diet CP, and 5.4% on Diet AHA. When Diet CP subjects were divided according to weight loss of gre ater than 5 kg and less than 5 kg , those who lost greater than 5 kg weight had a mean 17.3% reduction in blood total cholesterol versus 8.4% in those losing less than 5 kg. HDL-C rose 6% on Diet CP but changed little on AHA. The dramatic differences in mortality (Table_13) and CHD events (50 vs. 82 respectively, p<0.001) between diets were already evident after one year. The short period for effect suggests that factors of diet other than those contributing lipid changes, or other confounders, are involved.

In the Lyon Diet Heart Study, perhaps for the first time, a traditional diet concept was trialed in 227 another culture . However the Mediterranean diet protocol was introduced t o a population living only 100 km from the Mediterranean coast, and was modified in olive oil content to accommodate local preferences for other oils. The Lyon Diet Heart Study aimed to test the coastal Mediterranean diet typically rich in fruits, nuts, green and root vegetables, legumes, bread and other grains, olive oil and fish, and low in meats (poultry preferred) and animal and dairy fats. Butter and cream were to be replaced with a supplied margarine, moderate red wine was allowed with meals. Because patients would not accept olive oil as the only fat, a rapeseed oil-based margarine was supplied free to families of experimental subjects. The margarine comprised a fatty acid profile similar to olive oil - 15% SFA, 48% oleic, 5.1% trans -unsaturated fat and was higher in linolenic acid (16.4% vs. 8.6%) and LNA (4.8 vs. 0.6%) than usual margarine. This composition was considered advantageous for presumed benefits on platelet reactivity due to LNA. Cooking and salad oils were limited to rapeseed and olive oils. Dietary differences are listed in Table_15. Participants were presumed to be already following an AHA diet at recruitment, similar to the control diet assessment. There were no differences in blood lipid levels between intervention and control groups after a mean of 27 months follow-up, although significant differences in plasma fatty acids, vitamin E and vitamin C, reflecting dietary compliance, were reported. Instruction involved an initial instruction visit, an eight week follow-up and then yearly visits. Mean SFA intakes were 8.3% and 11% of energy for intervention and control groups, total fat intakes were -1 -1 30.5% and 32.7% and total PUFA intakes 4.52 g.d and 5.71 g.d . The authors report more than 70% reduction in m ajor coronary events (risk ratio 0.24; 95% CI, 0.07 to 0.85) and cardiovascular deaths (risk ratio 0.27; 95% CI, 0.12 to 0.59) and total mortality (risk ratio 0.30; 95% CI, 0.11 to 0.82) in the intervention group, and attribute most of the effect to the LNA content of diet. The protection against death, especially sudden cardiac death and all cardiovascular events was evident after only two months on the experimental diet. This study has not been repeated, and interpretation of the results continues to be debated, mostly on account of statistically low numbers of subjects and improbability of such a dramatic 252,253,254 effect from dietary factors alone . The authors have now published their techniques for 255 randomization and control of bias . The diet is not strictly a replication of the coastal Mediterranean diet due to the high content of rapeseed oil. Lack of reduction in blood total cholesterol levels may be related to higher intakes of SFA relative to PUFAs and low P:S ratio. These differences between end-point outcomes for control and experimental groups were 255 maintained up to four years after the first MI . Nineteen months after the completion of the study, more than 90% of the study participants were available for an extended follow-up assessment. After a mean of 46 months post-MI, there were 275 events in 144 experimental and 83 control subjects. For cardiac deaths and non-fatal MI the relative risk was 0.28 (95% CI, 0.15 to 0.53), and for primary and secondary endpoints combined 0.33 (95% CI, 0.21 to 0.52), for the intervention versus control diet groups. Risk was associated with blood total cholesterol; each -1 increase of 1 mmol.L increased the risk of recurrence by 20-30%. Thirty-four percent of control and 26.5% of experimental subjects were on lipid-lowering agents after four years. The final follow-up assessment included dietary analysis. Total fat, SFA, dietary cholesterol, and linoleic acid intakes were significantly lower, and oleic acid, linolenic acid and dietary fibre intakes were higher, in the experimental subjects compared with the control group subjects. The Oslo Diet -Heart Study of 412 men randomized 1-2 years after their first MI differed from the 251 Oslo Diet and Smoking Trial in that the diet was very rich in PUFAs, 20% of energy . The diets of a subset of compliant subjects were analysed. Linoleic acid supplied 39.7% of total fats (8% of energy), linolenic 6.7% (2.6% of energy), and other polyenoic fatty acids 6.3% (2.5% of energy) 251 due to fish and cod liver oil intakes. Saturated fats were 21.4% of total fat and MUFAs 25.7% . The P:S ratio was 2.4, and total fat 39% of energy. These especially compliant subjects achieved a 29% blood total cholesterol reduction from baseline, for the whole trial.

The dietary instruction was similar to that of the Diet and Smoking Trial excepting that a special butter substitute was made from soy oil and skim milk powder, until PUFA margarines became available. To increase the PUFA, soy oil was the only linoleic-rich oil on the market at the time. -1 The trial specified 500 ml.wk , taken by spoon if necessary, but also contributing to the intake of LNA. Advice to limit sugar intake was given. The substantially reduced five year mortality data is reported in the Table_13. Major CHD relapse was the only significantly different finding between groups (61 and 81 intervention and control, p<0.05). At 11 years of follow-up, five to six years after completion of the five year intervention, total mortality was 101 and 108 for intervention and control groupsrespectively, and CHD mortality was 79 and 94 (p= 0.097). Fatal MI was 44% lower in the intervention group (p=0. 004). No person from the original group had been lost to follow-up. Kallio et al have not reported detail of the dietary intervention used in their comprehensive 228 rehabilitation and secondary prevention programme . In the second year significantly more intervention subjects were taking beta-blocking agents, however the difference in mortality was greatest in the first year when beta-blocking agents were used equally between groups. The programme involved li festyle advice, including dietary instruction from a Dietitian, but blood total cholesterol was not reduced, and differences between groups were due to an increase in the control group. Angiographic trials

Although acute coronary events are triggered by multi-factorial events, angiographic trials have shown that dietary patterns have significant benefits for coronary arteries. Bucher et al included the STARS and Lifestyle Heart Trial in their meta-analysis of diet trials and CHD and all -cause 1 mortality, but at publication these trials had experienced only four and one deaths respectively . None of the experimental group patients used lipid-lowering agents, in these trials. In the STARS angiographic trial 90 men with CHD were randomized to receive usual care, 230 dietary treatment alone or diet plus cholestyramine resin . Mortality and CHD event outcomes were reported after three years follow-up. On the trial, the diet -only group achieved a 14% blood total cholesterol reduction from baseline while the diet -plus-Cestyramine group experienced a 25% decrease in cholesterol. High -density -lipoprotein-cholesterol levels did not change. In the dietary prescription, 27% of energy was from total fat, 8% to 10% from SFAs, 8% from omega-6 -1 PUFA and omega-3 PUFAs, P:S ratio 0.9 to 1.0, dietary cholesterol was 100 mg.4 MJ , and -1 plant-derived soluble fibre intake equal to 3.6 g polygalacturoneate per 4 MJ or 28 g.d total dietary fibre. In the STARS Study the proportion of patients showing overall progression of coronary narrowing was less in the diet -only and cholestyramine groups, 15% and 12% respectively, compared to 46% of the usual care group. The mean absolute width of the coronary segments studied decreased by 0.201 mm in usual care, 0.003 mm in diet -only and increased by 0.103 mm in the cholestyramine group. Further study found that in univariate linear regression analysis, progression of disease over 39 months as measure d by decrease in minimum absolute width of coronary segments, was directly related to energy intake (p<0.001), absolute intakes of total fat (p<0.001), SFA (p<0.001), MUFA (p= 0.016) and dietary cholesterol (p= 0.06).

Table 15. The Lyon Diet Heart Study. M ean intake of foodstuffs after 1 to 4 years follow -up in the two groups 256 (Adapted from Renaud et al ). Foods and nutrients

Control group

Lyon diet group

(n=192)

(n=219)

Meat

60.4

40.8

Deli foods

13.4

6.4

Poultry

52.8

57.8

Fish

39.5

46.5

Cheese

35.0

32.0

Dairy, butter and cream

16.6

2.8

145.0

167.0

Foods (g/d)

Bread Cereal/grain

99.0

94.0

Vegetables

288.0

316.0

97.0

91.0

Potato Fruit

203.0

251.0

Pulses/legumes

9.9

19.9

Margarine

5.1

19.0

16.5

15.7

149.0

152.0

Oils Wine Nutrients Total energy (MJ.d -1)

9.0

8.1***

% of energy Protein

16.6

17.2

Total lipid

32.7

30.5**

SFA

11.7

8.3***

18:1

10.3

12.9***

18:2

5.3

3.6***

18:3n- 3

0.27

0.81***

20:4n- 6#

0.070

0.041

20:5n- 3#

0.070

0.065

Alcohol

6.4

5.5

P:S ratio

0.69

0.65

Vitamin A (µg.d -1) #

548.0

279.0

Vitamin C (mg.d-1)

101.0

115*

Vitamin D (µg.d-1) #

2.8

1.6

Vitamin E (mg.d-1)

12.9

11.6*

Carotene (µg.d -1) #

5,539.0

Cholesterol (mg.d-1) #

Controls n=218, intervention n=227 Renaud et al

320.0

6,478.0 217***

256

Significantly different from control group * p<0.05, ** p<0.01, ***p<0.001.

These associations remained significant for total fat and SFA in multiple linear regression analysis adjusting for age and risk factors. Further analysis revealed correlations between minimum absolute width of coronary segments with palmitic, stearic, palmitoleic, and elaidic (t 18:1) acids and with intakes greater than three times per week of full-fat dairy products, fatty meat and meat products and foods high in both CHO and SFA (p<0.05 became non-significant 229 after adjustment for SFAs) . This diet was a carefully researched multi-component, low SFA, high fibre diet but there were no significant independent associations between width of coronary segments and PUFA, protein, 257 CHO, alcohol, dietary fibre intakes or P:S ratio . The Lifestyle Heart Trial is one of the most restrictive dietary patterns tested for prevention of 231 CHD relapse . The original study was reported in 1990, after one year. Thirty-five of the original 48 participants completed five years of study. The primary end -point was angiography. In this trial 28 subjects with known CHD were randomized to a very low fat, vegetarian diet comprised of 70-75% of energy from CHOs, 15-20% from protein, and 10% from fat plus moderate aerobic exercise, stress management and group support meetings. The control group were typically following an AHA St ep I diet, without other components of the lifestyle package. After one year, quantitative angiography of coronary artery lesions showed regression in average percent diameter stenosis from 40% to 37.8% in the intervention group, but progression from 42.7% to 46.1% in the 20 control patients. Overall 80% of the experimental -group patients had an average change towards regression, without the use of lipid-lowering drugs, while over half of control patients had progression. Overall adherence to the lifestyle changes was directly correlated with changes in percentage diameter stenosis and was sufficient to explain the observed differences, and were more important than age. These effects are seen when compared with a programme that is more likely to be used in practice. After five years further regression had occurred in the experimental group and differences between groups for percent diameter stenosis and minimum diameter were statistically 258 significant . Total fat content of the diet had increased slightly in the experimental group after five years (6.22% and 8.51% of energy at year one and five respectively), but the control group were now reporting risk reduction behaviour consistent with AHA Step II diet and were exercising. No lipid-lowering drugs have been used in the intervention group but 60% of control subjects have used lipid-lowering agents from year one to year five. In another report, patients following this lifestyle programme were able to avoid revascularisation procedures for at least 3 259 years . Intervention subjects have sustained a 5.8 kg weight loss at year five, after an initial loss of 10.9 kg in the first year, while control subjectsâ&#x20AC;&#x2122; weight has not changed. In the intervention group, LDL-C levels dropped 40% in the first year and were maintained at 20% less than baseline levels at year five, in those still in the study. In the Leiden Intervention Trial, 39 subjects with stable angina participated in a highly supervised, intervention using a vegetarian diet with 16.8% of energy from PUFAs and less than 232 8% from SFAs . The study design did not include a control group or a control diet. After two years progression of disease was shown in 21 of 39 patients, coronary lesion growth was correlated wit h blood total cholesterol to HDL-C ratio and was significant in patients who had values for blood total cholesterol to HDL-C ratio that were higher than the mean (>6.9). No coronary lesion growth was observed in patients with blood total cholesterol to HDL-C less than 6.9 throughout the trial, or who initially had higher values that were significantly lowered by the dietary intervention (Table_13 ). Schuler et al randomized 113 patients with stable angina after angiography, to a low fat phase three AHA diet (<20% of energy from fat) with intensive exercise, or a control usual care 233 group . After 12 months repeat angiography based on minimal lesion diameter, demonstrated progression of coronary lesions in 23% of intervention patients and 48% of control patients, and regression was seen in 32% of intervention and 17% of control patients. By comparison, new 217 lesion development reduced by 23% to 55% in seven trials of statin therapy . 72

Summary Secondary prevention trials have provided the most effective study group for short term or accelerated effect when studying interventions that modify dietary pattern. There have now been at least nine trials of dietary pattern modification that have achieved overwhelming results. The major shortcoming of these trials is that none have been repeated in another population. Trials describing dietary detail such as the Singh trial in India, the Lyon Diet Heart Study in France, the STARS Study in the UK the Oslo Study in Finland or the Lifestyle Heart Trial in the USA, need to be trialed in NZ. In common, these trials are reduced in dietary fat, restricted in SFA, with a low animal to plant food ratio and high intakes of fruits and vegetables, and except for the Lifestyle Trial, a source of unsaturated fats.

