Spinal Neuraxial Modulatin of Ventricular Excitability - Mechanisms and Therapeutics

心室兴奋性的脊髓神经轴调节 - 机制和治疗

• 批准号: 10226887
• 负责人: JEFFREY L ARDELL
• 金额: $ 57.62万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-02 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226887
• 关键词: Acute; Affect; Animal Model; Arrhythmia; Autonomic nervous system; Cardiac; Cardiovascular system; Cause of Death; Cells; Chronic; Clinical; Communication; Data; Development; Electrophysiology (science); Event; Functional disorder; GABA Antagonists; Gap Junctions; Goals; Heart; Heart Abnormalities; Human; Injury; Ischemia; Knowledge; Molecular; Molecular Probes; Myocardial; Myocardial Infarction; Myocardial Ischemia; Neural Pathways; Neurostimulation procedures of spinal cord tissue; Nociception; Output; Pathologic; Pathway interactions; Play; Preventive; Process; Reflex action; Regulation; Reperfusion Therapy; Resolution; Role; Secondary to; Signal Pathway; Signal Transduction; Spinal; Spinal Cord; Spinal Ganglia; Stress; Tachyarrhythmias; Techniques; Therapeutic; Time; United States; Ventricular; Ventricular Arrhythmia; acute stress; base; cardioprotection; design; dorsal horn; effective therapy; experimental study; gamma-Aminobutyric Acid; heart rhythm; innovation; insight; neural circuit; neural network; neurochemistry; neuroregulation; neurotransmission; novel; novel therapeutics; painful neuropathy; prevent; public health relevance; receptor; relating to nervous system; response; sudden cardiac death; transcriptome

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.

项目总结/摘要 由于室性快速性心律失常（VT）引起的心源性猝死（SCD）是心脏病患者死亡的主要原因。 美国的自主神经系统的失调，特别是交感神经兴奋， 在缺血性心脏病继发心律失常的病理生理学中的作用。脊髓是 作为控制心脏交感神经反射的主要连接点。然而，在这方面存在着重大差距。 了解在脊髓水平调节心脏兴奋性。脊髓神经调节疗法- 脊髓刺激（SCS）和背根神经节（DRG）刺激显示出减少VT的前景， 但这些创新方法的治疗益处的潜在机制在很大程度上仍然未知。 这项建议的目的是确定脊髓如何处理心脏传入冲动， 心肌缺血，并解释神经调节疗法如何减少室性心律失常， 更有效和更广泛的使用。 在这个提议中，假设独特的心脊髓神经网络整合了心脏传入神经， 信号在心肌缺血（MI）和控制交感神经兴奋，从而调节mammogenesis。 此外，MI触发心脏脊髓神经回路的病理性重塑，这增加了心肌梗死的发生。 交感神经兴奋SCS和DRG刺激，通过诱导GABA信号传导减少交感神经输出 在脊髓中的通路，减少心室兴奋性和心律失常后慢性MI。重要的是， 初步的功能数据显示，在急性I/R期间， GABA受体拮抗剂，支持这一假设。真实的时间PCR也显示GABAA和GABAA的表达。 MI期间脊髓中的SCS治疗增加了GABAB受体。因此，心脏传入神经的调节 对脊髓的神经输入提供了抑制过度交感神经反射激活的新靶点 和心律失常。为了从机制上理解这种方法的治疗潜力， 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。 拟议的研究将评估脊髓中心脏兴奋性调节的新机制， 水平具体目标1旨在提供对脊髓加工的作用的机械理解， 传入心脏神经输入。大鼠心脏脊髓神经网络的电生理和神经化学改变 当经受额外的心脏应激（急性心肌梗死）时，将慢性心肌梗死与健康心脏进行比较 缺血/再灌注）。慢性心肌梗死诱导心肌细胞病理性重塑的分子机制 将表征心脏脊髓神经网络。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脊髓神经网络重构和心肌交感神经兴奋 将识别MI。拟议的研究将提供框架，以最大限度地发挥 神经调节在缓解慢性MI心脏和神经重塑中的作用。

项目成果

Spinal cord stimulation mitigates the myocardial ischemia induced sympathoexcitation by suppressing the spinal neural synchrony and intermediolateral nucleus hyperactivity.

脊髓刺激通过抑制脊髓神经同步性和中间外侧核过度活跃来减轻心肌缺血引起的交感兴奋。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Salavatian,Siamak;Wong,Benjamin;Fritz,JonathanR;Kuwabara,Yuki;Varghese,ChristopherG;Howard-Quijano,Kimberly;Armour,Andrew;Foreman,RobertD;Ardell,JeffreyL;Mahajan,Aman
• 通讯作者: Mahajan,Aman

Spinal Cord Stimulation Reduces Ventricular Arrhythmias by Attenuating Reactive Gliosis and Activation of Spinal Interneurons.

脊髓刺激通过减少反应性神经胶质和脊柱中间神经元的激活来减少心室心律不齐。

• DOI: 10.1016/j.jacep.2021.05.016
• 发表时间: 2021-10
• 期刊: JACC. Clinical electrophysiology
• 作者: Howard-Quijano K;Yamaguchi T;Gao F;Kuwabara Y;Puig S;Lundquist E;Salavatian S;Taylor B;Mahajan A
• 通讯作者: Mahajan A

Progression of myocardial ischemia leads to unique changes in immediate-early gene expression in the spinal cord dorsal horn.

• DOI: 10.1152/ajpheart.00337.2018
• 发表时间: 2018-12
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: L. Saddic;Kimberly J. Howard-Quijano;Jasmine P Kipke;Y. Kubo;E. Dale;D. Hoover;K. Shivkumar;M. Eghb

Spinal Anesthesia Reduces Myocardial Ischemia-triggered Ventricular Arrhythmias by Suppressing Spinal Cord Neuronal Network Interactions in Pigs.

• DOI: 10.1097/aln.0000000000003662
• 发表时间: 2021-03-01
• 期刊: Anesthesiology
• 影响因子: 8.8
• 作者: Omura Y;Kipke JP;Salavatian S;Afyouni AS;Wooten C;Herkenham RF;Maoz U;Lashgari E;Dale EA;Howard-Quijano K;Mahajan A
• 通讯作者: Mahajan A

Innovations in Practices and Technologies That Will Shape Perioperative Medicine.

将塑造围手术期医学的实践和技术创新。

• DOI: 10.1213/ane.0000000000006439
• 发表时间: 2023
• 期刊: Anesthesia and analgesia
• 影响因子: 5.7
• 作者: Mahajan,Aman;Mythen,MontyMichael
• 通讯作者: Mythen,MontyMichael