Perturbed Sodium and Calcium Fluxes in Atrial Fibrillation

项目总结：房颤（AF）是最常见的心律失常（影响约1-2%的 一般人群），导致生活质量明显下降，死亡率增加， 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。患者 散发性房颤发作（阵发性房颤）更适合于节律控制治疗，但目前的局限性 药物治疗导致阵发性AF进展为持续性和慢性AF，其特征在于广泛的 促进AF维持的重构（“AF引起AF”）。发展急需的新 房颤的治疗策略取决于对细胞功能异常的理解 （重塑离子通道，Ca和Na处理和细胞信号传导），以及神经激素调节 触发并维持心房的心律失常了解这些复杂的生物化学和 生物物理功能需要也在多个物理尺度上集成的定量系统模型。到 为了解决这一复杂问题，我们的目标是开发一个综合的和定量的建模和仿真， 框架，结合实验来源的数据，调查AF中出现的问题。我们 提出一个紧密结合的实验和计算研究，利用 Grandi博士和Chiamvimonvat博士在加州大学戴维斯分校和Dobrev博士在 埃森大学。该项目将开发和验证一套用于调查的建模工具 机制上：（1）钙和钠稳态紊乱，CaMKII过度活化，β-肾上腺素能 激发有助于早期和慢性人类AF中细胞后去极化和触发活动;（3） 靶向心脏Na通道和心房特异性的抗心律失常药物的有效性和安全性（AF选择性） 小电导钙激活钾通道，以促进合理的药物设计。我们认为， CaMKII信号传导如何与离子和Ca和Na处理重塑以及神经激素协同作用 调节，可能会脱落AF管理的机械见解。每一个目标包括制定和敏感性 新模型分析（Sobie博士是顾问），人体样本验证研究， 具体的假设。模型和数据将通过软件和数据库自由广泛地分发 由格兰迪博士的实验室和科学网络网站支持的基础设施。

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.