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.

这种PPG应用的目的是通过从机制水平上了解室颤(VF)的发病机制，开发一种合理的治疗心源性猝死的方法。这些研究人员以前的合作使人们认识到，膜电压驱动的动态因素，如电恢复和兴奋性，有助于室颤期间波的启动和维持。我们演示了两种类型的VF。1型室颤与陡峭动作电位时程恢复、正常兴奋性和多子波有关。2型室颤与平坦的动作电位恢复、兴奋性降低和时空周期性有关。我们还开发了同时绘制地图的方法 正常和病变兔脑室的膜电位(V)和细胞内钙(CaI)，并检测空间和机电时程和CaI的瞬变。初步结果表明，除电压驱动的动态因素外，CAI周期是控制动态波形稳定性的多个方面的关键因素，包括空间交替、室性心动过速(VT)到VF的转变，以及在VF过程中新波的产生。我们还证明，空间交替和时程异质性显著地受到潜在结构异质性的影响，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动力学和电/解剖组织异质性之间的相互作用，我们将使用 在完整的兔脑室同时记录光电压和CAI标测和微电极跨膜电位，以确定V-CAI循环动力学、空间交替和波形破裂之间的关系。我们将研究升高的CaI和自发的钙释放在创造不和谐的交替和波群启动和维持室颤中的作用。具体目标1将集中在正常的兔脑室。特定的AIMS 2和3将分别聚焦于由于非缺血性心肌病和缺血性心肌病而导致的组织电解剖异质性增加的病变的兔脑室。数据分析和解释将与项目1、2和4中的理论研究相互促进。我们预计这些研究将提高对室颤机制的理解，并导致更好地管理有心脏性猝死风险的患者。