Stephen Seely. Cambridge World History of Food. Editor: Kenneth F Kiple & Kriemhild Conee Ornelas. Volume 1, Cambridge University Press, 2000.
The central organ of the human circulatory system, the heart, must be among the most remarkable creations of nature. In the longest-living individuals, it works continuously for a hundred or more years, executing something like 4,000 million working strokes and moving 350,000 cubic meters of blood, enough to make a small lake. In individuals who die of heart disease, it is not, as a rule, the heart itself that fails but some auxiliary mechanism, like one of its arteries, or the pacemaker. If an artery, supplying a small part of the heart, is blocked, the tissues receiving oxygen and nutrients from that vessel die. If the area involved is not so large as to endanger the entire heart, the damage is gradually repaired by the immune system. The dead cells are removed but cannot be replaced; the gap they leave is filled with scar tissue. While the repair is carried out, the heart continues to work.
Among other remarkable properties of the heart is a virtual immunity from cancer and a good resistance to inflammatory diseases. When the body is at rest, the heart contracts approximately once every second. Its contraction—the systole—lasts about one-third of a second; its relaxation period—the diastole—two-thirds of a second. During hard physical exercise, the heart rate increases about three times.
The arterial system is like a many-branched tree. Its trunk, the aorta, is about three centimeters in diameter at its origin. The branches become progressively smaller and end in a network of capillaries of microscopic size. On the return side, blood is collected by small venules, which join to form veins and end in two large venous trunks. The entire length of the system is more than enough to encircle the earth.
The function of the circulatory system is to deliver nutrients to the cell population of the body and to collect their waste products. The system is water-borne, but a very small quantity of water carries a comparatively enormous cargo. The volume of water in the blood, and that of the substances dissolved or floating in it, are approximately equal.
A water-based transport system can readily transport water-soluble substances, but those are only a small part of the nutrients carried in blood. The most difficult technical problem is the transport of gases, notably oxygen and carbon dioxide. These are soluble, but only sparsely so in water. If they were carried only in aqueous solution, a very large quantity would be required for their transport. The problem is solved by the use of iron porphyrin, a substance that can readily take up oxygen and equally readily release it. The porphyrins are incorporated in large hemoglobin molecules, with molecular weight of 64,000, and these, in turn, are incorporated into red blood cells. It is interesting to note that the mammalian type of hemoglobin is the end product of a long process of development in evolutionary history. Invertebrate blood contains a large variety of hemoglobin-like substances (erythrocruorins), with molecular weights ranging from 17,000 to 1,250,000, in some cases copper-based compounds being used instead of iron. Red blood cells constitute about 40 percent of the blood by volume. Allowing an equal quantity of water for their flotation, 80 percent of the total capacity of the circulatory system is engaged in the task of oxygen transport.
Similar difficulties are presented by the transport of lipids and other hydrophobic substances. If they were simply released in water, they would stick to each other and to vessel walls. There are two solutions to the problem. One is the conjugation of a water-insoluble molecule with one or more other molecules to form a water-soluble complex. The other expedient is the use of carrier proteins. These are large molecules in comparison with the lipids they carry, serving, in effect, as packing cases for them. The protein molecule turns a hydrophilic outer surface to the watery medium in which it floats, and can pack a large quantity of hydrophobic molecules inside, shielded from contact with water.
The protein carrier with its lipid cargo constitutes a lipoprotein. As the carrier protein is heavier than water, the lipid it carries is lighter; the specific weight (or density) of their combination depends on the proportion of the two constituents. When the cargo of transport proteins is mainly cholesterol, they constitute low-density lipoproteins (LDL). Some lipoproteins carry cholesterol and other lipids from dead cells to the liver for reuse or excretion. They transport a small quantity of lipids; hence, they constitute high-density (HDL) lipoproteins.
The aqueous portion of the blood, the plasma, carries a variety of organic and inorganic substances, such as blood sugar (glucose) and salts. Among them are three kinds of proteins, albumin, globulin, and fibrinogen, serving various functions. The chemical messengers, hormones, which have to be transported from organs that produce them to receptors in other parts of the body, are always in transit in the blood, and so are enzymes, vitamins, and the like.
Moreover, the circulatory system is the highway that invading microorganisms try to use for spreading in the body, and cancers also spread by blood-borne fragments. To cope with these hazards, the system is defended by the immune mechanism, notably by several types of white blood cells (polymorphonuclear leukocytes, lymphocytes, and monocytes). The function of these cells is to seek out, ingest, and kill invading microorganisms, penetrate areas of infection, and phagocytose foreign matter and dead cells. The circulatory system is also the target organ of several plant toxins, some of which can act as vasodilators or constrictors, blood coagulants, or anticoagulants. The rye fungus ergot, for example, is such a powerful constrictor of peripheral blood vessels that, in the past, it created numerous epidemics in countries where rye was an important food item. The toxin ergotamine, mixed with rye flour, was capable of cutting off the circulation of the limbs, causing death by gangrene.
Apart from the effect of poisons upon them, arteries are subject to several other disorders (see the section “Specific Hazards of the Circulatory System). Larger arteries are more vulnerable than small arteries.Veins are not entirely trouble free but, in comparison with arteries, are notable for their smooth functioning and resistance to disease. They do, of course, work under less onerous conditions than arteries.
Not surprisingly, arterial disorders are among the leading causes of mortality in advanced countries with older populations. In a few countries, they are responsible for more mortality than all other causes combined. The current worldwide yearly toll of coronary artery disease is about two million deaths, to which cerebrovascular disease (strokes) add half a million. Disorders of the peripheral circulation can cause deaths, but since the elimination of ergotism, the numbers are small.
