ADVANCES IN CARDIOVASCULAR-COPPER RESEARCH
Leslie M. Klevay
United States Department of Agriculture, Agricultural Research Service,Grand Forks Human Nutrition
Research Center, Grand Forks, ND, USA
Based on remarks at the First International Bio-Minerals Symposium of the International Association of
Bioinorganic Scientists in Salt Lake City where Dr. Klevay received the Klaus Schwarz Commemorative Medal.
Some of the concepts also were presented at the workshop “Ischemic Heart Disease and Malnutrition” at
Experimental Biology ‘01 in Orlando and at the XVII World Congress of the International Society for Heart
Research in Winnipeg.
Abstract
Copper frequently is low in the Western diet so closely associated with heart disease risk.
Some of these diets are in the intake range used in successful depletion experiments of men
and women and are low in comparison to suggested, desirable intakes.
Assessment of nutritional status for copper is difficult. More than a dozen research articles
reveal low organ copper and low activities of enzymes dependent on copper in people with
cardiovascular disease. The nearly 80 identified anatomical, chemical and physiological
similarities between animals deficient in copper and people with ischemic heart disease
support the concept that these low concentrations of copper and low enzyme activities are
indicative of poor copper status. Some links between the copper deficiency theory on the
etiology and pathophysiology of ischemic heart and other general explanations for this illness
have been found.
The nutritional essentiality of copper was established for animals in 1928 when growth and
hemoglobin improved after rats fed a cow’s milk diet were supplemented with copper;
nutritional scientists studying copper became preoccupied with hematology for more than half
a century(1). Now there is more research on cardiovascular effects of copper deficiency than
on hematology(1).
Although a link between copper and the cardiovascular system began to be made in 1939 by
Bennetts and Hall(2), this shift in emphasis occurred gradually from the early 1970’s(1,3).
Emphasis in this review will be restricted to copper deficiency and cardiovascular disease.
Copper in the Western Diet
Four successful copper depletion experiments with diets of conventional foods and involving
more than 30 men and women have been summarized(4,5) revealing that daily copper intakes
of 0.65 to 1.02 mg were insufficient. Approximately one-third of daily diets in Belgium,
Canada, the United Kingdom and the United States are within this range(6,7).
Recent results on daily intakes of 80 men and women randomly selected in Baltimore are
consonant(8). It is possible to interpolate the graph of these authors to reveal 36 and 60% of
daily copper intakes are less than the recently published Estimated Average Requirement and
the Recommended Dietary Allowance, respectively, for adults(9).
Assessment of Nutriture
Assessment of nutritional status, or nutriture, is not always easy. Dann and Darby(10)
described five zones of nutriture from saturation, i.e., maximal storage without early toxicity, to
clinically manifest nutritional disease which, when severe, can be diagnosed without the
assistance of the laboratory. Although they emphasized vitamins, their principles are equally
applicable to trace elements(11). Golden(12) includes copper among the nutrients that are
reduced in tissue concentration in deficiency.
Numerous experiments with animals support this statement. Prohaska (13) tabulated some
cuproenzymes that are altered in copper deficiency. Extracellular superoxide dismutase, lysyl
oxidase and Cu, Zn-superoxide dismutase (EC 1.15.1.1) were prominent. Lysyl oxidase (EC
1.4.3.6) is required for the cross linking of collagen and elastin. The superoxide dismutases
protect against oxidative damage. Enzyme activities and copper concentrations are
suggested as being potentially useful in diagnosing copper deficiency with no single indicator
being adequate in all situations(9). Decreased tissue concentration or decreased enzyme
activity may correspond to Dann and Darby’s third and fourth zones of nutriture: potential and
latent deficiency disease(10).
Signs of Low Copper Nutriture?
Several authors have found a decrease in the concentration of copper in the presumably
normal heart muscle of people with ischemic heart disease in comparison to accident victims,
et c.(14-18). Low copper in leucocytes has been found in men with poor coronary arteries on
angiograms(19) and in Japanese who live in Brazil where heart disease risk is high in
comparison to Japan, where risk is low(5,20). Tilson and Dubick et al. found low liver copper(21)
and decreased aortic superoxide dismutase(22), respectively, in people with aortic aneurysm.
