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

描述(申请人提供)：长QT综合征(LQTS)是一种复极障碍，其特征是QT间期显著延长，在多形性室速(PVT)发作时反复晕厥，称为尖端扭矩(Torsade de Pointes，TDP)，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(EADS)引发的，在复极离散度增强的情况下，这会导致折返和室速。EADS和PVT的诱发与交感神经张力增加有关，这可能会增加复极的离散度，加剧折返性心律失常的条件。此外，心率变化，如短-长-短周期长度(停顿依赖模式)或心率加速往往在TDPS形成之前，这表明EADs的产生和复极的离散动态地依赖于先前的周期长度历史。尽管进行了大量的研究，但对EADS和TDPS的确切机制和条件尚不清楚。这项建议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剧EAD诱导和室性早搏的条件。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钙瞬变相关联。我们建议使用Korn博士的实验室建立的新型长QT综合征转基因兔模型(LQT1和LQT2)，并利用跨膜电位和钙瞬变的同步光学标测来研究LQT相关的心律失常机制。我们假设LQT1兔的心律失常是由于交感神经刺激引起的心脏复极储备和钙超载的失衡所致，从而引发EADS并支持TDPS的维持。相反，在LQT2兔中，我们假设动态复极变化，如不和谐交替，在再入形成及其退化为室颤中起关键作用。我们将测量完整心脏的时程和钙的动态变化，以研究钙瞬变和时程对异丙肾上腺素或不静注异丙肾上腺素时心率变化的适应性，以确定可增加钙超载和时程离散度的周期变化模式。我们将使用两台摄像机从整个心脏表面绘制EADS的传播图，并识别震源活动之前局部周期长度变化的模式，以此来研究PVT的维持。我们将绘制APD的动态变化图，包括不协调交替及其节线行为，并与组织异质性和钙处理相关联，以确定造成不协调交替和PVT的主要因素。本研究将为LQT相关心律失常的机制研究提供理论依据，为进一步的分子研究奠定基础。公共卫生相关性：项目简介长QT间期综合征(LQTS)是一种以QT间期显着延长为特征的复极障碍。LQTS患者在多形性室速发作时反复晕厥，导致心源性猝死。最常见的先天性LQT，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，将这些突变与心律失常联系起来的机制尚不清楚。这项建议使用转基因兔模型和高速成像设备来研究这些LQT的心律失常机制。这些数据将为长QT间期相关心律失常的遗传和电生理因素提供更完整的知识。这一增强的知识应该导致更有效的战略，以预防广泛的遗传性和获得性心脏病的猝死，并对公共卫生产生有意义的好处。

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.