Specific Hazards of the Circulatory System
The foregoing review attempts to show the complexity and potential vulnerability of the circulation system. However, the exact causes of the most important arterial disorders are still not known, and the intent in this essay is to highlight a few specific hazards that could be relevant to their pathogenesis.
When the heart contracts, it compresses its own blood vessels, the coronary arteries, so that although it supplies all other organs in the body with blood, it cannot supply itself. The perfusion of the heart is effected by an auxiliary mechanism, working on the same principle as a flywheel in a mechanical system by drawing energy from a prime mover in one part of a power cycle and returning it in another part. The corresponding mechanism in the circulation is an elastic reservoir, consisting of the aorta and parts of its large-branch arteries. During systole the walls of the reservoir are distended, storing energy in their stretched elastic tissues; during diastole they contract, generating sufficient pressure to maintain blood flow in the circulation, including the by-then-relaxed coronary arteries. This arrangement, however, makes the nutrition of the heart dependent on the elasticity of the aorta and the other arteries that constitute the elastic reservoir. Several aspects of the aging process can bring about the deterioration of the elastic properties of tissues, representing a special hazard for the heart.
A similar problem arises in connection with the blood supply of the artery wall. The walls of arteries have a cell population that must be supplied with oxygen and nutrients like any other tissue. The difficulty in supplying them arises from the fact that the artery wall is compressed by the blood flowing through it, with a radial pressure gradient across it, the inside being more compressed than the outside. Large arteries have their own blood vessels, the vasa vasorum, which enter them on the outside and per-fuse the outer half of the artery wall.They cannot per-fuse the inner half, because the pressure available to force blood through these small arteries is insufficient to overcome the compression of that part of the artery. Consequently, the inner half of the artery wall must obtain oxygen and nutrients from blood flowing through the artery. The technical problems associated with this process are probably the basic causes of arterial disorders.
Oxygen and water-soluble nutrients can apparently diffuse through the layer of cells—the endothelium—that constitute the inner lining of the artery wall, and there are no known disorders caused by deficiencies of such nutrients. The main difficulty is the transfer of lipids from arterial blood to tissues in the inner half of the artery wall. As mentioned, lipids in the blood are carried by large protein molecules, which do not diffuse into tissues. Cells in need of them have to capture them by means of surface receptors that bind lipoproteins on contact (Goldstein and Brown 1977). The receptors are located in a special area of each cell’s surface, the coated pit. When receptors have captured a sufficient quantity of lipoproteins, the coated pit sinks into the cell and unites with a lysosome, the digestive organ of the cell (Simonescu, Simonescu, and Palade 1976; Anderson, Brown, and Goldstein 1977).
A brief description of the construction of the artery wall is needed at this point. The artery wall is a three-layered structure. Its inside, the intima, consists of a single layer of flat endothelial cells and a thin, liquid-filled subendothelial space. The second layer, the media, forms the bulk of the artery wall. It consists of elastic laminae and smooth muscle in varying proportions. The largest arteries, such as the aorta, are mainly elastic; those next in size, mainly muscular. The muscles of the media form peripheral bands, the contraction of which can reduce the lumen of the artery, regulating blood flow through it. Thus they reduce blood flow to organs at rest and increase it to organs in a state of high activity. However, individual smooth muscle cells also exist in the artery wall and perform the same duties as fibroblasts in other tissues. They can secrete various types of elastic and nonelastic fibers that are used mainly in the repair of injuries. Lastly, the outer layer of the wall is a tough connective-tissue covering.
The exact causes of the most important artery disease, atherosclerosis, are not known with certainty. A plausible explanation of the pathogenesis of the disorder is the following: The endothelial cells of the intima, in direct contact with blood inside the artery, capture lipoproteins in the plasma, as do other cells, by means of surface receptors. They do this not only for their own use but also for the supply of other cells in the inner half of the artery wall. Receptors in coated pits sink, as usual, into the interior of the endothelial cell, but in this case, they travel through the cell to emerge on its other side, where they discharge their load of lipoproteins into the subendothelium (Schwartz et al. 1977).
The hazard of the process, at least in prosperous countries, is not that they cannot transfer enough lipids into the subendothelium, but that they transfer too much. Presumably, if a cell captures lipoproteins from blood for its own use, it ceases to produce surface receptors when its needs are satisfied, but if it does so for other cells, it does not receive clear signals when to stop. The quantity actually transferred may depend on the availability of lipoproteins in the plasma.
In developing countries where the population lives on a barely adequate, or less than adequate, diet, the lipoprotein concentration in the plasma is correspondingly low, and the risk of endothelial cells over-supplying the cell population of the median layer of the artery wall is small. In prosperous countries, hyperlipidemia is common, presumably resulting in the almost universal occurrence of fatty suffusions in the intima of some arteries.
Such accumulations of lipoproteins, beginning in infancy or early childhood, could be the initiating event in atherosclerosis, even if the given description is only a simplified—possibly oversimplified—account of the earliest stage of atherosclerosis. Fatty streaks make a patchy appearance in the aorta and some other large arteries.The coronary circulation is usually more heavily involved than others, so that the concentration of lipoproteins in the plasma cannot be the only factor involved in pathogenesis.
