How dietary deficiency, genes and a toxin can cooperate to produce arteriosclerosis and ischemic heart disease.

Four classes of agents capable of producing human illness have been identified: toxicity, heredity, infection and deficiency. Examples of how members of these classes of etiologic agents can cooperate to produce illness were shown. The copper deficiency theory of ischemic heart disease and the homocysteine theory of arteriosclerosis were examined using concepts about cooperation. The Western diet so closely associated with these illnesses often is low in copper. Copper deficiency decreases the activity of methionine synthase which contributes to elevation of homocysteine, and of paraoxonase which impairs hydrolysis of homocysteine thiolactone, an inhibitor of lysyl oxidase. This copper-dependent enzyme initiates the cross-linking of collagen and elastin in arteries and bone. High homocysteine also impairs superoxide dismutase, a copper-dependent enzyme important in oxidative defense. Some genes affecting paraoxonase activity may respond to dietary copper. The copper deficiency theory of ischemic heart disease and the homocysteine theory of arteriosclerosis are inextricably entwined.

Hair as a biopsy material: trace element data on one man over two decades.

BACKGROUND: Hair mineral analyses are being performed frequently both with and without medical advice. Reasons for analysis often are ill defined. OBJECTIVE: To assess variability of trace element data both within a series of samples from an individual and among mean values published from other research laboratories. DESIGN: Many samples of hair were collected carefully from a healthy man over a comparatively long period of time and were processed and analyzed under standard conditions. Extensive published data from other research laboratories also were reviewed and compared. RESULTS: Coefficients of variation for trace elements in hair of the donor ranged from 17 to 74% for the essential elements copper, selenium and zinc and from 53 to 121% for the potential intoxicants aluminum, cadmium and lead. The ratio of high mean to low mean for values published by others on hair samples from healthy people ranged from two for selenium and zinc to 18 for aluminum. CONCLUSIONS: Hair analysis should be based on a diagnostic hypothesis such as cadmium intoxication or copper deficiency rather than on the ease of analysis or attempts to explain vague symptoms because within-person variability is large and interlaboratory agreement on normal values is poor.

Ischemic heart disease as deficiency disease.

Four classes of agents capable of producing human illness have been identified: toxicity, heredity, infection and deficiency. The leading paradigm for the etiology and pathophysiology of ischemic heart disease in the 20th century was that of intoxication by too much of the wrong kind of dietary fat. This overemphasis on lipid metabolism persists because important data are neglected and because of inattention to details. For example, heart disease risk does not correlate with fat intake within nations in contrast to between nations. Also development of ischemic heart disease involves inter alia arterial spasm, cardiac rhythm, metabolism of connective tissue, glucose and homocysteine, plus paraoxonase activity and thrombus formation which generally are unaffected by dietary fat. Homocysteine thiolactone accumulates when homocysteine is high. This lactone specifically inhibits lysyl oxidase which depends on copper to catalyze cross linking of collagen and elastin in arteries and bone. The lactone is hydrolyzed by paraoxonase, activity of which can be decreased by copper deficiency. Just as cholesterol was an important focus for heart disease as intoxication, homocysteine can become an excellent focus for a paradigm shift to heart disease as deficiency because supplementation with several nutrients can alter homocysteine metabolism and decrease its plasma concentration. These supplements include betaine, copper, folate, pyridoxine and vitamin B-12. Opportunities for research on ischemic heart disease as deficiency disease are plentiful.

Determination of an acute no-observed-adverse-effect level (NOAEL) for copper in water.

A prospective, double-blind controlled study was designed to determine the acute no-observed-adverse-effect level (NOAEL) of nausea in an apparently healthy population of 179 individuals who drank copper-containing water as the sulfate salt. Subjects were recruited at three different international sites and given a blind, randomly selected dose (0, 2, 4, 6, or 8 mg Cu/L) in a bolus of 200 ml (final total copper dose was equivalent to 0, 0.4, 0.8, 1.2, and 1.6 mg) once weekly over a consecutive 5-week period. Gastrointestinal (GI) symptoms of nausea, abdominal pain, vomiting, or diarrhea were screened for a period of up to 24 h. Nausea was the most frequently reported effect and was reported within the first 15 min of ingestion. For the combined trisite population (n=179), 8, 9, 14, 25, and 44 subjects responded positively to one or more GI symptoms at 0, 2, 4, 6, and 8 mg Cu/L, respectively. Analysis of the data demonstrated a clear dose response to the combined positive GI effects and to nausea alone. Statistically significant greater reporting of effects occurred at 6 and 8 mg Cu/L. Therefore, an acute NOAEL and lowest-observed-adverse-effect level of 4 and 6 mg Cu/L (0.8 and 1.2 mg Cu), respectively, were determined in drinking water for a combined international human population.

