Lifelong Prevention of Arteriosclerosis
As explained in previous chapters, the role of homocysteine in human arteriosclerosis has been clarified by clinical and epidemiological studies over the past two decades. Experimental and laboratory studies have documented homocysteine's role in the genesis of plaques, progression of arterial narrowing, and complications of thrombosis of arteries to the vital organs. In human populations the control of blood homocysteine levels by known risk factors for arteriosclerosis, including diet, genetic background, gender, toxic factors, hormones, drugs, exercise, aging and lifestyle, have been explored sufficiently to suggest, for individuals at risk, lifelong strategies for the prevention of arteriosclerosis. ]
The importance of a new theory about a given disease is judged by the ability of individuals at risk to prevent or cure that disease by practical application of the theory. Consider these examples: (1) John Snow's theory, which linked cholera to contaminated water in 18th-century London, was put to a practical test when he demonstrated that removing the pump handle of a suspected contaminated well prevented cholera in the people using water from the contaminated well. (2) Louis Pasteur's theory, which linked immunity to rabies with exposure to killed rabies virus from the dried spinal cords of infected rabbits, was dramatically applied to individuals at risk for the disease. A child doomed to die of rabies because of rabid wolf bites was saved by Pasteur's attenuated rabies virus vaccine treatments. (3) The devastating effects of scurvy, beri-beri and pellagra were definitively dealt with when scientists identified key vitamins in foods—ascorbic acid, thiamine and niacin— that would prevent or cure these nutritional deficiency diseases. In all of these cases, an individual at risk could avoid the effects of a devastating infectious or nutritional disease by applying the theory explaining the origin of disease.
One of the most appealing features of the homocysteine theory is its simplicity and ease of application to the prevention of arteriosclerosis. Although the scientific details of the homocysteine theory are complex in many respects, any lay person can understand the basic principles of the theory, which attributes increased risk of vascular disease to increased blood levels of homocysteine, i.e., the higher the homocysteine level, the greater the risk. A person at risk needs to understand that homocysteine is derived from methionine, a normal amino acid building block of all proteins in the diet. This derivative of a normal amino acid can damage the artery walls if allowed to accumulate excessively in the body's blood and tissues. The other basic concept that is important to understand is that the level of homocysteine in the blood is controlled by the action of three B vitamins—B6, B12 and folic acid— within the body. By consuming an optimal diet containing an abundance of these vitamins over a period of months and years, an individual at risk can achieve a lifelong measure of protection against development of arteriosclerosis.
When confronting the possibility of developing a disease of aging such as arteriosclerosis, it is important to realize that some risk factors can be modified or improved, but other factors cannot be changed. It is also important to understand which factors can be changed, how this will reduce the risk of disease, and why other risk factors— especially age, gender and genetic background—can be minimized but not removed by control of diet and lifestyle.
The most valuable single study of the influence of risk factors on homocysteine levels is the Hordaland study from Norway. 2 In this study a cross-section of a population at risk was studied. A total of 7,591 normal men and 8,585 normal women, aged 40 to 67, with no history of serious disease was studied. Blood homocysteine levels were higher in men than women (10.8 vs. 9.1 micromoles per liter), and the levels increased with age in both sexes (12.3 and 11.0 micromoles per liter, respectively, at ages 65 to 67). The level of blood homocysteine increased significantly with the number of cigarettes smoked per day for both men and women in all age groups. The combined effect of age, gender and smoking was prominent, resulting in a homocysteine level that was 4.8 micromoles per liter higher in older male smokers, aged 65 to 67 (13.2) than in younger women nonsmokers, aged 40 to 42 (8.4). Moderate exercise produced somewhat lower homocysteine levels in both men and women compared with inactive subjects, but the effect was in the range of 1 micromole per liter lower for active vs. sedentary subjects. The results of dietary intake of fruits and vegetables and added vitamin supplements were also found to affect blood homocysteine levels, producing differences of 0.8 and 1.4 micromoles per liter in the fruit and vegetable eaters and supplement users, respectively.
The results of the Hordaland study and many other smaller epidemiological studies confirm that the risk of complications of arteriosclerosis, especially heart attack, stroke and generalized vascular disease, can be decreased by controlling the risk factors of diet, smoking and exercise that contribute to elevation of blood homocysteine. Several studies have also suggested that risk of disease is correlated with blood homocysteine levels even in the normal range. This finding means that careful attention to all of the controllable factors affecting blood homocysteine will promise protection from disease. If the blood homocysteine level can be kept in the 8 to 10 micromole per liter range, a significant measure of protection against the development and progression of arteriosclerosis is assured.
As mentioned before, certain important factors influencing risk of arteriosclerosis by elevation of blood homocysteine levels cannot be changed. These include age, genetic background and gender. However, beneficial dietary and lifestyle improvements can significantly lengthen life and improve health until the onset of senescence. As Chapter 6 discusses, the processes that control aging and senescence are only partially understood by medical science. Nevertheless, current knowledge of aging is helpful in increasing those trends toward longer life expectancy that are apparent in major developed countries. This knowledge includes the principles of the homocysteine theory. Experts in gerontology (the science of aging) anticipate that healthful years can indeed be added to the present life expectancies of 73 to 76 years for men and 77 to 84 years for women. The total achievable life span is not currently known precisely, but evolution and genetic control of the aging process appear to limit human life span to a maximum of about 100 to 120 years.
The influence of genetic background on risk of arteriosclerosis, like the influence of aging, is only partially understood. Although genetic inheritance cannot be changed, hereditary effects on the processing of homocysteine can be controlled in some instances by increasing the quantity of vitamins B6, B12 and folic acid needed to control blood homocysteine level. In this way dietary and nutritional strategy can help overcome the deleterious effects of heredity on the risk of arteriosclerosis. This concept is well-established in other areas of nutritional knowledge, and it has long been known that individuals require different amounts of vitamins and minerals for optimal health according to their genetic makeup. 3 If a parent carries a defective gene for controlling homocysteine, his or her children can be tested for the presence of this gene by new techniques of molecular biology. If the children are found to have the unfavorable gene, this knowledge can be used to increase the quantities of B vitamins in the diet or by supplements to control blood homocysteine levels.
Besides age and genetic background, the only other major risk factor for arteriosclerosis that cannot be changed is gender. For many years men have been known to develop coronary heart disease and other manifestations of arteriosclerosis at an earlier age than women in susceptible populations. In fact, women enjoy a measure of protection against arteriosclerosis until after menopause, when their risk rapidly approaches that of men. This protection is attributed to the production of estrogen and other hormones by the ovary during the reproductive years.
In many epidemiological studies the level of blood homocysteine has been found to be lower in women than in men of the same age. Generally, the level of homocysteine is about 2 micromoles per liter less for women than for men. After the menopause, homocysteine levels increase about 2 micromoles per liter in women. At age 65 to 67 the homocysteine level for women reaches 10.5, and the corresponding level for men of the same age is 12.5 micromoles per liter. The persistently higher level of blood homocysteine for men in all age groups may be related to testosterone production by the testis, increased muscle mass and other factors that have not been studied in detail. The effect of contraceptive hormones, replacement estrogen therapy and antiestrogen drugs to modify risk of arteriosclerosis are discussed in a subsequent section of this chapter.
Arteriosclerosis is a disease which begins in childhood and adolescence, develops gradually and insidiously without symptoms during the early adult years, and first strikes, often suddenly, in men in the 40s, 50s and 60s. The onset in women is generally delayed until their 50s and 60s. Because of the silent, gradual and prolonged onset of arteriosclerosis, the most successful strategy for prevention must start in childhood and continue in adolescence and adulthood, providing the elder years with little risk of developing heart attack, angina pectoris, stroke, kidney failure or peripheral vascular disease. This lifelong strategy requires control of known modifiable risk factors, especially consumption of an optimal diet; moderate physical activity and avoidance of tobacco, drug and alcohol abuse. The best way to carry out this preventive strategy is outlined and discussed in succeeding sections of this chapter.
For those adults who find themselves developing symptoms, signs and effects of arteriosclerosis because of poor nutrition, substance abuse, sedentary lifestyle or deleterious genetic background, the homocysteine theory offers guidance concerning those measures which may improve one's chances for prevention or regression of established disease. Once the disease has become established and symptomatic, however, intensive preventive measures need to be combined with medical and surgical therapy in some cases to improve life expectancy and quality of living. These measures are best coordinated with physicians and surgeons who specialize in the treatment of established vascular disease. The nutritional preventive strategies specified by the homocysteine theory can contribute in a major way to successful control of established arteriosclerosis.
