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: 8268461
• 负责人: Bum-Rak Choi
• 金额: $ 38.24万
• 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/8268461
• 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（由申请方提供）：长QT综合征（LQTS）是一种复极障碍，特征为QT间期显著延长和多态性VT（pVT）发作期间复发性晕厥，称为尖端扭转型室性心动过速（TdP），可导致心源性猝死。目前的共识是，LQT相关心律失常是由早期后除极（埃兹）触发引发的，在复极离散度增强的情况下，EAD导致折返和pVT。埃兹和pVT的诱导与交感神经张力增加相关，这可能会增加复极的离散度，加重折返性心律失常的病情。此外，心率变化，如短-长-短周期长度（暂停依赖模式）或心率加速通常先于TdPs形成，这表明埃兹的产生和复极离散度动态依赖于先前的周期长度历史。尽管进行了大量的研究，但埃兹和TdPs的确切机制和条件尚未明确。本提案的总体目标是研究长QT相关心律失常的机制，包括作为折返底物的组织特征以及加重EAD诱导和pVT的条件。解决这些问题需要映射心脏复极的动态变化，从不同的区域和识别EAD传播的优先位置，并将其与完整心脏中的Ca 2+瞬变相关联。我们建议使用新的转基因兔模型的长QT综合征（LQT 1和LQT 2）由Koren博士的实验室和研究LQT相关的心律失常机制，同时使用跨膜电位和Ca 2+瞬变的光学映射。我们假设LQT 1家兔的心律失常是由交感神经刺激引起的心脏复极储备和Ca 2+超负荷之间的失衡引起的，这启动了埃兹并支持TdPs的维持。相反，在LQT 2兔中，我们假设动态复极变化如不一致交替在折返形成及其退化为VF中起关键作用。我们将测量完整心脏的APD和Ca 2+的动态变化，以研究在有或没有输注异丙肾上腺素的情况下，Ca 2+瞬变和APD对心率变化的适应性，以确定可增加Ca 2+过载和APD离散度的周期长度变化模式。我们将通过使用两台相机从心脏的整个表面绘制埃兹的传播并识别局灶性活动之前的局部周期长度变化的模式来研究pVT的维持。我们将绘制APD的动态变化，包括不协调的交替和它们的结线行为，并与组织异质性和Ca 2+处理相关，以确定产生不协调的交替和pVT的主要因素。本研究将为LQT相关心律失常的发生机制提供新的认识，为进一步的分子研究奠定基础。公共卫生关系：长QT综合征（LQTS）是一种以QT间期显著延长为特征的复极障碍。LQTS患者在多形室性心动过速发作期间表现出反复发作的晕厥，这导致心源性猝死。最常见的先天性LQTS形式，1型和2型（LQT 1和LQT 2），是由编码延迟整流钾电流的基因突变引起的。然而，将这些突变与心律失常联系起来的机制尚不清楚。本研究建议使用转基因兔模型和高速成像设备研究这些LQTS中的心律失常机制。这里获得的数据应该提供更完整的知识到遗传和电生理因素参与长QT相关心律失常。这一知识的提高应导致更有效的战略，以预防猝死在广泛的遗传性和获得性心脏疾病与有意义的公共卫生利益。