Reentrant Activity in Cultured Cardiac Cell Monolayers

培养的心肌单层细胞的重入活性

• 批准号: 7185808
• 负责人: LESLIE TUNG
• 金额: $ 39.74万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-08 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7185808
• 关键词: Adherent Culture; Affect; Aleurites; Anisotropy; Arrhythmia; Calcium; Calcium Channel; Calcium Oscillations; Cardiac; Cell model; Cells; Cellular Membrane; Characteristics; Classification; Coculture Techniques; Condition; Coupling; Cultured Cells; Dyes; Evaluation; Experimental Models; Fibroblasts; Goals; Heart Atrium; Heterogeneity; Ion Channel; Island; Knowledge; Length; Location; Maps; Membrane; Membrane Potentials; Myoblasts; Myocardial; Neonatal; Optics; Pathway interactions; Pattern; Play; Property; Rattus; Research; Research Personnel; Research Project Grants; Role; Site; Skeletal Muscle; Skeletal Myoblasts; Specific qualifier value; Tachycardia; Testing; Thromboplastin; Tissue Engineering; Tissues; Ventricular; Work; base; cell type; genetically engineered virus; monolayer; programs; regional difference; voltage

DESCRIPTION (provided by applicant): Reentrant mechanisms play a primary role in many types of cardiac arrhythmias. Functional reentry, in the form of spiral waves, underlies many tachycardias as well as fibrillation, but the dynamic properties of spiral wave stability and breakup are still not well characterized. Previous work from our lab has demonstrated that sustained spiral wave activity can be induced and systematically studied in monolayers of cultured neonatal rat ventricular cells. The focus of this work will be on the properties of spiral waves, and particularly how they are influenced by islands of tissue heterogeneities that include altered ion channel expression, gap junctional coupling, and ectopic foci. Tissue engineering approaches will be utilized to permit a systematic evaluation of different types of heterogeneities at specified locations. We propose to use voltage- and calcium-sensitive dyes and multi-site optical mapping to track the reentrant activity in cardiac cell monolayers. We will test the hypotheses, (1) Regional differences in cellular membrane properties can anchor reentrant waves and alter cycle length, (2) Heterogeneities in tissue microstructure result in discontinuous propagation and amplify the anchoring effects of anatomical obstacles, (3) Lines of block during reentry originate from microheterogeneities, and their length is modulated by excitability, wavelength and tissue anisotropy, (4) Islands of altered ion channel expression may suffice to initiate spiral wave breakup, particularly under conditions of reduced cell-cell coupling, and (5) Triggered activity and afterdepolarizations can cause spiral wave breakup but require critical mass and critical coupling. These aims exploit the properties of the cultured cell monolayer as a well-controlled, versatile and quantitative experimental model for basic studies of clinically important, reentry-based arrhythmias.

描述（由申请人提供）：折返机制在许多类型的心律失常中发挥主要作用。螺旋波形式的功能性折返是许多心动过速和颤动的基础，但螺旋波稳定性和破裂的动态特性仍然没有得到很好的表征。我们实验室之前的工作表明，可以在培养的新生大鼠心室细胞单层中诱导和系统研究持续的螺旋波活动。这项工作的重点将是螺旋波的特性，特别是它们如何受到组织异质性岛的影响，包括改变的离子通道表达、间隙连接耦合和异位灶。将利用组织工程方法对特定位置的不同类型的异质性进行系统评估。我们建议使用电压和钙敏感染料和多位点光学测绘来追踪心脏细胞单层中的折返活动。我们将测试以下假设：（1）细胞膜特性的区域差异可以锚定折返波并改变周期长度，（2）组织微观结构的异质性导致不连续传播并放大解剖障碍的锚定效应，（3）折返期间的阻挡线源自微观异质性，其长度受兴奋性、波长和组织的调节 各向异性，（4）离子通道表达改变的岛可能足以引发螺旋波分裂，特别是在细胞间耦合减少的条件下，以及（5）触发的活动和后去极化可以导致螺旋波分裂，但需要临界质量和临界耦合。这些目标利用培养细胞单层的特性作为一种控制良好、多功能和定量的实验模型，用于临床重要的基于折返的心律失常的基础研究。