The role of dynamic changes in repolarization and calcium transients in Long QT r

复极化和钙瞬变动态变化在长 QT 过程中的作用

• 批准号: 8127732
• 负责人: Bum-Rak Choi
• 金额: $ 38.63万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127732
• 关键词: Acceleration; Action Potentials; Address; American; Animal Model; Arrhythmia; Behavior; Bolus Infusion; Calcium; Cardiac; Characteristics; Code; Consensus; Data; Disease; Electrocardiogram; Exhibits; Frequencies; Generations; Genes; Genetic; Genetic Predisposition to Disease; Goals; Health Benefit; Heart; Heart Diseases; Heart Rate; Heterogeneity; Imaging Device; Infusion procedures; Isoproterenol; Kinetics; Knowledge; Laboratories; Lead; Length; Link; Location; Long QT Syndrome; Maintenance; Maps; Measures; Membrane Potentials; Modeling; Molecular; Mutation; Nerve; Nodal; Optics; Oryctolagus cuniculus; Patients; Pattern; Play; Population; Potassium; Preparation; Prevention strategy; Public Health; Recording of previous events; Recurrence; Role; Speed; Sudden Death; Surface; Syncope; Syndrome; Testing; Time; Tissues; Torsades de Pointes; Transgenic Organisms; Variant; Ventricular Tachycardia; base; insight; loss of function; mutant; novel; novel strategies; promoter; public health relevance; sudden cardiac death; tool

DESCRIPTION (provided by applicant): The long QT syndrome (LQTS) is a repolarization disorder characterized by marked prolongation of the QT interval and the recurrent syncope during episodes of polymorphic VT (pVT), called Torsade de Pointes (TdP), which leads to sudden cardiac death. The current consensus is that LQT-related arrhythmias are initiated by the firing of early afterdepolarization (EADs), which in the presence of an enhanced dispersion of repolarization results in reentry and pVTs. The induction of EADs and pVTs has been associated with increased sympathetic tone, which could likely augment the dispersion of repolarization, exacerbating conditions for reentrant arrhythmias. In addition, heart rate variation such as short-long-short cycle length (pause-dependent mode) or acceleration of heart rates often precedes TdPs formation, suggesting that generation of EADs and dispersion of repolarization are dynamically dependent on previous history of cycle lengths. Despite intense studies, the exact mechanisms and conditions for EADs & TdPs are not clearly understood yet. The overall goals of this proposal are to investigate mechanisms of long QT related arrhythmias including tissue characteristics as substrate for reentry and conditions that exacerbate EAD inductions and pVTs. Addressing theses questions requires the mapping of dynamic changes in cardiac repolarization from different regions and identifying preferential locations of EAD propagations, and correlating it with Ca2+ transients in the intact heart. We propose to use novel transgenic rabbit models of long QT syndrome (LQT1 and LQT2) created by Dr. Koren's laboratory and investigate LQT related arrhythmia mechanisms using simultaneous optical mapping of transmembrane potentials and Ca2+ transients. We hypothesize that arrhythmias in LQT1 rabbits are caused by sympathetic stimulation- induced imbalance between cardiac repolarization reserve and Ca2+ overload, which initiates EADs and supports the maintenance of TdPs. By contrast, In LQT2 rabbits, we hypothesize that the dynamic repolarization changes such as discordant alternans play a critical role in reentry formation and its degeneration into VF. We will measure dynamic changes in APD and Ca2+ from intact heart in order to investigate the adaptation of Ca2+ transients and APD to heart rate changes with or without infusion of isoproterenol to identify the pattern of cycle length change that can augment Ca2+ overload and APD dispersion. We will investigate maintenance of pVTs by mapping the propagation of EADs from the whole surface of the heart using two cameras and identifying patterns of local cycle length changes that precede focal activity. We will map dynamic changes in APDs including discordant alternans and their nodal line behavior and correlate with tissue heterogeneities and Ca2+ handling to identify major factors that create discordant alternans and pVTs. This study will provide mechanistic insights of LQT related arrhythmias which can be used as a basis for further molecular studies. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE The long QT syndrome (LQTS) is a repolarization disorder characterized by marked prolongation of the QT interval. Patients with LQTS exhibit the recurrent syncope during episodes of polymorphic VT, which causes sudden cardiac death. The most common forms of congenital LQTS, type 1 and type 2 (LQT1 and LQT2), are caused by mutations in the genes coding for the delayed rectifying potassium currents. However, mechanisms linking these mutations to cardiac arrhythmias are not clearly understood. This proposal investigates arrhythmia mechanisms in these LQTS using transgenic rabbit models and high speed imaging devices. The data obtained here should provide more complete knowledge into the genetic and electrophysiologic factors involved in long QT related arrhythmias. This enhanced knowledge should lead to more effective strategies for prevention of sudden death in a broad spectrum of genetic and acquired cardiac disorders with meaningful public health benefits.

