Ventricular Fibrillation in a Globally Ischemic Heart: From Cell to ECG

描述（由申请人提供）：拟议项目的广泛，长期目标是为心室颤动（VF）的治疗提供合理的基础，心室颤动是心源性猝死的主要原因。室性心动过速的发作会导致心脏停止供血，从而导致身体和心脏本身缺血（缺乏血液流动）。长时间缺血会改变心脏状态，使大多数除颤和心肺复苏的尝试无效。经验证据表明，VF心电波形的结构可以预测患者的生存。这种联系的性质尚不清楚。然而，心电波形反映了维持VF的电小波的时空组织。因此，了解VF的时空组织与缺血之间的联系机制是确定存活因素的必要步骤，特别是在VF/缺血时间延长后。在这里，我们建议使用单细胞、全心脏和全动物研究的组合来建立细胞电生理特异性改变、纤颤波的时空动力学和ECG波形之间的联系。总的假设是，缺血引起的内向和外向电流平衡的变化，以及动作电位与细胞内钙循环之间的耦合，导致动作电位形状的动态不稳定。这种不稳定性转化为传播小波的渐进无序，并解释了心电波形周期性的逐渐丧失。具体目标是：1。目的：分析模拟缺血性心室房颤条件下离体心室肌细胞动作电位和钙瞬态动态不稳定的机制。2. 分析模拟和真实全心缺血性室颤期间AP和Ca瞬态动态不稳定导致传导异常的机制。3. 建立动作电位的时间规律、传播小波的动态和心电在VF自然演化过程中的联系。心室颤动是心源性猝死的主要原因。拟议的研究将解释心室颤动期间电活动变化与心脏血流停止之间的生理机制。同时也为VF心电图的判读提供了科学依据。这将有助于优化院外心脏骤停情况下的除颤和心肺复苏。

DESCRIPTION (provided by applicant): 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.