Dietary Prevention of Arteriosclerosis
In its simplest form, an optimal diet to prevent arteriosclerosis consists of abundant fresh vegetables and fruits, whole grains and legumes, limited quantities of fresh meat and dairy products, a minimum of highly processed and packaged foods, and strictly limited consumption of fats and sugars. This diet will provide sufficient vitamins B6, B12 and folic acid to prevent excessive accumulation of homocysteine in the blood and other tissues of the body. Unfortunately, it is all too common for children, young adults and the elderly to consume a diet containing few if any vegetables and fruits, large quantities of meat and dairy products with an emphasis on highly processed, preserved and packaged foods which contain excessive fats and sugars. The typical American diet of fast convenient foods is the major cause for the high risk of arteriosclerosis and its complications of coronary heart disease, stroke, kidney failure and generalized vascular disease in the U.S. This pattern of food consumption is unfortunately highly profitable to the food industry, which relentlessly promotes and advertises poor eating habits.
Since the discovery of vitamins in the early 20th century, nutritionists have studied in great detail the quantity of each vitamin that is needed to prevent deficiency disease. These studies have led to the concept of the RDA (recommended dietary allowance) and the RDI (recommended dietary intake) of virtually all known constituents of foods, including vitamins, minerals, trace elements, protein, fat and carbohydrate. The RDA for each nutrient is decided by a panel of expert nutritional scientists and medical scientists who are convened by the National Research Council in Washington D.C., sponsored by the National Academy of Sciences, the Institute of Medicine, and the National Academy of Engineering. 4 After evaluating all available scientific studies of each food constituent, the panel decides "the levels of intake of essential nutrients considered, in the judgment of the Committee on Dietary Allowances of the Food and Nutrition Board on the basis of available scientific knowledge, to be adequate to meet the known nutritional needs of practically all healthy persons."
The concept of the RDA is that a sufficient quantity of a vitamin or other nutrient in the diet will maintain health and prevent deficiency disease. In regard to the homocysteine theory of arteriosclerosis, there has been until recently little available information about the quantities of vitamins B6, B12 and folic acid needed to prevent elevation of homocysteine in the blood. In an exhaustive review of human vitamin B6 requirements in 1978 by a conference sponsored by the National Research Council, for example, there was no consideration of the possibility that inadequate or marginal vitamin B6 intake could be related to elevation of blood homocysteine and susceptibility to arteriosclerosis. 5 Thus the RDA for vitamin B6 of 2.2 mg per day for adult men, 2.0 mg per day for adult women and 2.6 mg per day for pregnant or lactating women was established without considering the evidence that chronic vitamin B6 deficiency causes arteriosclerosis by elevation of blood homocysteine.
Folic Acid and Vitamin B6
In the case of folic acid, the RDA for adult men and women was set at 400 micrograms (meg) per day in 1980. In 1989, however, the RDA for folic acid was lowered to 200 meg per day, primarily because large segments of the U.S. population failed to consume the established RDA of 400 meg. Because of persuasive evidence that dietary deficiency of folic acid in pregnant women leads to birth defects in newborn infants, especially neural tube defects such as spina bifida and anencephaly, the Food and Drug Administration has recently ruled that sufficient folic acid be added to enriched foods, starting in 1998, to assure a minimum intake of 400 meg of folic acid per day for pregnant women. Folic acid will be added to rice, grains, pasta, bread and other enriched foods that are consumed by wide segments of the population.
Since publication of the lowered RDA for folic acid (200 meg) in 1989, 4 an important study of 1,160 elderly subjects in the Framingham Heart Study, aged 67 to 96, has concluded that blood levels of homocysteine become elevated if the dietary folic acid intake is less than 250 meg per day. 6 Folic acid intakes in the 250 to 400 meg range were associated with slight elevation of blood homocysteine in the range of 11 to 12 micromoles per liter, and intakes greater than 400 meg per day were associated with blood homocysteine levels of 10 to 11 micromoles per liter. This discovery demonstrates that the RDA for folic acid of 200 meg is insufficient to prevent significant elevation of blood homocysteine in the elderly. In a follow-up study of 1,041 subjects from the same population, the degree of thickening of the wall of the carotid artery to the brain by arteriosclerosis was shown to be correlated with the level of blood homocysteine. 7 Blood homocysteine levels in the range of 10 to 18 micromoles per liter in men and levels of 13 to 18 in women were correlated with carotid arteriosclerosis.
In a study of 304 patients with coronary arteriosclerosis and 231 control subjects, elevated blood homocysteine levels of greater than 14 micromoles per liter were found in 50 percent of the patients. 8 In the analysis, risk of coronary arteriosclerosis was found to correlate with blood homocysteine levels even in the presumed normal range of 8 to 12 micromoles per liter. Low levels of vitamin B6 in the blood were found in 10 percent of the patients, significantly correlating with elevation of blood homocysteine compared to control subjects. A similar correlation was found with vitamin B6 intake and blood levels of vitamin B6 in the elderly Framingham Heart Study subjects. 6 Low folic acid and vitamin B6 intakes and low blood levels of these vitamins were found to correlate with elevation of blood homocysteine in a study of 130 patients with heart attack, compared to 118 control subjects. 9
In summary, the results of these and other studies show that the amounts of dietary folic acid and vitamin B6 that are required to prevent abnormal elevation of blood homocysteine are 350 to 400 meg per day of folic acid and 3 to 3.5 mg per day of vitamin B6. This figure for sufficiency of vitamin B6 agrees well with the estimate that an intake corresponding to 4 to 4.3 milligrams per day of vitamin B6 in humans is needed to prevent arteriosclerosis in pyridoxine-deficient monkeys. 10 This amount of B6 is almost twice the current RDA for this vitamin. 4
Vitamin B12
In the case of vitamin B12, the RDA is only 3 meg per day for adults. 4 Unlike folic acid and vitamin B6, which are widely distributed in foods of animal and plant origin, vitamin B12 is formed only by bacteria, fungi and algae. Yeast, plants and animals cannot make vitamin B12 for themselves and are dependent upon microorganisms for this essential vitamin. In the human diet vitamin B12 is supplied primarily by foods of animal origin (meats and dairy products) where the vitamin is accumulated by the action and growth of microorganisms. This extremely low quantity of vitamin B12 is absorbed in the human stomach and intestine by the action of a protein made in the stomach called intrinsic factor. This factor complexes with vitamin B12 in the stomach, and the complex is absorbed in the end portion of the small intestine. Additional protein factors in the blood (transcobalamin I and II) are required for transport of vitamin B12 to the liver and other organs. Most normal adults who eat foods of animal origin consume about 5 to 8 meg per day of vitamin B12, more than an adequate intake to meet the established RDA for this vitamin.
In the elderly and in ulcer disease, the absorption of vitamin B12 may be impaired by inflammation of the stomach. In the nutritional deficiency disease pernicious anemia, there is a total failure of absorption of vitamin B12 because of deficiency of the intrinsic factor required for absorption. Such total vitamin B12 deficiency may cause severe or fatal anemia and neurological damage to the spinal cord if untreated by injections of vitamin B12. Strict vegetarians may develop pernicious anemia after 20 to 30 years because of failure to consume meat and dairy products that supply vitamin B12. It is only in subjects with low levels of vitamin B12 in the blood due to absorptive problems that the blood homocysteine becomes elevated, generally in the 13 to 15 micromoles per liter range. 6 In fact, elevation of blood homocysteine is now widely used by hematologists as an indicator of inadequate vitamin B12 absorption or inadequate dietary folic acid intake.
Protein
Homocysteine is derived only from methionine, one of the 20 amino acids of all proteins, as explained in Chapter 3. Because all proteins contain methionine, dietary deficiency of methionine is not found in well-nourished populations. In populations with inadequate dietary protein consumption, however, the failure of normal growth and development in children is partly attributable to inadequate intake of the amino acids of proteins, including methionine. Excessive dietary intake of methionine is toxic in experimental animals, and the toxicity is partly counteracted by increased vitamin B6, which helps to convert excess homocysteine from methionine into cystathionine, the safe form for excretion. The RDA for protein is 63 grams per day for adult men and 50 grams per day for adult women.
