Antiarrhythmic Mechanisms of Bilateral Cardiac Sympathetic Decentralization

双侧心脏交感神经分散的抗心律失常机制

• 批准号: 9182901
• 负责人: Olujimi A Ajijola
• 金额: $ 17.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9182901
• 关键词: Action Potentials; Acute; Address; Animals; Arrhythmia; Attenuated; Autonomic nervous system; Beds; Behavior; Bilateral; Biological Neural Networks; Cardiac; Cardiac Electrophysiologic Techniques; Career Choice; Cephalic; Cervical; Cessation of life; Characteristics; Chest; Cicatrix; Clinical; Conflict (Psychology); Data; Decentralization; Development; Development Plans; Disease; Doctor of Philosophy; Electrophysiology (science); Elements; Enhancers; Excision; Exhibits; Family suidae; Foundations; Future; Ganglia; Gap Junctions; Goals; Grant; Heart; Heterogeneity; Hormonal; Infarction; Inferior; Injury; Intervention; Investigation; Lead; Life; Link; Mediastinal; Mediating; Mentors; Mentorship; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Nature; Nerve; Nervous System Physiology; Nervous system structure; Neurons; Neuropeptides; Neurosciences; Operative Surgical Procedures; Organ; Pathway interactions; Patient Care; Patients; Pattern; Peripheral; Pharmacology; Physicians; Play; Process; Property; Reflex action; Regulation; Research; Research Methodology; Research Technics; Residual state; Resolution; Role; Scientist; Signal Transduction; Site; Spinal; Spinal Cord; Stress; Structure; Structure of stellate ganglion; Sympathetic Ganglia; Techniques; Therapeutic; Time; Tissues; Training; Training Programs; Translating; Translations; Ventricular; Ventricular Arrhythmia; autonomic reflex; base; bench to bedside; career development; electrical property; experience; improved; in vivo; indexing; insight; knowledge base; neurochemistry; neuroregulation; neurotransmission; novel; novel therapeutics; public health relevance; relating to nervous system; response; skills; stressor; structural biology; sudden cardiac death; tool

 DESCRIPTION (provided by applicant): This proposal describes the five-year mentored training program devised to facilitate the career development of Olujimi A. Ajijola MD PhD, into an independent physician scientist, capable of high-level scientific investigation. The important role of the intrinsic cardiac nervous system (ICNS) in the beat-to-beat regulation of cardiac contractile and electrophysiologic function is increasingly recognized, yet, it remains poorly understood. In the long term, the candidate seeks to develop a scientific and clinical niche in the field of "intrinsic- neurocardiology", initially in the basic aspects, and in the future, "bedside" application of fundamental findings from studying ICNS physiology in normal and diseased states. The end objective of this career track is to develop therapeutic strategies modulating the ICNS (and higher cardiac neuro-regulatory centers) for patient care. The short- to intermediate-term goals of the candidate are to develop an expertise in neuroscience, and to expand his skill sets to include neuroscientific research methods and techniques, building on his expertise in cardiac structural biology and electrophysiology, and foundations in neuroscience. The career development plan for Dr. Ajijola have the following key elements: 1) mentorship by two well-recognized and invested experts in the fields of neuroscience (including ICNS physiology) and cardiac electrophysiology; 2) didactic and hands on training in developing an expanded knowledge base, scientific research tools, and techniques in neuroscience; 3) continued expansion of cardiac electrophysiologic expertise; and 4) a pathway for tracking the candidate's overall development, and the gradual assumption of independence, expected to be fully realized by the conclusion of the grant period. The proposed track has already been initiated, with preliminary data reinforcing the scientific aims of the proposal. The research objectives of the present proposal are to identify the mechanisms by which a clinically successful neuromodulatory therapy, bilateral cardiac sympathetic decentralization (BCSD), imparts antiarrhythmic benefits. Imbalances in neuro-hormonal activation resulting from neuronal remodeling within the cardiac neural-axis occur following significant cardiac injury. These imbalances lead to excessive and destabilizing efferent cardiac sympathetic neurotransmission. BCSD, the resection of the lower pole of the stellate ganglion and the sympathetic ganglia at the 2nd through 4th thoracic levels, likely eliminates these efferent cardiac sympathetic inputs from reaching the heart, however, the mechanistic translation of this effect to cardiac neuro- regulation, especially in infarcted myocardium, is unknown. We hypothesize that the intrinsic cardiac nervous system (ICNS), as the final integrator of cardiac afferent and efferent neurotransmission, is the end-target for BCSD. Specifically, BCSD mitigates the abnormal integration and processing of neurotransmission, to and from the heart, and remodeling of structural and functional elements within the ICNS, induced by enhanced sympathetic inputs originating from higher neural centers. By so doing, BCSD, via the ICNS, attenuates cardiac action potential duration heterogeneity, and enhanced myocyte automaticity, two known mechanisms of arrhythmogenesis under states of enhanced sympathetic tone. We plan to exploit this clinically beneficial antiarrhythmic therapy to understand how cardiac information is processed within the ICNS, and the cardiac electrophysiologic consequences of stochastic ICNS signaling patterns before and after BCSD. Combining high resolution cardiac electrophysiologic mapping with in vivo recordings of neuronal signals within the ICNS, this proposal will identify novel interactions within the cardiac nervous system and their electrophysiologic consequences. In specific aim 1a, we will determine how information is processed within the ICNS in normal and infarcted hearts, before and after BCSD performed immediately after infarction, or delayed till remodeling changes have set in. In aim 1b, we will examine how ICNS structural and neurochemical (i.e. neuropeptide) properties are altered by infarction, and impact of stabilizing efferent input by BCSD. In aim 2, we will assess how post-infarct ICNS signaling impacts cardiac electrophysiological properties by performing high resolution focal and global electrophysiologic mapping in infarcted hearts with an without BCSD; and further the differences between immediate post-infraction BCSD, and delayed BCSD. Cardiac and neuronal electrophysiologic mapping of this nature has not been previously performed. Impactful findings derived from these animal studies will form the basis for future "bench" to "bedside" studies aimed at developing novel or improving current neuromodulation therapies for treating ventricular arrhythmias.

