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、长期目标是为室颤(VF)的治疗提供合理的基础，VF是导致心脏性猝死的主要原因。室颤的发作会导致心脏停止供血，从而导致体内和心脏本身的缺血(血液流动不足)。长时间的缺血改变了心脏状态，使得除颤和心肺复苏的大部分尝试都是徒劳的。经验证据表明，VF心电波形的结构对存活有预测作用。这种联系的性质尚不清楚。然而，心电波形反映了维持室颤的电小波的时空组织。因此，了解室颤的时空组织与缺血之间的联系是确定存活因素的必要步骤，尤其是在室颤/缺血时间延长后。在这里，我们建议使用单个细胞、整个心脏和整个动物研究的组合来建立细胞电生理的缺血特异性改变、纤颤波的时空动力学和心电波形之间的联系。总的假设是，缺血引起的内向和外向电流平衡的改变，以及动作电位和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性混乱，并解释了心电波形中周期性的渐进性损失。具体目的是：1.分析模拟缺血室性心动过速条件下分离的心肌细胞动作电位和钙瞬变的动态不稳定性机制。2.分析模拟和真实全心缺血性室颤时，AP和Ca瞬变的动态不稳定性导致传导异常的机制。3.建立动作电位的时间规律性、子波的传播动力学与心电图室颤在原位自然演化过程中的联系。室颤(VF)是心源性猝死的主要原因。这项拟议的研究应该解释室颤期间电活动的变化与心脏血流停止之间的生理机制。为VF心电的解释提供科学依据。这将有助于优化院外心脏骤停时的除颤和心肺复苏。

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.