Others have found decreases in copper dependent enzymes in people with abnormal
cardiovascular physiology or structure. Vivoli et al.(23) and Bergomi et al.(24,25) found inverse
correlations between blood pressure and superoxide dismutase activity and lysyl oxidase,
respectively, in hypertension.
The results of Russo et al. were similar(26). Angiogram patients with a history of myocardial
infarction had less superoxide dismutase in plasma than similar patients without such a
history(27). Decreased activity also was found in diseased coronary arteries(28). Perhaps
people with low enzyme activities are people who habitually eat diets low in copper. If so, then
ischemic heart disease corresponds to Dann and Darby’s fifth zone of nutriture: clinically
manifest deficiency disease(10). These observations can be interpreted as evidence of copper
deficiency only if other observations are corroborative.
Rock et al.(29) supplemented healthy, middle-aged people with copper and found their red
cells to be less easily oxidized in vitro after six weeks of supplementation. This experiment
reveals that healthy people may benefit from higher copper intakes.
Similarities Between Copper Deficiency and Ischemic Heart Disease
Tables 1-3 summarize anatomical, chemical and physiological similarities between animals
deficient in copper and people with ischemic heart disease. Tabulation of these similarities
began in 1987(30). The titles of the tables were changed from ‘similarities between’ to ‘the
anatomy of ’ in 2000(5). The number of tabulated entries has grown more than 6-fold from the
dozen(31), when I first began to notice the likeness of the two syndromes, until now.
The work of numerous authors is incorporated into Tables 1-3. Their work has been cited in
earlier writings; citation of most primary references is omitted here for the sake of brevity.
Table 1. The Anatomy of Copper Deficiency and Ischemic Heart Disease
Aortic valve thickening
Arterial
Elastic degeneration
Fibrosis
Foam cells
Hemorrhage (intramural)
Mucopolysaccharide increase
Necrosis
Smooth muscle proliferation
Atrial
Thrombosis
Bone density decrease
Coronary artery
Dissecting aneurysms
Elastic fragmentation
Hyalinization
Necrosis
Smooth muscle degeneration
Sudanophilia
Thrombosis
Hemopericardium
Hemothorax
Myocardial infarction
Pericarditis
Pleural effusion
Ruptured papillary muscle
Small stature
Ventricular
Aneurysm
Calcification
Edema
Fibrosis
Hemorrhage (focal)
Hypertrophy
Infiltration
(neutrophil and round cell)
Myocyte-myocyte struts decreased
Necrosis (myocardial cell)
Rupture
Thrombosis (endocardial)
Table 2. The Chemistry of Copper Deficiency and Ischemic Heart Disease
Decreased
Cardiac copper
Cardiac iron
Dihomo-y-linolenic acid
Hepatic zinc
Lecitin:cholesterol acyltransferase
Leucocyte copper
Lipoprotein lipase
Na/K-ATPase
Myocardial cytochrome oxidase
Plasma retinol
Exacerbated by
Homocysteine
Ironb
Salt
a - Risk factor. See Table 1 for further explanation.
b - Newly added, see text.
Increased
Cardiac sodium
Cholesterolemiaa
Serum ferritin
Homocysteinemiab
Thiobarbituric acid reactive substances
Thromboxane A2/prostacyclin
Triglyceridemia
Uricemia
Mitigated by
Aspirin
Beer
Clofibrate
Table 3. The Physiology of Copper Deficiency and Ischemic Heart Disease
Abnormal electrocardiograms
Blocks
bundle brancha
first degree
second degree
third degree
Decreased
Arterial dilation with acetylcholine
Blood pressure under load
Glucose tolerancea
Hearing
Longevity
Exacerbated by
His-ventricular interval increased
Pathological Q waves
P wave morphology altered
QT interval increased
R waves are tall
ST segmenta
Ventricular premature beats
Pregnancy
Increased
Blood pressurea
Euglobulin clot lysis time
Female thrombosis
Male sudden death
a - Risk factor. See Table 1 for further explanation.
It is important to realize that each entry in these tables represents observations made both on
deficient animals and sick people, often based on several observations on each group. My
seven intervening theoretical articles cite hundreds of research articles. Enumeration and
citation here are restricted either to similarities found recently or to recently found references
to similarities found earlier.