Interactions among dietary fat, mineral status, and performance of endurance athletes: a case study.

In a pilot study, performance measures and mineral metabolism were assessed in 3 male endurance cyclists who consumed isoenergetic, isonitrogenous diets for 28-day periods in a randomized, crossover design in which dietary carbohydrate, polyunsaturated, or saturated fat contributed about 50% of daily energy intake. Peak aerobic capacity [62 ml/(kg á min)] was unaffected by diet. Endurance capacity at 70-75% peak aerobic capacity decreased with the polyunsaturated fat diet. Copper retention tended to be positive only with saturated fat. Less iron and zinc were retained (intake - losses), and fecal losses of these minerals increased with the polyunsaturated fat. Blood biochemical measures of trace element nutritional status were unaffected by diet, except serum ferritin, which tended to decrease during consumption of the polyunsaturated fat diet. These preliminary results suggest that diets high in polyunsaturated fat, particularly linoleic acid, impair absorption and utilization of iron and zinc, and possibly magnesium, and may reduce endurance performance.

Iron overload can induce mild copper deficiency.

Dietary copper in the U.S. often is lower than that proved insufficient for men and women under controlled conditions. Iron overload can have adverse effects on copper nutriture and can produce cardiac disease in people. The hypothesis that iron can interfere with copper utilization to produce adverse effects related to cardiovascular function was tested. Rats were fed a diet high in iron and marginal, but not deficient in copper for comparison with similar diets containing iron at the recommended amount. Copper and iron were measured by atomic absorption spectroscopy; cholesterol was measured by fluorescence, ceruloplasmin was measured by oxidase activity and hematology was done by an automated cell counter. When dietary copper was 2.0 mg/kg of diet, high iron decreased (p<0.008) cardiac and hepatic copper, plasma copper and ceruloplasmin, and increased (p<0.02) cardiac weight, hepatic iron and plasma cholesterol. When dietary copper was increased to 2.5 mg/kg, copper in heart and plasma decreased (p<0.04) and hepatic iron increased (p=0.001) with high iron but other effects disappeared. No harmful changes in hematology, such as hematocrit, mean corpuscular volume, etc. were found. High iron increased the dietary copper requirement of the animals. People with iron overload may benefit from copper supplementation, particularly if they habitually consume a diet low in copper.

Copper deficiency halves serum dehydroepiandrosterone in rats.

DHEA (dehydroepiandrosterone) is a hormone often taken as a dietary supplement to prevent the normal decline with age and in the hope of preventing heart attacks. Rats in two experiments were made deficient in copper by standard methods and criteria. Copper deficiency decreased DHEA in serum by approximately 50%. People who associate higher serum concentrations of DHEA with health probably should eat a diet adequate in copper.

Cardiovascular disease from copper deficiency--a history.

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.

A diet high in whole and unrefined foods favorably alters lipids, antioxidant defenses, and colon function.

OBJECTIVE: Diets rich in whole and unrefined foods, like whole grains, dark green and yellow/orange-fleshed vegetables and fruits, legumes, nuts and seeds, contain high concentrations of antioxidant phenolics, fibers and numerous other phytochemicals that may be protective against chronic diseases. This study compared the effects of a phytochemical-rich diet versus a refined-food diet on lipoproteins, antioxidant defenses and colon function. METHODS: Twelve hyperlipidemic women followed two diets for four weeks starting with a refined-food diet. Subjects then directly crossed over to the phytochemical-rich diet. Duplicate, fasting serum lipids and single, fasting antioxidant enzymes were measured at the end of the four-week refined-food diet period (baseline) and again at the end of the phytochemical-rich diet period. RESULTS: Total energy and total fat intake were similar during both diet periods, but there was a decrease in saturated fat (SFA) of 61% in the phytochemical-rich diet group. Dietary fiber, vitamin E, vitamin C and carotene intakes were 160%, 145%, 160% and 500% more, respectively, than during the refined-food diet period. The phytochemical-rich diet induced a drop of 13% in total cholesterol (TC) (p < 0.05) and 16% (p < 0.001) in low density lipoprotein-cholesterol (LDL-C). Erythrocyte superoxide dismutase decreased 69% (p < 0.01) and glutathione peroxidase dropped 35% (p < 0.01). Colon function was improved on the phytochemical-rich diet. CONCLUSIONS: A diet abundant in phytochemically-rich foods beneficially affected lipoproteins, decreased need for oxidative defense mechanisms and improved colon function.

Lack of a recommended dietary allowance for copper may be hazardous to your health.