Another hazard arises from the fact that arteries must be self-sealing in case of injuries; otherwise, small injuries may cause fatal hemorrhages. Injuries are sealed in the first instance by platelets—small discs 2 to 4 micrometers (mm) in diameter—circulating in immense numbers in the bloodstream. When the wall of a blood vessel is injured, collagen—a tough connective tissue inside it—is exposed. Collagen apparently attracts platelets, which immediately adhere to it. The platelets then release a substance that attracts more platelets and that makes them sticky, causing them to aggregate and form a temporary plug.This is subsequently converted into a more stable clot, after a complicated set of reactions, by fibrin. The latter is produced by the conversion of the soluble plasma protein, fibrinogen, into an insoluble substance. The fibrin originally forms a loose mesh, but ultimately it becomes a dense, tight aggregate.
This essential defense mechanism can become a life-threatening hazard, because advanced atherosclerosis can result in the ulceration of the artery wall, which, in turn, may invoke the clotting reaction. The ultimate result can be a thrombus, occluding the artery.
Atherosclerosis begins with the already mentioned lipid suffusions—the fatty streaks—in the subendothelium of some arteries. The space immediately beneath the single layer of endothelial cells inside the artery is originally small, but it is gradually extended by lipid deposits. The accumulating lipids are mainly cholesterol esters (cholesterol with an attached fatty acid molecule). Cholesterol can act as a weak base and, combined with a weak fatty acid, constitutes the equivalent of an inorganic salt. As there are many types of fatty acids that can combine with cholesterol, there are many types of cholesterol esters. The most important esters are oleates and linoleates, which are cholesterol combined with oleic and linoleic acid, respectively.
Cholesterol is a highly stable waxy substance, an essential constituent of every single cell in the body. The flexibility of the animal body, in comparison with the more rigid structure of plants, is due to the fact that the outer shell of plant cells is cellulose, a comparatively rigid substance, whereas that of animal cells is a complex, three-layered construction, containing proteins and lipids, including cholesterol. These cell membranes combine toughness with flexibility. In addition to the cell itself, its organelles have similar membranes.
The usefulness of cholesterol does not alter the fact that its accumulations in the artery wall can become harmful. Not known with certainty is why deposits of cholesterol esters accumulate inside artery walls. The possibility that if the density of lipoproteins in the plasma is high, endothelial cells transfer more than the required quantity from the blood to the subendothelium has been mentioned. The arising fatty streaks are visible without magnification as yellowish lines or small patches on the luminal surface of the artery. These streaks are flat, or only slightly raised, so that they do not obstruct blood flow and are not known to cause any clinical symptoms; hence, they appear to be harmless.
Fatty streaks appear in large arteries, particularly the aorta, at a very early age, probably in infancy. They are universal in children of all races in all parts of the world, but in developing countries they disappear in early childhood, whereas in prosperous countries they persist and spread. They occupy about 10 percent of the aorta in children; in adult life the affected area may increase to 30 to 50 percent.
In spite of their apparent innocuousness, fatty streaks may not be entirely harmless. They may, for instance, impede the diffusion of oxygen and water-soluble nutrients from blood flowing through the artery to tissues of the artery wall covered by them. But whatever the reason, the immune mechanism of the body treats them as foreign matter. The lipid accumulations are immediately invaded by phagocytes (monocytes), making their way into the lesions from arterial blood. They are apparently capable of separating adjacent endothelial cells slightly and slipping through the gap. Inside the fatty streak they engulf cholesterol esters until they are swollen with them. The lipid-laden phagocytes presumably attempt to leave the site of the lesion, but unlike other tissues, arteries are not drained by lymphatics, making it difficult for phagocytes to find their way out. Occasionally they can be found in the blood, and so some can escape, but many of them die in the attempt, so that ultimately dead foam cells, as lipid-laden monocytes are called, become the main constituents of fatty streaks.
Subsequently, fatty streaks are invaded by another type of cell: individual, motile smooth muscle cells, migrating into the lesion from the media. These perform the same function as fibroblasts in other tissues. They are cells capable of secreting various elastic and nonelastic fibers, used mainly in the repair of injuries. The fibers bridge over gaps in tissues separated by the injury. As far as possible, they attempt to restore the status quo ante, but when this is not possible, they do a serviceable repair. The ends of a broken bone, for instance, would initially be held together by inelastic fibers until new bone is formed to fill the gap. Under natural conditions, the bone would heal crookedly because the repair mechanism does not have the power to reset it in its original form.
Another function of fibroblasts is to encapsulate foreign matter in the body. If the immune mechanism is powerless to deal with some invading microorganism, an attempt might be made to encapsulate its colonies, as, for instance, in tuberculosis. This is essentially the function that fibroblasts of smooth muscle origin appear to fulfill in fatty streaks. Probably they attempt to break up a continuous layer of lipids, dead phagocytes, and other cell debris into a number of separated accumulations, which are then encapsulated by layers of fibrous tissue. This is how the archetypal lesion of atherosclerosis, the fibrolipid plaque, is thought to arise. The two basic components of the fibrolipid plaque are a white cap of connective tissue and an underlying pool of necrotic debris. The proportion of the two components can vary considerably, and so can the extent of the lesion and the number of fibrous caps in it. In the advanced stage of the lesion, the fibrous caps can be so numerous that they give the luminal surface of the artery wall the porridge-like appearance from which the disorder takes its name.
