K Srinath Reddy, All India Institute of Medical Sciences, New Delhi, India
© 2005 Elsevier Ltd. All rights reserved.
the finest studies in this area. They examined carefully the data from the 10 American Lipid Research Clinics. They observed that the etiology of their findings was unknown but they found the total and LDL cholesterol levels varied inversely with length of day. The level of HDL cholesterol varied much less, but its variation was correlated directly with ambient temperature. The foregoing does not reduce the importance of measuring cholesterol levels but makes it important to take into consideration the subjects' physical and mental state as well as time of year.
Figure 2 attempts to summarize the many factors now considered to play a role in the formation of the atherosclerotic plaque.
See also: Cholesterol: Sources, Absorption, Function and Metabolism; Factors Determining Blood Levels. Coronary Heart Disease: Hemostatic Factors; Prevention. Diabetes Mellitus: Etiology and Epidemiology. Fats and Oils. Fatty Acids: Trans Fatty Acids. Hyperlipidemia: Overview; Nutritional Management. Lipids: Chemistry and Classification. Lipoproteins.
Ginsburg HN (1998) Lipoprotein physiology. Endocrinology Metabolism Clinics of North America 27: 503-519.
Coronary heart disease (CHD) is the leading cause of death in the world. While it is well established as the foremost contributor to mortality in most developed countries, it is also a major and rapidly rising cause of death in many developing countries. Global health transitions, which have seen substantial changes in age-specific coronary mortality rates across the world, in the past half a century, have also been associated with changes in nutrition, which explain a large part of the rise or fall of CHD-related death rates.
Diet and nutrition have been extensively investigated as risk factors for CHD. Many dietary factors have been linked directly to an increased or decreased risk of CHD or to major established risk factors of CHD like high blood pressure, disordered blood fats (dyslipidemia), diabetes and metabolic syndrome, overweight and obesity, and also to emerging risk factors like inflammatory markers and homocysteine. Nutrition influences atherogen-esis, thrombosis, and inflammation - all of which are interconnected pathways that lead to CHD.
Observational epidemiological studies and clinical trials have contributed to a wide body of knowledge of the role that some nutrients (like saturated and trans fats, salt, and refined carbohydrates) play in increasing the risk of CHD and of the protective effect of other nutrients (such as fruit and vegetables, poly-unsaturated fats, nuts, and fish) against CHD. This knowledge has been successfully applied both in public health and in clinical practice to reduce the risk of CHD in populations as well as in individuals. The present state of that knowledge, as relevant to prevention of CHD, is summarized below.
Global Trends in CHD as a Reflection of Nutrition Transition
Coronary heart disease accounted for 7.2 million deaths in 2002, which forms a large fraction of not only the total number of deaths worldwide due to cardiovascular diseases (16.6 million) but also of the global total number of deaths from any cause (57million). While age-specific coronary mortality rates have declined in the industrial countries over the past three decades, the absolute burdens of CHD continue to be high. CHD death rates are rising in the developing countries, where about half of these deaths occur below the age of 70 years. In Eastern and Central Europe CHD mortality rates rose sharply in the 1980s and 1990s and have only recently shown signs of stabilization, albeit at high levels.
These changes in CHD mortality rates have accompanied well-documented or clearly discernible shifts in the nutritional state of the populations. The decline of CHD mortality in Western and Northern Europe was linked to a reduction in the consumption of unhealthy fats (saturated fats and trans fats) and salt as well as an increased consumption of fruits and vegetables. This is best documented in The Netherlands and Finland. Similarly, the recent decline of CHD mortality in Poland was explained by the increase in fruit and vegetable consumption and growing substitution of vegetable fats for animal fats. Similar evidence of a favorable nutrition transition preceding the decline in CHD mortality rates is available from other developed countries like the US, Canada, Australia, and New Zealand.
The developing countries have, however, witnessed a recent transition in the opposite direction. China, for example, has experienced a large increase in fat consumption over the past two decades, accompanied by a progressive rise in the mean plasma cholesterol levels of the population as well as in the CHD mortality rates. Other developing countries are also increasingly adopting unhealthy dietary patterns that augment the risk of CHD.
