Elements of Ischemic Heart Disease Leslie M. Klevay Perspectives in Biology and Medicine, Volume 20, Number 2, Winter 1977, pp. 186-192 (Article) Published by Johns Hopkins University Press DOI: https://doi.org/10.1353/pbm.1977.0069
For additional information about this article https://muse.jhu.edu/article/405206/summary
Access provided at 19 Nov 2019 18:31 GMT from University of Cambridge
ELEMENTS OF ISCHEMIC HEART DISEASE* LESLIE M. KLEVAYÎ
Ischemic heart disease is the leading cause of death in the United States [I]. Previously termed coronary heart disease [2], this disease causes about 35 percent of deaths, twice as many as are caused by malig-
nant neoplasms or cancer. Considering the number of people of various ages in the population of the United States [3] and the prevalence of coronary heart disease [4], 11.5 percent of men and 8.8 percent of women between the ages of 45 and 79 have definite or suspect disease. In the United States, risk of ischemic heart disease is higher among men than among women, among smokers of cigarettes than among nonsmokers, among diabetics, and among those with certain abnor-
malities of the electrocardiogram. Risk also increases with age, with blood pressure, and with the concentration of cholesterol in serum [5]. Other factors associated with risk of this disease are protean and are
apparently dissimilar. These factors, the dissimilarity of which may be more apparent than real, may modify those enumerated above. Risk is high in the industrialized part of the world where diets usually contain large amounts of fat and sucrose and small amounts of vegetable fiber.
Within industrialized countries there is no epidemiologic association of risk with the amount or type of fat consumed [6-8]. Within these countries risk is high where soft water is available [9, 10]. Sedentary men have a higher risk than do men who exercise [H]. Consumption of human milk in infancy [12] and cirrhosis of the liver [13, 14] apparently are protective; chronic kidney disease seems to increase risk [15, 16]. Many other environmental factors such as stress and the consumption of coffee, tea, aspirin, and vitamin D have been associated with increased or decreased risk.
In addition to these factors, 29 elements (fig. 1) have been related to the epidemiology of ischemic heart disease or to the metabolism of cholesterol or other lipids. This list of elements is meant to be inclusive rather than exclusive. Reviews were selected for references in prefer*Based upon a lecture at the 169th National Meeting of the American Chemical Society, April 9, 1975, Philadelphia. tResearch Medical Officer at the Human Nutrition Laboratory, U.S. Department of Agriculture, Agricultural Research Service, Grand Forks, North Dakota 58201.
186 J Leslie M. Klevay ¦ Ischemic Heart Disease
VA
III ?
VI A
VII A
5
?a
Mg
IVB
VB
VI B
2Ö~~ 21 Ca
VII 25
Cr 42
Zr
26
Mn
27
Fe
2T
Co
43
46
Nb Mo!
30
Ni
Cu 47
32
Ge As Se
Zn 48
49
50
Cd
Sn
Hg
Pb
52
Sb
Te
75 88
85
89
•*
6
Ce 90
95
100
101
102
103
Fig. 1.—Elements of ischemie heart disease. Elements identified by symbol have been implicated in the epidemiology of ischemic heart disease or in the metabolism of choles-
terol or other lipids. References to fig. 1 follow (numbers refer to the atomic numbers of the elements).
3. A. W. Voors. Am. J. Epidemiol. 93:259, 1971. 9. D. S. Bernstein, N. Sadowsky, D. M. Hegsted, C. D. Gurí, and F. J. Stare. J. Am. Med. Assoc. 198:499, 1966.
