Spinal Neuraxial Modulatin of Ventricular Excitability - Mechanisms and Therapeutics

项目摘要/摘要 室性快速性心律失常(VT)引起的心脏性猝死(SCD)是 美国。自主神经系统的失调，特别是交感神经兴奋，起着重要作用。 在缺血性心脏病继发心律失常的病理生理中的作用。脊髓服务于 作为控制交感神经反射到心脏的主要连接点。然而，在这方面有很大的差距 在脊髓水平上理解心脏兴奋性的调节。脊椎神经调节疗法- 脊髓刺激(SCS)和背根神经节(DRG)刺激，显示出减少VTS的希望， 但这些创新方法的治疗益处背后的机制在很大程度上仍不清楚。 这项建议的目标是确定脊髓如何处理心脏传入冲动 并解释神经调节疗法如何减少室性心律失常，导致 它们的使用更加有效和广泛。 在这个方案中，假设独特的心脏脊髓神经网络整合了心脏的传入 在心肌缺血(MI)期间的信号和控制交感兴奋，从而调节心律失常的发生。 此外，心肌梗死还会触发心脏脊髓神经回路的病理性重构，从而增加心肌梗死的发生率。 交感神经兴奋。刺激SCS和DRG，通过诱导GABA信号减少交感神经输出 减少慢性心肌梗死后的心室兴奋性和心律失常。重要的是 初步功能数据显示，SCS在急性I/R期间的抗心律失常作用在存在时被取消 GABA受体拮抗剂，支持这一假说。实时荧光定量聚合酶链式反应显示GABAA和GABAA的表达 心肌梗死时脊髓GABAB受体在SCS治疗中增加。因此，心脏传入的调节 脊髓的神经输入是抑制交感神经反射过度激活的新靶点 和心律失常。为了从机械上理解这种方法的治疗潜力，建议 实验将评估神经调节对心脏脊髓神经网络和心室兴奋性的影响。 拟议的研究将评估在脊髓调节心脏兴奋性的新机制。 水平。特定的AIMS 1旨在提供对脊髓加工的作用的机械性理解 心脏传入神经输入。心脏脊髓神经网络的电生理和神经化学改变 慢性心肌梗死将与承受额外心脏应激(急性)的健康心脏进行比较 缺血/再灌流)。慢性心肌梗死诱导心肌细胞病理性重构的分子机制 将以心脏脊髓神经网络为特征。在具体目标2和3中，SCS和DRG 刺激减少慢性心肌梗死患者心脏脊髓神经网络重构和心肌交感神经兴奋 我会被指认出来的。拟议的研究将提供框架，以最大限度地发挥治疗潜力 神经调节在缓解慢性心肌梗死患者心脏和神经重构中的作用。

Project Summary/Abstract Sudden cardiac death (SCD) due to ventricular tachyarrhythmias (VT) is the leading cause of death in the United States. Dysregulation of the autonomic nervous system, specifically sympathoexcitation, plays a major role in the pathophysiology of cardiac arrhythmias secondary to ischemic heart disease. The spinal cord serves as a major nexus point for control of sympathetic reflexes to the heart. However, there are major gaps in the understanding of regulation of cardiac excitability at the level of the spinal cord. Spinal neuromodulation therapies- spinal cord stimulation (SCS) and dorsal root ganglion (DRG) stimulation, show promise towards reducing VTs, but the mechanisms underlying the therapeutic benefits of these innovative approaches remain largely unknown. The goal of this proposal is to determine how the spinal cord processes cardiac afferent impulses during myocardial ischemia and to explain how neuromodulation therapies reduce ventricular arrhythmias, leading to their more effective and expansive use. In this proposal, it is hypothesized that unique cardiospinal neural networks integrate the cardiac afferent signals during myocardial ischemia (MI) and control sympathoexcitation, thereby modulating arrhythmogenesis. Further, MI triggers pathologic remodeling of cardiospinal neural circuits, which increase myocardial sympathoexcitation. SCS and DRG stimulation, reduce sympathetic output through induction of GABA signaling pathways in the spinal cord, reducing ventricular excitability and arrhythmias after chronic MI. Importantly, preliminary functional data shows anti-arrhythmic effects of SCS during acute I/R were abolished in the presence of GABA receptor antagonists, supporting the hypothesis. Real Time PCR also shows expression of GABAA and GABAB receptors is increased by SCS therapy in spinal cord during MI. Thus, modulation of cardiac afferent neural inputs to the spinal cord presents a novel target for suppression of excessive sympathetic reflex activation and cardiac arrhythmias. To mechanistically understand the therapeutic potential of such approaches, proposed experiments will evaluate the effects of neuromodulation on cardiospinal neural network and ventricular excitability. The proposed studies will evaluate novel mechanisms of regulation of cardiac excitability at the spinal level. Specific aims 1 is designed to provide a mechanistic understanding of the role of spinal cord processing of afferent cardiac neural inputs. Electrophysiological and neurochemical alterations in cardiospinal neural network in chronic MI will be compared with healthy hearts when subjected to additional cardiac stress (acute ischemia/reperfusion). Molecular mechanisms through which chronic MI induces pathologic remodeling of the cardiospinal neural network will be characterized. In specific aim 2 and 3, mechanisms by which SCS and DRG stimulation reduce cardiospinal neural network remodeling and decrease myocardial sympathoexcitation in chronic MI will be identified. The proposed studies will provide the framework to maximize the therapeutic potential of neuromodulation in mitigation of cardiac and neural remodeling in chronic MI.