Denis M. Medeiros

A unified perspective on copper deficiency and cardiomyopathy.

Abstract Dietary copper restriction in rats results in cardiomyopathy. In rats fed copper-restricted diets from weaning for 5 to 8 weeks, a concentric hypertrophy is apparent, whereas postweaning copper restriction does produce cardiomyopathy without apparent hypertrophy. Both sets of circumstances appear to affect the integrity of the basal laminae of cardiac myocytes and capillaries. In rats fed copper-restricted diets from weaning, decreases in cytochrome c oxidase are related not only to coppers role as a coenzyme, but also to a marked decrease in the nuclear encoded subunits of the enzyme complex. Decreased levels of the δ-subunit of ATP synthase have been observed. However, such aberrations in mitochondrial enzymes, as well as morphologic alterations, apparently do not affect cardiac levels of ATP. This review suggests mechanisms of cardiac adaptation and initiation factors leading to cardiac hypertrophy. We present a hypothetical working model explaining the events leading to cardiac failure in the copper-deficient rat heart based on the present body of knowledge, and compare the pathology with other models of cardiomyopathies.

Femurs from rats fed diets deficient in copper or iron have decreased mechanical strength and altered mineral composition

A study was conducted to evaluate the influence of copper and iron deficiencies upon femur mineral content and biomechanical properties. Radiogrametry and single photon absorptiometry were used to evaluate femur bone mass. Long-Evans male rats were fed purified diets either adequate or deficient in the selected element from weanling until 9 weeks of age. Results demonstrate that in rats fed both the copper and iron restricted diets, the breaking strength was significantly decreased in both femurs. Lower levels of iron and copper were observed in the livers of the respected trace element restricted groups, and femur iron and copper were depressed in both of these groups as well. Femur Cu:Zn was decreased in the copper deficient group and femur zinc levels were elevated in the iron deficient group. Copper and iron restricted rats had smaller cortical and, larger medullary area in a portion of the femur, 1/4 from the distal end, as determined by radiogrametry, but there were no differences at the mid point or proximal portions of the femurs. The influence of iron restriction upon the decreased bone biomechanical strength is a novel finding and deserves further attention, in that iron deficiency anemia is a prevalent public health problem. J. Trace Elem. Exp. Med. 10:197–203, 1997.

Marginal copper-restricted diets produce altered cardiac ultrastructure in the rat.

Abstract To determine if chronic ingestion of a diet containing a marginally low level of Cu could cause deleterious alterations in cardiac ultrastructure, male offspring were nursed by dams fed a diet containing either 6.7 or 2.8 mg Cu/kg from midgestation through lactation before weaning to the same diet. Conventional measures of Cu status, including growth, relative heart weight, tissue concentrations of Cu, ceruloplasmin activity, and tissue activity of Cu, Zn-superoxide dismutase (SOD) were similar in both dietary treatment groups at 5.5 months of age. However, significant increases in the number and volume of lipid droplets and an increased incidence of pathological abnormalities in mitochondria and basal laminae were observed in sections of hearts from rats chronically fed the diet containing 2.8 mg/kg Cu. Reduction of the dietary level of Cu from 2.8 to 1.3 mg/kg from 4 to 5.5 months of age caused significant reductions in the concentration of Cu in serum and liver, but Cu content, Cu, Zn-SOD activity, pathological scores, and morphometric parameters in hearts were not modified by the greater restriction of dietary Cu in adult rats. This study suggests that abnormalities in cardiac ultrastructure occurred in rats chronically fed diets marginally low in Cu, despite minimal changes in conventional biochemical indicators of Cu status.

Cardiac nuclear encoded cytochrome c oxidase subunits are decreased with copper restriction but not iron restriction: gene expression, protein synthesis and heat shock protein aspects.

