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）的治疗提供合理依据，室颤是心脏性猝死的主要原因。VF的发作导致心脏停止泵血，这导致身体和心脏本身的缺血（缺乏血流）。长时间的缺血会改变心脏状态，使大多数除颤和心肺复苏的尝试都无效。经验证据表明，VF ECG波形的结构是生存的预测。这种联系的性质仍然不明。然而，ECG波形反映维持VF的电小波的时空组织。因此，了解VF的时空组织与缺血的联系机制是确定存活因素的必要步骤，特别是在VF/缺血的延长时间之后。在这里，我们建议使用单细胞，整个心脏，和整个动物的研究相结合，建立一个缺血特异性的细胞电生理学改变，时空动态的反射波，和ECG波形之间的联系。总的假设是，缺血诱导的内向和外向电流之间的平衡的变化，以及在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解体，并解释了ECG波形中周期性的渐进性损失。具体目标是：1.分析模拟缺血性室颤条件下心室肌细胞动作电位和钙瞬变动态不稳定的机制。2.分析在模拟和真实的缺血性VF期间，AP和Ca瞬变的动态不稳定性导致整个心脏传导异常的机制。3.建立动作电位的时间规律性、传播小波的动力学和原位自然VF演变期间的ECG之间的联系。心室颤动（VF）是心脏性猝死的主要原因。拟议的研究应该解释将VF期间电活动的变化与心脏血流停止联系起来的生理机制。为室颤心电图的判读提供科学依据。这将有助于在院外心脏骤停的情况下优化除颤和心肺复苏。

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.