The pathogenesis of CHD is mediated through the interconnected pathways of atherogenesis (fat deposition in the walls of the coronary arteries to form plaques), thrombosis (blood clotting over disrupted plaques) and inflammation (which initially damages the blood vessel walls and continues to destabilize the plaques). Nutrition has a major role in influencing each of these pathways and often provides the connecting link between them.
Major coronary risk factors include an abnormal blood lipid profile (especially plasma cholesterol and its subfractions), high blood pressure, and diabetes. Overweight and obesity (both the general and central patterns) are also associated with an increased risk of CHD. Nutrition has a powerful influence on all of these risk factors, with an unhealthy diet pattern tending to elevate them and a healthy diet pattern reducing the levels of risk. Diet becomes especially important in the context of the metabolic syndrome (a complex of central obesity, high blood pressure, dyslipidemia, and glucose intolerance), an entity which is being increasingly identified as a major risk factor for CHD. Nutrition is also linked to the propensity to develop cardiac arrhythmias, in the setting of CHD, and is an important predictor of sudden cardiac death. These links between dietary patterns and several specific nutrients not only manifest as fat deposition in the arteries, plaque growth, plaque instability, and thrombosis but are evident much earlier in the natural history of CHD, as endothelial dysfunction (inability of the arteries to dilate normally), elevated levels of inflammatory markers (such as C reactive protein), and increased intimal medial thickness of arterial walls. These precede and predict the clinical manifestation of CHD.
Nutrients and CHD Dietary Fats: Cholesterol
The relationship between dietary fats and cardiovascular disease (CVD), especially CHD, has been extensively investigated, with strong and consistent associations emerging from a wide body of evidence accrued from animal experiments, as well as observational studies, clinical trials, and metabolic studies conducted in diverse human populations. This relationship was initially considered to be mediated mainly through the atherogenic effects of plasma lipids (total cholesterol, lipoprotein fractions, and triglycerides). The effects of dietary fats on thrombosis and endothelial function as well as the relationship of plasma and tissue lipids to the pathways of inflammation have been more recently understood. Similarly, the effects of dietary fats on blood pressure have also become more evident through observational and experimental research.
Cholesterol in the blood and tissues is derived from two sources: diet and endogenous synthesis. Dairy fat and meat are major dietary sources. Dietary cholesterol raises plasma cholesterol levels. Although both high-density lipoprotein (HDL) and low-density lipoprotein (LDL) fractions increase, the effect on the total/HDL ratio is still unfavorable, but small. The upper limit for dietary cholesterol intake has been prescribed, in most guidelines, to be 300 mg day-1. However, as endogenous synthesis is sufficient to meet the physiological needs, there is no requirement for dietary cholesterol and it is advisable to keep the intake as low as possible. If intake of dairy fat and meat are controlled, then there is no need for severe restriction of egg yolk intake, although some limitation remains prudent.
Saturated Fatty Acids (SFAs)
The relationship of dietary saturated fat to plasma cholesterol levels and to CHD was graphically demonstrated by the Seven Countries Study involving 16 cohorts, in which saturated fat intake explained up to 73% of the total variance in CHD across these cohorts. In the Nurses' Health Study, the effect of saturated fatty acids was much more modest, especially if saturates were replaced by carbohydrates. The most effective replacement for saturated fatty acids in terms of CHD prevention is by polyunsaturated fatty acids (PUFAs). This agrees with the outcome of large randomized clinical trials, in which replacement of saturated and trans fats by polyunsaturated vegetable oils effectively lowered CHD risk.
Trans-Fatty Acids (t-FAs)
t-FAs (Trans-Fatty Acids) are geometrical isomers of unsaturated fatty acids that assume a saturated fatty acid-like configuration. Partial hydrogenation, the process used to create t-FAs, also removes essential fatty acids such as LA (Linoleic Acid) and ALNA (Alpha Linolenic Acid). Metabolic studies have demonstrated that t-FAs render the plasma lipid profile even more atherogenic than SFAs, by not only elevating LDL cholesterol to similar levels but also decreasing HDL cholesterol. As a result, the ratio of LDL cholesterol to HDL cholesterol is significantly higher with a t-FA diet (2.58) than with a SFA diet (2.34) or an oleic acid diet (2.02). This greatly enhances the risk of CHD. Evidence that intake of t-FAs increases the risk of CHD initially became available from large population-based cohort studies in the US and in an elderly Dutch population. Eliminating t-FAs from the diet would be an important public health strategy to prevent CHD. Since these are commercially introduced agents into the diet, policy measures related to the food industry practices would be required along with public education. t-FAs have been eliminated from retail fats and spreads in many parts of the world, but deep-fat fried fast foods and baked goods are a major and increasing source.
