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Biomedical subjects

L M Klevay

Publications and source records attributed to L M Klevay.

At least 73 records · Page 4Linked to original sources

Ischemic heart disease. A major obstacle to becoming old.

Four classes of etiologic agents that cause human illness have been discovered. Sometimes members of two or more classes of agents cooperate to cause illness. Knowledge of etiology is necessary if a disease is to be eradicated. The leading causes of death in the United States have changed dramatically in the last century. Infection has been replaced by chronic illnesses of obscure etiology. Ischemic heart disease is the leading cause of death in middle age and is the major obstacle to becoming old. There are numerous similarities between animals deficient in copper and people with ischemic heart disease. The most important of these similarities are glucose intolerance, hypercholesterolemia, abnormal electrocardiogram, hyperuricemia, and hypertension, as these characteristics are predictive of risk of ischemic heart disease. No other nutritional insult has produced these characteristics in experiments with animals; men fed diets low in copper have been found to have increased cholesterol, decreased glucose tolerance, and abnormal electrocardiograms. The process that results in ischemic heart disease is remarkably similar to that of copper deficiency. Links have been found between copper metabolism and several hypotheses on the origin of ischemic heart disease. Several aspects of the lipid hypothesis can be interpreted in terms of copper metabolism. More features of the etiology, pathogenesis, and pathophysiology of ischemic heart disease can be explained in terms of copper deficiency than can be explained by any other environmental insult.

Adolescent↗

The effect of copper deficiency on heart microsomal phosphatidylcholine biosynthesis and concentration.

The effect of dietary copper deficiency on phosphatidylcholine biosynthetic enzymes, phosphatidylethanolamine methyltransferase, phosphatidyldimethyltransferase and choline phosphotransferase of heart microsomes was measured in rats. The data indicated that dietary copper deficiency can alter phosphatidylcholine biosynthesis and concentration in microsomal membranes of the heart. There was a significant decrease in the specific activity of choline phosphotransferase. There was a significant decrease in the concentration of total phospholipid-P, phosphatidylcholine-P, phosphatidylethanolamine-P, phosphatidylinositol-P, sphingomyelin-P and cardiolipin-P in the microsomes of the copper deficient animals. There was a significant decrease in the concentration of copper in microsomes of heart and liver in the copper deficient animals.

Animals↗

Atrial thrombosis, abnormal electrocardiograms and sudden death in mice due to copper deficiency.

Approximately 20 years ago a diet high in lard and sucrose was described that produced extensive cardiovascular damage in adult mice. Atrial thrombosis, myocardial necrosis and sudden death were frequent. These experiments were repeated as closely as possible; the adverse effects were prevented by a drinking solution containing 10 micrograms copper/ml. Lack of copper also was associated with anemia, cardiac enlargement and abnormal electrocardiograms. Bradycardia, coupled beats, ectopic ventricular foci, premature atrial beats and prolonged PR interval were found. Lack of copper had no effect on cholesterol in plasma. The results may be germane to ischemic heart disease and the thrombotic susceptibility of women who use oral contraceptives or are pregnant frequently, because copper metabolism is altered in these conditions.

Animals↗

Alteration of the connective tissue network of striated muscle in copper deficient rats.

The connective tissue network in striated muscle, consisting principally of collagen is arranged in a three dimensional network and is intimately associated with muscle function. Previous studies have shown that animals maintained on a copper-deficient diet undergo myocardial hypertrophy and exhibit cardiovascular lesions such as ventricular aneurysms that eventually rupture. A deficiency of copper in the diet is known to inhibit lysyl oxidase, a metalloenzyme requiring copper as a cofactor and which is also responsible for collagen and elastin crosslinking. Examination by scanning and transmission electron microscopy of skeletal and cardiac muscle from rats maintained on copper-deficient diets showed both gross and microscopic lesions to the connective tissue network. Immunohistochemical staining by light microscopy with antibodies against lysyl oxidase showed that the enzyme was equally present in both control and experimental animals. Fluorescent staining for antibodies against collagen types I and III showed similar results. From these studies we concluded that the collagen secreted during hypertrophy was not crosslinked by lysyl oxidase due to the absence of the copper cofactor. This resulted in the failure of the connective tissue network to transmit and distribute the increased force associated with myocardial hypertrophy and resulted in myocardial aneurysms.

Animals↗

Increased cholesterol in plasma in a young man during experimental copper depletion.