Foods of animal origin, such as meat, eggs, milk and cheese, generally contain more protein than most plant foods. In addition, the protein of animal foods contains two to three times as much methionine as the protein of plant foods. Because of this fact, human populations that are mainly vegetarian consume less methionine than those that consume meat and dairy products. Most plant foods contain larger amounts of vitamins B6 and folic acid to help prevent excessive conversion of methionine to homocysteine, compared to animal foods. If a human population consumes primarily proteins of animal origin, the diet must also contain abundant amounts of vitamin B6 and folic acid to prevent excessive conversion of methionine to homocysteine. Unfortunately, processing, cooking and storing foods causes major losses of these vitamins, leading to marginal dietary intakes and the eventual elevation of blood homocysteine levels. Although a recent study found no correlation between dietary methionine intake and levels of blood homocysteine, the study population did not contain identified vegetarians for comparison with subjects consuming abundant animal foods. 9
The U.S. population currently consumes 14 to 18 percent of food calories in the form of protein. 4 Approximately 65 percent of the protein is from animal sources such as meat and dairy products; 16 to 20 percent of protein is from grain products such as bread, cereals and pasta; and 15 to 20 percent is from vegetable protein such as legumes and soy products. A diet that contains only one-third animal protein and two-thirds vegetable protein yields 60 to 85 percent of the amount of methionine in meat and eggs. These figures show that consumption of a predominantly vegetarian diet supplies somewhat less methionine than a diet containing a predominance of meat, dairy and egg protein. Accordingly, an optimal diet for prevention of arteriosclerosis would emphasize an adequate dietary intake of vitamins B6 and folic acid (see Table 1, page 158) to prevent excessive conversion of the methionine of either animal or vegetable protein to homocysteine.
The importance of vitamin B6 and folic acid in controlling the blood homocysteine level was dramatically demonstrated with an experimental study of severe deficiencies of these vitamins in animals. 11 Deficiency of folic acid causes an elevation of blood homocysteine in fasting animals, yet an oral dose of methionine by stomach tube has no effect on the blood homocysteine level. In contrast, deficiency of vitamin B6 causes no elevation of blood homocysteine in the fasting state, but an oral dose of methionine causes a dramatic rise in blood homocysteine within one hour, lasting about five hours. These results suggest that chronic deficiency of folic acid in a human population causes elevation of blood homocysteine in the fasting state, and chronic vitamin B6 deficiency causes high elevation of blood homocysteine in the several hours following a meal containing abundant methionine from dietary proteins.
An important biochemical theory was advanced to explain these observations in experimental animals and in human subjects. 12 According to this theory, the methionine derivative, adenosyl methionine, synthesized in the liver from methionine administered to rats or from the methionine of dietary protein in man, decreases the conversion of homocysteine to methionine by the enzyme dependent upon vitamins B12 and folic acid and increases the conversion of homocysteine to cystathionine by the enzyme dependent upon vitamin B6. If methionine is in excess, increased adenosyl methionine is produced in the liver. When only folic acid is deficient, increased adenosyl methionine produced from excess methionine does not decrease the enzymatic conversion of homocysteine to methionine, and the homocysteine level in blood remains elevated and unchanged. When only vitamin B6 is deficient, increased adenosyl methionine produced from excess methionine does not increase the enzymatic conversion of homocysteine to cystathionine, and the homocysteine level in blood becomes highly elevated. After several hours, the excess homocysteine is converted back to methionine by the enzyme that is dependent upon folic acid and vitamin B12.
Carbohydrates and Fats
The other major components of the diet—fats and carbohydrates—are also important in determining dietary consumption of vitamin B6 and folic acid. Both of these vitamins are soluble in water and insoluble in fats. As a result, the more dietary fat that is consumed, the less vitamin B6 and folic acid will be available for absorption. In a diet that contains 40 to 50 percent of calories as fat, for example, the remaining components of the diet, foods with carbohydrates and protein, must supply all of the requirement for vitamin B6 and folic acid. In a diet that contains very little fat, in the range of 10 to 20 percent of calories, the foods containing 80 to 90 percent of calories as carbohydrate and protein are better able to supply the vitamin B6 and folic acid requirements. In general, the greater the fat content of the diet, the greater the risk of marginal deficiencies of vitamin B6 and folic acid. The lower the fat content of the diet, the lower is the risk of marginal deficiencies of these vitamins.
Carbohydrates are supplied in the diet in two principle forms, complex starches and simple sugars. Starches are consumed as vegetables, whole grains and legumes—foods that contain appreciable amounts of vitamin B6 and folic acid. Foods of animal origin also contain carbohydrates in somewhat lower amounts than foods of plant origin.
Fresh meats, liver and eggs contain abundant amounts of vitamin B12 and appreciable amounts of vitamin B6 and folic acid if the foods are not excessively processed, heated or preserved.
In contrast to starches, sugars are frequently consumed in prepared, cooked or baked foods that contain cane or beet sugar, corn syrup or fruit sugars. These sugars are highly processed carbohydrates that contain no vitamins or minerals. The higher the sugar content of the diet, the less these sugar-rich foods are able to supply vitamin B6 and folic acid. In a diet that contains abundant sugar from candies, cakes, ice cream or frozen yogurt, the required intake of vitamins B6, B12 and folic acid is completely dependent upon other constituents of the diet. Consumption of a diet with 25 to 30 percent of calories as sugar and 40 to 50 percent of calories as fats, therefore, forces the body to obtain its dietary requirement for B vitamins from the remaining 20 to 35 percent of food calories. Thus failure to consume adequate whole grains and vegetables plus a diet rich in sugars and fats leads to marginal or frankly deficient intakes of vitamin B6 and folic acid.
Processed Foods
Food processing, preservation and storage lead to significant losses of vitamin B6 and folic acid, which are destroyed by milling, heating, chemical additives, radiation and storage. The losses of these vitamins, compared to fresh, raw ingredients, ranges from a low of 10 to 15 percent by freezing foods, to as much as an 85 to 90 percent loss by refining rice or wheat to prepare white rice, rice flour or white flour. If a diet contains processed ingredients, along with a high content of sugars and fats, the deficiencies of vitamin B6 and folic acid may become marginal to serious over a period of months and years and can lead to elevation of blood homocysteine, arterial damage and arteriosclerosis.
Besides arteriosclerosis, another common complication of a diet with abundant sugars, fats and processed foods is obesity. The control centers for appetite in the brain produce eating behavior sufficient to supply the body with adequate vitamins and minerals for survival. If the diet is seriously deficient in multiple nutrient factors because of high sugar and fat content, the brain requires consumption of larger quantities of food to obtain these nutrients. The tendency then is to overconsume calories from sugars a ad fats, leading to obesity. In susceptible individuals, this dietary pattern also increases the risk of developing diabetes, which also seriously increases the pace of arterial damage and development of arteriosclerosis.
Fiber
Fiber is the indigestible starch-like roughage of plant foods. Fiber may either be soluble, e.g., fruit pectins, or insoluble, e.g., vegetable lignins and celluloses. In either case, the fiber component remains in the stomach, intestine and colon during digestion of food. Because fiber is not digested or absorbed into the bloodstream, it contributes no calories and has no nutritional value. Fiber fills the stomach, producing satiety, decreases the absorption of fats and sugars and increases the intestinal contents, promoting regular elimination. The fiber of plant foods is rich in vitamins and minerals which are lost during refining and processing. Numerous medical and epidemiological studies have shown an inverse relation between consumption of dietary fiber and many major diseases of developed societies, including arteriosclerosis. 13 For these reasons, an optimal diet for preventing arteriosclerosis contains abundant fiber from plant foods. 14
Vitamin E and Other Antioxidants
Another vitamin, tocopherol or vitamin E, has also been found helpful in preventing arteriosclerosis and coronary heart disease. Numerous studies have shown that dietary intake of vitamin E either in fresh vegetables and whole grains or in supplements decreases risk of coronary disease by as much as 50 percent, 15,6 Recent studies affirm the importance of vitamin E in prevention and control of arteriosclerosis, which was first advocated by the Shute Clinic in Canada in the 1950s. Attempts to prove the beneficial effects of beta-carotene supplements have not yet been successful. However, vitamin C, bioflavonoids and other antioxidant compounds are under study for possible beneficial preventive effects in controlling arteriosclerosis. In one study, men with arteriosclerosis who had survived myocardial infarction were shown to have lower blood homocysteine, cholesterol, LDL and triglycerides following treatment with troxerutin, a bioflavonoid, in combination with vitamin B6, folic acid, vitamin B12, choline and riboflavin. 17
Minerals
For many years it has been known that susceptibility to arteriosclerosis and coronary disease are inversely related to hardness of the water supply. 18 In particular, magnesium, calcium, bicarbonate, sulfate and fluoride were found to confer protection against coronary heart disease when present in the drinking water. Magnesium is an important factor in aiding the enzymatic digestion and utilization of foods by organs of the body. Magnesium is essential for the action of the enzymes that process proteins and the amino acids methionine and homocysteine. Zinc is also an important factor in numerous functions of the body, including expression of DNA and the aging process. All of these mineral elements are seriously depleted when whole grains are refined into white flour and white rice, amounting to losses of 50 to 90 percent.