The fibrolipid plaques are elevated above the surface of the intima and thus represent an obstruction to smooth blood flow. It must be remembered, however, that the lesions are virtually universal in the population of advanced countries. They begin in early childhood and last throughout life, causing no discomfort or inconvenience of any kind for decades. Indeed, in the majority of the population they remain silent until death from some other cause. They can be best conceptualized as a potentially lethal disorder, but one that is generally under the firm control of the defense mechanism of the body.
In the last, uncontrolled stage of atherosclerosis, arteries densely covered by fibrolipid plaques may ulcerate, possibly leading to the adhesion of platelets to the lesions and ultimate thrombus formation. Ulcerated arteries may calcify. The much-thickened intima of the artery wall can fissure, become partly detached, and cause the condition known as an aneurysm. If the lumen of the artery, already narrowed by fibrolipid plaques, is further obstructed by a thrombus or aneurysm, it may become completely occluded, cutting off the blood supply of tissues served by the given artery.
To repeat, the basic cause of atherosclerosis in prosperous countries is thought to be excess lipid intake, and preventive efforts throughout the century have been directed at the reduction of fats in the diet. The main difficulty has been that an effective reduction of lipids seems to require such a Spartan diet that the population of advanced countries has not been persuaded to adopt it. Much evidence, however, is available to suggest that even if this assumption is correct, it can be only a part of the story. There must be other contributory factors that determine why arterial disorders become a lethal disease in some individuals and remain in their harmless, controlled stage in others.
For example, there are considerable differences between the geographical distribution of coronary artery disease and cerebrovascular disease (strokes). The latter appears at a lower level of prosperity, the highest mortality rates occurring in moderately prosperous countries, such as Bulgaria and Portugal, where the consumption of animal fats is comparatively low. With increasing prosperity and increasing fat consumption, mortality from strokes tends to drop. Thus 40 years ago, the world leader in stroke mortality was Japan. The dramatic rise of prosperity in that country was accompanied by considerable changes in diet, the consumption of animal fats increasing by about 50 percent. At the same time, there was a sharp decrease in the incidence of strokes, and stroke mortality is now approximately half that of 40 years ago. The lipid theory of atherogenesis does not differentiate between atherosclerosis in coronary arteries and atherosclerosis in cerebrovascular arteries, and so the fall of cerebrovascular mortality in Japan (as well as a similar sharp fall in the United States in the first half of the twentieth century) provides directly contradictory evidence.
If possible, preventive measures should eliminate atherosclerosis completely, but if that is not a practical possibility, preventing the transition from the controlled to the uncontrollable stage would be nearly as useful. Therefore, an understanding of the basic process of atherogenesis is not enough. It is also necessary to investigate contributory causes and other factors that promote or retard its development. Well-known factors of this nature are cigarette smoking, diabetes, and hypothyroidism, all of which may promote atherogenesis and hasten the onset of its terminal stage, but which fall far short of providing a complete explanation. The low prevalence of coronary artery disease in Japan, for instance, has not been changed by heavy smoking habits. The effect of smoking, diabetes, and hypothyroidism is probably not specific to arterial disease, but is rather a general weakening of the immune mechanism.
Progress toward a better understanding of the causes of artery diseases can proceed along two lines. One is the study of the pathogenetic process itself. If that were completely understood, the causes might be self-evident. Until then, important pointers may be provided by epidemiological studies. Knowledge of the parts of the earth in which artery diseases are highly prevalent and of those in which they are not should throw light on the conditions that promote or retard the disorders and to help in an underdstanding of their causative agents.
Arterial disorders have a distinct geographical distribution. They are generally very low or nonexistent in poor countries but are the leading cause of mortality in some of the most prosperous countries. Such a pattern creates the impression that the circulatory system, in spite of its complexity and potential vulnerability, is well able to cope with its natural hazards. Prosperity may have introduced some new condition—perhaps a surfeit of food in place of scarcity—that has changed a trouble-free mechanism into one susceptible to trouble.
An alternative possibility is that the difference is the result of the prolongation of life in prosperous countries. Arterial disorders appear in old age; therefore, the longer duration of life increases their share among causes of mortality. Yet another possibility is that the difference is the result of racial characteristics, Europeans being more vulnerable than Asians or Africans. Climatic conditions could be another factor, with arterial disease being more prevalent in temperate than in warm climates.
Epidemiological studies have eliminated a number of these possibilities. For instance, immigrant studies have disposed of the racial hypothesis. Black people may be free of arterial disease in Africa, but in the United States they are as vulnerable as American whites. Nor is the prolongation of life a satisfactory explanation. When mortality rates are compared in the same age groups in developing and advanced countries, it is still only the population of prosperous countries that is highly vulnerable to arterial disease. The critical factor appears to be diet. Thus, when population groups migrate from poor to prosperous countries, they, or their descendants, gradually become subject to the mortality patterns of their hosts. Migrants going from prosperous to poor countries take their diseases with them. This is, presumably, because migrants from poor to prosperous countries are willing enough to adopt the food of their hosts, but those moving in the other direction are not willing to embrace the poorer diet of their hosts.
Yet although such epidemiological studies have produced useful results on general points, they have brought little progress in matters of detail, such as the identification of food items connected with specific disorders, or finding the reason for the epidemiological peculiarities of some disorders. Why, for example, is worldwide mortality from coronary disease highest in Finland and that from strokes in Bulgaria?
One reason for the apparently limited usefulness of epidemiology is the intrinsic difficulty of the task. The diet of prosperous countries consists of something like a thousand food items, containing a million chemical substances, all potential suspects. None, however, is strongly poisonous, suggesting that perhaps the pathogenic agent may not be present in just one food item but in several, in different proportions, so that the correlation between the disease they collectively cause and one of the food items may only be weakly positive.
