The broad, long-term goal of the proposed project is to provide a rational basis for the treatment of ventricular fibrillation (VF), a major cause of sudden cardiac death. The onset of VF causes the heart to stop pumping blood, which leads to ischemia (the lack of the blood flow) in the body and in the heart itself. Prolonged ischemia alters the cardiac state in such a way that it makes most of the attempts of defibrillation and cardio-pulmonary resuscitation futile. Empirical evidence indicates that the structure of VF ECG waveform is predictive of survival. The nature of this connection remains unknown. However, the ECG waveform reflects the spatiotemporal organization of electrical wavelets which sustain VF. Therefore, understanding the mechanisms linking the spatiotemporal organization of VF to ischemia is a necessary step towards determining the factors of survival, especially after prolonged times of VF/ischemia. Here we propose to use a combination of single cell, whole heart, and whole animal studies to establish a link between ischemia-specific alterations of cellular electrophysiology, spatiotemporal dynamics of fibrillatory waves, and the ECG waveform. The overall hypothesis is that the ischemia-induced changes in the balance between inward and outward currents, as well as in the coupling between the action potential and intracellular calcium cycling, lead to a dynamic instability in the action potential shape. This instability translates into a progressive disorganization of propagating wavelets and explains the progressive loss of periodicity in the ECG waveform.
The specific aims are: 1. To analyze the mechanisms of dynamic instabilities of the action potential and Ca transient in isolated ventricular myocytes subjected to simulated conditions of ischemic VF. 2. To analyze mechanisms whereby dynamic instabilities of the AP and Ca transient cause conduction abnormalities during simulated and real ischemic VF in the whole heart. 3. To establish the link between the temporal regularity of the action potential, the dynamics of propagating wavelets and the ECG during natural VF evolution in-situ. Ventricular fibrillation (VF) is major cause of sudden cardiac death. The proposed research should explain physiological mechanisms linking the changes in the electrical activity during VF to the arrest of blood flow in the heart. It should also provide a scientific basis for the interpretation of VF ECG. This should help to optimize defibrillation and cardio-pulmonary resuscitation in the setting of out-of-hospital sudden cardiac arrest.
|Garg, Vivek; Taylor, Tyson; Warren, Mark et al. (2015) Î²-Adrenergic stimulation and rapid pacing mutually promote heterogeneous electrical failure and ventricular fibrillation in the globally ischemic heart. Am J Physiol Heart Circ Physiol 308:H1155-70|
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|Taylor, Tyson G; Venable, Paul W; Booth, Alicja et al. (2013) Does the combination of hyperkalemia and KATP activation determine excitation rate gradient and electrical failure in the globally ischemic fibrillating heart? Am J Physiol Heart Circ Physiol 305:H903-12|
|Venable, Paul W; Taylor, Tyson G; Sciuto, Katie J et al. (2013) Detection of mitochondrial depolarization/recovery during ischaemia--reperfusion using spectral properties of confocally recorded TMRM fluorescence. J Physiol 591:2781-94|
|Shibayama, Junko; Taylor, Tyson G; Venable, Paul W et al. (2013) Metabolic determinants of electrical failure in ex-vivo canine model of cardiac arrest: evidence for the protective role of inorganic pyrophosphate. PLoS One 8:e57821|
|Taylor, Tyson G; Venable, Paul W; Shibayama, Junko et al. (2012) Role of KATP channel in electrical depression and asystole during long-duration ventricular fibrillation in ex vivo canine heart. Am J Physiol Heart Circ Physiol 302:H2396-409|
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|Venable, Paul W; Taylor, Tyson G; Shibayama, Junko et al. (2010) Complex structure of electrophysiological gradients emerging during long-duration ventricular fibrillation in the canine heart. Am J Physiol Heart Circ Physiol 299:H1405-18|
|Wasmund, Stephen L; Pai, Rakesh K; Freedman, Roger A et al. (2009) Modulation of the sinus rate during ventricular fibrillation. J Cardiovasc Electrophysiol 20:187-92|
|Shvedko, Alexander G; Warren, Mark D; Shome, Shibaji et al. (2008) Influence of the skeletal muscle activity on time and frequency domain properties of the body surface ECG during evolving ventricular fibrillation in the pig. Resuscitation 78:215-23|
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