Perturbed Sodium and Calcium Fluxes in Atrial Fibrillation

项目摘要：房颤(房颤)是最常见的心律失常(影响~1-2%的 (一般人口)，导致生活质量显著降低，死亡率增加，这是由于 血流动力学改变，进行性房室功能障碍，以及栓塞性中风。患有疾病的患者 散发性房颤(阵发性房颤)更适合节律控制治疗，但在电流方面有限制 药物治疗使阵发性房颤进展为持续性和慢性房颤，其特点是广泛 有利于房颤维护的重塑(“房颤产生房颤”)。发展急需的新能源 房颤的治疗策略取决于对细胞功能异常的更好理解 (重塑的离子通道、钙和钠的处理以及细胞信号)，以及神经激素调节 引发并维持心房的心律失常。了解这些复杂的生化和蛋白质之间的相互作用 生物物理功能需要量化的系统模型，这些模型也需要在多个物理尺度上进行集成。至 针对这一复杂问题，我们的目标是开发一种集成的、定量的建模和仿真 框架，纳入来自实验来源的数据，以调查房颤中新出现的问题。我们 建议将实验研究和计算研究紧密结合起来，利用 加州大学戴维斯分校的格兰迪和钱维蒙特博士与多布列夫博士之间的跨学科协同 埃森大学。该项目将开发和验证一套用于研究 机制：(1)钙钠动态平衡、CaMKII过度激活和β-肾上腺素能 激发对早期和慢性房颤细胞后除极和触发活动的影响； 以心脏钠通道和心房特异性为靶点的抗心律失常药物的有效性和安全性(房颤选择性) 小电导钙激活的钾通道，有利于合理设计药物。我们认为，这种理解 CaMKII信号如何与离子、钙和钠处理重塑以及神经激素协同作用 监管，可能会让人对房颤的管理产生机械性的洞察。每个目标都包括公式和敏感度 新模型的分析(索比博士是一名顾问)，人体样本的验证研究，以及 具体的假设。模型和数据将通过软件和数据库自由和广泛地分发 由格兰迪博士的实验室和科学关系网提供支持的基础设施。

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. Patients with sporadic AF episodes (paroxysmal AF) are more amenable to rhythm control treatment, but limitation in current pharmacotherapy causes paroxysmal AF to progress to persistent and chronic AF, characterized by extensive remodeling that facilitates AF maintenance (“AF begets AF”). The development of urgently needed new strategies for AF treatment hinge upon improved understanding of how abnormalities in cellular function (remodeled ion channels, Ca and Na handling, and cellular signaling), together with neurohormonal regulation trigger and sustain arrhythmia in the atria. Understanding the interactions of these complex biochemical and biophysical functions requires quantitative systems models that also integrate over multiple physical scales. To address this complex problem, we aim at developing an integrative and quantitative modeling and simulation framework, incorporating data from experimental sources, to investigate emerging questions in AF. We propose a closely integrated combination of experimental and computational studies that takes advantage of interdisciplinary synergy between Drs. Grandi & Chiamvimonvat at UC Davis and Dr. Dobrev at Universitätsklinikum Essen. The project will develop and validate a suite of modeling tools used to investigate mechanistically: (1) how derangements in Ca and Na homeostasis, CaMKII hyperactivation, and β-adrenergic challenge contribute to cellular afterdepolarizations and triggered activity in early and chronic human AF; (3) the efficacy and safety (AF-selectivity) of antiarrhythmic drugs targeting cardiac Na channels and atrial-specific small conductance Ca-activated K channels, to facilitate rational drug design. We contend that understanding how CaMKII signaling synergizes with ionic and Ca and Na handling remodeling, as well as neurohormonal regulation, may shed mechanistic insight into AF management. Each aim includes formulation and sensitivity analysis of new models (Dr. Sobie is a consultant), validation studies with human samples, 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.