Other trace minerals such as chromium, copper, manganese, fluoride, selenium and molybdenum are required in small quantities for optimal health. Consumption of whole grains, fresh meats and seafoods and fresh vegetables will assure an adequate intake of these elements. Insufficient intake of iodine causes hypothyroidism because of decreased formation of thyroid hormone. Severe iodine deficiency causes goiter, elevation of blood homocysteine levels, 19 increased blood cholesterol and lipoproteins and thus increased susceptibility to coronary heart disease. Adequate intake of iodine is assured by occasional consumption of seafood and the use of iodized salt.
Iron must be consumed in adequate quantities to prevent anemia and to promote healthy growth and development. Recent studies have suggested that excessive iron intake may predispose to increased risk of arteriosclerosis. Iron and homocysteine are known factors which cause damage to fats and proteins when LDL reacts with oxygen radicals in developing arteriosclerotic plaques. In experimental animals, the feeding of excess homocysteine causes increased uptake and storage of iron in the liver and other tissues. The possible role of excess dietary iron in the promotion of arteriosclerosis in human populations is currently under investigation by medical scientists.
Other Dietary Factors
Certain other trace compounds in the diet are known to be capable of converting homocysteine to methionine in the body by biochemical reactions. These nutrients, especially betaine, dimethyl thetin, and S-methylmethionine, are present in foods such as beets, garlic and onions. Consumption of these nutrients may prove to be of importance in counteracting hyperhomocysteinemia. 20 Other sulfur compounds in garlic and onions, such as alliin, may also be found in future studies to be helpful in preventing high blood homocysteine levels.
An interesting protective effect of dietary fish intake against arteriosclerosis was discovered in Greenland Eskimos, whose traditional diet contains large amounts of cholesterol and fats from whale blubber. The active nutrient in fish that confers this protection is omega-3 unsaturated fish oil. The effect of fish oil is to lower blood homocysteine levels in men with high blood fats. 21 Unsaturated plant oils, such as corn oil, also prevent elevation of blood homocysteine and prevent arteriosclerosis in experimental animals. 22 Unsaturated fish and plant oils also act in the body to prevent the damaging effects of oxygen radicals on cells and tissues. Fish is also an abundant source of vitamin B6, which controls elevated blood homocysteine.
As discussed in Chapter 2, oxycholesterols, the products of reaction of highly purified cholesterol with oxygen, rapidly cause arteriosclerotic plaques in monkeys and rabbits. On the other hand, highly purified cholesterol, protected from the oxygen of air, causes no change in the arteries when fed or injected into experimental animals. The highly damaging oxycholesterols are found in foods in which cholesterol is subjected to heating and exposure to the oxygen of air during food processing, cooking and preservation. 23 Examples of foods that contain these oxy-cholesterols are dried egg yolk, dried milk powder and foods fried in heated oils. The oxycholesterols of these foods are absorbed into the blood during digestion where they become concentrated in the low-density lipoprotein (LDL) fraction of the plasma. When lipoproteins are taken up by arterial wall cells, the cholesterol oxides that are released cause damage to artery wall cells and tissues, promoting arteriosclerotic plaque development. These oxycholesterol compounds are present in human arteriosclerotic plaques. Another source of these oxycholesterols results from the modification of LDLs by oxygen radicals that occurs in arterial wall cells. The homocysteine that is released from aggregates of LDL within arterial wall cells also promotes formation of oxycholesterols by affecting the way oxygen is used in these cells, causing accumulation of reactive oxygen radicals. 1
An Optimal Diet for Health
The most important prerequisites for a healthful diet are quality, freshness, variety and proper nutritional balance. Most adults know which foods are to be avoided. However, in today's busy world, the average person is in a hurry, impatient with the need to shop for and prepare meals, and eager to minimize expense. Yet, the investment of time and money in good nutrition will yield significant lifelong benefits to health and longevity. Health is a precious commodity at any age. Maintaining good health through a high-quality diet will greatly enhance the enjoyment and fulfillment of life.
First and foremost, an optimal diet will feature food that is fresh or minimally processed and composed of the finest ingredients. The modern agricultural and transportation systems of contemporary America offer a wonderful year-round selection and variety of these foods. The most nutritious fruits and vegetables are those that are selected, cooked and consumed as quickly after harvesting as possible. Everyone knows that homegrown or local fruits and vegetables have the most flavor; they are also the richest in vitamins, minerals and other essential ingredients. In the seasons when local produce is unavailable, an amazing selection of fresh fruits and vegetables is shipped to most areas of America by truck, rail or air.
How does one face cleaning, cooking and preparing all that fresh produce? One way to approach this task is to view food preparation as a form of relaxation after a busy day at work. With practice, an experienced home cook can prepare a nutritious dinner in 45 to 60 minutes. Peeling two or three varieties of fresh vegetables and steaming them takes about 15 to 20 minutes. A pan of brown rice, cracked wheat, beans or lentils can be simmering on the stove for 15 to 45 minutes while the preparation of vegetables and salad is in progress. A fresh salad every day can be assembled in 5 to 10 minutes and dressed with fresh lemon juice or vinegar and olive oil. Depending upon the season, the salad may consist of different varieties of lettuce and other dark leafy greens, cucumbers, tomatoes, onions, carrots, celery, peppers, fennel, small amounts of avocado or other raw vegetables. A small portion of fish, chicken or meat may be added as a source of protein several times a week.
A properly prepared, home-cooked dinner will provide a minimum of three to six servings of fresh vegetables, salad and fruits per day. One to three fruits at breakfast and a vegetable and a fruit at lunch will bring the total to 6 to 10 servings of these foods every day. Day after day, week after week, month after month, consistent consumption of 6 to 10 servings of fresh vegetables and fruits will provide the vitamins, minerals, fiber, antioxidants and other nutrients that are needed to process the proteins, starches and fats in the rest of the diet.
As previously noted, vitamin B6, folic acid, and vitamin B12 are the three vitamins that are necessary for preventing a buildup of homocysteine, when proteins are broken down in the body. Vitamin B6 is abundant in many fresh vegetables whole grains and fruits as well as in meats and fish. Folic acid, abundant in leafy dark green vegetables and whole grains, is also abundant in liver. Vitamin B12 is required in extremely low amounts and is available only in foods of animal origin such as meat, eggs, fish and dairy products. In Table 1 the amounts of these three vitamins are listed for a variety of foods.
Table 1
SOURCES OF VITAMIN B6, FOLIC ACID AND VITAMIN B12 IN FOODS
Food Vitamin B6 Folic acid Vitamin B12
Homocysteine and Individual Risk
The Homocysteine Revolution
Food
Vitamin B6 Folic acid Vitamin B12
Plum, 1 medium
Pork
Potato, 1 large
Rice, brown, 1 cup
Rice, while, 1 cup
Salmon, fresh fillet
Spinach, 4 large leaves
Squash, acorn, x h
Squash, summer, large
Strawberries, 6 medium
Sweet potato, 1 medium
Tomato, 2 medium
Tuna, fresh fillet
Tuna, canned
Wheat flour, whole, 1 oz.
Wheat flour, white, 1 oz.
Yeast, baker's, one small
cake Estimated daily intake,
adult 526 Estimated
elderly 6 Optimal daily intake
1.1-1.3
3-3.5
194-357
daily intake, 1.3-1.6 174-220
350-400
4.5
5-15
The values for each vitamin arc determined by microbiological growth assays, taken from the U.S. Department of Agriculture data hand books 24 * 5 and the National Research Council Reports. 525
The most important sources of calories in freshly prepared meals are the complex carbohydrates found in whole grains, breads, pastas, beans, peas and other legumes. Potatoes, yams, squashes, turnips and other root vegetables are also a good source of carbohydrate calories. The skins of these vegetables provide some of the vitamins, minerals and antioxidant nutrients of these foods.
