The general aims of the study are to test the hypothesis that the pathophysiologic changes that occur in furazolidone-induced dilated cardiomyopathy in turkey poults and dilated cardiomyopathy in man are caused by abnormal intracellular Ca++ handling and to determine the subcellular effects of preventative and therapeutic interventions on intracellular electrophysiology and intracellular Ca++ handling. Furazolidone-induced cardiomyopathy is an inexpensive model of dilated congestive cardiomyopathy which rapidly produces a high yield of uniformly affected individuals. This well-characterized model of dilated cardiomyopathy possesses structural and functional similarities to human diseases. A large amount of indirect information has accumulated to suggest that intracellular Ca++ handling is abnormal in cardiomyopathies of various etiologies; the Ca++ indicator aequorin will be used to determine how changes in intracellular Ca++ handling are related to the progressive histopathological, mechanical, and electrical changes that occur in this model of cardiomyopathy. Left ventricular papillary muscles or trabeculae carneae from control and furazolidone-treated turkey poults will be chemically loaded with aequorin, a bioluminescent indicator that emits light when it combines with calcium. Isometric tension development and the aequorin light signal (a measure of the intracellular Ca++ transient) will be simultaneously recorded. Three groups of turkey poults will be studied: 1) controls, 2) furazolidone-treated, and 3) furazolidone plus preventative of therapeutic drug treated. Action potentials will be recorded using a floating electrode technique. The amplitude and duration of the action potential will be used to monitor changes in the electrical properties of cells which will be correlated with the light and tension responses. Human working myocardium from patients with dilated cardiomyopathy and endstage heart failure undergoing cardiac transplantation will also be studied. By directly recording Ca++ transients in actively contracting myopathic cardiac fibers, it will be possible to address the functional significance of abnormalities in intracellular Ca++ handling that have been reported by other investigators. In addition, these studies will provide new information of potential clinical relevance regarding the effects of prophylactic and therapeutic interventions on myopathic muscle.
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