Signs of copper depletion were produced in a healthy man by an amount of dietary copper (0.83 mg/day) similar to that in some contemporary diets. Urinary and fecal loss of copper exceeded intake. Plasma copper, ceruloplasmin, and superoxide dismutase activity in erythrocytes decreased. Cholesterol in plasma increased, and hematologic indices were unchanged. Lipid metabolism may be a more sensitive index of copper nutriture than are changes in hematology. The findings support the hypothesis that inadequate copper nutriture or altered copper metabolism contributes to the occurrence of ischemic heart disease.

Adult↗

Changing patterns of disease: some nutritional remarks.

In the last century the way of life and the way of death have changed in the United States. Infectious diseases have been replaced by diseases of apparently complex origin. Inborn errors of metabolism are more common than the classical deficiency diseases. The discovery of vitamins and the essentiality of trace elements occurred in the 20th century. Plenty of characteristics have been identified to assess vitamin nutriture; methods of assessing trace element nutriture are less well developed. Newly discovered aspects of copper physiology are potentially useful in establishing requirements.

Animals↗

Influence of type and amount of dietary lipid on plasma lipid concentrations in endurance athletes.

Changes in plasma total cholesterol, triglyceride, and lipoprotein concentrations were assessed in three male endurance cyclists who consumed isoenergetic diets for 28-day periods in which carbohydrate, polyunsaturated fat, or saturated fat contributed about 50% of the daily energy intake. Dietary cholesterol was similar among the diets. Maximal aerobic capacity was maintained at 62 ml O2/(kg X min). Body weights were held within 3% of admission levels. The polyunsaturated fat diet significantly (p less than 0.05) reduced mean fasting plasma total cholesterol in comparison to the saturated fat and carbohydrate diets (160 versus 254 and 243 mg/dl, respectively). Similarly, the polyunsaturated fat diet depressed (p less than 0.05) mean plasma triglycerides relative to the saturated fat and carbohydrate diets (37 versus 62 and 79 mg/dl, respectively). No significant dietary effects were seen on high-density lipoprotein cholesterol. The observed changes in plasma total cholesterol were not significantly different than the values predicted by the Keys' equation, delta CHL = 1.35(2 delta S-delta P) + 1.5 delta Z. We conclude that under controlled conditions in which physical activity is constant l) dietary lipid differences influence fasting serum lipid and lipoprotein concentrations among men with high energy expenditures, and 2) the Keys' equation gives useful predictions of changes in plasma total cholesterol among vigorous men consuming different types and amounts of dietary lipid.

Adult↗

Changes in plasma zinc content after exercise in men fed a low-zinc diet.

For 30 days five healthy men aged 23-57 yr consumed a diet adequate in zinc (8.6 mg/day); they ate a low-zinc diet (3.6 mg/day) for the next 120 days and then received a zinc-supplemented (33.6 mg/day) diet for 30 days. Copper intake was constant at 1.8 mg/day. Aerobic capacity was determined periodically during each diet period. Relative zinc balance (% of control) declined during depletion (r = -0.28, P less than 0.009). Pre- and postexercise zinc concentrations decreased when dietary zinc was restricted (r = -0.61, P less than 0.0001 and r = -0.78, P less than 0.0001) and increased with supplementation (r = 0.61, P less than 0.008 and r = 0.76, P less than 0.0003, respectively). Both plasma zinc and hematocrit increased (P less than 0.01) after maximal exercise. To minimize the effect of hemoconcentration during exercise, the van Beaumont quotient (J. Appl. Physiol. 34: 102-106, 1973) was calculated using pre- and postexercise hematocrit and plasma zinc. The initial quotient of 1.8 +/- 1.8% (mean +/- SE) declined (P less than 0.05) to -7.4 +/- 2.3% during depletion. With zinc repletion, the quotient increased to 6.9 +/- 3.6%, which was greater (P less than 0.05) than the quotient in depletion but similar to the initial quotient. The quotient was a strong predictor (r = 0.71, P less than 0.0005) of the change in relative zinc balance during zinc depletion. In contrast, no changes were found in plasma copper content. These data suggest that zinc mobilization from tissues is impaired during zinc depletion, and they validate the use of the van Beaumont quotient as an index of change in body zinc stores.

Adult↗

Receptor-binding changes in copper-deficient rats.