Possibly an equally important factor retarding progress might be regarded as a self-inflicted injury. Although the identification of the true causes of artery diseases is difficult, nothing is easier than the presentation of suspects on the basis of superficial arguments. Some of the favorite concepts of popular medicine, such as the particularly harmful effect of saturated fats or the assumed protective effect of dietary fiber, garlic, onions, and the like, are not the results of epidemiological studies but of superficial observations, or they are simply guesses.
An early comparison was that between the “low-protein, lowfat, high-fiber” diet of this or that African tribe and the “high-protein, high-fat, low-fiber” diet of prosperous countries, giving rise to the fiber industry. In fact, the differences between the diets of African tribesmen and the population of rich countries are innumerable. The tribesmen eat fewer apples, chocolates, and cabbages than do people in the West and do not take a sleeping pill at night and a tranquilizer in the morning.The main virtue of fiber is probably the fact that it is a nonfood that may help to prevent over-nutrition.
When it was pointed out that Eskimos—whose diet was not a lowfat, low protein, high fiber one—did not suffer from arterial diseases, the objection was sidestepped with the suggestion that they consumed the unsaturated fat of marine animals, not the hard fat of land animals. When it was pointed out that the French consumed as much animal fat and proteins as the British, yet the mortality from coronary disease in France was about a third of that in Britain, the “protective” effect of garlic, onions, and red wine was suggested as a possible explanation. Not even a guess is available as to how garlic, onions, and the like might protect the circulatory system. Yet such ideas, for some reason, are immediately taken up by the media and popular medicine, often impeding serious research. It may also be well to remember that the first task of research is to discover the causes of arterial disease. When those are known, attention can be turned to protective effects, but before they are known with certainty, protective effects are usually invoked to cover discrepancies between facts and theory.
A new line of approach emerged in the 1940s with the Framingham study. The basic idea was to recruit a large number of participants and keep a record of their food consumption until they all died. Then the diet of those who died of coronary disease could be compared with that of the participants who died of other diseases, providing valuable information about the dietary causes of coronary disease. In some of the later trials, the protocol was slightly changed. Some participants were persuaded to change their habits (for example, to reduce fat intake, or to give up smoking), whereas others were allowed to continue with their customary diets and other practices. Thus, prospective studies became intervention trials. A large number of these were conducted in many countries, among others by M. R. Garcia-Palmieri and colleagues (1980), the Multiple Risk Factor Intervention Research Group (1982), and G. Rose, H. D. Turnstall Pedoe, and R. F. Heller (1983).
Neither the Framingham trial nor its many successors, however, have produced clear evidence identifying the causes of coronary disease, and some of the results have been contradictory. At least one of the reasons for the poor performance of prospective studies is likely to be the gross inaccuracy of the food consumption data they collect. The data are obtained by means of periodic samplings by the method of “24-hour recall,” and are subject to several errors. A one-day sampling in, let us say, a month is unlikely to be truly representative of food consumption for the whole period. The data, as collected, are nonquantitative, and the quantities must be estimated by the conductors of the trial. There have to be errors of recall. These are in addition to several confounding factors, such as individual sensitivities to food toxin. If an individual dies of a food-related disorder, it is not necessarily because his consumption of the food was too high. Another possibility is that his resistance to its toxic effect was too low. Also to be remembered is that atherosclerosis is a virtually universal disorder in prosperous countries. Thus, those participants in a trial who die of other diseases may also be in an advanced stage of atherosclerosis. Finally in the case of intervention trials, the persuasion aimed at one group of participants to change habits (such as quitting smoking) is often little different from that directed at the other group by doctors and the media.
This writer suggests that food consumption statistics of advanced countries provide more reliable information regarding the type and quantity of food consumed in a community than do data collected individually in periodic samplings. Statistics are not free of errors, but they are unlikely to be of such magnitude that two studies can produce directly contradictory results. Comparing population groups rather than individuals has, at least, the advantage of eliminating individual susceptibilities. The results of a statistical study conducted by this writer (Seely 1988) is recapitulated in the following section.
A Statistical Study
When searching for the correlation between one or more food items and mortality from a given disease, statistics are likely to present a blurred image. This is partly on account of chance correlations and indirect correlations, and partly on account of statistical errors. Food consumption statistics of prosperous countries, for example, include a large amount of waste, whereas death certificates may give erroneous causes of death. Prosperity-related diseases can be positively correlated with virtually any aspect of that prosperity, such as the number of two-car families in a community, as well as with the consumption of the food item that is the presumed actual cause of disease. The consumption of a number of luxury foods increases together with prosperity. All such errors tend to mask the connection between real causes and effects. In an attempt to sharpen the image, the following expedient was tried.
Let us consider a statistical study in a group of prosperous countries, such as the 21 countries of the Organization of Economic Cooperation and Development (OECD), for which both mortality and food consumption statistics are available (Seely 1988).The object is to see if a consistent association can be found between mortality from coronary artery disease and the consumption of one or more food items. It may be advantageous to restrict the initial search to the four countries with the highest, and the four countries with the lowest, mortality from coronary disease because the contrast between the two groups may bring the critical differences between them into sharper focus. The range of mortality between the two groups is wide. Male coronary mortality in the leading country, Finland, is about eight times as high as in the country with the lowest mortality, Japan. The average male coronary mortality in the four leading countries—Finland, Ireland, United Kingdom, and Sweden—is four times as high as in the low-mortality group—Spain, France, Portugal, and Japan. Thus it seems unlikely that a food item, the consumption of which in the low-mortality group exceeds that in the high-mortality group, can play a significant part in the causation of coronary disease, and thus it can be excluded from the list of suspects with a reasonable degree of confidence.
