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Leslie M. Klevay, Cardiovascular Disease from Copper Deficiency—A History, The Journal of Nutrition, Volume 130, Issue 2, February 2000, Pages 489S–492S, https://doi.org/10.1093/jn/130.2.489S
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ABSTRACT
Although the nutritional essentiality of copper was established in 1928, a preoccupation with hematology delayed the discovery of cardiovascular disease from copper deficiency for more than a decade. Anatomical studies of several species of deficient animals revealed, interalia, aortic fissures and rupture, arterial foam cells and smooth muscle migration, cardiac enlargement and rupture, coronary artery thrombosis and myocardial infarction. Abnormal biochemistry in deficiency probably contributes to these lesions, e.g., decreased activities of lysyl oxidase and superoxide dismutase which result in failure of collagen and elastin crosslinking and impaired defense against free radicals. Copper deficiency also decreases copper in hearts and other organs and cells and increases cholesterol in plasma. Abnormal physiology from deficiency includes abnormal electrocardiograms, glucose intolerance and hypertension. People with ischemic heart disease have decreased cardiac and leucocyte copper and decreased activities of some copper-dependent enzymes. Copper depletion experiments with men and women have revealed abnormalities of lipid metabolism, blood pressure control, and electrocardiograms plus impaired glucose tolerance. The Western diet often is as low in copper as that proved insufficient for these people. Knowledge of nutritional history can be useful in addressing contemporary nutritional problems.
The nutritional essentiality of copper was established for mammals when anemic and stunted Rat 621 grew and built hemoglobin rapidly after his diet of whole cow's milk was supplemented with ∼1 mg copper sulfate for 6 d/wk (Hart et al. 1928, Klevay 1997). A decade and a half would pass before copper and the cardiovascular system were linked. As often occurs in nutrition, illness of domestic animals prompted nutritional discovery.
“Falling Disease” was an enzootic disease of dairy cattle characterized by seasonal incidence and sudden death (Bennetts and Hall 1939). The disease constituted a “grave economic problem.” Some herds experienced an annual mortality of 5–40%. Although sudden death had been reported in bulls, it was most frequently observed when cows were being brought in to be milked or were being driven out to paddock. Some cows had fallen on the milker after a bellow and a toss of the head.3 Death frequently appeared to be instantaneous. Although the authors mentioned anemia, excessive and cloudy pericardial fluid, and low copper status of both animals and pasture, the disease was said to be of “undetermined ætiology.” Although it “seemed very unlikely that a mineral deficiency per se could be the cause of sudden death,” its contribution was suspected.
Anatomy
Early connections between copper deficiency and abnormal cardiovascular anatomy were found in three locations in three different species of mammal. Bennetts et al. (1942) noted cardiac fibrosis in 19 of 21 fatal cases of bovine copper deficiency in Western Australia. “The changes noted appear to be essentially a patchy fibrosis involving replacement of atrophied muscle cells with connective tissue.” There are some similarities between the figures published in 1942 and > 35 y later (Allen and Klevay 1978). Bennetts regarded the sudden death (“falling disease”) merely as the terminal manifestation of severe copper deficiency and not a separate disease entity.
Later, Shields et al. (1962) found numerous cardiovascular lesions among 26 swine made deficient in Utah with a diet based on evaporated milk. The most important cardiac lesions were myocardial infarction and ruptured papillary muscles with intramural hemorrhage. Vascular lesions included aortic fissures and rupture, medial thickening of the aorta and intramural hemorrhages in carotid, coronary and other thoracic arteries. They also found that copper deficiency produced greater cardiac enlargement than iron deficiency when animals were matched by hematocrit.
Although cardiac enlargement in copper deficiency was noted first by Schultze (1939), he mentioned the phenomenon only briefly. Kelly et al. (1974) confirmed the enlargement and also credited others (Dallman 1967, Gubler et al. 1957).
A short time later, Ball et al. (1963) began to publish changes in cardiovascular anatomy found in mice fed a diet high in lard in Mississippi. Atrial thrombosis was most obvious, but coronary necrosis, coronary thrombosis, myocardial necrosis and ventricular calcification also were found. Mortality was high. Two decades later, it was found that adequate dietary copper (Klevay 1985) could prevent the atrial lesions and eliminate premature mortality. Copper was an antidote to fat intoxication.
Coulson and Carnes (1963) noted that 22 of 33 pigs deficient in copper died of cardiovascular causes, 11 with fatal coronary artery disease. Continuation of this work revealed smooth muscle proliferation (Carnes et al. 1965), a finding confirmed by Hunsaker et al. (1984) and Hill and Davidson (1986). Hunsaker et al. (1984) also noted migration of smooth muscle cells in aortas of marginally copper-deficient rats. Arterial foam cells also were found in deficient swine (Waisman et al. 1969).
