Novel mechanisms and treatment of arrhythmia during resuscitation

复苏期间心律失常的新机制和治疗

基本信息

批准号：
9886863
负责人：
KENNETH LAURITA
金额：
$ 66.9万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-10 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886863
关键词：
Acute Arrhythmia Biological Markers Blood Circulation Cardiac Clinical Collaborations Complex Coupling Data Development Distress Electrocardiogram Electrophysiology (science)Emergency Medicine Emergency research Environment Functional disorder Future Gap Junctions Heart Heart Arrest Hospitals Ischemia Link Machine Learning Mechanics Metabolic Modeling Myocardial Ischemia Myocardium Outcome Patients Pattern Phase Public Health Reperfusion Therapy Resuscitation Risk Sum Techniques Testing Therapeutic Translating Treatment Efficacy United States United States National Institutes of Health Ventricular Fibrillation Ventricular Tachycardia base effective therapy epicardial mapping hemodynamics improved improved outcome in vivo in vivo Model insight instrument instrumentation mortality novel novel therapeutics predictive marker prevent rearrest signal processing translational model

项目摘要

Resuscitation from sudden cardiac arrest (SCA) is typically initiated in patients with ongoing ischemia and ventricular fibrillation (VF) or tachycardia (VT) that, even if successful, is commonly followed by repeated rearrest. Despite significant efforts to improve resuscitation from SCA, survival remains poor prompting NIH to identify resuscitation as a high priority for emergency care research. Beat-to-beat alternans of cellular repolarization in the myocardium (repolarization alternans) is a substrate for arrhythmias, is rampant during resuscitation, and is manifested on the ECG as T-wave oscillations that can alternate (2:1) or as more complex oscillations. In preliminary studies, we observed in resuscitation patients and in an in vivo translational model of resuscitation from SCA, that rearrest due to VT/VF is preceded by T-wave oscillations that are complex; whereas, rearrest due to pulseless electrical activity (PEA) is preceded by increased T-wave oscillations that alternate. Accordingly, we contend that when T-wave oscillations are complex, repolarization alternans in the myocardium is spatially discordant, which is repolarization alternans occurring out-of-phase in adjacent regions and is highly arrhythmogenic. In contrast, when T-wave oscillations alternate, repolarization alternans in the myocardium is spatially in-phase (concordant), which poses no known immediate arrhythmia risk but is associated with mechanical dysfunction and, thus, PEA. Finally, in the absence of any repolarization alternans, risk of rearrest due to PEA or VT/VF is low. We hypothesize that during resuscitation rearrest due to VT/VF or PEA is strongly linked to repolarization alternans in the myocardium that is spatially discordant or not, respectively, and that specifically targeting the underlying mechanisms can prevent rearrest due to VT/VF and, possibly, PEA. In addition, the full spectrum of ECG T-wave oscillations can be utilized to predict no rearrest and rearrest from VT/VF or PEA and, thus, be used in the future as a biomarker to guide therapy and significantly improve outcomes. Our hypotheses will be tested with the following aims. 1) Determine the mechanistic relationship between cellular repolarization alternans and rearrest due to VT/VF or PEA in an in vivo model of resuscitation. 2) Determine if targeting the mechanisms of repolarization alternans can prevent rearrest during resuscitation, thereby gaining additional mechanistic insight. 3) Develop and test an ECG biomarker for predicting risk of rearrest due to VT/VF and PEA in resuscitation patients. To achieve these aims, we will utilize sophisticated instrumentation and signal processing in an in vivo translational model of resuscitation as well as in pre-hospital and in- hospital resuscitation patients. We have also established a highly translational collaboration that combines expertise in emergency medicine, cardiac arrhythmia, and clinical electrophysiology. Our scientific environment provides a unique opportunity to develop a better understanding of arrhythmia mechanisms relevant to resuscitation in order to develop novel and effective therapies.

心脏骤停 (SCA) 的复苏通常是在持续缺血和心室衰竭的患者中开始的。颤动（VF）或心动过速（VT），即使成功，通常也会出现反复的重新休息。尽管显着努力改善 SCA 的复苏，但生存率仍然很低，促使 NIH 将复苏列为高度优先事项用于紧急护理研究。心肌细胞复极化的逐搏交替（复极化 alternans）是心律失常的基础，在复苏期间猖獗，并在心电图上表现为 T 波可以交替 (2:1) 或更复杂的振荡。在初步研究中，我们观察到复苏患者和 SCA 复苏的体内转化模型中，由于 VT/VF 导致的重新停止之前是 T 波复杂的振荡；然而，由于无脉电活动 (PEA) 导致的重新停顿之前会出现 T 波增加交替的振荡。因此，我们认为，当 T 波振荡复杂时，复极交替心肌中的空间不一致，即相邻区域异相发生复极交替，是高度致心律失常的。相反，当 T 波振荡交替时，心肌中的复极交替是空间同相（一致），不会造成已知的直接心律失常风险，但与机械性相关功能障碍，因此，PEA。最后，在没有任何复极交替的情况下，由于 PEA 或 VT/VF 导致再次停搏的风险是低的。我们假设，在复苏过程中，由于 VT/VF 或 PEA 导致的再停与复极交替密切相关分别在空间不协调或不协调的心肌中，并且专门针对底层机制可以防止由于 VT/VF 和可能的 PEA 导致的重新逮捕。此外，心电图 T 波振荡的全频谱可用于预测 VT/VF 或 PEA 的无再静止和再静止，因此，在未来可用作生物标志物指导治疗并显着改善结果。我们的假设将通过以下目标进行检验。 1）确定体内模型中由于 VT/VF 或 PEA 导致的细胞复极化交替与再静止之间的机械关系复苏。 2) 确定针对复极交替机制是否可以防止在复苏，从而获得额外的机制见解。 3) 开发并测试心电图生物标志物以预测以下风险复苏患者中由于 VT/VF 和 PEA 导致的再次复苏。为了实现这些目标，我们将利用先进的复苏体内转化模型以及院前和院内的仪器和信号处理医院复苏病人。我们还建立了高度转化的合作，结合了以下领域的专业知识：急诊医学、心律失常和临床电生理学。我们的科学环境提供了独特的有机会更好地了解与复苏相关的心律失常机制，以便发展新颖有效的疗法。