It is well documented that membrane excitability and excitation-contraction coupling are altered in the hypertrophied heart and that ventricular hypertrophy is a risk factor for the development of arrhythmias. Considerable evidence has accumulated to suggest that """"""""electrical remodeling"""""""" occurs in the hypertrophied heart and that this reflects, at least in part, changes in the expression/properties of repolarizing, voltage-gated K+ currents. The experiments proposed here will test this hypothesis directly in a mouse model of pressure overload-induced left ventricular hypertrophy. The functional consequences of hypertrophy on the properties and distributions of ventricular voltage-gated K+ channels will be determined, and experiments focused on exploring the molecular mechanisms underlying """"""""electrical remodeling"""""""" of voltage-gated K+ channels in these cells will be completed. In addition, transgenic and targeted deletion strategies will be exploited to test the specific hypotheses that there are two, molecularly distinct, components of (mouse ventricular) IK,slow and that alpha subunits of the Kv 3 subunits underlie (mouse ventricular) Iss. A sophisticated combination of electrophysiological, biochemical, molecular genetic, immunohistochemical and imaging techniques will be exploited in mice to achieve the stated aims of this proposal. We anticipate that the studies outlined here will provide fundamentally important new insights into the effects of pressure overload-induced left ventricular hypertrophy on repolarizing voltage-gated K+ channels, as well as into the molecular mechanisms underlying """"""""electrical remodeling"""""""" in the hypertrophied heart. In the long term, these insights should translate into more effective treatment strategies to reduce the risk of sudden death and the mortality and morbidity associated with myocardial hypertrophy and failure.
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