Approximately 35 anatomical changes produced by copper deficiency have been tabulated from the work of numerous authors (Klevay 2000). Important findings in addition to those above are arteries with elastic degeneration and fragmentation, arteries with smooth muscle degeneration, along with ventricular and coronary artery aneurysms.
Chemistry
The hearts of people who have died from ischemic heart disease are low in copper (Anderson et al. 1975, Chipperfield and Chipperfield 1978, Penttilä et al. 1986, Wester 1965, Zama and Towns 1986). Uninfarcted heart muscle from infarction victims was compared with similar samples from accident victims and others who died of causes unrelated to ischemic heart disease. Kinsman et al. (1990) found a significant correlation (r = 0.67) between copper in leukocytes and the degree of patency of the coronary arteries of men. Japanese people living in Brazil had less copper in leukocytes than Japanese people living in Okinawa (Klevay 2000, Mielcarz et al. 1997) where heart disease is less common. Bergomi et al. (1997) found an inverse correlation between lysyloxidase activity in serum and both systolic and diastolic blood pressure in untreated, mild essential hypertension. Among patients evaluated by coronary angiography, those with a history of myocardial infarction had lower concentrations of extracellular superoxide dismutase than those without infarction (Wang et al. 1998).
All enzymes known to depend on copper for activity are oxidative (Prohaska 1990). Some of these enzymes are important for cardiovascular health. Crosslinking of arterial collagen and elastin requires lysyl oxidase, a copper enzyme (Owen 1982). Arterial proteoglycan metabolism also is disrupted by copper deficiency (Radhakrishnamurthy et al. 1989).
Copper-zinc superoxide dismutase is found in various tissues, is dependent on copper for activity (Owen 1982) and is protective against free radicals (McCord 1985, Southorn and Powis 1988). It has been suggested that copper is an antioxidant nutrient for cardiovascular health (Allen and Klevay 1994, Klevay 1990a). Malondialdehyde and thiobarbituric acid reactive substances are indices of peroxidation that are increased in the serum in coronary artery disease and angina pectoris (Mendis et al. 1995, Sakuma et al. 1997) and in plasma of copper-deficient rats (Klevay 2000, Saari et al. 1990). Russo et al. (1998) found lower plasma copper and lower erythrocyte superoxide dismutase activity and higher malondialdehyde in people with newly diagnosed essential hypertension compared with normotensive people matched for age. Dubick et al. (1999) found that copper, zinc superoxide dismutase activity in aortas of people with abdominal aneurysms was decreased by more than two thirds.
Cholesterol metabolism and copper utilization were linked when a high ratio of zinc to copper ingested produced hypercholesterolemia in rats (Klevay 1973 and 1987b). A similar phenomenon was observed first in people by Hooper et al. (1980) who found dislipidemia in men with zinc supplements. Human hypercholesterolemia from a diet of conventional foods low in copper was observed first in a 29-y-old man (Klevay et al. 1984). Hypercholesterolemia from copper deficiency in several species has been found in at least 22 independent laboratories world-wide (Klevay 2000).
Physiology
Keil and Nelson (1934) were probably the first to observe altered physiology in copper deficiency with what is now called glucose intolerance. This phenomenon has been confirmed in men (Klevay et al. 1986). Although electrocardiograms were done on some of the cattle studied by Bennetts, abnormalities were found first in deficient rats (Klevay and Viestenz 1981, Kopp et al. 1983). Men fed diets of conventional foods low in copper have had cardiac arrhythmias (Klevay et al. 1984, Reiser et al. 1985).
Rats depleted of copper after they reach adult size become hypertensive (Klevay 1987a, Medeiros 1987), perhaps from impaired vasodilation in response to acetylcholine (Saari 1992). Women fed diets of conventional foods low in copper had increased blood pressure during sustained handgrip (Lukaski et al. 1988).
Thoughts from the 1990s
Sudden death in “Falling Disease” caught the attention of early students of copper deficiency, even though they were unable to explain its origin. Others mentioned mortality in experimental copper deficiency but most apparently paid little attention (Ball et al. 1963, Coulson and Carnes 1963, Gallagher et al. 1956, Kelly et al. 1974, Waddell et al. 1928). Few (Ball et al. 1963, Coulson and Carnes 1963, Teague and Carpenter 1951) kept score. In the paper immediately preceding that on Rat 621, Waddell et al. (1928) inserted small daggers into figures to indicate death.
Bennetts et al. (1942) assumed that the ultimate cause of sudden death in copper deficiency was either ventricular fibrillation or heart block. To my knowledge, fibrillation has not been recorded in copper deficiency, perhaps because most recordings have been on rats, which are small animals with small hearts that are resistant to fibrillation, and perhaps because fibrillation causes rapid death. Electrocardiograms were recorded in a multiyear study of bovine copper deficiency; “quite extensive fibroic lesions may occur without any abnormality being detected … within a few weeks of death” (Bennetts et al. 1948). They also alluded to involvement of the conduction system (Bennetts et al. 1948). In view of their dependence on “two Perth medical practitioners,” subtle effects may have been overlooked because of an apparent lack of recordings on supplemented cows and possible subtle, species differences in cardiograms. It seems likely that early bovine electrocardiography was not very good because human electrocardiography has improved greatly in a half century. I experienced some initial difficulty sorting rat cardiograms into groups to identify abnormalities from copper deficiency.
