Quantifying the role of myocyte ultrastructure in atrial health and disease

量化心肌细胞超微结构在​​心房健康和疾病中的作用

• 批准号: 10473869
• 负责人: Eleonora Grandi
• 金额: $ 44.08万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10473869
• 关键词: Affect; Architecture; Arrhythmia; Atrial Fibrillation; Atrial Function; Behavior; Blood Pressure; Cardiac; Cardiomyopathies; Cell physiology; Cell surface; Cells; Centers for Disease Control and Prevention (U.S.); Chronic; Complex; Computer Models; Computer software; Coupled; Couples; Coupling; Data; Databases; Development; Disease; Disease Progression; Electrophysiology (science); Event; Exhibits; Failure; Fibrosis; Fracture; Functional disorder; General Population; Goals; Health; Heart Atrium; Heart Diseases; Heart failure; Heterogeneity; Human; In Situ; Infrastructure; Lead; Link; Literature; Maintenance; Maps; Measures; Membrane; Modeling; Molecular; Muscle Cells; Myocardial Contraction; Myocardium; Nature; Oryctolagus cuniculus; Outcome; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Persons; Pharmacotherapy; Population; Predisposition; Process; Progressive Disease; Quality of life; Research; Role; Site; Structure; Systolic heart failure; Testing; Therapeutic; Tissues; Treatment outcome; Variant; Ventricular Dysfunction; base; design; embolic stroke; experimental analysis; experimental study; hemodynamics; human tissue; improved; insight; mortality; multi-scale modeling; novel; pressure; simulation; stroke risk; targeted treatment; tool; treatment strategy

PROJECT SUMMARY: Atrial fibrillation (AF) is the most common cardiac arrhythmia (affecting ~1-2% of the general population), resulting in markedly reduced quality of life and increased mortality, due to a combination of altered hemodynamics, progressive atrial and ventricular dysfunction, and embolic stroke. Many diseases and conditions, like heart failure, are known to contribute to pathological changes leading to AF. Limitations in current therapy allow AF paroxysms to progress to persistent and chronic AF, as a result of extensive atrial structural and electrical changes that facilitate AF maintenance (“AF begets AF”). The development of urgently needed new strategies for AF treatment hinges upon improved understanding of how abnormalities in cellular function trigger and sustain arrhythmia in atrial tissue. At the cellular level, a hallmark structural change of many chronic cardiac diseases is degradation of the intricate membrane architecture that couples cardiac electrical excitation to intracellular Ca2+ release and myocardial contraction (EC coupling) – i.e., the transverse tubule (TT) structures, which project orthogonally from the cell surface to its interior and thereby synchronize EC coupling throughout the cell. Degradation of the TT architecture is generally associated with arrhythmia, but it is not yet clear whether TT loss is a direct contributor to arrhythmia, a compensatory maladaptation, or an epiphenomenon. This is even less clear in atria, as atrial myocytes exhibit a vastly variable range of TT architectures, with prominent axial tubules. Further, TT degradation induced by the process of isolating atrial myocytes (vs. denser TTs in intact tissues) and challenges in experimentally detubulating intact cardiac tissue has so far limited the design of mechanistic myocyte and tissue studies. As a result, the literature surrounding the role of subcellular structural (ultrastructural) remodeling in AF has remained fractured, and currently we know relatively little about its role in contributing to AF pathophysiology. The overarching goal of this proposal is to discriminate the role of changes in atrial myocyte ultrastructure from other disease-associated sequelae by combining detailed multi-level experimental analyses of rabbit atrial myocytes and rabbit and human atrial tissues with extensive quantitative multi-scale computational modeling. The project will develop and validate a suite of modeling tools used to investigate the mechanisms by which: (1) naturally occurring variations in atrial TTs influence EC coupling and membrane stability in isolated atrial myocytes; (2) tissue gradients in TT organization influence tissue-level electrophysiological and EC coupling outcomes; (3) ultrastructural remodeling synergizes with ionic remodeling to favor atrial arrhythmogenesis in atrial cardiomyopathy. We contend that quantifying the role of atrial ultrastructure in AF pathology may shed new mechanistic insight into AF management. Each aim includes rigorously generated and validated modeling frameworks, informed by novel experiments in atrial myocytes and tissues, and testing of specific hypotheses. Models and data will be distributed freely and widely via software and database infrastructure supported by Dr. Grandi's lab and scientific networking sites.

项目摘要：心房颤动 (AF) 是最常见的心律失常（影响约 1-2% 的心律失常） 一般人群），导致生活质量显着下降和死亡率增加，原因是 血流动力学改变、进行性心房和心室功能障碍以及栓塞性中风。许多疾病和 众所周知，心力衰竭等疾病会导致导致房颤的病理变化。目前的限制 由于广泛的心房结构损伤，治疗允许 AF 阵发发展为持续性和慢性 AF。 以及促进 AF 维护的电气变化（“AF 产生 AF”）。急需发展 房颤治疗的新策略取决于对细胞功能异常如何发生的更好理解 触发并维持心房组织的心律失常。在细胞水平上，许多慢性疾病的标志性结构变化 心脏病是耦合心脏电兴奋的复杂膜结构的退化 细胞内 Ca2+ 释放和心肌收缩（EC 耦合）——即横管 (TT) 结构， 从细胞表面垂直投射到其内部，从而在整个过程中同步 EC 耦合 细胞。 TT 结构的退化通常与心律失常有关，但尚不清楚是否 TT 丢失是心律失常、代偿性适应不良或附带现象的直接原因。这就算了 心房中的情况不太清楚，因为心房肌细胞表现出各种各样的 TT 结构，具有突出的轴向结构 小管。此外，隔离心房肌细胞过程诱导的 TT 降解（相对于完整的心房肌细胞中更密集的 TT） 组织）和实验上拔管完整心脏组织的挑战迄今为止限制了设计 机制肌细胞和组织研究。因此，围绕亚细胞结构作用的文献 房颤的（超微结构）重塑仍然支离破碎，目前我们对其在房颤中的作用知之甚少。 有助于 AF 病理生理学。该提案的总体目标是区分变革的作用 通过结合详细的多层次研究心房肌细胞超微结构免受其他疾病相关后遗症的影响 对兔心房肌细胞以及兔和人类心房组织进行广泛定量的实验分析 多尺度计算建模。该项目将开发和验证一套建模工具，用于 研究以下机制：(1) 心房 TT 自然发生的变化影响 EC 耦合和 离体心房肌细胞的膜稳定性； (2) TT组织中的组织梯度影响组织水平 电生理学和 EC 耦合结果； (3)超微结构重塑与离子重塑协同作用 有利于房性心肌病的房性心律失常发生。我们认为量化心房的作用 房颤病理学的超微结构可能为房颤治疗提供新的机制见解。每个目标包括 严格生成和验证的建模框架，由心房肌细胞的新颖实验提供信息和 组织，并检验特定假设。模型和数据将通过软件自由、广泛地分发 以及由 Grandi 博士的实验室和科学网站支持的数据库基础设施。