Therapeutic dietary patterns and risk factor trials Large intervention trials: Diet and risk factors Healthy individuals Diet Heart Feasibility Study 260

This trial was a pilot for a diet -heart trial involving 1,000 subjects . Different levels of total fat and SFA were trialed with very intensive counselling. Results included 10-14% reductions in blood total cholesterol. Food changes included supplied meat, baked products, oil, and low fat dairy products. A duplicate protocol was applied to 192 males in a mental hospital at the same time. The residential study achieved 100% of the predicted cholesterol lowering, while the free 196 living subjects achieved 75% of t hat predicted . Womenâ&#x20AC;&#x2122;s Health Trial Vanguard

This trial was designed as a pilot for a trial to test whether a low fat diet would reduce risk of 261 breast cancer in 264 women . Dietary instruction mainly foc ussed on fat intake and was individually specific. Changes in dietary fibre were not reported but total fat intakes dropped from 39% of energy to 22% in the intervention group, and CHO intakes increased from 44-59% of energy after 24 months of dietary intervention. Ratio of PUFAs to SFAs did not change since this was not addressed in the education. Blood total cholesterol levels decreased by 6.3% after 12 months in the intervention group. Energy intakes from meat halved, poultry and fish, and vegetables remained much the same, fruit intake increased by 40%, sweet intakes reduced by 36%, and separated fats and oils decreased to 44% of baseline levels, by 24 months. This study has been repeated in a larger population of 2,208 women including minority groups with a 262 smaller (10%) reduction in percentage of energy from total fat . High risk individuals Chicago Coronary Prevention Evaluation Programme

In a non-randomized, non-controlled study 519 individuals with at least two risk factors were individually instruc ted with specific dietary detail, bi -weekly then quarterly, and followed for at 263 least five years, after recruitment through industrial firms . In a subset of 150 subjects, reported reductions in total fat to 30% and SFA to 10% of energy, and reductions in energy and cholesterol intakes, were consistent with a mean blood total cholesterol reduction of 10% at four years (p<0.001). Body weight decreased 4.2% (p<0.001). Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT)

Subjects in this large scale drug trial participating in a 90 day diet/recruitment phase before randomisation reported reductions in body weight, dietary SFA and dietary cholesterol intakes 264 and increases in dietary PUFA, by 24-hour recall . These results were associated with blood total cholesterol and LDL-C reductions (mean pre - to post-diet blood total cholesterol decreased 73

265

8%) . The 6,494 subjects were instructed for lipid lowering designed to reduce blood total cholesterol by 3-5%. Significant diet responders were excluded from the main study. The total 3,806 subjects finally randomized in the main study had mean 4% reductions in blood total cholesterol levels during the dietary run-in. There was no control group since this was the placebo group in this short study. At the end of the study seven years later, the 1,899 placebo subjects (diet only treatment for lipid lowering) had maintained reductions of 4.8% in blood total cholesterol and 8.6% in LDL-C from their mean recruitment levels (LRC), which continued to be 264 associated with the reported dietary intake . The cholesterol lowering diet was assessed annually and clinic visits were twice monthly. Body weight and blood pressure did not change during the study but the percentage who smoked decreased. Community intervention trials: Diet and risk factors Healthy individuals The OXCHECK Study

This study assessed the effects of health checks in usual care patients by nurses in five suburban general practices in Bedfordshire UK, and was reported in 1994 after the first year of a 266 four year study . Nurses were instructed to counsel patients according to risk factors (including dietary instruction) using set protocols for repeat measurements. Blood total cholesterol, DBP and SBPs were all 2.3-2.5% lower in the intervention versus control group, but smoking reduction was not different between groups. Reported dietary changes from a food frequency questionnaire showed that of attendees (1,616 men and women) at re-examination, 19% fewer than controls (3,988 men and women) said they used full cream milk and 16% fewer used butter 247 and hard margarine. No improvement in mortality rates had been detected at four years . The Eating Patterns Study

This low intensity intervention involved a self-help book and physician endorsement encouraging use of lower fat, higher fibre food choices and a positive attitude in subjects recruited from 267 primary care practices . The self-reported 12 month outcomes included reductions in total fat -1 intake (1.5% of energy) and increase of 0.55 g.4.2MJ fibre, in the intervention group (n=859 vs. 959 in the control group). No significant changes in blood total cholesterol or (self-reported) BMI 267 were detected . High risk individuals Cost Effectiveness of Lipid Lowering Study

High risk individuals (n=681) identified with two risk factors in addition to elevated blood total cholesterol received intensive group education includi ng cooking and preparing food, led by a nurse or doctor, for personal risk factor management in addition to the usual care received by the 268 control subjects . After one year the intervention group had significant reductions in fat intake (p<0.001) and incre ases in fibre intake (p<0.001), lower blood total cholesterol concentrations and lower overall risk scores compared with the control group but there were no improvements in blood pressure, smoking, exercise or mortality (only 1.5 years duration). Hypertension and Detection and Follow -up Programme

This trial of 11,000 hypertensive individuals screened from a general population, involved diet, smoking, weight and exercise changes according to risk but the emphasis was use of 269 antihypertensive agents, for five years . Despite no change in smoking rates or blood total cholesterol levels, blood pressure reduction reduced mortality and morbidity from CHD and stroke (odds ratio, all-cause mortality 0.82; 95% CI, 0.71 to 0.95, CHD mortality 0.88; 95% CI, 247 0.69 to 1.11) .

John Hopkins Education Hypertension Study

This smaller trial of 400 hypertensive individuals from a clinic setting, utilised weight reduction, general health advice with counselling and family support , and antihypertensive medications for 270 five years . The odds ratio for all-cause mortality was 0.39 (95% CI, 0.18 to 0.84) and for CHD 247 mortality was 0.37 (95% CI, 0.16 to 0.88) for the experimental group versus the control . Other Community Studies

A number of other community studies have involved dietary and risk factor education of varying intensity in usual care but mixed risk populations with total participation rates of 200-9,300 individuals. These ha ve been conducted in primary care settings : the British Family Heart Study the Abington Study, the Tromso Family Trial and in occupational groups: the Primary Prevention 271,272,273,274,275 of Hypertension Trial, the Take Heart Study . These trials have reported very little on dietary assessment and risk factor reduction has been very small. Meta-analyses of Risk Factor Trials

Two meta-analytical studies have reported risk factor outcomes from trials of primary prevention, where change of diet has been a major compon ent of the intervention. Ebrahim and Davey Smith systematically reviewed and meta-analysed RCT testing more than one (multiple) risk factor 247 intervention for preventing CHD in workforces or in primary care . The nine trials measuring 206,207,208,209,249,266,268,269,270 clinical outcomes have been discussed above . Only the two hypertension trials above, the Hypertension Detection and Follow-up Study and the John 269,270 Hopkins Study, achieved reductions in mortality . Five trials measured risk factor outcomes 271,272,273,273,271 alone . A further 21 trials found in the western literature did not meet criteria for randomisation, risk factor measurement, application of the intervention or duration of at least 26 weeks of follow-up. All selected trials reported dietary intervention aiming to change dietary patterns. Two trials did not report smoking or blood total cholesterol reduction and three trials did not report blood pressure suggesting less focus on these risk factors in these 206,269,271,272,273 trials . The reviewersâ&#x20AC;&#x2122; conclusions were that changes in risk factors were modest and related to the pharmacological treatment-mainly anti-hypertensives -less than 3% were taking cholesterol 249,268 lowering drugs by the end of intervention in any study but two . In the only study involving HMGCoA reductase inhibitor drugs, the number of subjects taking cholesterol lowering agents 268 were equal between intervention and control groups at the end of the intervention . The pooled odds ratios for total and CHD mortality were 0.97 (95% CI, 0.92 to 1.02) and 0.96 (0.88 to 1.04) respectively. The authors state that a small but potentially important 10% reduction in mortality may have been missed due to methodological differences. They project that national and fiscal changes aimed at food and social changes would be more effective than a reliance on health education programmes applied to community and workforce populations. Brunner et al meta-analysed the effects of randomized controlled single-factor (diet) interventions targeting cardiovascular risk factors in free-living subjects, where less than 25% were diagnosed with CHD (primary prevention), none took cardiovascular drugs and were 276 followed up for at least three months . Of 17 trials in the analysis, ten measured blood total cholesterol, and eight measured blood pressure, three measured only dietary variables (energy from fat as % of non-alcoholic energy) and four measured only blood pressure. Interventions mainly utilised group teaching or individual counselling. The most intensive trial, involving -1 monthly visits with a Dietitian achieved a blood total cholesterol reduction of -0.8 mmol.L but all 277 trials demonstrated reductions of blood total cholesterol . The estimated overall mean net -1 reduction for trials of three to six months was -0.28 mmol.L (95% CI, -0.42 to 0.15) and trials -1 extending to nine to 18 months -0.22 (95% CI, -0.39 to 0.05) mmol.L . Overall net change in DBP for trials three to six months was -0.7 (95% CI,-1.5 to 0.0) mm Hg and in SBP -1.3 (95% CI, -2.4 to 0.3) mm Hg and in trials nine to 18 months -1.2 (95% CI, -2.6 to 0.2) and -1.9 (95% CI, -3.0 to 0.8) respectively. Studies measuring change in fat intake indicated a proportional net reduction of 6% of energy, excepting for two breast cancer prevention studies achieving 40% 261, 278 reductions . The nine to 18 month results represented 3.7% and 1.4% reductions in blood

total cholesterol and DBP respectively, translating into an estimated 14% reduction in CHD risk taking regression dilution bias into account. In community studies, poor clinical and/or biochemical outcomes appear to be at least as common as successful outcomes. Variations in duration and intensity of studies, and the selection of subjects, reduces the usefulness of meta-analyses. Randomized controlled trials impose limit ations on the nature of interventions that may be tested, and may be of more value 247 for examining high risk rather than population and social approaches to prevention . Changes in dietary pattern appear to require intensive dietary monitoring and occur in an already changing food environment, tending to preclude clear differences between intervention and study groups. Multiple dietary end -points may overcome these secular trends. Problems inherent in self 279 reporting of behaviours are also to be considered in the interpretation of outcomes . Dietary instruction has been inconsistent in content and intensity throughout the studies of the meta-analyses but dietary patterns were modified mainly for fat intake to lower cholesterol and for salt and/or energy to lower blood pressure. Community studies of primary prevention are not to be rejected for lacking the results of clinical dietary trials. Freedman et al, in discussing the monitoring of results in the Women’s Health Initiative Study argue that prevention trials should emphasise more global measures of health and not simply a single targeted disease (or single risk factor) particularly when an intervention 280 may reduce the incidence of one disease but increase the incidence of others . Multiple risk factor trials enable the test of multiple variables or the “best overall dietary pattern” since it is impossible to change just one aspect of diet, and that in practice dietary changes occur 279 together . However if change is not achievable or sufficient to yield a wide-scale benefit then new approaches and study designs will be necessary. Confounding influences such as lack of control for multiple risk factors and differences in dietary methodology, application techniques, population genetic make-up and the community settings, will all affect response rates. Summary

Large dietary intervention trials reduce blood total cholesterol levels in healthy and high-risk populations . Community trials that involve education for changing dietary patterns tend to produce only small changes but trials targeting blood pressure combined with other lifestyle interventions have produced reductions in CHD mortality in high risk populations. Therapeutic dietary patterns: Lipids and lipoproteins

Hyperlipidaemia has been the focus of recommended anti -coronary dietary patterns in westernised countries for the four decades leading up to the 1990's. Metabolic studies testing the effectiveness of di etary change on lipids have provided the evidence for current dietary recommendations. Study results have been as highly variable as has individual responsiveness. The effectiveness of cholesterol -lowering diets is enhanced when individualised counselling is 196 used, follow-up is maintained and weight reduction is achieved . Genetic and compliance issues are also contributory. Since the Keys and Hegsted equations were published, seven meta-analyses and two ex tensive reviews have specifically analysed the effects of diet on lipids and 281,282,283,284,285,286,287,288 lipoproteins . Lipid and lipoprotein responses to dietary fat and cholesterol