Monounsaturated Fatty Acids (MUFAs)
The only nutritionally important MUFA is oleic acid, which is abundant in olive and canola oils and also in nuts. The epidemiological evidence related to MUFAs and CHD is derived from studies on the Mediterranean diet (see below), as well as from the Nurses' Health Study and other similar studies in the US.
Polyunsaturated Fatty Acids (PUFAs)
PUFAs are categorized as n-6 PUFAs (mainly derived from linoleic acid) and n-3 PUFAs (mainly present in fatty fish and also derived from alpha-linoleic acid). Clinical trials, in which n-6 PUFAs (containing lino-leic acid) were substituted for SFAs showed a greater impact on reduction of both plasma cholesterol and CHD risk, in contrast to trials where low-fat diets were employed.
Much of the epidemiological evidence related to n-3 PUFAs is derived from the study of fish consumption in populations or interventions involving fish diets in clinical trials. Fish oils were, however, used in a large clinical trial of 11300 survivors of myocardial infarction. After 3.5 years of follow-up, the fish oil group (1gday-1) had a statistically significant 20% reduction in total mortality, 30% reduction in cardiovascular death, and 45% decrease in sudden death.
The Lyon Heart Study in France incorporated an n-3 fatty acid (alpha-linolenic acid) into a diet that was altered to develop a 'Mediterranean diet' intervention. In the experimental group, plasma ALNA and EPA (Eicosapentenoic Acid) increased significantly and the trial reported a 70% reduction in cardiovascular mortality at 5 years. Total and LDL cholesterol were identical in the experimental and control groups, suggesting that thrombotic and perhaps arrhythmic events may have been favorably influenced by n-3 PUFAs. Since the diet altered many other variables, such as fiber and antioxidants
(by increasing fruit and vegetable consumption), direct attribution of benefits to n-3 PUFAs becomes difficult to establish.
The proportions of SFAs, MUFAs, and PUFAs as constituents of total fat intake and total energy consumption have engaged active attention, in view of the strong relationship of these fatty acids to the risk of CHD. The reduction of SFAs in the diet has been widely recommended, but its replacement has been an area of debate, as to whether the place of reduced SFAs should be taken by MUFAs, PUFAs, or carbohydrate. Both MUFAs and PUFAs improve the lipo-protein profile, although PUFAs are somewhat more effective. In view of this, several recent dietary recommendations suggested that SFAs should be kept below 10% of daily energy intake (preferably reduced to 7-8%), MUFAs should be increased to 13-15%, and PUFAs raised to 7-10% of daily energy, with the total fat contributing to less than 30% of all calories consumed. These may need to be adjusted for populations who consume less quantities of total fat, so as to ensure an adequate intake of MUFAs and PUFAs even under those circumstances. The emphasis is now shifting from the quantity of fat to the quality of fat, with growing evidence that even diets with 30-35% fat intake may be protective if the type of fats consumed are mostly from the MUFA and PUFA categories. Enhancing the nutritional quality of dietary fat consumption, to provide greater cardiovascular protection, may be attempted by decreasing the sources of saturated fats and eliminating t-FAs in the diet, increasing the consumption of foods containing unsaturated fatty acids (both MUFAs and PUFAs), and decreasing dietary cholesterol consumption.
Diets which are high in refined carbohydrates appear to reduce HDL cholesterol levels and increase the fraction of small dense LDL, both of which may impact adversely on vascular disease. This dyslipidemic pattern is consistent with the elevation of plasma triglycerides and is typical of the 'metabolic syndrome.' Carbohydrate diets with high glycemic index might adversely impact on glucose control, with associated changes in plasma lipids, and have been linked to an increased risk of CHD.
