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: 10319909
• 负责人: Jeffrey S. Crocker
• 金额: $ 3.87万
• 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/10319909
• 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（心室心律失常； VT/VF）的心脏猝死（SCD）夺生更多的生命 每年在美国，与所有与疾病有关的死亡原因总结在一起。心力衰竭的患者 （HF）SCD风险最高。对连接HF和SCD的潜在机制的理解不足 设计新的，更有效的疗法。 SCD机械研究的最大限制是 缺乏具有人类HF的关键特征的合适的非遗传实验模型。我们已经开发了一本小说 满足这些标准并表明不良适应性β-肾上腺素（β-AR）响应能力导致的模型导致 心脏线粒体活性氧（ROS）的增加，导致钙的演变降低 心脏功能，并增加VT/VF和SCD。我们的实验室进行的先前研究表明，（1）失败 心脏暴露的β-AR反应性降低和电稳定性不佳，可以通过 副交感神经（即毒蕈碱）受体的激活和（2）ROS水平升高直接与差有关 通过ROS清除可以防止心脏功能和SCD。 慢性迷走神经刺激（VNS）是改善左心室（LV）功能的新疗法 HF患者的临床试验。但是，慢性VN的基本机制在很大程度上尚不清楚。 此外，慢性VNS对SCD的影响尚未研究。急性VNS终止心律不齐，而 慢性VNS可能会延长心脏复活性并容易患心律失常，尤其是在HF患者中 通常具有延长的心电图QT间隔。确定慢性VN是否确实是安全的 在人类中治疗HF的方法仍然是一项重要任务。 我们的初步发现表明，尽管慢性VNS确实延长了心电图QT间隔，但 用慢性VN处理的动物显示QT间隔异质性和SCD发病率降低。到 确定慢性VN是否通过ROS或与毒蕈碱相关的机制承认其有益的影响，我们将 测试慢性VNS通过减少钙演化，能量来阻止VT/VF和SCD的假设 在压力超负荷心脏的LV肌细胞中的需求，氧化应激和自主功能障碍 压力。我们的假设将根据以下目的进行检验： 目标1：确定慢性VN对自主平衡，HF，VT/VF和SCD的影响 目标2：确定慢性VN对氧化应激，能量和工作量的影响，在失败的LV肌细胞中 AIM 3：确定慢性VN对良好心脏中机电耦合和SCD风险的影响 这么远，我们已经表明，慢性副交感信号传导代表了一种新的治疗方法 scd。这个高度影响力的项目将使我们能够（1）改善用于HF治疗的慢性VN时， （2）提供一种新颖的，有效的SCD治疗疗法，目前不存在，（3）生成新的 通过直接靶向慢性VNS，SCD和HF的基本机制的研究途径。