Autonomic remodeling and modulation as mechanism and therapy for sudden cardiac death in heart failure

致死性心律失常（室性快速性心律失常; VT/VF）引起的心源性猝死（SCD）夺去了更多的生命 在美国，每年的死亡人数比所有与疾病有关的死亡原因的总和还要多。心力衰竭患者 (HF)SCD风险最高。对HF和SCD之间联系的潜在机制了解不多， 设计新的、更有效的疗法。SCD机制研究的最大限制是 缺乏具有人类HF关键特征的合适的非遗传实验模型。我们已经开发出一种新颖 模型满足这些标准，并表明适应不良的β-肾上腺素能（β-AR）反应性导致 增加心肌线粒体活性氧（ROS），导致钙紊乱，减少 心功能，VT/VF和SCD增加。我们实验室以前的研究表明，（1）失败 心脏表现出β-AR反应性降低和电稳定性差，这可以通过以下方式逆转： 副交感神经（即毒蕈碱）受体的激活，和（2）增加的ROS水平直接与不良的 通过清除ROS可以预防心功能和SCD。 慢性迷走神经刺激（VNS）是一种很有前途的改善左心室功能的新疗法， HF患者的临床试验。然而，慢性VNS的潜在机制在很大程度上是未知的。 此外，慢性VNS对SCD的影响还有待研究。急性迷走神经刺激终止心律失常， 慢性VNS可延长心脏复极，易发生心律失常，特别是在 心电图QT间期延长。确定慢性VNS是否真的是安全的 治疗人类HF的方法仍然是一项重要的任务。 我们的初步研究结果显示，虽然慢性VNS确实延长了心电图QT间期， 用慢性VNS治疗的动物显示QT间期异质性和SCD发生率降低。到 确定慢性VNS是否通过ROS或毒蕈碱相关机制产生有益作用，我们将 验证慢性VNS通过减少钙紊乱、能量消耗和心肌保护来预防VT/VF和SCD的假设。 压力超负荷心脏起搏过程中左室心肌细胞的需求、氧化应激和自主神经功能障碍 应力我们的假设将根据以下目标进行检验： 目的1：确定慢性VNS对自主神经平衡、HF、VT/VF和SCD的影响 目的2：确定慢性迷走神经刺激对衰竭左室心肌细胞氧化应激、能量学和工作负荷的影响 目的3：确定慢性VNS对离体心脏机电耦合和SCD风险的影响 到目前为止，我们已经表明，慢性副交感神经信号传导代表了一种治疗糖尿病的新方法。 SCD。这个极具影响力的项目将使我们能够（1）改善慢性VNS治疗HF的效果， (2)为SCD治疗提供了一种新的、有效的疗法，而目前还没有这种疗法，以及（3）产生新的 通过直接靶向慢性VNS、SCD和HF的潜在机制的研究途径。

Sudden cardiac death (SCD) from lethal heart rhythms (ventricular tachyarrhythmias; VT/VF) claims more lives each year in the United States than all disease-related causes of death combined. Patients with heart failure (HF) have the highest SCD risk. Poor understanding of underlying mechanisms linking HF and SCD preclude design of new, more effective therapies. The foremost limitation for mechanistic studies of SCD has been the lack of a suitable, non-genetic experimental model with key features of human HF. We have developed a novel model that fulfills these criteria and showed that maladaptive β-adrenergic (β-AR) responsiveness results in increased cardiac mitochondrial reactive oxygen species (ROS), leading to calcium derangement, decreased cardiac function, and increased VT/VF and SCD. Previous studies performed by our lab show that (1) failing hearts exhibit decreased β-AR responsiveness and poor electrical stability which can be reversed through activation of parasympathetic (i.e. muscarinic) receptors, and (2) increased ROS levels are directly linked to poor cardiac function and SCD can be prevented through ROS scavenging. Chronic vagus nerve stimulation (VNS) is a promising new therapy for improving left ventricular (LV) function in clinical trials of HF patients. However the underlying mechanisms for chronic VNS are largely unknown. Furthermore, the effect of chronic VNS on SCD has yet to be studied. While acute VNS terminates arrhythmia, chronic VNS may prolong cardiac repolarization and predispose to arrhythmias, especially in HF patients who typically have prolonged electrocardiographic QT intervals. Establishing whether chronic VNS is truly a safe approach for treating HF in humans remains an important task. Our preliminary findings revealed that although chronic VNS did prolong the electrocardiographic QT interval, animals treated with chronic VNS displayed decreased QT interval heterogeneity and SCD incidence. To determine if chronic VNS confers its salutary effects by way of ROS or muscarinic-related mechanisms, we will test the hypothesis that chronic VNS prevents VT/VF and SCD by reducing calcium derangement, energy demand, oxidative stress, and autonomic dysfunction in LV myocytes during pressure-overload cardiac stress. Our hypothesis will be tested pursuant to the following aims: Aim 1: Determine the effect of chronic VNS on autonomic balance, HF, VT/VF and SCD Aim 2: Determine the effect of chronic VNS on oxidative stress, energetics, and workload in failing LV myocytes Aim 3: Determine the effect of chronic VNS on electromechanical coupling and SCD risk in excised whole hearts Thus far, we have shown that chronic parasympathetic signaling represents a novel approach for treatment of SCD. This highly impactful project will allow us to (1) improve upon delivery of chronic VNS for HF treatment, (2) provide a novel, effective therapy for SCD treatment where none currently exist, and (3) generate new avenues of research through direct targeting of the underlying mechanisms for chronic VNS, SCD, and HF.