In our statistical study, the source of mortality data are mortality statistics of the World Health Organization (1983-6) and that of food consumption are statistics of the Organisation for Economic Co-operation and Development (1981). Mortality statistics are for 1983, or the nearest available year; food consumption statistics are for 1973. The reason for the time interval between them is that foods containing some mildly noxious substance result in a disorder only after a long delay. The exact interval cannot be estimated, but empirical observations suggest that 10 years is reasonable.
In order to ensure that no food item for which consumption statistics are available is overlooked, it is necessary to consider all food appearing in them. As noted, the diet of prosperous countries includes about a thousand food items, yet the statistics give consumption figures for about 50 items. There is obviously no guarantee that foods not appearing in statistics cannot be causative agents for a disorder, but at least it can be said that all major food items are included in the statistics. The possible connection between a food item and a disease can be verified by the calculation of correlation coefficients. The simplest case of perfect correlation is exact proportionality between the consumption of a food item and mortality from a given disease. In other words, if in a country the consumption of x coexists with a number of deaths from a disease, y, then in other countries, where the consumption of that food is 2, 3, or 4 times higher than in the first country, mortality is also 2, 3, or 4 times higher. In a more realistic case the relationship is y = ax + b, where a and b are constants, and correlation is perfect if mortality in every country corresponds exactly to the value obtained from the equation. Perfect positive correlation is expressed by the correlation coefficient 1, entire lack of correlation by the coefficient 0, and perfect negative correlation by -1.
The results of the study are reproduced in Table IV.F.4.1. This shows the correlation coefficients calculated for each item appearing in the cited food consumption statistics for eight countries. Table IV.F.4.2 shows male age-compensated mortality rates in these countries and gives some of the more important food consumption figures from which the correlation coefficients in Table IV.F.4.1 were calculated. The highest positive correlations in Table IV.F.4.1 are as follows: oats 0.95, whole milk 0.91, milk proteins (excluding cheese) 0.91, milk fats (excluding butter and cheese) 0.91, sugar 0.90, total milk protein 0.86, beer 0.86, total milk fats 0.84, total animal fats 0.77, total animal proteins 0.74.
When correlations were checked for all 21 OECD countries, the high correlation with beer was found to be spurious. The countries with the highest beer consumption, notable Germany, Austria, the Netherlands, and Denmark, have only moderately high mortality from coronary disease. The other correlations, including that of oats, were confirmed.
The most surprising finding of the study is the near-perfect correlation between coronary mortality and the consumption of oats. At the time of the investigation, we could offer no explanation or even a suggestion as to what constituent of oats could have a connection with arterial disorders, but an attempt at an explanation follows shortly.
Table IV.F.4.1. correlation coefficients between age-compensated male mortality rates from ischaemic heart desease and the consumption of various food in 8 member countries of the Organization of Economic Cooperation and Development. The 8 countries comprise the 4 with the highest coronary mortality ((Finland, Ireland, U.K., Sweden) and the 4 with the lowest mortality (Spain, Portugal, France, Japan). Source of mortality data: World Health Organization statistics for the year 1983 (or nearest); source of food consumption data: statistics of the Organisation of Economic Cooperation and Development for the year 1973.
|Barley||0.20||canned or smoked||-0.55|
|Rice||-0.55||Fish, protein content||-0.79|
|Nuts||-0.52||Dried & condensed milk||0.05|
|Pulses and nuts, total||-0.74||Butter||0.77|
|Other vegetables, protein content||-0.89||Total milk, proteins||0.86|
|Citrus fruit||0.26||Milk proteins without cheese||0.91|
|Other fresh fruit||-0.79||Total milk fats||0.84|
|Fruit, conserved or dried||0.62||Milk fats without butter||0.90|
|Total fruit||-0.55||Milk fats, without butter & cheese||0.91|
|Beef and veal||0.45||Wine||-0.65|
|Mutton||0.30||Total animal proteins||0.74|
|Poultry||-0.36||Total animal fats||0.77|
|Horse meat||-0.35||Total plant proteins||-0.74|
|Other meats||-0.47||Total plant lipids||-0.62|
|Total meat, proteins||0.33||Total fats||0.53|
Source: S. Seely (1988). Reproduced from International Journal of Cardiology, 20 (1988) p. 185, with the permission of the publishers, Elsevier Science Publishers, Amsterdam.
The connection between milk consumption and coronary disease has been suspected for a long time, based mainly on the geographical correspondence between them. Figure IV.F.4.1 shows this graphically for member countries of the Organisation for Economic Co-operation and Development. Many papers have been published on the subject, notably by J. C. Annand (1961), K. A. Oster (1971), J. J. Segall (1980), and S. Seely (1981), although the authors could not agree on the mechanism of interaction between milk and the arteries. It is interesting to note from Table IV.F.4.1 that whatever the noxious constituent of milk may be, some process in cheese manufacture appears to destroy it.
Sugar is also a long-standing suspect. However, the main objection to the suspicion is that no reasonable proposal has ever been put forward to explain why and how sugar might have an adverse effect on arteries (Yudkin and Roddy 1964).
