The relationships among key features of cardiac electrical activity, such as electrical restitution, discordant alternans, wave break and reentry, and the onset of certain types of ventricular tachycardia and fibrillation have been characterized extensively under the condition of constant pacing. However, it is unlikely that the case of constant, rapid pacing applies directly to the clinical situation, where the induction of ventricular tachyarrhythmias is typically associated with the interruption of normal cardiac rhythm by a few premature beats. We therefore propose to investigate the effects of small numbers of premature stimuli as they relate to the development of tachyarrhythmias. We focus specifically on how and under what circumstances they create dynamic heterogeneity and conduction block, and how these phenomena interact with intrinsic heterogeneity and the anatomical structure of the heart to promote or discourage the development of reentry, ventricular tachycardia and fibrillation. Specifically, we propose to: 1) conduct computational and actual experiments to determine whether the mechanisms predicted by a new theoretical model to cause initiation of VT and/or VF actually occur; 2) investigate how and to what extent the spatial heterogeneity of ion channel properties and the heterogeneity of refractoriness secondary to key features of ventricular anatomy interact with dynamical heterogeneity to facilitate the onset of VT/VF; 3) analyze human electrophysiology study data and ICD and pacemaker stored data to check for consistency with our theory; 4) explore strategies for preventing tachyarrhythmias that will be potentially useful in future ICD and pacemaker pacing algorithms. A combination of optical mapping and in vivo experiments, computer modeling and dynamical theory will be used to conduct the research. An understanding of these mechanisms will help to identify key electrical phenomena in the onset of ventricular tachycardia and fibrillation. Drug and electrical therapies can then be improved by targeting these specific phenomena. PUBLIC HEALTH RELEVANCE: A small number of abnormal beats is often responsible for the induction of ventricular fibrillation (VF), a frequently lethal heart rhythm. This study evaluates a promising new theory that predicts which combinations of the abnormal beats leave the heart tissue vulnerable to the development of this deadly disorder and when these combinations are likely to exist. The study thus could lead to new electrophysiological protocols to establish risk for VF, to drug therapies to prevent VF, and to improved implantable devices that are cognizant of heartbeat sequences predicted to induce VF.