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（由申请人提供）：该提案描述了为期五年的指导培训计划，旨在促进 Olujimi A. Ajijola 医学博士的职业发展，使其成为一名能够进行高水平科学研究的独立医师科学家。人们越来越认识到内在心脏神经系统（ICNS）在心脏收缩和电生理功能的逐搏调节中的重要作用，但人们对其仍知之甚少。从长远来看，候选人寻求在该领域发展科学和临床利基 “内在神经心脏病学”领域，最初是基础方面，未来是“床边” 应用正常和患病状态下 ICNS 生理学研究的基本发现。该职业轨迹的最终目标是制定调节 ICNS（和高级心脏神经调节中心）以进行患者护理的治疗策略。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，并以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基础为基础，扩展他的技能，包括神经科学研究方法和技术。 Ajijola博士的职业发展计划有以下关键要素：1）由两位神经科学（包括ICNS生理学）和心脏电生理学领域公认和投资专家的指导； 2) 开发扩展的知识库、科学研究工具和神经科学技术的教学和实践培训； 3）持续扩展心脏电生理学专业知识； 4) 跟踪候选人整体发展的途径，以及逐步实现独立性的途径，预计在资助期结束时完全实现。拟议的轨道已经启动，初步数据强化了该提案的科学目标。本提案的研究目标是确定临床上成功的神经调节疗法（双侧心脏交感神经去中心化（BCSD））提供抗心律失常益处的机制。严重心脏损伤后，心脏神经轴内的神经元重塑会导致神经激素激活失衡。这些不平衡导致心脏传出交感神经传递过度且不稳定。 BCSD，即切除第 2 至第 4 胸节的星状神经节下极和交感神经节，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制转化，特别是在梗塞心肌中，尚不清楚。我们假设内在心脏神经系统（ICNS）作为心脏传入和传出神经传递的最终整合器，是 BCSD 的最终目标。具体来说，BCSD 减轻了来自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，这是由来自高级神经中枢的交感神经输入增强引起的。通过这样做，BCSD 通过 ICNS 减弱了心脏动作电位持续时间的异质性，并增强了心肌细胞的自律性，这是交感张力增强状态下心律失常发生的两种已知机制。我们计划利用这种临床上有益的抗心律失常疗法来了解 ICNS 内如何处理心脏信息，以及 BCSD 前后随机 ICNS 信号模式的心脏电生理后果。该提案将高分辨率心脏电生理图与 ICNS 内神经元信号的体内记录相结合，将确定心脏神经系统内的新相互作用及其电生理后果。在具体目标 1a 中，我们将确定在梗塞后立即执行 BCSD 之前和之后，或延迟到重塑变化开始之前，正常心脏和梗塞心脏的 ICNS 内如何处理信息。在目标 1b 中，我们将研究梗塞如何改变 ICNS 结构和神经化学（即神经肽）特性，以及 BCSD 稳定传出输入的影响。在目标 2 中，我们将通过在有或没有 BCSD 的梗塞心脏中进行高分辨率局部和整体电生理图测来评估梗塞后 ICNS 信号传导如何影响心脏电生理特性；并进一步区分了违规后立即 BCSD 和延迟 BCSD 之间的差异。以前尚未进行过这种性质的心脏和神经元电生理图测。从这些动物研究中得出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，旨在开发新颖的或改进当前治疗室性心律失常的神经调节疗法。