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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