A Multi-Scale Approach to Cardiac Arrhythmia: from the Molecule to the Organ

治疗心律失常的多尺度方法：从分子到器官

• 批准号: 8708950
• 负责人: GIDEON KOREN
• 金额: $ 141.61万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708950
• 关键词: Ablation; Action Potentials; Affect; Animal Model; Arrhythmia; Biochemical; Biological; Calcium; Calcium Oscillations; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cartoons; Cells; Complex; Computer Simulation; Coupled; Data; Disease; Electrophysiology (science); Estrogens; Experimental Models; Feedback; Female; Frequencies; Genes; Genetic; Genetic Models; Goals; Gonadal Steroid Hormones; Health Benefit; Heart; Heart Diseases; Heterogeneity; Hormones; Human; Incidence; Investigation; Ion Channel; Knowledge; Lead; Life; Long QT Syndrome; Maps; Measurement; Measures; Mediating; Membrane; Modeling; Molecular; Muscle Cells; Mutation; Myocardial; Myocardial dysfunction; Neonatal; Optics; Orchiectomy; Organ; Oryctolagus cuniculus; Pattern; Pharmaceutical Preparations; Phase; Play; Population; Prevention strategy; Progesterone; Property; Proteins; Public Health; Publishing; Relative (related person); Risk; Risk Factors; Role; Sudden Death; System; Tachyarrhythmias; Testing; Time; Tissue Engineering; Tissues; Transgenic Animals; Transgenic Organisms; Validation; Variant; Ventricular; Ventricular Arrhythmia; Ventricular Tachycardia; Weather; Work; atrioventricular node; biophysical properties; improved; innovative technologies; insight; loss of function; male; minimally invasive; mortality; mutant; protective effect; public health relevance; research study; sudden cardiac death

DESCRIPTION (provided by applicant): The overall goal of this proposal is to investigate new mechanisms that underlie SCD through the application of innovative technology, computer modeling and the use of new genetic models of long QT syndrome type 1and type 2 (LQT1 and LQT2). This multi-pronged approach includes the investigation of orchiectomized male LQT2 rabbits and LQT1 rabbits that underwent ablation of the AV node (LQT1-AVB). Studies at the cellular levels with myocytes derived from these rabbits will be used to investigate the role of sex hormones in modulation of the function of key proteins that regulate calcium dynamics in cardiomyocytes. Since the calcium (Ca) transients and action potential dynamics are bi-directionally coupled through Ca-induced-Ca-release and the feedback of the Ca transient on Ca-sensitive membrane current (ICa,L, INCX, and IKs), assessing the relative contributions of unstable Ca cycling and altered repolarization to triggered activity is in general difficult. Here e propose to investigate the subcellular Ca cycling dynamics first without Vm influence to characterize RyR sensitivity, and then with a clamped action potential waveform to investigate the uni-directional effect of Vm on Ca cycling dynamics (i.e. without feedback of Cai on Vm), thereby identify conditions leading to arrhythmogenic whole cell Cai oscillations, Vm dynamics without CaT influence to study EADs facilitated by reopening of ICa,L in the presence of altered repolarization, and finally bi-directionally coupled free Cai and free Vm dynamics to investigate synergistic effects of Cai oscillations and reopening of ICa,. Iteration will consist of functional electrophysiological measurements of the specific currents and their biophysical properties, and biochemical and electrophysiological studies (as well as measured subcellular Ca dynamical properties-spark frequency and Ca wave threshold), to calibrate relevant ranges of computational model parameters to be used in the exploration of arrhythmogenic state (unsafe zone) and safe zone (no spontaneous arrhythmias or SCD). Studies at the tissue and organ levels will examine the role synchronization of the triggered activity combined with bi-stable wave conduction (bi- excitability) and tissue heterogeneities mediate the R-on-T phenomenon as well as test whether short-long-short sequence increases EAD formations and tissue heterogeneities, thus self propels until the onset of TdP and weather TdP and PVT are maintained by Ica-mediated wavefronts and chaos synchronization.

描述（由申请人提供）：该提案的总体目标是研究通过应用创新技术，计算机建模以及使用长QT综合征1型和2型2型（LQT1和LQT2）的新遗传模型的新机制。这种多管齐下的方法包括对经过AV节点（LQT1-AVB）进行消融的Orchiectomized雄性LQT2兔子和LQT1兔子的研究。用这些兔子得出的肌细胞在细胞水平上进行的研究将用于研究性激素在调节心肌细胞中调节钙动力学的关键蛋白功能中的作用。由于钙（CA）瞬态和动作电位动力学在CA诱导的CA释放上是双向耦合的，并且CA瞬态在CA敏感的膜电流（ICA，L，INCX和IKS）上的反馈评估了不稳定的CA循环和对不稳定的启动的相对贡献，对触发的活动的相对贡献是一般困难的。 Here e propose to investigate the subcellular Ca cycling dynamics first without Vm influence to characterize RyR sensitivity, and then with a clamped action potential waveform to investigate the uni-directional effect of Vm on Ca cycling dynamics (i.e. without feedback of Cai on Vm), thereby identify conditions leading to arrhythmogenic whole cell Cai oscillations, Vm dynamics without CaT influence to study EADs facilitated by reopening ICA，L在发生变化的情况下，最后是双向耦合的游离CAI和游离VM动力学，以研究CAI振荡和ICA重新开放的协同作用。迭代将由功能 特定电流及其生物物理特性的电生理测量以及生化和电生理研究（以及测量的细胞亚细胞CA动力学特性Spark Spark Spark频率和CA波阈值），以校准相关的计算模型参数的相关范围，可用于探索网状细胞型（无效区域）（无效区域）。在组织和器官水平上的研究将检查触发活性的作用同步与双稳定的波传导（双兴奋性）和组织异质性介导R-ON-T现象介导R-ON-T现象，并测试短 - 短序列的作用，并通过ICAPERS和PREPERS WARKERS WIST和PREPERS WARD WARD WARD WEARS ICPON和PV WARGERS WIST PREVEN和PEV WARD延长，直到TDP和PEV waver wrave。和混乱同步。