Vegetables are best prepared and cooked by baking or steaming with a minimum of heat and peeling only if necessary. Avoid boiling these foods in large amounts of water. Vitamin B6 and folic acid are very sensitive to loss through heating.
Brown rice, bulgar wheat, barley and other grains, including whole grain breads and pastas, provide a good balance of carbohydrate calories, moderate protein, low fat, and abundant vitamins and minerals. The most nutritious bread is prepared from whole grain flours, such as multigrain bread or whole wheat bread made from stone-ground flour. Homemade bread from these flours can be prepared once or twice per month on the weekend with a mixer or a bread machine. Extra loaves can be frozen for later use. Some bakery or health food store breads of this type are often as nutritious as the home-baked variety.
Fresh meats, fish, eggs, butter, milk, cream and cheese are at the top of the U.S. Department of Agriculture food pyramid, which means that these components of a healthful diet should be used sparingly and in small quantities to provide flavor and interest rather than to provide a major source of calories. Two to four ounces of meat, poultry, fish or eggs provide more than adequate animal protein in a single day. By reducing the quantity of animal foods, the number of calories from animal fat is minimized. In addition, animal foods need not be consumed every day. For those who wish to avoid meat, a serving of several ounces of eggs, milk or cheese several times per week will provide adequate vitamin B12 to prevent anemia and a buildup of homocysteine in the blood. Vegans who consume no animal products of any kind need to supplement their diets with 0.1 mg vitamin B12 per day (or 1 mg intramuscular injection per month) to prevent vitamin B12 deficiency.
To summarize, an optimal diet for health consists of 6 to 10 servings of raw, lightly cooked or steamed fresh vegetables or fruits; 2 to 3 servings of starchy vegetables, whole-grain bread, cereal or pasta; and one small serving of meat, poultry, fish, eggs, milk or cheese. Flavor and interest are provided by herbs, spices, vegetable or fruit sauces, with small quantities of a vegetable oil such as olive oil, corn oil or canola oil. Faithful adherence to such a beneficial diet will add satisfying, healthy years to your life by helping to prevent heart disease, cancer and other diseases of aging.
Notably absent from this healthful diet are pastries, pies, cakes, heavy fried foods, rich meat sauces, candies, sugary desserts, sugared cereals, sugared soft drinks and other similar temptations. Avoiding totally or greatly minimizing calories from these prepared, baked or cooked foods with high fat or high sugar content will constitute a major improvement in the diet at any age. Not only will this strategy help to prevent weight gain, but it will also shift the diet to foods with fewer calories and beneficial balanced nutrients.
Selecting the Best Processed Foods
The purposes of food processing are to increase flavor, palatability and storage potential. Some common examples of food processing are the preparation of flour from whole grains, the extraction of sugar from sugar beets, sugar cane or corn, and the separation of fats and oils, such as butter from milk and vegetable oils from olives or grains. Separating the protein, carbohydrates and fats of whole foods enhances their flavor, palatability and storage life. However, major losses of vitamins, minerals and fiber occur in all of these examples of food processing. In the case of the refining of wheat into white flour, followed by chemical bleaching, the losses of vitamins, minerals, essential oils and fiber are as much as 90 percent, compared to whole-grain wheat. In the case of extraction of sugar, the final product is chemically pure sucrose, containing none of the vitamins, minerals, essential oils or fiber present in whole beets, sugar cane or corn. Separation of olive oil from olives removes virtually all of the water-soluble vitamins, minerals and fiber that are present in whole olives. Cold-pressed olive oil, on the other hand, does contain antioxidant nutrients that have been found to be beneficial.
The selection of minimally processed, unbleached high quality flour is essential for preparation of the most nourishing bread or pasta. Unbleached, nonbromated, enriched white flour from durum wheat is the best for making pasta. Stone-ground whole wheat flour is best for making whole wheat bread. Multigrain breads are made from flours of this type, milled from different grains. Stone-ground, whole corn meal is best for making corn bread, tortillas, or cornmeal pancakes. During the past two decades, food manufacturers have introduced numerous excellent flours of the minimally processed type.
If the preparation of fresh, home-baked breads and pasta is not possible, many excellent products are now available from food manufacturers and bakeries. Whole wheat or multigrain breads of excellent quality are available from local bakeries or from large-scale food manufacturers. Heavy white breads made from minimally processed or stone-ground flour are preferable to the light, cottony breads made from highly processed white flour.
Hot or cold cereals provide a serving of whole grain food for breakfast. In colder months, a bowl of cooked whole wheat cereal or oatmeal, topped with fruit and a small quantity of whole milk or light cream is a tasty, satisfying, healthful breakfast. Whole grain dry cereals without added sugar are an excellent substitute in the warmer months. Highly enriched cereals are satisfactory, provided that bran, fiber and other components of minimally processed grains are present. Highly sugared cereals should be avoided entirely.
Brown rice is a major cereal grain that supplies protein, fiber, carbohydrate, vitamins and minerals in a healthful combination. Cooking brown rice takes longer (45 minutes) than polished white rice, but the rewards are improved flavor and better nutritional value. Other cooked cereals, such as bulgar cracked wheat, millet, barley, rye or quinoa, are a convenient, tasty, highly beneficial source of whole grains. The more highly refined, processed and purified the cereal derivative, the less desirable from the nutritional point of view.
Canning, Freezing, Drying and Storing Foods
Traditional methods of food preservation and storage can offer satisfactory alternatives to fresh vegetables, fruits, whole grains, legumes, meat and dairy foods. However, in each instance the traditionally preserved foods are inferior to fresh foods with regard to nutritional quality and value. The protective coating devised by nature for fresh foods is preferable to an artificial package prepared by a manufacturer. For example, peeling an orange or grapefruit and eating the fruit or squeezing the juice is preferable to buying a canned or frozen orange or grapefruit juice. Using a fresh egg in cooking is preferable to using powdered or dried eggs.
In the case of dried egg yolks, food processing adds a dangerous ingredient that potentially damages arteries. Cholesterol is a normal constituent of all animal foods.
Cholesterol is protected in the body against the oxygen of air by an elaborate combination of antioxidant vitamins, minerals and enzymes. Highly purified cholesterol that is protected against the oxygen of air causes no damage to the arteries of animals. When the cholesterol of animal foods is exposed to the oxygen of air by food processing, as in spray drying, highly damaging cholesterol oxides are formed. Powdered egg yolks, widely used in the manufacture of prepared foods, are known to contain these highly damaging cholesterol oxides. Eggs, as fresh as possible, are a safe alternative to dried egg yolks. Fresh eggs can be safely stored in the refrigerator for one to two weeks because of the highly effective antioxidant systems that they contain. However, eggshells slowly admit oxygen, and, after several weeks, these antioxidants are overcome, and cholesterol oxides begin to form. The fresher the egg, the lower the risk of containing these dangerous cholesterol oxides.
Canning as a process for preserving foods was invented in the early 19th century to support the troops of Napoleon's armies. Any military quartermaster knows that "an army travels on its stomach." Canning offered a mobile and convenient source of nourishment that lasts for months, regardless of the season of the year. Do canned foods contribute to arteriosclerosis and coronary heart disease? In the canning process, food is cooked and heated to a high temperature. The cans are sealed hot to exclude as much air as possible. Two of the vitamins that are the most sensitive to this form of food preservation are vitamin B6 and folic acid. Canning is known to decrease the vitamin content of foods by as much as 35 percent. As a result, larger quantities of canned foods must be consumed to equal the amount of vitamins present in fresh foods.
Freezing as a method of food preservation became available in the 1920s and 1930s, when refrigerators and freezers were manufactured on a large scale for commercial and home use. To prevent deterioration of frozen foods, particularly vegetables and fruits, the food is first blanched. This process involves the rapid heating of food in water for a short period of time at the boiling point. The heat inactivates the food's enzymes that otherwise would cause slow deterioration of the food while frozen. Unfortunately, this heating step also destroys approximately 10-15 percent of the vitamins that are sensitive to heat. Two of the most sensitive vitamins to destruction by heat are vitamin B6 and folic acid. Again somewhat larger amounts of frozen vegetables or fruits must be consumed to provide the quantity of these vitamins supplied by fresh foods.