Howell’s meta-analysis applies multiple regression analysis to the plasma lipid and lip oprotein responses to dietary fat and cholesterol in 224 dietary studies published between 1966 and 281 1994 . The aim was to develop prediction models from a wide range of studies and study subjects excluding trials reporting weight loss, or studying the effects of supplements, fish oils, trans -unsaturated fat or hydrogenated fats. The comparisons for each study were derived within the intervention group, between initial and final values, for dietary change an d blood lipid response variables. The prediction equations indicated that compliance with a diet of less than -1 30% fat energy, less than 10% SFA energy and 300 mg.d dietary cholesterol will lead to a 5% 76

reduction in plasma total and LDL-C compared with the average American diet as identified in -1 NHANES II; 37% fat energy, 385 mg.d cholesterol, PUFA 7% energy, MUFA 17% energy, SFA 289 13% energy . Howell et al concluded that the regression models were little affected by interactions with other 281 dietary factors, initial dietary intakes or blood lipid concentrations, study or study subjects . This confines the effects of dietary lipids to plasma lipids and lipoproteins. Many trials achieving greater cholesterol lowering than 5% may have been influenced by choice of subject and previous diet. This analysis, whilst addressing the finite effects of a modified lipid diet, did not explain the effects of greater reductions in SFA or change in other nutrients or foods, and ignores other components of the dietary pattern. This same diet, less than 30% of energy from total fat, less than 10% from SFAs and 300 mg 290,291 cholesterol has been recommended since the first AHAand NCEP Diets . The AHA and NCEP Step I and II diets, the most studied cholesterol -lowering diet programmes in the world, 290,291 were initially both published in 1988 (updated 1996 and 1993 respectively) . The AHA and NCEP diets are identical. Step I diet is defined as: less than 30% of total energy as -1 fat, 8 to 10% as SFA, P:S ratio greater than 1.0, dietary cholesterol less than 300 mg.d and energy intake to achieve desirable body weight. In Step II, SFA is further reduced to 7% or less -1 of energy, P:S increased to 1.4 and dietary cholesterol further reduced to less than 200 m g.d . The AHA Statement on the efficacy of hypocholesterolaemic dietary interventions states that Step I diet can be expected to lower LDL-C by 7-9% and Step II diet by 10-20% and further 292 reduction of fat and SFA (Step III) by 20-25% . Recently, blood total cholesterol lowering of 1015% has been attributed to metabolic ward studies or externally regulated dietary intake, and 282,286 argued as too difficult for free -living individuals to achieve . A wide variation in individual blood total cholesterol response has been reported for the NCEP 293,294,295 Step I diet (50 men) and the NCEP Step II diet (72 men and 48 women) . Non-responders number 5-25% of different populations, but in 15-25% of individuals, dietary therapy provides 296 LDL-C lowering equivalent to drug therapy . Individual response also depends upon baseline dietary habits and subsequent degree of lifestyle change. Mensink and Katan meta-analysed 27 metabolic ward trials addressing the effects of fatty acids 283 on blood lipids and lipoproteins before recommendations uniformly involved dietary fibre . While these trials addressed differences in sources of dietary fats, sources of CHO and fibre (non-starch polysaccharide), and fatty acids were not controlled between studies. The translation of these strictly controlled an d precisely defined regimes, followed for short periods of time, into dietary patterns for populations to practice for a lifetime, first requires the observation of such diets in free-living subjects. Nutrient analysis, whether or not confined to energy and dietary lipids does not however, represent potential food factors within dietary patterns of free-living individuals that may also contribute to reduction of CHD or risk. Lewis and Katan investigated the additive effects of 257 changes in nutrients, in a st rictly controlled institutional feeding experiment . The addition of -1 fruit, vegetables and cereal fibre (55 g.10.5MJ dietary fibre) to a modified fat diet (27% energy as fat, P:S ratio 1.0) increased the reduction of blood total cholesterol from 22-29%, LDL-C -1 lowering from 26.5-34.5%. The addition of fruit, vegetables and cereal fibre (43 g.10.5MJ dietary fibre) to a 40% fat energy diet with P:S ratio 1.0 produced an intermediate effect. The researchers then tested this optimal diet in 37 normal and hyperlipidaemic free-living subjects achieving mean reductions in total plasma cholesterol, LDL -C and TGs of 22%, 25% -1 297 and 24% respectively. The dietary pattern provided 52 g.8.4MJ fibre . Such diets have been criticised as unrealistic, however other trials achieving ten to greater than 20% reductions in 282,283,286,287 blood total cholesterol and LDL -C have been reported in free-living subjects . Among trials included in two recent meta-analyses of lipid lowering diets in free-living subjects Tang et al, and Yuh-Poth and Kris -Etherton et al, some used more comprehensive modification 286,287 of the whole dietary pattern with variable intensity, rather than a simple lipid focus . Close scrutiny of these analyses can reveal dietary explanations for those studies not achieving greater 77

than 10% blood total cholesterol reduction from baseline values. Most of these trials report methods and results for change of dietary lipids alone, and do not report other aspects of diet or how dietary fat modification may affect the quality of the CHO component of diet. Dietary interventions to lower blood total cholesterol

In their systematic review of RCTs of dietary interventions to lower blood total cholesterol (19 trials with 28 comparisons, of at least four weeks duration and published before1996), Tang et al has separated the effects of AHA Step I-style {a}, Step II-style diets {b}, high PUFA diets {c} and 286 low fat diets {d} in free-living i ndividuals . This study eliminated multiple factor interventions and trials involving weight loss. Cholesterol lowering greater than 10% in the experimental group compared with the control group was report ed for six trials, either at the end of the trial or at 12 months: Sciarrone et al 1992 {a}, Ehnholm et al {a}, Watts et al {b}, National Diet-Heart Study 2A and 2D 1968 {b}, and Leren 1966 {c} where diet {a} equals less than 30% total energy as fat, 8% -1 to 10% as SFA, P:S ratio greater than 1.0, dietary cholesterol less than 300 mg.d and energy intake to achieve desirable body weight and diet {b} equals less than 30% total energy as fat, 7% -1 or less as SFA, P:S ratio greater than 1.4 and dietary cholesterol, less than 200 mg.d dietary 229,251,260, 298,299 cholesterol (Table_16). All six trials involved dietary modification above the lipid modification required by the categories. They also recorded higher intensity ratings for dietary education and greater prediction for cholesterol reduction using the Keys formula. However the apparent com parison with a control group did not demonstrate the full cholesterol lowering efficacy for some of the diets in this analysis. Entry to study effects led to cholesterol reductions in some control groups, and increases in others while others stayed the same. In several studies the reported control diet was in fact another diet study or control subjects took on similar but lesser dietary changes as the 218,221,222,230,298,299,300,301,302,303 experimental group . In one study the experimental and control 225 groups involved some subjects on concurrent dietary changes for another study . When comparisons are made between baseline values and the end of the study period within individuals, five other studies join those achieving greater than 10% blood total cholesterol 218,221,301,300,303 reduction . Excepting for the last two trials which have been discussed previously (Table_13), the nine trials are distinguished from other trials by instruction to increase wholegrain, fruit and vegetable intakes, in addition to the dietary lipid changes required by the 218,221 Step I or Step II diet, high PUFA or low fat specifications . Enhanced cholesterol lowering may be a subtle independent or combined effect of plant sterols, different types of fibre, flavonoids, plant proteins or other plant structures within the food choices for these diets. One of these studies directly compared the AHA diet with added dietary fibre and without added dietary 300 fibre . Total cholesterol lowering was 13% and 9% respectively. Of those intervention studies not ac hieving 10% cholesterol lowering from baseline values, 304 excepting for one trial , none reported instruction to increase fibre intake, four trials had low 272,302, 305,306 mean baseline blood total cholesterol levels , two had no instruction to change the P:S 305, 307 304,308, ratio , two did not achieve dietary targets for SFA intakes , four lack clear dietary data 226,272,302,304 272 at baseline for assessment and one had limited dietary assessment and less intensive education.

Table 16. Dietary instruction additional to dietary lipid modification. (Studies from Tang et al meta-analysis 286 achieving greater 10% blood total cholesterol reduction ). Trial

Dietary instruction 298

At least 3 srv.d-1 vegetables, and 2 srv.d-1 fruit, dried fru it supplied and high fibre advice, and modified sodium intake.

Sciarrone

299

Strongly encouraged use of vegetables, including beets, and berries and fruits, some foods were supplied.

Ehnholm Watts

230

AHA 2A

Plant-derived soluble fibre equivalent to 3.6 g polygalacturonate, high fibre individualised advice.

260

Defined exchange diet and 5 servings vegetables per day.

260

Defined exchange diet and 5 servings vegetables per day.

AHA 2D

251

Encouraged fibre-rich bread and use of vegetables, included stopping smoking, reduced stress, exercis e and lifestyle advice.

Leren Kuusi

301

Anderson

Strongly encouraged use of vegetables, including beets, and berries and fruits. 300

Demark- Wahnefried

Included specific high fibre advice. 303

Included advice for high intake of oatbran.

Effect of dietary interventions on cardiovascular risk factors

The Yu-Poth and Kris Etherton meta-analysis of RCTs has specifically analysed the NCEP Step I and Step II dietary program on cardiovascular risk factors but also mixes trials with differing dietary criteria, including trials achieving weight loss, as short as three weeks duration and as 287 long as several years, but the criteria s pecifies that subjects are free-living . Some studies are 286 duplicated in the Tang study . Trials selected for this analysis achieving greater than 20% (Table_17) and 10-20% blood total cholesterol reductions (Table_18), demonstrate nutritional and food qualities in common. These qualities support a recommendation to modify whole dietary patterns for reducing risk of CVD. In the absence of intervention trials where a traditional dietary patterns of a lower risk population has been tested in a high risk population, observation of the instruction used in these very successful trials may explain some epi demiological associations. Trials in this meta-analysis not achieving greater than 10% blood total cholesterol reduction can be explained by the whole dietary pattern. -1

Mean baseline blood total cholesterol levels in all of these studies are less than 7 mmol.L -1 206 except for the Hjermann study (mean 8.7 mmol.L ) . In five studies the mean baseline -1 305, 309,310,311,312 cholesterol level was less than 5.5 mmol.L . The methodologies used in these trials differ in several aspects. In the Oslo Diet and Smoking Trial, subjects were individually 206 counselled according to their dyslipidaemia and need for weight reduction . The general dietary principles were comprehensive. For subjects with elevation of blood total cholesterol as the only risk factor, the main instruction was reduction of SFA and a small increase in PUFAs (after 4 years, PUFA intake was 7.1% of energy in the cont rol group compared with 8.3% in the intervention group). For lunches, foods recommended were fibre -rich bread, with/without margarine, fish and vegetable fillings were preferred, low fat dairy and meats were also acceptable. Skimmed milk only and one egg per week were allowed. Dinner meals were fish, whalemeat, or low fat meats with potatoes and vegetables. Polyunsaturated oils were to be used for cooking, baking and sauces, and fruit eaten for desserts. Sugar and alcohol intakes were addressed where indicated for elevated TGs and/or weight control. Advice to stop smoking and dietary advice was also given to the spouses of the subjects (who were all men), in group teaching. Blood HDL -C levels almost doubled in this study, possibly reflecting the length of t his study.

Table 17. Trials achieving greater than 20% total and LDL -C reduction (identified from Yu Poth Trial

Duration

Biochemical changes

206

299

Ehnholm

Women Men

309

Dietary composition

% change from baseline

Hjermann

287

% Energy

Ratio*

Intake

LDL- C

HDL- C

Wgt loss (kg)

Total fat

SFA

P:S

Fibre (g)*

4 yr

-19.6

-28.6

75.7

-32.1

-3.6

28(NR)

8(NR)

1.0

6 wk 6 wk

-21.4 -23.5

-23.8 -25.9

-15.9 -18.6

-16.5 -22.9

NR -0.7

24(39)

9(22)

1.18

6.6 (4) (crude) NR

-4.5

-38.2

-11.0

30(35)

8(11)

1.0

9 mths

-20.0

-20.5

312

1 yr

-20.8

-19.7

-43.6

-11.0

29(36)

0.97

26(19)

231

1 yr

-24.3

-37.2

-3.0

22.3

-10.1

7(32)

<1.0

Yes

3 wk 3 wk

-24.4 -20.8

-25.1 -20.7

-11.7 -19.4

-37.9 -40.0

-3.3 -5.1

<10(NR)

Yes

3 wk

-22.0

-23.2

-19.7

-26.4

-4.0

<10(NR)

2(NR)

1.24

Yes

4 yr

-16.6

-23.3

-11.8

-19.8

-3

24(32)

7(10)

1.05

Yes

Dengel Katzel

Ornish

Barnard Barnard Haskell * NR

313

314

315

Women Men

Value in bracket is diet at baseli ne. Not reported.

The dietary detail was very similar for the Ehnholm study, in North Karelia, Finland. For both studies the baseline diet was very high in total fat (around 40% of energy) and SFA (18 to 20% 299 energy), due to high intakes of dairy fats . This study was lower in total fat and the 18% -1 -1 reduction in HDL-C in this study, was a drop from 1.40 mmol.L to 1.14 mmol.L , however the study was only six weeks long. It involved intensive family educ ation and twice weekly home visits from Dietitians. Modified strategic food items were PUFA margarine, skim milk, lean meats, low fat sausage and cheese to replace regular items, and specific increase in use of vegetables, beets, berries and fruits. The Dengel and Katzel studies are from the same research group, the “Fitness After 45 Research Programme”, and these nine to 12 month studies have relied on substantial weight 309,312 loss for their dramatic lipid lowering effects . Both studies also achieved significant lipid lowering in the non-weight loss arms of the study and are reported in the 10-20% cholesterol lowering bracket (Table_18). Although using Step I diets, these studies involved intensive education with weekly evaluations, precise calculation and instruction of energy requirements using food exchange lists, and small numbers of subjects. The Ornish diet, the “Lifestyle He art Trial”, is a low fat vegetarian diet, allowing ad libitum 231 consumption of fruits, vegetables, whole grains and legumes . The only animal products allowed were one cup of non-fat milk or yoghurt daily and egg white. The diet had less than 10% of energy from fat, 70-75% from CHO. Coffee was not allowed. Some meals were provided. That -1 -1 mean TG levels increased from 2.38 mmol.L to 2.91 mmol.L , suggests that some subjects were hypertriglyceridaemic at baseline. This increase was not significantly different from the control group. High density lipoprotein cholesterol was not compromised by this very low fat diet. The blood total cholesterol to HDL-C ratio improved, and the LDL-C:HDL-C ratio improved significantly. Table_17 shows cholesterol reduction for the first year, however mean cholesterol reduction for subjects remaining in intervention at five years continued at 16.5% lower than 259 baseline when subjects were already stabilised on a diet with 31.5% energy from fat . 313,314