The observations on people are based mainly on epidemiology and pathology, although some
are from noninvasive, diagnostic procedures. The observations on animals are taken from
numerous experiments on copper deficiency made since 1928(32). Together, these collected
observations and their accompanying discussion in my earlier writing provide the basis for
what may become a unified theory of the etiology and pathogenesis of ischemic heart
disease(33). In retrospect, many of the experiments can be considered successful attempts to
produce characteristics of ischemic heart disease in animals deficient in copper.
As noted above, the superoxide dismutases dependent on copper protect against oxidative
damage. The thiobarbituric acid reactive substances in Table 2 are indicative of oxidative
damage.
Because animals deficient in copper can be somewhat protected from this deficiency by
dietary antioxidants and because the hypercholesterolemia, hypertension, hypercoagulability
of blood(34) and endothelial vasodilator function have evidence of impaired oxidative
defense(35), copper may be an antioxidant nutrient for cardiovascular health (34).
Anatomy
Rate of loss of bone mineral density in the hip was associated directly with increased mortality
from coronary heart disease(36). Cardiac enlargement in copper deficiency has been found
again(37).
Chemistry
Aspirin mitigated copper deficiency(38,39), at least in part, by increasing liver copper(40). Serum
cholesterol is low in people with Wilson’s disease, probably because of the increased liver
copper(33). Observations from Framingham showing that uricemia can be used to predict heart
disease mortality have been confirmed(41,42).
Elevated plasma homocysteine is an independent risk factor for premature coronary
atherosclerosis in men(43). Homocysteine is increased in plasma of rats deficient in copper(44);
high homocysteine also interferes with copper utilization(45).
Salonen, et al.(46) suggested high stored iron, as assessed by serum ferritin, is an
independent risk factor for coronary heart disease. Rats fed marginal copper can be made
deficient by a high intake of iron(47). Copper in heart, liver and plasma was decreased and
plasma cholesterol was increased.
Physiology
The decreased hearing in elderly people exacerbated by hypertension and
hypercholesterolemia(48) increases the association between hearing loss and ischemic heart
disease(5). This phenomenon may result from a greater sensitivity to noise if feeding
cholesterol to chinchillas(49) produces alterations in copper utilization as have been found in
other species(50,51) (see below).
The Lipid Hypothesis
The lipid hypothesis probably is the most widely accepted and most intensively studied
hypothesis on the origin of ischemic heart disease. In brief, large amounts of dietary fat are
toxic. Failures of the lipid hypothesis in addition to those mentioned here can be found in
earlier writings(5,30,33,52-54).
This hypothesis, in reality at least three separate hypotheses(30,52,53), has failed to explain
much of ischemic heart disease. Most important, perhaps, are the lack of relationship of fat
intakes to risk when data are collected in single nations(52,55), freedom from heart disease with
high plasma cholesterol and heart disease with low cholesterol(5), and lack of association
between dietary fat intake and serum cholesterol(56,57). If nearly everyone in the wealthiest
nations eats too much of the wrong kind of fat, then dietary fat is not of epidemiologic
interest(55).
Epidemiology has not revealed that women eat less, or better fat, than men. Nor is there an
experiment showing that women (or female animals) tolerate fat better than men (or male
animals). Differences in fat consumption cannot explain why men with ischemic heart disease
tend to die suddenly(5,58,59) and women tend to die with thrombosis(5,58), seasonal variations in
cholesterol or statistical associations between paired risk factors such as serum uric acid and
cholesterol(5). Plasma homocysteine also can be predicted by measurement of total
cholesterol or blood pressure in Norwegians(60). Other characteristics of ischemic heart
disease unexplained by dietary fat were discussed earlier(5).
Recently a systematic review of 27 trials stating the intention to reduce or modify fat intake
revealed that cardiovascular mortality could be reduced by these measures. Longer trials
provided stronger evidence of protection, but there was little effect on total mortality(61). It
seems that this dietary change can change the words (not the date) on the death
certificate(62,63). Other dissents from the lipid hypothesis are available(64-67).
Animal Models of Human Disease
Agents suspected of causing human illness should be able to produce characteristics of the
illness in animals. This production may be difficult, and may not occur for all phenomena or in
all species. In general, medicine has advanced when illnesses similar to those of people have
been produced in animals by putative agents. Skepticism is proper when an hypothesis has
been advanced for many years and yet evidence from animals is minimal or lacking.
