The goal of this research project is to test the Restitution Hypothesis of ventricular fibrillation (VF). The Restitution Hypothesis proposes that both action potential duration restitution and conduction velocity restitution (i.e., their dependence on the previous diastolic interval) are critically important in the generation and maintenance of VF and that targeting cardiac restitution can lead to effective antifibrillatory therapy. The investigators propose that both dynamic and fixed factors modulate cardiac vulnerability to fibrillation. The dynamic factor refers to the recovery kinetics of cellular ionic currents from previous activations (restitution properties). In contrast, fixed factors refer to intrinsic heterogeneities in cardiac tissues. These include """"""""built-in"""""""" anatomic non-uniformity and regional electrophysiological variations in active (action potential-related) and passive (diffusive) membrane properties in normal or diseased hearts. The investigators plan to use cardiac optical mapping, computerized electrode mapping, standard glass microelectrode recording techniques and histopathological analyses of cardiac anatomy to study the importance of these factors in the development of wavebreak and VF. Specific objectives are: 1) Do wavelength oscillations result in wavebreak? The investigators will perform studies in the normal swine right ventricle to measure restitution properties and to determine whether or not wavelength oscillations precede wavebreak. 2) Do antifibrillatory interventions based on altering restitution properties suppress wavelength oscillations and prevent wavebreak in the normal ventricle? The investigators will use bretylium, verapamil and diacetyl monoxime (DAM) to reduce the slope of the restitution curve of normal ventricles in situ and in vitro. These experiments will be used to determine if flattening restitution prevents wavebreak in normal ventricles despite the presence of anatomic complexities. 3) How does increased structural heterogeneity in the setting of cardiac disease influence restitutions's role in wavebreak during the transition from ventricular tachycardia (VT) to VF? The investigators will evaluate the importance of restitution versus fixed heterogeneity, as a cause of wavebreak in three different models: dogs with healed myocardial infarction, dogs with pacing-induced heart failure and human cardiomyopathic hearts explanted during transplant surgery. 4) Are restitution-based antifibrillatory interventions effective at preventing wavebreak, which maintains VF in diseased hearts? The investigators will determine whether or not flattening of APD restitution by bretylium, verapamil and DAM prevents wavebreak and VF despite increased structural heterogeneity of the diseased ventricles in three models. These studies will promote a better understanding of the pathogenesis of VF and may provide breakthrough advances in antifibrillatory therapy and in the prevention of sudden cardiac death.
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| Chen, Peng-Sheng; Tan, Alex Y (2007) Autonomic nerve activity and atrial fibrillation. Heart Rhythm 4:S61-4 |
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