The long term objective of this SCOR application is to investigate the arrhythmogenic mechanisms responsible for sudden cardiac death in patients with coronary heart disease and ventricular hypertrophy. These two disorders are responsible for the vast majority of the 300,000 sudden cardiac deaths annually in the US. The unifying theme through all of the studies is that structural abnormalities of the myocardium that affect cell-to-cell communication lead to electrophysiological disturbances responsible for cardiac arrhythmias. Some of these abnormalities, once identified, can be corrected or modified, with elimination or reduction in the frequency of cardiac arrhythmias. Further, recognition of these abnormalities in animal models will lead to increased specificity and sensitivity in identifying patients at risk for sudden cardiac death and to new therapeutic interventions. Through interactive and collaborative studies, we will pursue the following four major hypotheses: 1) myocardial remodeling alters the number, distribution or function of several important cardiac structures, including gap junctions and autonomic innervation patterns, that are directly and indirectly responsible for normal cell-to-cell communication; 2) these alterations in gap junctions and innervation patterns are different in the various cardiomyopathies and produce different electrophysiological patterns that result in ventricular arrhythmias of different mechanisms; 3) correction of these abnormalities with genetically-engineered cells will restore the electrophysiology toward normal patterns and help prevent the development of ventricular arrhythmias; and 4) establishing the patterns of abnormalities in innervation and cell-to-cell communication in the animal models will provide insight into identifying and treating patients at risk for sudden cardiac death. Six projects and 2 cores have been assembled to address these objectives. Project 1 (Pressler) identifies and attempts to repair abnormalities in gap junctions; Project 2 (Warner) identifies and attempts to repair alterations in autonomic innervation and electrophysiology; Project 3 (Field) uses intracardiac grafting techniques in an effort to effect myocardial regeneration and long term delivery of cardioprotective compounds to repair or correct the underlying abnormalities; Project 4 (Hutchins) bridges the animal and clinical projects by providing noninvasive imaging patterns of sympathetic and muscarinic innervation as well as general myocardial function; Project 5 (Mulholland) develops new PET tracers to study abnormalities of the myocardium and innervation; and Project 6 (Zipes) interacts with all projects and investigates the autonomic and electrophysiologic patterns in a patients with coronary disease and ventricular hypertrophy. The cores include a histopathology core (Pressler) that will provide tissue histology resources, and an administration core (Zipes) responsible for the day-to-day operation of the SCOR. This SCOR application combines the methodologies of molecular biology and protein biochemistry with in vitro and in vivo animal electrophysiology studies in order to explore and understand the causes and mechanisms of arrhythmias responsible for sudden cardiac death in patients.
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