Table IV.F.4.2. Sample data on which Table IV.F.4.1 is based. Mortality rates below denote age-compensated male mortality rates (European standard) from ischaemic heart disease. Food consumption in grams/day
|High-mortality group||Low-mortality group|
|Beef & veal||61.6||50.0||57.8||43.5||32.7||34.0||77.6||32.7|
|Milk protein (without cheese)||39.4||31.8||19.3||24.9||10.2||5.5||10.9||4.0|
Source: S. Seely (1988). Reproduced from International Journal of Cardiology with the permission of Elsevier Science Publishers.
The food items, for the possible atherogenic effect of which reasonable explanations are available, are animal fats and proteins. Yet, as shown by Table IV.F.4.1, the correlation coefficients between them and coronary mortality are considerably weaker than those found for oats, milk, and sugar. Clearly, this helps to demonstrate the complexity of the problem.
Perhaps a clue to the resolution of some of these difficulties can be found by considering one distinguishing feature that cow’s milk and oats have in common: They both have a high calcium content. That of cow’s milk is 120 milligrams (mg) per 100 grams (g) (as compared with 31 mg per 100 g of human milk); the calcium content of oats is 80 mg per 100 g (McCance and Widdowson 1980). Hence, we arrive at the possibility that the missing link in the pathogenesis of coronary disease is the excessively high calcium content of the Western diet.
Calcium in the Western Diet
What might be called the “natural human diet” is low in calcium, as are present-day diets in most developing countries, where the daily intake amounts to about 200 to 500 mg. The calcium content of the European diet was probably the same in past centuries, giving rise to the frequent occurrence of calcium deficiency disease—rickets—in children.
The large increase in the calcium content of the Western diet came with the increasing use of cow’s milk as a staple food for all age groups. The calcium content of milk is high, and it serves the needs of infants whose rapidly growing skeletons need a comparatively large amount. Calves grow at 4 times the rate of human infants; hence, cow’s milk contains 4 times as much calcium as human milk. The average intake of milk and dairy products in prosperous countries is usually between ¼ and ½ liter a day, containing 300 to 600 mg calcium. Three hundred mg is sufficient to convert the intake from other foods into an abundant 600 to 700 mg, and half a liter of milk into an excessive 900 to 1,000 mg. In many Western countries, the calcium intake from cow’s milk is more than that from all other foods combined.
Calcium is an essential nutrient, but in the ideal case, the dietary intake should not exceed requirements because the excretion of the surplus is a difficult task. The requirement of the human body can be estimated from the following data: The adult body contains about 1,100 grams of calcium, 99 percent of which is in the skeleton. The remaining 1 percent is needed for various essential functions, such as the generation of nerve impulses, muscular contraction, blood coagulation, and so forth. The skeleton reaches its maximum size and weight at the age of 35 years. While the skeleton is growing, it takes up a daily average of 80 mg calcium. After the age of 50 years, the skeleton begins to shrink, releasing calcium.
All body fluids contain calcium. About 100 mg is lost daily in urine and about 15 mg in sweat, though with hard physical exercise, sweating can excrete 80 mg calcium in a day. In addition, digestive fluids, such as saliva and pancreatic juice, discharge calcium into the digestive tract, and this amount is not completely reabsorbed. Allowing 150 mg calcium daily for this loss, the calcium requirement of a young adult, depending on physical exercise, amounts to 330 to 390 mg/day, and that of an old person about 240 mg/day. The dietary intake should exceed the needs of the body by about 20 percent to allow for calcium passing unabsorbed through the intestines, making the daily requirement for a hard-working young adult 470 mg, that of old people 290 mg. When the risk of coronary heart disease is considered, we are mainly interested in the older age groups. In their case, a possible dietary calcium intake of the order of 1,000 mg is several times the quantity they need, and that from milk alone can be twice that amount.
The uptake of calcium from the small intestine is a controlled process, so that an excessive dietary intake does not necessarily mean that calcium finding its way into body fluids must also be excessive. Control is exercised by a vitamin D metabolite, cholecalciferol, synthesized in two steps in the liver and kidney. This metabolite is the signal for the synthesis of a carrier protein in the intestine, which is the actual transfer agent for calcium through the intestinal wall. If the calcium content of the plasma is already adequate, the synthesis of cholecalciferol is discontinued, and the excess calcium passes unabsorbed through the alimentary canal. However, newly born infants do not yet possess this control mechanism. In their case, milk sugar, lactose, facilitates the absorption of calcium from the small intestine by a simple diffusion process. Under natural conditions, this facility does not involve a health hazard because when infants are weaned, lactose disappears from their diet. In a prosperous society, however, infants are never weaned, in the sense that lactose remains in their diet from birth to death. Not only is milk, therefore, high in calcium but its lactose content also enables it to bypass the control mechanism of the body (Bronner 1987).
It might be mentioned that when milk is fermented, lactose is converted into lactic acid, a biologically inactive substance. Fermented milk and its products, such as cheese, are very high in calcium but do not provide the facility for evading the intestinal control for its absorption. This is the probable reason that the correlation between mortality from coronary disease and cheese consumption is much weaker than it is with the consumption of whole milk.
If the quantity of calcium absorbed from the intestine exceeds requirements, a good excretory mechanism exists for disposing of the excess. The kidneys normally excrete about 100 mg/day. Concentration of calcium in the urine (hypercalciuria) involves the risk of stone formation in the kidneys, but a second excretory mechanism is available to support them. The surplus calcium becomes protein bound and is excreted by the liver, not the kidneys. In individuals in prosperous countries, the concentration of protein-bound calcium in the plasma, 1.16 millimoles (mmol) per liter (l), is nearly as high as that of diffusible calcium, 1.34 mmol/l (Ganong 1987), demonstrating that calcium intake in Western countries, indeed, tends to be excessive.