The radiation of foods with X-rays or gamma rays has been advocated to increase the shelf life of a variety of foods. Radiation of this type floods the food with activated oxygen and free radicals. These reactive chemicals in irradiated foods combine with cholesterol to produce dangerous cholesterol oxides. Three of the most sensitive vitamins to the effects of this type of radiation are vitamin B6, folic acid and vitamin B12. Radiation of food with gamma rays is likely to increase the risk of arteriosclerosis because the process causes oxidation of cholesterol and essential fats and also destroys the vitamins that are needed to prevent a dangerous buildup of homocysteine in the blood.
Many preserved foods processed by a variety of methods have a long shelf life and need little or no refrigeration. This is because the essential vitamins and other trace nutrients of these foods are intentionally depleted so that bacteria or insects cannot use the food for growth, preventing rapid spoilage of the food.
However, a more insidious form of food poisoning is caused by the damage to foods by destruction of vitamin B6, folic acid and vitamin B12 through heat, exposure to oxygen or slow bacterial growth. Foods depleted of these vitamins in this way may hasten arterial damage by allowing a buildup of blood homocysteine. It is best to prepare only enough food for one meal and to discard any small amounts of leftover food. Larger quantities of leftover food can be adequately preserved by covering and promptly refrigerating or freezing. Such leftover food should be consumed within a day or two.
Lifestyle Factors and Homocysteine Levels
Smoking
The most important controllable lifestyle factor, besides an optimal diet, is cessation of cigarette smoking. The Hordaland study from Norway clearly documents that nonsmokers have a lower level of blood homocysteine than smokers, in the range of 1 to 2 micromoles per liter. 2 A possible explanation is that the carbon monoxide of cigarette smoke combines chemically with a form of vitamin B6, causing inactivation of the vitamin and impairing the ability of the body to dispose of excess homocysteine by conversion to cystathionine. Since cigarette smoke contains over 600 different toxic substances besides carbon monoxide, other factors may also contribute to heart disease risk associated with smoking. An example may be the free radical compounds produced by burning tars that can modify lipoproteins in the wall of the artery, hastening plaque development.
The addictive properties of the nicotine in cigarette smoke have received attention from pharmacologists and medical scientists employed by the tobacco industry, government, universities and the private sector. The results of these studies have shown that nicotine addiction is at least as powerful and as difficult to overcome as the addictions to heroin or cocaine. Recent medical studies have also shown that nicotine affects brain function in a way similar to other addictive drugs. An individual's ability to overcome nicotine addiction and to cease smoking varies with several factors, including psychological dependency, nutrition, state of health, age and gender, among others. Almost every person who tries to overcome nicotine addiction and dependency needs help during the withdrawal phase. Nicotine patches, gum, hypnotic suggestion, group therapy, hot baths and other strategies may help to overcome withdrawal symptoms.
The best strategy for avoiding the great health risks of smoking is preventing the beginnings of nicotine addiction in childhood. However, because of peer pressure, availability of cigarettes, the stress of adolescence and many other causes, children and adolescents are highly vulnerable to this form of substance abuse. Parents may have difficulty preventing nicotine addiction in their children because of the difficulty of controlling these complex behavioral factors. By accepting the rebellious nature of developing adolescents, by setting an example of nonsmoking, by material inducements and other inventive methods, parents should help their children to escape this destructive habit.
Drugs and Toxins
Over the past several decades, a wide variety of drugs, solvents and other toxic substances has been found to cause elevation of blood homocystine levels. 27 Chemother-apeutic drugs for cancer such as methotrexate, antiepilep-tic drugs such as phenytoin and antihypertensive drugs such as hydrochlorothiazide have been found to increase blood homocysteine levels. Many of these drugs are known to antagonize the action of folic acid or vitamin B6 in the body, causing abnormalities in the control of blood homocysteine. The need of the individual for the therapeutic benefits of these drugs needs to be weighed against the risk of elevated blood homocysteine in hastening the onset and complications of arteriosclerosis. In the case of azaribine, a potent chemotherapeutic drug that was used for treatment of refractory psoriasis, the observation of heart attack, stroke and thrombosis of peripheral blood vessels associated with elevation of blood homocysteine led the U.S. Food and Drug Administration in 1976 to withdraw the drug from general use. 28
A striking example of a toxic chemical in the workplace, carbon disulfide, was uncovered during an investigation of increased risk of myocardial infarction among viscose rayon production workers. 29 The high risk of arteriosclerosis and heart attack in these workers was attributed to antagonism of vitamin B6, leading to increased blood homocysteine levels. 30 Another commonly used anesthetic gas, nitrous oxide, also known as "laughing gas," has been found to increase the blood homocysteine level by interfering with the ability of vitamin B12 to convert homocysteine to methionine. 27 Because of the relatively brief periods of exposure to nitrous oxide in patients, the added risk of arteriosclerosis is probably minimal. However, the potential hazard of exposure to nitrous oxide among anesthetists or industrial workers and the resulting elevated blood homocysteine over a period of years should be studied.
Exercise
The importance of exercise in preventing arteriosclerosis and coronary heart disease was popularized by the eminent American cardiologist, Paul Dudley White, during the 1950s and 1960s. He inspired a generation of medical scientists and practitioners to examine the effect of a sedentary lifestyle on the progression of arteriosclerosis. In meeting with Dr. White at his office in Boston two years before his death, I was privileged to explain to him how I had discovered the causal link between elevation of blood homocysteine and vascular disease. His response was, "This is a red-letter day in my understanding of heart disease!" He understood very well that lack of exercise was predominantly a contributory factor in susceptibility to coronary heart disease and that complex genetic, dietary and toxic factors are the most important in causation.
In the past two decades the importance of moderate exercise in delaying the onset of arteriosclerosis and benefitting longevity has become widely studied and popularized. Exercise programs have been found to increase levels of high density lipoprotein (HDL) in the blood, contributing to a favorable decrease in the ratio of total cholesterol to HDL. Studies of runners, athletes and marathoners compared to those with sedentary lifestyles have shown a significant but limited reduction of blood homocysteine amounting to 1 to 2 micromoles per liter that is attributed to exercise. 2 Nevertheless, in individuals who have developed arteriosclerosis and coronary heart disease because of their nutritional, genetic or lifestyle history, vigorous exercise may precipitate heart attack, even in a well-conditioned athlete. By chance, I met and conversed briefly with Jim Fixx, a proponent of exercise and conditioning to prevent coronary heart disease, only two days before he died of a heart attack while jogging. He had evidently ignored early signs of heart disease in himself and failed to seek proper medical and surgical therapy.
Stress
While a considerable effort by medical scientists has attempted to relate stress and type A personality to coronary disease susceptibility, a causal role for these factors has not definitely been established. Psychological stress reduction techniques have been claimed to be beneficial in this regard. However, the opposite point of view, that susceptibility to arteriosclerosis from nutritional, genetic or toxic factors may account for a stress-prone personality, has not received adequate investigation. The effects of homocysteine on brain function are incompletely understood, but neurophysiologists have clearly demonstrated that homo-cysteic acid, the fully oxidized form of homocysteine, is a very potent exciter of brain function. Animals treated with high doses of homocysteine thiolactone develop seizures, and some children with homocystinuria have increased risk of convulsions. A recent limited study showed that patients with fibromyalgia/chronic fatigue syndrome have highly elevated levels of homocysteine in cerebrospinal fluid. 31 These studies suggest that increased levels of homocysteine and related compounds in the brain may modify behavior to produce stressful personality traits or neuropsychiatric disorders.
Alcohol Use
Recent studies have shown that people who chronically abuse alcohol have elevated blood homocysteine levels. 33 Chronic excessive alcohol intake frequently leads to serious depletion of body stores of folic acid. The severity of folic acid deficiency may be reflected in anemia and prominent abnormalities of the bone marrow in the production of red blood cells, platelets and white cells. Deficiency of folic acid predisposes to an elevation of blood homocysteine because of the failure of conversion of homocysteine to methionine, as explained in Chapter 3. Alcohol also has prominent toxic effects on the function of the liver, leading to the accumulation of fat and cirrhosis of the liver. Although occasional patients with severe liver disease have been observed to have a degree of protection against arteriosclerosis, there are numerous examples of severe arteriosclerosis with stroke, coronary heart disease, kidney failure and peripheral vascular disease developing in chronic alcoholics. The idea that alcohol can somehow prevent deposition of fat and cholesterol in the walls of arteries because it may "dissolve the fat" is totally erroneous. Alcohol dissolves preferentially in plasma and exerts its toxic effects mainly on liver function. The elevation of blood homocysteine in alcoholics from folic acid deficiency produces arteriosclerosis by effects on arterial wall cells and tissues, and the function of the liver in producing lipoproteins is impaired by the toxicity of alcohol.