The two Barnard studies are from the Pritikin Longevity Centre, California . In these two reports, although apparently meeting criteria for this analysis, before and after lipid testing was only three weeks apart, and subjects were strictly speaking institutionalised. They report the results of the 26 day residentia l educational programme at the centre. During the programme subjects were served and taught to prepare meals in accordance with the eating plan, attended lectures and a supervised exercise programme. The diet was less than 10% fat energy, P:S ratio 80

1.24, and 75-80% of energy was from CHOs. Animal foods were limited to low fat dairy products -1 and less than 100 g.wk fish or poultry week. Carbohydrate sources were vegetables, fruits, legumes and whole grains. -1

Dietary fibre was estimated as 35-40 g.4.2 MJ of energy intake. No alcohol or caffeine was allowed. The modest weight loss needs to be interpreted with respect to the short time frame. No individual dietary analysis was performed, and there was no control group. The HDL-C reduction is to be expected given the short time frame, very low fat diet, and extent of blood total cholesterol lowering. The Ornish and Barnard studies have been dismissed as impractical for the average person, and long term outcomes of very low fat diets continue to be debated, but the results on blood lipids and blood pressure are impressive, especially when there is weight loss, and are indicative of 316,317,318,319,320,321 the potential effects of dietary pattern changes . The studies in this section include another study from the Finnish grou p of Ehnholm et al, 325 achieving similar results . The Katzel and Dengel studies are the weight maintaining intervention groups of the two studies reported with greater than 20% cholesterol reduction. Other t rials in this section include another Finnish trial, using a similar protocol and diet as the 301 Ehnholm study . By six weeks Group I achieved 18% blood total cholesterol reduction and similar HDL-C reduction as at 12 weeks. A subset of this trial (II reported above), were provided with a half butter/half margarine mixture in place of the PUFA margarine to alter the P:S ratio of the total diet from 1.0 to 1.2, to 0.4 to 0.5. This difference reduced the extent of cholesterol reduction, but in neither group was the drop in HDL-C attenuated by this reduction in PUFA. The large drop in HDL-C may be due to the dramatic reduction in dietary SFA and the short duration of the study. The Dietary Alternatives Study, studied four levels of fat intake within the NCEP guidelines, 30%, 26%, 22% and 18% of energy, with fibre intake from foods progressively increased from the 322 highest to lowest fat diets . Target fat levels were not quite achieved, nor were the cholesterol responses linear with fat restriction. The 22% fat energy diet achieved LDL-C lowering similar to -1 the 26% fat energy diet, TGs rose 28% but remained in the normal range (1.4 mmol.L from 1.1 -1 mmol.L ), suggesting no advantage for lipid lowering from reducing fat intake to less than 25% of energy. Subjects in the Singh studies were already consuming low fat, low SFA diets prior to 223, 323,324 baseline . In the mortality study previously discussed (Table_13), all subjects were recruited and stabilised on a prudent diet in hospital and in the Indian Diet Heart Study, subjects 324 with CVD were recruited through public media and all were instructed in AHA Step I diet . Control subjects in both studies were eating equivalent to an AHA Step I diet. The results -1 therefore undermine the full lipid-lowering potential of this very high fruit (>500 g.d of fruit and vegetables) semi -vegetarian diet. In study and control diets, meat and eggs were replaced with fish, vegetarian products and nuts and hydrogenated oils, cheese, butter and clarified butter were replaced with soy beans, soy, sunflower or peanut oil and cottage cheese. Subjects were encouraged to eat plenty of legumes -1 -1 and cereals, nuts and seeds, both groups eating eggs 4-5 wk and meat 1-2 wk . In addition, the specific intervention group were instructed to increase fruit and vegetable intakes to greater -1 than 400 g.d and to increase pulses, nuts and fish. More than 70% of their fibre intake was soluble fibre or from fruit and vegetables, especially exotic fruits like guava, banana, stargooseberries, papaya, grapes, limes and traditional Indian vegetables and additional legumes. In the specific diets the P:S ratio increased from 0.62 upto 1.33, MUFA intakes remained stable while SFAs dropped from 10% down to 7% of energy. Antioxidant nutrient intakes increased significantly, and animal protein comprised less than 3% of energy.

Table 18. Trials achieving 10-20% blood total cholesterol reduction (identified from Yu Poth et al Trial

Duration

Biochemical changes from baseline % change from baseline

Enholm

Wt loss (kg)

Total fat

SFA

P:S

Fibre (g)*

6 wks

-13.5

-18.7

-9.9

-5.1

-1.1

23 (39)

7 (23)

0.98

3 mths

-11.8

-10.3

-7.1

-25.8

-1.0

28 (36)

0.89

26 (19)

9 mths

-10.6

-15.4

-2.4

30 (35)

8(12)

0.87

2.9/MJ

Men

12 wks

-9.5

-10.7

-10.8

1.5

22 (38)

10(20)

0.9(0.2)

-15.9

-17.3

-17.9

-1.5

22 (38)

8(20)

0.4(0.2)

Women

12 wks

-12.9

-15.2

9.5

23 (38)

10(20)

0.9(0.2)

-15.2

-16.9

-16.4

-3.9

-1.5

22 (38)

8(20)

0.4(0.2)

1 yr

-10.4

-14.1

0.8

2.5

-3

26(38)

7 (13)

1.0

29(20)

1 yr

-9.0

-18.9

-4.4

28.4

-2

22(36)

6(12)

1.0

33(20)

Dengel

326

223 323 324

Singh

327

310

Kasim

52(27)

No No No Yes No Yes

1 yr

-12.7

-12.3

6.1

-14.9

-7.6

24(26)

7 (10)

1.9

12 wks

-9.1

-10.0

3.3

-11.2

-3.7

28(NR)

6 (NR)

6 wks

-9.5

-10.8

4.2

-12.3

-1.7

25(27)

8(12)

1.06

48.4(24)

4 wks

-13.5

-16.8

6.7

-1.9

-3.6

25(27)

7(12)

1.3

48.9(24)

8 wks

-11.5

-13.1

-3.8

-3.1

-1.5

28 (37)

9 (13)

0.73

8 wks

-8.0

-9.6

-5.3

-4.3

-1.8

28 (37)

10 (13)

0.67

No Yes

1 yr

-6.5

-12.8

-7.7

17.4

-3.4

18 (36)

6 (12)

48(NR)

2 yrs

-10.1

-3.0

-1.22

7 (12)

2.5

329

6 wks

-16.2

-11.6

-17

-4.7

18 (36)

Yes

328

-9.5

-10.7

-10.8

1.5

23 (38)

10(20)

0.9(0.2)

23(8)

Arntzenius Seim Baer

Intake

309

Davidson

Ratio*

HDL- C

Katzel

Knopp

% Energy

LDL-C

312

Kuusi

Dietary composition

325

301

287

Value in bracket is dietary value at baseline.

Not reported.

Davidson et al studied subjects who habitually consumed high fat diets, with Step I diets (diet I) 327 and Step I diet with five quick service meals per week (diet II) . Although these diets were not very rich in fibre, the dietary fat reduction was substantial. The dietary education was intensive and individualised involving provision of dietary scales and food portions, counselling in counting grams of fat, a commitment to individual lifestyle goals, and exact instruction in energy intake to maintain body weight. Diet I achieved better cholesterol reduction. Weight loss was predicted to explain 25% of the blood total cholesterol reduction. The Stanford Coronary Risk Intervention Project (SCRIP), was an intensive multiple risk factor trial over 4 years. It involved three grades of intervention: minimum to maximum. The focus of dietary education mainly concerned dietary fats, however by the fourth year 90% of intervention subjects were taking lipid-lowering medications, obscuring the impact of dietary chan ges. The Leiden Intervention Trial was an angiographic study, in which the lipid responses to the 232 vegetarian diet were reported . The paper does not provide dietary detail but describes intensive supervisi on. Fibre intake was not reported but the P:S ratio and vegetarian nature of the diet suggest a high fibre intake. Subjects were already consuming a relatively high PUFA diet at recruitment (mean P:S ratio, 0.91), but then reduced SFA intake by 50% and dou bled their PUFA intake. These changes were confirmed by linoleic acid content of blood cholesteryl esters and compatibility with Keys score predictions. Baer et al studied 80 management level employees in a comprehensive work -site nutrition 328 education programme in Cincinatti . The intensive and individualised dietary education used computer printout feedback, personal goal setting, and specific advice for the Step I diet and to 82

increase dietary fibre intake. Seim and Holtmeier et al trialed a low fat, low sodium diet also with 329 a high fibre component and an exercise programme . These important studies of middle -range cholesterol reduction provide dietary patterns of practical efficacy for reducing CHD. High plant food and fibre intakes, a P:S ratio of greater than 0.85, inclusion of physical activity and weight loss have enhanced the outcomes of changes in dietary patterns. When the full dietary pattern is considered, explanations can be suggested for the 12 t rials that failed to achieve greater than 10% blood total cholesterol reduction. Some trials did not meet 293,311, 330,331,332 dietary targets or the reduction in fat intake was very small . These and others report dietary lipid instruction exclusively without reference to specific increase of wholegrain, fruit and vegetable intake or dietary fibre, and/or do not mention control of refined sugar or starch 293,311,330,331,332, 333 intake . Others included no instruction to increase unsaturated fats or the P:S ratio or the subjects were already on fat -modified diets prior to recruitment to the 227,233,278,310 study . In the Dietary Alternatives Study, the highest fat level (27% of total energy) 326 also had the smallest increase in dietary fibre . The baseline blood total cholesterol level was low for other studies and the Boyd study of healthy women, demonstrated greater cholesterol 278,310,311 reduction the higher the baseline cholesterol level . In the Campbell’s Centre for Nutrition and Wellness Trial, the large numbers suggest a 334 community approach . Five hundred and sixty men and women from 10 medical centres were involved in a programme in which half the subjects were randomized to receive their main meals in pre-packaged form to which they added extra fruit, vegetables and low fat dairy servings. The remaining subjects were instructed to self-select their own diets, but were instructed how to achieve the same nutrient intake as the packaged diet. The dietary aims were to achieve total energy intakes comprising 17% from fat, 62% from CHO, and to otherwise meet nutritional guidelines for SFAs, refined sugars, fibre and micronutrients. Subjects on the pre-packaged diet -1 reported total fat intakes of 18% of energy, 6% of energy from SFAs and 30-35 g.d of fibre -1 daily. The self-selected subjects reported 25% and 8%, and 21-27 g.d respectively. Weight loss was 4.6 kg for the pre-packaged diet and 3.2 kg for the self selected diet, and blood pressures improved over the ten weeks of the study. Blood cholesterol reductions were 5.5% and 5% -1 respectively possibly due to low baseline cholesterol levels (5.69 mmol.L ), low baseline SFA intakes – 10% -11% of energy, less supervision than other studies, and that for such high CHO intakes, the fibre content appears low. High density lipoprotein cholesterol levels dropped 2.6% and 1.7% respectively. For these two meta-analyses, the criteria for identifying Step I and II diets was confined to dietary lipids and dietary cholesterol. Together with an increase in “complex CHOs”, these were the original AHA 1980's guidelines for Step I and II diets. It wasn’t until 1996 that the AHA released new guidelines with specific recommendations for dietary fibre, fruit, vegetable and 335 wholegrain cereal intakes and liberalisation of MUFAs and reduction of PUFAs . The NCEP 336 updated in 1994 however fats remain the major focus of both guidelines . Those dietary trials instructing subjects to specifically increase dietary fibre and/or whole grain and plant foods rather than “complex CHOs” were ahead of the new guidelines and clearly achieved better results. Summary

Compared to the traditional approach of dietary lipid modification, a large number of dietary trials demonstrate greater efficacy for improving blood lipids and lipoprotein with a more comprehensive approach. Optimal lipid lowering requires both a reduction in SFAs to less than 8% of energy and a change in P:S ratio, even in very low fat diets. Nutrient analysis does not account for potential food factors within dietary patterns of free-living individuals that may also improve risk factors. Increased consumption of fibre and phytochemical-rich foods with a substantial increase in wholegrain, fruit and vegetable intakes, add to the lipid modifying potential of diet. Enhanced cholesterol lowering may be a subtle independent or combined effect of plant sterols, different types of fibre, flavonoids, plant proteins or other plant structures within the food choices for these diets. Therapeutic diets have the potential to achieve mean reductions in LDL-C and TGs of up to 35%, and reductions of 10-20% are common. Individual intensity of 83

dietary education, risk profile and dietary responsiveness are factors determining the potential outcomes of the dietary intervention. Trials failing to achieve greater than 10% blood total cholesterol reduction, either do not meet dietary targets or the reduction in SFA intake from baseline is very small or the intervention does not report increase of wholegrain, fruit and vegetable intake or dietary fibre in the group studied and/or do not mention control of refined sugar or refined starch (high GI) intake or do not increase the P:S ratio or baseline blood total cholesterol levels are low. Therapeutic dietary patterns: Blood pressure