It is surprising how few of the characteristics of ischemic heart disease have been produced
in animals fed various amounts and types of dietary lipid (5). Abnormal electrocardiograms,
glucose intolerance and hyperuricemia are prominent among these characteristics.
Experimental production in animals of characteristics of ischemic heart disease is particularly
important in view of Stehbens’ contention(65,66) that coronary heart disease and
atherosclerosis are not as closely associated as is generally believed.
Conversely, when putative agents produce illness in animals only because of unsuspected
properties such as a chemical impurity, the hidden characteristic is revealed to be the actual
agent. Examples are the minor constituent of tryptophan supplements in producing the
eosinophilia myalgia syndrome(68,69) and contaminated meperidine in rapidly producing acute
severe parkinsonism(70).
There has been much effort devoted to producing atherosclerosis, in contrast to ischemic
heart disease, in animals. Experimental diets containing cholesterol or cholesterol plus cholic
acid to produce atherosclerosis were introduced in the first quarter of the 20th century. These
diets were shown to disrupt copper utilization later(50,51); results have been confirmed and
extended(71-73). It may be appropriate to revise interpretations of experiments in which these
dietary additives were used and to reformulate resulting hypotheses. Phenomena attributed to
dietary cholesterol in reality may have been the result of copper deficiency as was found for
some diets high in lard(74) without the additives. Copper deficiency seems to produce lesions
both resembling atherosclerosis and characteristics of ischemic heart disease in animals.
General Explanations of Ischemic Heart Disease
Long ago I read a poem(75) which seems to apply to ischemic heart disease. Blind men visited
an elephant to learn its properties. Each evaluated only part of the elephant, but attempted to
conceptualize its entirety. Individual inferences were correct, were narrow and were
inadequate to characterize the elephant as a whole (Figure 1). The elephant was thought to
be similar to a rope, a tree, a wall, et c.
I think it is important to consider all aspects of ischemic heart disease, not only those aspects
related to lipid metabolism(54). Chamberlin(76) urges ‘’the method of multiple working
hypotheses’’ when studying complex phenomena to promote thoroughness and to prevent
neglect of important data. Theories attempting to explain important natural phenomena have
been found wanting historically if they explained only limited characteristics of the
phenomena(77,78). Kuhn argues that theories incorporating other theories contribute to
scientific progress(30,33,79).
McCormick(80) has referred to the multifactorial aetiology of coronary heart disease as a
dangerous delusion. I have illustrated how the term ‘’multifactorial’’ could have been applied
to pellagra(81), scurvy(53) and beri beri(55) if it had been in the medical vocabulary when these
illnesses were considered as complicated as is ischemic heart disease today. It is, and has
been, my hope that ischemic heart disease eventually will be simplified to the degree that
these deficiency diseases have been simplified.
Questions arise. What produces the phenomena in Tables 1-3 and other characteristics of
ischemic heart disease such as arterial spasm and endothelial damage, connective tissue
damage...thrombi, and so on(33,53,54)? What determines who lives long and who dies early of
ischemic heart disease when people eat the Western diet for a lifetime?
Four general explanations have been advanced to answer these questions. The lipid
hypothesis may have outlived its usefulness(5) and will not be discussed further. The
homocysteine hypothesis of McCully(82,83) and the iron hypothesis of Sullivan(67,84,85) provide
unifying ideas(5) that may be helpful in understanding the origins of the many phenomena of
ischemic heart disease.
Barker has advanced the fetal programming hypothesis in two editions of his book (54). In brief,
small babies who do not catch up in growth in a year are likely to be hypertensive and
glucose intolerant in middle age. Numerous research articles develop and refine the ideas of
these authors.
The copper deficiency theory is offered as the simplest and most general explanation of the
etiology and pathophysiology of ischemic heart disease(5). Some links between this theory
and other explanations that have been proposed have been provided here and
elsewhere(30,52). Copper deficiency has produced more characteristics of ischemic heart
disease in animals than has any other nutritional insult. This production supports the belief
that low copper concentrations and low activities of enzymes dependent on copper in people
with cardiovascular disease are signs of poor copper nutriture. If copper deficiency is the
leading nutritional deficiency, world wide, of agricultural animals(86), can people be far behind?
Figure 1
Legend
The poem can be found at http://www.wordfocus.com/word-act-blindmen.html. My thanks to my
cousin Theodore C. Klevay for the cartoon used with permission.
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