Most soluble fibers reduce plasma total and LDL cholesterol concentrations, as reported by several trials. Fiber consumption strongly predicts insulin levels, weight gain, and cardiovascular risk factors like blood pressure, plasma triglycerides, LDL and
HDL cholesterol, and fibrinogen. Several large cohort studies in the US, Finland, and Norway have reported that subjects consuming relatively large amounts of whole-grain cereals have significantly lower rates of CHD.
Though several cohort studies showed significant reductions in the incidence of cardiac events in men and women taking high-dose vitamin E supplements, large clinical trials failed to demonstrate a cardiopro-tective effect of vitamin E supplements. Beta-carotene supplements also did not provide protection against CHD and, in some trials, appeared to increase the risk.
The relationship of folate to CVD has been mostly explored through its effect on homocysteine, which has been put forward as an independent risk factor for CHD. Reduced plasma folate has been strongly associated with elevated plasma homocysteine levels and folate supplementation has been demonstrated to decrease those levels. Data from the Nurses' Health Study in the US showed that folate and vitamin B6, from diet and supplements, conferred protection against CHD (fatal and nonfatal events combined) and suggested a role for their increased intake as an intervention for primary prevention of CHD. Recommendations related to folate supplementation must, however, await the results of ongoing clinical trials. Dietary intake of folate through natural food sources may be encouraged in the meanwhile, especially in individuals at a high risk of arterial or venous thrombosis and elevated plasma homocysteine levels.
Flavonoids are polyphenolic antioxidants, which occur in a variety of foods of vegetable origin, such as tea, onions, and apples. Data from several prospective studies indicate an inverse association of dietary flavonoids with CHD. The role of these and other phytochemicals (such as plant stanols and sterols) in relation to CHD needs to be elucidated further.
High blood pressure (HBP) is a major risk factor for CHD. The relative risk of CHD, for both systolic and diastolic blood pressures, operates in a continuum of increasing risk for rising pressure but the absolute risk of CHD is considerably modified by coexisting risk factors (such as blood lipids and diabetes), many of which are also influenced by diet. A cohort study in Finland observed a 51%
greater risk of CHD mortality with a 100 mmol increase in 24-h urinary sodium excretion. Several clinical trials have convincingly demonstrated the ability of reduced sodium diets to lower blood pressure. A meta-analysis of long-term trials suggests that reducing daily salt intake from 12 g day-1 to 3gday-1 is likely to reduce CHD by 25% (and strokes by 33%). Even more modest reductions would have substantial benefits (10% lower CHD for a 3-g salt reduction). The benefits of dietary potassium in lowering blood pressure have been well demonstrated but specific effects on CHD risk have not been well studied. Keeping the dietary sodium:potassium ratio at a low level is essential to avoid hypertension.
A systematic review reported that nine of ten ecological studies, two of three case-control studies, and six of sixteen cohort studies found a significant protective association for CHD with consumption of fruits and vegetables or surrogate nutrients. In a 12-year follow-up of 15 220 male physicians in the US, men who consumed at least 2.5 servings of vegetables per day were observed to have a 33% lower risk for CHD, compared with men in the lowest category (<1 serving per day). A follow-up study of NHANES (National Health and Nutrition Examination Survey), a large national survey in the US, also reported a coronary protective effect of regular fruit and vegetable intake. Persons who consumed fruits and vegetables 3 or more times a day were at 24% lower risk than those who consumed less than one portion a day. A global study of risk factors of CHD in 52 countries (INTERHEART) also reported low consumption of fruit and vegetables to be a major risk factor, across all regions.
In the UK diet and reinfarction trial, 2-year mortality was reduced by 29% in survivors of a first myocardial infarction in those receiving advice to consume fatty fish at least twice a week. A meta-analysis of 13 large cohort studies suggests a protective effect of fish intake against CHD. Compared with those who never consumed fish or did so less than once a month, persons who ate fish had a lower risk of CHD (38% lower for 5 or more times a week, 23% lower for 2-4 times a week, 15% lower for once a week, and 11% lower for 1-3 times a month). Each 20 g day-1 increase in fish consumption was related to a 7% lower risk of CHD.
