权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10551803
负责人：
Rishi Arora
金额：
$ 75.59万
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/10551803
关键词：
Acute Apoptosis Arrhythmia Biological Models Cardiac Cardiac Electrophysiologic Techniques Cardiac Myocytes Cardiology Cell Death Characteristics Chronic Chronic Phase Data Denervation Diagnosis Disparity 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 Induction Pathologic Pathology Pathway interactions Patients Phase Phosphatidylethanolamine Prognosis Proteomics Reperfusion Therapy Research Research Personnel Residual state Risk Role Shapes Signal Pathway Signal Transduction Specificity Technology Testing Tissues Ventricular Arrhythmia acute coronary syndrome cell type clinical diagnosis clinical practice clinically relevant detection method functional disability image guided in vivo in vivo imaging injured insight knowledge base myocardial injury nerve supply novel personalized care prognostic value response risk prediction spatiotemporal tissue injury tissue mapping 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。