11. L. K. Dahl. J. Exp. Med. 112:635, 1960. 12. M. S. Seelig and H. A. Heggtveit. Am. J. Clin. Nutr. 27:59, 1974. 16. J. Stamler, R. Pick, and L. N. Katz. Circ. Res. 6:442, 1958. 19. G. R. Meneely and C. O. T. Ball. Am. J. Med. 25:713, 1958. 20. See text reference [25]. 23. L. L. Hopkins and H. E. Mohr. Fed. Proc. 33:1773, 1974. 24. W. Mertz. Physiol. Rev. 49:163, 1969. 25. E. A. Doisy, Jr. In: D. D. Hemphill (ed.). Trace substances in 26. 27. 28.
health—VI, pp. 193-199. Columbia: Univ. Missouri Press, 1973. E.K. Amine and D. M. Hegsted. J. Nutr. 101:1575, 1971.
environmental
D. B. Louria, M. M. Joselow, and A. A. Browder. Ann. Intern. Med. 76:307, 1972.
F.H. Nielsen, D. R. Myron, S. H. Givand, T.J. Zimmerman, and D. A. Ollerich. J. Nutr. 105:1620, 1975.
29, 30. See text reference [24]. 32.H. A. Schroeder. J. Nutr. 94:475, 1968.
33,34, 40, 41. See 32 above.
42. E. J. Underwood. Trace elements in human and animal nutrition, pp. 132-135. New York: Academic Press, 1971.
48 H. M. Perry, Jr. J. 50-52. See 32 above.
Am. Dietet. Assoc. 62:631, 1973.
53. See text reference [17].
58. G. Magnusson. Acta Pharmacol. Toxicol. 20, suppl. 3:1, 1963. 80. H. Selye. Experimental cardiovascular diseases, pp. 295, 308. New York: SpringerVerlag, 1970. 82. See 80 above, pp. 295, 307, 308, 595.
enee to experimental articles; recent articles received favor over early articles. References were selected to provide citation of as many authors as possible. Molybdenum was included because of the metabolic interac-
tion between copper and molybdenum. Premises
My first attempts to understand the etiology of ischemic heart disease in 1963 were not aided by considering the disease to be of multifactorial etiology [17]. In some respects all diseases are multifactorial; however, I could think of no disease, the etiology of which was comprehensible, that could not be explained in terms of, at most, a few simple principles. It seemed more likely that ischemic heart disease was a group of diseases
with similar manifestations analogous to dropsy or jaundice. These conditions were once thought to be entities, but now have been subdivided. It has been useful to divide diseases into two classes by whether or not the etiologies are comprehensible or incomprehensible. The comprehensible class is divided further in table 1 . The dates attached to the
subclasses are approximate and undoubtedly represent the latest times
at which these concepts were first recognized. Although it is possible that ischemic heart disease will be found to have
a new type of etiology when it is transferred from the incomprehensible class to the comprehensible class, it presently seems prudent to assume that well-established mechanisms will predominate. It seems likely that ischemic heart disease ultimately will be found to be of toxic origin, to be due to deficiency, or to be a combination of these two mechanisms.
It is assumed that infection and heredity probably will not be found to
be important determinants of risk. Some families have more members afflicted with ischemic heart disease than do other families. This
phenomenon is known as clustering or aggregation. "The aggregation of coronary heart disease does not necessarily support a theory of hereditary etiology, since coronary heart disease is extremely widespread and families share a common environment as well as common genes" [17]. TABLE 1 Classification of the Etiology of Comprehensible Diseases
Toxic (before Aristotle, 384-322 b.c.)
Hereditary (before the Talmud, a.d. 50) Infectious (before Boccaccio, a.d. 1353)
Deficiency (before Lind, a.d. 1747)
188 J Leslie M. Klevay · Ischemic Heart Disease
The association between the availability of hard water and a low risk of ischemic heart disease has been a primary stimulus to this work [9, 10]. The hardness of water may partially characterize the environmental factors that cause the risk of disease to vary by a factor of two and three-fourths from region to region in the United States [18]. Of similar importance was the demonstration of the adverse effects on animals of imbalances and antagonisms between nutrients [19, 20].