Blood pressure is a risk factor for hypertension and cardiovascular events including MI and 337 stroke . Reductions of 5-6 mm Hg of DBP have been associated with 14% reductions in CHD 338 and 40% reductions in stroke rates . High intakes of vegetable products, vegetarian diets and fruit have been associated with lower blood pressure levels and low stroke rates world102,103,104,337, 339,340,341 wide . The blood pressure response to a vegetarian diet has been attributed 342,343 to multifactorial nutrient changes . In two populations of Tanzania eating low fat -1 unprocessed diets, a natural dietary pattern including 300-600 g.d of fish is associated with 344,345 lower blood pressure and less hypertension than a vegetarian group . Dietary associations with blood pressure are affected by body weight and sodium intake. He et al report observational evidence that 2,688 non -overweight individuals, followed for an average of 19 years, had no increased risk of CHD, stroke or all-cause mortality with increasing -1 sodium intake whereas in 6,797 overweight individuals intakes of greater than 112 mmol.L -1 sodium per 7452 kJ versus less than 62.8 mmol.L per 7,452 kJ, increased relative risk for stroke incidence and stroke mortality by 1.51 (95%CI,1.06 to 2.14, p for trend=0.02) and 2.18 (95% CI, 1.21 to 3.94, p for trend =0.005) respectively, and CHD mortality by 1.41 (95% CI, 0.96 to 2.06, p for trend=0.03), CVD mortality 1.63 (95% CI, 1.16 to 2.27, p for trend<0.001) and all 346 cause mortality 1.43 (95% CI, 1.19 to 1.72, p<0.001) . There was little difference between risk whether sodium to energy ratio or absolute sodium intakes were used as the independent variable. In trials of ovo-lacto-vegetarian diets, blood pressure was reduced in normotensive and hypertensive individuals by 4-6 mm Hg for SBP and 1-3 mm Hg for DBP compared with control 342, 347,348,349,350,351 diets, but appears unrelated to plant protein intake . In comparison, reduction of -1 -1 salt intake by 100 mmol.L . d will reduce SBP and DBPs by 6.3 mm Hg and 2.2 mm Hg respectively in hypertensives over age 44 years, and SBP only by 2.4 mm Hg in hypertensives under age 44 and by 1 mm Hg in normotensive individuals or 5.8/2.5 mm Hg SBP/DBP in 352,353 hypertensives, and 2.3/1.4 in normotensive individuals . -1

Increase of fruit and vegetables intakes to more than 500 g.d in conjunction with a low totaland SFA diet lowers blood pressure in normotensive and mildly hypertensive individuals, and has 223,224, 354,355 reduced CHD mortality in men with MI, when the only change in diet . The majority of dietary intervention trials for the treatment and/ or prevention of elevated blood pressure have studied excess body weight, or alcohol or salt intake which can each raise blood pressure, and/or physical activity which may lower blood pressure. These interventions do not necessarily change dietary patterns or there has been no monitoring or reporting of dietary modification during the trial. Oily fish or fish oil reduce blood pressure to a small degree in untreated hypertensives but even 356,357,358 less in normotensives, especially when salt is restricted . Including a daily fish meal (3.65 g omega-3 PUFAs) in a weight loss diet had additive effects on blood pressure reduction in overweight hypertensive subjects compared with control subjects, SBP/DBP reductions were 6.0/3.0 mm Hg with fish alone, 5.5/2.2 mm Hg with weight loss alone (5.6 kg), and 13.0/9.0 mm 359 Hg with both interventions . The same fish intake and weight loss (5.6 kg), decreased TGs 38% (p<0.001), and increased HDL -C 24% (p=0.04), in overweight treated hypertensive subjects compared with controls, and improved factors of insulin resistance associated with hypertension. 360 Fish without weight loss achieved 29% and 26% changes respectively . 84

There is now a body of evidence that maintaining an adequate dietary mineral intake, specifically of calcium, magnesium, and potassium, protects against high blood pressure in humans and 343,361,362,363 adequate dietary intakes are recommended to reduce the risk of hypertension . Trials augmenting diets with calcium, potassium and magnesium have generally involved use of supplements, with an inconsistent pattern of results. The recent Canadian evidence-based recommendations for â&#x20AC;&#x153;Lifestyle modifications to prevent and control hypertensionâ&#x20AC;? reviewed the evidence and concluded that supplements of these minerals are not recommended as a means of preventing a rise in blood pressure, and for the treatment of hypertension, intakes of 352 supplements above the recommended daily intake were not recommended . A recent metaanalysis of 42 calcium supplementation trials found reductions of SBP and DBP of -1.44 mm Hg (95% CI, -2.20 to -0.68, p<0.001) and -0.84 mm Hg (95% CI, -1.44 to -0.24 p< 0.001) 364 respectively . Simultaneous lifestyle interventions involving three to five lifestyle factors lower the relative risk of developing hypertension by 13% to 51% in normotensives and significantly reduce blood 354, 365,366,367,368,369,370,371,372 pressure or use of anti -hypertensive therapy in hypertensives . The diets 371,372,373 in trials of hypertensives were reduced in sodium and/or alcohol and/or energy . Two very effective trials increased milk intake in subjects with typically low calcium intakes, one a trial 354,371 of Japaneseand the other comprised a high proportion of African -American subjects . There have been more than eight trials of weight loss in hypertensives with reductions of 4-13.3 mm Hg in SBP and 3-11 mm Hg in DBPs, and more than three trials in normotensives with 1.3-5.1 372, 374,375,376,377,378,379,380 mm Hg reductions in SBP and 0.0-2.8 mm Hg reductions in DBPs . 342

The effects on blood pressure of diets rich in SFAs (and or high GI) are less clear . In the vegetarian diets lowering blood pressure, P:S ratios varied from 0.77 to 0.94 compared with 0.38 342,343,348,349,350 to 0.55 in the control omnivorous diets . When SFA was increased using dairy and meat products, and cereal, vegetable, olive oil and fruit intakes were decreased in consumers of typical (Italian) Mediterranean diets, SBP rose 2.6 mm Hg and 4.8 mm Hg for men and women 381 respectively (p<0.05 and p<0.01) . The P:S ratio fell from 0.40-0.48, to 0.22-0.23, and calcium -1 -1 intakes were higher on the high SFA diet (1.3 g.d vs. 1.0 g.d at baseline). When Sacks et al -1 fed 21 strict vegetarians 250 g.d of beef daily for four weeks, SBP increased significantly by 3% 382 over controls . However when 54 omnivore normotensive volunteers were randomly allocated to low or high P:S ratio (0.3 and 1.0) diets, for six weeks, there were no consistent differences in 383 group mean blood pressures at the end of the diet periods . It has been postulated that the effect of individual nutrient manipulations on blood pressure may be too small to detect when studied in isolation but that several nutrients with small effects on 354 blood pressure studied together may accumulate significant benefits . Since supplemented nutrients do not reduce blood pressure as well as vegetarian diets do, the nutrient profile of foods and the nutrient interactions within and between foods via the dietary pattern may be more important for overall effects on blood pressure. The DASH Study was designed in response to epidemiological evidence that dietary patterns characterised by high intakes of certain minerals and fibre were associated with blood 354 pressure . DASH was a multi-centre, randomized, controlled feeding trial testing the effects on blood pressure after 8 weeks, of a control dietary pattern, relatively low in potassium, magnesium and calcium and fibre, and a fat and protein profile typical of consumption in Boston USA at the time of the study in 1995, and two experimental diets. The first experimental diet was high in fruits, vegetables, whole cereals products, low -fat dairy products, fish, chicken, and lean meats designed to be low in SFA, sugar and cholesterol; moderately high in protein; and high in minerals and fibre (the DASH diet). The second experimental diet tested only the effects of increased fruits and vegetables and was as rich in potassium, magnesium and fibre as the other experimental diet (and more than double that of the control diet), but its fat, protein and calcium content resembled that of the control dietary pattern. The study population was 459 healthy men and women, 67% African-American or from other minority groups, with SBP less than 160 mm Hg, and DBP 80-95 mm Hg. This study specifically tested dietary patterns using commonly consumed food items rather t han single nutrients, and all

food for the experimental diets was supplied for the participants. Body weights and sodium content of the diets were held constant, and no significant weight loss occurred during the study. Compared with the control diet, the DASH diet reduced SBP/DBP significantly in the total group by 5.5/3.0 mm Hg (p<0.001 for each), in African-Americans by 6.9/3.7mm Hg (p<0.001 for each), in Caucasians by 3.3/2.4 mm Hg, in hypertensives defined as 140/90 mm Hg or higher by 11.6/5.3 mm Hg (p<0.001 for each) and in non-hypertensives by 3.5/2.2 mm Hg (p<0.001, 354,384 p= 0.003 respectively) . The non-obese subgroup on the DASH diet reduced SBP/DBPs by 5.6/2.5 mm Hg (p<0.001 and<0.01 respectively) and the obese subgroup 5.9/3.6 mm Hg (p<0.001 for each). The fruit and vegetable diet also reduced blood pressure 2.8/1.2 (p = 0.001, p= 0.07) compared with control diet, and in the other subgroups but to a lesser extent â&#x20AC;&#x201C; 30-60% of the reduction with the DASH diet. This effect was similar to the results of a meta-analysis of 33 potassium supplementation 385 trials . It was particularly effective in the hypertensive subgroup with SBP/DBP reductions of 7.1/2.8 mm Hg (p<0.001 and p<0.01 respectively). The effects were prominent within two weeks and remained for the 6 weeks. The subgroup analysis has shown that the DASH dietary pattern is effective for both treatment and prevention of hypertension, in both obese and non-obese people, and is as effective as many drug monotherapies. The DASH trial also indicates that a mildly deficient intake of certain dietary ingredients especially in combination can create or worsen hypertension. -1

The DASH diet had a sodium content of 2.8 g.d and a new trial measuring the effects of t hree different levels of sodium intake may reveal even greater benefits for this effective non384 pharmacological therapy (dietary pattern) for blood pressure . Nevertheless this trial demonstrates that the effects of diet on blood pressure are not confined to salt intake and weight loss. Inadequate calcium intake from dairy products has previously been identified as a dietary 386 pattern most prevalent in individuals with untreated hypertension . An analysis of NHANES I data has supported this association and identified the relative absence of fruits and vegetables in 387 the American diet as the second best predictor of elevated blood pressure . Primary prevention trials reporting blood pressure changes

Ebrahim and Davey -Smith have reviewed multiple risk factor primary prevention trials reporting 247 blood pressure changes . In four studies with none or few participants using antihypertensive 266,272,273,273 agents SBP reduced by 0.6-2. 5 mm Hg, and DBP by 0.4-1.2 mm Hg . In one study, the Family Heart Study the programme led to much greater blood pressure reductions of 6.2-7.3 271 mm Hg in SBP and 3.0-3.5 mm Hg in DBP . The Oslo Diet and Smoking Trial, otherwise a very 247 effective interve ntion, apparently observed no changes in blood pressure . In two trials of high risk hypertensives, diet and lifestyle changes reduced CHD mortality in conjunction with drug 269,270 treatment . Secondary prevention and risk factor trials reporting blood pressure changes

Of the secondary prevention trials reported in Table_13, that provide blood pressure data only 223,228,231,232 four report significant reductions in blood pressure . In the Singh study, SBP and DBPs reduced 8.2 mm Hg and 5.8 mm Hg respectively compared with controls (p<0.05 for 223 each) . Absolute reductions were greater than this since the control group also reduced their blood pressures. In this and the study of Kallio et al, significant reduction in body weight may 228 have contributed to blood pressure changes . In the Leiden Intervention Trial the reduction in SBP from baseline was in the absence of a control group, but this and the Lifestyle Heart trial 231,232 were vegetarian diets . In the Lifestyle Heart Trial, SBP and DBP reductions of 8.6 mm Hg and 6.6 mm Hg respectively from baseline, were not significantly different from the control group reductions of 8.4 mm Hg and 5.5 mm Hg respectively, and weight loss may have contributed 231 more to the decrease than the low salt vegetarian diet . Risk factor trials reporting blood pressure changes

Of the cholesterol reducing trials reported in the previous section, few report blood pressure 260 data. Minor reductions were reported in the National Diet Heart Studies . Pritikin diet, another 313 high vegetable product diet (Barnard et al ) reported 7 and 6 mm Hg reductions in SBP and 86

DBPs but without a control comparison. In the Dietary Alternatives Study reductions in blood 322 pressure were similar across four levels of fat intake . In the Indian Diet Heart studies and Woodâ&#x20AC;&#x2122;s study weight loss may have contributed to significant reductions in blood 224,311,324 pressure . Apart from the Wood studies, all of these studies reported increases in plant foods and fibre, in addition to modification of dietary fat intakes. Sciarrone, Beilin and Rouse, using a factorial design, studied the independent and additive effects of sodium restriction and a low fat, high P:S ratio, high fibre diet on blood pressure in a 298 predominantly drug-treated group of hypertensives . Four regimens, low fat/high fibre and high fat/low fibre with and without sodium restriction were test ed for eight weeks each. Sodium restriction, but not the low fat, high fibre diet, reduced blood pressure by 6 mm Hg SBP. The authors suggest that the drug therapy (thus rendering patients to normotensive) may have influenced the diet effect. Nevertheless, the low sodium, high fibre, low fat combination improved all risk factors most. Total fat has no effect and type of fat none or minor effects and dietary fibre no effect on blood pressure in dietary studies of normotensive or mildly hypertensive, or hypercholesterolaemic 329,383,388,389,390,391,392,393,394,395,396,397,398,399,400,401,402,403,404,405,406,407 individuals . When both fibre and fat are changed simultaneously, blood pressure is lowered in normotensive individuals and in hypertensive type 2 diabetic individuals possibly reflecting the fruit and vegetables 408,409,410,411,412 intakes . Summary

Dietary patterns leading to reduction in dietary sodium, reduction of energy intake in overweight individuals s ufficient to reduce body weight, and an increase of whole plant foods, especially fruit and vegetables, each reduce blood pressure very effectively and regular intakes of low fat dairy products and/or fatty fish may enhance the effects. Together these changes may produce blood pressure reductions exceeding 13 mm Hg SBP and 11mm Hg DBP, equivalent to the effect of many antihypertensive agents. Other changes in dietary fat and fibre do not appear to influence blood pressure in normotensive normal weight individuals, but may have small effects in hypertensives.

