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Copper deficiency results in alterations in lipid metabolism that include elevations in serum cholesterol and triglycerides and a decrease in whole-body respiratory quotient. Copper-deficient animals are also leaner even though electron micrographs of the myocardium present increased lipid droplet accumulation. To address whether a compromised copper status impacts triglyceride deposition in a tissue-specific manner, the activity of lipoprotein lipase was measured in adipose tissue and cardiac and skeletal muscle. Weanling rats fed a copper-restricted diet (<1 ppm) for 6 wk demonstrated a greater than twofold increase in cardiac lipoprotein lipase activity concomitant with a significant reduction in adipose tissue lipoprotein lipase activity. Skeletal muscle lipoprotein lipase activity was not altered by the copper-deficient state. The results of this study suggest that copper deficiency may induce a tissue-specific alteration in lipoprotein lipase activity in rats, which may contribute to the notable deposition of lipid substance in myocardium and the concomitant general body leanness.

The cuproenzymes lysyl oxidase, cytochrome-c oxidase, and superoxide dismutase are key factors in understanding the cardiac hypertrophy and cardiomyopathy associated with dietary copper restriction. The role of copper in cardiac lipid and energy metabolism as a consequence of changes in some of these enzyme activities in comparison with what is known about normal cardiac substrate utilization is discussed here. While the decrease in the nuclear encoded subunits of cytochrome-c oxidase in hearts from copper-deficient rats is known, new evidence suggests that other factors, such as ATP synthase metabolism may be exerting an influence upon this observation. While this review focuses on newer knowledge about energy and fatty acid metabolism in copper deficiency, the extracellular matrix is considered as well. This complex interplay of extracellular and cellular events in copper restriction is outlined as a model for further studies of this unique model of concentric hypertrophy.

Pigs were made copper (Cu)-deficient to evaluate cardiac function and pathology, and electrocardiography. Fifteen-day-old pigs were fed a Cu-restricted diet over an 8 wk period and compared to Cu-adequate diet-fed pigs. Cardiac effects were examined concerning gross morphometry and ultrastructure, echocardiography, and electrocardiography, as well as serum cholesterol levels. The Cu-restricted diet-fed pigs exhibited a marked deceleration of growth and lower hematocrit, hemoglobin, and liver and serum Cu concentrations compared to the Cu-adequate diet-fed pigs. The Cu-restricted diet-fed pigs developed a significantly greater heart weight:body weight ratio, along with greater diastolic measures of ventricular wall and internal dimension relative to body weight. Electrocardiography in the Cu-restricted diet-fed pigs revealed one instance of electrical alternans and an intraventricular conduction disturbance and several instances of T-wave inversion. The Cu-restricted pigs also displayed a prolonged QT interval at the closure of study. Increased mitochondrial volume density and mitochondria:myofibril volume density ratio were observed in the Cu-restricted pig electron micrographs along with excessive lipid and glycogen inclusion and focal degradation of Z-lines, intercalated disk, and sarcomeres. Copper-restriction in young pigs results in cardiac pathology and electrical disturbances. These alterations are similar to those reported for young Cu-restricted rodents. Given then that many cardiac manifestations of developed Cu-deficiency appear conserved across specie lines, the potential for human disturbances in response to severe Cu-deficiency may be plausible.

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.

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) and dP/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.