 描述（由适用提供）：该提案描述了为支持Olujimi A. Ajijola MD博士的职业发展而设计的五年培训计划，成为了一位独立的物理科学家，能够具有高级科学研究。内在心脏神经系统（ICN）在心脏收缩和电生理功能的beat-beat调节中的重要作用越来越多地认识到，但它仍然很糟糕。从长远来看，候选人试图在 “内在神经心理学”的领域，最初是在基本方面和将来的“床边”领域 在正常状态和失职状态下研究ICNS生理学的基本发现的应用。这一职业轨道的最终目标是制定理论策略调节患者护理的ICN（和更高的心脏神经调节中心）。候选人的短期到中期目标是发展神经科学方面的专业知识，并将其技能扩大到包括神经科学研究方法和技术，基于他在心脏结构生物学和电生理学方面的专业知识以及神经科学领域的基础。 Ajijola博士的职业发展计划具有以下关键要素：1）由两名公认和投资专家在神经科学领域（包括ICNS生理学）和心脏电生理学领域的精神训练； 2）教义和动手培训，以开发扩展的知识库，科学研究工具和神经科学技术； 3）持续扩展心脏电生理专业知识； 4）一种跟踪候选人的整体发展以及独立的成绩的途径，预计将通过赠款期结束来充分实现。拟议的曲目已经启动，并有了初步数据，加强了该提案的科学目的。本提案的研究目标是确定临床成功的神经调节疗法，双侧心脏交感神经分散化（BCSD）的机制，赋予了抗心律失常的益处。严重心脏损伤后心脏神经轴内神经激素重塑引起的神经激活的失衡。这些失衡导致过度和破坏有效的心脏交感神经传递。 BCSD，恒星神经节的下极的切除和在第二至第四胸腔水平上的交感神经节，很可能从达到心脏的机械转换到心脏神经内部调节，尤其是在尚未出现的心肌中，这可能会消除这些有效的心脏交感神经输入。我们假设内在心脏神经系统（ICN）是心脏传入和有效神经传递的最终整合物，是BCSD的最终目标。具体而言，BCSD减轻了神经传递的异常整合和处理，往返心脏，以及ICN中结构和功能元件的重塑，这是由源自较高神经元中心的增强的交感神经输入引起的。通过这样做，BCSD通过ICNS减弱心脏作用潜在的持续时间异质性，并增强了心肌自动化，这是增强的交感神经态状态下心律失常发生的两种已知机制。我们计划探索这种临床上有益的抗心律失常疗法，以了解ICN中心脏信息的处理方式，以及BCSD之前和之后的随机ICN信号传导模式的心脏电生理后果。将高分辨率心脏电生理学映射与ICN中神经元信号的体内记录相结合，该建议将确定心脏神经系统中的新型相互作用及其电生理后果。 In specific aim 1a, we will determine how information is processed within the ICNS in normal and infarcted hearts, before and after BCSD performed immediately after infarct, or delayed till remodeling changes have set in. In aim 1b, we will examine how ICNS structural and neurochemical (i.e. neuropeptide) properties are altered by infarct, and impact of stabilizing effective input by BCSD.在AIM 2中，我们将通过在没有BCSD的梗塞心脏中进行高分辨率的局灶性和全局电生理学映射来评估感染后ICNS信号传导如何通过进行高分辨率的局灶性和全局电生理图来影响心脏电物质的特性；进一步进一步，即立即分配后BCSD和延迟的BCSD之间的差异。以前尚未进行这种性质的心脏和神经元电生理图。从这些动物研究中得出的有影响力的发现将构成未来的“卧床”研究的基础，旨在开发新的或改善目前的神经调节疗法以治疗心室心律不齐。