Several large epidemiological studies, the best known among them being the Adventist Health Study, demonstrated that frequent consumption of nuts was associated with decreased risk of CHD. The extent of risk reduction ranged from 18% to 57% for subjects who consumed nuts more than 5 times a week compared to those who never consumed nuts. An inverse dose-response relationship was demonstrated between the frequency of nut consumption and the risk of CHD, in men as well as in women. Most of these studies considered nuts as a group, combining many types of nuts (walnuts, almonds, pistachio, pecans, macadamia nuts, and legume peanuts).
Soy is rich in isoflavones, compounds that are structurally and functionally similar to estrogen. Several animal experiments suggest that intake of these isoflavones may provide protection against CHD, but human data on efficacy and safety are still awaited. Naturally occurring isoflavones, isolated with soy protein, reduced the plasma concentrations of total and LDL cholesterol without affecting the concentrations of triglycerides or HDL cholesterol in hypercholesterolemic individuals.
Dairy consumption has been correlated positively, in ecological studies, with blood cholesterol as well as coronary mortality. Milk consumption correlated positively with coronary mortality rates in 43 countries and with myocardial infarction in 19 regions of Europe.
The relationship of alcohol to overall mortality and cardiovascular mortality has generally been J-shaped, when studied in Western populations in whom the rates of atherothrombotic vascular disorders are high. The protective effect of moderate ethanol consumption is primarily mediated through its effect on the risk of CHD, as supported by more than 60 prospective studies. A consistent coronary protective effect has been observed for consumption of 1-2 drinks per day of an alcohol-containing beverage but heavy drinkers have higher total mortality than moderate drinkers or abstainers, as do binge drinkers.
Composite Diets and CHD The Mediterranean diet
The traditional Mediterranean diet has been described to have eight components:
1. high monounsaturated-to-saturated fat ratio;
2. moderate ethanol consumption;
3. high consumption of legumes;
4. high consumption of cereals (including bread);
5. high consumption of fruits;
6. high consumption of vegetables;
7. low consumption of meat and meat products; and
Most of these features are found in many diets in that region. The characteristic component is olive oil, and many equate a Mediterranean diet with consumption of olive oil.
A secondary prevention trial of dietary intervention in survivors of a first recent myocardial infarction (the Lyon Heart study), which aimed to study the cardioprotective effects of a 'Mediterranean type' of diet, actually left out its most characteristic component, olive oil. The main fat source was rapeseed oil. Vegetables and fruits were also increased in the diet. On a 4-year follow-up, the study reported a 72% reduction in cardiac death and nonfatal myocardial infarction. The risk of overall mortality was lowered by 56%. Large cohort studies in Greece and in several elderly European population groups have also recently reported a protective effect against CHD and better over all survival in persons consuming a Mediterranean type of diet. The protection was afforded by the composite diet rather than by any single component. Improvement in metabolic syndrome and reduction of inflammatory markers has also been observed with this diet, which may explain part of the protection against CHD.
A composite diet, employed in the Dietary Approaches to Stop Hypertension (DASH) trials, has been found to be very effective in reducing blood pressure in persons with clinical hypertension as well as in people with blood pressure levels below that threshold. This diet combines fruits and vegetables with food products that are low in saturated fats. The blood pressure lowering effect is even greater when the DASH diet is modified to reduce the sodium content. Though the effects on CHD prevention have not been directly studied, the blood pressure and lipid-lowering effects of the low salt-DASH diet are likely to have a substantial impact on CHD risk.
A reduced risk of CVD has been reported in populations of vegetarians living in affluent countries and in case-control comparisons in developing countries. Reduced consumption of animal fat and increased consumption of fruit, vegetables, nuts, and cereals may underlie such a protective effect. However, 'vegetarian diets' per se need not be healthful. If not well planned, they can contain a large amount of refined carbohydrates and t-FAs, while being deficient in the levels of vegetable and fruit consumption. The composition of the vegetarian diet should, therefore, be defined in terms of its cardioprotective constituents.
