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）是最常见的心律不齐（影响约1-2％ 一般人口），由于组合而导致生活质量明显降低和死亡率增加 血液动力学改变，进行性心房和心室功能障碍以及栓塞性中风的改变。许多疾病和 如心力衰竭，疾病已知会导致导致AF的病理变化。当前的局限性 由于广泛的心房结构 以及促进AF维护的电动变化（“ AF BEGES AF”）。迫切需要的发展 AF治疗的新策略取决于对细胞功能异常的理解的改善 触发和维持心律不齐的心房组织。在细胞级别，许多慢性的标志性结构变化 心脏疾病是伴侣心脏电兴奋的复杂膜结构的降解 到细胞内Ca2+释放和心肌合同（EC耦合） - 即，横向管（TT）结构， 哪个从细胞表面到其内部正交的项目，从而同步EC耦合 细胞。 TT体系结构的降解通常与心律不齐有关，但尚不清楚是否清楚 TT损失是心律不齐，补偿性疾病或epiphenomenon的直接贡献者。这甚至是 心房中不太清楚，随着心房肌细胞表现出大量可变的TT体系结构，具有突出的轴向 小管。此外，通过隔离心肌细胞的过程诱导的TT降解（与完整的密度tts相比 迄今为止，组织）和实验隔离性心脏组织的挑战已限制 机械心肌和组织研究。结果，围绕亚细胞结构作用的文献 （超微结构）AF中的重塑仍被骨折，目前我们对其在 促进AF病理生理学。该提案的总体目标是区分变化的作用 在其他与疾病相关后遗症的心肌细胞超微结构中，通过结合详细的多层次 兔房屋心肌细胞和兔子和人类心房组织的实验分析具有广泛的定量 多尺度计算建模。该项目将开发并验证一套建模工具 研究以下机制：（1）心房TTS中自然发生的变化影响EC耦合和 孤立心肌细胞中的膜稳定性； （2）TT组织中的组织梯度影响组织级 电生理和EC耦合结果； （3）超微结构重塑与离子重塑协同作用 有利于心房心脏病中心律失常的发生。我们认为，量化房屋的作用 AF病理学中的超微结构可能会给AF管理带来新的机械洞察力。每个目标都包括 严格生成和经过验证的建模框架，由心肌细胞中的新型实验和 组织和特定假设的测试。模型和数据将通过软件自由和广泛分发 以及Grandi博士实验室和科学网站支持的数据库基础架构。