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

基本信息

批准号：
10673911
负责人：
Eleonora Grandi
金额：
$ 42.71万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/10673911
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 Variant Ventricular Dysfunction base design embolic stroke experimental analysis experimental study hemodynamics human tissue improved insight mortality multi-scale modeling novel novel therapeutic intervention pressure simulation stroke risk synergism targeted treatment tool treatment and outcome

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 Variant Ventricular Dysfunction base design embolic stroke experimental analysis experimental study hemodynamics human tissue improved insight mortality multi-scale modeling novel novel therapeutic intervention pressure simulation stroke risk synergism targeted treatment tool treatment and outcome

展开

项目摘要

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.