Consumption of alcohol in moderate quantities of one to two drinks per day, depending on body weight, has long been known to increase longevity when compared to the life span of abstainers from alcohol. Recently, the so-called "French paradox," the low incidence of arteriosclerosis and coronary heart disease despite high levels of fat and cholesterol in the French diet, has been attributed to the natural antioxidant pigments and bioflavonoids of red wine. 34 It is said that Thomas Jefferson advocated consumption of wine rather than spirits, saying, "1 think it is a great error to consider a heavy tax on wines as a tax on luxury; on the contrary, it is a tax on the health of all our citizens." Another possible explanation for the "French paradox" is the consumption of abundant fresh vegetables and fruits in the French diet and the popularity of fois gras and liver pate in French cuisine. Liver is a rich source of vitamin B6, folic acid and vitamin B12, which all prevent elevation of blood homocysteine.
Analysis of patterns of coffee and tea consumption in the Hordaland homocysteine study 2 concluded that heavy consumption of filtered, boiled or instant coffee, more than nine cups per day, was associated with a 13 to 16 percent increase in blood homocysteine levels. 35 No effect was seen from decaffeinated coffee, and there was a suggestion of a lowering effect on blood homocysteine levels with tea consumption.
Genetic Background, Sex Hormones and Aging
Analysis of the familial incidence of early-onset arteriosclerosis has estimated that genetic background is of importance in approximately one-third of cases of coronary heart disease. 3637 An important cause of this familial predisposition to coronary heart disease is an abnormal inherited form of methylenetetrahydrofolate reductase that is sensitive to heating. This thermolabile reductase has been estimated to affect as many as five percent of the general population in the homozygous form 38 and as many as 38 percent of a French Canadian population in the heterozygous form. 39 An individual from a family that carries this mutation requires more folic acid in the diet or from supplements to prevent elevation of blood homocysteine, compared with an individual without this genetic defect. 37 Therefore, an individual with this genetic background would be advised to consume a lifelong supplement of at least 1,000 meg per day of folic acid to insure that plasma homocysteine is kept at a low level, preventing early-onset arteriosclerosis and coronary heart disease.
The parents of children with the most common form of homocystinuria have been studied intensively by medical scientists for evidence of increased risk of arteriosclerosis. Since homozygous homocystinuria caused by this genetic defect (when both parents carry the gene) has an incidence of about 1 per 60,000 to 1 per 200,000 in various populations, the expected incidence of heterozygous cystathionine synthase deficiency (when one parent carries the gene) is estimated to be about 1 per 100 to 1 per 200 in the general population. In studying patients with early-onset arteriosclerosis and elevated blood homocysteine levels, medical scientists have suggested that in 25-30 percent of these cases one parent carries the gene for cystathionine synthase deficiency. These findings are based on the results of the methionine loading test, which measures the degree of elevation of blood homocysteine following an oral dose of methionine. The results were confirmed in some cases by enzyme analysis of cells cultured from the skin of these patients. In studying heterozygous cystathionine synthase deficiency by techniques of molecular biology, however, no correlation could be found between this genetic defect and susceptibility to arteriosclerosis. At the present time, therefore, the evidence that this genetic defeet can predispose to arteriosclerosis and coronary heart disease is inconclusive.
As explained in Chapter 3, about 50 percent of cases of homozygous homocystinuria caused by cystathionine sxiuhase deficiency respond to large doses of supplemental vitamin B6. A survey of 629 of these cases concluded that the risk of developing thrombosis was decreased by vitamin B6 therapy. 40 Certainly any individual with a family history of homocystinuria, either in ancestors or in descendants, would be well-advised to consume a lifelong supplement of 10 to 25 mg per day of vitamin B6. Supplemental vitamin B6 may help to limit the elevation of homocysteine in the blood to normal postprandial levels following a protein meal containing methionine. Further studies by medical scientists are in progress to evaluate the advisability of vitamin B6 supplements in families that carry hidden genetic defects for homocystinuria.
Other genetic defects that are involved in controlling plasma levels of homocysteine may be uncovered by future scientific investigation. The cases of homocystinuria caused by methyl transferase deficiency are quite rare, and there is no current information regarding whether vitamin B12 or folic acid supplements are beneficial in heterozygous members of families that carry this genetic defect.
Chapter 2 explains that genetic defects in lipoprotein and cholesterol processing by the liver and other cells of the body predispose to early-onset arteriosclerosis. In the disease hypercholesterolemia the extreme elevations of low density lipoprotein (LDL) and total cholesterol in the plasma are caused by a genetic defect in the receptor which transports LDL into cells. The extreme elevation of blood cholesterol in these cases damages the walls of arteries because the arterial lining cells are continuously exposed to increased quantities of lipoprotein that contains homocysteine. Reducing homocysteine levels in these individuals by combined supplemental therapy with vitamin B6, folic acid and vitamin B12 may theoretically be beneficial because this approach reduces the homocysteine content of lipoproteins. However, no medical studies of this approach have yet been reported in persons with familial hypercholesterolemia. The genetic defects involving lipoproteins underlying other familial predispositions to arteriosclerosis, such as combined familial dyslipidemia or syndrome X with hypertension, diabetes and central obesity, are less well understood by medical scientists. The possible effects of vitamin supplements on these diseases have not been studied.
A family history of arteriosclerosis and heart disease implies a major contribution of genetic factors in causation. A study comparing identical with fraternal adult male twins concluded that the homocysteine level is genetically influenced, although the levels were in the normal range for both groups. 41 Other nongenetically determined factors that influence susceptibility to arteriosclerosis are lifestyle factors in families. Dietary practices, smoking history, exercise habits and other risk factors may be greatly influenced by family tradition. Families who eat a vegetarian or Mediterranean-style diet, engage in athletic activities and do not smoke are more likely to produce heart-healthy offspring than those who smoke, avoid exercise and a high-fat, high-sugar diet with an abundance of snack and processed foods.
Numerous medical conditions that may be determined genetically to some degree have a major effect on the risk of arteriosclerosis and coronary heart disease. These conditions include diabetes mellitus, hypertension, high levels of blood cholesterol or lipoprotein(a) and decreased thyroid function. Effective, intensive medical therapy is usually required to control these medical conditions, favorably decreasing risk of vascular disease to some extent. Despite control of diabetes by diet, drugs or insulin, however, vascular disease complications frequently shorten the life span of individuals with diabetes. No specific influence of early diabetes has yet been found to control blood homocysteine level, but the kidney failure that is frequently found in diabetics significantly elevates homocysteine levels and hastens the progression of vascular disease. Hypertension is correlated with elevated blood homocysteine in a number of studies, including the Hordaland study, 2 but the effect of controlling hypertension on homocysteine levels has not been determined. High homocysteine levels have been suggested to exacerbate the narrowing of small blood vessels that is commonly found in diabetes and hypertension.
Sex Hormones
Women enjoy a measure of protection against arteriosclerosis during the reproductive years with a much lower incidence of coronary heart disease than men of the same age. This protective effect is ascribed to secretion of the female sex hormones estrogen and progestin by the ovary. Following menopause, however, the risk of arteriosclerosis and coronary heart disease in women rapidly increases, reaching rates comparable with those of men in their late 50s, 60s and 70s in susceptible populations. Because the ovary ceases to secrete female sex hormones after menopause, the level of homocysteine in plasma increases from
8 to 10 micromoles per liter in premenopausal women to
9 to 12 micromoles per liter in postmenopausal women. 2
The use of supplemental estrogens in postmenopausal women reduces the risk of coronary heart disease by as much as 50 percent 43 and decreases blood homocysteine levels significantly.
The association of high-dose estrogen and progestins for oral contraception with thrombosis and arteriosclerosis was related to the antivitamin B6 effects of oral contraceptives, causing elevation of blood homocysteine. 45 Subsequent studies have confirmed that oral contraceptives cause episodic elevation of blood homocysteine 46 and cause damage to the lining cells of arteries, called endothelial cells. 47 Low-dose oral contraceptives that are in current use have a lower but still significantly elevated risk of thrombosis compared with the older high-dose preparations. Women using oral contraceptives may benefit from moderate doses of supplemental vitamin B6 of 10 to 50 mg per day to decrease the edema, psychological effects and risk of thrombosis that may occur.