描述（由申请人提供）：长 QT 综合征 (LQTS) 是一种复极障碍，其特征是 QT 间期显着延长，并且在多形性 VT (pVT) 发作期间反复出现晕厥，称为尖端扭转型室性心动过速 (TdP)，这会导致心源性猝死。目前的共识是，LQT 相关的心律失常是由早期后除极 (EAD) 的激发引发的，在复极离散度增强的情况下，会导致折返和 pVT。 EAD 和 pVT 的诱导与交感神经张力的增加有关，这可能会增加复极的分散性，从而加剧折返性心律失常的情况。此外，心率变化，例如短-长-短周期长度（暂停依赖模式）或心率加速通常先于 TdP 形成，这表明 EAD 的生成和复极的分散动态地依赖于先前的周期长度历史。尽管进行了大量研究，但 EAD 和 TdP 的确切机制和条件尚不清楚。该提案的总体目标是研究长 QT 相关心律失常的机制，包括作为折返基质的组织特征以及加剧 EAD 诱导和 pVT 的条件。解决这些问题需要绘制不同区域心脏复极的动态变化图，确定 EAD 传播的优先位置，并将其与完整心脏中的 Ca2+ 瞬变相关联。我们建议使用 Koren 博士实验室创建的新型长 QT 综合征（LQT1 和 LQT2）转基因兔模型，并使用跨膜电位和 Ca2+ 瞬变的同步光学测绘来研究 LQT 相关的心律失常机制。我们假设 LQT1 兔子的心律失常是由交感神经刺激引起的心脏复极储备和 Ca2+ 超载之间的不平衡引起的，这会启动 EAD 并支持 TdP 的维持。相比之下，在 LQT2 兔子中，我们假设动态复极变化（例如不一致的交替）在折返形成及其退化为室颤中发挥关键作用。我们将测量完整心脏中 APD 和 Ca2+ 的动态变化，以研究在输注或不输注异丙肾上腺素的情况下 Ca2+ 瞬变和 APD 对心率变化的适应性，以确定可增加 Ca2+ 过载和 APD 分散的周期长度变化模式。我们将通过使用两个摄像头绘制 EAD 从心脏整个表面的传播情况并识别焦点活动之前的局部周期长度变化模式来研究 pVT 的维持。我们将绘制 APD 的动态变化，包括不一致的交替值及其节点线行为，并与组织异质性和 Ca2+ 处理相关联，以确定产生不一致的交替值和 pVT 的主要因素。这项研究将提供 LQT 相关心律失常的机制见解，可作为进一步分子研究的基础。公共卫生相关性：项目叙述 长 QT 综合征 (LQTS) 是一种复极障碍，其特征是 QT 间期显着延长。 LQTS 患者在多形性 VT 发作期间表现出反复晕厥，导致心源性猝死。先天性 LQTS 最常见的形式为 1 型和 2 型（LQT1 和 LQT2），是由编码延迟整流钾电流的基因突变引起的。然而，这些突变与心律失常之间的联系机制尚不清楚。该提案利用转基因兔模型和高速成像设备研究了这些 LQTS 的心律失常机制。这里获得的数据应该可以提供关于长 QT 相关心律失常所涉及的遗传和电生理因素的更完整的知识。这种知识的增强应该会导致更有效的策略来预防广泛的遗传性和获得性心脏病中的猝死，并具有有意义的公共健康益处。