Life-threatening arrhythmias have complex and multifactorial pathophysiologies, among which are structural predisposing influences, acute risk factors that trigger fatal arrhythmias, and individual susceptibility based on genetic determinants.
The specific aims of this proposal are to use an experimental model of healed myocardial infarction (HMI) in cats to provide understanding of: (1) the mechanisms by which chronic ischemic heart disease predisposes to life-threatening arrhythmias; (2) the electrophysiology of transient triggering factors; and (3) individual animal susceptibility to arrhythmic responses. Three hypotheses will be tested: (1) regional hypertrophy in hearts with HMI regulates electrophysiology by altering regional ion channel function in ways similar to changes caused by global hypertrophy; (2) local changes in ion channel function in areas of regional hypertrophy cause susceptibility to the generation of afterdepolarizations and triggered activity, and predispose to reentry by dispersion of refractoriness; and (3) paired studies of ion channel currents in myocytes and T-lymphocytes will demonstrate homologous characteristics and responses to interventions. The latter will allow the use of the T-lymphocyte as a surrogate for myocytes for screening individual animals for responses to acute triggers. Conventional patch-clamp techniques will be used to study four membrane currents (ICa,L, IK, Ito, I K-ATP) in myocytes and IK -like and Ito -like currents in T-lymphocytes. After determining baseline regional characteristics in HMI, including epicardial and endocardial differences, the effect of transient triggering influences, such as ischemia/reperfusion and proarrhythmic substances on ion channels will be determined. In parallel, the comparative responses of paired myocytes and lymphocytes from the same animals will be established. The goals of this work are to define the mechanisms by which regional hypertrophy in HMI contributes to electrophysiologic heterogeneity and the potential for generating arrhythmias, and the development of a method for screening specific individual animal responses to arrhythmogenic triggering factors using circulating T-lymphocytes.
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