Electrical remodeling is the term used to describe the electrophysiological changes occurring in chronic cardiac diseases associated with an increased tendency for atrial or ventricular arrhythmias. Changes reflecting remodeling in readily measured electrophysiologic characteristics (action potential duration, individual ionic currents) have been observed in large animal models with arrhythmias closely resembling those in humans. In the dog model of chronic complete AV block (CAVB), biventricular hypertrophy occurs along with substantial increases in action potential duration that render the animals prone to developing torsade de pointes during exposure to class III antiarrhythmic agents. Similarly in chronic atrial fibrillation (both human and various pacing-induced animal models), electrical remodeling of atrial myocytes produces a cellular substrate that perpetuates the arrhythmia (""""""""atrial fibrillation begets atrial fibrillation""""""""). Evidence points to long term changes in gene expression as an important element in the genesis of these arrhythmia prone states. However, our knowledge of the identity and temporal sequence of changes in gene expression underlying these two conditions is not comprehensive. We propose to use microarray technology to survey global patterns of gene transcription in dog hearts that occur following chronic AV block and with pacing-induced atrial fibrillation. This work has been made feasible by the prior development of a canine cDNA array in our laboratories at Vanderbilt University. Our canine microarray will enable us to examine changes in gene expression in hypertrophied ventricular myocardium of CAVB dogs and assess differences between subgroups of animals that exhibit susceptibility or resistance to drug-induced torsade de pointes. We will also be able to characterize the transcriptional remodeling in atrial myocardium associated with induction of atrial fibrillation in dogs subjected to rapid atrial pacing. Robust statistical analyses of microarray data will be used to direct appropriate validation experiments using separate methods. These studies will provide new insights into the pathogenesis of arrhythmia susceptibility and contribute to identifying potential new targets for therapeutic interventions. ? ?
