Novel mechanisms and treatment of arrhythmia during resuscitation

心脏骤停（SCA）的复苏通常在持续缺血和心室重构的患者中启动。 房颤（VF）或心动过速（VT），即使成功，通常也会重复再停。尽管取得了重大 尽管努力改善SCA的复苏，但生存率仍然很低，促使NIH将复苏确定为高度优先事项 用于急救护理研究。心肌细胞复极化的搏动交替（复极化 交替）是心律失常的基质，在复苏期间猖獗，并且在ECG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， 患者和在SCA复苏的体内转化模型中，由于VT/VF导致的再骤停之前是T波 振荡是复杂的;而由于无脉电活动（PEA）的再逮捕之前，T波增加 交替的振荡。因此，我们认为，当T波振荡是复杂的，复极交替 在心肌中是空间不一致的，这是在相邻区域中异相发生的复极交替， 是高度致癌的。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），不构成已知的即刻心律失常风险，但与机械性 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导致的再停搏的风险是 低我们假设在复苏过程中，由于VT/VF或PEA引起的再骤停与复极交替密切相关 在心肌中，分别是空间不一致的或不一致的，并且特异性靶向下面的 机制可以防止由于VT/VF和可能的PEA而导致的再次心跳骤停。此外，心电图T波振荡的全频谱 可用于预测VT/VF或PEA的无再停搏和再停搏，因此，将来可用作生物标志物， 指导治疗并显著改善结果。我们的假设将以下列目标进行检验。1)确定 在体模型中细胞复极交替与VT/VF或PEA引起再阻滞之间的机制关系 复苏。2)确定靶向复极交替的机制是否可以防止再阻滞， 复苏，从而获得额外的机械洞察力。3)开发和测试用于预测以下风险的ECG生物标志物： 复苏患者因VT/VF和PEA而再次停搏。为了实现这些目标，我们将利用先进的 仪器和信号处理在复苏的体内转化模型以及在院前和在 医院复苏病人。我们还建立了高度转化的合作关系， 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， 新的和有效的治疗方法。

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.