The 10th edition of Recommended Dietary Allowances (RDA) did not include an RDA for copper; rather a safe and adequate daily intake was suggested. Criteria, history and uses of RDAs were summarized along with data on dietary intakes, balance and depletion experiments, low (fats and oils, skim milk and yogurt) and high (legumes, mushrooms, nuts and seeds) copper foods and hazards of zinc supplements. Bone disease and cardiovascular disease from diets-low in copper have been studied in animals for decades. Men and women fed diets close to 1 mg of copper per day, amounts quite frequent in the US, responded similarly to deficient animals with reversible, potentially harmful changes in blood pressure control, cholesterol and glucose metabolism, and electrocardiograms. Women supplemented with trace elements including copper experienced beneficial effects on bone density. These data exceed similar data on magnesium, selenium and zinc and are sufficient for establishing an RDA. Ischemic heart disease and osteoporosis are likely consequences of diets low in copper. Numerous anatomical, chemical and physiological similarities between animals deficient in copper and people with ischemic heart disease have been noticed. Association between osteoporosis and low copper status deserves further inquiry. Augmenting low copper diets with high copper foods may be beneficial. Committees that establish RDAs should return to the traditions of the first nine editions and make recommendations that promote health and nutritional welfare, meet functional needs, prevent disease and promote public welfare.

Vascular superoxide dismutase deficiency impairs endothelial vasodilator function through direct inactivation of nitric oxide and increased lipid peroxidation.

Nitric oxide (NO) and superoxide are both constitutive products of the endothelium. Because NO is readily inactivated by superoxide, the bioactivity of endothelium-derived NO (EDNO) is dependent on local activity of superoxide dismutase (SOD). We examined the effects of chronic inhibition of copper-zinc SOD (CuZnSOD) using a rat model of dietary copper restriction. Male weanling Sprague-Dawley rats were fed a Cu-deficient diet and received either no Cu replacement (Cu-deficient) or Cu in the drinking water (Cu-sufficient). Compared with Cu-sufficient animals, Cu-deficiency was associated with a 68% reduction in CuZnSOD activity and a 58% increase in vascular superoxide as estimated by lucigenin chemiluminescence (both P < .05). Compared with Cu-sufficient animals, arterial relaxation in the thoracic aorta from Cu-deficient animals was 10-fold less sensitive to acetylcholine, a receptor-dependent EDNO agonist, but only 1.5-fold less sensitive to A23187, a receptor-independent EDNO agonist, and only 1.25-fold less sensitive to authentic NO (all P < .05). In contrast, acute inhibition of CuZnSOD with 10 mM diethyldithiocarbamate produced a more uniform reduction in sensitivity to acetylcholine (8-fold), A23187 (10-fold), and NO (4-fold; all P < .001). Cu-deficient animals demonstrated a 2.5-fold increase in plasma-esterified F2-isoprostanes, a stable marker of lipid peroxidation, that correlated inversely with arterial relaxation to acetylcholine (R = -.83; P < .0009) but not A23187 or authentic NO. From these findings, we conclude that chronic inhibition of CuZnSOD inhibits EDNO-mediated arterial relaxation through two mechanisms, one being direct inactivation of NO and the other being lipid peroxidation that preferentially interrupts receptor-mediated stimulation of EDNO.

Ultrastructural and functional analyses of nephropathy in calmodulin-induced diabetic transgenic mice.

BACKGROUND: Previous animal models of diabetic nephropathy have used diabetic animals for which the underlying defect was either uncertain or the diabetes was induced by potentially specific toxins. In this report, we describe the renal abnormalities in a transgenic mouse model that develops early-onset diabetes due to overexpression of calmodulin in pancreatic beta cells. METHODS: Renal tissues were collected from normal and transgenic mice at 112, 182, and 300 days. These were prepared for light microscopic observation, stained with polyethylenimine (for anionic sites), or rendered acellular by detergent extraction prior to observation by transmission and scanning electron microscopy. Morphometric analysis of glomerular basement membrane thickness was carried out by the "orthogonal intercept" method. Twelve-hour urine samples of fed and fasting mice were collected for urine volume and glucose and protein analyses. Blood glucose, blood urea nitrogen, serum insulin, and creatinine were determined in 60-90-day-old and 255-day-old mice by established methods. RESULTS: Morphometric analyses revealed age-related and transgene-related increases in glomerular basement membrane thickness. A 22% increase in transgenic diabetics over controls was seen at 112 days of age that developed to increases of 43% and 37% at 182 and 300 days of age, respectively. Mesangial matrix area was also increased markedly in transgenic mice. Surprisingly, even in the oldest diabetic mice, there was no reduction in anionic sites. Moreover, despite an eightfold increase in urine volume, these mice did not become significantly proteinuric. CONCLUSIONS: These results indicate that proteinuria of diabetes may be delayed or prevented by maintenance of a normal complement of glomerular basement membrane anionic sites. They also demonstrate that transgenic mice can provide a valuable model for discriminating between different aspects of diabetic nephropathy.