One may wonder why hypercholesterolemia and abnormal electrocardiograms of copper deficiency were not discovered much earlier, considering the numerous experiments that have been done since 1928. Altered lipid metabolism might have been noticed if triglyceridemia had been much greater. Hypercholesterolemic plasma is more or less transparent; only hypertriglyceridemia can produce plasma that looks like cream. Most of the earlier students of copper deficiency were preoccupied by hematology. In contrast, I was looking for effects of trace elements on cholesterol (Klevay 1977 and 1987b), although I was not particularly interested in copper deficiency after completing a thesis on bile acids and dietary fat. By the time we had 13 of 15 deficient rats die suddenly over the course of several days (Allen and Klevay, unpublished), we were ready to record cardiograms having been inspired by Paul D. White's cardiograms on whales. We had seen some pretty bad looking hearts in deficient rats (Allen and Klevay 1978, Kopp et al. 1983, Viestenz and Klevay 1982) and had assumed that their function was poor.
Bennetts et al. (1942) were the first to note the similarity of cardiac fibrosis in “Falling Disease” to that in humans after arteriosclerosis. In contrast Carnes et al. (1965) denied the likelihood that copper deficiency had any bearing on human atherosclerosis (Klevay 1990b). However, smooth muscle proliferation (Carnes et al. 1965, Hill and Davidson 1986, Hunsaker et al. 1984), migration (Hunsaker et al. 1984) and arterial foam cells (Waisman et al. 1969) are important in the early stages of the atherosclerotic process in humans (Klevay 1990b). Decades passed before the next suggestion that copper deficiency could be important in human heart disease (Anderson et al. 1975, Klevay 1973 and 1990b).
Low cardiac copper in ischemic heart disease, better coronary arteries in men with higher white blood cell copper, higher copper in Japanese leukocytes in Okinawa, decreased lysyloxidase in human hypertension and decreased superoxide dismutase with myocardial infarction are consonant with the concept that copper nutriture of people with ischemic heart disease is poor. The data on superoxide dismutase are consonant with the suggestions (Klevay 1996, Tilson 1982) that abnormalities of copper utilization contribute to the formation of aneurysms. Because the cardiac enlargement (Dallman 1967) and abnormal cardiograms (Viestenz and Klevay 1982) of copper deficiency are reversible with the treatment of deficiency, one wonders about the possibility of copper treatment in these seemingly low copper states. It is interesting that abnormal electrocardiograms (Klevay et al. 1985), abnormal cardiac histology (Klevay et al. 1994) and abnormal arterial structure (Hunsaker et al. 1984) have been found in animals mildly deficient in copper without obvious alteration in peripheral, copper chemistry.
It seems clear that people respond to diets low in copper similarly to several species of animals. To date, >100 men and women have resembled animals in their responses to diets low in copper or to zinc supplements (Klevay 1990b and 1998). The low copper diets contained amounts of copper similar to those readily available to the U.S. population; some of the doses of zinc supplements do not exceed the RDA by very much (Klevay 1998). More than 75 anatomical, chemical and physiologic changes are common to both animals deficient in copper and people with ischemic heart disease.
The copper deficiency theory on the etiology and pathophysiology of ischemic heart disease has been developed in a series of papers over two decades; the most important or recent include Klevay 1990a, 1990b, 1998 and 2000). The theory has evolved, has been modified and has attempted to incorporate newer concepts and findings such as aspirin, beer, homocysteine, iron overload and oxidative damage. It is offered as the simplest and most general explanation of ischemic heart disease, the leading cause of death in the industrialized world.
LITERATURE CITED
Footnotes
Presented as part of the History of Nutrition Symposium entitled “Trace Element Nutrition and Human Health” given at the Experimental Biology 99 meeting held April 17–21 in Washington, DC. This symposium was sponsored by the American Society for Nutritional Sciences. The proceedings of this symposium are published as a supplement to The Journal of Nutrition. Guest editors for the symposium publication were Harold H. Sandstead, the University of Texas Medical Branch, Galveston, TX and Leslie M. Klevay, the U.S. Department of Agriculture Agricultural Research Service Grand Forks Human Nutrition Research Center, Grand Forks, ND.
Prof. George K. Davis witnessed similar events early in his work on “Quick Death” in the Florida Everglades. Copper deficiency in cattle often is secondary to excessive dietary molybdenum.
Author notes
The U.S. Department of Agriculture, Agricultural Research Service, Northern Plains Area, is an equal opportunity/affirmative action employer and all agency services are available without discrimination.
