Antiarrhythmic Mechanisms of Bilateral Cardiac Sympathetic Decentralization

 描述(由申请人提供)：本建议书描述了旨在促进Olujimi A.Ajijola医学博士的职业发展成为具有高水平科学研究能力的独立内科科学家的五年指导性培训计划。心脏固有神经系统(ICNS)在心脏收缩和电生理功能的节拍调节中的重要作用已被越来越多地认识到，但它仍然知之甚少。从长远来看，候选人寻求在科学和临床领域开拓利基市场 “内在神经心脏病学”领域，最初是在基础方面，未来是“床边”。 ICNS生理学研究的基本结果在正常和疾病状态下的应用。这一职业轨迹的最终目标是开发治疗策略，调节ICN(和更高级别的心脏神经调节中心)，用于患者护理。应聘者的中短期目标是发展神经科学方面的专业知识，并在心脏结构生物学和电生理学以及神经科学基础的基础上，扩大他的技能集，包括神经科学研究方法和技术。Ajijola博士的职业发展计划包括以下关键内容：1)由神经科学(包括ICNS生理学)和心脏电生理学领域的两位公认的和有投资的专家进行指导；2)在开发扩大的神经科学知识库、科学研究工具和技术方面进行教学和动手培训；3)继续扩展心脏电生理学专业知识；以及4)跟踪候选人的全面发展和逐渐独立的途径，预计在资助期结束时完全实现。拟议的轨道已经启动，初步数据加强了该提议的科学目标。本建议的研究目标是确定临床上成功的神经调节疗法--双侧心脏交感神经分散(BCSD)--提供抗心律失常益处的机制。在严重的心脏损伤后，心脏神经轴内神经元重塑导致的神经激素激活失衡。这些失衡导致过多和不稳定的传出心脏交感神经传递。切除2~4胸段星状神经节的下极和交感神经节，可能会消除这些传出的心脏交感神经传入到达心脏，然而，这种作用到心脏神经调节的机制转换，特别是在梗死心肌中，尚不清楚。我们假设心脏固有神经系统(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。具体地说，BCSD减轻了进出心脏的神经传递的异常整合和处理，以及ICN内结构和功能元素的重塑，这些都是由来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减弱了心脏动作电位时程的异质性和增强的心肌细胞自律性，这是交感神经张力增强状态下心律失常发生的两个已知机制。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内心脏信息是如何处理的，以及BCSD前后随机ICNS信号模式的心脏电生理后果。结合高分辨率的心脏电生理标测和ICNS内神经元信号的活体记录，这一建议将识别心脏神经系统内的新的相互作用及其电生理后果。在特定的目标1a中，我们将确定在正常和梗死心脏的ICNS中，在梗死后立即进行BCSD之前和之后，或延迟到重塑改变开始时，ICNS中的信息是如何处理的。在目标1b中，我们将研究脑梗塞如何改变ICNS的结构和神经化学(即神经肽)特性，以及BCSD对稳定传出输入的影响。在目标2中，我们将评估梗塞后ICNS信号如何通过对没有BCSD的梗塞心脏进行高分辨率局部和全局电生理标测来影响心脏电生理特性；以及进一步比较梗塞后即刻BCSD和延迟性BCSD之间的差异。这种性质的心脏和神经元电生理标测以前从未进行过。从这些动物研究中得出的有影响力的发现将成为未来旨在开发新的或改进目前用于治疗室性心律失常的神经调节疗法的“长凳”到“床边”研究的基础。

 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.