Non-reentrant arrhythmias: ectopic nexus hypothesis

描述(申请人提供)：心律失常由脉冲传播异常(基于再入)或脉冲启动异常(局部或异位)引起。再入心律失常的发展，包括围绕解剖或功能块的激发波旋转，在体外和体内都观察到了，从概念上来说是很好的理解。相比之下，我们对异位(非折返性)心律失常的理解有很大差距。为了获得对这一过程的初步了解，我们建议使用一系列可用的心肌组织模型(包括实验和理论模型)，在这些模型中将创建梗死样区域。我们的初步研究表明，异位心律失常的发展是通过一个必要的步骤进行的，我们称之为异位连接(En)，它指的是受损心脏组织的一种功能状态，在这种状态下，多个耦合不良的异位源形成了一个瞬时的“繁殖”微环境，在这个微环境中，异位活动从单个细胞发展到局限于损伤区域的缓慢传播的异位波。来自周围健康组织的激发波不能侵入EN，允许缓慢的异位波与正常传播模式并存。随后EN条件的缓解导致异位波的逃逸，导致心律失常。EN是一个新的概念，如果它真的发生在体内，对心律失常和室颤的理解和临床治疗都有重要的意义。然而，我们以前的研究中采用的实验和理论模型有几个局限性，EN概念与体内心律失常的相关性需要进一步建立。具体地说，我们需要知道EN是否仅限于2D培养的心肌细胞或一组特定的实验条件，电活动如何与使用钙瞬变获得的数据匹配，EN是否发生在3D环境中，以及许多其他问题。本申请的目的是为这些问题提供答案，以建立EN的病理生理学意义。

DESCRIPTION (provided by applicant): Cardiac arrhythmias arise from abnormalities of either impulse propagation (reentry-based) or impulse initiation (focal or ectopic). The development of reentry arrhythmias, which involves rotation of an excitation wave around an anatomical or functional block, was observed both in vitro and in vivo and conceptually is well understood. In contrast, our comprehension of ectopic (non-reentrant) arrhythmias has a major gap. To gain initial insights into this process we propose to use a range of available models of cardiac tissue (both experimental and theoretical) in which infarct-like area will be created. Our preliminary studies have revealed that development of ectopic arrhythmias proceeds via an essential step, which we named an ectopic nexus (EN) It refers to a functional state of an injured cardiac tissue in which multiple poorly-coupled ectopic sources form a transient "breeding" microenvironment in which ectopic activity develops from individual cells into slowly propagating ectopic waves confined to the area of injury. The waves of excitation from surrounding healthy tissue fail to invade the EN, allowing slow ectopic waves to co-exist side-by-side with normal propagation pattern. Subsequent relief of EN conditions results in an escape of the ectopic waves leading to an arrhythmia. The EN is a novel concept, which, if it does occur in vivo, has important implications for both understanding and clinical treatment of arrhythmias and ventricular fibrillation. However, experimental and theoretical models employed in our previous studies had several limitations and the relevance of the EN concept to in vivo arrhythmias needs to be further established. Specifically, one needs to know whether EN is limited to 2D cultures of cardiac cells or to a specific set of experimental conditions, how electrical activity match data obtained using calcium transients, whether the EN occurs in a 3D environment, and many other questions. The goal of this application is to provide answers to these questions in order to establish a pathophysiological significance of EN.