Specific dietary patterns Trials of Vegetarian dietary patterns ,

Vegetarian dietary patterns have reduced blood lipid levels and blood pressure and are postulated to influence lipid peroxidation, thrombogenesis and are likely to influence tHcy levels 231,232,342,348,349,350, 413,414,415,416 and GI of diets . There are no diet-only intervention studies with sufficient numbers of participants or sufficient duration to demonstrate effects on CHD or allcause mort ality. The Leiden Intervention Trial and the Lifestyle Heart Trial discussed previously, 231,232 have demonstrated angiographic improvements in cardiovascular lesions (Table_13) . -1

Other dietary trials have used semi-vegetarian diets, Singh et al allowed 1-2 srv.wk of meat -1 223,313,314 and Barnard allowed 100 g.wk fish or poultry, with significant reductions of lipid levels . These diets encouraged large servings of fruits and vegetables whole grains and legumes. Four of the above studies were residential programmes of short duration and three were without a 313,314,315,415 control group . The Singh study of secondary prevention, was the only study to test (and find) reduction in CHD (and all -cause) mortality however the Lyon Diet Heart Study, allowed -1 only 280 g.d of meat weekly and also demonstrated significantly reduced mortality 223,227 (Table_13) . The results of studies where omnivores are fed a vegetarian diet have demonstrated that diet is a major determinant of the plasma lipi d and lipoprotein differences between vegetarians and non-vegetarians. Reductions in blood total cholesterol range from 10-13% to greater than 231,313,314,315,348,349,350,415 20% . When low SFA l ean meat and low/non-meat diets are compared, LDL-C is 9% lower after the low/non -meat diet and up to 32% lower when fruits and vegetables

231,324,350

-1

are also increased . When strict vegetarians were fed 250 g.d of meat daily for four 382 weeks blood total cholesterol rose by 19% while HDL-C levels remained unchanged . -1

The reintroduction of meat fat to a very low fat diet including 250 g.d of very lean meat and return to baseline levels of blood total cholesterol suggests that the main effects of blood lipids of 417 dietary meat, are likely due to the meat fat . Howeve r, studies have demonstrated substantial -1 -1 lipid lowering with dietary intakes including 180 g.d or 500 g.d of lean meat 202,239,350, 418,419 daily . In an extension of the dietary studies to develop a diet for the STARS Study, Watts et al compared a fat modified diet and the same diet supplemented with foods rich in 229,418 dietary fibre, with a reference diet typical of the UK diet in 1984 . The two intervention diets -1 provided 180 g.d of lean meats daily and similar percentage energy content of both PUFA and MUFA, but the higher fibre diet contained less total and SFA, and more CHO than the fat modified diet. Blood LDL -C fell 11% on the fat -modified diet and 23.8% on the fat -modified, high fibre diet, compared with the reference high fat diet. In the LA Veterans Study blood total -1 202 cholesterol fell 20% after a lipid modified diet including 180 g.d of red meat daily . After a very -1 low fat diet (9% to 10% fat energy, 3.8% SFA energy) containing 400-500 g.d of lean beef daily -1 and high content of fruit, vegetables and cereals (approximately 30 g.d fibre), LDL-C fell 1314% within two weeks, from the levels on the baseline diet (mean 35% fat energy; 16% SFA 419 energy) . The benefits of vegetarian diets compared with another healthy lifestyle has been tested by 350 Kestin et al . Using an incomplete block design, three diets -regular Australian, a prudent lean meat diet and an ovo-lacto-vegetarian diet, were tested for six weeks. Blood pressure reductions were similar after the two prudent diets but the ovo -lacto-vegetarian diet achieved twice the -1 blood total cholesterol lowering (10% reduction vs. 5%). The prudent meat diet included 250 g.d of lean meat daily replaci ng 60% of the plant protein in the ovo -lacto-vegetarian diet and the vegetarian diet used meat substitutes made of wheat protein. The two diets were matched for energy, type of fat, CHO, potassium, sodium, calcium and magnesium, non-starch polysaccharide and cellulose. The postulated benefits of vegetarian eating to reduce CHD risk include other lifestyle factors, and the whole dietary pattern: higher intakes of vegetable protein, wholegrain foods, PUFAs, fruit, vegetables, and other fibre containing foods while avoiding meat, fish and poultry and their products. In terms of nutrient factors, higher intakes of PUFAs (and higher P:S ratio), fibre, vitamin C, vitamin E, magnesium, calcium and potassium and lower intakes of protein, SFA and MUFAs, have all been postulated as having effects. Factors affecting one risk factor may not affect other risk factors. Clustering of risk factors is often associated with clustering of unhealthy lifestyle 420 characteristics . Whether vegetarian diets have health advantages over other healthy lifestyle dietary patterns has been the subject of epidemiological and intervention studies. Principal components analysis and step-wise multiple regression analysis has been used to investigate further the associations between changes in diet lipid and lipoprotein concentrations 413,421,422 and blood pressure . They found that three principal components accounted for 92% of the variation in intakes of major nutrients when lipid and lipoprotein levels were studied and 83% of the variation when blood pressure was studied. Where a change in a variable was significantly associated with a change in diet one factor appeared primarily responsible for the change. The factor associated with change in lipids comprised increase in fibre and PUFA and decrease in protein intake. The factor associated with reduced blood pressure comprised increased intake of PUFAs, fibre, vitamin C, vitamin E, calcium, magnesium and reduced intake of protein and vitamin B 12, independent of changes in body weight or sodium intake. Rouse et al and Margetts et al introduced ovo-lacto-vegetarian diets to regular meat -eaters in 423,424 normotensive and untreated hypertensive subjects . The diets aimed to mimic the dietary patterns of ovo-lacto-vegetarian SDAs and meat -eating Mormons in Perth in the 1980's. They were randomized, controlled cross -over trials with diet periods of six weeks and a control group 424 who continued with their usual meat diet. In one of the trials, diets were analysed and 38-45% of energy in both experimental and control diets was from total fat. These trials, although carried 88

out in the 1980's have provided the most definitive evidence for the effects of lacto-vegetarian diets on blood pressure. In Margetts trial the main nutrient changes identifying the vegetarian dietary pattern from the healthy pattern included an increase in the P:S ratio and intake of fibre, calcium, and magnesium and a decrease in the intake of protein and vitamin B12. A specific component in vegetarian diets that provides most benefit remains unknown. Several studies have investigated individual components of vegetarian diets as proposed mechanisms of action: Fats

The effects on blood and adipose tissue lipid and lipoprotein levels of changing dietary fats from animal origin to unhydrogenated fats of vegetable origin is well established. Recently, Sanders et al replaced 10% of CHO energy with olive oil, safflower oil or butter in a low fat (10% of energy) -1 vegetarian diet containing 1 egg.d , in three groups of 10 normocholesterolaemic subjects first 416 stabilised for two weeks on the low fat, vegetarian diet . The addition of butter reversed the lipid lowering effects (-12% blood total cholesterol for the first two weeks) of the low fat vegetarian diet (<6% energy as SFAs) whereas the reduced cholesterol levels were unchanged by the addition of either of the two oils. 343,393

Beilin and Sacks have reviewed the effects of fats on blood pressure . They concluded that the evidence is not strong for a specific effect of a low SFA or a high PUFA intake or a high dietary P:S ratio, typical of vegetarian diets, when independent of energy intake and/or weight changes. Many studies fail to adjust for other nutrients and/or energy intake, which affect blood pressure. Beilin reviewed 10 studies, suggesting that in trials of normotensive subjects with small numbers of participants the chances of finding significantly different effects of fats on blood 343 pressure is less likely . The lack of effect of fats on blood pressure concurs with the study of Sciarrone discussed in the previous section. Protein

The effects of soy protein on blood lipid levels have been reviewed and soy as a replacement for animal protein decreases blood total cholesterol and LDL -C and TGs without reducing HDL-C, 110 especially in those with higher initial blood total cholesterol concentrations . When macronutrient variables, grains and vegetables are held constant, in a low fat diet with P:S ratio 0.5, differences in blood total cholesterol lowering between animal and soy protein diets become less obvious and when soy protein replaces animal protein in an NCEP Step I diet, all levels of 425,426 initial blood total cholesterol concentrations are reduced . The relationship between protein within a vegetarian dietary pattern and blood pressure is, -1 however, less clear. Supplements of 58 g.d of wheat and soy protein fed to vegetarians for six -1 weeks did not change blood pressure when mean daily intakes of protein were 63 g.d and 119 -1 -1 394 g.d in placebo (7 g.d protein supplements) and supplemented diets respectively . When supplements of either meat or non -meat protein comprising 60% of daily protein intake, were fed to normotensive omnivores there were no statistical differences in blood pressures at the end of 427 a 12 week randomized trial . Fibre and flavonoids

Dietary fibre and flavonoids are strongly correlated with other nutrients and micronutrients within dietary patterns, so that it is difficult to establish an independent association with risk factors. Since they cannot be isolated from a vegetarian diet, their effects can only be tested with supplements that are out of context with how they otherwise occur in veget arian diets. Beilin has reviewed six studies of the effects on blood pressure when dietary fibre is increased in various diets or without control of the background diet, and concluded that dietary fibre is not 420 independently associated with blood pressure l owering . Meta-analyses of the effects of soluble fibre, (the active form of dietary fibre for lipid-lowering) on cholesterol lowering suggest that no greater than 2-3% reduction in blood total cholesterol, or -1 less than 0.13 mmol.L reduction per 3 g of soluble fibre, can be expected from the additional

428,429

fibre a vegetarian diet may provide 120 anticipated as a new area of study .

. The antioxidant potential of vegetarian diets can be

-1

After a supplement of 55 mg.d of the isoflavonoids, genistein, biochanin, daidzein and formononetin for eight weeks, there was no significant difference in blood pressures compared 430 with placebo, in subjects with high-normal blood pressures . Safety

The American Dietetic Association has reviewed the evidence for nutritional adequacy of vegetarian diets, in their position statement “Vegetarian Diets”. For lacto-vegetarian diets, there are no major nutrient concerns providing the m ain food groups are chosen in the recommended quantities (Table_1). Summary

Exclusion of meat products from dietary patterns increases the consumption of CHO-rich plant foods such as fruits, vegetables, cereals, pulses and nuts . Vegetarian diets compared with low fat, fibre-rich omnivore diets lower blood total and LDL-C levels and blood pressure. These benefits are likely to be greater when comparisons are with higher fat non- vegetarian diets. Partial vegetarian diets appear to have effects equivalent with those of lacto-vegetarian diets. Dietary patterns including very lean meat do not inhibit the effects of reducing animal fat intake. Although multiple dietary differences between vegetarian and non -vegetarian diets obscure the precise mechanisms of benefit, the substitution of plant oils for meat fats, increased intakes of micronutrients and a wider variety of the hundreds of phytochemicals present in plant foods including folate, and the significant effects of soy, are obvious candidates. Trials of Mediterranean dietary patterns

There are no RCTs investigating the effects of a “Mediterranean” dietary pattern in cohorts living far from the Mediterranean. Due to the paucity of clinical trial data, despite the popularity of the concept of a “Mediterranean” diet, this section discusses evidence that may support the idea that Mediterranean style diets may be useful as a therapeutic dietary pattern for cardiovascular intervention. Despite its wide use by the popular literature and health educators alike the term “Mediterranean Diet” is not a scientifically defined dietary pattern. There is no single Mediterranean diet with a given composition of foods, nutrient profile and non-nutrient food factors. Popular theory that populations with high rates of cardiovascular risk should adopt components of a “Mediterranean Diet” generally discuss the dietary patterns of Southern Italy or Greece as consumed in the 1960's. Dietary fat intakes in the Mediterranean region at that time ranged from ar ound 30% of energy in Southern Italy to greater than 40% of energy in Crete. The Cretan diet is interesting because of its very high olive oil intake and its apparent “healthiness” in its innocuous nature. The quantity of oil in the Cretan diet leaves only 45-50% of energy intake to supply other nutrient -rich components of diet. In Southern Italy 70% of the total fat came from separated fats, 431 mainly olive oil, since fat spreads were not used on breads . Twenty-eight percent of energy came from fat. Fish was consumed by populations near the sea, most countries did not traditionally add fat spreads to bread, although bread intake was high. Eight characteristics identify traditional dietary patterns in Mediterranean countries •

High ratio of unsaturated (usually MUFA) fats to SFAs.

•

Moderate intake of alcohol, mainly in the form of wine.

•

High consumption of legumes.

•

High consumption of fruit.

•

High consumption of vegetables (>400 g.d ).

•

High consumption of grains and cereals inc luding bread.

432

-1

•

Moderate consumption of milk and dairy products, mostly as cheese.

•

Low consumption of meat and meat products.

Nutrient qualities derived from modifying dietary patterns using all eight Mediterranean diet 137 variables have been substantiated by evidence previously reported : •

Low in SFA and trans -unsaturated fat, and dietary cholesterol.

•

Adequate to high protein content.

•

High CHO content.

•

Enhanced PUFA content.

•

High fibre, low GI.

•

Rich in folate and vitamin B6.

•

Rich in β-carotene, vitamin C and α-tocopherol, polyphenols and xanthocyanins.

•

Rich in potassium, magnesium and calcium.

•

Moderate in alcohol, sugar and salt.

•

Adequate in all other known essential nutrients.

