The identification and pathophysiology of non-infarcted but injured myocardium in the post-ischemic heart

摘要-在缺血后心脏中，对损伤但未梗死的心肌了解相对较少， 我们称之为中间区，因为它既不正常也不梗塞。我们最近发现 有证据表明，中间区不仅仅是一个“较小的梗死”，但有一套独特的病理 特征，并显著导致心脏损害。这些新奇的发现 通过克服技术挑战。我们开发了一种高灵敏度的磷脂酰乙醇胺（PE）- 基于成像技术，能够映射中间区域，否则会被错过 常规方法。通过影像学引导的病理分析，我们发现，与梗死相比， 在所有细胞类型都有坏死的区域中，在中间区域中，不同的细胞类型以不同的方式存活。 存活的心肌细胞（残余收缩力）和交感神经元丢失之间的差异 （神经支配障碍）在电生理学中造成混乱。长期以来，中间区表现出功能性 缺乏与肥大相关的信号传导激活。数据有力地支持了中间体 区具有显著的收缩功能障碍以及作为心律失常的基质。因此， 对于评估心肌损伤的全部范围和预测 心律失常的风险。基于这些发现，我们提出了一个中心假设，即中间区 构成了导致缺血后心脏的心功能障碍的独特病理实体。的 将在三个综合和协同的具体目标中检验假设：1）改进体内成像 用于映射中间区的方法，并在成像中表征该组织的病理学， 引导方法; 2）确定中间区的信号变化; 3）调查 是一个过渡带。总的来说，积极识别中间区的能力 提供了关键的技术突破。通过了解信号，病理和功能 我们的发现最终将对丰富知识基础产生变革性的影响， 和塑造ACS的临床实践。

ABSTRACT - In the post-ischemic heart, relatively little is known about the injured-but-not-infarcted myocardium, which we call the intermediate zone as it is neither normal nor infarcted. We recently identified compelling evidence that the intermediate zone is not merely a "lesser infarct", but has a set of unique pathological characteristics and contributes significantly to cardiac impairment. These novel discoveries were made possible by overcoming a technological challenge. We developed a high-sensitivity phosphatidylethanolamine (PE)- based imaging technique, enabling the mapping of the intermediate zone which is otherwise missed by conventional methods. Using imaging-guided pathological analyses, we discovered that, in contrast to the infarct zone where there is necrosis across all cell types, in the intermediate zone different cell types survive differently. This disparity between surviving cardiomyocytes (residual contractility) and loss of sympathetic neurons (dysinnervation) creates chaos in electrophysiology. Chronically, the intermediate zone exhibits functional deficiency with signaling activation associated with hypertrophy. The data strongly support that the intermediate zone has significant contractile dysfunction as well as being a substrate for arrhythmias. As such, there are significant prognostic values both for assessing the full scope of myocardial impairment and for predicting the risk for arrhythmias. Based on these findings, we propose a central hypothesis that the intermediate zone constitutes a distinct pathological entity which contributes to cardiac dysfunction in the post-ischemic heart. The hypothesis will be tested in three integrated and synergistic Specific Aims: 1) to refine the in vivo imaging methodology for mapping the intermediate zone, and characterize the pathology of this tissue in an imaging- guided approach; 2) to determine the signaling changes in the intermediate zone; and 3) to investigate the roles of the intermediate zone in arrhythmogenesis. Collectively, the ability to positively identify the intermediate zone in vivo provides a critical technological breakthrough. By understanding the signaling, pathological and functional changes in this tissue, our findings will ultimately have a transformative impact on enriching the knowledge base and shaping clinical practices in ACS.