Keshan disease is a cardiomyopathy which occurs in selenium (Se)-deficient humans. Studies in China, where the only severely Se-deficient populations are known, have demonstrated that Se supplementation can eradicate Keshan disease. A factor besides Se-deficiency is involved in the pathogenesis of Keshan disease because not all Se-deficient people develop it. We postulate that oxidant stress from infections and/or drugs is the additional factor. Se, acting through the selenoenzyme glutathione peroxidase, is a major oxidant defense; and studies in animals have demonstrated that Se deficiency predisposes them to injury from oxidant stresses of several types. Human and animal studies are proposed to test this hypothesis. The human studies would be conducted in China where Se-deficient subjects are available. Plasma levels of hydroperoxides and malonaldehyde and breath ethane will be measured as indices of oxidant injury. Healthy Se-deficient and control subjects will be studied before, during, and after 2 weeks of Se supplementation to seek evidence that Se deficiency is associated with oxidant injury. S-deficient and control subjects with infections will be studied while ill and after recovery to determine if the oxidant stress of infection causes more oxidant injury in Se-deficient subjects than in controls. These studies should indicate whether oxidant injury is worsened by Se deficiency in humans. Animal studies are required to assess the association of cardiac injury with oxidant stress. Pigs will be used because they develop a cardiomyopathy when they become Se and vitamin E deficient. Pigs will be fed a diet severely deficient in Se but containing adequate vitamin E to prevent the spontaneous cardiomyopathy. The Se-deficient pigs and control pigs will be subjected to oxidant stresses. Chronic oxidant stress in the form of daily administration of oxidant drugs and acute oxidant stress in the form of hydroperoxide infusion will be tested. The oxidant stress indices will be measured and cardiac function (echocardiography) and pathology will be determined. Attempts will be made to correlate cardiac injury with oxidant stress and to assess the effect of Se deficiency. These studies are designed to examine oxidant stress in the heart in Se deficiency. They should, however, also give some indication of its effects in Se-replete subjects and this may shed light on infection-associated cardiac dysfunction.

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National Heart, Lung, and Blood Institute (NHLBI)
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Nutrition Study Section (NTN)
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University of Texas Health Science Center San Antonio
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Hill, K E; Burk, R F (1997) Selenoprotein P: recent studies in rats and in humans. Biomed Environ Sci 10:198-208
Hill, K E; Xia, Y; Akesson, B et al. (1996) Selenoprotein P concentration in plasma is an index of selenium status in selenium-deficient and selenium-supplemented Chinese subjects. J Nutr 126:138-45
Burk, R F (1993) Clinical effects of selenium deficiency. Prog Clin Biol Res 380:181-90
Hill, K E; Lloyd, R S; Burk, R F (1993) Conserved nucleotide sequences in the open reading frame and 3' untranslated region of selenoprotein P mRNA. Proc Natl Acad Sci U S A 90:537-41
Burk, R F; Hill, K E (1993) Regulation of selenoproteins. Annu Rev Nutr 13:65-81
Kato, T; Read, R; Rozga, J et al. (1992) Evidence for intestinal release of absorbed selenium in a form with high hepatic extraction. Am J Physiol 262:G854-8
Burk, R F (1991) Molecular biology of selenium with implications for its metabolism. FASEB J 5:2274-9
Burk, R F; Hill, K E (1990) Use of perfused organs in measurement of drug-induced oxidant stress. Methods Enzymol 186:759-66
Burk, R F (1989) Recent developments in trace element metabolism and function: newer roles of selenium in nutrition. J Nutr 119:1051-4
Xia, Y M; Hill, K E; Burk, R F (1989) Biochemical studies of a selenium-deficient population in China: measurement of selenium, glutathione peroxidase and other oxidant defense indices in blood. J Nutr 119:1318-26

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