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.

此 PPG 应用的目的是通过在机制层面了解心室颤动 (VF) 的发病机制，开发一种合理的心源性猝死治疗方法。这些研究人员之前的合作已经认识到膜电压驱动的动态因素（例如电恢复和兴奋性）有助于室颤期间波破裂的启动和维持。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相关。 2 型 VF 与 APD 恢复平坦、兴奋性降低和时空周期性相关。我们还开发了同时绘制地图的方法 正常和患病兔心室的膜电位 (V) 和细胞内钙 (Cai)，并检测空间和机电 APD 以及 Cai 瞬时交替。初步结果表明，除了电压驱动的动态因素外，Cai 循环是控制动态波稳定性多个方面的关键因素，包括空间交替、室性心动过速 (VT) 到 VF 的过渡以及 VF 期间新波断的产生。我们还证明了空间交替和 APD 异质性受到潜在结构异质性的显着影响，例如，乳头肌插入左心室游离壁。与 PPG 的中心主题一致，为了研究 VF 中 V-Caj 动力学与电/解剖组织异质性之间的相互作用，我们将使用 在完整的兔心室中同时进行光电压和 Cai 映射以及微电极跨膜电位记录，以确定 V-Cai 循环动力学、空间交替和波断之间的关系。我们将研究 Ca 升高和自发 Ca 释放在产生不和谐的交替和启动和维持 VF 的波断中的作用。具体目标 1 将集中于正常兔子的心室。具体目标 2 和 3 将重点关注分别由于非缺血性心肌病和缺血性心肌病而导致电解剖组织异质性增加的患病兔心室。数据分析和解释将与项目 1,2 和 4 中的理论研究互动地促进。我们期望这些研究将增进对心室颤动机制的理解，并更好地管理有心源性猝死风险的患者。