Male weanling Sprague-Dawley rats were fed a copper-deficient diet for 40 days. Copper-deficient rats weighed significantly (p less than 0.001) less (175 +/- 7 g) than copper-supplemented rats (230 +/- 6 g). Hematocrits were also significantly (p less than 0.001) decreased in deficient as compared to control animals from 43 +/- 0.6 to 30 +/- 2.7%. The binding of 3H-QNB to striatal and cerebellar membrane muscarinic receptors from control and deficient rats increased from 594 +/- 25 to 704 +/- 31 (p less than 0.02) and from 19 +/- 2 to 28 +/- 3 (p less than 0.01) pmol/g protein, respectively. Similarly, 3H-muscimol binding to GABA receptors (cerebellum) also increased from 39 +/- 5 to 58 +/- 3 (p less than 0.02) pmol/g protein. 3H-diazepam binding to benzodiazepine receptors in deficient versus control animal frontal cortex membranes decreased from 92 +/- 8 to 75 +/- 5 (p less than 0.02) pmol/g protein, respectively. These results may help explain CNS manifestations of copper deficiency.

Animals↗

Copper and zinc in selected foods.

Few data on the copper and zinc contents of convenience items and frozen foods have been reported in the literature. In this study, selected meats, frozen vegetables, and convenience items were analyzed for copper and zinc content by atomic absorption spectrophotometry. Foods found to have the highest copper content tended to be highest in zinc as well. Beef liver was an outstanding source of both minerals. Protein foods were generally good sources of zinc, supplying more than 2 mg/100-gm serving. Foods containing more than 0.2 mg copper per 100 gm were considered to be good sources. Examples included chicken livers, garbanzo beans, frozen Mexican-style dinner, and frozen brownies. Most of the other foods analyzed contained relatively small amounts of copper and zinc. Nevertheless, the contribution of such foods to the total daily copper and zinc intake illustrates the desirability of including a wide variety of foods in the diet.

Animals↗

Maximal oxygen consumption as related to magnesium, copper, and zinc nutriture.

Forty-four healthy male university athletes and 20 untrained men underwent maximal treadmill exercise testing to determine the relationship between maximal oxygen consumption and various measurements of elemental nutriture. Hb and mean plasma and erythrocyte concentrations of magnesium, copper, and zinc were within established norms for both groups after a 12-h fast. Mean plasma copper concentration was significantly (p less than 0.01) higher in the athletes (90 +/- 14.3 versus 81 +/- 8.0 micrograms/dl). Average maximal oxygen consumption also was significantly (p less than 0.001) higher in the athletes [4.5 +/- 0.5 versus 3.3 +/- 0.6 L/min and 55.5 +/- 7.1 versus 47.0 +/- 6.0 ml/(kg x min)]. Plasma magnesium was significantly correlated (r = 0.46; p less than 0.002) with maximal oxygen consumption, ml/(kg x min), among the athletes. This relationship persisted when the effect of Hb concentration was removed by covariance analysis (p less than 0.005). Only a weak association (r = -0.32; p = 0.17) was found between oxygen consumption and plasma magnesium in the untrained men. We hypothesize that ionic magnesium may facilitate oxygen delivery to working muscle tissue in trained subjects.

Adult↗

Physiological and metabolic characterization of a cardiomyopathy induced by chronic copper deficiency.

Male weanling rats were made copper deficient with a purified diet containing all known essential dietary nutrients except copper. Copper deficiency was verified by indirect (anemia, growth retardation, hypercholesterolemia, gross pathology, and abnormal electrocardiograms) and direct (tissue copper analysis) criteria. His bundle electrographic and electrocardiographic changes detected in the copper-deficient group consisted most notably of depressed His-Purkinje system conductivity and S-T segment depression. Phosphorus-31 nuclear magnetic resonance spectroscopic analysis of cardiac, renal, and hepatic tissue perchloric acid extracts revealed significant metabolic changes associated with the dietary copper deficiency, including a generalized marked decrease in ATP and phosphocreatine levels and a corresponding increase in inorganic orthophosphate and ADP levels in the various tissues. Tissue-specific changes consisting of elevated ribose 5-phosphate (heart), phosphocholine (heart), and inosine monophosphate (kidney) and decreased glycerol 3-phosphorylethanolamine (liver) and glycerol 3-phosphorylcholine (liver) levels were detected in copper-deficient rats. Microscopic examination of heart tissue from copper-deficient rats revealed extensive disruption of mitochondrial fine structure, including fragmentation of cristae and inner and outer mitochondrial membranes, which resulted in pronounced vacuolization throughout the tissue. Although the physiological and metabolic disturbances manifested in hearts from copper-deficient animals generally mimic myocardial responses to chronic ischemia, the observed changes are interpreted in a broader context to represent the appearance of a copper-dependent cardiomyopathy.

Animals↗

Clofibrate hypocholesterolemia associated with increased hepatic copper.

