WAVE DYNAMICS IN NORMAL AND DISEASED RABBIT HEARTS

正常和患病兔心脏中的波动力学

• 批准号: 7108467
• 负责人: PENG-SHENG CHEN
• 金额: $ 35.9万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-10 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108467
• 关键词: action potentials; calcium; calcium flux; disease /disorder prevention /control; electrophysiology; heart electrical activity; heart function; intracellular transport; laboratory rabbit; mathematical model; membrane potentials; microelectrodes; pathologic process; sudden cardiac death; therapy design /development; ventricular fibrillation

The objective of this PPG application is to develop a rational approach to therapy of sudden cardiac death through understanding of the pathogenesis of ventricular fibrillation (VF) at the mechanistic level. Previous collaboration between these investigators has led to the recognition that membrane voltage-driven dynamic factors, such as electrical restitution and excitability, contribute to initiation and maintenance of wavebreak during VF. We demonstrated two types of VF. Type 1 VF is associated with steep action potential duration (APD) restitution, normal excitability and multiple wavelets. Type 2 VF is associated with flat APD restitution, reduced excitability and spatiotemporal periodicity. We also developed methods to simultaneous map membrane potential (V) and intracellular calcium (Cai) in normal and diseased rabbit ventricles, and to detect spatial and electromechanical APD and Cai transient alternans. Preliminary results suggest that, along with voltage-driven dynamic factors, Cai cycling is a critical factor that controls multiple aspects of dynamic wave stability, including spatial alternans, ventricular tachycardia (VT) to VF transition, and the generation of new wavebreaks during VF. We also demonstrated that the spatial alternans and APD heterogeneity are significantly influenced by underlying structural heterogeneity, for example, by the insertion of papillary muscle into the left ventricular free wall. Consistent with the central theme of the PPG, to study the interaction between V-Caj dynamics and electrical/anatomical tissue heterogeneity in VF, we will use simultaneous optical voltage and Cai mapping and micoelectrode transmembrane potential recordings in intact rabbit ventricles to determine the relationship between V-Cai cycling dynamics, spatial alternans and wavebreak. We will investigate the role of elevated Cai and spontaneous Ca release in creating discordant alternans and wavebreaks initiating and maintaining VF. Specific Aim 1 will concentrate on normal rabbit ventricles. Specific Aims 2 and 3 will focus on diseased rabbit ventricles with increased electroanatomical tissue heterogeneity, due to non-ischemic cardiomyopathy and ischemic cardiomyopathy, respectively. Data analysis and interpretation will be facilitated interactively with theoretical studies in Projects 1,2 and 4. We expect that these studies will improve the understanding of the mechanisms of ventricular fibrillation and lead to better management of patients at risk of sudden cardiac death.

该PPG应用的目的是通过理解机械水平的心室纤颤（VF）的发病机理来开发一种理性的心脏死亡治疗方法。这些研究者之间的先前合作使人们认识到，膜电压驱动的动态因素（例如电恢复和兴奋性）有助于VF期间的波浪破裂的启动和维护。我们演示了两种类型的VF。 1型VF与陡峭的动作电位持续时间（APD）恢复，正常兴奋性和多个小波有关。 2型VF与平坦的APD恢复，降低兴奋性和时空周期性有关。我们还开发了同时地图的方法 正常和患病的兔心室中的膜电位（V）和细胞内钙（CAI），并检测空间和机电APD和CAI瞬态替代品。初步结果表明，与电压驱动的动态因素一起，CAI循环是控制动态波稳定性的多个方面的关键因素，包括空间替代品，心室心动过速（VT）到VF过渡，以及VF期间新波形的产生。我们还证明了空间替代品和APD异质性受到潜在的结构异质性的显着影响，例如，将乳头肌肉插入左心室游离壁中。与PPG的中心主题一致，以研究VF中V-CAJ动力学与电气/解剖组织异质性之间的相互作用，我们将使用 完整兔心室中的同时光电电压和CAI映射和微电极跨膜电势记录，以确定V-CAI循环动力学，空间替代品和波浪破裂之间的关系。我们将调查升高的CAI和自发CA释放在创建不和谐的替代方案和波浪破坏和维护VF方面的作用。特定的目标1将集中于正常的兔心室。具体目的2和3将分别由于非缺血性心肌病和缺血性心肌病而侧重于患病的兔心室，具有增加的电解组织异质性。数据分析和解释将通过项目1,2和4的理论研究进行交互性促进。我们希望这些研究将改善对心室纤维化机制的理解，并能够更好地管理有突然心脏死亡风险的患者。