It was assumed that a substance of potential importance in the etiology of ischemic heart disease would have the following characteristics. It would be biologically active, preferably in lipid metabolism and in small amounts, and would be soluble in water. It would be widely distributed
in the environment but would be neither omnipresent nor evenly distributed. It would be present in food or water because environmental influences on human metabolism are most likely to produce effects via
the digestive system.
Experiments and Hypothesis Preliminary experiments with several metallic elements were done between 1964 and 1970 in which a salt was fed to animals as either a
dietary component or as a constituent of drinking water. After an ap-
propriate interval the degree of lipid deposition in the aortas and hearts or the concentration of cholesterol in the blood plasma of the animals was evaluated. Deposits of lipid are important in the sometimes lethal disruption of the oxygen supply of the heart muscle during a heart attack [17]; the concentration of cholesterol in serum [21] and plasma
[22] is useful in the prediction of risk of ischemic heart disease. High concentrations of cholesterol in plasma are associated with high risk. In 1970 evidence began to accumulate that an increase in the dietary ratio of zinc to copper could increase the concentration of cholesterol in plasma of rats. The experiments were repeated, the data were published and the zinc/copper hypothesis was proposed [23]. This hypothesis [24], which has been developed in a series of papers
[25-28], states that an imbalance in regard to zinc and copper is the preponderant factor in the etiology of ischemic heart disease. The imbalance is either a relative or an absolute deficiency of copper characterized by a high ratio of zinc to copper. Discussion
Before a disease becomes comprehensible, so many apparently dissimilar observations are recorded that it is easy to conclude that risk of Perspectives in Biology and Medicine ¦ Winter 1977 | 189
disease is random or that the disease has a vast number of determinants.
In the latter case the disease is considered to be of multifactorial origin. In 1850 and 1915, when cholera and pellagra were being transferred from the incomprehensible to the comprehensible class of diseases, they were considered to be as complicated as is ischemic heart disease today.
Snow [29] and Goldberger [30] showed that certain characteristics of
water and diet were closely associated with risk of cholera and pellagra, respectively, and that these characteristics were often common to apparently dissimilar observations. When the vibrio and the vitamin eventually were found to be the most important characteristics of water and diet in
regard to these diseases, transfer to the comprehensible class was complete.
Zinc and copper have the characteristics assumed to be necessary for importance in the etiology of ischemic heart disease. Considering the protean nature of the factors and the number of elements associated
with risk of ischemic heart disease, the zinc/copper phenomenon can be considered of paramount importance only because it seems to fulfill
Selye's triad [31]. That is, the phenomenon is "true, generalizable and surprising at the same time."
When the original experiments were published [23] an increase in the concentration of cholesterol in plasma due to a high zinc/copper had been found in five experiments, in two environments during 3 years [23], and no reference common to cholesterol, copper, and zinc had been found in 31 years oí Nutrition Reviews [32]. Since then the experiments have been repeated successfully and many ways by which the
generalizable nature of the hypothesis can be tested have come to mind.
For example, the low risk of heart disease where drinking water is
hard made it desirable to determine whether supplementation of human diets with calcium would result in a decrease in the concentration of
cholesterol in serum. It was found that this experiment already had been done several times with the expected result. Other predictions based upon the hypothesis or logical consequences of the hypothesis also had been tested. Many apparently dissimilar observations were collected, interpreted, and associated with zinc and copper in a manner consonant with the hypothesis [24]. Summarized in tables 2 and 3, all data are based
upon observations upon people except some of those in the last column
of table 2.
Szent-Györgyi has been quoted [33]: "Research is to see what every-
body has seen and think what nobody has thought." Kuhn [34] has shown how rapid progress is made when "scientists see new and differ-
ent things when looking with familiar instruments in places they have
looked before." It seems likely that seeing ischemic heart disease as a disorder of zinc and copper metabolism will prove useful. 1 90 I Leslie M. Klevay ¦ Ischemic Heart Disease
TABLE 2
Epidemiology of Ischemic Heart Disease (IHD) Environmental Characteristic
Possible Explanation
Diets low in fat & sucrose & high in vegetable fiber ................. Nursing of infants ................ Cirrhosis of the liver .............. Exercise .........................
