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U.S. Department of Agriculture,2 Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONAnatomyChemistryPhysiologyThoughts from the 1990sREFERENCES |
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KEY WORDS: • copper deficiency • Falling Disease • ischemic heart disease
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONAnatomyChemistryPhysiologyThoughts from the 1990sREFERENCES |
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, 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.
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Anatomy |
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TOPABSTRACTINTRODUCTIONAnatomyChemistryPhysiologyThoughts from the 1990sREFERENCES |
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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.
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Chemistry |
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TOPABSTRACTINTRODUCTIONAnatomyChemistryPhysiologyThoughts from the 1990sREFERENCES |
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, 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
).
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Physiology |
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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
).
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Thoughts from the 1990s |
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TOPABSTRACTINTRODUCTIONAnatomyChemistryPhysiologyThoughts from the 1990sREFERENCES |
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, 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.
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FOOTNOTES |
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2 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.
3 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.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONAnatomyChemistryPhysiologyThoughts from the 1990sREFERENCES |
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