Perturbed Sodium and Calcium Fluxes in Atrial Fibrillation

心房颤动中钠和钙通量的扰动

• 批准号: 9276787
• 负责人: Eleonora Grandi
• 金额: $ 39.39万
• 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 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276787
• 关键词: Action Potentials; Acute; Address; Adrenergic Agents; Affect; Age; Anti-Arrhythmia Agents; Arrhythmia; Atrial Fibrillation; Behavior; Biochemical; Biological Models; Biophysics; Calcium/calmodulin-dependent protein kinase; Calmodulin; Cardiac; Cardiac Electrophysiologic Techniques; Cell physiology; Cells; Chronic; Clinic; Complex; Computer Simulation; Computer software; Cyclic AMP-Dependent Protein Kinases; Data; Databases; Dependence; Development; Disease; Disease Progression; Drug Design; Drug Interactions; Drug Targeting; Electrophysiology (science); Failure; Formulation; Functional disorder; Gated Ion Channel; General Population; Heart Atrium; Heart Diseases; Heart failure; Homeostasis; Human; Hyperactive behavior; Image; Impairment; Investigation; Ion Channel; Ion Channel Gating; Kinetics; Lead; Link; Maintenance; Mathematics; Measurement; Mediating; Mediator of activation protein; Membrane Potentials; Modeling; Molecular; Molecular Conformation; Muscle Cells; Nodal; Pathology; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiological; Population; Potassium Channel; Predisposition; Progressive Disease; Publishing; Quality of life; Radiofrequency Interstitial Ablation; Recurrence; Refractory; Regulation; Research; Research Infrastructure; Risk; Safety; Sampling; Signal Pathway; Signal Transduction; Sinus; Site; Sodium; Source; Specificity; Stroke; Study models; System; Systolic heart failure; Testing; Therapeutic; Tissues; Treatment outcome; Ventricular; Ventricular Dysfunction; base; burden of illness; channel blockers; computer studies; drug efficacy; effective therapy; experimental study; hemodynamics; human data; improved; indium arsenide; insight; mathematical analysis; mathematical model; models and simulation; mortality; nerve supply; novel; novel therapeutics; patch clamp; prevent; ranolazine; release of sequestered calcium ion into cytoplasm; response; sobriety; synergism; tool; validation studies; virtual; voltage

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.

项目摘要：心房颤动（AF）是最常见的心律失常（约占美国人口的1-2%）