For additional information about this article https://muse.jhu.edu/article/405206/summary
Access provided at 19 Nov 2019 18:31 GMT from University of Cambridge
ELEMENTS OF ISCHEMIC HEART DISEASE* LESLIE M. KLEVAYÎ
Ischemic heart disease is the leading cause of death in the United States [I]. Previously termed coronary heart disease [2], this disease causes about 35 percent of deaths, twice as many as are caused by malig-
nant neoplasms or cancer. Considering the number of people of various ages in the population of the United States [3] and the prevalence of coronary heart disease [4], 11.5 percent of men and 8.8 percent of women between the ages of 45 and 79 have definite or suspect disease. In the United States, risk of ischemic heart disease is higher among men than among women, among smokers of cigarettes than among nonsmokers, among diabetics, and among those with certain abnor-
malities of the electrocardiogram. Risk also increases with age, with blood pressure, and with the concentration of cholesterol in serum [5]. Other factors associated with risk of this disease are protean and are
apparently dissimilar. These factors, the dissimilarity of which may be more apparent than real, may modify those enumerated above. Risk is high in the industrialized part of the world where diets usually contain large amounts of fat and sucrose and small amounts of vegetable fiber.
Within industrialized countries there is no epidemiologic association of risk with the amount or type of fat consumed [6-8]. Within these countries risk is high where soft water is available [9, 10]. Sedentary men have a higher risk than do men who exercise [H]. Consumption of human milk in infancy [12] and cirrhosis of the liver [13, 14] apparently are protective; chronic kidney disease seems to increase risk [15, 16]. Many other environmental factors such as stress and the consumption of coffee, tea, aspirin, and vitamin D have been associated with increased or decreased risk.
In addition to these factors, 29 elements (fig. 1) have been related to the epidemiology of ischemic heart disease or to the metabolism of cholesterol or other lipids. This list of elements is meant to be inclusive rather than exclusive. Reviews were selected for references in prefer*Based upon a lecture at the 169th National Meeting of the American Chemical Society, April 9, 1975, Philadelphia. tResearch Medical Officer at the Human Nutrition Laboratory, U.S. Department of Agriculture, Agricultural Research Service, Grand Forks, North Dakota 58201.
186 J Leslie M. Klevay ¦ Ischemic Heart Disease
VA
III ?
VI A
VII A
5
?a
Mg
IVB
VB
VI B
2Ö~~ 21 Ca
VII 25
Cr 42
Zr
26
Mn
27
Fe
2T
Co
43
46
Nb Mo!
30
Ni
Cu 47
32
Ge As Se
Zn 48
49
50
Cd
Sn
Hg
Pb
52
Sb
Te
75 88
85
89
•*
6
Ce 90
95
100
101
102
103
Fig. 1.—Elements of ischemie heart disease. Elements identified by symbol have been implicated in the epidemiology of ischemic heart disease or in the metabolism of choles-
terol or other lipids. References to fig. 1 follow (numbers refer to the atomic numbers of the elements).
3. A. W. Voors. Am. J. Epidemiol. 93:259, 1971. 9. D. S. Bernstein, N. Sadowsky, D. M. Hegsted, C. D. Gurí, and F. J. Stare. J. Am. Med. Assoc. 198:499, 1966.
