MOLECULAR MECHANISMS OF VENTRICULAR TACHYCARDIA

点击翻译按钮获取中文摘要

DESCRIPTION (adapted from the applicant's abstract): Idiopathic ventricular tachycardia (VT) is a generic term that describes various forms of VT that occur in patients without structural heart disease, metabolic or electrolyte abnormalities, or in the absence of the long QT syndrome. Through the application of electrophysiologic techniques and pharmacological probes, several distinct mechanistic entities have been identified in the last decade. Two forms of VT, paroxysmal exercise-induced VT and repetitive monomorphic VT, typically originate from the right ventricular outflow tract (RVOT) and present with a left bundle branch block (LBBB) inferior axis morphology. These tachycardias are mediated by intracellular calcium overload and terminate with b-blockers, verapamil, vagal maneuvers and adenosine, and are thought to be due to cAMP-mediated triggered activity. The applicant hypothesizes that a molecular defect in the G protein coupled-b-adrenergic receptor signaling pathway might result in constitutive elevation of intracellular cAMP and VT due to triggered activity. Such a defect could arise from a somatic mutation present at the site of origin of VT. Somatic cell mutations in G proteins that elevate intracellular cAMP levels have been described in a number of endocrine tumors. Since myocardial cells do not divide after cardiogenesis is complete, this would necessitate that the mutation occur in utero. The proposed studies test the hypothesis that certain forms of ventricular tachycardia arise from somatic cell mutations which abnormally stimulate cAMP generation in cardiac tissues. Specific Aims of this proposal are: (1) To identify mutations in genes encoding G proteins and other components of cAMP-dependent signal transduction pathways that might cause or facilitate VT; (2) To determine the cellular localization of new mutations that might be identified; (3) To test the effects of mutations which may be identified in (1) for their effects on cAMP accumulation by transfection of cells in culture; and (4) To develop an animal model for VT by locally expressing mutant genes which we would predict to confer an arrhythmogenic phenotype.