Novel mechanisms and treatment of arrhythmia during resuscitation

从心脏骤停(SCA)开始复苏通常是在持续缺血和心室的患者中开始的 纤颤(VF)或心动过速(VT)，即使成功，通常也会反复发作。尽管意义重大 从SCA改善复苏的努力，存活率仍然很低，促使NIH将复苏列为高度优先事项 用于紧急护理研究。心肌细胞复极的节拍交替(复极 交错(Alternans)是心律失常的底物，在复苏过程中猖獗，在心电图上表现为T波 可以交替(2：1)的振荡或更复杂的振荡。在初步研究中，我们观察到在复苏过程中 在从SCA复苏的体内翻译模型中，由于室性心动过速/室颤引起的再停搏先于T波 振荡是复杂的；然而，无脉搏电活动(PEA)引起的再停搏之前会有T波的增加 交替的振荡。因此，我们认为当T波振荡是复杂的时，复极交替 在心肌中是空间不协调的，这是在相邻区域和 是高度心律失常的。相反，当T波振荡交替时，心肌中的复极交替是 空间同相(协调)，不构成已知的直接心律失常风险，但与机械相关 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而再次被捕的风险是 很低。我们推测，在复苏过程中，由于室速/室颤或PEA引起的再停搏与复极交替密切相关。 在心肌中，分别是空间不协调的或不协调的，以及专门针对潜在的 机制可以防止因VT/VF和可能的PEA而再次被捕。此外，心电信号T波振荡的全频谱 可以用来预测VT/VF或PEA没有再捕获和再捕获，因此，未来可以作为生物标志物用于 指导治疗并显著改善结果。我们的假设将通过以下目标进行检验。1)确定 细胞复极交替与体内VT/VF或PEA引起的再停搏的机制关系 对复苏的信心。2)确定针对复极交替的机制是否可以防止在 复苏，从而获得额外的机械洞察力。3)开发和测试心电生物标记物，用于预测高血压的风险 复苏患者VT/VF和PEA引起的再停跳。为了实现这些目标，我们将利用先进的 体内复苏平移模型中的器械和信号处理，以及在医院前和医院内。 医院的复苏病人。我们还建立了高度翻译的协作，将专业知识结合在一起 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一个独特的 有机会更好地了解与复苏相关的心律失常机制，以便制定 新颖有效的治疗方法。

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.