11. L. K. Dahl. J. Exp. Med. 112:635, 1960. 12. M. S. Seelig and H. A. Heggtveit. Am. J. Clin. Nutr. 27:59, 1974. 16. J. Stamler, R. Pick, and L. N. Katz. Circ. Res. 6:442, 1958. 19. G. R. Meneely and C. O. T. Ball. Am. J. Med. 25:713, 1958. 20. See text reference [25]. 23. L. L. Hopkins and H. E. Mohr. Fed. Proc. 33:1773, 1974. 24. W. Mertz. Physiol. Rev. 49:163, 1969. 25. E. A. Doisy, Jr. In: D. D. Hemphill (ed.). Trace substances in 26. 27. 28.
health—VI, pp. 193-199. Columbia: Univ. Missouri Press, 1973. E.K. Amine and D. M. Hegsted. J. Nutr. 101:1575, 1971.
environmental
D. B. Louria, M. M. Joselow, and A. A. Browder. Ann. Intern. Med. 76:307, 1972.
F.H. Nielsen, D. R. Myron, S. H. Givand, T.J. Zimmerman, and D. A. Ollerich. J. Nutr. 105:1620, 1975.
29, 30. See text reference [24]. 32.H. A. Schroeder. J. Nutr. 94:475, 1968.
33,34, 40, 41. See 32 above.
42. E. J. Underwood. Trace elements in human and animal nutrition, pp. 132-135. New York: Academic Press, 1971.
48 H. M. Perry, Jr. J. 50-52. See 32 above.
Am. Dietet. Assoc. 62:631, 1973.
53. See text reference [17].
58. G. Magnusson. Acta Pharmacol. Toxicol. 20, suppl. 3:1, 1963. 80. H. Selye. Experimental cardiovascular diseases, pp. 295, 308. New York: SpringerVerlag, 1970. 82. See 80 above, pp. 295, 307, 308, 595.
enee to experimental articles; recent articles received favor over early articles. References were selected to provide citation of as many authors as possible. Molybdenum was included because of the metabolic interac-
tion between copper and molybdenum. Premises
My first attempts to understand the etiology of ischemic heart disease in 1963 were not aided by considering the disease to be of multifactorial etiology [17]. In some respects all diseases are multifactorial; however, I could think of no disease, the etiology of which was comprehensible, that could not be explained in terms of, at most, a few simple principles. It seemed more likely that ischemic heart disease was a group of diseases
with similar manifestations analogous to dropsy or jaundice. These conditions were once thought to be entities, but now have been subdivided. It has been useful to divide diseases into two classes by whether or not the etiologies are comprehensible or incomprehensible. The comprehensible class is divided further in table 1 . The dates attached to the
subclasses are approximate and undoubtedly represent the latest times
at which these concepts were first recognized. Although it is possible that ischemic heart disease will be found to have
a new type of etiology when it is transferred from the incomprehensible class to the comprehensible class, it presently seems prudent to assume that well-established mechanisms will predominate. It seems likely that ischemic heart disease ultimately will be found to be of toxic origin, to be due to deficiency, or to be a combination of these two mechanisms.
It is assumed that infection and heredity probably will not be found to
be important determinants of risk. Some families have more members afflicted with ischemic heart disease than do other families. This
phenomenon is known as clustering or aggregation. "The aggregation of coronary heart disease does not necessarily support a theory of hereditary etiology, since coronary heart disease is extremely widespread and families share a common environment as well as common genes" [17]. TABLE 1 Classification of the Etiology of Comprehensible Diseases
Toxic (before Aristotle, 384-322 b.c.)
Hereditary (before the Talmud, a.d. 50) Infectious (before Boccaccio, a.d. 1353)
Deficiency (before Lind, a.d. 1747)
188 J Leslie M. Klevay · Ischemic Heart Disease
The association between the availability of hard water and a low risk of ischemic heart disease has been a primary stimulus to this work [9, 10]. The hardness of water may partially characterize the environmental factors that cause the risk of disease to vary by a factor of two and three-fourths from region to region in the United States [18]. Of similar importance was the demonstration of the adverse effects on animals of imbalances and antagonisms between nutrients [19, 20].
It was assumed that a substance of potential importance in the etiology of ischemic heart disease would have the following characteristics. It would be biologically active, preferably in lipid metabolism and in small amounts, and would be soluble in water. It would be widely distributed
in the environment but would be neither omnipresent nor evenly distributed. It would be present in food or water because environmental influences on human metabolism are most likely to produce effects via
the digestive system.