Hearts from rats fed a copper-deficient (Cu-) diet have decreased levels of nuclear-encoded peptides of cytochrome c oxidase (CCO). Studies were conducted to determine whether iron deficiency would lead to a similar finding, whether mRNA transcripts and the chaperonin heat shock proteins (HSP) 60 and 70 from hearts of Cu- rats were decreased as compared with copper-adequate controls and whether synthesis of mitochondrial and nuclear encoded peptides differed as affected by diet copper. In study 1, weanling rats were assigned to one of three groups (n = 6 in each group): (1) control copper and iron adequate fed rats; (2) Cu- rats and (3) iron-deficient (Fe-) rats. Western blotting of nonmyofibrillar cardiac proteins revealed that the nuclear encoded peptides of CCO from the Cu- rats were markedly decreased as compared with control and Fe- rats. Mitochondrial encoded subunits did not appear to differ by treatment groups. Iron-deficient rats had similar nuclear encoded peptide levels as those of controls. In study 2, mRNA transcripts from Cu- (n = 4) and control copper adequate (n = 4) rats did not appear to differ for subunits II and IV, which correspond to mitochondrial and nuclear encoded subunits, respectively. In study 3, levels of HSP 60 and 70 from hearts of Cu- rats (n = 3) did not differ from Cu+ rats (n = 3). In study 4, infusion of 3H-(4,5)-leucine into the hearts of Cu+ and Cu- rats suggested there was no difference in synthesis of the nuclear encoded peptides by copper status and some indication there was enhanced breakdown of the nuclear encoded peptides among the Cu- rats. As expected, more isotope was incorporated into the mitochondria of Cu- rats than Cu+ rats. These results demonstrate an independent effect of copper upon the apparent decrease in the nuclear encoded subunits of CCO, the effect of copper upon the CCO subunits is probably post-transcriptional and that translocation of the nuclear encoded subunits from the ribosomes to the mitochondria via the chaperonin proteins is not a primary defect in explaining these observations in hearts from Cu- rats and synthesis of the nuclear encoded subunits of CCO in not impaired in copper deficiency.

Dietary iron deficiency results in cardiac eccentric hypertrophy in rats.

Abstract This study reports the presence of eccentric cardiac hypertrophy in rats made anemic by feeding an iron-deficient diet. Male weanling Sprague-Dawley rats were provided free access to diets either adequate (n = 9) or inadequate in iron (n = 8) for a period of 7 weeks from weanling or until 10 weeks of age. At that time, blood was obtained for hematocrit and hemoglobin determination, and liver and hearts were collected for further analysis. Liver non-heme iron levels confirmed that the rats were iron-deficient, and the very low hematocrit and hemoglobin values revealed the presence of physiological anemia. Despite the lighter body weights in the iron-deficient rats, this group had greater absolute heart weights and heart:body weight, clearly demonstrating the presence of cardiac hypertrophy. Iron-deficient rats had elevated heart rates but lower norepinephrine levels than control rats. Sagittal sectioning of all hearts allowed for the measurements of the wall thicknesses, lumen volume, and width dimensions. Results revealed significantly greater left ventricular lesser diameter, apical thickness, and left ventricular volume in hearts from iron-deficient rats compared to iron-adequate rats. The hypertrophy pattern present in iron-deficiency anemia is in contrast to other nutritional models of hypertrophy, such as copper-deficiency, where a concentric hypertrophy occurs both in the presence and absence of anemia.

Cardiac nucleotide levels and mitochondrial respiration in copper-deficient rats

1. Male weanling Long-Evans rats were randomly assigned to either copper-adequate (6.0 mg Cu/kg feed) or copper-deficient (< 1.0 mg Cu/kg feed) diets for a 5 week period. 2. Cardiac ATP levels and energy charges did not differ between the two groups. Levels of NAD and phosphocreatine as well as the sum of pyridine nucleotides were greater in copper-deficient rats compared with copper-adequate rats using HPLC analysis. 3. Mitochondrial respiratory control ratios and oxygen consumption rates from copper-deficient rat hearts were depressed, although ADP:O ratios were similar to copper-adequate rat hearts.

Cardiac nonmyofibrillar proteins in copper-deficient rats

Cardiac nonmyofibrillar proteins from copper-deficient rats appear to have diminished quantity of selected peptides. Identification of some of these peptides was the objective of the present study. Male weanling Long-Evans rats were fed either copper-adequate (n=6) or copper-deficient (n=6) diets for 5 wk. At the end of 5 wk, the rat hearts were removed, quick frozen in liquid nitrogen, and non-myofibrillar proteins separated using sodium-dodecyl-sulfate poly-acrylamide gel electrophoresis (SDS-PAGE). A peptide in the 16-kDa mol-wt region was diminished in copper-deficient rats. Blotting of gels to an Immobilon-P membrane and subsequent sequencing of the amino acids identified the peptide as the δ subunit of mitochondrial ATP synthase. Blotting of gels to nitrocellulose followed by Western blot assay for cytochrome C oxidase using antibodies against the enzyme complex revealed decreased protein content in the copper-deficient rat for this enzyme, primarily the nuclear encoded subunits.