The diets of Greeks Cretans and Italians have been changing since the 1960's and it is generally held that the newly emerging diets are an unlikely model for a cardioprotective vascular dietary 431, 432,433 pattern . Neither the diet of Southern Italy nor the diet of Crete have be en the subject of RCTs. The Lyon Diet Heart a secondary prevention study, aimed to replicate the Cretan diet but found 227 the French participants could not tolerate the olive oil requirement . A rapeseed oil margarine made up the oil deficit and may have carried more important ingredients than olive oil. For the remarkable results on CHD mortality (see the secondary prevention section earlier). The lipid content of the diet was 30% of energy, the SFA content 8.3%, and MUFA 12.9 and PUFA 4.5% of energy. There were very few differences between the experimental and control diets -1 (Table_15) for most foods excepting fat sources and modest increases in vegetables (30 g.d ), -1 -1 -1 fruit (50 g.d ) and bread consumption (20 g.d ), a slight increase in fish and legumes (10 g.d ). -1 Table margarine and oil intake was 35 g.d . There was a 33% decrease in meat, and virtual -1 exclusion of butter and cream (from 17 g.d ). These differences between groups were not sufficient to demonstrate decreases in blood pressure or lipid levels that were significantly different from the control group. However participants were already on AHA diets prior to recruitment and control subjects continued on AHA diets during the study. Blood total cholesterol fell by 9% in the experimental group and by 4.7% in the control group. The study highlights the importance of total diet or modification of the total dietary pattern when targeting all risk factors. The type of olive oil used in countries or studied populations varies in the degree of refining and subsequent retention of natural antioxidants and phytochemicals, which in turn, may be important for reducing cardiovascular risk. Ehnholm et al also aimed to test a Mediterranean diet in their study of Finnish families in North 299 Karelia . To increase the oil content, a “filled” milk was made with oils, but only 25% of energy was from fat. The 54 diet subjects decreased SFA intakes from 22% to 9% of energy with mean reductions in blood total cholesterol of 23.5% and 21.3% for men and women, respectively. Vegetable and fruit intakes were increased, but this was not a MUFA diet, 9.2% and 6.4% of energy was from PUFA and MUFAs respectively, P:S ratio 1.18. Despite this dramatic reduction in blood total cholesterol levels over six weeks, HDL-C did not decrease the same as LDL -C, the LDL-C to HDL-C ratios reduced by 9%. The DASH and Singh diets (see secondary prevention trials) were designed along the lines of a 223,354 “low fat” concept of Mediterranean diet, 25% of energy from fat, without the excess oil . In these diets PUFA content was about 70% that of MUFA.

Monounsaturated oils versus carbohydrates or polyunsaturated oils

One postulated benefit of a Mediterranean dietary pattern is the uniquely rich content of MUFAs in the form of olive oil. Proposed benefits of dietary patterns high in MUFAs over those rich in CHOs, include less TG elevation, less HDL-C lowering and equivalent LDL-C lowering when 283 replacing SFAs, have been suggested by Mensink and Katan . Less reduction of HDL-C and equivalent LDL-C lowering with MUFA versus PUFAs when substituted for SFAs, was initially 434 proposed after analysis of a very high fat liquid diet, in a subset of the study participants . Polyunsaturated oils versus monounsaturated oils

In experimental studies, linoleic acid generally lowers blood total cholesterol and LDL -C more 141 than oleic acid. Linoleic-rich oils produce the highest ratio of HDL-C to LDL-C . Elaidic acid and 18:0, stearic acid lower total and LDL -C relative to 12:0 to 16:0 SFAs but less so than oleic 141 acid . Monounsaturated fats as a group tend to be neutral for effects on blood lipids when substituted for SFAs in controlled feeding experiments using regression analysis and metaanalyses of large numbers of diet studies conducted under metabolic ward 56,57,58,281,282 conditions . In Clarke's meta-analysis of 227 metabolic ward studies isocaloric replacement of SFAs by -1 equivalent CHO to 10% of energy was associated with a 0.52 mmol.L reduction of blood total 282 cholesterol . Isocaloric replacement of 5% of CHO energy by PUFAs reduced blood total -1 cholesterol by a further 0.13 mmol.L whereas replacement with MUFAs had little effect. A -1 -1 reduction of 200 mg.d of dietary cholesterol was associated with a further of 0.13 mmol.L -1 -1 reduction. Together these changes were equivalent to 0.76 mmol.L of which 0.62 mmol.L was of LDL-C. The analysis of Howell at al found that change in blood total cholesterol correlated 281 most with change in SFAs (r= 0.80), and PUFA (r= 0.62) . Change in LDL-C and HDL-C correlated most with chan ge in SFA intake and the correlation between change in PUFA and LDL-C was greater than for HDL-C. The only significant relation between changes in VLDL-C or plasma TG concentrations levels and changes in dietary variables was for PUFA (r= -0.37 and r= 0.40 respectively). Changes in MUFA were only related to changes (positively) in blood total cholesterol and HDL-C. In meta-analyses of controlled dietary studies using common plant and vegetable oils rich in unsaturated fats where dietary fatty acids were the sole variable, MUFA were mildly hypocholesterolaemic (half that of PUFA) but ratios of MUFA and PUFAs and/or stearic acid to 283,288 SFAs varied widely between studies . The MUFA effect may be masked, when 12:0-16:0 fatty acids or dietary cholesterol intakes are high, or MUFA intakes are low, suggesting that animal and plant origin MUFA sources may need to be separated in these analyses. Unlike 58,141,283 PUFA, the lipid lowering does not appear independ ent of SFA displacement . Howard et al found that in an NCEP Step I diet containing 30% of energy from total fat, with all other dietary variables held constant, the substitution of PUFAs for MUFAs from 3-14% of energy resulted in a progressive decline in total and LDL-C and less TG elevations without an effect on 435 HDL-C . The magnitude of the cholesterol -lowering response was greater in those with higher baseline cholesterol levels and less in those who were more obese. This effect of PUFA rich diets to reduce TG levels, when compared with MUFA diets in metabolic ward studies, is consistent with the meta-analyses of Gardner and Kraemer and Howell et al (224 studies), and the review by Kris Etherton and Yu, and the evidence that long chain marine omega-3 PUFAs 141,281,285 lower TG levels . Two studies have assessed trials where SFAs in the trial diets were controlled, the test 141,285 specifically comparing effects of diets rich in either MUFA or PUFA . In the Kris -Etherton review, of 11 studies comparing diets rich in either MUFA or PUFA, none showed significant 141 differences for change in blood total cholesterol, LDL -C, TGs or HDL-C between diets . In seven of 11 trials, energy from total fat was 30% or less. Eight st udies demonstrated greater LDL-C lowering with the PUFA diet (non-significant relative to MUFA), and this was more apparent when 9-14% of PUFA energy was substituted for MUFA. Total fat intakes comprised

30-40% of energy and PUFA content was greater than 10% of energy in all studies. Triglyceride levels were higher after the MUFA diets in all studies, significantly in two. A meta-analysis comparing the effects of MUFA versus PUFA was published by Gardner and 285 Kraemer . In six of 14 MUFA diets the PUFA content was equal to 7% or more of energy, and in nine of 14 studies the total fat was 33 -45% of energy. Both diets reduced blood total cholesterol and LDL-C when substituted for SFAs. High-density -lipoprotein cholesterol and TG changes were not significantly different from SFA diets. There were no significant differences in blood total cholesterol, LDL-C or HDL-C between diets. This absence of effect was observed across a wide range (5-25% of energy) of MUFA versus PUFA substitution. Consistently lower TG effects were seen with the PUFA diets and the overall pooled effect was of borderline significance (p= 0.05). The majority of studies achieved greater (non-significant) LDL -C reduction with PUFA, especially when the MUFA diets were low in PUFA content, but there was a wide range of total fat intakes, baseline lipid levels and subjects. A subset analysis with control for total fat did not change the results. In studies where high PUFA were compared with high MUFA diets, providing a high proportion of fatty acids from nuts, two studies showed greater blood total cholesterol reduction with PUFA diet and one with MUFA and in the two studies measuring HDL-C or TG levels there were no 436,437,438 significant changes in either for any diet . Truswell and Choudrey have reviewed ten trials comparing MUFA oils finding that canola and high oleic sunflower oils lower total and LDL-C levels significantly more than olive oil, the latter 439 containing least PUFA . Compared with canola oil, olive oil, has twice the SFA content, less than 50% of the PUFA content, is low in omega-3 PUFA content and has less vitamin E and less phytosterols than canola oil. Soy and high oleic sunflower oils have higher polyunsaturation, linolenic and less SFAs than olive oil. In a NZ study, no differences in lipoprotein concentrations between 40% fat energy diets high in PUFA or MUFA (PUFA 10% of energy) were found in 28 free-living, mild-moderately hyperlipidaemic subjects but both diets significantly reduced blood total cholesterol, LDL-C, and 440 HDL-C concentrations in comparison with a typical NZ (SFA) diet, after six weeks . In summary, the differences in blood lipids after diets rich in PUFA-rich oils or MUFA-rich oils are relatively small when total fat intakes are low (<30 % of energy), but this may depend on PUFA content of MUFA -rich diets, and/or the P:S ratio. Benefits of olive oil are more likely related to the higher polyphenol content of extra virgin olive oil or effects on LDL-C oxidation, than to effects on lipid levels. Monounsaturated oils versus carbohydrates (low fat diet)

The meta-analysis by Mensink and Katan suggested that substitution of fat by CHO yields little if 283 any improvement in coronary risk . Translation of these results into practice remains speculative since they are not consistent with epidemiological observations of dietary patterns in free-living populations. The study was of 27 metabolic ward trials using diets of mixed composition, and some were liquid diets. Only one study was as long as 90 days (mean length of eight trials was 21 days or less, 15 were 30 days or less, 12 were greater than 30 days and of these three greater than 60 days). Two authors were involved in at least 14 of the 27 studies, suggesting that dietary structure may have been similar for many studies. Of the 37 intervention studies in Yu Pothâ&#x20AC;&#x2122;s meta-analysis of diets 30% or less of fat energy, in free-living subjects, 18 287 comparisons measured outcomes of longer duration than three months . None demonstrated significant TG elevations from baseline, and only two trials (diets <25% fat) demonstrated reduction of HDL-C from baseline. When MUFA are compared with CHO as a replacement for SFAs, the whole diet changes so that the comparison is more of dietary pattern than MUFA versus CHO. The trial high CHO diets (usually 50-60% of energy) are also low fat diets (20-25% of energy) and the high MUFA diets (usually 35% to 40% of energy from fat) are also low CHO diets (fat usually 40% of energy). If either fibre or protein are held constant the excess CHO in the high CHO diet is likely to be refined and to exert a higher after meal glycaemic/insulinaemic response. The ratio of 93

unsaturated to SFAs is also lower on high CHO diets (usually less than 2:1 vs. the MUFA diet 283,285, 441 ratio greater than 2.6:1 and up to 9:1 . Carbohydrate diets are often discussed as containing a content of â&#x20AC;&#x153;complexâ&#x20AC;? CHOs but give no information about the potential glycaemic response of such diets. Despite these confounding influences, meta-analyses do not support clear advantages for increasing MUFAs when compared with CHO or PUFAs at usual intakes. Kris Etherton and Yu reviewed eight studies comparing a MUFA diet with a high CHO diet (duration 21-84 days) in 141 healthy subjects and four in subjects with type 2 diabetes mellitus . In four of the 12 studies, total fat contributed 25% or more of energy intake. In the three studies reporting significantly lower blood total cholesterol or LDL-C after the MUFA diet, SFA intakes were higher or PUFA were lower on the CHO diet. Seven studies (including three type 2 diabetes mellitus studies) reported lower TG levels and six reported higher HDL-C levels after the MUFA diet but type of CHO and fibre were not compared. In a meta-analysis of nine crossover trials in individuals with type 2 diabetes mellitus (seven were metabolic ward studies), mean CHO intakes on the high CHO diets were 55 -60% of energy 442 and in eight of 10 studies, fat energy was 20-25% of total energy . Protein as a percentage of energy was well controlled in all studies suggesting that the excess CHO in the high CHO diet was low fibre/lower wholefood. In this meta-analysis diets of only two to four weeks (one six weeks) duration demonstrated 19% lower fasting TGs and 22% lower VLDL -C levels, modest -1 reduction in blood glucose (-0.23 mmol.L , 95% CI, -0.39 to -0.06) but no significant differences for fasting plasma insulin, blood LDL -C, blood total cholesterol or HDL-C after the MUFA diet compared with after the CHO diet. In studies predating this analysis, high fibre, high CHO diets 443,444 were not associated with significant increases in glucose or TG levels . An exclusive role for MUFAs, rather than PUFAs, as a substitute for a portion of CHO intake in diabetic individuals remains unclear due to the small number of comparisons with PUFAs. The high fruit and vegetable content of the Mediterranean diet is likely to promote reduction of energy intake and improve antioxidant intake, both vital to the treatment of type 2 diabetes mellitus. A recent study has shown no differences in lipid, lipoprotein or glucose responses in relatives of 445 type 2 diabetes mellitus, between diets either high in CHO or olive oil . In another NZ study a low fat (22% of energy), high CHO diet compared with a high SFA diet (18% of energy) reduced blood total cholesterol and LDL-C (p<0.001), and reduced HDL-C 446 slightly (non-significant) in 36 healthy free -living men . The LDL-C to HDL-C ratio improved significantly (p= 0.004) with no change in TG levels. The CHO diet (59% of energy) included increased grain, vegetables, legumes and fruit intakes. The transient nature of increases in TG levels and HDL-C lowering after high CHO diets of differing quality (complex vs. simple, high vs. low GI) compared with higher fat MUFA and/or PUFA diets, requires further study in longer term trials. Other potential mechanisms

