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

摘要-在缺血后心脏中，对受损但未梗死的心肌知之甚少， 我们称之为中间区，因为它既不是正常的，也不是梗塞的。我们最近发现了令人信服的 证据表明，中间带不仅仅是“较小的梗塞”，而且有一套独特的病理改变。 并对心脏损害有很大贡献。这些新奇的发现成为可能 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，使得能够映射否则将错过的中间区域 传统的方法。使用成像引导的病理分析，我们发现，与脑梗塞相反 所有类型的细胞都有坏死的区域，在中间区域，不同类型的细胞存活不同。 存活的心肌细胞(残余收缩能力)和交感神经元丧失之间的差异 (神经紊乱)在电生理学上造成混乱。从长期来看，中间带表现出功能性 与肥大相关的信号激活的缺陷。数据有力地支持了中间人 地带有显著的收缩功能障碍，也是心律失常的底物。因此，有以下几种 对评估心肌损害的全部范围和预测 有发生心律失常的风险。基于这些发现，我们提出了一个中心假设，即中间带 构成了一个独特的病理实体，导致了缺血后心脏的功能障碍。这个 假设将在三个综合和协同的具体目标中得到验证：1)改进活体成像 绘制中间带图的方法，并在成像中表征该组织的病理- 引导性方法；2)确定中间区的信号变化；3)研究其作用 在心律失常发生中的中间区。总而言之，积极识别中间地带的能力 体内试验提供了一项关键的技术突破。通过了解信号、病理和功能 这种组织的变化，我们的发现最终将对丰富知识库产生变革性的影响 以及塑造急性冠脉综合征的临床实践。

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.