Mechanistic Determinants of Pacing-induced Cardiac Memory

描述(申请人提供)：“心脏记忆”是指在窦性心律或心房起搏期间T波的变化，其向量追踪先前的室性起搏或心律失常间期的QRS波群的向量。心脏记忆的重要性不仅在于它在心脏起搏治疗和节律控制方面的临床影响，还在于它提供了一个窗口，将控制复极化的机制从分子决定因素转化为人类表达。通过研究心脏记忆，我们可以跟踪从体表心电图和心电向量图记录的激活启动的复极变化，通过心脏表面的复极图，心外膜、中层心肌和心内膜的动作电位，影响兴奋和复极的成分缝隙连接和离子通道，以及通过信号分子和基因转录及其翻译，似乎机械地负责在心电和向量机上记录的波形。在我们的研究方案中，这个翻译序列中的每一步都被考虑在内，这些方案既有简约主义的(提出关于分子机制的问题)，也有一体化的(为心脏原位合成这些信息)。尤其重要的是，所研究的T波变化反映了心肌复极可逆或不可逆重塑的特性。心脏重构是心脏对生理和病理压力的一种基本反应。到目前为止，我们的研究强调了长期的心脏记忆，这种记忆是由数天-数周的起搏引起的，并至少部分依赖于基因转录的改变，以使其发生和持续。然而，最近的实验提供了重要的线索，影响了我们对短期记忆(由几分钟-几小时的步调引起的)以及它向长期记忆的转变的理解。因此，我们5年更新应用的总体目标是：了解机制：(A)启动短期心脏记忆，(B)确定从短期记忆到长期记忆的转变，以及(C)确定长期记忆的维持和逆转。我们的一般假设是，心室起搏改变心肌局部伸展，以(A)通过离子通道的运输启动短期记忆，以及(B)启动转录变化，其下游表达导致长期心脏记忆。我们进一步假设：(C)这些变化在表达上是区域性的，可以修改或逆转。研究将在我们完整的犬模型中进行，在分离的心脏组织中，在分解的心肌细胞中和在细胞系中进行。尽管我们使用了来自不同学科的各种技术，但这项研究是由电生理驱动的。这种方法不是简化论者，而是试图合成信息，以便我们能够更好地理解和影响一个临床上重要的问题。

DESCRIPTION (provided by applicant): "Cardiac memory" refers to T wave changes during sinus rhythm or atrial pacing whose vectors track those of the QRS complexes during prior intervals of ventricular pacing or arrhythmia. The importance of cardiac memory is not only in its clinical impact with regard to cardiac pacing therapies and rhythm control but in its provision of a window for translating mechanisms that control repolarization from molecular determinant to human expression. Studying cardiac memory lets us follow activation-initiated repolarization changes recorded from the body surface ECG and VCG, through repolarization maps of the cardiac surface, action potentials in epicardium, midmyocardium and endocardium, the component gap junctions and ion channels that influence excitation and repolarization, and through the signaling molecules and gene transcription and its translation that appear mechanistically responsible for waveforms recorded on ECG and VCG. Every step in this translational sequence is considered in our research protocols, which are both reductionist (asking question regarding molecular mechanism) and integrative (synthesizing this information for the heart in situ). Of particular importance is that the T wave changes studied reflect a property of myocardial repolarization to remodel reversibly or irreversibly. And remodeling is a fundamental response of the heart to physiologic and pathologic stresses. To date, our research has emphasized long-term cardiac memory, induced by days- weeks of pacing and dependent-at least in part - on altered gene transcription for its occurrence and persistence. However, recent experiments have provided important leads impacting on our understanding of both short-term memory (induced by minutes-hours of pacing) and its transition to long-term memory. Hence the overall goal for our 5 year renewal application: is to understand mechanisms (a) initiating short-term cardiac memory, (b) determining the transition from short- to long-term memory and (c) determining maintenance and reversal of long-term memory. Our general hypotheses are that ventricular pacing alters myocardial stretch regionally to (a) initiate short-term memory via trafficking of ion channels and (b) initiate transcriptional changes whose downstream expression leads to long-term cardiac memory. We further hypothesize that (c) these changes are regional in their expression and can be modified or reversed. Studies will be performed in our intact canine model, in isolated cardiac tissues, in disaggregated myocytes and in a cell line. Although we use a variety of techniques from diverse disciplines, the research is electrophysiologically-driven. Rather than being reductionist, the approach attempts to synthesize information so that we can better comprehend and impact on a clinically important problem.