Copper metabolism is important in the etiology of ischemic heart disease according to a new hypothesis. Hypercholesterolemic people may be more likely to be malnourished in copper than normocholesterolemic people. Clofibrate was fed to rats as a component of a diet that produces copper deficiency. Rats fed clofibrate had 20 to 29% (P less than 0.003) lower concentration of cholesterol in blood plasma and higher copper in liver (47 to 78%, P less than 0.025) and plasma (19 to 25%, P less than 0.03). The experiments are a successful test of the hypotheses that clofibrate is active in animals malnourished in copper and that the change in cholesterol metabolism induced by clofibrate may be the result of a change in copper metabolism. Clofibrate is a member of a class of cholesterotropic and cuprotropic chemicals.

Animals↗

A randomized trial of copper therapy in rats with electrocardiographic abnormalities due to copper deficiency.

Abnormalities of the ECG were induced in rats by a diet deficient in copper. Abnormalities of the ST segment, bundle branch block, supraventricular beats, ventricular beats, and wandering pacemaker were found. Ventricular aneurysm, hemothorax, pleural effusion, cardiac rupture, and hemopericardium also occurred. Gross pathology and abnormal electrophysiology were not closely associated. Electrocardiograms of 12 rats were found to have abnormal ST segments. Rats with similar electrocardiographic abnormalities were assigned to pairs, one member of each pair was selected for treatment with copper by coin toss. Gross pathological findings of treated and untreated rats were similar. Treatment improved the survival of the group and the ECGs of four of the six. These findings were related to certain aspects of ischemic heart disease and to dietary copper in the industrialized part of the world.

Animals↗

Postheparin plasma lipoprotein lipase in copper-deficient rats.

Postheparin plasma lipoprotein lipase has been investigated in male sprague-Dawley rats fed a diet deficient in copper. Deficiency was verified by the detection of anemia, hypercholesterolemia and decreased myocardial copper. Three experiments were done; they showed significant decrease in enzyme activity (40-47% reduction) in deficiency. Copper may be required for the formation of the activator complex of the enzyme. Decreased lipoprotein lipase activity may be responsible for the hypertriglyceridemia of copper deficiency, and that may also explain its hypercholesterolemia.

Animals↗

Aortic sudanophilia an zinc-copper ratios in the liver of vervet monkeys fed different types of dietary fibre.

Vervet monkeys (Cercopithecus aethiops pygerethrus) were fed a semipurified diet containing 40% sucrose, 25% casein, 14% hydrogenated coconut oil and 15% fibre for 6 months. Alfalfa, cellulose, or wheat straw was the source of the fibre. All the diets led to aortic sudanophilia, but the group fed wheat straw had the highest copper level in the liver and the least sudanophilia. The order to severity of the sudanophilia, the ratio of zinc to copper in the fibers, and the ratio of zinc to copper in the liver were: alfalfa-fed group greater than cellulose-fed group greater than wheat straw-fed group. These findings, which may have resulted from the relatively large amount of copper in the wheat straw, are consonant with observations on lipid metabolism in other species.

Animals↗

Effects of dietary fiber from wheat, corn, and soy hull bran on excretion of fecal bile acids in humans.

Effects of dietary fiber on bile acid excretion and fecal bile acid concentration have been studied for seven subjects fed 26 g of either soft white wheat bran, corn bran, soybean hulls, or hard red spring wheat bran. Results indicate that even in a controlled study using a metabolic word, individual subject variation has a major impact on fecal bile acid excretion. This observation has not been fully appreciated in previous human studies. No significant change in the composition of fecal bile acids could be associated with the decrease in serum lipid levels previously reported. A method for the isolation and quantitation of fecal bile acids is described which does not require purification by thin-layer chromatography. A preliminary study of lyophilized fecal samples stored at -10 to -30 degrees C showed very little or no change in bile acid content. Samples stored at room temperatures for 11 months showed a substantial reduction in bile acid content.

Bile Acids and Salts↗

Whole body surface loss of trace metals in normal males.

Whole body surface losses of zinc, copper, and iron were measured in 13 male volunteers who lived in a controlled environment for 4 to 9 months. For 88 daily samples, the mean losses for zinc, copper, and iron were 0.50, 0.34, and 0.33 mg/day (3.9, 26, and 2.1% of the mean dietary intakes, respectively). There was a large variance in metal losses with no significant differences in variance within-versus-between subjects or on the same-versus-different diets. The surface losses of zinc and iron increased the apparent dietary requirements determined by balance measurements only 5 and 3%, respectively, while the increase in copper requirement due to surface loss was 25 to 30%.

Adult↗