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

缺血后心脏非梗塞但损伤心肌的识别和病理生理学

基本信息

批准号：
10156372
负责人：
Rishi Arora
金额：
$ 76.62万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10156372
关键词：
Acute Apoptosis Arrhythmia Biological Models Cardiac Cardiac Electrophysiologic Techniques Cardiac Myocytes Cardiology Cell Death Characteristics Chronic Chronic Phase Data Denervation Diagnosis EFRAC Electrophysiology (science)Event Evolution Exhibits Functional disorder Goals Heart Heterogeneity Hypertrophy Image Imaging Techniques Impairment Infarction Injury Investigation Ischemia Knowledge Life Link Maps Measurement Methodology Methods Molecular Myocardial Myocardial Ischemia Myocardial dysfunction Myocardium Necrosis Neurons Oxidative Stress Pathologic Pathology Pathway interactions Phase Phosphatidylethanolamine Prognosis Proteomics Reperfusion Therapy Research Research Personnel Residual state Risk Role Shapes Signal Pathway Signal Transduction Specificity Testing Tissues Ventricular Arrhythmia acute coronary syndrome base cell type clinical Diagnosis clinical practice clinically relevant functional disability image guided in vivo in vivo imaging injured insight knowledge base myocardial injury nerve supply novel personalized care prognostic value response spatiotemporal tissue injury tool transcriptomics

项目摘要

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.

摘要 - 在缺血后的心脏中，人们对受伤但未梗死的心肌知之甚少。我们称之为中间区，因为它既不正常也不梗塞。我们最近发现了引人注目的有证据表明，中间区不仅仅是“较小的梗塞”，而是具有一系列独特的病理学特征特征并显着导致心脏损伤。这些新发现成为可能通过克服技术挑战。我们开发了高灵敏度磷脂酰乙醇胺（PE）- 基于成像技术，能够绘制中间区域的地图，否则会错过常规方法。使用影像引导的病理分析，我们发现，与梗塞相比所有细胞类型均出现坏死的区域，在中间区域，不同细胞类型的存活情况不同。存活的心肌细胞（残余收缩力）和交感神经元损失之间的差异（神经失调）造成电生理学混乱。长期来看，中间区表现出功能性与肥大相关的信号激活缺陷。数据有力地支持了中间该区域具有显着的收缩功能障碍并且是心律失常的基础。因此，有对于评估心肌损伤的全部范围和预测心肌损伤具有重要的预后价值心律失常的风险。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功能障碍的独特病理实体。这假设将在三个综合和协同的具体目标中得到检验：1）完善体内成像绘制中间区域的方法，并在成像中表征该组织的病理学引导方法； 2) 确定中间区域的信令变化； 3）调查角色心律失常发生的中间区。总的来说，积极识别中间区域的能力 in vivo 提供了关键的技术突破。通过了解信号传导、病理性和功能性如果该组织发生变化，我们的发现最终将对丰富知识库产生变革性影响并塑造 ACS 的临床实践。