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: 8476251
• 负责人: Bum-Rak Choi
• 金额: $ 36.4万
• 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 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8476251
• 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.

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间隔显着延长和在多态性VT（PVT）发作期间被称为torsade de Pointes（TDP），导致心脏突然死亡。当前的共识是，与LQT相关的心律不齐是由早期过度化（EADS）发射引发的，而在增强的复制分散体的情况下，这会导致重新进入和PVT。 EAD和PVTS的诱导与同情性语调的增加有关，这可能会增加重极化的分散体，加剧重入性心律不齐的条件。此外，心率变化，例如短距离周期长度（暂停依赖性模式）或心率加速通常先于TDPS形成，这表明EADS的产生和复极化的分散是动态取决于先前的循环长度的历史。尽管进行了激烈的研究，但尚未清楚地了解EADS和TDP的确切机制和条件。该提案的总体目标是研究长期QT相关心律不齐的机制，包括组织特征，作为重新进入的底物和加剧归纳和PVT的条件的底物。解决这些问题需要从不同区域进行心脏复极化的动态变化，并确定EAD传播的优先位置，并将其与完整心脏中的Ca2+瞬变相关联。我们建议使用由Koren博士实验室创建的长QT综合征（LQT1和LQT2）的新型转基因兔模型，并使用跨膜电位和CA2+瞬变的同时光学映射研究LQT相关的心律不齐机制。我们假设LQT1兔中的心律失常是由心脏复极储备和Ca2+过载之间的交感神经诱导的失衡引起的，这会启动EADS并支持TDP的维护。相比之下，在LQT2兔子中，我们假设动态复极化发生了变化，例如不一致的替代品在重新进入形成及其退化为VF中起关键作用。为了研究Ca2+瞬变的适应和APD的适应性，我们将测量APD和Ca2+的动态变化，并随着或不输注异丙肾上腺素的心率变化，以识别可以增加Ca2+过载和APD分散体的循环长度变化的模式。我们将使用两个摄像头映射从心脏的整个表面的EAD进行映射，并识别焦点活性之前的局部周期长度变化的模式来研究PVT的维护。我们将绘制APD的动态变化，包括不一致的替代品及其淋巴结行为，并与组织异质性和CA2+处理相关，以识别产生不和谐的替代品和PVT的主要因素。这项研究将提供与LQT相关的心律不齐的机械见解，可以用作进一步分子研究的基础。

项目成果

Short-Long Heart Rate Variation Increases Dispersion of Action Potential Duration in Long QT Type 2 Transgenic Rabbit Model.

短-长心率变化增加了长 QT 2 型转基因兔模型中动作电位持续时间的离散度。

• DOI: 10.1038/s41598-019-51230-9
• 发表时间: 2019
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Kim,TaeYun;Jeng,Paul;Hwang,JungMin;Pfeiffer,Zachary;Patel,Divyang;Cooper,LeroyL;Kossidas,Konstantinos;Centracchio,Jason;Peng,Xuwen;Koren,Gideon;Qu,Zhilin;Choi,Bum-Rak
• 通讯作者: Choi,Bum-Rak

Calcium measurements from whole heart using Rhod-2.

使用 Rhod-2 对整个心脏进行钙测量。

• DOI: 10.1007/978-1-62703-086-1_13
• 发表时间: 2013
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Choi,Bum-Rak