The general purpose of this study is to determine the etiology of the contractile dysfunction that develops with hypertrophy and failure of mammalian working myocardium and to use this knowledge as a rational basis for designing specific therapeutic and preventative interventions. We plan to test the hypothesis that different stimuli to hypertrophy produce distinct alterations in cardiac excitation-contraction coupling and intracellular Ca++ handling. Experiments will be performed using isolated papillary muscles from ferret models of right ventricular hypertrophy and/or failure induced by pressure-overload, volume-overload or thyroxine treatment. Recordings will be made of the mechanical and electrical activity, and intracellular Ca++ levels and transients in muscles from hypertrophied animals and their age- matched controls. Particular attention will be directed towards identifying mechanical and electrical abnormalities that correlate with a) alterations in cytoplasmic Ca++ handling, b) changes in the Ca++ sensitivity of the contractile apparatus, c) cellular and extracellular structural changes, and d) abnormalities in energy utilization and supply. We will evaluate the functional significance of the changes that we identify by comparing the systolic and diastolic responses of control vs. hypertrophied muscles to common physiologic and pathophysiologic conditions including tachycardia, stretch and hypoxia. We will determine whether the development of acute or chronic failure in our hypertrophied models occurs due to an exacerbation of hypertrophy-induced cellular and extracellular abnormalities or if additional pathophysiologic mechanisms are involved. Particular attention will be given to evaluating whether the level of systolic and/or diastolic dysfunction can be directly correlated with the degree of hypertrophy that is present. We will use interventions with known subcellular actions to determine the etiology of the abnormalities identified in hypertrophied and failing muscle. Particular attention will be given to identifying agents that correct or prevent inotropic and/or lusitropic dysfunction and that may have clinical utility in the management of patients with hypertrophy and cardiac dysfunction. These studies should increase our understanding of the functional significance of the subcellular changes that occur with three major etiologies of hypertrophy, and help to further define the role of Ca++ in the development of the hypertrophic response.
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