Non-reentrant arrhythmias: ectopic nexus hypothesis

描述（由申请人提供）：心律失常由脉冲传播（基于折返）或脉冲起始（局灶性或异位）异常引起。 在体外和体内均观察到折返性心律失常的发展，其涉及兴奋波围绕解剖或功能阻滞的旋转，并且在概念上是很好理解的。 相反，我们对异位（非折返性）心律失常的理解有很大的差距。 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脏组织模型（实验和理论），其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重要的步骤进行的，我们将其命名为异位连接（EN）。它是指受损心脏组织的一种功能状态，其中多个耦合不良的异位源形成一个短暂的“繁殖”微环境，其中异位活动从单个细胞发展为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无法侵入EN，从而允许缓慢的异位波与正常传播模式并排共存。 EN条件的后续缓解导致异位波的逃逸，从而导致心律失常。 EN是一个新的概念，如果它确实发生在体内，对心律失常和室颤的理解和临床治疗都有重要意义。 然而，在我们以前的研究中采用的实验和理论模型有一些局限性，EN概念与体内心律失常的相关性需要进一步确定。 具体来说，人们需要知道EN是否限于心脏细胞的2D培养物或特定的实验条件，电活动如何匹配使用钙瞬变获得的数据，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.