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: 8804849
• 负责人: Olujimi A Ajijola
• 金额: $ 13.31万
• 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/8804849
• 关键词: Action Potentials; Acute; Address; Animals; Anti-Arrhythmia Agents; Arrhythmia; Attenuated; Autonomic nervous system; Beds; Behavior; Bilateral; Biological Neural Networks; Cardiac; Cardiac Electrophysiologic Techniques; Cephalic; Cervical; Cessation of life; Characteristics; Chest; Cicatrix; Clinical; Conflict (Psychology); Data; Decentralization; Development; Development Plans; Doctor of Philosophy; Electrophysiology (science); Elements; Enhancers; Excision; Exhibits; Family suidae; Foundations; Future; Ganglia; Gap Junctions; Goals; Grant; Hand; Heart; Heterogeneity; Hormonal; Infarction; Inferior; Injury; Investigation; Lead; Life; Link; Maps; 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-Centered Care; Patients; Pattern; Peripheral; 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; 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（由申请人提供）：本提案描述了旨在促进Olujimi A职业发展的五年期辅导培训计划。Ajijola MD PhD，成为一名独立的医生科学家，能够进行高水平的科学调查。心脏固有神经系统（ICNS）在心脏收缩和电生理功能的逐搏调节中的重要作用越来越被人们所认识，然而，它仍然知之甚少。从长远来看，候选人寻求发展科学和临床利基在 “内在-神经心脏病学”领域，最初是在基础方面，将来是“床边” 在正常和患病状态下研究ICNS生理学的基本发现的应用。这个职业轨道的最终目标是制定治疗策略，调节ICNS（和更高的心脏神经调节中心）的患者护理。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，并扩大他的技能组合，包括神经科学研究方法和技术，建立在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的基础上。Ajijola博士的职业发展计划有以下几个关键要素：1）由两位在神经科学领域公认和投入的专家指导（包括ICNS生理学）和心脏电生理学; 2）在开发扩展的知识库，科学研究工具和神经科学技术方面的教学和实践培训; 3）继续扩展心脏电生理学专业知识;以及4）追踪候选人的全面发展和逐步假设独立的途径，预计将在资助期结束时完全实现。提议的轨道已经启动，初步数据加强了提议的科学目标。本提案的研究目标是确定一种临床上成功的神经调节疗法，双侧心脏交感神经分散（BCSD），赋予抗抑郁益处的机制。严重心脏损伤后，心脏神经轴内神经元重塑导致神经激素激活不平衡。这些失衡导致过度和不稳定的传出心脏交感神经传递。BCSD，即切除第2至第4胸部水平的星状神经节和交感神经节的下极，可能会消除这些传出心脏交感神经输入到达心脏，然而，这种效应对心脏神经调节的机械转化，特别是在梗塞心肌中，尚不清楚。我们假设，心脏内在神经系统（ICNS），作为心脏传入和传出神经传递的最终整合者，是BCSD的最终靶点。具体来说，BCSD减轻了往返心脏的神经传递的异常整合和处理，以及ICNS内结构和功能元件的重塑，这些都是由源自高级神经中心的交感神经输入增强引起的。通过这样做，BCSD通过ICNS减弱心脏动作电位时程异质性，并增强肌细胞自律性，这是交感神经张力增强状态下的两种已知的心肌发生机制。我们计划利用这种临床有益的抗心律失常治疗，以了解如何在ICNS内处理心脏信息，以及BCSD前后随机ICNS信号模式的心脏电生理后果。结合高分辨率心脏电生理映射与ICNS内的神经元信号的体内记录，该建议将确定心脏神经系统内的新的相互作用及其电生理后果。在具体目标1a中，我们将确定在梗死后立即进行BCSD之前和之后，或延迟至重塑变化开始时，在正常和梗死心脏中ICNS内如何处理信息。在目标1b中，我们将研究ICNS的结构和神经化学（即神经肽）特性如何被梗死改变，以及BCSD稳定传出输入的影响。在目标2中，我们将评估梗死后ICNS信号传导如何影响心脏电生理特性，方法是在有无BCSD的梗死心脏中进行高分辨率局灶性和全局电生理标测;并进一步研究梗死后即刻BCSD和延迟BCSD之间的差异。这种性质的心脏和神经元电生理标测以前没有进行过。从这些动物研究中获得的有影响力的发现将为未来的“实验室”到“床边”研究奠定基础，这些研究旨在开发新的或改善目前用于治疗室性心律失常的神经调节疗法。