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

自主神经重塑和调节作为心力衰竭心源性猝死的机制和治疗

• 批准号: 9911551
• 负责人: Jeffrey S. Crocker
• 金额: $ 3.82万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911551
• 关键词: Action Potentials; Acute; Address; Adrenergic Agents; American; Animals; Antibodies; Antioxidants; Arrhythmia; Autonomic Dysfunction; Bioenergetics; Calcium; Canis familiaris; Cardiac; Cause of Death; Cavia; Chronic; Clinical Trials; Coupling; Development; Dilated Cardiomyopathy; Disease; Doctor of Philosophy; Echocardiography; Electrocardiogram; Equilibrium; Exhibits; Experimental Models; Feedback; Felis catus; Free Radicals; Genetic Models; Goals; Heart; Heart Rate; Heart failure; Heterogeneity; Human; Hypertension; Hypertrophy; Incidence; Left; Left Ventricular Function; Link; Mediating; Methods; Mitochondria; Modeling; Molecular; Muscarinic Acetylcholine Receptor; Muscarinic M3 Receptor; Muscarinics; Muscle Cells; Optics; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pharmacology; Process; Protein Isoforms; Reactive Oxygen Species; Receptor Signaling; Research; Role; Sarcomeres; Signal Pathway; Signal Transduction; Stress; Tachyarrhythmias; Telemetry; Testing; Therapeutic; Training; Translating; Treatment Failure; United States; Ventricular; Work; Workload; cardiac resynchronization therapy; clinically relevant; desensitization; design; effective therapy; heart function; heart rhythm; improved; in vivo; insight; mortality; mortality risk; non-genetic; novel; novel strategies; novel therapeutics; pressure; prevent; sudden cardiac death; targeted treatment; therapeutic target; therapy design; vagus nerve stimulation

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.

致命心律（室性快速心律失常；VT/VF）导致的心源性猝死 (SCD) 夺去了更多人的生命 在美国，每年的死亡人数比所有疾病相关死亡人数的总和还要多。心力衰竭患者 (HF) 的 SCD 风险最高。对 HF 和 SCD 之间联系的根本机制了解不足，无法排除 设计新的、更有效的疗法。 SCD 机制研究的首要限制是 缺乏具有人类心衰关键特征的合适的非遗传实验模型。我们开发了一本小说 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 心脏线粒体活性氧（ROS）增加，导致钙紊乱，减少 心脏功能，并增加 VT/VF 和 SCD。我们实验室之前进行的研究表明 (1) 失败 心脏表现出β-AR反应性下降和电稳定性差，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，以及（2）ROS水平升高与不良反应直接相关。 心脏功能和 SCD 可以通过 ROS 清除来预防。 慢性迷走神经刺激（VNS）是一种有前途的新疗法，可改善左心室（LV）功能 心力衰竭患者的临床试验。然而，慢性 VNS 的潜在机制在很大程度上尚不清楚。 此外，慢性 VNS 对 SCD 的影响仍有待研究。虽然急性 VNS 可以终止心律失常， 慢性 VNS 可能会延长心脏复极时间并导致心律失常，尤其是心力衰竭患者 通常心电图 QT 间期延长。确定慢性 VNS 是否真正安全 治疗人类心力衰竭的方法仍然是一项重要任务。 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， 接受慢性 VNS 治疗的动物表现出 QT 间期异质性和 SCD 发生率降低。到 确定慢性 VNS 是否通过 ROS 或毒蕈碱相关机制赋予其有益作用，我们将 检验慢性 VNS 通过减少钙紊乱、能量来预防 VT/VF 和 SCD 的假设 压力超负荷心脏过程中左室肌细胞的需求、氧化应激和自主神经功能障碍 压力。我们的假设将根据以下目标进行检验： 目标 1：确定慢性 VNS 对自主平衡、心力衰竭、室速/心室颤动和 SCD 的影响 目标 2：确定慢性 VNS 对衰竭左室肌细胞氧化应激、能量和工作负荷的影响 目标 3：确定慢性 VNS 对切除的整个心脏的机电耦合和 SCD 风险的影响 到目前为止，我们已经证明慢性副交感神经信号传导代表了治疗以下疾病的一种新方法： SCD。这个具有高度影响力的项目将使我们能够 (1) 改进用于心力衰竭治疗的慢性 VNS 的交付， (2) 为目前不存在的 SCD 治疗提供一种新颖、有效的疗法，以及 (3) 产生新的疗法 通过直接针对慢性 VNS、SCD 和 HF 的潜在机制的研究途径。