In the Health professionals follow-up study in the US, a prudent diet pattern was characterized by higher intake of vegetables, fruits, legumes, whole grains, fish, and poultry, whereas the Western pattern was defined by higher intake of red meat, processed meat, refined grains, sweets and dessert, French fries, and high-fat dairy products. After adjustment for age and other coronary risk factors, relative risks, from the lowest to the highest quintiles of the prudent pattern score, were 1.0, 0.87, 0.79, 0.75, and 0.70, indicating a high level of protection. In contrast, the relative risks, across increasing quintiles of the western pattern, were 1.0, 1.21, 1.36, 1.40, and 1.64, indicating a mounting level of excess risk. These associations persisted in subgroup analyses according to cigarette smoking, body mass index, and parental history of myo-cardial infarction.
The traditional Japanese diet has attracted much attention because of the high life expectancy and low CHD mortality rates among the Japanese. This diet is low in fat and sugar and includes soy, seaweeds, raw fish, and a predominant use of rice. It has been high in salt, but salt consumption has recently been declining in response to Japanese Health Ministry guidelines.
The powerful relationship of specific nutrients, food items and dietary patterns to CHD has been persuasively demonstrated by observational epidemiologi-cal studies (which indicate the potential for primary prevention in populations) and by clinical trials (which demonstrate the impact on secondary prevention in individuals).
Atherosclerotic vascular diseases (especially CHD) are multifactorial in origin. Each of the risk factors operates in a continuous manner, rather than across an arbitrary threshold. When multiple risk factors coexist, the overall risk becomes multiplicative. As a result of these two phenomena, the majority of CHD events occurring in any population arise from any individuals with modest elevations of multiple risk factors rather than from the few individuals with marked elevation of a single risk factor.
These phenomena have two major implications for CHD prevention. First, it must be recognized that a successful prevention strategy must combine population-wide interventions (through policy measures and public education) with individual risk reduction approaches (usually involving counseling and clinical interventions). Second, diet is a major pathway for CHD prevention, as it influences many of the risk factors for CHD, and can have a widespread impact on populations and substantially reduce the risk in high-risk individuals. Even small changes in blood pressure, blood lipids, body weight, central obesity, blood sugar, inflammatory markers, etc., can significantly alter the CHD rates, if the changes are widespread across the population. Modest population-wide dietary changes can accomplish this, as demonstrated in Finland and Poland. At the same time, diet remains a powerful intervention to substantially reduce the risk of a CHD-related event in individuals who are at high risk due to multiple risk factors, prior vascular disease, or diabetes.
A diet that is protective against CHD should integrate: plenty of fruits and vegetables (400-600 g day-1); a moderate amount of fish (2-3 times a week); a small quantity of nuts; adequate amounts of PUFAs and MUFAs (together constituting about 75% of the daily fat intake); low levels of SFAs (less than 25% of the daily fat intake); limited salt intake (preferably less than 5 day-1); and restricted use of sugar. Such diets should be culturally appropriate, economically affordable, and based on locally available foods.
National policies and international trade practices must be shaped to facilitate the wide availability and uptake of such diets. Nutrition counseling of individuals at high risk must also adopt these principles while customizing dietary advice to specific needs of the person. CHD is eminently preventable, as evident from research and demonstrated in practice across the world. Appropriate nutrition is a major pathway for CHD prevention and must be used more widely to make CHD prevention even more effective at the global level.
See also: Alcohol: Absorption, Metabolism and Physiological Effects; Disease Risk and Beneficial Effects; Effects of Consumption on Diet and Nutritional Status. Antioxidants: Diet and Antioxidant Defense; Observational Studies; Intervention Studies. Cholesterol: Sources, Absorption, Function and Metabolism; Factors Determining Blood Levels. Coronary Heart Disease: Hemostatic Factors; Lipid Theory. Dietary Fiber: Role in Nutritional Management of Disease. Fatty Acids: Monounsaturated; Omega-3 Polyunsaturated; Omega-6 Polyunsaturated; Saturated. Fish. Folic Acid. Fruits and Vegetables. Nuts and Seeds. Potassium. Sodium: Physiology; Salt Intake and Health. Vegetarian Diets.
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