The effective excretory mechanism ensures that most of the surplus calcium is eliminated, but a small fraction escapes and is ultimately precipitated in soft tissues. Under normal conditions, this process is so slow that a large dietary calcium excess can be tolerated for decades, the calcification of soft tissues becoming a health hazard only in old age. Misuse, however, can overwhelm the excretory mechanism. In the 1950s, for example, it was customary to treat gastric ulcer patients with large quantities of milk, amounting to about 2 liters per day, until a disproportionately high mortality from coronary disease was observed among them (Briggs et al. 1960). Two liters of cow’s milk contains 2.4 grams of calcium, together with lactose facilitating its absorption from the intestine. The calcium absorbed from this source by the body may amount to a daily intake of 1.8 grams, perhaps 6 times the amount needed by elderly individuals. The excretory mechanism may well be incapable of dealing with such a gross excess.
As noted, excess calcium that cannot be excreted ultimately finds its way into soft tissues. Large arteries, notably the aorta, are particularly vulnerable to calcification. The heavy calcification of the aorta in individuals who died of heart disease was already observed by the pioneers of medicine in the nineteenth century, who correspondingly called the disorder “the hardening of the arteries.”
Calcium deposits in arteries have two important pathological effects. One is the calcification of athero-sclerotic plaques. A recent autopsy study by A. Fleckenstein and his group (1990) has found that athero-sclerotic lesions appear to attract calcium from their earliest stage onward. Fatty streaks already contain, at an average, 10 times as much calcium as the surrounding normal arterial tissue. Normal atherosclerotic plaques contain 25 times as much, advanced plaques in individuals who died of coronary disease, 80 times as much. Such advanced plaques are, in effect, calcium plaques. Calcium compounds, mainly apatite, constitute about half of their dry weight, cholesterol and its compounds about 3 percent. It is calcium that gives advanced plaques bulk and rigidity and makes them potential obstacles to blood flow.
Secondly, mural deposits of calcium in the aorta and other large elastic arteries encroach on their elasticity. As pointed out, these arteries constitute an elastic reservoir that is distended when the heart injects a volume of blood into it during systole, storing energy in its stretched elastic tissues. The contraction of the reservoir generates diastolic pressure and maintains blood flow in the circulatory system when the heart is at rest. As the heart compresses its own arteries when it contracts, its perfusion is entirely dependent on an adequate diastolic pressure.
If the elasticity of the reservoir deteriorates, an increasing systolic pressure is needed to maintain diastolic pressure at a given value. Perfusion failure in a part of the heart occurs when the aging, partly calcified elastic reservoir cannot generate sufficient pressure to force an adequate quantity of blood through narrowed and obstructed coronary arteries. Calcification is involved both in the reduction of diastolic pressure generated by the reservoir and in the obstructions presented by advanced atherosclerotic plaques. Thus, calcium excess in Western diets may well be the most important factor in the pathogenesis of coronary artery disease (Seely 1989, 1991). If the populations of Western countries were alerted to this possibility and advised to reduce their consumption, a large reduction in mortality could well be the result.
In a recent trial (Woods et al. 1992), coronary patients were treated with magnesium sulphate with beneficial results. A possible explanation is that the excretion of the four main electrolytes—sodium, potassium, calcium, and magnesium—is an interlinked process. The most difficult task of excretion for the kidneys arises when the intake of these minerals is unbalanced, high in some, low in others. Thus in the 1960s, rats on a high-cholesterol diet also had their food unbalanced in electrolytes, with an excessive sodium-potassium and calcium-magnesium ratio (Sos 1965). The rats died of repeated, humanlike heart attacks, but their lives could be prolonged if the imbalances were moderated. Thus, if human diet has an excessive calcium content, the best remedy would be its reduction, but failing that, an increase in magnesium intake can be beneficial.
As mentioned in the section “A Statistical Study,” epidemiological studies show a positive correlation between mortality from coronary artery disease and the consumption of oats, as well as of milk. The calcium content of oats, 80 mg/100 g, is high, but the strong correlation with coronary disease would probably arise only if they also contained some substance promoting the absorption of their calcium from the intestines. An oat grass, Trisetum flavescens, is known to contain vitamin D 3, capable of causing calcinosis in grazing animals, but no data are available to show that this also applies to cultivated oats.
The apparent connection between mortality from coronary disease and climate has been noted. The countries with very high mortality, such as Finland, Latvia, Lithuania, and Russia, have cold climates. In warmer climates, mortality is generally lower and, in tropical countries, very low or nonexistent. This may be explained by corresponding differences in calcium excretion. In a cold climate, the amount of calcium excreted by sweating is usually small, whereas a person doing hard physical work in the tropics can lose more fluid, and possibly more calcium, in sweat than in urine.
If arterial calcification is one of the main causes of death from coronary disease—the “skeleton in the atherosclerosis closet,” as a recent article called it (Demer 1995)—this could be a blessing in disguise.
The most important source of dietary calcium is one easily identifiable food item, cow’s milk—hence, arterial calcification is preventable. The best way of achieving such prevention would be the reduction of milk consumption, particularly by elderly people. An alternative course might be the elimination of lactose from fresh milk. As mentioned, the worldwide toll of coronary disease is about two million deaths per year. The possibility deserves careful consideration.