Sudden cardiac death is the leading cause of death in America. Electrical defibrillation (DF) is an effective, and widely executed, cure for the major cause of sudden cardiac death, ventricular fibrillation. Yet, despite many years of intense research, the mechanisms of electrical defibrillation are still poorly understood. The long-term goal of this research is to further our understanding of the mechanisms of defibrillation, and to improve the clinical practice of electrical defibrillation. More specifically, this proposal is for a preliminary investigation into the mechanisms of a newly discovered phenomena, the rapidly paced upper limit of vulnerability (ULV/RAP). A stimulus delivered in the T-wave (or electrical recovery phase) of a normal cardiac cycle can induce ventricular fibrillation (VF). However, there is an upper limit to the stimulus strength that will induce VF. In other words, where a weak stimulus will induce VF when delivered in the T-wave, a strong stimulus may leave the subject in normal sinus rhythm. On the other hand, if that same strong stimulus is given after a brief period of rapid pacing to the point of hemodynamic compromise, the T-wave stimulus may again induce fibrillation. The sudden induction of VF by a formerly benign stimulus is the ULV/RAP phenomena. Three hypotheses for the proarrhythmic effect of the rapid pacing are presented here: (H1) the hemodynamic compromise is associated with geometric or mechanical changes in the heart, causing a change in the electric field of the stimulus, (H2) the rapid pacing makes the cells activate at a rate which forces changes in the cellular dynamics, or (H3) the hemodynamic compromise causes ischemic effects (such as hypoxia) which are proarrhythmic. The first specific aim of this proposal is to develop a simplied (reduced T-wave scanning) ULV/RAP measurement sequence, which would facilitate the second specific aim, and could present a safer substitute for current intraoperative DF testing. The second specific aim is to determine which of H1-H3 is valid. Three animal studies are proposed. The first animal study will test several reduced T-wave scanning procedures. The second will test for the ULV/RAP phenomena with rapid activation, but without geometric or ischemic changes. Finally, the third animal study will test for the ULV/RAP phenomena in the presence of geometric changes, but without changes in ischemic effects, and in the presence of changing ischemia without geometric changes.
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