Other physiological consequences of altering dietary unsaturated composition are as yet unclear. Influences on apolipoproteins, lipoprotein sub-classes, blood pressure, blood glucose, platelet 285 function and indices of thrombosis and cancer remain undetermined . A proposed role for MUFAs in the modulation of gene expression for endothelial leukocyte adhesion molecules, an 447 initiating step in the progression of atherosclerosis, may i nvolve PUFAs as well . Oleate-enriched LDL -C with lower PUFA content is more resistant to oxidative modification in vitro after a high MUFA diet than after a high PUFA diet and reduces LDL -C induction of monocyte adhesion to endothelial cells but this is inconsistent with in vivo observational 448,449,450,451 studies . Not all Mediterranean countries use olive or other MUFA oils exclusively. The tendency of MUFAs to reduce oxidative modification of LDL-C remains confined to studies in vitro, using blood drawn from s ubjects consuming high intakes of either MUFAs or PUFAs. However the results are not different when total fat intakes between diets remain around or less 452 than 30% of energy and solid foods are used . The traditional Mediterranean diet contains an exemplary profile of antioxidant nutrients and non-nutrient factors, as likely to protect against 94

lipid oxidation as the dietary MUFA content, however higher fat intakes may be protected by a specific ratio of fatty acids. Extra virgin olive oil contains a higher c ontent of polyphenols and other antioxidants than refined oil and demonstrates greater resistance of LDL-C to oxidation than refined oil but similar fatty acid profiles in plasma and LDL-C in a study of patients with peripheral vascular disease and appears to protect LDL-C from susceptibility to oxidation in the 453,454 presence of long chain PUFAs intakes as fish oil . However, olive oil may not have advantages above other MUFA oils for antioxidant potential especially those oils with higher content of antioxida nts and plant sterols that may also reduce absolute levels of LDL-C, such as 455 sunflower oil . Blood antioxidant capacity and plasma concentrations of antioxidants can be increased with 456,457,458 dietary manipulation, especially increases of fruit and vegetable intake . Different 459 populations have varying blood antioxidant levels . The plasma fatty acid composition the Lyon experimental diet group is similar to that of a Japanese population with very low CHD mortality, and characterised by a rich content of omega 256 3 PUFAs and very long chain PUFAs . In Mediterranean and Asian diets, unsaturated fats are derived primarily from plant and vegetable oils. In Mediterranean countries, other sources of PUFA (in particular linolenic acid) such as purslane, nuts and soy may complement olive oil 460 intakes (13% total PUFA and 1% LNA) . Factors of Mediterranean and Asian diets, such as 256 their PUFA content may contribute inhibitory effects on arrhythmias or platelet reactivity . Saturated fat intakes are low in Mediterranean and Asian diets (3% to 10% of energy) and many 14 populations consume semi -vegetarian diets . The Cretan and Corfu c ohorts of the Seven -1 -1 Countries Study consumed only 35 g.d meat (Japanese cohorts, averaged 8 g.d meat) while -1 256 the other nine Mediterranean cohorts consumed a mean of 140 g.d meat . Summary

Active comp onents that reduce CHD risk in traditional coastal Mediterranean-style diets are likely to be associated with, but not due to, their MUFA content. An independent positive effect of MUFAs on specific CHD risk factors, above that of other dietary constituents, is so far unclear and limited to in vitro antioxidant effects that may be attenuated by improved antioxidant intake in the comparison diet. Oils and foods rich in MUFAs may contain PUFAs, antioxidant compounds, folate and dietary fibre. The evidence does not support a clear role for a particular oil (such as olive, canola, soy, sunflower, safflower or other nut or seed oils), in terms of the classical risk factors measured in RCTs. The positive benefits of Mediterranean diets can be thus far attributed to their semi-vegetarian characteristics and high fruit, vegetable, grain, legume and nut content together with a low content of animal products. Traditional coastal Mediterranean and Asian dietary patterns have in common, a low SFA content and a high content of fruits, vegetables, legumes and/or nuts and grains, and are associated with low rates of CHD. The specific protective factors remain unclear and benefit cannot be attributed to a single food or food constituent. The combined effects of the foods inherent in these dietary patterns influence the oxidant potential of the diet, LDL -C levels, clotting factors, blood pressure and resistance to LDL-oxidation.

Non-randomized population studies Usual risk populations North Karelia Project

Although not a randomly allocated controlled trial, this mass-media project aimed at primary prevention of CVD in an entire area of eastern Finland, where at the commencement of the 461,462 project CHD mortality was reportedly the highest in the world . The nutrition programme targeted blood total cholesterol levels and utilised mass media, community health education, 95

personal and group counselling, and promoted environmental changes to support the dietary 167 changes . Dietary objectives included reduction of SFA intakes, and increased PUFA and vegetable intakes. It particularly targeted use of low fat dairy products and removal of visible fat since dairy products played a major dietary role in this rural farming area. After 10 years of the programme, reported dietary changes in a sample of the population were paralleled by changes in blood total cholesterol levels. The reductions of 11-12% in cholesterol levels were almost matched by the control community after the 10 years. Five to 8% reductions in DBP were reported in the intervention community but blood pressure differences were only 3-5% between the two communities after 10 years. This influence on the whole Finnish population is discussed in the epidemiological section above. The reported changes in dietary pattern included reduction of dairy fat and spreads for bread, increase in fruit and vegetable intake with significant 14% and 20% reductions for women and men respectively, in SFA scores. At 10 years more than 70% of subjects were still usi ng butter. Steeper declines in mortality rates have been seen in this part of Finland. This study has also reported socio-economic influences on food choice showing that lower socioeconomic men made more change yet did not achieve the dietary SFA reductions of higher socioeconomic groups. Stanford Five-City Project

Another mass -media, non-randomized project, this study compared two treatment cities 463 (n=133,800) and two control cities (n=197,000) . Interventions included dietary change for blood total choles terol, blood pressure and weight management. Each adult in the treatment cities received approximately 527 educational episodes over 2.5-5 years. Social learning theory, communication-behavioural change, community organisation and social marketing methods were used. A randomly selected cross -sectional population sample of around 1,250 subjects in treatment and control cities were surveyed. Forty percent of the baseline sample completed all follow-up surveys. In the treatment compared with control cities blo od total cholesterol levels were 2% lower and blood pressure 4% lower, while smoking and estimated composite CHD and all-cause mortality risk scores decreased. Knowledge scores increased significantly. This study 464,465 was preceded by the Stanford Three Community Study . From three populations of around 13,000 and 15,000, approximately 360 randomly selected subjects from each of the test communities and the control community, were surveyed. The test communities received a detailed mass media programme and dietary assessment suggested significant changes in SFA and dietary cholesterol intakes. Blood cholesterol levels were lower in treatment cities at the end of the programme but were not lower than baseline levels. 466

Other large scale population projects have been reported . In three towns in rural South Africa blood total cholesterol and smoking rates decreased, but in a Swiss four town study and an 466, 467,468,469 Australian three town study only smoking rates dropped . The USA Minnesota and Pawtucket Heart Projects, independently achieved only small results for any risk factor and when pooled with the Stanford Five -City Project the intervention effects of the three studies were in the 470,471,472 expected direction of benefit but not significant . Summary

Population interventions require mass-marketing strategies and a large fiscal commitment. They need to directly target those specific risk factors prevalent in the population, using methods that demonstrate definite outcomes from a change of diet ary pattern. Relevant confounding influences such as increasing rates of obesity require persistent monitoring. Strategic subsidising of recommended food items has been one of the most successful mass interventions so far tested.

Developing an ideal dietary pattern Table_19 compares the average daily intake of foods and nutrients reported by individuals from study cohorts in populations experiencing low rates of CHD, with those of participants in several successful primary and secondary prevention trials that reported reduced rates of CHD events and/or CHD mortality. These dietary patterns typically have in common: a variable absolute fat -1 -1 -1 content and daily intakes of less than 150 g.d meat, 10 g.d or more of pulses, 400 g.d of -1 breads/cereals/grain/potatoes, 200 g.d or more of vegetables (excluding potato), greater than -1 -1 -1 100 g.d of fruit, greater than 20 g.d of fish, greater than 15 g.d of plant oil products, milk, -1 -1 usually greater than 15 g.d of cheese, less than one egg, and 0-20 g.d of sugar. Only one of these diets is very low in fat (Japan), and a similarly low fat diet (the Lifestyle Heart Study) is the only low fat intervention undertaken for sufficient length of time to assess outcomes for CHD. There is insufficient information reported about the Lifestyle Heart Study diet to be included in the table. Japanese fat intakes have increased since the study reported in the table, and now include significant animal and plant fats. There is presently insufficient evidence to support a recommendation for a very low fat intake (<20% of energy). Table 19. Dietary Patterns. Comparison of selected populations associated with low CHD risk and interventions studies that lowered CHD risk. Study type

Epidemiological studies 1 Crete Japan2 Mediter3 S. Italy 4 2

Dietary Composition % of Energy Total fat SFA MUFA PUFA Linolenic Linoleic Fibre (g.d -1) Foods (g.d -1) Meat/poultry Fish Milk Low-fat dairy Bread/Cereal/Grain Vegetables Potatoes Fruit

40 9 27 4

12 3.8 3.8 5

22-30 6-13 11-20 2-7

33 -

149 34 1-200+ 416 160 181 130

44 15 72 477 243 33 126

35 18 235 410 191 190 464

8 39 28 481 198 65 34

Pulses/legume 30 91 18 Table margarine 0 5 Added oils/dressing 95 Incl 60 Cheese 13 0 20-30 Butter Eggs 25 29 Animal protein Vegetable protein Sugar Nuts/seeds s Serving. SP Secondary prevention. 1 From references 135,227,256,432 . 3 Nine Mediterranean cohorts have been averaged. 5 de Lorgeril et al227 . 7 Miettinen et al203 . 9 Appel et al354 .

23 0 50 15 10 -

Diet trials Finnish LA Vet8 Hosp7

Lyon5

Singh6

30.5 8.3 12.9 4.4 0.8 3.6 18.6

23.8 7.2 8.0 8.6

34 8.5 11.5 12.7 1.7 10.7 -

39 9 14 15

25.6 7.0 10.0 6.8

105 46 3 118 261 316 Incl 251 20 19 16 32 2.8 7

52 0.3s 575 Incl Incl

147 58 0 0 202 197 398 110

160 26 0 0 2s 2s 2s

DASH9

31 139 Incl 360 98 283 345 Incl 280+ 692+juice 11 17 9 27 22 25

5 28 17 52 18 23 23 45 3.8 9.6 PP Primary prevention. Incl Included in figure immediately above. 2 Cohorts averaged for Japan and Greece. 4 1960's Southern Italy figures from ref 431. 6 Singh et al223 . 8 Dayton et al238.

abbreviations AHA

American Heart Association

ATBC

Alpha Tocopherol, Beta Carotene Cancer Prevention Study

BMI

Body Mass Index

CARE

Cholesterol and Recurrent Events Trial

CARET

Beta Carotene and Retinol Efficacy Trial

CCPT

Chicago Coronary Prevention Trial

CHAOS

Cambridge Heart Antioxidant Study

CHO

Carbohydrate

CHD

Coronary Heart Disease

Confidence Interval

CV D

Cardiovascular Disease

DART

Diet and Reinfarction Trial

DASH

Dietary Approaches to Stop Hypertension

DBP

Diastolic Blood Pressure

DHA

Docosahexenoic Acid

DNSBA

Dietary and Nutrition Survey of British Adults

EPA

Eicosapentenoic Acid

EURAMIC

European Anti oxidant Myocardial Infarction and Breast Cancer

Glycaemic Index

HDL-C

High Density Lipoprotein Cholesterol

INTERSALT

International Study of SALT

LED

Low Energy Diet

LDL-C

Low Density Lipoprotein Cholesterol

LNA

Alpha Linolenic Acid

Lp (a)

Lipoprotein (a)

LRC-CPPT

Lipid Research Clinic Coronary Primary Prevention Trial

MEDLINE

Medical Literature Analysis and Retrieval System Online

MeSH

Medical Subject Heading

Myocardial Infarction

MONICA

Monitoring of Trends and Determinants in Cardiovascular Diseas e

MRFIT

Multiple Risk Factor Intervention Trial

MUFA

Monounsaturated Fat

NAS

Normative Aging Study

NCEP

National Cholesterol Education Program

NHANES

National Health and Nutrition Examination Survey

NHLBI

National Heart, Lung and Blood Institute

NSP

Non-S tarch Polysaccharide

New Zealand

NZDA

New Zealand Dietetic Association

OPPT

Oslo Primary Prevention Trial

PTCA

Percutaneous Transluminal Coronary Angioplasty

PUFA

Polyunsaturated Fat

RDA

Recommended Daily Allowance

RCT

Randomized Controlled Trial

Scandinavian Simvastatin Survival Study

SBP

Systolic Blood Pressure

SFA

Saturated Fat

STARS

St Thomasâ&#x20AC;&#x2122; Atherosclerosis Regression Study

Triglyceride

tHcy

Total Homocysteine

TOHP

Trials of Hypertension Prevention

TONE

Trial of Nonpharmacologic Interventions in the Elderly

USDA

United States Department of Agriculture

United Kingdom

USA

United States of America

VLED

Very Low Energy Diet

VLDL-C

Very Low Density Lipoprotein Cholesterol

Waist Circumference

WHO

World Health Organisation

WHR

Waist to Hip Ratio

WOSCOPS

West of Scotland Coronary Prevention Study

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