Decreased high density lipoprotein cholesterol and apoprotein A-I in plasma and ultrastructural pathology in cardiac muscle of young pigs fed a diet high in zinc

Abstract People who supplement their diets with extra zinc usually have potentially harmful changes in lipoprotein metabolism. Because zinc can interfere with copper metabolism and copper deficiency has produced similar changes in lipid metabolism in animals and people, the hypothesis that lipid alterations from high zinc intakes are accompanied by changes in copper metabolism was tested. Progenies of swine fed a high zinc (5000 mg/kg diet) or normal zinc (150 mg/kg diet) diet during pregnancy and lactation were weaned to practical diets of natural products containing similar amounts of zinc. Concentrations of apoprotein A-I (p

Comparative aspects of cardiac ultrastructure, morphometry, and electrocardiography of hearts from rats fed restricted dietary copper and selenium.

Comparative cardiac ultrastructure, morphometry, and electrocardiography after dietary copper and selenium restriction were examined. Male weanling Long-Evans rats were fed diets that were either adequate in both copper and selenium (Cu+/Se+) or restricted in either Cu (Cu−) or Se (Se−) for 8 wk. At wk 8, electrocardiograms (ECG) anddP/dts were obtained and heart tissue was utilized for electron microscopy. Upon examination, Cu− rats were anemic, exhibited a greater heart: body weight ratio, and developed concentric hypertrophy characterized by an enhanced thickening of the left and right ventricular free walls, and interventricular septum. ECG recordings from lead aVF in the Cu− group showed a greater R wave amplitude in comparison to the Cu+/Se+ group. Se− rats recorded a greater left ventricular +dP/dtmax than both the Cu+/Se+ and Cu− groups.Cardiac myofibril volume densities were decreased in both Cu− and Se− rats in comparison to the Cu+/Se+ rats. In addition Cu− rats showed a greater mitochondria: myofibril ratio. Sarcomere contractile protein disarray was present in both the Cu− and Se− groups. Se− myocytes also showed evidence of edema and mitochondrial fragmentation. The subcellular alterations suggest that similarities exist in the cardiac remodeling processes associated with copper and selenium restrictions.

Reported Adoption of Dietary Fat and Finer Recommendations Among Consumers

OBJECTIVEnTo identify constraints in adopting dietary fat and fiber recommendations.nnnDESIGNnA questionnaire was mailed to a sample of the general population, a convenience sample of persons with heart disease and cancer in 11 states, and registered dietitians in 5 states. The survey included questions on demographic and attitudinal factors that were correlated with specific practices to reduce fat intake and increase fiber intake.nnnSETTINGnFrom the general population sample of 6,206 eligible respondents (return rate of 51.5%), those selected were respondents who indicated that they would adopt a dietary recommendation if it were good for them (n = 2,682). Subsamples from the general population were matched to 362 registered dietitians and 147 persons with cancer or heart disease on selected demographic variables. Factors associated with adoption of specific behaviors were identified.nnnSTATISTICAL ANALYSIS PERFORMEDnStatistical analysis included chi 2, factor analysis, and analysis of variance.nnnRESULTSnThe majority of persons who said they would adopt a fat-reducing behavior if it were good for their health reported practicing that behavior often or usually. More than 60% reported consuming whole grains; however, only 15% reported eating fruits and vegetables frequently. Among the general population sample, those more likely to practice a behavior had the following characteristics: female, college educated, older than 60 years, white, higher income, no children younger than 18 years, perceived health status as excellent, and absence of chronic disease. Registered dietitians and those with chronic disease were also more likely to follow dietary fat and fiber recommendations.nnnAPPLICATIONSnNutrition education messages that lead to increased consumption of dietary fiber need to be developed. Nutrition educators should provide strategies for consumers for increasing use of fruits and vegetables in all meals. Good taste and convenience are critical components. The food industry may assist by providing a wider array of convenience entrees or side dishes that feature produce and whole grains.