A chemotherapeutic antiestrogen drug, tamoxifen, is currently widely used in the treatment of breast cancer and certain other forms of cancer. Long-term treatment of breast cancer patients with tamoxifen was found to reduce the risk of cardiovascular mortality. The reduced risk of cardiovascular mortality was related to the lower levels of blood homocysteine produced by tamoxifen therapy. 48
Since normally secreted estrogens and progestins of the ovary have a protective effect against vascular disease, does the secretion of testosterone by the testis in men exacerbate arteriosclerosis? It is known that men have a greater percentage of body muscle mass and muscle protein than women and that their dietary requirement for protein is greater. Very little attention has been paid by medical scientists to the effect of testosterone and synthetic androgenic steroid hormones on blood homocysteine levels. Synthetic androgenic steroids appear to hasten the onset of vascular disease and heart attack, but it is unknown whether this risk is attributable to elevated blood homocysteine levels.
Subtle or overt deficiency of thyroid gland function has long been known to predispose to arteriosclerosis and coronary heart disease. In some cases, the level of blood cholesterol and LDL is increased in hypothyroidism. Studies of blood homocysteine in hypothyroidism have also shown elevated levels of homocysteine, explaining increased risk of vascular disease. 194950 Treatment of hypothyroidism with thyroid hormone may decrease vascular disease risk over a period of years.
High Cholesterol
Individuals with significantly elevated levels of total blood cholesterol and LDL have an increased risk of developing vascular disease. The treatment of this condition with diet, drugs, hormones and exercise is fraught with difficulty because of the resistance to lowering of blood cholesterol through intensive medical therapy. The recent limited success of statin drugs in reducing cholesterol levels and vascular disease risk is tempered by the unpleasant side effects, expense and potential toxicity of these drugs on muscles and the optic lens and from demonstrated carcinogenic effects in animals. The effect of dietary supplements of vitamin B6, folic acid and vitamin B12 in lowering blood homocysteine, cholesterol and LDL was demonstrated in a small number of patients with elevated cholesterol levels, 17 but the effect on vascular disease risk has not been determined. Theoretically, a significant decrease in the homocysteine content of LDL by this strategy should be beneficial because the strategy also decreases formation of LDL aggregates containing homocysteine.
In individuals with advanced arteriosclerosis and symptoms of coronary, cerebrovascular or peripheral vascular disease, a variety of advanced surgical techniques are available for excising, expanding, grafting or bypassing segments of arteries that are severely narrowed by arteriosclerosis. Angioplasty, endarterectomy or bypass grafts relieve symptoms and improve longevity in many cases, but a frequent complication of these procedures is a recurrence of the narrowing of arteries or formation of new arteriosclerotic plaques in the treated arterial segments. The potential effect of delaying or preventing these complications of surgical therapy by intensive dietary treatment and supplemental vitamin B6, folic acid and vitamin B12 is under study in some medical centers, but the results of this strategy remain to be determined.
Aging
Elevation of blood homocysteine levels is correlated with aging in men and women, and aging is a strong risk factor for development of arteriosclerosis. The fundamental nature of the aging process is incompletely understood, as explained further in Chapter 6. Nevertheless, it is well-established that decreased dietary intake, decreased blood levels and effects on blood homocysteine of vitamin B6, folic acid and vitamin B12 are correlated with aging. 651 Because of decreased caloric intake of nutrients and difficulties with absorption and mastication in the elderly, supplemental vitamins and minerals, including the B vitamins that control homocysteine levels, are advisable. The suggested intake of moderate quantities (10 mg of vitamin B6, 1.0 mg of folic acid, and 0.1 mg of vitamin B12 per day) of these supplemental vitamins may help to delay or ameliorate the rise in blood homocysteine levels that occurs in aging.
Prevention of Arteriosclerosis
Many clinical studies and surveys over the past decade have clearly shown the effectiveness of dietary improvements and supplemental vitamin B6, folic acid and vitamin B12 in lowering blood levels of homocysteine. In a study from South Africa, for example, these supplemental vitamins were found to decrease elevated blood homocysteine levels by over 50 percent. 52 After discontinuing these vitamin supplements for four months, blood homocysteine levels again rose. A second period of vitamin supplementation was effective in lowering blood homocysteine over a six week trial, while a diet with fewer processed foods that contained adequate levels of the B vitamins was less effective in lowering blood homocysteine. In the Hor-daland study from Norway, consumption of B vitamin supplements had a more consistent and stronger effect in lowering blood homocysteine than consumption of vegetables and fruits. 2
The effectiveness of vitamin supplementation and dietary modification on lowering blood homocysteine is well established, but the reduction of cardiovascular disease and other complications of arteriosclerosis by lowering homocysteine levels is in the early stages of study. In a comparison of 750 vascular cases with 800 controls, a multicenter European study concluded that consumption of vitamin B6, folic acid or vitamin B12 reduced the risk of vascular disease by approximately two thirds. 53 A retrospective study of over 3,000 cases out of a total population of 24,000 during a five-year period of vitamin B6 therapy (50 to 200 mg per day) for carpal tunnel syndrome and related disorders reduced the risk of acute heart attack and angina pectoris by almost three-fourths. 54 In persons taking vitamin B6 supplements for more than one year, there was also an apparent increase in longevity.
Although current studies are suggestive of a preventive effect of dietary modification and vitamin supplementation on arteriosclerosis and its complications, final proof will only be conclusively obtained from a long-term prospective prevention trial. In such a trial, large numbers of subject? would be assigned randomly to groups with and without control of blood homocysteine levels by diet, vitamin supplementation or drug therapy. All of the known risk factors for arteriosclerosis would be closely monitored and analyzed statistically for effects on homocysteine levels and occurrence of vascular disease. After a trial period of five to ten years, a significant reduction of the number of cardiovascular and other complications of arteriosclerosis in the group with low blood homocysteine, produced by diet, vitamin supplementation or high dose vitamin therapy, compared with groups with high blood homocysteine levels, would constitute final proof of the effectiveness of this approach. Although a number of studies of this type are currently in the planning stage, no large-scale trial has yet been funded.
For almost three decades the mortality rate for coronary heart disease and other forms of arteriosclerosis has been declining steadily in the United States, as discussed in Chapter 2. An analysis of consumption of synthetic vitamin B6 in the U.S. food supply concluded that the decline in vascular disease since 1968 is correlated with consumption of significant quantities of synthetic vitamin B6. 55 The incidence of coronary heart disease in Finland had been among the highest in the world for several decades, but during the past decade the incidence has declined significantly, and surveys have shown low homocysteine and lipoprotein^) levels among cases and controls. 56 Whether the low levels of homocysteine and the declining incidence of arteriosclerosis in Finland are attributable to the consumption of B vitamins has not been clarified. The recent decision of the U.S. Food and Drug Administration to add supplements of folic acid to grains, cereals, rice, pasta, bread and other enriched foods commencing in 1998 promises to continue the decline in vascular disease in the U.S. 1 This strategy, when implemented, is estimated to prevent as many as 50,000 deaths from coronary heart disease annually in the U.S. S7
Some of the anticipated benefits to the individual from control of vascular disease through application of the homocysteine theory of arteriosclerosis are total freedom from or delayed onset of heart attack, stroke and peripheral vascular disease. As a result, further increases in life expectancy and improved health in the elderly are expected. Improved dietary practices and control of lifestyle factors may also have beneficial effects on the risk of other degenerative diseases and conditions associated with aging, including cancer, degenerative osteoarthritis, rheumatoid arthritis and other autoimmune diseases, obesity, hypertension and diabetes. Although the total human life span may not be increased by these measures, the anticipated benefit is an improved state of gradual and healthful aging.
REFERENCES
1. Kilmer S. McCully, "Homocysteine and Vascular Disease." Nature Medicine 2:386-389, 1996.
2. Ottar Nygard, Stein Emil Vollset, Helga Refsum, Inger Sten-svold, Aage Tverdal, Jan Erik Nardrehaug, Per Magne Ue-land and Gunner Kvale, "Total plasma homocysteine and cardiovascular risk profile. The Hordaland homocysteine study." Journal of the American Medical Association 274:1526-1533, 1995.
3. Roger J. Williams, The Wonderful World within You: Your Internal Nutritional Environment (New York: Bantam Books, 1977).
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