Experiments and Hypothesis Preliminary experiments with several metallic elements were done between 1964 and 1970 in which a salt was fed to animals as either a
dietary component or as a constituent of drinking water. After an ap-
propriate interval the degree of lipid deposition in the aortas and hearts or the concentration of cholesterol in the blood plasma of the animals was evaluated. Deposits of lipid are important in the sometimes lethal disruption of the oxygen supply of the heart muscle during a heart attack [17]; the concentration of cholesterol in serum [21] and plasma
[22] is useful in the prediction of risk of ischemic heart disease. High concentrations of cholesterol in plasma are associated with high risk. In 1970 evidence began to accumulate that an increase in the dietary ratio of zinc to copper could increase the concentration of cholesterol in plasma of rats. The experiments were repeated, the data were published and the zinc/copper hypothesis was proposed [23]. This hypothesis [24], which has been developed in a series of papers
[25-28], states that an imbalance in regard to zinc and copper is the preponderant factor in the etiology of ischemic heart disease. The imbalance is either a relative or an absolute deficiency of copper characterized by a high ratio of zinc to copper. Discussion
Before a disease becomes comprehensible, so many apparently dissimilar observations are recorded that it is easy to conclude that risk of Perspectives in Biology and Medicine ¦ Winter 1977 | 189
disease is random or that the disease has a vast number of determinants.
In the latter case the disease is considered to be of multifactorial origin. In 1850 and 1915, when cholera and pellagra were being transferred from the incomprehensible to the comprehensible class of diseases, they were considered to be as complicated as is ischemic heart disease today.
Snow [29] and Goldberger [30] showed that certain characteristics of
water and diet were closely associated with risk of cholera and pellagra, respectively, and that these characteristics were often common to apparently dissimilar observations. When the vibrio and the vitamin eventually were found to be the most important characteristics of water and diet in
regard to these diseases, transfer to the comprehensible class was complete.
Zinc and copper have the characteristics assumed to be necessary for importance in the etiology of ischemic heart disease. Considering the protean nature of the factors and the number of elements associated
with risk of ischemic heart disease, the zinc/copper phenomenon can be considered of paramount importance only because it seems to fulfill
Selye's triad [31]. That is, the phenomenon is "true, generalizable and surprising at the same time."
When the original experiments were published [23] an increase in the concentration of cholesterol in plasma due to a high zinc/copper had been found in five experiments, in two environments during 3 years [23], and no reference common to cholesterol, copper, and zinc had been found in 31 years oí Nutrition Reviews [32]. Since then the experiments have been repeated successfully and many ways by which the
generalizable nature of the hypothesis can be tested have come to mind.
For example, the low risk of heart disease where drinking water is
hard made it desirable to determine whether supplementation of human diets with calcium would result in a decrease in the concentration of
cholesterol in serum. It was found that this experiment already had been done several times with the expected result. Other predictions based upon the hypothesis or logical consequences of the hypothesis also had been tested. Many apparently dissimilar observations were collected, interpreted, and associated with zinc and copper in a manner consonant with the hypothesis [24]. Summarized in tables 2 and 3, all data are based
upon observations upon people except some of those in the last column
of table 2.
Szent-Györgyi has been quoted [33]: "Research is to see what every-
body has seen and think what nobody has thought." Kuhn [34] has shown how rapid progress is made when "scientists see new and differ-
ent things when looking with familiar instruments in places they have
looked before." It seems likely that seeing ischemic heart disease as a disorder of zinc and copper metabolism will prove useful. 1 90 I Leslie M. Klevay ¦ Ischemic Heart Disease
TABLE 2
Epidemiology of Ischemic Heart Disease (IHD) Environmental Characteristic
Possible Explanation
Diets low in fat & sucrose & high in vegetable fiber ................. Nursing of infants ................ Cirrhosis of the liver .............. Exercise .........................
