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Nutrient Metabolism

Regression of Dietary Copper Restriction-Induced Cardiomyopathy by Copper Repletion in Mice¹

Laila Elsherif^*, Lipeng Wang^*, Jack T. Saari and Y. James Kang^*,**,2

^* Departments of Pharmacology and Toxicology and ^** Medicine, University of Louisville School of Medicine, Louisville, KY 40202 and U.S. Department of Agriculture Human Nutrition Research Center Grand Forks, ND 58202

²To whom correspondence should be addressed. E-mail: yjkang01{at}louisville.edu.

Dietary copper deficiency (CuD)³ leads to cardiac hypertrophy in various animal models. We showed recently that heart failure develops after hypertrophy in FVB mice fed a CuD diet. The present study was undertaken to determine whether CuD-induced cardiac failure is reversible upon copper repletion (CuR). Dams of FVB mice were fed a CuD diet (0.3 mg/kg) starting from d 3 postdelivery; the weanling pups were fed the same diet until CuR with 6.0 mg/kg Cu in the diet at 4 or 5 wk of age. CuR at 4 wk of age prevented the body weight loss; at 5 wk of age, it resulted in the regaining of the lost weight caused by CuD. A significant regression of CuD-induced cardiac hypertrophy was observed in the CuR mice. Histopathological examination revealed that CuR eliminated CuD-caused lipid deposition in the myocardium, and electron microscopy demonstrated that CuD-induced ultrastructural changes such as mitochondrial swelling and organelle structural disarray were all reversed in the CuR mice. Hemodynamic analysis showed that the CuD-depressed systolic and diastolic parameters such as the maximal rate of left ventricular pressure rise (+dP/dt) and decline (-dP/dt), and the contraction and relaxation times were completely recovered in the CuR mice. Furthermore, the CuD-blunted myocardial responses to the ß-adrenergic agonist, isoproterenol, were also restored in the CuR mice. This study thus demonstrates for the first time that CuR results in the regression of heart failure induced by CuD as demonstrated by the reversal of depressed cardiac hemodynamic and contractile function and the restored responsiveness to ß-adrenergic stimulation.

KEY WORDS: • cardiomyopathy • cardiac function • copper deficiency • copper repletion • heart hypertrophy

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